Sex & Gender-Based Women's Health

Sarah A.
Tilstra
Deborah Kwolek
Julie L. Mitchell
Brigid M. Dolan
Michael P. Carson
Editors
Sex- and Gender-Based

Women’s Health
A Practical Guide for Primary Care
123
Sex- and Gender-Based Women’s Health
Sarah A. Tilstra • Deborah Kwolek
Julie L. Mitchell • Brigid M. Dolan
Michael P. Carson
Editors
Sex- and Gender-Based

Women’s Health
A Practical Guide for Primary Care
Editors
Sarah A. Tilstra Deborah Kwolek
University of Pittsburgh School of Medicine Harvard Medical School, Massachusetts General
Division of General Internal Medicine Hospital
Department of Medicine Department of Medicine
Pittsburgh, PA Boston, MA
USA USA
Julie L. Mitchell Brigid M. Dolan

Medical College of Wisconsin Northwestern University Feinberg School
Milwaukee, WI of Medicine, Division of General Internal
USA Medicine and Geriatrics
Department of Medicine
Michael P. Carson Chicago, IL
Hackensack Meridian School of Medicine USA
at Seton Hall, Jersey Shore University
Medical Center
Department of Medicine
Neptune, NJ
USA
ISBN 978-3-030-50694-0 ISBN 978-3-030-50695-7 (eBook)

https://doi.org/10.1007/978-3-030-50695-7
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Preface
Women’s health had traditionally been envisioned as breast, reproductive, and gynecologic
care historically addressed by our obstetrics and gynecology partners, but beginning in the
1990s, primary care physicians began to take an active role in providing women’s healthcare,
developing teaching curricula and performing research specific to women’s health issues. We,
as physicians providing primary care, appreciate that women and gender diverse patients are
much more complex. The optimal care of our patients requires knowledge and skills which
integrate primary medical care, mental health care, breast care, and gynecologic care into each
evaluation with attention to adept communication, trust building, and an understanding of
social factors. In one afternoon, we see patients with concerns ranging from osteoporosis,
depression, intimate partner violence, vaginal bleeding, irritable bowel syndrome, headaches,
and urinary incontinence—sometimes in a single encounter. As primary providers, we must
also have expertise in family planning, cancer screening, and well-woman examinations. Our
patients expect comprehensive care, yet studies of residency training reveal that few residency
programs in internal medicine offer dedicated training in women’s health, and upon graduation
many residents feel unprepared and are unable to demonstrate competency to care for female
patients [1, 2].
In response to this need, it is with great pride that we present this sex- and gender-based
women’s health curriculum written by a host of women’s health physician educators, research-
ers, and clinicians. This work fulfills our long-term goal to produce a resource written explic-
itly for primary care providers to both guide the care of women and gender diverse patients and
to educate learners in this discipline. This book does not serve as a comprehensive review of
all available literature, but instead is tailored to the essential components necessary to care for
the sex- and gender-specific preventive, medical, psychological, and social needs of our
patients. This text is based upon the principles of evidenced-based medicine and includes
review of clinical guidelines. Expert opinion and pearls from senior women’s health experts
have been added to provide nuance in patient care and to fill knowledge gaps on subjects not
well studied as of this writing.
There is no right or wrong way to use this book. It can be used as a quick point-of-care clini-
cal reference for a specific topic (i.e., contraception) or as a longitudinal curriculum for learn-
ers. While this text is organized into eight parts of related content, the reading of this text is not
intended to be strictly linear. To assist non-linear readers, chapters are extensively
cross-referenced.
We focus on practical issues in the outpatient setting and we do not intend to limit our audi-
ence to a single specialty or credential. This text is for generalist physicians, nurse practitio-
ners, and other practitioners in primary care. In the same way that we have chosen to be
inclusive in the definition of the female patient (women and gender diverse people), we encour-
age interprofessional discussion and learning of this content.
We are passionate about promoting sex- and gender-based women’s health (SGBWH) edu-
cation for learners at all levels; thus, we have designed this book to aid educators. Each chapter
has clear, measurable learning objectives and multiple-choice questions to check understand-
ing. Clinician-educators preparing a discussion or lecture on a selected topic could assign a
chapter to residents, fellows, or students as a pre- or post-read. We encourage providers who
vii
viii Preface
have a large population of women patients to consider reading the book in its entirety. Academic
leaders seeking to raise awareness of SGBWH could use this book as part of a developmental
effort.
We are extremely honored and grateful to have been trained, mentored, and inspired by a
cadre of fierce women’s health advocates, expert clinicians, research pioneers, and gifted edu-
cators. It would be a disservice to them to write this book and ignore the history and evolution
of the work that preceded us. This book is the result of the intersection of female academic
leadership; the advancement of women’s health policy, research, and education; the under-
standing of the health impact of social and gender disparities; and the integration of women’s
health with sex-and gender-based medicine. With great esteem, we dedicate Chaps. 1 and 2 to
Drs. Melissa McNeil, Carol Bates, Paula Johnson, Ann Nattinger, Molly Carnes, Sandra
Levison, Ana Nunez. Lucia Beck Weiss, Karen Carlson, Karen Freund, Saralyn Mark, Janet
Henrich, Wendy Klein, Jan Werbinski, Abby Spencer, Marjorie Jenkins, Vivian Pinn, Pam
Charney, Peter Garner, Richard V. Lee, Karen Rosene-Montella, Bill Baron, and many, many
others. We also acknowledge and thank the original leaders in the women’s health centers of
excellence program and the women’s health movement in general, and those who now con-
tinue to carry on the important work of promoting women’s health and sex- and gender-based
medicine regionally, nationally, and internationally.
We must express our deepest gratitude to all of the phenomenal contributing authors of this
book: for their energy, patience, time, and willingness to contribute to this text on their days
off, during their scarce free time, and after their kids and partners were asleep. We are deeply
appreciative of our chairs, chiefs, and clinical colleagues who supported us, covered for us, and
in many other ways supported our work over the past 2 years. Thank you to Springer and espe-
cially Ms. Stephanie Frost, our Deputy Editor, for her constant support, admirable laugh, orga-
nizational skills, and persistent emails. We dedicate this book to our patients, who are the
reason we practice medicine. Your wisdom has inspired us to keep learning, researching, teach-
ing, and finding ways to improve the way we provide care and has kept us grounded as advo-
cates and role models. To our mentees and learners, this book is for you. Thank you for pushing
us to be the best versions of ourselves, to reflect on our faults, and for motivating us to do
everything better the next day.
Finally, and most importantly, we are forever indebted to our families and friends: our par-
ents, partners, and children who have literally sacrificed so that this volume could be com-
pleted. Without your love and support, none of this would have been possible.
We conclude with the hope of improving the healthcare of our patients through interdisci-
plinary collaboration and education, and inspiring a new generation of women’s health
providers.
Sarah A. Tilstra Pittsburgh, PA, USA

Deborah Kwolek Boston, MA, USA
Julie L. Mitchell Milwaukee, WI, USA
Brigid M. Dolan Chicago, IL, USA
Michael P. Carson Neptune, NJ, USA
References
1. Spencer AL, Kern LM. Primary care program directors’ perceptions of women’s health education: a gap in
graduate medical education persists. J Women’s Health. 2008;17:549–56.
2. Hsieh E, Nunez-Smith M, Henrich JB. Needs and priorities in women’s health training: perspectives from
an internal medicine residency program. J Women’s Health. 2013;22:667–72.
In Gratitude
Most importantly to my wife Miriam who pulled, and still pulls, double duty creating and
maintaining our Home, and the boy and the girl, Evan and Leah. They are why I walk so
quickly on rounds: to complete all the work that needs to be done for our patients, but then get
home for dinner ASAP. Albie and Karen who got me here, passed on the ability to do it, and
taught me how to get through the toughest of times. My high school (yes high school) lacrosse
coach and teammates for lessons on focus, support, and striving for excellence.
The Obstetric Medicine pioneers and mentors who created this awesome career path with
clinical challenges and research opportunities for a guy who is apparently blissfully naïve
enough not to be afraid, and who trained me to be a true diagnostician and internist. To the
people I’ve met through NASOM and SGIM, my academic homes that provide the deepest
sense of family and professional satisfaction. The residents and students who by their growth
let me know directly and indirectly that my passion for what I do is appreciated and does
achieve my goal of at least playing some role in helping them develop as professionals. The
people who offer the highest compliment by trusting me to be their doctor, and Dr. Elliot Frank
who trusted me with the resources to pursue research and academic projects. Finally, to my
co-editor-siblings who taught me, and allowed me to join them to be the favorite brother on this
project.
• Michael P. Carson
Thank you to our fearless leader, Dr. Sarah Tilstra, and to the community of women’s health
educators and researchers who have collaborated on this book; I appreciate having had the
opportunity to learn from the knowledge and wisdom of the group. I am eternally grateful for
the village of mentors who led me to a career in women’s health and education—particularly
Dr. Raquel Buranosky, Dr. Melissa McNeill, Dr. Jane Sillman, Dr. Paula Johnson, and Dr. Lori
Tishler—and the students, residents, and patients who provide continual inspiration. My
efforts on this book and otherwise in life are steadfastly supported by Curtis and Connor D,
whose laughter and kindness bring joy into every day.
• Brigid M. Dolan
Lovingly dedicated to my mother Rena Thorstensen-Gomez, who lives with the Lord, and
to my father Robert Gomez, who is a devoted scholar and teacher. To my extraordinary hus-
band, Dr. Christopher Kwolek, my true love and best friend since our first day of medical
school at UCSF. To our daughters and sons—Sarah, Rachel, Bekah, Maddy, Josh, Danny,
Robert, Jonathan, and Joel. Thank you for your loving support, sacrifice, and encouragement.
To my sisters Terri, Jeanne, Rebekah, and Jessica and their daughters. To Cecilia, Lucie, the
extended family, and the life group. To my patients, thank you for the privilege of allowing me
to serve as your physician. A special thanks to my MGMG practice family, and to the leader-
ship at MGH. To the inspirational leaders, mentors, teachers, colleagues, trainees, and students
who together have worked towards the advancement of women’s health especially at the
University of Kentucky, the VA Women’s Health Program, Harvard Medical School, SGIM,
and beyond. Chapter 1 was written in your honor. To Sarah, Julie, Michael, and Brigid, thank
ix
x In Gratitude
you for the joyful opportunity of working with you on this project, for your collegiality, and for
your incredible tenacious commitment to scholarship in women’s health.
• Deborah Kwolek
My contribution to this text would not be possible without the love and support of my hus-
band Rob Thielke and our children Jim, John, and Charlotte Thielke. I must also thank Dr.
Sarah Tilstra for her vision for the book and her confidence in me, Dr. Ann Nattinger for her
longstanding, wise mentorship, and my co-editors who I can now call my BFFs. I have found
inspiration from my teachers, my learners, and of course my patients. This work has truly been
my privilege.
• Julie L. Mitchell
This work would not have been possible without the support and mentorship of the Pitt
Women’s Health Program under the guidance of Dr. Melissa McNeil, where I am honored to
have been trained, sponsored, influenced, and inspired. To my mentors and work wives, Drs.
Raquel Buranosky, Carla Spagnoletti, Rachel Bonnema, Meg McNamara, Deborah DiNardo,
Jen Corbelli, and Anna Donovan, from whom I have learned to work smarter, and am forever
grateful for your encouragement, friendship, and laughs. To Jeremy, my boys Brandon and
Zachary, and Nana, for your love, sacrifice, and sanity. To Julie Mitchell, Deborah Kwolek,
Brigid Dolan, and Michael Carson—my new forever family, thank you for your trust in this
project, comic relief, perseverance, attention to detail, and dedication to excellence. Finally, to
my patients and learners who make this work so special, foster humility, challenge my curios-
ity, and facilitate joy—even on the hardest days—thank you.
• Sarah A. Tilstra
Contents
Part I Foundations of Women’s Health and Gender Based Medicine
1 Women’s Health and Sex- and Gender-Based Medicine: Past,

Present, and Future�� 3
Deborah Kwolek and Marjorie R. Jenkins
2 High-Value Health Care: Perspectives from the Sex- and Gender-based
Care Lens�� 27
Julie L. Mitchell
3 The Female Sex- and Gender-Specific History and Examination �� 41
Eliana Bonifacino and Jennifer Corbelli
Part II Gynecologic Health and Disease
4 Patient-Centered Contraceptive Counseling �� 53

Emmanuelle Yecies and Sonya Borrero
5 Menstruation and Secondary Amenorrhea �� 71
Rachel S. Casas and Cynthia H. Chuang
6 Polycystic Ovary Syndrome�� 83
Azadeh Nasseh and Jenna Sarvaideo
7 Abnormal Uterine Bleeding�� 99
Raj Narayan and Benjamin D. Beran
8 Menopause�� 117
Molly Ainsman Fisher, Akeira L. Johnson, and Rachel A. Bonnema
9 Female Sexual Function and Dysfunction �� 127
Juliana M. Kling and Holly N. Thomas
10 Fibroids, Endometriosis, and Ovarian Cysts�� 141
Amy H. Farkas, Sarah A. Tilstra, and Alda Maria R. Gonzaga
11 Gynecologic Emergencies�� 157
Michael Lund and Jill C. Costello
12 Vaginitis and Vulvar Conditions �� 165
Swati Shroff and Janice Ryden
13 Sexually Transmitted Infections �� 187
Janice Ryden
14 Cervical Cancer and Human Papillomavirus: Prevention and Screening �� 213
Nicolette A. Oleng’, Halle G. Sobel, and Deborah Kwolek
xi
xii Contents
15 Gynecologic Malignancies �� 231

Christine A. Prifti, Deborah Kwolek, Whitfield Board Growdon,
and Kerri Palamara
Part III Breast Health and Disease
16 Benign Breast Conditions�� 259

Brielle M. Spataro and Amy Fitzpatrick
17 The Primary Prevention of Breast Cancer: Risk Assessment,
Genetic Screening, Chemoprevention, and Modifiable Risk Factors�� 275
Jennifer Rusiecki and Deborah Kwolek
18 Breast Cancer Screening �� 297
Anna Golob, Traci A. Takahashi, and Kay M. Johnson
19 Breast Cancer Diagnosis and Management�� 313
Mita Sanghavi Goel and Aarati Didwania
20 Care of the Breast Cancer Survivor �� 329
Sarah Merriam and Deborah DiNardo
Part IV Common Medical Conditions
21 Cardiovascular Disease in Women Part 1: Sex and Gender

Differences in Cardiovascular Conditions and Risk Factors�� 347
Alexandra M. Goodwin, Agnes Koczo, Sarah A. Jones,
Melissa A. McNeil, and Brigid M. Dolan
22 Cardiovascular Disease in Women Part 2: Prevention,
Identification, and Treatment of Cardiovascular Disease�� 361
Agnes Koczo, Alexandra M. Goodwin, Melissa A. McNeil,
and Sarah A. Jones
23 Urinary Incontinence�� 375
Katherine E. Twist and Halle G. Sobel
24 Urinary Tract Infections�� 383
Jane S. Sillman and Michael P. Carson
25 Bone Health and Osteoporosis�� 393
Jordana Friedman, Aletia Farmer, and Jacqueline Carey Fister
Part V Chronic Pain Disorders
26 General Approach to Chronic Pain�� 407

Andrea E. Carter and Melissa A. McNeil
27 Irritable Bowel Syndrome �� 417
Rachel Vanderberg, Amy D. Lu, and Jana G. Hashash
28 Headaches �� 429
Rachel Brook and Deborah Kwolek
29 Fibromyalgia�� 453
Anita Leon-Jhong and Sarah A. Tilstra
Contents xiii
30 Interstitial Cystitis/Bladder Pain Syndrome �� 461

Sumana Koduri
31 Chronic Pelvic Pain�� 471
Christina I. Ramirez, Sarah A. Tilstra, and Nicole M. Donnellan
32 Opioid Use Disorder�� 485
Alfred Shoukry and Melissa A. McNeil
Part VI Mental Health
33 Depressive and Anxiety Disorders�� 497

Rebecca Gitlin and Alexandra E. Mieczkowski
34 Eating Disorders and the Female Athlete Triad�� 523
Brianna Rossiter and Anna K. Donovan
Part VII Selected Populations
35 Intimate Partner Violence and Sexual Trauma�� 537

Raquel A. Buranosky and Jennifer S. McCall-Hosenfeld
36 Care of Sexual Minority Women�� 555
Eloho Ufomata and Carla Spagnoletti
37 Gender Affirming Care �� 563
Eloho Ufomata and Megan McNamara
38 Care of the Female Veteran �� 573
Sophia M. Reljanovic and Megan McNamara
Part VIII Pregnancy
39 Obstetric Medicine�� 583

Lisa B. Bernstein, Michael P. Carson, Meredith O. Cruz, Rachel K. Harrison,
Amanda Johnson, Anna Kho, Beth Lewis, and Sarah A. Tilstra
Index�� 617
Contributors
Benjamin D. Beran, MD Froedtert & Medical College of Wisconsin, Department of

Obstetrics and Gynecology, Wauwatosa, WI, USA
Lisa B. Bernstein, MD Emory University School of Medicine, Department of Medicine,
Atlanta, GA, USA
Eliana Bonifacino, MD, MS University of Pittsburgh Medical Center, Division of General
Internal Medicine, Pittsburgh, PA, USA
Rachel A. Bonnema, MD, MS, FACP University of Texas Southwestern Medical Center,
Dallas, TX, USA
Sonya Borrero, MD, MS Center for Women’s Health Research and Innovation (CWHRI),
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Center for Health Equity Research and Promotion (CHERP), VA Pittsburgh Healthcare
System, Department of Medicine, Pittsburgh, PA, USA
Rachel Brook, MD David Geffen School of Medicine, UCLA, Department of Internal
Medicine, Los Angeles, CA, USA
Raquel A. Buranosky, MD, MPH University of Pittsburgh Medical Center, Department of
Medicine, Pittsburgh, PA, USA
Michael P. Carson, MD Hackensack Meridian School of Medicine at Seton Hall, Jersey
Shore University Medical Center, Department of Medicine, Neptune, NJ, USA
Andrea E. Carter, MD, MS University of Pittsburgh School of Medicine, Division of General
Rachel S. Casas, MD, EdM Division of General Internal Medicine, Penn State Milton S.
Hershey Medical Center, Hershey, PA, USA
Cynthia H. Chuang, MD, MSc Division of General Internal Medicine, Penn State Milton S.
Jennifer Corbelli, MD, MS University of Pittsburgh Medical Center, Division of General
Jill C. Costello, MD Department of Medicine/Division of Rheumatology, Medical College of
Wisconsin, Milwaukee, WI, USA
Meredith O. Cruz, MD, MPH/MBA Froedtert and the Medical College of Wisconsin,
Department of Obstetrics and Gynecology, Milwaukee, WI, USA
Aarati Didwania, MD, MSCI Northwestern University, Feinberg School of Medicine,
Division of General Medicine & Geriatrics, Chicago, IL, USA
xv
xvi Contributors
Deborah DiNardo, MD, MS VA Pittsburgh Healthcare System, Department of Medicine,

Pittsburgh, PA, USA
Brigid M. Dolan, MD, MEd Northwestern University Feinberg School of Medicine, Division
of General Internal Medicine and Geriatrics, Department of Medicine, Chicago, IL, USA
Nicole M. Donnellan, MD Magee-Womens Hospital of University of Pittsburgh Medical
Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, Pittsburgh, PA,
USA
Anna K. Donovan, MD, MS IM Residency Training Program, University of Pittsburgh
Medical Center-Presbyterian, Department of Medicine, Division of General Internal Medicine,
Pittsburgh, PA, USA
Amy H. Farkas, MD, MS Department of Internal Medicine, Medical College of Wisconsin,
Clement Zablocki VA, Milwaukee, WI, USA
Aletia Farmer, MD University of Kentucky, Department of Internal Medicine/Women’s
Health, Lexington, KY, USA
Molly Ainsman Fisher, MD Allegheny Health Network, Pittsburgh, PA, USA
Jacqueline Carey Fister, MD University of Kentucky, Department of Internal Medicine/
Women’s Health, Lexington, KY, USA
Amy Fitzpatrick, MD, MS Boston Medical Center/Boston University School of Medicine,
Department of Internal Medicine, Boston, MA, USA
Jordana Friedman, MD, FACP Northwestern University, Feinberg School of Medicine,
Department of Internal Medicine, Chicago, IL, USA
Rebecca Gitlin, PhD Los Angeles County Department of Mental Health, Los Angeles, CA,
USA
Mita Sanghavi Goel, MD, MPH Northwestern University, Feinberg School of Medicine,
Division of General Medicine & Geriatrics, Chicago, IL, USA
Anna Golob, MD Department of Medicine, University of Washington and VA Puget Sound
Healthcare System, Seattle, WA, USA
Alda Maria R. Gonzaga, MD, MS University of Pittsburgh School of Medicine, Departments
of Medicine and Pediatrics, Pittsburgh, PA, USA
Alexandra M. Goodwin, MD New York University, Bellevue Hospital Center, Department
of General Internal Medicine and Clinical Innovation, New York, NY, USA
Whitfield Board Growdon, MD Massachusetts General Hospital, Department of Obstetrics,
Gynecology and Reproductive Medicine, Division of Gynecologic Oncology, Boston, MA,
USA
Rachel K. Harrison, MD Medical College of Wisconsin, Department of Obstetrics and
Gynecology, Milwaukee, WI, USA
Jana G. Hashash, MD, MSc Department of Internal Medicine, Division of Gastroenterology,
Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
American University of Beirut, Beirut, Lebanon
Marjorie R. Jenkins, MD, MEdHP, FACP University of South Carolina School of Medicine
Greenville, Greenville, SC, USA
Contributors xvii
Kay M. Johnson, MD, MPH Department of Medicine, University of Washington and VA

Puget Sound Healthcare System, Seattle, WA, USA
Amanda Johnson, MD University of Colorado School of Medicine, Department of Obstetrics
and Gynecology, Aurora, CO, USA
Akeira L. Johnson, MD Clement Zablocki VA, Department of General Internal Medicine,
Milwaukee, WI, USA
Sarah A. Jones, MD, MS University of Pittsburgh Medical Center, Department of Internal
Anna Kho, MD Emory University School of Medicine, Department of Medicine, Atlanta,
GA, USA
Juliana M. Kling, MD, MPH, NCMP Mayo Clinic, Department of Women’s Health Internal
Medicine, Rochester, NY, USA
Agnes Koczo, MD University of Pittsburgh Medical Center, Department of Internal Medicine,
Pittsburgh, PA, USA
Sumana Koduri, MD Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital,
Department of Obstetrics and Gynecology, Milwaukee, WI, USA
Deborah Kwolek, MD Harvard Medical School, Massachusetts General Hospital, Department
of Medicine, Boston, MA, USA
Anita Leon-Jhong, MD University of Pittsburgh Medical Center, Division of General
Beth Lewis, MD, MPH Jacobi Medical Center, Department of Obstetrics and Gynecology,
Bronx, NY, USA
Amy D. Lu, MD San Francisco VA Medical Center, University of San Francisco Medical
Center, San Francisco, CA, USA
Michael Lund, MD Department of Obstetrics and Gynecology, Medical College of Wisconsin,
Milwaukee, WI, USA
Jennifer S. McCall-Hosenfeld, MD, MSc The Pennsylvania State University College of
Medicine, Department of Medicine, Hershey, PA, USA
Kerri Palamara, MD Center for Physician Well-Being, Massachusetts General Hospital,
Department of Medicine, Boston, MA, USA
Megan McNamara, MD, MS Case Western Reserve University School of Medicine, Louis
Stokes Cleveland VA Medical Center, Department of Medicine, Cleveland, OH, USA
Melissa A. McNeil, MD, MPH University of Pittsburgh Medical Center, Department of
University of Pittsburgh School of Medicine, Division of General Internal Medicine, Pittsburgh,
PA, USA
Sarah Merriam, MD, MS VA Pittsburgh Healthcare System, Department of Medicine,
Pittsburgh, PA, USA
Alexandra E. Mieczkowski, MD, MS UPMC Presbyterian Shadyside and Children’s
Hospital of Pittsburgh of UPMC, Division of General Internal Medicine, General Academic
Pediatrics, Pittsburgh, PA, USA
Julie L. Mitchell, MD, MS, FACP Medical College of Wisconsin, Milwaukee, WI, USA
xviii Contributors
Raj Narayan, MD, FRCOG, FACOG Froedtert & Medical College of Wisconsin,
Department of Obstetrics and Gynecology, Wauwatosa, WI, USA
Azadeh Nasseh, MD, MSc Boston Medical Center, Boston University School of Medicine,
Department of Internal Medicine, Section of GIM, Boston, MA, USA
Nicolette A. Oleng’, MD Boston University School of Medicine, Department of General
Internal Medicine, Boston Medical Center, Boston, MA, USA
Christine A. Prifti, MD Boston University Medical Center, Department of Medicine,
Women’s Health Unit, Boston, MA, USA
Christina I. Ramirez, MD Magee-Womens Hospital of University of Pittsburgh Medical
Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, Pittsburgh, PA,
USA
Sophia M. Reljanovic, MD Case Western Reserve University School of Medicine, Louis
Stokes Cleveland VA Medical Center, Department of Women’s Health, Cleveland, OH, USA
Brianna Rossiter, MD VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
University of Pittsburgh School of Medicine, Department of Medicine, Division of General
Jennifer Rusiecki, MD, MS University of Chicago, Department of General Internal Medicine,
Chicago, IL, USA
Janice Ryden, MD, FACP Johns Hopkins University School of Medicine, Johns Hopkins
Community Physicians, Department of Internal Medicine (retired), Baltimore, MD, USA
Jenna Sarvaideo, BA, DO Medical College of Wisconsin, Department of Medicine, Division
of Endocrinology, Milwaukee, WI, USA
Alfred Shoukry, MD UPMC, Department of Internal Medicine, Pittsburgh, PA, USA
Swati Shroff, MD, MS Sidney Kimmel Medical College, Thomas Jefferson University,
Department of Medicine, Philadelphia, PA, USA
Jane S. Sillman, MD Brigham and Women’s Hospital, Department of Medicine, Boston,
MA, USA
Halle G. Sobel, MD, FACP Robert Larner MD, College of Medicine at The University of
Vermont, Department of General Internal Medicine, Burlington, VT, USA
Carla Spagnoletti, MD, MS University of Pittsburgh, Department of Medicine, Pittsburgh,
PA, USA
Brielle M. Spataro, MD, MS University of Pittsburgh Medical Center, Department of
Traci A. Takahashi, MD, MPH Department of Medicine, University of Washington and VA
Puget Sound Healthcare System, Seattle, WA, USA
Holly N. Thomas, MD, MS University of Pittsburgh, Department of Medicine, Pittsburgh,
PA, USA
Sarah A. Tilstra, MD, MS, FACP University of Pittsburgh School of Medicine, Division of
General Internal Medicine, Department of Medicine, Pittsburgh, PA, USA
Katherine E. Twist, MD University of Kentucky, Department of Internal Medicine,
Lexington, KY, USA
Contributors xix
Eloho Ufomata, MD, MS University of Pittsburgh School of Medicine, Department of

Rachel Vanderberg, MD, MS Division of General Internal Medicine, University of
Pittsburgh, Pittsburgh, PA, USA
Emmanuelle Yecies, MD Advanced Fellow in Women’s Health, Department of Medicine, VA
Pittsburgh Healthcare System, Pittsburgh, PA, USA
Department of General Internal Medicine, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA
Glossary of Commonly Used Abbreviations
and Acronyms
ACOG American College of Obstetricians and Gynecologists

ACS American Cancer Society
AI Aromatase inhibitor
ASCO American Society of Clinical Oncology
BMD Bone mineral density
BMI Body mass index
BMP Basic metabolic panel (includes sodium, potassium, chloride, bicarbonate,
blood urea nitrogen, creatinine, glucose, calcium)
BPS Bladder pain syndrome
BRCA BReast CAncer gene
BSO Bilateral salpingo-oophorectomy
BV Bacterial vaginitis
CA-125 Cancer antigen 125
CAD Coronary artery disease
CBC Complete blood count
CBE Clinical breast exam
CBT Cognitive behavioral therapy
CDC Center for Disease Control and Prevention
CMP Comprehensive metabolic panel (includes a BMP + total protein, albumin,
bilirubin, alkaline phosphatase, aspartate amino transferase, alanine amino
transferase)
COC Combined oral contraceptive
COPD Chronic obstructive pulmonary disease
CT Computed tomography
CVD Cardiovascular disease
DCIS Ductal carcinoma in situ
DEXA or DXA Dual energy x-ray absorptiometry
DHEA-S Dehydroepiandrosterone sulfate
DM Diabetes mellitus
DSM V Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ED Emergency department
EMG Electromyography
FDA US Food and Drug Administration
FRAX Fracture Risk Assessment Tool
FSH Follicular stimulating hormone
GAD-7 Generalized Anxiety Disorder-7
GDM Gestational diabetes mellitus
GERD Gastroesophageal reflux disease
GSM Genitourinary syndrome of menopause
HCV Hepatitis C virus
HIV Human immunodeficiency virus
HMO Health Maintenance Organization
xxi
xxii Glossary of Commonly Used Abbreviations and Acronyms
HPA Hypothalamic-pituitary-adrenal axis

HPV Human papillomavirus
HR Hazard ratio
HT Hormone therapy
HTN Hypertension
IC Interstitial cystitis
ICS Inhaled corticosteroid
ICU intensive care unit
IOM Institute of Medicine (now known as NAM)
IUD Intrauterine device
LABA(s) Long acting beta2 agonist(s)
LCIS Lobular carcinoma in situ
LEEP Loop Electrosurgical Excision Procedure
LGBTQ Lesbian, gay, bisexual, transgender, queer/questioning
LH Luteinizing hormone
LV Left ventricle or left ventricular
IHD Ischemic heart disease
INR International normalized ratio
IPV Interpersonal violence
MAOI Monoamine oxidase inhibitors
MDI Metered-dose inhaler
MHT Menopausal hormone therapy
MRI Magnetic resonance imaging
MSM Men who have sex with men
NAM National Academy of Medicine (formerly IOM)
NAMS North American Menopause Society
NIH National Institutes of Health
NCCN National Comprehensive Cancer Network
NNT Number needed to treat
NSAID Nonsteroidal anti-inflammatory drug
OC Oral contraceptive
OCP Oral contraceptive pill
OR Odds ratio
PCOS Polycystic ovary syndrome
PCP Primary care provider
PET Positron emission tomography
PHQ-9 Patient Health Questionnaire-9
PID Pelvic inflammatory disease
POP Progestin only pill
RCT Randomized controlled trial
RR Relative risk
SBE Self-breast exam
SERM Selective estrogen receptor modulators
SNRI Serotonin-norepinephrine reuptake inhibitors
SSRI Selective serotonin reuptake inhibitors
STI Sexually transmitted infection
TAH Total abdominal hysterectomy
TAHBSO Total abdominal hysterectomy with bilateral salpingo-oophorectomy
TCA Tricyclic antidepressant
TSH Thyroid stimulating hormone
WHO World Health Organization
US Ultrasound
USPSTF United States Preventive Services Task Force
Part I
Foundations of Women’s Health and
Gender Based Medicine
Women’s Health and Sex- and Gender-
Based Medicine: Past, Present, 1
and Future
Deborah Kwolek and Marjorie R. Jenkins
Learning Objectives Lidia, a 42-year-old cisgender woman (pronouns she/

her/hers), presents to her primary care provider for an
1. Describe the evolution of the women’s health
annual exam. She has no new complaints except for
movement from reproductive health to the compre-
occasional insomnia and hot flashes. She has a history
hensive sex- and gender-informed care of women.
of a breast biopsy and two pregnancies complicated by
2. Discuss major research advances in women’s health
preeclampsia and gestational diabetes, but the pro-
that affect clinical care.
vider did not ask about breast or reproductive history
3. Give examples of nonreproductive sex-based dif-
and therefore this data is not revealed. She is given a
ferences that are clinically relevant in primary care.
physical without breast or gynecologic examination.
4. Describe how the knowledge and skills needed for
breast care, gynecologic care, mental health care,
and health-care delivery are integrated in the pri-
mary care of women. Introduction
5. Discuss women’s health and sex- and gender-based
medicine curricula for medical student, interprofes- Every cell has a sex, and all bodies are influenced by gender.
Integrating results from research investigating sex and gender
sional, resident, and continuing education. differences into medical education, training, and clinical prac-
6. List educational interventions to advance education tice will improve care for all [1].
in sex- and gender-based care for all learners.
7. Explain urgent needs, persistent gaps, and future Women’s health is much more than reproductive health. The
directions in the field of sex- and gender-based field of women’s health has evolved over the years from a
women’s health. focus on reproductive organs to an understanding that sex-
based differences exist throughout the body, and that gyne-
cologic care, medical care, breast care, and mental health
care must be integrated to take care of the whole woman.
Sex- and gender-based medicine (SGBM) is a newer field
which emerged from the women’s health movement. SGBM
studies sex as a biological variable (SABV) and applies find-
ings individually to all persons in the context of gender influ-
ences [2–5]. Sex- and gender-based women’s health
(SGBWH) is the integration of SGBM and women’s health.
To advance the field of SGBWH, researchers and educa-
tors in women’s health join forces with the proponents of
D. Kwolek (*) sex- and gender-based medicine and use an interprofessional
Harvard Medical School, Massachusetts General Hospital, approach to promote sex-based research, education, and
Department of Medicine, Boston, MA, USA clinical care. Persistent deficits, including the lack of
e-mail: [email protected]
SGBWH knowledge and skills among health professionals,
M. R. Jenkins and the lack of research studies that report findings accord-
University of South Carolina School of Medicine Greenville,
ing to sex and gender variables, must be remediated [5].
Greenville, SC, USA
© Springer Nature Switzerland AG 2020 3

S. A. Tilstra et al. (eds.), Sex- and Gender-Based Women’s Health, https://doi.org/10.1007/978-3-030-50695-7_1
4 D. Kwolek and M. R. Jenkins
This volume is part of the solution, providing a core cur- Table 1.1 Definition of sex- and gender-based women’s health
(SGBWH)
riculum for primary health-care providers that covers com-
mon women’s health issues as seen through the lens of Sex- and gender-based women’s health (SGBWH) is devoted to
facilitating the:
SGBM. The mastery of the material in this book will provide
Preservation of wellness.
a solid foundation to provide sex- and gender-informed care Prevention of illness.
to all women within the broader goal of excellent primary Patient-centered approach to conditions.
care for all persons. SGBWH includes conditions which:
Are unique to women.
Have epidemiology, manifestations, management strategies, and/
or prognoses which are affected by sex and gender.
oundations of Women’s Health and Sex-
F A SGBWH approach:
and Gender-Based Medicine Cultivates the study of sex and gender differences.
Recognizes the contribution of multidisciplinary and
interprofessional teams.
efining Sex- and Gender-Based Women’s
D Incorporates the individual’s personal experience of health and
Health illness.
Recognizes the diversity of health needs over the life cycle and
What is sex- and gender-based women’s health (SGBWH), how these needs reflect differences in race, class, ethnicity,
culture, sexual orientation, gender, levels of education, and
and what distinguishes a SGBWH provider or curriculum?
access to medical care.
SGBWH is a mindset, a paradigm shift, and a set of core Includes the empowerment of women, as for all patients, to be
competencies. It takes on a number of public health issues, informed participants in their own health care with shared
employs a way of doing research which includes women as decision-making.
Seeks to help resolve gaps, inequities and disparities within
participants, asks whether and why sex and gender differ-
health care.
ences exist, and, most importantly, poses the question, “Are
Adapted from the National Academy for Women’s Health Medical
these differences clinically meaningful?” SGBWH is a body Education (NAWHME) Women’s Health in the Curriculum [9]
of knowledge, a set of skills, and a model of comprehensive,
integrated, and informed clinical services. SGBWH is con-
cerned with community outreach and addressing disparities
through advocacy, so as to care for the underserved, mem- Lidia self-refers for mammography, and afterwards she is
bers of minority populations, low-income individuals, and notified that she has calcifications seen on her mammo-
immigrants, with equity. SGBWH values promoting women gram that should be biopsied. She is anxious about her
and underrepresented minorities into leadership positions, referral to the breast center, stating that she had a bad
and accommodating providers in their roles as family care- experience in the past with doctors “who did not explain
givers while pursuing their professional career. anything to her” and did not listen to her concerns.
SGBWH is patient-centered and considers the whole per-
son in the context of their social environment and cultural
context. It affirms that sex is a biological variable (SABV) Core Values: What Do Patients Want?
and that gender is a social construct; both factors influence
the health of every person. In order to personalize health A guiding principle in SGBWH is to provide excellent health
care, sex and gender must be factored into the care of each care which aligns with the priorities and values of patients.
and every patient [6–8]. A suggested definition of SGBWH An interdisciplinary, inclusive approach to health care based
is displayed in Table 1.1 and is adapted from an original defi- on sex- and gender-specific data is sought by consumers of
nition of women’s health from 1997. The terminology used health care, especially women [10]. To answer the question
to describe the concept of women’s health has changed over of what patients want, the authors propose the following core
the years, but the basic principles and core values have per- values based on decades of literature on deficiencies in wom-
sisted and progressed. en’s health, focus groups, and studies of consumer demands
The ideal women’s health provider takes women’s con- in women’s health and primary care [9–12]:
cerns seriously and acknowledges biopsychosocial factors 1. The respect for the value of an informed patient’s choice.
that impact health. The provider is knowledgeable of hor- Patients have the right to self-determination based on
monal and reproductive conditions unique to women and of adequate and accurate information and a presentation of
relevant differences between men and women in nonrepro- options which is understandable to the patient. Individuals
ductive conditions. Providers should be skilled at painless want the opportunity to ask questions and for providers to
exams, respectful interactions, effective communication, and respect their autonomy in making medical decisions.
shared decision-making methods. For specialists, knowledge Informed consent is an example of this component and,
of sex and gender differences in their specialty is required. more recently, shared decision-making.
1 Women’s Health and Sex- and Gender-Based Medicine: Past, Present, and Future 5
• Clinical example: A 40-year-old’s primary care pro- aradigm for the Scope of Practice
P
vider has explained the increased risk of false-positive in the Primary Care of Women
mammogram results, which might require additional
diagnostic interventions, but supports the patient’s ulti- Early in the women’s health movement, a paradigm for
mate decision to begin mammography at 40. primary women’s health care was put forth as the inte-
2. The respect for a patient’s values and the patient’s per- gration of primary care gynecology, primary care psy-
spective. The values and beliefs that are important to patients chiatry, and primary care medicine [9]. We suggest that
should be honored by the provider and taken seriously. the paradigm be modified: (1) adding breast health and
• Clinical example: A woman with ductal carcinoma in medical care of the pregnant patient as essential compo-
situ (DCIS) chooses bilateral mastectomy for treatment nents of the primary care of women, (2) including sex
and prophylaxis. This patient should subsequently be and gender aspects, (3) expanding psychiatry to include
supported in her decision, even if some providers might the psychosocial aspects of sex and gender, and (4)
view the chosen treatment as “overkill.” emphasizing the influence of the reproductive hormonal
3. The right to comprehensive, integrated care. influences and sex- and gender-based differences in all
Fragmentation is a problem within medical care and domains (see Fig. 1.1 below).
especially for women patients who have breast and gyne- Sex- and gender-based primary care for women integrates
cologic issues. breast health, ob-gyn, primary care, and behavioral health.
• Clinical example: Models of integrated care include Each patient is also understood within the context of gender
one-stop shopping women’s health centers, collabora- identity, gender expression, natal sex, sexual orientation,
tive care, and primary care with seamless referral net- sexual behavior, family composition and dynamics, educa-
works to specialists. tional level, employment, cultural background, religious
4. The right to sensitive, private, painless care including background, ethnic heritage, racial identity, genetic heritage,
permission-seeking, proper draping, gentle positioning, lifestyle habits, and life phase.
skilled providers and care teams, and trauma-informed
care. Clinical settings and patient encounters should feel
safe to patients.
• Clinical example: Extra care should be taken to drape Lidia returns to clinic with multiple issues. Her biopsy
patients, pull curtains, and prevent interruptions and revealed atypical hyperplasia, and she is debating
intrusions at all times and especially when a patient is whether to take tamoxifen for chemoprevention. She is
undergoing a breast, genital, or rectal examination. also having hot flashes and bloating and is feeling
5. The right to be cared for by providers who are knowl- depressed and anxious. She is pleased to hear that
edgeable and skilled in women’s health and sex- and these issues can all be addressed by her primary care
gender-based medicine. Women assume that their health- provider, who explains that hot flashes affect sleep, and
care providers are knowledgable about common breast sleep affects mood. Further, tamoxifen can make hot
issues, gynecologic issues, mental health issues, meno- flashes worse. After a lengthy discussion of risks and
pause, and sex- and gender-informed aspects of care. benefits, she decides to start tamoxifen and
• Clinical example: Perimenopausal and menopausal venlafaxine.
symptoms with hot flashes, night sweats, poor sleep,
and irritability are common. Providers should recog-
nize this constellation of symptoms and be familiar
with treatment options and understand their own limits Primary care
and scope of practice. Sex & gender psychiatry and
based primary care medicine
6. The right to evidence-based health care that is supported social aspects of care
by data from scientific studies which included women and
reported outcomes by sex. Sex and gender
based primary care
• Clinical example: Aspects of cardiovascular disease for women
(CVD) have significant similarities and differences
between men and women which impact risk, evalua- Primary care Primary care
tion, treatment, and prognosis. Primary care providers breast health and disease obstetrics and gynecology
should take an obstetric history from all women and
recognize that the obstetrical complications of gesta-
tional diabetes and hypertensive disorders of preg- Fig. 1.1 The integration of multiple domains in the primary care of
nancy increase a woman’s future risk of CVD [9, 13]. women
he History of Women’s Health and Sex-

T Industry and the Private Sector Alongside federal actions,
and Gender-Based Medicine pharmaceutical companies, managed care organizations, private
foundations, and nonprofit organizations provided dollars and
The women’s health movement of the 1960s began as women held educational conferences to fuel an explosion of research
became dissatisfied with the lack of information available to and public awareness in women’s health. Pharmaceutical com-
them and the lack of choices regarding their medical care panies established women’s health divisions to study and mar-
[14]. Medicine was taught without reference to sex and gen- ket hormone replacement, antidepressants, statins, and
der except for in the reproductive system. The 70 kg man was osteoporosis treatments. Estrogen replacement therapy (ERT)
presented as the normal human body, and women’s bodies was viewed as a fountain of youth because early observational
were thus considered as “other” [4]. Pressure mounted for studies supported its use for the prevention of cardiovascular
women’s rights, and in 1985, the National Institutes of disease and osteoporosis. Managed care organizations viewed
Health (NIH) commissioned a task force to study the need women, who constitute more than half the American population
for increased research with women as subjects. The report and almost two-thirds of the population aged 65 and older, as
documented the dearth of research on women and the lack of the key consumers to decide where families would spend their
inclusion of women in clinical trials. Medical research at that healthcare dollars. Women are greater users of healthcare ser-
time did not include women subjects as they were a “pro- vices than men, and women strongly influence health care utili-
tected population,” which meant that there was little data on zation because they often manage health care for their family.
the risks and benefits of medications and treatments in For these reasons, increased attention was paid to the wants and
women [15, 16]. needs of women patients.
In the 1990s, the state of both women’s medical care and

omen’s Health 1990–1999: An Explosion
W of education in women’s health was described as “a patch-
of Research and New Initiatives work quilt with gaps” because it was fragmented and had not
adequately prepared physicians to deliver comprehensive
Federal Action and Funding The Women’s Health Equity care to women [6]. In response, models of integrated clinical
Act of 1990 created the Office for Research in Women’s care for women were created.
Health (ORWH) at the NIH, with an initial $14 million bud-
get. The ORWH provided the blueprint for decades of medi- Professional Education in Women’s Health Whereas wom-
cal research and support for the women’s health movement en’s health had previously been equated with reproductive
to the present. The mandate for women’s health research health, attention was drawn toward the content of medical cur-
included every organ system, the effects of sex hormones ricula and residency programs to train providers in the compre-
throughout the body, and the psychosocial aspects of health hensive care of women. The American Association of Medical
[17, 18]. Colleges (AAMC) surveyed medical curricula and found that
women’s health topics were generally not covered in medical
In the largest trial of its time, the Women’s Health curricula outside of obstetrics and gynecology (ob-gyn) [3].
Initiative was funded with $625 million in 1991 to longitu-
dinally study the influence of hormone replacement therapy The traditional internal medicine curriculum covered only
(as it was called then) and diet on cardiovascular disease two-thirds of necessary skills for the care of women [21, 22],
and colon cancer. Osteoporosis was another major focus of with deficiencies primarily in gynecology. Family medicine
the study [19]. Prior assumptions about results in men residencies traditionally included more gynecology than
being valid in women needed to be tested. Further, the NIH internal medicine programs, but many program directors in
published guidelines that were modified to ensure that the family medicine reported that teaching on women’s health
safety and efficacy of drugs in women were demonstrated issues apart from traditional ob-gyn topics was inadequate
prior to their release and clarified that research findings [23]. Competencies were established at multiple levels to
should be analyzed according to men versus women improve women’s health education; curricula were analyzed
patients [17, 20]. This funding and critical mass of activity and modified to expand the knowledge and skills of health-
lead to the founding of the Society for Women’s Health care providers.
Research. During this time, there was an explosion of interest and
A few years later, congress established federal offices of participation in women’s health education at all levels, in
women’s health within each of the major agencies: the research in women’s health, and in improving clinical ser-
Centers for Disease Control (CDC), the Food and Drug vices to women. The first textbooks on women’s health for
Administration (FDA), the Health Research and Services primary care were written, interdisciplinary women’s health
Administration (HRSA), the Veteran’s Administration (VA), clinics were founded, and many regional and national con-
and the Department of Health and Human Services (DHHS). ferences focusing on women’s health were held [24–26].
Academia and Centers of Excellence in Women’s stand more clearly the nature of human biology and how it is
Health Academic centers applied for grant dollars which compromised by disease, and to develop more effective
were earmarked for women’s health concerns. Federal funding treatments for disease in both sexes” [29, 30].
to establish academic centers of excellence (COEs) in women’s
health was made available, and academic medical centers com- Proponents of women’s health in the 1990s included sex-
peted to receive COE designation and funding. The COE pro- and gender-based differences as part of the definition and
gram was funded from 1995 to 2007; necessary components scope of women’s health. The NIH revised its guidelines on
were: research, clinical care, education, community outreach, the inclusion of women and minorities in clinical research in
and leadership. Concurrent action by the Veterans Affairs (VA) 1994, stating that all studies were expected to analyze results
Administration offered competitive grant funding for women’s and conclusions for women and men [20].
health fellowships in partnership with medical schools creating It was in 2001, however, when the Institute of Medicine
women’s health clinics and, in so doing, trained faculty to facil- (IOM) published the report “Does Sex Matter?”, that the
itate future training and research. sex- and gender-based medicine movement became more
universally recognized and moved into the mainstream [5].
Additionally, women’s health and SGBM research had Scientific discovery has elucidated sex differences
new outlets to disseminate their findings. The Journal of throughout the human body and gender influences on diag-
Women’s Health and Gender-Based Medicine launched in nosis and care delivery (Table 1.2). It is now accepted that
1992; the publication continued as the Journal of Women’s sex is a biological variable based on chromosomal comple-
Health in 2002 and became the official journal of the ment (XX, XY, and other sex chromosome combinations),
American Medical Women’s Association (AMWA) in 2008. having an impact on anatomy and physiology, and must be
addressed in scientific research. Gender is a social con-
struct which, among other concepts, includes self-repre-
omen’s Health 2000–2009: Establishing
W sentation to society and the environment’s response based
Sex- and Gender-Based Medicine on that representation. The textbook Principles of Gender-
Specific Medicine (Legato et al) had international contrib-
Growth in Women’s Health Throughout the next decade, utors and was published in 2004 [29].
women’s health continued to grow and expand. The NIH
published a six-volume Agenda for Research in Women’s
Health for the twenty-first Century [27] which revealed a Table 1.2 Examples of sex and gender factors relevant to research and
blueprint of continued needs in research across all aspects of clinical care
health. Research programs enrolled women subjects, and the Genetic and cellular Anatomic and
physiological
effects of female hormones throughout the body were topics
Individual gene expression and Size of organs and blood
of intense research. The NIH started the Building mutations. vessels.
Interdisciplinary Research Careers in Women’s Health Chromosomal variations. Body size.
(BIRCWH) program, which is a mentored career- Cellular level differences. Body composition.
development program to promote careers in women’s health Cellular receptors for hormones. Pharmacodynamics and
pharmacokinetics.
and sex differences research. Since the program was created Liver metabolism of
in 2000, at least 77 grants to 41 institutions supporting more drugs.
than 613 junior faculty members have been awarded by Breast tissue in women
ORWH and BIRCWH program cosponsors [28]. versus men.
Reproductive organs.
Sex differences in organ
The curricula at schools of dentistry, nursing, pharmacy, function.
and allied health professions were analyzed for content in Surgical alterations of
women’s health. Interprofessional education expanded. anatomy.
Hormonal Psychosocial
Education in women’s health increased and improved at all
In utero hormonal milieu. In utero influences/
levels. (See section on Education below.) Hormonal effects on cells, tissues, and stressors.
organs. Psychosocial stressors.
Establishing Sex- and Gender-Based Medicine Marianne Hormonal fluctuations across the life Caregiving demands.
Legato, MD, who subsequently wrote the textbook Principles span: Puberty, menstruation, Gendered societal
pregnancy, lactation, and menopause. expectations.
of Gender-Specific Medicine observed, “When we make the Reproductive potential. Adverse childhood
unwarranted assumptions that results in men will apply Exogenous hormones. events.
equally to women, we miss the opportunities that studying Trauma and intimate
women would give us: to define new questions, to under- partner violence.
9. Chronic obstructive pulmonary disease (COPD) is more

Lidia calls asking for a refill of zolpidem 10 mg nightly severe despite lower smoking exposure in female
which was started by another provider several years patients as compared to male patients [40].
ago. She admits that she is often sleepy the next day 10. Zolpidem has different dosage recommendations for
after she takes the medication. Lidia’s provider tells men and women. Zolpidem is metabolized more slowly in
her that the approved maximum dose of zolpidem is women leading to dangerously high doses persisting
5 mg for women, as opposed to 10 mg for men. Lidia until the next day, with an increased incidence of subse-
learns that there are differences in drug metabolism quent car accidents [41].
between the sexes and that women, more than men,
have high zolpidem levels the day following drug Some Signs of Stalled Women’s Health Efforts Sex- and
ingestion. gender-based knowledge increased over the decades because
of research in women’s health and sex and gender differ-
ences. With the increased emphasis on sex and gender, how-
Sex and Gender Differences That Make a Difference Many ever, there was concern that the original mandate to integrate
sex and gender differences are clinically meaningful. women’s health throughout health professional education
Examples include: might become sidelined [42].
1. After consuming the same amount of alcohol, women The COE program was defunded in 2007, and the survival
have higher blood alcohol levels than men, even allow- of women’s health centers was dependent upon each home
ing for size differences, which is partly because women institution’s willingness to continue the previously estab-
have lower levels of alcohol dehydrogenase in their lished programs. Enthusiasm and dollars to explore hormonal
stomachs than men [31]. therapies decreased when preliminary reports from the wom-
2. Multiple studies have demonstrated that, compared to en’s health initiative found that postmenopausal hormone
men, women generally have a lesser extent of both overt therapy use was not universally beneficial, with concern for
and subclinical coronary atherosclerosis [32], but tradi- breast cancer risk and increased cardiovascular events [19].
tionally feminine gender traits, such as being a care-giver Many of the original leaders who pushed the women’s
versus a primary income producer for a family, nega- health movement forward subsequently retired, focused on
tively affects the prognosis in recovery from acute coro- other areas of academia, or otherwise lost steam due to
nary syndromes more than sex of the patient [33]. reduced resources and institutional support. Increased inter-
3. Women are more likely to develop Heart Failure with est and funding for primary care centers of excellence (not
preserved Ejection Fraction (HFpEF) than men [34]. specific to women), the study and correction of disparities,
4. Women are more susceptible to fatal torsades de pointes the rise of interprofessional education (formerly called mul-
than men when taking the anti-arrhythmic medications tidisciplinary education in older literature), and the emphasis
sotalol, disopyramide, or amiodarone [35]. on sex and gender as unique variables in the care of
5. Women are more likely than men to suffer a second heart patients replaced much of the prior focus on women’s health.
attack within one year of their first heart attack [36]. Although in the late 2000s the emphasis on women’s
6. Autoimmune diseases are more common in women than health education began to wane, in 2008, the American
men, and the XX sex chromosome complement has been Medical Women’s Association (AMWA) renewed their com-
shown to be disease promoting in some autoimmune dis- mitment to defining and disseminating a shared curriculum
eases as compared to XY. Pregnancy reduces relapse in in women’s health. The goal of complete curricular reform
cell-mediated but not antibody-mediated diseases, sug- with the inclusion of women’s health and sex- and gender-
gesting a protective role for high levels of estrogen [37]. based medicine gained momentum in the following decade
7. After menopause, women lose more bone mass than and continues into the present [43, 44].
men, which is why 80% of people with osteoporosis are Lasting impact from the COE program was achieved at a
women. However, men are more likely than women to large number of centers in the form of continued research in
die after an osteoporotic hip fracture. The majority of women’s health, expansion beyond traditional women’s
research on osteoporosis is conducted in women, and health through sex- and gender-based medicine, persistence
less is known about treatment efficacy in men [38]. of many women’s health clinics, and continued influence in
8. Cluster headaches are more common in men but are many medical, dental, nursing, pharmacy, allied health, and
more common in women than previously believed. Aura public health educational curricula. Women were promoted
with cluster headache is equally common in both sexes, in academic medicine, endowed chairs in women’s health
but women are much more likely to experience sensory, were funded, and many graduates of women’s health fellow-
language, and brainstem auras than men [39]. ships were productive in academic careers.
he Collaboration of Women’s Health and Sex

T resources for practitioners and patients interested in
and Gender Medicine 2010 to 2020: SGBWH, including a sex and gender bibliography, a national
Addressing Gaps in Research sex- and gender-based physician registry, and links to educa-
tional materials [1]. The Collaborative has taken a leading
Women’s health, as a movement, was at a nadir in the early role in curricular reform in sex and gender-based health edu-
2010’s. The general consensus appeared to be that focused cation, including several summits in sex- and gender-based
women’s health educational efforts were no longer needed, education [1, 44, 48–50].
having been adequately addressed and remediated. At the
same time, the Institute of Medicine (IOM) published a
report which showed that large gaps remained in research on Lidia, now age 53, took tamoxifen for 5 years without
women’s health concerns [45]. A closer look at research complication and is now postmenopausal. She pres-
efforts found that, although women were included in research ents with substernal chest pain on exertion. She is
studies and clinical trials at increasing rates, the analysis of screened by her PCP for diabetes, tobacco use, choles-
data by sex or gender was often not completed or reported. terol, and family history for cardiovascular risk fac-
There are many barriers to changing the status quo of sex- tors. On further questioning, her provider discovers
and gender-blind reporting within the scientific literature that Lidia has a history of gestational diabetes and
(discussed in more detail below; see section on future preeclampsia. Lidia undergoes an exercise stress test
directions). which is negative, but because of her prenatal risk fac-
On the basic science level, there was an increased aware- tors, she is referred to a cardiologist who has a special
ness that cellular research must be conducted with knowl- interest in heart disease in women.
edge of the sex of the cell, whether XX, XY, or other. Animal
research should be conducted on female and male animals,
as appropriate, with the results indicating the sex of the
animals. Models of Clinical Care for Women
A subsequent national IOM workshop summary on sex-
specific reporting of scientific research disputed the notion In response to women’s demands and market forces, many
that gaps in SGBM and WH had been adequately remedi- integrated clinics providing women’s health have been
ated and urged that further efforts were needed [46]. established.
Governmental and funding agencies started taking note of Obstetrics and gynecology practices and maternity care
gender and sex disparities. In 2010, the Canadian Institutes centers hired more female doctors and widwives, provided
of Health Research established policies requiring research- private birthing rooms for deliveries, upgraded facilities, and
ers to include both sex and gender as critical variables in all became more comprehensive in scope. Fertility centers and
studies or clinical trials, as did the European Commission in abortion services have also been called women’s health cen-
2013. In 2016, the NIH began requiring that US grant pro- ters, despite the narrow foci. Research of women’s prefer-
posals include information as to how sex, but not necessar- ences in the past found that patients of reproductive age were
ily gender, would be incorporated as a biological variable in often more satisfied with their care from ob-gyns than from
research studies. The World Health Organization urges that internal medicine primary care providers, suggesting that
sex and gender be incorporated into health-care policy young women highly value providers with expertice in
worldwide [47]. reproductive health [51].
The field of SGBM has grown over the last two decades, Diagnostic women’s health centers arose, providing
but as a grassroots effort, not with an influx of monetary mammography, DXA scans, and other radiological services.
resources. Collaboration was forged between prior leaders in Some centers provided needle biopsies when needed.
WH and the proponents of SGBM, and the two fields were Comprehensive breast centers were formed to improve the
merged into a new focus. The Sex and Gender Women’s quality of breast services. These centers were multidisci-
Health Collaborative (SGWHC) was formed in 2012 and plinary and offered mammography often with same-day
spurred renewed efforts at research, educational, and clinical interpretation. Consultation with a multidisciplinary team of
reform. Founding organizations included the American dedicated breast surgeons, oncologists, plastic surgeons, and
Medical Women’s Association, the American College of radiation oncologists became the norm for patients diagnosed
Women’s Health Physicians, and the Society for Women’s with cancer in some areas. Volunteer groups and national
Health Research. Collaborating institutions include the organizations, including the Susan Komen Foundation [52],
Laura W. Bush Institute for Women’s Health and multiple assisted women with patient education and comprehensive
national and international academic institutions. The Sex and care including spiritual care, help with wigs and fashion,
Gender Women’s Health Collaborative website lists lymphedema treatment, support groups, and other services.
Primary care-based women’s health clinics, staffed by

primarily women providers and often interprofessional in Three months later, Lidia’s symptoms have progressed,
nature, employed physicians, NPs, social workers, and/or and she is evaluated by a cardiologist. Given her
mental health providers working together. A key exam- symptoms and risk factors of gestational diabetes and
ple was the Women’s Health Associates at Massachusetts preeclampsia, she is sent for a nuclear stress test. The
General Hospital, founded in 1985 by Dr. Karen Carlson. stress test is positive, and cardiac catheterization
The US Department of Health and Human Services used this reveals significant coronary artery disease. Lidia
clinic as a model to subsequently aid in the development of would like to know if her sex and ethnic background as
numerous National Centers of Excellence in Women’s an Indian American affect her prognosis.
Health [53].
Many women’s health clinics added elements across dis-
ciplines and increased care integration. Centers might
have included primary care, gynecologic care, osteoporosis ommunity Outreach, Disparities,
C
screening, prevention and treatment, menopausal care, breast and Health Equity
screening, diabetic education, urinary incontinence screen-
ing and treatment, and the primary treatment of depression, Sex- and gender-based women’s health (SGBWH) is con-
anxiety, and premenstrual syndrome (PMS) in one clinical cerned with public health and barriers to care for patients:
space. Referral networks identified providers in various spe- literacy issues, minority issues, socioeconomic issues, cul-
cialties with a special interest in women’s health including tural competency, care of underserved populations, and the
women’s cardiology, women’s health gastroenterology spe- interaction between medicine and social, societal, and legal
cializing in functional bowel problems, rheumatologists who factors. The original COEs were each required to focus
treated women with fibromyalgia, and mental health provid- attention on a specific underserved population. Campaigns to
ers who were sensitive to women with a history of trauma, raise awareness of women’s health issues and to empower
and skilled in the gender-specific needs of women. These and educate women have been a priority among women’s
clinics enjoyed strong relationships with ob-gyn and breast health advocates. In the 1980s, the AIDS epidemic cast atten-
centers. In some cases, all of these elements were brought tion on the needs and health issues of the gay community, but
together in the same physical space to make a truly compre- less was known about lesbian health and the needs of trans-
hensive women’s health center. In other cases, a “Center gender individuals. From the beginning, the women’s health
Without Walls” was founded which did not exist in a single movement partnered with women’s studies experts to address
physical space but consisted of a network of providers, clin- the needs of lesbian women. (See Chap. 36 on Care of Sexual
ics, and services for the comprehensive care of women. Minority Women and Chap. 37 on Transgender Care.) Today,
women’s, minority, and LGBT issues are often housed
Veterans Affairs In 1990, the Veterans Administration (VA) together in offices on disparities and/or equity at individual
recognized and acknowledged that it was not providing ade- academic institutions.
quate care to its growing number of women veterans who had Disparities result in disproportionate morbidity and mor-
the same rights to health care as male veterans. Many women tality, and providers should be aware of the lower screening
veterans had experienced sexual abuse or harassment in the rates, suboptimal diagnostic testing, loss of patients to fol-
military or had a history of trauma prior to enlisting in ser- low-up, less comprehensive treatment, and overall worse
vice. The VA assigned Women Veterans Coordinators at each prognosis in certain demographic groups, including immi-
medical center who acted as case managers to address the grants and sexual minorities (See section on disparities in
needs of women veterans. The VA funded women’s health Chap. 14 on Cervical Cancer and Human Papillomavirus).
centers throughout the VA system and mandated that women Women are overrepresented in the United States within the
veterans’ clinical care be sensitive to the privacy and safety poor and underserved populations. There is a need for cultur-
concerns of its patients [54]. The VA held continuing educa- ally sensitive patient education and strategies to overcome
tion conferences on women’s issues and veteran- specific barriers to care for populations at risk. For instance, in the
issues to train its providers. The conferences addressed post- United States, HPV vaccination is widely available and free
traumatic stress disorder (PTSD), sexual traumas, mental for children. Culturally sensitive reframing of the vaccine
health, and other subjects in interprofessional care. The VA debate allowed parents who were initially concerned that
clinics serve as training sites for medical students, residents, HPV vaccination would lead to teenage promiscuity to
and fellows [55]. The VA further provided funding for wom- instead understand HPV vaccination as routine care. Gaps
en’s health clinical fellowships which have trained many still remain for those who have poor access to health care
leaders in women’s health [56]. (See Chap. 38 on Care of the (e.g., rural and low-income populations) in the United States
Female Veteran.) and worldwide. (See Chap. 2 on High-Value Health Care.)
The women’s health construct recognizes race as a com- Medicine found that many women receive incomplete and
plex factor in health care which is affected by country of poorly coordinated care for their routine and comprehensive
birth, country of residence, income, educational level, diet, health concerns, in part due to deficiencies in the education
and activity. While ignoring race as a factor is not advised, of physicians. The Council stated that changes in undergrad-
defining race can be problematic. In the United States and uate and graduate medical education, in addition to continu-
elsewhere, populations are becoming more racially mixed. ing medical education, were needed to adequately address
Many shared decision-making tools and risk calculators the comprehensive health needs of women [3]. In 1998, sys-
include race as a variable, but validation for various races tematic surveys of american medical school curricula by the
may be limited. An example is the Gail model that: was devel- Association of American Medical Colleges (AAMC) found
oped in White women, underestimates risk in Black women, significant gaps in medical education concerning women’s
is not well validated in Hispanic or Asian women, and has no health, and changes were recommended [42, 61]. Studies of
data on women from India [57]. Another example is genetic curricula in dental, pharmacy, nursing, public health, and
screening; the BRCA 1 and 2 genes are known to be very allied health professional schools had similar findings, and
common (1 in 40) in the Ashkenazi Jewish population. What an expert panel convened to make recommendations for
is less well known is that BRCA genes have been found to be interprofessional collaboration in women’s health curricula
relatively common in Hispanic women in the Southwest in 2012 [62].
United States; 25% tested positive for BRCA in a high-risk Importantly, studies found that most medical schools did
breast cancer clinic population [58]. not routinely offer material on women’s health and gender-
There is further concern that bucketing women into racial based physiology as a focused course of study, except as pre-
categories may lead to unintended differences in health-care clinical and clinical electives with limited influence on the
delivery processes—that is, when the intention is to call out overall curriculum [60, 61]. Traditional clerkship rotations
important disparities in order to address them, sometimes, the fragmented the care of women: internal medicine and sur-
action of labeling itself may lead to disparate treatments. One gery presented nonreproductive aspects of care, and ob-gyn
must proceed with caution when collecting sociodemographic focused on reproductive- and gender-specific issues. As a
history to assess risk and design an approach to management. result, relevant menstrual, obstetrical, gynecologic, and sex-
Standard processes and treatments for all people, regardless ual histories were often omitted in the history and physical
of race or other kinds of minority status, are both the goal and notes written by students and residents during non-ob-gyn
a core strategy to address disparities and counteract uncon- rotations [9, 60, 63].
scious bias. Women’s health education teaches that variation Women’s health was a catalyst for reform in medical edu-
is expected, and an emphasis is placed upon competence for cation in which sex- and gender-based content and women’s
culturally sensitive care of every person [59]. health beyond reproductive health are weaved into under-
graduate curricula. Concepts in complexity science and
physiological variation, together with advances in medical
Lidia is very grateful for the excellent sex- and gender- educational methods, facilitated the curricular change [59].
based care she has received and wants to know why Throughout the next decade, there were continued efforts
more health-care providers do not seem to know about to advance women’s health education at all levels, and inter-
women’s health and sex and gender differences rele- disciplinary curricula were developed (see section on
vant to clinical care. resources at the end of the chapter) [9, 64, 65]. Despite
national attention to women’s health education, however, the
women’s health content in medical education at most institu-
tions continued to be suboptimal [42, 66, 67]. Innovative
ducation in Women’s Health and Sex-
E instructional methods used to introduce women’s health
and Gender-Based Medicine knowledge and skills into medical curricula included
problem-based learning cases [68–70], web-based modules
Women will never receive optimal care until all health-care pro- [71], standardized patient workshops, and structured clinical
viders are fully trained to meet their needs. The goal is to
improve training in the care of women in the full range of wom-
instructional modules (SCIM), which are a form of modified
en’s health issues and thus end the fragmentation of women’s objective structured clinical examinations (OSCE) [72, 73].
health care [60]. Substantial curricular changes required support from the
highest levels of academic institutions, faculty development,
The road to educational changes in women’s health and sex- awareness campaigns, and the designation of a center or pro-
and gender-based medicine began in the 1990s and has been gram to spearhead efforts [74–76].
filled with challenges. In 1995, the Council on Graduate An early model for integrating women’s health issues into
Medical Education’s (COGME) Fifth Report on Women and the entire medical school curriculum and the barriers and
solutions to implementing the new curriculum were detailed Another challenge is that SGBWH often lacks an aca-
in publications from educational innovators at Drexel’s (for- demic home within health professional schools, and there-
merly MCP Hahnemann) Center of Excellence in Women’s fore, resources and opportunities for promotion and influence
Health [70, 76]. Other institutions, especially the Centers of among SGBWH faculty can be limited. Furthermore,
Excellence in Women’s Health, were also successful in inte- SGBWH adherents are diverse in terms of field of study and
grating women’s health into their curricula, leveraging grant specialty, which makes concerted efforts to cohesively
money, institutional support, and buy-in from leaders in the advance the field difficult. Academic meetings tend to cater
academic medical centers. Federal mandates and commit- to one field or specialty, and faculty members often have lim-
ment from organizations such as the AAMC provided incen- ited funds for travel. Lastly, most faculty who focus on wom-
tive for the efforts. At that time, women’s health curricula en’s health are women taking care of women, and there is
were disseminated to partnering institutions and adapted to concern that the field is marginalized within professional
an interprofessional audience of learners [77–80]. education and academics partly for this reason [42, 76, 86].
As the emphasis on sex- and gender-based medicine has Potential solutions to the continued challenge of integrat-
increased, the Sex and Gender Women’s Health Collaborative ing women’s health and sex- and gender-based medicine into
(SGWHC) and seasoned educators have worked toward the curricula include defining interprofessional competencies
inclusion of sex- and gender-based medicine into medical and learning objectives, developing shared curricula, raising
and interprofessional curricula [44, 48–50]. In 2011, in col- awareness, obtaining external and internal funding, auditing
laboration with the National Board of Medical Examiners and inclusion of SGBWH content on licensure and board
(NBME), the SGWHC audited the National Board of examinations, enhancing faculty development programs,
Medical Examiners (NBME) exams for women’s health and establishing dedicated offices or programs within academic
sex and gender content [1, 48]. In 2012, the first sex and centers, encouraging participation of key faculty on curricu-
gender educational summit was held, and a plan was out- lum committees, developing faculty rewards for scholarship
lined to introduce sex and gender content into medical cur- in SGBWH, and enforcing faculty accountability for includ-
ricula [49]. In 2015, 2018, and 2020, additional summits ing relevant sex- and gender-based information in their
were held with increased participation and expanding scope teaching, research, and clinical endeavors. Curricular change
to include interprofessional education and international teams which include curriculum influencers, student or resi-
partners [44, 50]. dent champions, institutional leaders, and content experts
In order to influence lasting and meaningful change, edu- can be particularly effective as change agents [49]. Ob-gyn,
cation must occur at all levels: undergraduate education in all as the only medical specialty wholly devoted to women, has
health professional schools, graduate medical education, fac- provided leadership nationally and locally in the women’s
ulty development, and continuing education. Faculty devel- health arena and continues to be a key ally in this intrinsi-
opment and resident education are critical for the cally multidisciplinary and interprofessional effort [1, 76,
improvement of direct patient care and equally important for 85, 86]. Key steps in the planning and integration of SGBWH
teaching students in the classrooms and inpatient care set- content into existing curricula are detailed in Table 1.3.
tings. It is essential that basic knowledge, attitudes, and skills
in women’s health and sex- and gender-based medicine are
disseminated throughout all aspects, and to all members, of raduate Medical Education: Resident
G
the medical enterprise [42, 59, 76, 81, 82]. Curricula and Fellowship Training
Despite the many activities, reports, and roundtable dis-
cussions focusing on SGBWH, curricular integration of sex- The American Board of Internal Medicine (ABIM) and the
and gender-based medicine in US medical schools is not American Academy of Family Physicians (AAFP) have
widespread [83–86]. Changes at a small school or program stated that the knowledge and clinical skills required for the
or in individual courses are easier than changing the whole care of women must be addressed within the context of the
curriculum at a large school or program [59]. Barriers to general skills acquired by residents. Traditionally, internal
integration include the saturation of curricula and competi- medicine (IM) residencies have had limited training in gyne-
tion for instructional time, a lack of buy-in from leadership, cology, and no training in obstetrics, and for this reason,
limitations on finances, and the shortage of champions and focused attention in women’s health-care training is needed
experts in sex- and gender-based medicine and women’s in IM [21–23]. Competency in women’s health among pri-
health within the faculty. A major challenge is the lack of mary care providers is important for both patient safety and
tangible resources, such as a curricular roadmaps or tool kits, patient satisfaction. There is concern that IM residents are
to readily guide faculty, staff, and learners through the orga- not adequately prepared to care for women of reproductive
nizational navigation, institutional negotiation, and resource age, women aged 18–34 years, which may lead to decreased
allocation needed to sustain curricular change [76, 86]. patient satisfaction and quality of care [51, 87–89].
Table 1.3 Integrating sex- and gender-based women’s health Interdisciplinary educational and patient care partnerships
(SGBWH) into curricula [9, 70, 76, 85, 86]
between ob-gyns and primary care providers, which help
1. Identify and recognize barriers. bridge this gap, have been well received by trainees and pro-
(a) Saturation of curriculum and competition for instructional mote a comprehensive view in the care of women patients [1,
time.
64, 90–96].
(b) Lack of an academic home for women’s health and sex- and
gender-based medicine. When developing a curriculum in women’s health for IM
(c) Lack of faculty and residents familiar with sex- and gender- residents, there are numerous resources which may be of use.
based medicine. The ABIM expectations for women’s health competencies
(d) Lack of clinical opportunities for students and trainees. and the published blueprint of topics for the ABIM exam
(e) Lack of funding to support programming, administration, and define the scope of training required for all internal medicine
faculty time.
residents [97–99]. The ABIM exam blueprint lists primary
(f) Lack of women or key supporters in leadership to promote the
importance and inclusion of SGBWH subject matter. medical content categories and the percentage assigned to
2. Develop an implementation plan. each for a typical exam: obstetrics-gynecology and psychia-
(a) Obtain internal or external funding if possible. try make up 3% and 4%, respectively, of the total examina-
(b) Develop and perform a needs assessment to (1) identify tion questions. Moreover, women’s health and preventive
targeted learners, (2) audit and review the existing curricula to health care are listed as “cross-content areas” and are rele-
determine gaps in SGBWH content, and (3) identify the
information that is most needed by the learners.
vant to all of the content categories. Together, women’s
(c) Assess institutional readiness and available resources: Buy-in health and prevention comprise 12% of the examination
from the leadership within a professional school, department, questions [99]. Other sources which inform the development
or residency program director is essential. Meet with the dean, of women’s health curricula include lists of competencies;
chairs, program directors, course directors, and clerkship surveys of residents, residency directors, and graduated resi-
directors.
(d) D etermine scope of what is to be taught: List of competencies
dents; preventive services guidelines; and recommendations
and learning objectives. from experts and educators in women’s health [21,
(e) Teach: Identify opportunities to integrate SGBWH content 100–104].
into existing curricula, and highlight relevant sex and gender To prepare residents in the comprehensive care of women
differences wherever possible. Develop new courses, lectures, patients, topics specific to women and reproductive health
small group sessions, cases, and clinical opportunities.
(f) Identify key faculty, residents, and students for collaboration
issues, menopause, breast care, preconception care, and care
and influence of the pregnant patient must be included in the curriculum.
(i) Form a task force to meet regularly and to build and sustain Sex- and gender-based concepts, that acknowledge sex as a
momentum for change biological variable, should be woven throughout all aspects
(ii) Designate representatives to represent SGBWH education of the broader curriculum [21, 100–104].
on curricular committees and case discussion meetings
A summary of current curricular recommendations for all
(g) Provide faculty development and faculty rewards to increase
participation internal medicine residents is outlined in Table 1.4. The list
(h) Build a searchable repository of information references, aligns closely with the content of this book. The ABIM blue-
cases, lectures, and resources print of what internists should know and the Federated
3. Execute the plan. Council for Internal Medicine (FCIM) recommendations are
(a) Thread awareness of SGBWH throughout the curriculum by comprehensive in the list of topics required. The Women’s
asking all speakers to address issues of sex and gender
Preventive Services Initiative (WPSI) lists the knowledge
differences in lectures and tutorials. The expectation can be
specified in the letter of invitation to speakers. needed for screening and prevention, and these topics should
(b) Ask “what if?” ask all teachers and learners to reflect on the be addressed as an integral part of primary care and wellness
incorporation of diversity and gender issues into their lectures visits. Surveys of residents, program directors, and women’s
and case discussions. Ask, “what if this was a woman, a health experts identify areas of greatest continued need, spe-
transgender individual, an uninsured patient? How would this
change the teaching points discussed?”
cifically topics which may not be covered sufficiently in
(c) Augment curricula and faculty development with SGBWH existing internal medicine curricula.
additions such as special speakers, SGBWH grand rounds, In addition to specific topics for inclusion in internal med-
and clinical elective experiences. icine curricula, interrelationships between reproductive and
(d) Add innovative online modules, podcasts, and health nonreproductive aspects of care are critical to patient care.
informational technology (IT) education.
Specifically, breast and ob-gyn histories belong in complete
(e) Implement SGBWH clinical skills workshops utilizing
models or standardized patients. history and physical examinations performed on each patient;
4. Review: Assess, evaluate, and respond to feedback. for example, complications of pregnancy, gestational diabe-
(a) Develop evaluation tools. tes, and preeclampsia influence the risk of diabetes and car-
(b) Regularly evaluate and assess using continuous improvement diovascular disease in later life, and a history of atypical
cycles to check and adjust. hyperplasia of the breast increases the future risk of breast
(c) Involve learners and perhaps patients in the reflective critique.
Table 1.4 Summary of women’s health curricular content needs for internal medicine residencies [21, 22, 90, 99–104]
ABIM WPSI: Greatest need per PD,
Blueprint/ABIM Well-woman residentd, and women’s
Domains Knowledge and skills topics recsa/FICMb carec health experte surveys
Health maintenance Lifestyle: Diet, activity, and obesity X X N/A
Habits: Alcohol, tobacco, and substance use X X N/A
Immunizations X X N/A
Health screening X X N/A
Breast health General breast care X X X=E
Risk assessment and BRCA testing X X X = S, C
Prevention: Chemoprevention X X x
Benign breast conditions: Lumps, pain, and discharge X – X = E, D,M
Cancer principles of management X – X=M
Survivor care X – X
Family planning Assess reproductive plans X X X=C
Preconception counseling X X X=C
Contraception: OC, IUD, and LARC X X X = C, P
EC, medical abortion, abortion, and infertility X – N/A
Pregnancy and Medical problems in pregnancy X X X
postpartum care Ectopic pregnancy X – X
Mastitis and breastfeeding X X x
Gynecology Sexually transmitted infections X X X = D,M
Vaginitis/vulvovaginal disorder X X X = D, M
Abnormal bleeding/menstrual disorders X – X=D
Dysmenorrhea X – X=M
Pelvic pain: Fibroids, endometriosis, and ovarian cysts X – X=D
Sexual function/dysfunction X – X=D
Menopause Symptoms X – X=M
Hormonal therapy X – X = C, P
Genitourinary atrophy X – X
Mental health/ Depression/mental health disorders X X X = D,M
social aspects of Intimate partner violence X X X=S
health Sexual trauma/rape X – X=S
Eating disorders X – X=D
Chronic pain X – x
Lesbian/bisexual health care X – X=M
Urogynecology Urinary incontinence X X X = D,M
Urinary tract infections X X N/A
Cancer screening Breast X X X = E, S
and principles of Cervical X X X = E, S, D, R
management Colon and lung X X N/A
Uterine, ovarian, and vulvar/vaginal X – N/A
Medical topics Cardiovascular disease in women X X X
relevant to Osteoporosis and fall prevention X X X = S, M
SGBWH PCOS/endocrine disorders X – X=D
Irritable bowel syndrome X – X=M
Migraine headache X – N/A
Sex- and gender-related differences X – N/A
Abbreviations: X included in competency recommendations, guidelines, or high priorities as identified by surveys, x lower priority topics as identi-
fied by surveys, (−) outside scope of recommendations, BRCA breast cancer gene, CVD cardiovascular disease, DM diabetes mellitus, EC emer-
gency contraception, HTN hypertension, IUD intrauterine device, LARC long-acting reversible contraceptive, N/A not applicable, content not
included in surveys, OC oral contraceptives, PCOS polycystic ovary syndrome, PD program director, recs recommendations
a
Recommended from the American Board of Internal Medicine (ABIM) and certifying exam blueprint [21, 99]
b
FCIM = the Federated Council for Internal Medicine [22]
c
WPSI = the women’s preventive services initiative: evidence-based prevention and screening [90]
d
Surveys of residents and program directors [100–103]
e
Most important women’s health educational topics for inclusion in residency training per internal medicine women’s health experts.
Recommendations are further classified as C = counsel, E = exam, S = screen, D = diagnose, R = refer, and M = prescribe or manage [104]
Table 1.5 Resident surveys: the value of clinical experiences in wom- Table 1.6 Curriculum implementation opportunities [76, 86]
en’s health and relevance for practice after residency [100, 102]
Opportunities Tips
Clinical experiences listed in • Women’s cardiologyb Teaching • Clinical skills • Audit content of
descending order of priority by • STI and HIV forums and workshops current curriculum
current residentsa • Menopausal health formats • Standardized patients • Letter to presenters
• Bone metabolism/ • Noon conferences asking all faculty to
osteoporosis • Resident reports address sex and
• Intimate partner violence/ • Preclinical gender biology and
women’s shelterb conferences clinical differences
• Breast health • Ground rounds in teaching and
• Mental health • Directed readings lectures as
• Gynecology • Problem-based appropriate
• Sports injuries in womenb learning modules • Sex and gender
• Urogynecology • Journal clubs distinctions taught
• Maternal medicine • Women’s health across all subjects
• Reproductive endocrinology seminars • Identify faculty
Women’s health topics needing • STI and HIV • Continuity clinic with special
increased emphasis in residencya,c • Menopausal health experiences expertise or interest
• Bone metabolism/ • Specialty clinic and form women’s
osteoporosis experiences health education
• Breast health • Online modules, working group
• Mental health webinars, materials
• Gynecology Faculty • Annual faculty • I t is essential that
• Urogynecology development development all faculty are on
HIV human immunodeficiency virus, STI sexually transmitted and Continuing workshops board with respect
infection Medical • Grand rounds to sex as a
a
Residents in a single IM program [102] Education presentations biological variable
b
Topics not included in survey (CME) • Women’s health and essential
c
Women’s health subjects that graduated physicians from a single IM conferences women’s health
program felt least prepared for but were most needed in practice after • Online modules, content
residency [100] webinars, materials
Primary Care Residents in Internal Medicine The knowl-

cancer. Essential residency training in medical procedures edge and skills in women’s health recommended for primary
relevant to women’s health includes the Pap test and obtain- care residents are more advanced than those required of cat-
ing endocervical cultures [9, 91]. egorical residents. Primary care residents, in addition to gen-
Clinical experiences, especially time spent in specialty eral awareness of sex and gender issues within the
clinics, are effective for developing competency and are subspecialties, should have increased training in gynecology
highly valued by residents. Surveys of current and graduated and breast care, STI evaluation, menopausal treatment,
residents, however, suggest that the current level of training osteoporosis screening, and primary mental health care.
in women’s health during residency is not adequately prepar- Supplemental clinical experiences in gynecology, bone
ing trainees for practice after residency [100, 102, 105]. (See health, women’s cardiology, endocrinology, psychiatry, and
Table 1.5). breast health should be offered if available. Additional train-
Ideally, residency programs should use a written curricu- ing in gynecologic procedures, such as IUD insertion, is of
lum in women’s health. Opportunities to include women’s interest to some residents [21]. A survey of program direc-
health in curricula include didactics, reading lists, case-based tors in primary care revealed that areas of relative weakness
learning, workshops, and clinical experiences in continuity in existing curricula include preconception counseling, con-
and specialty clinics [9]. Many methods of instruction in traception, abnormal bleeding, mental health, intimate part-
women’s health are described in literature, but few have been ner violence (IPV), menopause, sexual trauma, rape, urinary
vigorously evaluated [106]. Direct clinical experiences are incontinence, osteoporosis, and polycystic ovary syndrome
superior, when available for provider education. Faculty (PCOS). In contrast, relative strengths include depression,
development, especially for continuity clinic preceptors, is pelvic examinations, cancer screening, hypertension, diabe-
essential to reinforce learning introduced in didactic sessions tes mellitus, and cholesterol treatment [105].
or through assigned readings [70, 76, 82, 107].
Interdisciplinary clinical training between IM and ob-gyn Women’s Health Tracks in Internal Medicine Tracks in
residents has been shown to be effective in women’s health women’s health typically focus the majority of the continuity
education and is valued by trainees [1, 65, 74, 89, 91, 94, 95]. care experience for residents on women patients. Additional
(See Table 1.6). seminars, journal clubs, and specialty clinical training bring
an advanced level of women’s health focus to these trainees. 59]. A survey of internal medicine and family medicine
The women’s health track (WH track)—the first of its kind— teaching faculty at five academic medical centers found that
was established in 1994 by Dr. Melissa McNeil for residents internal medicine faculty perceived a significantly greater
with a strong interest in developing expertise in health issues need than family medicine attending physicians for fac-
that are unique to women, are more common in women, and ulty development in women’s health, especially in breast
present differently in women [108]. There are approximately care, medical problems in pregnancy, and gynecologic topics
eight known women’s health track residencies available in [82]. Similar results were found in a survey of primary care
internal medicine that offer additional experience in gynecol- providers (PCPs) when asked about continuing medical edu-
ogy, mental health, endocrine, comprehensive women’s cation (CME) in women’s health. Breast care, heart disease
health or VA women’s clinics, and breast centers [109]. in women, osteoporosis, intimate partner violence, mental
Although there are women’s health tracks as well as post- health, and gynecologic topics were in high demand [81].
graduate women’s health fellowships, there is no additional Grand rounds and other seminars, continuing education con-
ACGME distinction accrediting the women’s health focus ference opportunities, and focused faculty development in
and expertise. Published works provide descriptions of wom- women’s have been described as effective and as being well
en’s health tracks and provide data showing that graduates of received among medical educators [74–78, 82].
women’s health tracks tend to become leaders in women’s
health and to be academically productive [110–112]. Interprofessional Education (IPE) IPE is an international
movement relevant to health-care redesign that fits nicely
Women’s Health Fellowships Women’s health fellowships with the SGBWH paradigm: patient-centered and holistic.
train health-care providers in the multidisciplinary and Women’s health care in the past has been fragmented, and
advanced needs of women patients within the paradigm of IPE promotes a remedy for fragmented care: the collabora-
SGBWH as defined in this chapter. Dr. Saralyn Mark tive care of patients. Nurse practitioners, nurses, and mid-
described the first fellowship, which incorporated advanced wives provide excellent gender-sensitive care to patients and
learning in endocrinology, gynecology, psychiatry, cardiol- comprise a large proportion of attendees at CME confer-
ogy, breast health, domestic violence, and the medical care of ences focusing on primary care women’s health. Nurse prac-
pregnant patients [113]. The VA women’s health fellowships titioners in women’s health have held their own annual
were instituted in 1993 and included additional curricula on women’s health conference for over 20 years [116].
the health needs of women veterans, post-traumatic stress dis-
order (PTSD), sexual trauma, assault, and harassment. These Education in SGBWH should be integrated throughout
multidisciplinary fellowships were supported by academic the curriculum of all health professions students, not just
departments and included training in research and investiga- medical students. In an early project, women’s health was
tion. Other similar fellowships not associated with the VA fol- integrated into the curricula of the medical, dental, phar-
lowed. Graduates of women’s health fellowships have been macy, nursing, and allied health schools as well as the inter-
shown to become leaders in women’s health in academic nal medicine residency at one institution. This adapted
medical centers and to have academically productive careers. curriculum was spread further to 15 health-care professional
A review of fellowships and a listing of known fellowships schools throughout the country [77, 78]. Today, more health-
are available in published form [56, 109, 114]. care professionals in dentistry, pharmacy, public health, and
allied health fields are benefiting from increased women’s
There is debate on whether women’s health fellowship health curricula in the classroom and have interest and exper-
training should be a separate certification within internal tise in topics specific to SGBWH. Examples of relevent clin-
medicine, like geriatrics, or remain as an uncertified area of ical topics include oral and facial pain, bone loss in the jaw,
concentration. Thoughtful articles have been written detail- hormonal impacts on gum disease, pharmacokinetic and
ing the pros and cons of such a proposal, and at present, there medication efficacy differences between the sexes, ligamen-
is no additional women’s health specialty certification or rectal laxity in women, sports injuries in women, best prac-
ognition within internal medicine [114, 115]. tices in health communication, social determinants of health,
and public health issues related to SGBWH.
In 2013, the Health Research and Services Administration
aculty Development and Continuing
F (HRSA) published “Women’s Health Curricula: Final Report
Education for Health Professionals on Expert Panel Recommendations for Interprofessional
Collaboration Across the Health Professions” [62]. The
Faculty Development and Continuing Education There is report defined core competencies, examined existing wom-
continued need for programs to possess a cadre of trained edu- en’s health education efforts and literature, and made recom-
cators who are fully equipped to teach trainees and mendations for the dissemination of women’s health
peers about women’s health and gender-based medicine [2, curricula across the health professions: medicine, nursing,
pharmacy, dentistry, public health, and social work. The size the need to move beyond ‘fixing the women’ to a systemic,
institutional approach that acknowledges and addresses the
report also contains a model to assess institutional readiness impact of unconscious, gender-linked biases that devalue and
for integrating sex- and gender-based women’s health across marginalize women and issues associated with women, such as
disciplines. their health [85].
In 2018, the American Dental Education Association
(ADEA) and the NIH ORWH cosponsored an expert round- Although leaders and champions of both sexes are needed
table titled “Women’s Health in Interprofessional Education to make progress in the fields of sex and gender medicine
and Collaborative Care.” The convening report, logic and women’s health, senior women are especially needed
model, and strategies for medicine, dentistry, nursing, phar- in leadership so that changes within academia are not just
macy, and public health are available electronically to pieces and happenstance [59]. The issue of leadership
health and allied professions schools and organizations to development for women came into focus as an area of great
use in curriculum development, collaborative care, and need as academic centers acknowledged the very low num-
experiential treatment and learning [117]. The growth of bers of women, and especially women with children, in the
interprofessional education provides a plethora of opportu- fields of science and medicine, in academics or the highest
nities for the various disciplines to work together to pro- ranks of those respective fields, in politics, and in other
mote women’s health education throughout undergraduate positions of leadership. The underrepresentation of women
and graduate education. Medical education research and minorities was a problem because those in leadership
engages clinician educators, whose promotion may depend set the tone and the agenda and made decisions concerning
on scholarly activity and research endeavors, to develop priorities and resources. Additionally, the optics of major-
platforms outside of the traditional biomedical research ity race men dominating these areas limited the self-advo-
environments. cacy of women and vulnerable groups [119, 120].
At academic institutions, tenure clocks made it extremely
difficult for women to be promoted on the traditional “7 year
Research in SGBWH up or out” if they parented children or bore children during
this time. Part-time and flextime positions are not universally
The women’s health movement spurred awareness and cre- available at academic institutions, and when they were, part-
ated a community, which in turn led to funding streams, poli- time positions often came with distinct disadvantages: faculty
cies, and new organizations that then allowed an explosion of must often be full-time to have tenure or to sit on important
research in women’s health and sex- and gender-based medi- committees such as the university senate. Maternity leave was
cine (see section on history above) [18, 85, 118]. Many wom- generally not available or was limited, and only full-time fac-
en’s health and SGBM investigations were sorely needed, for ulty were eligible for full benefits. Some women were
example, studies of postmenopausal estrogen and progestins expected to go back to work full-time at the hospital after a
and of breast-conserving surgery for breast cancer. Once con- one- to two-week break after giving birth [120].
ducted, the results of these studies changed practice and fur- Although many men take substantial responsibility for the
ther demonstrated the need. The concurrent emphasis on care of children, women traditionally bore a disproportionate
women’s health curricula and training as well as leadership load of household responsibilities and were more likely to
development in women’s health built a pipeline of interested work part-time than men due to parenting responsibilities
researchers and topics of study. The research that followed [121–123]. Further, the physical and biological challenges of
fills the chapters of this textbook. pregnancy, childbirth, and lactation are experienced nearly
exclusively by women. The problem this poses for women in
academics was eloquently explained by the American
Lidia is now 62 and feeling well. She is very grateful Association of University Professors in 2000:
for the excellent sex- and gender-based women’s
Raising a child takes 20 years, not one semester. American
health care she has received. She would like to invest women, who still do the vast majority of child care, will not
in the future of health care and agrees to fund a Chair achieve equality in academia so long as the ideal academic is
in Women’s Health from her business profits. defined as someone who takes no time off for child-rearing.
With teaching, research, committee assignments, and other
responsibilities, pre-tenure academics commonly work many
hours of overtime. Defining job requirements in this way tends
to eliminate virtually all mothers, so it is not surprising the per-
eadership and Advancement: Challenges
L centage of tenured women in U.S. colleges and universities has
climbed so slowly [120].
and Solutions
Over the past few decades, there have been notable improve-
We conclude with recommendations to promote progress ments in workplace options and procedures: pregnancy pro-
beyond the apparent glass ceiling that is preventing further
advancement of women’s health and women leaders. We empha-
tections, the Family Medical Leave Act (FMLA), maternity
leave, modified responsibilities, unpaid leave opportunities, Future Directions in SGBWH

and leave for adoption. Despite these changes, there are per-
sistent areas of need: paid maternity leave, paternity leave, To end the perpetual fragmentation of women’s health across
childcare issues, and work schedules that coincide with the health-care delivery environment, educators and clini-
school schedules. The COVID crisis of 2020 brought these cians in primary care must be well versed in conditions spe-
issues into sharp focus as schools and daycares were cific to women such as pregnancy, menopause, and
closed, causing academic and clinical productivity to plum- gynecological cancers and also be able to apply clinically
met for many faculty. meaningful sex and gender differences into clinical practice.
Furthermore, there are issues which require careful atten- Concrete steps toward addressing current gaps include the
tion for continued improvement: biases toward women and following:
minorities in hiring and promotions, sexual harassment, and • Using precise terminology for sex and gender.
career trajectories which are compatible with child-rearing • Continuing research into sex and gender differences and
and work-life balance. Regardless of sex or gender, students, the dissemination of significant findings.
residents, faculty, and community physicians are encouraged • Integrating sustainable sex- and gender-based curricula
to be creative and assertive with their supervisors, deans, throughout health professional education.
program directors, and department heads to explore flextime • Increasing attention to training in ob-gyn topics within
and part-time job offers, shared positions, “reduced f ull-time” internal medicine and other primary care programs.
9–11 month faculty appointments, modified responsibilities, • Conducting innovative medical education research to
and reentry programs to allow parents to attend to child-rear- determine best practices in SGBWH education.
ing or other personal and family responsibilities while • Promoting leadership and advancement of faculty com-
remaining active in the health care community. Telehealth mitted to SGBWH in the academic environment.
and virtual visits, which became the norm in the setting of • Advocating for the funding and promotion of SGBWH
the COVID crisis, and the flexiblity afforded by virtual clin- research and educational programs.
ics and meetings, may be a positive addition to the options • Supporting clinicians, faculty, and staff so that they can
available to physicians trying to manage academic and fam- provide an empathic experience for all patients.
ily demands. Most importantly, parents should be able to It is time to conceptualize women’s health in the context
advocate for workweek expectations that are compatible of primary care which is personalized to each individual
with both successful careers and raising the next generation based on sex, gender, and genetics. This conceptual shift
without feeling targeted, marginalized, or inadequate. will require collaborative and parallel efforts on three fronts:
In order to advance women in medicine, the COE pro- research, education, and clinical care. Researchers need to
gram included a leadership development component which consider sex and gender as biological variables in study
was not limited to women [124]. National organizations and design to provide the evidence on which to base clinical
institutions started leadership trainings, such as the practice. Publishers and editors need to ensure accuracy in
Association of American Medical Colleges (AAMC) women the reporting of data by sex and gender, and professional
in leadership courses for junior and senior faculty and the societies need to develop sex- and gender-specific protocols
Executive Leadership in Academic Medicine (ELAM) pro- and guidelines. Educators need to incorporate concepts of
gram. The NIH, in addition to its career development awards, sex- and gender-based evidence into all levels of health-care
has grants which help women return to research careers who education. Primary care providers must incorporate women-
have taken time off for child-rearing. The Building specific knowledge and skills and broad concepts of sex and
Interdisciplinary Research Careers in Women’s Health gender into all aspects of health care [48, 50, 85].
(BIRCWH) program continues to fund individuals to prepare
them for research careers and advancement in academic
medicine. Selected Organizations and Resources
Women’s health as an academic focus in research and
education, combined with leadership programs, has enabled he Society of General Internal
T
many qualified women to advance in academic medicine and Medicine (SGIM)
other arenas of leadership, as most women’s health research-
ers and educators are, in fact, women. Providers who have The Women’s Health Education Interest Group was formed
completed fellowships in women’s health have become lead- within the Society of General Internal Medicine (SGIM) in
ers within the women’s health field and in academia [56]. 2001 to foster the ability of women’s health educators to net-
Endowed chairs in women’s health provide top leaders in work, share resources, lobby, develop uniform curricula, and
women’s health with the resources and gravitas needed to keep abreast of scientific discoveries. The membership
make a continued impact in academic medicine [125]. quickly grew to include faculty members from throughout
the country. Many of those individuals and their mentees are tiated and continues to build a novel digital resource library
authors in this book. SGIM has an active commission which of sex- and gender-specific materials to be adopted and
sponsors and promotes events in SGBWH and advocates for adapted into medical education and clinical practice, resid-
the promotion of women in academia. The SGIM annual ing at http://www.sgwhc.org [1]. The website also includes a
meeting program provides many faculty development oppor- national practitioner database, links to educational materials,
tunities in SGBWH. SGIM, along with other national organi- and other resources:
zations, are helping to achieve the promise of providing all
physicians with a solid foundation for providing the gender- • The 2011 collaboration with the National Board of
sensitive and specific care that women want and expect Medical Examiners (NBME) to evaluate the examina-
(https://www.sgim.org/) [126]. tions’ women’s health and sex and gender content [48].
• The 2012 Sex and Gender Medical Education Summit
hosted by Mayo Clinic. Online conference report: https://
irectory of Residency and Fellowship
D www.liebertpub.com/doi/full/10.1089/jwh.2012.4193
Programs in Women’s Health [49].
• The 2015 Sex and Gender Health Education Summit.
Sponsored by the Association of Academic Women’s Health Online proceedings: https://bsd.biomedcentral.com/arti-
Programs (AAWHP), https://womenshealth.vcu.edu/pdf201 cles/supplements/volume-7-supplement-1 [51].
5/2015DirectoryofResidency.pdf [127], and published in the • The 2018 International Sex and Gender Health Education
Journal of Women’s Health, the directory describes active Summit: Advancing Curricula Through a Multidisciplinary
programs and provides contact information. “The mission of Lens. Online proceedings: https://www.sghesummit2018.
the AAWHP is to improve the health of women through lead- com/ [44].
ership in research, education clinical models, and commu-
nity partnerships. This mission is carried out through
networking, leadership and mentoring collaborative projects, exas Tech Health Sciences Center’s Laura
T
lobbying and advocacy, political and social commentary, W. Bush Institute (TTUHSC LWBI)
education of policymakers, partnership with national organi-
zations, and creation of interdisciplinary innovative TTUHSC LWBI is widely viewed as a global leader for sex
models.” and gender health curricular materials. Their website www.
sexandgenderhealth.org [129] houses a repository of peer-
reviewed sex and gender educational resources. These
he American Medical Women’s Association
T resources, including slide sets with speaker notes, simulation
(AMWA) cases, and interactive modules, have been adapted for use
across schools of medicine, pharmacy, nursing, and allied
AMWA was one of the first organizations concerned with health. LWBI has equally partnered with AMWA and Mayo
advancing the field of women’s health and developed the Clinic on the 2015 and 2018 Sex and Gender Health
Advanced Curriculum on Women’s Health for faculty devel- Education Summits and is committed to future Summit
opment and continuing education (https://www.amwa-doc. sponsorships.
org/) [128]. AMWA also sponsors an annual congress on
women’s health. AMWA is committed to the integration of
sex and gender evidence into health professionals’ curricula. merican College of Obstetricians and
A
To this end, AMWA has been a premier sponsor for the 2015, Gynecologists: The Women’s Preventive
2018, and 2020 Sex and Gender Health Education Summits Services Initiative (WPSI)
(www.sghesummit2018.org) [44].
An Advisory Panel comprised of representatives from the
American College of Obstetricians and Gynecologists
he Sex and Gender Women’s Health
T (ACOG) and three other major professional organizations rep-
Collaborative (SGWHC) resenting the majority of women’s health-care providers,
including the American Academy of Family Physicians
The Sex and Gender Women’s Health Collaborative (AAFP), the American College of Physicians (ACP), and
(SGWHC) is now formally a part of AMWA. Founding orga- the National Association of Nurse Practitioners in Women’s
nizations included the American Medical Women’s Health (NPWH). In addition, three individuals who were
Association, the College of Women’s Health Physicians, and members of the Institute of Medicine’s 2011 Committee on
the Society for Women’s Health Research. The SGWHC ini- Preventive Services for Women serve as Advisory Panel mem-
bers. The Advisory Panel will guide the work of the WPSI and tion at AAMC member medical schools and teaching hospi-
ensure that the initiative delivers a consistent message (https:// tals. Their portfolio, formal or informal, may include: gender
www.womenspreventivehealth.org/) [130]. ACOG provides equity, career advancement, women’s recognition, including
numerous resources for the care of women patients, and for awards, and women’s recruitment and retention throughout
patient education through its organization. the continuum of academic medicine” [from website]
(https://www.aamc.org/members/gwims/) [135].
ational Association of Nurse Practitioners

N
in Women’s Health (NPWH) The American College of Physicians (ACP)
This organization provides women’s health continuing edu- The ACP offers learning resources for physicians, with mul-
cation through a society journal and annual conferences. In tiple modules applicable to women’s health and many offer-
addition, there is a mobile app to be used at well-women ing CME and MOC. Most activities are free to ACP members
visits. Members can have joint membership with ACOG (https://www.acponline.org/online-learning-center/womens-
(https://npwomenshealthcare.com/about-npwh/) [131]. health) [136].
he National Institutes of Health (NIH) Office

T he American Academy of Famiy Physicians
T
for Research on Women’s Health (ORWH) (AAFP)
The NIH Sex as a Biological Variable and Inclusion policies The AAFP offers its members learning resources and confer-
help to ensure that women and female biology in general are ences specific to women’s health, and is a participant in the
factored into every stage of research. Sex and gender influ- multidisicplinary WPSI (https://www.aafp.org) [137].
ence health and disease, and considering these factors in
research informs the development of prevention strategies
and treatment interventions for both women and men (https:// Summary Points
orwh.od.nih.gov/) [132]. A no-cost online course is available
to educate clinicians and researchers in the issues related to 1. Women’s health began as reproductive health but has
studying sex and gender differences: https://orwh.od.nih. expanded to include the knowledge that every cell has a
gov/sex-gender/online-courses-sex-gender-differences sex and that sex and gender aspects of care apply to the
[133]. whole women.
2. Major research advances include the inclusion of women
and minorities in research studies and the realization that
The Society for Women’s Health Research sex as a biological variable must be acknowledged in all
medical research.
The Society for Women’s Health Research (SWHR) is a 3. Examples of sex-based differences include drug dosages,
national nonprofit dedicated to promoting research on bio- differences in coronary artery disease between the sexes,
logical differences in disease and improving women’s and the effect of estrogen in nonreproductive organ
health through science, policy, and education (https://swhr. systems.
org/) [134]. 4. The comprehensive primary care of women requires the
integration of medical, gynecologic, mental, and breast
health domains.
he Association of American Medical
T 5. Education in SGBWH includes both add-on topics and
Collges: Group on Women in Medicine the integration of sex and gender throughout all topics.
and Science 6. The integration of sex- and gender-based women’s health
into curricula requires needs assessments, champions,
The Association of American Medical Colleges (AAMC) learner advocates, content experts, edits of cases through
Group on Women in Medicine and Science (GWIMS) a sex and gender lens, and the support of institutional
“advances the full and successful participation and inclusion leaders.
of women within academic medicine by addressing gender 7. Urgent needs and persistent gaps in the sex- and gender-
equity, recruitment and retention, awards and recognition, specific care of women include an increased knowledge
and career advancement. Advocates for women’s advance- of genetics, appropriate use of sex and gender terminol-
ment and leadership may become members of GWIMS, and ogy, and sex- and gender-based research which breaks
those members may be either from the faculty or administra- out findings by sex and gender.
Review Questions C. Inequities in the pay between men and women faculty
vanished in academic medicine due to actions by pro-
1. In what year did the National Institutes of Health (NIH) fessional societies.
first mandate the inclusion of women in medical research? D. Promoting leadership for women faculty is consid-
A. 1975 ered an important component in the success of wom-
B. 1980 en’s health programs and curricular change.
C. 1990 The correct answer is D. The promotion of women to
D. 2016 positions of leadership is considered to be a critical step
The correct answer is C. In 1985, the NIH established a in the sustainability of women’s health as a focus in medi-
task force to study the inclusion of women in medical cine beyond ob-gyn. However, women continue to be
research. The report led to the mandate that women be underrepresented at the highest ranks of academic medi-
included in medical research in 1990. In 1994, the NIH cine despite the increased number of women entering
clarified that research results should be reported as men medical school as students. The reasons for inequities in
or women, but it was not until 2016 that the NIH required pay and promotion are complex and continue to need
sex as a biological variable be included in all NIH propos- remediation within academia. Child-bearing and child-
als [20, 27, 46]. rearing are time-consuming activities over the course of a
2. Which of the following is an example of a sex-based lifetime, and the impact of this commitment is not fully
difference? addressed by tenure and promotion criteria [85, 125].
A. Women like to wear dresses more often than men.
B. Women are more likely to stay home with children
than men.
C. Women’s cells usually have two X chromosomes. References
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High-Value Health Care: Perspectives
from the Sex- and Gender-based 2
Care Lens
Julie L. Mitchell
Learning Objectives
uadruple Aim: Better Care, Healthier
Q
1. Describe the elements of the quadruple aim and People, Smarter Spend, and Joy in Work
gender differences in access, quality, cost, and care
experience. Excellence in health care is a balancing act: It is the art of
2. Compare and contrast examples of low-value and providing the right care at the right time in the right place to
high-value care in women. the right person in the right way. High-value care means
3. Describe strategies to achieve high-value care for timely access to necessary care and not more. It means care
women including systems engineering, shared is provided in the emergency department when it is an emer-
decision-making, and best use of care teams. gency, in the hospital when the condition is acute, and in the
4. Explain how pay-for-value arrangements can clinic or at home otherwise. Moreover, it means care that is
improve care in women. individualized to the needs of the patient and put into the
5. Discuss the impact of care disparities and social context of the woman’s life (medical, social, psychologic,
determinants of health and the importance of gen- and spiritual). Primary care providers, with comprehensive
der equity and advocacy. training, continuity practices, and relationship-centered atti-
tudes, are well suited to provide high-value care and, indeed,
they do [1].
The triple aim of quality, affordability, and patient experi-
ence was first described as “care, health, and cost” by Don
Berwick and others [2]. Recognizing the potential to burn
Barb, a 68-year-old retired administrative assistant, out providers while attempting to meet the triple aim,
returns to your office for a prevention visit. She explic- Bodenheimer and Sinsky added a fourth aim: “improved
itly requests this visit be coded as a Medicare annual work life of health-care providers,” shortened to “joy in
wellness visit. Barb asks for ovarian cancer screening, work” [3]. Underscoring the importance of this fourth aim,
specifically an ultrasound and CA-125 test, as has been one set of primary care redesign architects found that achiev-
done the last few years annually. About 10 years ago, ing health-care excellence was critically dependent on the
her sister had ductal breast cancer in situ, and she has engagement of the physicians and other team members pro-
always been worried about cancer. She also comes to viding care [4].
her appointment with a newspaper article on choles-
terol medications and has some questions about it.
Access to Care Including Prevention
One component of high-value care is access to care, which is

dependent on insurance status for American women. In a
2016 survey, 59% of women aged 18–64 years were enrolled
in employer-sponsored health insurance, a rate that is similar
to men [5]. Yet women are more likely than men to be cov-
ered by government-sponsored insurance: 21% of non-
J. L. Mitchell (*)
elderly adult women report Medicaid or other public
Medical College of Wisconsin, Milwaukee, WI, USA
e-mail: [email protected] insurance vs. 17% of men, and 55% of Medicaid b eneficiaries

28 J. L. Mitchell
are female. Medicaid covers low-income women and chil- documenting a care plan all require effective communication
dren, but eligibility varies notably by state statute and poli- skills. While patients from both genders prefer a participa-
cies. For example, the percent of women aged 18–64 years tory decision-making style [9], there are gender differences
reporting Medicaid insurance ranges from 8 to 31% by state in expectations that affect patients’ satisfaction with care.
[5]. Women who are older than 65 or who are disabled are For example, in clinic visits, women base their satisfaction
eligible for Medicare; 55% of Medicare beneficiaries are level on “informational content, continuity of care, and mul-
women [5]. tidisciplinarity,” while men look to “personal interest shown
Prevention is a coverage requirement for all health plans in them by their providers” [10].
compliant with the Affordable Care Act. United States Some women prefer female providers, clinics set up for
Preventive Services Task Force (USPSTF) grade A–B rec- only women and one-stop shopping for women’s health care.
ommendations are the standard for preventive benefits [6]. In To that end, specialized women’s health clinics meet a mar-
practice, many women nonetheless end up paying some out- keting need, although it is not clear if these clinics provide
of-pocket costs for prevention: women in private health plans care of higher value [11]. Women of reproductive age can
reported some personal expenditures for Pap and related ser- receive primary care either from primary care specialties
vices (23%) and for mammograms (16%) [7]. (like internal medicine or family medicine) or from
For women enrolled in Medicare, like in our case, the obstetrics-gynecology; this care may or may not be coordi-
annual wellness visit (AWV) is an opportunity to review nated. Health-care organizations who wish to be successful
risks, provide preventive care, and choose evidence-based in providing high-value care must seek to create comprehen-
high-value services. Medicare purposefully designed their sive, coordinated options for women.
benefits to include a free annual visit for prevention with its In contrast to men, women are more likely to serve as the
own billing code. Non-Medicare plans also accept an annual family caregiver, bringing kids and older adults to their doc-
prevention visit billed with a prevention code. The use of tor appointments and influencing the motivations and health
these prevention codes saves out-of-pocket costs for patients behaviors of the adult men in their lives. In a 2016 survey,
and potentially assists in tracking for continuous process 79% of mothers indicated they usually decide about their
improvement. children’s doctor, compared to only 22% in a similar survey
of fathers [7]. Additionally, about 80% of those working in
health care, a field that employs about 10% of American
Experience of Care: Communication, workers, are women; yet only 40% of health-care leaders are
Relationships, and Teams women [12]. These roles in society may influence women’s
expectations and agendas when coming to care.
Patient experience has become an established, measurable To help provide high-value care, primary care physicians
dimension of high-value care [8]. Some have argued that working in advanced medical homes lead care teams consist-
“patient satisfaction” isn’t a valid measure of quality either ing of nurses, medical assistants, patient care representa-
because patients, as laypersons, are unable to assess care or tives, and others. These care teams can extend the reach of
because patients are only satisfied when they are happy, physicians, improve care quality, and bring improved job
healthy, or receive the services (tests, medications) they satisfaction to all care team members [4, 13, 14]. To achieve
think they need. However, several studies have shown cor- these outcomes, all team members must work collaboratively
relation between patient experience ratings and more tradi- with clear, standard processes and have the tools they need to
tional measures of quality, such as adherence to clinical do their job. Everyone on the team can benefit from working
treatment guidelines, and this correlation persists when at the top of their license and actively incorporating the
adjusted for patient mix and when patients are directed to expertise each team member brings.
evaluate their experience (not their feelings). Patient-reported There are many ways care teams can create high value.
experience surveys are best used to evaluate patient-provider Some examples include constructing visits for specific time
interactions, especially when specific to a certain event or with care team members depending on the visit concern;
service (such as a hospitalization) and closely timed to that using pre-visit planning, rooming, and outreach to address
event or service. Additionally, there is evidence that when clinical care gaps; and training nurses in patient education
patients are more engaged with their care, patients may and shared decision-making. For instance, a clinic appoint-
choose less resource use rather than more [8]. ment may have 10 min budgeted for rooming, with an
Women’s roles in society and unique needs as patients can appointment time for check-in and an appointment time for
lead to expectations and preferences that differ from those of the physician 10 min later. At rooming, a nurse may provide
male patients. For all patients, communication is a critical and review preventive care pamphlets or electronic links, a
part of high-value care; history taking, shared decision- scribe may document the history and exam, and a nurse may
making, patient education, motivational interviewing, and pend the requested diagnostic code/revenue code combina-
2 High-Value Health Care: Perspectives from the Sex- and Gender-based Care Lens 29
tion for the physician to sign. Finally, care teams may help igh-Value Care and Strategies to
H
patients by extending their reach outside the health system, Improve Value
connecting patients with community organizations (such as
support groups or city health departments), and taking Value is defined as quality divided by cost. High-value care
advantage of medical management resources (such as a nurse may be care that provides clinical excellence (high quality),
line or social workers) at patients’ health insurance is inexpensive (low cost), or, more commonly, is both. Low-
companies. value care is care that is ill-advised, expensive, or both.
In addition to improved job satisfaction, advanced medi- Currently, American health-care practices include substan-
cal homes with features of accessible coordinated care, tial waste: About one-fifth of care is likely unnecessary, and
patient-centered communication, and team-based care are about one-fifth of our spend is likely wasted, based on sur-
associated with higher patient experience ratings [15]. veys of physicians and published reports [17, 18]. In an anal-
Moreover, patient experience ratings suffer when physicians ysis of 1.5 million commercially insured patients, Reid found
turnover [16]: further evidence to the interdependence of the 8% received low-value services in 2013, representing $33
elements of the quadruple aim. million or $22 per person [19]. In Oregon, Charlesworth
found similar rates of low-value services (11–15%) between
populations insured by Medicaid and commercial plans, with
Your medical assistant enters Barb’s concerns (annual geographic variations suggesting physician practice patterns
wellness visit, requests for ovarian cancer screening, are the primary explanation [20]. In Medicare populations,
newspaper article on cholesterol medications) in your Schwartz found 25% of beneficiaries were affected by low-
electronic health record while you review previous value services [21].
testing. For the past 10 years, Barb has had annual In general, one can define high-value preventive care as
pelvic ultrasounds and CA-125 tests that have been care that is recommended as Grade A or B by the USPSTF
negative. On history, she has no symptoms of ovarian (see Table 2.1). High-value care interventions can be found
or breast cancer and no updates to her family history. in evidence-based guidelines that weigh cost as well as qual-
ity. Increasingly, research studies are reporting not only the
Table 2.1 High-value preventive services in women, defined as USPSTF recommendations with Grades A–B (including only those recommenda-
tions that are different than for men) [6]
USPSTF
Population Recommendation Grade
Age-based recommendations
Women aged 21–65 years The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology A
alone in women aged 21–29 years. For women aged 30 to 65 years, the USPSTF recommends
screening every 3 years with cervical cytology alone, every 5 years with high-risk human
papillomavirus (hrHPV) testing alone, or every 5 years with hrHPV testing in combination with
cytology (cotesting)
Women of reproductive age The USPSTF recommends that clinicians screen for intimate partner violence (IPV) and provide B
or refer women who screen positive to ongoing support services
Women aged 50–74 years The USPSTF recommends biennial screening mammography B
Women 65 years and older The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent B
osteoporotic fractures
In pregnant women
All pregnant women The USPSTF recommends that clinicians screen all pregnant women for HIV, including those A
who present in labor who are untested and whose HIV status is unknown
The USPSTF recommends screening for hepatitis B virus (HBV) infection in pregnant women at A
their first prenatal visit
The USPSTF recommends early screening for syphilis infection in all pregnant women A
The USPSTF recommends screening for preeclampsia in pregnant women with blood pressure B
measurements throughout pregnancy
The USPSTF recommends that clinicians ask all pregnant women about tobacco use, advise them A
to stop using tobacco, and provide behavioral interventions for cessation to pregnant women who
use tobacco
Pregnant women and new The USPSTF recommends providing interventions during pregnancy and after birth to support B
mothers breastfeeding
(continued)
30 J. L. Mitchell
Table 2.1 (continued)

USPSTF
Population Recommendation Grade
Pregnant women, during the The USPSTF strongly recommends Rh(D) blood typing and antibody A
first pregnancy-related care
visit
Pregnant women at The USPSTF recommends screening for asymptomatic bacteriuria with urine culture for pregnant A
12–16 weeks’ gestation women at 12–16 weeks’ gestation or at their first prenatal visit, if later
Asymptomatic pregnant The USPSTF recommends screening for gestational diabetes mellitus (GDM) B
women, after 24 weeks of
gestation
Selected pregnant women
Pregnant women who are at The USPSTF recommends the use of low-dose aspirin (81 mg/day) as preventive medication after B
high risk for preeclampsia 12 weeks of gestation
Unsensitized Rh(D)-negative The USPSTF recommends repeated Rh(D) antibody testing for all unsensitized Rh(D)-negative B
pregnant women women at 24–28 weeks’ gestation, unless the biological father is known to be Rh(D) negative
Women at increased risk
Postmenopausal women The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent B
younger than 65 years at osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk
increased risk of osteoporosis of osteoporosis, as determined by a formal clinical risk assessment tool
Women who have family The USPSTF recommends that primary care providers screen with one of several screening tools B
members with breast, ovarian, designed to identify a family history that may be associated with an increased risk for potentially
tubal, or peritoneal cancer harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive
screening results should receive genetic counseling and, if indicated after counseling, BRCA
testing
Women who are at increased The USPSTF recommends that clinicians engage in shared, informed decision-making with B
risk for breast cancer women who are at increased risk for breast cancer about medications to reduce their risk. For
women who are at increased risk for breast cancer and at low risk for adverse medication effects,
clinicians should offer to prescribe risk-reducing medications, such as tamoxifen or raloxifene
Sexually active women
Sexually active women The USPSTF recommends screening for chlamydia and gonorrhea in sexually active women age B
24 years and younger and in older women who are at increased risk for infection
Women who are planning or The USPSTF recommends that all women who are planning or capable of pregnancy take a daily A
capable of pregnancy supplement containing 0.4–0.8 mg (400–800 μg) of folic acid
health outcomes of interventions but also their cost- more on clinical practices that have little value (“no value
effectiveness in terms of dollars per quality-adjusted life- care”) rather than looking critically at the cost-effectiveness
year (QALY) [22]. This measure serves to compare a variety [25]. For example, only 2% of the Choosing Wisely recom-
of interventions in a standard way, though it is difficult to mendations cited cost-effectiveness research [25].
pick a single cutoff for “high-value care,” given that society’s In prioritizing the implementation of interventions that
willingness to pay for a given service depends on the context increase value, it is useful for both providers and patients to
(high-resource or low-resource environment), the case (the remember that we all take responsibility for the overall cost
age of the individual, the condition, and the alternatives), and of health care, and we all pay for it as well, since the market
individual patient preferences. For these reasons, there is no reacts to high spending by increasing premiums or refusing
universally accepted threshold for cost-effective care. to pay for certain services. Moreover, “when society spends
Importantly, physicians and provider groups can increase on low-value healthcare, it’s coming at the expense of doing
high-value care by improving adherence to evidence-based things like hiring more teachers, hiring more police officers,
practices. This is the usual quality work many hospitals and rebuilding our schools, and rebuilding our infrastructure”
clinics perform and certainly a goal of primary care. A criti- [26]. While these principles apply to women’s as well as
cal complementary strategy is to avoid low-value care. men’s health care, the overall cost of care for women is
Commonly performed low-value care services are starting to higher than for men, primarily because of maternity care,
be defined, particularly by the Choosing Wisely campaign and so improving the rate of high-value care in women may
[23] and researchers studying overuse in Medicare popula- have more impact overall.
tions [24]. The common low-value services in these lists are In the future, precision medicine may help us better
manageable in number, and so adjusting practice patterns to define the circumstances that make services high value.
address these services may also be manageable. While an Consider breast cancer screening with mammography,
important starting point, some argue that these lists focus where the current recommendations are largely based sim-
ply on age. Yet like all screening tests, the effectiveness of tive (about $26,000 per QALY), improved the benefit-to-
mammography in reducing cancer deaths depends on the harm ratio, and largely maintained the benefits of screening.
risk of the population for breast cancer. While age is the Notably, a shift from age-based to precision-based screen-
strongest risk factor for breast cancer, other epidemiologic ing requires a shift in thinking; currently, the barriers are
and genetic risk factors change the pretest probability. What numerous, including de-implementation of low-risk screen-
if we screened based on risk, omitting routine mammogra- ing, a willingness to prioritize preventing the harms of
phy on low-risk individuals over age 50? In a modeling screening, and incorporation of genomic testing into prac-
study, Pashayan and colleagues demonstrated that risk-strat- tice [28].
ified screening, compared to age-based screening, resulted In our case, the patient requested ovarian cancer tests and
in 71% fewer overdiagnoses and about $720,000 in savings, imaging, which is a preventive service since she has no signs
with the trade-off of 9.6% fewer breast cancer deaths averted or symptoms. Ovarian cancer screening is not recommended
[27]. In terms of absolute risk, this model resulted in 262 by the USPSTF [6]. Additionally, Choosing Wisely specifi-
breast cancer deaths, 23 more than if using an age-based cally calls this out as a low-value service [29]. A sample of
strategy, but also only 30 cases of overdiagnosis, 75 less low-value services, including services with Grade D rating
than if using an age-based strategy. This risk-stratified sce- by the USPSTF, relevant recommendations from Choosing
nario, where the threshold for high risk was a 10-year risk of Wisely, and items specific to women and on researchers’
3.24%, had the highest net monetary benefit, was cost-effec- low-value lists, is in Table 2.2.
Table 2.2 A sample of low-value women’s health services [6, 21, 29]
Population Recommendation Reference
Asymptomatic women who do The USPSTF, Society for Gynecologic Oncologists, and ACOG recommend against screening [6, 29]
not have a high-risk hereditary for ovarian cancer in asymptomatic women
cancer syndrome
Asymptomatic women American Society of Clinical Pathologists recommends against population-based screening for [29]
25-OH vitamin D deficiency
Nonpregnant women American Academy of Family Physicians recommends against performing pelvic exams on [29]
asymptomatic women, unless necessary for guideline-appropriate screening for cervical cancer
Women who have never The USPSTF recommends against screening for abdominal aortic aneurysms [6]
smoked
Women not at increased risk The USPSTF recommends against both 1) routine genetic counseling or BRCA testing in [6]
for breast cancer women whose family history is not associated with an increased risk for potentially harmful
mutations in the BRCA1 or BRCA2 genes and 2) the routine use of medications, such as
tamoxifen or raloxifene, for risk reduction of primary breast cancer in women who are not at
increased risk for breast cancer
Women older than 65 years and The USPSTF, ACOG, and the American Academy of Family Physicians recommend against [6, 21,
women younger than 21 years screening for cervical cancer in women older than 65 years who have had adequate prior 29]
screening and are not otherwise at high risk for cervical cancer and women younger than
21 years
Women who have had a The USPSTF recommends against screening for cervical cancer in women who have had a [6, 29]
hysterectomy hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous
lesion (i.e., cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer
Postmenopausal women The USPSTF recommends against the use of combined estrogen and progestin in [6]
considering hormone therapy postmenopausal women and against the use of estrogen alone in postmenopausal women who
for primary prevention of have had a hysterectomy for primary prevention
chronic conditions
Postmenopausal women The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D and [6]
1000 mg or less of calcium for the primary prevention of fractures in community-dwelling,
postmenopausal women
Women with a history of bone American College of Rheumatology recommends against a repeat BMD test within 2 years [21, 29]
mineral density testing
Women with vertebral Literature recommends against vertebroplasty or kyphoplasty [21]
osteoporotic fractures
Women with overactive bladder American Urogynecological Society recommends against cystoscopy, urodynamics, or [29]
diagnostic renal and bladder ultrasound in the initial workup of an uncomplicated overactive
bladder (OAB) patient
(continued)
32 J. L. Mitchell

Population Recommendation Reference
Women with irregular or American Society for Reproductive Medicine recommends against obtaining follicle-stimulating [29]
abnormal bleeding hormone (FSH) levels in women in their 40s to identify the menopausal transition as a cause of
irregular or abnormal menstrual bleeding
Women with suspected thyroid American Society of Clinical Pathology recommends against multiple tests in the initial [29]
disease evaluation of a patient with suspected thyroid disease. Order thyroid-stimulating hormone
(TSH), and if abnormal, follow up with additional evaluation or treatment depending on the
findings
Pregnant women American Academy of Family Physicians and ACOG recommend against scheduled elective, [29]
non-medically indicated inductions of labor or Cesarean deliveries before 39 weeks, 0 days
gestational age
While a provider may wish to avoid low-value services,

Table 2.3 Applying test characteristics to a screening test. Example
talking with patients about making choices based on value test with 95% sensitivity and 95% specificity in a hypothetical popula-
can be challenging. An NEJM perspectives roundtable tion of 1000 persons with 0.1% point prevalence of the condition. In
gives several practical tips on conversing with patients this example, the positive predictive value is 2% (1/51)
about low-value services [26]. First, providers should be Disease is Disease is
transparent with patients about their reasoning, clearly present absent
describing their practice norms and expectations and citing Test is 1 50 51
positive True positivea False positive All with positive
society guidelines or Choosing Wisely to back up their test
statements. Generally, providers should focus on the clini- Test is 0 949 949
cal harms more than the dollar costs. Second, providers negative False negativea True negative All with negative
should have a script for common scenarios, such as Paps or test
pelvics after 65 years, and sum up their script with a recom- 1 999 1000
All with All who are All population
mendation to avoid a low-value service. If the provider disease well
questions whether a generally low-value service has value a
95% sensitivity would yield 0.95 with a true-positive and 0.05 with a
for a certain individual, he or she can begin a discussion false-negative test; numbers are rounded to whole numbers
with a lead-in such as “On the whole, {this service} is
doing all that harm to get very little benefit. Given that, In screening, where, by definition, we are testing a low- or
what do you think you want to do?” average-risk population, most people do not have the prob-
lem for which we are screening. Thus, a good screening test
needs a very high specificity. For example (see Table 2.3), if
You have a frank conversation with the patient about
the test’s specificity (the percent of persons without the prob-
ovarian cancer screening, her concerns, and goals of
lem that test negative, the true negative rate) is 95%, the
care. You discuss the downstream effects of over-testing
remainder with a positive test will actually be well, making a
and check for understanding. She agrees that screen-
5% false-positive rate. The impact of a 5% false-positive rate
ing ultrasounds and blood tests are not needed. Your
is amplified when screening because so many of the popula-
visit then turns to other prevention recommendations.
tion are well. Continuing the example, in a population that
According to your records, her last mammogram was
has a 0.1% point prevalence (1 out of 1000 have the prob-
three years ago and her last Pap was normal at age 63.
lem), a 5% false-positive rate means 50 of 1000 people test
Using the atherosclerotic cardiovascular disease
positive but are well. Since we know 1 of these 1000 has the
pooled cohort calculator, Barb has a 10-year risk of
problem, there would be 51 positive tests, but only 1 of those
a cardiovascular event of 7.5%.
51 actually has the problem. The positive test yields mean-
ingful information only 2% of the time, thus a low positive
predictive value.
Test Characteristics Only half of clinicians have a working knowledge of these
concepts [30]. And yet understanding when to order tests and
The reason ovarian cancer screening tests are not recom- how to interpret the results is critical to high-value care, lest
mended is that the available tests have unacceptably high physicians fall prey to ordering unnecessary tests or placing
false-negative and false-positive rates. In other words, the too much importance on a positive result. Providers who lack
predictive value of a positive and the predictive value of a understanding of critical test characteristics can underesti-
negative test are too low. mate the harm caused by an inappropriately ordered test.
Shared Decision-Making ing discussions [31]. Examples of decision aids can be

found on the Internet: The Mayo Clinic website [33] tools
Shared decision-making involves talking with patients to include osteoporosis management, and Health Decisions
help explain the concepts of value, test characteristics, and [34] includes cardiovascular prevention and breast cancer
best practices to come to a joint decision when selecting screening. Similarly, pamphlets [35] and videos [36]
appropriate preventive care or other services. Often, there is directed at educating patients are available and can be
no one “right answer”; thus, primary care providers fre- selected to match the patient’s learning style and technology
quently face situations where the next best step is shared savvy. It is important to have diverse materials, picturing
decision-making. Using the breast cancer screening (Chap. individuals of all colors, available in multiple languages to
18) and cervical cancer screening (Chap. 14) recommenda- engage all patients. Additionally, sometimes decision aids
tions and the information given, most providers would ask for a race or ethnicity designation but unfortunately
appropriately advise the patient in our case to obtain a mam- don’t allow for all realities such as women who are more
mogram and forego a Pap without much hesitation. However, than one race or who are American Indian; often, this is
her borderline cardiac risk (Chap. 21) should direct the clini- because calculators are based on research populations that
cian to a shared decision-making discussion. didn’t include these designations. For women in this situa-
Engaging patients in shared decision-making can be a tion, providers can choose between the option with the best
challenge. First, it can be time-consuming and difficult to fit fit or not answering. Finally, providers who need training on
in a prevention visit, particularly one with multiple preven- shared decision-making can use Agency for Healthcare
tion items needing a discussion within a limited appointment Research and Quality’s SHARE materials online [37].
duration. Of note, women have more prevention recommen-
dations than men (see Table 2.1). Second, situations that
require shared decision-making often are the same situations ystems Engineering and Process
S
where data is lacking, recommendations are conflicting, or Improvement
relatively new information changes established practices.
Thus, these are situations where providers may not have an Systems engineering is a way of thinking that allow provid-
internal script for the discussion, may not have materials to ers to achieve the quadruple aim by solving problems like
help aid the conversation, or may bring their own biases. For finding time for shared decision-making. Health-care organi-
example, regarding mammographic screening of women in zations that use systems engineering tools like Lean [38] or
their forties, Keating and Pace describe several factors pre- Six Sigma have a set of reproducible process to discover
venting a practice change to shared decision-making instead problems and solve them. This often means improving the
of reflexively ordering a mammogram. These include general process itself but, in other cases, requires adjusting the man-
biases toward testing, concerns about litigation, more pay- agement system, how processes coordinate, and how people
ment for testing and less payment for conversations, dis- interact with the process.
agreement with the guidelines, and inaccurate understanding The use of systems engineering to enhance the care of
of the harms, such as overdiagnosis [31]. Third, we must be women is best illustrated with an example. Consider breast
aware that risk is frequently processed emotionally rather cancer screening. The USPSTF recommends mammo-
than cognitively [32]. Often, both clinicians and patients graphic screening at least every 2 years. If an organization
anticipate and try to avoid the regret of not doing something has a quality goal of breast cancer screening and patients
rather than understand the harms of doing something. In are not meeting this goal, the organization labels “failure to
breast cancer screening, this harm is overdiagnosis, which meet breast cancer screening goal” as the problem and then
remains largely invisible. It is difficult to disentangle values takes the first step to map out the processes in place that
and beliefs from facts when discussing risk, but the primary address breast cancer screening. It may be that a standard
care provider is in a very good position to elicit what matters process is lacking—for example, the only identified pro-
to the patient. cess is to expect PCPs to note the gap and order mammo-
grams when due. Other organizations, may have a process
Tips in Providing Shared Decision-Making The best way to or combination of processes, such as (1) outreach between
address these challenges is a combination of patient-cen- visits by non-physician care team members, (2) pre-visit
tered materials, appropriate pre-visit preparations and dur- processes and/or point-of-care reminders for care team
ing-visit education conducted by medical home care team members to order mammograms before the visit or on
members, and managed agendas to match the time avail- rooming, (3) heightened awareness of the goal and current
able. Decision aids and patient education materials with performance with visual boards and team meetings, or (4)
easy-to-understand graphics on risk improve decision-mak- expanding the impact of primary care physicians with
34 J. L. Mitchell
Name the problem and map out ment”) expect is not the process that is actually happening,
current processes with those doing
the work. Consider whether
barriers must be identified and addressed. In a primary care
current process are actually being clinic, “management” may not be simply defined: Is it the
carried out and how processes
Plan
interact.
physician in a physician-led care team? Is it the medical
director or clinic manager? Are all stakeholders on the same
Modify a process,
add a new process, page? If the answers to these questions are not clear, it’s time
or make a change in to map out the management system.
Adjust Do the management
system. Alternately, the process may work but only for selected
patients (seen by a certain clinician or with a given insurance
Adjust based on type or of a certain socioeconomic group) or only for breast
findings, in a Check if the change made a cancer screening and not cervical cancer screening. Here,
continuous quality Study difference by measuring the
improvement cycle. overall outcome, or the performance or outcome data, preferably with drill-down
outcome of a process step. capability, can help identify the root cause of the problem.
Consider variation between
subpopulations.
The problem may be a matter of training, motivation, or
resources. Alternatively, it may be that populations respond
Fig. 2.1 Quality improvement cycle differently to interventions. For example, studies have dem-
onstrated that in the case of breast cancer screening, Black
advance practice providers or in coordination with women may have a distrust of mammograms, and therefore
obstetrics-gynecology clinicians. a phone call alone may be less likely to convince them to
Mapping the current process means developing a diagram schedule the overdue exam [40]. Finally, the problem may be
of who does exactly what when. The care team members a lack of data. Women, because of fragmented care, often get
who perform the work must be part of the mapping process, screenings in multiple systems, and reports may not be
both to understand what is truly happening and then to par- appropriately sent or scanned into the primary care provid-
ticipate in brainstorming for improvement. This mapping ers’ system.
process may be done when a problem is identified but ideally
happens periodically to continually improve a working pro-
cess. In a PDSA (Plan/Do/Study/Act or Adjust) improve-
ment cycle model [39], this mapping is the “plan” step. The Your medical assistant, in a pre-visit planning process,
next step would be to “do,” that is, select a modification or an identified that Barb was overdue for a mammogram
addition to the current process to make the improvement. See according to your records and called Barb before the
Fig. 2.1. visit about the need for a mammogram. In response to
For example, if the current state is a practice where annual that call, Barb brings in her records of a mammogram
mammography was left to PCPs to order at the point of care, a done last year that was ordered by an ob-gyn in a
strategy to increase the rate of mammography would be to health system closer to her home. The mammogram
ensure that patients are coming in at least every 1–2 years for was normal.
preventive care. For patients insured by Medicare, health-care
organizations can take advantage of the annual wellness visit
(AWV) benefit and set up systems to remind patients that an ublic Reporting and Pay-for-Performance
P
appointment is due every 12 months. If physician visits are Measures
limited due to demand, practices can develop a process where
advanced practice providers (APPs) see the patients for the To highlight high-quality care and assist patients in selecting
AWV and partner with physicians to provide any needed com- high-quality providers, facilities, and health insurance plans,
plex medical services at another visit. organizations such as the Center for Medicare Services [41],
Once the process is improved, it is incumbent on the team National Committee for Quality Assurance [42], and regional
to measure if the change made a difference. The idea is to not health improvement organizations publicly report perfor-
only name the problem but to decide on how the problem is mance. These publicly available scorecards often include
measured and tracked. For example, did the breast cancer measures of prevention, chronic condition management,
screening rates improve? If not, did patients at least receive patient experience, and cost and utilization, and health sys-
an AWV yearly? This step is called “study” in a PDSA cycle. tems or providers are compared against an average or bench-
The final step would be to “adjust” to make the process mark. In general, metrics are selected if they represent
better. services or conditions that are relevant for a large number of
Often, even a perfect process is not enough to achieve the people, and consensus exists regarding the best practice for
goal. If the process that the organization’s leaders (“manage- that service or condition that can reliably be measured. While
simply the act of public reporting increases transparency and on the size of the population (number of members) rather
likely quality, more often these measure sets have an impact than the number of services, called population-based pay-
if they are used in pay-for-performance programs for provid- ments. Another arrangement is paying for an “episode of
ers or hospitals or used to hold payers accountable [43]. care,” such as a joint surgery or a pneumonia hospitalization
as a bundle, including all related care in a time window such
Pay-for-Value Programs CMS uses pay-for-performance as 30-days.
programs to incent high-value care for providers and hospi- Like publicly reported services, quality or cost measures
tals [41]. The program for physicians and other eligible clini- that are linked to a payment often include women’s health
cians is called the Quality Payment Program, and this services. Obstetric care is often paid as an episode; there is a
program was legislated by the 2015 law called the Medicare single “global payment” for all services associated with the
Access and CHIP Reauthorization Act (MACRA). Most pro- pregnancy and delivery, up until 6 weeks of delivery, with the
viders in large groups need to participate in one of two tracks fee often dependent on the complexity of the pregnancy. This
or be subject to a fine. To participate in the Merit-based arrangement encourages coordinated care throughout the
Incentive Payment System (MIPS), providers select from a pregnancy and the use of the least expensive yet appropriate
list of over 100 metrics (including core measure sets for pri- level of care. For example, episode-based payment encour-
mary care and for obstetrics-gynecology), report their results ages hospitals to keep costs of supplies and durable medical
to CMS, and then are paid or fined in a zero-sum program. equipment low, to only admit when necessary, and to avoid
Alternatively, providers and their health systems can partici- unnecessary days in the hospital. At the same time, episode-
pate in the Advanced Alternate Payment Models track, where based payment encourages providers to manage diabetes,
the model for payment meaningfully shifts from traditional appropriately vaccinate for influenza, and screen for infec-
fee-for-service to value-based payment. Quality, cost, and tions to limit complications in pregnant women. The advan-
experience measures are publicly shared on either Physician tages of the bundled payment arrangement end with the end
Compare for providers or Hospital Compare for hospitals. date of the bundle, however. Postpartum care and other
health care may become uncoordinated or unavailable (as
Many services for women are linked to commonly happens in some state Medicaid plans) at the 6-week post-
reported measures. For example, breast cancer screening, partum mark [47].
cervical cancer screening, and chlamydia screening are Insurance programs, both commercial and governmental,
posted on regional quality improvement organizations’ sites can also be designed to incentivize patients to be more cost-
[44, 45], at NCQA’s rating of health plans [42], and are avail- conscious. Consumer-driven health plans shift first payments
able for MIPS reporting [41]. Similiarly, Hospital Compare and a higher percentage of costs to patients by using high
reports the elective delivery and mammogram follow-up deductibles and co-insurance. These benefit designs do lower
rates [41]; the National Healthcare Quality and Disparity overall costs, as patients defer services, some of which are
Report reports breast cancer mortality, HPV vaccination, and unnecessary or low value [48]. However, some of these
advanced cervical cancer rates [46]; and CMS’s Star Ratings deferred services are high value. In a study of Medicare man-
Program for Medicare health plans includes breast cancer aged health plans before the enactment of the Affordable
screening, osteoporosis management after a fracture, and Care Act, the biennial mammography rate was 8% less
improving bladder control rates [41]. State-run Medicaid among women who had to share in the cost of a mammo-
plans often have similar measures. As these measures are gram [49]. More rigorous study and innovation are needed to
more strongly linked to payment models, improving high- realize the benefits of these plans without putting patients at
value care for women becomes not only the right thing to do risk for skipping needed care.
but also a sound business decision.
Cost of Care for Women

lternative Payment Models and Value-
A
Based Insurance Design When considering systems design and insurance payments,
it is important to remember that per capita lifetime expenses
As mentioned, governmental and commercial insurance car- are generally higher for women (about $360k) than for men
riers are increasingly paying providers and facilities based (about $270k). About 40% of this difference can be explained
on the value they provide rather than simply based on the by the longer life span of women [50]. Women live about 8%
services rendered. There are a wide variety of payment longer than men, and about half of all health-care expenses
arrangements, for instance (1) paying for an outcome like a occur in people over the age of 65 years independent of gen-
quality metric (discussed above), (2) sharing in savings or der (due to medical conditions, disability, and end-of-life
risk determined by the total cost of care, or (3) paying based care that occur in older patients). The remainder of the
36 J. L. Mitchell
difference in expenditure is likely due to pregnancy and care and outcomes in women. To illustrate, Black women die
childbirth [51], a necessary burden of health-care services of breast cancer at twice the rate of Latinas or Asian women;
that is carried by only women, despite the fact that both sexes American Indian women are much less likely to receive pre-
are often required for pregnancy to occur. natal care than Asian or White women; and White women are
Currently, US law does not allow differences in insurance more likely to receive birth control than Hispanic or Black
premiums by gender, also known as “gender rating,” and women. The origins and solutions to sex-based disparities
most Americans agree with this core principle of the can inform and complement understanding and problem-
Affordable Care Act [52]. Additionally, the American solving for other disparities.
College of Physicians states in a position paper “health insur- One foundational step providers can take to address ineq-
ers should not be allowed to charge women higher premiums uity is to look in the mirror. Often, without conscious recog-
or impose higher cost sharing on women because of their sex nition, we make assessments and decisions based on our
or gender” [53]. backgrounds and experiences; in other words, we harbor
Thus, care for women is an important target for organiza- implicit bias. To change that bias, we must first be aware of
tions aiming to improve affordability. In value-based arrange- it. Providers can learn of their implicit biases by taking an
ments, providers, payers, and patients all benefit from online survey [55]. Armed with the results, providers might
reducing the cost of care in women. Moreover, when mea- feel empowered to identify biases when they see them, use
sures like breast cancer screening are part of a population- their names (e.g., call out “racism”), and shift from the
based payment arrangement, these payments can be majority perspective to the minority perspective [56]. Many
earmarked for care teams to assist primary care providers in institutions and specialty organizations are focused on work-
closing care gaps. ing with providers to reduce the impact of implicit bias;
availing oneself of these opportunities when offered may be
the first needed step in providing the equitable care we all
aspire to give.
At the conclusion of your clinic session, you huddle
with your care team and review your quality measures.
Your mammogram rate is 88%, which is better than the
Social Determinants of Health
average in your clinic. However, your rate for Black
women is 77%, while your rate for White women is
While most of this text is about “health care,” the provision
95%. Your care team enacts its process for continual
of health care determines only about 10% of health [57]. Far
quality improvement to address this disparity.
more important are behavior and genetics (together 70%),
plus “social circumstances,” which contribute about 15% to
premature death. Social determinants of health include finan-
Equity and Disparities cial resource strain, education, food and housing security,
social support, employment, and insurance status. These fac-
As mentioned, population health refers to the health out- tors contribute to one another and to health behaviors, as do
comes of a group of individuals, but it also includes the “dis- the living environment, cultural background.
tribution of such outcomes within the group” [54]. Thus, Since insurance eligibility often depends on employ-
equity of care—in terms of both patient characteristics (sex ment, income, marriage to a spouse with insurance bene-
and gender, race, creed, sexuality, or certain conditions) and fits, and/or minor children, instability in any of these
system processes and outcomes (access, effective communi- factors can lead to fragmentation in care, limited access, or
cation, costs of care, or care team support)—is also a critical frequent changes of the enrolled health insurance plan.
component of the quadruple aim. While pursuing high-value This is especially the case for women, who are more likely
care for women, systems engineering and team-based care than men to rely on government programs, marriage, and
programs must address and work to eliminate health being a parent for care. Women, like men, can experience
disparities. gaps in insurance coverage, yet rates of uninsured declined
In the pages that follow, this textbook includes many markedly with the enactment of the Affordable Care Act.
examples of gender differences in the receipt of care and the In 2016, 11% of non-elderly adult women were uninsured
outcomes of care. For example, the conditions that affect (down from 18% in 2013); meanwhile, 13% of men (down
women veterans are different than in men; heart disease from 20% in 2013) were uninsured [5].
manifests differently in women, with different risk factors, The presence of insurance doesn’t mean unlimited access
and worse outcomes; and sexually transmitted infections to health care; some high-deductible health plans have such
have different and often more severe consequences in high out-of-pocket costs that, outside of a catastrophe, ben-
women. Just as gender impacts health equity, race affects eficiaries are priced out of access beyond preventive care.
About half of uninsured women delayed or went without voices and professional societies can and should make a
care because of costs, but 21% of those with private insur- difference [59]. At our core, we are advocates, putting the
ance and 25% of those with Medicaid also delayed care or interests of our patients before our own. Interested readers
went without [7]. Comparing women overall to men overall, are directed to relevant society’s position papers such as
26% of women delayed care or went without care compared ACP’s position on women’s health [53], ACOG’s position
to 19% of men. Women, who on average earn less than men, on access [60], and the AAFP’s position on violence [61].
may be more affected by the rising costs of health care. Advocacy efforts by health professionals are another
Finally, 42% of women who have trouble paying for medical important, if often overlooked, avenue toward high-value
bills report difficulty paying for basic necessities such as care for women.
food and housing because of medical bills.
Getting to the doctor also requires time and transporta-
tion. About one-quarter of women delayed or went without Summary Points
care because they couldn’t take time off work; that number
rises to one-third of low-income women [7]. Similarly, 9% of 1. The quadruple aim is a four-part goal to achieve high-
women delayed or went without care because of transporta- quality care, a meaningful care experience for patients,
tion barriers, a figure that increases to 19% when considering job satisfaction for providers, and all at an affordable
only low-income women. Further, these transportation prob- cost. Access to health care is often dictated by health
lems are significantly worse among Black and Hispanic insurance status; about 60% of non-elderly women have
women. employer-sponsored health insurance and 20% have
Medicaid.
2. Examples of high-value care include recommended pre-
Covid-19 and Public Health vention measures such as breast cancer screening in 50-
to 74-year-old women, chlamydia screening in sexually
The Covid-19 pandemic is a stark reminder that the U.S. active women 24 years and younger, or supporting breast-
healthcare system is primarily a system of clinical care deliv- feeding interventions in pregnant women and new moth-
ery to individuals. In contrast, public health functions such ers. In contrast, low-value care may be measures that
as controlling epidemics, contact tracing, and return-to-work aren’t evidence-based (such as screening for vitamin D
or return-to-school strategies are the domain of governments deficiency), with limited cost-effectiveness (such as rou-
and local health departments. While men and women have tine BRCA genetic testing) or both (such as elective
similar infection rates when exposed, men tend to have a delivery before 39 weeks).
more severe disease course and worse outcomes. However, 3. Health care organizations can put systems in place to
Covid-19 has deepened existing disparities based on socio- improve care for women and LGBTQ populations by
economic determinants of health. Women are more likely to using teams to promote timely preventive care and
work in healthcare (essential work with exposure risk), work chronic disease management, creating a culture of con-
part-time or in the informal economy (which does not supply tinuous quality improvement, and prioritizing shared
health insurance), and be the primary caregiver of children decision-making.
(forcing a choice between employment/insurance and care- 4. Measures targeting women such as breast cancer screen-
giving for school-aged children at home during the pan- ing are commonly included in pay-for-value arrange-
demic). Thus, Covid-19 may have a more significant indirect ments and publicly reported scorecards of performance.
impact on women. Achieving high-value care requires attention to care for
women, including maternity care.
5. Population health management means improving the out-
Health Policy and Advocacy comes of the group as well as the outcomes within the
group. Gender equity, reducing disparities, addressing
While this textbook largely works to help guide our actions social determinants, and professional advocacy are
at the bedside in hospitals or in clinics, critical elements of important components of high-value care.
high-value care for women and LGBTQ populations are
most impacted when providers influence societal attitudes
and/or health policy. This textbook does not suggest pro- Review Questions
viders enter the world of partisan politics. Indeed, provid-
ers must remain impartial and care for all persons, as 1. One population health tenet is to achieve all four objec-
dictated by the 2017 World Medical Association Declaration tives of the “quadruple aim.” Which objective is included
of Geneva [58]. Yet physicians must be aware of how of our in the quadruple aim?
38 J. L. Mitchell
A. Reducing health system costs such as clinical infor- B. Hire a medical assistant to call all women in the age
matics and analytics range who are due for a mammogram to come in for a
B. Improving the quality of care such as the rate of breast mammogram
cancer screening C. Poll a convenience sample of Black women served by
C. Decreasing the number of for-profit health-care orga- your clinic about why they aren’t getting mammograms
nizations to improve coordination with community D. Map the current process and use performance data
organizations informed by observations of the care team to identify
D. Increasing the number of patients seen per day to less effective and missing steps
improve access The correct answer is D. The core tenet of systems engi-
The correct answer is B. The quadruple aim is to neering quality improvement is to understand current
improve the experience, quality, and vitality of prostate before planning a future state [38]. Often, the best
viders while keeping spend in check [3]. Reducing ideas for planning the future state come from those doing
costs are aimed at reducing low-value care or bring- the work, so the map of the current state and its review
ing transparent discussions of cost into treatment should include persons directly involved. After this, it
plans when options are available. Clinical informatics may be that the suggestion is to outreach to those due for
and analytics often develop or inform process mammograms or poll patients.
improvement which can increase high-value care. 4. Your health care organization is part of an accountable
Access is an important aspect of patient experience; care organization that has an opportunity for shared sav-
the ways to improve access are to decrease rate of ings in a pay-for-value contract. However, to be eligible
uninsured and to make clinicians available by ensur- for shared savings, your organization must meet a quality
ing adequate number of primary care physicians and performance threshold. This threshold includes measures
using alternate methods of patient encounters such as such as breast cancer screening, chlamydia screening,
advance practice providers. patient experience ratings, and prenatal care visits. Your
2. Which of the following is an example of a low-value composite rate is 55%, but the required threshold is 70%.
service? To achieve maximum shared savings, your best next step
A. Annual cervical cancer screening in ages 21–64 is to
B. Osteoporosis screening at age 65 years A. Plan a team meeting to study your composite
C. Elective delivery after 40 weeks gestational age performance
D. Breast MRI for breast cancer screening in BRCA B. Lower the rate of uninsured at your clinic
mutation carriers C. Reduce the rate of early elective Cesarean sections
The answer is A. Low-value services are listed by D. Reduce your breast cancer spending
Choosing Wisely [29]; one example is scheduling an The correct answer is A. Pay-for-value contracts encour-
elective delivery before 39 weeks of gestation. High- age health-care organizations and payers to work together
value preventive care is Grade A–B rating by USPSTF as they both benefit from reducing unnecessary spending
[6]. USPSTF recommends cervical cancer screening and low-value care [43]. In this scenario, your group may
every 3–5 years depending on patient factors, osteoporo- not share in savings even if it is achieved because the
sis screening beginning at age 65 years, and breast cancer quality composite score is not at threshold, so your best
screening, including MRI in those at high-risk for breast bet is to work on the quality score in a PDSA cycle with
cancer in women aged 50–74 years. your team.
3. Your health-care organizations’ breast cancer screening
rate is 55%, using a numerator of at least every 2-year
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The Female Sex- and Gender-Specific
History and Examination 3
Eliana Bonifacino and Jennifer Corbelli
provider can introduce the topic (e.g., “In the next part of our
Learning Objectives visit, I will be asking questions regarding your gynecologic
1. Describe the components of a female gender- health”) and “normalize” the interview by explaining that
specific history and review of systems. these are common and important health-related questions
2. List the components of a standard pelvic that are asked of all patients. A female gender-specific his-
examination. tory contains the components outlined in Table 3.1.
3. List key differences among major guidelines on the • Menstrual History: Includes the age of menarche, men-
indications for pelvic examinations. strual cycle length, date of last menstrual period, and age
4. Identify populations that may require adaptations of menopause, if indicated. Record bleeding patterns and
of the pelvic examination. quantity, and note menses that are absent, irregular, very
5. Describe the components of a standard clinical long and heavy, or if there is intermenstrual bleeding. In
breast examination. appropriate patients, providers should ask about meno-
pausal symptoms including menstrual irregularity, hot
flushes, and vaginal dryness. Postmenopausal bleeding
should be recorded as it could reflect underlying pathol-
The Female Gender-Specific History ogy. (See Chap. 7 on Abnormal Uterine Bleeding and
Chap. 8 on Menopause).
Introduction • Contraception: The patient’s current method of contra-
ception, previous methods utilized, and duration of hor-
A gender-specific history is often performed as part of a monal treatments are noted. If the patient is not using
comprehensive annual examination or a well-woman visit to contraception, explore facilitators and barriers to the use
elicit information about relevant past medical history, screen of contraceptive methods, and ask the patient their imme-
for sexual dysfunction, discuss family planning and contra- diate plans should they become pregnant (See Chap. 4 on
ceptive choices, and uncover potential risk factors for future Patient-Centered Contraceptive Counseling).
health conditions. Due to the nature of the information dis- • Obstetrical History and Reproductive Plans: Future
cussed in this encounter, some women may feel uncomfort- reproductive plans, previous pregnancies, pregnancy
able or anxious discussing their health history. This requires complications, and medical comorbidities of pregnancy
that providers practice sensitive and culturally conscious are recorded. Exploring a patient’s future reproductive
care. plans allows providers to discuss preconception counsel-
In general, it is optimal to begin a new patient visit with ing or offer appropriate contraceptive counseling.
the patient dressed and sitting on a chair, as opposed to Determine the number of prior pregnancies, and record
gowned, or on the examination table. When taking a history, age of first birth which is applicable to breast cancer risk.
language should be sensitive to patient concerns: avoiding Terminations, miscarriages, or ectopic pregnancies, mode
implied judgment, colloquial terms, or innuendo [1]. Prior to of delivery, and gestational age at delivery are recorded
asking questions that may be uncomfortable in nature, the (See Chap. 39 on Obstetric Medicine).
–– Gravidity and Parity: Two conventional systems exist
E. Bonifacino (*) · J. Corbelli for documenting a patient’s obstetric history. One sys-
University of Pittsburgh Medical Center, Division of General tem for documenting obstetric history includes a
descriptive prefix GXPXTabXSabXEctXLCX, representing

42 E. Bonifacino and J. Corbelli
Table 3.1 Essential components of the female sex- and gender-specific system follows the format GxPTPAL. In this system, the
history number of pregnancies in a patient’s life is designated as
Chief complaint/HPI/medications/allergies/past medical and gravidity (G), with X representing the total number. The
surgical history numbers following the patient’s parity (P) designate
Gynecologic and reproductive history
outcomes of the patient’s pregnancies: term deliveries
Menstrual history:
Age at menarche. (T), preterm deliveries (P), all other pregnancies (A),
Menstrual pattern. and living children (L). Using this system, G3P1112 would
Age of menopause. refer to a patient who has had two pregnancies, one full
Contraception: term, one with a preterm birth, and one abortion, who
Current/prior methods.
Facilitators/barriers. currently has two live children [2].
Family planning. –– Complications of Pregnancy: A history of obstetric
Obstetrical history and reproductive plans: complications, even past a woman’s childbearing
Gravity/parity/age at first live birth/future plans. years, may affect risk of cardiovascular disease and
Complications of pregnancy: DM, HTN, preeclampsia, other.
Lactation/length of lactation/plans. diabetes and should be recorded. A history of gesta-
Gynecologic history: tional diabetes, preeclampsia, preterm delivery, pla-
History of STIs/cervical cancer screen/HPV. cental abruption, and infants who were small for
Other gynecologic diagnoses. gestational age can increase the patient’s risk for pre-
Sexual history/activity:
Sexual orientation/practices/partners. mature heart disease and cardiac death [3, 4].
Sexual function. Gestational diabetes greatly increases risk of the devel-
Breast history opment of future maternal diabetes.
History of chest radiation. –– Record maternal complications of pregnancy: peripar-
Family history of breast or ovarian cancer/risk genetic mutation. tum cardiomyopathy, pulmonary edema, or gestational
Mammogram and breast density.
History of breast biopsy and result/treatments/breast surgery.
hypertension. Hypertensive or placental insufficiency
Family and genetic history syndromes include preeclampsia/eclampsia, HELLP
Cancers: Breast, ovarian, fallopian tube, endometrial, uterine (Hemolysis, Elevated Liver enzymes, Low Platelet
cancer. count) syndrome, AFLP (Acute Fatty Liver of
GI malignancy, other cancers. Pregnancy), or HUS/TTP (Hemolytic Uremic
Known mutation in patient or family member, genetic testing,
and result.
Syndrome/Thrombotic Thrombocytopenic Purpura).
CAD/DM/HTN. • Lactation: Providers should discuss breastfeeding history
Osteoporosis. or plans for lactation. Lactation is protective for breast
Social history cancer and has protective associations with multiple
Living situation. maternal cardiovascular risk factors [5].
Job/occupation/education.
Intimate partner violence.
• Gynecologic History: Human Papillomavirus (HPV) vac-
Lifestyle habits cination doses, date and results of prior Papanicolaou
Exercise/diet. (pap) test and HPV screening, and evaluation of any
Smoking/alcohol use/substances. abnormal pap tests are recorded. Colposcopies and treat-
Review of systems ments of any cervical intraepithelial neoplastic (CIN)
Breast: Pain/lump/discharge/axillary mass/breast awareness. lesions should be noted. (See Chap. 14 on Cervical Cancer
Gyn: Bleeding/ pain/discharge/prolapse/pruritus/external lesions/
and Human Papillomavirus).
dyspareunia/bloating/menopausal symptoms.
Urinary: Incontinence/retention/dysuria/frequency. • Past or current gynecologic diagnoses: ovarian cysts,
Abbreviations: HPI history of present illness, DM diabetes mellitus, uterine fibroids, polycystic ovary syndrome (PCOS),
HTN hypertension, HPV human papillomavirus, CAD coronary artery infertility, endometriosis, structural abnormalities, cervi-
disease, STI sexually transmitted infection, GI gastrointestinal cal or uterine polyps, procedural, and gynecologic surgi-
cal histories should be noted.
the patient’s gravidity (G), parity (P), therapeutic abor- • Sexual History: The comprehensive wellness visit also
tions (Tab), spontaneous abortions (Sab), ectopic preg- presents an ideal time to perform a complete sexual his-
nancies (Ect), and living children (LC). Each of these is tory. Providers should practice sensitivity when asking
followed by the number of each event a patient has questions regarding a patient’s sexual history as some
experienced [2]. G2P2TAB1LC2 would describe a patient patients may feel uncomfortable disclosing this informa-
who has had two pregnancies, two births, one abortion, tion. This history includes questions about sexual prac-
and who currently has two live children. This system tices, sexual dysfunction, sexual orientation, characteristics
requires less memorization and communicates essential and number of partners, types of sexual intercourse, his-
information to other providers. Another, though similar, tory of sexually transmitted infections (STI), use of barrier
3 The Female Sex- and Gender-Specific History and Examination 43
contraception, presence of dyspareunia, vaginal bleeding –– Screening for Intimate Partner Violence (IPV): The
with intercourse, and decreased sexual libido. One should United States Preventive Task Force (USPSTF),
always aim to assess patients for high-risk sexual behavior American College of Obstetricians and Gynecologists
for contraction of sexually transmitted infections such as (ACOG), and other professional societies recommend
human immunodeficiency virus (HIV) and be sure to that IPV screening be performed at well-women visits [7,
counsel appropriately. (See Chap. 4 on Patient-Centered 8]. Language used in charting should be specific and fac-
Contraceptive Counseling, Chap. 9 on Female Sexual tual such as “Patient states that….” and should clearly
Function and Dysfunction, and Chap. 13 on Sexually document symptoms and physical exam findings.
Transmitted Infections). Providers should keep in mind that the medical record
• Breast Health and Screening History: Age and frequency may be viewed by the patient or possibly others and
of mammograms; history of abnormal mammograms; should exercise appropriate care. A recent systematic
breast density; prior breast biopsies and results; personal review found that screening for IPV increased the rates of
history of breast cancer; history of breast surgery includ- identification of patients/survivors. It has been harder to
ing cosmetic surgery, breast reduction, benign breast con- prove that increased screening decreases IPV; however,
ditions; and breast changes including masses, focal pain, identifying victims to offer support is important [9]. For
discharge, pruritus, or change in the appearance of skin more information, see chapter on IPV and sexual trauma
(including erythema and flaking) are recorded [6]. Family for a complete discussion of interviewing techniques.
history is discussed below, but a cancer history is • Lifestyle Habits: Exercise/diet/smoking/alcohol and other
extremely important to assess for cancer risk. If a woman substance use.
is at high risk for breast cancer because of a very strong
family history, known genetic mutations, a history of Review of Systems (ROS) Note that the following catego-
atypical hyperplasia, lobular carcinoma in situ (LCIS), or ries may not be included on a standard ROS template and
a greater than 20% lifetime risk of breast cancer, then pre- may need to be asked directly:
ventive measures such as screening MRIs, chemopreven-
tion, genetic testing, and referrals to or evaluations by 1. Breast: pain/lump/discharge/galactorrhea/axillary mass/
breast surgeons should be recorded (See Chap. 17 on the breast awareness.
Primary Prevention of Breast Cancer). Lactation history 2. Gynecologic: abnormal or irregular bleeding/pain/dis-
should be recorded, as discussed above. charge/prolapse/pruritus/external lesions/dyspareunia/
• Family and Genetic History: Asking specifically about a bloating/menopausal symptoms.
family history of breast, ovarian, fallopian tube, uterine, 3. Urinary: incontinence/retention/dysuria/frequency.
and colorectal cancer is important as certain genes have
been linked to familial cancer syndromes. All cancers in
first-, second-, and third-degree relatives may be relevant The Pelvic Examination
to breast and ovarian cancer risk. The age that the relative
was diagnosed with cancer is important. A family history Indications
of known or suspected genetic syndromes which increase
breast cancer risk should be recorded. A family history of A pelvic examination is indicated in women with a gyneco-
colonic polyps or colon cancer is very relevant. For exam- logic symptom or concern including vaginal discharge,
ple, a patient whose aunt had early-onset colorectal can- abnormal bleeding patterns, pelvic pain, urinary inconti-
cer at age 39 may be at higher risk of ovarian, uterine, and nence, dyspareunia, sexual concerns, or abdominal pain.
gastrointestinal tract cancers if they have the genetic Additionally, a pelvic examination may be needed for cervi-
mutation for Lynch syndrome. (For further information cal cancer screening and evaluation of some sexually trans-
see the section on “genetic screening” in Chap. 17, the mitted infections. There is controversy regarding the utility
Primary Prevention of Breast Cancer.) Family history of of routine screening pelvic examinations beyond what is
diabetes, hypertension, hyperlipidemia, and cardiovascu- described above.
lar disease with age of onset should be noted (See Chap.
21 on Cardiovascular Disease in Women Part 1: Sex and
Gender Differences in Cardiovascular Conditions and Guidelines for Screening Pelvic Examinations
Risk Factors.)
• Social History: Should contain information on living situ- In 2014, the American College of Physicians (ACP) published
ation, occupation, and education. Intimate partner vio- guidelines for screening pelvic examinations, in asymptomatic,
lence screening and history of trauma are part of the social nonpregnant women, based on the results of a systematic
history. review of the literature [10]. No conclusion could be drawn
about the effect of screening pelvic examination on the diagno- terectomy and bilateral salpingo-oophorectomy for benign
sis of asymptomatic pelvic inflammatory disease (PID), benign causes who are asymptomatic. Care should be taken to
gynecologic conditions, or malignancy, excluding cervical and ensure that the cervix was removed because patients may not
ovarian. Harms associated with screening pelvic examination be aware of the details of their surgery. Forgoing this routine
include patient’s pain, fear, and embarrassment, as well as the internal examination should only be considered in patients
potential for increased unnecessary surgical procedures. Based who have no history of HIV and immunosuppression, no
on the results of this review, the ACP recommended against exposure to diethylstilbestrol (DES) in utero, and no prior
performing routine screening pelvic examinations in asymp- cancer or precancerous lesions such as vulvar intraepithelial
tomatic, nonpregnant women. Several other national and inter- neoplasia or cervical intraepithelial neoplasia II or III [12].
national organizations support this stance [11, 12]. Periodic external exams and exams for symptoms are still
The USPSTF and ACOG, however, do not support or appropriate. For further information, see Chap. 14 on
refute this recommendation. The USPSTF published a rec- Cervical Cancer and Human Papillomavirus and Chap. 15 on
ommendation statement after review of the literature on Gynecologic Malignancies.
screening pelvic examinations, concluding that there is insuf-
ficient evidence to support or refute the performance of a rou-
tine screening pelvic examination in asymptomatic women Chaperones
[9]. ACOG published an independent review of the literature
and, in 2018, concluded that current data is inadequate to sup- A chaperone is a trained health-care worker who accompa-
port or refute an annual screening pelvic examination. ACOG nies the patient and provider in the exam room during an
recommends that obstetrician-gynecologists should discuss intimate exam. Friends and family members cannot serve
the risks and potential benefits of pelvic examination for as chaperones but can be in the room at the time of the
asymptomatic women with their patients and reach a shared exam at the patient’s discretion. No uniform policy exists
decision about whether or not to perform an exam [13]. among US state medical or osteopathic boards regarding
Conflicting guidelines may impact patient understanding the presence of a chaperone in the examination room for
and adherence to routine gynecologic care. In a recent cross- intimate examinations [15]. Many studies suggest that
sectional study examining patient beliefs regarding pelvic patient preferences regarding the presence of chaperones
examination guidelines, over half of patients believed that vary, although many patients may prefer not having a chap-
they should undergo yearly screening pelvic examination, erone present [16]. An ACOG committee opinion statement
and over half were unaware of the new guidelines released specifies that a chaperone should be available upon patient
by ACP [14]. The lack of awareness poses challenges for request regardless of the provider’s gender and that the
shared decision-making between provider and patient as patient should have the opportunity to talk with the pro-
knowledge about guidelines can impact decisions. In another vider in the absence of the chaperone [17]. Chaperones can
study, women who were given the ACP guideline summary provide many benefits including attending to patient’s emo-
to review were much less likely to report wanting to undergo tions and positioning, assisting with equipment and testing
routine pelvic examination when compared to women who samples, and acting as a third-party witness should there be
had read a previous ACOG guideline recommending contin- a disagreement between patient and provider about what
ued screening pelvic examinations (OR 0.12) [11]. occurred during the examination. One should check with
The editors agree that yearly routine pelvic examinations institutional policies regarding chaperones as many institu-
are unnecessary for asymptomatic women; however, periodic tions require chaperones during all sensitive exams.
exams to obtain cervical cancer screening samples may be
performed according to guidelines. Any complaint of pain,
bleeding, or sexual dysfunction should be investigated with a Positioning
pelvic exam, and the vulva (external exam) should be exam-
ined periodically as part of a routine skin check since many During a typical pelvic examination, the patient assumes the
dermatologists do not examine this area. Students and resi- dorsal lithotomy position. Although the patient’s feet are
dents training for primary care should be adequately trained commonly placed in footholds, or stirrups, some data sug-
to perform external and internal pelvic examinations. gest that examination without the use of footholds decreases
patient discomfort with pelvic examination [18]. The
perineum should rest about 2 inches off the end of the exam
Discontinuation of Pelvic Examinations table as this allows for better access to the pelvic organs. If
footholds are not used, the speculum handle will need to face
The choice to discontinue the screening pelvic examination upward to obtain a cervical sample. Alternate positions may
can be considered in patients who have undergone total hys- be necessary for women with mobility limitations.
Mitigating Patient Anxiety dure without pain, then the exam should not be attempted,
and alternative methods of evaluation including possible
Some women report feeling fear, anxiety, or embarrassment referral should be considered.
about pelvic examinations. A 2014 systematic review evalu-
ating the harms of pelvic examination found that between
10% and 80% of women experience these emotions during Components of a Pelvic Examination
or before pelvic examination. Many women also experienced
pain or discomfort during pelvic examinations, ranging The pelvic examination traditionally consists of three major
between 10% and 60%. Of concern, this review also points components: (1) examination of the external genitalia; (2)
out that many studies indicate an association of pain or dis- internal examination of the vagina and cervix, performed
comfort with decreased likelihood of returning for a subse- with a speculum; and (3) bimanual examination of the uterus,
quent examination [10]. adnexa, ovaries, and pelvic muscles [12].
In addition to assuring proper privacy, draping, and room 1. Examination of External Genitalia.
temperature, providers can do several things to mitigate This component of the pelvic examination involves
patient anxiety. Woman should be asked about history of visual inspection of the perineum, mons pubis, and labia
sexual intercourse. Women who have not previously had majora and minora. During this inspection, providers
penetrative vaginal intercourse, are not currently sexually may identify any areas suspicious for neoplasia, folliculi-
active, have dyspareunia, or are postmenopausal are at risk tis, candida infections, condylomas, other lesions, or
of an uncomfortable or painful examination. Women with ulcers. Providers can also note hair distribution, and in
anxiety, post-traumatic stress disorder, or a history of trauma appropriate patients, can help determine Tanner stages.
are also at risk. Interventions to ensure a painless exam and As a component of an external examination, the provider
mitigate anxiety include discussing the exam in advance: can also examine for Bartholin and Skene glands.
communicate that the patient is in control of the examination Bartholin glands, which are not usually palpable in nor-
and can request for it to end at any moment, and explain the mal states, are located immediately internal to the hymen
procedure prior to starting as well as during each step [19]. and are located bilaterally in the upper third of the vaginal
Throughout the examination, providers should continue to introitus. Skene glands, also not usually palpable in
interact with the patient and frequently assess for signs of healthy states, are located adjacent to the urethral orifice.
discomfort. Signs of distress can include breath holding, Clitoromegaly or virilization should be noted.
gripping the table or gown, and squinting the eyes shut. 2. The Speculum Examination.
Vocalization by the patient, such as gasping, mumbling, The speculum examination involves visualizing the
cursing, or yelling, or physical reactions, such as kicking, vaginal canal and cervix. A speculum is inserted into the
moving further away from the examiner, or closing one’s vagina in a downward motion, allowing the provider to
legs, are obvious signs of severe distress [20]. In order to examine the vaginal mucosa for lesions or atrophy. The
mitigate mild distress, providers can instruct the patient in provider can also observe for the presence of discharge
deep rhythmic breathing [21] or to Valsalva to relax the pel- and note color, consistency, and odor. Next, the specu-
vic floor. Other potential techniques to mitigate patient’s lum is carefully advanced, and the blades are opened to
moderate to severe distress include using mental imagery, reveal the patient’s cervix. After location of the cervix,
progressive muscle relaxation, and meditation [20]. Difficult the provider notes any discolorations, lesions, or masses
cases should be referred to a gynecologist. In cases of severe on the cervix, as well as locating strings from an intra-
physical or emotional distress and in clinical scenarios where uterine contraceptive device, if appropriate. Samples for
pelvic exam is needed, pelvic examination can be performed pap and STI testing are taken and then the speculum
under anesthesia. should be removed. The speculum is removed by gently
In postmenopausal women, estrogen treatment for backing the blades off the cervix and then allowing the
6 weeks prior to the exam can be offered if the patient is not blades to fall closed while still in the vaginal vault. This
sexually active or has significant dyspareunia. If there is any avoids closing the blades on the cervix and allows the
concern that the exam will be uncomfortable, the initial step speculum to be withdrawn from the vagina completely
can be examination with one gloved finger which is moist- closed. Providers should take care to avoid pinching
ened either with water or with a small amount of water-based vaginal mucosa, skin, or hair between the blades as they
lubricant (be aware that lubrication may interfere with ade- close. The walls of the vagina should be visually
quate sampling for a pap test; check with your facility). The inspected for lesions, especially if using a clear plastic
exam should be gentle, and gentle downward pressure should speculum, while withdrawing the speculum. The specu-
be applied to the posterior introitus to induce relaxation of lum is then completely withdrawn, concluding this part
the levator ani. If the examiner cannot perform this proce- of the exam.
Providers are sometimes unable to see the cervix when tion [23]. Other resources include online video demonstra-
the speculum blades are opened. In these occasions, pro- tions [24].
viders can first slowly retract the speculum a small
amount which can bring the cervix into view. If adjust-
ments to position do not allow providers to visualize the Pelvic Examinations with Accommodations
cervix, removing the speculum and performing a biman-
ual exam may help providers localize the relative position Examination of the Patient with Disabilities
prior to reinsertion of the speculum [20]. Alternatively, a
single gloved finger can be inserted prior to the speculum The examination of a patient with physical or developmental
insertion to assess the position of the cervix. disability poses unique challenges for patients and providers.
3. Bimanual Examination. Despite the challenges, reproductive health care is as impera-
The next portion of a comprehensive pelvic examina- tive in disabled patients as it is in nondisabled patients.
tion is a bimanual examination. To perform a bimanual Patients with disabilities are as likely as their nondisabled
examination, the provider inserts their index and middle counterparts to engage in sexual activity [25] and more likely
finger of one hand into the vagina and places the other to have experienced sexual assault [26, 27]. Given the diver-
hand on the patient’s lower abdomen. Using the inserted sity of types of disability, an individualized approach is often
fingers, providers can locate the cervix and, by moving best.
the cervix, can assess for cervical motion tenderness. For patients with disabilities, provision of additional time
Subsequently by lifting the cervix with the internal fin- for examination, tables with adjustable heights to facilitate
gers and performing a downward sweeping motion with transfer to and from wheelchairs, and wheelchair-accessible
the external hand on the abdomen, the provider can assess clinics should be provided. Depending on the specific physi-
the uterine position and approximate size. In order to cal disability, alternative positions for pelvic examination
assess the adnexa and ovaries, the inserted fingers can be could be considered including knee-chest positions (laying
angled toward each vaginal fornix individually, and the sideways) and frog or diamond positions [28]. Additionally,
abdominal hand can again sweep downward in an attempt providers should be aware of disease-specific considerations
to push the ovary toward the inserted hand for palpation. for examination, including the avoidance of latex in patients
In this portion of the examination, the ovaries and adnexa with spina bifida due to the high rates of allergy [29]. The
would be palpable only by the inserted fingers, not the speculum positioning may need to be modified to accommo-
abdominal hand, for size, tenderness, and irregularities. date various positions.
Note it is uncommon to feel both ovaries in a patient;
body habitus and ovary position make it difficult to pal-
pate the entire ovary and adequately characterize its posi- Examination of Adolescents
tion and size.
Tissue paper should be offered to patients at the conclu- The frequency of screening pelvic examination of the ado-
sion of the exam for cleaning purposes, and a menstrual lescent patient is declining due to changes in age recommen-
pad should be offered if any bleeding is noted, which is dations for cervical cancer screening and newer methods to
common if any sample are obtained from the cervix. screen for sexually transmitted diseases. However, external
pelvic examination is recommended by the American
Academy of Pediatrics as part of a routine comprehensive
Teaching Pelvic Examinations physical exam [30]. A diagnostic speculum and bimanual
exam may be indicated when a patient presents with symp-
The intimate nature of a pelvic examination poses chal- toms, menstrual irregularities, or a report of abuse. When
lenges in training providers to perform these examinations. performing a pelvic examination on an adolescent patient,
Many studies have evaluated the benefits of the use of stan- there are several key considerations. An examination may be
dardized patients to teach pelvic examinations to a variety anxiety-provoking and communication regarding steps of the
of clinical trainees. The use of standardized patients was examination is important. Some examination techniques
associated with improved clinical performance when include providing the patient with a mirror to engage the
assessed through clinical assessment, objective-structured patient in the examination, or examining a child in the moth-
clinical examinations, self-assessment, and location of er’s lap [31]. A narrower Huffman speculum may be used in
abnormalities [22]. Additionally, the use of simulation for younger adolescents. Contrary to guidelines for adults, a
teaching pelvic examinations has been shown to lead to chaperone is strongly recommended for pelvic examinations
improved examination skills when compared to no interven- in adolescent patients [30].
Examination of Women Aged 65 and Over floor and supporting ligaments and tissues. Risk factors
include pregnancy, especially vaginal delivery, age, and less
Though the older adult may not need further screening pelvic so obesity, pelvic surgery, and occupations requiring heavy
examinations, diagnostic pelvic examinations may be indi- lifting [34].
cated. When a pelvic examination is needed in an older adult, In the dorsal lithotomy position, the patient should be
several considerations are appropriate. Many older women asked to strain or “bear down” to visualize the vaginal walls
may have difficulty with the traditional dorsal lithotomy and any descent of the pelvic organs near the introitus. The
position due to arthritis, contractures, or other medical con- speculum can then be split in half so that it makes two
ditions. Providers performing pelvic examination should “L”-shaped single-blade specula. One single speculum blade
consider alternative positions, similar to women with physi- is then placed posteriorly to retract the posterior wall of the
cal disabilities [32]. Given the increased incidence of atro- vagina while the provider observes the anterior wall for pro-
phic vaginitis in this population, the liberal use of lubricant lapse of the bladder (cystocele) while the patient bears down.
can also be considered. Many older women have had a total The procedure is repeated, this time retracting the anterior
hysterectomy for either a benign or malignant reason. The vaginal wall with the single blade placed anteriorly, paying
remaining vaginal cuff can be very proximal to the introitus attention not to press against the urethra or clitoris and
or very deep. To prevent discomfort or injury to the cuff, be observing the posterior vaginal wall for prolapsed rectum
cautious when inserting a speculum into this area when the (rectocele). During both these exams, the provider should
depth of the vaginal cuff is unknown. Preexamination with also observe the cervix for prolapse of the uterus. Validated
one finger as described above is recommended. and standardized scoring systems are useful for documenta-
tion to compare severity of prolapse over time and avoid sub-
jective ratings that may otherwise differ between providers.
xamination of Patients with Atrophic
E The authors recommend either routine use of the simplified
Vaginitis Pelvic Organ Prolapse Quantification System [35] or at a
minimum, recording the level of descent in terms of the
Patients that have undergone menopause or that are on tes- number of centimeters distal or proximal to the introitus and
tosterone for gender-affirming therapy are at risk of develop- its location (central, anterior, or posterior). See Chap. 23 on
ing atrophic vaginitis. Due to lack of the vaginal lubrication Urinary Incontinence to learn more about the treatment of
and thinned mucosae that are characteristics of the condition, prolapse.
patients with atrophic vaginitis can experience pain or even
traumatic ecchymosis or laceration with pelvic examinations
[33]. As in examination of the older woman, generous lubri- Examination of Patients with Vulvodynia
cation may be used. Vaginal estrogen used 2–6 weeks prior
to examination, as well as topical lidocaine, may be used Patients who have vaginismus or vulvodynia may experience
with pelvic examination; however, no studies have examined discomfort with pelvic examinations, particularly with pal-
the efficacy of these strategies [1]. Using the smallest specu- pation of the labia and introitus and speculum insertion. In
lum to adequately visualize the cervix will be most comfort- order to mitigate this discomfort, generous amount of lubri-
able for the patient. For cervical cancer screening, vaginal cant or topical lidocaine may be utilized. If spasm occurs, the
sampling for HPV may be sufficient. (See Chap. 14 on exam may need to be deferred [1]. In patients with vulvo-
Cervical Cancer and Human Papillomavirus.) dynia, cues to “relax” by the provider feel frustrating and do
not lead to relaxation of the pelvic muscles [36]. See Chap.
31 on Chronic Pelvic Pain for more information regarding
xamination of Patients with Pelvic Organ
E physical exam techniques in patients with pelvic pain and the
Prolapse evaluation of vulvodynia.
Pelvic organ prolapse is a common condition, and a specific

exam procedure is required to accurately diagnose it and its xamination of Sexual or Gender Minority
E
severity. This specialized examination should occur either Patients
when women present with urinary leakage, stool inconti-
nence, pelvic pressure, the feeling of a vaginal or pelvic Significant health-care disparities exist among patients who
bulge or something “falling out” or when prolapse is seen are from sexual minority groups. Women who identify as les-
grossly during the pelvic exam for other reasons. Pelvic bian or bisexual are less likely to present for annual physical
organ prolapse occurs when the bladder, uterus, or rectum examinations and less likely to have had cervical cancer
descends into the vaginal space due to weakness in the pelvic screening than heterosexual women [37]. Cultural
competence is of utmost importance when performing a pel- ine all breast tissue, borders of the examination field should
vic examination for sexual or gender minority patients. It is include the clavicle, the sternum, the midaxillary line, and
important to discuss each patient’s individual history without across the ribs inferior to the breast [40]. Overall, a standard-
making prior assumptions based on external expressions of ized technique is best, with studies indicating that a vertical-
gender. For further information on sexual and gender minori- strip, or “lawn mower,” pattern is most effective [41, 42]. For
ties, see Chap. 36 on Care of Sexual Minority Women and palpation, the index, middle, and ring fingers should be used
Chap. 37 on Transgender Care. together, creating small circles with three different levels of
pressure: light, medium, and deep. The nipple should be pal-
pated in the same method as the rest of the breast, without
xamination of Patients with a History
E squeezing or attempting to express fluid.
of Sexual Trauma Factors associated with superior accuracy of the breast
examination for detection of masses included longer dura-
Patients with a history of sexual trauma are found to be at tion of examination, use of correct technique, and greater
highest risk for distress associated with pelvic examination experience of the examiner [42]. The recommended amount
[38]. A 2014 systematic review found nine studies that of time for the examination is 3 minutes per breast [43].
reported on harms of pelvic examination for women with a Examination does not differ in women who have had
history of sexual violence. The majority of studies reporting breast implants or mastectomy. In women who have had
fear, anxiety, distress, or embarrassment found that women mastectomy, the vertical-strip pattern can be used to palpate
who had experienced sexual trauma were at higher risk for the chest wall.
experiencing these emotions [10]. Though patients may not
always disclose sexual abuse in clinical situations, the major-
ity of patients favor being asked by a provider regarding Self-Breast Examination
physical and sexual abuse history [39]. In addition to the
strategies referenced in the “Mitigating Patient Anxiety” sec- The self-breast examination (SBE) is no longer routinely
tion above, providers can offer the option of counseling, recommended as a way to screen for breast cancer as SBE
make a statement to normalize anxiety, offer chaperone or has been shown to increase the rate of breast biopsies for
gender concordant care, and at times can be offered anxio- benign findings without any decrease in breast cancer mor-
lytic therapy [1]. tality [44]. However, many women practice SBE and often
ask questions about SBE. It should be encouraged for women
to have “breast awareness” and that any abnormal finding
Clinical Breast Examination including a mass or lump, breast pain, nipple discharge, or
axillary nodularity be brought to the attention of the pro-
The clinical breast examination is frequently performed as vider. Women should also alert the provider of any change in
part of a comprehensive physical examination. Prior to family history which might increase the risk of breast- or
beginning the examination, the patient should be situated on ovarian-inherited malignancy. See Chap. 18 on Breast
the exam table with a gown opened in the front. The clinical Cancer Screening regarding the guidelines and utility of self-
breast examination includes two primary components: and clinical breast examination.
inspection and palpation. The inspection portion begins with
the patient sitting with her hands on her hips. Providers
should then visually inspect the breasts for symmetry, skin Summary Points
changes, or other abnormalities. Subsequently, the axillary
and supraclavicular lymph nodes should be examined. In 1. In addition to a comprehensive general medical history, a
order to examine the lymph nodes, the patient’s arm should complete female gender-specific history should include a
be supported at a 45-degree angle with the elbow relaxed. complete sexual history, a pregnancy-specific history
Using finger pads, the axillae should be palpated, taking care including maternal and obstetric complications, a breast
to examine the entire anterior, posterior, and media wall. The history, screening for female cancer risk, a female spe-
supraclavicular lymph nodes should be examined subse- cific review of systems, and a comprehensive menstrual
quently, palpating along the length of the superior aspect of history from menarche to menopause.
the clavicle. 2. A standard complete pelvic examination includes both an
For the next part of the examination, the provider should external and internal examination, including visual
assist the patient to lie flat on the examination table. With the inspection of the external genitalia, speculum examina-
patient’s arm resting above her head, the provider or patient tion of the vagina and cervix, and a bimanual examination
can expose the breast to be examined. In order to best exam- of the uterus, adnexa, and pelvic floor muscles.
3. There are disparate guidelines that address indications this should be in addition to visualization of the cervix
for a screening bimanual examination, with many major and not in lieu of [38].
medical organizations (ACP, AAFP) recommending 2. A 40-year-old woman presents to her primary care pro-
against and some stating that there is insufficient evi- vider’s office for a Pap test. She has no significant past
dence to make a definitive conclusion (USPSTF, medical history. Her last menstrual period occurred
ACOG). 2 weeks ago, and she reports regular 28-day cycles with
4. There are many populations of patients in which pelvic no excessive bleeding or cramping. She uses a levonorg-
examination accommodations may need to be made: estrel intrauterine device (IUD) for contraception and
those patients with vaginal atrophy, patients with a his- reports one male sexual partner. She expresses anxiety
tory of sexual trauma, patients with physical and develop- about the pelvic examination.
mental disabilities, and patients who identify as sexual or Which of the following factors is known to contribute
gender minority. Health-care providers should be aware to increased anxiety surrounding pelvic examination?
of potential challenges and provide empathic and sensi- A. History of sexual trauma.
tive care. B. History of IUD placement.
5. Though there are no official standards, a clinical breast C. History of remote childbirth.
examination should include visual inspection and D. History of sexually transmitted infection.
palpation. The correct answer is A. In a 2014 systematic review,
women who had a history of sexual trauma were more
likely to experience fear, anxiety, distress, or embarrass-
Review Questions ment with pelvic examination. History of IUD place-
ment, history of remote childbirth, and history of sexually
1. A 20-year-old woman presents to her primary care pro- transmitted infections have not been found to be associ-
vider’s office for an annual wellness examination. She is ated with increased anxiety surrounding pelvic examina-
currently sexually active with one male partner and uses tion [14, 41].
condoms for contraception regularly. Her last menstrual
period was 2 weeks ago, and she is concerned about some
thin vaginal discharge and mild spotting but denies men- References
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Part II
Gynecologic Health and Disease
Patient-Centered Contraceptive
Counseling 4
Emmanuelle Yecies and Sonya Borrero
Learning Objectives does not drink alcohol or use any illicit substances.
1. Compare different patient-centered approaches for She is sexually active with two to three partners per
eliciting reproductive goals, preferences, and pri- year. Her menses are regular, lasting 5 days every
orities from patients related to contraception and 28 days, with minimal pain and moderate bleeding.
pregnancy.
2. List currently available contraceptive methods.
3. Compare and contrast the mechanism of action,
efficacy, duration of action, and return to fertility of Reproductive Goals Counseling
the various contraceptive methods.
4. Discuss side effect profiles, contraindications, and Despite advances in contraceptive technology and access,
noncontraceptive benefits of each method. 45% of pregnancies in the United States are reported as unin-
5. Provide counseling regarding emergency contra- tended, with higher rates reported among women of color
ception and abortion for patients with contraceptive and low-income women [1]. In recent years, experts and
failure or for patients at risk of unwanted pregnancy organizations, including the American College of
who are not using prescription contraception. Obstetricians and Gynecologists (ACOG) and the Centers
for Disease Control and Prevention (CDC), have recom-
mended that physicians and other care team members dis-
cuss reproductive goals with patients [2]. Using
patient-centered approaches, providers can gather informa-
Jenna is a 22-year-old woman who presents for routine
tion about patients’ reproductive goals, desires, and/or pref-
medical care. Her medical history includes hypothy-
erences in order to guide counseling with an end goal of
roidism treated with levothyroxine and migraines with
helping patients to achieve healthy pregnancies when desired
aura treated with topiramate. She is a daily smoker but
and prevent unwanted pregnancies [3].
Often implicit in reproductive goals assessments is the
assumption that women hold clear and binary pregnancy
intentions: that is, at a given time, women either do or do not
desire pregnancy. The subsequent counseling strategy (either
preconception counseling or contraceptive counseling) is
E. Yecies then dependent on which of these opposing goals women
Section of Women’s Health, VA Palo Alto Healthcare System, express. However, research demonstrates that women often
Palo Alto, CA, USA
have nuanced feelings and thoughts about pregnancy that can
S. Borrero (*) be conflicting, even contradictory, and can fluctuate some-
Center for Women’s Health Research and Innovation (CWHRI),
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA times rapidly. Thus, open-ended, nonjudgmental questions
regarding reproductive goals can elicit richer, more nuanced
Center for Health Equity Research and Promotion (CHERP), VA
Pittsburgh Healthcare System, Department of Medicine, preferences that can guide meaningful, patient-centered dis-
Pittsburgh, PA, USA cussions that may include both preconception and contracep-
e-mail: [email protected] tive counseling [4].

54 E. Yecies and S. Borrero
One widely promoted strategy to assess reproductive covered to guide providers in counseling their patients.
goals, developed by the Oregon Foundation for Reproductive Finally, common noncontraceptive benefits and contraindi-
Health, is called One Key Question™ (OKQ) [5]. This initia- cations will be outlined for each method to guide safe and
tive encourages providers to ask all women of childbearing appropriate selection.
capacity, “Would you like to become pregnant in the next There are various frameworks that can be used to organize
year?” The advantage of this strategy is its simplicity, par- currently available reversible contraceptive methods. Here,
ticularly in short clinical visits, and it is a valuable starting we have chosen to cluster the methods in three general cate-
point for providers developing their counseling skills. A gories related to duration of action and method effectiveness
potential downside of this method is that it may be perceived with typical use: long-acting reversible contraceptives
by patients as a binary yes/no question and may not elicit or (LARCs), short-acting reversible contraceptives (SARCs),
accommodate ambivalent, indifferent, or ambiguous and nonhormonal/barrier methods.
thoughts and feelings about pregnancy. In addition to the information presented here, providers
Another approach to reproductive goals assessment pub- may refer to the US Selected Practices Recommendations
lished in the literature is the PATH questions, which can help (US SPR) for further information on initiating and managing
to elicit long-term goals as well as short-term needs. These different contraceptive methods and the US Medical
questions explicitly leave room for women to express ambiv- Eligibility Criteria for Contraceptive Use (US MEC) for
alence about pregnancy desires [4]. The PATH questions guidance on absolute and relative contraindications to spe-
include three open-ended questions that assess pregnancy cific contraceptive methods [6, 7]. Additional Web-based
attitudes, timing, and how important prevention is to the resources available to both providers and patients include
patient: plannedparenthood.org and bedsider.org [8, 9]. Finally, pro-
viders should remember to counsel patients that only con-
1. Do you think you might like to have (more) children at doms protect patients against the transmission of sexually
some point? transmitted infections (STIs). Condoms may be paired with
2. If considering future parenthood, when do you think that any other method of contraception if there is any concern
might be? about STI exposure.
3. How important is it to you to prevent pregnancy (until
then)?
Long-Acting Reversible Contraceptives
As data, including comparative data, on these approaches
and others are still lacking, there is no clear optimal approach I ntrauterine Devices (IUDs)
to eliciting reproductive goals. Providers should consider Intrauterine devices (IUDs) are inserted into the uterus to
using either method, or another patient-centered approach provide long-acting reversible contraception. Two catego-
altogether, tailored to their comfort and patient population. ries of IUDs have been approved in the United States:
copper-containing (nonhormonal) IUDs (ParaGard™) and
progestin- releasing IUDs (Mirena™, Kyleena™,
Nonpermanent Contraceptive Options Liletta™, Skyla™). Specific considerations about these
subtypes are listed below. IUD effectiveness is approxi-
mately 99%, with failure rates less than 1% with both per-
fect and typical use [10]. IUDs may be offered to women
Jenna shares her responses to the PATH questions, of all ages and parities [11–13]; both the American
revealing that she would like to delay having children Academy of Family Physicians (AAFP) and ACOG spe-
for at least a couple of years. Preventing pregnancy is cifically recommend offering these methods to adoles-
very important to her until then as she is completing a cents and nulliparous women [13, 14] as the belief that
rigorous social work program and wants to graduate nulliparous women are not eligible for IUDs remains a
before juggling parenthood. She currently uses con- barrier to access.
doms when needed but is interested in learning more IUDs are placed by trained providers, and requirements
about her contraceptive options. for credentialing vary across different institutions.
Contraindications to placement include cervical cancer,
endometrial cancer, structural pelvic diseases, acute infec-
This section reviews currently available reversible contra- tion, and pregnancy [7]. Providers should determine the
ceptive methods. For each method, special attention will be patient’s last menstrual period and date of last unprotected
placed on mechanism of action, effectiveness, duration of sexual intercourse, assess the risk of pregnancy, and perform
action, and return to fertility. In addition, accessibility and a pregnancy test prior to insertion (Fig. 4.1). If a patient has
convenience, menstrual changes, and side effects will be a high risk of pregnancy but has a negative pregnancy test at
4 Patient-Centered Contraceptive Counseling 55
believed to prevent pregnancy by causing the same foreign

How To Be Reasonably Certain a body reaction as copper IUDs in addition to providing local
Woman Is Not Pregnant progestin effects: thickened cervical mucus and changes in
the endometrial lining [18, 25]. These IUDs have various
A healthcare provider can be reasonably certain that a woman is FDA-approved duration of use from 3 to 5 years, though the
not pregnant is she has no symptoms or signs of pregnancy and
she meets any of the following criteria: Mirena™ IUD has been used off-label for up to 7 years [26].
• is ≤ 7 days after the start of normal menses These devices are not currently approved for emergency
• has not had sexual intercourse since the start of last normal contraception, though studies are underway. The most com-
menses mon side effect is irregular bleeding, particularly in the first
• has been correctly and consistently using a reliable method of
contraception year [23]. By 2 years of use, amenorrhea is reported by 12%
• is ≤ 7 days after spontaneous or induced abortion (13.5 mg IUDs) up to 30–50% (52 mg IUDs) of women [27,
• is within 4 weeks post-partum. In addition 28]. Other reported side effects include acne, vaginal dis-
• is fully or nearly fully breastfeeding (exclusively breastfeeding or
the vast majority [≥85%] of feeds are breastfeeds), amenorrheic,
charge, and abdominal pain [29]. In addition to broad IUD
and < 6 months post-partum contraindications, levonorgestrel- releasing IUDs are also
contraindicated in breast cancer [7]. Noncontraceptive ben-
Fig. 4.1 How to determine if a woman is not pregnant [6]. (Adapted efits of the 52 mg LNg IUDs include decrease in menorrha-
from Curtis et al. [6])
gia and dysmenorrhea (FDA approved for this indication),
reduction in endometriosis- related pain and endometrial
insertion, a pregnancy test should be performed 2–3 weeks hyperplasia, and lower rates of endometrial, ovarian, and
after insertion. cervical cancer [30–33].
If STI screening is indicated according to STI screening
guidelines, screening may be done at the time of IUD place- Subdermal Implant
ment and, if positive, antibiotics may be given with the IUD The subdermal implant (Nexplanon) is a single-rod implant
being placed. If, however, there is evidence on exam of active containing etonogestrel, a progestin metabolite. The proges-
purulent cervicitis, IUD insertion should be delayed until tins present in the implant provide contraceptive effects via
after treatment and documented clearance of the infection [6, two mechanisms [34]. First, etonogestrel decreases sperm
15]. There is no data to support self-IUD string checks, but a migration by causing changes in cervical mucus and tubal
follow-up visit with a provider may be scheduled based on motility. Second, the high doses of etonogestrel present in
provider and patient preference [6]. Return to fertility is the implant inhibit gonadotropin hormone secretion, leading
prompt after IUD removal, and pregnancy can occur almost to the inhibition of follicle maturation and ovulation. The
immediately after removal, even though return of regular implant is greater than 99% effective, with typical and per-
menses typically occurs in 1–2 months for levonorgestrel- fect use failure rates less than 1% [35]. The implant has been
IUD users [16, 17]. approved for contraception for up to 3 years, although evi-
dence suggests that it may be effective for longer durations
Copper IUDs [36]. Studies of prior subdermal implants have demonstrated
One copper-containing IUD has been approved in the United that circulating levels of hormones are undetectable 1 week
States, TCu380A (ParaGard™). It is believed to prevent after removal [37]. As a result, return of ovulation occurs
pregnancy in two ways: an inflammatory reaction to the for- within 3 months of removal in 91% of women [38].
eign body in the uterus and local changes caused by copper The implant can be inserted and removed in the office by
release, including sperm toxicity and impaired implantation providers who have been trained in the procedure. This 3-h
[18, 19]. The copper IUD has been FDA approved for con- training is offered by Merck and covers counseling, inser-
traception for up to 10 years and has been used off-label for tion, and removal, allowing providers to quickly expand their
up to 12 years [20]. In addition, copper IUDs may be placed ability to initiate this method in their own practice [39]. No
for emergency contraception within five days of unprotected physical examination or testing is necessary prior to inser-
intercourse [21, 22]. The most common side effect of cop- tion. The implant is placed in the inner upper arm. It should
per IUDs is an increase in length, discomfort, and/or heavi- be easily palpable, but the device is radio-opaque and can be
ness of menstrual bleeding, although this rarely causes seen on plain films if its location is in question.
significant drops in hemoglobin in previously non-anemic The safety and side effect profile of etonogestrel implants
women [23, 24]. are well studied [35]. Irregular, unscheduled bleeding is the
most common side effect and also the most common reason
Progestin IUDs for discontinuation [35]. The number of bleeding days and
Currently, four progestin-containing IUDs have been spotting is highest in the first 3 months of use and stabilizes
approved in the United States, which release varying during the second and third years of use. After the initial
amounts of levonorgestrel (LNg). Progestin IUDs are bleeding patterns plateau, approximately 20% of women
report amenorrhea. However, a study of 90-day reference Appropriate counseling about side effects of DMPA is
periods demonstrated that 17% of women had bleeding epi- crucial to ensure appropriate contraceptive selection and
sodes lasting longer than 14 days, and 6% had more than five continuation [52]. All women experience menstrual changes.
bleeding episodes. Headaches are reported in up to 16% of In the first few months of use, unscheduled bleeding is very
users. Weight gain averaged around 2.8 pounds after 1 year common and progresses to amenorrhea in nearly 50% of
and 3.7 pounds after 2 years of use and was reported by 12% users by one year [53]. There is some historical controversy
of users. Other notable side effects include acne vulgaris about weight gain with DMPA, but recent data demonstrate
(12%), mastalgia (10%), and abdominal pain (5%). mean weight gain is typically no more than 2 kgs in
There are few medical contraindications to the use of the 12 months [54]. DMPA may also trigger headaches, ner-
etonogestrel implant, with only active breast cancer noted as vousness, and abdominal pain [49]. Concern about bone
an absolute contraindication to use. Other conditions such as demineralization prompted the FDA to issue a warning about
severe decompensated cirrhosis, ischemic heart disease, and prolonged use in adolescents and young adults, but evidence
liver tumors confer risks that likely outweigh the advantages shows there is recovery of bone mineral density after cessa-
of this contraceptive method [7]. Some medications lower tion, and neither ACOG nor the WHO believe the evidence
the effectiveness of the implant, including efavirenz-based should limit the duration of DMPA use or prompt additional
antiretroviral regimen and certain antiepileptics [40–42]. bone mineral density screening [55–58].
Notably, this method has not been studied in women with a Like other progestin-based contraceptives, DMPA is con-
BMI greater than 30 kg/m2, but there is no evidence that traindicated in breast cancer [7]. Other potential contraindi-
effectiveness is compromised in these women [43]. cations include decompensated cirrhosis, liver tumors, and
Although the etonogestrel implant is solely approved for ischemic heart disease.
contraception, some data exist about its use in endometriosis, DMPA has several noncontraceptive benefits owing to its
where it was non-inferior to depot medroxyprogesterone mechanism of action [59]. Heavy menstrual bleeding and
acetate (DMPA) in relief of pain symptoms [44]. There are associated anemia decrease as women trend toward amenor-
no other reported noncontraceptive benefits. The implant is rhea. Endometriosis-related pain and endometrial hyperpla-
not approved for emergency contraception. sia decrease, as well as rates of pelvic inflammatory disease
and cervical cancer. DMPA is not approved for emergency
contraception.
Short-Acting Reversible Contraceptives
Pill
Injectable The “pill” refers to the broad category of contraceptives
Depot medroxyprogesterone acetate (DMPA) is an inject- taken as a daily oral medication. Often the most recognizable
able progestin contraceptive administered subcutaneously method due to its long history and availability, patients will
(104 mcg) or intramuscularly (150 mcg) every 3 months. Its often use the term to refer to any one of many different for-
mechanism of action is similar to that of the implant with mulations. These formulations can generally be broken up
dual progestin effects: cervical mucus changes and inhibi- into two subcategories, progestin-only and combined
tion of ovulation [45]. With perfect use, DMPA is a highly estrogen-progestin pills.
effective contraceptive with a failure rate of 0.2% [46].
However, typical use failure rate is closer to 6%, thought to Progestin-Only Pills (POPs)
be due to late return for repeat injections [46]. Effectiveness Also known as the “minipill,” progestin-only pills are taken
is not decreased due to body weight owing to the high doses daily by mouth. The mechanism of action is similar to the
of circulating progestins [47]. Unlike the previously other progesterone-based methods detailed previously
described methods, DMPA may cause a delay in return to including cervical mucus changes and thinning of the endo-
fertility of several months (up to 18 months in a small sub- metrial lining, but inhibition of ovulation is less consistent
set), and women who would like to become pregnant soon [60]. Efficacy of POPs is significantly affected by user
after discontinuation may want to consider a different dependability as this method requires daily use within a
method [48, 49]. small time window to be effective for pregnancy prevention
DMPA is typically administered in the office, although (typically 3 h) [46]. Even delaying a dose by several hours is
studies suggest self-injection with a subcutaneous formu- enough to risk contraceptive failure. As such, return to fertil-
lation may improve adherence and access [50, 51]. No ity is prompt after discontinuing this method.
testing or physical examination is necessary aside from If a patient misses a pill, she should be counseled to take
ascertaining that a woman is not pregnant. Once injected, it immediately upon remembering (and in addition to any
no monitoring or follow-up is indicated until the next dose also due at that time), and she should use a “backup”
injection at 3 months. method, such as condoms, or avoid sexual intercourse for at
least two days after reinitiation of the pill so that cervical than the risk associated with pregnancy. Most women toler-
mucus has a chance to thicken [6]. No physical exam or labo- ate estradiol doses of 20–35 mcg, and pills >35 mcg are no
ratory tests are indicated at the time of prescription of POPs, longer used for contraception [66, 67]. Generally, it is rec-
and no follow-up is required in the absence of side effects. ommended to use the lowest estradiol dose possible that is
The most prevalent side effect of POPs is unscheduled acceptable for the patient in terms of breakthrough bleeding
bleeding and spotting [61]. There is an increased prevalence and side effects.
of follicular ovarian cysts, and women should be reassured Progestin components are often categorized by genera-
that no intervention is required [62]. POPs do not lead to tion. Second-generation progestins (such as levonorgestrel
weight gain [54]. and norethindrone) are the most androgenic and may cause
There are few contraindications to POPs though breast adverse metabolic effects. Third-generation progestins (such
cancer is an “absolute” contraindication [7]. Similar to other as norgestimate) have fewer androgenic properties but may
progestin-based contraceptives, liver tumors and decompen- be associated with a slightly increased risk of VTE [68].
sated heart disease are relative contraindications. Progestin- Fourth-generation progestins (most famously drospirenone)
only pills are typically used in women who have are considered antiandrogenic but have also been associated
contraindications to estrogen use but desire a pill form of with an increased risk of VTE [69]. Without compelling rea-
contraception. POPs appear to have a protective effect sons to push for fourth-generation progestin use, such as
against endometrial cancer [63]. severe acne likely to benefit from antiandrogenic properties,
most providers will select second- or third-generation
Combined Oral Contraceptive Pills (COCs) progestins.
Estrogen-progestin pills are also taken daily by mouth. COCs The type and frequency of side effects of COCs relate to
have several mechanisms of action contributing to their con- their estrogen content and type of progestin. Early side
traceptive effects including suppression of gonadotropin- effects including headache, mastalgia, and nausea typi-
releasing hormone and inhibition of the luteinizing hormone cally improve within the first few months [70].
(LH) surge, thereby preventing ovulation [64]. In addition to Breakthrough bleeding is common and expected for the
these estrogen effects, COCs also benefit from the progestin- first few months; after 3 months, an increase in the dose of
related contraceptive actions as detailed above in the POP estradiol may be considered to decrease breakthrough
section. COCs have a perfect-use failure rate of 0.1%; bleeding [66]. There is a small increase in blood pressure
however, this number rises to 8% with typical use as efficacy and incidence of myocardial infarction [71]. For this rea-
relies on daily use and prompt refills [46]. son, women with a history of heart disease and those over
In the event of missed pills, women should be counseled 35 who smoke should not be prescribed COCs [72].
to take the missed dose as soon as is remembered (and in However, pregnancy also elevates these risks, so providers
addition to any dose otherwise due) [6]. If two or more doses should consider risk-benefit counseling in women who
have been missed, she should also be counseled to use may not be open to other, potentially safer contraceptive
backup contraception or avoid sexual intercourse for seven options. Migraines with aura are also considered contrain-
days. COCs may be prescribed monthly (21 active pills fol- dications to COC use as these women are at increased risk
lowed by 7 placebo pills) or with extended cycling (84 active of stroke [73]. History of VTE is an absolute contraindica-
pills followed by 7 placebo pills) for fewer withdrawal bleeds tion given the already known increased risk of VTE across
[65]. Blood pressure should be checked before initiation and all COCs. The increased risk of VTE appears to be
then at routine care [6]. However, in the absence of side increased severalfold in obese women [74]. Other contra-
effects, no additional follow-up is necessary other than rou- indications include any pro-thrombotic states, acute liver
tine care. disease, and undiagnosed vaginal bleeding [7]. As with all
There are a multitude of COC formulations, and options hormonal contraceptives, breast cancer is an absolute
available to each patient may vary based on their insurance contraindication.
formulary. When selecting a COC, a provider must make Although estrogen-containing pills are not contraindi-
decisions about both the estrogen and progestin components. cated during lactation, they have been inconsistently impli-
The estrogen is typically ethinyl estradiol and can be dosed cated in decreasing milk supply [75]. As such, different
from 10 mcg to 35 mcg per day. Women experience more contraception methods may be more appropriate in postpar-
breakthrough bleeding at the lower end of the dosing spec- tum women who are breastfeeding [6].
trum and more estrogenic side effects such as mastalgia, nau- There are many noncontraceptive benefits associated with
sea, and bloating at the higher end of the spectrum. the use of COCs [76], including reducing hirsutism, acne,
Additionally, there is theoretical higher risk of venous throm- menorrhagia, dysmenorrhea, endometriosis pain, and symp-
boembolism (VTE) with higher estrogen doses, although the toms of premenstrual syndrome. While only some COCs
absolute risk of VTE is low for most women and far lower carry a specific FDA approval for acne reduction, this benefit
is mediated via estrogen’s role in increasing sex- Nonhormonal/Barrier Methods

hormone-binding globulin production from the liver and so
may be seen with any COC formulation. COCs may also These methods are considered to have lower efficacy for
help control bleeding secondary to fibroids. Finally, COCs pregnancy prevention. However, they are often easily avail-
use is associated with a decrease in rates of colon cancer, able and may be appropriate for women whose goals or con-
endometrial cancer, and ovarian cancer. traindications make the previously described methods less
desirable. All of these methods are quickly reversible and do
Transdermal Patch not cause a delay in return to fertility.
The “patch” is a transdermal combined hormonal contracep-
tive containing ethinyl estradiol and norelgestromin. Its Male Condom
mechanism of action is the same as that of COCs. The trans- Male condoms are made from one of three types of mate-
dermal patch is applied weekly for 3 consecutive weeks rial: latex, natural membrane, and synthetic (typically
(21 days total) to the abdomen, upper arm, or buttock, fol- polyurethane). They may contain spermicide or lubricant
lowed by a patch-free week to facilitate a withdrawal bleed. (or neither). Almost all studies have been conducted on
Some women may be interested in extended use, where the latex condoms. Used alone, condoms have around an 18%
patch-free week and withdrawal bleed are skipped. Backup failure rate with typical use versus 2% with perfect use
method should be used if a patch is not replaced within [46]. Mechanism is based on barrier protection with or
2 days of a scheduled switch date [6]. without spermicidal effects depending on the type of con-
The efficacy, return to fertility, side effects, contraindi- dom used.
cations, and noncontraceptive benefits of the transdermal Male condoms are easily obtained without a prescription
contraceptive patch are similar to those of COCs [77, 78]. at any number of places including pharmacies, grocery
Some women develop irritation at the site of the patch, par- stores, and gas stations. They are relatively inexpensive
ticularly those with a history of sensitive skin. There is (often less than a dollar per condom) and can be easily car-
some concern about slightly increased risk of thrombosis ried by both men and women. Disadvantages of male con-
(approximately twofold) in patch users compared to COCs dom use include disruption of sexual activity, decreased
[79]. Finally, obese women may have higher rates of con- sensation reported by some men or women, and sometimes
traceptive failure [80]. improper fit [84]. They may require counseling to ensure
effective use. In addition, women opting to rely on male con-
Vaginal Ring dom use for contraception must have partner cooperation
The “ring” is a vaginal-combined contraceptive containing and support.
ethinyl estradiol and etonogestrel. The systemic estrogen The main contraindication to typical condom use is a
absorption is lower than other combined contraceptives [81]. latex sensitivity, although men can switch to synthetic mate-
It is self-inserted into the vagina, left in for 3 weeks, and then rial or natural membrane. In addition, latex condoms should
removed for a withdrawal bleed for 1 week before a new one not be paired with oil-based lubricants.
is reinserted. Some women also opt for continuous use where Noncontraceptive benefits of condoms include STI pro-
women replace the ring without allowing for the week of tection. Unlike previously described methods, condom use is
withdrawal bleeding [82]. If the ring is accidentally taken the only strategy that serves as both contraception and pro-
out, the US SPR has a detailed algorithm about management tection against STI [85]. As such, it should be paired with
depending on time since removal [6]. any of the other methods if STI protection is desired in addi-
The other characteristics of this contraceptive method tion to contraception. Of note, natural membrane condoms
(including return to fertility, efficacy, side effects, contraindi- are more porous and may not carry the same STI protection
cations, and noncontraceptive benefits) are similar to those that latex and synthetic condoms do [86]. Patients should be
of COCs [78]. In addition, ring users may have an increase in counseled not to rely on natural membrane condoms for STI
vaginal discharge and vaginitis. protection.
Of note, a new combined hormonal contraceptive ring
(Annovera™) was recently approved by the FDA, although Internal Condom
it is not yet available for prescription. Containing ethinyl The internal (or “female”) condoms can be made of natural
estradiol and segesterone acetate, it is intended to last thir- latex, synthetic latex, and polyurethane. They have an outer
teen 28-day cycles (3 weeks inserted, 1 week removed) [83]. ring that anchors them in place and cover the cervix, vagina,
It is expected to carry the same risks and benefits as previ- and introitus. Annual failure rates are around 21% with typi-
ously approved combined hormonal contraceptive methods, cal use (5% with perfect use) [87]. They may be more diffi-
but the extended duration of use may facilitate continuation cult to obtain due to low prevalence of use (less than 1% of
and adherence. manufactured condoms are internal) and are more expensive
(usually around 2 dollars per condom). Mechanism of action, Sponge

contraindications, and STI protection benefits mirror those The sponge is a spermicidal-impregnated polyurethane
of male condoms. matrix available over the counter. It contains nonoxynol-9
which is activated when the sponge is wetted. The mecha-
Spermicide nism of action is similar to that of diaphragms, although fail-
The only spermicide available in the United States is non- ure rates are closer to 24% for multiparous women (12%
oxynol-9 (N-9), a chemical that impairs sperm motility by among nulliparous women) [46]. The sponge is self-inserted
damaging the body and flagella. Spermicide is available over up to 24 h before intercourse and should be removed 6 h after
the counter in many formulations including foam, gel, cream, the last episode of intercourse. In all, the sponge should be
and suppository. It costs between 60 cents and $3 per dose. removed within 30 h of insertion. It is single use and should
Typical use failure rate is nearly 20% per year when used be discarded after removal. Each sponge costs approximately
alone [88]. 5 dollars.
Spermicide should be applied to the vagina prior to each Relative contraindications and side effects mirror those of
episode of intercourse (at least 10 min prior for the supposi- the diaphragm. Allergy or sensitivity to polyurethane, N-9,
tory to allow for dispersion). Intercourse should not be and sulfa should preclude use.
delayed longer than an hour without reapplication.
Relative contraindications include allergy to nonoxynol-9 Fertility-Awareness-Based Method
and use in women who are at high risk of STI (particularly With these methods, women track changes in the menstrual
HIV) transmission [89]. N-9 use appears to be associated cycle to avoid pregnancy [95]. Also called “natural family
with higher rates of HIV acquisition, potentially due to planning,” these methods involve identifying the date of ovu-
spermicide-induced mucosal irritation [90]. Side effects lation and the associated days of fertility and abstaining from
include vaginal (and penile) irritation, increased UTI fre- intercourse or using alternative methods of contraception
quency, and slight increase in rates of bacterial vaginosis [88, during those days. Conversely, these methods can also be
91, 92]. used to assist in conception. With perfect use, annual preg-
nancy rates are between 3% and 5%, but with typical use,
Diaphragm pregnancy rates are closer to 24% annually [96]. Some
This is a reusable cup-shaped device that a woman places described methods include standard days (SDM), 2 days
against her cervix. It is used in conjunction with spermicide, (TDM), and symptothermal. For patients who desire addi-
and its mechanism of action is primarily spermicidal in additional information about fertility awareness methods, a num-
tion to creating a barrier to block sperm from entering the ber of Web-based resources including bedsider.org (https://
cervix. Failure rates approach 12% per year with typical use, www.bedsider.org/methods/fertility_awareness#how_to)
although the failure rate appears to be highest in multiparous and plannedparenthood.org (https://www.plannedparent-
women [46]. Most diaphragms must be fit to the patient, hood.org/learn/birth-control/fertility-awareness) can provide
typically by a gynecologist, but at least one type (commer- more details [97, 98]. Smartphone applications are also
cial name Caya) is considered single size and can be pur- available, including Natural Cycles™, which has been
chased directly from a pharmacy. Diaphragms are typically granted FDA approval.
covered by insurance when prescribed and fitted by a
provider. Withdrawal
Women are taught to insert their diaphragm with spermi- The withdrawal method involves the male partner pulling out
cide prior to intercourse. It should then remain in place at his penis prior to ejaculation to keep semen out of the vagina.
least 6 h from the last episode of intercourse but no more This method can be up to 96% effective with perfect use, but
than 24 h. patients should be counseled that typical use results in annual
Relative contraindications to diaphragm use include fre- pregnancy rates up to 22% [46]. In addition, this method
quent UTIs, allergy to the components (silicone or latex), requires trust and reliance on a woman’s partner, so partner
history of toxic shock syndrome, and any contraindications support is essential in selection of this method.
to spermicide use (see section on spermicide). Side effects At the time of writing, the Affordable Care Act (ACA)
and complications include increased risk of UTI, likely sec- mandates that at least one form of all FDA-approved meth-
ondary to spermicide-induced changes in the vaginal flora, ods (and emergency contraception) be covered by health
vaginal irritation, and toxic shock syndrome (TSS) [93, 94]. insurance plans provided by all employers and educational
TSS is rare and almost exclusively associated with >24 h of institutions with no cost sharing. This excludes male birth
continuous use. control including male condoms and vasectomies.
Contraceptive Counseling Strategies Family planning experts and guidelines, including the
CDC’s Quality in Family Planning, have promoted
approaches that optimize patient centeredness, both in terms
of how women prefer to make contraceptive decisions and
You prepare to counsel Jenna about her options and
with regard to method selection itself [107, 108]. While
consider the best approach to help her in selecting the
some patients may prefer to make fully autonomous deci-
right method for her needs.
sions (consumerist model) and others may prefer to have
their providers make strong recommendations (directive
model), research has indicated that most women prefer a
If reproductive goals counseling determines that the shared decision-making approach [109]. Shared decision-
patient has a contraceptive desire or need, the next step is to making combines features of both patient-driven and
engage in counseling to guide method selection. Similar to provider-driven approaches to allow a provider to guide a
reproductive goals counseling, there are multiple frame- woman to the best method based on her individual context.
works to approach contraceptive counseling. Common coun- Shared decision-making is a strategy that can help enhance
seling strategies can be broadly grouped into consumerist patient centeredness when selecting a contraceptive method
models (patient-driven), directive models (provider-driven), because it explicitly centers the discussion around a wom-
or a shared decision-making approach [99]. an’s preferences and priorities for method characteristics. To
Within the consumerist model, there are two main achieve successful shared decision-making, a number of fac-
approaches observed in clinical practice, both of which pri- tors must be considered to guide patients in selecting the best
oritize patient autonomy [100]. In an “informed choice” method for their needs.
model, the provider shares objective information about vari-
ous methods but does not participate in the selection itself.
The downside of this model is that the provider does not nec- Preferred Efficacy
essarily help patients understand how their preferences relate
to method characteristics, and the information shared is not Given that ambivalence is common, efficacy is not always
tailored to the specific needs of the patient. In a “foreclosed” the most important factor guiding women’s contraceptive
model, the provider shares information only about methods decisions. Thus, rather than assuming that all women will
asked about by the patient. A limitation of this model is that prioritize efficacy, providers should ask women whether this
women may not have a complete or accurate picture of the is something they value. Questions about importance of effi-
range of all available methods. cacy should also elicit ideal frequency of use of the method.
In directive counseling, providers conduct counseling Particularly because non-LARC methods have different effi-
with the goal of promoting a specific course of action. For cacy based on patient adherence, it is crucial to elicit whether
example, there has been a strong push toward LARC selec- a woman prefers and can adhere to frequent use, such as
tion given its high effectiveness, with references to these daily pills or weekly patches. A woman who reports wanting
methods as “first line” by the American Academy of effective contraception above all would likely benefit from a
Pediatrics (AAP) and ACOG [101, 102]. However, in LARC method, especially if she reports difficulty in adher-
encouraging adoption of these methods, providers may be ing to prescribed medication schedules (e.g., erratic work
making assumptions about a patient’s priorities rather than hours may interfere with remembering to take a daily pill at
attending to the fact that women have many different goals, the same time every day).
preferences, and needs when it comes to their contracep-
tion. “Encouragement” to select specific methods, espe-
cially when they do not align with stated preferences, can Preferred Side Effect Profile
thus be perceived as pressure and be counterproductive
[103–105]. This may be particularly problematic in mar- To optimize success with a selected contraceptive method, it
ginalized communities, given the history of family plan- is crucial to adequately elicit a patient’s preference or toler-
ning abuses targeting low-income women and women of ance regarding side effects [104, 110]. Certain side effects
color. One recent qualitative study explored patient experi- may be tolerable to some patients while leading to discon-
ences with implicit pressure, in which providers’ subtle tinuation for others. This particularly applies to menstrual
cues appeared to favor certain contraceptive methods [106]. changes, as can be illustrated by the levonorgestrel
The young women of color included in the study had high IUD. Some women desire amenorrhea, while others prefer
rates of rapid discontinuation of chosen methods, with monthly menses and would be better served selecting a
some patients curtailing future health-care visits and subse- method that does not affect their menstrual cycle [111].
quent contraceptive use. Providers should make sure to assess women’s understand-
ing of the safety of amenorrhea with contraception when avoidance of side effects over efficacy. Focusing on the
women state a preference for having menstrual cycles. Even methods that a woman will use successfully based on her
if amenorrhea is desired, some women may not tolerate the preferences can optimize method satisfaction, adherence,
unscheduled bleeding often seen in the initial months or may and continuation.
want to avoid it at particular times in their lives [112]. Only Finally, contraception counseling should not exclude ster-
eliciting such preferences allows a thorough discussion ilization procedures, particularly in women who have com-
regarding the experience with each method and appropriate pleted or do not desire childbearing. Both female and male
selection. sterilization should be explored in appropriate patients as
permanent contraceptive choices if desired.
Pattern of Sexual Activity

I nitiating Contraception and Facilitating
This information may also help a provider guide a patient’s Adherence
decision; a woman who is sexually active once a year may
have a different view of risk/benefit profiles of various meth-
ods compared to a woman who is sexually active weekly or
Jenna shares that she has trouble remembering to take
daily. Similarly, number of partners or relationship status
medications on a daily basis. She is reluctant to have a
may affect their preferred contraceptive profile.
procedure for insertion of a contraceptive device.
Given that she has a history of migraines with aura,
you recommend avoiding estrogen-based methods
Need for Privacy
(such as the vaginal ring or transdermal patch). Based
on this discussion, Jenna selects medroxyprogesterone
Providers should also inquire about a woman’s need for pri-
injections.
vacy as some women may need to select methods based on
discreetness and ability to conceal use [113–116].
Reproductive coercion (behavior to control contraception
and pregnancy outcomes of sexual partners) has been identi- When a woman selects a contraceptive method, the next
fied in up to 16% of relationships, with intimate partner vio- steps are to ensure adequate initiation and help patients opti-
lence co-occurring in 32% of these relationships [117] (see mize adherence. The first step is to ensure that a woman is
Chap. 35 on “Intimate Partner Violence and Sexual Trauma” not currently pregnant. A set of criteria has been developed
for additional information). The use of discreet contraceptive by the CDC to assist providers in ascertaining patients’ preg-
methods has been identified as a potential harm reduction nancy status [6] (Fig. 4.1). The use of these criteria is par-
strategy for women in abusive relationships. If a woman ticularly important when initiating hormonal methods or the
voices a preference or need to keep her contraceptive use copper IUD.
hidden, medroxyprogesterone injection may be a good Once pregnancy is reasonably ruled out, methods can be
option. Alternatively, an IUD can be inserted and the strings prescribed or inserted. Using the “quick-start” method is the
trimmed to the level of the cervical os or canal, making them current standard of care to optimize initiation and adherence
nearly invisible. Depending on the exact circumstances, [6]. “Quick-start” allows that any method can be started on any
other methods may or may not be appropriate. day of a woman’s menstrual cycle so long as backup methods
are used for 7 days after initiation. Notable exceptions to the
7-day rule include progestin-only pills which require only
Desired Return to Fertility 2 days of a backup method and copper IUDs which are imme-
diately effective and require no backup method.
Timeline to desired pregnancy may also affect the appropriate- Once a method is started, there are steps a provider can
ness of various methods. For example, medroxyprogesterone take to improve adherence and continuation. Providing the
injection is unlikely to be an appropriate method to recom- maximum number of months of contraceptive methods at a
mend to a patient who desires pregnancy within a year, given single fill (e.g., dispensing 3 or 12 months of medication at
that the delay in return to fertility can be up to 2 years [48, 49]. one time) has been demonstrated to improve continuation
Depending on the preferences elicited regarding the above and adherence [118]. This has prompted laws in twelve states
factors and medical contraindications, providers should and the District of Columbia mandating that pharmacies dis-
adjust the scaffolding that they offer patients for decision- pense (and insurances pay for) a 12-month supply at each fill
making. For example, the commonly used tiered-effectiveness if desired by the patient. In addition, while annual visits are
scaffold may not be appropriate for a patient who values recommended, there is no role for refusing to prescribe con-
traception for a patient who is not up to date on cervical can- once the LH levels have begun to rise (and levonorgestrel is
cer screening or who has not had a pelvic examination [119]. no longer effective) [127]. It may be taken up to 120 h after
This is highlighted in the AAFP’s “Choosing Wisely” recom- unprotected intercourse. Ulipristal has a failure rate of 1.4%
mendations [120]. or prevents approximately two-third of expected pregnancies
Finally, it is important that providers ensure timely access [123, 124]. While less effective in obese women, ulipristal is
for removal of provider-controlled methods such as IUDs more effective than levonorgestrel EC; for obese patients
and subdermal implants, especially when women would like desiring oral EC, ulipristal is the preferred agent [128]. Of
early removal of their device. Counseling regarding discon- note, access to ulipristal remains limited, with one study
tinuation and removal should be provided at the time of finding less than 10% of pharmacies having the ability to
initiation. immediately fill a prescription [129]. Providers prescribing
ulipristal should consider verifying pharmacy availability at
the time of prescription.
Emergency Contraception and Abortion
Yuzpe Regimen
Emergency Contraception This regimen was introduced in 1974 and allows women to
take a combination of pills from standard COC prescriptions
Emergency contraception (EC) refers to contraception used to reach a dose of 200 mcg of ethinyl estradiol and 1 mg
after unprotected intercourse to minimize the chance of levonorgestrel [130]. In certain areas or for privacy reasons,
unwanted pregnancy. There are various methods that can be this method may be more accessible for patients than other
used for emergency contraception. More information can be EC methods. It should be initiated within 72 h of unprotected
obtained through US SPR or the Princeton Emergency intercourse. It is less efficacious than other methods and has
Contraception website [6, 121]. more side effects (nausea, vomiting, headaches, mastalgia)
due to the high estrogen dose, so it is rarely recommended
Copper IUD when other methods are available [123]. Non-levonorgestrel
The copper IUD is the most effective form of emergency progestins have not been studied.
contraception (96.9–100% effective), although it remains All women should be counseled about emergency contra-
off-label for EC use in the United States [21]. The device ception, regardless of whether they are using another method
should be inserted within five days of unprotected inter- of contraception [131]. Some women may only need EC in
course and may remain in place as long as desired (up to the case of contraceptive failure, while some may actually
10 years) for contraception. prefer to rely on EC for contraception, particularly if they
have infrequent intercourse or contraindications to more
Levonorgestrel effective methods. As all of these methods must be initiated
More commonly known as Plan B™, levonorgestrel is avail- within 72–120 h of unprotected intercourse for efficacy, it is
able with or without a prescription. It should be covered by reasonable to counsel women about the use of EC and to
insurance when obtained by prescription; however, insur- make it available to them prior to needing it [6]. Exploring a
ance reimbursement is more variable when purchased over woman’s preferred EC method and providing advance pre-
the counter (non-covered cost is approximately $40). The scriptions help improve access and use should they have
mechanism of action is thought to be a delay in ovulation unprotected intercourse [131]. This practice may also help to
[122]. Levonorgestrel has a failure rate of 2–3% when used defray costs for those with insurance as prescription levo-
within 72 h of unprotected intercourse, which equates to a norgestrel EC is covered, but over-the-counter formulations
theoretical decrease of 50% in expected pregnancies [123, may not be. Advance prescriptions do not increase the rate of
124]. Levonorgestrel may be taken as one dose (1.5 mg sin- unprotected intercourse.
gle tablet) or two doses (0.75 mg tablets taken 12 h apart), According to ACOG, no follow-up visit is routinely
although the former is recommended due to increased conve- required after the use of EC. A pregnancy test should be
nience without compromising efficacy or increasing side obtained if no bleeding occurs within 3–4 weeks of taking
effects [125]. Obese women (BMI > 30 kg/m2) have a four- EC [131].
fold risk of pregnancy compared to underweight and normal
weight women and should be counseled about the limitations
of this method [126]. Abortion
Ulipristal Elective termination, also known as induced abortion, is an

Ulipristal is an antiprogestin medication available by pre- option available to women in the United States, although
scription only. It is effective by delaying ovulation, even there is significant variability in access and options depend-
ing on the patient’s location. There are two categories of Table 4.1 Starting specific contraceptive methods [6]
elective terminations: medical and surgical abortions. Both Backup
options are safe and effective in appropriate patients, and the Method method Before initiationa
choice is typically made based on gestational age, availabil- Copper IUD Not Bimanual examination and
needed cervical inspection
ity, and patient preference [132].
Levonorgestrel IUD 7 days Bimanual examination and
Medical abortion is the termination of a pregnancy with cervical inspection
medications alone, typically using mifepristone (an antipro- Implant 7 days None
gestin) combined with misoprostol for patients in the United Injectable (DMPA) 7 days None
States. Patients are given the initial dose of medication in a Combined hormonal 7 days Blood pressure
health-care facility and then return home for the ensuing contraception measurement
days while the termination occurs. Medical abortion is avail- Progestin-only pill 2 days None
able until a gestational age of 70 days based on the first day Adapted from Curtis et al. [6]
a
Must also be reasonably certain that a woman is not pregnant by meet-
of the last menstrual period or ultrasound dating. Medical
ing any one of the following criteria: is ≤7 days after the start of nor-
abortion comprises approximately 22% of abortions at mal menses; has not had sexual intercourse since the start of last
≤8 weeks and 1.2% of abortions at >8 weeks [133]. The suc- normal menses; has been correctly and consistently using a reliable
cess rate of medical abortion is 92–98%, with the other 2–8% method of contraception; is ≤7 days after spontaneous or induced
abortion; is within 4 weeks postpartum; is fully or nearly fully breast-
requiring surgical evacuation [134]. Side effects include
feeding (exclusively breastfeeding or the vast majority [≥85%] of feeds
cramping, nausea, and vomiting. Significant complications are breastfeeds), amenorrheic, and <6 months postpartum (CDC SPR)
are rare (0.65% of women) and include endometritis, infec-
tions, and hemorrhage (secondary to uterine atony or retained
products of conceptions) [135]. Contraindications to this We recommend exploring acceptability of elective termi-
method include the presence of a hemorrhagic disorder or nation particularly for women who indicate that it is impor-
anticoagulation. Advantages of medical abortion over surgi- tant for them to avoid pregnancy but are not using
cal abortion are the decreased amount of time in clinical set- contraception or effective contraception. In addition, abor-
tings and, for some patients, the feeling that they have a tion access and acceptability should be explored among
higher degree of control over the process [136]. Acceptability women with chronic medical conditions that would be nega-
of this method is high (nearly 82% satisfaction), and 81% tively impacted by pregnancy (or vice versa) and women
would choose the same method if a future abortion was using teratogenic medications who decline contraception or
required [137, 138]. effective methods (Table 4.1).
Surgical abortion techniques vary depending on gesta-
tional age. In the first trimester, the procedure is typically
uterine dilation and suction aspiration. The procedure is per- Summary Points
formed in a clinical setting (including outpatient or free-
standing clinics), and termination is completed prior to 1. The use of standardized questions, such as One Key
patients returning home. Successful termination occurs in Question or the PATH questions, can help identify wom-
>95% of cases of surgical abortion with complication rates en’s reproductive goals and need or desire for contracep-
of approximately 9 per 1000 [134, 139]. Major complication and contraceptive counseling.
tions are rare (0.71 per 1000) and include perforation, infec- 2. Numerous contraceptive options are available to patients,
tion, cervical laceration, hemorrhage, and retained products including long-acting reversible contraceptives (IUDs,
of conception [139]. There are no true contraindications to implants), short-acting reversible contraceptives (pills,
surgical abortion; however, in women with large fibroids or patches, and rings), and barrier or nonhormonal methods.
other anatomic abnormalities, medical abortion may be pre- 3. When counseling about contraception, patient prefer-
ferred if gestation is <10 weeks given potentially complicat- ences about method characteristics including effective-
ing anatomy. Advantages of surgical abortion over medical ness, menstrual changes, and relevant side effect profiles
abortion include more rapid confirmation of successful ter- should guide the conversation to help patients select the
mination and higher patient satisfaction (92%) [137]. most appropriate method for them.
Providers should feel comfortable counseling women 4. The CDC MEC is a reliable resource to identify contrain-
about where to seek abortion services if a patient wishes to dicated methods of contraception in various medical
learn about or desires an abortion. These services include comorbidities.
intra-institutional resources, free-standing clinics, and/or 5. Contraceptive counseling should include counseling
Planned Parenthood. The local family planning division of regarding options in the case of contraceptive failure and
OB/GYN may also be able to provide additional local private exploring attitudes toward and providing appropriate
options. resources regarding EC and abortion.
Review Questions concerns, she may have a difficult time using these meth-
ods reliably, though these options should still be explored
1. A 36-year-old woman presents for her annual visit. She with her. Finally, male condoms are the least effective of
reports being sexually active with one male partner for the above methods and thus would not be the best single
the last 6 months. She is not currently using contracep- method for contraception, given her priority of avoiding
tion. Which of the following is a patient-centered ques- pregnancy. However, this patient should be counseled that
tion to assess reproductive goals and preferences? condoms are the only method that prevents STI transmis-
A. “Are you trying to become pregnant?” sion and can be used in conjunction with any of the other
B. “Would you like to become pregnant in the next methods [140].
year?”
C. “Can we start you on birth control?” 3. A 27-year-old woman presents for an annual physical
D. “Why are you not using contraception?” complaining of worsening acne. Her physical exam
The correct answer is B. “One Key Question” is one reveals cystic acne on her temples and chin. She is sexu-
recommended approach for eliciting reproductive goals. It ally active with one male partner, and they are using con-
is a potential first step to open conversations about repro- doms. She reports that she would really like to get her
ductive desires, intentions, or concerns. It may help discern acne under control. Menstrual history reveals irregular
the need for preconception counseling and/or contracep- periods, averaging approximately five menses per year.
tion counseling. “Are you trying to become pregnant?” Which of the following might be an appropriate
assigns intentions to the patient that she has not expressed, recommendation?
and this assumption may feel judgmental to a patient who A. Medroxyprogesterone injection (e.g.,
may not be actively trying to conceive despite not using Depo-Provera™)
regular contraception. Similarly, “why are you not using B. Levonorgestrel intrauterine implant (e.g., Mirena™)
contraception?” may indicate judgment from the provider C. Norgestimate/ethinyl estradiol COCs (e.g., Sprintec)
of what the patient should be doing, prior to clarifying her D. Etonogestrel subdermal implant (e.g., Nexplanon™)
intentions. Finally, “can we start you on birth control?” The correct answer is C. This patient seems to be suf-
assumes the patient is interested in preventing pregnancy at fering from hormonal acne and oligomenorrhea, which
this time, which she may not yet have expressed [5]. could be suggestive of PCOS. Combined oral contracep-
tives (COCs) have been demonstrated to have noncontra-
2. A 21-year-old college student presents to clinic. She has ceptive benefits that include improvement of acne, and
recently become sexually active and reports that her high- they can also regulate menses, decreasing unopposed
est priority in choosing a contraceptive method is avoid- estrogen and associated endometrial cancer risk.
ing pregnancy. She often forgets to take medications like Levonorgestrel intrauterine implants, etonogestrel sub-
antibiotics, so would prefer a method that she doesn’t dermal implants, and medroxyprogesterone injections
have to think about too much. She does not have any med- have not demonstrated to have any benefits for acne or
ical comorbidities and does not want to become pregnant PCOS and would not be particularly beneficial in this
in the next few years. Which of the following methods patient [141].
will likely best match her stated preferences?
A. Levonorgestrel intrauterine implant (e.g., Mirena™) 4. A 38-year-old woman with a history of complex
B. Male condoms migraines presents to the office with worsening menor-
C. Medroxyprogesterone injection (e.g., Depo-Provera) rhagia. Since menarche, she has had painful heavy peri-
D. Etonogestrel/ethinyl estradiol vaginal ring (e.g., ods, once requiring admission for a transfusion. She has
NuvaRing™) been missing work due to her menses and is desperate to
The correct answer is A. This patient is expressing try something to lighten or eliminate them. She is not
preferences that match with long-acting, highly effective sexually active and does not want any more children.
contraceptive. She would benefit from counseling about She is not interested in surgery as it would mean missing
LARCs, either an intrauterine implant or a subdermal more work. Which option will decrease her bleeding and
implant. She would be an excellent candidate for an intra- pain the most?
uterine implant given her reported difficulty in adherence A. Etonogestrel implant (e.g., Nexplanon)
to medications. The vaginal ring and medroxyprogester- B. Combined oral contraceptive cycled continuously
one injection are considered less effective than LARCs, C. Levonorgestrel intrauterine implant (e.g., Mirena)
and their efficacy depends on reliable timing of the medi- D. Medroxyprogesterone injection (e.g., Depo-Provera)
cations (monthly and every 3 months, respectively). Since The correct answer is C. This patient’s menorrhagia
she endorses missed medication doses even for short-term would best be managed with levonorgestrel intrauterine
device since most women experience amenorrhea or at 3. Johnson K, Posner SF, Biermann J, Cordero JF, Atrash HK,
least a decrease in bleeding days and severity on this con- Parker CS, et al. Recommendations to improve preconception
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Menstruation and Secondary
Amenorrhea 5
Rachel S. Casas and Cynthia H. Chuang
Secondary amenorrhea is defined as the absence of men-

Learning Objectives ses for three cycles or 3 to 6 months in previously menstruat-
1. Differentiate the clinical presentations of physio- ing women [1]. Primary amenorrhea is the absence of onset
logic, hypothalamic/pituitary, ovarian, and struc- of menses at age 15 for women with secondary sexual char-
tural causes of amenorrhea. acteristics (breast enlargement, body hair, hip widening) or
2. Describe an approach to diagnostic testing in a at age 13 in women without secondary sexual characteristics
patient with secondary amenorrhea based upon sus- [1]. Important causes of primary amenorrhea are congenital,
pected etiology. leading to hormonal dysregulation and anatomical dysgene-
3. Formulate a treatment plan to manage secondary sis at the level of the hypothalamus (Kallmann syndrome),
amenorrhea and associated health risks based upon gonads (Turner syndrome), uterus (Mayer-Rokitansky-
diagnosis. Kuster-Hauser syndrome, androgen insensitivity syndrome),
4. Identify when a patient with amenorrhea should be outflow tract (transverse vaginal septum, imperforate
referred to a subspecialist for advanced diagnostic hymen), or entire reproductive tract (5-alpha reductase defi-
testing or treatment. ciency). As it is unusual for women to present to adult pri-
mary care with a new diagnosis of primary amenorrhea, the
remainder of this chapter will focus on secondary
amenorrhea.
Rosalia is a 35-year-old woman who presents to pri-
mary care clinic with no menses for the past 6 months.
She underwent menarche at age 14 with regular men- Epidemiology
ses until a year ago when her cycles started to occur
less frequently. The prevalence of secondary amenorrhea is approximately
3–5% of women worldwide [2–4]. After excluding preg-
nancy, the most common causes of secondary amenorrhea
are hypothalamic suppression (34%), polycystic ovary syn-
drome (PCOS) (28–73%), hyperprolactinemia (13–15%),
primary ovarian insufficiency (POI) (12%), thyroid dysfunc-
tion (2–15%), and Asherman syndrome (7%) [3, 5, 6]. About
1% of women are affected by POI before age 40, with inci-
dence rates of about 10 per 10,000 person-years in women
ages 15–29 and 76 per 10,000 person-years in women ages
30–39 years [7].
R. S. Casas (*) ∙ C. H. Chuang

Division of General Internal Medicine, Penn State Milton S.

72 R. S. Casas and C. H. Chuang
Female HPG Axis Physiology
The majority of secondary amenorrhea is caused by hor-

monal dysregulation of the hypothalamic-pituitary-gonadal
(HPG) axis (Fig. 5.1). Normally, gonadotropic-releasing
Hypothalamus hormone (GNRH) released by the hypothalamus stimulates
+ release of FSH and luteinizing hormone (LH) from the ante-
GnRH rior pituitary, which then stimulate estrogen and progester-
one release from the ovaries. Estrogen and progesterone
Anterior provide regulatory feedback to the HPG axis at the levels of
pituitary the hypothalamus and pituitary.
Hormones of the HPG axis regulate menstruation
– + + (Fig. 5.2). In the early follicular phase, a rise in FSH stimu-
– + lates recruitment of ovarian follicles and increased estrogen
LH FSH production. Estrogen at first stimulates follicle growth and
+
endometrial proliferation and suppresses LH release in the
follicular phase. Once estrogen rises to higher levels, it trig-
Ovaries gers an LH surge and release of an oocyte from the follicle
(ovulation). In the luteal phase, the follicle transforms into a
+ corpus luteum which produces estrogen and progesterone,
preparing the endometrial lining for potential implantation.
Estrogen Progesterone
The corpus luteum atrophies if not fertilized, and the subse-
quent decrease in progesterone stimulates menstruation.
Hormonal dysfunction leading to disruption of the men-
Fig. 5.1 Hypothalamic-pituitary-gonadal (HPG) axis in women strual cycle can occur at any level of the HPG pathway.
(Reprinted from Hiller-Sturmhofel and Bartke [8])
Fig. 5.2 The normal

menstrual cycle [9] (Source:
Histology
Ovarian
This Wikipedia and

Wikimedia Commons image
is from the user Chris 73 and Maturing Corpus Degenerate
Follicle Ovulation
Follicle Luteum C. Luteum
is freely available at
//commons.wikimedia.org/
wiki/File:MenstrualCycle.png 37ºC
under the creative commons Body Temperature
cc-by-sa 3.0 license)
36ºC
Luteinizing Hormone
Estradiol Progesterone
Follicle-Stimulating
Hormones
Hormone
Follicular Phase Luteal Phase

Ovulation
Menstruation
Endometrial
Histology
1 3 5 7 9 11 13 15 17 19 21 23 25 27
2 4 6 8 10 12 14 16 18 20 22 24 26 28
Day of Menstrual Cycle
(Average values. Durations and values may differ between
different females or different cycles.)
5 Menstruation and Secondary Amenorrhea 73
Pathophysiology Table 5.1 Medications associated with hyperprolactinemia [11]

Psychiatric medications Antipsychotics (typical and atypical)
This chapter is organized into sections that discuss the physi- Tricyclic antidepressants
SSRIs
ologic, structural, pharmacologic, hypothalamic/pituitary
MAO-I
(low FSH), ovarian (high FSH), and other endocrine causes Others: trazodone, buspirone,
of amenorrhea. Notably, many of the above conditions alprazolam
(including POI, breastfeeding, and other chronic diseases) Estrogens Combined oral contraceptives
are not reliable inducers of anovulation and amenorrhea; Gastrointestinal Antiemetics: prochlorperazine,
medications metoclopramide
patients who do not desire pregnancy should be offered con-
H2 antagonists: cimetidine, ranitidine
traceptive counseling (please see Chap. 4, Patient-Centered Antihypertensives Methyldopa, reserpine, verapamil
Contraceptive Counseling). Other Opiates
Cocaine
Physiologic Hypothalamic/Pituitary (Low FSH/LH)

Pregnancy and menopause are important causes of amen- Hypothalamic or functional amenorrhea is due to a decrease
orrhea and are described further in Chap. 39, Obstetric in GNRH secretion, which can occur in the setting of weight
Medicine, and Chap. 8, Menopause, respectively. Regular loss, excessive exercise, disordered eating, poor nutrition, and
breastfeeding causes amenorrhea through secretion of pro- chronic disease. Hypothalamic amenorrhea is a diagnosis of
lactin by the pituitary, which inhibits GNRH and subse- exclusion [14]. Chronic disease such as advanced kidney and
quently suppresses the menstrual cycle. liver disease, malignancy, and malabsorption with associated
malnutrition and weight fluctuations can lead to hypotha-
lamic amenorrhea and alterations in hormone metabolism.
Structural Women with low body mass index (BMI) and disordered eat-
ing can present with thin body habitus, enlarged parotid
Uterine procedures and operations including dilation and glands, and lanugo. The female athlete triad (amenorrhea/
curettage, or infections like endometritis, can cause cervical oligomenorrhea, low energy availability with or without dis-
stenosis and/or intrauterine scarring known as Asherman ordered eating, and decreased bone density) is further detailed
syndrome. Both of these conditions can lead to outflow in Chap. 34, Eating Disorders and the Female Athlete Triad.
obstruction of menses. Pituitary tumors can cause excess or deficient hormone
secretion. Tumor compression through mass effect can lead
to panhypopituitarism, including deficiency of LH, FSH, and
Pharmacologic thyroid-stimulating hormone (TSH), with resulting men-
strual dysfunction. Patients with prolactinomas can present
Contraceptives, including continuous or extended com- with galactorrhea, headaches, and vision changes.
bined oral contraceptives (COC), hormonal intrauterine Central hypogonadism can result from infiltration or
devices (IUDs), and intramuscular medroxyprogesterone destruction of the hypothalamus and/or pituitary. Infiltrative
acetate, commonly induce amenorrhea. There is no physi- causes can include hemochromatosis, amyloidosis, inflam-
ologic requirement for regular menses in women using matory disorders (sarcoidosis, lymphocytic hypophysitis,
these forms of contraception [10]. With each of these Wegener’s granulomatosis), infectious diseases (tuberculo-
methods, amenorrhea is due to constant progestin levels in sis, syphilis, meningitis), or malignancy (carcinoma, lym-
the uterus that thin the endometrium. COCs and medroxy- phoma, leukemia) [15]. Other causes of damage to these
progesterone acetate additionally prevent cyclical thicken- structures include traumatic brain injury, radiation, and isch-
ing of the endometrium through hormonal suppression of emia. Pituitary ischemia in the setting of postpartum hemor-
the HPG axis [10]. rhage (Sheehan syndrome) generally presents with difficulty
Other medications affect prolactin release through breastfeeding and other symptoms of panhypopituitarism
inhibition by dopamine or stimulation by serotonin (anti- such as fatigue, weight change, cold intolerance, decreased
psychotics, antidepressants, prokinetics, antihyperten- appetite, decreased libido, hair loss, and constipation.
sives) and GNRH suppression (opioids and In addition to pituitary tumors, hyperprolactinemia occurs
glucocorticoids) [11–13]. Elevated prolactin leads to with physiologic conditions (stress, breast stimulation),
feedback inhibition of GNRH with resulting HPG axis endocrine disorders (Cushing’s disease, acromegaly, hypo-
suppression (Table 5.1). thyroidism, PCOS), neurologic disorders (seizures), sys-
temic disease (chronic renal or liver disease), and medications associated weight loss can lead to hypothalamic amenorrhea;
(as discussed in the pharmacologic section) [11, 12]. autoimmune thyroid disease is also associated with POI [19].
Ovarian (High FSH) Clinical Manifestations
Primary ovarian insufficiency, POI, also previously called

premature menopause and primary ovarian failure, is defined
as dysfunction or depletion of ovarian follicles with cessa- Rosalia is sexually active with one male partner and
tion of menses before age 40 years [16, 17]. Patients may uses condoms intermittently. She has been pregnant
present with hot flashes, sleep disturbance, depression, sex- twice, with one cesarean section and one spontaneous
ual dysfunction, and night sweats. miscarriage. She takes ibuprofen as needed for men-
Various conditions are associated with POI, including strual cramps and otherwise denies medication and
congenital disorders (Turner syndrome, fragile X, and Bloom substance use. There are no known gynecologic or
syndrome), signal defects (FSH/LH receptor or G protein endocrine issues in her family.
mutation), enzyme deficiency (aromatase or 17/20-lyase),
iatrogenic causes (chemotherapy, radiation), endocrine/auto- The evaluation of amenorrhea should include a detailed
immune diseases (Hashimoto’s thyroiditis, Graves’ disease, medical, surgical, and social history. A complete review of
diabetes mellitus type 1, autoimmune adrenal insufficiency), systems should be documented particularly targeting men-
and infection (mumps) [16, 17]. Other tumors that can dis- struation, sex, pregnancy, intrauterine procedures, and medi-
rupt ovarian function include granulosa, theca, teratoma, cations (Table 5.2) [21, 22]. History questions should focus
metastatic, and androgen-producing tumors. on a potential neurologic, endocrine, or gynecologic etiology
for amenorrhea. Family history should include menstrual
history of first-degree family members, puberty delay
Other Endocrine Disorders (delayed or incomplete sexual maturation, primary amenor-
rhea), genetic disorders (Turner syndrome, Bloom syndrome,
Hyperandrogenism fragile X), chronic illness (especially autoimmune and endo-
Hyperandrogenic anovulation occurs through multiple endocrine), and infertility. Physical exam should include BMI,
crinologic conditions. PCOS is the most common cause of cranial nerves (especially II, VI, VI), visual fields, thyroid
mildly elevated androgens and menstrual dysfunction, with (enlargement, tenderness, nodules), skin (dryness, lanugo,
mechanisms detailed further in Chap. 6, Polycystic Ovary hirsutism, acne), breast (tenderness, enlargement, nipple dis-
Syndrome. Obesity, independent from PCOS, can also lead charge), and a pelvic exam (vaginal dryness, cliteromegaly,
to menstrual anomalies due to dysregulation of metabolic, adnexal mass, uterine enlargement).
endocrine, and inflammatory pathways, including increased
peripheral conversion of androgens to estrogen by aromatase
in adipose tissue [18]. In Cushing’s syndrome, excess adre-
nocorticotropic hormone (ACTH) production by the pitu-
Rosalia has experienced episodes of feeling hot,
itary increases secretion of both cortisol and androgens from
flushed, and sweaty lasting a few hours. Her review of
the adrenals [19]. Direct glucocorticoid suppression of
systems is otherwise negative. On exam, her BMI is
GNRH secretion and feedback inhibition by hyperandrogen-
26.6 kg/m2, and she is in no distress with unremarkable
emia may also result in hypogonadotropic hypogonadism
visual field, thyroid, breast, abdominal, pelvic, and
and menstrual dysfunction [19]. Nonclassical adrenal hyper-
skin exams.
plasia due to 21-hydroxylase deficiency can present with
secondary amenorrhea and symptoms and physical exam
findings of hirsutism in adult women [20]. With acromegaly,
pituitary compression can occur along with direct growth Evaluation
hormone effects on gonadal function [13]. Exogenous andro-
gens and androgen-secreting ovarian or adrenal tumors are All women with amenorrhea should first have pregnancy
important to exclude. testing with a urine or serum hCG test. Pregnancy remains
the most common cause of secondary amenorrhea and should
Thyroid Dysfunction always be excluded in the evaluation of menstrual changes.
Both hyper- and hypothyroidism influence menses through In nonpregnant women, initial evaluation should focus on
effects on GNRH secretion, prolactin, steroid metabolism, the most common endocrinologic causes of amenorrhea with
and sex hormone-binding globulin [19]. In hyperthyroidism, a serum prolactin and TSH [21, 23].
Table 5.2 Clinical manifestations of secondary amenorrhea [19] itary adenoma, while medications rarely cause prolac-
Etiology Symptoms and relevant Physical exam tinemia >100 ng/mL [12]. If the serum prolactin is elevated
history findings but <100 ng/mL, evaluate for contributing medications
Physiologic (Table 5.1) or medical conditions such as primary hypo-
Pregnancy Breast tenderness, Breast tenderness thyroidism. Next steps would include discontinuing these
nausea, vomiting, and/or enlargement,
abdominal pain, abdominal medications if feasible, in collaboration with prescribing
increased urinary distension specialists as appropriate. The prolactin level should be
frequency, weight repeated in the early morning, or consider a pituitary MRI
gain if potentially contributing medication cannot be discontin-
Outflow tract
ued [13].
Asherman Cyclical pelvic pain, Enlarged, tender
syndrome/cervical prior uterine or uterus (not always
Obtaining an initial FSH level can also be considered [13,
stenosis cervical procedures, present) 22, 24]. While elevated FSH can suggest ovarian failure and
recurrent pregnancy low/normal FSH can suggest hypothalamic/pituitary disease,
loss, prior this hormone level fluctuates with the menstrual cycle
chemotherapy or
radiation
(Fig. 5.2). The FSH level should ideally be checked within
Hypothalamic/pituitary the first 5 days following onset of menses, which can be chal-
Hypothalamic Weight loss, excessive Thin body habitus, lenging in the setting of amenorrhea.
amenorrhea exercise, disordered enlarged parotid If these initial tests are unrevealing, further evaluation of
eating, poor nutrition, glands, lanugo hypothalamic/pituitary or ovarian causes should occur as
psychosocial stressors
discussed below.
Pituitary tumor Galactorrhea, Visual field deficits,
headaches, vision nipple discharge
changes
Sheehan syndrome Significant blood loss Hypotension Additional Testing
during birth, difficulty
breastfeeding, fatigue,
weight change, cold
Progesterone Withdrawal
intolerance
Ovarian In women with amenorrhea, progesterone (medroxypro-
Primary ovarian Hot flashes, sleep Vaginal dryness gesterone acetate 10 mg or norethindrone acetate 5 mg
insufficiency and disturbance, orally daily for 7–10 days) will induce a withdrawal bleed
menopause depression, sexual
dysfunction, night
in women who have sufficient endogenous estrogen to
sweats build an endometrial lining and who do not have outflow
Ovarian tumor (or Abdominal pain, Abdominal mass, obstruction. Low estrogen can occur in patients due to POI
androgen- rapid-onset hirsutism cliteromegaly, male or gonadotropin deficiency (hypothalamic amenorrhea,
producing tumor) pattern baldness, Sheehan syndrome, hyperprolactinemia, hypothyroidism,
acne, facial hair
Other endocrine disorders
pituitary tumors, Cushing’s syndrome). The utility of pro-
PCOS Weight gain, acne, Male pattern gesterone withdrawal testing, or “challenge” as it is known
hirsutism baldness, acne on clinically, has been questioned in women with amenor-
back/trunk, facial rhea. For example, about 50% of women with POI may
hair, acanthosis have withdrawal bleeding due to varied ovarian function
nigricans
[22, 25].
Thyroid Heat or cold Dry skin, brittle
dysfunction intolerance, nails, thyroid If possible, obtain lab tests (FSH, LH, estradiol)
palpitations, diarrhea, enlargement/ 1–5 days after withdrawal bleeding starts [23]. Low or
constipation, hair tenderness inappropriately normal FSH and LH with low estradiol
loss, fatigue,
suggests hypothalamic/pituitary disease, and high FSH
depression
Hypercortisolism Weight gain, acne, Hypertension, (with or without elevated LH) and low estradiol suggest
hirsutism, weakness, buffalo hump, POI (Table 5.3). In POI, FSH levels are in the menopausal
headache, fatigue, rounded face, purple range (30–40 mIU/mL) with estradiol less than 50 pg/mL
depression, easy striae, central [16]. As ovarian function can fluctuate in POI, FSH and
bruising obesity, muscle
atrophy, thin skin estradiol should be checked on at least two occasions at
least 1 month apart [17, 24]. An increased LH: FSH ratio
can be observed in PCOS but is often not present with this
Prolactin elevated to >100 ng/mL is usually due to a condition and is not part of the diagnostic criteria for
pituitary adenoma and should prompt a brain MRI [12, PCOS (please see Chap. 6, Polycystic Ovary Syndrome,
21]. Prolactin levels >200 ng/mL are diagnostic of pitu- for further discussion).
Table 5.3 Expected hormone responses in conditions causing second- dditional Testing for Primary Ovarian
A
ary amenorrhea
Insufficiency
Disorder GNRH FSH/LH Estrogen Androgens
Hypothalamic amenorrhea ↓ ↓ ↓ → In a patient diagnosed with POI not associated with a known
Hyperprolactinemia ↓ ↓ ↓ → syndrome, consider screening for fragile X (FMR1 premuta-
Sheehan syndrome ↑ ↓ ↓ →
tion), autoimmune thyroid disease (TPO), diabetes (fasting
Primary ovarian ↑ ↑ ↓ →
insufficiency glucose or hemoglobin A1c), and autoimmune adrenal dis-
Polycystic ovary syndrome →a LH: ↑→ ↑ ease (indirect immunofluorescence or 21-hydroxylase
↑→ [CYP21] immunoprecipitation) [17]. In one study of women
FSH:→ with secondary amenorrhea due to POI, 32% were found to
GNRH levels may be normal, but with increased pulse frequency [26]
a
have autoantibodies, with 10% having clinically evident
autoimmune disease (hypothyroidism, Graves’ disease, dia-
Testing for Androgen Excess betes mellitus, Addison’s disease) [30]. Additional studies in
women with POI showed that 24–25% had anti-TPO anti-
In patients with symptoms or physical exam findings of bodies, 6% had FMR1 permutations, and 3% had adrenal
androgen excess, total testosterone and autoimmunity [30–33].
dehydroepiandrosterone- sulfate (DHEA-S) should be Additional workup for systemic and autoimmune disease
checked. DHEA-S is preferred to DHEA due to its longer can be based upon symptoms and signs of these conditions,
half-life and lower variability [23]. Marked elevations in including free T4, erythrocyte sedimentation rate, serum pro-
total testosterone (>200 ng/dL) or DHEA-S (>700 ng/dL) tein, BMP, CBC, antinuclear antibody, rheumatoid factor,
suggest an androgen-producing tumor from the ovaries or and corticotropin stimulation tests [17, 21]. Consider karyo-
adrenals, respectively. More mildly elevated androgen values typing to identify chromosomal abnormalities, especially in
should prompt an evaluation for other causes of hyperandro- women less than 30 years, as 13% of these younger women
genic anovulation, for example, nonclassical adrenal hyper- may have an abnormal karyotype [24, 34]. Evaluate for
plasia (morning serum 17-OH hydroxyprogesterone), enlarged, polycystic ovaries which can be seen with autoim-
hypercortisolism (24-hour urine cortisol or dexamethasone mune oophoritis and 17,20 desmolase insufficiency with a
suppression test), and acromegaly (serum IGF-1). pelvic ultrasound [35]. Testing for ovarian antibodies and
ovarian biopsy are not currently recommended [36].
Imaging and Procedures

You diagnose Rosalia with primary ovarian insuffi-
Obtain a transvaginal ultrasound in the setting of an abnor-
ciency. Rosalia asks you about the health implications
mal pelvic exam, suspicion for anatomical anomaly, history
of this condition and if she can become pregnant again.
of prior intrauterine procedures or infection, or highly ele-
vated testosterone. Consider an MRI brain if symptoms,
exam, or laboratory workup suggests an intracranial process.
Adrenal CT should be completed in the setting of highly
Treatment
elevated DHEA-S. Women with Asherman syndrome should
be referred for hysteroscopy, which is considered the most
Treatment of secondary amenorrhea can be challenging
accurate method for diagnosis of this condition in compari-
and depends on the etiology and concomitant medical con-
son to transvaginal ultrasound, hysterosalpingography, and
ditions. Most often, primary care providers work closely
transcervical sounding [27–29].
with specialists and subspecialists to diagnose and manage
these patients. All conditions with amenorrhea may lead to
infertility and other health risks based upon underlying
hormone status (Table 5.4). Women with a diagnosis
Rosalia has a negative urine hCG, normal TSH and
known to cause infertility who desire pregnancy should be
prolactin, and elevated FSH. A progesterone with-
referred to a reproductive endocrinologist without delay.
drawal test does not result in vaginal bleeding, a
Timing of referral to specialists depends upon the diag-
repeat FSH and LH is elevated, and estradiol is low. A
nosed condition and expertise of the primary care provider
transvaginal ultrasound shows normal uterine and
(Table 5.4).
ovarian size and position.
The following references provide more detailed clinical
guidelines for management of the conditions in Table 5.4:
Table 5.4 Treatment of causes of secondary amenorrhea

Etiology Health implications Treatment Where/when to refer
Hypothalamic/pituitary
Hypothalamic Bone density loss Nutrition Nutritionist
amenorrhea Exercise modification Psychologist/psychiatrist as needed
Stress reduction
Cognitive behavioral therapy
Calcium and vitamin D supplementation
Combined oral contraceptives
Pituitary tumor Dependent on size and Surgery Endocrinology and neurosurgery upon
functionality of tumor Radiation diagnosis
Medication suppression (e.g., dopamine
agonists for hyperprolactinemia)
Sheehan syndrome Panhypopituitarism Corticosteroid, thyroid, sex hormones, and Endocrinology upon diagnosis
growth hormone supplementation
Ovarian
Primary ovarian Urogenital atrophy Combined oral contraceptive Consider endocrinology,
insufficiency Vasomotor symptoms Combined cyclical hormone therapy rheumatology, and genetics during
Osteoporosis Calcium and vitamin D supplementation initial evaluation of etiology.
Cardiovascular disease Reproductive technology Gynecology if persistent sexual
Increased all-cause dysfunction beyond expertise
mortality Endocrinology if osteoporosis with
first-line treatments
Ovarian tumor Virilization Surgery Gynecology or gynecology-oncology
upon diagnosis
Outflow tract
Asherman syndrome/ Chronic pelvic pain Hysteroscopic lysis of adhesions Gynecology for diagnosis and
cervical stenosis management
Multifactorial
PCOS Endometrial hyperplasia Combined oral contraceptives Nutritionist
Metabolic syndrome Metformin Endocrinology as needed
Antiandrogens
Fertility treatment
Thyroid dysfunction Cardiovascular risk Hypothyroidism: thyroid hormone Endocrinology as needed
Hypothyroidism: replacement
Myxedema Hyperthyroidism: surgery, iodine ablation,
Hyperthyroidism: medication suppression
thyrotoxicosis
Cushing’s syndrome Metabolic syndrome Surgery and/or radiation (if tumor present) Endocrinology at diagnosis
Hypertension Medication suppression of corticosteroid Neurosurgery if intracranial tumor
production (e.g., metyrapone) or receptors present
(e.g., mifepristone)
hypothalamic amenorrhea [37, 38], hyperprolactinemia/pitu- (0.02 mg) ethinyl estradiol and a second-generation proges-
itary tumor [39, 40], hypopituitarism [41], POI [42], ovarian tin (e.g., levonorgestrel 0.01 mg/day) is considered first-line
tumor [43], Asherman syndrome [29], PCOS [44, 45], thy- treatment. Additional information for this condition can be
roid dysfunction [46, 47], and Cushing’s syndrome [48]. found in the cited clinical practice guidelines and in Chap.
34, Eating Disorders and the Female Athlete Triad, in the
section on the female athlete triad [37, 38].
Hypothalamic Amenorrhea
The mainstay of treatment for hypothalamic amenorrhea Polycystic Ovary Syndrome

includes treatment of the underlying chronic condition if
present. Multidisciplinary teams involving primary care, In women with PCOS that do not desire pregnancy, COCs
nutrition, and psychiatry may be most effective in the setting are typically used to regulate menses and provide contracep-
of an underlying eating disorder. Pharmacologic treatments tion. Symptoms of excess androgen, particularly acne, are
can include calcium and vitamin D supplementation for pre- most often managed with COCs, specifically those contain-
vention of bone loss and combined oral contraceptives ing third- or fourth-generation progestins with higher rela-
(COCs) for regulation of menses, endometrial protection, tive antiandrogenic activity compared to early generation
and pregnancy prevention. Generally, use of low-dose progestins. Antiandrogen medications, such as spironolac-
tone, can also help with hair growth and acne but can cause hormone doses and can be used in conjunction with other
hypotension and electrolyte imbalance. Topical creams and contraceptive methods such as IUDs and barrier methods. If
cosmetic routes, like hair plucking and electrolysis, are often pregnancy is desired, options include awaiting spontaneous
used by patients for hirsutism. Women with PCOS who have conception, oocyte donation, and embryo donation [57, 62].
amenorrhea for over 3 months should have induced menses To optimize bone health, women with POI should also
with a progesterone withdrawal bleed. Providers should have strive for regular weight-bearing exercise; 1200 mg of cal-
a low threshold to obtain an endometrial biopsy in the setting cium per day, preferably through diet than supplements; and
of prolonged amenorrhea or abnormal uterine bleeding given 1000 IU of vitamin D per day [63]. Bisphosphonates are not
the increased risk for endometrial hyperplasia and malig- currently recommended for reproductive age women due to
nancy with this disorder. Metformin can improve weight the long half-life of this medication, teratogenicity, and
loss, insulin resistance, and fertility in women with uncertain safety profile in this population [16, 64].
PCOS. Women with PCOS who desire pregnancy should be Monitoring of women with POI should focus on cardio-
managed in coordination with an infertility specialist. vascular risk factors, with regular blood pressure and weight
Additional information for this condition can be found in the measures, screening for dyslipidemia and diabetes, and
cited clinical practice guidelines and in Chap. 6 on Polycystic counseling on lifestyle modification if appropriate. Dual
Ovary Syndrome [44, 45]. energy X-ray absorptiometry (DEXA) is recommended to
evaluate for bone density loss in women with POI, but there
is a lack of consensus about timing of testing, testing inter-
Primary Ovarian Insufficiency vals, and appropriate treatment [16, 17, 52–54].
Treatment of POI should focus on minimizing associated

cardiovascular disease, bone density loss, mortality, sexual Tumors and Endocrinopathies
dysfunction, and psychosocial stress [16, 49–56]. Women
with POI may benefit from a multidisciplinary team to While some endocrinopathies such as thyroid disorders or
address their complex medical and psychosocial care, espe- PCOS are managed in primary care, many other causes of
cially if a primary cause of POI is identified [55–57]. secondary amenorrhea discussed in this chapter are co-
If the cause of POI is idiopathic and not treatable or amen- managed with specialists. Primary care providers should ini-
orrhea continues with treatment, cyclical combined hormone tiate an evaluation of patients with secondary amenorrhea
therapy (HT) or COCs are recommended to prevent bone and facilitate referral as needed to endocrinologists, gyne-
density loss and increase quality of life [42, 58, 59]. Women cologists, rheumatologists, geneticists, or neurosurgeons
should be evaluated for contraindications to hormones who may play a role in managing patients with these
(please see Chap. 4 on Patient-Centered Contraceptive conditions.
Counseling and Chap. 8 on Menopause for more details),
although the findings of the Women’s Health Initiative may
not apply to younger women with POI [42]. Examples of
cyclical combined HT include estrogen (estradiol 100 μg/
Following a discussion about the health risks associ-
day transdermal, conjugated equine estrogen 0.625–1.25 mg
ated with POI, Rosalia would like to attempt another
oral/day, or micronized estradiol 1–2 mg oral/day) and pro-
pregnancy. You start a prenatal vitamin and refer her
gesterone, which can be dosed daily (100 mg micronized
to reproductive endocrinology.
progesterone oral/day or medroxyprogesterone acetate 2.5–
5.0 mg/day) or at higher dosing for 12 days per month
(200 mg micronized progesterone oral/day or medroxypro-
gesterone acetate 10 mg oral/day) [42]. Current recommen- Summary Points
dations are to continue hormonal treatment until the age of
natural menopause (50–51 years) [42]. 1. The history and physical exam in women with amenor-
Women with POI have a 5–10% chance of spontaneous rhea should focus on signs of intracranial, uterine, ovar-
pregnancy due to varied ovarian function [60]. For this rea- ian, and endocrine anomalies to guide the differential and
son, women with POI not desiring pregnancy should use diagnostic workup.
contraception. COCs provide more hormone than needed for 2. Pregnancy is the first diagnosis of exclusion in all presen-
physiologic replacement but have the added benefit of con- tations of amenorrhea, with TSH, FSH, and prolactin as
traception. However, the effectiveness of COCs for contra- the next initial testing in nonpregnant women.
ception in this population is uncertain due to potentially 3. Amenorrhea can be associated with health risks including
inadequate suppression of FSH [17, 61]. HT provides lower infertility, osteoporosis, and endometrial hyperplasia
depending upon the etiology, with treatment individual- and hair or skin changes. Her BMI is 38, and skin,
ized to minimize these risks. abdominal, thyroid, and pelvic exams are normal. Her
4. Patients should be referred to subspecialists if the workup medications include metformin. Testing includes a nega-
reveals neurologic, endocrinologic, or gynecologic tive urine pregnancy test, normal TSH and prolactin, and
abnormalities beyond the scope of your practice. a slightly elevated FSH. A progesterone withdrawal test
results in vaginal bleeding. What is the next best step in
evaluating this patient’s amenorrhea?
Review Questions A. Androgen testing
B. Repeat FSH and estrogen
1. A 35-year-old woman with a history of dysmenorrhea C. Karyotype
presents to clinic with pelvic pain and amenorrhea. She D. Transvaginal ultrasound
has not had a period in 4 months and has experienced a The correct answer is B. While this patient does have risk
few days of bilateral cramping pelvic pain each month. factors associated with PCOS (obesity and insulin resis-
Her history is notable for three prior pregnancies, one tance), her elevated FSH is not consistent with this diag-
elective dilation and curettage, and two cesarean sections. nosis and more suggestive of POI. Progestin withdrawal
She had a copper intrauterine device placed for contra- testing generally results in withdrawal bleeding in women
ception 2 years ago. On pelvic exam, the patient has a with sufficient endogenous estrogen to build an endome-
non-tender uterus of normal size. Which of the following trial lining, including PCOS, and no outflow tract obstruc-
tests is most likely to diagnose this patient’s underlying tion. While women with POI typically have reduced
condition? production of estrogen, ovarian function can vary with as
A. Hysteroscopy many as 50% of women with POI having a withdrawal
B. Transvaginal ultrasound bleed [25]. The next best step would be to repeat an FSH
C. CT abdomen and pelvis and estrogen 1 to 5 days following the onset of menses
D. MRI brain from the progestin withdrawal. If FSH is again elevated,
The correct answer is A. This patient’s history of cyclical this would confirm a diagnosis of POI.
pelvic pain with multiple intrauterine procedures is sug- It can be reasonable to check androgens when there is a
gestive of amenorrhea due to uterine adhesions (Asherman high clinical suspicion for PCOS, but this patient does not
syndrome). Uterine anomalies in women with uterine have any symptoms or physical exam findings of andro-
adhesions are not always detected on physical exam. gen excess. A karyotype should be checked in this patient
Transvaginal ultrasound has been found to have a sensi- if POI is confirmed with an additional high FSH given her
tivity of 0 to 52% in the diagnosis of uterine adhesions age of less than 30 years. This patient does not have any
compared to hysteroscopy (gold standard) [27, 28]. In the abnormalities on pelvic exam to prompt transvaginal
primary care setting, transvaginal ultrasound may be a ultrasound as a next step, but if POI is confirmed, this
reasonable first diagnostic imaging study, especially in a study can be considered to evaluate for enlarged, multi-
patient with a palpable uterine or adnexal anomaly on cystic ovaries which can be seen with autoimmune
pelvic exam. In patients with suspected uterine adhe- oophoritis and 17,20 desmolase insufficiency.
sions, however, a normal transvaginal ultrasound should 3. A 38-year-old woman with a history of Graves’ disease
not preclude a referral for hysteroscopy, which has a treated with iodine ablation with resulting hypothyroid-
higher sensitivity for diagnosing this disorder. ism presents to clinic with 5 months of amenorrhea. She
Hysteroscopy also has the added benefit of providing an otherwise feels well and review of systems is negative.
opportunity for treatment (lysis of adhesion) upon She is sexually active with a male partner and does not
diagnosis. desire pregnancy. She takes levothyroxine daily and does
This patient does not have symptoms or physical exam not currently use contraception. Her vitals and physical
findings of an intracranial process to prompt an MRI exam are normal and a pregnancy test is negative. Initial
brain. A CT abdomen could be considered if the patient workup shows a normal TSH and prolactin with an ele-
had physical exam, symptoms, or laboratory findings of vated FSH. A progesterone withdrawal test did not pro-
hyperandrogenism of a suspected adrenal source. duce a withdrawal bleed, with repeat labs showing an
2. A 28-year-old woman with a history of obesity and pre- elevated FSH and low estrogen. What is the next best step
diabetes presents to clinic with amenorrhea for the past in management of this patient?
6 months. She is sexually active with a male partner and A. Combined cyclic hormone therapy
uses condoms regularly. She feels fatigued at times but B. Bisphosphonate
denies weight change, heat/cold intolerance, diarrhea, C. Levonorgestrel intrauterine device
constipation, palpitations, abdominal pain, galactorrhea, D. Combined oral contraceptive
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Polycystic Ovary Syndrome
6
Azadeh Nasseh and Jenna Sarvaideo
Epidemiology
Learning Objectives
1. List the diagnostic criteria for PCOS. Polycystic ovary syndrome (PCOS) is the most common
2. Discuss the diagnostic work-up for PCOS. endocrine disorder seen in women of childbearing age [1–3]
3. Describe the underlying pathophysiology of PCOS. with an estimated prevalence between 5% and 16% depend-
4. Demonstrate knowledge of metabolic abnormali- ing on the population studied and the criteria applied [1, 4].
ties in patients with PCOS such as insulin resis- PCOS has been identified as a complex and heterogenous
tance, diabetes, and hyperlipidemia. disorder that results from the interaction of diverse genetic
5. Describe short-term and long-term sequela associ- and environmental factors and can lead to adverse reproduc-
ated with PCOS, including symptoms of androgen tive and metabolic complications in affected women [5]. The
excess, endometrial cancer risk, and depression. syndrome was first described by Stein and Leventhal in 1935
6. Formulate a treatment plan for a patient with PCOS and encompasses three cardinal features, oligo-anovulation,
that addresses weight management, symptoms of polycystic ovaries, and hyperandrogenism and/or hyperan-
androgen excess such as acne/hirsutism, endome- drogenemia [4, 6]; further discussion of each of these fea-
trial cancer prevention, and metabolic abnormali- tures will follow below. PCOS is a common cause of
ties, if present. infertility in women due to oligo-anovulation [2, 3] and can
7. Discuss how to address infertility issues in women be associated with a wide range of metabolic abnormalities
with PCOS. such as insulin resistance, diabetes mellitus type 2, hyperlip-
idemia, and increased risk of cardiovascular disease [2, 3, 7].
It can be accompanied by symptoms of androgen excess
such as acne and hirsutism, increased risk of endometrial
Shazia is a 32-year-old woman here for a new annual cancer, and depression [5, 7, 8]. Therefore, primary care pro-
visit who notes irregular menses. For 6 years, she has viders must be familiar with the diagnostic criteria and basic
had fewer than six menses per year and her last men- steps in management for PCOS to identify and treat this dis-
strual period was 5 months ago. The irregularities order in their patients.
worsened after she gained weight in the past few years.
She is sexually active and is not using any form of con-
traception since she does not believe she can become Diagnostic Criteria and Phenotypes
pregnant. You highly suspect PCOS.
Over the past three decades, significant efforts have been
made to classify PCOS. The first formal attempt was made at
the National Institutes of Health (NIH) conference, April
A. Nasseh 1990 [9]; the NIH criteria served as a standard for research-
Boston Medical Center, Boston University School of Medicine, ers and clinicians for more than a decade. Based on NIH cri-
Department of Internal Medicine, Section of GIM,
teria, clinical or biochemical hyperandrogenism (HA) and
Boston, MA, USA
chronic oligo-anovulation (OA) were considered key diag-
J. Sarvaideo (*)
nostic features of PCOS, after exclusion of related disorders
Medical College of Wisconsin, Department of Medicine, Division
of Endocrinology, Milwaukee, WI, USA [7]. In 2003, a consensus workshop in Rotterdam,
e-mail: [email protected] Netherlands, developed new diagnostic criteria, the

84 A. Nasseh and J. Sarvaideo
Rotterdam criteria, which added ultrasound characteristics patients may experience more pronounced menstrual
for polycystic ovary morphology (PCOM) to the NIH crite- irregularities [14, 15] and is at a higher risk for metabolic
ria definition. The 2003 Rotterdam criteria required the pres- dysfunction such as insulin resistance, atherogenic dys-
ence of two of the following three findings: signs of clinical lipidemia, and obesity [7, 14, 16, 17] when compared with
or biochemical hyperandrogenism; chronic ovulatory dys- women diagnosed with nonclassic or non-hyperandro-
function (OD); and the presence of polycystic ovary mor- genic PCOS phenotypes (phenotypes C and D). Phenotype
phology, after exclusion of secondary causes [7, 10, 11] C, “ovulatory PCOS,” generally includes women with
(Table 6.1). As a growing body of evidence supported the preserved ovulation who show an intermediate level of
presence of hyperandrogenism as a key factor in the patho- symptoms [18, 19] compared with patients with other
physiology of PCOS and a strong predictor of the associated subtypes. Phenotype D, also defined as “non-hyperandro-
metabolic dysfunctions [12], a task force assembled in 2006 genic PCOS” [7], has the mildest degree of metabolic dys-
by the Androgen Excess and PCOS Society proposed the function and the lowest prevalence of metabolic syndrome
AE-PCOS criteria. These criteria require the diagnosis of of all subtypes [14, 19, 20].
PCOS to be based on the presence of clinical or biochemical
hyperandrogenism in combination with ovarian dysfunction
(i.e., OD or PCOM), excluding other causes [13]. Given the Pathophysiology
multiplicity of criteria that could cause confusion in clinical
practice, the NIH sponsored an Evidence-Based Methodology The most consistent biochemical abnormality in women
PCOS Workshop in 2012 that addressed the benefits and with PCOS is an overproduction of androgens [8]. There are
drawbacks of existing diagnostic criteria [11]. As a result, two main sources of androgen production in women: the
the panel recommended the use of the broader Rotterdam ovaries and the adrenal glands. It has been hypothesized that
2003 criteria, while also providing detailed description of the in most PCOS cases, intrinsic dysregulation in ovarian ste-
different PCOS phenotypes defined by above criteria [7, 11]. roidogenesis results in functional ovarian hyperandrogenism
Based on the 2012 NIH criteria, four clinical pheno- (FOH) (Fig. 6.1). This inherent abnormality is further influ-
types can be defined for PCOS (Table 6.2). Phenotypes A enced by other hypothalamic-pituitary axis factors, includ-
and B are defined as “classic PCOS.” This group of ing higher baseline gonadotropin-releasing hormone (GnRH)
Table 6.1 PCOS diagnostic criteria

Hyperandrogenism Ovulatory Polycystic ovarian
(HA) dysfunction (OD) morphology (PCOM) Other requirements
NIH 1990 [9] + + Both required
(oligo-anovulation)
Rotterdam 2003 [10] + + + Two of three required
Androgen Excess and PCOS + +/− +/− HA + either OD or PCOM
Society 2006 [13]
NIH 2012 Extension of + + + Two of three required; phenotypes
Rotterdam 2003 [11] added (see Table 6.2)
Reprinted from Lizneva et al. [7], with permission from Elsevier
Table 6.2 NIH 2012 PCOS phenotypes and clinical features

Phenotype D:
Phenotype A: Phenotype B: Phenotype C: non-
Clinical presentation classic PCOS classic PCOS ovulatory PCOS hyperandrogenic
Hyperandrogenism + + + −
Ovulatory dysfunction + + − +
Polycystic ovary + − + +
morphology
Clinical features ↑ menstrual irregularities Intermediate levels of insulin, androgens, Mildest form:
↑ obesity, insulin resistance, atherogenic lipids, and metabolic syndrome ↓↓ metabolic
metabolic syndrome syndrome
↑ risk of hepatic steatosis ↓ androgens
↑ anti-mullerian hormone levels ↓ menstrual
irregularity
Reprinted from Lizneva et al. [7], with permission from Elsevier
6 Polycystic Ovary Syndrome 85
Hypothalamus
GnRH Functional ovarian hyperandrogenism
Pulse frequency
Sex steroids
Pituitary Theca cells : response to LH
LH androgen production
FSH Granulosa cells:
Inhibin B
Anti-Mullerian
Hormone Hyperandrogenism
Sex steroids Chronic oligo- anovulation

Ovarian follicle Premature Polycystic ovarian
luteinization of morphology
ovarian follicle
Insulin resistant
hyperinsulinemia
Ovary
Adiposity
Fig. 6.1 This figure depicts the main processes involved in the patho- and development of polycystic ovaries. The picture also depicts contri-
physiology of PCOS. Functional ovarian hyperandrogenism (FOH) is bution of the hypothalamus-pituitary axis. Patients with PCOS can have
the cardinal proposed feature, and it can explain the different clinical increase in pulse frequency of GnRH. This can lead to a higher LH
manifestations of PCOS. LH acts on theca cells of ovarian follicles to production (compared to FSH), which at the end can contribute to
start the process of follicle development and stimulates androgen pro- enhanced androgen production by ovaries. Sex steroids produced by
duction. Theca cells in women with PCOS have an exaggerated ovaries have negative regulatory feedback on gonadotropins. It is
response to LH that leads to increase in androgens. Meanwhile, granu- hypothesized that the hypothalamus-pituitary axis is less responsive to
losa cells of antral follicles respond to FSH for further development. this feedback in PCOS patients as well. Insulin-resistant hyperinsu-
Inhibin-B produced by granulosa cells has an inhibitory feedback on linemia can have an independent contributory role in pathophysiology
FSH. It also increases androgen production in theca cells. Patients with of PCOS. Insulin synergizes with LH to stimulate theca cells’ androgen
PCOS have elevated levels of inhibin-B. Anti-mullerian hormone production. Insulin also, similar to androgens, enhances luteinization of
(AMH) is another key player in control of follicular growth. Its levels ovarian follicles. Hyperinsulinemia can trigger peripheral adiposity,
are increased in PCOS due to excessive number of growing follicles. It and adiposity can in turn worsen insulin resistance. The figure does not
can also have a suppressing effect on FSH. Androgens accelerate depict the contribution of the adrenal glands to androgen production
luteinization of ovarian follicles (a part of normal follicular develop- (functional adrenal hyperandrogenism), which is seen either alone (in a
ment). However, when in excess, they can cause premature luteiniza- smaller number of patients) or as an adjunct to FOH
tion and follicular growth arrest. This leads potentially to anovulation
pulse frequency and reduced hypothalamic feedback Functional Ovarian Hyperandrogenism (FOH)
response to circulating sex steroids [6, 8]. This in turn leads
to hypersecretion of luteinizing hormone (LH) and subse- Normal ovarian function: Ovulation takes place due to
quent enhanced ovarian androgen synthesis and folliculo- synchronized activity between the hypothalamus, pituitary,
genesis. Insulin-resistant hyperinsulinemia also plays an and ovarian follicles (see Chap. 5 on Menstruation and
important role in PCOS. Insulin has been shown to enhance Secondary Amenorrhea). In the follicular phase, theca cells
the response of androgen-producing theca cells in the ovaries express LH receptors; LH stimulates the production of
to LH stimuli. In a smaller number of PCOS cases, dysregu- androstenedione from its precursor cholesterol [6].
lation at the adrenal zona reticularis causes hyperandrogen- Androstenedione, an androgen, is required for ovarian estro-
ism by increased production of dehydroepiandrosterone gen biosynthesis. A delicate balance exists between adequate
(DHEA) [1]. and overproduction of androgens (Fig. 6.2).
women with PCOS tend to have higher baseline AMH levels

LH due to a higher number of growing follicles. Initially, insulin
Cholesterol
and androgen promote the primordial to primary follicle
transition until FSH becomes the primary regulator at the
early antral follicle stage [1]. However, FSH is decreased in
PCOS due to elevated levels of AMH, which is in a negative
Androstenedione regulatory feedback loop with FSH as stated above.
Theca cell Therefore, follicle maturation arrest occurs.
Follicle
Hypothalamic-pituitary axis: Gonadotropin-releasing
Androstenedione hormone (GnRH) is secreted in a pulsatile manner to stimu-
late FSH and LH secretion from the pituitary. Changes in
Estrone
amplitude and frequency of the GnRH pulse determine the
Estradiol
Granulosa Cell amplitude and frequency of LH and FSH production through-
out the menstrual cycle. At higher pulses, GnRH promotes
Estradiol the production of LH, while lower pulsation frequencies
FSH enhance the production of FSH. In women with PCOS,
accelerated GnRH-LH pulsatile activity as well as decreased
Fig. 6.2 Depiction of the organization and regulation of the major ste- sensitivity of the hypothalamus to negative feedback from
roid biosynthetic pathways in the small antral follicle of the ovary ovarian steroids leads to higher LH production [1, 6]. Higher
according to the two-gonadotropin, two-cell model of ovarian steroido- LH pulses generally lead to higher production of ovarian
genesis. LH stimulates androgen formation within theca cells
androgens.
Ovarian function in PCOS: There are several proposed Hyperinsulinemia: Insulin resistance is common in both
mechanisms to explain anovulatory cycles in PCOS. obese and lean women with PCOS. Insulin has a direct role
on ovaries and enhances androgen production from theca
Theca cell dysfunction: Women with PCOS are suspected to cells in response to an LH stimulus (Figs. 6.1 and 6.2). It is
have intrinsic abnormalities in the ovarian theca cells’ ste- proposed that with higher insulin levels, both ovarian theca
roidogenesis which leads to hyperandrogenemia. In vivo and cells and adrenal zona reticularis cells have enhanced andro-
in vitro studies have shown overexpression of P450 enzymes gen production in response to LH and ACTH, respectively.
along with LH receptors in ovaries of women with PCOS
(21). This hyper-responsiveness can increase androgen pro-
duction. When produced in excess, androgens cause an arrest Genetics
in follicular maturation, cause follicular atresia, and hinder
ovulation [5]. Familial clustering of PCOS suggests a genetic basis.
Heritable traits that have been identified as PCOS risk factors
Granulosa cell dysfunction: Granulosa cells convert andro- are maternal PCOS, polycystic ovary morphology, hyperan-
gens coming from the thecal cells to estradiol by aromatase. drogenemia, and metabolic syndrome [1]. Phenotypic fea-
In women with PCOS, there seems to be a relative aromatase tures associated with PCOS such as hyperandrogenism and
deficiency likely due to inhibition by anti-mullerian hormone metabolic abnormalities can be seen in aggregate in certain
(AMH). Therefore, there is limited conversion of androgens families, suggesting a genetic cause. An example is sisters
to estrogens, leading to hyperandrogenemia [22]. In addition with hyperandrogenism and metabolic derangements, with
to AMH, inhibin-B is a peptide that is produced in granulosa or without menstrual irregularities. Several susceptibility
cells and is in a reciprocal negative regulatory feedback loop genes have been implicated, especially in the region of insu-
with FSH. It is essential and permissive for thecal androgen lin receptor genes [21]. Defects in androgen steroidogenesis
production. Women with PCOS tend to have elevated serum as well as beta cell function have been observed in brothers
inhibin-B as well as AMH [23]. of women with PCOS, manifesting itself as elevated levels of
dehydroepiandrosterone-sulfate (DHEA-S) and increased
Polycystic ovary morphology (PCOM) and role of anti- risk for type 2 diabetes [21]. Furthermore, it is thought that
mullerian hormone (AMH): The ovaries of women with PCOS evolved to preserve anabolism and reproductive
PCOS often show an excessive number of follicles. AMH is capacity via increased androgen and insulin production in
an important intrafollicular regulator of follicle growth, and times of nutritional deprivation [1].
Clinical Manifestations of hirsutism can be assessed by assigning a score of 0–4

based on the density of terminal hairs [13, 21, 29, 30]. A total
score of 8 or greater based on the 95th percentile of the data
Shazia noted that she had her upper lip waxed regu- originally collected by Ferriman and Gallwey may suggest
larly due to bothersome facial hair. She had moderate hirsutism. Race and ethnicity specific normative ranges are
acne across her upper back as well. Based on these not well established. Figure 6.3 depicts the visual scoring
features and her oligomenorrhea, PCOS is highest on method used for assessing hirsutism.
your differential. You discuss the diagnosis and work-
up with her. Acne: The prevalence of acne varies by ethnicity but is
estimated to affect 15–25% of patients with PCOS [10].
There is no consistent scoring for assessment, and it is
Ovulatory dysfunction with or without menstrual abnor- unclear how much PCOS raises the prevalence of acne over
malities: Ovulatory dysfunction typically presents with that in the general population given a general prevalence of
obvious disruption in menstrual flow but can present sub- 5–20% [13].
clinically without obvious menstrual irregularity [13].
Androgenic alopecia: Women with PCOS who experience
Overt dysfunction: Overt dysfunction occurs for the major- androgenic alopecia tend to lose hair in the anterior midver-
ity of the patients with PCOS [9, 12, 24–26] in the form of tex area extending to the crown. The anterior hairline remains
oligomenorrhea, defined as vaginal bleeding episodes occur- intact in women with PCOS, and significant bitemporal scalp
ring at greater than 35-day intervals or less than ten bleeds hair recession is unusual except in virilizing syndromes [32,
per year. A much smaller percentage of patients present with 33]. The prevalence of androgenic alopecia is reported to be
polymenorrhea, defined as bleeding episodes occurring fre- as high as 22% in some studies [34].
quently with less than 25 days between cycles [13, 27].
Polycystic ovaries: Polycystic ovaries are defined by three
Subclinical ovulatory dysfunction: Roughly 15–40% of features: ovarian size and volume, stromal volume, and fol-
oligo-ovulatory patients with PCOS present with eumenor- licle size and number. Based on the Rotterdam criteria, poly-
rhea (cycles every 25–35 days in length) [13, 26, 28]. In cystic ovaries contain 12 or more follicles measuring 2–9 mm
eumenorrheic patients for whom there is a high suspicion of in diameter and/or increased ovarian volume >10 mL in at
PCOS, day 18–24 progesterone levels can clarify the diagno- least 1 ovary [35]. It should be noted that this definition can-
sis. Levels below 3 to 4 ng/mL may suggest an anovulatory not be used for women on oral contraceptives. The preva-
cycle but should be checked on at least two different occa- lence of polycystic ovaries in patients with PCOS is high: in
sions as the presence of one anovulatory cycle may not indi- one study, 60% of women met size criteria, while another
cate chronic anovulation [13]. 35% met follicular criteria [36–38].
Hyperandrogenemia or hyperandrogenism: Hyperandro

genemia refers to higher than normal levels of circulating Other Features Associated with PCOS
endogenous androgens, including testosterone (T), andro-
stenedione (A4), and DHEA-S [13]. Clinical features of ele- While the clinical criteria for diagnosing PCOS include ovu-
vated androgens (known as hyperandrogenism) include latory dysfunction, hyperandrogenemia or its clinical find-
hirsutism, acne, and androgenic alopecia [8, 13]. ings, or polycystic ovary features on ultrasound, a number of
other clinical features may accompany this syndrome
Hirsutism: Hirsutism refers to the presence of course, pig- (Fig. 6.4).
mented hair on the face and/or body in a male pattern distri-
bution, including the upper lip, chin, chest, upper back and Insulin resistance, hyperinsulinemia, and the metabolic syn-
shoulders, lower back, abdomen, upper arms, and thighs. drome: Impaired glucose tolerance or diabetes mellitus type
While the degree of hirsutism can vary based on race and 2 develops in about 40% of women with 1990 NIH-defined
ethnicity [13], hirsutism affects approximately 65–75% of PCOS by the fourth decade of life. Glycemic control wors-
patients with PCOS [16], including women of White, Black, ens with age and weight gain [8, 39]. Women with PCOS can
and Southeast Asian backgrounds. If a clinician is uncertain also have dyslipidemia, which manifests as lower levels of
regarding the presence of hirsutism, the Ferriman-Gallwey high-density lipoprotein (HDL) cholesterol, increased levels
score can be used to further quantify the degree of hirsutism of triglycerides, and increased low-density lipoprotein (LDL)
present [29, 30]. This score, originally introduced in 1961, cholesterol [40–42]. Metabolic syndrome is also highly
assesses terminal hair growth in nine body areas. The degree prevalent in patients with PCOS compared to BMI-matched
a Lip
Score 1 Score 2 Score 3 Score 4
b Chin
c Chest
d Upper Arm
Fig. 6.3 Facial and body terminal hair growth scored according to the Calif) and ring flash (Vivitar Macroflash 5000, Vivitar Corp). For film,
modified Ferriman-Gallwey method. All were taken on women who Kodacolor VR 200 ISO film (Eastman Kodak Co, Rochester, NY, USA)
had not used laser or electrolysis for at least 3 months, not depilated or was used. Representative areas were selected. All photographs of hair
waxed for at least 4 weeks, and not shaved or plucked for at least 5 days were anonymized and all identifying information removed, meeting
before the photograph. The photographs depict scores of 1 through 4 for current Institutional Review Board for Human Use and Health Insurance
the upper lip (a), chin (b), chest (c), arm (d), upper abdomen (e), lower Portability and Accountability Act of 1996
abdomen (f), upper back (g), lower back (h), and thighs (i). The areas A score of 0–4 based on the density of hair is given in each region;
were photographed with a standard single-lens reflex camera (Nikon scores >8 are suggestive of hirsutism (Reprinted from Yildiz et al. [31],
N50, Nikon Corp, Melville, NY, USA) equipped with a macro lens by permission of Oxford University Press)
(Vivitar 50 or 100 mm Auto Focus Macro, Vivitar Corp, Newbury Park,
e Upper Abdomen
f Lower Abdomen
g Upper Back
h Lower Back
i Thighs
Fig. 6.3 (continued)

controls [25, 43]. Despite the higher prevalence of obesity higher CVD events. This is likely explained by the later onset
among patients with PCOS, not all of the metabolic abnor- of clinical CVD in women and paucity of studies in older
malities can be explained by BMI. Studies suggest that even women with history of PCOS [8].
lean PCOS women exhibit a higher prevalence of insulin
resistance and dyslipidemia compared to weight- and age- Increased risk of endometrial cancer: Women with PCOS
matched controls. have risk factors for endometrial cancer including obesity,
metabolic abnormalities, and chronic oligo-anovulation
Newer studies have suggested links between PCOS and resulting in prolonged exposure of the endometrium to unop-
surrogate markers of cardiovascular disease (CVD) such as posed estrogen. Therefore, it has been shown that women
increased left ventricular mass, endothelial dysfunction, and with PCOS that have oligomenorrhea can have a 2.7-fold
subclinical vascular disease [8]. Nevertheless, there is lim- increase in risk of developing endometrial cancer compared
ited data to suggest that women with PCOS are experiencing to the general population [8, 44] (see also Chap. 15 on
Gynecologic Malignancies). Endometrial protection is a key
focus of PCOS treatment (see below).
Oligo- Hyperandrogenism Glucose
anovulation intolerance
Infertility: Women with PCOS are at increased risk for
infertility due to anovulatory cycles. They also have higher
Endometrial risk of preterm delivery, gestational diabetes, and preeclamp-
PCOS Dyslipidemia
hyperplasia
sia [8].
Depression Psychosocial issues: The prevalence of depression and anxi-

Infertility and anxiety NAFLD Sleep apnea ety is higher in women with PCOS than in the general popula-
disorder tion [45]. These symptoms may be even more pronounced in
young adult women concerned with fertility but can affect
Fig. 6.4 Clinical components of PCOS. This figure illustrates the clin-
women of all ages with respect to weight and body habitus
ical features of PCOS that need to be carefully assessed and addressed.
NAFLD refers to nonalcoholic fatty liver disease (Reprinted from and clinical signs of androgen excess [46, 47]. Figure 6.5 dis-
Trikudanathan [21], with permission from Elsevier) plays the effect of PCOS on women, at different stages of life.
Weight excess
Visceral adiposity Obesity
Irregular menses Carbohidrate Intolerance Type II diabetes
Dis-/anovulation Dyslipemia Dyslipemia
Acne /Seborrhoea Infertility Cardiovascular
Hyperandrogenism/Hirsutism Pregnancy complications disease/Arterial
Insulin resistance hypertension
Adipose tissue dysfunction Endometrial cancer
Excessive post-natalcatch-
up weight gain
Premature adrenarche
Premature pubarche
Premature menarche
Fetal programming
IUGR
Born SGA
Fig. 6.5 Main clinical and metabolic manifestations of polycystic ovary syndrome according to women’s stage of life (Reprinted by permission
from Springer Nature, [47]). IUGR= Intrauterine Growth Restriction, SGA= Small for Gestational Age
Diagnostic Evaluation hyperandrogenism, including clinical features like hirsutism

or acne, or biochemical features such as elevated testosterone
It is essential to start with a detailed history and physical exam or DHEA-S; chronic ovulatory dysfunction; and/or the pres-
when evaluating a patient for PCOS. The history should ence of polycystic ovaries on imaging, preferably on trans-
include questions about (1) onset of menses and menstrual vaginal ultrasound. Once the diagnosis of PCOS is secured,
patterns; (2) hirsutism, specifically on the chin, jawline, chest, patients should be screened for diabetes, hyperlipidemia, and
back, breasts, and stomach; (3) acne; (4) weight gain or the metabolic syndrome. Diabetes screening options include fast-
inability to lose weight; (5) the presence of galactorrhea; (6) ing blood glucose, hemoglobin A1c and 2-hour oral glucose
behaviors and practices to offset symptoms such as plucking/ tolerance test (OGTT). Hemoglobin A1c is often used instead
waxing hair, acne treatments, excessive exercise/dieting, and of OGTT for patient convenience, though A1c alone may miss
taking medications that may mask or induce symptoms like patients with isolated postprandial hyperglycemia. A fasting
hormones or steroids; and (7) family history, specifically blood glucose or A1c may also underestimate the degree of
regarding the presence of endocrinopathies, PCOS, cardiovas- insulin resistance for these patients. Screening every 3 years
cular disease, lipid disorders, and diabetes. The exam should for those with normal results and annual screening for those
focus on the skin looking for acne, alopecia, striae, and hirsut- with impaired results is recommended.
ism; the presence of a goiter or thyroid nodule; adiposity; vir- It is also important to note that assessments of free testos-
ilization which may result from an androgen-producing tumor; terone levels are more sensitive than the measurement of
and the genitourinary tract, evaluating for clitoromegaly and total testosterone for the diagnosis of hyperandrogenic disor-
uterine and ovarian abnormalities. ders [1, 13, 21]. Table 6.3 provides an outline of the recom-
It is important to consider other possible diagnoses that can mended evaluation for different features associated with
mimic PCOS and to evaluate for these conditions. For exam- PCOS.
ple, in women presenting with hyperandrogenism, consider-
ation should be given to nonclassic congenital adrenal
hyperplasia (NCCAH) and/or androgen-secreting tumors. For Shazia had mild elevation of her testosterone and normal
a woman with oligomenorrhea as her presenting feature, preg- thyroid function tests, prolactin, and FSH. Her ultrasound
nancy, hypothyroidism, hyperprolactinemia, primary ovarian did not have features of polycystic ovaries. She asks how
insufficiency, and Cushing syndrome should be considered best to manage her symptoms and if she is at risk of any
(see Chap. 5 on Menstruation and Secondary Amenorrhea). other conditions—she read that PCOS can lead to infer-
According to the 2003 Rotterdam criteria, a diagnosis of tility and endometrial cancer and is worried.
PCOS is made when two of the following are present: signs of
Table 6.3 Differential diagnosis and diagnostic evaluation by clinical feature of PCOS
Clinical feature Differential diagnosis Diagnostic evaluation
Ovulatory dysfunction Pregnancy Urine HCG
Thyroid disorders TSH, free T4
Hyperprolactinemia Prolactin
Primary ovarian insufficiency FSH, estradiol
Cushing syndrome Salivary cortisols, 24-hour urine
Structural gynecologic disease cortisol, dexamethasone
suppression test
Pelvic ultrasound
Hysteroscopy
Hyperandrogenism Nonclassic congenital adrenal Morning 17-OH progesterone
hyperplasia (NCCAH) Testosterone, free and total
Androgen-secreting tumors DHEA-S
Metabolic complications: Obesity, insulin resistance, Thyroid disease TSH, free T4
metabolic syndrome, dyslipidemia, hepatic steatosis Diabetes OGTT, A1c, and/or fasting glucose
Physical inactivity and/or diet Liver function tests, lipid panel
Primary lipid disorder
Other familial disorders of metabolism
Endometrial hyperplasia Structural causes of AUB (polyps, Transvaginal ultrasound
adenomyosis, leiomyoma) Endometrial biopsy
Endometrial cancer
Infertility Includes all of the above conditions Work-up for ovulatory dysfunction
and/or hyperandrogenism
Referral to fertility specialist for
additional evaluation
PCOS Treatment enstrual Regulation and Endometrial

M
Protection
The goals of treatment for PCOS are to restore menses and/
or ovulation, reduce hyperandrogenism, and/or reduce the Oral contraceptive pills (OCPs): OCPs are useful for
risk of developing associated complications such as diabetes women with oligomenorrhea, hirsutism, and acne and/or
(Table 6.4). Treatment of PCOS should target the patient’s those who desire contraceptive benefit [53]. The most com-
most bothersome symptoms (i.e., hirsutism) and/or compli- monly used OCPs contain both estrogen and progestin, also
cations that can cause harm (i.e., anovulatory cycles, meta- known as combined oral contraceptive pills (COCs)
bolic syndrome). Not all treatments recommended for PCOS (Table 6.4). The estrogen component increases sex hormone-
will treat all complications of PCOS; therefore, patient and binding globulin (SHBG), which binds testosterone and
provider together must outline a management plan based on helps reduce hirsutism. One specific combination shown to
patient preferences, clinical manifestations, and medical have benefit in patients with PCOS includes both ethinyl
comorbidities. estradiol and a low-androgenic progestin such as norgesti-
One key goal of PCOS treatment includes reducing insu- mate; in general, any COC is fine. Patients need to be coun-
lin resistance. Weight loss, medications, and bariatric sur- seled that there is an increased risk of venous
gery are all employed to achieve this goal with improvement thromboembolism, along with potential increase in blood
in ovulation and hyperandrogenemia as the final outcome pressure, triglycerides, and HDL cholesterol levels [53] (see
[48]. A weight reduction of as little as 5% can restore ovu- Chap. 4 on Patient-Centered Contraceptive Counseling).
lation in up to 60% of patients with PCOS [49]. The
Endocrine Society Clinical Practice Guideline suggests the Progestin therapy: Women may choose to take progestin-
use of exercise therapy along with diet modification as first- only therapy for endometrial protection. Examples include
line treatment to manage obesity in women with PCOS medroxyprogesterone acetate 5–10 mg or micronized pro-
[50]. Based on studies on rodent models, it is suggested gesterone 200 mg for 10–14 days monthly or continuous
that early intervention with dietary restrictions and exercise therapy with norethindrone 0.35 mg daily. The latter also
in young adolescents with PCOS as well as in prepubertal provides contraception. Unlike COCs, progestin-only ther-
children at risk of PCOS may improve metabolic, repro- apy will not reduce symptoms of acne or hirsutism as estro-
ductive, and endocrine parameters. This improvement is gen is required for SHBG to increase and subsequently bind
caused by regulation of the neuropeptides in the hypotha- testosterone.
lamic-pituitary-gonadal axis [50, 51]. Pretreatment weight
loss has also been studied as infertility treatment in Intrauterine device (IUD): COCs are recommended as first-
PCOS. Pretreatment lifestyle modification and weight loss line therapy given the multiple potential benefits described
for 16 weeks, with or without concurrent oral contraceptive above. For women who cannot or choose not to take COCs,
therapy, is associated with a significant improvement in the IUDs can provide endometrial protection and contraception for
ovulation rate and an even greater increase in live birth a woman with oligomenorrhea. While IUDs can be either hor-
rates as compared to immediate fertility treatment without monal (levonorgestrel-releasing) or nonhormonal, only the
lifestyle modification [49, 52]. levonorgestrel-releasing hormone has endometrial protective
The following sections will be organized by treatment effect. For primary care providers who do not place IUDs,
modalities that target specific symptoms and manifestations referral to a gynecologist can facilitate IUD placement, particu-
of PCOS. larly for patients who desire highly effective contraception.
Table 6.4 Specific therapies to address PCOS symptoms or complications

Restore Reduce Improve metabolic Reduce endometrial Improve
menses hyperandrogenism syndrome cancer risk fertility
Weight loss √ √ √ √ √
Combined oral contraceptives √ √ √
Levonorgestrel IUD √
Metformina √ √ √
Spironolactone √
Topical acne medications or hair √
removal
Clomiphene or letrozole √
Adapted from McCartney and Marshall [48]
a
May have modest (3%) impact on weight loss
Metformin: Metformin can be useful for women who do not lesions. Combination with topical retinoids may be indicated
want to take OCPs but have oligomenorrhea. Recall that insu- if comedones are also present. Finally, salicylic acid is a
lin resistance and hyperinsulinemia are part of the pathophys- comedolytic agent that is available over the counter in 0.5%
iology of PCOS. By acting to improve insulin resistance, to 2% strengths. If acne is treatment-resistant, scarring, or
metformin can both impact patients’ glucose metabolism and causing severe distress, oral isotretinoin may be appropriate,
oligomenorrhea. A recent study found that metformin, at a and referral to a dermatologist should be made [54].
dose of at least 1000 mg daily, restored menses in at least
42% of women within 6 months of treatment [58].
Metabolic Complications
Metformin has been available for use for many years and
has a mostly tolerable adverse effect profile. The most com- Weight loss and exercise can help to improve the metabolic
mon adverse effect is GI distress such as bloating and diar- profile in patients with PCOS. Metformin can be used for
rhea, which occasionally resolves after a few weeks of use. treatment of prediabetes and diabetes. Newer treatments
Metformin does not seem to have a significant effect on hir- such as liraglutide, a GLP-1 agonist, can help treat diabetes
sutism, and it may increase pregnancy risk given its effect to mellitus type 2 in women with PCOS while also mediating
restore menses and ovulation; patients who do not desire weight loss.
pregnancy require effective contraception.
Infertility
Hyperandrogenism
It is important for women with PCOS to know that they are
Spironolactone: If a patient is bothered by hirsutism and indeed fertile but that it may be more challenging to conceive
acne, spironolactone, an anti-androgen, is an option. due to anovulation. Some women with PCOS conceive natu-
Spironolactone works by competing with dihydrotestoster- rally; when they do not, ovulation induction is possible with
one (DHT) for binding to the androgen receptor and inhibits medical management and/or assisted reproduction tech-
enzymes involved in androgen biosynthesis. In general, it is niques. As stated earlier, metformin can restore ovulation in
recommended to start patients on a COC for 6 months, and if some patients, but referral to a reproductive endocrinologist
desired reduction in hirsutism is not attained, spironolactone is encouraged if patients do not conceive after 6 months to
can be started [50]. There is danger that a male fetus could be 1 year of unprotected and frequent intercourse.
feminized by spironolactone therapy, so women desiring Clomiphene, a selective estrogen receptor modulator
treatment with spironolactone also require adequate contra- (SERM), and letrozole, an aromatase inhibitor (AI), have
ception. The typical effective dose is 50–100 mg twice daily been studied for use in ovulation induction (Fig. 6.6). Both
and the clinical effect is dose-dependent. Despite these high inhibit the negative feedback of estrogen at the hypothala-
doses, patients with normal blood pressure tend to tolerate mus with a consequent increase in ovarian stimulation by
spironolactone quite well. It is also important to be mindful endogenous gonadotropin [55]. A randomized trial of ovula-
that spironolactone could cause adverse effects including, tion induction involving women with PCOS and infertility
but not limited to, hypotension, hyperkalemia, kidney injury, showed a higher live-birth rate among women who received
GI discomfort, and headache. clomiphene than among women who received metformin
Other treatment options: In addition to COCs and spirono- Hypothalamus +/-

lactone, topical agents can be used to treat bothersome acne. (clomiphene)
Commonly used topical therapies include, but are not limited
GnRH
to, benzoyl peroxide, retinoids, sulfone agents, and salicylic
+/-
acid. Both oral and topical antibiotics are often used in con- Pituitary
junction with these therapies. Benzoyl peroxide is an anti-
bacterial agent that kills P. acnes and is mildly comedolytic. LH, FSH
Strengths available for acne treatment range from 2.5% to Aromatase
Ovary
10%. Topical retinoids are vitamin A derivatives and are both (letrozole)
comedolytic and anti-inflammatory. Examples are tretinoin Testosterone Estrogen

(0.025–0.1% in cream or gel), adapalene (0.1%, 0.3% cream
or 0.1% lotion), and tazarotene (0.05%, 0.1% cream, gel,
foam). The sulfone agent, dapsone 5% gel, is available as a Fig. 6.6 Mechanisms of actions of clomiphene, a selective estrogen
twice-daily agent. It works primarily for inflammatory receptor modulator (SERM), and letrozole, an aromatase inhibitor
alone (22.5% vs. 7.2%). There was an even greater live-birth Review Questions
rate in the combination therapy group (26.8%) [56]. However,
a subsequent randomized trial from 2014 compared clomi- 1. Jane is a 30-year-old woman who visits in your office for
phene 50 mg daily to letrozole 2.5 mg daily and found more her annual exam. She has recently gained 15 pounds. Her
live births in the group that took letrozole (27.5% to 19.1%). BMI is now 29. One of her friends who had a recent
There was also significantly more ovulation, conception, and weight gain was diagnosed with a condition called “poly-
pregnancy. This effect was most significantly seen in women cystic ovarian syndrome” or (PCOS). She is worried that
with a BMI >30.3 to <=39.4 kg/m2 [57]. she also has this condition. Which of the following would
be needed so that you can make the same diagnosis for
her?
Mental Health A. Menstrual cycles between 24 and 28 days, mild acne,
mildly elevated insulin levels
As noted above, depression is more common in patients with B. Prolonged episodes of amenorrhea, A1c in 6 range,
PCOS than in those without. Patients with PCOS should be low normal FSH
screened using common primary care depression screening C. Menstrual cycles generally >35 days apart, increased
tools like the PHQ-2 and PHQ-9. If positive, standard treat- hair growth under chin area, normal range A1c
ments should be offered (see Chap. 33 on Depressive and D. Transvaginal ultrasound showing enlarged ovaries
Anxiety Disorders). with multiple cysts, normal testosterone level, and
Addressing patients’ concerns in regard to their signs and impaired glucose tolerance test
symptoms of hirsutism, as well as providing appropriate The correct answer is C. Although most of the features
counseling and timely referral to specialists when it comes to described in the answer choices above can be associated
their concerns about fertility, can be important in managing with PCOS, the criteria for diagnosis require generally
patients with PCOS. two out of the three characteristics of chronic oligo-
anovulation, signs and symptoms of hyperandrogenism
or hyperandrogenemia, and polycystic ovarian morphol-
Summary Points ogy on ultrasound [4, 6]. This is based on the most
recent and agreed-upon criteria for diagnosis of PCOS
1. PCOS is a common disorder in women of childbearing (2012 extension of Rotterdam criteria) [7, 10]. Oligo-
age. It is important to ask about each woman’s menstrual anovulatory cycles are generally defined as vaginal
pattern and consider PCOS in women who report oligo- bleeding episodes occurring at greater than 35-day
menorrhea or other menstrual changes. intervals or less than ten bleeds per year. A much smaller
2. The main clinical features of PCOS are oligo-anovulation, percentage of patients present with polymenorrhea,
androgen excess, and polycystic ovaries. Two of these defined as bleeding episodes occurring frequently with
three features are necessary to diagnose PCOS according less than 25 days between cycles [13, 27].
to the currently used Rotterdam criteria. Hyperandrogenemia refers to higher than normal levels
3. PCOS can be associated with a spectrum of metabolic of circulating endogenous androgens, including testos-
abnormalities such as impaired glucose tolerance and dia- terone (T), androstenedione (A4), and DHEA-S [13].
betes. Guidelines often recommend screening every Clinical features of elevated androgens (known as
3 years. Those with abnormal test results should be hyperandrogenism) include hirsutism, acne, and andro-
screened annually. genic alopecia [8, 13].
4. While a diagnosis of PCOS can be made clinically based Although PCOS can be associated with hyperinsulinemia
on history and physical examination, lab tests and ultra- and increased risk of diabetes (manifesting itself as eleva-
sound are often necessary to exclude other causes of tion in A1C or abnormalities in the glucose tolerance test)
oligo-anovulation and to assess hyperandrogenism. [8, 39], these endocrine abnormalities are not a part of
5. Treatments focus on reducing the risk of endometrial can- criteria for diagnosis of PCOS. FSH and other hormone
cer, improving insulin sensitivity, and reducing hirsutism. levels are only used to rule out other endocrine abnor-
Cornerstones of treatment include weight loss and hor- malities causing oligo-anovulatory pictures (i.e., primary
monal contraceptives; metformin is also frequently used. ovarian insufficiency). They are not a part of criteria for
6. Infertility and depression are common in patients with diagnosis of PCOS.
PCOS. Patients should be screened and treated for depres- 2. Tina is 35 years old. She is in your office to discuss her
sion, while patients who do not conceive within new onset of amenorrhea for almost 6 months. She used
6–12 months should be promptly referred to a reproduc- to have cycles every 26–28 days. She has noticed new
tive endocrinologist. hair growth under her chin area; she is embarrassed to
go out with her friends. What are the best next steps in D. Overproduction of testosterone from ovaries is always
her care? the primary cause.
A. You explain to her that she is a typical case of a condi- The correct answer is A. Functional ovarian hyperan-
tion called “polycystic ovarian syndrome or PCOS” drogenism is considered the cardinal feature leading to
and you think since she makes two out of three symptoms of PCOS [1]. Women with PCOS are sus-
Rotterdam criteria, no further work-up is necessary. pected to have intrinsic abnormalities in the ovarian theca
B. You explain to her that she is a typical case of a condi- cells’ steroidogenesis which leads to hyperandrogenemia
tion called PCOS, but to further confirm the diagno- [21]. This hyper-responsiveness can increase androgen
sis, you order a transvaginal ultrasound to assess her production and excess androgens can ultimately hinder
ovaries as well. ovulation [5]. Hyperinsulinemia plays a direct role on
C. You explain to her that although you suspect that her ovaries and enhances androgen production from theca
symptoms can be suggestive of PCOS, however given cells in response to LH stimulus. Insulin resistance is
new prolonged amenorrhea and new onset of hirsut- common in both obese and lean women with PCOS.
ism, you think further work-up including TSH, pro- LH and FSH production are mediated by GnRH secreted
lactin, FSH, and testosterone levels are necessary to from the hypothalamus. GnRH is generally secreted in a
rule out secondary causes of amenorrhea and pulsatile manner. At higher pulses, GnRH promotes the
testosterone-secreting ovarian tumors. production of LH in the pituitary gland, while lower pul-
D. You explain to her that although you suspect that her sation frequencies enhance the production of FSH. In
symptoms can be suggestive of PCOS, however to women with PCOS, accelerated GnRH-LH pulsatile
further confirm the diagnosis, you need to order an activity as well as decreased sensitivity of the hypothala-
insulin level and a glucose tolerance test. mus to negative feedback from ovarian steroids leads to
The correct answer is C. Your patient seems to have two higher LH production [1, 48]. Higher LH pulses gener-
out of three criteria for PCOS based on the Rotterdam cri- ally lead to higher production of ovarian androgens. That
teria (chronic anovulatory cycles based on her prolonged being said, the ovarian androgen production abnormali-
amenorrhea episode and hyperandrogenism manifesting ties are considered largely an inherent characteristic of
itself as increased hair growth under her chin area) [7]. the ovaries in patients with PCOS. In a smaller number of
Meanwhile, generally when making the diagnosis of PCOS cases, dysregulation at the adrenal zona reticularis
PCOS, one needs to rule out other causes of amenorrhea causes hyperandrogenism by increased production of
(especially a new onset of amenorrhea in this case). These DHEA [1].
can include but are not limited to hypothyroidism, hyper- 4. Eleanor is a 35-year-old female patient presenting with a
prolactinemia, primary ovarian insufficiency, and Cushing 6-month history of amenorrhea. You have confirmed she
syndrome (please see Table 6.3 in the text). Also, given the is not pregnant. Her TSH, prolactin, and FSH levels are
new onset of signs of hyperandrogenism, androgen levels normal. She has mild hirsutism and her testosterone lev-
need to be checked. Mild elevation is expected in PCOS. els are in the 40 range. At this point you make the diagno-
3. You make the diagnosis of PCOS for one of your patients sis of PCOS for her. What are some of the concerns that
Leslie, who had come to you with new onset of hair you make sure you should address with her?
growth in her upper lip area, and finding of polycystic A. You counsel her for weight loss, but given she has no
ovaries on her pelvic ultrasound for evaluation of inter- family history of diabetes, you don’t feel it is neces-
mittent heavy cycles. She informs you that she had been sary to check her for metabolic abnormalities.
a biology major while she was in college and is particu- B. You assess her family planning goals, and if she is not
larly interested to understand the underlying mechanism planning to get pregnant, you start her only on a norg-
for her syndrome. What are the cardinal features that con- estimate containing birth control.
tribute to the pathophysiology of polycystic ovary syn- C. Given her hirsutism is mild, there is no indication for
drome that are responsible for her symptoms? her to get started on any specific treatment.
A. Functional ovarian hyperandrogenism is the cardinal D. You screen her for depressive symptoms and you
feature in most patients and can be worsened by refer her to specialist as indicated.
insulin-resistant hyperinsulinemia. The correct answer is D. The cornerstones of treatment in
B. Functional ovarian hyperandrogenism is the cardinal patients with PCOS are weight loss, protection of the endo-
feature in most patients but is only seen in obese metrium against prolonged unopposed exposure to estro-
patients. gen (which can increase the risk of future endometrial
C. Overproduction of androgens from the ovaries is cancer), screening and treatment for metabolic abnormali-
mainly due to abnormalities of LH and FSH produc- ties such as diabetes and hypercholesterolemia, treating
tion from the pituitary. hirsutism or other signs of hyperandrogenism (based on
patient’s preferences), treatments to address infertility and/ revised criteria including anti-Mullerian hormone. Hum Reprod.
2014;29(4):791–801.
or to increase chance of ovulation, and screening and pro- 5. Baskind N, Balen A. Hypothalamic–pituitary, ovarian and adrenal
viding appropriate treatments for depression and other psy- contributions to polycystic ovary syndrome. Best Pract Res Clin
chosocial conditions associated with PCOS [49, 50, Obstet Gynaecol. 2016;37:80–97.
53–55]. When addressing endometrial protection, all the 6. Stein IF, Leventhal ML. Amenorrhea associated with bilateral poly-
cystic ovaries. Am J Obstet Gynecol. 1935;29(2):181–91.
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5. Rose, a patient that you recently diagnosed with PCOS, 10. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
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A. Metformin only Executive summary. Available at: https://prevention.nih.gov/docs/
B. Metformin and clomiphene programs/pcos/FinalReport.pdf. Accessed March 1, 2016.
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Abnormal Uterine Bleeding
7
Raj Narayan and Benjamin D. Beran
Table 7.1 Parameters of normal and abnormal uterine bleeding [11].

Learning Objectives
Descriptive term Definition
Irregular menstrual bleeding >20 days in individual cycle
1. Discuss the burden of abnormal uterine bleeding lengths in a year
(AUB). Absent menstrual bleeding No bleeding in a 90-day period
2. Define current terminology used to describe AUB Infrequent menstrual bleeding ≤2 episodes in a 90-day period
including heavy menstrual bleeding and intermen- Frequent menstrual bleeding >4 episodes in a 90-day period
strual bleeding. Prolonged menstrual bleeding >8 days in duration on a
3. Compare the clinical presentations of abnormal regular basis
uterine bleeding across the lifespan. Shortened menstrual bleeding ≤2 days in duration
4. Describe the steps used to evaluate AUB. Adapted from Fraser et al. [11]
5. Identify indications for treatment and referral to
gynecologists when managing AUB and postmeno- below the 25th percentile of national norms on six of the eight
pausal bleeding. subscales in the validated quality of life assessment: the SF-
36 scale [2]. Further, AUB is associated with sexual dysfunc-
tion [3, 4], psychological effects [3, 5, 6], and decreased
quality of life in the domains of social, professional, and fam-
Background ily life [3, 7]. Sexual function assessed by the Medical
Outcomes Study Sexual Problems Index showed that women
who failed medical management of AUB scored well below
Tamara is a 46-year-old woman, G3P3003, who pres- the typical age-adjusted mean [4]. Given the degree to which
ents for an episode of heavy vaginal bleeding. She has AUB impacts women’s quality of life, many argue that the
been changing an overnight pad every 2 to 3 hours for main outcome measure to determine effectiveness of any
2 to 3 days during her last three regular menstrual intervention should be improvement in quality of life rather
periods. She reports frustration with her symptoms; than merely the actual blood loss [8]. Additionally, the annual
she has a long flight next week and is worried the direct cost to society (in the United States) associated with
bleeding will worsen while she is traveling. heavy menstrual bleeding is estimated to be as high as $1.55
billion with annual indirect costs as high as $36 billion [2].
AUB refers to uterine bleeding patterns that differ from
Abnormal uterine bleeding (AUB) is one of the most com- normal, established patterns (Table 7.1) or which negatively
mon presenting complaints of reproductive age women and impact a patient’s quality of life [8]. The FIGO Menstrual
results in a third of all outpatient gynecologic visits [1]. Disorders Working Group further divides AUB into two cat-
Studies have shown that AUB significantly decreases quality egories: acute and chronic. Acute AUB is a clinical diagnosis
of life for women aged 18–54 years; women with AUB scored based on a perceived need for immediate intervention in the
setting of an episode of heavy menstrual bleeding. Chronic
AUB is defined by the FIGO Menstrual Disorders Working
R. Narayan (*) · B. D. Beran Group as “bleeding from the uterine corpus that is abnormal
Froedtert & Medical College of Wisconsin, Department of
in volume, regularity, and/or timing that has been present for
Obstetrics and Gynecology, Wauwatosa, WI, USA
e-mail: [email protected] the majority of the last 6 months” [9].

100 R. Narayan and B. D. Beran
Fig. 7.1 PALM-COEIN

classification of abnormal Polyp Coagulopathy
uterine bleeding [13].
Adenomyosis Ovulatory dysfunction
(Reprinted from Best Practice
Submucous
and Research Clinical Endometrial
Leiomyomas
Obstetrics and Gynaecology, Other
Munro [13], © 2017, with Malignancy & hyperplasia Iatrogenic
permission from Elsevier)
Not otherwise classified
Leiomyomas SM - 0 Pedunculated intracavitary

subclassification Submucous
1 <50% intramural
system
2 ≥50% intramural
O - Other 3 Contacts endometrium; 100% intramural
4 Intramural
5 Subserous ≥50% intramural
6 Subserous <50% intramural
7 Subserous pedunculated
8 other (specify e.g. cervical, parasitic)
Two numbers are listed separated by a hyphen, By convention,
the first refers to the relationship with the endometrium while the
Hybrid second refers to the relationship to the serosa. One example
leiomyomas is below
(impact both Submucous and subserous, each with
2-5
endometrium less than half the diameter in the
and endometrial and peritoneal cavities,
serosa) respectively.
Traditional descriptions of patterns of abnormal uterine Leiomyomas, which patients commonly refer to as
bleeding are based on abnormal frequency, duration, and fibroids, are further classified because of their high preva-
quantity of flow and include such terms as menorrhagia, lence. Subserous fibroids typically cause pressure symptoms
metrorrhagia, menometrorrhagia, hypermenorrhea, hypo- when they are large but do not lead to menstrual abnormali-
menorrhea, polymenorrhea, polymenorrhagia, epimenor- ties. Intramural and submucous fibroids often cause heavy
rhea, epimenorrhagia, metropathia hemorrhagica, menstrual bleeding. Submucosal fibroids which protrude into
dysfunctional uterine hemorrhage, and functional uterine the cavity of the uterus cause intermenstrual or irregular
hemorrhage [10]. However, these terms are often subjective, bleeding. The diagnoses are not mutually exclusive. Many
and studies have shown that these descriptions are inaccurate women will have incidental structural findings with nonstruc-
[11]. Instead, terms such as abnormal uterine bleeding tural causes of abnormal uterine bleeding. This is particularly
(AUB), heavy menstrual bleeding (HMB), prolonged men- true of leiomyomas that often coexist with other conditions
strual bleeding (PMB), heavy and prolonged menstrual such as endometrial hyperplasia, cancer, or polyps.
bleeding (HPMB), and intermenstrual bleeding (IMB) are
recommended to describe specific symptoms [11]. Tamara reports that she had normal periods until age
Notably, AUB refers to women who are premenopausal; 44. Since then, her periods have been irregular, occur-
any bleeding in women who are postmenopausal is abnormal ring every 1–3 months. She endorses intermittent hot
and requires prompt evaluation (see section below and Chap. flashes at night.
15 on Gynecologic Malignancies).
lassification of Causes of Abnormal Uterine

C Pathophysiology
Bleeding (PALM-COEIN)
Normal Menstrual Cycle
In 2011, the FIGO Working Group on Menstrual Disorders
proposed a new classification system for causes of abnormal The normal menstrual cycle relies on a complex and intricate
uterine bleeding [12, 13]. In this system, the causes of AUB relationship between the hypothalamus, pituitary gland, ova-
are broadly divided into structural causes and nonstructural ries, and uterus. Hormonal signals are sent bidirectionally
causes. The acronym PALM-COEIN was created to aid from the hypothalamus and pituitary gland to the ovaries,
memory and recall (Fig. 7.1) [13–15]. some with agonistic effects and others with antagonistic
7 Abnormal Uterine Bleeding 101
effects. When all feedback loops function properly, the men- enstrual Bleeding and Endometrial
M
strual cycle occurs in a predictable nature every 24–35 days Hemostasis
[16]. The cycle is typically divided into three phases: follicu-
lar, ovulatory, and luteal (see also Chap. 5 Menstruation and Just as prostaglandins and hemostatic factors such as platelet
Secondary Amenorrhea, Fig. 5.2). aggregation and thrombus formation are critical to bleeding
and hemostatic processes throughout the body, these factors
also play a role in menstrual bleeding patterns and endome-
Follicular Phase trial hemostasis. Endometrial prostaglandin production plays
a significant role in endometrial shedding and regeneration
The follicular phase represents the initial 10–14 days of the [17, 18]. Activity of COX-2, an enzyme essential in prosta-
normal menstrual cycle. During this phase, a dominant fol- glandin synthesis, is elevated in the endometrium of women
licle is recruited for ovulation from a pool of antral folli- with heavy menstrual bleeding providing evidence of
cles. Follicle-stimulating hormone (FSH) from the pituitary increased inflammation and prostaglandin activity in women
gland stimulates estrogen production in ovarian granulosa with heavy menstrual bleeding [19].
cells, which in turn inhibits further FSH secretion. The Endometrial hemostasis facilitates the end of menstrual
dominant follicle survives the decreasing FSH levels as bleeding and is achieved through the effects of local endo-
local effects of estradiol enhance FSH action for this folli- crine, immunological, and hemostatic factors. Tissue factor
cle selected for ovulation. The continued rise in estradiol and thrombin control menstrual bleeding via the activation
stimulates endometrial proliferation and eventually leads to of coagulation factors, while fibrinolysis prevents clot orga-
a surge in release of luteinizing hormone (LH) from the nization within the uterine cavity. Plasminogen activator
pituitary gland [16]. inhibitors and fibrinolysis inhibitors that control plasmino-
gen activators and plasmin activity maintain this balance
[20]. Platelet aggregation, fibrin deposition, and thrombus
Ovulatory Phase formation occur in sequence. Abnormalities of uterine bleed-
ing can result from imbalance of the hemostatic factors.
The ovulatory phase is a brief phase occurring at the end of A systematic review [21] found no variation in von
the follicular phase, typically during the 10th–14th day of Willebrand factor (VWF), factor VIII, factor XI, factor XIII,
the menstrual cycle. The beginning of the LH surge precedes fibrinolytic factors, or fibrinogen levels throughout the men-
ovulation by approximately 34–36 hours [10]. LH stimulates strual cycle in most of the studies. However, in studies where
progesterone production in the granulosa and theca cells, cyclic variation was noted, the lowest levels occurred during
which facilitates ovulation of a mature oocyte. the menstrual and early follicular phases, especially for
VWF, factor VIII, and platelet function tests. Given these
findings, menstruation and the early follicular phase are the
Luteal Phase optimal times to pursue hemostatic testing (see Laboratory
Testing, below) [21].
While the follicular phase is dominated by estrogen produc-
tion, the luteal phase is dominated by progesterone secretion
produced by the corpus luteum, a temporary endocrine tis- bnormal Uterine Bleeding: Structural
A
sue from the remnant of the dominant ovulatory follicle. Causes -(PALM)
Progesterone promotes a transition to a secretory endome-
trium [16] in preparation for possible implantation of a fer-
tilized embryo. In the absence of a pregnancy, the luteal
Tamara stopped using combined hormonal contracep-
phase is consistently 14 ± 1 days in length following ovula-
tion at age 35 after tubal sterilization. She had a nor-
tion [16]. In the absence of human chorionic gonadotropin
mal, HPV negative Pap smear 2 years ago. There is no
(hCG) from a pregnancy, the corpus luteum undergoes attri-
history of breast, endometrial, or ovarian cancer in
tion, and levels of progesterone and estradiol fall. This with-
her family.
drawal of progesterone and estradiol leads to shedding of
the endometrium and resultant menstrual bleeding. The first
day of bleeding represents the first day of the follicular
phase of a new menstrual cycle. The normal length of bleed- The FIGO classification system of AUB, “PALM-
ing is 4.5–7 days with a majority of the menstrual blood COEIN,” relegates structural causes of AUB to the initial
flow occurring in the first 3 days [16]. portion, “PALM.” Polyps, adenomyosis, leiomyomas, and
malignancy are considered structural etiologies and
require visualization with imaging or histopathology for after removal of the uterus; endometrial biopsy is not useful
diagnosis [14]. [14, 22, 26].
Polyps Leiomyoma
Endometrial and endocervical polyps are epithelial prolifera- Leiomyomas (also known as “myomas” and “fibroids”) of
tions comprised of glandular, vascular, fibromuscular, and the uterus are benign fibromuscular tumors, with each lesion
connective tissue [14, 22]. Prevalence of polyps is unknown arising from a single smooth muscle cell [14, 28]. Nearly
since the majority are asymptomatic. However, in a Danish 70% of Caucasian women and 80% of African-American
population study, when 622 randomly selected women were women develop leiomyoma by age 50 [14, 28, 29]. While
evaluated using ultrasound and sonohysterography, 7.8% highly prevalent, only 20–50% of women develop AUB as a
had polyps, and the prevalence rose from 0.9% in 20–29- result of the leiomyoma [14, 30]. Given that the location of a
year age group to 9.3% in ≥30-year age group and from leiomyoma frequently determines a patient’s symptoms, a
5.8% in premenopausal to 11.8% in postmenopausal women secondary classification system requires evaluating the rela-
[23]. Polyps may demonstrate fewer hormone receptors than tionship of the leiomyoma to the endometrium, myome-
typical endometrium, making them less responsive to the trium, and uterine serosa [14, 29]. Submucosal leiomyomas.
cyclic changes of the menstrual cycle [24]. Some polyps pro- contact or deviate the endometrium and are most likely to
trude from the cervical os and are visible on physical exam cause AUB regardless of size [14, 29]. The initial leiomyoma
with a speculum. In other cases, polyps are diagnosed with diagnosis can be made by ultrasonography or MRI. When
transvaginal ultrasonography (especially saline-infusion needed, clarification of submucosal location can be per-
sonography), hysteroscopy, or endometrial biopsy. Polyps formed using saline-infusion sonography, MRI, or hysteros-
frequently coexist with submucosal leiomyomas; they may copy [14, 27]. Gynecologists planning myomectomy, uterine
also be misdiagnosed as submucosal leiomyomas on ultra- fibroid embolization, or ablation often obtain MRI for surgi-
sound [22]. Endometrial and endocervical polyps are usually cal planning; primary care providers will usually defer order-
benign, but a minority of polyps may have atypical or malig- ing MR imaging to colleagues in gynecology.
nant cells [14]. For this reason, polyps are often removed and
sent to pathology for diagnosis [24].
Malignancy and Premalignant Lesions
Adenomyosis Malignancies that lead to abnormal uterine bleeding include

cervical cancer, endometrial cancer, and sarcomas, while
One of the best descriptions of adenomyosis dates back to ovarian cancer rarely presents with AUB [22, 31]. The main
1972: “adenomyosis may be defined as the benign invasion risk factor for cervical cancer development is human papil-
of endometrium into the myometrium, producing a diffusely lomavirus (HPV) infection acquired via sexual activity
enlarged uterus which microscopically exhibits ectopic non- (Chap. 14 on Cervical Cancer and Human Papillomavirus)
neoplastic, endometrial glands and stroma surrounded by the [32]. Endometrial hyperplasia is more common than uterine
hypertrophic and hyperplastic myometrium” [25]. This often cancer, and the WHO 2015 classification separates this diag-
leads to painful heavy menstrual bleeding, though adeno- nosis into two groups: hyperplasia without atypia and atypi-
myosis may also be asymptomatic [26]. Reported risk fac- cal hyperplasia/endometrial intraepithelial neoplasia [33].
tors for the development of adenomyosis include multiparity Unopposed estrogen exposure leads to higher risk for most
and uterine procedures such as endometrial curettage, termi- common types of endometrial cancer. Conditions with
nation of pregnancy, or cesarean delivery [26]. Many studies chronic anovulation such as polycystic ovary syndrome
report a 20–35% population prevalence, with some reports (PCOS), obesity, or improper administration of exogenous
suggesting a range of 5– 70% [14, 26]. Patients with adeno- hormonal therapy are some sources of unopposed estrogen
myosis often report painful or heavy, regular menstrual [34]. Uterine sarcomas are rare with risk factors such as
bleeding. However, clinical symptoms are neither sensitive increasing age, long-term use of tamoxifen, and previous
nor specific [26]. Adenomyosis may be focal or diffuse. pelvic radiation [22]. No imaging technique alone can diag-
Diagnosis can be made with ultrasonography or magnetic nose these conditions definitively, though ultrasound or MRI
resonance imaging (MRI), although diagnostic criteria may be pursued when there is a high clinical suspicion [22].
may vary [26, 27]. Histologic diagnosis is usually made only Endometrial biopsy, endometrial curettage, or hysterectomy
allow a definitive tissue diagnosis [22, 35]. See Chap. 15 on strual cycles are spaced more than 38 days apart (see Chap.
Gynecologic Malignancies for more information. 5 on Menstruation and Secondary Amenorrhea) [14, 22, 35].
Nonstructural Causes of AUB-COEIN Endometrial Causes
Coagulopathy Endometrial causes of AUB are based on molecular level

abnormalities that affect proper vasoconstriction and lead to
As many as 13% of women affected by AUB may have a increased fibrinolysis and vasodilation [39, 20]. Clinical test-
coagulopathy, the most common of which is von Willebrand ing of these changes is not currently available; thus, this clas-
disease (vWD) [14, 22]. Most coagulopathies are inherited, sification remains one of exclusion when a patient is shown
and other examples include hemophilia type A (factor VIII to have a structurally normal uterus, normal menstrual cycle,
deficiency) and type B (factor IX deficiency), platelet dys- and lack of coagulopathy [39, 20]. For example, women pre-
function, and various other factor deficiencies [36]. A senting with intermenstrual bleeding without any obvious
detailed history will accurately identify up to 90% of women structural causes or iatrogenic causes such as hormonal treat-
with coagulopathies. Evaluation for coagulopathy is indi- ment may have endometrial causes.
cated if there is a positive history (Fig. 7.2) [37].
Iatrogenic Causes
Ovulatory Disorders
Iatrogenic causes of AUB include all pharmacologic thera-
Failure of ovulation contributes to AUB through prolonged pies prescribed for other purposes but result in unscheduled
endometrial proliferation, and the lack of progesterone leads or heavy menstrual bleeding (see Table 7.2) [13, 14, 22].
to instability of the endometrium and causes irregular ripen- Exogenous estrogens and/or progestins, especially those
ing and shedding of the endometrium. This leads to unpre- dosed in a continuous fashion, can lead to AUB based on the
dictable erratic bleeding [12, 14, 22, 35, 37, 38]. This is a progestin component inducing a gradual atrophy and even-
common occurrence in the first 2–3 years following men- tual fragility of the endometrium. Progestin-containing intra-
arche because the hypothalamic-pituitary-ovarian (HPO) uterine devices (IUDs) and progestin-only contraceptives
axis is immature and is also common in the perimenopausal such as depot medroxyprogesterone acetate and etonorg-
years – up to 8 years preceding menopause [36]. estrel contraceptive implant (Nexplanon™) commonly cause
Numerous endocrinopathies also contribute to ovulatory AUB during the initial months of therapy [13, 14].
dysfunction including polycystic ovary syndrome (see Chap. Anticoagulant or antiplatelet therapies (e.g., warfarin, low-
6 on Polycystic Ovary Syndrome), uncontrolled diabetes molecular-weight heparin, and heparin) often contribute to
mellitus, and thyroid dysfunction [12, 14, 22, 35]. Additional AUB through their desired interference with proper coagula-
risk factors for abnormal uterine bleeding include obesity, tion pathways [13]. Antidepressants and other medications
anorexia, weight loss, mental stress, and extreme levels of
exercise [14, 22]. Diagnosis of ovulatory dysfunction should
be suspected with a history of amenorrhea or when men- Table 7.2 Common causes of medication-induced AUB
Class Medications
Hormonal Combined oral contraceptive pills, combined
contraceptives hormonal vaginal ring, depot
1. Structured history— positive screen if: medroxyprogesterone acetate, etonorgestrel
a. Excessive menstrual bleeding since menarche, or implant, levonorgestrel intrauterine device
b. History of one of the following—postpartum hemorrhage, Hormonal Androgens, danazol, tamoxifen, selective
surgery-related bleeding, or bleeding associated with dental work, medications progesterone receptor modulators,
or gonadotrophin-releasing hormone agonist and
c. History of two or more of the following— bruising greater than antagonist, menopausal hormone replacement
5 cm once or twice/ month, epistaxis once or twice/month, frequent therapy
gum bleeding, family history of bleeding symptoms. Anticoagulants Warfarin, heparin, low-molecular-weight
2. Initial laboratory evaluation: Complete blood cell count heparins, rivaroxaban, apixaban, clopidogrel
Anticonvulsant Valproic acid
Fig. 7.2 Primary evaluation for an underlying disorder of hemostasis
Antibiotics Rifampin, griseofulvin
in females with excessive menstrual bleeding [37]. (Reprinted from
Fertility and Sterility, Kouides et al. [37], © 2005; with permission from Antidepressants SSRI, SNRI, tricyclic antidepressants
Elsevier) Antipsychotic Typical and atypical classes
that affect serotonin or dopamine levels can contribute to hair [36]. Pelvic examination including the use of speculum
AUB by altering prolactin release, leading to infrequent is rarely required in adolescence as STI testing can be
menstruation [13, 14]. obtained noninvasively, structural abnormalities can be iden-
tified with imaging, and cervical cancer screening is not indi-
cated until 21 years of age [36].
AUB Not Otherwise Classified
This classification is reserved for conditions that are poorly Mid-reproductive Years
defined or rare. Current examples include arteriovenous mal-
formations, cesarean scar defects, myometrial hypertrophy, Even after the HPO axis has attained maturity, anovulation
and chronic endometritis not related to an IUD [13, 14, 22, can occur due to obesity, polycystic ovary syndrome (PCOS),
40, 41]. As these conditions become better understood, they or hypothyroidism [38]. The work-up of suspected ovulatory
may be reclassified. dysfunction is similar to that in the adolescent and focuses
on identifying patients with menstrual cycle lengths outside
the normal range of 24–35 days. The presence of intermen-
Evaluation strual bleeding may suggest a structural abnormality such as
a polyp or submucosal leiomyoma [41]. Pelvic pressure or
History and Physical Examination urinary frequency may suggest an enlarged uterus from leio-
myoma or adenomyosis. Medication list should be carefully
reviewed (Table 7.2).
On exam, Tamara’s vitals show a BP of 126/76, HR 80, Concern for malignancy or hyperplasia should be based
and a BMI of 30. Her abdominal exam is nontender first on BMI and then on age, as BMI greater than 30 kg/m2
without hepatosplenomegaly, and her pelvic exam is has been shown to increase risk of endometrial hyperplasia
normal other than moderate vaginal bleeding. or malignancy fourfold [42]. Age greater than 45 and BMI
over 30 in a younger woman are often used as criteria for
endometrial biopsy (see below and Chap. 15 on Gynecologic
An appropriate evaluation for AUB begins with a thor- Malignancies). Physical exam may reveal a pelvic mass sug-
ough history and physical examination tailored to the gestive of a fibroid uterus. Features of hyperinsulinemia such
patient’s age. While details of menstrual flow are helpful, as acanthosis nigricans or hyperandrogenism evidenced by
with excessive amounts defined as changing pads or tampons excessive facial hair and acne suggest PCOS. Speculum
every 1–2 hours or bleeding longer than 7 days [35], it is examination should be performed to look for vaginal or cer-
important to recall that the definition of AUB is bleeding that vical abnormalities, and bimanual examination for uterine
negatively impacts a patient’s quality of life [8, 13]. irregularities or adnexal masses.
Adolescence Perimenopause
While the hypothalamic-pituitary-ovarian (HPO) axis coor- Ovulatory dysfunction is the leading cause of AUB in the
dinates to initiate menarche, it often takes 12–18 months, perimenopause and can occur up to 8 years prior to actual
sometimes even up to 36 months, to fully mature [36, 38]. menopause [35]. The evaluation of these patients is other-
During this maturation process, ovulatory dysfunction is wise similar to the mid-reproductive years. Adenomyosis is
common and is the leading cause of AUB in the adolescent one of the most common causes of AUB in this time period,
girl [36, 38]. The simplest measure of ovulation is a men- though it is often a diagnosis of exclusion given the limita-
strual cycle length within the normal 24- to 35-day range but tions of current imaging modalities in its detection [25, 26].
can also be suggested by presence of premenstrual breast
tenderness, cyclic mood changes, and cramping [38]. A care-
ful sexual history will provide insight toward possible sexu- Postmenopausal Patients
ally transmitted infection (STI) or pregnancy. Additionally,
especially in adolescents with anemia from AUB, screening Postmenopausal bleeding (PMB) is not typically considered
for coagulopathy should be undertaken using a structured a subtype of AUB. The high prevalence of endometrial
process (Fig. 7.2). hyperplasia and malignancy in patients who present with
Physical exam should focus upon height, weight, body PMB requires a different approach than for the groups dis-
mass index (BMI), and Tanner staging of breasts and pubic cussed above. Prompt evaluation of postmenopausal bleed-
ing is imperative since as many as 1–14% of women will be endometrial thickness >4 mm requires further evaluation
diagnosed with endometrial cancer [43]. Ninety percent of with endometrial sampling [43]. Endometrial thickness
women with endometrial cancer present with vaginal bleed- ≤4 mm has a greater than 99% negative predictive value for
ing [43]. A thorough evaluation is needed before any treat- endometrial cancer. Women with an endometrial stripe
ment is initiated. ≤4 mm need no further evaluation unless bleeding persists
The evaluation of postmenopausal bleeding begins with [43]. Of note, an incidental finding of an endometrial stripe
an appropriate assessment of menopausal status. Diagnosis >4 mm in a postmenopausal woman who does not have vag-
of menopause is based primarily on history of amenorrhea inal bleeding does not need further evaluation, though an
for 12 months [44]. However, many women have infrequent individualized approach based on risk factors is reasonable
cycles during the perimenopause, making it difficult to [43].
diagnose postmenopausal bleeding. Although there is sig- In patients who require endometrial sampling, an office
nificant intra- and intersubject variability in hormone lev- biopsy is indicated. Office endometrial biopsy is accurate but
els, use of laboratory testing for follicle-stimulating may yield inadequate tissue in 10% of women. In another
hormone (FSH) and estradiol can help identify presence or 10% of women, an attempt at office biopsy fails due to
absence of ovarian function in patients with abnormal inability to visualize the cervix, cervical stenosis, or a dis-
bleeding in women under 45 years of age. Persistently ele- torted uterus [44]. Focal abnormalities such as endometrial
vated FSH and low estradiol in the presence of amenorrhea polyps can be missed in up to 18% of women [45]. An abnor-
for more than 12 months would be consistent with post- mal endometrial stripe and persistent vaginal bleeding are
menopausal status. indications for referral to a gynecologist for further evalua-
The most common cause of postmenopausal bleeding is tion with saline-infusion sonohysterography or hysteroscopy
atrophic endometrium in 60–80% of patients [45]. Hormone [45]. Please see Chap. 15 on Gynecologic Malignancies for
replacement therapy accounts for another 15–25%, and more information.
benign endometrial or endocervical polyps in 2–12% [45].
Other causes are leiomyomas, cervicitis, vaginitis, trauma, or
anticoagulation [45]. Laboratory Testing
Endometrial cancer occurs in up to 14% of patients with
postmenopausal bleeding and warrants investigations for
early diagnosis [43]. Risk factors for endometrial cancer in Given the duration and severity of bleeding, a CBC is
the postmenopausal state include elevated estrogen from obtained which shows a hemoglobin of 11 gm/dL. A
peripheral aromatization of androgens in obesity, exogenous urine pregnancy test was negative.
estrogen in the form of prescribed or over-the-counter medi-
cations or supplements, or an estrogen-secreting neoplasm
[44]. Women with hereditary nonpolyposis colon cancer Figure 7.3 describes additional laboratory evaluation for
have a lifetime risk of endometrial cancer in the range of patients presenting with AUB. In all patients, a pregnancy
42–60% [44]. Medical comorbidities such as history of poly- test should be performed as the initial step in the evaluation
cystic ovary disease, type 2 diabetes mellitus, family history of abnormal uterine bleeding. Additional tests to consider are
of gynecologic malignancy, or history of atypical endome- complete blood counts (CBC) to evaluate severity of bleed-
trial cells on cervical cytologic screening are additional risk ing and thyroid-stimulating hormone testing to assess for
factors for endometrial cancer [43]. Use of tamoxifen as thyroid-induced abnormal bleeding [12, 35, 41]. When inter-
adjuvant therapy for breast cancer carries a 3–6 times risk of preting test results, hemoglobin and/or hematocrit levels
endometrial cancer compared to nonusers [44]. may not accurately reflect the degree of menstrual blood loss
A thorough history and physical examination are essential in some women. Leiomyomas often have higher erythropoi-
to determine the cause of postmenopausal bleeding and dis- etin activity and are occasionally associated with erythrocy-
tinguish between uterine, cervical, vaginal, vulvar, urethral, tosis [48]. The UK’s National Institute for Health and Care
and rectal bleeding [44]. Appropriate consultation with a Excellence (NICE) recommends thyroid function screening
gynecologist is required for further evaluation. only in the presence of signs and symptoms of thyroid dis-
The next step in evaluation of uterine bleeding includes ease [8]. The healthcare provider must always ensure cervi-
endometrial sampling or transvaginal ultrasonography [44]. cal cancer screening is up to date and give consideration to
Transvaginal ultrasonography is the most cost-effective testing for Chlamydia trachomatis, especially in high-risk
approach in the initial evaluation of postmenopausal bleed- populations [12, 41].
ing [46, 47]. Transvaginal ultrasonography effectively Coagulopathy should be considered as the cause of AUB
assesses endometrial thickness. The American College of based on a thorough history, particularly in adolescents or
Obstetricians and Gynecologists recommends that any adult patients with concerning features. One approach to
Fig. 7.3 Suggested workflow

for laboratory evaluation of Urine pregnancy test
AUB Complete blood count
Thyroid stimulating hormone
All patients with AUB
Cervical cancer screening
(if due)
High risk sexual behavior present? yes no
Chlamydia and Gonorrhea testing
Coagulopathy history screen (see Fig 7.2)
positive
negative
Prothrombin time
Partial thromboplastin time
Platelet count
Abnormal or high suspicion for Normal or low suspicion for

coagulopathy coagulopathy
Von-Willebrand -Ristocetin cofactor activity End of routine laboratory

Von-Willebrand factor antigen testing
Factor VII
assessing a patient’s risk for coagulopathy is presented in intermenstrual bleeding is suggestive of a structural abnor-
Fig. 7.3. Patients who meet criteria should be evaluated with mality that may be identified primarily through imaging [8,
complete blood count (to rule out thrombocytopenia), pro- 12, 22, 38, 41]. Imaging of the uterus using two-dimensional
thrombin time (PT), and partial thromboplastin time (PTT). If ultrasonography with color-flow Doppler interrogation is
these tests are abnormal or in patients with a history otherwise commonplace as an adjunct to pelvic examination.
suggestive of von Willebrand disease, further testing with von Gynecologists may also perform saline sonohysterography,
Willebrand ristocetin cofactor activity, von Willebrand factor which can further enhance the capability to distinguish sub-
(vWF) antigen, and factor VIII is appropriate [49]. tle abnormalities, diagnose AV malformations [40], and
increase accuracy to distinguish benign from malignant con-
ditions especially with leiomyomas [50]. MRI can be used to
Imaging diagnose adenomyosis or to map leiomyomas prior to abla-
tion or surgical removal.
A pelvic ultrasound is obtained; the uterus measures

8 cm × 5 cm × 3 cm and the ovaries are normal. Ultrasonography
Ultrasonography of the female pelvis may be performed via a

An imaging study is indicated whenever pelvic examina- transabdominal and/or transvaginal approach. Transabdominal
tion is unsatisfactory or suggests an abnormality and when images give a global view of pelvic structures but sacrifice
initial noninvasive medical management fails. Additionally, detail. Transvaginal ultrasonography increases the resolution
of images, allowing improved evaluation of the endometrium Endometrial Biopsy

and ovaries. However, transvaginal imaging is not recom-
mended for the adolescent or virginal patient. The American College of Obstetricians and Gynecologists rec-
If identifiable menstrual cycles are present, performance ommends endometrial biopsy for all women with AUB over the
of ultrasonography on days 4–6 of the cycle improves evalu- age of 45. In women under the age of 45, endometrial biopsy
ation of the endometrium for structural abnormalities as it is should be performed when significant risk factors for exposure
the thinnest during these days [38]. Although in postmeno- to unopposed estrogen are present or if the patient does not
pausal women, the correlation between endometrial thick- respond to medical therapy, especially if intermenstrual bleed-
ness and pathologic abnormality has been standardized, in ing is present [12, 38, 41]. Adolescent patients almost never
premenopausal patients there is no accepted normal maxi- need a biopsy except when there is a lack of response to medical
mal thickness of the endometrium. However, measurements therapies [38]. The UK NICE Guidelines suggest endometrial
above 15 mm may raise suspicion of abnormality [38]. biopsy for persistent intermenstrual bleeding or nonresponsive
Sensitivity and specificity of transvaginal ultrasonography AUB in women over age 45 [8]. While patient age dominates
for endometrial pathology are only 56% and 73%, respec- these clinical guidelines to determine when to perform a biopsy,
tively [12], and it has been shown that this imaging tech- there is new data suggesting that BMI should be given higher
nique alone may miss one out of every six intracavitary priority, with an indication for endometrial biopsy in any patient
lesions [38, 41]. For this reason, additional imaging with with AUB and a BMI greater than 30 kg/m2 [42].
sonohysterography and/or endometrial biopsy is also
needed.
Diagnostic Hysteroscopy
Sonohysterography Hysteroscopy involves the insertion of an endoscope through

the cervical canal and using a medium (most commonly nor-
Sonohysterography, also known as hysterosonography or mal saline) to distend the uterine cavity. This allows full
saline-infusion sonography, involves instilling saline through visualization of the cavity and has a 94% sensitivity and 89%
a transcervical catheter to distend the endometrial cavity dur- specificity for detecting intracavitary pathology [35]. This
ing transvaginal ultrasonography. It is well established that procedure can be performed on a conscious patient in the
sonohysterography improves evaluation for intracavitary office or in the operating room on a sedated or anesthetized
pathology with sensitivities ranging from 96 to 100% and patient. It is not recommended as a first-line test for AUB
negative predictive values of 94–100% [22, 35, 38, 41]. evaluation [8] but is reserved for women with inconclusive
However, there is controversy regarding the recommenda- imaging or endometrial biopsy or those with persistent treat-
tions for performing sonohysterography or routine transvagi- ment failure. The “see-and-treat” principle is preferred by
nal ultrasonography as the first-line imaging test for many as abnormalities can be diagnosed and immedi-
evaluation of AUB [8, 41]. ately treated with targeted biopsy or removal [22, 38].
Magnetic Resonance Imaging (MRI) Diagnostic Laparoscopy
MRI is not recommended as a first-line imaging modality AUB alone is not an indication for diagnostic laparoscopy. As
for AUB evaluation [8, 12]. However, MRI does offer most structural causes of AUB are intracavitary, evaluation
advantages for localizing leiomyomas with precision espe- should focus on the endometrial cavity, such as hysteroscopy or
cially in the enlarged uterus [12], and adenomyosis is more sonohysterography. Laparoscopy only allows examination of
easily diagnosed using MRI. Ultrasonography alone pro- the external uterine contour, fallopian tubes, and ovaries. While
vides 72% sensitivity and 81% specificity, while MRI pro- endometriosis may be diagnosed with laparoscopy, it is not a
vides 77% sensitivity and 89% specificity for diagnosis of recognized cause of AUB, but rather a cause of dysmenorrhea,
adenomyosis [26]. dyspareunia, and infertility which often coexist with AUB.
Invasive Testing Treatment
Tamara is referred to a gynecologist for an endome- Tamara follows up with the gynecologist, where her treat-
trial biopsy. The results show fragments of an endome- ment options are discussed and include hysteroscopy,
trial polyp and proliferative endometrium. There was endometrial polypectomy, hormonal therapy options with
no evidence of hyperplasia or malignancy. levonorgestrel IUD, or other progestin therapies.
Medical Management for 5 days reduced menstrual bleeding by 54% compared to

placebo [53]. Another RCT found a significant reduction in
Management of acute severe uterine bleeding is addressed in menstrual blood loss (40.4%) with significant improvement
Chap. 11 on Gynecologic Emergencies. Fortunately, a major- in limitations to activities with tranexamic acid 3.9 g/ day for
ity of patients will present without acute, severe features and 5 days when compared with placebo [56]. Although there is
can be managed as discussed below. a theoretical risk of thromboembolic complications with
tranexamic acid, population studies have not shown an asso-
Expectant Management ciation [57, 58]. Caution is advised when combining
Treatment is tailored to the patient’s need by taking a detailed tranexamic acid and estrogen-containing oral medications
assessment of presenting symptoms, their impact on quality due to the concern for thrombosis [59].
of life, and their potential for worsening. Since there is no
reliable way to objectively measure menstrual blood loss, Other Specific Nonhormonal Therapies
and there is poor correlation between actual blood loss and In women with associated comorbidities complicating
women’s perception of bleeding, hematocrit is often indi- abnormal uterine bleeding, appropriate treatment is neces-
cated to determine severity of blood loss [8, 51]. However, in sary, usually in consultation with a hematologist. Women
the absence of premalignant or malignant conditions, with hemophilia A with factor VIII levels greater than 5%,
patient’s symptoms often dictate the appropriateness of vWD type 1, and some patients with vWD type 2 can be
expectant management. Since obesity and low BMI can both effectively treated with desmopressin [60]. Administered as
be associated with AUB, weight management is an essential an injection (0.3 microgram/kg IV) or as a nasal spray (150
component. Healthy diet and iron supplementation can help microgram), it is particularly effective in acute hemorrhage
delay onset of iron deficiency anemia. or prior to invasive procedures [60]. Factor VIII concentrate
containing vW factor is indicated specifically for treatment
Nonhormonal Options of vWD type 3, vWD type 2B, when there is a poor response
to desmopressin in vWD types 1 and 2A, and for severe
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) acute hemorrhage when a patient is in need of emergent sur-
The anti-inflammatory effect of NSAIDs occurs through gery [60]. The FDA approved recombinant vWF concentrate
inhibition of cyclooxygenase (COX), the enzyme that cata- in 2015 for use in adults with vWD. Although NSAIDs are
lyzes the transformation of arachidonic acid to prostaglan- not effective, tranexamic acid and hormonal treatments are
dins and thromboxanes [16]. This results in inhibition of effective in women with vWD [60].
prostaglandin synthesis. NSAIDs are effective first-line ther- Evaluation and treatment of pelvic infections such as cer-
apies for abnormal uterine bleeding [52]. NSAIDs are par- vicitis, endometritis, and pelvic inflammatory disease is indi-
ticularly useful in women trying to conceive or have other cated if history is suggestive of these conditions. (See Chap.
contraindications to hormonal therapy. 13 on Sexually Transmitted Infections.) Endometriosis and
Oral mefenamic acid 500 mg three times a day for 5 days pelvic congestion syndrome may also be associated with
from day 1 of menses resulted in a 20% reduction of mean abnormal uterine bleeding and dysmenorrhea. Individualized
blood loss compared to placebo [53]. In another double- treatment is necessary to treat these conditions. (See Chap.
blind crossover study, naproxen and mefenamic acid were 31 on Chronic Pelvic Pain.)
compared and found to reduce menstrual blood loss by 46%
and 47%, respectively [54]. Adverse effects include nausea, Hormonal Options
vomiting, and abdominal pain. NSAIDs are contraindicated During the secretory phase of the menstrual cycle, progester-
if there is a coexisting bleeding disorder, platelet dysfunc- one – with its potent anti- inflammatory property – prevents
tion, severe gastroesophageal reflux disease, or other known endometrial shedding. In the absence of a pregnancy, the cor-
contraindications to NSAID use. pus luteum regresses and progesterone levels decline. There
is a sudden release of inflammatory mediators and endome-
Tranexamic Acid trial breakdown ensues [61]. Progesterone is therefore an
The fibrinolytic system plays an important role in menstrua- effective way to combat anovulatory bleeding. Both estrogen
tion. Heavy menstrual bleeding is associated with increased and progesterone are highly effective in modifying endome-
levels of tissue plasminogen activator and reduced levels of trial shedding. The choice of hormones to treat abnormal
plasminogen activator inhibitor 1 [55]. Tranexamic acid is a uterine bleeding is determined less by the etiology and more
synthetic lysine that acts as an antifibrinolytic agent, reduc- by patient preference, ability to comply, side effect profile,
ing tissue plasminogen activator activity in the endometrium and cost-effectiveness. It is notable that a majority of hor-
and elsewhere in the body. A randomized controlled trial monal treatments for abnormal uterine bleeding also pre-
(RCT) showed that tranexamic acid 1 gram, every 6 hours, clude pregnancy [62].
Combined Hormonal Treatment Progestational Agents

Combined hormonal contraceptives contain estrogen and Progesterone and its synthetic derivatives induce secretory
progesterone and are available in oral and parenteral routes change and endometrial atrophy and can be used in AUB
(vaginal ring and transdermal patch). Although the use of especially in women where estrogen is contraindicated [71].
combined estrogen-progesterone formulations for treatment Oral progestogens have been studied in randomized con-
of heavy menstrual bleeding is considered a class effect, trolled trials. Norethindrone acetate and medroxyprogester-
only the combination of oral estradiol valerate with dieno- one acetate, two commonly used progestogens, were assessed
gest has been approved by the US Food and Drug as a short 2-week course as well as a long course lasting at
Administration (FDA) and the European Union for treat- least 21 days per cycle. Trials of the 2-week course of pro-
ment of abnormal uterine bleeding. A pooled analysis of gestogen (used from day 15 or 19 to day 26 of the cycle)
two randomized controlled studies showed that after showed low effectiveness when compared to danazol,
6 months of treatment, median menstrual blood loss tranexamic acid, nonsteroidal anti-inflammatory drugs
decreased by 88% with this formulation compared with (NSAIDs), or levonorgestrel IUD in the treatment of AUB
24% with placebo [63]. The combined formulations are [71]. The results for the longer course of progestogens were
used either in cyclic or continuous regimens depending on more positive. When used for 21 days of the cycle, progesto-
patient preference, the etiology of AUB being treated, and gens led to a significant reduction in menstrual blood loss,
the presence of comorbidities. Extended cycle regimens that though levonorgestrel IUD remained more effective than
reduce the frequency of menstruation are particularly useful oral progestogens [71]. A 21-day course of progestogen use
in patients with anemia, coagulopathy, menstrual migraine, is more effective than the 14-day course: the former led to a
dysmenorrhea, or for occupational reasons (i.e., women sol- 63–78% reduction in menstrual blood loss, while the short
diers with limited ability to manage irregular bleeding). course of progestogens resulted in only a 2–30% reduction in
Cycle control can be achieved with all types of monophasic menstrual blood loss [72, 73]. Oral progestogens are associ-
or triphasic oral contraceptive pills [64–66]. Triphasic com- ated with adverse effects such as headaches, bloating, breast
bined contraceptive pills containing the newer progestins tenderness, weight gain, and acne [69].
(desogestrel, gestodene, and norgestimate) have better cycle
control compared with those with norethindrone or levo- Long- acting injectable progestin Treatment with depot
norgestrel [64]. medroxyprogesterone acetate (DMPA) every 3 months given
High-dose combined oral contraceptive pills are also use- intramuscularly or subcutaneously leads to amenorrhea in
ful in acute heavy uterine bleeding, and this is addressed in 50% of women [74]. However, the side effects such as irreg-
Chap. 11 on Gynecologic Emergencies [65]. ular bleeding, weight gain, acne, and bloating affect the
The side effects include mood changes, headaches, nau- acceptability of this intervention [70]. Irregular bleeding
sea, fluid retention, breast tenderness and, rarely, venous from DMPA use can be controlled temporarily with short
thromboembolism, stroke, or myocardial infarction [8]. The courses of COX2 inhibitors [75] or estrogen [76]. There is an
thromboembolic risk is estrogen dose-dependent and also association of thromboembolism with the use of injectable
varies with type of progestin. For example, when compared progestins [77] with odds ratio ranging from 2.2 to 3 com-
to nonusers, odds ratio (OR) for thromboembolic events are: pared to nonusers, although this risk may translate to few
levonorgestrel formulations OR 3.6, gestodene OR 5.6, women in absolute numbers [78]. There is also an increased
desogestrel OR 7.3, and drospirenone OR 6.3. Despite the risk of decreased bone mineral density with injectable
elevated risk, the absolute risk remains quite low for all for- medroxyprogesterone acetate [79], but this appears to be
mulations in women without additional thromboembolic risk reversible over a few years after stopping therapy [80].
factors [67]. The transdermal combined contraceptive patch
has a twofold higher thromboembolic risk compared to The levonorgestrel intrauterine device (LNG IUD) is a
norgestimate- containing oral contraceptive pill [68]. highly effective treatment for women with nonstructural
Norgestimate is a third-generation progestin, like desoges- AUB as well as structural causes such as adenomyosis and
trel, and is less androgenic and a weaker progestin than levo- small leiomyomas. The progestin component leads to inhibi-
norgestrel [60]. An additional benefit of combined hormonal tion of endometrial proliferation and eventual atrophy of the
formulations is the contraceptive effect. Contraindications to endometrial tissue. As noted above, the LNG IUD is more
the use of estrogen-containing formulations include a history effective than other medical therapies for heavy menstrual
of deep vein thrombosis, presence of cardiovascular risk fac- bleeding [81]. Patients experienced consistent reduction in
tors, and a history of smoking in women over 35 years of vaginal bleeding of greater than 72% in the first 3 months of
age. Please see Chap. 4 on Patient-Centered Contraceptive treatment with further reduction of bleeding during the first
Counseling for more information [69, 70]. year of use that was maintained for up to 4 years of use [81].
When compared to endometrial ablation, satisfaction rates Medical treatment of specific conditions Endometrial
and quality of life measures were similar [82]. While both hyperplasia without atypia is best managed by referral to
treatments improved quality of life, the LNG IUD appeared gynecologists where it can be managed with continuous pro-
more cost-effective than hysterectomy for up to 10 years gestin therapy. Typically, patients and gynecologists will
after treatment [82]. choose between depot medroxyprogesterone acetate
Levonorgestrel IUD is associated with minor adverse (DMPA), continuous oral norethindrone acetate (5 mg daily),
effects such as irregular vaginal bleeding compared with oral megestrol (10 mg daily), and levonorgestrel IUD [89].
therapy. There was a 7% expulsion rate mainly in the first Biopsies should be repeated periodically to ensure resolution
6 weeks and a 1:1000 risk of uterine perforation during inser- of endometrial hyperplasia.
tion [72]. Although it is also likely to suppress ovulation
especially in the first year of use, LNG IUD causes less sys-
temic side effects compared to oral or injectable progestins Surgical Management
[73]. Other side effects of levonorgestrel IUD include breast
tenderness, ovarian cyst, acne, and pain [72]. Surgical management of AUB is indicated when the patient
Gonadotrophin-releasing hormone agonists as well as exhausts trials of medical management and continues to have
antagonists suppress the pituitary-ovarian axis and decrease bothersome bleeding [8]. The precise procedure should be
follicle-stimulating hormone as well as luteinizing hormone. based upon findings from the evaluation. Newer technolo-
This results in a hypogonadal-menopause-like state. The gies such as uterine fibroid embolization, magnetic
resulting endometrial atrophy causes amenorrhea, with rates resonance-guided focused ultrasound ablation of leiomyo-
of 90% reported [83]. There is also a temporary decrease in mas, and myolysis (destruction of leiomyoma) using radio-
size of leiomyomas. However, side effects such as vasomotor frequency energy provide multiple minimally invasive
symptoms, vaginal atrophy, bone loss, and depression are uterus-preserving options for women. Similar advances in
common and preclude its prolonged use [61]. This therapy is operative hysteroscopy techniques for removal of intrauter-
most useful preoperatively in patients with leiomyomas and ine pathology, global endometrial ablation using different
in patients with endometriosis associated with AUB. energy sources, and minimally invasive hysterectomy have
Danazol is a weak androgen that inhibits follicle- radically transformed the choices available to treat AUB.
stimulating hormone and luteinizing hormone. It is found to
reduce menstrual blood loss more effectively than placebo,
progestins, NSAIDs, or combined oral contraceptive pills Minimally Invasive Options
[84]. Significant androgenic side effects such as hot flashes,
myalgia, acne, and weight gain limit its use. It is an FDA- Most surgical therapies for AUB can be performed in a mini-
approved medication for heavy menstrual bleeding but is mally invasive fashion, allowing faster recovery, shorter hos-
only used when other hormonal methods, NSAIDs, pitalization, and quicker return to normal daily activities.
tranexamic acid, and surgery are contraindicated.
Selective progesterone receptor modulators (SPRMs) Hysteroscopy
inhibit proliferation in the endometrium resulting in amenor-
rhea [30, 85]. Two landmark randomized controlled trials [86, Polypectomy
87] have studied the use of oral ulipristal acetate in women Detection of endometrial polyps during evaluation of AUB
with heavy menstrual bleeding associated with fibroid uterus. should prompt referral for hysteroscopic removal.
Approximately 50% of the patients in the 5-mg daily ulipris- Hysteroscopy allows complete visualization of the endome-
tal acetate group and 70% of the patients in the 10-mg daily trial polyp and ensures complete removal. Endometrial
group became amenorrheic within the first 10 days. Headache curettage without concurrent hysteroscopy does not ensure
and breast discomfort were the most common adverse events complete removal of the polyp [90]. Similar to diagnostic
in the ulipristal acetate groups. Both doses of ulipristal were hysteroscopy, this procedure can be performed safely in the
non-inferior to once-monthly leuprolide acetate in controlling office, which reduces costs and increases patient satisfaction
uterine bleeding and were significantly less likely to cause hot due to convenience and reduced recovery time [8, 12].
flashes. SPRMs cause benign endometrial changes that are Polypectomy has been shown to reduce 75–100% of AUB
not precancerous [88]. Although the use of ulipristal for leio- symptoms when endometrial polyps are diagnosed [35].
myoma is not approved by the FDA, it is approved in the
European Union for this indication. Reports of elevated liver Myomectomy
enzymes in a few patients have resulted in a recommendation Submucosal leiomyomas are candidates for removal via hys-
to closely monitor liver function in patients taking ulipristal teroscopy when they measure less than 4–5 cm in largest
for more than 3–6 months [88]. diameter [91]. Larger size and increased depth of leiomyoma
penetration into the myometrium increase the need for multi- fluoroscopic guidance, embolic material is targeted to
ple procedures for complete removal [92]. If the leiomyoma occlude the blood vessels supplying symptomatic fibroids
completely traverses the myometrium and contacts or distorts [95]. Relative contraindications include solitary fibroids
the uterine serosa, hysteroscopic approaches are contraindi- measuring greater than 10 cm in diameter or a multi-fibroid
cated due to the risk of uterine perforation. This can be uterus greater than 20 weeks’ gravid size [95]. Although
assessed well with transvaginal ultrasonography, but MRI is desire for fertility is considered a contraindication, reports of
the best modality to identify the proximity of leiomyoma to healthy pregnancies after uterine fibroid embolization exist.
the uterine serosa [92]. Hysteroscopic resection of leiomyoma The main concern in pregnancy after uterine fibroid emboli-
allows a patient to retain fertility and may reduce the incidence zation is a morbidly adherent placenta [95]. Recovery is
of recurrent pregnancy loss [93]. Hysteroscopic myomectomy faster than surgical treatments and there is a lower rate of
is an outpatient procedure with a short recovery time for the major complications [95]. However, at 5 years post-
patient. Risks of this procedure include uterine perforation, procedure, there is a 28% reintervention rate after uterine
fluid and electrolyte disturbances from intravasation of disten- fibroid embolization compared to 9% after non-hysteroscopic
sion medium into the blood vessels, hemorrhage, and intra- myomectomy or hysterectomy [95].
uterine adhesions which can negatively impact fertility [92].
agnetic Resonance-Guided Focused
M
Endometrial Ablation Ultrasound Ablation (MRgFUS)
Endometrial ablation is a procedure where the endometrium, MRgFUS uses high-intensity ultrasound waves to destroy
down to its basal layer, is either resected or destroyed perma- fibroids in order to improve symptoms of bulk pressure or
nently in order to decrease uterine bleeding. The procedure is AUB. This procedure is also performed under conscious
often performed in the gynecologist’s office or an outpatient sedation by interventional radiologists. Pain is typically mild,
surgery center under local anesthesia along with oral, intra- but treatment sessions last several hours and occasionally
muscular, or intravenous pain relief and sedation. It can require additional sessions [95]. A patient lies in prone fash-
only be considered in women who no longer desire fertility. ion on a specially designed bed while real-time MRI guides
As endometrial ablation itself does not act as an effective ultrasound beams to focus into a fibroid and cause coagula-
contraception, the provider must ensure the patient has reli- tive necrosis. The FDA has approved its use in women desir-
able contraception in place or combine the ablation proce- ing future pregnancy [95]. Contraindications are similar to
dure with permanent sterilization. those for MRI such as the presence of shrapnel, metal
Endometrial ablation is generally accepted as appropriate implants, or defibrillators [95]. Patient satisfaction remains
for patients with a uterus less than 10 weeks’ gravid size and high, with a similar reintervention rate (23% over 4 years) to
having a regular uterine cavity. Some endometrial ablation uterine fibroid embolization in a non-comparative study [95].
devices have shown success in the presence of <3 cm submu-
cosal leiomyomas [8, 94]. Rates of amenorrhea vary in reports yolysis: Radiofrequency Thermal Ablation
M
from 15 to 72%, but 85–98% of women report satisfaction with Myolysis is also known as radiofrequency thermal ablation
the reduction in bleeding [94]. However, levonorgestrel IUDs and is available in a laparoscopic or hysteroscopic platform
have been shown to have similar efficacy in reducing menstrual for use by trained gynecologists. Under intraoperative ultra-
blood loss compared to endometrial ablation for at least 2 years sound guidance, electrode arrays are deployed into fibroids
following initiation of therapy [94]. to cause coagulative necrosis via radiofrequency ablation.
Short-term complications of endometrial ablation include Compared to laparoscopic myomectomy, laparoscopic
endometritis (2.0%), urinary tract infection (1.67%), and myolysis showed the ability to treat more fibroids (98.6%
hematometra (1.48%) [94]. If future pregnancy occurs, versus 80.3%) while incurring less blood loss and shorter
increased rates of ectopic pregnancy (7.5%), preterm birth hospitalization [95]. Pregnancy appears safe following
(25%), and morbidly adherent placenta (7.5%) may occur myolysis, but data is limited. There is limited availability of
[94]. Lastly, up to 20–25% of women report pain after endo- this procedure in the USA.
metrial ablation, and many proceed to a hysterectomy at a
later date [94]. This is most common when leiomyoma, ade-
nomyosis, or pelvic endometriosis are present and is more Other Surgical Options
probable if the patient has also undergone bilateral tubal
occlusion at any time [26, 94]. Abdominal Myomectomy
Large submucosal, any intramural, and any subserosal leio-
terine Fibroid Embolization
U myoma thought to be causing AUB or bulk symptoms can be
Uterine fibroid embolization is performed by interventional removed through abdominal myomectomy. Some consider it
radiologists with the patient under conscious sedation. Under the gold standard procedure for patients desiring preserva-
tion of fertility with pregnancy rates of 57–69% following classified). Many patients will have AUB from more than
the procedure [96, 97]. Shorter recoveries are seen with min- one cause.
imally invasive options, including laparoscopy and minilapa-
rotomy, compared to laparotomy. Complication rates of
abdominal myomectomy are between 8% and 11% and Evaluation
include infection and blood loss with a need for transfusion
[96]. Recurrence of leiomyomas is common following myo- 1. A thorough history and physical exam should be performed
mectomy with rates of 11.7% after 1 year and 84.4% at in all patients, including menstrual history, sexual history,
8 years. However, reoperation rates remain low with only and a structured screening history for coagulopathy.
16% of patients needing it over 8 years [96]. 2. Evaluation will vary based on age and comorbidities.
3. The preferred method of imaging for AUB is ultrasonog-
Hysterectomy raphy of the pelvis, especially transvaginal sonography.
Hysterectomy involves the complete removal of the uterus 4. Endometrial biopsy should be performed in all women over
and is the only definitive therapy of AUB [97]. Quality of life age 45, considered in all women with BMI > 30 kg/m2,
is typically improved within 3 months of surgery [97]. and in those women failing to respond to therapies.
Similar to abdominal myomectomy, hysterectomy can be 5. Postmenopausal bleeding is never normal; the approach
accomplished with shorter recovery times if a laparoscopic differs from that of AUB in that all patients with post-
or vaginal approach is used, while laparotomic route needs a menopausal bleeding require immediate evaluation in
longer recovery period. One randomized controlled trial conjunction with a gynecologist.
allocated 63 women aged 30–50 years with at least 2 months
of AUB to medical management or hysterectomy [98]. The
hysterectomy group had significantly more improvement in Medical Management
multiple quality of life domains and sexual functioning but
used more healthcare resources in the first 12 months follow- 6. Nonhormonal options such as NSAIDs and tranexamic
ing randomization. Within 24 months of randomization, 16 acid are first-line therapies.
of the 30 women allocated to medical management under- 7. Hormonal therapies are more cost-effective when admin-
went hysterectomy. The authors concluded that with AUB istered parenterally (depot medroxyprogesterone injec-
refractory to medical management at 6 months, better symp- tions, levonorgestrel intrauterine device), but a
tom improvement was seen with hysterectomy than contin- combination of estrogen and progesterone via either com-
ued medical management [98]. bined oral contraceptive pill or vaginal ring may provide
a more acceptable bleeding profile.
Tamara opts for the placement of a levonorgestrel

IUD. At her follow-up primary care visit 4 months Surgical Management
later, she notes resolution of her abnormal uterine
bleeding. While she continues to endorse hot flashes, 1. Surgical management is often the preferred management
they are minimally bothersome at this point, and she is for structural causes of AUB and may be a component of
happy with her treatment. therapy for nonstructural causes as well.
2. There are numerous surgical options for managing AUB
which can often be performed in noninvasive or mini-
mally invasive fashion; patients may retain the ability to
Summary Points safely conceive pregnancies after some surgical
interventions.
Pathophysiology
1. Abnormal uterine bleeding is defined as bleeding that

creates a bothersome negative effect on quality of life; R eview Questions
there are no specific duration, frequency, and quantity of
bleeding limits to the diagnosis. 1. A 40-year-old woman with a BMI of 42 kg/m2 presents
2. The FIGO classification system of AUB, “PALM- with irregular heavy menstrual bleeding that occurs two
COEIN,” is a useful mnemonic to remember structural to three times a year. The next step in the evaluation must
causes (polyps, adenomyosis, leiomyomas, and malig- rule out the following condition:
nancy) and nonstructural causes (coagulopathy, ovulatory A. Idiopathic thrombocytopenic purpura
dysfunction, endometrial, iatrogenic, and not otherwise B. Atypical endometrial hyperplasia
C. Polycystic ovary syndrome only pill is not effective in controlling menstrual bleeding
D. Coagulation disorder and is a contraceptive. Clomiphene citrate is a selective
E. Menopause estrogen receptor modulator used to induce ovulation and
The correct answer is B. This patient has a history of is not indicated in a patient with regular cycles who is
irregular periods that suggests anovulatory bleeding. In likely to be ovulating.
addition, her obesity results in excessive peripheral aro-
matization of androgens to estrogen. The endometrium is 4. A 56-year-old multiparous woman reports that she had a
therefore exposed to unopposed estrogen. The most 3-day episode of light vaginal bleeding 2 months earlier.
important condition to rule out, with an endometrial Her past episode of menstrual bleeding was 2 years ear-
biopsy, would be endometrial hyperplasia, atypical hyper- lier. Pelvic examination is normal and cervical cancer
plasia, or endometrial cancer [12]. Idiopathic thrombocy- screening is up to date. The next step in evaluation is:
topenic purpura and coagulation disorder present with A. Reassurance that sometimes ovulation can occur spo-
regular heavy menstruation along with history of other radically during the first few years of menopause.
bleeding sites such as petechiae, epistaxis, and bleeding B. Discuss the importance of continuing contraception
gums [44]. Menopause results in absence of menstrual to prevent unplanned pregnancy.
bleeding. C. Discuss the need for further evaluation with pelvic
sonography to evaluate the endometrial thickness.
2. A 30-year-old nulliparous woman, who is trying to con- D. Explain that she will need endometrial biopsy if she
ceive, complains of regular, monthly, heavy menstrual has another episode of vaginal bleeding.
bleeding. Her BMI is 28, and her hemoglobin measures The correct answer is C. Postmenopausal bleeding
10gm/dL. Her last normal period started 4 days ago. The needs appropriate evaluation to rule out endometrial can-
next step in the evaluation most likely to determine the cer and hyperplasia. Other causes of postmenopausal
cause of heavy menstrual bleeding is: bleeding in this patient include endometrial polyp or
A. Serum iron panel genital atrophy. The initial approach to a woman with
B. Pelvic ultrasonography postmenopausal bleeding is to evaluate the endometrium
C. Serum quantitative hCG with transvaginal ultrasonography. Depending on the
D. von Willebrand panel thickness of the endometrium, she may need office endo-
The correct answer is B. Common causes of heavy metrial biopsy [43]. Reassurance without further evalua-
regular menstrual bleeding in a 30-year-old woman tion or waiting for recurrent bleeding is not appropriate
include leiomyomas and adenomyosis [15]. Thyroid dys- and may lead to delayed diagnosis of endometrial cancer.
function and coagulation disorders are less common Follicle-stimulating hormone is not indicated and does
causes. Serum iron is not indicated in most women unless not help in the evaluation of postmenopausal bleeding.
oral iron therapy fails to correct the anemia even after Although there is a small possibility that this patient is
control of heavy menstrual bleeding [8]. While a urine not in menopause, likelihood of pregnancy in a 56-year-
pregnancy test is cost-effective and indicated, a quantita- old who has not had a spontaneous period for 2 years is
tive hCG assay is not indicated. very low.
3. A 35-year-old nulliparous woman, who is trying to con- 5. An 18-year-old nulliparous woman presents with irregu-
ceive, complains of regular monthly heavy menstrual lar vaginal bleeding over the last 2 weeks. Based on your
bleeding. She desires treatment to reduce the 7 days of office records, she is compliant with depot medroxypro-
heavy bleeding. The best option for management would gesterone injections for contraception. The next step in
be: the evaluation of her AUB is:
A. Clomiphene citrate A. Urine pregnancy test
B. Levonorgestrel IUD B. TSH, LH, and FSH
C. Mefenamic acid C. von Willebrand panel
D. Combined oral contraceptive pill D. Testing for chlamydia
E. Progesterone-only pill The correct answer is D. Cervicitis, salpingitis, and
The correct answer is C. NSAIDs are the first line for pelvic inflammatory disease can present with irregular
treatment of heavy menstrual bleeding in ovulatory cycles vaginal bleeding and are common in sexually active
as well as anovulatory cycles [8, 41, 57] and do not pre- women under the age of 25 [12, 36]. Abnormal uterine
clude pregnancy. Since the patient is actively trying to bleeding in a young woman on progestin-only contracep-
conceive, levonorgestrel IUD and combined oral contra- tion of short duration does not need any other evaluation
ceptive pill are not indicated although they are effective in since breakthrough bleeding is a common side effect of
treating heavy menstrual bleeding [8]. The progesterone- any hormonal contraception, particularly progestin-only
types. The perfect use of depot medroxyprogesterone mcw.edu/content.aspx?bookid=1758&sectionid=118165489.

Accessed 24 Nov 2018.
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Menopause
8
Molly Ainsman Fisher, Akeira L. Johnson,
and Rachel A. Bonnema
Learning Objectives Definition

1. Define menopause and describe the related changes
in hormones. Change in the menstrual cycle is the defining feature of
2. Describe the clinical manifestations of menopause. menopause. During the late reproductive years, women often
3. Compare and contrast the hormonal and nonhor- experience subtle changes in flow and length of their cycles.
monal medications used to treat the symptoms of During perimenopause, women undergo marked fluctuations
menopause. in sex hormone levels; cycles become more variable typi-
4. Examine the evidence behind the safety of hor- cally with lengthening cycles, followed by skipped cycles
monal therapy and counsel a patient about the risks and episodes of amenorrhea, with increasing frequency of
and benefits. anovulatory cycles [1]. The hormonal fluctuations at this
time, including declining estrogen levels, contribute to neu-
rochemical changes within the central nervous system and
lead to vasomotor menopausal symptoms [2].
Sasha is a 53-year-old female who presents to your Menopause is a clinical diagnosis defined retrospectively
clinic for worsening symptoms of vaginal irritation as 12 months without a menstrual cycle. For women over
and intermittent hot flashes. She has had no vaginal 45 years of age, this change in menses can be expected and
bleeding for 18 months; prior to that her menses were further testing is often not necessary. The average age of
irregular for 2 years. She describes five to six hot menopause is 51, though it can normally occur between ages
flashes per day, lasting less than 30 minutes each, and 45 and 55 (or even later) [3]. Though likelihood of pregnancy
has developed drenching night sweats. She describes does significantly decrease at this age, pregnancy is in the
her vaginal symptoms as very dry in between episodes differential diagnosis of amenorrhea after age 45, and a preg-
of discharge. She is happily married to her husband of nancy test is warranted if the patient is having sex without
28 years. Recently when they have tried to engage in contraception. If other symptoms are present, consideration
vaginal penetrative intercourse, it feels as if her geni- of thyroid testing is reasonable. Though elevated FSH is
tal skin is “ripping.” She sometimes wears a panty expected in a postmenopausal woman, an elevated FSH is
liner because of thin vaginal discharge and she is wor- not required to make the diagnosis, and checking an FSH
ried she may have an infection. She also wonders if the level can be misleading. Therefore, clinicians should make a
infection has caused her night sweats. clinical diagnosis of menopause in a woman over age 45
with 12 months of amenorrhea in the absence of other causes.
M. A. Fisher Clinical Manifestations

Allegheny Health Network, Pittsburgh, PA, USA
A. L. Johnson The most common manifestation of both perimenopause and
Clement Zablocki VA, Department of General Internal Medicine, menopause is vasomotor instability, occurring in approxi-
Milwaukee, WI, USA
mately 75% of women [2]. Vasomotor symptoms (VMS) are
R. A. Bonnema (*) described as hot flashes and sweating that last for less than
University of Texas Southwestern Medical Center,
Dallas, TX, USA 5 minutes and are often followed by a chill. Hot flashes are
e-mail: [email protected] referred to as night sweats when they occur at night. VMS

118 M. A. Fisher et al.
are regulated by the anterior hypothalamus [4]. Increased tion a critical time for women who may be vulnerable to
cutaneous blood flow from inappropriate peripheral vasodi- anxiety disorders [2].
lation leads to the feeling of warmth. There is evidence that It is extremely common for women to complain of forget-
cigarette smoking may worsen VMS, but evidence that other fulness and issues with concentration during perimenopause,
factors (obesity, inactivity, and socioeconomic) contribute and while female sex hormones are important in cognitive
has been inconclusive [5]. The duration of VMS is variable: function [8], longitudinal studies have not confirmed cogni-
half of women experience resolution within 5 years, but tive decline in menopause [9]. Perimenopausal women with
about 10% women will report VMS for 10–12 years after increased anxiety or depression are at higher risk for mem-
menopause. Women who experience VMS earlier in the peri- ory problems. Additionally, sleep disturbance can also con-
menopausal transition tend to experience them longer into tribute to cognitive complaints. Further research is needed to
postmenopause [2]. better define the relationship between menopause and cogni-
Genitourinary syndrome of menopause (GSM) is caused tive dysfunction. Currently, there is no known association
by a hypoestrogenic state and is characterized by an increase between timing of menopause, change in hormones, and risk
in the vaginal pH, vaginal dryness, loss of labial fullness, and for dementia [9].
loss of vaginal rugae and elasticity. Second to vasomotor Women often note back and joint pain during perimeno-
symptoms, GSM is one of the most common complaints of pause/menopause, independent of associated osteoarthritis.
menopausal women. Unlike vasomotor symptoms that Unfortunately, many of the issues already outlined as occur-
improve with time, symptoms of GSM typically worsen ring during menopause can contribute to pain, such as sleep
throughout a woman’s life with progressive decline in estro- disturbance or depression. The complaint of pain in meno-
gen levels. pausal women can be related to endogenous hormone
GSM should be evaluated clinically with a pelvic exam. changes, medications that alter hormone effects (such as aro-
The exam should begin with full inspection of the vulva, matase inhibitors), situational stress, or concomitant meno-
assessing for evidence of vulvar agglutination and clitoral pausal symptoms [10].
phimosis, in addition to inspection for any lesions or skin
changes. A small or pediatric speculum can be used with
adequate lubrication for the internal exam. Inspection of the Sasha’s general exam is normal. Her vulva is erythem-
vaginal tissue should include examining for any evidence of atous without any lesions or ulcerations. Upon inser-
loss of rugae, petechiae, or cervical lesions. Normal vaginal tion of a Pederson speculum, you see that her vaginal
tissue may be replaced with less elastic tissue that appears mucosa has a pale and shiny appearance with a loss of
thinner, shinier, and easily friable. Measuring vaginal pH can vaginal rugae. There are petechiae and her vaginal pH
assist in the diagnosis; due to loss of estrogen, menopausal is 6. She does not have any evidence of bowel or blad-
vaginal pH is >4.5. A bimanual exam is not required unless der prolapse. The cervix appears grossly normal.
there is a necessity to evaluate for pelvic pain or pelvic floor Sasha is very interested in potential treatments to help
dysfunction. improve her sexual health, decrease her vaginal dis-
Many perimenopausal and menopausal women will charge, and get rid of her disturbing night sweats.
experience a multitude of other symptoms including sleep
disturbances, mood changes, cognitive complaints, and
musculoskeletal issues. Sleep disturbances can be second-
ary to hot flashes or night sweats and may be compounded Treatment
by anxiety and depression symptoms. Sleep issues may
also be exacerbated by obstructive sleep apnea, which The initial approach to women with menopausal symptoms,
affects more women in postmenopause than premeno- specifically vasomotor symptoms, is to start with lifestyle
pause [2]. modifications. Suggestions such as lowering room tempera-
Multiple studies have shown that women in the meno- tures, using fans, dressing in layers, and avoiding triggers
pausal transition are more likely to report a depressed mood such as spicy foods or alcohol may be helpful. If those do not
than premenopausal women. One study demonstrated that alleviate symptoms or if women have severe VMS, it is
women were significantly more likely to report depressive appropriate to consider pharmacologic therapy.
symptoms during early perimenopause, late perimenopause, Menopausal hormone therapy (MHT) is the mainstay of
and postmenopause [6], and women with a personal history symptom management. It is defined as estrogen or combined
of depression are at risk of relapse during the menopausal estrogen-progestin therapy to treat menopausal symptoms
transition [7]. Data also shows that anxiety levels may be [11]. MHT has been the topic of much debate over the past
increased during perimenopause, independent of a prior his- several decades. Several large clinical trials have caused the
tory of anxiety disorder, thus making the menopausal transi- pendulum of best practices in MHT prescribing to swing
8 Menopause 119
back and forth. It is important for prescribers to understand sure to higher concentrations of endogenous estrogen
the history and scientific literature of MHT in order to best increases a woman’s risk of breast cancer, exogenous estro-
provide patient-centered counseling on its use. Current con- gen may do the same. A large meta-analysis suggested that
sensus is that in healthy, recently menopausal women with for each year a woman uses MHT, her risk of breast cancer
symptoms, the benefits of MHT outweigh its risks [11]. increases by 2.3% [14]. It is important to note that most of
The Women’s Health Initiative (WHI) was designed to these women were using CEE/MPA, which are no longer the
evaluate longitudinal hormone use for the prevention of heart recommended first-line MHT formulations. The WHI dem-
disease in postmenopausal women, as was common practice onstrated an increased risk for breast cancer with CEE/MPA
at the time [12]. This randomized clinical trial examined the therapy, although these women were older than most who
use of conjugated equine estrogens (CEE) combined with would benefit from MHT for symptom control, and increased
medroxyprogesterone acetate (MPA) in over 27,000 women age is an important risk factor for breast cancer [12, 15]. The
aged 50–79 years. The trial was ended early due to safety attributable risk of breast cancer in the WHI CEE/MPA
concerns; results demonstrated an increased risk of cardio- group, where the average age was 63 years, is less than 1
vascular disease, stroke, venous thromboembolism, and additional case of breast cancer diagnosed per 1000 users
breast cancer among women who used hormones compared annually. To put this in perspective, this risk is less than the
with placebo [12]. Multiple studies have since been pub- risk associated with two daily glasses of wine and similar to
lished reexamining these data by age and time since meno- the risk associated with obesity or low physical activity [16].
pause leading to development of the timing theory, which is Please see Chap. 20 on Care of the Breast Cancer Survivor
that MHT is safer in younger menopausal women. Since the for treatment of hot flashes in breast cancer survivors.
WHI, much of the relevant scientific exploration tested this
theory.
Deciding which patients are good candidates for MHT isk of Coronary Heart Disease, VTE,
R
requires a stepwise process that weighs the risks and benefits and Stroke with MHT
of the treatment. MHT is extremely effective in managing
symptoms and has been approved by the Food and Drug Age appears to play a strong role in the effects of MHT on
Administration (FDA) for bothersome vasomotor symptoms, cardiovascular disease. A 2015 Cochrane review found that
premature ovarian insufficiency, and genitourinary symp- MHT initiated fewer than 10 years after menopause lowered
toms [11]. However there are risks associated with this treat- CHD in postmenopausal women, reduced all-cause mortal-
ment, which are influenced by patient age, number of years ity, and showed no increase in stroke, though there was an
since menopause, comorbidities, and family history. MHT is increased risk of VTE [17]. Further studies have shown that
considered to be safest in women who are less than 60 years the formulation of estrogen and progesterone may have an
of age or within 10 years of menopause onset [11]. Risks impact on this VTE risk. For estrogens, lower oral doses or
include potentially higher rates of breast cancer, coronary transdermal doses may have a lower risk, and vaginal estro-
heart disease (CHD), and venous thromboembolic (VTE) gen carries no increased risk at all [18]. For progestins,
disease. These are discussed in detail below. Absolute con- micronized progesterone may carry a lower risk for throm-
traindications include unexplained vaginal bleeding, prior bosis. Medroxyprogesterone acetate (MPA) has been associ-
estrogen-sensitive breast or endometrial cancer, coronary ated with an excess risk of CHD and breast cancer when
heart disease, stroke, dementia, personal history or inherited administered with conjugated estrogen. The WHI did dem-
high risk of thromboembolic disease, severe active liver dis- onstrate an increased risk in CHD in women who started
ease, porphyria cutanea tarda, or hypertriglyceridemia [11]. MHT more than 10 years postmenopause [12]. A meta-
For women who have an intact uterus, unopposed estro- analysis of 19 randomized controlled trials, including the
gen therapy carries a high risk of endometrial hyperplasia WHI, demonstrated that for women of all ages, MHT was
and cancer [13]. Therefore, women with a uterus must be on associated with an extra 6 strokes, 8 cases of VTE including
either progestin or bazedoxifene to protect the uterus from pulmonary embolism (PE), and 4 cases of pulmonary embo-
the negative effects of estrogen. It is important to note the lism (PE) per 10,000 women; the risk of CHD was not sig-
estrogen alone carries different risks than combined estrogen nificant [17].
and progestin. These risks are discussed in detail below.
Benefits of MHT
Risk of Breast Cancer with MHT
MHT has been demonstrated to have significant health ben-
There is a complicated relationship between MHT and the efits beyond improving quality of life by alleviating meno-
risk for breast cancer. Theoretically, since prolonged expo- pausal symptoms, although it is not recommended to use
MHT for the prevention of any disease [11]. MHT prevents Prescribing MHT
bone loss in postmenopausal women by inhibiting osteoclast-
driven bone resorption and reducing the rate of bone remod- The first step of initiating MHT is deciding if a woman is a
eling. It therefore prevents osteoporosis and fractures [19]. good candidate. Women who are less than 60 years old or
In addition, MHT has been shown to decrease the risk of type less than 10 years postmenopause, and do not have absolute
2 diabetes mellitus, decrease the accumulation of abdominal contraindications or excess cardiovascular or breast cancer
adipose tissue, as well as decrease the incidence of colorectal risks, are eligible for MHT [20]. The algorithm depicted in
cancer [15]. Fig. 8.1 outlines how to determine a patient’s candidacy for
Fig. 8.1 Algorithm for Algorithm for Menopausal Therapies

menopausal therapies
(Reprinted from Stuenkel
et al. [20], by permission of Initial history Consider
• Is she having menopausal symptoms? No nonhormonal
Oxford University Press)
• Is she interested in menopausal hormone therapy? options
• Is she age <60 years or <10 years since menopause?
Yes
Focused history: contraindications to hormonal

therapies
• Absolute contraindications: unexplained vaginal Consider
bleeding, stroke, TIA, MI, PE, VTE, breast or Present nonhormonal
endometrial cancer, and active liver disease options
• Relative contraindications: diabetes,
hypertriglyceridemia, active gallbladder disease,
increased risk of CHD or breast cancer, migraines with
aura
Absent
Assess cardiovascular risk

using ASCVD calculator
• <5% 10-year risk is low High risk Consider
• 5-10% 10-year risk is moderate nonhormonal
• >10% 10-year risk is high options
Low or
moderate* risk
Assess breast cancer risk using Consider

High risk nonhormonal
BCRA risk calculator
options
• <1.67% 5-year risk is low
• 1.67-5% 5-year risk is moderate
• >5% 5-year risk is high
Low or
moderate^ risk
Good candidate for hormone therapy
* For moderate cardiovascular risk, use transdermal estrogen and add micronized progesterone if she
has a uterus
^ For moderate breast cancer risk, use with caution
TIA = transient ischemic attack; MI = myocardial infarction; PE = pulmonary embolism; VTE = venous
thromboembolism; CHD = coronary heart disease
8 Menopause 121
hormonal therapy. Examples of hormonal formulations are The initial recommendation is to start with transdermal
seen in Table 8.1. 17-beta estradiol. A large meta-analysis has shown no
Once a patient has decided to initiate MHT, the first step increased risk of VTE with transdermal estrogen [22]. There
is choosing an estrogen. Estrogen comes in multiple forms may also be a decreased risk of stroke with transdermal as
and all systemic forms are equivalent for treating symptoms. opposed to oral, but the data are conflicting [20]. If the
Table 8.1 Selected hormonal options for menopausal symptoms

Commonly prescribed estrogens
Mode of
delivery Preparation Example products and typical doses Costa Comments
Oral Micronized estradiol Estrace 0.5–2.0 mg/d $18 Structurally identical to estrogen made by
premenopausal ovary
Conjugated equine Premarin 0.3–1.25 mg/d $200 Used in the Women’s health initiative (WHI)
estrogen (CEE) trial
Esterified estrogen Menest 0.3–1.25 mg/d $100
Estropipate Ogen 0.75–3 mg/d $20
Transdermal Twice-weekly estradiol Vivelle-dot 0.025–0.1 mg/d $85
patch
Weekly estradiol patch Climara 0.025–0.1 mg/d $75
Topical estradiol gel Elestrin 0.06% (dosing varies based on $105 Can be transferred to other people or pets by
brand and product) skin contact
Topical estradiol spray Evamist 1.53 mg/spray $160 Can be transferred to other people or pets by
skin contact
Vaginal Estradiol ring – with Femring 0.05–0.1 mg/d $530 Cost/unit, lasts for 90 days
systemic effects
Estradiol ring – with only Estring 7.5 mcg/d $500 Cost/unit, lasts for 90 days
local effects Only for genitourinary symptoms
Estradiol tablet Vagifem 10 mcg/tab, 2–3 times per $170 Only for genitourinary symptoms
week
Estradiol or CEE cream Estrace 0.1 mg/g, 2–3 times per week $100 Only for genitourinary symptoms
Premarin 0.625 mg CEE/g, 2–3 times
per week
Commonly prescribed progestins (often used in conjunction with systemic estrogen formulations)
Mode of Product
delivery Preparation names Doses Cost Comments
Oral Medroxyprogesterone acetate Provera Cyclic: 5–10 mg/d for 12 days $12 Most common, used in WHI
(MPA) each calendar month
Continuous: 1.25–2.5 mg/d
Micronized progesterone Prometrium Cyclic: 200 mg/d for 12 days each $50 Avoid brand name if peanut
calendar month allergy, generic is safe
Continuous: 100 mg/d
Intrauterine Levonorgestrel-releasing Mirena Change every 5 years
Commonly prescribed combined estrogen/progestins

Mode of delivery Preparation Example products Doses Cost Comments
Oral CEE/MPA Prempro 0.3 mg/1.50 mg $220 Continuous
0.625/5 mg
Estradiol/norgestimate Prefest 1 mg/0.09 mg $160 Cyclic
Estradiol/norethindrone acetate Activella, Mimvey 0.5 mg/0.1 mg $110 Continuous
1 mg/0.5 mg
Ethinylestradiol/norethindrone acetate Jevantique Lo 0.5 mg/2.5 mcg $105 Continuous
Jinteli 1 mg/5 mcg $115 Continuous
Estradiol/drospirenone Angeliq 0.5 mg/0.25 mg $220 Continuous
1 mg/0.5 mg
Transdermal Estradiol/norethindrone CombiPatch 0.05 mg/0.14 mg $190 Twice weekly
0.05 mg/0.25 mg
Estradiol/levonorgestrel Climara pro 0.045 mg/0.015 mg $220 Weekly
(continued)

Combined estrogen/selective estrogen receptor modulator (SERM)
Mode of delivery Preparation Product names Doses Cost Comments
Oral CEE/bazedoxifene Duavee 0.45 mg/20 mg $210 Continuous
SERM
Mode of Product
delivery Preparation names Doses Cost Comments
Oral Ospemifene Osphena 60 mg $250 FDA approved for dyspareunia and genitourinary syndrome of
daily menopause;
No increased risk of venous thromboembolism or breast cancer
a
Lowest estimated retail cash price calculated per month (note insurance may have different pricing) [21]
patient prefers the oral route, either oral 17-beta estradiol or hormonal treatment and strongly weighing the risks and ben-
conjugated estrogen can be used. The downside of oral estro- efits of continuing beyond 5 years [11]. Once a woman has
gen is that it results in a procoagulant effect and increases decided to stop MHT, there are no data suggesting a differ-
sex hormone-binding globulin (SHBG), thyroid-binding ence between a gradual taper and an abrupt stop [25]. One
globulin, cortisol-binding globulin, triglycerides, and mark- reasonable approach would be to counsel a woman to stop
ers of inflammation such as C-reactive protein [20]. It is MHT, but if she develops symptoms, provide instruction on
advisable to start with the lowest dose and titrate the dose a gradual taper over weeks to months. The taper may be cus-
based on symptoms. tomized to patient routines. For example, a woman could
Medication interactions must be considered when initiat- initially stop taking the hormones only on weekends and
ing estrogen therapy. For women who are taking anticonvul- gradually taper during the week, making sure to avoid dose
sants such as phenytoin and carbamazepine, an increased changes and tapering during times of stress.
dose of estrogen may be necessary due to increased hepatic
clearance of estrogen [23]. In women receiving T4 replace-
ment, oral estrogen may increase T4 requirements since Nonhormonal Options
there is an increase in thyroid-binding globulin.
For women with a uterus, estrogen must be combined Nonhormonal medications can be considered for women
with a progestin or a selective estrogen receptor modulator who have contraindications to MHT or prefer not to take hor-
(SERM) known as bazedoxifene to protect against endome- mones. These primarily include antidepressants and gaba-
trial proliferation and the development of endometrial can- pentinoids. First-line therapy includes SSRIs and SNRIs,
cer. If progestins are not included in combination with the which seem to reduce vasomotor symptoms by 25–69%
provided estrogen formulation, women most commonly take [26]. Low-dose paroxetine is the only antidepressant that is
oral micronized progesterone. While a continuous method is FDA approved for this indication. There are no head-to-head
favored (100 mg daily), women who are perimenopausal (or trials comparing SSRIs and SNRIs. Table 8.2 outlines spe-
within 2 years of menopause) may benefit from a cyclic cific nonhormonal medications options to treat menopausal
method if they have irregular bleeding. Some women have symptoms.
difficulty tolerating oral progesterone due to bloating and Gabapentin and pregabalin can also be used to treat VMS
mood changes. These women can consider using a [27]. Gabapentin has shown similar efficacy to SNRIs and
levonorgestrel-releasing intrauterine device (IUD). works particularly well for women with night sweats [28].
For women who do not tolerate oral progesterone or a Clonidine has historically been used to manage VMS, but not
levonorgestrel-releasing IUD, a conjugated estrogen/baze- as effectively as those outlined above, and has more side
doxifene combination can be considered. One caution is that effects. Since hot flash symptomatology gradually wanes
there is an increased risk of VTE in patients using bazedoxi- with time, revisiting the need for non-pharmacological ther-
fene when compared with placebo [24]. There are no avail- apy every year is necessary.
able data comparing the VTE risk of estrogen/bazedoxifene
vs. estrogen/progesterone.
Deciding on the duration of MHT can be challenging. Genitourinary Syndrome of Menopause
When women first initiate MHT, they should be seen within
1–3 months to evaluate efficacy and side effects [20]. Once Since some women begin to experience symptoms of the
on a stable dose, they should be seen every 6–12 months for genitourinary syndrome of menopause (GSM) in the peri-
symptom monitoring. The decision to continue MHT should menopausal state, it is important to discuss the treatment
be reevaluated annually, targeting the shortest duration of options available early in the midlife transition. As women
8 Menopause 123
Table 8.2 Nonhormonal options for menopausal symptom management

Medication class Formulations Comments
Antidepressants SSRI Paroxetine Only nonhormonal agent FDA approved for VMS; inhibits CYP2D6 so should be avoided in
tamoxifen users (different class recommended)
Citalopram
Escitalopram
SNRI Venlafaxine No benefit seen beyond 75 mg/d SR
Desvenlafaxine
Gabapentinoids Gabapentin Start with 300 mg qhs and uptitrate; BID dosing can also be used if needed
Pregabalin Effective, less well studied
Anticholinergics Oxybutynin Dosage varies; watch for typical anticholinergic side effects (dry mouth, constipation)
SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, VMS vasomotor symptoms
progress into menopause and the postmenopausal state, preference may determine decision-making. When first initi-
symptoms may worsen resulting in painful vaginal inter- ating treatment for severe GSM, a vaginal cream is recom-
course and genitourinary (GU) symptoms such as burning mended; a vaginal tablet may not be able to be inserted
and dryness. Due to the difficulty in achieving and sustaining comfortably or absorbed adequately, and a vaginal ring may
adequate lubrication for comfortable vaginal penetration in also be difficult to insert due to vaginal atrophy or stenosis.
women who suffer from GSM, treatment discussions should Later, one can transition from one form of local estrogen
include long-term goals. Painful vaginal intercourse can therapy to another, and these switches occur commonly
result in decreased sexual desire, distress, and avoidance of based on change in symptoms, treatment goals, and individ-
vaginal sexual intercourse altogether. Depending on mutual ual preference [29].
decision-making, longer treatment options may be discussed Local estrogen preparations have not been shown to have
as long as risks do not outweigh benefits. an increased risk of breast or endometrial cancer. Patients
Treatments for GSM include nonhormonal and hormonal should be instructed on appropriate use; if local estrogen
treatment options. Vaginal moisturizers can be purchased cream is used more frequently than prescribed, systemic lev-
over the counter and used two to three times weekly for els can be detected. Duration of treatment varies with indi-
maintenance therapy in mild to moderate cases of symptoms vidual goals and response to treatment; however, many
of GSM [29]. Many vaginal moisturizers are water-based women will have return of symptoms with cessation of local
and treat GSM symptoms by replenishing moisture to the estrogen. Explaining long-term safety at initiation of treat-
vaginal tissue. This is a good option for women who are ment may help patients achieve treatment goals.
opposed to, have contraindications to, or have an intolerance
to local estrogen therapy. Patients should be counseled that
vaginal moisturizers require continual adherence for symp-
Sasha opted to start vaginal estrogen treatments but
tom improvement and maintenance therapy.
preferred not to use a systemic treatment for her night
Vaginal lubricants are for as needed use, typically for
sweats. At a 6-month follow-up visit, her vaginal symp-
improvement in sexual symptoms, and can be combined with
toms and dyspareunia have improved, but she is still
vaginal moisturizers and local estrogen therapy. There are
having night sweats that are now causing significant
many types of vaginal lubricants that can be found over the
disruption to her sleep. She also has developed multi-
counter. Women should be counseled on the options of sili-
ple hot flashes during the day. Sasha would also like to
cone, water-based, and hybrid lubricants. Water-based lubri-
revisit possible treatments for her vasomotor symp-
cants are typically thinner in consistency and may not
toms, in particular wondering if there is something
provide adequate relief for vaginal intercourse if GSM
“natural” that she can use.
symptoms are severe. Silicone-based lubricants are typically
thicker in consistency but may produce an oily residue if
copious amounts are used in one setting. Hybrids are a blend
of both water and silicone and typically have a consistency Women frequently request information on the effect of
that is thicker than water, but thinner than silicone-only complementary and alternative medicine (CAM) on VMS
lubricants. Patients should be advised to sample a few brands and menopausal symptoms in general. These types of treat-
to find the product that works best [30]. ment are easily accessible without visiting a physician and
Hormonal treatment for GSM includes local estrogen generally acceptable to women who may otherwise be con-
creams, vaginal and oral estrogen tablets, and a vaginal ring. fused or hesitant about menopausal symptoms and treat-
FDA-approved vaginal treatments available in the United ments. Most studies of CAM for menopausal symptoms have
States all deliver estrogen that may treat GSM, but patient demonstrated CAM to be ineffective or are comprised of
limited, biased data [31]. Cognitive behavioral therapy immune disease or may remain unknown. Typically, these
(CBT) and hypnosis are two therapies that have shown statis- women have secondary amenorrhea and FSH levels >40 IU/l
tically significant efficacy in decreasing VMS [31]. (drawn twice, at least 4 weeks apart) and may be experienc-
Phytoestrogens may have some effect on VMS as compared ing typical menopausal symptoms as outlined above [34].
with placebo but have no demonstrated effect on night sweats These women are at significant risk for osteoporosis and car-
[32]. However, questions remain regarding optimal phytoes- diovascular disease. Thus, true hormone replacement should
trogen type, dosing, and whether certain types of women be initiated to maintain health and avoid increased risk for
may respond better to phytoestrogens than others [31]. heart disease and increased mortality [34]. In these women,
Other options with only limited data showing benefit because they may still require reliable protection from preg-
include weight loss, mindfulness, and stellate ganglion nancy, using oral contraceptive pills is appropriate.
block. Weight loss has been shown to be helpful in decreas- Pre- and postmenopausal women with breast cancer typi-
ing VMS but is difficult and takes time to achieve. cally experience significant menopausal symptoms particu-
Mindfulness can help women manage the stress of VMS and larly while on endocrine therapy. Unfortunately, many
menopausal symptoms without changing their severity. women report adverse impacts of endocrine therapy on qual-
Stellate ganglion block, injection of local anesthetic in the ity of life, and these symptoms can result in early treatment
sympathetic nerve region of the neck, has previously been discontinuation, in turn affecting treatment outcomes [35].
used for pain management. Initial studies have been promis- Though data is not conclusive, available information has led
ing; a sham-controlled trial demonstrated improvement in the majority of guideline committees to consider MHT to be
moderate to severe VMS and intensity of VMS [33] with contraindicated in breast cancer survivors [36]. Nonhormonal
stellate ganglion block. agents as seen in Table 8.2 are recommended for women
Many lifestyle changes or mind-body techniques can with VMS. SSRIs may lead to inhibition of CYP2D6 enzyme
have overall health benefits but haven’t shown specific which can negatively affect the activity of tamoxifen.
improvement in VMS including regular exercise, yoga, and Paroxetine is a particularly potent inhibitor of CYP2D6 and
paced respiration. Acupuncture has been shown to be benefi- should be avoided in women taking tamoxifen; the authors
cial for VMS as well as quality of life when compared with recommend SNRIs or gabapentinoids as safer options in in
no treatment. However, when acupuncture is compared with breast cancer survivors with hot flashes on tamoxifen [36].
sham acupuncture, there is no significant difference in out- GSM is quite common in breast cancer survivors, and
comes [31]. Delaying effective treatments for menopause for women should initiate treatment with vaginal moisturizers
patients to solely work on these methods is not recom- and add lubricants for dyspareunia. Use of low-dose vagi-
mended, though they may have positive effects on health nal estrogen in breast cancer survivors does not have robust
overall. Ineffective therapies that should not be routinely rec- safety data. One observational study looked at low-dose
ommended include over-the-counter supplements and herbal vaginal estrogen and found no increased breast cancer
remedies (i.e., black cohosh, evening primrose oil, dong recurrence risk during a 3.5-year mean follow-up. In gen-
quai, flaxseed, hops, vitamins) [31]. eral, the use of vaginal estrogen in breast cancer survivors
Understanding a patient’s treatment goals and providing has been discouraged; only in consultation with the oncolo-
supportive, patient-centered care plans remains the corner- gist should a vaginal ring, which provides a daily fixed dose
stone in managing menopause. Helping patients understand of hormone and has low risk of systemic absorption, be
treatment options, and why they are effective or recom- considered [36].
mended, assists women in navigating a challenging life
change. It is important to revisit treatment options as symp-
toms develop or if treatments fail. Some patients may not be Summary Points
initially interested in systemic therapies, but as symptoms
progress and wear on overall well-being, women may feel 1. Menopause is a clinical diagnosis defined retrospectively
differently about medications or effective mind-body as 12 months without menses.
therapies. 2. Women going through the menopausal transition may
experience a range of symptoms including vasomotor,
genitourinary, mood, and sleep. These symptoms are the
Special Populations result of hormonal fluctuations.
3. Optimal care of menopausal women requires understand-
Patients with spontaneous primary ovarian insufficiency ing the differences between local and systemic hormonal
(formerly called premature ovarian failure) are diagnosed therapy, the utility of nonhormonal therapy, and when to
based on amenorrhea and estrogen deficiency in women less use either alone or in combination, to manage
than age 40. Etiology can be chemotherapy, surgery, or auto- symptoms.
8 Menopause 125
4. Hormonal therapy is the most effective treatment for The correct answer is A. This patient is perimeno-
menopausal symptoms. Counseling on systemic hor- pausal and a good candidate for hormonal therapy. In
monal therapy should include a small attributable risk of patients like Paula, with moderate to severe symptoms
breast cancer and VTE. While there are favored methods, and no risk factors, hormonal therapy is considered to
choice of a specific formulation will depend on multiple be first-line treatment. This should include daily oral
patient factors, and shared decision-making is critical. or transdermal estrogen. Since this patient has an intact
uterus, she also requires progesterone to prevent endo-
metrial hyperplasia. In perimenopausal or newly
Review Questions menopausal (<2 years) women, cyclic progesterone is
better tolerated than continuous progesterone because
1. A 48-year-old female with no significant past medical there is less breakthrough bleeding. Women who are
history presents to discuss her periods. Over the past more than 2 years out from menopause should be on
6 months, her periods have become more irregular and continuous progesterone.
she has had difficulty sleeping. She is currently sexually 3. A 57-year-old woman presents for evaluation of insom-
active with her husband of 25 years and is not using con- nia. She has had severe night sweats for the last 3 years.
traception. She is on no medications. She doesn’t complain of significant hot flashes during the
Which of the following is the next best step in diag- day. She never feels she gets restful sleep due to her
nostic workup? drenching night sweats requiring a change of clothes and
A. Endometrial biopsy constant adjustments of her bed covers. She has a past
B. FSH medical history of venous thromboembolism, and she is
C. TSH currently on no medications and does not smoke. Her
D. Urine pregnancy test exam, including vital signs, is normal.
E. CBC Which of the following is the best treatment for this
The correct answer is D. This patient is likely perimeno- patient’s night sweats?
pausal; however she is still having menstrual cycles and is A. Amitriptyline
sexually active without contraception. Therefore, preg- B. Gabapentin
nancy must be ruled out prior to a workup for menopause. C. Mirtazapine
If her pregnancy test is negative, she can be diagnosed D. Sertraline
with perimenopause based on clinical history. Endometrial E. Zolpidem
biopsy is not indicated as she is not having heavy bleed- The correct answer is B. This patient is experiencing
ing. FSH and LH levels vary and are therefore not used night sweats as the most problematic symptom of meno-
routinely for diagnosis. TSH would be reasonable if she pause. Gabapentin is a medication that particularly tar-
were showing other signs of a thyroid disorder. CBC gets night sweats and can be dosed every night with
would only be necessary if you are worried that her men- minimal daytime effects. Selective serotonin receptor
strual bleeding is leading to an anemia. inhibitors (SSRIs) can be effective for hot flashes, but are
2. A 54-year-old female with past medical history of hyper- not more effective for night sweats. However, sertraline is
tension had her last menstrual period 10 months ago, and not particularly known to have beneficial effects for hot
since then she has had no vaginal bleeding. She is suffer- flashes and should not be the first nonhormonal agent
ing from debilitating hot flashes and has started missing chosen to manage hot flashes. Amitriptyline and mir-
work and social activities due to her discomfort. She has tazapine are not known to have any effect on hot flashes
no family history of breast cancer, and her annual mam- or night sweats. Zolpidem, while effective for short-term
mograms have all been normal. She denies any personal management of insomnia, is not known to have any effect
history of DVT or stroke, and her uterus is intact. Her on night sweats. A safer method of managing this patient’s
ASCVD risk score shows a 3% risk of a cardiovascular insomnia is to target the underlying cause, which is her
event. Her BP is 128/84 on medication. She is interested night sweats, rather than initiate zolpidem treatment.
in hormonal therapy but is worried about the associated
risks.
Which is the best next step for therapy? References
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Female Sexual Function
and Dysfunction 9
Juliana M. Kling and Holly N. Thomas
in relationship to sexuality; it is not merely the absence of

Learning Objectives disease, dysfunction or infirmary. Sexual health requires a
1. Define healthy female sexual function and frame- positive and respectful approach to sexuality and sexual rela-
works for understanding female sexual response. tionships, as well as the possibility of having pleasurable and
2. Discuss the impact of female sexual dysfunction safe sexual experiences, free of coercion, discrimination and
(FSD). violence” [7]. According to the WHO, a woman’s physician
3. Screen for and diagnose FSD. should play a key role in maintaining sexual health.
4. Use a biopsychosocial approach in the evaluation Sexual dysfunction imparts a major negative impact.
and treatment of FSD. Women with sexual dysfunction have significantly lower
quality of life scores compared to women without sexual
dysfunction [4, 5, 8]. The quality of life scores of women
with hypoactive sexual desire disorder are similar to those of
Susan is a 58-year-old female who has been happily individuals with chronic back pain and diabetes [5]. Women
married for 30 years with previously healthy sexual with sexual dysfunction have 3–5 times higher odds of low
function. For the last year, she has noticed distressing general happiness [9], 11 times higher odds of sexual dis-
sexual function issues and is wondering if anything satisfaction, and 2–3 times higher odds of relationship dis-
may help. satisfaction [4]. Ninety-six percent of women with hypoactive
sexual desire disorder feel that they are “letting their partner
down” [4].
emale Sexual Function: Definition, Impact,
F Several models of female sexual response have been pro-
and Framework posed and provide a framework for evaluating and diagnos-
ing female sexual dysfunction (FSD). The most commonly
Healthy sexual function is a vital part of many women’s discussed models are the Masters and Johnson model and the
lives. Women report that sexual enjoyment is important for Basson model (Figs. 9.1 and 9.2) [10–12]. The Masters and
their overall health [1], and studies have found that impaired Johnson model was developed in the 1960s and applies to
sexual function is associated with decreased relationship sat- both women and men. This model is linear and illustrates
isfaction, decreased quality of life, and other negative health sexual response progressing from excitement to plateau,
outcomes such as depression and low self-image [2–6]. orgasm, and then resolution. Helen Singer Kaplan, recogniz-
Sexual health is defined by the World Health Organization ing that sexual desire is an important component of sexual
(WHO) and Pan American Health Organization (PAHO) as response, subsequently created a three-phase model with
“a state of physical, emotional, mental, and social well-being desire, excitement, and orgasm, called the Masters-Johnson-
Kaplan model [13]. Dr. Paul Robinson believed the Masters
and Johnson model did not adequately distinguish between
J. M. Kling (*) the excitement phase and plateau phase, so he presented a
Mayo Clinic, Department of Women’s Health Internal Medicine,
modification as well [14].
Rochester, NY, USA
e-mail: [email protected] Further critique of the linear model as it pertains to female
sexual functioning led to the development of an alternative
H. N. Thomas
University of Pittsburgh, Department of Medicine, framework. In 2000, Dr. Rosemary Basson proposed a circu-
Pittsburgh, PA, USA lar model that is believed to better explain women’s sexual

128 J. M. Kling and H. N. Thomas
Sexual response cycle ual stimuli. Hence, desire does not always need to precede
arousal, as it does in the previous frameworks. This impor-
tant distinction is supported by research demonstrating sig-
nificant overlap in women’s conceptualization of desire and
arousal [15–17].
There is disagreement about which model most accu-
rately aligns with women’s experiences. A systematic review
Arousal
in 2011 found 13 original studies and 1 review article that

evaluated aspects of these models, with only 2 directly
comparing the 2 models [18]. There was limited evidence
that most women identified with the linear model, although
these studies utilized the Female Sexual Function Index
(FSFI) to assess sexual function, which is based on the
Masters-Johnson-Kaplan model. It may be that aspects of
t
n
each model are applicable to different women at different
en
ea
tio
as
m
lu
at
rg
stages in their lives. For example, one study showed women

ite
so
Pl
O
c
Re
Ex
were more likely to agree with the Basson model if they were
Time
postmenopausal or if they were found to have sexual dys-
function as defined by the FSFI [19]. Incorporating aspects
Fig. 9.1 Masters-Johnson model of sexual response (Adapted from of each framework can be helpful when evaluating women
Masters and Johnson [10]) with sexual health concerns.
SEEKING OUT Prevalence and Epidemiology of FSD

EMOTIONAL
AND BEING
INTIMACY
RECEPIVE TO
Prior research indicates that sexual problems are highly prev-
alent among women. One of the largest US studies found
EMOTIONAL that 43% of women will report a sexual problem, the most
SEXUAL
& PHYSICAL
STIMULI common being low desire [9]. Notably, this study found that
SATISFACTION
sexual problems are more prevalent in women than men.
SPONTANEOUS
SEXUAL DRIVE Biologic However, a sexual problem does not cross the threshold to
Psychological sexual dysfunction unless it causes significant personal dis-
tress. One of the only studies to assess distress found that
while 43% of US women report sexual problems, 12% of
AROUSAL
SEXUAL women have sexual problems causing significant distress [6].
AND SEXUAL
DESIRE
AROUSAL This is still a significant proportion of women. While report-
ing of sexual problems increases with older age, distress
associated with sexual problems peaks at midlife.
Fig. 9.2 Basson model of female sexual response (Adapted from [11, There are differences in sexual function across racial and
12]. Adapted with permission from Thomas and Thurston [12], with ethnic groups. Studies are mixed regarding Black women,
permission from Elsevier) with some studies [6, 20] showing they have lower odds of
sexual dysfunction compared to White women and others [9,
response, especially for those in long-term relationships 21, 22] showing higher odds. Studies are more consistent
[11]. The model includes both physical and emotional satis- regarding Hispanic and Asian American women; they have
faction as important outcomes of sexual activity, such that higher odds of sexual dysfunction compared to White women
these two factors may lead to higher emotional intimacy and [21, 23, 24].
subsequently greater receptivity and interest in sexual stim- Less is known about sexual function in sexual minorities.
uli, creating a circular feedback loop. Furthermore, sexual Despite a popular misconception that many lesbian couples
activity is not always prompted by desire and instead could cease sexual activity over time, most studies report that lesbian
result from feelings of emotional intimacy with one’s partner women have better sexual function and satisfaction compared
that may lead her to be more receptive to sexual stimulation. to heterosexual women [25–27]. The risk factors for sexual
Sexual arousal and desire often co-occur and may be the dysfunction are similar in lesbian women and heterosexual
result of sexual stimuli and not the impetus that leads to sex- women, including aging, relationship dissatisfaction, and
9 Female Sexual Function and Dysfunction 129
mood symptoms [28, 29]. However, dyadic desire discrepan-

cies (when partners have discordant desires) and internalized Biology
homophobia have been associated with sexual dysfunction (e.g. physical health,
among lesbian women as well [29, 30]. There are fewer stud- neurobiology,
endocrine function)
ies among transgender individuals, and sample sizes are small.
For both male-to-female and female-to-male transgender indi-
viduals, sexual function is typically worse than in cisgender
individuals [31, 32], but hormone treatment and gender- Sociocultural Psychology
Biopsychosocial
affirming surgery appear to improve sexual function [32–34]. (e.g. upbringing, Model (e.g. performance
cultural norms and anxiety, depression)
These latter studies are limited by lack of control groups. expectations)
Interpersonal
emale Sexual Function Changes with Aging
F
and Menopause (e.g. quality of current
and past relationships,
intervals of abstinence,
life stressors, finances)
Both aging and menopause lead to physiologic changes in
women that may impact sexual function. Up to half of post-
menopausal women experience vaginal dryness due to
declining estrogen levels [35], referred to as the genitouri- Fig. 9.3 Biopsychosocial mode of female sexual function [47, 48]
(Adapted from Rosen and Barsky [47] and Levine [48])
nary syndrome of menopause (GSM), previously known as
atrophic vaginitis or vulvovaginal atrophy [36]. Dryness can
lead to dyspareunia, which can in turn decrease sexual desire
Figure 9.3 illustrates each of these areas, as well as examples
and contribute to pelvic floor muscle hypertonicity and deep
of factors within each area. For the patient in the case, start-
pelvic pain. Vaginal dryness negatively impacts sexual func-
ing with an assessment of her menopause status, symptoms
tion during menopause [37, 38]. Although a few smaller lon-
including presence or absence of vaginal dryness or dyspa-
gitudinal studies found stable reports of desire and sexual
reunia, is important. Then, inquiring about interpersonal,
activity during midlife [19, 39–41], most large age-adjusted
psychological, and sociocultural factors will provide a full
studies have demonstrated worsening sexual function during
picture of possible culprits to her symptoms and assist in
the menopausal transition [19, 39, 40, 42–44]. Interpretation
next steps in the evaluation.
of these studies can be challenging; the contributing biopsy-
chosocial factors are complex, there is not one standard sex-
ual function instrument used, and most studies do not assess
Screening for FSD
distress. (See Chap. 8 on Menopause for a discussion of gen-
eral management of menopause.)
Given that the prevalence of sexual problems among women
is high and has a significant negative impact on quality of life
and relationships, it is reasonable to routinely screen for sex-
Importance of a Biopsychosocial Approach ual problems during preventative visits. The vast majority of
patients want their primary care providers to discuss sexual
Generally, these longitudinal studies of menopausal women
problems [49–51], but only a very small proportion of provid-
highlight a common theme [12]: menopausal factors are only
ers actually do [49, 50], and patients are hesitant to bring it up
a part of the picture, and other important aspects of a wom-
themselves [51]. Screening rates are even low among spe-
an’s life impact sexual function. These aspects include many
cialty providers, such as urogynecologists [52, 53]. Providers
psychosocial as well as health variables including partner
cite concerns about time constraints, lack of training, socio-
loss or absence of a sexual partner, changes in the quality of
cultural differences, and lack of treatment options as reasons
relationships with partners, lower socioeconomic status,
for failure to screen [53–55]. Brief screening instruments can
insomnia, depression, stress, anxiety or other mood symp-
assist primary care providers in screening for sexual dysfunc-
toms, children living at home, and declining overall health
tion among their female patients (Table 9.1). Tips for screen-
[19, 37–41, 44–46]. Many of these aspects can impact wom-
ing in the primary care setting include [62]:
en’s sexual function at any stage. Hence, it makes most sense
to view female sexual function through a biopsychosocial • Establish a good rapport.
model which takes into consideration biologic as well as • Normalize screening for sexual problems.
psychological, interpersonal, and sociocultural factors inde- • Avoid assumptions about patients’ sexual behavior (i.e.,
pendently and as they interact with each other over time. number of partners, sexual orientation).
Table 9.1 Selected screening instruments for female sexual guages and age groups and for multiple sexual disorders
dysfunction [64]. It is a 19-item questionnaire with scores ranging from
No. 2.0 to 36.0, with a lower score indicating worse sexual func-
of tion. A total FSFI score of less than 26.55 identifies women
Instrument items Sensitivity Specificity Notes
with sexual dysfunction [65]. Although studies have shown
Sexual Function 34 70–83% 62–80% Low feasibility
Questionnaire in primary care that midlife and older women tend to have lower scores [66],
(SFQ) [56] setting given no widely accepted scoring adjustments have been made for
number of items this population. The FSFI does not include questions about
Brief Profile of 7 96% 97% Only validated sexual distress. The Female Sexual Distress Scale-Revised
Female Sexual for women with
Function hypoactive
(FSDS-R) is a 13-item scale with scores ranging from 0 to 52
(B-PFSF) [57] sexual desire that measures sexual distress, and a score higher than 11
disorder indicates clinically significant sexual distress [67].
Decreased 4 84% 88% Focuses on The Diagnostic and Statistical Manual (DSM-5) has
Sexual Desire desire only defined four distinct types of female sexual dysfunction:
Screener (DSDS)
[58] Female Orgasmic Disorder, Female Sexual Interest/Arousal
Female Sexual 6 93% 94% Assesses Disorder (FSIAD, previously known as two entities –
Function Index-6 multiple Hypoactive Sexual Desire Disorder (HSDD) and Female
(FSFI-6) [59] domains, good Sexual Arousal Disorder (FSAD) in the DSM IV), Genito-
performance
Pelvic Pain/Penetration Disorder (previously referred to as
Kriston et al. 1 76% 77% Very brief, but
single item [60] lower sensitivity vaginismus and dyspareunia), and Substance/Medication-
and specificity Induced Sexual Dysfunction [68]. They are described overall
Sexual 10 Not Not No validation as a “heterogeneous group of disorders that are typically
Complaints available available data published characterized by a clinically significant disturbance in a per-
Screener for
Women (SCS-W)
son’s ability to respond sexually or to experience sexual
[61] pleasure.” As such, diagnosis requires that symptoms have
been present for at least 6 months, cause clinically signifi-
cant distress in the patient (not just her partner), and are not
• Screen for sexual problems with patients clothed to avoid explained by another factor, such as GSM or a relationship
vulnerability. issue (Table 9.2 includes DSM-5 components for diagnosis).
Each disorder should be specified as lifelong or acquired and
A positive screen indicates that the provider should move include the degree of severity (mild, moderate, or severe) as
on to a full sexual health assessment. well as if it is generalized or situational.
Since desire disorders are the most prevalent sexual health
problems in women [6], it is important to note that the diag-
Susan started noticing a decreased libido about a year nostic category replacing HSDD in the DSM-5, Female
ago, and she’s tried various strategies including a spe- Sexual Interest/Arousal Disorder, has not been validated in
cial date night once a week, but to no avail. She denies clinical research studies [69, 70]. It is not uniformly accepted
any vaginal dryness or dyspareunia since starting vag- by experts in the area, and HSDD is still recognized by cer-
inal estrogen 3 years ago. She is still able to reach tain groups including the International Society for the Study
orgasm, but it takes her much longer than before. of Women’s Sexual Health [71].
Evaluation of FSD
emale Sexual Dysfunction: Domains
F
and Definitions As with any medical concern, the assessment of a sexual
problem should begin with a comprehensive history and
Female sexual function is complex and multifactorial, so physical examination. Keeping in mind the biopsychosocial
diagnosing sexual dysfunction requires familiarity with these model (Fig. 9.3), the history should include discussion of
complexities. There are validated instruments available that medical, psychological, emotional, interpersonal, and socio-
help to characterize and define female sexual function [12, cultural factors that may be contributors, including asking
63]. The most common instrument is the Female Sexual about a history or current evidence of emotional, physical, or
Function Index (FSFI), which includes six domains of sexual sexual abuse, and their beliefs toward sex, aging, menopause,
function including desire, arousal, lubrication, orgasm, pain, and their body image. Both adverse childhood experiences
and satisfaction, and has been validated in multiple lan- and more recent trauma can play a role in FSD. Previous
Table 9.2 Four types of female sexual dysfunction by Diagnostic and importance of asking if her partner is experiencing any
Statistical Manual (DSM-5) sexual health issues (e.g., low libido, erectile dysfunction),
Disorder Components for diagnosis as that can be a factor affecting them both.
Female Significant change in orgasm occurring most of After a thorough history, a physical examination includ-
Orgasmic the time (75–100%) with either (1) reduced
ing a pelvic examination is essential. Attention should be
Disorder orgasm intensity or (2) absence, infrequency, or
delay of orgasm paid to blood pressure, heart rate, peripheral pulses, and sen-
Female Sexual Complete lack of or significant reduction in sation [75], as abnormalities in these areas may explain
Interest/ sexual interest or sexual arousal with three out of underlying pathophysiology contributing to sexual dysfunc-
Arousal six of the following either absent or decreased: tion. On the pelvic examination, particular attention should
Disorder (1) sexual interest, (2) erotic fantasies or
(FSIAD)a thoughts, (3) initiation of sexual activity or
be paid to vulvovaginal conditions such as GSM, vaginitis,
responsiveness to a partner’s attempts to initiate dermatoses, and neoplasia. An assessment of the pelvic floor
sex, (4) pleasure and excitement, (5) sensations should also be performed, looking for hypo- or hypertonicity
during sexual activity, and (6) response to sexual or prolapse [74]. Pelvic floor dysfunction is generally
cues
described as a deep pelvic pain associated with penetrative
Genito-Pelvic Includes difficulties with one or more of the
Pain/ following symptom dimensions that is persistent sex that can radiate to the inner thigh or low back and often
Penetration or recurrent: (1) tightening of the pelvic floor times persists after penetration [76]. Generally, laboratory
Disorderb muscle when vaginal penetration is attempted; testing and ultrasound evaluation is unnecessary unless a
(2) pain, burning, or tension during or when secondary issue is suspected. Assessing hormone levels is
vaginal penetration is attempted; (3) decrease in
or no desire for intercourse; and (4) anxiety or typically not necessary, since estrogen and testosterone lev-
fear of pain, pelvic or vulvovaginal, as a result of, els do not consistently correlate with sexual dysfunction [77,
during penetration, or in anticipation of 78]. Based on the history and physical examination, provid-
penetration ers may consider testing for sexually transmitted infections,
Substance/ A clinically significant sexual dysfunction
Medication- developed soon after or during intoxication with
vaginal infections, thyroid testing, blood counts, or pelvic
Induced Sexual or withdrawal of a substance capable of ultrasound if the primary concern is pelvic pain.
Dysfunction producing sexual dysfunction or after exposure to
such a medication
And the dysfunction does not only occur during a
course of delirium On further questioning, it turns out that Susan had
Adapted from the American Psychiatric Association [68] started a selective serotonin reuptake inhibitor (SSRI)
a
Previously known as two entities – Hypoactive Sexual Desire Disorder just prior to the onset of her symptoms for situational
(HSDD) and Female Sexual Arousal Disorder (FSAD) in the DSM IV depression related to the loss of a parent. She has been
b
Previously referred to as vaginismus and dyspareunia feeling well from a mood perspective and asks if stop-
ping the medication will help her sexual function.
gynecologic history including surgery or trauma during
childbirth should be elicited. Other factors common during
midlife and menopause that may impact sexual function and
should be discussed include sleep problems, depression, Antidepressant-Associated Sexual Dysfunction
anxiety, and substance use [12, 46, 72]. If a relationship issue
is identified, consider referral to a therapist certified by the Susan’s scenario is a good example of why a thorough medi-
American Association of Sexuality Educators Counselors cal history, including reviewing all medications, is pertinent
and Therapists (AASECT). If an abuse issue is identified, to evaluating and treating FSD. Medications and medical
please see Chap. 35 on Intimate Partner Violence and Sexual disorders that are associated with sexual problems are dis-
Trauma. cussed in Table 9.3. Since depression and sexual dysfunction
A detailed sexual history is also critical and should be are closely correlated [117], it is not uncommon to see
completed in a nonjudgmental manner that is culturally sen- women with FSD on antidepressant medications [117, 118].
sitive and considers the patient’s background and lifestyle The risk of a sexual side effect on an antidepressant is
[73, 74]. Providing a safe space and time for a woman to approximately 40%, and sexual side effects can occur with
share will improve the ability to identify the true culprit(s) SSRIs, serotonin norepinephrine reuptake inhibitors
for the complaint [12]. For example, a woman may report a (SNRIs), and tricyclic antidepressants (TCAs) alike. Among
primary issue with orgasm, but upon further questioning, the those who experience sexual side effects, 83% report prob-
provider learns that the patient’s partner has erectile dysfunc- lems with arousal, 72% report problems with desire, and
tion, and the patient does not want to ask him about non- 42% report problems with orgasm [79–82].
penetrative activities that could improve her ability to orgasm When starting an antidepressant for a patient at risk of
out of fear of upsetting him. This example also highlights the FSD, bupropion or mirtazapine may be preferred options, as
Table 9.3 Medical and psychiatric issues that may impact sexual • Switching antidepressants, with preference to antidepres-
function sant without adverse sexual effects, also mixed results
Medical Genitourinary syndrome of menopause [37, 38] [123, 134].
Cardiovascular disease [87]
Diabetes mellitus [91, 92] It is important to take into consideration the degree of dis-
Neurologic disease (stroke, spinal cord injury, tress related to the sexual side effect, as well as the risk of
multiple sclerosis) [94, 95] relapse of depression, when deciding on an appropriate strat-
Hypertension [93] egy. For our patient’s scenario, it is appropriate to facilitate
Breast, ovarian, uterine, and cervical cancer titration off of her antidepressant and then arrange short-
[96–100]
interval follow-up to reassess her mood and sexual function.
History of gynecologic surgery [101]
Chronic renal failure [102–104]
Urinary incontinence [105, 106]
Psychiatric Major depressive disorder [88, 89] One of her friends was just started on flibanserin, and
Generalized anxiety [88, 89] she’s wondering if that’s appropriate for her. If not,
History of emotional, physical, or sexual abuse [9, she wants to know what will work for her.
90]
Medications Antidepressants (selective serotonin reuptake
inhibitors, serotonin norepinephrine reuptake
inhibitors, tricyclic antidepressants, monoamine
oxidase inhibitors), antipsychotics, benzodiazepines General Approach to the Treatment of FSD
[79–86]
Opiates/narcotics [71] All women with FSD can be counseled on general lifestyle
Cancer therapies (for breast and gynecologic cancer) recommendations including regular exercise, adequate sleep,
[96, 107–109]
maintenance of a healthy weight, stress management, dedi-
Antihypertensives (beta-blockers, alpha-blockers,
diuretics)a [110–112] cating time to connect with her partner, and increasing her
Antiepileptics (particularly gabapentin, topiramate, exposure to sexual stimuli [12]. Encouraging women to use
and phenytoin) [113–115] open communication with their partners about their sexual
Hormones (oral contraceptives, estrogens, needs, as well as exploring new types of sexual activity or
progestins, antiandrogens, GnRH agonists) [116] positions, can be helpful. Discussing normative sexual
Amphetamines [116]
behaviors is also important, such as the fact that orgasm from
Steroids [75]
vaginal penetration is unusual and most women require clito-
Data on antihypertensives and sexual dysfunction in women are mixed
a
ral stimulation. Referring her to resources such as books or
websites with additional information may help. Book exam-
they have fewer sexual side effects [83–86, 119, 120]. Since ples include Come as You Are [135], Becoming Orgasmic
almost half of patients with untreated depression may experi- [136], Getting the Sex You Want [137], and Naked at Our Age
ence sexual dysfunction [121], it is important to assess sex- [138], and websites include the North American Menopause
ual function prior to starting the antidepressant and then in Society (menopause.org) [139].
follow-up. It is important to counsel patients starting antide- Given its complexity, female sexual dysfunction is often
pressant medication that sexual side effects are common, but best treated using a multidisciplinary team that includes a
often improve after the first 1–2 weeks using the medication. medical provider, a pelvic floor physical therapist, and a sex
For patients that develop sexual dysfunction while on an therapist. Pelvic floor physical therapist uses common physi-
antidepressant, first-line options include: cal therapy techniques, such as stretching and biofeedback,
• Augmentation therapy by adding another drug to counter- while focusing on the pelvic floor either to relax or strengthen
act the adverse sexual effects, such as mirtazapine or higher the muscle. Working with a trained sex therapist can particu-
doses of bupropion (150 mg twice daily) [122, 123]. larly be helpful for those experiencing relationship issues.
• Behavioral therapies (exercise, scheduling sexual activity, Patients may be referred to the American Association of
psychotherapy, vibratory stimulation) [124–128]. Sexuality Educators, Counselors, and Therapists (ASSECT)
website (https://www.aasect.org) to identify trained thera-
Other options in selected situations include:
pists in their area [140].
• Sildenafil (specifically for arousal dysfunction) [129]. After a thorough biopsychosocial approach has been uti-
• Testosterone [130] or acupuncture [131], although only lized to evaluate and diagnose FSD, treatment should focus
evaluated in small, limited studies. on the specific disorder identified (Female Orgasmic
• Watchful waiting for 4–8 weeks, mixed results [123, 132]. Disorder (FOD), Female Sexual Interest/Arousal Disorder
• Dose reduction or a brief drug holiday, mixed results (FSIAD), Genito-Pelvic Pain/Penetration Disorder, and
[123, 133]. Substance/Medication-Induced Sexual Dysfunction) and the
only plays a modest role [147]. Testosterone treatment has

For all types of female sexual dysfunction:
• Self care (exercise, sleep, healthy weight, stress management) been associated with improvements in many aspects of sex-
• Increase exposure to sexual stimuli ual functioning including subjective arousal, desire, and
• Enhance intimacy and communication with partner
• Behavioral interventions (sex therapy, CBT, mindfulness-based strategies) orgasm, as well as decreases in distress related to HSDD/
• Pelvic floor physical therapy FSAID [148–150]. The Endocrine Society guideline sug-
gests a 3- to 6-month trial for women meeting criteria for
Orgasmic
disorder:
Pain disorders: HSDD/FSAID with close clinical and laboratory evaluation
HSDD: Arousal disorder: • Treat GSM, if
• Flibanserin • Sexual aids:
• Directed present monitoring for signs of hyperandrogenism such as acne, hir-
masturbation
• Testosterone (Eros device,
• Sensate focus
• Topical lidocaine sutism, and dyslipidemia [151]. Testosterone can be con-
(off-label) vibrators) • TCAs or
therapy gabapentin verted to estrogens, so potential risks also include venous
• Sexual aids • Vestibulectomy thromboembolism as well as dysplasia of the breast and
endometrium. It should not be used in women with a history
Fig. 9.4 Treatment approach to female sexual dysfunction disorders of VTE or hormone-responsive cancer [152]. Despite the rise
of the use of compounded testosterone, there remains a lack
identified causes contributing to this disorder (biologic, psy- of regulation, and concentrations of testosterone in com-
chological, interpersonal, or sociocultural factors) (Fig. 9.4). pounded products can vary widely [153]. Long-term safety
and efficacy data on testosterone are lacking.
There are also non-pharmaceutical options that are effec-
Treatments for HSDD and Non-pain Disorders tive for HSDD, including sex therapy, cognitive behavioral
therapy, or mindfulness-based strategies [154–156].
Flibanserin is the first FDA-approved treatment for HSDD in Cognitive behavioral therapy, which focuses on altering
the United States and is indicated for premenopausal women behaviors and thoughts that distract or inhibit sexual
so it would not be indicated for the patient described above. thoughts, has been found to be effective in as many as 44%
It has been studied and found to be effective in postmeno- of women with sexual health concerns [154]. Sensate focus,
pausal women, but use in postmenopausal women would be a strategy involving the partner with graded non-demand
off-label. Flibanserin is taken daily, not on an as needed sensual touching, can help reduce anxiety and decrease
basis, since it acts centrally as a 5-HT1A agonist and 5-HT2A avoidance of sensual touching to help improve communica-
antagonist [141]. Candidates for flibanserin should not have tion and reintroduce intimacy between couples.
any other medical, psychological, or relationship issues Psychotherapy, a recognized treatment strategy for HSDD,
identified as their root cause of FSD. Since alcohol increases focuses on modifying emotions, behaviors, beliefs, and
the risk of hypotension and syncope with flibanserin [142], thoughts, as well as relationship communication and behav-
women must be counseled and sign an agreement that they iors that interfere with desire [71].
will not drink alcohol while taking the medication. Additional Female arousal and orgasmic disorders can be improved
common adverse events include dizziness, nausea, fatigue, with directed masturbation and sensate focus [157]. Manual
and somnolence [142]. Studies have demonstrated improve- stimulation with vibrators or the Eros device, a small, hand-
ment in satisfying sexual events, sexual desire scores, and held medical device for clitoral application, may increase
FSFI desire domain scores with flibanserin [143], but some sensation and lubrication and enhance orgasm [158, 159].
point to an unfavorable risk-benefit profile [144]. If after an
8-week trial there is no improvement, it should be discontin-
ued. Prescribers and pharmacies must be certified to pre-
Susan titrates off of her SSRI and notices improvement
scribe and dispense flibanserin.
in her libido, but now reports deep dyspareunia. On
There is no FDA-approved formulation of testosterone for
exam, she has pelvic floor hypertonicity. After a few
use in women available in the United States. Despite this, it
weeks of successful pelvic floor physical therapy, she is
is widely used off-label for the treatment of HSDD, since
happy to report a healthy sexual relationship.
increasing research has shown its efficacy for this condition
[145, 146]. Of note, most research has been done on post-
menopausal women, many surgically menopausal, who were
on testosterone in combination with estrogen. Androgen lev- Treatments for Sexual Pain Disorders
els are not used to define an androgen deficiency syndrome
in women: testosterone levels do not consistently correlate Genital sexual pain disorders are most effectively managed
with female sexual function [78], in part because of the dif- by a multidisciplinary team including a physician, pelvic
ficulty in accurately measuring testosterone, but also since floor physical therapist, and sex therapist [160, 161]. It is
female sexual function is complex and androgen status likely important to advise patients to stop engaging in painful
sexual activity and seek treatment, as continued painful with decreased quality of life, decreased relationship sat-
experiences can increase situational anxiety and result in isfaction, depression, and poor self-image.
increased pelvic floor tension and pain [161]. If GSM is pres- 3. Providers should regularly screen for and address
ent, vaginal moisturizers, vaginal estrogen, ospemifene, or FSD. FSD is diagnosed based on DSM-5 criteria and
physical therapy may be offered (see Chap. 8 on Menopause requires a history of persistent sexual symptoms causing
for further discussion). significant distress.
Cognitive behavioral therapy, biofeedback, and 4. A comprehensive biopsychosocial approach is the most
mindfulness-based approaches have been shown to be help- effective for evaluating and treating FSD. Utilizing a mul-
ful for pain disorders [162–168]. Additional targeted thera- tidisciplinary team including a medical provider, a pelvic
pies for genito-pelvic pain or penetration disorders that have floor physical therapist, and a sex therapist can provide
been tried with mixed results include topical lidocaine [169, the most benefit.
170], antidepressants such as tricyclic antidepressants [171],
anticonvulsants such as gabapentin [172], or vestibulectomy
[172–175], although the latter is reserved for women who Review Questions
have failed less invasive treatments first.
The case vignette highlights that many factors may con- 1. Female sexual response has been described by various
tribute to FSD, and a multidisciplinary team approach is the models. The model which includes both physical and
best way to assure adequate treatment of all biopsychosocial emotional satisfaction as important outcomes of sexual
contributors. In addition, this case demonstrates the concept activity is called the:
that FSD symptoms and contributors may overlap and evolve A. Masters-Johnson model
over time, reinforcing the importance of an ongoing, trusting B. Basson model
relationship with a primary care professional. Regular fol- C. Masters-Johnson-Kaplan model
low-up with patients with FSD allows for identification and D. Robinson model
proper referral for other issues that may arise or be contribut- The correct answer is B. Several models of female sexual
ing to their sexual health. response have been proposed and provide a framework
for evaluating and diagnosing female sexual dysfunction
(FSD). The most commonly discussed models are the
Conclusion Masters and Johnson model and the Basson model. The
Masters and Johnson model was developed in the 1960s
Sexual function is an important part of most women’s lives. and applies to both women and men. This model is linear
FSD is under-identified and undertreated and should be and illustrates sexual response progressing from excite-
screened for during routine preventative examinations. ment to plateau, orgasm, and then resolution. The Basson
Untreated sexual dysfunction is associated with decreased model includes both physical and emotional satisfaction
relationship satisfaction, decreased quality of life, depres- as important outcomes of sexual activity. These two fac-
sion, and low self-image. A comprehensive, biopsychoso- tors may lead to higher emotional intimacy and subse-
cial approach to evaluation, diagnosis, and treatment quently greater receptivity and interest in sexual stimuli,
exploring all psychological, emotional, interpersonal, and creating a circular feedback loop. Furthermore, the
sociocultural contributing factors is best. Treatment of FSD Basson model highlights that sexual activity is not always
should focus on the underlying diagnosis. General recom- prompted by desire, and instead feelings of emotional
mendations for all patients with FSD include increasing intimacy with one’s partner may lead her to be more
exposure to sexual stimuli such as erotic literature, schedul- receptive to sexual stimulation. Sexual arousal and desire
ing sex, decreasing stressors, as well as focusing on overall often co-occur and may be the result of sexual stimuli and
general health such as adequate sleep, exercise, and a not the impetus that leads to sexual stimuli.
healthy diet. 2. Female sexual problems are prevalent, with rates as high
as 43%. The most common female sexual problem
reported is with:
Summary Points A. Lubrication
B. Orgasm
1. Sexual health is an important part of many women’s lives C. Desire
and is defined as “a state of physical, emotional, mental D. Arousal
and social well-being in relationship to sexuality.” The correct answer is C. The most commonly reported
2. Female sexual dysfunction is common, estimated to female sexual problem is low sexual desire. Although
affect 22–43% of women worldwide. FSD is associated 43% of US women report sexual problems, 12% of
women have sexual problems causing significant distress. her antidepressant with a flare of her depression, this is
Reporting of sexual problems consistently increases with not a good option. Augmentation therapy with higher
older age, but reporting of sexual problems causing dis- doses of bupropion (150 mg twice daily) has been shown
tress peaks at midlife. to improve antidepressant-induced FSD.
3. Female sexual dysfunction is defined as a sexual problem
accompanied by:
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Fibroids, Endometriosis, and Ovarian
Cysts 10
Amy H. Farkas, Sarah A. Tilstra, and Alda Maria R. Gonzaga
Learning Objectives Epidemiology

1. Describe the clinical presentation and diagnostic
evaluation related to uterine fibroids. Fibroids, also known as leiomyomas, are benign tumors of
2. Counsel women on the management options avail- smooth muscle in the uterus. Fibroids are the most common
able to treat bleeding and/or bulk symptoms sec- benign tumor in reproductive age women with a cumulative
ondary to fibroids. incidence of up to 70% in White women and up to 80% in
3. Explain the clinical presentation and treatment of Black women by age 50 [1]. One-third of women affected
endometriosis. by fibroids will be symptomatic [2], and roughly one-quar-
4. List the differential diagnosis, diagnostic work-up, ter of these women will have symptoms severe enough to
and management of ovarian cysts. require treatment [3]. The two strongest risk factors for
5. Assess the risk for ovarian cancer in women with an developing fibroids are age (until menopause) and Black
ovarian cyst and determine when referral to gyne- race [4], though the reasons why Black women experience
cology oncologist is appropriate. more symptoms and complications from fibroids than White
women are unknown and require further study [3]. Other
risk factors include nulliparity, use of oral contraceptives
prior to age 16, and obesity [5, 6]; genetics may also play a
Fibroids (Leiomyomas) role given that chromosomal abnormalities in fibroids have
been documented [6]. Increasing parity, diets rich in fruits
and vegetables, and the use of injectable progesterone con-
Georgette is a 46-year-old woman who presents to traception serve as protective factors against the develop-
clinic complaining of fatigue and increasingly heavy ment of fibroids [6].
menses. While manageable in her 30s, her menstrual
cycles are now heavier and occasionally she passes
clots. Her hemoglobin is 7.2 g/dl. Physiology and Pathophysiology
Fibroids grow from the myometrium and are classified by

their location in the uterus [7]. The International Federation
of Gynecology and Obstetrics has developed a detailed clas-
sification system which assigns fibroids a number 0–9 based
on their relation to the endometrium (lower number) and
A. H. Farkas serosal surface (higher number) [8]. In general, submucosal
Department of Internal Medicine, Medical College of Wisconsin, fibroids arise from the myometrium nearest the uterine cav-
Clement Zablocki VA, Milwaukee, WI, USA
ity and often extend into the cavity itself; intramural fibroids
S. A. Tilstra are located completely within the myometrium, and subsero-
University of Pittsburgh School of Medicine, Division of General
Internal Medicine, Department of Medicine, Pittsburgh, PA, USA
sal fibroids are derived from the myometrium nearest the vis-
ceral surface of the uterus and can grow on the external
A. M. R. Gonzaga (*)
University of Pittsburgh School of Medicine,
surface of the uterus. Both submucosal and subserosal
Departments of Medicine and Pediatrics, Pittsburgh, PA, USA fibroids can be pedunculated, i.e., can grow on a stalk [7, 8].

142 A. H. Farkas et al.
The location of the fibroid impacts the symptoms that a Data are inconclusive regarding the role that fibroids play
woman may experience [9]. in infertility and miscarriage. While both submucosal fibroids
There is limited data regarding the natural history of and intramural fibroids have been associated with infertility,
fibroids and both substantial growth and regression are com- it is difficult to determine causality [13]. Fibroids are present
mon [10]. Hormones were initially hypothesized to play a in approximately one-quarter of women seeking treatment
role in fibroid growth because fibroids are not found before for infertility, but are only thought to cause infertility in 13%
puberty and tend to regress in size following menopause. of infertile women [14]. A 2009 systematic review found that
Additionally, smooth muscle cells in fibroids express higher the benefit of myomectomy in infertile women varied based
rates of steroid hormone receptors, growth factors, and on the location of the fibroid; myomectomy in women with
growth factor receptors relative to normal myometrium. submucosal fibroids may improve fertility rates, while
These receptors make fibroid tissue exquisitely sensitive to women with intramural fibroids had no change in conception
estrogen, progesterone, and growth factors such as vascular rate or pregnancy after myomectomy [13]. However, a
endothelial growth factor (VEGF), which helps to facilitate Cochrane review conducted in 2012 found insufficient evi-
aberrant growth [6]. dence from randomized controlled trials to support myomec-
tomy for women with infertility regardless of fibroid location
[15]. Couples with infertility require a complete assessment
Given Georgette’s low hemoglobin and heavy men-
for both partners before concluding that fibroids are the
strual cycles, you suspect an intrauterine lesion. A
cause of infertility. At the time of publication, experts recom-
transvaginal ultrasound demonstrates a large submu-
mend offering myomectomy to women struggling with infer-
cosal fibroid.
tility thought to be due to fibroids, but only to those with
submucosal fibroids [16].
With regard to miscarriage rates, previous literature has
Clinical Manifestations found an increased risk of spontaneous abortion among
women with fibroids; however, the most recent meta-analysis
The most common presenting symptoms of fibroids are conducted in 2017 found no such association in an analysis
heavy vaginal bleeding and bulk symptoms [11, 12]. of more than 20,000 pregnant women in the general obstetric
Submucosal fibroids, because they are located close to the population [17].
endometrium, often present with dysmenorrhea, heavy
menses, or abnormal uterine bleeding (see Chap. 7 on

Abnormal Uterine Bleeding). Some of these women may Differential Diagnosis
not recognize their bleeding as abnormal and may present
with symptoms related to iron deficiency anemia such as Women will either present with the incidental finding of a
fatigue, pallor, dyspnea, or pica, which refers to cravings fibroid or with a symptom for which fibroids can be on the
for soil, raw starches, or ice. Large fibroids in any location differential diagnosis. As described earlier in the chapter,
can produce bulk symptoms, which can be vague in nature abnormal uterine bleeding (AUB) and dysmenorrhea are
and hard for patients to describe. Women may complain of common; it is critical to consider the full differential for
heaviness or pain in their pelvic region [12]. If the fibroid is AUB even in the setting of a known fibroid [9]. While fibroids
pushing on or obstructing the bladder, they may have uri- are one cause of AUB, other causes include endometrial pol-
nary symptoms such as retention or urge incontinence or yps, endometrial hyperplasia or carcinoma, adenomyosis,
may experience problems with defecation if the fibroid is thyroid disease, coagulopathies, and medications. It is
obstructing the colon. Fibroids can also cause bloating, important to consider the risk for endometrial hyperplasia or
impact sexual function, and cause dyspareunia in some carcinoma and indications for endometrial biopsy in these
women [9, 12]. women [10]. Risk factors for endometrial cancer fall under
While women may present with abnormal uterine bleed- the umbrella of exposure to unopposed estrogen and include
ing or bulk symptoms, many women with one or more early menarche, late menopause, chronic anovulation, and
fibroids are asymptomatic. In this case, fibroids may be first obesity. Women with a family history of genetic cancer syn-
apparent on physical examination. Providers may feel a pel- dromes such as Lynch syndrome are also at increased risk
vic mass or an enlarged or abnormally contoured uterus dur- [18]. Please see Chap. 7 on Abnormal Uterine Bleeding and
ing the bimanual exam. Subserosal fibroids can be palpated Chap. 15 on Gynecological Malignancies for more
as a distinct mass on abdominal exam. In addition to detec- information.
tion on physical examination, some fibroids are incidentally Since bulk symptoms are hard to describe for some
noted on abdominal and pelvic imaging obtained for other women, fibroids should be on the differential diagnosis for
indications [1]. any woman presenting with pelvic pressure, urinary inconti-
10 Fibroids, Endometriosis, and Ovarian Cysts 143
nence, bloating, constipation, sexual dysfunction, and dyspa- bleeding should also trigger an evaluation for anemia and
reunia as women may present with any of these symptoms iron deficiency as young women can be asymptomatic even
[7]. Pelvic pain is less common with fibroids but may repre- at very low hemoglobin levels. Additionally, an endometrial
sent torsion or degeneration of the fibroid [7]; therefore, one biopsy may be appropriate for certain women at higher risk
should consider a wide differential in women presenting for endometrial hyperplasia and carcinoma and considered
with pelvic pain including endometriosis, adenomyosis, for any woman greater than 45 that presents with heavy vagi-
prior pelvic inflammatory disease, adhesions, myofascial nal bleeding [25]. See Chap. 7 on Abnormal Uterine Bleeding
pelvic pain syndrome, as well as urologic and gastrointesti- for a detailed review of the evaluation for vaginal bleeding.
nal causes of chronic pelvic pain. While fibroids can cause Additional imaging should be obtained if a provider sus-
urinary symptoms due to mass effect on the bladder, neuro- pects that gastrointestinal or urologic conditions are contrib-
genic causes of urinary retention, incontinence, and diffi- uting to bulk symptoms, especially if there is concern for an
culty with defecation must also be explored [19]. Bloating in abdominal mass or ascites on exam.
the abdomen in women with a pelvic mass should raise con-
cern for a malignancy, particularly if it is associated with
Georgette is seen by gynecologist and an endometrial
early satiety or ascites [20]. Keep in mind that fibroids are
biopsy is obtained, which is normal. After discussing
common and their presence on exam or imaging does not
her management options with gynecologist, she
ensure causation of clinical complaints [21]. History, physi-
chooses to undergo endometrial ablation to reduce her
cal exam findings, and diagnostic work-up must be thorough
bleeding.
to exclude other disease processes occurring concomitantly.
Once a diagnosis of fibroids has been made, one must also
consider uterine sarcoma in the differential diagnosis of
fibroids. Albeit a rare gynecologic malignancy, uterine sar- Treatment Strategies
comas and benign leiomyomas can be indistinguishable in
clinical presentation and imaging [7]. Unfortunately, there Only women with symptomatic fibroids need to be treated
are currently no definitive means to diagnose uterine sar- [7]; it is appropriate to monitor women clinically who pres-
coma among women presenting for fibroid treatment; how- ent with minor symptoms. There is no evidence to support
ever, patients who present with growth of a suspected fibroid, routine imaging of these women [7] as most often, fibroids
have excessive bleeding, or have progressive symptoms in regress in size and cause fewer symptoms over time, particu-
the postmenopausal period should prompt consideration for larly after the menopause [26]. For symptomatic women, the
malignancy [7]. Risk factors such as advanced age, history of treatment options are divided into women who are experi-
pelvic irradiation, genetic cancer syndromes, and tamoxifen encing bleeding symptoms versus those who have bulk
use can also be taken into account when choosing to pursue symptoms.
a cancer evaluation [22]. Endometrial biopsy and MR imag-
ing may indicate the presence of a uterine sarcoma, but nor- anaging Bleeding Symptoms
M
mal studies do not rule it out [23, 24] . Please see Chap. 15 Medications are considered the first line of therapies to con-
on Gynecologic Malignancies for more information. trol bleeding and improve quality of life for women who are
experiencing heavy bleeding. Nonsteroidal anti-inflammatory
medications (NSAIDs) have been shown to help reduce
Diagnostic Strategies heavy bleeding and pain associated with menstruation, but
there are no studies that document these effects for women
When fibroids are suspected, transvaginal ultrasound is the with symptoms thought to be secondary to fibroids. Despite
preferred imaging modality to confirm diagnosis. If an this, moderate to high doses (600–800 mg 2–3 times per day
abdominal mass is palpated on exam, an abdominal ultra- of ibuprofen) are used either just before or at the first sign of
sound should also be ordered. menstruation to help with symptoms [9]. Oral contraceptive
It is important to complete appropriate testing for women pills, both combination and progesterone-only pills, can help
presenting for bleeding and bulk symptoms even after to reduce bleeding in women with fibroids [7, 9]. A Cochrane
fibroids are confirmed on imaging. For women with heavy review conducted in 2013 found that progesterone intrauter-
menstrual bleeding or intermenstrual bleeding, testing for ine devices (IUDs) were effective at reducing heavy vaginal
pregnancy, thyroid disease, and coagulation disorders should bleeding secondary to fibroids and are considered an excel-
be done [10]. Coagulation defects in platelets and the coagu- lent management option by both the American College of
lation cascade can cause menorrhagia; thus, checking a CBC Obstetricians and Gynecologists (ACOG) and the Society of
with platelets, PT/INR/PTT, and von Willebrand disease Obstetricians and Gynaecologists of Canada (SOGC) [7, 9].
screen is appropriate in this population. Chronic heavy There are concerns that women with fibroids may have
higher expulsion rates of IUDs than women without [9, 25] fertility between surgery and embolization [28]. When com-
due to the irregular contour of the uterine cavity or malposi- pared to myomectomy, women who underwent uterine artery
tion; however, these rates are very low and women should embolization have higher rates of re-intervention and future
not be deterred from considering IUD placement. While hysterectomies but have lower rates of procedural complica-
there is some evidence demonstrating that tranexamic acid, tions [21, 28, 29]. MRI-guided focused ultrasound therapy
an antifibrinolytic that works by inhibiting plasmin, can uses ultrasound thermal ablation to treat bulk symptoms
reduce menorrhagia in women with fibroids [27], it is not from fibroids. It is a well-tolerated treatment with improve-
currently recommended as a treatment strategy by either ment in both fibroid size and quality of life [30], though little
ACOG or SOGC [7, 9]. data exist regarding how ultrasound therapy compares to
When medications do not adequately address bleeding alternative treatments [29]. There are documented cases of
symptoms, hysteroscopic myomectomy (surgical removal of successful pregnancy following ultrasound therapy but the
the fibroid) or endometrial ablation can be considered. For data remains limited [30]. Despite their success, many
women who desire fertility preservation, hysteroscopic myo- women who choose uterine-sparing options will often
mectomy is the first-line option for women with submucosal require a second procedure, with estimates as high as
fibroids [7]. Hysteroscopic myomectomy, where the fibroid 15–17% [29].
is surgically resected, improves bleeding symptoms and Hysterectomy is the most common procedure for women
potentially improves pregnancy rates by restoring the shape experiencing bulk symptoms and is the most definitive treat-
of the uterine cavity, which may have been distorted by the ment for either bleeding or bulk symptoms [16, 29].
fibroid [13]. For women who do not desire future fertility, Hysterectomy is only appropriate for women who no longer
endometrial ablation may be an option. Ablation is accom- desire fertility. There are surgical risks associated with hys-
plished by insertion of a probe into the uterine cavity via the terectomy [10], and new data suggest that women who
cervix; heat (most commonly radiofrequency), cold, or undergo hysterectomy, even with ovarian preservation, have
mechanical means is/are used to destroy the endometrial lin- an increased risk of cardiovascular disease [31]. There is also
ing [10]. It is important to remember that women who have data to suggest that women who choose hysterectomy have
undergone ablation still require contraception as ablation higher quality of life following the procedure [2].
does not necessarily cause infertility and pregnancy compli-
cations can increase following the procedure [10].
When to Refer
anaging Bulk Symptoms
M
For women who are experiencing bulk symptoms, Women with persistent bleeding despite optimal medical
gonadotropin- releasing hormone (GnRH) agonists can therapy should be referred to gynecologist to consider addi-
reduce the size of fibroids; however, they are not considered tional evaluation and procedural management. Additionally,
a long-term option given their significant side effect profile women with abnormal uterine bleeding in the setting of
including hot flashes, vaginal dryness, and bone health con- fibroids who are over 45 years of age require endometrial
cerns. Use should be limited to 6 months [9]. GnRH agonists biopsy; biopsy should also be considered for younger women
can be helpful as a short-term bridge to menopause or used with BMI >30 [25, 32].
prior to a planned surgical intervention to help reduce the
size of the fibroids preoperatively [9].
Three uterine-sparing options for management of bulk Endometriosis
symptoms include myomectomy, uterine artery emboliza-
tion, and MRI-assisted ultrasound therapy. Myomectomy (as
described above) is the preferred option for women who Lynda is a 34-year-old woman who presents to clinic
wish to preserve their fertility. It has similar complications to discuss painful menstrual cycles. She mentions that
and risks as hysterectomy. Uterine artery embolization is an she finds sex painful and that she and her husband
interventional radiology procedure which treats the entire have been attempting to conceive for the past year
uterus by injecting embolizing particles into the uterine without success.
arteries. While there have been reports of successful preg-
nancies following uterine artery embolization, it is not the
preferred method for women who desire future pregnancy as
limited data suggest that pregnancy rates may be better Epidemiology
among women who undergo myomectomy [21]. There is
some concern for loss of ovarian function following emboli- Endometriosis, the presence of endometrial gland tissue
zation, but a recent systematic review found no difference in implanted on peritoneal surfaces outside the uterus, occurs
conservatively in 10–11% of women [33, 34]. In women Table 10.1 Symptoms and corresponding odds ratios present in
women with endometriosis vs. women without endometriosis [37]
diagnosed with infertility, the estimated prevalence lies
between 25% and 50% [35, 36], while 40–80% of women Symptom Odds ratio (95% CI)
with chronic pelvic pain have been reported to have endome- Subfertility 8.2 (6.9–9.9)
Dysmenorrhea 8.1 (7.2–9.3)
triosis [36–38]. As endometriosis is definitively diagnosed
Ovarian cysts (endometriomas) 7.3 (5.7–9.4)
by laparoscopic tissue biopsy, prevalence and incidence rates
Dyspareunia and/or postcoital bleeding 6.8 (5.7–8.2)
vary widely between studies. As a result, women are often Abdominopelvic pain 5.2 (4.7–5.7)
older than 30 years of age when they are diagnosed with Menorrhagia 4.0 (3.5–4.5)
endometriosis [33].
Non-Hispanic White women are diagnosed with endo-
metriosis more commonly than women of other racial and often feels “crampy” but can be sharp and stabbing at times.
ethnic backgrounds [33]. Risk factors for endometriosis As the disease progresses, patients often develop chronic,
include early menarche and late menopause (which allows occasionally debilitating, pelvic pain. Sexual activity, par-
for increased exposure to estrogen over time), menstrual ticularly deep vaginal penetration, can trigger pain as the
outflow obstruction, and short menstrual cycles [34]. anterior and posterior cul-de-sacs and the pouch of Douglas
Protective factors include multiple pregnancies and pro- are common sites for endometrial implants [40]. Patients can
longed lactation [34]. also struggle with bowel and bladder symptoms such as nau-
sea, abdominal distention, tenesmus, dysuria, or hematuria
due to inflammation associated with endometrial implants
Physiology and Pathophysiology within the bowel wall, bladder, genitourinary tract, and
abdominal wall [41].
The pathophysiology of endometriosis is not well under- Up to half of women with infertility will be diagnosed
stood but may be secondary to implantation of endometrial with endometriosis [35, 36], and patients may be unaware
tissue outside of the uterus as a result of retrograde men- that they are affected until they try to conceive. The exact
struation [39]. Implantation of this estrogen-sensitive tissue mechanism and extent as to how endometriosis affects fertil-
onto the peritoneal surface of the abdomen elicits a local ity is unknown; researchers postulate that inflammation,
inflammatory response. This pathogenic inflammatory cytokine activity, macrophage activation, and mechanical
response can lead to debilitating pain at or near the sites of obstruction affect hormone concentrations, oocyte develop-
endometrial implants due to local scarring, development of ment and release, sperm motility, embryo transport, endome-
adhesions, distortion of the pelvic anatomy, and alterations trium receptivity, and implantation [44]. Patients with
in the neuronal pathways that process pain [39]. Implantation endometriosis often experience significant debility due to
on ovarian tissue is common and results in endometrial lined chronic pain and decreased fertility. Additionally, women
ovarian cysts (chocolate cysts or endometriomas) that are with endometriosis may suffer from concomitant depression
seen in 55% of affected women. Endometrial implants are and/or anxiety related to their endometriosis [45].
found on the peritoneum of the pelvic floor (35% of affected The diagnosis of endometriosis can lag by months or
women), uterus (11%), fallopian tubes (1–4%), bladder years as clinical symptoms can be vague and nonspecific. In
(1%), and rectum (0.5%) [40]. There are rare case reports of one study of American women with surgically confirmed
more distant endometrial tissue implants, such as on the liver endometriosis, symptom onset occurred an average of
[38], within the bowel wall [41], and within the pleural space 11.73 ± 9.05 years before diagnosis [46]. In that study,
[42]. All endometrial tissue is hormone sensitive; thus women with chronic pain due to endometriosis had a delay
women tend to be relatively more symptomatic at the time of in diagnosis of 9.21 ± 6.21 years between 1979 and 1984,
the menses. When hormones are altered by medication or by which decreased to 4.63 ± 4.62 years between 1990 and
menopause, symptoms often improve [43]. 1995; in women with infertility due to endometriosis, the
delay in diagnosis decreased from 3.52 ± 2.53 to
2.93 ± 2.57 years, respectively [47]. Increased physician
Clinical Manifestations awareness of endometriosis has likely contributed to
improvements in time to diagnosis [47].
Women with endometriosis experience a wide array of Most women will have a normal pelvic exam, but some
symptoms. Most commonly, patients describe chronic dys- patients will have rectovaginal nodularity, limited motion of
menorrhea; dyspareunia; abdominal, back, or pelvic pain; the uterus or ovaries, an adnexal mass, or tenderness in the
and fatigue (Table 10.1). The pain of endometriosis is vari- posterior fornix on exam. A rectovaginal exam may be indi-
able and often occurs with menses, usually starting a few cated in order to allow palpation of the uterosacral ligament
days before and lasting until the cycle is complete. The pain and rectovaginal septum that can harbor painful nodules rep-
Table 10.2 Differential diagnosis of chronic pelvic pain symptoms; this is the preferred path of evaluation and treat-
Gynecologic Non-gynecologic ment by the Society of Obstetricians and Gynaecologists of
Endometriosis Irritable bowel syndrome Canada (SOGC) [48]. This is because the gold standard of
Pelvic inflammatory disease Inflammatory bowel disease diagnosis is direct visualization and tissue biopsy, often
Pelvic adhesions Interstitial cystitis completed during diagnostic laparoscopy, or cystoscopy,
Ovarian cysts or masses Myofascial pain syndrome colonoscopy, or speculum exam if there are endometrial
Fibroids Pelvic floor dysfunction
implants outside of the peritoneal cavity. Laparoscopy is
Adenomyosis Depression
indicated when medical management fails, with a goal of
Vulvovaginal atrophy Trauma and sexual abuse
Pelvic congestion syndrome both confirming the presumed diagnosis and treating symp-
toms via debulking [48]. Endometriosis can be staged at
laparoscopy using the Revised Classification of Endometriosis
Table 10.3 Differential diagnosis of female infertility
Staging system form by the American Society for
Structural/tubal Reproductive Medicine [49], ranging from Stage I, minimal
factors Ovulatory dysfunction Others
disease, to Stage IV, severe disease. Disease staging is the
Pelvic Polycystic ovary Antiphospholipid
inflammatory syndrome syndrome standard approach for reporting surgical findings; however, it
disease does not correlate with severity of pain or predict responsive-
Endometriosis Primary ovarian failure Genetic factors ness to treatment [50].
Adhesions from Functional Unexplained Prior to a laparoscopy, providers can obtain imaging stud-
pelvic surgery hypothalamic ies to aid in diagnosis. Transvaginal ultrasonography (TVUS)
amenorrhea
reliably detects endometriomas, which are cystic masses aris-
Cervical stenosis Hyperprolactinemia
Uterine anomalies Medical illness (e.g, ing from ectopic endometrial tissue within or on the ovary
(e.g., septate uncontrolled diabetes [51]. TVUS has a sensitivity and specificity of 89% and 91%,
uterus) mellitus) respectively, for endometriomas when an ovarian mass is
Uterine fibroids Thyroid disease adequately visualized; however, it can miss smaller lesions
Advanced maternal age [51]. TVUS can also reliably detect deeply infiltrating endo-
metriosis (serosal/muscular layer) in the rectal region with a
resenting endometrial implants. Additionally, examination sensitivity and specificity of 98% and 99% but may miss
during menstruation may provide a better assessment of pain more superficial lesions [52]. The use of magnetic resonance
and help detect deeply infiltrating disease [48]. imaging (MRI) to aid in detection of endometriosis has been
studied but performs less accurately than ultrasonography
[53]. However, MRI can be used to evaluate for other struc-
Differential Diagnosis tural lesions in the pelvis if there are questionable findings on
TVUS. Given the lower cost of ultrasonography and higher
Given the vague symptoms associated with endometriosis, a detection rates, it is the preferred initial imaging modality in
lengthy differential diagnosis should be considered for the patients suspected to have endometriosis. If no lesions are
two most common manifestations: chronic pelvic pain found on TVUS, this does not exclude a diagnosis of endome-
(Table 10.2) and infertility (Table 10.3). A careful history triosis. CA-125, a cancer marker for ovarian cancer, has been
and physical exam can help differentiate disorders associated studied extensively but has limited utility in the diagnosis of
with chronic pelvic pain. See Chap. 31 on Chronic Pelvic endometriosis given its poor sensitivity and specificity [54].
Pain to appreciate how patients with endometriosis present
differently than patients with other causes of pelvic pain.
There are also full chapters dedicated to Irritable Bowel Treatment Strategies
Syndrome (Chap. 27), Sexually Transmitted Infections
(Chap. 13), Interstitial Cystitis (Chap. 30), Chronic Pelvic Approaches to treating endometriosis are best organized by
Pain (Chap. 31), and Intimate Partner Violence and Sexual symptom management.
Trauma (Chap. 35).
reatments for Chronic Pelvic Pain
T
Due to Endometriosis
Diagnostic Strategies Nonsteroidal anti-inflammatory drugs (NSAIDs) are the
most common first-line treatment for pain, as they have been
Most providers err on the side of making a “presumed” diag- shown to reduce symptoms of dysmenorrhea. However, there
nosis of endometriosis based on history, physical exam find- is inconclusive evidence that NSAIDs are more effective
ings, and the absence of objective findings for other causes of than placebo in treating endometriosis [55].
Hormonal treatments that suppress ovarian function ity. Two main types of surgical interventions have been stud-
reduce disease activity and pain associated with endometrio- ied, laparoscopic excision of endometrioma cyst walls and
sis. Ovarian suppression limits the hormonal exposure to ablation of endometrial implants. Overall, these interventions
endometrial tissue outside of the uterine cavity, which in turn are similar in improving pregnancy and live birth rates but
limits the local inflammatory response, chronic scarring, and this is based on low-quality data [59]. Patients should be
neuronal dysfunction. Evidence supports the use of com- counseled that laparoscopic surgical intervention could be a
bined hormonal oral contraceptives, administered either promising modality for women with mild or moderate disease
cyclically or continuously, and continuous progestins (e.g., in reducing pain and improving fertility, but decisions about
medroxyprogesterone acetate, norethindrone, cyproterone the efficacy, type, and timing of procedure must be made in
acetate, or dienogest) [56]. The most effective treatment for consultation with their surgeon [59, 62].
pain relief from ovarian suppression is gonadotrophin- If surgical resection of endometrial tissue is unsuccessful,
releasing hormone analogues (GnRHa) such as leuprolide or referral for assisted reproductive technology (ART) is indi-
goserelin, which are associated with relief of pelvic tender- cated. In vitro fertilization (IVF) is also recommended as
ness and painful menstrual cycles when compared with pla- first-line treatment for women with advanced disease due to
cebo or no treatment [57]. However, these agents are often the risk of decreasing ovarian reserve during surgery [63].
poorly tolerated due to clinical manifestations of the “medi- There is no role for ovarian suppression with combined oral
cal menopause” they induce, such as hot flashes and vaginal contraceptive, GnRHa, medroxyprogesterone acetate, or dia-
dryness [57]. Low-dose estrogen-progestin add-back thera- zole in the treatment of infertility [64]. However, some data
pies can minimize these side effects [56]. Moderate-quality suggest using GnRHa prior to IVF for women with infertility
evidence demonstrates that levonorgestrel intrauterine sys- secondary to endometriosis to increase pregnancy rates [63].
tem controls pain better than expectant management [58]. There is no evidence that complementary medicine treat-
This is likely due to the local effect of progestin on the pelvic ments of acupuncture and Chinese herbal medicine are effec-
tissues and not due to ovarian suppression though the exact tive in managing the pain or infertility associated with
mechanism is unclear [58]. endometriosis [65, 66]. However, patients should be encour-
Laparoscopic ablation or excision of lesions reduces pain aged to seek treatments that they feel minimize their pain and
at 6 months when compared with diagnostic laparoscopy. increase their quality of life.
Excision of endometrioma cyst walls appears more effective
at controlling pain than ablation. However, surgical resection
of endometriomas does reduce ovarian reserve and can nega- When to Refer
tively impact fertility. Strategies should be taken during such
surgeries to minimize the damage to the normal ovary to Primary care providers should be comfortable identifying and
optimize future fertility, and patients should be informed of treating women with presumed endometriosis. If symptom
these risks before proceeding [58, 59]. control cannot be achieved with hormonal methods (continu-
Endometriosis recurs after surgery, with rates ranging ous progestins or combined oral contraceptives) or supportive
from 10% to 50%. Regardless of the amount of endometrio- care (NSAIDs), then referral to gynecologist for medical (i.e.,
sis visualized and removed during laparoscopy, patients’ GnRHa) and/or surgical evaluation and treatment is appropri-
pain may progress or remain unchanged. Expectations of ate. Any couple who has been attempting to conceive for
treatments should be discussed with patients, and realistic greater than 1 year should be referred for an infertility assess-
goals should be set, especially prior to any invasive interven- ment, especially if the woman has chronic pelvic pain. When
tion. Additional therapies include the FDA-approved oral a woman is unsuccessful in conceiving after 6 months and she
GnRH antagonist elagolix, and the potential use of immuno- is over 35 years old, referral to gynecologist or reproductive
therapy or aromatase inhibitors [60, 61]. endocrinologist is recommended [67].
reatments for Infertility Due to Endometriosis

T
As noted above, endometriosis frequently leads to infertility. Ovarian Cysts
Patients with endometriosis and infertility should undergo a
work-up to identify reversible causes; this work-up may be
initiated by the primary care provider but is ideally performed Juliana is a 32-year-old woman who presents to you
in conjunction with the patient’s gynecologic care provider for follow-up after a visit to the emergency department
and/or a reproductive endocrinologist. Once endometriosis is for right-sided abdominal pain. While she was in the
established as the cause of the infertility, treatment focuses on emergency department, she had a CT scan and was
attempting to restore normal ovulation and anatomy by told that she has an ovarian cyst.
removing endometrial tissue and adhesions in the pelvic cav-
Epidemiology these simple cysts resolved, and none of these 2763 women
developed ovarian cancer [76]. The rest of this chapter will
Ovarian cysts are common in women of all ages. Reproductive focus on evaluation and management of simple ovarian cysts.
age women develop a functional cyst every month as the With regard to other cyst types, endometriomas and
ovary prepares for ovulation. The prevalence of ovarian cysts mature teratomas can be managed expectantly with serial
in premenopausal women is variable, anywhere from 7% in imaging [72]. Surgical removal of endometriomas can nega-
healthy women [68] to 35% in first- or second-degree relatively affect ovarian reserve [77] and therefore should be
tives of patients with ovarian cancer [69]. Despite the cessa- avoided when possible.
tion of menses, postmenopausal women develop ovarian
cysts as well. Data from the Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial found that among postmeno- Clinical Manifestations
pausal women, 14% had a simple unilocular cyst detected on
initial transvaginal ultrasound with a 1-year incidence of Ovarian cysts often produce no symptoms; however, for
new cysts of 8% [70]; however other studies have docu- women who do experience symptoms, pelvic or abdominal
mented the prevalence in postmenopausal women as low as pain is the most common presenting complaint [78].
2.5% [71]. The vast majority of cysts are asymptomatic and Ovarian cysts cause abdominal or pelvic pain by mass
discovered incidentally on imaging or during physical exam effect on the surrounding structures in the pelvis, acute
[72]. The difficult job that providers face is determining stretching of the ovarian cortex during rupture, or from
which cysts are likely benign and which are more concerning peritoneal irritation from a ruptured or slowly leaking cyst
for ovarian malignancy. that causes a local inflammatory reaction. Women present-
ing with increased abdominal girth and bloating should
raise the concern for ovarian cancer compared to a benign
Physiology and Pathophysiology ovarian cyst [78]. The presence of an ovarian cyst in a
woman with abdominal or pelvic pain may not be the cause
There are several different types of ovarian cysts including of her pain, and additional work-up is indicated depending
functional or simple cysts, hemorrhagic cysts, endometrio- on presenting symptoms.
mas, and mature teratomas (dermoid cyst). A functional or
simple cyst occurs as a follicle develops and fails to rupture
or after a follicle ovulates but the corpus luteum continues to Juliana has noticed the pain on the right side of her
increase in size instead of involuting. Hemorrhagic cysts lower abdomen for about a month. It is worse with her
occur when there is bleeding into a functional cyst or corpus menstrual cycles. She reports pain with sexual inter-
luteum [73]. As discussed above, endometriomas result course, particularly deep penetration. On exam, there
when endometrial tissue is located inside an ovarian cyst and is tenderness in the right adnexa; however, there is no
may present with symptoms of endometriosis. Mature terato- enlargement or nodularity and the exam is otherwise
mas, the most common type of ovarian germ cell tumor, normal.
appear as complex cysts. They are derived from all three
germ cell layers and generally made up of different types of
tissue including hair, teeth, skin, muscle, and connective tis-
sue [74]. Differential Diagnosis
The majority of cysts are benign, even in postmenopausal
women, and will resolve over time. In 1 study of pre- and The differential diagnosis of an adnexal mass includes both
postmenopausal women, 3511 adnexal masses were identi- benign and malignant etiologies (Table 10.4) [72].
fied, of which 1148 were classified as unilocular cysts. In the A thorough history informs the differential diagnosis of
group of unilocular cysts, only 11 were malignant on patho- an adnexal mass, with particular focus on ovarian cancer risk
logical exam for a malignancy rate of <1%; however, on factors. Age is the number one risk factor for ovarian cancer;
pathology reports, 7 of the 11 unilocular cysts had solid com- the average age at diagnosis is 63 years, and risk continues to
ponents; thus they had been misclassified as benign on ultra- rise with age [79]. Providers also need to take a detailed fam-
sound prior to surgical resection [75]. In another study, ily history, including breast cancer, ovarian cancer, and
15,106 women over the age of 50 were screened with trans- familial cancer syndromes, such as BRCA 1&2. Women
vaginal ultrasound, and 18% (2763) of participants were with a family history of ovarian cancer but without a BRCA
diagnosed with a simple cyst, all of which were less than history have a lifetime risk of ovarian cancer of 5–8.1% [80,
10 cm in diameter. After 6.3 years of follow-up, two-thirds of 81], whereas women who have the BRCA gene have a life-
Table 10.4 Differential diagnosis of adnexal mass [72] ness and characteristics of the vaginal discharge to help eval-
Benign Malignant uate for infection, (3) pain with palpation in the anterior or
Functional cysts Epithelial carcinoma posterior vaginal fornix or “studding” along the pelvic floor
Endometrioma Germ cell tumor or rectovaginal wall that may indicate endometrial implants
Hemorrhagic cysts Sex cord or stromal tumor or malignancy, and (4) peritonitis, abdominal masses, and
Mature teratoma (dermoid) Metastatic cancer costovertebral tenderness that may reflect GI and GU pathol-
Cystadenoma (mucinous or serous)
ogy. Patients often have pain with manipulation of the ova-
Hydrosalpinx
ries and/or uterus when infection (PID or TOA), torsion, or
Paratubal cysts
Fibroid an ectopic pregnancy is present. (See Chap. 11 on
Mullerian anomalies Gynecologic Emergencies.) Peritonitis is nonspecific but
Medical emergencies indicative of an acute, inflammatory issue (PID, TOA, tor-
Tubo-ovarian abscess sion, ruptured ectopic, GI pathology, malignancy) that needs
Ectopic pregnancy immediate evaluation. A fixed, firm, or irregular mass; bilat-
eral masses; and/or the presences of ascites should raise con-
time risk of ovarian cancer of up to 46% [82]. Additional risk cern for ovarian malignancy [72]. In asymptomatic women,
factors for ovarian cancer include nulliparity, early men- a normal pelvic exam is not uncommon as data suggest that
arche, late menopause, and obesity [79]. See Chap. 15 on even in ideal settings with experienced providers, the pelvic
Gynecologic Malignancies for additional information. exam is insensitive in detecting adnexal pathology [85–88].
Beyond assessing the risk for malignancy, it is also impor- Every patient must have a pregnancy test. If the preg-
tant to evaluate for any gynecological complaints that may nancy test is positive and the patient is having abdominal
require more urgent management in the setting of adnexal pain, she must be immediately evaluated for an ectopic preg-
tenderness or a pelvic mass. While a cyst may cause pain, nancy. If untreated, patients have an 18% chance of rupture,
one should consider evaluation for ovarian torsion, pelvic which can lead to life-threatening hemorrhage [89].
inflammatory disease (PID), tubo-ovarian abscess (TOA), Transvaginal ultrasound with Doppler is the preferred
acute hemorrhage into a cyst or rupture, or an ectopic preg- imaging modality for adnexal masses [72]. If patients pres-
nancy, particularly if the pain is acute in nature [83]. Patients ent after ovarian cysts are noted on non-ultrasound imaging,
with infectious etiologies like PID and TOA may have fevers, transvaginal ultrasound should be performed next as neither
chills, nausea, vomiting, peritonitis, vaginal discharge, and a CT nor MRI are first-line modalities to evaluate the adnexa
history of unprotected sex or new sexual partner(s). The pain [72]. Ideally, the ultrasound should be performed by an expe-
from ovarian torsion is often described as unilateral and “col- rienced technician and interpreted by a radiologist with
icky,” as the ovary twists upon itself and the blood supply to expertise in pelvic ultrasound. As cysts grow, it is possible
the gonad is compromised. Patients can have sharp unrelent- that ultrasound imaging can be incomplete. When an ultra-
ing pain from an ectopic pregnancy and, if ruptured, signs of sound report indicates that all of the borders of a large cyst
hemodynamic instability and peritonitis [83]. Acute rupture are not visible, due to patient anatomy or body habitus, a
of the cyst can cause severe pain that may mimic an abdomi- follow-up pelvic MRI can assess for septations and/or solid
nal catastrophe. Rupture can be triggered by sexual activity components [90].
and tends to occur late in the menstrual cycle, between days In 2010, the Society of Radiologists in Ultrasound pro-
20 and 26. While hemorrhage from a ruptured ovarian cyst duced consensus guidelines for the interpretation of ovarian
can occur, hemodynamic compromise from this is rare [84]. cysts. Per these guidelines, simple cysts measuring <3 cm in
Gastrointestinal and urological causes of pain such as appen- diameter in premenopausal women and <1 cm in postmeno-
dicitis, diverticulitis, and nephrolithiasis can also mimic pain pausal women are considered normal and do not need to be
caused by an ovarian cyst and must be ruled out. A complete described in an ultrasound report. Any cyst larger than these
history and review of systems can help guide the differential thresholds should be characterized in an ultrasound report
diagnosis. [73]. The ultrasound report should describe the size and lat-
erality of the adnexal mass, the components of the mass (cys-
tic versus solid), any septations (thin versus thick and single
Diagnostic Strategies versus multiple), and any papillary or nodular projections in
the mass. Doppler flow assesses vascular flow to the cyst
All women with pelvic pain or an asymptomatic, inciden- [72]. These guidelines also provide descriptions and recom-
tally discovered ovarian mass should undergo a complete mendations for follow-up of other common adnexal cysts
abdominal and gynecological exam. The provider should be including hemorrhagic cysts, endometriomas, and dermoids,
assessing for (1) the size, shape, mobility, tenderness, and all of which have distinctive appearances on ultrasound.
position of the ovaries and uterus, (2) cervical motion tender- Recommendations are largely based on size of the cyst,
Table 10.5 Ultrasound findings for ovarian cysts [72] prompt referral to gynecology oncologists for further evalu-
Concerning ultrasound ation [72].
Reassuring ultrasound findings findings For postmenopausal women presenting with an adnexal
Size up to 10 cm in diameter Cysts larger than 10 cm in mass, a CA-125 should be checked near the time of the first
diameter
ultrasound. The ACOG guidelines recommend referral to
Thin smooth walls Thick/multiple septations
Absence of septations Papillary projections/solid
gynecologic oncologist when a patient’s CA-125 level is
components greater than 35 U/ml in the presence of an adnexal mass [72].
Absence of papillary projections/ Doppler flow A low CA-125 in the setting of an ovarian mass at any age,
solid components especially with concerning features, does not rule out malig-
Absence of Doppler flow Presences of ascites nancy, and further work-up should be pursued.
Beyond CA-125, other tumor markers associated with
germ cell tumors include b-hCG, L-lactate dehydrogenase,
menopausal state, and any concerning findings on ultrasound and alpha-fetoprotein [72]. While there has been research
[73]. The American College of Obstetricians and assessing the use of biomarker panels and multivariate
Gynecologists (ACOG) published a practice bulletin in 2016 assays, these are not first-line diagnostic tests [72]. A Risk of
on the management of adnexal masses. This bulletin encour- Ovarian Malignancy Algorithm (ROMA) has been devel-
ages providers to focus on ultrasound findings of the cyst as oped to risk stratify women with ovarian cysts into groups at
opposed to the size of the cyst at presentation. The biggest either low or high risk for ovarian malignancy prior to under-
change in these guidelines when compared to previous rec- going surgical intervention for ovarian cysts that have already
ommendations is the “10-cm rule” – stable asymptomatic been identified as needing surgical intervention based on
simple cysts in pre- or postmenopausal women can be fol- imaging or clinical findings. Most often used by the surgical
lowed until they reach 10 cm in size without surgical inter- team, this algorithm includes CA-125, menopausal status,
vention, as the risk of malignancy is extremely low. and epididymis protein 4 [93]. In a meta-analysis epididymis
Table 10.5 includes descriptions of reassuring and concern- protein 4 had a pooled sensitivity of 81% and a pooled speci-
ing ultrasound findings [72]. ficity of 91% for the detection of ovarian malignancy [94].
After ultrasonography, laboratory evaluation may be
appropriate based on a patient’s other presenting symptoms
and signs. Providers should obtain urine HCG testing in all Juliana’s pregnancy test is negative. You suspect she
women of reproductive age. A complete blood count and STI may have endometriosis. You send her for a transvagi-
testing should be considered for an infectious etiology of an nal ultrasound that demonstrates a 4-cm endometri-
adnexal mass such as a tubo-ovarian abscess [72, 91]. oma in her right ovary.
The most studied biomarker for ovarian malignancy is
CA-125; however, providers must understand the limitations
to its use. CA-125 will be elevated in about 80% of patients
with epithelial ovarian cancer but is only elevated in 50% of Treatment Strategies
patients with Stage 1 disease [92]. It is also not the primary
cancer marker in ovarian cancers that present in premeno- Treatment is based on the patient’s symptoms, ultrasound
pausal women, such as germ cell tumors and sex cord stro- characteristics, and risk for malignancy. When a woman is
mal tumors. CA-125 can be elevated by any process which asymptomatic, a simple cyst up to 10 cm in diameter can be
irritates the perineum such as normal menses, pelvic inflam- followed with expectant management regardless of meno-
matory disease, and endometriosis [92]. Given these limita- pausal status if the cyst has been adequately imaged [76].
tions in specificity, CA-125 is less predictive of malignancy Benign disease, such as endometriomas or mature teratomas,
in premenopausal woman and should not be used to distin- can also be managed expectantly [72]. While oral contracep-
guish between a benign and malignant adnexal mass [72]. tive pills have been recommended in the past for the suppres-
For premenopausal women, it is reasonable to check a sion and treatment of functional ovarian cysts, a 2014
CA-125 if an ovarian mass has concerning features on ultra- systematic review found them to be of no benefit [95]. In
sound, but note that it is not recommended to check a symptomatic women, gynecology referral for possible surgi-
CA-125 in every premenopausal female with an ovarian cal excision is reasonable for a cyst of any size. However, in
mass without discretion, especially in the setting of a simple young women, it is important to consider future fertility and
cyst on imaging. Guidelines do not recommend a specific preservation of normal ovarian tissue should be emphasized
cutoff or range of CA-125 that would make an ovarian mass [72]. When concerned that the cyst may represent an ovarian
in a premenopausal woman more concerning for malignancy, malignancy, the patient should be referred for immediate
but based on expert opinion, a level of >200 U/ml should gynecologic oncology evaluation [72].
Monitoring Summary Points
The interval between initial and repeat imaging has not 1. Uterine fibroids are common and can be asymptomatic;
been well established for patients presenting with benign when symptomatic, women present with heavy vaginal
cysts [72]. The American Academy of Family Physicians bleeding and/or bulk symptoms such as heaviness, pain,
suggests repeating a transvaginal ultrasound 4–12 weeks or problems with urination or defecation.
after the initial test; this interval is often practiced clini- 2. Medical and surgical management options for fibroids
cally [91]. Repeat imaging serves two functions: (1) to vary based on which symptoms predominate and include
judge growth or recession and (2) to confirm the findings NSAIDs, hormonal methods, IUDs, myomectomy, endo-
of the first ultrasound. Many adnexal masses will exhibit metrial ablation, uterine artery embolization, MRI-guided
intermediate findings that are often benign but not obvi- ultrasound therapy, and hysterectomy.
ous enough to establish a clear diagnosis with one evalua- 3. Endometriosis often presents with dysmenorrhea, dyspa-
tion. For example, a fluid-filled simple cyst may have a reunia, and menorrhagia but can also be asymptomatic,
single thin septation or a small amount of calcium in the with the diagnosis determined only during infertility
wall. Similarly, features consistent with a hemorrhagic evaluation.
cyst, endometrioma, or dermoid cyst are often not obvious 4. Numerous options can alleviate pain secondary to endo-
on the first imaging study but become clearer as time pro- metriosis: NSAIDs, combined oral contraceptive pills,
gresses [91]. levonorgestrel IUD, medroxyprogesterone acetate, and
With regard to the timing and duration of monitoring, GnRH agonists.
some experts recommend monitoring stable cysts without 5. Patients with infertility secondary to endometriosis
solid components for 1 year and stable cysts with solid should be referred for consideration of surgical interven-
components for 2 years [96]. The rationale behind this tion to remove endometrial implants or in vitro fertiliza-
recommendation stems from a study in which women over tion (IVF).
50 years old with ultrasound-detected complex adnexal 6. When evaluating an ovarian cyst, consider both benign
masses were followed with serial ultrasounds prior to sur- etiologies such as simple cysts, endometriomas, hemor-
gical resection. Masses diagnosed as epithelial tumors at rhagic cysts, and mature teratomas and malignant etiolo-
surgical resection had all demonstrated growth on or gies such as ovarian cancer. Assessment includes a
before 7 months of follow-up [76], inferring that cancers transvaginal ultrasound, obtaining a CA-125 level, and a
will see growth most often within the first year of ultra- risk assessment for ovarian cancer.
sound follow-up. Because the studies that evaluated sur- 7. Indications for early referral to gynecology oncologist
veillance of ovarian cysts used both ultrasound and include an elevated CA-125 (>35 U/ml in postmeno-
CA-125 levels, it is recommended that in postmenopausal pausal woman), ultrasound findings concerning for
women with cysts, a CA-125 level is drawn at each fol- malignancy, a fixed or nodular pelvic mass, ascites, or
low-up ultrasound [97, 98]. Should the CA-125 level evidence of distance metastasis.
trend above 35 U/ml in the presence of an adnexal mass in
a postmenopausal woman, a referral to gynecology oncol-
ogist is recommended [72]. Review Questions
1. A 31-year-old woman presents to your office with menor-

When to Refer rhagia and anemia. Her transvaginal ultrasound demon-
strates a large submucosal fibroid. She is considering
For symptomatic women, referral to gynecologist for pos- having a third child. What is the best management option?
sible surgical removal of a cyst is appropriate. It is impor- A. Hysteroscopic myomectomy to remove the fibroid
tant to emphasize that if there is any concern for malignancy, B. IUD insertion to manage bleeding until she is ready to
such as elevated CA-125, ultrasound findings suggestive of have her third child
malignancy, nodular or fixed pelvic mass, ascites, or evi- C. Uterine artery embolization
dence of metastasis, then a woman should be referred to D. Endometrial ablation
gynecology oncologist as opposed to a general gynecolo- The correct answer is A. Myomectomy should be the
gist. Evidence suggests that women with ovarian cancer first-line treatment for women considering additional
have increased survival when managed by gynecologic children because there is evidence that it may improve
oncologists [72]. pregnancy rates. A progesterone IUD could help manage
bleeding symptoms and if she is opposed to procedural 5. A 35-year-old woman presents after a transvaginal ultra-
options could be considered appropriate. Both uterine sound obtained for heavy menstrual bleeding demon-
artery embolization and endometrial ablation should be strated a 6-cm simple cyst without septations or solid
reserved for women who have completed childbearing [7, components. She has no risk factors for ovarian cancer
9]. and no family history of breast or ovarian malignancy.
2. A 54-year-old postmenopausal woman presents to your She asks if this could be ovarian cancer. How would you
office with a complaint of heaviness in her pelvis and uri- advise her?
nary incontinence for the last several years. On exam, her A. You recommend referral to gynecology oncologist for
uterus is enlarged. A transvaginal ultrasound demon- consideration of surgical excision of the cyst.
strates a large subserosal fibroid that abuts her bladder. B. You recommend a repeat ultrasound in 6–12 weeks
What is the best management option for her symptoms? and reassure her that the risk of malignancy is low.
A. GnRH agonist C. You recommend a repeat ultrasound in 6–12 weeks
B. Hysterectomy with a CA-125 and reassure her that the risk of malig-
C. Endometrial ablation nancy is low.
D. Hysteroscopic myomectomy D. You recommend she obtain a MRI to better categorize
The correct answer is B. A GnRH agonist would not be the cyst before making a decision on referral to gyne-
appropriate as she is already postmenopausal. Endometrial cology oncologist.
ablation and hysteroscopic myomectomy would not The correct answer is B. Her cyst is simple appearing on
address her bulk symptoms [7, 9]. ultrasound. She is premenopausal, and given that she
3. A 26-year-old woman presents with dyspareunia and dys- has no concerning features on ultrasound, she does not
menorrhea. She has tenderness with her gynecological need to have a CA-125 drawn. It would be appropriate
exam particularly with deep palpation in the posterior to reimage her in 6–12 weeks to assess for resolution or
fornix. She denies any bowel or bladder symptoms. You stability of the cyst. Should the cyst change and become
suspect endometriosis and obtain a transvaginal ultra- more concerning for malignancy, a CA-125 would be
sound to exclude other pathology; it is normal. What indicated [72].
would be the best next step?
A. Empiric treatment with combined oral contraceptive
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Gynecologic Emergencies
11
Michael Lund and Jill C. Costello
this reason, all primary care providers should be familiar

Learning Objectives with early recognition of pregnancy, as well as emergencies
1. Describe the evaluation of vaginal bleeding in early that can occur early in pregnancy.
pregnancy and refer appropriately.
2. Distinguish the most common causes of acute pel-
vic pain in the reproductive-age female patient and Pregnancy Testing and Differential Diagnosis
identify emergency situations.
3. Compare the presentations and management of There have been tremendous advances in pregnancy testing
ovarian emergencies, including ovarian torsion, over the past several decades. Point-of-care urine pregnancy
ruptured cysts, and cyst hemorrhage. tests, both at home and in clinics, have improved to the point
4. Diagnose acute, heavy vaginal bleeding in the non- that a negative test will exclude pregnancy with high sensi-
pregnant patient and identify emergencies. tivity when used for pregnancies advanced enough to result
in complications. All pregnancy tests rely on the detection of
human chorionic gonadotropin (hCG) in serum or urine.
While there are several forms of hCG, the relevant subunit is
the “beta”-molecule. This can be measured qualitatively in
Sophia is a 29-year-old female patient who presents to urine or serum or quantitatively in serum [1].
your office complaining of new-onset left lower quad- Pregnancy is by far the most common cause of secondary
rant pain. She is uncertain of the exact date of her last amenorrhea in the reproductive-age patient. Any woman of
menstrual period but has been spotting for the past few reproductive age who gives a history of a prolonged men-
days. Because she is a reproductive-age woman having strual interval (the number of days between the first day of
new pelvic pain, you order a urine pregnancy test in consecutive cycles), especially when associated with other
your office, which is positive. symptoms such as bleeding or abdominal pain, should
undergo urine pregnancy testing even when she does not
consider herself at risk for pregnancy. Obtaining pregnancy
aintain High Suspicion for the Possibility
M tests in women of child-bearing age, as a routine habit, will
of Pregnancy prevent the occasional missed pregnancy which could result
in life-threatening complications such as ruptured ectopic
First-trimester bleeding is one of the most common compli- pregnancy.
cations of pregnancy. The diagnosis can be more challenging The differential diagnosis of bleeding in early pregnancy
because many patients do not realize they are pregnant. For can be limited to three major entities: spontaneous abortion,
ectopic pregnancy, and threatened abortion (but ultimately
viable pregnancy). As noted earlier, keeping a high suspicion
M. Lund (*) for ectopic pregnancy will result in work-up of more patients
Department of Obstetrics and Gynecology, Medical College of but should prevent important misses in diagnoses.
Wisconsin, Milwaukee, WI, USA
e-mail: [email protected] Ectopic pregnancy occurs in 2–3% of recognized preg-
nancies. The cardinal symptoms are abdominal pain, bleed-
J. C. Costello
Department of Medicine/Division of Rheumatology, Medical ing, and a positive pregnancy test. It is difficult to define a
College of Wisconsin, Milwaukee, WI, USA “typical” description of abdominal pain or bleeding that

158 M. Lund and J. C. Costello
should prompt one to consider this diagnosis. Risk factors after cardiac activity has been documented on ultrasound,
include anything that can cause dysfunction of the fallopian the results will not affect management and therefore do not
tubes: previous history of sexually transmitted infection provide value. The hCG level for patients in early pregnancy
(especially Chlamydia trachomatis), endometriosis, previ- serves two main purposes: first, the trend over time can be
ous tubal ligation, known pelvic adhesions, or previous pel- used to predict normal or abnormal outcome, and second, the
vic surgery [2, 3]. level is associated with an expectation of when an intrauter-
As the early gestation implants into the lumen of the fal- ine pregnancy should be visualized by ultrasound (the con-
lopian tube in cases of ectopic pregnancy, there can be pain cept of the “discriminatory zone” discussed below).
associated from distension of this very sensitive organ as In a normally progressing, viable pregnancy, the hCG
well as bleeding that results initially from muscular invasion level will rise in a characteristic manner. Though the com-
of the tube and eventually from rupture of the tube itself. mon mnemonic is “the level should double every two days,”
While initially pain tends to be unilateral, by the time of this is an oversimplification; in reality, the level should rise
tubal rupture it can be diffuse and severe. Pain from an ecto- by only 53% every 48 hours [5, 6]. If this more conservative
pic pregnancy may be described as “cramping” or “sharp.” rule is used, 99% of normal intrauterine pregnancies will fol-
low the rule; using an expected rise of 35% increases this to
99.9% of normal pregnancies [7]. In general, the level should
Transvaginal ultrasound performed the same day be followed over at least two 48-hour intervals before any
reveals a normal uterus (without obvious pregnancy), management decisions are made. If the level does not rise by
a 2-cm cyst in the left ovary, and a small amount of free the expected amount, ectopic pregnancy or spontaneous
pelvic fluid. You order a serum hCG which is 3425 IU. abortion is much more likely. If the level falls, it should be
checked regularly until negative, unless an intrauterine preg-
nancy had previously been confirmed by ultrasound. This is
done to reduce concern for retained tissue after spontaneous
Diagnosing Ectopic Pregnancy
abortion or chronic ectopic pregnancy.
An intrauterine pregnancy is normally seen by trans-
When the urine or serum pregnancy test is positive in a
vaginal ultrasonography at a quantitative hCG level of
patient presenting with abdominal pain or bleeding, the diag-
1500–3500 mIU/mL [6], with the wide range depending
nostic approach relies on immediate quantitative
on both patient characteristics (e.g. body habitus) and
measurement of hCG combined with prompt transvaginal
operator characteristics (e.g. skill of the ultrasonographer
ultrasonography. Normally, the hCG level is obtained first to
and quality of the equipment being used). Each ultraso-
avoid unnecessary imaging (e.g., if the hCG level is very low,
nography unit typically uses a standardized level referred
the ultrasound will likely be normal). When the hCG level is
to as the discriminatory zone. The practical use of this is as
significantly elevated (>100 mIU/mL) and ultrasound cannot
follows: if the hCG level is well above the discriminatory
be performed at the site of initial patient evaluation, the
zone and no intrauterine pregnancy is seen, there is high
patient should be transferred to a facility where imaging can
suspicion for ectopic pregnancy, especially if the patient
be accomplished on the same day; this may often be the
has not passed tissue vaginally or the hCG level is known
emergency department. Ultrasonography serves two practi-
to be rising; if the hCG level is below this discriminatory
cal purposes here: first, if an intrauterine pregnancy can be
zone, the level is typically followed every 48 hours until it
documented, ectopic pregnancy is almost excluded – except
is above the zone, at which time ultrasound is repeated. If
for the rare but increasingly frequent heterotopic pregnancy
an intrauterine pregnancy is then seen, suspicion for ecto-
[4], where both intrauterine and ectopic pregnancy occur in
pic pregnancy is markedly reduced, whereas concern
the same patient. Second, in some cases the ectopic gestation
remains high if it is not seen.
can be visualized as either an obvious gestational sac outside
of the uterus (sometimes with cardiac activity) or, more com-
monly, as an adnexal mass separate from the normal ovary
and with or without free fluid, which suggests bleeding in the You repeat the quantitative HCG level 48 hours later
pelvis. The presence of free fluid in the pelvis of the patient and it is now 4251 IU/mL. You have already arranged
from our vignette should be a red flag to the care team that for the patient to be seen in obstetrics/gynecology
the patient may be experiencing ectopic pregnancy. clinic today. After checking other labwork, the obste-
The quantitative hCG level is useful only in the circum- trician discusses medical management and surgical
stance of early pregnancy, before an intrauterine pregnancy management with your patient.
with cardiac activity has been documented. When ordered
11 Gynecologic Emergencies 159
Management of Confirmed Ectopic Pregnancy age patient from menarche to menopause who presents with
abnormal vaginal bleeding or acute abdominal pain. Prompt
Options for management of ectopic pregnancy are medical referral to a gynecologist can improve future fertility, reduce
and surgical. Expectant management is rarely recommended complications, and in many cases, be life-saving, as ectopic
as it can have life-threatening consequences, with the excep- pregnancy is still responsible for 1 out of 16 maternal deaths
tion being the rapidly falling hCG level in a pregnancy of in the United States [11].
unknown location.
Medical management has become much more popular
over the past two decades. Methotrexate can be administered Maria is a 15-year-old female patient who comes to
intramuscularly in a single-dose, two-dose, or multiple-dose urgent care today complaining of severe right lower
protocol (with increasing success rate but increasing side quadrant pain. The pain has been intermittent over the
effects, respectively). The single-dose protocol is the most past few days, but today has become constant and
common because of ease of administration and low side more severe (she rates it 9/10). Though the triage nurse
effect burden – the initial dose is 50 mg methotrexate per reported to you that she appeared to be in distress, she
meter squared body surface area. The hCG level is then fol- appears relatively comfortable when you interview
lowed weekly until negative. Any rise or plateau in the hCG her. Urine pregnancy test is negative.
level (as opposed to falling) should prompt repeat dosing or
surgical intervention [6, 8]. Contraindications to medical
management include hematologic, hepatic, or renal dysfunc-
tion; a complete blood count, hepatic function panel, and Adnexal Torsion
creatinine are evaluated prior to administration to ensure
patient safety. Adverse effects of systemic methotrexate used As noted early in this chapter, one of the challenges for
for ectopic pregnancy are fortunately rare, with stomatitis the busy primary care provider is distinguishing true
and transient elevations in transaminases being most emergencies from nonemergencies when symptoms and
common. signs can be similar. Among the gynecologic emergen-
Surgical management includes either the removal of the cies, adnexal torsion is one of the key “can’t miss” diag-
tube containing the ectopic pregnancy (i.e. salpingectomy) noses, because the consequence of delayed recognition is
or removal of only the gestation through a small slit in the potential loss of one ovary, fallopian tube, or both. This
fallopian tube (i.e. salpingostomy) [6, 9]. The decision can have dramatic effects on the patient’s future fertility
depends on the condition of the tube, whether rupture has and gonadal function.
already occurred, the woman’s desire for future fertility, and Adnexal torsion is defined as the twisting of the ovary,
her history of previous tubal surgery or ectopic pregnancy. and usually the fallopian tube, around its own supportive
Future fertility appears to be similar when comparing metho- pedicle, which contains the ovarian artery and vein. Torsion
trexate protocols and salpingostomy [10]. can be intermittent or complete and can involve one or many
Recurrence rates for ectopic pregnancy average 10–25% twists. Interestingly, the right ovary is more at risk for torsion
with a history of one or two ectopic pregnancies, respec- than is the left ovary, likely due to the longer length of the
tively [3]. right utero-ovarian ligament or the presence of the sigmoid
colon in the left pelvic space, which restricts left ovarian
movement.
Adnexal torsion can occur in any age group but is most
The patient chooses medical management and is given
common during the reproductive years. It is a frequent cause
methotrexate on the day of diagnosis. She is compliant
of abdominal pain in adolescents as well as a frequent indi-
with follow-up and has her hCG level monitored
cation for surgery in adolescents. However, it can also occur
weekly with appropriate drop each week until the level
in premenarchal or postmenopausal females (accounting for
reaches zero. Six months later, she attempts pregnancy
about 17% of torsions).
again and conceives a normal intrauterine pregnancy.
The most common risk factor for adnexal torsion is the
presence of an adnexal mass. It is believed that the increased
size and weight of the adnexal mass predisposes the organ to
In summary, the role of the primary care provider is to twist, though torsion can be seen in adnexae without any
recognize bleeding complications early by always including abnormal mass [12]. In most cases, the ovaries are enlarged,
pregnancy in the differential diagnosis of any reproductive- even if there is not a discrete ovarian cyst or mass [13].
luteal phase of the menstrual cycle and cause more constant,

On examination, temperature 97.8, heart rate 88, localized, pain than adnexal torsion. These generally resolve
respiratory rate 20, and blood pressure 102/65. with time. Ruptured ovarian cysts are typically identified on
Abdomen is soft, nondistended, with mild tenderness in ultrasound, occurring from mid-cycle to menses, and can
right lower quadrant but without rebound and without cause more diffuse pain because the cystic fluid or blood
guarding. Pelvic examination is remarkable for mild- leaks into the peritoneum, causing significant irritation. The
moderate right adnexal tenderness. presence of significant free fluid in the pelvis suggests rup-
ture of a cyst. Pelvic inflammatory disease must also be con-
sidered in the differential diagnosis (Please see Chap. 13 on
Clinical Manifestations of Adnexal Torsion Sexually Transmitted Infections).
Other causes of abdominal pain, such as acute appendici-
There is no “typical” presentation of adnexal torsion. tis, can also occur in female patients with similar symptoms
However, patients may present with a similar progression of and findings. For example, a patient with acute appendicitis
symptoms. Pain generally begins unilaterally and is often may experience cervical motion tenderness on examination
initially described as mild and crampy. Patients rarely pres- because of local peritoneal inflammation. A thorough
ent for care at this point due to the mild nature of the pain. abdominal and pelvic examination should be performed in
The pain may become colicky, with increased frequency and any female patient with pelvic pain.
duration of the episodes; between episodes, the pain may
resolve almost completely. In most cases, pain will eventu-
ally become severe and constant, and at this stage patients
Maria’s ultrasound reveals a 6 cm right adnexal mass.
generally seek emergency care. When pain becomes con-
The radiologist cannot specifically identify vascular
stant, the character can vary from cramping to sharp, stab-
flow in the mass.
bing, or gnawing pain, and the location can be more diffuse,
potentially radiating to the back, and is often associated with
peritoneal signs such as rebound tenderness. Commonly,
nausea and vomiting accompany the pain at this stage. Pelvic Unfortunately, history and examination findings have low
examination becomes challenging because of significant ten- predictive value for diagnosing adnexal torsion. Transvaginal
derness; if a patient allows a bimanual examination at this ultrasound is the most useful tool for diagnosis, though the
point, the exam typically reveals a unilateral adnexal mass. sensitivity and specificity have varied across studies.
Physiologically, pain occurs due to intermittent obstruc- Ultrasound is most useful for determining whether an
tion of inflow and outflow of blood to the ovary and tube. adnexal mass is present on the same side of unilateral pain –
Because of lower pressure relative to the ovarian artery, the if there is no adnexal mass and the ovaries appear normal in
ovarian vein is almost always obstructed first; this leads to size, torsion is less likely. In addition, color flow doppler of
worsening edema (and mass) within the ovary and the initial the ovarian artery and vein can show obstructed flow. Results
pain. The ovary may undergo hemorrhage and increasing must be interpreted with caution, as torsion can occur despite
size as it distends with blood that enters but cannot exit. The the presence of bidirectional vascular flow; conversely, tor-
ovary may rupture at some point or may continue to twist sion may not be present even in the case of suspected absent
until eventual obstruction of arterial flow, at which point vascular flow [12].
necrosis occurs.
Colicky, but steadily worsening, unilateral pain can be the
most helpful symptom to suspect torsion in many cases. In Management and Referral
general, signs suggesting infection are not present until
necrosis begins to occur. Given limitations of testing, clinicians must maintain a
high suspicion for adnexal torsion and a low threshold for
referral to a gynecologist. Torsion can only be definitively
Differential Diagnosis diagnosed via surgery (usually laparoscopy). While in the
past treatment necessitated removal of the affected ovary
The differential diagnosis of abdominal or pelvic pain in and tube, modern practice calls for simple untwisting of
female patients is extensive; history remains the first and the adnexa and removal (either immediately or delayed) of
most important diagnostic step. Ultrasound consistent with any adnexal pathology. Some believe removing the cystic
adnexal masses suggests a possible gynecologic etiology, but mass later may lead to less bleeding or destruction of the
functional ovarian cysts are ubiquitous and may be unrelated ovary, which may be edematous or even necrotic at the ini-
to her pain. Hemorrhagic ovarian cysts typically occur in the tial surgery. There is ongoing debate about whether the
ovary should be fixed (sutured) to the uterus or pelvic side- hypotension, symptoms of dizziness or orthostasis, and
wall to prevent recurrence. active or profuse ongoing bleeding. Obtaining vascular
access and readying blood products are key steps if the
patient has already lost significant blood. If a patient’s vital
You refer Maria to a gynecologist in your practice and signs are unstable or if she endorses worrisome symptoms,
express your concern for adnexal torsion. The gyne- she should be immediately transferred to a facility or loca-
cologist agrees and operates a short while later. tion that can transfuse blood, observe the patient, and
Operative findings include a right ovarian cyst, and potentially perform surgery, typically an emergency
the tube and ovary are both twisted three times. After department.
untwisting, the ovary and tube appear normal. The As discussed in Chap. 7 on Abnormal Uterine Bleeding,
cyst is left for removal at a future date. the major etiologies of bleeding are classified by the PALM-
COEIN system: Polyps, Adenomyosis, Leiomyoma,
Malignancy; Coagulopathy, Ovulatory, Endometrial,
Iatrogenic, Not Otherwise Classified [14–16]. Think of the
In summary, adnexal torsion typically occurs in the pres-
first four etiologies (PALM) as structural causes and the sec-
ence of a unilateral adnexal mass, can occur in young or old
ond five as nonstructural causes (COEIN). Structural causes
patients, and often follows a pattern of worsening, colicky,
are typically identified by ultrasound.
unilateral pain. While ultrasound can be helpful establishing
The most likely causes of bleeding that require emer-
the diagnosis, sensitivity and specificity are suboptimal
gency department evaluation are nonstructural causes, espe-
necessitating early gynecology referral. Maintaining this
cially coagulopathy and ovulatory dysfunction (also known
“better safe than sorry” approach can potentially result in the
as anovulatory bleeding). Coagulopathy (e.g. von Willebrand
preservation of a patient’s ovary and/or fallopian tube.
disease) should be suspected in young women with heavy
menstrual bleeding since menarche, women with a history of
surgical or significant obstetric bleeding, women with fre-
Audrey is a 32-year-old G0 female patient with a his- quent bruising, epistaxis, or gum bleeding, and women with
tory of irregular menses. She does not have a history of a family history of bleeding disorder. Recommended testing
abnormal Pap tests (Pap was normal last year) or includes partial thromboplastin time, prothrombin time, von
other gynecologic problems. Over the past 12 months, Willebrand panel including ristocetin cofactor, and platelet
she has had only five menstrual cycles and has not function [15]. A suggested workup is discussed in Chap. 7 on
been able to predict when the next will begin. Her last Abnormal Uterine Bleeding.
menses started ~90 days ago. Today, she started bleed- Once bleeding disorders and structural disorders are
ing very heavily. excluded, the most likely diagnosis is anovulatory bleeding,
which is also the most likely overall cause of acute, heavy
vaginal bleeding. Normally, follicle-stimulating hormone
Acute, Heavy Vaginal Bleeding (FSH) leads to the development of several follicles in each
ovary. Estradiol levels increase causing proliferation of the
The diagnosis and management of abnormal vaginal bleed- endometrial lining. Ovulation occurs after the luteinizing
ing – usually, but not always uterine in origin – can be quite hormone (LH) surge, and the corpus luteum (ovulation cyst)
complicated and is described in detail in Chap. 7 on Abnormal secretes progesterone, which converts the endometrial lining
Uterine Bleeding. It is important for the primary care pro- to a secretory, stable histology. When progesterone levels
vider to recognize when bleeding becomes severe enough to drop 14 days later, an organized withdrawal menses will
be considered a gynecologic emergency. A primary care pro- occur. For details, see Chap. 5 on Menstruation and
vider can manage initial steps in treatment to help patients Secondary Amenorrhea.
avoid significant consequences. If ovulation does not occur for any reason, the endome-
Most episodes of acute, very heavy vaginal bleeding will trium will continue to proliferate under the influence of
occur during the reproductive years. The first step in man- estradiol, and can become dyssynchronous and disorganized,
agement for women presenting with heavy bleeding is to eventually leading to unpredictable and potentially very
exclude pregnancy with a point-of-care urine pregnancy heavy bleeding. Additionally, ongoing proliferation is a sig-
test. The management of pregnancy-associated bleeding nificant risk factor for the development of endometrial
after the first trimester is beyond the scope of this textbook. hyperplasia and eventually carcinoma; risk for endometrial
Next, vital signs should be reviewed to determine patient hyperplasia and carcinoma increases with age as well as
stability, and patients should be assessed for tachycardia or body-mass index.
responsive malignancy, thromboembolic disease, or smok-

Urine pregnancy test is negative. On examination, you ing—progestin therapy can be started with either medroxy-
are unable to see her cervix because of bright red progesterone acetate (10–20 mg PO three times daily) or
blood filling the vagina. After removing as much of the norethindrone therapy (5–10 mg three times daily).
blood as possible, you note that there is active, brisk Alternately, intravenous estrogen therapy (25 mg every
bright red bleeding from the cervix. Blood pressure is 4 hours) can be used to stop acute bleeding. It is important to
98/70, heart rate 95. Upon completing your examina- note that there is little to no difference in onset of action;
tion, your patient complains of dizziness. however, both oral and IV estrogen can lead to significant
nausea and the IV route avoids loss of medication due to
vomiting [15].
Approach to Management Tranexamic acid, a fibrinolysis inhibitor, can also reduce
heavy menstrual bleeding by up to 50%. The typical dosing
After pregnancy has been ruled out, a careful examination is 1300 mg every 8 hours for up to 5 days. While there was
should be performed. The provider should look for systemic theoretical concern for thrombosis with this class of medica-
signs of illness and evidence of coagulopathy. The primary tions, multiple studies have not demonstrated this when used
purpose of the pelvic examination is to assess the volume for acute heavy vaginal bleeding.
and degree of bleeding and to determine whether the uterus If bleeding continues after several days of IV or oral high-
feels “normal” in size and shape. Active bleeding from the dose estrogen therapy, gynecologic consultation is recom-
cervix that requires multiple swabs to evacuate for visualiza- mended for consideration of surgical therapy. The treatment
tion is considered heavy. Similarly, when a patient endorses of choice will depend on the patient’s age and fertility status;
syncope, near-syncope, passage of large clots, or bleeding hysterectomy is incompatible with future fertility, and endo-
for prolonged periods of time, she requires careful evalua- metrial ablation and uterine artery embolization are rela-
tion, as these symptoms suggest high-volume bleeding. tively contraindicated. Simple uterine curettage (D&C) will
Consideration should be given to endometrial sampling to be effective in many patients, but its effects are only tempo-
evaluate for hyperplasia or carcinoma. Patients at higher risk rary. Hysteroscopy is useful for identifying structural, focal
include women >35 years old, women with a prolonged his- lesions but can be challenging in cases of active bleeding.
tory of anovulation, obesity, or polycystic ovary syndrome. Following hormonal manipulation of very heavy uterine
This can be done using a simple suction device such as the bleeding, it is recommended to continue hormones at the
Pipelle. Often, the degree of vaginal bleeding will make this “usual” daily dose (i.e. one combined oral contraceptive pill
challenging (because only blood is obtained), and, in those daily or a standard low dose of progestin) for several cycles
cases, sampling should occur once bleeding is stabilized. (taken continuously). This prevents further withdrawal
Typically, endometrial biopsy is performed by gynecologists bleeding for several cycles and permits repletion of red blood
though some primary care providers may do this testing as cells and recovery from the episode. A withdrawal period
well. should then be allowed, and discussion should occur with the
patient regarding long-term plans for continuing or discon-
tinuing the medication.
Because of her significant bleeding, Audrey is trans-
ferred to the emergency department where she receives
two 14-gauge IVs and fluids. Her hemoglobin is 9; her Audrey feels better after IV fluids and her hemoglobin
other labwork including coagulation studies is remains stable over 4 hours. You advise her to take a
normal. 30-microgram pill three times daily until bleeding
stops completely, then decrease to one pill daily. You
emphasize the need for further evaluation with ultra-
Treatment sound and endometrial biopsy (if she has any risk fac-
tors for endometrial hyperplasia).
The fastest and most effective therapy for anovulatory bleed-
ing is hormonal. Treatment can be instituted with estrogen
alone, progestin alone, or a combination of the two. The sim- Conclusion
plest therapy is to start combination oral contraceptives at an
estrogen dose of 30–35 micrograms two or three times daily All primary care providers should be aware of the initial
until bleeding slows or stops. For patients who cannot take diagnosis and management of gynecologic emergencies such
estrogen—such as those with a personal history of estrogen as ectopic pregnancy, adnexal torsion, and abnormal uterine
bleeding that lead to significant blood loss. It is important to D. Ask the patient to return to your office in 48 hours to
recognize the severity of the concerns, so patients may determine whether her pain is worse or better
receive necessary emergency care when appropriate. The correct answer is C. Bleeding in the first trimester
Through a standardized approach, the risk of delaying ther- requires immediate evaluation. However, the stable
apy can be minimized. patient does not necessarily need to be evaluated in the
emergency setting. Because spontaneous abortion and
ectopic pregnancy can lead to significant bleeding or
Summary Points other complications, expectant management is not a rea-
sonable option in most cases. While ultrasound is nor-
1. The differential diagnosis of acute abdominopelvic pain mally part of the evaluation, in most cases having the
in the female patient includes gynecologic and non- hCG result first is more useful. A very low hCG level
gynecologic causes and relies on a thorough menstrual negates the need for ultrasound in stable patients as the
and sexual history. ultrasound likely wouldn’t provide useful information
2. The most common cause of secondary amenorrhea in the (neither a normal pregnancy nor ectopic pregnancy would
reproductive-aged patient is pregnancy; any patient who be expected to be seen), whereas a very high hCG level
is late for regular menses or presents with undiagnosed suggests that the ultrasound may be more useful in mak-
abdominopelvic pain should have a point-of-care urine ing a diagnosis.
pregnancy test.
3. The diagnosis of adnexal torsion is challenging and 2. An 18-year-old patient being seen in your urgent care
remains a clinical diagnosis. While ultrasound can be clinic. She complains of gradually worsening abdominal
helpful, a high suspicion and low threshold for surgical pain that started on the right and occurs in episodes that
consultation are key to early diagnosis and treatment. last several hours each with near-total resolution of pain
4. Acute vaginal hemorrhage in the nonpregnant patient is between episodes. However, she has been in much more
generally best managed with aggressive hormonal ther- pain over the past 8 hours and notes that ibuprofen no
apy, sometimes requiring hospitalization until initial longer controls her pain. Vitals are: T 38.1C, HR 96, RR
effect is noted. Diagnostic tests should be performed to 20, BP 124/80. Pain 9/10. On examination, you note nor-
rule out malignancy or pre-malignancy when suspected. moactive bowel sounds but significant tenderness with
Surgical management in the acute phase is rarely rebound in the right lower quadrant. She is unable to
necessary. cooperate with pelvic examination.
Which of the following is true regarding her
presentation?
A. Adnexal torsion occurs most commonly in the pre-
Review Questions pubertal female.
B. If ultrasound is performed and flow is seen to both
1. A 37-year-old comes to your office complaining of irreg- ovaries, ovarian torsion should be considered excluded
ular menses and the gradual onset of lower abdominal from the differential diagnosis.
pain. Upon further questioning, she states that her last C. The sign most suggestive of adnexal torsion would be
menstrual period was exactly 5 weeks ago and she is not the presence of an adnexal mass on ultrasound.
using contraception. Her menses are normally very regu- D. If adnexal torsion is confirmed, standard of care is
lar (every 29 days). The abdominal pain started 4–5 days unilateral oophorectomy as the ovary has likely under-
ago, was vague in character and location, but is now gone necrosis.
sharper and more left-sided than right. Neither acetamin- The correct answer is C. Though there are many causes
ophen nor ibuprofen has relieved her discomfort. A urine of acute pelvic pain in the female patient, adnexal torsion
pregnancy test was positive in your office today. Vitals are is one of the most important to consider, as failure to diag-
as follows: T 37.6 C, HR 68, RR 12, BP 108/64. Pain is nose early can lead to necrosis of the ovary, tube, or both.
3/10. Adnexal torsion can occur at any age, but is most com-
What is your next best management step? mon during the reproductive years. Pain is typically uni-
A. Transfer the patient by ambulance to the nearest emer- lateral and gradually grows more severe; pain can also
gency department for evaluation occur in a colicky pattern. Adnexal mass is usually (not
B. Arrange for her to have a pelvic ultrasound at the always) appreciated on pelvic examination or ultrasound.
nearest hospital Ultrasound findings can include changes in the Doppler
C. Draw a stat serum hCG level in your office or lab flow to or from the ovary, but the sensitivity and specific-
ity of this finding are limited [12]. Adnexal torsion is
treated surgically, but conservation of the adnexa (and While pelvic ultrasound may be useful to evaluate non-
simple untwisting of the twisted pedicle is now standard hormonal causes of bleeding, treatment should not be
of care). delayed for those results.
3. A 44-year-old is in the emergency department complain-

ing of heavy vaginal bleeding. She has type II diabetes References
and polycystic ovary syndrome. Her menses have been
1. Cole LA. The hCG assay or pregnancy test. Clin Chem Lab Med.
irregular over the past year, every 35–65 days. Her last 2012;50(4):617–30.
normal menses was approximately 55 days ago. She then 2. Ankum WM, Mol BW, Van der Veen F, Bossuyt PM. Risk
started bleeding 14 days ago and it has been progressively factors for ectopic pregnancy: a meta-analysis. Fertil Steril.
heavier. Today, she has been passing lemon-size clots and 1996;65(6):1093–9.
3. Barnhart KT, Sammel MD, Gracia CR, Chittams J, Hummel
changing pads every 30–40 minutes. She is lightheaded AC, Shaunik A. Risk factors for ectopic pregnancy in women
when standing. Vitals are: T 36.5C, HR 104, RR 18, BP with symptomatic first-trimester pregnancies. Fertil Steril.
88/48. Pain 2/10 (described as intermittent cramps). Urine 2006;86(1):36–43.
pregnancy test is negative. 4. Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds
MA, Wright VC. Ectopic pregnancy risk with assisted reproductive
Which of the following is true regarding her technology procedures. Obstet Gynecol. 2006;107(3):595–604.
management? 5. Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med.
A. Endometrial biopsy is not indicated to rule out endo- 2009;361(4):379–87.
metrial hyperplasia or carcinoma as she is not yet 6. Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet
Gynecol. 2006;107(2 Pt 1):399–413.
menopausal. 7. Seeber BE, Sammel MD, Guo W, Zhou L, Hummel A, Barnhart
B. After ordering labs, it would be reasonable to dis- KT. Application of redefined human chorionic gonadotropin curves
charge the patient to complete the full workup as an for the diagnosis of women at risk for ectopic pregnancy. Fertil
outpatient. Steril. 2006;86(2):454–9.
8. Lipscomb GH, Stovall TG, Ling FW. Nonsurgical treatment of
C. Because it is critical to the diagnosis, no treatment ectopic pregnancy. N Engl J Med. 2000;343(18):1325–9.
should be initiated until pelvic ultrasound has been 9. Rabischong B, Larraín D, Pouly J-L, Jaffeux P, Aublet-Cuvelier B,
performed. Fernandez H. Predicting success of laparoscopic salpingostomy for
D. The irregular cycles suggest that the most likely diag- ectopic pregnancy. Obstet Gynecol. 2010;116(3):701–7.
10. Hajenius PJ, Mol F, Mol BWJ, Bossuyt PM, Ankum WM, Van
nosis is anovulatory bleeding. der Veen F. Interventions for tubal ectopic pregnancy. Cochrane
The correct answer is D. Often, patients who present Gynaecology and Fertility Group, editor. Cochrane Database Syst
to the emergency department with heavy vaginal bleed- Rev [Internet]. 2007 [cited 2018 Mar 23]; Available from: http://
ing have avoided seeking help for an extended period of doi.wiley.com/10.1002/14651858.CD000324.pub2.
11. Creanga AA, Syverson C, Seed K, Callaghan WM. Pregnancy-
time, so this complaint should always be taken very seri- related mortality in the United States, 2011–2013. Obstet Gynecol.
ously. In this case, the vital signs and description of 2017;130(2):366–73.
bleeding call for rapid labwork, hemodynamic stabiliza- 12. Sasaki KJ, Miller CE. Adnexal torsion: review of the literature. J
tion (including transfusion as necessary), and immediate Minim Invasive Gynecol. 2014;21(2):196–202.
13. Geimanaite L, Trainavicius K. Ovarian torsion in children: manage-
treatment to slow her bleeding, generally requiring at ment and outcomes. J Pediatr Surg. 2013;48(9):1946–53.
least a short hospitalization [15]. Her history of polycys- 14. Munro MG, Critchley HOD, Fraser IS. The FIGO classification of
tic ovary syndrome and progressively more irregular causes of abnormal uterine bleeding: Malcolm G. Munro, Hilary
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Menstrual Disorders. Int J Gynaecol Obstet. 2011;113(1):1–2.
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including significant obesity or long-term anovulation. aged women. Obstet Gynecol. 2012;120(1):197–206.
Vaginitis and Vulvar Conditions
12
Swati Shroff and Janice Ryden
Learning Objectives Maureen is a 32-year-old woman who calls your office

1. Discuss the differential diagnosis of vaginal complaining of a one-week history of vaginal
discharge. discharge.
2. Compare and contrast the signs and symptoms of
the three common types of vaginitis, i.e., bacterial
vaginosis, vulvovaginal candidiasis, and
trichomoniasis. Vaginitis
3. List the management options for the three com-
mon types of vaginitis. Introduction
4. Identify when recurrent vaginitis warrants chronic
management. By definition, vaginitis is inflammation of the vagina, most
5. Describe management strategies for contact commonly caused by an infection. Bacterial vaginosis (BV),
vaginitis. vulvovaginal candidiasis (VC), and trichomoniasis account
6. Describe general therapeutic measures for patients for a majority of vaginal infections. In a review of studies
with vulvar problems. evaluating women presenting to primary care, BV was the
7. Discuss the importance of prescribing ointments most common etiology followed by VC and lastly trichomo-
rather than creams for vulvar conditions. niasis [1]. Less commonly vaginitis has a noninfectious eti-
8. Identify the risks of untreated lichen sclerosus and ology, as in the case of vaginitis associated with menopause
vulvar lichen planus. (discussed in Chap. 8 on “Menopause”), contact dermatitis,
9. Compare the varied and subtle presentation of vul- and desquamative inflammatory vaginitis.
var malignancies and the importance of timely
biopsy of any undiagnosed lesions.
10. Describe the presentation and management strate- Infectious Vaginitis
gies of vulvodynia, including provoked vestibulo-
dynia and generalized unprovoked vulvodynia. Epidemiology
BV is the most common cause of vaginitis in women of

child-bearing age, affecting almost one-third of women in
the United States (U.S.) at any given time [2]. BV is caused
by an alteration in the normal vaginal flora, where high con-
centrations of anaerobic bacterial species such as Gardnerella
S. Shroff (*) vaginalis replace the protective Lactobacillus species in the
Sidney Kimmel Medical College, Thomas Jefferson University, vagina. Many studies show douching and cigarette smoking
Department of Medicine, Philadelphia, PA, USA
are risk factors for BV acquisition [3–6]. While studies con-
J. Ryden sistently show an association between sexual activity and
Johns Hopkins University School of Medicine, Johns Hopkins
Community Physicians, Department of Internal Medicine (retired), BV, it remains unclear whether this is caused directly by
Baltimore, MD, USA sexual transmission or the impact of sexual activity on

166 S. Shroff and J. Ryden
Lactobacillus vaginal colonization [7–9]. Therefore, BV is is the sole complaint. A lack of perceived odor makes BV
not classified as a sexually transmitted infection (STI). less likely (LR, 0.07 [95% confidence interval (CI), 0.01–
Vulvovaginal candidiasis is the second most common 0.51]) [1].
infectious cause of vaginitis, affecting an estimated 75% of VC usually presents with a thick, curd-like, white dis-
women during their lifetime [10]. Candida albicans is charge without any odor; however, at times the discharge
responsible for 85–95% of VC infections while Candida gla- may be yellow or thin or even absent. Describing a “cheesy”
brata accounts for most of the remaining infections [10]. discharge increases the likelihood of VC (likelihood ratio
Candida primarily enters the vagina from the surrounding [LR], 2.4; 95% CI, 1.4–4.2) [1]. VC is often associated with
perianal area but does not necessarily result in symptomatic pruritus, burning, dyspareunia, and dysuria. Pruritus is fre-
vaginitis [10], as up to 30% of asymptomatic women are quently the dominant, and at times the only, symptom of
colonized with Candida as part of their normal vaginal flora VC. A lack of itching makes the diagnosis of VC less likely
[11]. Yeast infections occur in celibate women; however, risk (range of LRs, 0.18 [95% CI, 0.05–0.70] to 0.79 [95% CI,
is increased with sexual activity, particularly receptive oro- 0.72–0.87]) [1]. On exam, women infected with VC may
genital sex [10]. Uncontrolled diabetes; immunosuppres- have accompanying vulvar erythema and edema; the pres-
sion; estrogen exposure from pregnancy, estrogen-containing ence of inflammatory signs is more commonly associated
contraception, or postmenopausal hormone treatment; recent with VC (range of LRs, 2.1 [95% CI, 1.5–2.8] to 8.4 [95%
antibiotic or corticosteroid use; and douching are other CI, 2.3–3.1]) [1].
important risk factors as well [10, 12]. Women with trichomoniasis characteristically complain
Trichomoniasis is caused by the flagellated protozoan of vaginal discharge that may be associated with burning,
Trichomonas vaginalis (T. vaginalis) and is the most preva- dysuria, dyspareunia, and less commonly pruritus. Exam
lent nonviral STI in the U.S. [13] and worldwide. typically reveals copious, thin, malodorous, green-yellow
Trichomoniasis is transmitted exclusively through sexual discharge that pools in the posterior fornix, although a less
contact. Risk factors for trichomoniasis and STIs more gen- “classic” thick discharge of different color is present nearly
erally include unprotected sex and multiple sexual partners half the time. When present, bubbles in the discharge are
(For more details on STIs see Chap. 13 on “Sexually fairly specific for trichomoniasis.
Transmitted Infections”). Despite these generalizations, the features of the three
common types of vaginitis overlap significantly and varia-
tion in presentation is common. Moreover, coinfection with
Maureen describes the discharge as thin, white, and more than one type of vaginitis is not unusual. One should
associated with pruritus. She denies fevers, chills, therefore not rely solely on history and exam to make the
abdominal pain, and dysuria. She has only had sex diagnosis.
with her husband in the last 5 years. She has an intra-
uterine device in place for contraception and does not
use condoms. Maureen says her symptoms remind her of a bacterial
vaginosis infection in the past, and she requests a pre-
scription for oral metronidazole.
Clinical Manifestations
Vaginitis caused by BV, VC, or trichomoniasis may be Diagnosis and Differential Diagnosis
asymptomatic. When symptomatic, the most common symp-
tom of vaginitis is vaginal discharge. Odor and pruritus are While over-the-counter treatments for vaginitis are com-
two other possible symptoms, and these are particularly monly purchased, studies indicate that patient self-diagnosis
helpful in distinguishing the cause of vaginitis. It is also is frequently incorrect [14]. Moreover, in addition to the
important to characterize the volume, consistency, and color three common infectious agents, the differential diagnosis of
of the vaginal discharge, as well as evaluate for any associ- vaginal discharge includes physiologic discharge, noninfec-
ated symptoms. Since dysuria commonly occurs with vulvar tious vaginitis, cervicitis, and pelvic inflammatory disease
irritation resulting from vaginal discharge, the differential (PID).
diagnosis for women reporting dysuria extends beyond the Physiologic or normal vaginal discharge is typically
urinary tract. transparent or white (although it may turn yellow upon
BV classically presents with a thin, homogenous, white drying) and varies with the menstrual cycle. It is flocculent,
discharge with a fishy odor, caused by the release of amines meaning it is a liquid base containing flecks of solid mate-
from anaerobic bacterial overgrowth. The volume of dis- rial, and it does not adhere to the vaginal walls but rather
charge can be minimal, and sometimes disagreeable odor pools in the posterior fornix when the patient is recumbent.
12 Vaginitis and Vulvar Conditions 167
Young women are often unaware that physiologic discharge must be interpreted carefully. Urine specimens are helpful
is normal; patient education is facilitated by asking, “Is for office pregnancy testing, which should be performed for
your current vaginal discharge different from your usual women at risk.
vaginal discharge?” Leukorrhea, a thick, whitish or yellow- Vaginal pH testing is an underutilized but helpful test. A
ish discharge, results from estrogen exposure and is often sample of vaginal discharge from the lateral vaginal wall can
seen in pregnancy and with use of the contraceptive vaginal be tested with narrow range pH paper, although lubricating
ring. gel can alter the pH and should not contaminate the tested
Excluding PID (and cervicitis as well, since this can prog- sample. Vaginal pH in a premenopausal woman ranges from
ress to PID) is critical in the evaluation of any woman com- 4 to 4.5, because estrogen promotes glycogen production by
plaining of vaginal discharge, as, unlike vaginitis, PID is the vaginal epithelium, which acts as a substrate for lactic
commonly associated with significant morbidity and, albeit acid production by inhabitant lactobacilli. An elevated pH in
rarely, mortality. (See Chap. 13 on “Sexually Transmitted a premenopausal woman suggests BV or trichomoniasis (or
Infections”.) All patients complaining about vaginal dis- a mixed infection) and helps exclude yeast, but is less useful
charge should be questioned regarding abdominal pain, deep in postmenopausal women, who lack this estrogen effect and
dyspareunia, intermenstrual bleeding, subjective fevers or whose vaginal pH is normally greater than 5 [15].
chills, and nausea/vomiting. The sexual history should assess To prepare a wet mount, a small amount of discharge
for multiple partners, new partners (defined as contact begin- should be obtained from the lateral vaginal wall and placed
ning within 2 months) and unprotected sex. on two slides. One drop of saline should be added to one
slide and one drop of 10% potassium hydroxide (KOH)
should be added to the other and a cover slip should be
Evaluation: Examination and Testing placed over each sample. Providers should “whiff” the
KOH slide to assess for the presence of a fishy odor. A
Women presenting with vaginal discharge require a full positive “whiff test” is predictive of BV (LR, 3.2 [95% CI,
evaluation that includes pelvic examination, the whiff test, 2.1–4.7]), while lack of odor is associated with VC (LR,
pH testing and office microscopy (or point-of-care testing 2.9 [95% CI, 2.4–5]) [1]. However, a positive “whiff test”
or laboratory microsopy). A specimen for gonorrhea/chla- is also commonly found with trichomoniasis, due to over-
mydia testing is also usually collected. The pelvic exami- growth of anaerobes following oxygen consumption by
nation provides valuable information in a patient with trichomonads.
vaginitis and is essential to exclude an upper tract infec- The saline slide should be viewed first (Fig. 12.1) [16],
tion (PID). Cervicitis is also a concern, and while most while the KOH slide is allowed to sit for one to two minutes
often the cervix appears normal in the setting of cervicitis, to allow lysis of the cell membranes of vaginal epithelial
subtle visible abnormalities are occasionally evident, such cells to enable easier detection of budding yeast and hyphae.
as cervical edema or scant discharge from the cervical os. Slides should be viewed at low power 10x setting first, but
PID sometimes presents with cervical discharge, but the optimal viewing occurs at the higher 40x setting. When
more reliable finding is tenderness on bimanual exam— examining a saline wet mount, the appearance of the squa-
either cervical motion tenderness or uterine or adnexal ten- mous cells should be assessed, the leukocyte presence should
derness (covered in Chap. 13 on “Sexually Transmitted be roughly quantified to determine if excessive, and several
Infections”). high power fields should be carefully scanned in search of
Vaginal or cervical specimens for chlamydia and gonor- trichomonads and fungal elements—although the latter are
rhea testing are usually collected at the time of the exam more easily detected on the KOH slide. The saline wet mount
when possible infection with STIs is a concern. This swab should be reviewed promptly (within 15 minutes of collec-
can be discarded if ultimately deemed unnecessary but is tion), while trichomonads are still motile.
used in certain presentations; for instance, if the bimanual The saline wet prep may demonstrate clue cells, which
exam raises concern for PID, if the wet mount exam shows are epithelial cells coated with coccobacilli (best appreciated
excess leukocytes but no culprit organism (suggesting pos- at the margins of the cells) (Fig. 12.2) [17] or motile tricho-
sible cervicitis or PID), or if the wet mount examination monads (Fig. 12.3) [17]. The presence of increased leuko-
uncovers Trichomonas (an STI). cytes (defined as >10 per high-powered field or a ratio of
Urinary symptoms such as dysuria commonly accom- leukocytes to epithelial cells exceeding 1:1) (Fig. 12.3) may
pany vaginitis and can stem from possible etiologies that indicate infection with Trichomonas or suggest the diagnosis
range from inflamed vulvar mucosa, urethritis from a sexu- of cervicitis or PID – especially if a culprit organism is not
ally transmitted infection or a urinary tract infection. seen on microscopy. Excess leukocytes can also be seen with
Likewise, pyuria on urine testing may originate from con- noninfectious forms of vaginitis.
tamination of the specimen with an inflammatory vaginal The KOH slide is next reviewed for budding yeast and
discharge rather than the urinary tract itself, and therefore hyphae (Fig. 12.4) [17]; several (approximately twenty)
Fig. 12.3 Trichomoniasis. This saline wet mount of vaginal sampling

shows numerous Trichomonads, which appear pear shaped, oval, or
round and similar in size to the surrounding leukocytes, which are pres-
ent in increased numbers. Detection of this protozoan is aided by its
wriggling motion and the whipping action of its rotatory flagellae.
Image from CDC Public Image Library, CDC/Credit Joe Miller [17]
Fig. 12.1 Saline Wet Mount (“Wet Prep”). This saline wet mount of
vaginal sampling from an asymptomatic woman depicts normal find-
ings. The vaginal epithelial cells (“squamous cells”) appear smooth,
leukocytes are not increased, and no trichomonads or fungal elements
are seen. Close inspection also reveals numerous tiny rod-shaped bacte-
ria (Lactobacillus) throughout the field. Image from the University of
Washington STD Prevention Training Center [16]. Used with
permission
Fig. 12.4 Vulvovaginal Candidiasis. This saline wet mount depicts the
two possible microscopic findings of yeast, namely the pseudohyphae/
hyphae (nonbranching/branching) filamentous structures and spores,
Fig. 12.2 Bacterial Vaginosis. This saline wet mount of vaginal sam- which are round or oval bodies that are smaller than erythrocytes and
pling depicts two vaginal epithelial cells, the lower one appearing identifiable by their thick cell walls. The KOH slide is preferred, as lysis
fairly normal and the upper one studded with bacteria --a “clue cell.” of surrounding cellular material aids in detecting these fungal elements,
The clue cell’s roughened, speckled appearance is best appreciated at which are nonetheless often elusive. Saline: 40x objective. Image from
the cell margins. Diagnostic criteria for BV require that at least 20% of the University of Washington STD Prevention Training Center [16].
the epithelial cells be “clue cells.” Note that leukocyte numbers are not Used with permission
increased. Image from CDC Public Image Library, CDC/Credit
M. Rein [17]
high-power fields should be examined, as the sensitivity of Cultures are generally unhelpful for diagnosing vaginitis
this test is poor. Sometimes the diagnosis of vulvovaginal due to the polymicrobial nature of the vagina and because
candidiasis must be made without observing yeast buds or many culprit organisms represent normal flora that can be
hyphae. In such situations one should also consider the pos- cultured from asymptomatic women. In addition, cultures
sibility of contact dermatitis, as the two entities share a num- are costly and delay diagnosis and treatment. Rarely, cultures
ber of clinical features. play a role when the diagnosis is unclear, such as symptom-
BV is diagnosed by the presence of three out of four of atic women with repeatedly negative testing, or in women
Amsel criteria, which include the presence of a thin, homog- whose symptoms persist after treatment.
enous vaginal discharge; vaginal pH > 4.5; a positive whiff
test; and clue cells on wet prep. The sensitivity and specific-
ity of Amsel criteria are 69% and 93%, respectively [18]. Maureen comes to the office for evaluation. Her exam-
Recall also that leukocyte numbers are not increased in the ination is notable for white curd-like discharge, with
setting of BV, in contrast to trichomoniasis [19]. erythema and swelling noted both in the vagina and
The sensitivity of the wet mount for detecting trichomo- vulva. The whiff test is negative and her vaginal pH is
nads is only fair (51–65%) [5] and therefore when the organ- 4.5. Bimanual exam reveals no tenderness. The wet
ism is not seen on office microscopy yet there is continued mount is notable for normal-appearing epithelial cells
concern for this infection, additional testing should be pur- and no trichomonads. The KOH slide reveals budding
sued, typically by adding Trichomonas NAAT testing to the yeast and hyphae. You diagnose her with a yeast infec-
vaginal swab specimen collected for chlamydia and gonor- tion. She asks about treatment and how to prevent
rhea testing. future infections.
Of note, trichomonads are sometimes reported inciden-
tally on cervical cytology reports. While liquid-based Pap
testing is not sensitive for diagnosing trichomoniasis, its
specificity is as high as 99% and treatment is indicated with- Treatment
out further testing [20]. On the other hand, conventional Pap
smear testing is neither sensitive nor specific, and therefore Bacterial Vaginosis (BV) The Centers for Disease Control
should not be used to diagnose trichomoniasis, although and Prevention (CDC) recommends treating symptomatic
such a report should trigger patient evaluation [21]. women diagnosed with BV [5]. Recommended and alterna-
Newer point-of-care rapid antigen and DNA-amplification tive oral and topical treatment regimens are listed in
tests may be useful when offices lack a microscope, provid- Table 12.1. A Cochrane review found clindamycin and met-
ers lack experience in examining wet mounts, or administra- ronidazole had equivalent rates of clinical cure (91% and
tive protocols do not permit point-of-care microscopy. The 92%, respectively) [23]. The review also confirmed oral and
wet mount, as a provider-performed microscopy procedure, topical preparations had comparable effectiveness. Topical
is subject to regulations under CLIA (Clinical Laboratory treatments are associated with fewer adverse effects than oral
Improvement Amendments) and thus even i nterested, trained metronidazole, which causes a transient metallic taste and
primary care providers may not be able to perform micros-
copy depending on the protocols at their clinic sites. Studies Table 12.1 Bacterial vaginosis: treatment regimens [5]
indicate the BD Affirm VPIII test, a DNA probe assay, is Recommended Alternative
more sensitive for diagnosing BV (sensitivity 95–100%), VC Metronidazole 500 mg orally twice Tinidazole 2 g orally once
(90–100%), and trichomoniasis (90 to 100%) compared to daily for 7 daysa daily for 2 daysa
Metronidazole vaginal gel 0.75%, Tinidazole 1 g orally once
office microscopy [18, 22], and the CDC encourages its
one applicatorful (5 g) daily for 5 daysa
wider use [5]. However, disadvantages of this newer semi- intravaginally once daily at bedtime
automated office-based technology are its cost and the time for 5 daya
required to run some of the tests (approximately 45 min). Clindamycin creamb 2%, one Clindamycin ovulesb 100 mg
Also, this technology fails to provide additional information applicatorful (5 g) intravaginally intravaginally once daily at
once daily at bedtime for 7 days bedtime for 3 days
that is evident on microscopy, such as the presence of inflam-
Clindamycin 300 mg orally
mation, the number of lactobacilli or the degree of estrogen twice daily for 7 daysc
effect on the squamous epithelial cells. A second option Adapted using data from Workowski and Bolan [5]
when office microscopy is unavailable is to submit a speci- a
Patients taking metronidazole and tinidazole should be advised to
men for wet mount evaluation to be performed by a lab. avoid consuming alcohol during use and for 24 and 72 h thereafter,
Some labs also include rapid antigen or DNA-amplification respectively, due to a possible risk of disulfiram-like reaction
b
Topical clindamycin is oil-based and may weaken latex or rubber prod-
tests as a routine component of wet mount processing and ucts (i.e. condoms and diaphragms)
interpretation. c
Oral clindamycin is not FDA-approved for this indication
sometimes nausea and vomiting. However, oral preparations Table 12.2 Characteristics of uncomplicated vs. complicated vulvo-
may be more convenient for patients, and topical prepara- vaginal candidiasisa [10]
tions are often more expensive. Uncomplicated Complicated
Importantly, alcohol consumption should be avoided dur- ≤3 episodes per year Recurrent VC (≥4 episodes per year) OR
AND
ing treatment with oral or vaginal metronidazole until 24 h
Mild to moderate Moderate to severe symptoms OR
after completion of therapy to avoid a disulfiram-like reac- symptoms AND
tion (e.g. flushing, nausea, vomiting, headaches). Tinidazole Probable infection Candida species other than C. albicans OR
is an alternative treatment that carries similar risk, and due to with C. albicans AND
this medication’s longer half-life, alcohol must be avoided Healthy, nonpregnant Adverse risk factors (e.g. pregnancy,
for 72 h after ingestion. Pregnant women with symptomatic woman poorly controlled diabetes,
immunosuppression)
BV may be treated with the same oral and topical treatment
Reprinted from The Lancet, Vol. 69/Number 9577, Sobel JD,
regimens recommended for nonpregnant women with BV,
Vulvovaginal candidosis; pgs 1961–1971, © 2007, with permission
with the exception that tinidazole should be avoided in preg- from Elsevier
nancy [5]. a
The distinction between Uncomplicated and Complicated VC has
Partner therapy is currently not recommended for male or management implications, as complicated VC infections require a lon-
ger course of treatment (see text). See text also for chronic suppressive
female partners of women diagnosed with BV. A recent sys-
regimen for recurrent VC
tematic review concluded that high quality evidence shows
antibiotic treatment for male sexual partners of women with
BV does not increase the rate of clinical or symptomatic vaginitis, a two-week course of intravaginal boric acid or
improvement, and low-quality evidence suggests that male topical flucytosine may be effective [5, 29]. For women with
partner treatment does not decrease recurrence rates [24], severe vulvar inflammation, a low potency topical corticoste-
while another systematic review concluded that six random- roid ointment may be applied for up to 48 h until the antifun-
ized controlled trials (RCT) had significant flaws and insuf- gal medication can take effect. For treatment of VC in
ficient power to detect a reasonable effect size [25]. There pregnancy, only topical azole therapies are recommended,
have not been any RCTs specifically evaluating the treatment typically for a 7-day duration [5, 28]. Partner therapy is not
of female sexual partners. However, for women who have indicated for VC infections.
sex with women, studies consistently indicate high rates of Occasionally VC treatment failures using topical regi-
concordant BV infections. Therefore, some experts recom- mens result from patients mistakenly choosing to apply topi-
mend providing education on proper cleaning of sex toys as cal therapy to the vulva only and not the vagina. In certain
well as avoiding sexual activity during active infections, settings it may be beneficial to emphasize the need for intra-
though no studies to date show these behaviors reduce BV vaginal treatment to eradicate the source of infection.
recurrence rates [26].
Trichomoniasis In contrast to BV and VC, treatment for
Vaginal Candidiasis (VC) Since Candida can be a constitu- trichomoniasis is indicated in both asymptomatic and
ent of the normal vaginal flora, women found to have yeast symptomatic women and partner therapy is indicated as
on wet mount should be treated only if symptomatic. If well, since trichomoniasis is sexually transmitted (see
symptomatic, it is important to differentiate between Chap. 13 on “Sexually Transmitted Infections” for further
uncomplicated and complicated VC infections [10] (See
detail regarding partner therapy). Both metronidazole and
Table 12.2). Uncomplicated VC infections can be treated tinidazole are FDA-approved for the treatment of trichomo-
with a 1-, 3-, or 7-day course of a topical azole or a single niasis, and standard therapy is 2 g orally of either drug.
dose of an oral azole, whereas complicated VC infections Topical antimicrobials are not recommended because they
require a regimen of longer duration, typically a 7- to 14-day are unlikely to achieve therapeutic levels in the urethra and
course of a topical azole or three doses of an oral azole sepa- perivaginal glands where the protozoan can also live [28].
rated by 72 h. Oral azoles (e.g. fluconazole) and topical An alternative regimen is metronidazole 500 mg orally
azoles (e.g. butoconazole, clotrimazole, miconazole, etc.) twice daily for 7 days. The recommended regimen for treat-
have comparable cure rates. While adverse effects and drug ment of trichomoniasis in pregnancy is oral metronidazole
interactions are less of a concern with topical azoles, women as a single 2 g dose. Both metronidazole and tinidazole
typically prefer the convenience of the oral formulation, and have similar efficacy, but tinidazole is significantly more
oral fluconazole 150 mg is commonly prescribed [27]. expensive [5]. Recall that during and following ingestion of
metronidazole and tinidazole, alcohol must be avoided for
The optimal treatment for non-Candida albicans VC is 24 and 72 h, respectively. Women treated for trichomonia-
unclear, but first-line therapy is treatment with a topical or sis should be assigned an appointment within 3 months to
oral non-fluconazole azole drug (e.g., itraconazole) for screen for reinfection. (For details see section on Recurrent
7–14 days [5, 28]. For azole-refractory Candida glabrata Vaginitis, Follow Up and Sequelae.)
Table 12.3 Summary of evaluation and treatment of infectious vaginitis

Type (% prevalence)a Etiology Symptoms and signsb Office testingc Treatment
Bacterial vaginosis Gardnerella Odor Whiff test positive Metronidazole,
(22–50%) vaginalis, anaerobic Sometimes mild pain or pH > 4.5 oral or topical
bacteria pruritus Clue cells on microscopy, comprise Clindamycin,
Homogenous, thin, clear/white/ ≥20% of epithelial cells topical
gray, malodorous discharge
Vulvovaginal Candida albicans; Pruritus or “burning” Dysuria Whiff test negative Azoles, oral or
candidiasis Less commonly C. and dyspareunia also common Normal pH (3.8–4.5) topical
(17–39%) krusei or C. White, thick, odorless Budding yeast and hyphae on
glabrata discharge, but sometimes gray microscopy (best seen on KOH slide);
and thin, sometimes absent no excess leukocytes (saline slide)
Vulvar and vaginal
inflammation evident
Trichomoniasis Trichomonas Discomfort (irritation, Whiff test often positive Metronidazole,
(4–35%) vaginalis soreness, etc.) pH > 4.5 oral
Dyspareunia, dysuria, Motile trichomonads on microscopy Tinidazole, oral
Pruritus along with excess leukocytes; clue cells
Green-yellow, frothy discharge often present as well
Vaginal inflammation evident
Normal physiologic No disagreeable odor or other Whiff test negative Reassurance if
discharge symptom pH 3.8–4.5 (premenopausal); needed
Clear or white flocculent pH 5–7 (postmenopausal)
discharge that does not adhere Smooth-appearing epithelial cells with
to vaginal walls few clue cells (<20%) on microscopy,
only occasional leukocyte
Data from Anderson et al. [1]
a
Prevalence per review of studies of symptomatic women presenting in primary care
b
Patient symptoms and vaginal discharge characteristics may vary from the “classic” disease presentation as listed above, and there is overlap in
the features of the three types of infectious vaginitis. Coinfection is also common. These caveats underscore the importance of complete office
evaluation.
c
Point-of-care testing is an alternative to microscopy
A persistent trichomoniasis infection usually represents Recurrent Vaginitis, Follow-Up, and Sequelae
reinfection from an untreated sex partner, since treatment
resistance is uncommon. (See Chap. 13 on “Sexually Recurrent vaginitis is common. However, persistent symp-
Transmitted Infections” section on expedited partner ther- toms occasionally stem from misdiagnosis, thus repeat eval-
apy.) If a true treatment failure is suspected after a single uation should first be performed to exclude this possibility.
dose of a nitroimidazole, metronidazole 500 mg orally twice Patients confirmed to have recurrent vaginitis are often can-
daily for 7 days is recommended [5]. If this regimen also didates for chronic management, and sometimes benefit
fails, clinicians should consider treatment with metronida- from addressing potential risk factors.
zole or tinidazole at 2 g orally once daily for 7 days [5]. If More than half of patients diagnosed with BV experience
several 1-week regimens fail and both nonadherence and a recurrence within 1 year [31]. For women with multiple
reinfection are unlikely, the CDC can provide assistance with recurrences despite completion of recommended treatment
susceptibility testing and treatment of nitroimidazole- regimens, the only approved suppressive therapy is topical
resistant T. vaginalis (telephone: 404-718-4141; website: metronidazole (nocturnal application two nights per week
http://www.cdc.gov/std) [30]. Chronic Trichomonas carriage for 6 months) [26]. Alternatively, a small, randomized trial
is also possible (see next section). Table 12.3 summarizes the found that monthly oral metronidazole 2 g plus oral
etiology, symptoms, diagnosis, and treatment of infectious fluconazole 150 mg also reduced the incidence of BV and in
vaginitis. addition promoted colonization with normal vaginal flora
[32]. Patients with recurrent BV should also be advised that
the use of condoms and estrogen-containing contraceptives
In the next year, Maureen has three more episodes of may reduce recurrences [31, 33, 34]. (See Chap. 4 on
vulvovaginal candidiasis, and today you diagnose her “Patient-Centered Contraceptive Counseling” for safe pre-
with another yeast infection. She wonders how to avoid scribing of estrogen-containing contraception.) Smokers
another infection. should be informed that cigarette smoking is associated with
an increased risk of BV in a dose-dependent manner [35],
and some patients benefit from a reminder that douching Primary care physicians should not underestimate the
should be avoided [36]. importance of their work in diagnosing and treating
Approximately half of women diagnosed with VC will infectious vaginitis, as both bacterial vaginosis and
experience a recurrence, and 5 to 8% will suffer recurrent trichomoniasis are sometimes associated with serious
VC, defined as ≥4 episodes in 1 year [10]. Although most morbidity. BV appears to increase susceptibility to infec-
sufferers of recurrent VC are healthy women, one should tion with certain STIs such as Trichomonas, chlamydia,
screen for symptoms of uncontrolled diabetes, and testing and gonorrhea [46, 47], while trichomoniasis appears to
for diabetes should certainly be performed for postmeno- possibly increase the risk of PID [48]. Even more con-
pausal women [10]. Also, women with recurrent VC can be cerning, both BV and trichomoniasis increase a woman’s
made aware of modifiable risk factors such as the use of risk of acquiring HIV [49, 50] as well as her risk of trans-
estrogen-containing contraceptives and unprotected sexual mitting the HIV infection to others [51, 52]. Consequently,
activity – especially receptive orogenital sex, as well as some have advocated treating asymptomatic BV to reduce
douching and the use of panty hose and panty liners [37]. the spread of HIV; however, there is insufficient evidence
Others may benefit from learning that some women suffer to support this strategy at the current time. BV and tricho-
recurrent VC while ingesting a diet high in refined sugars moniasis are also associated with pregnancy complica-
(despite having normal serum glucose levels) and enjoy reso- tions such as preterm births [53, 54]; however, treatment
lution of the problem upon adoption of a healthier diet [38]. has not proved beneficial. Despite these potential compli-
Women with recurrent VC can be offered a 6-month cations, vaginitis is usually not associated with signifi-
course of chronic treatment. Since non-Candida albicans cant long-term sequelae, and patients should be
species may be responsible a vaginal culture should first be appropriately reassured.
obtained. Women should be made aware that treatment is
suppressive, not curative, and that typically episodes of VC
recur following completion of the regimen. Most women
Maureen meets the defined criteria for recurrent vul-
choose to continue episodic treatment, but for those who
vovaginal candidiasis. You screen her for diabetes and
desire chronic therapy the Infectious Diseases Society of
testing is negative. You offer her induction therapy fol-
America (IDSA) recommends treating recurrent VC with
lowed by 6 months of suppressive therapy. However,
10–14 days of induction therapy using a topical or oral azole
today Maureen admits that, despite previous office dis-
followed by oral fluconazole at 150 mg once per week for
cussions regarding lifestyle factors, she has continued
6 months [39]. Other beneficial measures for recurrent VC
her habit of drinking multiple glasses of sugary soda
include the use of the injectable contraceptive medroxypro-
throughout the day. Maureen states she would first pre-
gesterone acetate (Depo Provera) [40] and possibly daily
fer a trial of following a diet that is lower in refined
oral ingestion of yogurt that contains live cultures (confirma-
sugars and agrees to an appointment in 3 months. At
tory trials are needed) [41].
her follow-up visit Maureen is happy to report that she
One study found that up to 17% of women treated for
has had no further vaginal yeast infections.
trichomoniasis were reinfected within 3 months [42].
Because of high rates of reinfection, the CDC recommends
rescreening for trichomoniasis in all sexually active women
within 3 months of treatment [5]. Nucleic acid amplification Noninfectious Vaginitis
testing should be deferred for at least 2 weeks following
treatment due to concern for false positive results from The genitourinary syndrome of menopause (previously
persistent dead organisms. Also of note, a recent study sug- termed atrophic vaginitis and covered in Chap. 8 on
gests that while T. vaginalis may be undetectable months “Menopause”), contact vulvovaginitis, and desquamative
after treatment, it can nonetheless be present and persist in a inflammatory vaginitis are noninfectious causes of vaginitis.
dormant state, only to become evident on testing months to Since contact dermatitis typically involves the vulva more
years later in asymptomatic women reporting no new sexual than the vagina, it is covered in the Common Vulvar Problems
activity [43]. Chronic asymptomatic carriage would explain section of this chapter (see below).
the unusual older age distribution of trichomoniasis, as rates
of trichomoniasis are highest in women over 40 years of age
[44, 45]. The possibility of chronic asymptomatic T. vagina- Desquamative Inflammatory Vaginitis
lis carriage may be important to include as part of patient
counseling, particularly for patients who are abstinent or Desquamative inflammatory vaginitis (DIV) is an uncom-
report long-term monogamous relationships and are uncer- mon chronic vaginitis of unknown cause, although an
tain of how they acquired the infection. immune etiology is suspected. It occurs mainly in
Caucasian women, and while half of sufferers are of repro- Common Vulvar Problems
ductive age, peak incidence occurs in peri-menopausal
women [55]. Overview
Nearly all patients describe three symptoms: a purulent
vaginal discharge, severe dyspareunia, and vaginal dis- The vulva consists of the labia majora, labia minora, clitoris,
comfort [56]. Patients typically have symptoms for more vaginal vestibule, vaginal introitus, urethral meatus, and the
than 1 year before being diagnosed [57]. On exam, puru- openings of the ducts of the greater vestibular glands
lent discharge is seen. Evidence of vaginal inflammation (Fig. 12.5). The vulva serves to direct urine flow, prevent
is always present, either in the form of a spotted vaginal admission of foreign bodies into the vagina, and contribute
rash (either petechial or ecchymotic), diffuse vaginal ery- to sexual pleasure [60].
thema, or linear erosions. Occasionally the cervix is Although vulvar symptoms most commonly result from
involved with papules having a pale center (resembling discharge originating from the vagina or cervix, primary pro-
donuts) [57]. The vestibule is often also erythematous and cesses specific to the vulva also occur. These include contact
in extreme cases, an erythematous macular rash may be dermatitis (both irritant and allergic), dermatoses (e.g. pso-
evident on the vulva [56]. riasis, lichen sclerosus, lichen planus, and lichen simplex
The vaginal pH is always greater than 4.5. Saline wet chronicus), vulvar neoplasms, and vulvodynia. Although
mount shows an increase in parabasal cells, which are small, genital Candida infections are a common cause of vulvitis,
round immature epithelial cells that have a large nucleus and this topic is discussed in the Infectious Vaginitis section of
little cytoplasm. Inflammation is also evident, defined as the this chapter. Likewise, those sexually transmitted infections
leukocyte to epithelial cell ratio exceeding 1:1. Careful (i.e. herpes simplex virus, syphilis and low-risk human papil-
inspection also reveals an absence of lactobacilli [58]. lomavirus (HPV) that can cause vulvar lesions are covered in
Because of overlap in clinical presentation, it is some- Chap. 13 on “Sexually Transmitted Infections”.
times reasonable to exclude other diagnoses before making a
diagnosis of DIV, such as trichomoniasis (using PCR test-
ing), Group A Streptococcus (with vaginal culture) [56] and
lichen planus (by performing careful examination of the oral
cavity and skin). Of note, some clinicians suspect DIV may
be a variant of erosive lichen planus [59].
Retrospective studies suggest similar efficacy with
either topical clindamycin or vaginal corticosteroids. Both
act via anti-inflammatory effects. Clindamycin is known to
have such properties, and substitution with antibiotics hav-
ing similar antimicrobial activity is ineffective. In fact,
clinical response to any antibiotic other than clindamycin
(or response to estrogen therapy) excludes the diagnosis of
DIV.
Initial treatment consists of either nightly intravaginal
clindamycin or corticosteroids plus medication applied to
the vestibule for 4 weeks [58]. Nearly all patients demon-
strate remarkable initial improvement and after 4 weeks the
regimen is usually tapered to twice weekly maintenance
therapy. Thereafter progress slows and the majority of
women must continue maintenance treatment for longer than
1 year [58]. In addition to monitoring symptoms and physi-
cal exam, follow-up wet mount examination helps assess
progress. Assessment of vaginal pH, however, is not useful
in the setting of clindamycin use. Since treatment predisposes Fig. 12.5 Anatomy of the Vulva. The vulva consists of the labia
to yeast vaginitis, some providers prescribe suppressive ther- majora, labia minora, clitoris, clitoral hood, and vaginal vestibule. The
vaginal vestibule encompasses the space between the two labia minora
apy using fluconazole 150 mg weekly or, for women sus-
and contains the openings of the urethra, vagina, and ducts of the
pected of having DIV plus symptomatic vaginal atrophy, greater vestibular glands. Illustration © 2019, Jennifer E. Fairman,
topical estrogen. CMI, FAMI. Johns Hopkins University. Used with permission
History sometimes infectious disease specialists as well. Familiarity

with the available local expertise can benefit one’s patients
Most women do not recognize the vulva as an anatomic with vulvar conditions.
entity and are also unfamiliar with the term “vulva,” and
therefore typically refer to the area as the “vagina” or with
vague terminology. Using a term such as “external genital eneral Therapeutic Measures for Vulvar
G
area” when eliciting history can help clarify location. Studies Dermatitis
indicate that patients with vulvar complaints delay seeking
evaluation for months or even years due to embarrassment or For patients with vulvar problems, a number of measures can
anxiety. Clinicians should therefore be attentive to providing promote vulvar health, alleviate discomfort, and speed heal-
care in a nonjudgmental and supportive fashion. In addition ing. Underpants should be loose-fitting and made of absor-
to the usual medical, surgical, gynecological, sexual, social, bent material (such as cotton). Women may also benefit from
and family history and medication list, evaluation of vulvar avoiding tight pants, lycra garments and pantyhose, and
problems sometimes requires obtaining an extensive history wearing no underpants while sleeping. To avoid allergen
of all vaginal and vulvar contactants. exposure, underwear should be laundered with fragrance-
free detergent without fabric softener. Patients with acute
vulvar conditions often benefit from a daily warm bath (with-
Physical Examination out soap or bubble bath), plus tap water compresses twice
daily for 20 min. Wipes, deodorants, and douches contain
A proper pelvic examination includes thorough inspection of common irritants and/or allergens and their use should be
the vulva using adequate lighting—which in some settings is avoided. When washing, a bar of moisturizing rather than a
aided by the light source contained within the illuminated deodorant or liquid soap should be used, if soap is used at all.
plastic speculum held before the vulva. Familiarity with nor- Daily panty liners should also be avoided, and tampons are
mal variants in vulvar anatomy is important to avoid generat- less irritating to the vulva than pads.
ing unnecessary alarm. There is wide variation in the Several barrier options can provide symptomatic relief
appearance of the labia minora—from thin to thick and short from vulvar discomfort. Zinc oxide ointment serves as an
to long—at times long enough to protrude from between the excellent barrier that prevents irritating discharge or urine
labia majora. The two labia minora may be of differing size from contacting inflamed mucosa and can be applied on top
even in the same individual (“labial hypertrophy”), which is of medication if needed. Olive oil and petroleum jelly are
of no medical concern. In some individuals the free edge of moisturizers and skin protectants that are unlikely to cause
the labia minora may be hyperpigmented. In recent decades, allergy. In contrast, powders are best avoided on the vulva.
increasing numbers of women have sought cosmetic surgery Rubbing and scratching often exacerbate vulvar problems
for their external genitalia, and a recently affirmed ACOG and should be discouraged and the pruritus treated. Cool Sitz
statement recommends discussing with such patients the baths or cool packs applied to the vulva are helpful.
wide range of appearance of genitalia in normal women [61] Antihistamines such as hydroxyzine (25–50 mg) or the tricy-
as well as the unproven benefits and known risks of such clic antidepressant doxepin (10–25 mg) dosed once daily at
surgery [62]. bedtime can relieve nighttime itching. Cetirizine (5–10 mg)
may be dosed in the daytime, although a minority of patients
will experience sedation. Topical antihistamine preparations
eneral Testing Strategies for Vulvar
G should be avoided due to the risks of contact dermatitis and
Conditions sensitizing the patient to the antihistamine [63] as well as
poor efficacy [64].
The diagnosis of vulvar lesions is sometimes apparent from When prescribing topical treatment, ointments are pre-
clinical evaluation alone, but whenever the diagnosis is ferred over creams, which contain alcohols or preservatives
uncertain or lesions fail to respond to treatment, biopsy or that can cause irritant or contact dermatitis. Mid-potency
referral is indicated. The importance of promptly biopsying topical steroids, such as triamcinolone ointment 0.1% for up
undiagnosed vulvar lesions cannot be overemphasized given to 10–14 days, treat most acute problems. Prolonged use of
that vulvar malignancies assume a wide range of appear- topical steroids on the vulva can cause permanent skin
ances. Primary care physicians adept at performing skin changes such as striae or atrophy on the medial thighs or but-
biopsies can perform biopsies of the vulva; however, referral tocks, although usually not on the vulva itself. Most primary
to gynecology or dermatology is often warranted. Some ter- care physicians seek consultation from either a dermatolo-
tiary centers have specialized vulvovaginal clinics staffed by gist or gynecologist if either ultrapotent or long-term use of
either gynecologists or dermatologists, preferably both, and topical corticosteroids is needed.
Lidocaine ointment 5% is effective for temporary local Common causes of allergic vulvovaginitis include (1) fra-
pain control for patients with mucosal ulcers or for some grances (and therefore soaps, body washes, laundry deter-
types of vulvodynia. Over-the-counter benzocaine (Vagisil) gents, and pads and tampons that contain deodorant), (2)
should be avoided, as it is a common cause of allergic con- preservatives in topical medications, (3) topical medications
tact dermatitis. themselves—especially topical anesthetics (i.e. benzocaine
in Vagisil), topical antibiotics (i.e. neomycin and aminogly-
cosides), topical anti-fungals, and even topical corticoste-
Specific Conditions of the Vulva roids, (4) propylene glycol and (5) lanolin. Other relatively
common causes of allergic contact dermatitis include the
Contact Vulvovaginitis chemicals in the rubber and natural latex used in condoms
and diaphragms. Chemicals such as rosin or acrylates that
are in feminine hygiene or incontinence pads have also been
Cady is a 19-year-old who presents with “a yeast implicated. Over-the-counter topical formulations contain-
infection that just won’t go away.” She states she began ing botanical agents are becoming increasingly popular, and
suffering itching “down there” approximately 1 month these are important potential allergens. In patients with ano-
ago, and trials of two different over-the-counter yeast genital complaints, ingestion of spices and peppermint oil
treatments “just made it worse.” She has had difficulty are common culprits [67].
sleeping the past two nights due to the itching and
discomfort.
History
Most women with irritant vulvovaginitis report burning or

Contact vulvovaginitis is a common cause of vulvar
irritation, while those with allergic vulvovaginitis complain
symptoms and accounts for approximately half of patients
of itching [68], but symptom overlap occurs. Vaginal dis-
presenting to vulvar clinics [65]. The peaks in prevalence
charge is not often present.
occur between the ages of 10–20 years and 40–50 years [66].
When searching for the cause of contact dermatitis, an
Contact dermatitis may result from irritants (irritant contact
exhaustive history regarding potential exposures is fre-
dermatitis) or, less commonly, allergens (allergic contact
quently required, and occasionally, the exposures of the sex
dermatitis).
partner as well.
Irritant contact dermatitis results from exposure to
agents that cause direct injury to the skin cells or lipid bar-
rier. By contrast, allergic dermatitis develops only in sus-
ceptible individuals following exposure to an antigen that On pelvic exam, Cady’s vulva is diffusely erythema-
triggers an immunologic reaction. Irritant vulvovaginitis tous and swollen, and scattered erythematous papules
appears quickly, within minutes to hours of exposure, while are seen. Her vaginal mucosa appears normal, and
the allergic dermatitis is a form of delayed type hypersensi- there is no vaginal discharge. Her vaginal pH is nor-
tivity and onset is 24–48 h after exposure. Because of the mal, the whiff test is negative and no fungal elements
anatomical location of the vulva, allergic contact dermatitis or increased leukocytes are seen on microscopic exam-
may result from allergen exposure via several routes, ination of the wet mount and KOH prep.
including direct application of topical products, inadvertent
manual transfer from other body sites, exposure to allergen
in urine or feces following oral consumption, or systemic Examination
contact reactions.
Common causes of irritant vulvovaginitis include pro- Examination of the patient with contact dermatitis commonly
longed exposure to urine, sweat, feces, semen, and abnormal reveals vulvar erythema and swelling and well-demarcated
vaginal discharge. Spermicides, lubricants, irritants found in edematous papules and vesicles, which can ulcerate [69].
douches and other feminine hygiene products, harsh soaps Occasionally the vaginal mucosa is also involved, as in the
and detergents, and simply overzealous hygiene are other setting of contact dermatitis from douches, deodorant-con-
causes. Daily use of pads and panty liners can also cause an taining tampons, spermicides, etc. Contact dermatitis can eas-
irritant dermatitis due to friction. Topical medications con- ily be mistaken for candida vulvovaginitis; however, the lack
taining alcohols or certain acids are common culprits. of vaginal discharge or fungal elements on microscopy help
Feminine wipes and moist toileting wipes contain both irri- distinguish the two. Mild irritants may not always produce
tants and a common allergen. physical findings to accompany a patient’s symptoms.
Management The disease is also associated with risk of malignant trans-

formation to squamous cell carcinoma. Affected patients are
The treatment of either form of contact vulvovaginitis entails usually older than 50 years; however, the condition occurs in
permanent avoidance or elimination of the trigger plus tem- women of all ages and even girls; in one large study the mean
porary use of topical low- to mid-potency steroid ointments age at diagnosis was 55 years (range 18–86 years) [70].
such as desonide ointment 0.05% or triamcinolone ointment
0.1% for 2–4 weeks. Patients with severe pruritus should
also be treated with oral antihistamines or doxepin (see On pelvic examination, Luisa’s vulva appears abnor-
above). If an allergic contact dermatitis is suspected, referral mal: the mucosa is diffusely thickened and pale, and
to a dermatologist for patch testing is often helpful. the mucosa of the perineum and perianal areas is
When there are bullae or erosions on the vulva and the affected as well. Her labia minora appear shrunken
diagnosis is unclear, biopsy may be needed to rule out an and her introitus is narrowed.
immunobullous disorder [68]. Irritant vulvovaginitis may
complicate an underlying vulvar dermatosis, in which case
the diagnosis may be challenging. Sometimes contact der-
matitis may become infected with yeast or bacteria, in which
History and Examination
case systemic antibiotics are preferred over topical.
Patients with LS usually complain of itching, burning, and
introital dyspareunia; if anal involvement is present, patients
can experience painful defecation and anal fissures.
Although Cady suspected a yeast infection, the physi-
Examination reveals pallor and initially abnormal thickening
cal exam and microscopy findings are consistent with
of the vulva mucosa, which is usually diffuse but sometimes
contact dermatitis. An extensive history uncovers her
focal. When involvement is diffuse and includes the perineum
new habit of using moist toileting wipes beginning
and perianal areas, it can resemble a “figure 8.” Over time the
1 month ago. You recommend immediate and perma-
mucosa becomes abnormally thin and wrinkled (“cigarette
nent avoidance of all moist toileting wipes. You also
paper appearance”) and bruises can result from scratching
advise temporary use of cool Sitz baths and cool com-
the fragile mucosa. In the absence of trauma, vulvar ecchy-
presses and prescribe desonide ointment 0.05% to be
moses are virtually pathognomonic for LS [71, 72].
applied sparingly to the vulva twice daily for 14 days.
Adhesions, tissue resorption, and scarring affect the architec-
Given the severity of her itching you also prescribe
ture of the vulva: the clitoris may become sealed under the
cetirizine 10 mg daily in the morning and hydroxyzine
clitoral hood, the labia minora may shrink and even disap-
25 mg at bedtime.
pear altogether, and the introitus may narrow significantly
[72] (Fig. 12.6). Biopsy findings help distinguish the condi-
tion from lichen planus and malignant transformation [73].
Dermatoses
The four important dermatoses that affect the vulva are

lichen sclerosus, lichen planus, psoriasis, and lichen simplex A vulvar biopsy confirms the diagnosis of LS and you
chronicus. refer Luisa to a gynecologist for management. You
emphasize that even after the condition comes under
control, she will need lifelong treatment with topical
Your next patient of the morning is Luisa, a 55-year- steroids and monitoring every 6–12 months, due to the
old healthy woman who presents for a “routine Pap increased risk of SCC.
smear.” She complains of worsening vulvar itching and
entrance dyspareunia that began approximately 1 year
ago. Management
Ultrapotent topical corticosteroid ointments (i.e. clobetasol

Lichen Sclerosus ointment 0.05%) are the mainstay of treatment. At diagnosis,
the ointment is applied once daily for 1 month, followed by
Lichen sclerosus (LS, previously termed lichen sclerosus et every other day for 1 month, and then twice weekly for 1 month.
atrophicus) is an inflammatory, likely autoimmune, disease Thereafter regimens are less well defined and vary; common
that causes pigment and texture changes of the vulvar mucosa regimens include twice weekly clobetasol or substitution of a
and, left untreated, eventual destruction of vulvar structures. less-potent corticosteroid. Symptoms resolve within days or
likely effective in preventing vulvar cancer, as no cases were

seen among the compliant patients yet 4.7% of the noncom-
pliant patients were affected [70]. Since patients are often
tempted to quit treatment when they are no longer symptom-
atic, the importance of continuing long-term topical steroids
should be emphasized. Patients with LS also have a higher
likelihood of other autoimmune disorders such as thyroid
disease (incidence 16.3%) [75] and pernicious anemia, and
should be appropriately screened.
Because of the association of LS with thyroid disease

and pernicious anemia, you ask Luisa to obtain lab
work after today’s visit. You employ the teach-back
method to confirm she understands the importance of
long-term treatment and regular follow-up of this
condition.
Lichen Planus
Fig. 12.6 Lichen sclerosus (later stage). The vulvar mucosa is pale, Margaret is a 57-year-old woman who presents for
thin, and wrinkled. The right labium minus is markedly shrunken, the routine follow-up of her hypertension and arthritis, for
left labium minus is completely resorbed and the clitoris is buried under
a stenotic clitoral hood. In addition to destruction of her vulvar anat-
which she has taken metoprolol and ibuprofen for
omy, untreated LS places this patient at higher risk for vulvar carci- years. She reports 3 years of worsening pain and sore-
noma. Untreated vulvar lichen planus carries these same risks. Used ness “in my private area” and reveals she quit having
with permission intercourse 1 year ago due to entrance as well as deep
dyspareunia. She states she finally mustered enough
weeks of initiating treatment but pallor and atrophy take longer courage to see her gynecologist last month and was
to respond. Spontaneous resolution can occur; however, most diagnosed with lichen planus. She is now under the
recommend continuing topical steroid treatment indefinitely. care of a dermatologist.
Some women require alternative therapies such as immuno-
modulators, and surgery is sometimes needed to treat adhe-
sions. Most women diagnosed with LS are managed by either
a gynecologist or dermatologist, since management requires As with lichen sclerosus, lichen planus (LP) is an inflam-
the use of ultrapotent topical corticosteroids and close monitor- matory, likely autoimmune, disorder that can lead to destruc-
ing for the possible development of vulvar cancer. tion of the normal architecture of the vulva, but LP can also
Women with LS have a 3–5% risk of developing vulvar involve the vagina as well. There are three main types: ero-
SCC, and thus even once the condition is stable patients sive, papulosquamous, and hyperkeratotic disease. Genital
require lifelong monitoring at least every 6–12 months, with LP can occur in isolation or as part of a systemic disease
prompt biopsy of suspicious areas. Scarring is not expected involving skin, hair, nails, or other mucosa. Women with the
to reverse, however, the mucosal thickening and pigment erosive form usually also have oral involvement, most com-
changes of LS are highly responsive to therapy. Any areas of monly in the form of ulcers on the buccal mucosa.
mucosa that appear “unresponsive” likely represent either
vulvar intraepithelial neoplasia (VIN) or squamous cell car-
cinoma (SCC)—especially if they appear as a pink patch or Margaret brings with her the dermatologist’s note,
a white raised lesion. Patients should also be counseled to which describes her vulva as brightly erythematous
report any lump, ulcer, or hardening of the skin [74]. and having erosions on the labia minora that are sur-
Cessation of therapy commonly leads to relapse and rounded by a white rim. Her vagina is described as
attendant risks for destruction of vulvar structures and vulvar brightly erythematous, shortened and coated with an
cancer. Although a controlled trial would now be unethical, a adherent film. She also has ulcers on her buccal
large longitudinal study following affected women for mucosa.
5 years suggested that continued corticosteroid treatment is
History and Objective Findings cates an unexplained association of vulvar LP with NSAID
and beta-blocker use, and experts recommend that consider-
Genital LP can be asymptomatic or cause itching, burning, ation be given to discontinuing these medications in women
post-coital bleeding, dyspareunia, or yellow vaginal dis- diagnosed with LP. The same study found that ACE-inhibitors
charge. The appearance of the vulva depends on which of the may be protective [78].
three LP variants is present. Erosive LP, the most common
and most destructive form, manifests as bright erythema and
erosions on the labia minora that are surrounded by a white
You inform Margaret of the unexplained association of
reticular rim. Left untreated, erosions can lead to scarring
LP with beta-blockers and NSAIDs, and she agrees to
with strictures, such as phimosis of the clitoris and stenosis
discontinue the metoprolol and ibuprofen and begin a
of the urethra or vaginal introitus. In advanced disease the
trial of lisinopril and acetaminophen. You emphasize
introitus may be reduced to a very small opening or the vulva
the importance of adhering to the dermatologist’s
may lose all landmarks and become “featureless.” In the
treatment plan in order to prevent further destruction
vagina, erosions and internal synechiae can cause eventual
of the vulvar and vaginal anatomy. You point out that
stenosis and loss of length of the vagina. The less common
even once her symptoms resolve, continued treatment
papulosquamous variant presents with polygonal, flat-topped
is important to prevent both destruction of her vulva as
papules with white reticulated borders (Wickhams’s striae)
well as cancer, and regular follow-up with the derma-
on the vulva that are reminiscent of the violaceous LP pap-
tologist at least once yearly allows for monitoring.
ules found elsewhere on the body. The third form of LP,
hyperkeratotic, exhibits hyperkeratotic lesions of the
perineum and perianal areas.
Biopsy is often nondiagnostic but helps exclude a neo- Psoriasis
plastic disorder. Diagnosis usually rests on vulvar examina-
tion and extravulvar manifestations of LP; formal diagnostic Approximately half of patients with psoriasis have involve-
criteria have been established [76]. ment of the genital area [79]. On the other hand, in 2–5% of
patients with psoriasis, the condition is confined to the geni-
tal area, which can present more of a diagnostic challenge. In
Management such instances, full body skin exam (particularly of the glu-
teal crease, umbilicus, scalp, fingernails, and toenails) can
As with lichen sclerosus, ultrapotent topical corticosteroid sometimes uncover unrecognized psoriasis and aid in estab-
ointments (e.g., clobetasol ointment 0.05%) are the first-line lishing the diagnosis.
treatment for LP of the vulva and are important to prevent Women with vulvar psoriasis experience pruritus but also
destruction of the vulvar architecture and reduce the risk of often report pain or burning of the vulva due to friction, per-
vulvar cancer [74]. In addition, measures must also be under- spiration, and maceration of lesions. On examination, the
taken to manage vaginal involvement. Hydrocortisone 25 mg mons pubis, the cutaneous vulva (the hair-bearing areas of
rectal suppositories should be placed intravaginally twice the labia majora) and the perianal areas are more often
daily, then reduced to twice weekly once symptoms improve. affected [80]. Psoriasis on the vulva can manifest as sym-
Alternatively, hydrocortisone enema foam (Colifoam) deliv- metric, brightly erythematous, shiny, thin plaques, some-
ered directly from the aerosol can [77] or placed in a vaginal times with satellite erythematous papules. If scale is scraped
applicator [74] can be used. To prevent vaginal stenosis, off it leads to punctate bleeding (Auspitz’s sign), which helps
patients either should also use dilators coated with cortico- confirm the diagnosis. However, on the vulva, scale is fre-
steroid ointment or engage in vaginal intercourse at regular quently absent [81]. A biopsy is usually not needed except
intervals. when the clinical diagnosis is uncertain or when lesions fail
Often monotherapy with topical corticosteroids is inade- to respond to treatment.
quate for treating the vulva. In such cases a calcineurin
inhibitor (tacrolimus ointment) or systemic therapies [74]
may be required. Surgical lysis of adhesions on the vulva or Management
in the vagina is also sometimes necessary. Patients with geni-
tal LP are usually managed by a dermatologist in conjunc- Treatment of genital psoriasis initially consists of low- to
tion with a gynecologist. mid-potency topical steroid ointments for 2–4 weeks or less,
Lichen planus also increases the risk of vulvar cancer, and followed by topical vitamin D analogues or topical calcineu-
therefore affected women should undergo monitoring at least rin inhibitors (e.g. tacrolimus ointment). These latter agents
every 12 months [73]. Of note, a large population study indi- are often poorly tolerated on the vulva due to stinging,
however, and systemic therapies must often be employed.

Unless the condition is easily controlled primary care pro-
viders usually refer patients with vulvar psoriasis to a
dermatologist.
Lichen Simplex Chronicus
Lichen simplex chronicus (LSC) is not a specific entity but

rather a term that describes lichenification – thickening and
hardening—of the skin caused by scratching. Lichen sim-
plex chronicus of the vulva usually develops in mid- to late-
adult life and is common, occurring in 0.5% of the American
population [73]. Patients experience intense pruritus, espe-
cially in the evening or during sleep, and consciously or
unconsciously scratch the area leading to an itch-scratch
cycle. A hallmark of the condition is that scratching pro-
vides temporary improvement in symptoms. LSC may
begin in normal skin in atopic individuals or arise second-
ary to an inciting condition such as psoriasis or an episode
of vulvovaginal candidiasis. In atopic individuals important
triggers include psychological distress arising from anxi-
ety, depression or worsening symptoms of obsessive-com-
pulsive disorder, or environmental factors such as heat, Fig. 12.7 Lichen simplex chronicus Lichen simplex chronicus
describes skin that is thickened and hardened as a result of chronic
sweating or friction [82]. Iron deficiency may sometimes
scratching. The condition is evident in this image by the thick and leath-
contribute to the compulsion to scratch and should be ery appearance of the labia minora and labia majora. When excoriations
excluded for women at risk (e.g. vegetarians, those with are also present the diagnosis is particularly straightforward. The root
menorrhagia, etc.) [83]. cause of the pruritus can be any of a variety of possible conditions,
some of which are psychologic. Used with permission
On exam, one or more erythematous or hyperpigmented,
scaling plaques with overlying excoriations can be found and
broken off hairs may be seen [84]. The labia majora are 10–25 mg can be substituted. Short fingernails are also rec-
mostly affected, and the condition is usually bilateral, but ommended [85]. Some patients benefit from cognitive
sometimes asymmetric or even unilateral, likely due to a behavioral therapy while others respond to treatment with
preference for scratching with the dominant hand. The SSRI medications such as citalopram 20 mg once daily,
affected skin usually appears erythematous (ranging from increasing gradually to 60 mg if needed [82]. Treatment is
pink if mild to bright or dusky red), but sometimes the ery- important as irreversible destruction and scarring of the
thema is masked by post-inflammatory hyperpigmentation vulva can occur.
[82]. If the condition is longstanding, the skin of the vulva Women affected by LSC should take particular care to
appears thick and leathery (Fig. 12.7). The combination of avoid any potential irritants or allergens. In addition to the
lichenification and excoriations makes the condition easy to usual measures some also recommend that affected patients
identify. Exam findings and diagnoses are more challenging wash only with water and use washable fabric feminine pads
when LSC is superimposed on another disorder, but biopsy and diapers [85]. Application of petroleum jelly throughout
is usually unnecessary. the day serves as an emollient and protectant.
Initial treatment entails ultra-potent topical corticoste-
roid, such as halobetasol propionate ointment 0.05% once
daily for a few weeks, followed by a mid-potency topical Malignant Vulvar Neoplasms
corticosteroid (such as triamcinolone acetonide ointment
0.01%) once or twice daily. Thick lesions that fail to respond Malignant lesions of the vulva are uncommon, representing
to topical therapy may require intralesional corticosteroid only 5% of all gynecologic malignancies. Squamous cell
injection. Tacrolimus ointment 0.1% has also been used. carcinoma is the most common of the vulvar malignancies
Nonsedating antihistamines (e.g., cetirizine) are dosed in the (90%), with malignant melanoma, sarcoma, basalioma,
daytime, and sedating antihistamines (e.g. hydroxyzine) are extramammary Paget disease, Bartholin gland cancer, and
dosed at bedtime. If pruritus is refractory, nightly doxepin verrucous carcinoma possible but rare [60].
The most common presentation of vulvar cancer is either Population studies also reveal that affected women have
a lump that the patient has noted herself or mild pruritus. higher rates of childhood physical or sexual abuse [94] as
Bleeding, pain, and discharge are indicative of advanced dis- well as higher rates of depression and anxiety prior to the
ease. Very often, vulvar cancer is asymptomatic and recog- onset of symptoms [95]. Not surprisingly, since vulvodynia
nized only on careful exam. frequently causes dyspareunia and can have a significant
Vulvar malignancies can assume a wide range of appear- negative impact on relationships, vulvodynia frequently
ances: they may be ulcerative, hyperkeratotic or warty, pres- causes depression and anxiety as well. (See Chap. 9 on
ent in almost any color, and can at times be multifocal. “Female Sexual Function and Dysfunction” for a discussion
Primary care providers should have a low threshold to refer of sexual pain disorders.)
for biopsy given the good prognosis when vulvar cancer is Affected patients usually present with a complaint of
treated early [60]. Unfortunately, studies indicate that burning, tingling, stinging, rawness or irritation. Pruritus is
patients with vulvar cancer usually delay office presentation not a prominent complaint. Most patients suffer symptoms
for 6 months [86] and providers fail to biopsy promptly. for 2 years before the diagnosis is made [96]. The intensity
(Vulvar malignancies are discussed further in Chap. 15 on of pain may fluctuate over time, and improvement may occur
“Gynecologic Malignancies”.) either spontaneously or following treatment [97]. Physical
exam is normal, with the exception that for a patient with
provoked vestibulodynia, gentle application of a cotton-
Vulvodynia tipped applicator to the vestibule causes tenderness. A care-
ful neurologic exam of the pelvic region is important to
Vulvodynia, defined as idiopathic vulvar pain of at least exclude another neurologic source.
3 months’ duration, is a common chronic pain disorder. Treatment for provoked vestibulodynia generally entails
Approximately 4% of U.S. reproductive-aged women are topical anesthetics for introital dyspareunia [83]. Lidocaine
affected at any given time and the lifetime prevalence is 5% ointment or lidocaine 2% gel can be applied 15–20 min
9.9% [87]. The direct health care costs of vulvodynia are cal- prior to intercourse and washed off immediately prior to
culated to be enormous [88] and the psychological toll penetration. Generalized unprovoked vulvodynia is man-
immeasurable. aged with a variety of different modalities including chronic
Per the 2015 nomenclature and classification, vestibulo- oral pain medications such as amitriptyline 5–25 mg nightly
dynia is defined as pain limited to the vestibule, and contrasts [96] or gabapentin begun at 300 mg nightly and increased
with generalized vulvodynia, which indicates pain affecting to as high as 1200 mg total dose per day [98]. TENS units
the entire vulvar area (but which more often is “mixed” and have also been used [99] as well as physical therapy when
includes vestibulodynia as well). A second distinction is a pelvic floor disorder is diagnosed. Individual or group
made between pain that is provoked (i.e. by intercourse, tam- cognitive-behavior therapy [100] appears helpful for some.
pon insertion, gynecologic exams, riding a bicycle, the sit- Surgical intervention with vestibulectomy is a last resort,
ting position) or unprovoked. since efficacy appears no better than cognitive behavioral
Histologic studies reveal an increased density of nocicep- therapy [101] and the risk of aggravating pain with surgery
tors at the vestibule of affected women [89]. Numerous is considerable [83]. When generalized unprovoked vulvo-
diverse triggers have been identified as likely leading to the dynia is resistant to treatment, pelvic and lumbosacral MRI
neuropathic changes. Sequelae from a resolved Candida vul- should be performed [83] to exclude another neurologic
vitis [90] and disruption of the hormonal environment from problem.
combined hormonal contraceptive (COC) use –particularly Women experiencing vulvodynia often experience dis-
when used prior to age 17 [91, 92]—appear to be possible missive behaviors from providers. Studies indicate that
causes of vulvodynia. Pelvic floor disorders resulting from a women with vulvodynia typically consult three physicians
singular event such as trauma, surgery, or childbirth have and are told their pain is “all in their head” before a diag-
also been implicated [88]. In general, any acute, painful sur- nosis is made [88]. Empathic communication is a critical
gical or medical condition (including an infection) involving component of patient care in this setting. An oral explana-
the vulva, urinary tract, or anus, may lead to vulvodynia— tion of vulvodynia followed by a written description of the
especially if the event occurred in a setting of emotional dis- diagnosis can perform many functions, including helping
tress [83]. In clinical settings the trigger is not always obvious to restore a patient’s self-esteem. In addition, the patient
nor sought. benefits when the physician expresses understanding and
Population studies show that at least half of vulvodynia empathy regarding the impact that vulvodynia symptoms
sufferers have at least one other pain condition, most com- have had on the patient’s life as this helps validate her
monly fibromyalgia or irritable bowel syndrome [93]. experience [83].
Summary Points 12. Patients with provoked vestibulodynia complain of

entrance dyspareunia, and the diagnosis can be made be
1. Bacterial vaginosis (BV), vulvovaginal candidiasis during the pelvic exam, when gentle application of a
(VC), and trichomoniasis are the most common causes cotton-tipped swab to the vestibule reproduces the pain.
of vaginitis in pre-menopausal women. Treatment includes appropriately timed topical anes-
2. When evaluating a patient with vaginal discharge, it is thetics as well as patient education.
important to include PID and cervicitis in the differen- 13. Generalized unprovoked vulvodynia is often treated
tial diagnosis. History taking should include a sexual with psychotropic pain medications such as tricyclic
history as well as questions regarding possible fever, anti-depressants or gabapentin, but other beneficial
pelvic pain, dyspareunia, changes in bleeding, and treatment options can be offered.
dysuria.
3. When a woman presents with vaginal discharge, a thor-
ough evaluation is needed. This includes history, pelvic
exam, whiff test, pH testing, and office microscopy (or Review Questions
point-of-care testing or laboratory microscopy).
4. Women require treatment for bacterial vaginosis and 1. Tamara is a 34-year-old woman who calls your office
vulvovaginal candidiasis only if symptomatic. complaining of vaginal discharge that started 2 days ago.
5. Trichomoniasis is a sexually transmitted infection that She tells you the discharge is thin, yellow, and malodor-
requires treatment, screening for other STIs and reevalu- ous. She denies dysuria and dyspareunia, but notes mild
ation within 3 months to exclude reinfection. Partner associated pruritus. She tells you she is sexually active
management is essential as well. with only her husband, and they do not use condoms. She
6. When a woman presents with recurrent BV or VC, she also says that her symptoms are similar to when she had a
should first undergo reevaluation to confirm the original bacterial vaginosis infection earlier this year, and you
diagnosis was correct. Risk factors should be assessed confirm in the medical record that she was diagnosed with
and she can be offered maintenance therapy or adjunc- bacterial vaginosis 6 months ago. She requests a prescrip-
tive measures. tion for oral metronidazole. What do you advise?
7. Irritant and allergic contact dermatitis are noninfectious A. An office visit is not required; prescribe metronida-
causes of vulvovaginitis. Patients report burning or pru- zole 500 mg orally twice daily for 7 days
ritus and exam findings may resemble candida vulvo- B. An office visit is not required; prescribe metronida-
vaginitis. Distinction can often be made by the lack of zole vaginal gel 0.75%, 5 g intravaginally once nightly
vaginal discharge on exam or fungal elements on for 5 days
microscopy. C. An office visit is not required; prescribe clindamycin
8. There are several general measures that support vulvo- 2% cream, 1 applicatorful once nightly for 7 days
vaginal health and provide comfort in the setting of vul- D. Advise her to come to the office to be evaluated
var inflammation, such as wearing loose-fitting cotton The correct answer is D: Advise her to come to the
undergarments, taking warm water baths, using zinc office to be evaluated [1]. Bacterial vaginosis (BV) is
oxide protectant, and avoiding panty liners, douches, typically associated with a thin, homogenous, malodor-
harsh soaps, wipes, and other irritants. ous discharge. It is not usually associated with any pain or
9. Since topical creams often contain alcohols or preserva- pruritus. However, none of these symptoms are diagnostic
tives that may be irritating to mucosal tissues, ointments of BV. While choices A and B are recommended treat-
are preferred for treating vulvar conditions. ment regimens for a confirmed diagnosis of BV, a proper
10. Lichen sclerosus and vulvar lichen planus are inflamma- evaluation that includes history, pelvic exam, and office
tory dermatoses that share two important possible microscopy is required to confirm the diagnosis and rule
sequelae: Left untreated, they can both cause destruction out cervicitis and PID. Choice C is an alternative treat-
of genital structures and increase the risk of vulvar ment regimen for BV.
cancer.
11. Vulvar cancers are rare but they can assume many 2. Sweta is a 37-year-old woman presenting for vaginal dis-
appearances – ulcerative, hyperkeratotic or warty, charge. She complains of thick, white discharge associ-
appear in almost any color and sometimes have a mul- ated with pruritus. She is not sexually active. She reports
tifocal presentation. Any undiagnosed vulvar lesion having three “yeast infections” in the last year and
that fails to respond to therapy should be biopsied believes this is another one. You perform a pelvic exam
promptly. and prepare a wet mount, confirming a diagnosis of
vulvovaginal candidiasis. Sweta is frustrated by the recur- pruritus are cetirizine in the daytime and hydroxyzine at
rent infections and wants to know what can be done. What night.
do you advise? 4. A 55-year-old woman presents for a “routine Pap smear.”
A. Prescribe a single dose of oral fluconazole 150 mg; She reports mild vulvar itching for the past year or two.
suppressive therapy is not indicated Her vulva appears abnormal with diffuse pallor and thin-
B. Prescribe three doses of oral fluconazole 150 mg sep- ning, and her labia minora appear markedly shrunken.
arated by 72 h; suppressive therapy is not indicated You recommend:
C. Prescribe 10 days of a topical azole or oral flucon- A. Referral to dermatology or gynecology
azole 150 mg, followed by oral fluconazole 150 mg B. Waiting for the results of her cervical cytology to
once per week for 6 months determine the next step
D. Prescribe a single dose of oral fluconazole 150 mg, C. A trial of watchful waiting
followed by oral fluconazole 150 mg once per week D. A trial of topical estrogen
for 6 weeks The correct answer is A. This presentation is classic for
The correct answer is choice C. Prescribe 10 days of a lichen sclerosus, which presents with focal or diffusely
topical azole or oral fluconazole 150 mg, followed by oral pale vulvar mucosa that is either abnormally thick (early
fluconazole 150 mg once per week for 6 months. This stage) or thin (later stage). LS requires treatment using
woman has complicated and recurrent VC, defined as ≥4 ultrapotent topical corticosteroids plus close monitoring
episodes per year. Given that she is frustrated by the fre- for the possible development of vulvar cancer. For this rea-
quent symptoms she should be offered a course of chronic son, patients with LS are usually managed by dermatolo-
therapy. For the management of recurrent VC, the gists or gynecologists. Cervical cytology has no bearing
Infectious Diseases Society of America recommends on the patient’s vulvar problem. Watchful waiting is inap-
10–14 days of induction therapy with a topical azole or propriate since without treatment the destruction of her
oral fluconazole followed by 6 months of maintenance vulvar anatomy will progress and the risk of vulvar cancer
therapy consisting of oral fluconazole 150 mg once is increased. The patient’s exam findings, particularly the
weekly [44]. A single dose of oral fluconazole (Choice A) changes to her labia minora, are too dramatic to be consis-
would be the correct choice if this was an uncomplicated tent with the genitourinary syndrome of menopause.
vulvovaginal candidiasis (VC) infection (e.g. ≤3 episodes
per year, mild to moderate symptoms), and choice B 5. A 75-year-old healthy woman presents complaining of
would be the correct answer if this was only complicated several months of progressive burning “in my private
VC and Sweta was not bothered by her symptoms. parts.” Her exam is notable for erosions with white bor-
ders on her labia minora as well as in her vagina. The
3. A 20-year-old woman presents complaining of 5 days of most likely etiology is:
severe vulvar pruritus. Following full evaluation, the two A. Genital psoriasis
of you determine that it is from an allergic dermatitis B. Lichen sclerosus
resulting from an allergy to the deodorant in her feminine C. Lichen simplex chronicus
pads, which she used for the first time beginning 1 week D. Lichen planus
ago. What do you recommend? The correct answer is D. The erosive form of lichen
A. She should soak in very warm baths for relief planus is the only chronic dermatosis of the vulva that
B. She should use a strong liquid soap to remove any also involves the vagina, and erosions with surrounding
residual antigen white reticular borders are characteristic. Psoriasis
C. She should immediately cease and permanently avoid involves plaques (not erosions). Lichen sclerosus presents
using this product (and perhaps all feminine products with pale mucosa that is either abnormally thick or thin.
that contain deodorant) Lichen simplex chronicus presents with plaques, licheni-
D. She should take diphenhydramine around-the-clock fication, excoriations, and broken-off hairs that all result
for relief of pruritus from excessive scratching.
The correct answer is C. Immediate and permanent
avoidance of the culprit antigen is the cornerstone of treat- 6. A 50-year-old healthy woman presents with vulvar pruri-
ing allergic contact dermatitis. In addition, topical steroid tus. Her pelvic exam reveals several symmetric erythema-
ointments and, if needed, oral antihistamines are used. tous plaques with rounded borders on the outer
Warm baths would aggravate the pruritus; cool Sitz baths (hair-bearing) aspects of the labia majora. No scale is
and compresses are helpful. Harsh soaps are never recom- seen. Which of the following is true?
mended on the vulva. Diphenhydramine would be too A. Examination of the scalp, gluteal cleft, umbilicus, and
sedating for daytime use; the preferred antihistamines for nails might uncover findings that support the diagnosis
B. This cannot be psoriasis since no silvery scale is 3. Klebanoff MA, Nansel TR, Brotman RM, Zhang J, Yu KF,
present Schwebke JR, et al. Personal hygienic behaviors and bacterial
vaginosis. Sex Transm Dis. 2010;37(2):94–9.
C. Biopsy is needed to confirm the diagnosis 4. Bradshaw CS, Walker SM, Vodstrcil LA, Bilardi JE, Law M,
D. These lesions are most likely malignant Hocking JS, et al. The influence of behaviors and relationships
The correct answer is A. The findings described are on the vaginal microbiota of women and their female partners: the
classic for psoriasis on the vulva; uncovering psoriasis WOW Health Study. J Infect Dis. 2014;209(10):1562–72.
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Sexually Transmitted Infections
13
Janice Ryden
Learning Objectives Your first patient of the day is Carol, a 21-year-old

1. Describe the health impact of sexually transmitted woman who had unprotected sex 1 week ago when she
infections and list measures that providers can encountered her old high school boyfriend at a party.
embrace to reduce the incidence of sexually trans- He texted her yesterday that she might have caught an
mitted infections (STIs). STI; his doctor just treated him for Chlamydia.
2. Perform an appropriate medical evaluation of a
woman reporting documented exposure to an STI,
including history, physical examination, testing, Sexually transmitted infections (STIs) are common and
empiric treatment, and screening for other STIs. carry significant negative impact on health. Even seemingly
3. Contrast the management of cervicitis caused by benign infections can facilitate HIV transmission and sus-
chlamydia or gonorrhea to the management of ceptibility in women. Many STIs can be associated with
women presenting with symptoms concerning for serious long-term sequelae, such as infertility, ectopic preg-
pelvic inflammatory disease (PID). nancy, spontaneous abortion, chronic pelvic pain, seronega-
4. Differentiate the characteristics of new genital tive arthritis, neurologic disease, cardiovascular disease,
ulcers caused by herpes simplex virus (HSV), syph- and malignancy. STIs may also affect offspring by increas-
ilis, and human immunodeficiency virus (HIV) and ing the risk of low birth weight, neonatal infection, and con-
discuss the best approach to diagnostic testing. genital anomalies.
5. Provide appropriate antiviral treatment for an initial Appropriate screening starts with an understanding of
HSV infection and contrast this with treatment risk factors. First, adolescents are at particularly high risk for
options for recurrent episodes. acquiring STIs; about half of the STIs in the United States
6. Counsel a patient regarding the natural history of are diagnosed in 15- to 24-year-olds [1]. Other identified risk
low-grade human papilloma virus (HPV) infection factors include unmarried status, new sex partner within the
and the management options for genital warts. past 60 days, multiple partners, history of a previous STI,
7. Identify patients who would benefit from pre- or illicit drug use, admission to a correctional facility, meeting
post-exposure prophylaxis for human immunodefi- partners on the Internet, contact with sex workers, women
ciency virus (HIV). having sex with women, and inconsistent condom use.
Regional and racial disparities in acquisition of STIs are also
present in the United States.
Providers can help optimize their patients’ health as well
as stem the STI epidemic by providing prevention counsel-
ing, STI screening, accurate diagnosis, prompt treatment,
and management of partners. In addition, vaccination can
prevent Hepatitis B and HPV infection. Chronic suppressive
J. Ryden (*) therapy for HSV-discordant couples and pre- and post-
Johns Hopkins University School of Medicine, Johns Hopkins exposure prophylaxis for those at high risk for HIV acquisi-
Community Physicians, Department of Internal Medicine (retired), tion are other effective, targeted strategies.
Baltimore, MD, USA

188 J. Ryden
Counseling on STI Prevention progesterone contraception has been allayed by a large ran-
domized trial [4].
Prevention counseling is most effective when delivered As counseling regarding condom use and safe-sex prac-
respectfully, in a nonjudgmental manner, and using language tices can be time-consuming in a busy practice setting,
appropriate for each patient. A thoughtful sexual history patients can also be directed to view a brief video on safer
allows counseling to be tailored to specific behaviors. The sex on their cell phone during an office visit (e.g., Safer Sex
CDC notes that abstinence from oral, vaginal, and anal sex or video: https://www.plannedparenthood.org/learn/stds-hiv-
involvement in a long-term, mutually monogamous relation- safer-sex/safer-sex). Studies show these videos are effective
ship with a partner known to be uninfected are the two most educational tools [2]. Practices can also be designed to use
reliable ways to avoid STI transmission. For patients who are appropriate team members for education (See Chap. 2 on
sexually active in relationships that are either not long-term High-Value Health Care).
or not mutually monogamous, providing counseling regard-
ing the use of condoms and advising STI testing of both per-
sons prior to initiating sexual activity with a new partner can TI Screening and Treatment: General
S
help prevent STI transmission [2]. Principles
When used correctly and consistently, male condoms are
highly effective in preventing the transmission of HIV, chla-
mydia, gonorrhea, and Trichomonas. (For discussion of After discussing condom use, Carol decides to keep a
Trichomonas please see Chap. 12 on Vaginitis and Vulvar female condom in her purse from now on. She is confi-
Conditions). Condoms are less effective in preventing cer- dent she did not “catch” any STIs since she has no
tain STIs like herpes, syphilis, or HPV, since skin-to-skin symptoms and asks you just to “double-check” for the
contact outside the area where condoms provide barrier pro- infection her partner reported. However, you suggest a
tection can enable transmission. The failure of condoms to different plan….
prevent STI transmission (and pregnancy) most often relates
to incorrect or inconsistent use, but studies indicate that male
latex condoms do break during 2% of vaginal intercourse niversal Screening of Asymptomatic
U
encounters [2]. Polyurethane condoms are more resistant to Individuals
deterioration and can be used with oil-based lubricants and
vaginal medications, but they have not been as extensively Since STIs are often asymptomatic, particularly in women,
studied regarding reduction in STI transmission and for this screening represents a valuable strategy to interrupt trans-
reason are currently FDA-recommended solely for latex- mission networks. Because chlamydia and gonorrhea are
allergic persons. Natural membrane condoms (“lambskins”) prevalent, often asymptomatic, and carry significant risks if
block passage of sperm but their large pore size permits pas- untreated, the United States Preventive Services Task Force
sage of viral STIs. (USPSTF) recommends annual screening for these two
Studies of the female condom lack data regarding STI infections in all sexually active women age 24 and younger,
prevention, but it may be equivalent or superior to the male as well as in older women felt to be at increased risk [5]. For
condom since its design provides barrier protection over asymptomatic women not needing a pelvic exam, self-
much of the vulva. The female condom is more expensive collected vaginal swabs are best for specimen procurement.
($2 per condom) but offers the advantage of allowing women The diagnostic yield of self-collected swabs is comparable to
control of the decision to use a condom. Its effectiveness physician-collected specimens and is associated with
with receptive anal intercourse has not been studied. The reduced time and patient barriers. Urine specimens have a
male condom should not be used in conjunction with the reduced sensitivity for detecting chlamydia and gonorrhea in
female condom [2]. females [6] but would be the specimen of choice in a woman
Although it may seem obvious, patients should be who has undergone hysterectomy including removal of the
advised that other forms of contraception offer no protec- cervix. Optimal urine specimens are collected without using
tion against HIV or other STIs. One should also inform a perineal wipe beforehand and include the initial portion of
patients that the spermicide nonoxynol-9 has been associ- the urine stream (“first-catch”), both steps different than for
ated with an increased risk of HIV acquisition, likely urinary tract infection testing.
through disruption of the genital epithelium [3], and there- The US Centers for Disease Control (CDC) also recom-
fore its use in pregnancy prevention should be limited to mends universal “opt-out” HIV screening for all Americans
monogamous couples known to be HIV negative. On the age 13–64 [2] with inclusion of older persons felt to be at
brighter side, prior concern regarding possible increased increased risk [7]. At the present time, the CDC recommends
risk of HIV acquisition with the use of injectable medroxy- annual Trichomonas screening only for HIV-infected women.
13 Sexually Transmitted Infections 189
The USPSTF specifically recommends against routine uni- artner Services and Expedited
P
versal screening of sexually active persons for herpes sim- Partner Therapy
plex virus (HSV) and Hepatitis B [8].
From a public health perspective, the diagnosis of a new STI
in one patient necessitates attention to their sexual partner(s)
STI Testing Following Potential Exposure as well. The term “partner services” includes the process of
ensuring that sexual partners of a patient diagnosed with an
STI are informed, educated, tested, empirically treated, and
You talk with Carol about receiving empiric treatment screened for other STIs. Most local health departments have
today and explain that the standard of care after known large caseloads and therefore may only be able to provide
STI exposure also includes a comprehensive evalua- partner services for new diagnoses of HIV [2], thus the
tion with history, physical exam, and testing for all responsibility often falls to individual providers. The treating
common STIs. provider should encourage patients to notify their partners or
patients can authorize their provider or public health depart-
ment to do so. The CDC recommends providers invite part-
Patients often present to the primary care setting after ners into the office for evaluation and treatment and also
unprotected sex requesting STI screening. Women with this suggests a joint appointment for simultaneous treatment
chief complaint should be screened for symptoms, and if when feasible [2].
none are present, they are managed with STI testing alone. Expedited partner therapy (EPT) is an alternative practice
As previously mentioned, the optimal method to screen for of treating the STI in sexual partners without evaluating them.
chlamydia, gonorrhea, and Trichomonas in an asymptomatic This practice has been validated for chlamydia and gonorrhea
woman is a self-collected vaginal swab specimen. infections in heterosexual couples. Studies show EPT is asso-
On the other hand, when a patient reports a recent known ciated with a significant decrease (as high as 29%) in the
exposure to a curable STI (e.g. chlamydia, gonorrhea, recurrence of infection in the index patient, although studies
Trichomonas, or syphilis), she undergoes testing but is also were performed with provision of medication, not a written
examined and empirically treated at that visit. The appropri- prescription [2]. Caveats include the need to clarify possible
ate evaluation includes a pelvic exam and, ideally, an oral drug allergies and pregnancy status, provide medication
exam and brief skin survey as well. A wet mount and collec- instructions, and provide written warnings to seek medical
tion of specimens for STI testing is obtained and empiric evaluation if symptoms—particularly symptoms of pelvic
treatment for the reported STI is prescribed. When treating inflammatory disease (PID)—are present. EPT appears par-
STIs, the CDC recommends optimizing adherence by ticularly effective for treating male partners of women
choosing single dose therapy whenever possible with on- patients. There are several drawbacks to EPT, including the
site administration using directly observed therapy when inability both to test partners for other STIs and to track their
feasible [2]. Testing for the reported infection is included respective partners. Also, when using EPT for gonorrhea, the
for verification purposes, as a confirmatory result allows preferred intramuscular treatment regimen is not possible and
notification of her respective sexual partners—namely per- an alternative regimen consisting of two oral medications
sons exposed within the past 60 days for most infections— must be substituted. EPT is legal in most but not all states;
as well as the local health department. Coinfection with further state-specific information is available from the CDC
another STI is common and is the reason for screening for at https://www.cdc.gov/std/ept/legal/default.htm [9].
other common or important STIs. Testing in a patient with a
known exposure to an STI therefore includes chlamydia,
gonorrhea, Trichomonas, HIV, and syphilis (and for the STIs and Pregnancy
unvaccinated patient, Hepatitis B). Due to the time required
for seroconversion, patients should be assigned an appoint-
ment to return in 3–4 weeks for repeat HIV and syphilis You note that Carol’s last menstrual period was 4 weeks
testing when there is significant concern. In situations where ago and advise office urine pregnancy testing.
there is substantial risk of acquisition of HIV and the patient
presents within 72 hours, nonoccupational post-exposure
prophylaxis for HIV can be offered (see section on “HIV Women presenting with STI concerns are often also at
Postexposure Prophylaxis”). Chlamydia, gonorrhea, syphi- risk for pregnancy. Assessment for possible pregnancy with
lis (including congenital syphilis), HIV infection, AIDS, menstrual history and point-of-care urine pregnancy testing
and chancroid are reportable diseases in every state, and is appropriate, as pregnancy may influence antibiotic choice
other STIs may be reportable in some states. or overall management. Also, although counseling for STI
190 J. Ryden
prevention emphasizes condom use, some women presenting specificity are 98.3% and 96.5% for chlamydia and 96.1%
with STIs may benefit from more reliable contraception in and 99.3% for gonorrhea [6]. The sensitivity of vaginal swab
addition to condoms. specimens is slightly superior to endocervical specimens,
urine [6], and liquid cervical cytology specimens [11].
At the current time, treatments for both chlamydia and gon-
STIs and Comprehensive Care orrhea are considered curative. However, patients diagnosed
with either infection should return 3 months following treat-
Patients presenting with STI concerns may derive benefit ment for retesting, due to the high incidence of reinfection [2].
from more comprehensive care. In addition to addressing
contraceptive needs, providers can offer the HPV vaccine to
eligible patients (i.e., women age 26 and younger who have Chlamydia
not already completed the series). (See Chap. 14 on Cervical
Cancer and Human Papillomavirus.) Also, counseling regard- Chlamydia trachomatis infection is most prevalent in young
ing STI risk reduction through condom use may have particu- persons (typically 4–5%) and particularly high (13.5%)
lar impact in the context of the patient’s presenting concern. among sexually active non-Hispanic Black persons ages
14–24 [12]. The higher rates seen amongst non-Hispanic
Black individuals should not be seen as related to ethnicity or
Specific Sexually Transmitted Infections heritage, instead due to social conditions that are more likely
to impact individuals from minoritized groups in the United
States, including but not limited to access to care. Its predi-
Carol’s pregnancy test comes back negative and she lection for young people is explained partly by unprotected
declines other contraceptive methods. She heard that sex with greater numbers of partners but also attributed to the
there is a urine test for chlamydia and requests this as greater prevalence of cervical ectopy in girls and young
she is in a hurry to get back to work. women, since columnar epithelium on the surface of the
external cervix may be more friable during intercourse.
Chlamydial transmission is efficient, with 70% of those
exposed to chlamydia acquiring a new infection [13]. While
Chlamydia and Gonorrhea General Overview approximately 20% of infected women undergo spontaneous
cure [14], asymptomatic infection can persist for over 3
Chlamydia and gonorrhea are the first and second most com- years [15]. Chronic carriage, as well as the unlikely but pos-
mon notifiable STIs in the U.S., with the incidence of chla- sible false positive laboratory result (3.5%) [16], may some-
mydia exceeding that of gonorrhea by a factor of 10. These times be responsible for a new diagnosis of chlamydia in a
two infections share a particular importance in that each has monogamous couple; such information may impact patients’
the ability to cause pelvic inflammatory disease (PID). decisions regarding relationships.
Unfortunately, the incidence of both infections has been ris- The majority of women with chlamydia infection are com-
ing since 2010 [2]. pletely asymptomatic [14], and when symptoms are present,
Misconceptions regarding chlamydia and gonorrhea are they are frequently subtle. Women with urethral involvement
common. Recent studies indicate that gonorrhea, like chla- sometimes report typical UTI symptoms, and some with chla-
mydia, is most often asymptomatic in both men (60–80%) mydia infection of the cervix may report a change in vaginal
and women (>85%) [10]. Also, in addition to the columnar discharge or intermenstrual or post-coital bleeding. These lat-
cells of the cervix, urogenital infection of either organism in ter symptoms can alternatively be associated with PID, and
women can also involve the urethra, Bartholin’s glands and certainly the report of either pelvic pain or heavier menses
Skene ducts. Consequently, chlamydia and gonorrhea trans- raises concern for this possible complication.
mission can occur through nonpenetrative sexual contact, On pelvic exam, the cervix infected with chlamydia most
and infection is possible in women who have previously often appears normal; however, occasionally there can be a
undergone hysterectomy. When sexually active women pres- watery or purulent endocervical discharge, easily induced
ent with UTI symptoms, the possibility of chlamydia or gon- endocervical bleeding or edematous ectopy (Fig. 13.1) [17].
orrhea infection needs to be considered, particularly when a If examination of the infected patient reveals either cervical
specimen demonstrates white blood cells with a negative motion tenderness or significant uterine or adnexal tender-
urine culture, or “sterile pyuria.” ness, then the infection has ascended to involve the endome-
Nucleic acid amplification testing (NAAT) for both chla- trium and/or salpinges, indicative of PID (see section “Pelvic
mydia and gonorrhea can be performed on vaginal or endo- Inflammatory Disease (PID)” regarding evaluation, manage-
cervical swab specimens, on liquid cytology specimens, or ment and counseling). At the time of the pelvic exam, NAAT
on urine. Vaginal swabs are optimal [2], as sensitivity and testing should be procured, ideally using a vaginal swab.
Table 13.1 Treatment regimens for uncomplicated chlamydia infec-

tion in nonpregnant adolescents and adults
Recommended regimens:
Azithromycin 1 g orally in a single dose
OR
Doxycycline 100 mg twice daily for 7 daysa
Alternative regimens:
Erythromycin base 500 m orally 4 times daily for 7 days
Erythromycin ethylsuccinate 800 mg orally 4 times daily for 7 days
Levofloxacin 500 mg orally once daily for 7 daysa
Ofloxacin 300 mg orally twice daily for 7 daysa
Reprinted from Workowski and Bolan for the CDC [2]
a
Doxycycline is contraindicated during the second and third trimesters
of pregnancy and in lactating women. Fluoroquinolones are contraindi-
cated in pregnant and lactating women. Erythromycin estolate is con-
traindicated in pregnancy
Table 13.2 Treatment regimens for uncomplicated gonococcal infec-

tion of the cervix, urethra and rectum in nonpregnant adolescents and
adults
Recommended regimen:
Ceftriaxone 250 mg IM in a single dose
PLUS
Azithromycin 1 g orally in a single dose
Alternative regimen:
If ceftriaxone is not available OR for use with expedited partner
Fig. 13.1 Edematous ectopy of cervix from chlamydia infection. therapy:
Other possible findings include a mucoid or watery endocervical dis- Cefixime 400 mg orally in a single dose
charge or easy bleeding; however, most often the cervix infected with
PLUS
chlamydia appears normal. (Image from the University of Washington
STD Prevention Training Center [17]. Used with permission) Azithromycin 1 g orally in a single dose
Uncomplicated chlamydial cervicitis or urethritis can be
treated with either a single dose of azithromycin 1 gram or alence; recall from above that health disparities in STI acqui-
doxycycline 100 mg twice daily for 7 days (Table 13.1). sition rates often reflect social determinants of health. In
Prompt treatment of chlamydia cervicitis is important in pre- addition, those having unprotected sex with multiple partners,
venting PID. Studies of untreated women with chlamydia those exchanging sex for drugs or money, incarcerated popu-
infection found that PID developed in 2–3% of women lations, military recruits, and travelers returning from outside
within 2 weeks of diagnosis, and 10% after 1 year [16]. the U.S. are considered high-risk [18].
Once laboratory results confirm the infection, sexual part- Most infected women are asymptomatic. If present,
ners having had contact within 60 days of diagnosis or symp- symptoms typically begin 5–10 days following exposure
tom onset should be notified, undergo evaluation, provide [18]. Possible symptoms of cervicitis include vaginal dis-
specimens for STI testing, and then receive empiric treat- charge, bleeding, pruritus, and dysuria. Gonorrhea infection
ment for chlamydia. Persons remain infectious until 1 week involving the urethra can produce classic UTI symptoms.
following azithromycin administration (or until completion PID occurs in 10–20% of women with untreated gonococcal
of the doxycycline regimen) and patients should be advised cervicitis and should be suspected if a potentially infected
to avoid sexual contact until both parties’ treatment is com- woman reports lower abdominal (pelvic) pain, intermen-
pleted and all symptoms have resolved. Due to the high inci- strual bleeding, or heavier menses.
dence of reinfection, patients should be retested in 3 months. Treatment of gonoccocal infection changed in 2010 due
to new resistance patterns [18] and mounting concern for
imminent spread of gonorrhea resistant to all available anti-
N. Gonorrhea biotics. The sole recommended treatment regimen now
includes dual antibiotic therapy using intramuscular ceftriax-
Infection with Neisseria gonorrhea is most prevalent in per- one together with oral azithromycin (Table 13.2).
sons between the ages of 15–24, non-Hispanic Blacks, and Doxycycline is a second-line option when azithromycin use
persons residing either in the southern U.S. or in a high-risk is not possible. Oral cefixime should be substituted only
community, defined by the CDC as a zip code with high prev- when ceftriaxone is unavailable or when expedited partner
192 J. Ryden
therapy is needed [2]. As with uncomplicated chlamydia P elvic Inflammatory Disease (PID)
infection, patients should abstain from sex until 7 days post-
treatment of themselves and their partners and until symp-
toms have resolved. As with chlamydia, all patients treated You explain why a full evaluation is needed and Carol
for gonorrhea should be retested in 3 months due to high agrees to stay for a pelvic exam. When providing his-
rates of reinfection. tory, she acknowledges lower abdominal cramping for
the past few days. She assumed that it was premen-
strual cramping though it is worse than her typical
Extragenital Chlamydia and Gonorrhea symptoms.
Infection
Extragenital chlamydia or gonorrhea infection may involve PID is relatively common, with a lifetime prevalence of
the rectum, pharynx, or conjunctiva. Anorectal infection 4–12% in the U.S. [19]. The typical host is a sexually active
with either organism in women can occur either from unpro- young person. PID most commonly results from the ascen-
tected receptive anal intercourse or via perineal spread. sion of chlamydia or gonorrhea infection in the cervix to the
While most women with anorectal infection are asymptom- upper genital tract, leading to complications such as endome-
atic, some develop acute proctitis with symptoms such as tritis, salpingitis, tubo-ovarian abscess or pelvic peritonitis. A
anal pruritus, rectal pain, bleeding, mucopurulent discharge, minority of PID cases are attributable to other culprit organ-
or tenesmus. Pharyngeal infection with either organism is isms, including the sexually transmitted Mycoplasma homi-
most often asymptomatic, but some report sore throat and nis, bacterial vaginosis pathogens, and respiratory or enteric
benefit from treatment. Treatment of pharyngeal gonorrhea pathogens [20] as well as possibly cytomegalovirus (CMV)
infection is associated with an approximately 10% failure [2]. The CDC emphasizes, however, that antibiotic regimens
rate, but test-of-cure is not recommended by the CDC unless for PID must always include coverage for both chlamydia and
an alternative regimen must be employed [2]. Gonococcal or gonorrhea, and a negative test result at the level of the cervix
chlamydia conjunctivitis is rare in adults but can result from does not exclude these infections in the upper tracts [2].
sexual activity (usually during oral sex), autoinoculation, Although PID is initiated by chlamydia or gonorrhea cervici-
nonsexual interpersonal contact, or fomites. Antibiotic tis, the infection quickly becomes a polymicrobial abscess,
requirements for conjunctivitis are generally greater and and consequently broad-spectrum antimicrobial treatment for
ophthalmology referral is indicated as well. In addition, for at least 14 days is required. PID rarely results in death, how-
gonococcal conjunctivitis, the CDC recommends a one-time ever serious sequelae sometimes result in the form of infertil-
eye irrigation as well as consultation with an infectious dis- ity, ectopic pregnancy, or chronic pelvic pain.
ease expert regarding treatment, as blindness can result [2]. Uncommonly, PID is related to IUD use resulting from
Another rare complication is gonococcal bacteremia (dis- chlamydia or gonorrheal cervicitis present at the time of
seminated gonococcal infection), which can arise 2–3 weeks insertion; symptoms develop within the first month follow-
following inoculation at any mucosal site and manifests as ing placement. PID is treated without removing the IUD,
either suppurative arthritis in a single joint or the arthritis- unless there is inadequate progress by 3 days [2]. PID rarely
dermatitis syndrome. occurs in postmenopausal women but when it does it usually
STI testing at the pharynx and rectum is performed using entails tubo-ovarian abscess, and gynecologic malignancies
the larger swab typically used for vaginal testing. Rectal are uncovered approximately half the time [21]. Chronic PID
specimens are often self-collected; proper technique is is also rare but can occur in untreated cases, or with unusual
important and proprietary instructions should be reviewed. organisms such as Actinomyces or tuberculosis [22].
Pharyngeal specimens are usually collected by the provider
since both the tonsils and the posterior wall of the orophar-
ynx are sampled. Testing extragenital sites is particularly Diagnosis
helpful when the patient has symptoms concerning for infec-
tion, or if testing at the genital site alone would not ade- PID is a clinical diagnosis. Physicians should have a low
quately screen the patient (such as for women engaging in threshold to diagnose PID and initiate therapy, as prompt treat-
only nongenital sexual contact, or for women with more than ment is necessary to prevent sequelae such as infertility, ectopic
one sexual partner and differing sites of sexual contact). pregnancy, and chronic pelvic pain [23]. Even asymptomatic
Testing at the genital site is paramount in women; however, PID can result in infertility [24]. Most women with PID report
since infection at this anatomic location is associated with lower abdominal (pelvic) pain. Other women may report non-
risk for PID. specific symptoms such as a change in bleeding pattern (e.g.
Table 13.3 Diagnosing pelvic inflammatory disease should they discontinue treatment for PID based on NAAT
A clinical diagnosis of PID should be made and presumptive test results if the original diagnosis was made with reason-
treatment given to appropriate hosts reporting lower abdominal pain able clinical certainty.
and lacking alternative diagnosis, if they have 1 of the 3 findings on
Imaging is unnecessary in most cases of PID, though it
pelvic exam:
EITHER can help to establish the diagnosis or determine its severity
Cervical motion tenderness [21]. Transvaginal ultrasound or pelvic MRI is indicated
OR when there is concern for possible tubo-ovarian abscess or
Uterine tenderness clinically severe PID (i.e., fever, peritoneal signs on exam,
OR nausea, or vomiting), or in the setting of an unsatisfactory
Adnexal tenderness pelvic examination. The presence of a tubo-ovarian abscess,
The likelihood of PID is further increased if there is also evidence thickened fluid-filled tubes, or tubal hyperemia on Doppler
of lower tract inflammation, consisting of
study confirms the diagnosis of PID. In general, MRI is more
EITHER:
Mucopurulent cervical discharge
sensitive than ultrasound but more expensive and less readily
OR available. If confirmation of endometritis is desired, endo-
Excess leukocytesa on saline “wet prep” of vaginal fluid metrial biopsy is sometimes but not always helpful and typi-
Reprinted from Workowski and Bolan for the CDC [2] cally 1 week is required for pathology results. Laparoscopy
a
Excess leukocytes is defined as >1 leukocyte per epithelial cell is considered the “gold standard” for diagnosing PID for
research purposes; however, laparoscopy fails to detect
endometritis or early salpingitis, and this invasive and expen-
heavier menses or intermenstrual spotting), change in vaginal sive procedure is not often utilized for diagnostic purposes.
discharge, or dyspareunia. The CDC urges clinicians to When the diagnosis of PID is in question, an abdominopel-
promptly initiate empiric therapy when a sexually active young vic CT may uncover an alternate etiology.
patient presents with pelvic pain that is not explained by other
likely causes if one of the following three exam findings is evi-
dent: cervical motion tenderness, uterine tenderness, or adnexal On pelvic examination your patient has no abnormal
tenderness [2]. A palpable mass or sense of fullness on biman- discharge and in fact her cervix appears completely
ual exam raises concern for complication with tubo-ovarian normal. She has mild uterine tenderness on bimanual
abscess, especially when accompanied by fever or leukocyto- exam and significant leukocytosis on saline wet mount.
sis. Tubo-ovarian abscess rupture can be associated with life- You make a clinical diagnosis of PID.
threatening sepsis, and thus such women are admitted to
hospital and undergo imaging and abscess management.
Patients with history and examination consistent with PID
should also undergo a wet prep, pregnancy testing, and Treatment
NAAT testing for chlamydia and gonorrhea. Excess leuko-
cytes on a wet prep or the presence of mucoid cervical dis- Antibiotic regimens for PID must include treatment for both
charge on speculum exam, both signs of genital tract chlamydia and gonorrhea as well as vaginal flora. For most
inflammation, increase the likelihood of PID (Table 13.3). patients, outpatient treatment with ceftriaxone 250 mg IM
While only half of women with PID have cervical discharge once and doxycycline 100 mg PO bid for 14 days provides
[21] and not all women have leukocytes on a wet prep, most appropriate treatment (Table 13.4). The CDC recommends
women with PID will have one of these two findings. If nei- consideration be given to adding metronidazole 500 mg PO
ther is present, consideration should be given to alternative bid to better treat anaerobes but notes that the medication’s
diagnoses [2]. A wet prep will also identify concomitant adverse effects are not always tolerated [2]. Additionally, a
infections with trichomoniasis or bacterial vaginosis (BV), recent Cochrane review failed to find improved PID out-
and the presence of these organisms may alter the treatment comes with the addition of metronidazole [19]. Patients
regimen (see Chap. 12 on Vaginitis and Vulvar Conditions). treated for PID should be reassessed in the office after
Pregnancy testing is performed for those at risk, as pregnant 48–72 hours to ensure clinical improvement.
women are admitted to hospital and treated with parenteral Inpatient treatment should be considered for patients with
antibiotics appropriate for pregnancy. While a positive chla- concerning features: severe PID accompanied by high fever,
mydia or gonorrhea result at the level of the cervix can help nausea, or vomiting; suspected tubo-ovarian abscess; poten-
confirm the diagnosis of PID, a negative result does not tial surgical abdomen; pregnancy; inability to tolerate or take
exclude infection in the upper tracts [2]. Clinicians should an outpatient oral regimen; or failure to improve at 72 hours
therefore not rely on NAAT testing to diagnose PID, nor on oral therapy. Patients without clinical improvement by
194 J. Ryden
Table 13.4 Treatment regimens for non-pregnant womena with pelvic Partner Notification and Follow-Up
inflammatory disease
Recommended outpatient regimens: As noted above, partner notification plays a crucial role in the
Ceftriaxone 250 mg IM in a single doseb management of PID. Empiric therapy for both chlamydia and
PLUS
gonorrhea is warranted for partners (regardless of the index
Doxycycline 100 mg orally twice daily for 14 daysc
patient’s results) and partners should be tested as well [2].
WITH OR WITHOUT
Metronidazole 500 mg orally twice daily for 14 days
Recommended parenteral regimensd: You talk with Carol about her diagnosis of PID and
Cefotetan 2 g IV every 12 hours initiate outpatient treatment with an injection of ceftri-
PLUS
axone in the office and a prescription for a 14-day
Doxycycline 100 mg orally (or IV) every 12 hoursc
course of oral doxycycline to begin today. You offer to
OR
Cefoxitin 2 g IV every 6 hours
help her contact her sexual partners to notify them of
PLUS their exposure and offer them an appointment for test-
Doxycycline 100 mg orally (or IV) every 12 hoursc ing and empiric treatment as well, but she has had no
OR other partners in the past 2 months. She is assigned a
Clindamycin 900 mg IV every 8 hours follow-up appointment in 3 days. At her follow-up
PLUS visit, her pelvic pain has resolved and she is tolerating
Gentamicin loading dose 2 mg/kg IV or IM, followed by antibiotic therapy. Carol now requests screening for
maintenance dose (1.5 mg/kg) every 8 hours
herpes, since she read on the Internet that this should
Reprinted from Workowski and Bolan for the CDC [2] be done.
a
For management of pregnant women with PID please consult [2]
b
If Ceftriaxone is unavailable then Cefoxitin 2 g IM in a single dose and
Probenecid 1 g orally administered concurrently in a single dose can be
substituted. Alternatively, other parenteral third –generation cephalo-
sporins (e.g. ceftizoxime or cefotaxime) can be substituted STIs Causing Genital Ulcers: HSV and Syphilis
c
Doxycycline is contraindicated in lactating women (and during the
second and third trimesters of pregnancy) In the United States, herpes and syphilis are responsible for
d
When tubo-ovarian abscess complicates PID then clindamycin
(450 mg orally four times daily) or metronidazole (500 mg twice daily) most infectious genital ulcers. The incidence of herpes has
should be used with the doxycycline to complete at least 14 days of been falling in recent decades while that of syphilis has been
therapy rising; however, herpes remains vastly more common [26].
Distinguishing the etiology of a genital ulcer clinically can
be a challenge, thus all patients presenting with a genital
72 hours should be hospitalized, have their diagnosis clari- ulcer should be tested for both herpes and syphilis and treated
fied, and transition to a parenteral regimen if PID is con- empirically for the more likely etiology. In addition to herpes
firmed. Recommended parenteral regimens include cefotetan and syphilis, the acute HIV syndrome can be a cause of pain-
2 g IV every 12 hours plus doxycycline 100 mg PO bid ful oral or genital ulcers [27]. If the patient who presents
(Table 13.4). Hospitalized patients can transition to oral ther- with a genital ulcer appears systemically ill with symptoms
apy 24–48 hours after demonstrating clinical improvement typical for acute HIV syndrome, testing for acute serocon-
and be discharged on doxycycline 100 mg PO BID alone to version should also be performed using combined HIV anti-
complete a 14-day course. gen/antibody testing.
A patient with tubo-ovarian abscess is hospitalized for a Bacterial superinfection sometimes complicates the clini-
minimum of 24 hours due to the risk of abscess rupture and cal picture, and genital ulcers can also sometimes result from
sepsis [2]. Transvaginal, ultrasound-guided aspiration of the yeast, rare infections such as chancroid or lymphogranuloma
abscess can avert the need for surgery in nearly all cases and venereum, or from noninfectious causes like aphthae, carci-
should be offered at the time of diagnosis [21]. Affected noma, fixed drug eruptions, or trauma from sexual activity.
patients are treated with a parenteral regimen that also For approximately one-quarter of all patients presenting with
includes metronidazole for anaerobic coverage. After initial a genital ulcer, no cause is found; often this is attributed to
therapy, patients should complete a 14-day course of false-negative test results, however, the above noninfectious
clindamycin 450 mg PO QID or metronidazole 500 mg PO causes are sometimes responsible. Women with persistent
BID in addition to the usual doxycycline. Alternative paren- genital ulcers or ulcers of unknown etiology should be
teral regimens can be found at the CDC website: https:// referred to dermatology and also ophthalmology (to help
www.cdc.gov/std/tg2015/pid.htm [25]. exclude Behcet’s disease). Importantly, genital ulcers
increase both the acquisition [28] and transmission [29] of sidered an unlikely cause of the ulcer, serologic testing for
HIV infection, and all patients with genital ulcers should syphilis should be ordered; HIV screening should be per-
undergo HIV testing for this reason. formed as well.
When positive, direct testing of the mucosal lesion for
HSV is more helpful than HSV serologies. The CDC identi-
Herpes Simplex Virus fies three situations where HSV serologies are helpful: when
a patient has recurrent genital symptoms but direct testing of
Herpes simplex virus (HSV) is a DNA virus that causes the lesion is negative; when there is a clinical diagnosis of
recurrent ulcerative lesions on the oral or genital mucosa. In herpes without laboratory confirmation; and when a patient’s
addition to oral and genital areas, other mucosal sites such as partner has genital herpes. In the first two instances, serologic
the ocular conjunctiva, nipple, and nose are vulnerable to testing helps clarify diagnosis. In the last scenario it deter-
infection. Genital infection can also involve the genital skin mines a patient’s susceptibility to infection and may guide the
(as opposed to mucosa) and in women even the buttock or couple’s decisions regarding condom use or suppressive anti-
upper thigh. Primary (but not recurrent) HSV infection can viral therapy. The CDC also states that screening for HSV
also involve the skin anywhere on the body, with finger using serologic testing can be considered for high- risk
involvement (herpetic whitlow) classic in health personnel as patients presenting for STI evaluation [2]. Note, however, that
well as occasionally accompanying genital infection in the the USPSTF advises against screening for HSV in the general
community [30]. population, citing an unacceptably high rate of false-positive
Following a typical incubation period lasting 3–7 days test results, potential for psychosocial harms, and lack of
(but sometimes as long as 3 weeks), primary genital herpes known benefit for treating asymptomatic HSV infection [35].
classically presents as one or more clusters of painful and If serologic testing for herpes is desired, only IgG anti-
tender vesicles, though vulvar vesicles quickly erode and fre- bodies should be ordered; IgM antibodies are generally
quently present as genital ulcers instead. The vesicles crust unhelpful since they are not type-specific and are associated
over then clear in 10–14 days. HSV then remains dormant in with more error as well [2]. IgG antibodies to HSV develop
nerve roots until reactivation, at which time vesicles recur at a few weeks after exposure and remain positive indefinitely.
the same site. Approximately one-third of patients will have Type-specific antibody tests should always be included, as
a “nonclassic” presentation consisting of fissures, cervicitis, clinical implications differ greatly for HSV-1 and HSV-2.
or dysuria [31]. Other patients have no visible mucosal Antibody to HSV-2 generally implies genital infection.
lesions but may have tender, bilateral, inguinal lymphade- Antibody to HSV-1 infection could indicate either orolabial
nopathy and a vaginal discharge instead. Primary perianal or or genital infection, but little can be concluded whether the
anal herpes infection usually presents with a painful mucosal HSV-1 antibody is relevant to the patient’s recent genital
ulcer along with rectal pain, itching, tenesmus, and dis- concern, since IgG HSV-1 antibody could possibly result
charge. Primary infection may be accompanied by low-grade from unrecognized orolabial infection acquired in child-
fever, malaise, and headache. hood. When needed, serologies are typically ordered at the
Serologic studies consistently reveal that only a small follow-up visit, and sometimes retesting 6–8 weeks follow-
minority (10–35%) of individuals with genital HSV are ing initial infection is required to detect antibody.
aware of their infection [32]. Sexual transmission to a sero-
negative person is as high as 70% when lesions are active
[33]; however, most transmissions occur during intervening Treatment
periods of asymptomatic shedding. Importantly, the presence
of genital HSV-2 infection increases the risk of HIV acquisi- The CDC recommends prompt initiation of oral antiviral
tion threefold [34]. treatment for all patients with suspected first-episode herpes
infection, without waiting for test results (Table 13.5).
Laboratory Testing
Table 13.5 Treatment regimens for initial episode of genital herpesa
To confirm the diagnosis, a swab sample should be obtained Acyclovir 400 mg orally 3 times daily for 7–10 days
from the base of an ulcer or a de-roofed vesicle and sent for Acyclovir 200 mg orally 5 times daily for 7–10 days
Valacyclovir 1 g orally twice daily for 7–10 days
either herpes cell culture or viral PCR testing; both tests uti-
Famciclovir 250 mg orally 3 times daily for 7–10 days
lize NAAT methods and provide type-specific results (i.e.
HSV-1 or HSV-2). Because viral shedding is intermittent, a
All patients with an initial episode of genital herpes should receive
false-negative results are possible, particularly when sam- antiviral treatment. Treatment duration can be extended if healing is
pling healing or recurrent lesions [2]. Recall that even if con- incomplete after 10 days of therapy
196 J. Ryden
Treatment is not curative nor does it impact the likelihood of symptoms. Patients require a prescription to keep a ready
recurrences. However, it can reduce the duration and extent supply of medication on hand in order to promptly initiate
of symptoms and reduce viral shedding, thereby decreasing therapy at the first sign of prodromal symptoms (often “tin-
the risk of transmission to others [2]. Rarely, initial HSV gling” at the site), as antiviral therapy is most effective when
infection can be severe or have associated complications, started within 24 hours.
such as urinary retention, disseminated disease, or meningo-
encephalitis; such patients require hospitalization and IV
acyclovir therapy. Topical acyclovir ointment has little ben- Counseling
efit and is not recommended [2].
Recurrent herpes outbreaks are milder than primary infec- Patients have described HSV, an incurable sexually transmit-
tion. These outbreaks occur in 90% of patients infected with ted disease, as a “devastating” diagnosis [36]. Patients should
HSV-2 but far fewer patients with genital HSV-1 infection be reassured that HSV is manageable and will not severely
[36]. The frequency of recurrence can vary but sometimes impact their sexuality [38]. Counseling may also include
may coincide with menses. Factors that suppress immune information regarding the variable nature of recurrences, the
function, such as physical or emotional stress, sleep depriva- risk of transmission to sex partners, and the occurrence of
tion, and illness, contribute to recurrences. subclinical shedding. Patients should inform potential sex
While recurrent episodes cannot be prevented altogether, partners of the infection, abstain from intercourse during
two pharmacologic strategies are available to minimize their recurrences, and use condoms at other times [2]. Condoms
impact: suppressive therapy with daily medication and epi- will also protect the patient from the known increased risk of
sodic therapy initiated at symptom onset (Table 13.6). All HIV acquisition.
patients diagnosed with a first episode of genital herpes Patients benefit from a scheduled follow-up appointment
should be offered suppressive therapy [2]. Suppressive ther- 3–4 weeks after the initial diagnosis for further supportive
apy reduces the severity and number of recurrences and is counseling as well as discussion of the options of episodic
often chosen by patients suffering frequent recurrences (>6 and suppressive therapy. Additionally, patients can be reas-
per year). Additionally, the use of valacyclovir 500 mg once sured that transmission of established HSV infection during
daily showed a reduced risk of transmitting genital herpes to vaginal delivery is rare (<1%) and that suppressive therapy
the uninfected partner [37]. Because the frequency of recur- during the last month of pregnancy can further reduce this
rences diminishes over time, a drug holiday is recommended risk. Patients should be counseled to inform their treating
after each 12-month period to assess the need for continued obstetrician of a history of HSV infection.
suppression [2]. Most patients choose episodic therapy Possible concerns regarding potential infidelity should be
instead, which shortens the course and severity of outbreak addressed directly [36]. Patients should be advised that a
partner may have had an unrecognized initial infection long
ago and is shedding virus asymptomatically. Alternatively,
Table 13.6 Suppressive and episodic treatment regimens for recurrent
many first episodes of clinically symptomatic genital herpes
genital herpes
actually represent a recurrence [39]. Thus, a new diagnosis
Suppressive regimens:
of genital herpes can occur in a monogamous couple without
Acyclovir 400 mg orally twice daily
Valacyclovir 500 mg orally once dailya
recent acquisition of HSV. Asymptomatic partners of a
Valacyclovir 1 g orally once daily patient diagnosed with genital HSV can be offered type-
Famciclovir 250 mg orally twice daily specific serologic testing.
Episodic regimens:
Acyclovir 400 mg orally 3 times daily for 5 days
Acyclovir 800 mg orally twice daily for 5 days
You explain to Carol that experts (USPSTF) discour-
Acyclovir 800 mg orally 3 times daily for 2 days
Valacyclovir 500 mg orally twice daily for 3 days
age testing for herpes unless patients have evidence of
Valacyclovir 1 g orally once daily for 5 days the infection, partly because the test is sometimes
Famciclovir 125 mg orally twice daily for 5 days incorrect. You advise her that she does not have any
Famciclovir 1 g orally twice daily for 1 day evidence of genital herpes at present but that she
Famciclovir 500 mg once, followed by 250 mg twice daily for should contact you promptly for evaluation if she
2 days develops any painful genital “sores.” You also notice
Reprinted from Workowski and Bolan for the CDC [2] that Carol forgot to go to the lab for HIV and syphilis
a
The Valacyclovir 500 mg once daily regimen might be a less-effective
serologies at her visit 3 days ago, and she agrees to
suppressive regimen for persons with very frequent recurrences (≥10/
year) [2]. However, this regimen was shown to reduce transmission to have this testing performed today.
seronegative partners in monogamous discordant relationships [37]
Syphilis that they are usually not painful, lack any overlying mucoid
material, and have “heaped up,” firm borders. Also, in con-
Syphilis is an acute and chronic systemic disease affecting all trast to HSV, the regional lymphadenopathy is nontender.
organ systems caused by the spirochete Treponema pallidum. Despite the distinctions in clinical presentation, a patient
The incidence of syphilis in the U.S. has been steadily rising presenting with a genital ulcer in the U.S. is nonetheless
following a nadir in 2000 [40]. Urban men who have sex with tested for both syphilis and herpes and immediately treated
men, half of whom are coinfected with HIV, now comprise for the more likely etiology.
the majority of cases [41]. Although only 11% of syphilis To help with diagnosis and guide management, syphilis
infections occur in women, concern is heightened due to the has been divided into stages: primary, secondary, and ter-
recent dramatic rise in the rate of congenital syphilis. tiary disease. A fourth entity, neurosyphilis, can occur at
Syphilis is most often spread through sexual contact, any stage of infection. A patient with primary syphilis
including oral sex, and rarely through kissing [36]. Infected develops a papule at the site of inoculation, but this is rarely
persons are most contagious in early stages of the disease, recognized as it rapidly evolves into an ulcer. Often, bilat-
when they have moist, mucocutaneous lesions [42] or spiro- eral nontender regional (usually inguinal) lymphadenopa-
chetes in the epidermis that can be transmitted through thy is present. The second stage, beginning 2–12 weeks
microabrasions created during sexual activity [43]. Syphilis following exposure, reflects organism dissemination and
can also be transmitted through transfusion of fresh blood, vasculitis. This stage can present with almost any symptom
via placental passage, or direct inoculation (usually of the including constitutional symptoms, arthralgias, various
fingers of health care workers). rashes, mucous patch lesions, hepatitis, and nephritis. The
The incubation period varies from 3 days to 3 months classic rash, which is pruritic in one-half of hosts [42], is
(average 3 weeks), after which time an ulcer (“chancre”) initially macular then papular and classically involves the
develops at the site of inoculation. Common locations palms and soles. Oval mucous patches can form on any
include the external genitalia, cervix, mouth, upper lip, peri- mucosal surface, and its correlates in warm intertriginous
anal area and anal canal, and the tongue (Fig. 13.2) [44]. areas are gray-white to erythematous fleshy excrescences
Care should be exercised when evaluating a patient present- termed condyloma lata. Another key feature of secondary
ing with possible syphilis, as all mucosal and skin lesions are syphilis is diffuse, nontender lymphadenopathy; involve-
potentially infectious. Sometimes more than one ulcer is ment of the epitrochlear nodes should suggest the diagnosis
present but at other times no lesion develops, or the lesion [42]. Tertiary syphilis involving cardiac lesions or gumma
goes unnoticed, as often happens with vaginal ulcers [43]. is now exceedingly rare in the U.S. due to antibiotic use for
Ulcers heal spontaneously in 2 weeks to 2 months, regardless unrelated illnesses. Neurosyphilis can occur at any stage of
of treatment. Syphilitic ulcers differ from those from HSV in infection. It can manifest in a number of ways: cranial
nerve dysfunction, meningitis, stroke, acute altered mental
status, auditory or ophthalmic abnormalities, or “late
changes” such as tabes dorsalis and general paresis.
Neurosyphilis is of particular concern for patients coin-
fected with HIV.
Congenital syphilis will occur in one-third of pregnant
women with untreated syphilis. Possible sequelae include
miscarriage, neonatal death, intrauterine growth retardation
or offspring born with congenital infection—with the more
common serious manifestations being bone or neurologic
defects. For this reason, the USPSTF recommends screening
all pregnant women for syphilis (“A” recommendation) [45].
In most states, performing this screening is mandated at the
first prenatal visit. Women at higher risk for acquiring infec-
tion should be retested for syphilis throughout pregnancy
and at delivery as well [41]. Antibiotic treatment is usually
Fig. 13.2 Chancre of primary syphilis on tongue. The ulcer of primary successful when administered prior to the middle of the sec-
syphilis differs from a herpes ulcer as it is painless, has “heaped-up” ond trimester. Pregnant women with syphilis are typically
borders and no overlying membrane. The tongue is a common site of
inoculation, as syphilis is frequently transmitted through orogenital sex managed in conjunction with neonatologists, as antibiotic
[44]. (Image from CDC Public Image Library, CDC/Credit Robert therapy can induce fetal distress.
E. Sumpter)
198 J. Ryden
Testing testing that is nonreactive. This may indicate one of three

possible scenarios: previously treated syphilis, untreated or
The diagnosis of syphilis is established using serologies. incompletely treated syphilis or a false positive treponemal
Serologic testing consists of two types: tests that detect antibody result. If the patient was previously treated for
Treponema-specific antibodies and those that detect anti- syphilis, and currently has neither evidence of disease nor
bodies to nontreponemal material; results from both tests recent exposure to syphilis, then no further acute manage-
must be thoughtfully considered (and sometimes compared ment is needed. If the previously treated patient reports
with previous results) before a diagnosis of current syphilis recent possible exposure, then repeating the nontreponemal
infection can be made. Treponema-specific tests detect test in 2–4 weeks helps to exclude recent repeat infection
antibodies against the organism and include the FTA-ABS, when the titer is not rising. If the patient has no prior history
the TP-PA and the EIA-based and CIA assays. Except for a of syphilis, then one should repeat testing using a different
minority (12–25%) of patients treated during primary syph- treponemal test (e.g. using FTA-ABS if TP-PA was previ-
ilis who revert to nonreactive [46], a positive Treponemal ously used). Those with a positive confirmatory treponemal
test usually remains positive indefinitely after treatment test should be evaluated and offered treatment. For those
and is therefore only able to indicate lifetime exposure to patients with a negative confirmatory test and low risk for
syphilis. Nontreponemal tests include the RPR and the syphilis infection, the initial treponemal test is deemed a
VDRL which detect antibodies directed against a false positive.
cardiolipin-lecithin-cholesterol complex that arises from Evaluation of the cerebrospinal fluid (CSF) is indicated
the interaction of host tissues with T. pallidum. One month when there is concern for ocular syphilis or neurosyphilis
may be required for antibody to become detectable, and and is also sometimes performed when titers fail to respond
thus when clinical suspicion of primary syphilis is high, a adequately to usual therapy, as the CSF may serve as a reser-
negative serology necessitates repeat testing in 2–4 weeks voir of untreated infection. CSF findings require careful
[47]. For this reason, assigning a close follow-up appoint- interpretation in the setting of syphilis, and expert consulta-
ment at the time of the initial visit is warranted. Despite tion is generally warranted. Likewise, those with possible
their poor specificity, the RPR and VDRL tests help distin- ocular syphilis are managed in conjunction with an
guish current syphilis infection from lifetime exposure, ophthalmologist.
since their antibody titers fluctuate with disease activity-- Direct testing of lesions for the Treponema pallidum
although in a minority of hosts the nontreponemal test can organism is typically available only at STD clinics, where
remain reactive for a few years following treatment--the clinicians perform darkfield examination of swab specimens
“serofast response”. On the other hand, false positive RPR taken from such lesions as nonoral ulcers or mucous patches,
and VDRL results occur in 1–2% of the U.S. population or from condyloma lata skin lesions. Such testing has limited
[48], in such settings as advanced age, chancroid, tubercu- sensitivity but is diagnostic when positive. More advanced
losis, SLE, HIV infection, intravenous drug use, pregnancy, direct testing methods (such as PCR testing of swab speci-
viral hepatitis, mononucleosis, and many other infections. mens for Treponema pallidum) are under development and it
When the results of both types of serologies are available is anticipated that they will contribute tremendously to the
and indicate possible current infection, it is often helpful to diagnostic process [42].
contact the local health department, as public health work-
ers can provide information such as prior treatment and
titer trends. Patients diagnosed with syphilis should have Management
repeat serologies in 6 and 12 months; a response to treat-
ment in syphilis patients is defined by resolution of symp- Penicillin, administered parenterally, is the preferred drug
toms and signs plus a fourfold decline in nontreponemal for treating persons in all stages of syphilis (Table 13.7) [2].
titers (or a change in 2 dilutions, e.g., from 1:16 to 1:4) Earlier stages can be treated with a single injection of intra-
when retested at 12 months. The same assay (RPR or muscular benzathine penicillin (Bicillin L-A). The CDC cau-
VDRL) should be used with serial testing [2]. tions that using the proper formulation of penicillin is
Since 2016, reverse screening algorithms that start with a important, as formulations with similar names may not pen-
treponemal test have been used. The reverse approach detects etrate sequestered sites such as the CNS or aqueous humor.
more cases of early syphilis, since treponemal antibodies are Late latent syphilis is treated with a series of 3 weekly intra-
detectable before non-treponemal antibodies and are less muscular penicillin injections while tertiary syphilis, neuro-
prone to false-negative results [49]. However, discordant syphilis, ocular syphilis, syphilis in pregnancy, and congenital
results may arise when using reverse testing, whereby a posi- syphilis all require intravenous penicillin G. Pregnant women
tive treponemal antibody test (e.g. positive FTA-ABS or with serious penicillin allergy require desensitization, as
TP-PA) triggers nontreponemal antibody (i.e. RPR or VDRL) there is no alternative regimen in pregnancy [2].
Table 13.7 Treatment regimens for syphilis lowed post-treatment similarly except titers are monitored at
Primary, secondary and early latent (<1 year) syphilis 6, 12, and 24 months, since it may take up to 2 years for the
Benzathine penicillin G (Bicillin L-A) 2.4 million units IM in a titer to decline fourfold.
single dose
Late latent syphilis, latent syphilis of unknown duration and tertiary
syphilis
Benzathine penicillin G (Bicillin L-A) 2.4 million units IM weekly
Partner Management
×3
Neurosyphilis and ocular syphilis The CDC identifies improvement in partner management as
Recommended regimen: a means to reverse the recent rise in the syphilis epidemic
Aqueous crystalline penicillin G 18–24 million units per day, [41]. Partners require evaluation, serologies and usually
administered as 3–4 million units IV every 4 hours or continuous empiric treatment. Because of the long incubation period,
infusion, for 10–14 days
Alternative regimen:
persons who have had sexual contact within 90 days with a
Procaine penicillin G 2.4 million units IM once daily person diagnosed with primary syphilis should be empiri-
PLUS cally treated for early syphilis, regardless of serology results.
Probenecid 500 mg orally 4 times daily, both for 10–14 days In contrast, partners whose sexual contact occurred more
Preferred alternative regimen for primary or secondary syphilis for than 90 days prior to the patient’s diagnosis should be treated
nonpregnant persons with penicillin allergy or for use in expedited based on clinical findings or serological results, unless
partner therapy
opportunity for follow-up is uncertain. The same is true for a
Doxycycline 100 mg PO twice daily for 14 days
person having had sexual contact within 6 months of a per-
Pregnant women
The penicillin regimen appropriate for their stage of infection
son diagnosed with secondary syphilis and 1 year for early
administered by a neonatologist in a timely fashion. latent syphilis.
Screening
Prior to treatment, patients should be warned of the pos-
sibility of the Jarisch-Herxheimer reaction, which is an acute In addition to all pregnant women, the CDC recommends
reaction occurring within 24 hours of the initiation of treat- screening for syphilis in the following groups of women:
ment for syphilis. This febrile response is often accompanied persons infected with HIV, those persons whose partners
by headache and myalgias. Antipyretics such as aspirin can have been diagnosed with syphilis [41] and anyone diag-
manage symptoms; attempts to prevent the reaction are inef- nosed with an STI [2]. The USPSTF recognizes other high-
fective [2]. risk groups who might also benefit from screening, namely
commercial sex workers, those who have been incarcerated,
and those belonging to certain racial or ethnic groups [45].
Follow-Up
Clinical and serologic follow-up is recommended at 6 and exually Transmitted Viruses (HIV, HBV, HCV,
S
12 months after treatment, but more frequent monitoring and HPV)
may be warranted if follow-up is uncertain or the potential
for repeat infection a concern. A patient whose titer rises at HIV
the 6-month follow-up should have the titer repeated in
2 weeks and if confirmed, reinfection suspected and the HIV is most often spread sexually, with the risk of transmis-
patient re-treated. If the titer fails to decline fourfold by the sion per episode of unprotected vaginal intercourse 0.1–
12-month follow-up the patient should receive additional 0.2%, while that for receptive anal intercourse higher at
clinical and serologic follow-up. The patient should be eval- 0.1–3% [50]. The risk of contracting HIV through oral sex is
uated again for HIV as well as for possible CNS syphilis extremely low, although transmission can be facilitated by
infection. If additional close follow-up cannot be ensured, menstruation or oral lesions such as bleeding gums.
the CDC recommends empiric retreatment, using the intra- Approximately 40,000 new infections occur yearly in the
muscular benzathine penicillin regimen used for late latent U.S., 20% of which are acquired by women. Disparities per-
syphilis (weekly injections for 3 weeks). It should be noted, sist in rates of HIV acquisition in the United States due to
however, that 15–20% of patients successfully treated do not interactions between a number of social determinants of
achieve the expected fourfold decline in nontreponemal titer, health, with individuals from African American and Hispanic
especially those with low initial titers. The optimal manage- groups disproportionally affected. The highest prevalence is
ment of such patients is unclear [2]. Latent syphilis is fol- found in transgender women, in whom approximately one-
200 J. Ryden
quarter (22–28%) are infected [51]. Safe sex counseling, Table 13.8 Common symptoms, signs, and laboratory abnormalities
associated with acute HIV syndrome
HIV screening, and reduction of other STIs known to pro-
mote HIV transmission and/or acquisition of HIV continue Common laboratory
Symptoms and signs abnormalities
to be important. Additional strategies include prevention of
Fever Leukopenia
HIV spread through improved recognition and prompt treat-
Malaise/fatigue Thrombocytopenia
ment of acute HIV infection; early referral for chronic HIV Night sweats Elevated transaminases
care; and for those persons at high risk of acquiring HIV, Headache
provision of nonoccupational post-exposure prophylaxis Myalgias
(nPEP) or preexposure prophylaxis (PrEP). Lymphadenopathy
Frequent cough or shortness of
breath
Screening Sore throat
Rash
Arthralgias
The CDC advises universal opt-out HIV screening for all
Diarrhea
persons age 13–64 in all health care settings. In addition, Anorexia
pregnant women [7] and patients presenting with STI con- Meningitis
cerns should be screened. Surveillance studies indicate that Vomiting
16% of HIV-positive Americans are unaware of their infec- Oral or genital ulcers
tion [2]; intensified screening efforts, prompt disease report- Thrush or esophageal candidiasis
ing, and effective partner management are critical steps to Data from Refs. [27, 52–56]
reduce this number.
urgently refer to an HIV specialist to initiate antiretroviral
therapy (ART, previously termed HAART) [2]. Prompt ini-
Acute HIV Syndrome tiation of antiretroviral therapy not only improves long-term
patient outcomes but also substantially reduces infectious-
Persons with acute HIV infection are highly contagious due ness and the risk of transmission. In addition, partners not
to high levels of virus in plasma and genital secretions. Up to known to be HIV-positive who have had contact within the
one-third of people with acute infection remain asymptom- 72 hours preceding the diagnosis should immediately receive
atic, but the majority experience the “acute HIV syndrome” post-exposure prophylaxis. One should also not overlook the
(previously called the “acute retroviral syndrome”). critical importance of providing immediate patient education
Symptoms typically begin 1–4 weeks following exposure regarding safe sex to avoid transmission to others.
and are variable and nonspecific (“flu-like”) but often include
fever, fatigue, sore throat, myalgias, night sweats, rash, head-
ache, diarrhea, and vomiting [27] (Table 13.8). By contrast, Vertical Transmission
nasal congestion is associated with a decreased likelihood of
acute HIV infection [52]. Not surprisingly, symptoms of Specific antiretroviral regimens taken throughout pregnancy
acute HIV syndrome are often mistakenly attributed to either can substantially reduce vertical transmission from the
influenza, “mononucleosis,” severe Streptococcal pharyngi- mother to offspring, from approximately 30% without medi-
tis or secondary syphilis. Heightened awareness to entertain cations to 2% with treatment [57]. Other perinatal measures
the diagnosis when evaluating adults presenting with flu-like include administering a brief course of antiretroviral agents
symptoms may significantly increase the number of identi- to the newborn and performing elective cesarean section at
fied cases. Also, directed effort to examine acutely ill, febrile 38 weeks for women with high viral loads. In the U.S. and
patients for the less common but more specific findings of other countries where the water supply is typically free of
acute HIV syndrome--such as skin rash, painful oral or geni- pathogens, HIV-positive mothers are advised not to breast-
tal ulcers, and axillary or inguinal lymphadenopathy-- could feed [2].
potentially improve clinical recognition of acutely infected
persons [27].
The rapid HIV antigen/antibody test should be used in Postexposure Prophylaxis
this setting. If results are negative and one remains con-
cerned, testing for HIV RNA (using a cut-off of >3000 cop- Since 2005, the CDC has recommended nonoccupational
ies/mL to avoid false-positive results) should be pursued. post-exposure prophylaxis (nPEP) for persons exposed to
Once the diagnosis is confirmed, one should assess the potentially HIV-infected body fluids through unprotected
patient’s psychological response and offer support, making sexual activity or needle sharing. The CDC promotes provi-
use of immediate referral when needed. One should also sion of nPEP by nonspecialists such as primary care provid-
ers and published updated guidelines in 2016 [58]. To be “flare,” expert consultation should be sought prior to its
eligible for nPEP, the exposure must entail substantial risk discontinuation.
and have occurred within 72 hours. The first step is rapid The exposed patient continuing nPEP undergoes the same
antigen/antibody HIV testing of the exposed patient to battery of laboratory testing at the 4–6 week follow-up, and
exclude established HIV infection. If results are negative or again at the 3-month follow-up visit. The HIV test obtained
not immediately available, providers should prescribe a at the 3-month follow-up (8 weeks following completion of
28-day course of the three- or four-drug regimen (Table 13.9), nPEP) is the final follow-up HIV serology [58]. Prevention
after careful review of the existing medication list for drug– counseling should also be provided at each visit. If there is
drug interactions and baseline ALT/AST and serum creati- concern for continued high-risk behavior at completion of
nine measurements. Due to risk of renal toxicity from the regimen, consideration can be given to prescribing preex-
tenofovir, patients must have a creatinine clearance ≥60 mL/ posure prophylaxis (see next section). Clinicians with ques-
min for standard nPEP. However, nPEP is commonly initi- tions regarding post-exposure prophylaxis can access expert
ated in healthy persons before lab results are available, espe- consultation at the national PEPline (888-448-4911/888-
cially on weekends or when patients are managed by phone. HIV-4911) [60]. Callers will receive a phone response within
Due to possible association with neural tube defects, dolute- 2 hours from an experienced clinician Monday through
gravir should not be used in women at risk for pregnancy or Friday between 9:00 a.m. and 8:00 p.m. ET or between
in the first trimester [59]; raltegravir should be selected 11:00 am and 8:00 pm on weekends and holidays. A guide
instead. In addition to the above testing, all should be for clinicians is also available online at nccc.ucsf.edu [61].
screened for routine STIs and women at risk should be tested
for pregnancy (Table 13.10). Women testing negative for
pregnancy should be offered emergency contraception, and Preexposure Prophylaxis
in some settings (i.e. sexual assault) offered empiric treat-
ment for chlamydia, gonorrhea and trichomoniasis. Although HIV-negative individuals at high risk for acquiring HIV may
nPEP appears highly effective in preventing HIV infection, take chronic, daily antiretroviral medication as preexposure
patients should be counseled to use condoms or practice prophylaxis, or PrEP. The Partners PrEP Trial showed a 66%
abstinence for the next 12 weeks to avoid potential transmis- reduction in HIV acquisition when HIV-negative women
sion to others, and to return promptly in the event of a flu- with HIV-positive male partners took daily tenofovir 300 mg/
like illness. The source individual should also be contacted emtricitabine 200 mg (Truvada). The risk reduction improved
to undergo HIV testing; if the source patient is found to be to 90% when nonadherent study subjects were excluded
HIV negative then nPEP can be discontinued. Because with- from analysis [62]. The FDA approved tenofovir 300 mg/
drawal of ART in patients with chronic hepatitis B infection emtricitabine 200 mg (Truvada) 1 tab daily for HIV preven-
can sometimes be associated with a life-threatening hepatitis tion for men and women in 2012.
Table 13.9 CDC-recommended 28-day regimens for nonoccupational

Table 13.10 Laboratory monitoring with use of pre- or post-exposure
post-exposure prophylaxis (nPEP) against HIVa
prophylaxis for HIVa [58, 63]
Recommended regimen:
HIV testing (preferably rapid Ag/Ab testing if available)
Tenofovirb 300 mg/emtricitabine 200 mg (coformulated as Truvada)
Creatinine and calculated creatinine clearanceb
once daily
AST/ALT
PLUS
Pregnancy testing
Raltegravirc (Isentress) 400 mg twice daily OR dolutegravirc, d
(Tivicay) 50 mg once daily Chlamydia and gonorrheac
Trichomonasd
Reprinted from Centers for Disease Control and Prevention,
Syphilis
U.S. Department of Health and Human Service [58]
a
Not for use in persons with chronic kidney disease. Please see CDC Hepatitis B and C
website for alternate regimens for these patients (www.cdc.gov/hiv/ a
For nPEP (nonoccupational post-exposure prophylaxis against HIV),
guidelines) testing is performed at baseline, at 4–6 weeks and at 3 months; For
b
Tenofovir can cause renal toxicity in those with existing kidney dis- PrEP (pre-exposure prophylaxis against HIV), testing is performed at
ease, and a creatinine clearance of ≥60 mL/min is required for these baseline and then every 3 months indefinitely while taking medication
regimens b
Creatinine clearance must ≥60 mL/min (by Cockcroft formula) to use
c
Raltegravir and dolutegravir should not be administered with sucralfate standard regimens given the risk of tenofovir toxicity
(Carafate) or calcium, magnesium, aluminum, iron, zinc or other buff- c
For asymptomatic women, chlamydia and gonorrhea testing can be
ered products performed on self-collected vaginal swabs, or on urine if the patient has
d
Dolutegravir is possibly associated with neural tube defects in off- undergone hysterectomy. Self-collected rectal specimens or physician-
spring and should be avoided in women at risk for pregnancy and dur- collected oral specimens can be used when needed
ing the first trimester d
Trichomonas testing should only be performed at the genital site
202 J. Ryden
The CDC recommends offering preexposure prophylaxis HIV transmission when their male partner takes ART and
to women at substantial risk of acquiring HIV, defined as (1) maintains a viral load <400 [67]. A second, slightly less safe
any woman having had condomless vaginal or anal sex in the option is for the HIV-negative woman to take PrEP while
previous 6 months with a man who either has HIV, has sex attempting conception. Sperm washing is an older strategy
with men, or who uses injection drugs or (2) any woman that removes seminal fluid and the HIV virus with it and is
diagnosed with gonorrhea or syphilis in the previous associated with the lowest risk of HIV transmission.
6 months [63]. ACOG suggests a more liberal definition of However, sperm washing requires a procedure-- either intra-
eligible women, including those “engaging in sexual activity uterine insemination (IUI) or in vitro fertilization. IUI is also
within a high HIV-prevalence area or social network” along the usual approach when the man is HIV-negative and
with a second risk factor such as inconsistent condom use, woman HIV-positive [69].
recent diagnosis of STI, drug use or alcohol dependence as
well as other possible criteria [64]. The USPSTF has drafted
a statement recommending PrEP for anyone at risk for HIV Hepatitis B
[65]. Others have suggested that clinicians simply trust
women to assess their own increased vulnerability to HIV Infection with Hepatitis B, a DNA virus, causes acute and
[66]. For women whose partners are known to be HIV- chronic hepatitis. Although acute hepatitis B is fatal in 1%,
positive, one should ascertain whether the partner(s) are tak- most adults clear the infection and only 2–6% develop
ing ART and if viral suppression is adequate, since HIV chronic hepatitis B infection. Chronic hepatitis B infection is
transmission does not occur when the HIV viral load is <400 incurable but suppressive therapy is indicated when specific
[67], making PrEP unnecessary. Often the partners’ clinical disease parameters are present, and management by a spe-
information is unknown to patients and PrEP is warranted. cialist is appropriate.
Once a woman is deemed a candidate for PrEP, clinical The hepatitis B virus is found in highest concentration in
assessment is needed to determine safety. A review of medi- blood but is also present in wound exudates, semen, vaginal
cations for drug–drug interactions is needed. Due to the risk secretions, saliva, tears, and bile. In the U.S. Hepatitis B is
of PrEP-induced mild bone loss, a bone health history should most often transmitted sexually or through injection drug
be taken and bone density assessment performed if osteopo- use. Less commonly, HBV is transmitted perinatally or via
rosis is suspected (see Chap. 25 on Osteoporosis). A history interpersonal contact, such as sharing a toothbrush or contact
and physical exam should also look for and exclude clinical with skin exudate or contaminated surfaces [70]. In addition,
features of existing HIV infection. Creatinine should be lapses in healthcare infection-control procedures, and set-
measured to confirm adequate renal function (≥60 mL/min). tings such as facilities for the disabled are associated with
Testing should include HIV screening as well as screening infection.
for other STIs (chlamydia, gonorrhea, syphilis, Trichomonas, The CDC identifies eventual eradication of hepatitis B
Hepatitis B, Hepatitis C) and pregnancy testing. These from the United States as an achievable goal. All pregnant
assessments are repeated at scheduled follow-up visits. women should be screened [7]; strategies to prevent vertical
When starting PrEP, patients can be counseled on the transmission have been recently intensified [71]. Sexual and
need for follow-up visits and laboratory testing every household contacts of infected persons are among the high-
3 months while taking the regimen. In addition, one should risk groups that should be screened (Table 13.11) and vacci-
emphasize the importance of strict adherence to the daily nated. Also, any nonimmune, sexually active adult not in a
dosing schedule to ensure efficacy; patients benefit from mutually monogamous relationship or seeking evaluation for
intentional discussion regarding an adherence strategy. an STI should be offered vaccination, as should any adult
Adequate PrEP drug levels are reached in the rectum 7 days that simply requests it [71]. Note that universal hepatitis B
after initiation of medication, but 20 days are required for the vaccination in infancy was implemented in the U.S. in 1991
vagina [63]. Experts at the national PrEP phone consultation with catch-up vaccinations for older children encouraged
center can answer clinicians’ questions at (855-448-7737, later in the 1990s, so most unvaccinated persons were born
855-HIV-PrEP) [68] and a clinicians’ guide is available at prior to then or in another country. Recently the CDC recom-
nccc.ucsf.edu [61]. If a patient contracts HIV despite taking mended identifying and screening immigrants and their off-
PrEP, a specialist should be contacted to immediately con- spring from at-risk countries (a color-coded map is available
vert the PrEP regimen to a full treatment regimen. The CD4 online [72]), particularly those persons from Asia (except
count, viral load, and viral resistance testing should be Japan) and the Pacific Islands, and to vaccinate their house-
ordered but conversion of treatment should not be delayed hold and sexual contacts when indicated. This effort is
while awaiting results. expected to reduce new cases [73].
HIV-negative women in HIV-discordant relationships When administered promptly (ideally within 24 hours)
attempting to achieve pregnancy have no concern regarding following an exposure, initiation of the hepatitis B vaccina-
Table 13.11 Screening for Hepatitis B and Hepatitis C infections [72, undergo curative treatment prior to pregnancy. Breastfeeding
78–80]
by a hepatitis C infected mother is encouraged, unless com-
Hepatitis B plicated by cracked or bleeding nipples.
Order all 3 tests: In addition to screening all persons with known risk fac-
Surface Ag: indicates active infection
tors for Hepatitis C [78, 79], the CDC now recommends uni-
Surface Ab: indicates protection, either from resolved infection
or vaccination versal screening of persons born between 1945 and 1965
Core Ab: indicates current or prior infection [80] (Table 13.11). Effective oral treatment has been avail-
Hepatitis C able since 2011, and now consists of either an 8- or 12-week
Screen with Hepatitis C Ab: Presence indicates past or current regimen.
infection.
If Hep C Ab is positive, proceed to Hepatitis C RNA testing
Presence of Hep C RNA indicates current infection enital Warts (Low-Risk Human Papilloma
G
Absence of Hep C RNA indicates resolved infection, either
from spontaneous cure or from successful treatmenta
Virus, HPV)
a
Rarely, absence of Hepatitis C RNA can alternatively indicate that the
original positive Hep C Ab test was a false positive result. On the other Genital warts (condyloma acuminata), typically caused by
hand, false negative Hepatitis C RNA results are possible, and testing low-risk HPV, affect 1% of the sexually active U.S. popula-
should be repeated when this is a concern tion at any given time with a lifetime incidence of approxi-
mately 10% [81]. HPV is the most common STI in the U.S.,
with approximately 75% of people infected with the virus at
tion series is also effective as post-exposure prophylaxis some point in their life, usually during the late teens or early
(although in particularly high-risk instances hepatitis B 20s. In most cases, the HPV infection is transient and cleared
immunoglobulin is simultaneously administered as well, at a by an appropriate immune response within 2 years [82]. For
separate body site). In situations where it is unknown whether those who fail to clear the infection, infection may be sub-
the patient is vulnerable, Hepatitis B serology testing is col- clinical or manifest as genital warts. Occasionally genital
lected, followed immediately by administration of the first warts involve coinfection with high-risk strains such as HPV
dose of the vaccine at the same office visit. The vaccination 16 or 18; in such instances the wart may contain foci of
series is completed depending on the results of testing. HSIL. Most genital warts are asymptomatic but some
patients report itching or pain. Sometimes warts are large
enough to interfere with toileting or intercourse [81]. Most
Hepatitis C commonly, however, it is patients’ psychosocial distress
related to cosmetic concerns that prompts treatment.
Hepatitis C virus is a cause of acute and chronic liver infec- Warts may assume a wide range variety of appearances,
tion and is transmitted primarily through percutaneous expo- from small, flat-topped or dome-shaped papules and pedun-
sure to infected blood, with sexual transmission a far less culated lesions to large cauliflower-like growths; they may
common cause. Heterosexual transmission of hepatitis C is be solitary or clustered. The texture may be smooth, cerebri-
rare in monogamous relationships. The HCV Partners Study form, or verrucous, and while frequently either skin-colored,
followed 500 HCV-discordant monogamous heterosexual gray, or brown, genital warts can sometimes be pink, red,
couples and found that sexual transmission in this setting purple or white [83]. Genital warts may involve any aspect of
was only 0.07% per year, or 1 out of every 190,000 sexual the anogenital epithelium, the anogenital tract itself or the
contacts [74], confirming results of prior similar studies [75, pubic skin, where they can sometimes be extensive in the
76]. Moreover, unlike with HIV, these rare transmissions context of shaving abrasions [84]. Low-risk HPV can also
could not be attributed to specific sexual activities such as cause conjunctival, nasal, oral, and laryngeal warts.
intercourse during menses or anal sex; such information is Genital warts are diagnosed using visual inspection.
relevant for patient counseling. The CDC therefore does not Biopsy is utilized only to exclude other etiologies if the
recommend condoms for HCV-discordant heterosexual cou- lesion appears atypical or fails to respond at all to treatment,
ples in stable, monogamous relationships. However, hetero- as both situations raise concern for possible malignancy
sexual transmission is higher (0.4–0.8% per year) in the [81]. Atypical findings that raise concern for verrucous carci-
setting of multiple partners or coinfection with another STI noma include warts that appear indurated or fixed to underly-
[77] and consequently, the CDC does recommend condom ing structures, or ulcerate, grow rapidly, increase in
use for hepatitis C-infected persons engaging in heterosexual pigmentation or otherwise change appearance [83]. Patients
activity in nonmonogamous contexts [78]. Perinatal trans- with warts located on the cervix, anal canal, or urethra are
mission is uncommon (4–7% of those born to infected moth- managed differently, however, as they require consultation
ers), but ideally infected women of reproductive age should with a specialist and often biopsy to exclude HSIL. Note that
204 J. Ryden
HPV testing is not helpful and has no role in the diagnosis of noses. Because treatment only eliminates the wart and not
genital warts [2]. the underlying HPV infection, it is common for warts to
Cauliflower-type genital warts resemble the condyloma recur, especially in the first 3 months after completing
lata of secondary syphilis, and this more serious cause should treatment.
always be excluded by obtaining syphilis serologies. Provider-applied therapies include weekly application of
Seborrheic keratoses may also be mistaken for genital warts. trichloroacetic acid (TCA) or bicholoroacetic acid (BCA).
Dermatology referral is indicated whenever the diagnosis is These agents are caustic and extra care should be taken to
unclear. prevent exposure of adjacent normal tissue. Some apply
Management entails observation or wart removal. Since petroleum jelly to surrounding mucosa beforehand, and after
spontaneous resolution of warts is common and treatment application of the medication, the treated area should dry
sometimes associated with adverse side effects, providers thoroughly (turn to white frost) before the patient sits or
can offer patients a 1-year trial of observation. Smoking ces- stands. Cryotherapy is effective; however, the CDC notes
sation, adequate sleep/nutrition, reduction of alcohol, and that providers must be trained due to concerns of over- and
other lifestyle modifications that impact the immune system undertreatment of genital warts [2]. Surgical therapy using
may reduce HPV infection or expression [2]. Some patients excision, electrocautery, or CO2 laser may be optimal treat-
opt for treatment, and in addition the CDC recommends wart ment for patients with large or extensive warts, warts failing
removal prior to sexual contact with a new sexual partner [2]. to respond to other treatments, and intraurethral warts. Note
A variety of patient-applied topical therapies are available that an appropriately ventilated room is required with laser
(Table 13.12). When a patient-applied therapy is prescribed, use to prevent transmission of virus to health personnel.
all warts should be carefully identified for the patient at the Patient education should emphasize that the low-risk
initial visit and clear instructions given regarding the treat- types of HPV responsible for genital warts differ from those
ment plan. A follow-up visit should occur several weeks later that cause cancer, and women with genital warts do not need
to assess the response to treatment. When successful, most Pap smears more often the standard guidelines. Because
warts are eliminated within 3 months of treatment, though genital warts can develop months or years after acquiring
rates of complete clearance range from 37% to 77% [81]. infection, the timing of HPV acquisition cannot be deter-
Lack of any response raises concern for other possible diag- mined nor can the warts be attributed to the current sex part-
Table 13.12 Patient-applied therapies for the treatment of external genital warts
Maximum
Agent Medication instructions Mechanism of action duration Adverse effects Precautions
Imiquimod Imiquimod 5% cream: Immune enhancer 16 weeks Redness, vesicles, May worsen autoimmune
Apply at bedtime 3 (stimulates erosions, conditions such as psoriasis or
nights per week; wash interferon, other hypopigmentation vitiligo
off 6–10 hours later cytokines) (sometimes permanent) Safety in pregnancy unknown
Imiquimod 3.75%
cream:
Apply at bedtime each
night; wash off
6–10 hours later
Podofilox Podfilox solution: Antimitotic agent 16 weeks Mild to moderate pain Contraindicated in pregnancy
Use cotton swab to that causes wart with application
apply to warts twice necrosis
daily for 3 days
followed by no
treatment of 4 days
Podofilox gel:
Same instructions
except apply with
finger
Sinecatechins Apply 0.5 cm strand to Anti-inflammatory, 16 weeks Erythema, pruritus, Genital, anal and oral sexual
15% ointment each wart 3 times daily antiviral, immune burning, pain, ulceration, contact must be avoided while
(green tea extract) using finger. Do not stimulation edema, vesicular rash ointment is on skin.
wash off. Has not been tested in patients
with HSV or HIV or other
immunocompromised state
Safety in pregnancy unknown
ner. Although sex partners ultimately tend to share HPV, Mosquito precautions are also recommended, including
often only one partner manifests the infection with warts. repellant, permethrin treatment for clothing, bed nets, win-
Condoms reduce the spread of HPV but offer incomplete dow screens, and air conditioning. The CDC recommends
protection since they do not cover all relevant anatomy. The any EPA-approved insect repellant, as all are considered
HPV vaccination is highly effective in preventing genital safe, even in the settings of pregnancy and breastfeeding.
warts; in countries with high vaccine uptake for one decade Zika virus has also been detected in the breast milk of
a 90% reduction in genital wart incidence has been observed infected mothers; however, there have been no reported
[85] (see Chap. 14 on Cervical Cancer and Human adverse outcomes and consequently the CDC recommends
Papillomavirus for more information regarding HPV breastfeeding throughout an active Zika infection, although
vaccination). it also advises continued monitoring of its website for
updated recommendations at https://www.cdc.gov/zika/pre-
vention/transmission-methods.html [91]. Case reports sug-
Emerging STIs gest that Zika is possibly transmitted through transfusion of
blood products, but confirmation is needed [92].
Zika Virus
Following the Brazilian epidemic in 2015, Zika spread to 33 Ebola

countries and territories in the Americas and Caribbean. In
the United States, the Zika virus has been identified in mos- The West Africa epidemic of 2014–2016 demonstrated the
quitos in Puerto Rico, Florida, and Brownsville, Texas. highly contagious nature of Ebola virus. Close contact alone
Despite the heroic achievements of the CDC to date, even- is sufficient to transmit the infection, though sexual trans-
tual spread of Zika in the continental U.S. is anticipated, mission also occurs. The virus is found in vaginal secretions
since virtually all states have had travel-related illness intro- and semen, and may persist in semen long after resolution of
duced, and most states harbor at least one of the two species illness; the longest documented duration is 565 days. For
of mosquito capable of transmitting infection. patients travelling to or from areas with known Ebola out-
Infection with the Zika virus, when symptomatic, usually breaks, counseling should include the WHO recommenda-
results in mild, self-limited illness. Clinical features include tion for male Ebola survivors to practice abstinence from all
a pruritic macular or papular rash (90% of patients); fever, types of sex or use condoms for 12 months or until two con-
arthralgias, and conjunctivitis (most patients); and myalgias, secutive semen samples are negative for virus. Ebola has also
headache, and retro-orbital pain (less than half of patients) been detected in vaginal fluid as long as 33 days following
[86]. When identified in Africa in 1953, Zika was considered recovery [93]; however, thus far there have been no reports
benign. However, recent outbreaks have been associated of female-to-male sexual transmission. Women with Ebola
with serious sequelae, such as Guillain-Barre syndrome in infection should not breastfeed because Ebola virus has been
affected individuals and congenital defects in the offspring detected in breast milk.
of women infected while pregnant, particularly microceph-
aly, neurologic deficits, and ocular defects [87]. Spontaneous
abortion has also been noted [86]. Summary Points
While primarily a mosquito-borne illness, Zika can also
be transmitted sexually. Male-to-female, female-to-male, 1. Primary care clinicians can provide effective STI pre-
and male-to-male sexual transmission have all been convention counseling by directing patients to watch a brief
firmed [88] and the virus persists in semen and vaginal secre- video on their cell phone while in the exam room.
tions for months beyond resolution of illness. To prevent 2. Annual chlamydia and gonorrhea screening is recom-
sexual transmission and congenital infection, the CDC rec- mended for all sexually active women and girls age 24
ommends condom use for a prescribed duration (3 months and younger, as well as for older women at increased
for men and 2 months for women) following recovery of risk. Universal HIV screening for all Americans aged
Zika illness or return from an infested area [89]. Pregnant 13–64 is also recommended.
women or women planning a pregnancy should either forego 3. Although some women note subtle symptoms, most
unnecessary travel to endemic areas or delay attempts at con- uncomplicated chlamydia and gonorrhea infections are
ception. Pregnant women with potentially exposed sexual asymptomatic and lack any signs on exam as well.
partners should either avoid sex or use condoms throughout 4. An asymptomatic woman reporting an unprotected sex-
the duration of the pregnancy [90]. The CDC currently rec- ual encounter can be screened for chlamydia, gonorrhea
ommends that pregnant women be screened at each prenatal and Trichomonas using a self-collected swab specimen.
visit using questions regarding potential Zika exposure. Any patient reporting documented exposure to an STI
206 J. Ryden
receives empiric treatment and also requires a full evalu- 15. Sexual transmission of Hepatitis C in stable, monoga-
ation to exclude complications such as PID or coinfec- mous heterosexual HCV-discordant couples is exceed-
tion with other STIs or BV. ingly rare and no precautions are needed. However,
5. Effective partner management is important to prevent transmission is facilitated in the settings of other STIs or
reinfection. The CDC suggests that physicians seek per- multiple partners, and the CDC recommends condom
mission from the patient to offer her sexual contact(s) use for Hepatitis C-infected persons in nonmonogamous
appointments for evaluation and treatment. contexts.
6. PID is diagnosed in the appropriate host whenever 16. Treatment of genital warts is often ineffective and does
abdominal pain is accompanied by either cervical not eliminate the underlying low-risk HPV infection.
motion tenderness, uterine tenderness, or adnexal ten- Patients not planning new sexual partnerships can be
derness, and there is no obvious alternative diagnosis. offered a 1-year trial of watchful waiting, as spontane-
Only half of women with PID have cervical discharge, ous resolution is common.
but such women usually have excess leukocytes on 17. Because the Zika virus persists in genital secretions fol-
microscopic examination of the wet mount. lowing resolution of the illness and can be spread sexu-
7. PID requires prompt treatment to help reduce the risk of ally by either men or women, the CDC recommends
sequelae, and empiric antibiotics are initiated at the time condom use for a prescribed duration (3 months for men
of presentation. and 2 months for women) following recovery from ill-
8. PID is a clinical diagnosis. Since negative chlamydia ness or return from an infested area. Recommendations
and gonorrhea testing does not exclude these infections for pregnant women are more stringent.
in the upper tracts, one should not rely on testing to 18. The Ebola virus persists in semen long after resolution
make the diagnosis, nor should a negative result lead one of the illness and male-to-female sexual transmission
to discontinue therapy for a diagnosis of PID made with has been documented. The WHO recommends that male
reasonable clinical certainty. Ebola survivors abstain from all types of sex or use con-
9. Partners of persons diagnosed with PID should be tested doms for 12 months, or until two consecutive semen
then empirically treated for both chlamydia and gonor- samples test negative for the virus.
rhea, regardless of the index patient’s results.
10. Patients presenting with a new genital ulcer should be
tested for HSV and syphilis, and then treated for the Review Questions
more likely etiology. A swab specimen of the ulcer
should be procured for herpes testing, and serologies 1. A 24-year-old woman presents for routine cervical cancer
ordered for syphilis. HIV testing is also indicated. If the screening. She and her boyfriend use latex condoms
ulcer is painful and accompanied by other symptoms coated with nonoxynol-9, except when they occasionally
consistent with the acute HIV syndrome one should test use “lambskins” (natural membrane condoms). She is
using the rapid HIV Ag/Ab test. If testing is negative but using injectable medroxyprogesterone acetate (Depo-
concern persists then further testing using HIV RNA Provera) for contraception as well. She is concerned
levels should be performed. about contracting HIV, since it is prevalent in her
11. Patients diagnosed with initial genital herpes infection community.
should be prescribed treatment at the time of presenta- You counsel your patient that she can reduce her risk
tion in order to reduce their infectiousness and to mini- of acquiring HIV by:
mize the risk of complications. A. Continuing to use condoms coated with nonoxynol-9
12. Women with recently diagnosed genital herpes infection spermicide.
benefit from close follow-up to receive further education B. Switching to plain latex condoms.
and counseling regarding their infection as well as a pre- C. Using a male latex condom together with a female
scription to begin either suppressive or episodic treatment. condom.
13. The CDC emphasizes strategies that PCPs can adopt to D. Switching to natural membrane (“lambskin”)
help curb the HIV epidemic: improved recognition and condoms.
prompt treatment of acute HIV infection, and providing E. Stopping the injectable contraceptive, medroxypro-
pre- and post-exposure prophylaxis to those at high risk gesterone acetate.
for HIV infection. The correct answer is B. Latex condoms have been
14. The CDC encourages Hepatitis B screening particularly shown to be effective in preventing the spread of HIV. On
for immigrants from at-risk countries, with vaccination the other hand, the use of nonoxynol-9 spermicide appears
of household and sexual contacts of those who test to increase the risk of HIV acquisition in users, likely by
positive. disrupting the genital epithelium [3]. The male and female
condom should not be used together [2]. Natural mem- needed to exclude PID, a serious complication that would
brane condoms have a large pore size that prevents the warrant more extensive antibiotic treatment and closer
passage of sperm but not viruses [2]. Previous concern monitoring [2, 21]. Confirmatory testing for the reported
regarding the possibility that the injectable contraceptive infection is collected prior to empiric treatment to allow
medroxyprogesterone acetate might increase a women’s notification of her other recent (within 60 days) sexual
risk of HIV acquisition has been laid to rest by a large contacts if the results are positive. Uncomplicated chla-
randomized trial [4]. mydia and gonorrhea infections are most often asymp-
tomatic and without clinical signs.
2. An 18-year-old woman presents to your office stating that
she read on the Internet that since she is now sexually 4. A 19-year-old woman who uses condoms most of the
active, she should undergo screening for herpes infection. time presents with the complaint of lower abdominal
She and her boyfriend are healthy college students who pain for 3 days. Her office pregnancy test is negative
use condoms consistently and neither of them have any and her urine dipstick is unremarkable. Her pelvic exam
relevant symptoms. is notable for uterine tenderness and cervical motion
Which of the following STI screening tests do you tenderness. You are concerned that your patient might
recommend? have PID.
A. No STI testing is needed since she faithfully uses Which additional finding is needed before you initiate
condoms treatment?
B. Chlamydia, gonorrhea, and HIV A. Fever >101 °F orally
C. Chlamydia, gonorrhea, syphilis, and HIV B. Mucoid discharge from the cervical os
D. Chlamydia, gonorrhea, and HSV C. Rebound tenderness on abdominal examination
The correct answer is B. The CDC and USPSTF rec- D. No additional findings are necessary before initiating
ommend annual screening for both chlamydia and gonor- treatment
rhea in all sexually active women and girls age 24 and E. Positive chlamydia or gonorrhea test result
younger, as well as in older women at increased risk [2, The correct answer is D. PID is a clinical diagnosis.
5]. The CDC also recommends universal HIV screening The CDC supports making the presumptive diagnosis and
in all Americans age 13–64, at least once. Although the initiating treatment in a susceptible host if no other cause
incidence of syphilis in the U.S. has recently increased can be found to explain a patient’s lower abdominal pain
dramatically, universal screening is not advised since if tenderness is noted on pelvic exam (either cervical
infection remains unlikely in persons lacking risk factors. motion tenderness, uterine tenderness or adnexal tender-
The USPSTF specifically recommends against routine ness). Only half of patients with PID have a cervical dis-
screening for herpes in asymptomatic hosts [7]. charge. (However, women with PID who lack this finding
usually do have evidence of inflammation in the form of
3. A 24-year-old woman presents for an acute appointment excess leukocytes on wet mount). Treatment of PID
stating that her boyfriend informed her that he was diag- should be initiated as soon as the clinical diagnosis is
nosed with chlamydia yesterday. What are the next steps made, without waiting for test results. It should also be
in management? noted that a negative chlamydia or gonorrhea test result in
A. Conduct a history; perform a pelvic exam; examine a the presence of PID is common and does not exclude this
wet mount of vaginal secretions; obtain specimens to infection in the upper tracts [2].
test for gonorrhea, chlamydia, and Trichomonas;
order syphilis and HIV serologies; and prescribe 5. A 45-year-old woman presents for urgent evaluation
empiric treatment for chlamydia. because of a 2-day history of a new painful “sore” on her
B. Order testing for chlamydia infection and treat the vulva. Pelvic examination reveals a 4 mm ulcer on her
patient only if the result comes back positive. vulva. Her pelvic exam is otherwise unremarkable and
C. Prescribe empiric treatment for chlamydia now. the patient appears well overall. The patient agrees to
D. Take a history, perform a pelvic exam, and prescribe undergo HIV testing. Appropriate steps to diagnose her
treatment if the patient has clinical evidence of chla- genital ulcer include:
mydia infection. A. Herpes simplex virus PCR testing via ulcer swab
The correct answer is A. The patient will be empiri- B. Herpes simplex virus PCR testing via ulcer swab and
cally treated for chlamydia based on documented expo- serologies for syphilis
sure; however, she is evaluated as well. In addition to C. PCR testing of the lesion for both herpes simplex
chlamydia infection, this patient is at risk for other STIs, virus and T. pallidum.
since coinfection is common. Clinical evaluation is also D. Serologies for both syphilis and herpes simplex virus
208 J. Ryden
The correct answer is B. In the U.S., infectious genital The correct answer is C. Warts can be treated using a
ulcers usually result from herpes or syphilis. Since the number of modalities; however, the success rate is only
clinical features of the two infections can overlap and fair and wart removal likely reduces but does not elimi-
coinfection is possible, patients presenting with genital nate the underlying HPV infection. While the CDC rec-
ulcers are always tested for both infections [2]. A swab ommends treating warts prior to initiating a sexual
specimen is used to obtain material from the base of the relationship with a new partner, in most other settings a
ulcer for type-specific HSV PCR testing, and serologies reasonable option is to withhold treatment for a year and
are ordered to diagnose syphilis. Since genital ulcers monitor for progress, as spontaneous resolution is com-
facilitate the spread of HIV, HIV testing is also recom- mon [2]. Genital warts typically result from infection with
mended for all patients presenting with genital ulcers [2]. benign (“low-risk”) serotypes of HPV and thus the rec-
ommended frequency of cervical cancer screening
6. A 23-year-old patient recently diagnosed with genital remains unchanged for women with genital warts. Genital
herpes infection returns for 3-week follow-up. The PCR warts are diagnosed by visual inspection and biopsy is
test of the ulcer isolated Herpes simplex virus type 2. unnecessary and unhelpful unless there are atypical fea-
Which of the following counseling points should be men- tures or a complete lack of response to treatment--either
tioned with respect to preventing future outbreaks? of which raises concern for possible malignancy [81].
A. Once suppressive therapy is begun it is usually contin- While it is likely that the HPV vaccine will not be thera-
ued indefinitely. peutic for this patient’s established HPV infection, the
B. Chronic suppressive treatment with valacyclovir has 9-valent vaccine will likely protect her from other HPV
been shown to reduce transmission of herpes to the serotypes, and women age 26 and younger are eligible for
uninfected partner in discordant couples. vaccination. Dedicated training in the use of cryotherapy
C. A recurrent outbreak will be completely prevented for the treatment genital warts is recommended [2].
when episodic treatment is begun at the first sign of
tingling. 8. A healthy 53-year-old woman calls you on Monday in the
D. If PCR testing had revealed HSV type 1 then suppres- late afternoon to report that she had unprotected sex with
sive therapy would be indicated. a friend late on Friday night. She knows he is HIV-positive
The correct answer is B. Chronic suppressive antiviral and is fairly confident that he is not getting medical care.
treatment will reduce recurrence rates of herpes outbreaks She has been trying to reach him by phone and tearfully
and greatly reduce viral shedding (which occurs even in asks if there is anything she can do for this high-risk expo-
the absence of outbreaks). For this reason, suppressive sure. How do you manage this patient?
therapy is the first-line treatment for an HSV-discordant A. Prescribe a 28-day regimen of tenofovir/emtricitabine
couple [2, 37]. Outbreaks wane over time and each year once daily and raltegravir 400 mg twice daily to begin
immunocompetent patients suffering few recurrences today, and order HIV testing as well as routine chem-
should be offered a trial off of suppressive therapy [2]. istries and STD testing.
Episodic treatment shortens the duration of symptoms B. Refer to an infectious disease physician to consider
and reduces the intensity of outbreaks but does not affect nonoccupational post-exposure HIV prophylaxis.
the recurrence rate. Persons with genital HSV-1 infection C. Start once daily tenofovir/emtricitabine indefinitely
are generally less prone to recurrences and are initially D. Advise her that she is presenting too late for post-
managed with episodic treatment. exposure prophylaxis
The correct answer is A. The patient should be pre-
7. A 25-year-old woman presents complaining of two scribed nonoccupational post-exposure prophylaxis
growths on her vulva. Examination reveals a cluster of (nPEP) for HIV, which is effective when instituted within
dome-shaped gray papules that are classic for genital 72 hours of exposure [58]. Prompt initiation is critical,
warts. Appropriate management entails: and thus waiting for HIV test results or referring to
A. Performing a Pap smear now and again in 1 year given another clinician is inappropriate. The most common reg-
her increased risk of cervical cancer imen in use is a 28-day course of a three-drug regimen
B. Biopsying the lesions to first confirm the diagnosis consisting of tenofovir- emtricitabine 300 mg/200 mg
C. Offering her several treatment strategies, including a (Truvada) once daily plus raltegravir (Isentress) 400 mg
trial of watchful waiting twice daily. Answer C is the two-drug regimen tenofovir-
D. Withholding the HPV vaccine, since she already has emtricitabine 300 mg/200 mg (Truvada), which is effec-
HPV infection tive for preexposure prophylaxis [63] but inadequate for
E. Performing in-office cryotherapy to destroy the wart post-exposure prophylaxis.
and eliminate the HPV infection
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May 26.
Cervical Cancer and Human
Papillomavirus: Prevention 14
and Screening
Nicolette A. Oleng’, Halle G. Sobel, and Deborah Kwolek
Learning Objectives Nina is a 53-year-old woman who presents to establish

1. Discuss the epidemiology and pathogenesis of cer- care. She emigrated from the Congo one year ago. She
vical cancer. lives with her three children and sister and works as a
2. Review current guidelines for cervical cancer medical assistant at a local clinic. She has a son of age
screening and HPV testing. 14 and two daughters aged 18 and 21. She delivered
3. Compare the recommendations for screening in all of her children at home in the Congo without com-
special populations: HIV positive, immune- plications. She did not have routine healthcare in her
compromised, DES exposed, and home country. She has never had a Pap or HPV test.
post-hysterectomy patients. Nina would like to know when she should bring in her
4. Describe current recommendations for HPV two daughters for Pap tests.
vaccination.
5. Interpret and manage the results of an abnormal
cytology or HPV test.
6. Evaluate and discuss disparities in cervical cancer Epidemiology
prevention, screening, and treatment.
Cervical cancer is a leading cause of cancer death in women
worldwide, but in the United States and other high-income
countries (HIC), where Pap tests are routinely performed,
invasive cervical cancer (ICC) deaths are uncommon.
Cervical cancer ranks as the 14th cause of cancer death in the
United States but as the second or third leading cause of can-
cer death in many low-income countries [1]. Persistent infec-
tion with high-risk strains of human papillomavirus (hrHPV
or HPV) causes >99% of cervical cancer worldwide, which
“implies the highest worldwide attributable fraction so far
reported for a specific cause of any major human cancer” [2].
Cervical cancer can be of squamous cell (approximately
80%), glandular cell (adenocarcinoma), or mixed adeno-
squamous origin, all of which are associated with HPV
N. A. Oleng’ (*)
infection. Rarely sarcoma, lymphoma, melanoma, and clear
Boston University School of Medicine, Department of General
Internal Medicine, Boston Medical Center, Boston, MA, USA cell adenocarcinoma occur on the cervix. Squamous cell
e-mail: [email protected] abnormalities can progress to cervical intraepithelial neopla-
H. G. Sobel sia (CIN), which is most common in the fourth decade of
Robert Larner MD, College of Medicine at The University of life. ICC peaks in the fifth decade of life. Mortality rates
Vermont, Department of General Internal Medicine & Geriatrics, increase with age, especially in women greater than 45 years
Burlington, VT, USA
[3]. Risk factors associated with the development of cervical
D. Kwolek cancer are related to both persistent infection with high-risk
Harvard Medical School, Massachusetts General Hospital,
HPV viral strains and host vulnerability.

214 N. A. Oleng’ et al.
Host vulnerability may include the following: vical cancer, and all references to HPV testing or screening
refer to screening for high-risk strains. Screening women
• HPV acquisition. Women with early age of sexual debut with cervical cytology (previously referred to as the Pap test)
or history of multiple sexual partners have increased vul- and/or HPV testing identifies individuals at risk of ICC and
nerability to HPV acquisition. detects those with abnormal cervical changes. The develop-
• The cervical transformation zone. Infection of the cervi- ment of ICC from initial HPV infection takes more than
cal transformation zone with HPV can predispose to cer- 15 years in many cases, and thus the detection and treatment
vical cancer for those with: a young age of first pregnancy, of precursor lesions is highly effective in preventing disease
a history of more than three pregnancies, STI coinfection, progression.
or oral contraceptive use for more than 5–10 years. HPV is easily transmitted through contact between indi-
• Host immunity or susceptibility. Women may have viduals from hand, skin, oral, vaginal, anal, penile, and scro-
increased susceptibility to HPV due to HIV infection, tal contact. It is not blood-borne. HPV is also spread by
immunosuppression, smoking, or in utero DES autoinoculation from one part of the body to another in an
exposure. individual. Women who are virgins or have sex only with
• Screening and follow-up. Women may lack appropriate women (WSW) can be HPV positive. Transgender men with
screening and follow-up which can lead to inadequate a cervix are also at risk. For these reasons, it is recommended
screening for cervical cancer, inadequate follow-up of an that all persons who have a cervix be screened regardless of
abnormal screening test, or inadequate treatment of lower sexual history or gender identity. Screening rates are unac-
genital tract neoplasias [2–8]. ceptably low in underserved populations, in those with mul-
tiple chronic illnesses, and in persons who lack or have poor
It is estimated that over 50% of all new cases of ICC occur access to insurance. Women under 30 and over 60 are less
in women who have never been screened or have been inad- likely to be screened [9]. Immigrants from LMIC countries
equately screened for cervical cancer [6]. Women lost to are at high risk as many have never been screened in their
follow-up after treatment for CIN or ICC are also at high country of origin and may not have been screened since their
risk. Worldwide, more than 80% of ICC cases occur in devel- arrival in the United States [12].
oping or low- and medium-income countries (LMIC) where
HPV vaccination, cervical cancer screening, and cervical
cancer treatment are limited [7]. Cervical Anatomy: The Transformation Zone
In the United States, significant disparities exist in the
incidence of and mortality from ICC. Between the years The development of ICC begins with the infection of the
2010 and 2014, the age-adjusted incidence of cervical cancer transformation zone (TZ) of the cervix (Fig. 14.1). The
in women of all ages was 7.4 cases per 100,000 women and transformation zone is the area of demarcation in which the
over 9 cases per 100,000 in Hispanic and Black women, squamous epithelium from the vagina meets the columnar
respectively [3]. In 2014, 12,578 women in the United States epithelium from the endocervix. The TZ is also referred to
were diagnosed with ICC, and 4115 women died of as the squamocolumnar junction (SCJ). The TZ undergoes
ICC. Mortality rates are highest in Black women in the metaplasia in which columnar cells transform into squa-
US. Published data and statistical analyses underestimate the mous cells. The TZ is not visible on the cervix until puberty,
racial disparity by up to 44% when corrections are not made but is found within the endocervix. With the onset of
for the high rate of prior hysterectomy in Black women [9]. puberty, the TZ moves from the endocervix to the ectocer-
Low-income, minority, chronically ill, uninsured or poorly vix. The ectocervix is the visible surface of the cervix.
insured, lesbian, transgender, immigrant women, and those Estrogen stimulation with puberty, oral contraceptive use,
with poor healthcare access are at higher risk for morbidity and pregnancy cause the transformation zone to become
and mortality due to cervical cancer, an inequity which must more prominent, erythematous, and metabolically active
be addressed by healthcare providers and policy-makers [4, with cell turnover. Increased cell replication and differentia-
9–11]. (See section on disparities below.) tion supports viral persistence and neoplastic changes.
During the teen and young adult years, the TZ is visible on
the cervix and is more exposed to possible HPV infection.
Screening and Prevention In adult women over 25–30 years of age, who are not preg-
nant or taking OCPs, the TZ recedes into the endocervix,
Invasive cervical cancer (ICC) is, in theory, entirely prevent- rendering the ectocervix more resistant to HPV infection
able. High-risk strains of human papillomavirus (hrHPV) and carcinomatous changes. The vulnerability of the TZ in
are the etiologic agents of 99% of all ICC and there are the early teen years is an important argument to encourage
highly effective vaccines to prevent the acquisition and teens to delay sexual activity, have fewer sexual partners, be
spread of hrHPV. Low-risk strains of HPV do not cause cer- selective of sexual partners, use condoms, and to be vacci-
14 Cervical Cancer and Human Papillomavirus: Prevention and Screening 215
Fig. 14.1 Progression from

hrHPV infection to invasive
Infection of the cervical transformation zone
cervical cancinoma with an hrHPV strain
Persistence of the hrHPV Cleared

hrHPV infection
Progression of
infected cells from
low grade to high
grade abnormalities
Appropriate
treatment and
follow up
Development of Routine
cervical carcinoma screening
(CIN3)
Appropriate
treatment and
follow up
Invasion of cervical
carcinoma (ICC)
nated against HPV. (See Chap. 13 on “Sexually Transmitted screening guidelines are followed. Screening recommenda-
Infections”.) tions vary by age and risk category.
Screening for Cervical Cancer Cervical Cytology: The Papanicolaou

(Pap) Test
The implementation of cervical cancer screening programs
over the past 40+ years has successfully reduced cervical The Pap test technique was first developed in the 1920s by
cancer incidence and mortality among women who have George Papanicolaou who studied microscopic vaginal
undergone Pap or cytology testing. Throughout this chapter, secretions from guinea pigs and learned to distinguish can-
and in the literature, the term Pap test is used interchange- cerous from noncancerous cells. This technique was not
ably with cytology testing. The incidence of cervical cancer noticed by the medical community until the 1940s [13]. The
in the United States has decreased from 14.8 per 100,000 Pap test has been the mainstay of cervical cancer screening
women a year in 1975 to 6.8 per 100,000 women a year in and has evolved over the years from a yearly smear on a glass
2014. The mortality rate from ICC in 1975 was 5.5 compared slide—the “Pap smear”—to liquid-based “thin prep” cytol-
to 2.26 in 2014 per 100,000 women a year [2]. The continued ogy specimen collection every 3–5 years. The thin prep was
mortality is thought to be due to ICC cases presenting in approved in 1996 by the FDA as the preferred option for
advanced stages in unscreened and inadequately screened obtaining cervical specimens, and the percentage of unsatis-
women, in women who have been lost to follow-up after factory cytology specimens has decreased since its use has
abnormal screening, or in woman who have received partial become widespread. Additionally, the liquid-based test has
treatments. the advantage of allowing the testing for gonorrhea, chla-
There are two major components to cervical cancer mydia, and trichomonas in the same vial. The Pap collection
screening: cytology and HPV testing. HPV testing identifies technique is as follows: the woman is asked to place her legs
women at risk for cervical abnormalities, and cytology iden- in foot rests in the dorsolithotomy position on an examina-
tifies actual cervical cell abnormalities. Neither test is 100% tion table, and she brings her bottom to the edge of the exam-
sensitive; however, the slow progression from HPV ination table. A speculum, moistened with water or a small
acquisition, to cervical cell abnormalities, to ICC allows for amount of water-based lubricant, is gently inserted into her
the detection of abnormalities on repeated sampling when vagina and then opened, and the cervix is visualized using a
light source. (See Chap. 3 on “The Female Sex and Gender “Gynecologic Malignancies” for a discussion of vaginal and
Specific History and Examination”.) vulvar cancers.)
To optimize the adequacy of the Pap test sample, mucus, Once transmitted, HPV can result in acute asymptomatic
discharge, or blood should not be removed from the cervix infection. High-risk strains are carcinogenic and increase
prior to the Pap collection. Women should avoid tampons, cervical cancer risk; low-risk strains cause genital warts.
douching, or intercourse prior to collection. The plastic HPV type 16 is the highest risk strain, followed by type 18.
spatula and cytobrush combination is preferred, which is Together these two strains account for about 70% of cervical
the most likely to adequately sample the transformation cancers and other HPV-related cancers of the genitourinary
zone. The contoured end of the plastic spatula is gently tract, anus, and oropharynx. In unvaccinated women, HPV
scraped against the cervix for 360 degrees to collect cervi- types 16 and 18 account for approximately 35.46% of the
cal cells. The brush is inserted most of the way into the HPV infections noted on Pap tests. The HPV genotypes 31,
cervical os and rotated for a ¼ to ½ turn. Rotation that is 33, 45, 52, and 58 are classified “other high risk” and are also
too vigorous may cause bleeding and thus decrease endo- associated with a higher risk of high-grade lesions in unvac-
cervical cell collection. The spatula and brush are placed in cinated women. Low-risk strains 6 and 11 cause most genital
the collection vial and swirled vigorously 10 times in the warts. The HPV vaccine used in the United States, Gardasil-9,
liquid and gently scraped with each other to remove cells, covers these nine strains of HPV: 16, 18, 31, 33, 45, 52, 58,
or the collection ends may be broken off the endocervical 6, and 11. Less common strains of carcinogenic HPV, and of
brush and spatula and placed into the liquid collection vial. low-risk HPV, are not covered by the currently available vac-
Endocervical brushes should not be used during pregnancy cination [19–21]. The majority of women who contract HPV
by primary care clinicians [14, 15]. If the os is stenotic and will clear the virus spontaneously within 1–2 years of infec-
will not allow endocervical cell collection, or if there are tion, but approximately 10% of women remain positive for 5
visible cervical abnormalities, gynecology should be or more years [22] (Table 14.1).
consulted. The regression of previously positive HPV infections is
The collection vial must be properly labeled with the presumed to be due to an adequate cell-mediated immune
patient’s identifying information, or it will be rejected by the response, while an increased persistence of HPV is observed
lab. The collection vial is sent to the laboratory with appro- in immunocompromised populations. It is not clear whether
priate orders. The laboratory analyzes the cervical cell cytol- HPVs are completely cleared or are maintained in a latent
ogy and will also perform any additional testing that is state in women who convert from HPV positive to HPV neg-
ordered, including HPV and sexually transmitted infection ative on co-testing [21].
screening. For a specimen to be satisfactory, sufficient squa- Women with a history of CIN, cervical cancer, recent
mous cells must be visible without obscuring inflammation abnormal Pap tests, HIV infection, organ transplant recipi-
or blood. The presence of endocervical cells and cells from ents, DES exposure, and other causes of immunosuppression
the transformation zone should be present and will be com- are at higher risk of ICC and are screened more frequently
mented upon by the pathologist [16]. than average-risk women (discussed in section on screening
guidelines). Patients with systemic lupus erythematosus or
rheumatoid arthritis on biologic disease-modifying antirheu-
High-Risk Human Papillomavirus (hrHPV)
HrHPV is the causative agent of cervical cancer and is the Table 14.1 Human papillomavirus strains [19–21]
most common STI in the United States. During 2013–2014, Covered by
the prevalence of genital HPV was 42.5% in the US adults HPV strain Type Causes Gardasil-9
aged 18–59 years. The highest prevalence was among the 16 High risk 55% of cervical Yes
cancers
Black population at 64.1%, followed by the Hispanic popu-
18 High risk 15% of cervical Yes
lation at 41.4% and was lowest in the Asian population at cancers
23.8%. The prevalence was 50–60% in women aged 25–34 31, 33, 34, 52, 58 “Other high Yes
and twice as high in women between the ages of 25 and 29 risk”
when compared to women between the ages of 30 and 39 35, 39, 51, 56, 59, “Other high No
[17, 18]. HPV is transmitted to the anogenital region through 68, 73, 72 risk”
26, 53, 66, 68, 73, 2 Probable No
mucosa to mucosa or skin to skin contact. HPV causes vagi-
high risk
nal, vulvar, anal/rectal, penile, and oropharyngeal neoplasia 6, 11 Low risk Common Yes
in men and women; however, the discussion of these malig- genital warts
nancies is beyond the scope of this chapter. (See Chap. 12 on 40, 42, 43, 44, 54, Low risk Common No
“Vaginitis and Vulvar Conditions” and Chap. 15 on 61, 70, 72, 81 genital warts
matic drug (DMARD) therapies and other biologic therapies Table 14.2 2018 USPSTF cervical cancer screening guidelines [28]
appear to have a higher risk of cervical cancer. It is important Age (years old) Screening recommendations
for clinicians to be up to date on screening guidelines and Under 21 No screening
HPV vaccination recommendations in these populations. 21–29 Cytology testing alone every 3 years. An HPV
test should only be performed for abnormal
Although studies are limited, annual screening is recom-
cytology results
mended for women with immunosuppression and for those 30–65 Co-testing with cytology and HPV testing every
on biologic therapies [23, 24]. 5 years, or
Smokers are at higher risk of cervical cancer and have HPV testing every 5 years, or
been found to obtain less frequent cervical cancer screening Cytology testing alone every 3 years
>65 Women who have had adequate routine
[8]. Tobacco use negatively impacts HPV clearance and
screening, with normal results in the prior
increases the risk of persistent HPV infections. The discov- 10 years can exit screeninga
ery of HPV infection and ASCUS or low-grade lesions can History of Women who have had a complete hysterectomy,
be a strong impetus for women to stop smoking: smoking hysterectomy with removal of the cervix, for benign reasons,
cessation is associated with increased regression of abnor- do not need Pap testsb
mal cervical lesions [25]. History of HPV Pap testing should still be performed in
vaccination HPV-vaccinated women
a
If a woman is over the age of 65 or with a prior hysterectomy and has
a history of precancerous or cancerous cervical lesions (CIN2 or
Cervical Cancer Screening Guidelines greater), Pap testing should continue for 20 years after the date of the
diagnosis (interval for screening not defined)
Cervical cancer screening guidelines have traditionally been
b
In a supracervical (also called subtotal or partial) hysterectomy, the
upper part of the uterus is removed, but the cervix is left in place.
based on consensus by expert groups, because evidence Screening should follow the recommended schedule for age. If the his-
from randomized-controlled trials is limited. Initially, Pap tory of hysterectomy type is unclear, a physical examination should be
smears were done yearly, and then in the mid-1990s until performed to document whether the patient has an intact cervix
2012, Pap screening frequency decreased to every 2–3 years.
In 2012, the US Preventive Services Task Force (USPSTF) The evidence for each of these recommendations is dis-
updated the 2003 recommendation on cervical cancer cussed below.
screening [26]. This was an important update as it incorpo-
rated human papillomavirus (HPV) testing into the recom- 1. Women under the age of 21 should not be screened with a
mendations. Between 2009 and 2011, the American Cancer Pap test regardless of sexual activity
Society (ACS), American Society for Colposcopy and
Cervical Pathology (ASCCP), and the American Society for There is very little evidence to support cervical cancer
Clinical Pathology (ASCP) developed a working group to screening in women under age 21 because cervical cancer is
jointly prepare cervical cancer screening guidelines. rare in this age group. Although HPV is acquired during sex-
Available evidence was reviewed and updated guidelines ual intercourse, there are multiple steps in the progression to
incorporating co-testing with cytology and HPV screening cancer; in this age group, abnormal test results are transient
were published [27]. as HPV tends to clear on its own. In addition, screening in
In 2018, the USPSTF published new updated guidelines this age group may increase harm associated with screening
[28] on screening for cervical cancer. It commissioned a due to the pain, anxiety, and cost associated with unneces-
decision analysis model [29] to evaluate at which age to sary screening and possible cervical procedures. Multiple
begin and end screening, the optimal interval for screening, cervical procedures, such as Loop Electrosurgical Excision
the effectiveness of different screening strategies, and Procedure (LEEP) or conization, may also have the untow-
the related benefits and harms of different screening strate- ard consequence of cervical incompetence, negatively
gies. Screening recommendations apply to all women who impacting future childbearing [29, 31].
possess a cervix regardless of sexual orientation, sexual his-
tory, or gender identity [30] (Table 14.2). The guidelines 2. Women aged 21–29 years should have a Pap test every
below do not apply to women with a history of precancerous 3 years. An HPV test should only be performed for abnor-
cervical lesions (CIN2 or greater on biopsy), cervical cancer, mal cytology results
HIV-positive status, immunocompromised status, or expo-
sure to diethylstilbestrol in utero, who need more intensive The evidence for screening women under the age of 30
screening based on expert opinion [27, 30]. Women under is largely based on modeling studies. There is very little
the age of 21 should not be routinely screened with a Pap test data looking at the optimal screening interval in this popu-
regardless of sexual activity. lation. By extending screening to every 3 years, the number
of colposcopies needed to evaluate abnormal Pap tests is Cytology alone every 3 years: Modeling studies suggest
reduced compared to annual screening [32]. When two- that co-testing, or HPV testing every 5 years, offered compa-
versus three-year screening intervals were compared, there rable benefits with cytology alone every 3years with regard
was no difference in cervical cancer burden after a 10-year to the detection and prevention of ICC. Modeling studies
follow-up interval. Other studies have supported the con- done in 2012 and cited in the 2018 USPSTF recommenda-
clusion that there is very little added benefit in having a tions also examined screening intervals from 1 to 5 years and
two-year screening interval compared to a three-year have not found evidence to support the use of screening
screening interval in women aged 21–29 years [32–34]. intervals longer than 3 years with cytology alone even in
Randomized controlled trials (RCTs) have not supported women with a history of negative cytology tests [29, 31]. In
reducing the screening interval, even when a woman has a other words, if HPV testing is not done, Pap tests are required
history of previous abnormal cytology results [34, 35]. (See every 3 years.
section on management of abnormal Pap tests below.) HPV testing alone in women over 25 years as an emerg-
The prevalence of HPV is high in young women and is ing primary screening strategy: The cobas ™ hrHPV test is
usually transient. Dunne et al. found that in women aged used for co-testing with Pap and is FDA approved [37] as a
20–24 years, the prevalence of high- and low-risk HPV was primary cervical cancer screening test for women >25 years
15.2% and 17.8%, respectively. After the age of 21–29 years, old. The strategy of using HPV screening starting at age 25
the prevalence of the high-risk HPV decreases in women is yet to be embraced in the US, but in Australia, HPV screen-
[35]. HPV testing either alone or as a co-test is not recom- ing alone is recommended every 5 years to women of ages
mended in the 21–29 age group because there is not an added 25–74 via a national screening program [38].
benefit over cytology alone. Women would be exposed to Arguments in favor of HPV testing alone: HPV testing
increased harms from overdiagnosis and overtreatment of alone has a higher sensitivity for detecting CIN3 or higher
transient infections, with increased pain, bleeding, anxiety, lesions at 76.1% in comparison to a sensitivity of 61.7% for
cervical procedures, and risks to future childbearing, similar the hybrid strategy similar to current US screening guide-
to women under age 21 [29, 31]. lines involving reflex HPV screening for ASCUS and 47.8%
for cytology alone [17]. Over a 5-year period, the probability
Age of Initial Screening A consensus conference in Italy in of developing lesions of CIN3 and above is similar between
2015 addressing cervical cancer screening in women already primary HPV testing and co-testing. Co-testing therefore
vaccinated against HPV recommended increasing the age of does not provide increased protection against CIN3 when
first initial screening for cervical cancer to 30 years old for compared to HPV testing alone. The concern with primary
girls vaccinated at age 12. This is based on the assumption HPV testing as a screening tool for women starting at
that at the age of 12, most girls have not had sexual inter- 25 years of age is that women less than 30 years have a high
course and hence have not been exposed to hrHPV. It is frequency of HPV infections that later regresses. There is the
important to note that the national rate of HPV vaccination is potential for overdiagnosis and overtreatment in women less
71% in cohorts of 12-year-old girls in Italy [36]. As the prev- than 30 years, which increases harm from cervical cancer
alence of HPV vaccination increases in the US, an increased screening.
age for initial screening might be considered.
4. Women over the age of 65 years who have had adequate
3. Women aged 30–65 years should be screened with cytol- screening can exit screening
ogy alone every 3 years, with HPV testing alone every
5 years, or with co-testing every 5 years Women who have a history of CIN2 or greater, are immu-
nosuppressed, or have not been adequately screened in the
HPV testing alone every 5 years in women 30 and older: prior 10 years, with normal results, are exceptions. Physicians
The USPSTF reviewed several randomized control trials may discontinue routine screening in women over the age of
comparing modalities of screening and interval between 65 who have been screened according to recommended
screenings to develop their 2018 recommendations. In four guidelines for the past 10 years and have met the following
trials that included >250,000 women, HPV testing alone with criteria within the 10 years before ceasing screening:
referral to colposcopy increased the rate of detection of
CIN3+ lesions and cancerous lesions compared to cytology • Three negative consecutive Pap tests (3 years apart) or
alone. In one trial, the rate of detection of invasive cervical • Two negative HPV tests (5 years apart), with the last test-
cancer at 5 years was higher with HPV testing alone (0.03%) ing having occurred within the last 5 years
compared to cytology alone (0.01%). The colposcopy rates
were higher in HPV testing alone compared to cytology alone The acquisition of new sexual partners after age 65 does
in one of the trials but comparable in the other 2 trials [28]. not change this approach to screening.
History of Neoplasia, Inadequate Screening, or Women who have received the HPV vaccine continue to
Smoking In women over the age of 65 who have had cervi- undergo cervical cancer screening according to current
cal lesions CIN2 or greater, Pap screening is continued for guidelines. Some modeling studies have looked at screen-
20 years after diagnosis. Some experts recommend contin- ing women in this population at a later age and with less
ued Pap screening for women over 65 who smoke, are DES frequency but this is not a currently accepted recommenda-
exposed, or are immunosuppressed. In women over the age tion [41].
of 65 who have not been adequately screened, screening for
hrHPV and abnormal cytology should be undertaken and
repeated at least once (editor’s view). Underserved, minority, ecommendations for Specific Populations
R
and immigrant women are at risk for inadequate, or no, and Exceptions to Routine Guidelines
screening and should be screened appropriately [14].
Cervical cancer screening guidelines in special populations
5. Women who have had a total hysterectomy with removal are primarily determined by expert opinion.
of the cervix for benign indications do not need Pap tests
Women who undergo a total hysterectomy with com- Immunocompromised Women

plete removal of the cervix for benign indications such as
fibroids or menorrhagia no longer need screening for cer- HIV-Infected Women There is limited evidence support-
vical cancer. Women who have a history of CIN2 or ing the current screening guidelines in HIV-positive women.
greater, are immunosuppressed, have a history of DES For women under the age of 30, if a baseline Pap test is nor-
exposure, or have not been previously screened are excep- mal, annual cytology should be performed. After three con-
tions. A Pap test in a woman without a cervix screens for secutive normal annual screening tests, the interval is spaced
vaginal cancer, which is extremely rare except as a recur- to 3 years. Co-testing is not recommended in HIV-positive
rence of cervical cancer [39, 40] or as a primary cancer in women under the age of 30. Women with HIV who are
a woman exposed to DES. If the cervix is left in place, as 30 years of age or older can be screened with cytology alone
in the case of a supracervical or “partial” hysterectomy, or with co-testing. If three consecutive annual tests are nor-
then routine screening guidelines should be followed. In mal, then screening can be extended to 3 years. If co-testing
many patients, it is not clear whether the cervix was is done with a normal result, the screening can extend to
removed during hysterectomy. The patient is often 3 years [42]. The incidence of invasive cervical cancer (ICC)
unaware of the distinctions in the types of hysterectomy. has not been found to decrease in HIV-positive women
Add this information to your problem list. Clues include treated with antiretroviral medications or in women who
the following: have rising CD4 counts due to treatment; therefore, increased
screening intervals are recommended in these women despite
• Why was the hysterectomy done? If possible, check or adequate HIV therapy [43].
send for gynecology notes. If for cancer, the cervix was
removed but continued screening is recommended. Immunosuppression from Drug Therapy Given that
• Was it a vaginal hysterectomy? A vaginal hysterectomy HPV is less likely to be transient in an immunosuppressed
removes the cervix, but be sure it was for a benign condi- population, screening is recommended at closer intervals.
tion before you discontinue screening. For women with organ transplants, cervical cancer screen-
• Was it a laparoscopic hysterectomy? It may be a partial ing is recommended annually with both cytology and HPV
hysterectomy which leaves the cervix intact. co-testing [44]. Women exposed to chronic immunosup-
• Check for abdominal wall scars which would indicate a pression such as those on biologic therapies may have a
possible abdominal “partial” hysterectomy, leaving the higher rate of cervical dysplasia and/or carcinoma but
cervix intact. guidelines based upon evidence on how to screen this popu-
• If not sure: Examine the woman and make a note if the lation is limited. Current recommendations are for annual
cervix is present. Check hrHPV and Pap test once. If HPV Pap tests [23].
is positive, and/or if unable to visualize the cervix for Pap,
refer to GYN. If negative, use clinical judgment about
further evaluation [40]. Diethylstilbestrol (DES) Exposure in Utero
6. Pap testing should still be performed in HPV-vaccinated Between 1938 and 1971, many women used DES as it was
women thought to improve pregnancy outcomes. At the time, it was
not known that DES would be associated with an increased Table 14.3 Definitions and abbreviations
risk for squamous cell carcinoma and adenocarcinoma of the Cytology – Pap test, which screens for abnormal cells of cervix.
cervix, clear cell adenocarcinoma of the cervix and vagina, Pap may also capture cells from the vagina, uterus, fallopian tubes,
and ovaries
and an increased risk of breast cancer in females who were
EC/TZ – Endocervical cells/transformation zone
exposed in utero. In the cohort of in utero DES-exposed
ECC – Endocervical curettage
women, who are now close to 50 years of age or older, Colposcopy – Magnified examination of the cervix, or other genital
screening of both the cervix and vagina is recommended tissues
with separate specimens obtained from each site [45]. The ASCUS – Atypical squamous cells of undetermined significance
specimens can be placed in the same vial as long as there is LGSIL – Low-grade squamous intraepithelial lesion
clear labeling that samples have been obtained from both ASC-H – Atypical squamous cells, cannot exclude high-grade
sites. A four-quadrant Pap test should be obtained, which lesion
HGSIL – High-grade squamous intraepithelial lesion
involves sampling of all walls of the vagina. Given the
AGC – Atypical glandular cells
increased risk of cervical neoplasia DES-exposed women,
AIS – Adenocarcinoma in Situ
annual cytology testing is recommended [46].
biopsy specimens outlined in the section on colposcopy and

After educating Nina about cervical cancer screening, listed in Table 14.5.
she undergoes a Pap test and the result shows abnor-
mal squamous cells of uncertain significance (ASCUS) Algorithms are complicated. In general, women who are
cytology and positive HPV “other high-risk” subtypes.
The results are explained to her, and she is advised that 1. Positive for HPV 16 or 18 – refer for colposcopy regard-
repeat cytology could be repeated in 1 year or she less of cytology results.
could be referred for colposcopy. She indicates that 2. Other high-risk HPV – co-test in 1 year, and refer if infec-
she would prefer to wait, but is having some family tion persists after 1 year.
issues and may be moving soon. She is advised that she 3. Pap with a persistent unsatisfactory or ASCUS finding –
should be evaluated as soon as possible and is warned refer for colposcopy.
of the dangers of not following up on abnormal tests. A 4. Pap results of LGSIL or worse – refer for colposcopy.
referral to gynecology is placed with a note indicating 5. Atypical glandular cells or worse – refer for colposcopy.
that there are concerns about the patient getting lost to
follow-up. When in doubt, referral to a gynecologist is always rec-
ommended (Table 14.4).
Given the anxiety associated with abnormal test results,
providers should discuss with patients the natural history of
Management of Abnormal Screening Results cervical cancer. HPV is usually cleared from the body in
1–2 years. Persistent HPV infection results in a small num-
Pap Collection – Results To be “satisfactory for evalua- ber of cases progressing to cancer. ASCUS and LGSIL on
tion,” squamous cells, endocervical cells, and transformation Pap are likely to regress: only 15% persist or progress. After
zone (TZ) cells must be present in the cytology sample, and biopsy, CIN lesions and some higher-grade lesions regress
excess blood or inflammatory cells cannot obscure results. on their own. The lag time between the development of can-
Generalists should be familiar with the management of cerous lesions from precancerous lesions is measured in
abnormal Pap test results in order to determine when repeat years. Women at highest risk are those who were never
testing or referrals are appropriate. Algorithms are available screened, were inadequately screened, or are lost to follow-
for managing abnormal Pap tests through the American up (Table 14.5).
Society for Colposcopy and Cervical Pathology (ASCCP) at If the patient tests positive for HPV 16 or 18, refer for
http://www.asccp.org/asccp-guidelines. The ASCCP also colposcopy. The rate of CIN3+ in persistent HPV 16 infec-
has an app containing algorithms for screening, manage- tion is 8.9% at 3 years, 23.8% at 5 years, and 47.4% at
ment, and follow-up that can be downloaded for a nominal 12 years. Failure to treat HPV 16 has high rate of progression
fee to a smartphone from www.asccp.org algorithms [40]. to malignancy. If HPV testing alone is used for screening,
Pap cytology terms are listed in Table 14.3. Low-grade and then only “other high-risk” HPV results need cytology to
high-grade intraepithelial lesions (LGSIL and HGSIL) used guide the referral decision. If cytology is negative, repeat co-
in this context are distinct from the histopathology terms of test in 1 year. With “other hrHPV” persistent infections on
low-grade and high-grade lesions which are used to describe two tests, the risk of CIN3+ at 12 years is 19.3% [47, 48].
Table 14.4 Pap results and suggested actions [27] Table 14.4 (continued)
Reflex or co-test Reflex or co-test
HPV result or Comment on HPV result or Comment on
Pap result immediate action follow-up Pap result immediate action follow-up
Negative for 21- to 29-year- Early repeat testing AIS Refer GYN
intraepithelial lesion or old, routine not justified, except Adenocarcinoma Refer GYN
malignancy (NILM) screening in high-risk women
Thick inflammation, blood, lack of squamous cells or cytolysis
a
with absent endocervical 30- to 65-year- Early repeat testing
cells or transformation old, if HPV not justified, except
zone (EC/TZ) negative, routine in high-risk women Table 14.5 HrHPV-only screening results and suggested action over
screening age 30 only (or over age 25) [40]
If HPV+ If 16/18+, refer for
colposcopy “other HPV screen Subsequent
high risk,” co-test test result cytology test Action
1 year Type 16/18 Normal or Refer for colposcopy
HPV unknown HPV now or Pap in positive abnormal
3 years Other Abnormal Refer for colposcopy
Unsatisfactorya Repeat If HPV+, or if hrHPV+
2–4 months unsatisfactory on Other Normal Repeat 12 months: if −/−, resume
repeat Pap, refer for hrHPV+ regular screening
colposcopy If HPV persists: refer for
Inflammation or If unsatisfactory, colposcopy
infection treat infection Negative See section Routine screening if cytology
and repeat on Pap results results are not available. Ok to base
Atrophy If unsatisfactory, decision on negative HPV alone
treat with
estrogen and
repeat
The rates of progression are the reason that evaluation, treat-
Normal cytology HPV− Routine screening
ment, and close follow-up are essential to prevent ICC.
HPV 16/18+ Refer for
colposcopy
Other hrHPV+ Repeat co-test
1 year Colposcopy and Biopsy
ASCUS HPV− Co-test 1 year
If repeat co-test
A full discussion of colposcopy and biopsy is beyond the
normal, repeat
co-test 3 years scope of this chapter. Briefly, the woman is asked to place
If ASCUS persists, her legs in foot rests in the dorsolithotomy position and the
refer for colposcopy cervix is visualized with a speculum. The cervix is painted
HPV+ Colposcopy if with acetic acid to reveal suspicious “acetowhite” lesions
16/18+, or repeat
cytology in 1 year.
which reveal HPV infection or other changes. The cervix is
If repeat is normal, examined with the colposcope which is basically a mounted
then routine microscope to magnify the cervix. Biopsy forceps and a
screening tenaculum are used to take samples from the acetowhite
Low-grade squamous HPV− Refer for
lesions for pathology. A sampling of endocervical cells,
intraepithelial lesion colposcopy
LGSIL HPV+ Refer for
called endocervical curettage (ECC), is obtained and sent to
colposcopy pathology. The designation of cervical intraepithelial neopla-
ASCUS/LGSIL HPV− Routine screening sia (CIN) refers to squamous cell abnormalities.
Pregnant or age 21–24 (cytology in Abnormalities of glandular cells (the mucus-producing
3 years) cells in the cervix) are referred to as AGC, AIS, or adenocar-
HPV+ Cytology 1 year
cinoma. The majority of cervical cancers arise from squa-
ASC-H Refer for
colposcopy mous cells, but adenocarcinoma has been increasing over the
HGSIL Refer for past few decades and comprises 20% of cervical cancers.
colposcopy Both types of cancers are caused by HPV and are treated in a
AGC Refer GYN Colposcopy and similar manner.
ECC The recommendations for the management of colposcopy
EMB if >35 years
old or risk factors and biopsy results are published by the ASCCP and are sub-
ject to change (see above). Principles of treatment are given
in Table 14.6, for the purpose of counseling patients. Actual
Table 14.6 Histopathology results from biopsy specimens obtained during colposcopy and suggested follow-up and treatment options [40]
Biopsy: path result and relevant Follow-up and treatment optionsb managed by gynecologic
history Significancea
consultant
CIN 1: Low grade – 90% will regress Co-test in 12 months and treat according to co-test results
Pap had been HPV +
ASCUS or LGSIL
CIN1: More intensive follow-up to insure that Co-test at 12 months
Pap had been ASC-H or HGSIL higher-grade lesions are not missed Or
Excision: unless pregnant or patient is 21- to 24-year-old
CIN2/ CIN2+ Treated for safety Treat with excision or T-zone ablation,
70% will regress in young women Then 1-year follow-up with co-test
Regression is lower, at 50% for HPV16+ If any abnormality on retesting: repeat colposcopy
CIN3/CIN3+ Precancerous: high-grade – 20–30% regress Treat with total hysterectomy
Or
Excision. If margin is negative, follow-up in 1–2 years
If margin is positive, re-excise or follow-up in 6 months
Invasive cancer Treat with hysterectomy, possible radiation
and chemotherapy depending on extent of
spread
HPV 16+ has lower regression rate and may require more aggressive treatment
a
Managed by gynecologic consultant

b
treatment and follow-up decisions are made in conjunction 4. Conization – LEEP or cold knife removes transformation
with gynecologic or gynecologic oncology specialist zone. Avoid in young women.
recommendations. 5. Hysterectomy – avoid in young women.
Ablative therapies are rarely used in the United States.

Nina is seen by gynecology, and a colposcopy and
Close monitoring is preferred over ablative or excisional
biopsy are performed. Her results return CIN1. She is
treatments in younger women, due to the high incidence of
educated about the results, and shared decision mak-
regression and because harm results from overscreening and
ing is used to discuss her options. Although this lesion
overtreatment. Younger women include those who have not
is likely to regress, and co-testing in 1 year is an option,
completed childbearing. In older women, if treatment is
there are concerns that she will return to the Congo
needed, LEEP is the most common modality. LEEP coniza-
and that she may get lost to follow-up. Gynecology is
tion is preferred to cold-knife conization, as LEEP can be
asked to discuss definitive treatment options with her
done in the office setting [49].
including ablative and excisional therapies.
Nina asks about preventive care for her children. She

Treatment Options for Cervical Neoplasia is advised that her daughters should start Pap screen-
ing at the age of 21 and should be vaccinated for HPV
The full discussion of algorithms and treatments for CIN2/3 with three doses starting as soon as possible. Her
are beyond the scope of this chapter. (See Chap. 15 on 14-year-old son should receive two doses of the HPV
“Gynecologic Malignancies, Cervical Cancer” section.) vaccine: one now and one in 6–12 months.
In general, there are five primary treatments which are
used in the treatment of precancerous lesions and carcinoma
in situ (CIN3):
HPV Vaccination
1. Cryotherapy – liquid nitrogen or freezing probe used to
freeze acetowhite lesions from cervix. Advantage: low HPV vaccination was introduced in the United States in
cost, used in “see and treat strategy” in some low-resource June 2006 to prevent hrHPV infection with the intention of
settings. Disadvantage: ablative, no biopsy specimen. decreasing the incidence, morbidity, and mortality related to
2. Loop electrosurgical excision procedure (LEEP) – heated cervical cancer. HPV vaccination is currently recommended
semicircular wire slices off abnormal tissue or removes for all children and is best administered before sexual debut
TZ. Advantage: biopsy specimen for pathology, can and exposure to the virus. The HPV vaccine is recom-
check margins. Avoid in young women. mended at ages 11–12 for both girls and boys but can be
3. Laser ablation – ablative therapy with laser. initiated at age 9 (see Table 14.7 below). Gardasil™, a quad-
Table 14.7 HPV vaccination recommendations [50, 53]

Patient category Age at initiation Vaccine specification
Routine vaccination for all 9–14 years for all persons Two-dose schedule
Dosing schedule by age 11–12 usual age of initiation
ACIP, CDC, ACOGa 15-26 years: vaccinate all until 26 Three-dose schedule
Immunosuppressed Initiate vaccine age 9 Three-dose schedule if
History of sexual abuse or assault 9–26 years for all persons immunosuppressed, or if initiated after age
Chronic illnesses 14
Selected unvaccinated individuals who would benefit from Vaccination approved to age 45 Three-dose schedule
vaccination
ACIP Advisory Committee on Immunization Practices, CDC Center for Disease Control, ACOG American College of Obstetricians and
a
Gynecologists
rivalent vaccine against 16, 18, 6, and 11, was approved in ent time, and fewer costs associated with bringing children
2006 and was initially offered to girls. The bivalent vaccine to the clinic for extra visits.
Cervarix ™ was licensed in 2009 and covers high-risk types • If the HPV vaccination series is initiated after the age of
16 and 18. HPV vaccination for boys was officially recom- 15 years, however, the three-dose series at 0, 2, and
mended by the Advisory Committee on Immunization 6 months is still recommended.
Practices (ACIP) in 2011. The latest vaccine, Gardasil 9™,
was approved in 2014 and is currently the only HPV vaccine
available in the US. Gardasil 9™ covers hrHPV 16 and 18; Approach to Previously Vaccinated
it also covers “other high-risk” strains 31, 33, 45, 52, and 58 Populations
which account for 15% of cervical cancers. The addition of
these other strains has the potential to increase the preven- For primary care providers who treat primarily adult patients,
tion of cervical cancer from 70 to 90% with vaccination. it is important to develop an approach to counseling patients
Gardasil-9™ also covers strains 6 and 11 which cause geni- who received partial HPV vaccination or who received HPV
tal warts [50]. vaccination with non-Gardasil-9 immunizations. The basic
Based on clinical trials with the 9 valent HPV vaccine principles are as follows:
(Gardasil-9™), the Advisory Committee on Immunization 1. If a person initiated vaccination for HPV prior to age 15
Practices (ACIP) issued a recommendation to administer a and received two doses of any of the three approved vac-
two-dose series to both females and males less than cinations at the recommended schedule, a third vaccine is
15 years, a recommendation approved by the FDA in not needed.
October 2016 [50]. The second dose is administered 2. The 9 valent HPV vaccine can be used to complete a vac-
between 6 and 12 months after the initial dose. When given cination series that was started with either a bivalent or
at these early ages, immunogenicity is excellent with only tetravalent vaccine.
two doses, with significantly higher titers obtained in those 3. For persons who have previously completed an earlier
who received the two-dose series before age 15 as com- HPV vaccine series, there is no recommendation for addi-
pared to those who were vaccinated with two doses at a tional vaccination with the new 9 valent HPV vaccine.
later age. Seroconversion rates of those who receive the 4. For interrupted vaccination series, continuation is recom-
two-dose vaccine before age 15 and those who receive a mended with no need to restart the series unless one or
three-dose vaccine are comparable. more of the intervals between doses was shorter than
The new two-dose schedule for teens less than 15 has sev- recommended.
eral advantages: Since the introduction of the HPV vaccine, there has been a
• Increased completion rates: the dose schedule facilitates decline in hrHPV infections and a decrease in high-risk
the completion of the vaccination series at two visits. The lesions. In the US, data from the HPV-IMPACT Project dem-
visits can be 12 months apart which correlates with the onstrated that cervical intraepithelial neoplasia (CIN2) lesions
spacing of many annual visits. and higher attributed to hrHPV 16/18 decreased from 53.6%
• Patient convenience: It is convenient for adolescents in 2008 to 28.45 in 2012 among women 18 years or older who
receiving the vaccine, the parents, and the providers had received at least one dose of the vaccine. Rates of initia-
through the elimination of extra clinical visits. tion and completion of HPV vaccination had been suboptimal
• Cost reduction: Overall costs are reduced with fewer vac- in the United States at that time. As of the year 2017, 66% of
cine dosages, lower administration costs, savings of par- girls between 13 and 17 had received at least one dose of the
vaccine, and only 49% were up to date on the HPV vaccine. 100,000, 95% CI (9.1–9.9), compared to the Black popula-
Fortunately, vaccination rates have been increasing by 5% per tion at 9.0 cases per 100,000, 95% CI (8.8–9.2); the White
year in the United States and there is a movement to provide population at 7.4 cases per 100,000, 95% CI (7.4–7.7); and
HPV vaccination worldwide, including low- and middle- the Alaskan and Indian Native population at 6.5 cases per
income countries (LMICs) [51, 52]. As vaccination rates 100,000, 95% CI (5.3–7.6) [17].
improve, the effectiveness of the HPV vaccine for preventing
HPV infections and subsequent cellular changes in the cervix
will be more fully realized. Disparities in Mortality
Vaccination is recommended for all persons age 9–26, ide-
ally at age 9–12. Catch-up vaccination for those not previously Race For the reasons noted above, the Black (African-
vaccinated for HPV is recommended for all persons through American non-Hispanic) population in the United States
age 26, regardless of sexual activity or gender. In 2018, the has the highest mortality rate from cervical cancer (per
FDA approved Gardasil-9™ use until age 45. Clinical judg- 100,000 women) at 3.7 deaths, compared to Hispanic
ment and shared decision making should be used to make vac- women at 2.6 deaths, White women at 2.2 deaths, and
cination decisions in adults aged 27–45 until guidelines are Alaskan Indian and Pacific Islander both at 1.8 deaths [3,
updated. Vaccination in adults over age 45 is not currently rec- 10, 11]. The mortality among Black women is significantly
ommended. Further study is needed to fully understand the underestimated for the following reason: women who have
risks and benefits of vaccination in the older cohort [53, 54]. had a total hysterectomy for benign reasons are no longer
at risk for cervical cancer. Data that does not correct for
hysterectomy status underestimates the mortality rate for
HPV Vaccination in Specific Populations cervical cancer in all races. Between 2000 and 2012, the
unadjusted overall mortality rate for all women was 3.4
The following recommendations are given for specific deaths per 100,000 women, compared to a higher rate of
populations: 5.0 deaths per 100,000 women when adjusted for hysterec-
• Children with a history of sexual abuse or assault: initiate tomy status. This underestimation is greatest among Black
vaccine at age 9, sooner than the normal 11–12 years of age. women. When stratified by race, Black women had a
• Medical conditions: for primary and secondary immuno- higher correction factor due to the higher rates of hysterec-
compromising conditions, the ACIP recommends the tomy in this population, with rates increasing from 5.7 to
three-dose HPV vaccination in those aged 9–26 due to the 10.1 per 100,000 women, compared to a change from 3.2
potential for reduction in cell-mediated or humoral immu- to 4.7 per 100,000 White women [55].
nity. Examples include patients with HIV or autoimmune
disease, patients taking immunosuppressive therapy, Socioeconomic status and differential access to care
patients who have had a transplant, or those receiving appear to be major factors contributing to disparities in can-
treatment for malignant neoplasms. cer mortality. Studies show higher mortality rates from cervi-
cal cancer in women of lower socioeconomic status. Women
in isolated geographic areas and those in medically under-
isparities in Cervical Cancer Prevention
D served areas, e.g., Appalachian women, have higher mortal-
and Mortality ity rates compared to other White women and to the US
average [55].
There are significant disparities in the prevention, incidence,
treatment, and mortality from cervical cancer in the United
States and around the world. Patient, physician, social, eco- Disparities in Screening
nomic, and system issues contribute to the discrepancy.
Race, structural racism, socioeconomic status, access to Age Women of all races and socioeconomic status at the
healthcare, geographic isolation, educational level, insur- extreme ends of the screening age recommendations between
ance, poverty, and other chronic medical illness adversely the ages of 23 and 29 and between 60 and 65 were less likely
affect outcomes. to be screened than women ages 30–59 [6].
Race American Indian and Alaska natives are least likely to

Disparities in Incidence receive a Pap within the previous 3 years according to the
CDC [56] at a rate of 60.9%. Native Hawaiians and Pacific
Between 2011 and 2015, the Hispanic population had the Islanders were screened at 64.9%, Hispanic at 68.6%, White
highest incidence of cervical cancer at a rate of 9.4 cases per women at 68.4%, and Black women at 74.6%.
Insurance Uninsured and underinsured women were most HPV Vaccination

likely not to be screened. In the 2015 survey data referenced In the HPV Vaccine Impact Monitoring (HPV-IMPACT)
above, there was an 80.5% Pap screening rate within 3 years Project [58], a significant difference in vaccination rates was
for those with insurance compared to 59.3% among those observed based on race/ethnicity and insurance coverage. Of
without insurance. the vaccinated women in the study, non-Hispanic White women
had a vaccination rate of 67.45% compared to 18% vaccination
Chronic Disease Women with one or more chronic dis- rate in non-Hispanic Black women and 10.3% vaccination rate
eases (e.g., kidney disease, arthritis, depression) are less in Hispanic women. Women with private insurance were more
likely to be screened [9, 56]. likely to be vaccinated (65.1%) compared to those with public
insurance (27.9%) and those without insurance (2.3%).
In the National Immunization Survey Teen (NIS-Teen)
Disparities: Follow-Up of Abnormal Pap Test for adolescents aged 13–17 years, Black or Hispanic adoles-
cents and adolescents living below the federal poverty level
Inadequate follow-up of abnormal results in women who were significantly less likely to complete vaccination series
have been screened is a significant risk to women and is [59].
caused by poor or inadequate access to care, nonexistent or In addition to access to care and cost, research has demon-
inadequate insurance coverage, inadequate surveillance sys- strated mistrust in vaccination, which stems from a legacy of
tems to track abnormal results and follow-up, and clinician unethical medical research, patients lived experiences of rac-
failure to adhere to recommended guidelines for the follow- ism in medical settings, and lack of accessible healthcare.
up of abnormal Pap test results causing delays in care. Specifically regarding HPV vaccination, vaccine acceptance
It is estimated that about 50 million women undergo Pap is lower amongst parents who expressed mistrust in govern-
tests per year, and 3.5% of these have cytological abnor- ment health agencies, though trust in health information from
malities requiring further follow-up. An analysis of data a physician or healthcare professional was not predictive of
from a program whose goal is to increase access to screen- vaccine acceptance [60]. Ongoing efforts by healthcare sys-
ing, diagnostic, and follow-up services among low-income tems and government agencies to repair this trust are needed.
and uninsured women between 1991 and 2000 showed poor Private insurances generally cover the cost of HPV vac-
adherence to guidelines for follow-up of abnormal tests in cination. The National Vaccine Program, Vaccines for
medically underserved areas. Only 44% of women with two Children (VFC), provides free vaccination for children and
abnormal tests were followed in accordance with the guide- adolescents through 18 years of age for people who would
lines at the time. Black or African-American women had the otherwise not be able to afford the vaccine [61]. Barriers to
lowest percentage of follow-up compared to other ethnic completion among low-income groups – lack of transporta-
groups, and Alaskan Natives and Native Americans had the tion, limited healthcare access, and work schedules – can
highest number of third Pap tests performed instead of a col- result in incomplete vaccination series even when vaccine
poscopy [57]. programs pay for the initial dose.
In a New Zealand study, among women with CIN3 who have A higher level of maternal education, having continuous
had punch or wedge biopsies with no subsequent treatment, the insurance coverage from age 11, and living in the Northeast
rate of cancer was 31.3% within 30 years. Of these women in were all associated with higher rates of vaccine completion
whom CIN3 persisted for 2 years, and punch or wedge biopsy [59].
had been the only treatment modality, 50.3% developed cancer
within 30 years. The failure to receive adequate treatment results
in an extreme risk of progression to cervical cancer. However, Disparities Among Foreign-Born Women
when treated and followed appropriately, the development of
cervical cancer after 30 years was 0.7% [48]. Data from the 2013 National Health Interview Survey (NHIS)
conducted by the National Center for Health Statistics reveal
HPV Prevalence that HPV vaccination initiation was higher among American-
Between 2013 and 2014, the prevalence of any genital HPV born women aged less than 26 years compared to foreign-
in the United States in individuals between the ages of 18 born women (27.1% verses 17.2%) [12]. Even when
and 59 according to the National Health and Nutrition controlling for confounders in a multivariate logistic analysis
Examination Survey (NHANES) was highest among the (demographic, economic, and healthcare variables), the dif-
Black population (64.1%). The Hispanic population had a ference remained unchanged. Regardless of the place of birth,
prevalence of 41.4%, the White non-Hispanic population had females were more likely to initiate vaccination compared to
a prevalence of 40.0%, and the Asian population a preva- males. Overall, younger foreign-born males had the lowest
lence of 23.8% [18]. access to healthcare compared to all other groups.
Insurance status and access to healthcare account for most they have received adequate recommended testing in the
of the differential rates in HPV vaccination. This is most evi- prior 10 years.
dent in the undocumented foreign-born persons who are not 3. HIV-positive, immune-compromised, DES-exposed, and
eligible for public health insurance and may not have valid women with a history of CIN2 or greater are at higher
social security numbers or funds to pay for private insurance. risk of cervical cancer and are screened more intensely
This is also supported in part by the finding that foreign-born than those outlined in the routine guidelines.
women in the higher-income group had similar HPV vacci- 4. HPV vaccination with Gardasil-9™ is approved for use
nation rates compared to their American-born high-income in persons aged 9–45. Current recommendations are for
group counterparts [12]. most children to be vaccinated with two doses at ages 11
and 12. Persons who start immunization older than
15 years of age should receive three doses at 0, 2, and
Potential Solution: Vaginal Sample
A 6 months. Immunocompromised persons should receive
Collection three doses, even if started at the younger age.
5. Algorithms for the management of abnormal Pap smears
This strategy is aimed at improving screening rates in and biopsy results are available online via a download-
unscreened, high-risk women who have barriers to regular able app from the ASCCP. Persons positive for HPV 16 or
screening including discomfort, costs, and clinical acces- 18, with persistent “other high-risk strains,” with cytol-
sibility. Patients may collect vaginal samples at home and ogy of ASC-H or greater, or with ASCUS/LGSIL with
send them in, with positive results necessitating a clinical HPV+ should be referred for colposcopy. CIN1 is low
visit and follow-up. It is not clear how this test compares grade and often regresses, whereas CIN2/3 are high-
to the accuracy of office-based screening, or whether fol- grade changes which need increased monitoring and/or
low-up of positive results would be adequate. Vaginal sam- treatment by gynecologists.
ple collection is not currently approved by the FDA. It is 6. Significant disparities exist among certain populations in
however endorsed by the World Health Organization the United States and also in low and middle income
(WHO) and is currently being studied in the United States countries including differences in HPV vaccination, cer-
[62, 63]. vical cancer screening, follow-up and treatment of
abnormal results, and mortality. These disparities are
particularly notable for low-income, minority, chroni-
Conclusion cally ill, immigrant, poorly insured women and those
with poor access to healthcare. Continued effort to reach
Cervical cancer continues to be a major public health burden a goal of universal HPV vaccination and universal cervi-
throughout the world and among underserved populations in cal cancer screening will help close these gaps in care.
the United States. HPV vaccination, cervical cancer screen-
ing, precursor lesion treatment, and adequate follow-up of all
women will advance the goal of saving the lives of women Review Questions
who die needlessly from invasive cervical cancer each year,
a largely preventable disease. 1. A 19-year-old woman presents to the clinic to establish
care with a doctor for adults. She had routine care with
her pediatrician and completed the HPV vaccine series.
Summary Points She has been sexually active for 2 years and is on oral
contraceptives. She was recently diagnosed with chla-
1. Ninety-nine percent of cervical cancer is caused by per- mydia and treated. Her mother told her that she needs a
sistent high-risk HPV strains that infect the transforma- Pap smear. Which of the following is recommended?
tion zone of the cervix and lead to precancerous and A. She should be tested for high-risk HPV now.
cancerous changes. B. She should have a Pap test with HPV co-testing now.
2. Routine cervical cancer screening guidelines call for Pap C. She should have a Pap test at age 21.
testing alone every 3 years from age 21 to 29. Women D. HPV testing should be performed at age 21.
ages 30–65 should be screened with either co-testing The correct answer is C. Pap testing should not start
every 5 years, hrHPV testing every 5 years, or Pap testing prior to age 21, even in sexually active women. HPV
alone every 3 years. With some exceptions, women who testing is not recommended for screening in women
have undergone a complete hysterectomy for benign con- under age 30 (25 in some countries) except as a reflex
ditions and women over 65 may exit screening assuming test for abnormal Pap results. Her recent chlamydia
diagnosis does not change these recommendations certain populations. Hispanic patients are an ethnic
[17, 30]. group that often has poor follow-up for abnormal test
2. A 66-year-old woman, who moved to the United States results, and undocumented persons are at particularly
from India 1 year ago, comes in to establish care. She high risk. There must be a secure plan to reach the
does not believe she has ever had a Pap test. She has patient and arrange for follow-up if the Pap test is
stopped menstruating and denies any postmenopausal abnormal. Telling her that she is high risk for cervical
vaginal bleeding or discharge. Which of the following is cancer is premature and may cause unnecessary anxi-
correct? ety. Obtaining prior medical records should be
A. She is asymptomatic and over age 65. Pap screening attempted, but the ability to follow-up on the current
is not needed. testing is more important at this visit. Colon cancer
B. She should be tested with yearly Pap smears for the screening is important, but will not be needed for
next 20 years because of her unknown history. 5 years [57].
C. She should receive the three-dose HPV vaccination 4. A 30-year-old woman presents with 9-year-old twins, a
series. girl and a boy. She asks if her daughter should get the
D. She should undergo Pap and HPV co-testing today. HPV vaccine. What are the current recommendations for
The correct answer is D. Women over 65 may exit HPV vaccination?
screening if they have been screened adequately in the A. Both children should be vaccinated at age 11 with two
past 10 years, with the most recent test in the last doses.
5 years. Clinical judgment should be used in recom- B. The daughter should be vaccinated at age 11, the son
mendations for her screening, but she should be at age 9.
screened now for HPV and cervical cancer and again in C. The daughter should be vaccinated with three doses,
3–5 years since she has not been adequately screened in the son with two doses.
the past 10 years. Yearly Pap smears are recommended D. Both children should be vaccinated now with two
for some high-risk women, but would not apply unless doses.
she was DES exposed, infected with HIV, immunosup- The correct answer is A. For children aged 9–14, the
pressed, or had a history of cervical or vaginal malig- ACIP recommends a two-dose schedule for male and
nancy within the last 20 years. HPV vaccination is not female patients, usually at ages 11–12. Children are
approved for persons over 45 years of age [17, 30]. vaccinated at age 9 in cases of immunosuppression or
3. An undocumented 40-year-old Hispanic woman, G1P1, sexual abuse. The vaccination is approved for persons
presents to the free mobile clinic for a Pap test. She and age 9–45, so clinical judgment can be used when
her family move frequently to find work. She does not making vaccination recommendations for adults [50].
remember how long ago she had her last Pap, but thinks it 5. A 31-year-old woman with HIV comes in to establish pri-
may have been abnormal. She is unsure if she has ever mary care. She was diagnosed with HIV at age 27 and has
had a colposcopy. She undergoes Pap and HPV co-testing had three normal annual Pap smears. Her most recent
today and the clinic social worker meets with her to dis- testing at age 30 was normal cytology and HPV negative.
cuss ways to get insurance and housing for her family, How often should she receive a Pap test in the future?
because they are homeless. A. Every 3 years for life.
Which of the following is the most important next step B. Every 5 years with HPV co-testing until age 65.
before the patient leaves the clinic today? C. Annually, may discontinue at age 65.
A. Tell her that she is high risk for cervical cancer and D. Biannually for life.
refer her to gynecology. The correct answer is A. The current guidelines for
B. Have her sign a release of information to get old HIV-positive women, which is based on limited data,
records from all the prior healthcare facilities where recommend annual Pap starting at the time of diagno-
she received care. sis. At age 30, co-testing should be done. If co-testing
C. Determine how she should be contacted to receive her is normal, the next testing can be delayed for 3 years.
Pap test results, and fully explain why follow-up is Screening does not end at age 65. These recommen-
very important. dations do not change based on the use of antiretrovi-
D. Discuss that colon cancer screening starts at age 45 if ral therapy, CD4 counts, or viral load [64].
she does not have a prior history of colorectal cancer. 6. A 32-year-old woman presents for care. She states that
The correct answer is C. Healthcare disparities should she is a virgin and is refusing a pelvic examination or Pap
be considered when seeing patients, and lack of test. She said that she was told by her last physician that
follow-up for abnormal results is a serious issue in she was at very low risk for cancer, and therefore, Paps
were not needed. Which of the following statements is behavioral risk factor surveillance system, 2014. Prev Chronic Dis.
2016;13:E154.
correct according to current guidelines? 10. Cervical Cancer Rates by Race and Ethnicity Centers for Disease
A. She is at risk of cervical cancer despite her sexual his- Control and Prevention: Division of Cancer Prevention and Control.
tory, and she should be made to sign an “against med- Centers for Disease Control and Prevention; 2017 updated June 19.
ical advice” form if she refuses testing. Available from: https://www.cdc.gov/cancer/cervical/statistics/
race.htm
B. All women should be screened for cervical cancer 11. Viens LJHS, Watson M, Markowitz LE, Thomas CC, Thompson
despite sexual history starting at age 21. TD, Razzaghi H, Saraiya M, Centers for Disease Control and
C. She should self-test for HPV and only get a Pap if the Prevention (CDC). Human papillomavirus–associated cancers—
results are positive. United States, 2008–2012. MMWR Morb Mortal Wkly Rep.
2016;65:661–6. https://doi.org/10.15585/mmwr.mm6526a1
D. Women who have sex with women, nuns, and virgins 12. De P, Budhwani H. Human papillomavirus (HPV) vaccine initia-
do not need Pap tests. tion in minority Americans. Public Health. 2017;144:86–91.
The correct answer is B. All persons with a cervix 13. Tan SY, Tatsumura Y. George Papanicolaou (1883–1962): discov-
should be screened for cervical cancer between the ages erer of the Pap smear. Singap Med J. 2015;56(10):586–7. https://
doi.org/10.11622/smedj.2015155.
of 21 and 65, regardless of sexual history, sexual orien- 14. https://www.cytopathology.org/specimen-collection-adequacy-req-
tation, or gender identity. Although persons who have uisition/. Accessed 23 May 2018.
never had penetrating sexual intercourse with a man 15. Tibbs RF, Wong JY, Logrono R. Enhancing recovery of endocervi-
may be at lower risk, HPV is spread through other cal component on gynecologic cytology specimens processed by
thin-layer technology. Acta Cytol. 2003;47:172–6.
forms of contact. A prior history of sexual contact or 16. Elumir-Tanner L, Doraty M, for the Southern Alberta Primary Care
sexual assault may be denied or not remembered by the Research Network (SAPCReN). Management of Papanicolaou test
patient. The idea of self-collection of a vaginal collec- results that lack endocervical cells. CMAJ. 2011;183(5):563–8.
tion for HPV screening has merit and is being suggested 17. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright
TL. Primary cervical cancer screening with human papillomavirus:
for screening in some lower-resource settings, but there end of study results from the ATHENA study using HPV as the
are no current guidelines to guide its use. If she refuses first-line screening test. Gynecol Oncol. 2015;136(2):189–97.
pelvic examination, she should not be pressured or trau- 18. McQuillan G, Kruszon-Moran D, Markowitz LE, Unger ER,
matized, but relationship building and patient education Paulose-Ram R. Prevalence of HPV in Adults Aged 18–69: United
States, 2011–2014. NCHS data brief. 2017(280):1–8.
may, in time, change her mind about the screening. 19. Paz-Zulueta M, Alvarez-Paredes L, Rodriguez Diaz JC, Paras-Bravo
Refusals of recommended care, and discussions of the P, Andrada Becerra ME, Rodriguez Ingelmo JM, et al. Prevalence
risks to the patient of not screening, should be clearly of high-risk HPV genotypes, categorized by their quadrivalent and
documented in the medical record [17]. nine-valent HPV vaccination coverage, and the genotype associa-
tion with high-grade lesions. BMC Cancer. 2018;18(1):112.
20. Stanley M. Immunobiology of HPV and HPV vaccines. Gynecol
Oncol. 2008;109:S15–21.
21. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder
S. Human papillomavirus and cervical cancer. Lancet.
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Gynecologic Malignancies
15
Christine A. Prifti, Deborah Kwolek,
Whitfield Board Growdon, and Kerri Palamara
Gynecologic Malignancies: An Overview

Learning Objectives
1. Review the epidemiology, risk factors, and preven- Gynecologic cancers include uterine, ovarian, cervical, vul-
tion of uterine, ovarian, cervical, vulvar, and vagi- var, and vaginal cancers. Annually, approximately 107,000
nal cancers. women in the United States and nearly 1 million women
2. Discuss screening, presenting symptoms, and early globally are diagnosed [1, 2]. Major risk factors include
diagnosis of uterine, ovarian, cervical, vulvar, and high-risk HPV (hrHPV), estrogen excess, smoking, immu-
vaginal cancers. nodeficiency, diethylstilbestrol (DES) exposure, and genet-
3. Describe the evaluation and staging of uterine, ics. Except for the Pap test and HPV testing, which are used
ovarian, cervical, vulvar, and vaginal cancers. to screen for cervical cancer, there are no approved screening
4. Explain the prognosis and typical treatment plans tests to detect gynecologic cancers in asymptomatic women
for uterine, ovarian, cervical, vulvar, and vaginal of average risk. Primary care providers assess risk, discuss
cancers. prevention strategies, and recognize and evaluate early
5. Describe the survivorship issues in women with gyne- symptoms. The primary symptoms in gynecologic malig-
cologic malignancies including the potential sequelae nancies are bleeding abnormalities, abdominal or pelvic pain
from therapeutic chemoradiation and surgery. or discomfort, bowel or urinary complaints, unexplained vul-
var pruritus, and masses or lesions.
The prognoses of gynecologic malignancies vary by can-
cer type and stage at diagnosis. Uterine cancer tends to be
associated with postmenopausal bleeding, is often diagnosed
early, and typically has a favorable prognosis. Ovarian can-
cer is often diagnosed in late stages and thus can have a rela-
tively poor prognosis. Cervical cancer is caused by persistent
HPV infection and is detected through routine screening
where resources are available. Vulvar cancers may be pre-
ceded by dermatologic etiologies, such as lichen planus, and
typically present with pruritus or lesions noted on routine
C. A. Prifti (*)
pelvic exam. Vaginal cancer is rare and primarily related to
Boston University Medical Center, Department of Medicine,
Women’s Health Unit, Boston, MA, USA hrHPV infection.
e-mail: [email protected] Several genetic syndromes, such as Lynch, Cowden, and
D. Kwolek BRCA 1 and 2 mutations, greatly increase the risk of gyne-
Harvard Medical School, Massachusetts General Hospital, cologic malignancies. Such patients require increased sur-
Department of Medicine, Boston, MA, USA veillance and should consider prophylactic surgery. Patients
W. B. Growdon should be screened during preventive visits for a family his-
Massachusetts General Hospital, Department of Obstetrics, tory of cancer or genetic mutations, and appropriate patients
Gynecology and Reproductive Medicine, Division of Gynecologic
should undergo genetic counseling and testing (see Chap. 17
Oncology, Boston, MA, USA
on “The Primary Prevention of Breast Cancer” for a discus-
K. Palamara
sion of genetic syndromes and screening).
Center for Physician Well-Being, Massachusetts General Hospital,

232 C. A. Prifti et al.
Table 15.1 Overview of gynecologic malignancies [3, 4]

Uterine cancer [5] Ovarian cancer [6] Cervical cancer [7] Vulvar cancer [8] Vaginal cancer [9]
Projected new 61,880 22,530 13,170 6070 5350
cases: annual
US 2019 [4]
Deaths: annual 12,160 13,980 4250 1280 1430
US 2015 [4]
Average age at 62 63 50 68 60
diagnosis
Mean 5-year 81.1% 47.4% 66.2% 71% (13% for vulvar 55–60% (13% for
survival: US melanomas) vaginal melanomas)
2008–2014
Major risk Estrogen excess; obesity; Uninterrupted hrHPV; hrHPV; hrHPV;
factors genetics (Lynch, Cowden ovulation; genetics immunosuppression; immunosuppression; immunosuppression;
syndromes) (BRCA 1 and 2, DESa lichen sclerosis DESa
Lynch syndrome)
Screening test None None HPV and Pap testing None None
Early detection Evaluation of Evaluation of Routine Pap; workup Biopsy of Workup of vaginal
postmenopausal bleeding or abdominal/GI/ of vaginal bleeding unexplained vulvar bleeding or
AUB; evaluation of pelvic symptoms; (classically postcoital) pruritis or lesions; discharge; biopsy of
incidental abnormal genetic testing in or discharge routine follow-up of suspicious lesions;
glandular, atypical certain lichen sclerosis incidental finding on
endometrial, or abnormal populationsb; Pap
squamous cells on Pap; incidental cancer
genetic testing in certain cells on Pap
populationsa (rarely)
Populations at risk are discussed in the sections on uterine and ovarian cancer
a
DES exposure may impact women born prior to 1971

b
The treatment for gynecologic malignancies may include Uterine Cancer

surgery, radiation, and/or chemotherapy and should be
managed by a gynecologic oncologist. Where clinically
appropriate, clinicians may attempt fertility preservation Keesha is a 65-year-old woman with a past medical his-
for younger women and consider definitive surgical tory of obesity (BMI 40) and non-insulin-dependent dia-
approaches such as hysterectomy for women who have betes mellitus who presents with 1 month of intermittent
completed childbearing. Survivorship care is important for vaginal bleeding. She had severe vasomotor symptoms
women who may have postsurgical and/or chemoradiation when she went through menopause 15 years ago and
sequelae resulting in gastroenterological, urological, neu- was treated with 12 months of combined estrogen and
rological, psychological, and sexual issues posttreatment. progestin therapy by her previous physician. She wants
Women may or may not be able to take estrogen therapy for to know if she should be concerned about the bleeding.
treatment-induced menopause, depending upon the type of
malignancy.
The prevention and early detection of gynecologic can-
cers relies on excellent comprehensive preventive care for Overview
women. In particular, educating women about how to recog-
nize symptoms that are warning signs for malignancy and Uterine cancer is the most common gynecologic malignancy
the conditions which require careful follow-up can prevent in the United States [1]. The majority of uterine cancers are
mortality. Access to care, lack of resources, fear, shame, type I endometrial cancers. These tumors are associated with
social stigma, religious traditions, limited education, or cul- estrogen excess, have a classic presentation of abnormal
tural beliefs may be barriers to care for patients. Healthcare bleeding, and are typically diagnosed early, leading to an
providers can help patients navigate these obstacles with overall favorable prognosis. Despite this, the incidence and
routine health education that empowers patients and contrib- mortality of endometrial cancer is increasing in the United
utes to early cancer detection (Table 15.1). States, which is thought to be related to rising rates of obe-
15 Gynecologic Malignancies 233
Table 15.2 Classification of uterine cancers [13, 14]

Endometrial type I Endometrial type II Sarcoma
Percentage of 80% 10–15% 5%
uterine cancers
Major risk Estrogen excess BRCA 1 and 2 for serous carcinoma Genetics, history of radiation
factors
Examples Endometrial Poorly differentiated endometrial adenocarcinoma Leiomyosarcomas, endometrial
adenocarcinoma (grade 1 (grade 3), clear cell and uterine serous carcinomas, and stromal tumors, and adenosarcomas
or 2) carcinosarcomas
Prognosis Good Poor Poor
sity [10]. Fat tissue converts androgen precursors to estro- • Type II tumors are less associated with estrogen excess,
gen, and the consequent estrogen excess out of proportion to are more aggressive, and have a less favorable prognosis.
progesterone levels is a major risk factor for type I endome- Type II endometrial cancer includes poorly differentiated
trial carcinoma. Although endometrial cancer is twice as (grade 3) endometroid tumors, papillary serous carcino-
common in Caucasian women as in Black women, Black mas, clear cell carcinomas, carcinosarcomas, and
women have a less favorable prognosis regardless of stage at choriosarcomas.
diagnosis [10]. Black women are more commonly diagnosed
with the more aggressive type II subtype for reasons that are Uterine sarcomas make up about 5% of uterine cancers.
not well understood, and rates of endometrial carcinoma are The most common subtypes are endometrial stromal sar-
increasing faster in Blacks as compared to White women coma, leiomyosarcoma, and undifferentiated uterine sar-
[11]. There are no currently available routine screening tests coma. The mean age at diagnosis is 60 years, and presenting
for uterine cancer, although some cases can be detected inci- complaints of abnormal vaginal bleeding and abdominal
dentally on Pap test, or during the evaluation of abnormal fullness are similar to endometrial cancer (see Table 15.2).
uterine bleeding. Most cases of uterine cancer are diagnosed
in the workup of postmenopausal bleeding and are still cur-
able when discovered. Pathophysiology and Risk Factors
Type I Endometrial Carcinoma Most cases of endome-

Keesha had a Pap test 1 year ago which was HPV+
trial adenocarcinoma arise from prolonged estrogenic stim-
with AGC-US cytology results. She was sent a letter
ulation of the endometrium, leading to endometrial
suggesting she come in for follow-up, but she does not
hyperplasia and atypical hyperplasia (also known as endo-
remember getting the letter. Her mother died of
metrial intraepithelial neoplasia; see discussion below on
“female cancer”; the details are unknown.
classification of noncancerous and precancerous endome-
trial lesions). Nonhormonal risk factors for endometrial
adenocarcinoma include increased age, genetic predisposi-
Epidemiology tion, and diabetes.
Uterine cancer is the fourth most common cancer in women Estrogen excess unopposed by progesterone is the most
in the United States, after lung, breast, and colorectal cancers
important risk factor for endometrial adenocarcinoma.
[1]. Worldwide, uterine cancer is the sixth most common Obesity, anovulation, estrogen-producing tumors, tamoxi-
malignancy in women [1, 12]. Endometrial cancer accounts fen, hormone replacement therapy with unopposed estrogen,
for 95% of uterine cancers, while the remaining 5% are sar-nulliparity, and early menarche or late menopause all increase
comas [13]. Endometrial cancer most commonly presents in estrogen exposure in the endometrium and therefore increase
women over 55-years-old, has a mean age at diagnosis of the risk of endometrial adenocarcinoma.
62 years, and is uncommon in women under 45 years of age Obesity increases estrogen exposure because adipose
[1, 5]. Endometrial cancer is subdivided into two types, cells convert androstenedione into estrone. As such, women
which reflect grading and histology: with BMIs greater than 30 have a two- to sevenfold increased
risk of endometrial cancer (odds ratio 1.5 for BMI 25 to <30;
• Type I tumors are estrogen-dependent, low- to moderate- 2.5 for BMI 30 to <35; 4.5 for BMI 35 to <40; 7.1 for
grade malignancies exclusively of endometrioid histol- BMI ≥ 40) [15, 16].
ogy. They comprise 85% of endometrial cancers and have Anovulation results in continuous unopposed estrogenic
an excellent prognosis. stimulation as without ovulation there is no corpus luteum to
produce progesterone. The corpus luteum, which develops in Table 15.3 Risk factors for endometrial cancer [15, 16]
the ovary after ovulation, produces progesterone until it dis- Type Risk factors Relative risk
solves in concert with the regular shedding of the endome- Estrogen- Type Obesity, BMI > 35–40 OR 1.5 for BMI
trium in the absence of implantation. Use of oral contraceptive associated I only 25 to <30; 2.5 for
uterine BMI 30 to <35;
pills, which regulates this hormonal milieu, is associated cancers 4.5 for BMI 35 to
with decreased endometrial cancer risk [16]. <40; 7.1 for BMI
Tamoxifen is a selective estrogen receptor modulator that ≥40
acts as an estrogen antagonist in breast tissue and an agonist Tamoxifen use 2–2.7
in the endometrium. Women on tamoxifen therapy for breast Chronic anovulation 3
(e.g., PCOS)
cancer treatment or prevention have a 2- to 2.7-fold increased
Unopposed estrogen 2–10
risk of endometrial cancer and should routinely be asked use (i.e.,
about symptoms of abnormal bleeding [17]. However, rou- inappropriately dosed
tine surveillance of asymptomatic women being treated with menopausal hormone
therapy)
tamoxifen either with transvaginal ultrasound or endometrial
Estrogen-producing Unknown
biopsy is not recommended due to low specificity and low tumors
positive predictive value in this population [18–20]. Nulliparity 2
Age is a significant risk factor for endometrial carcinoma. Early menarche Unknown
Ninety percent of cases occur in women aged greater than Late menopause 2
50 years [21]. Only 20 percent are diagnosed in premeno- Non- Type Increased age (50–70) Incidence rises
pausal women. Women with predisposing genetic cancer estrogen- I or with age
associated type Pelvic irradiation Unknown
syndromes have a higher incidence of premenopausal uterine uterine II Genetic syndromes: 13–50% lifetime
cancer than the sporadic cases that occur among other precancers Lynch syndrome risk
menopausal women [22]. Cowden syndrome
Diabetes is associated with an increased risk of endome- BRCA
trial cancer, though this is likely due to inflammatory factors
and comorbid obesity [23].
Genetics, specifically Lynch syndrome, known as heredi- Type II endometrial cancers do not have a clear precursor
tary nonpolyposis colorectal cancer or (HNPCC), is an lesion, are not associated with estrogen excess, are more
uncommon autosomal dominant disorder which affects less likely to be stage III or IV at diagnosis, and are more com-
than 1% of women and increases the risk of colon, endome- mon in Black women. For example, papillary uterine serous
trial, ovarian, brain, and other GI cancers. HNPCC patients carcinoma (USC) is a very aggressive tumor much like ovar-
have a lifetime risk of 40–60% of developing endometrial ian serous carcinoma. USC represents less than 10 percent of
cancer, which tends to develop 10–20 years earlier than endometrial cancer cases, but accounts for 40 percent of
endometrial cancers caused by sporadic mutations [22, 24]. deaths from endometrial carcinoma. Risk factors for these
Patients with Lynch syndrome require intensive screening tumors are described in Table 15.3.
for a variety of cancers, starting in their 20s, including yearly Risk factors for uterine sarcomas include Black race (for
endometrial biopsy (EMB). Patients should be referred to leiomyosarcoma), long-term tamoxifen use, and history of
gynecology for annual screening and consideration of pro- pelvic irradiation. Hereditary leiomyomatosis, renal cell car-
phylactic hysterectomy with bilateral salpingo-oophorectomy cinoma syndrome, and hereditary childhood retinoblastoma
after childbearing is complete [22]. There is also an increased are genetic syndromes associated with uterine sarcoma.
risk in patients with Cowden syndrome, BRCA 1 and 2, and
other genetic defects. Clinicians should consider genetic
counseling for patients diagnosed with endometrial cancer at Screening
age <50 years or who have a strong family history of colon
and endometrial cancer [22, 25, 26]. Positive genetic testing There are currently no recommended routine screening tests
impacts both screening and therapeutic options. When endo- to detect uterine cancer in asymptomatic patients. Routine
metrial cancer does arise in the setting of Lynch syndrome, Pap tests performed for cervical cancer may incidentally
these tumors tend to present with a high mutational burden detect uterine cancers based upon the presence of abnormal
due to DNA mismatch repair deficiencies that translate into a cells, such as atypical glandular cells after further investiga-
heightened response to immunotherapy [27]. tion is performed [28]. Patients at increased risk, including
Although it is a risk factor for many types of cancer, those on tamoxifen, should not receive surveillance ultraso-
smoking is associated with decreased endometrial cancer nography or endometrial biopsy, except those with genetic
risk [16]. syndromes. Imaging and EMB are invasive and expensive,
cause discomfort, and have not been shown to save lives [29, 44 years of age [5]. For postmenopausal women, a transvagi-
30]. Clinicians should “screen” for gynecologic cancer by nal ultrasound (TVUS) will usually exclude malignancy if
asking about abnormal vaginal bleeding, pain, bloating, or the endometrial stripe is less than 4 mm [31]. A thicker stripe
masses on review of systems. requires EMB, as does persistent bleeding (>3–6 months)
with prior negative workup. In premenopausal women over
45, an EMB is needed after the exclusion of pregnancy.
Clinical Presentation TVUS may be ordered to exclude structural lesions, but the
endometrial stripe thicknesses on transvaginal ultrasound are
Postmenopausal bleeding is the classical presentation of nondiagnostic in premenopausal women and tissue sampling
uterine cancer, though premenopausal women may present is needed. In women younger than 45-years-old with risk
with abnormal uterine bleeding (AUB). Nearly 70 percent of factors (see Table 15.3), evaluation with EMB should be per-
cases are confined to the uterus at time of diagnosis with a formed after the exclusion of pregnancy [32] (see Chap. 7 on
5-year survival rate of greater than 90 percent [5]. Women “Abnormal Uterine Bleeding”).
should be educated regarding symptoms of pain, bleeding, or
fullness which might indicate the presence of a gynecologic
Keesha is told that postmenopausal bleeding is abnor-
abnormality or cancer and be asked to report such symptoms
mal and that additional testing is needed. She is wor-
to their care providers.
ried and asks how likely it is that she has cancer.
Keesha reports that her bleeding is very light; she uses

Postmenopausal bleeding has many causes. The most
a panty liner a few times a week. A pelvic exam reveals
common cause is endometrial atrophy. Atrophic changes can
a normal-sized uterus, no blood in the vaginal vault,
cause bleeding from the lower pelvic organs as well as the
and no abnormal lesions of the cervix, vagina, or vul-
endometrium. Other benign causes include hyperplasia of
vae. Bimanual exam is normal. There is no cervical
the endometrium, polyps, fibroids, or hormonal therapy. Her
motion tenderness, and testing for sexually transmitted
risk of endometrial cancer is 3–20% [33, 34]. For a complete
infections and a stool guaiac are negative.
discussion, please see Chap. 7 on “Abnormal Uterine
Bleeding”, section on postmenopausal bleeding.
Evaluation and Diagnosis

Transvaginal ultrasound reveals an endometrial stripe
Endometrial cancer most commonly presents as postmeno- of 7 mm. Keesha is informed of the results, and an
pausal bleeding, or as an incidental Pap test abnormality in urgent referral to gynecology is requested for EMB. She
women over age 55. In premenopausal women, especially is quite anxious and wonders what to expect.
those over age 45 or with BMI > 30, abnormal uterine bleed-
ing (AUB), defined as heavy menstrual bleeding or intermen-
strual bleeding, may herald malignancy although a broad Endometrial Biopsy
differential diagnosis exists (see Chap. 7 on “Abnormal An endometrial biopsy (EMB) is typically a quick and sim-
Uterine Bleeding”). In postmenopausal women, all vaginal ple procedure that occurs in a physician’s office much like a
bleeding requires an evaluation to exclude malignancy. Pap test or IUD insertion. The most popular method in the
Similarly, all patients with abnormal glandular cells or atyp- United States utilizes the thin plastic Pipelle (registered
ical endometrial cells found incidentally on Pap test need an trademark) suction curette or equivalent device. Internists,
evaluation by gynecology. Further workup should include family practitioners, and NPs can perform EMB with mini-
endometrial and endocervical sampling and/or colposcopy in mal training though most women are referred to gynecolo-
addition to possible ultrasound or other tests to determine the gists when EMB is needed. Pregnancy is excluded prior to
source of the abnormal cells. In addition, any endometrial the procedure and a dose of oral NSAID is often given
cells seen on a Pap in women who are postmenopausal 20–30 min prior to the EMB to minimize cramping. The
should prompt further evaluation. patient assumes the dorsal lithotomy position and a specu-
Given the impact of menopausal status on the physiology lum is inserted. The cervix is visualized and cleaned, and
of vaginal bleeding and the increasing incidence of endome- then the thin soft plastic Pipelle is inserted through the cer-
trial cancer with age, the evaluation of abnormal bleeding vical os. Several samples are taken in succession by aspirat-
varies by the age of the patient. Seventy-seven percent of ing a small amount of endometrial tissue into the Pipelle
endometrial malignancies occur in women over 55, 16% in from four to six sites on the sides of the uterine cavity.
women 45–54 years of age, and only 7% in women under Providers should counsel patients that this may cause
cramping. The Pipelle tip is not withdrawn from the os Table 15.4 FIGO grading of endometrial carcinoma by histopathol-
ogy [43]
between samples. When sampling is complete, the Pipelle is
withdrawn, the tissue is placed in fixative, and the specimen Percentage of cases
Meaning (%) Classification
is sent to pathology for diagnosis. Cramping and bleeding
Grade Well differentiated 50 Type I
are usually mild and self-limited, clearing rapidly after the 1
procedure [35]. Grade Moderately 35 Type I
2 differentiated
ndometrial Hyperplasia and Precancerous
E Grade Poorly differentiated 15 Type II
Lesions 3
Women with excess estrogen stimulation often develop
endometrial hyperplasia which is most commonly diag-
nosed by endometrial biopsy (EMB). The clinical presenta-
tion of hyperplasia is identical to that of endometrial cancer, A gynecologist evaluates Keesha and performs an
and the diagnosis is made pathologically by EMB. The pathology report returns as adenocarci-
EMB. Traditionally, there were four types of endometrial noma. Keesha is referred to a gynecologic oncologist
hyperplasia, which were categorized as simple vs complex in for staging and treatment which starts with a total hys-
terms of cell architecture and with or without atypia [36]. In terectomy and bilateral salpingo-oophorectomy.
2015, the WHO revised its classification system into two cat- Following the diagnosis, Keesha calls and asks if she
egories: hyperplasia without atypia (nonneoplastic) and should start shopping for wigs in preparation for
atypical hyperplasia (endometrial intraepithelial neoplasm) chemotherapy.
[37]. The endometrial intraepithelial neoplasia classifica-
tion system is an alternate organizational schema [38]. The
discussion of the various classifications is beyond the scope Patients who are diagnosed with endometrial carcinoma
of this chapter. are referred to gynecologic oncologists for initial manage-
Atypical hyperplasia is precancerous and has a high inci- ment and treatment planning. For more advanced cancers,
dence of concurrent carcinoma (~42%) in an area of the radiation oncologists may help create a treatment plan. For
uterus not sampled by the biopsy [39]. Hyperplasia without patients requiring chemotherapy, in some centers, medical
atypia has a <5% risk of concurrent malignancy [40, 41]. oncologists specializing in gynecologic cancers will provide
Hyperplasia with or without atypia is comanaged with a patient care related to chemotherapy; in other centers, both
gynecologist. Sources of excess estrogen are eliminated, and surgical and chemotherapy management are managed by
treatment options include progestin therapy or hysterectomy. gynecologic oncologists. Patients often have questions about
The desire for future fertility and surgical risk will guide their diagnosis or potential treatment strategies as they await
management options. For women with atypical hyperplasia specialty appointments. The content included in this section
who have completed childbearing, hysterectomy is the safest may help primary care providers to help patients formulate
option. appropriate questions and anticipate common treatments
Strategies to reduce estrogen exposure include discontin- during that time.
uing medications containing estrogen, encouraging weight Endometrial carcinoma is classified by the International
loss, and treating PCOS or hyperprolactinemia that leads to Federation of Gynecology and Obstetrics (FIGO) grading
increased estrogen exposure from ovulatory dysfunction. In and staging systems (see Table 15.4). Grading is based upon
women not initially treated with hysterectomy, multiple histology of biopsy specimens, which are rated as Grade 1, 2,
options for administering progestins are available, including or 3, and staging is divided into four categories depending
oral, intrauterine device (IUD), intramuscular (IM), and upon the extent and spread of the disease (see section on
intravaginal preparations. Progesterone implants (i.e., “Staging” below). Grades 1 and 2 are classified as type I
Nexplanon™) have not been studied and are therefore not endometrial cancer, and Grade 3 is type II.
recommended. Common regimens include cyclic medoxy-
progesterone 10 mg daily for 14 days per month, continuous
megestrol acetate 20–40 mg daily, or a progestin-releasing Staging
IUD [42]. If progestins are used, response may be monitored
with serial biopsies at 3- to 12-month intervals. Women with Prior to deciding on the treatment course, uterine cancer
hyperplasia who fail medical therapy may undergo hysteros- must be staged. Tumors are classified as low or high risk
copy with directed dilation and curettage to further evaluate based on histopathology and grading. Endometrial cancer is
for cancer. not staged with imaging, but rather surgically via the joint
2010 International Federation of Gynecology and Obstetrics Table 15.5 Types of hysterectomy
(FIGO)/TNM classification system. Complete physical Type of
exam, pelvic exam, and CXR to exclude pulmonary metasta- hysterectomy Supracervical Simple Radical
ses are performed. Imaging with MRI is primarily ordered Description Removal of Uterus, cervix, Total
uterine body; fallopian tubes, hysterectomy and
for women who are not surgical candidates or for those who cervix left in and ovaries BSO, plus
wish to preserve fertility. place removed removal of
Standard staging surgery is a total hysterectomy with parametriuma and
bilateral salpingo-oophorectomy with or without pelvic and upper 1/3 of
vagina
para-aortic lymph node dissection. The ovaries and cervix
Sample Benign Endometrial Stage IA2 to IIA
are removed because they may contain endometrial cancer indications conditions cancer, cervical cancer
cells (“total” hysterectomy indicates removal of the cervix). early-stage
There is no consensus on which patients require lymph node cervical cancer,
staging, or what constitutes an adequate lymphadenectomy ovarian cancer
in regards to the number of nodes removed and extent of Connective tissue surrounding the uterus
a
lymphadenectomy. Lymph node resection can lead to lymph-

edema, which is a troubling side effect for endometrial can- TAHBSO is commonly used to refer to total hysterectomy
cer survivors. Because of the risks associated with and bilateral salpingo-oophorectomy. Technically, this is
comprehensive lymphadectomy, investigators now com- incorrect as the “A” stands for abdominal and this method is
monly employ sentinel lymph node dissections with fluores- used less today. In endometrial cancer, the use of laparos-
cent dye and infrared cameras. This universal and targeted copy has been shown to have equivalent oncologic outcomes
approach has been prospectively validated and is a part of the with decreased surgical morbidity when compared to open
NCCN guidelines [44]. surgery [48]. The newer terminology commonly used is
TLH/BSO. The DaVinci™ Robotic platform is a commonly
used tool to complete laparoscopic staging for endometrial
Treatment Strategies cancer though outcomes appear to be similar to nonrobotic
laparoscopy at a significantly higher cost [49].
Early-stage endometrial cancer is treated with curative-intent At diagnosis, approximately 72% of endometrial cancers
surgery. As the disease advances, radiation and/or chemo- are stage I, 12% are stage II, 13% are stage III, and 3% are
therapy may also become necessary. stage IV [50, 51]. Carcinoma in situ is a precancerous lesion
Premenopausal women who wish to preserve fertility and is not included in the FIGO staging system. The progno-
with stage I disease can sometimes be treated by hysterec- sis depends primarily on the stage of the tumor as well as
tomy with preservation of the ovaries. Conservative histology and grade. Table 15.6 summarizes the FIGO stag-
management of women with atypical endometrial hyperpla- ing for endometrial carcinoma, 5-year survival rate, and
sia or endometrial cancer to preserve future fertility is con- usual treatment.
troversial given the risk of disease progression. There are Many stage I–III tumors require the use of radiation and
reports of therapeutic success with progesterone therapy chemotherapy. Radiation therapy may take the form of
[45]. Such patients should be closely followed by gyneco- internal therapy with vaginal brachytherapy or external
logic oncology. The acceptance and availability of frozen beam pelvic radiation. If external been radiation is used, and
oocytes and ovarian tissue cryopreservation are promising ovarian preservation is desired, the ovaries can be surgically
technologies which further inform this type of decision [46]. moved out of the field of radiation. Radiation therapy often
The vast majority of women with endometrial cancer will has the unwanted side effects of cystitis, proctitis, and vagi-
undergo simple hysterectomy with or without removal of the nal changes.
ovaries and fallopian tubes. Rarely radical hysterectomies For metastatic or recurrent disease, chemotherapeutic
can be utilized if cervical involvement is suspected on preop- regimens containing a combination of cisplatin or carbopla-
erative exam, biopsy, or imaging to spare the patient the need tin, doxorubicin, and/or paclitaxel are often recommended.
for postoperative radiation, but this practice is uncommon These chemotherapy agents have numerous side effects
and has not been widely validated [47]. The various types of including nausea and vomiting, hematologic suppression,
hysterectomies that can be performed range from type I to and temporary hair loss. Renal toxicity and cardiotoxicity
type V and the surgical nuances are beyond the scope of this are feared complications. Women with stage IV disease for
chapter. A type I hysterectomy is simple, and type III is radi- whom there is no curative intent may be treated with hor-
cal (Table 15.5). monal treatments including tamoxifen or aromatase inhibi-
Table 15.6 Endometrial cancer prognosis and treatment by stage [50, 51]
Proportion of women 5-year
at this stage at time of survival rate
Stage diagnosis (%) Description (%) Usual treatment
I 72 Tumor limited to the body of the uterus 90 Hysterectomy/BSO +/− radiation if high-risk
(limited to endometrium or showing only features on biopsy
superficial invasion of myometrium)
II 12 Tumor has spread to the cervical stroma 69 Hysterectomy, possible radical hysterectomya
(involving the cervix or invading deeply with or without postoperative radiation
into the myometrium)
III 13 Tumor extends beyond the confines of the 50 Hysterectomy/BSO with lymph node
uterus but not outside the pelvis dissection, radiation, and/or chemotherapy
IV 3 Tumor extends outside the pelvis 15 No curative intent. Palliation includes primary
+/− distant metastases chemotherapy, attempted debulking, hormonal
therapy with progestins, tamoxifen or aromatase
inhibitors
tors which are generally well tolerated. Further discussion Women who have received radiation are more likely to have
of stage II–IV is beyond the scope of this chapter. bowel or bladder symptoms, especially in the first 1–2 years.
A full discussion is found in the section on survivor care at
the end of the chapter.
Keesha returns 6 months after her surgery with total
hysterectomy and bilateral salpingo-oophorectomy.
She was diagnosed with stage 1 endometrial adeno- Ovarian Cancer
carcinoma with low-grade histology (type I). She has a
follow-up appointment with her gynecologic oncolo-
gist later that week but wonders why she does not have Cindy, a 30-year-old G2P2, presents for an urgent
to do any imaging or lab work beforehand “like my care visit. Three weeks ago, her mother was diagnosed
friend with breast cancer.” with advanced ovarian cancer at age 50. Her mother is
an only child whose parents died in a car accident
many years ago. Cindy is very upset and wants to learn
more about her risk of ovarian cancer.
Survivorship Care
The greatest risk of recurrence in endometrial cancer patients

is within the first 2 years after treatment. The most common Overview
site of recurrence for stage I disease is the vagina. Following
therapy, patients should be seen every 3–4 months for 2 years Ovarian cancer has the highest fatality rate of the gyneco-
by a gynecologic oncologist to assess for symptoms of recur- logic malignancies [6]. This is because ovarian cancer may
rence and then every 6 months for the next 3 years. Physical be asymptomatic or present with vague abdominal symp-
exam includes speculum and bimanual pelvic exam. Most toms, delaying diagnosis until it is at an advanced stage.
vaginal recurrences are treated with radiation therapy. There is no validated method for screening asymptomatic
Vaginal Pap tests are no longer recommended as the sensitiv- women of average risk although several, including transvagi-
ity is poor [52]. Cytology is affected by radiation which nal ultrasound (TVUS) and serum CA 125 levels, alone and
decreases the yield and sensitivity of Pap tests. in combination, have been studied [54–56]. Multiple large
Surveillance imaging is obtained only if there are signs or prospective trials have studied routine transvaginal ultra-
symptoms of recurrence. Whole-body PET/CT scanning is sound with or without CA-125 as possible screening modali-
the imaging modality of choice [53]. ties. Though some stage shift has been described (i.e., cancer
During treatment, women are typically comanaged by diagnosis at early stages), no trial has demonstrated a sur-
their primary care provider and oncologist. After treatment, vival benefit. Routine screening in an asymptomatic, low-
depending on institutional resources, the primary care clini- risk population is therefore not recommended. Suspected
cian may be responsible for monitoring women for symp- ovarian cancer cannot be biopsied given the risk of seeding
toms of disease recurrence and assisting women in coping the peritoneum; the mass must be removed en bloc. Any pro-
with the long-term sequelae of therapy: treatment-induced posed screening strategy must therefore have high specificity
menopause, anxiety and depression, bowel and bladder since any positive test requires confirmatory surgery. The
issues, surgical adhesions, and issues with sex or intimacy. best current defenses against ovarian cancer include screen-
ing for genetic susceptibilities and maintaining a high index tumors affect women of all ages, germ cell tumors are more
of suspicion when patients present with vague symptoms. common in adolescents (see Table 15.7).
Epidemiology Cindy asks if she is at increased risk for ovarian can-

cer and whether she should go for genetic testing. She
Ovarian cancer is the leading cause of death from a gyneco- is asymptomatic and G2P2 and has never taken OCPs.
logic malignancy and has surpassed cervical cancer as the Family history reveals that aside from her mother, no
second most common type of gynecologic cancer in the one else in the family has had ovarian cancer; neither
United States, likely due to improved cervical cancer screen- she nor her mother has siblings. A paternal great aunt
ing [6, 7] (see Table 15.1). Despite overall advances in ovar- had breast cancer in her 70s, and there is no other
ian cancer treatment, mortality is essentially unchanged over family history of breast cancer or other cancers in men
the past three decades [57]. The average age at diagnosis is or women. Her ethnic background is Pakistani, with no
63 years old, with a 1.3% lifetime risk of developing the dis- Ashkenazi Jewish grandparents.
ease in women of average risk [6]. When caught early, sur-
vival rates improve markedly; however, screening is
ineffective, and most patients are not diagnosed until meta-
static symptoms appear. If ovarian cancer is found inciden- Risk Factors
tally and treated in stage 1, the 5-year survival rate is
approximately 90%. Unfortunately, only 15% of ovarian Ovarian cancer risk is increased primarily through genetic
cancers are diagnosed at this stage [6]. In contrast, stage IV factors, inflammation, and uninterrupted ovulation. BRCA
patients with distant metastasis at diagnosis have a 25% sur- mutations, Lynch syndrome, and Ashkenazi Jewish heritage
vival rate at 5 years [6]. have all been linked to ovarian cancer. BRCA1 mutation car-
riers have a 44% lifetime risk of ovarian cancer, and BRCA 2
mutation carriers have a 17% lifetime risk [61]. Patients who
Pathophysiology test positive for BRCA 1 or 2 or Lynch syndrome should be
referred to specialty care to consider a prophylactic bilateral
Ninety-five percent of ovarian tumors originate from the epi- salpingo-oophorectomy (see Chap. 17 on “The Primary
thelial ovarian cells and are referred to as epithelial ovarian Prevention of Breast Cancer”). Prophylactic surgery is prefer-
carcinoma [58]. The most common type of epithelial ovarian ably performed prior to 35–40 years of age, but after a woman
cancer is high-grade serous carcinoma. High-grade serous has completed her desired childbearing. Endometriosis, ciga-
carcinomas of the ovary, fallopian tube, and peritoneum have rette smoking, and PCOS lead to increased ovarian cancer
identical pathologic characteristics and clinical behavior and risk, likely related to chronic inflammation leading to cellular
therefore are treated in the same manner both in clinical damage and the need for repair [62]. Errors in copying the
practice and trials [59]. Recent data from women undergoing genetic code in the DNA repair process are thought to lead to
prophylactic bilateral salpingo-oophorectomy for BRCA increased cancer risk [62, 63].
gene mutations has revealed precursor neoplastic lesions in Ovarian rest, or time spent without ovulation events,
the fallopian tubes leading some investigators to assert that decreases the risk of ovarian cancer. When cells do not divide
the fallopian tube may be the organ of origin for a significant in the ovulation process, there is less risk of introducing error
subset of ovarian and peritoneal cancers [59, 60]. The when copying the genetic code. Parity and breastfeeding
remainder of nonepithelial ovarian cancers arise from the both increase ovarian rest and are associated with decreased
germ and stromal cells in the ovary. While sex cord stromal risk. Notably, combined oral contraceptives which inhibit
Table 15.7 Malignant ovarian tumors

Tumor type Cells of origin Epidemiology Malignant subtypes
Epithelial tumors Epithelial ovarian cells 95% of malignant ovarian tumors are Serous (most common), clear cell,
(epithelial ovarian epithelial ovarian carcinoma mucinoid, and endometrioid epithelial
carcinoma) carcinomas
Germ cell tumors Ova 2% of malignant ovarian tumors. Typically Immature teratomas, dysgerminomas,
impact young women and girls. Best choriocarcinomas, and endodermal sinus
prognosis (yolk sac) tumors
Sex cord stromal Ovarian stroma (granulosa, 1% of malignant ovarian tumors. More Granulosa cell (most common),
tumors theca, Sertoli, and Leydig common in postmenopausal women. Some Sertoli-Leydig
cells; fibroblasts) produce estrogen or androgens
ovulation decrease risk by 50% when used for at least Table 15.8 Risk factors and protective factors in ovarian cancer
[65–72]
10 years [64]. Tubal ligation and salpingo-oophorectomy
also reduce risk. Tubal ligation may be a proxy for multi- Factors associated with increased Factors associated with decreased
risk of ovarian cancer risk of ovarian cancer
party. IUDs likely “increase” risk because ovulation does not
Increasing age Previous pregnancy
cease with IUD use as it does with oral contraceptive pills Nulliparity History of breastfeeding
(see Table 15.8). Infertility Oral contraceptives
Patients with a strong family history of breast and ovarian Endometriosis Tubal ligation
cancer should be referred for genetic counseling and possible PCOS Salpingo-oophorectomy
Smoking
testing. Notably, genetic evaluation and possible testing are Use of an intrauterine device
recommended for anyone with a personal history of ovarian Cigarette smoking (mucinous
cancer, as well as anyone with a close relative with ovarian carcinomas)
cancer when testing the affected family member is not pos- Lynch syndrome
BRCA1 and 2
sible. A close relative is a first-, second-, or third-degree rela- Ashkenazi Jewish heritage
tion. Multiple organizations have issued guidelines, including
the American Cancer Society (ACS), the United States
Preventive Services Task Force (USPSTF), and the National justify routine screening. A persistent challenge in identify-
Comprehensive Cancer Network (NCCN). ing an appropriate screening test is that, with current diag-
The decision of whom to refer for genetic counseling and nostic methods, any positive screening test would then
testing ultimately resides with the physician and patient on likely necessitate a laparoscopy or laparotomy for further
an individualized basis. Of note, genetic testing is now investigation. A suspected ovarian cancer cannot be biop-
increasingly available to patients with home kits and send sied; it must be removed intact to avoid seeding the perito-
away DNA tests such as 23andMe™ which may bypass the neal cavity. Although ovarian cancer carries a high
initial consultation by the genetic counselor. Patients may be mortality, given that these procedures are associated with
referred to genetic counselors, or to gynecologic oncology, morbidity and the overall prevalence of ovarian cancer is
to discuss the implications of DNA tests obtained through low, the risks outweigh the benefits for available screening
outside sources. It should be noted that commercial DNA methods [55]. Several large, prospective randomized trials
tests are not validated and are not a substitute for the testing have examined the role of CA-125 and TVUS for ovarian
ordered by a certified genetic counselor. The results may not cancer screening in asymptomatic women and all failed to
be accurate or may only cover a few mutations or genetic lead to statistically significant mortality reduction and
variations for a given syndrome (see Chap. 17 on “The therefore did not reach their end points [73]. A test that
Primary Prevention of Breast Cancer” for further informa- looks for shed ovarian and endometrial tumor cells in endo-
tion on genetic syndromes and genetic screening). cervical brushings is currently being investigated, but will
face the same challenges [74].
The UK Collaborative Trial of Ovarian Screening is the
Cindy is informed that she and her mother should be largest randomized trial of both CA125 and TVUS methods
referred to a genetic counselor and that ovarian can- to date and showed a nonsignificant 15% reduction in mor-
cer screening with ultrasound, CA125, or other testing tality from ovarian cancer with multimodal CA-125 screen-
is not recommended, even for women at “increased” ing (95% CI −3 to 30 p = 0.10) [75]. The trial randomized
risk. If she is found to have a BRCA or a Lynch syn- approximately 200,000 women of average ovarian cancer
drome mutation, she would be considered “high” risk, risk into three groups: annual CA-125 screening, annual
and prophylactic salpingo-oophorectomy or other sur- transvaginal ultrasound, and no screening. Women in the first
gery should be considered. She wonders what symp- group were further stratified into normal CA-125 levels,
toms she should “watch out for” and what the downside indeterminate CA-125 levels, and elevated CA-125 levels.
would be to a transvaginal ultrasound, which was how Women with indeterminate CA-125 levels had a repeat
her mother’s mass was found. CA-125 drawn in 3 months, and women with elevated
CA-125 levels were evaluated with transvaginal ultrasound.
Findings from the trial suggest that one ovarian cancer death
may be prevented by screening 641 women with CA-125
Screening levels on an annual basis for 14 years. The investigators
observed that there were more stage I and II cancers observed
At present, there is no effective screening test for ovarian in the experimental arm suggesting a promising stage migra-
cancer. CA-125 levels and TVUS have been studied both tion signal, though this did not translate into a survival ben-
together and separately, but are not sufficiently specific to efit. The long term follow-up phase is in process.
Pelvic exam is not sensitive or specific enough to be a cer must be removed intact – puncturing an ovarian mass for
reliable method of screening for ovarian cancer, as it does a biopsy could lead to seeding throughout the peritoneal cav-
not reliably correlate with ultrasound or surgical findings, ity and therefore a worse prognosis. Preoperatively, abdomi-
even among experienced providers [76–78]. nal and pelvic imaging with CT or MRI may be used for
High-risk women with known genetic predispositions surgical planning. A CXR is obtained to exclude metastasis.
may benefit from screening in selected circumstances. A
women with BRCA 1 or 2, or Lynch syndrome, who has
rejected or wishes to postpone surgery, may be screened with Staging and Treatment Strategies
serial TVUS and/or CA-125 in coordination with a gyneco-
logic oncologist [79]. Ovarian cancer staging is based on operative findings (see
Table 15.9). For more advanced cases, surgery is used for
cytoreduction prior to beginning platinum-based chemother-
Clinical Presentation apy. The administration of chemotherapy prior to cytoreduc-
tive surgery (neoadjuvant) has been shown to have noninferior
Traditionally, ovarian cancer has been considered to be survival outcomes compared to surgery followed by chemo-
asymptomatic until the late stages. However, a sizable num- therapy allowing the clinician discretion based on patient
ber of women may have symptoms in early disease that are factors to decide how to best sequence care [81]. Regardless
missed. Ovarian cancer patients present with abdominal and of stage or the interval nature of chemotherapy, patients who
gastrointestinal symptoms such as bloating in over 70% of have high-quality, “optimal” debulking surgeries that remove
cases, pain in 58% of cases, constitutional symptoms in 50% as much tumor as possible have increased survival rates.
of cases, urinary symptoms in 34% of cases, and pelvic Chemotherapy regimens typically include paclitaxel plus
symptoms in 26% of cases [80]. A symptom index has been carboplatin and may be given intrapertonially and/or intrave-
developed to determine which women should be evaluated nously. Intraperitonal chemotherapy is introduced through
for ovarian cancer. Any of the following symptoms present an abdominal catheter and allows for higher doses of chemo-
more than 12 times per month for less than 1 year is consid- therapeutic agents with lesser effects on healthy tissue. Side
ered a positive screen: abdominal or pelvic symptoms of effects are related to the chemotherapy drugs (neuropathy
pain, bloating, increased abdominal size, and changes in and nephrotoxicity being most common), the port (catheter
appetite or early satiety [80]. malfunction), or the mechanism of infusion (abdominal pain
from instilling a large amount of fluid).
Evaluation and Diagnosis

Survivorship Care
Physical examination should include an abdominal exam
(attention to masses in the lower abdomen), breast exam, Following the completion of treatment, patients should be
pelvic exam, rectal exam with stool guaiac, and lymph node seen in the office for a history, general physical, and pelvic
exam (attention to inguinal and supraclavicular nodes). exam to monitor for recurrence. A pelvic exam should be
Imaging of patients with pelvic or lower abdominal symp- performed every 2–4 months for 2 years, then every
toms begins with a TVUS which visualizes the ovaries and 3–6 months for 3 years, and then annually after 5 years.
pelvic structures. If the TVUS is negative, and no other CA-125 levels, if they were elevated during the time of
explanation is found, patients should undergo an abdominal/ active disease, are typically checked at these visits follow-
pelvic CT and possible colonoscopy or urinary tract evalua- ing discussions between women and their clinicians on both
tion to evaluate all possible sources of the symptoms. the pros and cons of these measurements. A rise in CA-125
Ovarian cancer can present as peritoneal carcinoma alone or often but does not always signal recurrence, and following
as an incidental finding on imaging done for another pur- these levels has not been found to impact survival [84].
pose. A CA-125 should not be checked until concern for Other laboratory testing and imaging are obtained only as
ovarian cancer is established by imaging. If a suspicious clinically indicated, such as to investigate a concerning
lesion is identified on exam or imaging, the patient is symptom, exam findings, or rising CA-125 level. If not
referred to a gynecologic oncologist for urgent evaluation already completed, survivors should be referred for genetic
and surgical staging. counseling and undergo prophylactic mastectomy if appro-
Ovarian cancer is a histologic diagnosis that is made via a priate. If the cervix was removed during surgery, Pap tests
laparoscopy or laparotomy with surgical removal of the are no longer required.
ovary and fallopian tube, peritoneal lymph node biopsies, Many survivors have ongoing sequelae from treatment.
and/or pelvic washings. Masses suspicious for ovarian can- Neurotoxicity from platinum-based chemotherapy, gastroin-
Table 15.9 Ovarian cancer staging, 5-year survival, and treatment [82]
5-year
FIGO survival
stage Stage descriptiona (%) [83] Treatment
IA The cancer is only in the ovary (or ovaries) or fallopian tube(s) 78–93 If completely resected, observation. If
IB IA – Confined to one ovary, no surface involvement, no rupture upon removal high-risk features, treated with three to
IC1,2,3 IB – Both ovaries, no surface involvement, no rupture upon removal six cycles of platinum-based
IC1 – Confined to one or both ovaries, surgical spill chemotherapy
IC2 – Confined to one or both ovaries, capsule rupture prior to surgery,
surface involvement
IC3 – malignant cells in pelvic wash
IIA The cancer is in one or both ovaries or fallopian tubes and has spread to other 61–82 If completely resected, adjuvant
IIB organs within the pelvis (such as the uterus, bladder, sigmoid colon, or chemotherapy, typically paclitaxel plus
rectum) carboplatin, for six cycles
IIA – Extension or implant into uterus or fallopian tubes
IIB – Extension or implant into other pelvic organs
IIIA No longer confined to the pelvis; has spread into the abdomen 28–63 Surgical cytoreduction, intravenous or
IIIB IIIA1 – Cancer spread to pelvic and/or para-aortic lymph nodes intraperitoneal adjuvant platinum-based
IIIC IIIA2 – Microscopic tumor involvement in upper abdominal tissues or organs chemotherapy, consideration of
IIIB – Macroscopic tumor <2 cm in size involving upper abdominal tissues or maintenance therapy with poly ADP-
organs ribose polymerase inhibitors (PARPi) or
IIIC – Macroscopic tumor >2 cm in size involving upper abdominal tissues or bevacizumab
organs
IVA The cancer has spread to the inside of the spleen or liver, or outside the 19 Platinum-based chemotherapy before or
IVB abdomen after surgical cytoreduction,
IVA – Malignant pleural effusion consideration of maintenance therapy
IVB – Parenchymal liver or spleen metastasis, distant metastasis with PARPi or bevacizumab
testinal symptoms from surgery, abrupt menopause from undergo screening, are lost to follow-up, or who live in low-
ovarian removal, and sexual dysfunction are among the many and middle-income countries, cervical cancer is still a sig-
common symptoms. For a full discussion, please see the sec- nificant cause of mortality. Cervical cancer classically
tion on survivorship care at the end of the chapter. presents with postcoital bleeding.
Cervical Cancer Epidemiology
Worldwide, over 500,000 women are diagnosed with cervi-

Cindy is a 44-year-old G4P4 woman with a history of
cal cancer each year; of those, over half will die of the dis-
obesity and AUB. She had her last child at age 34 and
ease [85, 86]. The majority of cases (>85%) occur in
presents to the office to establish care because “I
low- and middle-income countries where cervical cancer is
haven’t had a physical since my gynecologist put that
the second most common cancer in women, compared to
copper IUD in 10 years ago. I think it’s time to take it
being the 16th most common cancer in US women [4].
out.” In the past she was HPV positive on screening,
Cervical cancer incidence peaks between the ages of 48 and
but was lost to follow-up. She has always had heavy
55, and the peak incidence of carcinoma in situ is between
periods, but now she notices that she is having bleed-
the ages of 25 and 40. It is estimated that 50% of invasive
ing after intercourse.
cervical cancer is diagnosed in women who have never had
a Pap test, who have not received cervical cancer screening
for 5–10 years, or who have been lost to follow-up after an
Overview abnormal Pap [87].
Cervical cancer is the only gynecologic cancer with a screen-

ing test, and all women should be screened with Pap and/or Pathophysiology and Risk Factors
HPV testing using evidence-based guidelines (see Chap. 14
on “Cervical Cancer and Human Papillomavirus”). Most High-risk HPV (hrHPV) is the underlying cause of 99% of
precancerous cervical abnormalities are diagnosed by cervical cancers, including squamous, adenosquamous, and
screening, and thus, invasive cervical cancer is relatively adenocarcinomas [85, 88]. When a woman’s immune system
uncommon in developed countries. For those who do not does not clear HPV from her body, the persistent viral infec-
tion leads to cellular atypia and slowly occurring premalig- findings are referred to gynecologic oncologists for evalua-
nant cellular changes in the basal layer in the cervical tion and treatment.
epithelium over time [88]. The length of time of hrHPV In low-resource settings where the Pap test is not avail-
infection, age, immunosuppressive conditions, multiparity, able, women may be screened by “visual inspection with
multiple partners, long-term oral contraceptive use, coinfec- acetic acid” (VIA) in which the cervix is inspected for ace-
tion with other sexually transmitted infections, and smoking towhite lesions indicative of HPV infection or premalignant
increase the risk of progression to cervical intraepithelial or malignant lesions. The “see and treat” approach further
neoplasia 3 (CIN3) [86, 89]. HPV-16 infections have the treats visible lesions with cryotherapy without cervical
lowest 18-month clearance rates and carry the highest likeli- biopsy or pathology [88]. These approaches lack sensitivity
hood of progression to CIN3 or cervical cancer compared to and specificity and have disadvantages, but lives are saved
other hrHPV infections [89] (see Chap. 14 on “Cervical with these programs when screening with Pap, colposcopy,
Cancer and Human Papillomavirus”). and biopsy are not available.
Diethylstilbestrol (DES) exposure also increases cervical
cancer risk and may impact women born prior to 1971. DES
was a “synthetic estrogen” prescribed to pregnant women Staging
from 1938 to 1971 when it was thought to prevent miscar-
riage and preterm birth. Women exposed to DES in utero The clinical staging of cervical cancer is accomplished by
should follow a specialized screening protocol. pelvic exam, biopsy, and imaging. Imaging to assess for
metastases and lymph node involvement is most often
PET-CT or PET-MRI [90]. Staging follows the FIGO system
Screening [91]. The prognosis worsens with advanced stages and
metastases – early-stage localized disease has a 91% 5-year
Cervical cancer is the only gynecologic cancer with a routine survival rate, whereas locally advanced and metastatic cervi-
screening test for average-risk women. Pap testing detects cal cancer 5-year survival rates are far lower (57% and 16%,
the vast majority of cervical cancers and precursor lesions, respectively), with a median survival of 8–13 months [85,
where resources are available. 90] (see Table 15.10). Cervical cancer metastasizes in two
ways: hematogenous metastases and lymphatic metastasis.
Hematogenous metastases carry a worse prognosis.
Clinical Presentation
Cindy is referred for colposcopy and biopsy, which
Women who are screened regularly for cervical cancer rarely
confirm invasive cervical cancer with extension to the
present with clinical signs and symptoms. Women who have
margins. A pelvic MRI reveals no extension of disease
not been screened adequately, and develop invasive cervical
beyond the cervix. She is referred to a gynecologic
cancer, may present with postcoital bleeding, pain, unpro-
oncologist, who recommends total hysterectomy.
voked vaginal bleeding, or foul-smelling discharge.
A Pap test and HPV co-test are obtained, as well as a

Treatment Strategies
cervical culture. Cindy’s Pap result returns suspicious
for invasive cervical cancer, + HPV 16. She is devas-
The treatment of cervical cancer depends upon the stage.
tated and wonders how this could happen to her and
Preinvasive disease (CIN3 and CIS) is treated with LEEP or
whether she is going to die from this. She asks what to
conization. In a LEEP (loop endocervical excision proce-
do next.
dure), the speculum is inserted, a paracervical block is
applied, and acetic acid is placed on the cervix to highlight
abnormal tissue. A small metal loop heated with an electric
Evaluation and Diagnosis current then slices an ovoid tissue specimen containing abnor-
mal cells, much like a wire cheese cutter takes a slice from a
In high-income countries, abnormal Pap tests that are posi- block of cheese. A second swipe deeper into the endocervical
tive for hrHPV are typically referred to a gynecologist for canal can then effectively replicate a conization procedure,
colposcopy and biopsy of suspicious lesions. It is important removing the transformation zone. A LEEP is an outpatient
that women return for follow-up and complete treatments in office procedure that removes less tissue than a cold-knife
a timely manner. High-grade biopsy results or carcinomatous conization, which is typically performed in an ambulatory
Table 15.10 Cervical cancer staging, prognosis, and treatment [7, 92, 93]
5-year
survival
Stage Description (%) Treatmenta
I The cancer has not grown beyond the cervix 80–93 Dependent on disease extension and desire for future fertility.
Options: conization, simple hysterectomy, radical
trachelectomy, radical hysterectomy, radiotherapy,
chemoradiation
II The cancer has grown beyond the cervix but has not 58–63 Radical hysterectomy for a subset of stage II patients;
spread to the walls of the pelvis or lower part of the radiosensitizing chemotherapy with concurrent radiation
vagina therapy
III The carcinoma involves the lower third of the vagina and/ 32–35 Radiosensitizing chemotherapy and volume-directed
or extends to the pelvic wall and/or causes concurrent radiation
hydronephrosis or nonfunctioning kidney and/or involves
pelvic and/or para-aortic lymph nodes
IV The carcinoma has extended beyond the true pelvis or 15–16 Platinum-based systemic chemotherapy with antiangiogenic
has involved the mucosa of the bladder or rectum (biopsy agents, palliative radiation, immune checkpoint inhibitors
proven)
surgery suite. Conization uses a scapel or laser to remove a Recurrence, if and when it occurs, is typically local or
“cone” of tissue at the os. Hysterectomy may be considered in regional. Patients should be reassured that the prognosis is
women for whom future childbearing is not a concern. typically favorable, even with locally advanced disease, and
The treatment of invasive cervical cancer depends upon that cervical cancer is not inheritable. It is important to set a
the degree of lymphovascular invasion and the patient’s clear follow-up plan, especially when care is returned to the
desire for future fertility. Fertility-sparing treatments may be primary care provider. The cancer survivor plan should be
safely performed in patients with early disease, but are not made in conjunction with the gynecologic oncologist and
recommended in patients with locally advanced or metastatic include specifications for the frequency of Pap testing, when
cancer [85]. In early-stage cancers, conization +/− lymph it is safe to space out Pap tests beyond 1 year, and when to
node sampling or trachelectomy (a surgery that removes the eventually stop. There are no set guidelines, but many gyne-
cervix, upper portion of the vagina, and pelvic lymph nodes) cologic oncologists continue annual Pap tests until age 65,
may be possible for women who desire future fertility. followed by every other year Pap tests as long as there is an
Women who have finished childbearing and have pelvic con- expected life expectancy of 5 years or more [94].
fined disease (stage < IIB) can undergo simple or radical hys- Approximately 30–50% of patients will have treatment fail-
terectomy or definitive radiation with curative intent. ure or recurrence, which is more common with large tumors
Treatment of metastases is based on location and may involve and with involved pelvic and para-aortic lymph nodes [95]. If
surgery, chemoradiotherapy, radiation, or chemotherapy. The recurrence is suspected, PET-CT is the recommended imaging
multitude of treatment modalities highlight the importance modality. When recurrence is limited to the cervix or vagina,
of referring women to experienced gynecologic oncologists curative intent surgery and radiation are the treatments of
for optimal care [85, 90, 92]. choice. Surgery is often chosen in patients who had prior radia-
During treatment, the patient is managed by a gyneco- tion therapy. Radiation is the treatment of choice in patients
logic oncologist. The role of the primary care clinician dur- without prior radiation, or who are not surgical candidates.
ing active treatment is primarily supportive: assisting in the Metastatic disease that is not amendable to surgery or radiation
management of complications and treating other medical is treated with cisplatin, paclitaxel, and bevacizumab.
conditions. Most cervical cancer patients have a good prognosis and
may return to primary care with long-term quality of life
issues that are sequelae of therapy. Cervical cancer survivors
Cindy undergoes total hysterectomy with close follow-
are able to take estrogen treatment, if needed, since cervical
up by her gynecologic oncologist. She is doing well
cancer is not related to estrogen exposure (see section below
and wants to discuss long-term plans and side effects
on care of the cancer survivor). If and when it appears likely
of treatment.
that the patient will survive for at least another 5–10 years,
then routine screening for other malignancies should resume.
Studies are underway on the utility of using therapeutic
Survivorship Care HPV vaccination in cervical cancer patients as a treatment
modality. These studies use formulations of HPV vaccina-
Patients with cervical cancer are monitored by gynecologic tions (not those in current use) which stimulate cellular
oncologists for at least 5 years following treatment. immunity [96].
Vulvar and Vaginal Cancers mous epithelia. These tissues are susceptible to persistent
HPV infection which can cause neoplastic changes. The
metabolically active transformation zone of the cervix is
Aditi is a 62-year-old woman who presents for her more vulnerable to neoplastic changes due to HPV than the
annual physical exam. She is due for a Pap test. On vulva or vagina, which are covered by stable, mature squa-
pelvic exam, a 5-mm white plaque is seen on her vulva. mous tissue – leading to high rates of cervical cancer com-
The lesion was not previously noted in the record and pared to vaginal and vulvar cancer. Cigarette smoking, HIV
Aditi was not aware of it. infection, and immunosuppression are cofactors which
increase the risk of HPV-related cancer.
Women with in situ DES exposure can have metaplastic
Overview tissue in the vagina and are at increased risk of vaginal can-
cers, including clear cell carcinoma.
Vulvar and vaginal cancers, the least common of the gyneco- Chronic inflammatory processes such as lichen sclerosis
logic cancers, typically present as asymptomatic lesions, or elevate the risk of vulvar malignancy due to increased cell
with pruritus, pain, or vaginal bleeding. Because the mor- turnover, which leads to greater chances for errors in DNA
phology of malignant lesions is variable, any lesion of the replication. Although hrHPV is responsible for the majority
vulva or vagina that is not obviously benign must be biopsied of vulvar intraepithelial changes on biopsy, tissues with
for definitive diagnosis. Most vulvar and vaginal malignan- lichen sclerosis give rise to the majority of malignancies.
cies are squamous cell cancers related to hrHPV or lichen Lichen sclerosis should be treated to reduce risk of progres-
sclerosis of the vulva. sion to malignancy, and all women found to have premalig-
nant or malignant lesions should be counseled to stop
smoking (see Chap. 12 on “Vaginitis and Vulvar Conditions”).
Epidemiology
Vulvar cancer is the fourth most common gynecologic Screening

malignancy (after uterine, ovarian, and cervical). US women
have a 0.3% lifetime risk of being diagnosed with vulvar There is no validated screening test for vulvar or vaginal can-
cancer, and the average age at diagnosis is 68 years [8]. cer. Women should be encouraged to report any abnormali-
Nearly 60% of vulvar cancers are confined to the primary ties which develop in the perineal region or vagina. All vulvar
site at diagnosis, 30% show regional spread, and 6% have and vaginal complaints need evaluation with inspection, pal-
distant metastasis. Survival for women in the United States pation, and diagnostic testing.
with vulvar cancer is 72.1% at 5 years. Seventy-five percent As noted above, women with a history of DES exposure
are squamous cell carcinomas; other types include mela- should have annual vaginal cytology. Women with lichen scle-
noma, basal cell carcinoma, clear cell carcinoma, Bartholin rosis should be followed by a gynecologist or dermatologist
gland adenocarcinoma, sarcoma, and Paget’s disease [97]. who specializes in this area for annual exams given the risk of
Vaginal cancer is the least common gynecologic malig- progression to squamous cell carcinoma in lichen sclerosis.
nancy. Metastatic disease to the vagina is more common than
primary cancers of the vagina. The mean age at diagnosis for
primary vaginal carcinoma is 60 years. Most lesions (83%) Acetic acid is applied to the vulvar lesion and it turns
are squamous cell carcinoma [98]. In utero DES exposure white. Aditi consents to take a secure photo of the
and hrHPV are known risk factors. Other subtypes include lesion for her medical chart. Aditi is told that she will
adenocarcinoma, sarcoma, clear cell carcinoma, and need a referral and probable biopsy to determine the
melanoma. cause of the lesion. She is agreeable, and arrange-
ments are made for her to see a gynecologist next
week. Aditi is understandably anxious and asks what
Pathophysiology and Risk Factors to expect.
hrHPV is a major risk factor for vulvar and vaginal cancers.

Persistent HPV infection may lead to precancerous changes
in the vulva and vagina similar to precancerous abnormali- linical Presentation, Evaluation,
C
ties in the cervix with atypia, intraepithelial neoplasia, and and Diagnosis
carcinoma in situ (see tables below). The cervix, vagina,
vulva, anus, and rectum to the dentate line are all derived Vulvar cancer is often asymptomatic, but may present with
from the same embryonic tissue which matures into squa- pruritus or palpable lesions. Vulvar cancer should also be
suspected in women with persistent vaginal itching refrac- out corresponding lesions. Additionally, vulvar intraepithe-
tory to treatment. Vaginal cancer typically presents with lial neoplasia (VIN) and vaginal intraepithelial neoplasia
vaginal bleeding or discharge, but may be asymptomatic (VaIN) often coexist with cervical intraepithelial neoplasia
[99]. Bleeding is usually scant spotting or postcoital. or cancer. The application of acetic acid turns HPV-infected
Review of systems at annual visits should contain ques- areas white, although this is not specific. A magnifying glass
tions regarding vulvar, vaginal, or pelvic pain, lesions, pruri- can be used for the examination if colposcopy is not avail-
tus, discharge, and bleeding (see Chap. 3 on “Sex and Gender able. Abnormal areas are biopsied.
Specific History and Examination”). Exams should include Categories of vulvar and vaginal intraepithelial neopla-
inspection of the vulva, as with the rest of the skin, even sia – histology and treatment options – are outlined in Tables
when internal pelvic examinations are not performed. Since 15.11 and 15.12.
many dermatologists do not include the vulva in their com- VIN lesions fall into three categories:
plete skin exam, the primary care clinician should be sure
women are monitored for lesions or abnormalities. • LSIL is benign, usually regresses, and does not require
During pelvic exams, the vaginal walls are palpated for treatment.
masses or induration and can be inspected for lesions or • HSIL is caused by HPV, is usually treated, and may prog-
irregularities during removal of the speculum. The most ress to cancer.
common site for vaginal tumors is the posterior wall of the • Differentiated VIN is associated with Lichen sclerosis and
upper one-third of the vagina, an area that can be visualized is most likely to be associated with malignancy.
with a careful speculum exam. Any abnormality should be
referred to gynecology for evaluation and possible biopsy. Vaginal biopsies may also reveal vaginal intraepithelial
Up to 20% of vaginal cancers are detected incidentally on neoplasia (VaIN). Invasive disease is excluded with vaginal
routine Pap testing [99].
The morphology of vulvar and vaginal lesions varies Table 15.11 Vulvar intraepithelial neoplasia (VIN) [100, 101]
greatly, and expertise is required for proper evaluation.
Name Description Therapy
Cancerous lesions may present as patches, plaques, nodules,
Vulvar LSIL Not precancerous. Flat Monitor. Most
or papules with red-, brown-, black-, white-, pink-, or flesh- (low-grade condyloma or HPV-related will regress. Stop
colored pigment. Any vulvar or vaginal lesion that cannot be squamous inflammatory changes smoking. Treat if
easily explained should be biopsied for definitive diagnosis. intraepithelial symptomatic
lesion)
The differential diagnosis for vaginal or vulvar carcinoma
Vulvar HSIL HPV related. May be Excision, or, less
includes physiologic or post-inflammatory hyperpigmenta- (high-grade associated with or progress commonly,
tion, warts, lichen planus, acanthosis nigrans, vulvar or vagi- squamous to squamous cell topical therapy
nal interepithelial neoplasia, melanocytic nevus, intraepithelial carcinoma with imiquimod
angiokeratoma, and seborrheic keratosis (see Chap. 12 on lesion)
Differentiated Not associated with HPV Excision
“Vaginitis and Vulvar Conditions”).
VIN (vulvar Typically associated with
Basal cell carcinoma and melanomas occur on the vulva intraepithelial lichen sclerosis. Less
and vagina. Vulvar and vaginal melanomas are more com- neoplasia) common than HSIL. Most
mon in Caucasian women and may present as a blue-black likely to be associated
with, or progress to,
mass, a black-brown mass, a nonpigmented plaque, or an
cancer
ulceration. Vaginal melanomas occur most frequently on the
distal one-third of the anterior vaginal wall. Sarcomas are
more common in children, classically present as a “bunch of Table 15.12 Vaginal intraepithelial neoplasia (VaIN)
grapes” protruding from the vagina, and can arise from any Name Description Therapy
structure in the lower genital tract. VaIN 1 LSIL (low-grade Pathology Close surveillance
Vulvar and vaginal cancers are diagnosed by biopsy of squamous intraepithelial involves lower only
lesion) 1/3 of the
suspicious lesions, which is usually performed by a gyne- epithelium
cologist. Most primary care offices do not have the expertise VaIN 2 HSIL (high- Pathology Treatment options
or equipment to evaluate these lesions without a consulta- grade squamous involves lower include surgical
tion. However, if desired, the clinician may obtain consent to intraepithelial lesion) 2/3 of the excision, laser
epithelium ablation, intracavitary
document the lesion with a photo in the medical record prior radiation, and topical
VaIN 3 (includes CISa) Pathology
to referral for biopsy. HSIL involves >2/3 therapy with
Vulvar and vaginal colposcopy are performed to look for of the imiquimod
lesions that may not be visible to the naked eye. Indications epithelium
include unexplained symptoms, or abnormal cytology with- carcinoma in situ
a
colposcopy and biopsy. Less than 10% of VaIN progresses to Staging workup includes a physical examination and chest
invasive vaginal carcinoma [102]. and skeletal radiography. Cystoscopy and anoscopy or proc-
Following treatment for precancerous conditions, women toscopy are preformed when indicated by history, physical
should be seen every 6 months for an exam, vaginal cytol- exam, or sexual practices, and a CT or MRI may be done for
ogy, and HPV testing for 2 years, after which they can be surgical planning (see Table 15.14).
followed annually by exam, vaginal cytology, and HPV co-
testing [103]. There is no consensus on when to stop annual
screening in this population although some clinicians stop Aditi’s biopsy comes back as positive for squamous
after age 65 if the previous five screens were normal. cell carcinoma. It is HPV positive and she is referred
to a gynecologic oncologist.
Staging
Vulvar cancer is staged via physical exam. Assessment Treatment Strategies

includes pelvic and rectal exam and inspection of the
perineum, anus, vagina, and urethra. The vulva, vagina, and Vulvar and vaginal cancers are managed by gynecologic
cervix are evaluated with colposcopy as multicentric lesions oncologists. Treatment for vaginal cancer is determined by
may occur. Imaging with pelvic and abdominal MRI or PET expert opinion and is extrapolated from the care of cervical
scan may be obtained to evaluate for concurrent pathology, and anal cancers. There are no randomized clinical trials for
metastatic disease, or surgical planning, especially when vaginal cancer as it is rare. Vulvar cancer is better studied.
symptoms are suggestive of possible metastatic disease, such For both cancers, surgical options, as well as radiation and
as bowel or bladder dysfunction, a tumor ≥4 cm, or if there chemotherapy, depend on the size and location of the cancer.
are palpable inguinal femoral notes (see Table 15.13). Low-risk disease is confined to the vagina and may be treated
Vaginal cancer is clinically (not surgically) staged via the with surgery alone. High-risk disease has spread to the pelvic
International Federation of Gynecology and Obstetrics wall, lymph nodes, or other structures. High-risk disease is
(FIGO) and Tumor, Node, Metastasis (TNM) system. treated with radiation +/− chemotherapy or surgery.
Radiation may involve brachytherapy, in which a probe is
inserted into the vagina to deliver therapy. Treatment alters
Table 15.13 Vulvar cancer staging, prognosis, and treatment [8, 104, the structure of the vagina and vulva, which may impact
105]
patient well-being.
5-year
Stage Description survival Treatment
IA, Tumor confined to the 86% Vulvectomy
IB vulva +/− inguinal node Survivorship Care
IA: < 2 cm, < 1-mm sampling, with or
invasion without Patients with a history of low-risk disease should be seen
IB: > 2 cm, > 1-mm postoperative
every 6 months for the first 2 years after diagnosis and then
invasion chemotherapy and
II Tumor of any size with radiation
extension to adjacent
perineal structures (lower Table 15.14 Vaginal cancer staging, prognosis, and treatmenta [106]
third of urethra, lower
third of vagina, anus) with 5-year
negative lymph nodes survival
III Tumor of any size with or 54% Stage Description (%) Treatment
without extension to I Cancer is confined to the 75–95 Surgery
adjacent perineal vagina +/− radiation
structures (lower third of II Cancer has grown through 50–80 Radiation
urethra, lower third of the vaginal wall, but does not +/−
vagina, anus) with positive extend to the pelvic wall or chemotherapy
inguinofemoral nodes nearby lymph nodes or surgery
IV Tumor invades other 54% III Cancer is growing into the 30–60 Radiation
regional (upper 2/3 18% if pelvic wall and has spread to +/−
urethra, upper 2/3 vagina) spread to nearby lymph nodes but not chemotherapy
or distant structures distant distant sites
organs IV Cancer has spread to distant 15––50%
or organs
tissues Survival rates given as ranges given relative rarity of this cancer [107]
a
annually. Women with a history of high-risk disease should During active treatment, side effects are managed by the
be seen every 3 months for the first 2 years, every 6 months oncology team. Once treatment is complete, the gynecologic
years 3 through 5, and then annually. All patients with a his- malignancy survivor may experience treatment-induced
tory of vaginal or vulvar cancer should have cervical or vagi- menopause; urinary, gastrointestinal, pelvic, and psycho-
nal Pap tests annually with HPV co-testing. If recurrence is logic symptoms; infertility; neuropathy; and intimacy or
suspected, PET CT is recommended [108]. sexual health concerns. Patients who undergo radiation ther-
apy and radical hysterectomies have the highest burden of
side effects and the lowest posttreatment quality of life [109,
Aditi is treated with local resection and returns to your 110]. Primary care providers should address long-term qual-
clinic for follow-up. Since her surgery, she has found ity of life issues, assess the burden of treatment-induced
sex less pleasurable. sequelae, and discuss options to treat identified problems
(see Chap. 20 on the “Care of the Breast Cancer Survivor”)
[11]. Symptoms and sequelae which are specific to surgery
or radiation, or that are worrisome for recurrent malignancy,
are of the Gynecologic Cancer Survivor
C should be referred back to the gynecologic oncologist for
in Primary Care evaluation and treatment (Fig. 15.1).
Care of the cancer survivor begins when the patient is diag-

nosed and continues throughout her life. The primary care ong-Term Complications in Survivors
L
provider (PCP) plays a critical role in this care and should be of Gynecologic Cancers
well versed in the issues which arise in cancer survivors. The
management of common sequelae is covered in detail in Gastroenterological Complications
other chapters of this volume and will not be repeated here,
except those that are unique to gynecologic cancer survivors Pelvic surgery and radiation therapy to the pelvis, both com-
(see Chaps. 8, 9, 20, 23, 27, 30, 31, and 33 on “Menopause, mon treatments for gynecologic malignancies, can have an
Female Sexual Function and Dysfunction”, “Care of the adverse impact on bowel and bladder function. Bowel dys-
Breast Cancer Survivor”, “Urinary Incontinence”, “Irritable function may be the result of tissue damage from radiation,
Bowel Syndrome”, “Interstitial Cystitis”, “Chronic Pelvic or postsurgical mechanical (related to adhesions) or neuro-
Pain”, and “Depressive and Anxiety Disorders” for in-depth pathic (related to disruption of sympathetic and parasympa-
discussions). thetic nerve fibers) changes. For some survivors, particularly
Fig. 15.1 Common side

• Bladder dysfunction • Social isolation
effects and sequelae in the
• Urinary Incontinence • Depression
gynecologic cancer survivor
• Urinary Retention • Anxiety
• Dysuria • Insomnia
• Fistulas • Fatigue
• Hematuria • Fear of recurrence
• Neuropathy • PTSD
• Loss of sensation • Trouble concentrating
Neurologic and
Psychologic
Urologic
Sexual
and
Gastroenterologic
Gynecologic
• Low libido • Change in bowel habits
• Dyspareunia • Proctitis
• Hot flashes • Rectal bleeding
• Vaginal dryness • Steatorrhea
• Vaginal bleeding • Diarrhea
• Lymphedema • Incontinence, urgency
in the case of ovarian cancer, initial cancer symptoms may prompting. In gynecologic cancer survivors, the NCCN
have been perceived as vague gastrointestinal distress. (National Comprehensive Cancer Network) recommends
Gastrointestinal symptoms may therefore be particularly dis- asking directly if the patient is sexually active and whether
tressing in ovarian cancer survivors who fear that the symp- they are having intercourse, if they are satisfied with their sex
toms signal recurrence. life, and if not, for how long? Providers should identify
As with any patient, the etiology of the presenting com- whether the problem is with pain, dryness/lubrication, fear,
plaint should be identified, and recurrent malignancy should lack of interest, decreased sensation, or orgasm [112]. A full
be excluded, when appropriate. Most therapy is supportive. discussion of the assessment and management is outlined in
Constipation, loose stools, urgency, and fecal incontinence Chap. 9 on “Female Sexual Function and Dysfunction”.
may be complications of treatment and are managed with Women sometimes deny problems initially but may be will-
increasing the intake of high-fiber foods or with the addition ing to discuss issues in the future, once the provider has
of stool bulking agents like psyllium. Constipation is man- shown an openness to discuss sexuality concerns.
aged with polyethylene glycol and Senna, a plant-derived Women who have been treated for a gynecologic malig-
stimulant laxative, as necessary (for further discussion, see nancy may have significant anatomic changes following sur-
Chap. 27 on “Irritable Bowel Syndrome”). gery and/or skin changes from radiation. Further, women
Radiation proctitis typically resolves on its own and is may be misinformed or have misconceptions about their
managed in the short term with hydration and antidiarrheal posttreatment anatomy and ability to be sexually active. For
agents as needed. Severe symptoms of proctitis may require example, a radical hysterectomy can make the vagina shorter
steroid enemas [111]. and vaginal stenosis may occur. Women may experience dif-
ficulty with body image after treatment, and alopecia of the
pubic hair may occur. Removal of the pelvic lymph nodes
Urologic and Neurologic Complications may also lead to lymphedema of the genital tissues, which
can be painful and have a significant negative impact on
Chemotherapy, radiation, and surgery can all impact uro- quality of life [109, 110]. Dryness and dysthesia are also
logic function. Radiation therapy is associated with the high- common issues after treatment. Vaginal infection, or bowel
est likelihood of urologic complications. Symptoms include or bladder incontinence, can also negatively impact sexual
incontinence, pain, frequency, urgency, and hematuria. health and should be addressed and treated appropriately.
Infection should be excluded and management should be tai- Treatment of sexual dysfunction should be targeted to the
lored to symptoms. Many of the urologic symptoms associ- specific complaint.
ated with radiation therapy will be treated similarly to other A pelvic exam can assess for areas of scarring, atrophy, or
causes of the same symptoms (see Chaps. 23 and 30 on stenosis that may be causing symptoms, and if needed,
“Urinary Incontinence and Interstitial Cystitis”). These reevaluation should be performed by the treating gynecologic
patients should be referred back to gynecology or to an urol- oncologist. Vaginal dryness can initially be managed with a
ogist or urogynecologist for evaluation and treatment. trial of moisturizers and lubricants (see Chap. 8 on
Neurologic complications are common in gynecologic “Menopause”, section on vaginal atrophy). For patients who
cancer survivors. Peripheral neuropathy often results from have experienced the vaginal shortening of a radical hysterec-
platinum-based chemotherapy and several other agents that tomy, advice can be given for some couples to adjust to this
are mainstays of chemotherapy for gynecologic cancers. change by using a penile ring to shorten the depth of penetra-
Some women may only have troublesome symptoms when tion or by cupping a hand around the base of the penis during
exposed to hot or cold temperatures, or tight clothing, and sex. Vaginal stenosis can be treated with dilators. Pelvic floor
should be encouraged to avoid triggers and/or wear gloves physical therapy may be helpful for many of these symptoms
and socks to reduce symptoms. Duloxetine is the suggested and can also help with urinary incontinence.
pharmacotherapy agent for refractory symptoms. For further Referrals to certified sex therapists who are experienced
discussion, see Chaps. 26 and 31 on the “General Approach in sexual issues after cancer treatment can provide special-
to Chronic Pain” and “Chronic Pelvic Pain”. ized cognitive behavioral therapy and practical approaches
to sexual dysfunction. Certified therapists can be found at
https://www.aasect.org/, and some cancer centers have spe-
Sexual and Gynecologic Complications cial clinics for this purpose [113] (for a full discussion, see
Chap. 9 on “Female Sexual Function and Dysfunction”).
Sexual dysfunction following treatment for gynecologic can- Radiation can also cause rectovaginal or vesicovaginal fistu-
cer is common. Primary care providers should proactively las, radiation cystitis or proctitis, and/or rectal strictures.
inquire in a sensitive and skilled manner about sexual health Women with these complaints should be referred to urology
as many women will not bring up this subject without or surgery for definitive treatment.
Chronic pelvic pain is another possible sequelae of ther- survivors of gynecologic malignancies will experience the
apy and may be related to the issues described above. best possible quality of life. The primary care provider is
Treatment is targeted to the etiology, and patients should be uniquely positioned to help patients identify issues and man-
comanaged with gynecology. age symptoms, provide expert referral, and coordinate care.
May gynecologic cancers cannot be safely treated with
fertility-preserving methods. Ideally, treatment’s impact on
reproductive potential is discussed prior to initiation of ther- Summary Points
apy as part of informed consent and shared decision making.
Women in need of support adjusting to this “new normal” 1. Review the epidemiology, risk factors, and prevention of
should be referred to counseling. uterine, ovarian, cervical, vulvar, and vaginal cancers.
(a) In the United States, uterine cancer is the most com-
mon gynecologic cancer and the 4th most common
Surgical and Treatment-Induced Menopause cancer overall in women. Rates of uterine cancer are
increasing, likely due to rising rates of obesity.
Many women who are survivors of gynecologic malignan- Ovarian cancer is less common, followed by cervical,
cies will experience treatment-induced menopause. The vulvar, and vaginal cancers (see Table 15.1).
symptoms of surgical menopause are similar to those experi- (b) Major risk factors for gynecologic malignancies
enced in natural menopause except that symptoms can be include unopposed estrogen exposure, hrHPV infec-
more severe and can come on suddenly. A full discussion of tion, in utero DES exposure, lichen planus, and cer-
the treatment of surgical menopausal symptoms is found in tain genetic syndromes: BRCA 1 and 2, Lynch, and
Chap. 8 on “Menopause:, and Chap. 20 on the “Care of the Cowden syndromes.
Breast Cancer Survivor”. Survivors of cervical, vaginal, or (c) Options for risk reduction are limited and include
vulvar malignancy are candidates for hormone therapy and maintaining a healthy weight, routine Pap and pelvic
have no restrictions for menopausal treatment options. exams, oral contraceptives, and proper referral for
Ovarian and uterine cancer survivors have traditionally patients at high genetic risk.
not been treated with hormonal therapy, as it is not safe for 2. Discuss screening, presenting symptoms, and early diag-
patients with certain types of tumors, or advanced malignan- nosis of uterine, ovarian, cervical, vulvar, and vaginal
cies. Recent data, however has shown that epithelial ovarian cancers.
cancer and early (stage I) endometrial cancer survivors may (a) Cervical cancer is the only gynecologic cancer with a
be appropriate candidates for hormone therapy; treatment recommended screening protocol for average-risk
should only be initiated in consultation with a patient’s treat- women.
ing gynecologic oncologist [114–116]. (b) The primary symptoms in gynecologic malignancies
are bleeding abnormalities, abdominal or pelvic pain
or discomfort, bowel or urinary complaints, unex-
Psychologic Complications plained vulvar pruritus, and masses or lesions.
(c) Early diagnosis of uterine, ovarian, vulvar, and vagi-
Many cancer survivors experience anxiety, depression, nal cancer is typically made based on clinical suspi-
PTSD, and fear of recurrence. Fatigue, trouble concentrat- cion prompting further evaluation, or by abnormal
ing, and insomnia are also common. The primary care clini- cells found on routine Pap test.
cian should actively monitor for these conditions and provide (d) Patients with in utero DES exposure lichen planus,
treatment. Anxiety and depression should be assessed with BRCA 1 and 2, Lynch, or Cowden syndrome may be
validated tools and shared decision-making used to develop candidates for specialized screening protocols or pre-
a treatment plan, which typically involves SSRIs and talk ventative surgery. Such patients should be referred to
therapy (for a full discussion, please see Chaps. 20 and 33 on specialty care.
“Care of the Breast Cancer Survivor”, and “Depressive and 3. Describe the evaluation and staging of uterine, ovarian,
Anxiety Disorders”). cervical, vulvar, and vaginal cancers.
Providers can educate their patients on the cancer surveil- (a) Gynecologic cancers are staged by the FIGO
lance plan, symptoms needing evaluation, and how to com- system.
municate concerns. Helping women identify peer support (b) Formal evaluation and staging of gynecologic can-
groups and ensuring regular check-ins on their well-being cers should be completed by a gynecologic
are also essential. A compassionate and patient-centered oncologist
approach, which is evidence based and integrates the exper- 4. Explain the prognosis and typical treatment plans for
tise of a multidisciplinary team of providers, will insure that uterine, ovarian, cervical, vulvar, and vaginal cancers.
(a) Gynecologic cancer should always be managed in 2. A 48-year-old woman of Ashkenazi Jewish descent pres-
conjunction with a gynecologic oncologist and pref- ents for her annual exam. Her last Pap co-testing was nor-
erably in a specialized treatment center with up-to- mal 3 years ago. She has no symptoms, but wants to be
date protocols and multispecialty support for women screened for ovarian cancer because her sister was diag-
undergoing treatment. nosed with metastatic ovarian cancer at age 50. She and
(b) Uterine cancer has the best prognosis of all the gyne- her sister were adopted, and she does not know her family
cologic cancers because it has a classic presentation history. She read that an ultrasound and CA-125 level
of abnormal uterine bleeding and is typically detected were the best screening procedures. What would be the
at an early stage. Ovarian cancer classically has the next step in her evaluation?
worst prognosis because the symptoms are often non- A. Pap co-testing
specific and is diagnosed at late stages. B. Referral for genetic counseling and testing
(c) Treatment varies by type of cancer and stage at diag- C. Transvaginal ultrasound and CA-125 level
nosis, but may include surgery, radiation, and/or D. Pelvic MRI
chemotherapy. E. PET scan
5. Describe the survivorship issues in women with gyneco- The correct answer is B. Ovarian cancer has a high mor-
logic malignancies including the potential sequelae from tality because most patients are asymptomatic until the
therapeutic chemoradiation and surgery. cancer has spread. Unfortunately, there is no reliable
(a) Posttherapy sequelae may include treatment-induced screening test for asymptomatic women, even for those
menopause; gastrointestinal, urologic, psychologic, with a family history. A large study in the United Kingdom
or neuropathic symptoms’ mental health issues; or recently showed that the harm of screening outweighed
sexual health concerns. the benefits because of the high incidence of false-posi-
tive findings which lead to unnecessary surgery. This
woman is at risk for the BRCA 1 or 2 genetic mutation
Review Questions based on her Ashkenazi Jewish descent and family history
of ovarian cancer in a close relative. She should be
1. A 58-year-old postmenopausal woman presents with vag- referred for genetic counseling and testing. If she is found
inal spotting which has been present for 1 month. She had to have a genetic syndrome which predisposes to ovarian
a normal Pap test last year. What is the next step in her cancer, then gynecologic referral is indicated, and pro-
management? phylactic bilateral salpingo-oophorectomy should be con-
A. Watchful waiting. Reevaluate if spotting persists more sidered to prevent ovarian cancer [75, 117].
than 6 months. 3. A 65-year-old woman presents with vaginal spotting for
B. Genetic testing to screen for high-risk mutations. 2 months. She has no history of malignancy and is not
C. Transvaginal ultrasound. sexually active. Her last Pap co-test was 2 years ago.
D. Repeat Pap test with HPV testing. The physical exam is significant for the absence of visi-
The correct answer is C. A postmenopausal woman with ble lesions of the vulva, vagina, or cervix, and there are
vaginal spotting or bleeding (PMB) requires evaluation no adnexal masses or tenderness. Vaginal atrophy is
to exclude endometrial malignancy. Pap tests are used to noted. Transvaginal ultrasound reveals an endometrial
screen for cervical cancer, but are not reliable to rule out stripe thickness of 2 mm. The most likely cause of her
endometrial cancer. Transvaginal ultrasound with mea- spotting is:
surement of the endometrial stripe is the first test used to A. Endometrial atrophy
evaluate a woman with postmenopausal bleeding. An B. Vaginal intraepithelial neoplasia (VIN)
endometrial stripe thickness over 4 mm is an indication C. Ovarian cancer
for endometrial biopsy to exclude malignancy when D. Uterine cancer
postmenopausal bleeding is present, although many E. Cervical cancer
gynecologists would perform an EMB first in cases of The correct answer is A. The most common cause of post-
PMB. Watchful waiting or repeat Pap test is not indi- menopausal bleeding (PMB) is endometrial atrophy. VIN
cated, as all postmenopausal bleeding requires evalua- is a very rare cause of vaginal bleeding, is typically caused
tion. Genetic testing is indicated in patients with a family by human papillomavirus (HPV). She tested negative for
history or personal history suspicious for inherited HPV 2 years ago, which makes VIN less likely. Ovarian
genetic syndromes associated with malignancy and cancer is not a common cause of PMB. Uterine cancer is
would not help to define the diagnosis in this case [31, of concern and must be excluded, but atrophy is more
33, 34]. common than cancer as a source of PMB. Cervical cancer
can present with PMB, but given her normal co-testing cal issues which may be impeding their sexual activity.
2 years ago, this is not a likely diagnosis [33, 118]. Estrogen may be contraindicated in patients with endo-
4. A 75-year-old woman who is in excellent health presents metrial cancer and should be prescribed in consultation
to establish care. She has not had a pelvic exam for with the gynecologic oncologist [119, 120].
10 years, as her previous primary care physician told her
that gynecologic exams were not necessary after the age
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Part III
Breast Health and Disease
Benign Breast Conditions
16
Brielle M. Spataro and Amy Fitzpatrick
complaints is first to exclude malignancy and then to manage

Learning Objectives the condition. In addition to evaluating and treating benign
1. Evaluate a patient with a palpable breast mass by breast conditions, patient education regarding breast health,
performing an appropriate history, physical exami- benign breast conditions, future cancer risk, and cancer pre-
nation, and evaluation. vention is paramount. This chapter discusses the broad range
2. Formulate evaluation and treatment plans for of benign breast conditions which present for evaluation to
benign breast masses based on BI-RADS classifica- the primary care provider.
tions and biopsy results.
3. Identify which classes and types of benign breast
masses increase the risk for breast cancer. Normal Breast Anatomy
4. Compare the presentation of different types of
breast inflammation and infection, and discuss Breasts are composed of milk-producing glands and sur-
appropriate treatment strategies. rounding fat. They rest on the pectoralis major but the breasts
5. Develop a differential diagnosis, evaluation, and themselves have no muscle tissue. Breast tissue is responsive
treatment plan for patients presenting with different to three main hormones: estrogen, progesterone, and prolac-
types of breast pain: cyclic, noncyclic, and tin. These hormones drive normal breast development,
extramammary. enlargement, and milk production. Each breast contains
6. Assess a patient presenting with nipple discharge about 15–20 lobes arranged in a circular fashion. Each lobe
including diagnostic testing as indicated. is, in turn, made up of many lobules. At the end of the lobes
are tiny bulblike glands where milk is produced. Ducts con-
nect the lobes, lobules, and glands and deliver milk to open-
ings in the nipple. The areola is the darker pigmented area
Benign breast conditions include a wide variety of presenta- around the nipple. Breast tissue is drained by lymphatic ves-
tions: asymptomatic incidental findings on mammography, sels that drain into the axillary lymph nodes [2] (Fig. 16.1).
palpated masses, breast infections, abnormal nipple dis-
charge, and breast pain. The incidence of benign breast con-
ditions peaks in the fourth and fifth decade of life, whereas Janet is a 35-year-old woman who presents with a pal-
breast cancer peaks at age 70. Benign breast conditions are pable breast mass in her right breast. She first noticed
much more common than breast cancer and are estimated to the mass 6 weeks ago and has noticed no changes
effect up to 90% of women at some time in their lives [1]. since that time. She has no pain, no family history of
The goal in the initial evaluation and management of breast breast cancer, no history of prior breast biopsies, or
history of chest irradiation. On clinical breast exam, a
1-cm, mobile, pea-sized mass, at 9:00, 5 cm from the
B. M. Spataro nipple, is appreciated.
University of Pittsburgh Medical Center, Department of Internal
A. Fitzpatrick (*) Every patient with a palpable breast mass should be eval-
Boston Medical Center/Boston University School of Medicine, uated and followed until there is a satisfactory diagnosis, and
Department of Internal Medicine, Boston, MA, USA
malignancy is excluded. The physician must take a thorough

260 B. M. Spataro and A. Fitzpatrick
–– Reproductive and gynecologic history: age of men-

arche, pregnancies and births including age of first
delivery, contraceptive use, age of menopause
–– Breast history: prior history of breast cancer, breast
masses, breast trauma, breast abnormalities or symp-
toms, prior imaging including breast density or abnor-
malities, prior biopsy and results, history of breast
Lymph nodes cancer and any surgery, radiation, chemoprophylaxis
or chemotherapy
–– Family history: breast or ovarian cancer in family
including age of diagnosis, other cancer history, or
Lobules Lobe known genetic testing
–– Habits: smoking, alcohol, diet, physical activity, living
situation, and occupation
Ducts
The Clinical Breast Exam
Nipple
The clinical breast exam (CBE) is a systematic and thorough
exam which is essential for evaluating all breast concerns. A
Areola careful CBE can take up to 6 min. During the exam, additional
history may be obtained, and general breast health education
Fat can be discussed. The patient should be gowned with the open-
ing of the gown in the front of the patient. Inspection of breast
National Cancer Institute
should take place while the patient is sitting or standing upright.
Fig. 16.1 Normal breast anatomy [3]. (Reprinted from NIH. The
Asymmetry, skin changes, puckering, nipple inversion, retrac-
National Cancer Institute [3]) tion, or discharge are noted, and supraclavicular and axillary
lymph nodes are palpated. The patient assumes the supine posi-
tion, and each breast examined, with the ipsilateral arm raised
patient history, perform a careful and systematic breast above the head, from the clavicle to the sixth rib and from the
examination, and order appropriate diagnostic imaging. An sternum to the midaxillary line. A systematic method, such as
overview of this process is outlined below. vertical lines, is used to ensure that no tissue is missed. Using
the pads of the index, middle, and ring fingers of one hand, the
breast tissue is palpated in three planes – superficial, medium,
The Comprehensive Evaluation of the Breast and deep – applying increasing pressure in a circular motion
(see Chap. 18 on “Breast Cancer Screening” for a detailed dis-
The following items should be included when evaluating a cussion and description of the CBE).
patient with breast concern [4, 5]: Any mass or thickening appreciated should be examined
closely. The approximate size, mobility, shape, texture, ten-
• Chief concern involving the breast(s) derness, and location should be described and documented.
• History of present illness: Standard descriptions of location include laterality, position
–– Elaboration of concern: presence of mass(es), pain, in the breast using a clockface nomenclature, distance in cen-
skin changes, nipple discharge, axillary symptoms, timeters from the edge of the mass to the nipple, and sub-
swelling, erythema, or fever areolar position or quadrant, such as upper versus lower and
–– Timing: duration of symptoms, change over time, medial (inner) versus lateral (outer). When ordering breast
change with menstrual cycle imaging or consultations, location needs to be described
–– Current reproductive status: last menstrual period, accurately [4, 5] (Fig. 16.2).
pregnancy status, breastfeeding status
• Past medical, social, and family history:
–– History of chest irradiation, any cancer, polycystic Breast Imaging
ovary syndrome (PCOS), and/or obesity
–– Medications (past and present): hormonal therapy, In patients over 30 years old with a palpable breast mass,
dopamine antagonists, selective serotonin reuptake focal pain, or pathologic nipple discharge, diagnostic mam-
inhibitors mography and ultrasound are recommended. In patients
16 Benign Breast Conditions 261
Fig. 16.2 Breast diagram 12 12

with superimposed clockface 11 1 11 1
Upper
and quadrants
10 2 10 2
9 3 9 3
8 4 8 4
7 5 7 5
6 6
Lower
Outer Inner Inner Outer
Right Breast Left Breast
under 30 years old, an ultrasound is recommended without

mammography. For the woman under 30 years old, observa- A diagnostic mammography and ultrasound are
tion over one or two menstrual cycles is an acceptable alter- ordered, and the results read BI-RADS 3, likely fibro-
native to imaging, for low clinical suspicion abnormalities. If adenoma. The patient wants to discuss the results.
the mass persists longer than 2 cycles, the mass should be
imaged. In high-risk or suspicious cases, however, consulta-
tion with a breast specialist is required, and MRI or mam- The patient’s palpable mass is most likely a fibroadenoma
mography may be recommended [6, 7]. based on mammography and ultrasound. A BI-RADS 3
In patients with an average cancer risk and a lesion of interpretation describes lesions that are most likely benign,
low suspicion, the negative predictive value of diagnostic but given their radiologic appearance, there is a less than 2%
mammography with ultrasound ranges from 97.4% to chance of malignancy (see Chap. 18 on “Breast Cancer
100% [6]. In general, women are average risk if there is no Screening” for table on BI-RADS categories and follow-up).
family history of breast or ovarian cancer, no history of BI-RADS 3 lesions must be monitored with short-interval
prior breast problems or breast biopsy, and no history of follow-up. Diagnostic mammography and ultrasound are
radiation to the chest prior to age 30 (please see Chap. 17 performed at 6, 12, and 24 months to ensure stability. If the
on “The Primary Prevention of Breast Cancer” and Chap. patient has other risk factors that increase the provider’s sus-
18 on “Breast Cancer Screening” for a full discussion of picion for underlying carcinoma, then core needle biopsy
assessing breast cancer risk). In higher-risk women or if should be performed [7].
clinical suspicion is high, consultation with a breast spe-
cialist and possible MRI or core needle biopsy should be
considered, even in the setting of negative imaging. An ifferential Diagnosis of Benign Breast
D
MRI should be performed, if needed, prior to biopsy, as a Lesions
biopsy can affect images. If biopsy is not performed after
consultation, then the patient needs close follow-up every Breast concerns are common, as are incidental findings on
6 months with CBE and imaging, usually ultrasound, to breast imaging. Most benign breast lesions, physiologic nip-
ensure stability, for 2 years. In addition, the patient should ple discharge, and breast pain collectively are blamed on
perform breast self-examination and practice breast aware- fibrocystic changes (FCC), or fibrocystic breast disease,
ness (see Chap. 18 on “Breast Cancer Screening”) and which is a broad clinical diagnosis encompassing many
report any changes in her symptoms urgently. Masses benign breast changes. FCC occurs most commonly in pre-
should be followed until there is a successful resolution. menopausal women and appears to be hormone related. The
As a risk management point, failure to diagnose breast definition of FCC is not standardized and may include all
cancer is one of the most common malpractice complaints. benign breast lesions or nonproliferative breast lesions only.
Careful documentation, open communication with the FCC has also been referred to as chronic cystic mastitis and
patient, and continued evaluation of patient concerns will mammary dysplasia. More specific diagnoses than the broad
help ensure that the patient is properly treated and satisfied term FCC help in determining the treatment needed and the
with care rendered. cancer risk for individual women.
Breast abnormalities which are biopsied, and given histo- A lipoma may present as a breast mass and reveals mature
logic diagnoses, are classified and treated according to the fat cells on biopsy. The recommended follow-up is clinical
risk of future malignancy for the patient (see Table 16.1 breast exam in 6 months; if lesion grows rapidly, it should be
below). The diagnoses are divided into three categories: non- excised [1, 8].
proliferative, proliferative without atypia, or atypical hyper- Fibroadenomas are the most common benign neoplasm
plasia. Nonproliferative lesions are benign and confer no of the breast and occur in 25% of asymptomatic women [1].
additional risk of cancer to the woman. Nonproliferative The peak incidence is 15–35 years of age. Lesions are hor-
lesions usually require no treatment, unless the mass is grow- monally dependent and present as highly mobile, firm, non-
ing, or if there is a concern for malignant potential. tender, palpable masses. Fibroadenomas are common breast
Proliferative lesions without atypia confer a slightly increased masses in young women, half of which are simple, or non-
risk of cancer, especially in a woman who is already at proliferative, and are not associated with an increased risk of
increased risk of breast cancer based on family history or breast cancer. One-half of fibroadenomas are complex, or
other risk factors. Some types of proliferative lesions are proliferative, and are described below [1, 8].
excised, and management is guided by a breast specialist (see The other nonproliferative breast conditions listed in
section below). Atypical hyperplasia is known to increase the Table 16.1 include papillary apocrine change, epithelial-
risk of breast cancer and women with this diagnosis should be related calcifications, mild hyperplasia of the usual type,
offered chemoprevention which can decrease the risk of ductal ectasia, nonsclerosing adenosis, and periductal fibro-
developing breast cancer by approximately 50%. These
patients should undergo risk assessment with the GAIL or
IBIS model to determine whether yearly MRI, in addition to Table 16.1 Benign breast lesions and the relative risk of future breast
cancer [8, 9]
routine mammography and increased surveillance, should be
performed (see Chap. 17 on “The Primary Prevention of Diagnosis based on clinical
evaluation including imaging and Relative risk of future breast
Breast Cancer” and Chap. 18 on “Breast Cancer Screening”). biopsy cancer
Nonproliferative lesions: No increased risk
Simple cystsa
Nonproliferative Benign Lesions Papillary apocrine change
Epithelial-related calcifications
Mild epithelial hyperplasia
Nonproliferative lesions are not associated with any increased Ductal ectasia
risk of future breast cancer. Cysts, the most common type of Nonsclerosing adenosis
benign breast disease, are fluid-filled round or ovoid struc- Periductal fibrosis
Simple fibroadenoma
tures. They are found in up to one-third of women aged Fat necrosis
35–50. Cysts are classified as simple or complex based on Galactocele
ultrasound findings. Simple cysts are benign and do not Lipoma
require treatment. If the cyst is bothersome, then a fine nee- Proliferative lesions without Slightly increased risk
dle aspiration (FNA) with drainage can be both curative and atypia: No family Family history
Epithelial hyperplasia (ductal or history of of breast
reassuring to the patient. Follow-up of simple cysts is not lobular) breast cancer cancer
needed. Complex cysts, also called complicated or atypical Sclerosing adenosis RR 1.3–1.9 RR 2.4–2.7
cysts, are diagnosed based on ultrasound findings of internal Radial scar
echos, thin septations, thickened or irregular walls, or absent Intraductal papilloma
Papillomatosis
posterior enhancement. Complex cysts are managed with Complex fibroadenoma
follow-up imaging to document stability or resolution. Hamartoma
Intracystic masses, when present, are managed as other solid Proliferative lesions with atypia: Increased risk of breast cancer
masses with biopsy, either excisional or core as indicated, to Atypical ductal hyperplasia No family Family history
(ADH) history RR 4.7–22
ensure appropriate tissue diagnosis. The risk of malignancy
Atypical lobular hyperplasia RR 4.1–4.3
for complex cysts is approximately 0.3% [8, 9]. (ALH)
Fat necrosis may present as a mass or as an oil cyst and Lobular carcinoma in situ RR 10.0
may be the result of breast trauma or surgery. Fat necrosis (LCIS)
may require biopsy, but once diagnosis is confirmed, no fur- Ductal carcinoma in situ (DCIS) RR 17.3 after biopsy without
treatmentb
ther treatment is necessary.
A galactocele is a cystic collection of fluid caused by an
a
Simple cysts may be diagnosed without biopsy, although fine needle
aspiration (FNA) with drainage may be curative. Complex cysts require
obstructed milk duct. The diagnosis is confirmed with aspi- additional evaluation to exclude malignancy
ration of milky fluid from the cyst. No further management is b
DCIS is a noninvasive malignancy with a variable history. RR of inva-
necessary. sive cancer is high without treatment [10, 11]
sis. These changes are benign and do not require additional with lesions of atypical hyperplasia, lobular carcinoma in
evaluation or treatment. situ (LCIS), ductal carcinoma in situ (DCIS), or invasive
breast carcinoma [8].
An intraductal papilloma is a tumor of the epithelium of
Proliferative Lesions Without Atypia mammary ducts that usually presents with serous or serosan-
guinous nipple discharge (see section “Nipple Discharge”).
Proliferative lesions without atypia are associated with an While central, single papillomas are not considered to be
increased risk of subsequent breast cancer. The relative risk premalignant or carry an increased risk of breast cancer,
(RR) of future breast cancer is 1.3–1.9 if there is no family there is a correlation between papillomas and atypical ductal
history of breast cancer and increases to 2.4–2.7 if there is a hyperplasia. Excisional biopsy is recommended with no fur-
family history of breast cancer [8, 9]. ther treatment needed, assuming benign pathology.
Complex Fibroadenoma. Approximately half of fibroade- Papillomatosis describes a minimum of five separate papil-
nomas are complex meaning they have proliferative changes: lomas. It is more likely to occur bilaterally and to have an
sclerosing adenosis, adenosis, or duct epithelial hyperplasia. associated in situ or invasive carcinoma than central papil-
Complex fibroadenomas confer a slightly higher risk for sub- lomas. It may indicate a slightly increased risk of breast can-
sequent cancer [9]. The management of proliferative lesions cer. Surgical excision of papillomatosis is recommended [8].
varies and is often based on size. The majority are monitored A small number of papillary tumors will be found upon exci-
closely with imaging every 6 months for 2 years to ensure sion to contain invasive carcinoma and should be treated
stability. Biopsy is indicated for lesions with suspicious accordingly.
findings on imaging, growth during the surveillance period, Phyllodes tumor is a benign fibroepithelial tumor of the
or increased clinical concern. Biopsy-proven fibroadenomas breast which arises from the connective tissue and may dis-
greater than 4 cm in size are removed surgically or treated play a spectrum of cellular changes like fibroadenomas.
with office-based, ultrasound-guided cryoablation [8, 12]. Women with Li-Fraumeni syndrome are at increased risk of
Epithelial hyperplasia is the most common form of pro- phyllodes tumors. Tumors with recurrent or malignant
liferative breast disease and refers to any increase in the behavior are identified by hypercellular stroma with atypia,
number of cells in the ductal space. Hyperplasia may involve increased mitoses, and infiltrative margins. Phyllodes tumors
cells of ductal or lobular origin. Hyperplasia is stratified into need to be surgically excised with clear margins, and recur-
three categories: mild, moderate, and florid. Mild hyperpla- rence is often treated with mastectomy [8]. Malignant phyl-
sia consists of three to four cell layers of epithelial cells, lodes tumors, those with distant metastases, are technically
moderate hyperplasia is greater than four cells in depth, and sarcomas and may be resistant to therapy. Malignant tumors
florid hyperplasia fills the ductal lumen, which may become are treated with surgical excision and may often require radi-
obliterated and distended [9]. Mild hyperplasia occurs nor- ation and sometimes chemotherapy.
mally as breast tissue responds to hormonal influences and is Adenomas are pure epithelial neoplasms that are further
not pathologic. Hyperplasia without atypia does not require classified as tubular, lactating, apocrine, ductal, or pleomor-
specific treatment, regardless of severity. phic. Adenomas usually present as a solitary palpable mass,
Adenosis of the breast is a proliferative lesion that consists do not recur, have no malignant potential, but may require
of an increased number of glandular components. Sclerosing excision due to mass effect [2, 8].
adenosis is a lobulocentric lesion of disordered acinar, myo- A hamartoma is an uncommon tumor and is composed of
epithelial, and connective tissue. Sclerosing adenosis can glandular, adipose, and fibrous tissue. Coincidental malig-
mimic infiltrative carcinoma histologically and therefore can nancy can exist, and therefore, surgical excision is recom-
be diagnostically challenging for pathologists. Microglandular mended [1, 8].
adenosis is a proliferation of round, small glands distributed
irregularly in dense fibrous or adipose tissue that recurs if not
completely excised [8]. These lesions may or may not be Janet returns 6 months later for follow-up with a clini-
excised, and no further treatment is needed. cal breast exam and repeat imaging. She is doing well
A radial scar is a fibroelastic core with entrapped ducts and believes the mass has gotten smaller. On clinical
surrounded by radiating ducts and lobules which can mimic exam, it is unclear whether the mass has changed in
carcinoma on mammography. The lesion often has the size. Repeat imaging shows a stable mass, likely fibro-
appearance of a scar, thus its name, although it is often not a adenoma. She is followed with imaging every 6 months
true scar. It is recommended that radial scars be completely for 2 years to ensure stability, at which point her mam-
excised when found on biopsy. Radial scars require careful mography changes to BI-RADS 2.
management as they may be premalignant markers or coexist
vention: with tamoxifen if she is premenopausal, and

Norah is a healthy 46-year-old woman who had a raloxifene or aromatase inhibitor therapy if she is postmeno-
screening mammogram. It is read as having suspicious pausal. The choice of hormonal therapy agents and duration
calcifications and is classified as BI-RADS 4. Norah is of therapy are discussed separately (see Chap. 17 on “The
referred for biopsy. Primary Prevention of Breast Cancer” for a full discussion).
Lobular neoplasia is a term which includes atypical lobu-
lar hyperplasia (ALH) and lobular carcinoma in situ (LCIS).
A core needle biopsy is recommended in cases where ini- Lobular neoplasia is nonmalignant and primarily affects pre-
tial imaging is read as BI-RADS 4 or 5 or if there is a high menopausal women. It is often multifocal and is bilateral in
clinical suspicion for invasive carcinoma, even if there is no a third of cases. Lobular neoplasia is usually an incidental
palpable mass [7]. A reading of BI-RADS 4 is “suspicious” finding on mammography or biopsy and traditionally has not
and the risk of malignancy ranges from low (2–9%) for 4A, been considered premalignant. Lobular abnormalities resem-
moderate (10–49%) for 4B to high (50–94%) for ble adipose cells in terms of density, can grow in a weblike
4C. BI-RADS 5 is “highly suggestive of malignancy” and pattern, are usually without calcifications, and can be invisi-
carries a risk of 95–100% for malignancy. ble on mammography, even if malignant. If lesions with the
If the results of a core needle biopsy are benign and con- pathologic diagnosis of atypical lobular hyperplasia (ALH),
cordant with imaging, these patients may return to routine or lobular carcinoma in situ (LCIS), are nonconcordant with
screening or continue short interval follow-up with CBE and imaging, or if the biopsy reveals pleomorphic LCIS, then
mammography every 6–12 months for a year. If there is a sig- surgical excision is recommended. However, if ALH or LCIS
nificant increase in size in the lesion or high clinical suspicion are concordant with imaging and are not pleomorphic, then
for carcinoma, then surgical excision is performed [8]. observation with physical exam and breast imaging every
Surgical excision is indicated for lesions that are indeter- 6–12 months for a year may be considered [7].
minate on core needle biopsy, benign, and image discordant The relative risk of subsequent breast cancer is increased 4
or show atypical ductal hyperplasia, mucin-producing times in women with ALH and is increased 10 times in patients
lesions, phyllodes tumor, or other histology of concern to the with LCIS compared to women without these lesions. Patients
pathologist. Some patients with flat epithelial atypia, papil- with ALH or LCIS should be offered chemoprophylaxis and
lomas, fibroepithelial lesions, or radial scars, in consultation increased surveillance (exam every 6–12 months and yearly
with a breast specialist, may be candidates for close monitor- mammography for the remainder of her life) to decrease the
ing rather than excision. Treatment decisions are agreed risk of breast cancer (see Chap. 17 on “The Primary Prevention
upon by the patient and breast specialist through shared of Breast Cancer”). Recent studies have called into question
decision-making [8]. the idea that ALH and LCIS have a more benign natural his-
tory than atypical ductal hyperplasia [7, 13].
Atypical ductal hyperplasia (ADH) is morphologically
Norah undergoes biopsy, and the pathology report similar to DCIS and is more likely to manifest as calcifica-
shows atypical ductal hyperplasia. She is seen by a tions on mammography then as a palpable mass. ADH is a
breast surgeon and has a subsequent surgical excision. high-risk, premalignant lesion and is a direct precursor to
Final pathology is consistent with “atypical ductal invasive ductal carcinoma. The associated risk of breast can-
hyperplasia, no invasive or in situ carcinoma seen.” cer is highest in the 5–15 years following the diagnosis of
The patient understands that her risk of breast cancer ADH and may occur in the ipsilateral or contralateral breast.
is increased and agrees to chemoprevention. She is Surgical excision is the standard recommendation for ADH
premenopausal and is prescribed tamoxifen (see Chap. lesions, as a significant percentage of lesions are upgraded to
17 on “The Primary Prevention of Breast Cancer”). DCIS or invasive carcinoma on surgical pathology [7].
Chemoprophylaxis with selective estrogen receptor modula-
tors (SERMs) or aromatase inhibitors (AIs) is recommended
for women with ADH. It should be noted that prophylactic
Proliferative Lesions with Atypia treatment is currently greatly underutilized by patients and
primary care providers despite the safety and efficacy of che-
Proliferative lesions with atypia are associated with an mopreventive agents (see Chap. 17 on “The Primary
increased risk of breast cancer. Atypical lesions are classified Prevention of Breast Cancer”) [13, 14]. DCIS is a noninva-
as lobular or ductal. Women with a history of atypical lobular sive malignancy and is discussed elsewhere (see Chap. 19 on
hyperplasia or atypical ductal hyperplasia should avoid “Breast Cancer Diagnosis and Management”).
exogenous hormones like hormonal contraceptives or hor- All women with a history of LCIS, ADH, or ALH are con-
mone replacement therapy and should be offered chemopre- sidered high risk for breast cancer. From the time of diagno-
sis, patients should have a breast risk assessment clinical tors are used. Major side effects of all antiestrogen treat-
encounter every 6–12 months. During this encounter, ments include hot flashes, vaginal atrophy, and menopausal
updated medical and family history should be reviewed to symptoms. AIs can be associated with fatigue and muscle
update risk assessment. The patient should have risk reduc- and joint aches; however, the side effects associated with pla-
tion counseling and a clinical breast exam. Annual screening cebo use are nearly equivalent to AI use [9]. Some AIs may
mammography is recommended to begin at the diagnosis of increase risk of thromboembolic events to a similar degree as
ADH/ALH or LCIS but not prior to age 30. Annual breast SERMs. A full discussion or AI and SERM use is beyond the
MRI is recommended in high-risk women over the age of 25 scope of this chapter.
who have an estimated lifetime risk of breast cancer greater
than 20–25 percent (see Chap.18 on “Breast Cancer
Screening”). Chemoprevention with a SERM or AI should Mastitis and Breast Abscess
be offered to all patients with ALH, ADH, or LCIS [5, 9] (see
Chap. 17 on “The Primary Prevention of Breast Cancer”). Adriana is a 42-year-old woman who reports severe
For chemoprevention, premenopausal women should be breast pain on the left for the past 8 h. She is breast-
offered tamoxifen, 20 mg per day for 5 years, which has been feeding her third child. She is advised by the nurse to
shown to decrease the risk of breast cancer by up to 49% in keep breastfeeding, get rest, apply warm and cold com-
women with ALH or LCIS. In premenopausal women with presses, and use nonsteroidal anti-inflammatory agents
ADH, the benefit is greater, and tamoxifen use has been (NSAIDS). She will come in to clinic tomorrow morning
associated with an 86% reduction in breast cancer risk. In to be seen if her symptoms do not improve by then.
postmenopausal women, the preferred treatment is raloxi-
fene 60 mg per day for 5 years. Raloxifene is as effective as
tamoxifen in decreasing the risk of invasive breast cancers
but may be slightly less efficacious in preventing DCIS. For Puerperal Mastitis
women with a uterus, this difference is offset by the fact that
raloxifene does not increase the risk of uterine cancer. The most common type of breast infection is lactational or
Both tamoxifen and raloxifene increase bone mass, and puerperal mastitis. The incidence ranges from 2% to 11% of all
raloxifene is approved in both the prevention and treatment breastfeeding women, although some studies have estimated
of osteoporosis. The risk of venous thrombotic events is the incidence to be as high as 27% [14, 15]. It most commonly
1–3/1000 for patients taking tamoxifen or raloxifene. occurs in the first 12 weeks of breastfeeding and often presents
Contraindications to the use of tamoxifen and raloxifene as a swollen, painful, and red breast. Women may develop a
include prior deep vein thrombosis, pulmonary embolus, low-grade fever and generalized malaise 12–24 h after symp-
thrombotic stroke, transient ischemic attack, or clotting dis- toms appear. Breast engorgement initially occurs due to poor
order. Major side effects include menopausal symptoms. milk drainage which can be caused by a number of factors,
Vaginal bleeding on tamoxifen must be further evaluated as including interrupted or erratic feeding patterns, a sudden
it is associated with an increased risk of endometrial cancer change in the number of feeds, skipped feedings, nipple trauma,
(see Chap. 15 on “Gynecologic Malignancies”). Ongoing tri- poor positioning and latch-on, a short frenulum in the infant,
als evaluating lower doses of tamoxifen for chemoprophy- mother or infant illness, and separation of mother and infant
laxis suggest comparable efficacy and lower complication with reduced frequency of breastfeeding [16].
rates to the traditional dose of tamoxifen 20 mg per day. If symptoms persist beyond 12–24 h, the condition is con-
Further study is needed to define optimal chemoprevention sidered to be infective lactational mastitis and bacteria are
strategies and increase the acceptance of chemoprevention found in both the milk and within the mother’s skin.
among patients and PCPs. Lactational infections are frequently located peripherally.
Aromatase inhibitors (AIs), including exemestane and Lactational infections are readily recognized and treated by
anastrozole, are prescribed to postmenopausal women who primary care or obstetric providers and therefore account for
cannot tolerate selective estrogen receptor modulators <15% of infections seen in breast clinics [17].
(SERMS). Exemestane, 25 mg daily, reduces breast cancer
incidence by 65% at 3 years. Anastrozole, 1 mg daily, reduces
the relative incidence of breast cancer by 53% at 5 years [9]. Adriana comes in to clinic the next day with increasing
The major disadvantage of AIs is the increased risk of pain. Any movement of the breast is excruciatingly
osteoporosis associated with antiestrogen therapy. Baseline painful, and there is a mass in the center of the painful
bone density should be evaluated in all postmenopausal area. She does not have a fever, but reports she has
women prior to starting treatment with SERMs or AIs and been experiencing shaking chills for the past 30 min.
monitored every 2 years, especially when aromatase inhibi-
When the treatment of lactational mastitis is delayed or seled about the prevention and management of blocked
inadequate, a lactational abscess may develop [14–16]. A ducts with adequate fluid intake, rest, frequent breastfeed-
palpable mass may be present and may represent a preexisting, warm compresses and gentle massage, and expulsion
ing breast mass, a blocked duct, or an abscess. If a palpable of duct plugs when possible.
mass is present, an ultrasound will differentiate the etiology,
i.e., whether edema, a mass, or an abscess is present. Women
can become toxic with high fevers and experience extreme Bridgette is a 40-year-old African American woman
pain, requiring intravenous antibiotics, intravenous fluids, who presents to clinic with a painful, warm, and ery-
analgesia, and ultrasound drainage of any fluid collection. thematous right breast. She reports that she developed
Fungal mastitis is a less common entity that presents with pain and redness around the areola which progressed
pain out of proportion to physical findings. Fungal mastitis into ulceration and drainage 2 days ago. Bridgette
occurs in the setting of thrush in the infant and is treated with reports the pain is so severe, that she is unable to wear
topical or oral antifungals for mother and infant. a bra and has not been able to sleep. She denies fevers
but reports that she has pain when she bumps or jostles
her right breast. She is not pregnant or breastfeeding,
reatment of Lactational Mastitis
T and her youngest child is 22-year-old.
and Abscess
Lactational mastitis generally does not require diagnostic

imaging. Symptomatic treatment with NSAIDS, cold or Nonpuerperal Mastitis
warm compresses, and complete emptying of the breast by
breastfeeding or pumping are recommended during the first Nonpuerperal, or nonlactational, mastitis is an uncommon
12–24 h. If symptoms persist for more than 12–24 h, then disorder and describes all the causes of inflammatory changes
antibiotics are recommended in addition to symptomatic in the breast not related to lactation. Nonpuerperal mastitis
treatment [14, 15]. may occur due to a ruptured cyst and may be self-limited;
In infective lactational mastitis or abscess, the most com- however, malignancy should be excluded.
mon causative organism is Staphylococcus aureus. Empiric Mammary duct ectasia, also referred to as periductal
antibiotic therapy for lactational mastitis depends upon mastitis, is a benign condition that becomes more common
methicillin-resistant Staphylococcus aureus (MRSA) risk as women approach menopause. The lactiferous ducts
and age of the newborn. Risk factors for MRSA include become shorter and wider and may become clogged. Initially,
recent hospitalizations, residence in a long-term care facility, squamous metaplasia of the cuboidal epithelium of the ducts
hemodialysis, a history of intravenous drug use (IVDU), a leads to increased keratin formation and obstruction of the
history of incarceration, and being a health-care worker. In duct lumen. Blockage of ducts with cellular debris results in
many communities, MRSA has become common without dilatation and, ultimately, the formation of a foreign body
significant risk factors. inflammatory reaction around the extruded keratin. A green-
Choices of antibiotics for empiric therapy include: ish discharge may be noted from the nipple. Secondary
infection may occur due to stagnation of the intraductal fluid,
• No MRSA risk factors: which predisposes to abscess formation and cutaneous fistu-
–– Dicloxacillin 500 mg four times daily or las [17, 18].
–– Cephalexin 500 mg four times daily or Nonpuerperal abscesses have been characterized into two
–– Clindamycin 300 or 450 mg three times daily (indi- types and are differentiated by location. Peripheral nonpuer-
cated if beta-lactam hypersensitivity present) peral abscesses are uncommon compared to central or peri-
• MRSA risk factors: areolar abscesses. Risk factors for the development of
–– Trimethoprim-sulfamethoxazole 1 double-strength nonpuerperal abscesses are Black race, obesity, and smoking
tablet twice daily (only if infant is >2 months old, or [18]. It is thought that nonpuerperal abscesses form as a
beyond the newborn period) or complication of mammary duct ectasia.
–– Clindamycin 300 or 450 mg three times daily Peripheral nonpuerperal abscesses are generally associ-
ated with trauma, acne, epidermal cysts, and chronic condi-
Treatment should be given for 10–14 days. tions such as diabetes and rheumatoid arthritis [17]. Central
Trimethoprim- sulfamethoxazole should not be used in or subareolar abscesses affect women in a wide age range,
mothers nursing newborns or in immunocompromised from teens to the eighth decade, with peak incidence in mid-
infants due to the increased risk of kernicterus. Lactational to late forties [17]. Subareolar abscesses may present unilat-
mastitis does not usually recur, but women should be coun- erally or bilaterally and symptoms vary depending on the age
of the patient. Younger patients often report more breast pain

than older patients. Palpable masses associated with this type Bridgette’s breast ultrasound revealed a large subare-
of breast infection are common and are generally associated olar fluid collection which was amenable to drainage.
with overlying erythema. Approximately 15–20% of women The patient was screened for MRSA risk factors and
with subareolar abscesses report discharge or drainage, and found to have none. She was prescribed cephalexin
infections often involve anaerobic bacteria. Nonpuerperal 500 mg four times daily for 7 days. During her follow-
abscesses frequently recur (>50%) and often require multi- up visit 2 weeks later, the patient was doing well with
ple drainage or surgical procedures. Fistulas form in up to resolution of her right breast abscess. Now, 3 months
one-third of recurrent cases and are associated with mixed later, Bridgette returns with the same symptoms.
aerobic and anaerobic infections [17].
Recurrences of subareolar abscesses are common and

Bridgette reports that she is nervous about having any occur in more than 50% of cases. Several risk factors are
sort of procedure and would like to avoid “needles” if associated with higher rates of recurrence and delayed recov-
possible. Her clinical breast exam is notable for swell- ery, including cigarette smoking, the presence of mixed flora
ing and erythema of the right areola extending into the infections, anaerobic infections, and Proteus organisms [17].
surrounding skin laterally, at 9 o’clock. There is a The relative risk of subareolar abscess recurring is directly
small open area that is draining purulent material. related to the intensity of cigarette smoking, with heavier
smokers more likely to experience recurrence [16]. The exact
mechanism by which smoking increases the risk of abscess
The treatment of nonpuerperal abscesses includes is not known; however, one theory is that squamous metapla-
ultrasound-
guided aspiration and drainage and antibiotic sia occurs in a similar fashion to the smoking-related squa-
therapy. Abscesses that are not amenable to ultrasound- mous metaplasia of bronchial mucosa, which is related to the
guided drainage are treated with antibiotics and warm com- level of smoking intensity. Nicotine and its metabolite coti-
presses. The most common organisms are Staphylococci, nine can be detected in breast milk within 30 min of smok-
Enterococci, anaerobic Streptococci, Bacteroides, and ing. Another theory suggests that smoking decreases the
Proteus. bioavailability of estrogen which negatively affects ductal
Empiric antibiotic therapy for nonpuerperal abscess [17, integrity [16].
18] include the following:
• No MRSA risk factors: Bridgette again underwent ultrasound-guided drain-

–– Amoxicillin-clavulanate 875–125 mg twice daily or age of her right breast abscess and was started back on
–– Dicloxacillin 500 mg four times daily or cephalexin. She admitted to smoking ½ pack per day
–– Cephalexin 500 mg four times daily for more than 20 years and reported that she would try
• If anaerobes are suspected (especially subareolar to cut back. On follow-up 2 weeks later, she had reso-
infections): lution of her abscess. Now, 2 months later, she presents
–– Clindamycin 300 or 450 mg three times daily PLUS with a third recurrence. On clinical exam, she has no
metronidazole 500 mg three times daily or drainage or discharge, but has more significant skin
–– Amoxicillin-clavulanate 875–125 mg twice daily or thickening, a 1-cm palpable mass, and a slight retrac-
–– Clarithromycin 500 mg PO BID, plus metronidazole tion of her right nipple on exam.
500 mg PO TID [19]
• MRSA risk factors:
–– Trimethoprim-sulfamethoxazole one double-strength In patients who present with signs of skin thickening, sub-
tablet twice daily or areolar mass, and retraction of the nipple, there is often con-
–– Doxycycline 100 mg twice daily or cern for a malignancy, such as inflammatory breast cancer.
–– Clindamycin 300 or 450 mg three times daily Mammographic findings in inflammatory breast cancer and
those found with subareolar abscess or infection often over-
Cases that are refractory to medical management are lap and can include skin thickening, trabecular prominence
referred for surgical intervention [17]. The optimal duration or edema, and asymmetric density [17]. Frequently, masses
of antibiotics is not known. Mild to moderate cases can be associated with inflammatory breast cancer are solid masses,
treated with 7 days of antibiotics, with more severe cases whereas those associated with abscess or infections are cys-
requiring 10–14 days of antibiotics [17, 18]. tic or mixed [17]. If imaging with breast mammogram and
ultrasound are not diagnostic, a biopsy will confirm the diag- Mastalgia or breast pain is a common complaint of women
nosis. In addition to inflammatory breast cancer, the differen- and the most frequent reason for breast-related office visits
tial diagnosis includes granulomatous mastitis, Mondor’s [22, 23]. One large population study showed that approxi-
disease (superficial thrombophlebitis of a vein in the antero- mately 50% of women experience breast pain with 41%
lateral thoracoabdominal wall), and sarcoidosis of the breast, reporting a negative impact on their sex life and 35% report-
or more rarely, cat scratch disease and tuberculosis of the ing a negative impact on sleep [22]. Other studies estimate the
breast. Further management depends upon biopsy and cul- prevalence as high as 70% [24]. Although some women visit
ture results, in consultation with a breast specialist. the doctor for breast pain out of fear for breast cancer, the
Granulomatous mastitis presents similarly to breast prevalence of breast pain is likely underreported because
abscesses and patients are generally referred to a breast clinicmany women do not go to the doctor for this problem.
after multiple unsuccessful antibiotic courses and drainage The history in the breast pain patient includes (1) the
attempts. Core needle biopsy provides a definitive diagnosis quality, location, duration, and radiation of the breast pain as
with the presence of nonnecrotizing granulomas that are well as triggering and alleviating factors; (2) breast symp-
negative for microorganisms in the setting of no other sys- toms such as a breast mass, nipple discharge, or skin changes;
temic granulomatous disease. The treatment for persistent or and (3) hormonal influences such as relation to menses, preg-
severe granulomatous mastitis includes corticosteroid ther- nancy, contraceptive use, and, in postmenopausal women,
apy or methotrexate [20]. hormonal therapies [25]. Medications are reviewed, because
some medications can be associated with breast pain (see
Bridgette has a diagnostic mammogram and repeat below). Risk assessment for breast cancer includes a detailed
ultrasound performed, which shows an irregularly reproductive, family, and medical history. The medical his-
shaped subareolar mass that is cystic with some inter- tory sometimes provides clues to extramammary etiologies.
nal debris and small associated fluid collection For example, hidradenitis suppurativa, neck or back arthritis,
(BI-RADS 4). A core needle biopsy is performed which fibromyalgia, depression, or anxiety may provide clues to
demonstrates inflammation but no granulomatous dis- underlying causes of the report of breast pain. Finally, a thor-
ease or malignancy. The patient is referred to a breast ough CBE should be performed.
surgeon for further evaluation. There are three broad classifications of breast pain includ-
ing cyclical, noncyclical, and extramammary breast pain.
Cyclical breast pain by definition occurs in premenopausal
Patients who fail medical management with ultrasound- women and fluctuates in intensity throughout the menstrual
guided drainage and antibiotics should be referred to breast cycle. Cyclical breast pain is generally diffuse and bilateral
surgeon for possible surgical excision of the abscess and although it may be worse in one breast and often occurs in
involved ducts. There have been several studies suggesting the upper outer quadrants, radiating to the axilla. Cyclical
that surgical excision of the abscess, affected ducts, and fis- breast pain starts during the luteal phase of the menstrual
tulae should be done early, on initial presentation, resulting cycle, increasing in intensity until the onset of menses. Some
in lower recurrence rates. One study showed the recurrence women report pain during the entire cycle, with intensifica-
rate after excision was 28% versus 79% after management tion of pain during luteal phase prior to the onset of menses.
without surgical excision [21]. Breast pain may increase in the luteal phase because luteal
hormones increase water content in the breast stroma [25].
Psychological factors may also play a role, as several studies
Breast Pain have shown higher rates of anxiety and depression in women
with breast pain compared to asymptomatic women, and
Tatiana is a 27-year-old Columbian woman who pres- mood may worsen in the premenstrual weeks [26]. Cyclical
ents to clinic complaining of cyclic breast pain for breast pain resolves spontaneously in 20–30% of women, but
4 months. She reports pain for 1–2 weeks at a time recurs in 60% of women [24]. Remission of cyclical mastal-
before the pain resolves. The pain seems worse in the gia can occur after hormonal events such as pregnancy or
weeks prior to menses. She reports she has more pain menopause [25].
on the left side than the right. When asked where the Noncyclical breast pain is intermittent or constant breast
pain is located, Tatiana indicates the entire breast is pain that is not related to the menstrual cycle. It is less com-
painful. She reports regular menses and denies the use mon than cyclical mastalgia and tends to be unilateral and is
of contraceptives. On clinical breast exam, the patient often localized to a quadrant of the breast. There is a spec-
has diffuse tenderness to palpation without a discrete trum, however, and some women present with diffuse breast
or dominant mass. pain that radiates to the axilla. Noncyclical breast pain tends
to present later in life and affects women in the fourth and
fifth decades, although many of the women are postmeno- physical exercise, relaxation training, dietary changes such
pausal at the onset of symptoms [25]. In the majority of as reducing dietary fat and reducing or eliminating caffeine,
cases, there is no identified cause for noncyclical breast pain; and warm or cold compresses. Vitamin E and evening prim-
however, some identified causes include trauma, mastitis, rose oil (EPO) are sometimes recommended although a
cysts, benign tumors, or cancer. The cause of noncyclical recent systematic review found that the effectiveness of vita-
breast pain is thought to be more anatomical than hormonal min E was unknown and that evening primrose oil (EPO)
[25]. Large pendulous breasts may cause ligamentous pain lacked efficacy [24]. Despite mixed reviews, EPO is recom-
and may be improved with the use of a well-fitting support mended by many breast specialists as a benign remedy which
bra [27]. may help some patients with breast pain. NSAIDs such as
There has been some association between medications diclofenac gel have been found to be effective in relieving
and noncyclical breast pain, especially with hormonal medi- breast pain and should be considered as a first-line agent, as
cations such as estrogen, progestin, and menopausal hor- benefits outweigh the risks for most women [24]. Women
monal therapy. Other medications associated with breast with large painful breasts who also experience neck or back
pain include some antidepressants (specifically selective pain may be candidates for breast reduction surgery.
serotonin reuptake inhibitors, SSRIs), antipsychotics, anti- Many women with cyclical breast pain experience relief
fungals, and methadone [25]. These medications are sus- with hormonal contraceptives which prevent the monthly
pected to cause breast pain through several pathways: hormonal fluctuations associated with ovulation; however,
antipsychotics and methadone (opiates) are thought to con- there have been no high-quality randomized controlled stud-
tribute to breast pain by their antagonism of dopamine recep- ies to evaluate efficacy [25]. In contrast, some women, espe-
tors in the CNS, which causes an increase in prolactin by the cially young women and teenagers, experience breast
pituitary gland. Antifungals are known to inhibit androgen swelling and tenderness when using oral contraceptives.
synthesis which increases breast tissue growth. Other hormonally active medications used to treat severe
There is also a high incidence of breast pain after breast breast pain, including danazol and tamoxifen, are effective at
surgery, including mastectomy, augmentation, reduction, reducing breast pain; however, they are associated with a
lumpectomy, and excision [25]. Noncyclical breast pain number of adverse effects and are not frequently used for this
responds poorly to treatment but tends to resolve spontane- purpose. Danazol is the only FDA-approved medication for
ously in half of women [24]. the treatment of mastalgia and it works by suppressing
Extramammary pain presents as breast pain but has many gonadotropin secretion, preventing the luteinizing hormone
other etiologies. The most frequent extramammary cause of surge, and inhibiting ovarian steroid formation. Its adverse
breast pain is costochondritis or other chest wall conditions effects include weight gain, deepening of the voice, menor-
including Tietze syndrome (swelling and pain of the 1st two rhagia, and muscle cramps [24, 25]. Tamoxifen is a selective
costo-sternal joints), slipping and clicking ribs, bruised or estrogen receptor modulator and is effective in reducing both
fractured ribs, and cervical arthritis [25]. Other extramam- cyclic and noncyclic mastalgia in clinical trials [25].
mary causes include fibromyalgia, back or shoulder pain, Tamoxifen increases the risk of potentially fatal events such
pericarditis, gastroesophageal reflux, cholelithiasis, or as blood clots, stroke, and endometrial cancer, and its adverse
angina [25]. Extramammary causes can usually be identified effects include hot flashes, mood swings, and gastrointestinal
on history and clinical breast exam; however, in the cases of symptoms [24]. Tamoxifen has the benefit of reducing breast
diffuse pain syndromes or patients who are unable to give an cancer risk and is discussed in Chap. 17 on “The Primary
accurate history, additional investigation may be required. Prevention of Breast Cancer”. Bromocriptine, a dopamine
Musculoskeletal causes of pain are treated with heat, nonste- agonist, has been shown to reduce breast pain; however, it is
roidal anti-inflammatory medication, and physical therapy as no longer licensed for this indication in the USA due to the
indicated. intolerable adverse effects of nausea, postural hypotension,
and constipation [25].
Treatment of Breast Pain

Tatiana reports that she had some improvement in pain
The majority of women who present with mastalgia are reas- after eliminating caffeine and buying a new, more sup-
sured after normal findings on evaluation (either clinical portive bra. However, she reports she is now having
breast exam or imaging) and decline other interventions [25]. more pain in her left breast on the lateral side. Her
Many nonpharmacological interventions are used to treat clinical breast exam is notable for focal tenderness in
cyclical or noncyclical breast pain; however, there are very the left breast, laterally, at 2 o’clock, 6 centimeters
few studies to support their efficacy. These interventions from the nipple.
include recommending a properly fitted and supportive bra,
Women with nonfocal breast pain can be provided reas-

surance and do not need diagnostic imaging. Nonfocal mas- The clinical breast exam reveals no breast masses and
talgia can be managed with both pharmacological and the patient demonstrates manual expression which
nonpharmacological treatments. produces a drop of milky fluid bilaterally. The dis-
Women with focal breast pain should be evaluated with charge tests negative for blood on Hemoccult. Serum
diagnostic imaging according to National Comprehensive prolactin and TSH are normal.
Cancer Network (NCCN) guidelines. Women under the age
of 30 are evaluated with a diagnostic breast ultrasound of the
painful area. Women aged 30 and over are evaluated with a Physiologic discharge often is bilateral, involves multi-
diagnostic bilateral mammogram and diagnostic breast ultra- ple ducts, tests negative for blood, and is associated with
sound [7, 27]. nipple stimulation or breast compression [29]. Galactorrhea
is a bilateral milky white discharge that is normal in women
who are pregnant or breastfeeding. After pregnancy, it is
The left breast ultrasound shows normal breast tissue normal to have discharge for up to 1 year after cessation of
and the patient is relieved. She is offered a trial of breastfeeding. Galactorrhea in nonpregnant, nonbreast-
diclofenac gel to the affected area; however, she does feeding women may be caused by hyperprolactinemia.
not want to take medication and will continue with life- Women presenting with galactorrhea should have a preg-
style and dietary changes. nancy test and prolactin level and thyroid-stimulating hor-
mone tests completed to rule out pregnancy or
endocrinopathy [29]. Medications, especially psychoactive
medications which inhibit dopamine, can raise prolactin
Nipple Discharge levels and cause galactorrhea, which is why it is important
to review the medication history of a woman with nipple
discharge. Medications associated with galactorrhea
Claudette is a 38-year-old woman presenting with
include phenothiazines, metoclopramide, risperidone,
bilateral nipple discharge. She states that when she
SSRIs, estrogen, and verapamil. Prolactin levels can be
squeezes her nipples, a small amount of milky fluid
quite high, as high as 200–300 ng/mL in women taking ris-
appears. She denies that the discharge is ever sponta-
peridone, a potent dopamine antagonist which can lead to
neous or bloody.
galactorrhea and menstrual irregularities. Pituitary imaging
is indicated in cases of high prolactin levels, especially
when levels are over 100 ng/mL, in the absence of dopa-
Nipple discharge is a chief concern for approximately 5% mine inhibitor use, or when headaches or visual symptoms
of women who are presenting to a health-care provider with are present. The evaluation and treatment of pituitary
breast-related concerns [28]. Nipple discharge can be a tumors is beyond the scope of this book.
symptom of breast cancer, and therefore, it causes a signifi- If the history and physical examination indicate that the
cant amount of anxiety for women. Nipple discharge is asso- discharge is physiologic, and breast cancer screening is up to
ciated with benign conditions in 97% of cases [28]. In the date, then no breast imaging is required. Women who are
evaluation and management of nipple discharge, the most expressing discharge should be counseled to avoid nipple
important factor is to determine whether the discharge is stimulation [27].
physiologic or pathologic. A thorough history and physical
exam should be done to characterize the discharge including
color, unilateral versus bilateral, spontaneous or only with Claudette returns to clinic 3 years later (age 41), with
manual expression, the number of ducts involved, and a chief concern of unilateral, spontaneous left nipple
whether it is associated with a mass or skin change. During discharge. Her clinical breast exam shows no breast
the clinical breast exam, the provider should attempt to elicit masses. There is spontaneous discharge from her left
the nipple discharge and, if possible, to identify the number nipple that is dark brown and guaiac positive.
of ducts involved. The discharge should be tested for blood
with a Hemoccult, or similar, test. Cytologic examination of
the discharge is no longer recommended because of the low Pathologic nipple discharge is often spontaneous, unilat-
sensitivity for detection of cancer and because the absence of eral, bloody, serous, or associated with a mass [27, 29] (see
malignant cells does not exclude cancer [27, 28]. Table 16.2 below).
Table 16.2 Nipple discharge [8]

Characteristics Evaluation Management
Pathologic Spontaneous, unilateral, single duct, < 30-year-old: ultrasound and Follow imaging recommendations (i.e., serial
discharge serous, sanguineous, or consider diagnostic mammogram imaging versus biopsy). May require excision if
serosanguinous ≥30-year-old: diagnostic mass present
mammogram and ultrasound Refer to breast surgeon for evaluation
If mammogram is BI-RADS
1–3, consider adding breast MRI
Physiologic Nonspontaneous: elicited with If <40-year-old, observation Educate patient to stop manual compression of
discharge squeezing or pinching If >40-year-old, recommend breast and nipple stimulation
Multiductal expression mammogram and, if negative, Optional to have a 3- to 6-month follow-up to
Color can be white, clear, yellow, observation reassess
green, gray, or brown Return to clinic if discharge becomes pathologic,
or if exam changes
The most common causes of pathologic nipple discharge without atypia, atypical hyperplasia, ductal carcinoma in
are intraductal papilloma, duct ectasia, infection, and carci- situ, lobular carcinoma in situ, or invasive carcinoma.
noma [27, 29]. Intraductal papilloma, discussed above, is Simple cysts and nonproliferative lesions do not increase
the most common cause of nipple discharge and has been the risk of subsequent breast cancer, but all other diagno-
reported in up to 57% of cases of pathologic nipple discharge ses potentially increase breast cancer risk.
[26, 27, 29]. Duct ectasia is another common cause of nipple 4. Lactational mastitis is common and antibiotics that are
discharge and has been identified in up to 33% of cases of effective against S. aureus are recommended for women
pathologic nipple discharge. Malignancy is associated with with symptoms that persist beyond 12–24 h. Women with
pathologic nipple discharge in 5–15% of cases [29]. risk factors for methicillin-resistant Staphylococcus
Pathologic nipple discharge always requires further investi- aureus (MRSA) should be treated with antibiotics that
gation. NCCN guidelines recommend breast ultrasound, and cover MRSA. Nonpuerperal breast abscesses are less
sometimes a diagnostic mammogram (at the discretion of common but are treated similarly to lactational mastitis
radiologist), in women under the age of 30 and both diagnos- with antibiotics and possible drainage. Underlying malig-
tic mammogram and ultrasound in women 30-year-old and nancy should be excluded.
older. If imaging is abnormal, the patient will proceed to tis- 5. Cyclic (diffuse, bilateral) breast pain is physiologic pain
sue biopsy. If the imaging is normal, the provider should that can be managed with lifestyle and dietary changes or
consider further evaluation with breast MRI or ductogram in medications such as acetaminophen, oral NSAIDs, or
consultation with a breast specialist [7, 27, 29]. topical diclofenac gel. Noncyclic or focal breast pain war-
rants diagnostic imaging to rule out underlying
pathology.
Summary Points 6. Physiologic nipple discharge is nonbloody, often bilat-
eral, and associated with nipple stimulation or breast
1. Patients presenting with a palpable breast mass should be compression. Women ≥40-year-old should have a mam-
evaluated with a thorough history, review of risk factors mogram and women <40-year-old should undergo educa-
for breast cancer, and a clinical breast exam [4]. Diagnostic tion and clinical observation. Pathologic nipple discharge
mammography and ultrasound should be performed on is spontaneous, unilateral, or bloody and always warrants
women over 30-year-old; those under 30-year-old should a diagnostic workup. For women ≥30-year-old, workup
have an ultrasound of the mass [5, 6]. includes a mammogram and breast ultrasound. In women
2. Further evaluation and treatment of breast masses is based <30-year-old, a breast ultrasound is recommended.
on the results of imaging and clinical suspicion. Some
lesions require biopsy, while others are diagnosed on radio-
logic findings alone. Treatment varies from close interval Review Questions
follow-up to surgical excision [1–7]. Persistent palpable
masses with negative imaging should be referred to a breast 1. A 25-year-old woman presents with a palpable mass in
specialist for further evaluation and possible biopsy. her left breast for the last 2 months. She denies any
3. Breast masses are cystic or solid. Cystic masses can be changes in the mass with her menstrual cycle and denies
simple or complicated. Solid masses can be classified by any breast pain. She is otherwise healthy, has never been
pathologic diagnosis as nonproliferative, proliferative pregnant, and has a mother who was recently diagnosed
with breast cancer at age 55. She has no other risk factors 3. A 34-year-old nurse, who is 6 weeks postpartum and
for breast cancer. On breast exam, there is a nontender, breastfeeding, reports pain, swelling, and redness of her
soft, round, mobile mass on the left. What is the next step right breast for the last 24 h with a low-grade temperature
in the evaluation of this patient? (100.1F). She is diagnosed with lactational mastitis. The
A. Diagnostic mammography of the left breast most appropriate management is:
B. Left breast ultrasound A. Nonsteroidal anti-inflammatory agents, compresses,
C. Bilateral breast ultrasound and expression of milk by feeding or pumping
D. Breast MRI B. Dicloxacillin 500 mg four times daily
The correct answer is B. NCCN and American College C. Cephalexin 500 mg four times daily
of Radiology (ACR) guidelines recommend ultrasound D. Clindamycin 300 mg four times daily
imaging for palpable breast masses in patients under the The correct answer is D. Clindamycin is an appropri-
age of 30 [6, 7]. Diagnostic mammography followed by ate choice for mastitis in a woman with risk factors for
ultrasound would be the first step in the workup of a MRSA, such as a nurse. Trimethoprim/sulfamethoxazole
patient over the age of 30; however, this patient is 25-year- DS (TMP/SMX) also covers MRSA but is contraindi-
old. Bilateral breast ultrasound is not indicated, as there cated in women who are breastfeeding newborn infants,
are no palpable lesions on the right breast. There is no younger than 2 months of age, due to the increased risk of
indication for right breast imaging. Breast MRI would be kernicterus [15, 16]. Symptomatic treatment is generally
inappropriate to order in this patient as an initial screen- effective for women with mild cases of inflammation who
ing test [6]. have been symptomatic for less than 24 h. If symptoms
persist for more than 12–24 h, then antibiotics are indi-
2. A 40-year-old woman presents for follow-up after screen- cated [15, 16]. Dicloxacillin and cephalexin are appropri-
ing mammography. The mammography was read as BI- ate antibiotic treatment choices for lactational mastitis in
RADS 3, with a small mass seen in her right breast, likely women who do not have risk factors for methicillin-
a fibroadenoma. An ultrasound to the area in question was resistant Staphylococcus aureus (MRSA). This patient is
consistent with a fibroadenoma. The patient is a healthy, a health-care provider (a nurse) who works in a hospital,
nonsmoker with no history of prior breast biopsy; she had and therefore, MRSA should be covered [15, 16].
her first child at age 18 and is not taking any chronic med-
ications. She has no family history of breast cancer. What 4. A 36-year-old woman presents with bilateral breast pain
is the next step in the management of this patient? that generally starts 2 weeks prior to her menses and
A. Refer her to breast surgery for evaluation and possible sometimes lasts 1 week after her menses. She reports the
surgical excision. pain is “everywhere.” Clinical breast exam is significant
B. Discuss the use of tamoxifen to reduce her risk of for diffuse, bilateral tenderness without palpable masses
developing breast cancer. or focal tenderness. Appropriate treatment would include:
C. Order a short interval follow-up with breast MRI in A. Counseling on dietary and lifestyle modifications
6 months. such as cutting down on caffeine, exercising several
D. Order a short interval follow-up with diagnostic breast days per week, and recommending a professionally
mammography and ultrasound in 6 months. fitted bra.
The correct answer is D. Follow-up imaging with diag- B. Recommending tamoxifen 10 mg daily for 3 months.
nostic mammography and ultrasound is recommended for C. Ordering a diagnostic bilateral mammogram for fur-
BI-RADS 3, likely benign imaging, every 6 months for ther evaluation
2 years [7]. Most likely this recommendation would have D. Ordering bilateral breast MRI to rule out dense
been made on the mammography report. There is no indi- breasts.
cation for surgical excision at this time given the low The correct answer is A. Dietary changes such as low-
clinical suspicion of malignancy and the likely benign fat, high-carbohydrate diets have shown some positive
reading on imaging. Tamoxifen is only indicated as che- effects in observational studies. Eliminating caffeine has
moprophylaxis in patients with a greater than 1.7% also been shown to be effective in small studies. Some
chance of developing a diagnosis of breast cancer in the women find relief with a well-fitted bra that provides sup-
next 5 years and patients with ADH, ALH, and LCIS, or port, or from compression with a sports bra. Tamoxifen
with certain genetic conditions [14]. can be used for severe breast pain; however, given the
While short-interval follow-up is indicated is patients potential adverse events associated with it, other options
with BI-RADS 3 imaging, there is no indication for MRI in should be tried and fail first. There is no indication for
this patient. MRI is indicated as a screening tool in patients imaging given the cyclical, diffuse nature of the pain and
with a lifetime risk for breast cancer of >20% [6, 7]. the fact that the patient is only 36-year-old which is below
the recommended age to start mammography in women at 6. Harvey JA, Mahoney MC, Newell MS, et al. ACR appropriateness
criteria palpable breast masses. J Am Coll Radiol. 2013;10:742–9.
average risk for breast cancer [7, 21, 22]. 7. National Comprehensive Cancer Network Clinical Practice
Guidelines in Oncology (NCCN Guidelines). Breast cancer screen-
5. A 40-year-old woman presents with spontaneous left- ing and diagnosis. Version 1.2017. June 2, 2017.
sided nipple discharge. She denies any blood in the dis- 8. Guray M, Sahin AA. Benign breast diseases: classification, diagno-
sis and management. Oncologist. 2006;11(5):435–49.
charge. On clinical breast exam, the patient has no masses 9. Schnitt SJ. Benign breast disease and breast cancer risk morphol-
and has a yellow discharge from her left nipple with pal- ogy and beyond. Am J Surg Pathol. 2003;27(6):836–41.
pation of the left breast. The discharge is guaiac negative. 10. Miller ME, Muhsen S, Olcese C, Patil S, Morrow M, Van Zee
What is the next appropriate treatment for the patient? KJ. Contralateral breast cancer risk in women with ductal carci-
noma in situ: is it high enough to justify bilateral mastectomy?
A. Provide reassurance as the patient is having non- Ann Surg Oncol. 2017;24(10):2889–97. https://doi.org/10.1245/
bloody nipple discharge that is not associated with s10434-017-5931-2.
any palpable mass. 11. Collins LC. Precursor lesions of the low-grade breast neoplasia
B. Tell the patient to monitor the discharge for the devel- pathway. Surg Pathol Clin. 2018;11(1):177–97.
12. The American Society of Breast Surgeons. Management of fibroad-
opment of blood and begin her screening mammo- enomas of the breast. 2008.
grams at age 50 as recommended by the USPSTF. 13. Hartmann LC, Radisky DC, Frost MH, et al. Understanding the
C. Order a diagnostic bilateral mammogram and a left premalignant potential of atypical hyperplasia through its natu-
breast ultrasound because the patient has pathologic ral history: a longitudinal cohort study. Cancer Prev Res (Phila).
2014;7(2):211–7.
nipple discharge. 14. National Comprehensive Cancer Network (NCCN) Clinical
D. Order a left breast ultrasound to assess for subareolar Practice Guidelines in Oncology. Breast cancer risk reduction.
dilated ducts. Version 1.2018. February 2, 2018.
The correct answer is C. Pathologic nipple discharges 15. Dixon JM, Khan LR. Treatment of breast infection. BMJ.
2011;342:d396.
are unilateral and spontaneous. The patient has a suspi- 16. Spencer JP. Management of mastitis in breastfeeding women. Am
cious or pathologic discharge and needs diagnostic imag- Fam Physician. 2008;78:727.
ing. Although a left breast ultrasound may show dilated 17. Kasales C, Han B, Smith JS, et al. Nonpuerperal mastitis and
ducts, imaging needs to include a diagnostic mammo- subareolar abscess of the breast. Am J Roentgenol. 2014;202(2):
W133–9.
gram in women over 30-year-old. Ultrasound is appro- 18. Trop I, Dugas A, David J, et al. Breast abscesses: evidence-
priate for pathologic discharge for women who are under based algorithms for diagnosis, management, and follow-up.
the age of 30. Because the patient is over 30-year-old, a Radiographics. 2011;31:1683–99.
diagnostic bilateral mammogram and a left breast ultra- 19. Jahanfar S, Ng CJ, Teng CL. Antibiotics for mastitis in breastfeed-
ing women. Cochrane Database Syst Rev. 2013;2:CD005458.
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College of Obstetricians and Gynecologist. ACOG committee
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Gynecol. 2007;109:479.
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The Primary Prevention of Breast
Cancer: Risk Assessment, Genetic 17
Screening, Chemoprevention,
and Modifiable Risk Factors
Jennifer Rusiecki and Deborah Kwolek
Learning Objectives
Introduction
1. Describe how lifestyle, genetic, reproductive, and
Breast cancer is the most common cancer in women and will
hormonal factors affect breast cancer risk.
affect 1 in 8 women in their lifetime. While breast cancer risk
2. Assess all women starting at age 18 for breast can-
increases as women age, peaking in the 70s, it remains a
cer risk, and teach breast awareness as part of rou-
leading cause of death for women in their 40s [1, 2]. Primary
tine preventive care throughout the life span.
care providers (PCPs) regularly recommend mammography
3. Using three basic questions, triage to determine
screening for women according to current guidelines, yet
which women will benefit from a detailed breast
more can be done to address the risk of cancer in individual
cancer risk evaluation, and formulate a personal-
patients. Approximately 10% of breast cancer cases are due
ized prevention plan.
to genetic factors, 40% are caused by known hormonal or
4. Appropriately identify women who would benefit
reproductive factors, and 40% are attributed to modifiable
from genetic testing.
risk factors [3]. With prudent lifestyle changes and judicious
5. Identify women with high-risk breast lesions and
use of chemoprevention, more than half of all breast cancers
counsel appropriate patients on the use of screening
could be prevented, representing 150,000 fewer breast can-
breast MRI and chemoprevention.
cer diagnoses and 20,000 fewer breast cancer deaths annu-
6. Co-manage prevention and screening for women at
ally in the USA [4].
highest risk with specialists.
Primary care providers (PCPs) are in the position, through
the provision of routine preventive care, to reduce breast can-
cer morbidity and mortality substantially. The United States
Preventive Services Task Force (USPTF) recommends that
Jeanne is a 35-year-old white woman who presents to breast cancer education and family history screening be pro-
establish primary care. She has no significant past vided to all women starting at age 18, analogous to the way
medical or surgical history. Her reproductive history is that adult patients are screened for cardiovascular risk fac-
significant for menarche at age 10, G1P1, and first tors [5]. After risk assessment, PCPs can recommend appro-
birth at age 30. She breastfed her infant for more than priate prevention.
1 year and took birth control pills for 5 years prior to Although proven prevention strategies are available, stud-
her pregnancy. Her BMI is 30 and she does not exer- ies suggest that screening mammography for all populations
cise regularly. She drinks a glass of wine every night. at risk and targeted interventions (Table 17.1) including
genetic screening, MRI imaging for women at high risk of
breast cancer, prophylactic mastectomy in extremely high-
risk patients, and the use of chemoprevention medications
J. Rusiecki (*) are grossly underutilized [6–8]. This inequity is largely due
University of Chicago, Department of General Internal Medicine, to the fragmented care that women receive and the lack of
Chicago, IL, USA
breast cancer prevention training for PCPs (see Chap. 1 on
“Women’s Health and Sex and Gender Based Medicine”).
D. Kwolek
The purpose of this chapter is to simplify breast cancer risk
Department of Medicine, Boston, MA, USA assessment and prevention with the goal that primary care

276 J. Rusiecki and D. Kwolek
providers will be equipped to address breast cancer preven- Table 17.1 Risk factors for breast cancer [9–16]
tion with all their women patients. Relative risk
(RR) Risk factor
Highest risk Chest radiation as child to age 30
RR > 4.0 Genetic factors:
reast Cancer Risk Assessments
B Personal or family history of known genetic
in Primary Care mutation
Hereditary breast and ovarian cancer
Risk Factors for Breast Cancer syndromes:
BRCA 1 and BRCA2, PALB2,
Peutz-Jeghers syndrome
Risk factors for breast cancer fall into four major categories, Li-Fraumeni syndrome – TP53
as seen in Box 17.1. PTEN hamartoma tumor, Cowden, RBBS
The degree of risk associated with each factor varies sub- Hereditary diffuse gastric cancer syndrome
Neurofibromatosis 1
stantially. Table 17.1 presents a list of known risk factors Strong family history of breast cancer – 1st or 2nd
grouped from strongest to weakest risk conferred. Protective degree relative with:
factors and factors for which there is currently not sufficient 2 + family members with breast cancer
proof of effect are also included. Bilateral breast cancer
Premenopausal breast cancer
Ovarian cancer
Male breast cancer
atient Evaluation and Documentation
P Personal history of ovarian cancer
at Preventive Visits Breast factors:
Personal history of breast cancer
Ductal carcinoma in situ (DCIS)
The authors recommend that “breast cancer risk” be a per- Lobular carcinoma in situ (LCIS)
manent entry in the problem list of each woman and that the Atypical ductal or lobular hyperplasia
information be reviewed and updated at annual preventive Moderate risk Genetic factors:
visits. At these visits, primary care providers should also RR 2.1–4.0 CHEK2 mutation carrier (checkpoint kinase 2)
Lynch syndrome
screen for current breast or gynecologic concerns. Past medi-
Ataxia telangiectasia
cal history should record breast and gynecologic histories, One first-degree relative with postmenopausal
such as age of menarche, parity, age of first live birth, age of breast cancer
menopause and hormonal therapies, as these details are used Breast factors:
in breast cancer risk calculators. A breast history includes Extremely or heterogeneously dense breast
tissue
any history of breast biopsies with results, breast imaging
Modest Genetic factors:
including density, and treatments given for any abnormali- RR 1.1–2.0 History of melanoma or thyroid cancer
ties. Family history, social history, and lifestyle habits should Personal history of endometrial cancer
be obtained with attention to factors which affect breast can- Breast factors:
cer risk (see Chap. 3 on “Sex and Gender Specific History History of one or more breast biopsies
Proliferative breast lesions without atypia
Hormonal/reproductive factors:
Early menarche (<12 years)
Age of first live birth at 30 years or older, or
nulliparity
Box 17.1 Categories of Risk Factors for Breast Cancer Never breastfed an infant
Breast cancer risk factors can be divided into major Late menopause (>55 years)
categories: Recent OC use (within past 10 years)
Recent use of HT (within past 5 years)
• Patient characteristics including sex, age, race, DES use during pregnancy or in utero DES
body mass index (BMI), and lifestyle habits. exposure
• Genetic factors as manifest through family history PCOS
or genetic testing. High circulating estrogens, androgens, IGF-1,
and IGFBP-3
• Breast factors including history of chest radiation,
Lifestyle factors:
breast density, and history of breast biopsy. Postmenopausal obesity or inactivity
• Reproductive and hormonal factors including men- Alcohol consumption
strual and obstetric histories. Current smoking
17 The Primary Prevention of Breast Cancer: Risk Assessment, Genetic Screening, Chemoprevention, and Modifiable Risk Factors 277
Table 17.1 (continued) Table 17.2 Breast cancer preventive interventions

Relative risk Preventive interventions which apply to all patients include:
(RR) Risk factor Lifestyle, hormonal, and reproductive review and counsel.
Protective Giving birth (compared to nulliparity) Breast awareness instruction.
RR <1.0 Four pregnancies or more (compared to one or Age-based mammography screening.
less) Advanced interventions offered to selected patients with higher
Age at first birth <25 years (compared to than average risk include:
>29 years)
Clinical breast exams.
History of breastfeeding
Use of tamoxifen or raloxifene Imaging with early mammography or MRI.
Physical activity Genetic counsel and screening.
Inconclusive Diet: Chemoprevention medication prescriptions.
data Soy intake Specialty referral to develop a comprehensive management plan.
Fruits and vegetable intake, olive oil, fish Prophylactic surgery.
Fat intake in diet, red meat
Vitamins A, E, C, D, beta carotene
Other factors:
In vitro fertilization access risk and discuss recommended interventions during
Less than 3 years HT the annual exam, a separate office visit should be scheduled.
Aspirin or other NSAIDs An algorithm for expedited risk assessment is found in
Bisphosphonate use
No known Abortion or pregnancy termination
Fig. 17.1. The results of the risk assessment and recommen-
effect Second-hand smoke dations can be formulated into a personalized prevention
Silicone implants plan for each woman [17].
Caffeine
Stress
Underarm deodorant or antiperspirant
Wearing a bra or a particular type of bra Jeanne has never had radiation to her chest. Her fam-
Environmental pollutants
Hair dye ily history is significant for breast cancer in her mother
Electric blankets at age 55, breast cancer in her sister at age 42, and
DCIS ductal carcinoma in situ, LCIS lobular carcinoma in situ, OC oral ovarian cancer in her maternal grandmother at
contraception, HT hormone therapy, DES diethylstilbestrol, PCOS approximately age 60. Her breast history is significant
polycystic ovarian syndrome, NSAID nonsteroidal anti-inflammatory for a breast biopsy 3 years ago with atypical ductal
drug, BRRS Bannayan-Riley-Ruvalcaba syndrome
hyperplasia.
and Examination”). Details from the history predict risk and

direct which risk calculator to use when a more specific risk
percentage is needed to guide management (see discussion valuation and Management Based
E
below on risk calculators). on Triage Question Answers
Based on the results of the risk assessment, preventative
strategies should be discussed for all women based on their Next steps, depending on the answers to the triage questions,
level of risk. An overview of preventative interventions is are discussed below.
outlined in Table 17.2.
Box 17.2 Three Questions to Triage for Increased Breast

Breast Risk Triage: Three Questions Cancer Risk
Three questions to start breast cancer risk assessment:
If a woman has no current breast concerns, then an expe- 1. Have you ever had radiation treatment to the chest
dited risk assessment can begin with three questions. If the for cancer or other conditions?
answer to all three questions is “no,” then no further assess- 2. Do you or your family members have a history of
ment is required beyond routine lifestyle counseling and age- cancer, or a genetic mutation associated with
based mammographic screening [17]. See Box 17.2. increased breast cancer risk?
Patients who answer “yes” to one or more of the three tri- 3. Have you ever had a breast biopsy or a diagnosis of
age questions have a potentially increased risk and require dense breasts on mammogram?
further evaluation; if time does not permit the PCP to fully
History of Chest High Risk Refer to Cancer

Radiation age <30 Yes Prevention Specialist for
years in patient?
consideration of
No Comprehensive Management
Strategies which may include:
-Annual MRI
Known genetic mutation -Annual Mammo
History of Cancer or with increased breast Yes
known genetic mutation Yes -Chemoprevention
cancer risk in patient? -Clinical Breast Exams and risk
with increased breast
cancer risk in patient Refer for genetic evaluation every 6-12 months
or family member? No counseling and testing -Prophylactic mastectomy if
No for BC mutation. Yes
LT risk >50%
High risk Fhx for Yes Is BC mutation found? -fertility counseling
inherited breast cancer* If Yes, treat as -genetic counseling
And/Or Genetic High Risk -screening for other
mutation with increased malignancies as indicated
breast cancer risk in No
by genetics and family history
family member?
No Calculate lifetime risk

using risk calculator:
Lower risk family Yes
Is lifetime risk >20%?
history for inherited
Yes If Yes, treat as
breast cancer?
High Risk.
If lifetime risk<20%:
History of Invasive Moderate Risk
calculate 5 year risk
Breast Cancer or DCIS? -Co-manage with
using risk calculator:
If yes, STOP: plan breast specialist
Is 5-yr risk >1.67%? Or
History of breast per Oncology -Start Mammo at 40
Yes Do any apply?
biopsy or dense -LCIS, ADH or ALH? or at age of diagnosis
breasts on No -age 65 and 1 FDRBC of high risk breast
mammography in -age 45 and >1 FDRBC lesion
patient? History of biopsy Yes -Discuss
proven high risk -age 45 and 1 FDR with
Yes BC<age 50? Chemoprevention
No breast lesion: LCIS, Medication
ADH or ALH? -age ≥40 and 1 FDR with
bilateral BC? -consider CBE
If Yes, treat as -re-evaluate
No Moderate Risk every 6-12 months for
change in risk
History of other
benign breast biopsy If No, treat as
or dense breasts on Average risk: re-
mammogram? evaluate annually for
change in risk
Average Risk No
Do not offer genetic testing, chemoprevention or MRI screening
Screening mammography according to age-based guidelines
Risk calculator use not necessary
All Patients
Lifestyle counseling: exercise, weight maintenance, smoking cessation, limit alcohol use
Identify and review modifiable risk factors
Teach breast awareness
Re-evaluate at preventive visits until at least age 75 if more than 5 year life expectance
Abbreviations: LCIS= lobular carcinoma in situ, ADH= atypical ductal hyperplasis, ALH= atypical lobular hyperplasia,
DCIS= ductal carcinoma in situ, FDRBC= first degree relative with breast cancer, FDR= first degree relative, BC= breast cancer,
MRI= magnetic resonance imaging, Mammo= mammogram, CBE= clinical breast exam Fhx= family history HR= High Risk
MR= Moderate Risk
*Per NCCN screening (Table 5) a high risk or suspicious family history includes 1) breast cancer in 2 or more family members on the same
side of the family (maternal or paternal); 2) a family history of premenopausal, bilateral, or male breast cancer, or 3) a family history
of ovarian cancer, or 4) colon, thyroid, peritoneal, endometrial, uterine or other cancers in multiple family members. Ashkenazi Jewish
descent increases the risk of BRCA mutation.
Figure is original to author Kwolek
References:5, 6, 9, 13, 14
hen the Answer Is “No” to All Three

W over 25-year-old, mammography and MRI screening can be
Questions: No Radiation, No Genetic or Family initiated [5, 20]. Patients are best managed in conjunction
History, and No Breast History with a breast cancer prevention specialist.
Women who answer no to all three questions have an aver-

age risk for breast cancer and do not need further risk eval- hen the Answer to Question Two Is “Yes”:
W
uation with a risk calculator or advanced interventions at Personal or Family History of Cancer or Genetic
this time. Mutations
The majority of women seen in primary care are in the
average risk category and should be counseled on lifestyle All patients who have a family history of cancer, or a sus-
prevention strategies, be taught breast awareness, and be pected genetic syndrome which increases cancer risk, require
screened according to age-based mammography screening further evaluation. Patients are triaged to determine whether
guidelines [18]. Reproductive and hormonal factors affect referral for genetic counseling and testing is indicated.
risk, but are not of sufficient strength, in the absence of fam- Advanced preventive interventions should be considered for
ily history, genetic, or breast history factors, to alter age- most patients (see Fig. 17.1).
based screening guidelines. Although the majority of cases Patients with a positive screen for family history or genet-
of breast cancer occur in this group, these women do not ics are further classified according to risk status: (1) known
require a detailed risk factor calculation and should not be genetic mutation, (2) family member with a known genetic
offered MRI screening, genetic testing, or chemoprevention mutation, (3) history suspicious for mutation, (4) strong fam-
[4, 19, 20]. Women should be reassessed periodically for ily history with negative genetic testing, or (5) one first-
changes in risk status by readdressing family history and degree relative with postmenopausal breast cancer.
breast history at routine preventive visits (see Chap. 18 on
“Breast Cancer Screening”). • Patient with a known genetic mutation
Patients with a BRCA mutation or other known genetic

hen the Answer to Question One Is “Yes”:
W mutation associated with an increased risk of breast cancer
History of Chest Radiation will need comprehensive management strategies and should
be co-managed with a breast cancer prevention specialist.
Patients with a history of childhood chest radiation require Table 17.4 lists the major known mutations associated
referral to develop a comprehensive management plan. with increased breast cancer risk, associated conditions, and
A history of childhood or young adulthood (10- to recommended prevention strategies.
30-year-old) radiation to the chest, although uncommon,
confers at 40% lifetime risk of breast cancer. These patients • Family member with a known genetic mutation
are primarily those who were treated for Hodgkin’s or non-
Hodgkin’s lymphoma as teens or young adults. Screening Patients, who have a first-degree relative with a BRCA
and prevention recommendations for high-risk patients are genetic mutation, or other genetic mutation associated with
outlined in Table 17.3. These patients should be seen at least breast cancer, should be referred for genetic counseling and
annually in primary care clinic to review family history, per- evaluation by a breast cancer prevention specialist.
form a clinical breast exam, and advise patients with risk- If genetic testing of the patient is negative, follow recom-
reduction counseling including consideration of mendations for strong family history with negative genetic
chemoprevention. Patients with this risk factor begin breast testing. If the genetic testing of the patient is positive, refer to
cancer screening with clinical breast exams 8–10 years after the specific mutation for recommended screening and co-
the radiation therapy was given up to age 25. For patients manage with specialist. See Table 17.4.
Fig. 17.1 Breast cancer risk triage: three questions for asymptomatic cious family history includes (1) breast cancer in 2 or more family
women [5, 6, 9, 13, 14]. Abbreviations: LCIS lobular carcinoma in situ, members on the same side of the family (maternal or paternal); (2) a
ADH atypical ductal hyperplasia, ALH atypical lobular hyperplasia, family history of premenopausal, bilateral, or male breast cancer; or (3)
DCIS ductal carcinoma in situ, FDRBC first-degree relative with breast a family history of ovarian cancer, or (4) Colon, thyroid, peritoneal,
cancer, BC breast cancer, MRI magnetic resonance imaging, Mammo endometrial, uterine or other cancers in multiple family members.
mammogram, CBE clinical breast exam, Fhx family history, HR high Ashkenazi Jewish descent increases the risk of BRCA mutation
risk, MR moderate risk. *Per NCCN screening (Table 17.5) a suspi-
Table 17.3 Breast cancer prevention using comprehensive management strategies for high-risk women [13, 14, 20, 21, 25–27]
Counseling and clinical exam,
including recommended visit Management of breast
High-risk type Screening breast imaging intervals cancer risk
History of chest radiation between Annual screening mammogram with or Age 18–25 clinical breast Co-manage with
age 10 and 30 years without tomography and exam starting 10 years after specialist
MRI starting 8–10 years after radiation radiation therapy every Consider
treatment, but not before age 25 6–12 months chemoprevention
Discuss breast awareness Consider
prophylactic
mastectomy
Known genetic mutation: BRCA 1, Age 25–29 annual breast MRIa Clinical breast exam every Co-manage with
BRCA 2, or other high-risk genetic Age 30–75 annual mammogram with or 6–12 months starting at age specialist
mutation (see Tables 17.1 and 17.4) without tomography and breast MRI 18 Consider
Age > 75, individualized discussion Discuss breast awareness chemoprevention
Consider
prophylactic
mastectomy
Family history of breast cancer Begin annual mammogram with or without Discuss breast awareness Co-manage with
without identified mutation and tomography 10 years younger than when Optional annual clinical specialist
lifetime risk >20% according to youngest family member developed breast breast exam, but continue Consider
IBIS or other risk assessment cancer, but not before age 30 annual preventive reevaluation chemoprevention
model Start annual breast MRI 10 years younger than
when youngest family member developed
breast cancer, but not before age 25
History of high-risk breast lesion: Annual screening mammogram with or Clinical breast exam every Co-manage with
LCIS, ADH, or ALH without tomography to begin at time of lesion 6–12 months specialist
diagnosis, but not before age 30 Discuss breast awareness Consider
Consider annual MRI starting at time of chemoprevention
diagnosis, but not before age 25
Lifetime risk >20% according to Annual screening mammogram with or Optional annual clinical Co-manage with
risk assessment tools based on a without tomography to begin at time of risk breast exam specialist
combination of factors exceeding 20% Discuss breast awareness Consider
Consider annual MRI at time of risk exceeding chemoprevention
20%. Stop when risk decreases below 20%
MRI magnetic resonance imaging, LCIS lobular carcinoma in situ, ADH atypical ductal hyperplasia, ALH atypical lobular hyperplasia, BCSC
Breast Cancer Surveillance Consortium, IBIS International Breast Cancer Intervention Study, BRCA BReast CAncer tumor suppressor gene
mutation
a
Breast MRI should be performed with contrast, during days 7–14 of menstrual cycle. For women <30 years, perform mammogram with or without
tomography if MRI is not available
• Family history suspicious for a genetic mutation considered for genetic counseling. Clinical decision making
as well as patient preference should be included in the dis-
A detailed cancer history will determine whether genetic cussion of genetic counseling referral. With advances in
referral for counseling and testing is indicated. genetic testing and the availability of home-based testing for
A detailed family history is conducted to review any can- a low cost, many patients will present with results obtained
cer diagnosis in first-, second-, and third-degree relatives. privately and will need counseling and confirmation of
For each cancer, the age of onset is noted. A suspicious fam- results.
ily history includes (1) breast cancer in two or more family
members on the same side of the family (maternal or pater- • Strong family history for breast cancer with negative
nal); (2) a family history of premenopausal, bilateral, or male genetic testing or without genetic testing in the patient
breast cancer; or (3) a family history of ovarian cancer, or (4)
colon, thyroid, peritoneal, endometrial, uterine, or other can- For patients with a strong family history of breast cancer,
cers in multiple family members. Ashkenazi Jewish descent but in whom a specific genetic syndrome is not found, pre-
increases the risk of BRCA mutation. The National ventive strategies, including MRI imaging and chemopreven-
Comprehensive Cancer Network (NCCN) guidelines [13] tion, may be indicated.
for referral for genetic counseling are outlined in Table 17.5. A “strong family history” is defined as either (1) one or
Table 17.5 is not a complete list of patients who should be more first-, second-, or third-degree relative(s) with pre-
Table 17.4 Selected genetic mutations and recommended comprehensive management strategies [13, 28–32]
Approximate age to Other cancers
begin mammography associated with
Prevalence Breast cancer Ovarian (Mammo) and/or syndrome or Other prevention
Genetic syndrome Gene (approximate) risk cancer risk MRI screeninga mutation considerations
PTEN Hamartoma PTEN 1/200,000 77% No Age 30–35 Endometrial, Consider
Tumor syndrome lifetime increase in Mammo follicular, or prophylactic
Cowden syndrome risk Age 30–35 MRI or papillary thyroid, mastectomy,
Bannayan-Riley- 5–10 years before colon polyps, hysterectomy,
Ruvalcaba the age of the renal cell and colectomy
syndrome youngest breast carcinoma Screen for
cancer case in the uterine cancer
family (whichever age 30–35
comes first) annually
Annual thyroid
ultrasound
Renal ultrasound
every other year
starting at age 40
Colonoscopy
starting at age 35
or earlier and
repeat every
5 years
Hereditary breast BRCA1 1/500 57% at age 40% at age Age 30 Mammo Prostate Consider
and ovarian cancer 1/40 Jewish 70 (often 70 Age 25 MRI prophylactic
syndrome triple mastectomy and
negative salpingo-
breast oophorectomy
cancer)
Hereditary breast BRCA2 1/500 49% at age 18% at age Age 30 Mammo Prostate, Consider
and ovarian cancer 1/40 Jewish 70 70 Age 25 MRI pancreas, and prophylactic
syndrome melanoma mastectomy and
salpingo-
oophorectomy
Li-Fraumeni TP53 1/500 54% at age No Age 30 Mammo Soft tissue Consider
Syndromeb 70 increase in Age 20 MRI sarcoma, prophylactic
risk osteosarcoma, mastectomy
central nervous
system tumors,
adrenocortical
malignancies
Hereditary diffuse CDH1 Unknown 52% at age No Age 30 Mammo Gastric cancers Consider
gastric cancer 75 (often increase in Consider adding prophylactic
syndrome lobular) risk MRI at 30 mastectomy and
gastrectomy
Hereditary breast PALB2 Unknown 35% at age Unclear Age 30 Mammo Pancreatic cancer Consider
and ovarian cancer (BRCA 2 75 association Age 25–30 MRI prophylactic
syndrome interacting (can occur surgery
protein) in males)
Peutz-Jeghers STK11 1/8000– 45% at age 18% at age Age 25 Mammo Colon cancer and Colonoscopy and
syndrome 1/200,000 70 70d Age 25 MRI polyps upper endoscopy
every 2–3 years
starting in late
teen years
Neurofibromatosis NF1 1/3000 8.4% at age No Age 30 Mammo Peripheral nerve Consider
type 1 (NF1) 50 increased Consider adding sheath tumors, mastectomy,
risk MRI ages 30–50 central nervous based on family
system tumors history
and gastro-
intestinal stromal
tumors
(continued)

Approximate age to Other cancers
begin mammography associated with
Prevalence Breast cancer Ovarian (Mammo) and/or syndrome or Other prevention
Genetic syndrome Gene (approximate) risk cancer risk MRI screeninga mutation considerations
CHEK 2 CHEK2 Not 28% No Age 40 Mammo Colon cancer Consider
available lifetime increased Consider adding mastectomy
risk MRI at 40 based on family
history
Colonoscopy
every 5 years
starting at age 40
Lynch syndrome MLH1a 1/2000 18% at age 24% Age 40 Mammo Colon and Consider
70 lifetime MRI based on endo-metrial prophylactic
risk other risk factorsc cancer salpingo-
oophorectomy
Colonoscopy age
20 every
2–5 years
Ataxia ATM Not 38% No Age 40 Mammo Consider
Telangiectasia available lifetime increased Consider adding mastectomy,
risk MRI at 40 based on family
history
a
Varies by family history and age of family member when diagnosed with breast cancer
b
Radiation sensitivity refers to the vulnerability of tissues exposed to radiation to develop secondary malignancies. Breasts in women less than
30 years of age are considered to be sensitive to radiation. Patients with Li-Fraumeni and NF1 are especially prone to radiosensitivity
c
only gene with increased risk of breast cancer in Lynch syndrome
d
Includes risk of ovarian, uterine, and cervical cancer
Table 17.5 National Comprehensive Cancer Network NCCN menopausal breast cancer (prior to age 45), bilateral dis-
Guidelines for referral to genetic counselor [13]
ease, ovarian cancer, or (2) at least two family members
First- or second-degree A known mutation with postmenopausal breast cancer (over age 50) [6]. The
relativea with any of the ≥2 breast cancer primaries in a
following single individual
lifetime and 5-year breast cancer risk is calculated for
Ovarian cancer women in this group using the International Breast Cancer
Metastatic prostate cancer Intervention Study (IBIS) risk calculator [24] to determine
Pancreatic cancer the appropriateness of MRI screening or chemoprevention
Male breast cancer
(see Box 17.3).
Anyone of Ashkenazi Jewish decent with a personal history of
breast or high-grade prostate cancer diagnosed at any age
Anyone with a personal history of ovarian or pancreatic cancer • One first-degree relative with postmenopausal breast
diagnosed at any age cancer
Family history of three or Breast, pancreatic or prostate
more of these cancers in any cancer
combination Melanoma, sarcoma,
For women who have only one first-degree relative with
adrenocortical carcinoma postmenopausal breast cancer, usually the mother, risk
Brain tumor or leukemia assessment with the Gail model is used to determine if the
Diffuse gastric, colon, patient should be offered MRI screening or chemoprevention
endometrial, thyroid, or kidney
cancer
medication.
Macrocephaly (large head) or Having a mother or sister with postmenopausal breast
hamartomatous polyps of the cancer is concerning to patients and is a moderate risk fac-
gastrointestinal tract tor for breast cancer (see Table 17.1). The Gail model cal-
Adapted with permission from the NCCN Guidelines® for Genetic/ culator [22] is used to quickly determine if women would
Familial High-Risk Assessment: Breast and Ovarian V.3.2019. © 2019
benefit from chemoprevention or MRI based on 5-year and
National Comprehensive Cancer Network, Inc. All rights reserved. The
NCCN Guidelines and illustrations herein may not be reproduced in lifetime risk percentages, respectively. If the patient also
any form for any purpose without the express written permission of the has dense breasts, the BCSC calculator [23] may be used
NCCN. NCCN makes no warranties of any kind whatsoever regarding as another measure. Starting annual mammograms at age
their content, use or application, and disclaims any responsibility for
40 can be considered for these women after a shared deci-
their application or use in any way
a
When possible, genetic testing should be performed on an affected sion-making discussion of risks and benefits [14, 21,
family member 25–27].
hen the Answer to Question 3 Is “Yes”:

W • History of atypical hyperplasia or lobular carcinoma in
History of Breast Biopsy or Dense Breasts situ (LCIS)
Patients with a history of biopsy-proven high-risk breast
Clinical or mammographic breast abnormalities may prompt lesions, namely, atypical hyperplasia or LCIS, should be
a breast biopsy, which is often benign. Even when noncan- evaluated for MRI screening schedules and chemoprevention
cerous, biopsy results contribute to breast cancer risk assess- strategies and be co-managed with a breast specialist [5]
ment. The pathologic report should be obtained to confirm (see Tables 17.3 and 17.6).
results, if not clear. In general, high-risk breast lesions should be removed,
and women who have not had an excisional biopsy should
• History of DCIS or invasive breast cancer be referred to a breast surgeon for possible excision. It is
common to find women who refused tamoxifen prophy-
The records of patients with a history of DCIS or invasive laxis after treatment for LCIS or atypical ductal hyperplasia
cancer are reviewed, when possible, to be sure that all recom- (ADH) or atypical lobular hyperplasia (ALH) many years
mended treatments have been completed. Many women will ago. A woman’s risk changes as she ages, as additional
have been given tamoxifen to prevent future breast cancer, but family members are diagnosed with cancer, and as her per-
those who declined may want to reconsider, and this is sonal breast history evolves. The issue of chemoprevention
decided together with a breast oncologist. The prevention of should be periodically reexplored in the context of the
breast cancer in survivors involves attention to both new can- patient’s changing risk status, current data, and perhaps a
cers and to the early detection of recurrence (see Chap. 19 on changed patient perspective on the importance of preven-
“Breast Cancer Diagnosis and Management”). Patients con- tive strategies.
tinue yearly mammography, breast exam, and management
according to a survivorship care plan prescribed by the oncol- • History of a proliferative breast lesion
ogist (see Chap. 20 on “Care of the Breast Cancer Survivor”).
Of note, women with DCIS or a history of invasive breast Proliferative breast lesions increase the risk of breast can-
cancer are excluded from risk prediction calculators. cer, especially in a woman with a positive family history for
breast cancer (see Chap. 16 on “Benign Breast Conditions”).
The Gail or IBIS (in cases with a strong family history) risk
Jeanne declined chemoprevention with tamoxifen at calculators [22, 24] are used to help determine whether the
the time of her atypical hyperplasia diagnosis and has patient should be offered chemoprevention medication or
not received follow-up care for this condition. MRI screening.
Table 17.6 Chemoprevention: patient selection, medication choice and precautions. High-risk conditions including childhood chest radiation,
known genetic mutations, and a history of high-risk breast biopsy benefit from specialty consultation in planning prevention strategies
Diagnosis or indication
any one of the following: Medication options Contraindications and precautions Adverse effects
Chest radiation before age 30a Premenopausal Hormonal and Reproductive All agents
Known genetic mutations increasing breast Tamoxifen 20 mg Pregnancy and lactation Venous
cancer riska daily Undiagnosed uterine bleeding thromboembolism
Lobular carcinoma in situ Postmenopausal Estrogen use Hot flashes
Atypical hyperplasia, ductal or lobular Tamoxifen 20 mg Cardiovascular Risk Fatigue
Any combination of risk factors with: daily Active or past history of venous Joint and muscle aches
>1.67% per NCCN (>3% per USPSTF) Raloxifene 60 mg thromboembolism (VTE), including deep Tamoxifen
5-year risk of breast cancer and >10-year daily vein thrombosis, pulmonary embolism, Endometrial
life expectance Anastrozole 1 mg and retinal vein thrombosis hyperplasia and cancer
>65 years with one first-degree relative daily Clotting disorder Avoid paroxetine,
with breast cancer Exemestane 25 mg Stroke or transient ischemic attack bupropion, and
>45 years with more than one first-degree daily Ischemic cardiac disease fluoxetine during use
relative OR one relative with bilateral Suggested Congestive heart failure Anastrozole and
breast cancer OR one first-degree relative duration: 5 years Increased cardiovascular risk: smoking, exemestane
with breast cancer under age 50 diabetes, hypertension Decreased bone mass
>40 years with one first degree relative and Osteoporosis
with bilateral breast cancer
Table adapted from data in the American Cancer Society, United States Preventative Services Task Force (USPSTF) 2019, and National
Comprehensive Cancer Network [5, 14, 25]
a
There is limited data on chemoprevention in these patients. Consultation with a breast cancer prevention specialist is advised
• History of a nonproliferative breast lesion

Box 17.3 Calculators for Breast Cancer Risk in Women
Nonproliferative breast lesions are not associated with an Without a History of Breast Cancer or DCIS
increased breast cancer risk; however, the Gail model Risk calculators:
includes a history of breast biopsy as one of the factors used
in risk calculations. Women undergo calculation of risk with • Gail model or NIH Breast Cancer Risk Assessment
the Gail model to determine whether chemoprevention medi- Tool (BCRAT) www.mdcalc.com/gail-model-
cation or MRI screening might be of benefit. breast-cancer-risk. Accessed 3/8/19 [22]
• Breast Cancer Surveillance Consortium (BCSC)
• Dense breasts on mammography www.tools.bcsc-scc.org/BC5yearRisk. Accessed
3/8/19 [23]
Breast density is a finding on mammography related to the • International Breast Cancer Intervention Study
ratio of glandular breast tissue to fat as interpreted by the radi- (IBIS) or Tyrer-Cuzick model www.ems-trials.org/
ologist. Density is primarily determined by genetics, but estro- riskevaluator. Accessed 3/8/19 [24]
gen use and premenopausal status can lead to slight increases
in density. Breasts that fall into “extremely dense” and “hetero-
geneously dense” classifications are often reported as “dense”
in the literature or in reports (about 40% prevalence). Increased
breast density increases the risk of cancer by both decreasing Box 17.4 Use of 5-Year and Lifetime Risk Percentages [5,
the sensitivity of mammography and as an independent risk 14, 25, 27]
factor. The risk associated with dense breasts also varies by the The 5-year risk is used to determine whether a woman
age of the patient. Dense breasts are more significant as a risk should be offered chemoprevention.
factor in postmenopausal women than in premenopausal
women. The Breast Cancer Surveillance Consortium (BCSC) • <1.67% average 5-year risk – do not offer
or International Breast Cancer Intervention Study (IBIS) calcu- chemoprevention
lators [23, 24] are used to determine whether these women • 1.68–3% moderate 5-year risk – may benefit from
would benefit from chemoprevention or MRI screening (see chemoprevention
Chap. 18 on “Breast Cancer Screening”). • >3% high 5-year risk – most likely to benefit from
chemoprevention
Jeanne is found to be at high risk on the basis of both The lifetime risk is updated yearly to guide ongoing
her family history and breast biopsy results. Her risk of screening with MRI.
breast cancer over the next 5 years and lifetime risk
were calculated using the IBIS risk calculator. The • <15% average lifetime risk – do not offer MRI
results were: 5-year risk 3.5%, lifetime risk 44%. screening
• 15–20% moderate lifetime risk – do not offer MRI
screening
Risk Calculators • >20% high lifetime risk – offer annual MRI in addi-
tion to mammography.
Risk calculators are used to determine a patient’s 5-year and
lifetime risk of breast cancer (see Box 17.3).
The Gail model, also known as the Breast Cancer Risk
Assessment Tool (BCRAT), is the most widely used and most does not use reproductive data. The BCSC calculates 5-year
easily available risk calculator. The Gail model cannot be and 10-year risk in women over 35 years.
used in patients with LCIS, increased breast density, or an The International Breast Cancer Intervention Study
extensive family history. The Gail model uses reproductive (IBIS) or Tyrer-Cuzick calculator is used for patients with:
factors, a history of breast biopsy and results, and history of more than two relatives with cancer, LCIS, dense breasts,
breast cancer in first-degree relatives in the calculations. The Ashkenazi Jewish heritage (due to increased risk of BRCA in
model calculates 5-year and lifetime risk percentage esti- that population), male breast cancer in the family, ovarian
mates in women over 35 years. cancer in the family, or cancer in second- and third-degree
The Breast Cancer Surveillance Consortium (BCSC) Risk relatives. The 5-year risk, 10-year risk, and lifetime risk esti-
Calculator incorporates breast density into calculations, but mates are calculated (see Box 17.4).
Developing a Personalized Prevention Plan Preventive Interventions
A personalized prevention plan (PPP) includes a discussion rinciples of Counseling and Explaining Risk
P
of lifestyle and behavioral modifications to reduce risk with to Patients
specific, actionable goals for the patient to follow. A copy of
the prevention plan can be provided to the patient, included Providers present a balanced perspective when counseling
in her medical record, and reviewed for progress at subse- women about breast cancer risk, recognizing that these dis-
quent visits. The prevention plan is revised periodically and cussions have the potential to invoke fear or stress. Providers
updated when there is a change in the patient’s health status, relay basic risk data and interpret the information using
family history, or risk factors. To aid clinical documentation, terms like “average risk” or “increased risk” [33].
a standardized form outlines risk and a PPP (see Fig. 17.2). Conversations focus on the provider and patient working
together as a team, utilizing shared decision making with the
goal of decreasing cancer risk.
Jeanne asks if she should have a mammogram. A thor- When explaining risks to patients, both the absolute and
ough breast cancer risk evaluation and a personalized relative risks (RR) are explained as necessary. For example,
prevention plan are discussed with the patient, using a a chemoprevention medication may lower the relative risk
standard form. (RR) of breast cancer by 50%, but if the absolute risk of the
cancer is low, then the benefit will be small. In the Breast
Cancer Prevention Trial, tamoxifen use in women at high
risk of breast cancer was associated with a RR of 0.51, which
Jeanne’s risk factor assessment: translates to a 49% reduction in the development of invasive
breast cancer compared to placebo. In terms of absolute risk,
1.3% of women in the tamoxifen arm developed breast can-
cer compared to 2.7% of women in the placebo arm, for an
Genetics: Positive family history for breast and ovar- absolute risk reduction of 1.4% [34].
ian cancer (major risk factor) To help patients understand risk factors, many factors can
be described as conferring a high, moderate, or modest
increase in breast cancer risk. Other factors have mildly pro-
tective effects or no known effect on breast cancer risk (see
Breast: Positive history of biopsy with atypical hyper- Table 17.1). Relative risk (RR) involves a comparison to
plasia (major risk factor) what is considered as the “standard level of risk.” For many
risk factors, the “standard level of risk” can differ based on
the author’s interpretation. Using the example of breast den-
sity, if fatty breasts (category A) are the “standard level of
Reproductive and hormonal: Age of menarche, age of risk,” the RR for extremely dense breasts (category D) is 4.5,
first birth increase risk placing breast density in the “high-risk” group of factors.
When the “standard level of risk” is scattered areas of fibro-
glandular density (category B), the RR for extremely dense
breasts (category D) is 1.3, conferring only a “modest”
Protective factor: History of breastfeeding increase in risk [15]. Statistical concepts may be confusing
to patients, and it is the responsibility of the PCP to put each
diagnosis and risk factor into perspective for the patient.
Lifestyle: Elevated BMI, lack of exercise, and alcohol

use Lifestyle Counseling
Physical Activity
The 2018 World Cancer Research Fund (WCRF) report on
Jean’s completed form, with assessment and plan, is in global cancer perspectives acknowledges that physical activ-
Fig. 17.3. Jeanne has questions about self-breast ity and achieving a normal weight is protective against post-
exams and use of alcohol. menopausal breast cancer (this resource is continuously
updated; see this link for updated review: https://www.wcrf.
Fig. 17.2 Use this standard Breast Cancer Risk Assessment/ Personalized Prevention Plan
form to uniformly collect
Age ____HT_____WT______BMI _____ Race*_______________________________
information on risk factors, to
aid in breast cancer risk 1. History of chest radiation age <30: Yes No
assessment, and to track a
2. Family history and genetics: Known genetic mutation: Yes-patient Yes-family No
personalized prevention plan.
This form is intended to print Prior genetic testing? Yes No ________ BRCA 1/ 2/ other mutation__________
and fill in blanks and circle Strong family history breast cancer risk: 2+ relatives/ male/ bilateral/premenopausal
yes or no; alternatively, a
smart form or phrase could be Family history other cancers: ovarian/ colon/ other (list)_______________________
customized to an electronic Postmenopausal breast cancer in one first degree relative only Yes No
health record. A nurse could
be trained to complete the 3. Breast history: History of biopsy(s): Yes No Number of biopsies? ________
history part of this form with Diagnosis: unknown/ non-proliferative/ proliferative/ ALH/ ADH/ LCIS/ DCIS/ cancer
the patient, to be confirmed
by the primary care provider. Treatment: excision/ chemoprevention/ mastectomy/ radiation therapy/ Chemotherapy
*Abbreviations: BMI body Completed treatment Yes/ No Declined Chemoprevention Yes/No
mass index, ALH atypical
lobular hyperplasia, ADH Mammogram or breast imaging (type, date, results): ___________________________
atypical ductal hyperplasia, Breast Density:_______Extremely Dense: Yes No
LCIS lobular carcinoma in
situ, DCIS ductal carcinoma 4. Reproductive and hormonal history:
in situ, RT radiation therapy, Age of menarche:____ Parity G__ P __ Age at first birth:______________________
SERM selective estrogen
Age of menopause: ___Breastfed infant? Yes/ No Duration (months)_____________
receptor modulators, HT
hormonal therapy. Make note H/o Hormonal contraceptive /HT / SERM/ AI use_____________________________
of Ashkenazi, Hispanic from
5. Lifestyle habits: Exercise:_____________________________________________
southwest USA, or other race
designation with increased Alcohol: Yes No How much:___________________________________________
incidence of BRCA or Smoking/ Nicotine/ Other substance: Yes No________________________________
increased risk of breast cancer
6. Risk Calculations: If #1-3 are negative, and breast cancer risk appears low, risk calculation
is not necessary; follow plan for average risk below.
Risk Calculation using Gail/ BCSC/ IBIS/ other: 5-year_______% lifetime______%
Low/ Moderate/ High (and Highest) risk as follows:
5-year <1.67%/ 1.68-3%/ >3% lifetime <15%/ 15-20%/ 20-49%/ (>50%)
7. Assessment and Plan: Risk-Average/ Moderate or unknown/ High Risk/ Highest Risk
Genetic Screen referral: Yes No ___________________________
___________________
Imaging early (mammogram less than 45 years) or MRI: Yes No_____________________
Chemoprophylaxis: Yes No _________________________________________________
Specialty referral for Comprehensive Management Strategies: Yes No_______
__________
Consider Prophylactic Surgery Yes No_________________________________________
Risk reduction goals: increase exercise/ decrease alcohol/quit smoking/ limit hormone Rx
Clinical Breast Exams: Yes No______ Teach breast awareness / Other__
______________
Referrals: Genetics/ Cancer Prevention/ Breast Surgeon/Medical Oncology/ other__________
Follow-up____________________________________________________________________
* make note of Ashkenazi, hispanic from southwest US, or other race designation with increased
incidence of BRCA or increased risk of breast cancer. {abbreviations: BMI= body mass index,
ALH= atypical lobular hyperplasia, ADH= atypical ductal hyperplasia,
LCIS= lobular carcinoma in-situ, DCIS= ductal carcinoma in-situ, RT=radiation therapy,
SERM= selective estrogen receptor
modulators, HT=hormonal therapy}
Figure original made by authors Kwolek, Rusiecki
Fig. 17.3 Case patient: Breast Cancer Risk Assessment/ Personalized Prevention Plan
personalized prevention plan
Age _35___HT_____WT______BMI___30__ Race*__White, non-Hispanic________________
worksheet
1. History of chest radiation age <30: Yes No
2. Family history and genetics:Known genetic mutation: Yes-patient Yes-family No
Prior genetic testing? Yes No ________ BRCA 1/ 2/ other mutation__________
Strong family history breast cancer risk: 2+ relatives/ male/ bilateral/premenopausal
Mom (50) & sister (42) breast ca, MGM ovarian ca

Family history other cancers: ovarian/ colon/ other (list)_______________________
Postmenopausal breast cancer in one first degree relative only Yes No
3. Breast history: History of biopsy(s): Yes No Number of biopsies? _____/___
Diagnosis: unknown/ non-proliferative/ proliferative/ ALH/ ADH/ LCIS/ DCIS/ cancer
Treatment: excision/ chemoprevention/ mastectomy/ radiation therapy/ Chemotherapy/none
Completed treatment Yes/ No Declined Chemoprevention Yes/No
Mammogram or breast imaging (type, date, results): __________none_________________
Breast Density:_______Extremely Dense: Yes No
4. Reproductive and hormonal history:
Age of menarche:__10__ Parity G_1_ P _1_ Age at first birth:_________30_____________
Age of menopause: ___Breastfed infant? Yes/ No Duration (months)____12 months_________
H/o Hormonal contraceptive /HT / SERM/ AI use OCP for 5 yrs, not current_____________
5.Lifestyle habits: Exercise:_not regularly___________________________
Alcohol: Yes No How much:__1 glass of wine per night_______________________
Smoking/ Nicotine/ Other substance: Yes No________________________________
6. Risk Calculations: If #1-3 are negative, and breast cancer risk appears low, risk calculation
is not necessary; follow plan for average risk below.
Risk Calculation using Gail/ BCSC/ IBIS/ other: 5-year__3.5_____% lifetime__44____%
Low/ Moderate/ High (and Highest) risk as follows:
5-year <1.67%/ 1.68-3%/ >3% lifetime <15%/ 15-20%/ 20-49%/ (>50%)
7. Assessment and Plan: Risk-Average/ Moderate or unknown/ High Risk/ Highest Risk
Genetic Screen referral: Yes No __request genetic testing results on other family members_____
Mammogram or MRI: Yes No ___start yearly mammogram, alternate with yearly MRI________
Chemoprophylaxis: Yes No __discussed tamoxifen with patient, will consider_______

Specialty referral for Comprehensive Management Strategies: Yes No refer breast center
Consider Prophylactic Surgery Yes No await genetic testing results
Risk reduction goals: increase exercise/ decrease alcohol/quit smoking/ limit hormone Rx_____
Clinical Breast Exams: Yes No______ Teach breast awareness / Other__
______________
Referrals: Genetics/ Cancer Prevention/ Breast Surgeon/Medical Oncology/ other__________
Follow-up_______3-6 months to follow-up on above plan__________________
org/dietandcancer/breast-cancer) [16]. Physical activity may lines and have been shown to have a toxic effect on normal
be protective against premenopausal breast cancers as well; mammary epithelial cells [40]. All smokers are counseled to
however, the report concluded the evidence was inconclu- quit in order to reduce the risk of cancer, including breast
sive. From a primary care perspective, it is still worthwhile to cancer, and the risk of cardiopulmonary diseases.
discuss weight loss with premenopausal women to avoid
obesity-related health complications as well as postmeno-
pausal obesity. In postmenopausal women, any level of phys- Reproductive and Hormonal Factor Counseling
ical activity appears protective, though a statistically
significant 20% reduction in breast cancer risk was seen in Pregnancy
women of all weights who performed more than 6.7 meta- Past pregnancy is not a modifiable risk factor for women, the
bolic equivalents (MET)-hr/week of physical activity (odds timing of pregnancy may not be possible, and the decision to
ratio [OR] 0.82; confidence interval [CI] 0.7–0.92) [35]. This plan a pregnancy has a myriad of considerations outside of
MET-hr/week is equal to briskly walking for 30 min 4 times the discussion of breast cancer risk. Pregnancy increases the
a week or 1 h of singles tennis a week. short-term risk and then lowers the long-term risk of breast
cancer. Nulliparous women have a 2.0 relative risk of breast
Postmenopausal Obesity cancer compared to women who have given birth to children,
Maintaining or achieving a normal postmenopausal weight and early pregnancy is protective against breast cancer in the
is an important reduction of breast cancer risk. A meta- long run [35]. Women who have their first child at or after
analysis of 17 studies evaluating postmenopausal breast can- age 30 are at an increased risk for breast cancer. Women with
cer risk demonstrated an increased risk of 1.03 (95% CI known genetic syndromes or elevated breast cancer risk who
1.01–1.04) per 2 kg/m2 point increase in body mass index wish to be become pregnant in the future may plan for preg-
(BMI). For example, in a woman with a height of 5 foot, 4 nancy at a younger age to help lower risk and to allow for
inches, increasing weight from 130 pounds to 142 pounds earlier prophylactic surgery when indicated.
represents a BMI increase of 2 and an increased risk of 3%.
Women with postmenopausal weight gain can decrease risk Breastfeeding
of breast cancer by 8% for each 5 kg/m2 reduction in BMI Women who have breastfed have a lower incidence of breast
[36]. The Nurses’ Health Study of postmenopausal women cancer compared to women who have not. It is proposed that
not using hormone therapy found that the women who main- women who breastfeed are exposed to lower levels of endog-
tained a weight reduction of at least 10 kg (22 pounds) had a enous sex hormones during the amenorrhea that accompa-
50% reduction in the risk of breast cancer [37]. Physicians nies lactation. A pooled analysis by the World Cancer
often counsel patients on the connection of physical activity Research Fund (WCRF) including 140,000 women from 30
and obesity to cardiovascular and diabetes risk, but the countries demonstrated a statistically significant 4.3%
importance of these factors in breast cancer risk is also decreased relative risk of breast cancer for every 12 months
important. of nursing compared to women who never breastfeed, which
persists through menopause. There is a dose-response effect
Alcohol Use in which a longer duration of breastfeeding produces further
Limiting alcohol use reduces the risk of breast cancer in both risk reduction, though a benefit is seen with as few as
pre- and postmenopausal women. There appears to be a 5 months of nursing [35]. While this is not always a modifi-
dose-dependent relationship, yet the 2018 WCRF report did able risk factor, reproductive aged women who plan to bear
not identify a threshold level of excessive alcohol consump- children are counseled on the benefits of lactation, including
tion, instead stating that the safest level is no alcohol [16]. the lifelong breast cancer risk reduction.
The Nurses’ Health Study found an increased breast cancer
risk (RR 1.15; 95% CI 1.06–1.24) for women who had 3–6 Hormonal Contraceptive Use
drinks per week [38]. A suggested limit to discuss with Studies have shown an increased risk of breast cancer in cur-
patients is no more than 1 drink a day and to have 2–3 rent users of oral contraceptives (OCs), which increases with
alcohol-free days a week to reduce their breast cancer risk. prolonged use, increased age, and triphasic formulations. A
Of note, current guidelines do not recommend that people recent study from Denmark including 1.8 million women
who do not drink alcohol start drinking for any reason [39]. over 10 years found that all forms of hormonal contraception
mildly increase the risk of breast cancer: for OCs, RR 1.20
Smoking (CI 1.14–1.26) and for progesterone IUDs, RR 1.21 (CI
Cohort studies suggest that long-term cigarette smoking 1.11–1.33) [41]. Women who are concerned for breast can-
leads to breast cancer development, as well as increased pro- cer risk are counseled to limit OC use to a duration of less
gression of existing breast cancer. Some components of than 5–10 years and to consider a different form of contra-
tobacco smoke have a carcinogenic effect on many cells ception after age 40 [42]. Of note, OC use is associated with
a decreased risk of ovarian cancer, and thus recommenda- if changes occur [13]. Specifically, women should pay atten-
tions are individualized for each patient. tion to their breasts when they dress or bathe and watch for
lumps, focal pain, discharge, or any other changes. Breast
Postmenopausal Hormone Therapy changes, and any changes in family history of cancer, should
Hormone therapy (HT) for the treatment of menopausal be brought to the attention of the PCP.
vasomotor symptoms has fallen in and out of favor over the
last 50 years. One of the major concerns that many women
and providers have with the use of hormones is the risk of Jeanne asks about lifestyle changes to reduce her risk
breast cancer. The Women’s Health Initiative (WHI) was a of breast cancer. She is advised to increase her exer-
16,000-women randomized controlled trial studying the use cise to at least 30 min, 3 times per week. She is advised
of HT. The study was stopped early, partially due to an to lower her BMI from 30 to 25 with healthy eating for
increased risk of breast cancer in the treatment arm. This risk a general health benefit. She is informed that alcohol
was seen only in the group of women receiving combined use increases the risk of breast cancer, and she should
estrogen and progesterone therapy, while the use of estrogen reduce intake to a few days per week or less. Breast
alone appeared to be protective (hazard ratio [HR] 1.25 for awareness is explained to Jeanne so that she will notify
estrogen+progesterone [E + P]; HR 0.77 for estrogen only) her physician of any changes in her breast, or changes
[43, 44]. There are important caveats to these data. First, the in her family history for cancer.
patients in the WHI were an older population (average age
63). Second, the long-term WHI study did not show a signifi-
cant difference in cancer mortality at 18-year follow-up for Age-Based Mammography Screening
combined E + P, although the trend was towards increased
risk (HR 1.44, 95% CI 0.97–2.15). The estrogen only arm, In average-risk patients, breast cancer screening is age-
however, continued to show a decreased risk (HR 0.55, 95% based. Screening mammography begins at age 45 or 50, but
CI 0.33–0.92). no later than 50 (see Chap. 18 on “Breast Cancer Screening”).
The Nurse’s Health Study, although a cohort study, may be
a better predictor of breast cancer risk with current HT pre-
scribing practices, since it was a younger patient group (aver- dvanced Interventions Offered to Selected
A
age age 56) and the majority of women who used hormone Patients
therapy did so for only 5 years in the perimenopausal and
early menopausal stages, in concordance with current guide- Clinical Breast Exams
lines. For all women using HT (E only and E + P), breast
cancer mortality in past and current HT users was not Clinical breast exams are essential for the evaluation of
increased: current users (RR 0.76, CI 0.56–1.02) and past breast complaints and are an important part of the follow-up
users (RR 0.83, CI 0.63–1.09) [45]. Women using only estro- of high-risk patients and patients with a history of cancer or
gen were stratified by duration of hormone use: an increase in DCIS (see Chap. 18 on “Breast Cancer Screening”).
breast cancer risk was not seen until after 5 years of estrogen
and did not reach statistical significance until after 15 years of
use [46]. Of note, the level of risk seen with 15 years of use is Referral for Genetic Counseling
equal to that of 1 alcohol drink a day (RR 1.1).
Hormone therapy has risks and benefits beyond breast The primary care provider is well positioned to perform a
cancer risk (see Chap. 8 on “Menopause”). Women can be detailed family history to assess genetic risk. The family his-
counseled that the risk of breast cancer from HT use is small tory includes a review of cancers in first-, second-, and third-
if used according to current guidelines. degree relatives with attention to the age at which each
family member was diagnosed. To assist in determining who
needs a referral, the USPSTF recommends a brief patient
Breast Awareness questionnaire such as the Ontario Family History Assessment
Tool, Manchester Scoring System, Referral Screening Tool,
Teach Breast Awareness to All Patients Pedigree Assessment Tool, or Family History Screen (FHS-
7), which are available on the USPSTF website [28]. Family
While we no longer recommend routine self-breast exams history factors associated with increased likelihood of poten-
for women, breast awareness is discussed with patients, tially harmful BRCA mutations include breast cancer diag-
including a discussion of the symptoms of breast cancer. nosis before age 50 years, bilateral breast cancer, presence of
Breast awareness empowers women to know the look and breast and ovarian cancer, one or more male family members
feel of their breast so as to present to a health-care provider with breast cancer, multiple cases of breast cancer in the
family, one or more family members with two primary types [48]. For younger patients who are hesitant to undergo mas-
of BRCA-related cancer, and Ashkenazi Jewish ethnicity tectomy and salpingo-oophorectomy, there are currently tri-
[28]. The National Comprehensive Cancer Network (NCCN) als underway investigating salpingectomy with delayed
guidelines to determine who should be referred for genetic oophorectomy since much of ovarian cancer is thought to
counseling are outlined in Table 17.5. Current guidelines originate in the fallopian tubes [29]. This is not part of the
recommend patients of Ashkenazi Jewish decent be tested NCCN guidelines at this time. The care of these patients is
for BRCA mutations, due to increased risk. Hispanic best performed in partnership with a comprehensive breast
Americans in the southwestern United States also have a cancer management program and primary care provider.
high risk, and providers must maintain a high degree of clini- Breast cancer screening recommendations for patients
cal suspicion in these populations [47]. positive for BRCA and other genetic mutations are outlined
The most recent drafted guidelines from the United States in Table 17.4. Prior to age 30, mammography is avoided, and
Preventative Services Task Force (USPSTF) suggest that screening with an MRI or ultrasound is recommended. After
PCPs who have received training in genetic counseling can age 30, yearly clinical exam, mammography, and MRI are
order genetic tests and provide counseling. It is suggested, recommended.
however, that primary care providers not order BRCA or Prophylactic mastectomy should be considered for patients
other genetic testing without the availability of genetic coun- with PTEN mutation, Li-Fraumeni syndrome, hereditary dif-
seling [28]. Patients benefit from a certified genetic counselor fuse gastric cancer syndrome, PALB2 mutations, or any other
to fully understand the risk, benefits, and implications of mutation which is associated with a greater than 50% lifetime
genetic testing. As genetic testing and DNA sequencing risk of breast cancer [13]. Patients with Peutz-Jeghers syn-
becomes more widespread and affordable, many patients will drome and Lynch syndrome need aggressive colorectal cancer
obtain testing through mail-in tests and present for advice; screening [30]. Depending on the mutation and vulnerabilities
therefore, PCPs should be prepared to discuss these results. of patients with genetic mutations, screening for colon cancer,
A challenge with genetic testing is to interpret the result in ovarian, thyroid, or other cancers might also be recommended.
the context of the individual patient and the risk of breast can- Chemoprevention is recommended in many cases of genetic
cer associated with each mutation (see Table 17.4). Genetic mutations if prophylactic mastectomy is not performed. Given
counseling will continue to be important as the list of muta- the complexity of genetically susceptible patients, co-manage-
tions associated with cancer expands. Patients who test at ment with specialists utilizing comprehensive management
home will need to be advised on preventive strategies if strategies is recommended (see Table 17.4).
genetic risk is identified. Currently, home testing panels vary
greatly as to which mutations are included, and therefore, a
negative test result is approached with caution in patients with Imaging with MRI and Early Mammography
a significant family history. Patients who qualify for genetic
testing (Table 17.5) are referred to a genetic counselor even if The decision as to when to start mammography, and whether to
they had a negative home test. The patient is advised to bring order MRI screening, depends on the overall risk of breast can-
the home test results to their appointment with the counselor cer. In general, early mammogram and MRI are recommended
to determine if additional testing is needed. for patients with a history of prior chest radiation, known
genetic syndrome, high-risk breast lesions, and those with a
> 20% lifetime risk of breast cancer. Despite the known benefit
reventive Care of Patients with BRCA
P of supplemental MRI screening for high-risk patients, it
and Other High-Risk Genetic Mutations remains underutilized. A recent study found that, despite rec-
ommendations, only 6% of high-risk women are currently
Hereditary breast and ovarian cancer syndromes (HBOCs), being screened by breast MRI [49] (for details, see Box 17.4).
the most common of which are BRCA1 and BRCA2 germline
mutations, are responsible for 30% of inherited breast cancers
[28]. BRCA genes are inherited in an autosomal dominant pat- Jeanne engages in a discussion about chemopreven-
tern and are mutations in a tumor suppressor gene. tion with tamoxifen to reduce her risk of breast cancer.
If a BRCA1 or BRCA2 mutation is detected, breast can- The potential risks of thromboembolism and vaginal
cer screening is adjusted as outlined in Table 17.3. The bleeding with this medication are discussed, and the
NCCN guidelines state that BRCA1- and BRCA2-positive patient is counseled about the warning signs of blood
women who have completed childbearing should undergo clots and possible uterine bleeding abnormalities. She
risk-reducing bilateral mastectomy and salpingo- is educated about the potential for menopausal symp-
oophorectomy [13]. Risk-reducing mastectomy has been toms such as hot flashes and vaginal dryness. She
shown to decrease the risk of developing breast cancer in agrees to start the medication.
patients with BRCA mutations by 95% (CI 41.4–100%)
hemoprevention: Effectiveness and Selecting

C factors to determine if a patient would benefit from these
an Agent medications [5]. This includes the following:
Evidence of Impact • Patients 65-year-old or older with one first-degree relative

Selective estrogen receptor modulators (SERM) and aroma- with breast cancer
tase inhibitors (AI) are the most common agents for primary • Patients 45-year-old or older with more than one first-
chemoprevention; they are also used to prevent recurrence of degree relative with breast cancer or one first-degree rela-
breast cancer. When used in select women, these medica- tive who developed breast cancer prior to age 50
tions can reduce the risk of estrogen-receptor-positive (ER+) • Patients 40-year-old or older with a first-degree relative
breast cancer by 50% [34]. For women with atypical hyper- with bilateral breast cancer
plasia, this can help reduce risk as much as by 86% [34].
Despite being one of the most effective prevention options, The USPSTF also has a “D” (evidence of harm) recom-
chemoprophylaxis remains underutilized with only 1% of mendation for using chemoprevention medications in women
eligible women taking the medications [50]. Some of the who are not at increased risk of breast cancer. “Women who
proposed barriers include limited knowledge of PCPs about are younger than 60 years and with no additional breast can-
chemoprevention, lack of prevention focus by oncologists, cer risk factors or women with a low 5-year risk should not
time constraints, and perceptions that fail to see breast cancer routinely be offered this medication as the harms of the med-
as a preventable disease [50, 51]. Patients may be concerned ication outweigh the benefit in this population” [5]. Women
about adverse effects and, while this is an important concern, over 60 years of age might qualify for chemoprevention with
these medications are generally well tolerated. Primary care no family history or high-risk breast lesion, but the increased
providers can help to move breast cancer from a treatment- risk of vascular events in older women must be considered in
focused disease to a potentially preventable disease with the the shared decision-making process.
use of chemoprevention. Providers who would like to gain more experience in man-
aging chemoprevention medications are encouraged to start
Candidates for Chemoprevention by offering chemoprevention to women with known atypical
While there is some variation in patient qualifications ductal hyperplasias and lobular carcinoma in situ. PCPs are
between guidelines, all are founded on identifying women at encouraged to identify and discuss risks and benefits with
an increased risk of breast cancer, either by identification of women who have a new diagnosis and with those who may
certain high-risk factors or by estimation of the 5-year risk of have refused or deferred chemoprevention in the past.
breast cancer. Current recommendations for women over age
35 are summarized in Table 17.6 [5, 14, 25]. The choice of elective Estrogen Receptor Modulators (SERMs)
S
calculator affects risk estimation (see Box 17.4). All of the SERMs block some estrogen receptors and stimulate oth-
guidelines support the use of the Breast Cancer Risk ers. These effects differ by each drug within this class of
Assessment Tool (or Gail model), but to determine 5-year medication. The two SERMs currently approved for breast
breast cancer risk, other calculators may be more appropri- cancer prevention are tamoxifen and raloxifene. Tamoxifen
ate. Women with dense breasts may be assessed using the blocks estrogen effects in the breast but has an estrogenic
BCSC tool. The IBIS model also incorporates breast density, effect on the uterus and bones. Tamoxifen increases the risk
a diagnosis of LCIS, Ashkenazi Jewish decent, family his- of endometrial dysplasia and uterine cancer and thus is
tory of breast or ovarian cancer in second-degree relatives, a typically reserved for premenopausal women and those
family history of male breast cancer, genetic findings of who have undergone a hysterectomy. In a review of pla-
BRCA 1 and 2, and other factors into its calculations. cebo-controlled trials, tamoxifen (RR 0.70 [95% CI, 0.59–
The American Cancer Society (ACS) and NCCN advise 0.82] or 7 cases in 1000 women) and raloxifene (RR 0.44
chemoprevention in women with a greater than 1.66% 5-year [95% CI, 0.27–0.71] or 9 cases in 1000 women) both dem-
risk and at least a 10-year life expectancy [14, 25]. The onstrated decrease in breast cancer among women who
USPFTS guidelines state that 1.66% 5-year risk treatment used these therapies [52].
cutoff may overestimate the benefit from risk-reduction Raloxifene has a similar profile to tamoxifen with agonist
medications and recommend 3% as the level of risk in which activity in the bone and lipids and an antagonist effect on the
patients may have a greater benefit from these interventions breast and uterus. Raloxifene is approved for chemopreven-
[5]. All guidelines support the use of these risk-reduction tion in postmenopausal women only and is approved for both
agents for 5 years to reduce the risk of future estrogen- the prevention and treatment of postmenopausal osteoporo-
receptor-positive cancers. sis. Both agents improve bone density which is important
Based on the 2019 USPSTF drafted guideline on chemo- since these medications are often given after peak bone mass
prophylaxis, clinicians can also use a combination of risk has been established (see Chap. 25 on “Osteoporosis”).
ontraindications to SERM Use

C addition to bone effects, other common adverse effects of
SERMs should not be used in women who have a history of AIs are worsening of vasomotor symptoms, vaginal dryness,
venous thrombosis or pulmonary embolism, a history of and joint pain. AIs should be used with caution for women
stroke, a condition increasing the risk of clotting such as pro- with a history of osteoporosis.
longed immobilization and pregnancy, or lactation. When
these medications are used in reproductive-aged women, it is
important to discuss contraceptive options, focusing on non- Jeanne returns to clinic 3 months later complaining of
estrogen options since estrogen will interact with the severe hot flashes 3–4 times a day, including nocturnal
SERM. While both SERMs carry the risk of thromboembo- symptoms. She notes feeling tired in the morning due
lism, the risk appears to be more pronounced with tamoxifen to poor sleep. She is still having regular periods. She
(RR 1.93 [95% CI, 1.41–2.64]) [52]. The most commonly would like to know if she should take hormones like her
reported adverse effects with both agents are vasomotor friend did when going through menopause, or if there
symptoms and vaginal dryness. are other options. The patient is counseled that her hot
In a direct comparison of tamoxifen and raloxifene in the flashes are an expected side effect of tamoxifen and
STAR trial, there were more invasive breast cancers with ral- that estrogen therapy is not appropriate. Nonhormonal
oxifene (RR 1.24, 95% CI, 1.05–1.47), suggesting a superi- options for treating the vasomotor symptoms of SERMs
ority of tamoxifen for chemoprevention; however, there were including SSRIs, SNRIs, and gabapentin are discussed.
fewer adverse events with raloxifene, including invasive She would like to try venlafaxine.
uterine cancer (RR 0.55, p = 0.003) and thrombosis (RR
0.75, p = 0.007). The absolute increased risk of thrombosis
with tamoxifen was 0.83 events per 1000 women (3.30 per anaging the Adverse Effects
M
1000 with tamoxifen vs 2.47 with raloxifene) [53]. It is of Chemoprevention
important to note that the effects of these medications on
overall survival are unknown because the length of follow-up Vasomotor symptoms can be bothersome to patients taking
is limited (longest study has a 13-year follow-up interval). either SERMs or AIs. Menopausal hormone therapy is not
Clinically, tamoxifen is used for chemoprophylaxis pri- appropriate for the treatment of vasomotor symptoms in
marily in premenopausal women and in postmenopausal women on these medications. Hot flashes are caused by a
women who have had a hysterectomy; raloxifene or AIs are complicated system of neurotransmitter changes due to low
used in postmenopausal women. Patients should plan to take estrogen levels, increased levels of FSH, and possible LH
the medication for 5 years, but women are free to stop the surges. Thermoregulatory control is destabilized as norepi-
medication at any time if they experience side effects. The nephrine, serotonin, GABA, and other neurotransmitters are
use of tamoxifen and AIs for secondary prevention in patients affected. This provides the mechanisms for pharmacologic
with DCIS and breast cancer is discussed in Chap. 19 on treatment when estrogen treatment is contraindicated (for fur-
“Breast Cancer Diagnosis and Management”. ther discussion see Chap. 8 on “Menopause”). Venlafaxine
and serotonin reuptake inhibitors (SSRIs) have been shown to
romatase Inhibitors (AIs)
A ameliorate hot flashes in women with a history of breast can-
AIs are used as adjuvant treatment in breast cancer (see cer [55]. Venlafaxine decreases the hot flash frequency by as
Chap. 19 on “Breast Cancer Diagnosis and Management”) much as 50% in breast cancer survivors and men with pros-
and can be used for chemoprevention. AIs block the conver- tate cancer taking androgen deprivation therapy. While a dose
sion of androgens to estrogen by aromatase thereby decreas- response was present, there was no additional improvement
ing the amount of circulating estrogen. Conversion of seen in venlafaxine doses above 75 mg daily [56]. Gabapentin
androgens is the main method of estrogen production after has also been shown to decrease frequency of hot flashes at
menopause, and therefore, this method is reserved for post- doses of 900 mg daily when compared to placebo [56].
menopausal women. Venlafaxine is the drug of choice for treating hot flashes
Two AIs have been studied for chemoprevention. in women on tamoxifen. Paroxetine, bupropion, and fluox-
Anastrazole, when compared to placebo, demonstrated a etine should be used with caution in women taking tamoxi-
lower incidence of breast cancer (HR 0.47, 95% CI 0.32– fen since they are strong inhibitors of the CYP2D6 enzyme.
0.68) [54]. Of note, there was a slightly higher incidence of This enzyme converts tamoxifen to its active metabolite;
fracture in the anastrazole group, though this was not statisti- inhibitors of this enzyme can decrease the effectiveness of
cally significant. Exemestane, when compared to placebo, tamoxifen. A Canadian cohort study estimates use of parox-
also demonstrated a lower incidence of breast cancer (HR etine results in 1 additional death for every 19 breast cancer
0.47, 95% CI 0.27–0.79). There was not a significant change patients taking tamoxifen for breast cancer treatment. This
in fracture risk between placebo and exemestane [25]. In effect has not been demonstrated with other SSRIs [57].
Venlafaxine minimally blocks the activity of the CYP2D6 Future Directions for Chemoprophylaxis
enzyme and is considered the preferred agent to use with
tamoxifen [58]. With advances in breast cancer risk assessment, genetic
Vaginal dryness and dyspareunia are also commonly counseling, and chemoprophylaxis, the goal is that many
reported by women taking both SERMs and AIs. The first- breast cancers will be prevented. Just as PCPs evaluate all
line treatments include water-based (KY and Astroglide) patients for cardiovascular risk, breast cancer risk should be
lubricants; olive and coconut oil can also be used for lubrica- evaluated in all women. The use of chemoprevention is a
tion. Vaginal moisturizers such as Replens can be helpful for powerful tool to reduce breast cancer risk in women over age
women who have symptoms outside of intercourse. These 35. Its clinical usefulness is currently limited by difficulty in
options will not reverse vaginal atrophy which requires tolerating adverse effects such as vasomotor symptoms.
estrogen to treat. The use of topical estrogens in women at Currently, a phase III clinical trial is underway to determine
high risk of breast cancer and in breast cancer survivors is if tamoxifen can be used at a 5-mg dose for secondary pro-
controversial; see Chap. 8 on “Menopause” for a discussion phylaxis in breast cancer with the hope that this would reduce
on the genitourinary syndrome of the menopause. the risk of adverse side effects [60]. If this is successful,
Bone health is an important consideration in all post- these data may be able to be extrapolated to a chemoprophy-
menopausal women but particularly in those taking AIs. laxis application.
Given the risk of osteoporosis with AIs, raloxifene is recom-
mended as the first-line chemoprevention agent for post-
menopausal women. There are no clear guidelines for bone Prophylactic Mastectomy
health in women using AIs for chemoprevention, but recom-
mendations for breast cancer survivors who are taking AIs Prophylactic mastectomy is generally offered to women with
may be applicable to this population. The American Cancer a lifetime breast cancer risk of over 50% after the completion
Society (ACS) and the American society of Clinical of childbearing. Very-high-risk women could undergo mas-
Oncology (ASCO) recommend a baseline DEXA scan for all tectomy before the completion of childbearing if needed.
women when starting AIs and again every 2 years [59]. In
addition to counseling on weight-bearing exercise, limiting
alcohol, and avoiding tobacco, the ACS/ASCO recommends Comprehensive Management Strategies
all women taking AIs also consider supplemental calcium
(1200 mg/day) and vitamin D3 (600–1000 U/day) [59]. For Women at very high risk of breast cancer are generally
women taking AIs found to have osteoporosis, bisphospho- women with history of chest radiation, genetic syndromes,
nates are the first-line treatment option (see Chap. 25 on lifetime risk >20%, or high-risk abnormal breast biopsies
“Osteoporosis”). (such as DCIS, LCIS, and atypical hyperplasia). These
Vaginal bleeding occurs in one-quarter of women taking women should be followed using comprehensive manage-
tamoxifen, due to the agonistic activity of tamoxifen on the ment strategies in conjunction with specialists who may
endometrium. This same mechanism is the cause of increased include breast oncologists or surgeons, gynecologists,
risk of endometrial hyperplasia, polyps, and cancer. genetic counselors, and radiologists. This team can devise a
Postmenopausal and premenopausal women with irregular plan to address screening, genetic counseling, general pre-
vaginal bleeding or a change in menstrual bleeding should be ventive strategies, chemoprevention, and prophylactic sur-
biopsied and referred to a gynecologist as necessary (see gery if indicated.
Chaps. 7 and 15 on “Abnormal Uterine Bleeding” and
“Gynecologic Malignancies, Section on Uterine Cancer”).
Summary Points
1. Breast cancer risk can be modified through lifestyle mod-

Jeanne starts venlafaxine 37.5 mg daily and titrates up ifications including weight loss, regular exercise, breast-
to 75 mg; her hot flash symptoms improve. She is now feeding, and decreasing alcohol intake.
having only 1–2 hot flashes a day, with nocturnal 2. All women should undergo a breast cancer risk assess-
symptoms about once a week, and finds this tolerable. ment by their primary care provider starting at age 18.
Vaginal dryness has not been a problem. The plan is to Patients should be educated on breast health and breast
continue the tamoxifen for a total of 5 years with ven- awareness, risk factors, and prevention strategies.
lafaxine 75 mg daily. 3. Women can be triaged with three questions about history
of chest radiation, family and genetic risk, and history of
breast biopsy to determine if further risk calculations will an appropriate screening regimen. Only patients with a
be helpful. A personalized prevention plan addresses greater than 20% lifetime risk require MRI or screening
modifiable risk factors, as well as screening and preven- mammograms before age 40.
tion strategies appropriate for each woman. 2. A 50-year-old premenopausal female presents to dis-
4. High-risk women, including those with known genetic cuss breast cancer risk. She is very upset that her best
syndrome, a history of chest irradiation, or a history of friend was recently diagnosed with breast cancer. Her
cancer, DCIS, LCIS, ADH or ALH, or lifetime risk of BMI is 35 and she regularly attends a yoga class on the
>20%, should be referred and co-managed with weekends. She has 5–7 alcoholic drinks a week. There
specialists. is no family history of breast or ovarian cancer.
5. Patients with (1) a family history of ovarian cancer, (2) a Mammogram earlier this year was normal with density
family history of male breast cancer, (3) breast cancer “almost entirely fat.” Her 5-year breast cancer risk by
in 2 or more family members on the same side of the Gail model is 0.8% and lifetime risk 9.5%. She would
family, or (4) a family member diagnosed with breast like to know what she can do to reduce her risk of breast
cancer at a young age (<45-year-old) should be referred cancer. Which of the following interventions would
to a genetic counselor. Women at high risk may benefit decrease her risk of breast cancer?
from chemoprevention or adding MRI to mammogram A. Encourage her to decrease her alcohol consumption
screening. to less than 4 drinks per week and to work towards
6. Use of SERMS and AIs in high-risk women (>1.66% weight loss
5-year risk) over age 35 can decrease breast cancer risk B. Advise her to avoid soy in her diet as this has weak
by approximately 50%. PCPs can become comfortable in estrogen-like properties.
prescribing SERMs for the primary prevention of breast C. Advise her to start taking tamoxifen daily for the next
cancer in selected patients. 5 years
D. Encourage her to limit caffeine to less than 200 mg
Acknowledgments The authors would like to acknowledge Diane daily
Altkorn for her assistance in reviewing this chapter and Jacqueline Falk The correct answer is A. Reducing her alcohol consump-
for her patient and skilled assistance in the graphic design of Fig. 17.1.
tion and losing weight have both been shown to reduce
breast cancer risk. She should also increase her physical
activity. While taking a chemoprevention agent like
Review Questions tamoxifen may reduce her risk of breast cancer, it is not
indicated in women with a 5-year risk of <1.67% by Gail
1. A 37-year-old G1P1 female presents for a new patient or IBIS [14, 22, 23, 25]. Soy and caffeine do not affect
appointment. Her family history is significant in that her breast cancer risk.
maternal grandmother had breast cancer and her maternal 3. Which of the following is a known adverse effect of
aunt died of breast cancer at age 44. Her mother and sister raloxifene?
have not had any breast disease. Her Gail 5-year risk A. Raloxifene, like other SERMS, can increase the risk
score is 1.4% and lifetime risk is 10%. In addition to a of osteoporosis
complete history and physical, what is the next step for B. Raloxifene can increase the risk for deep venous
her in regards to breast cancer screening and prevention? thrombosis and pulmonary embolism
A. Start mammograms when she turns 40 and screen C. Raloxifene can increase the risk of ovarian cancer
annually D. Raloxifene can increase the risk of uterine cancer
B. Order mammogram now and refer for genetic The correct answer is B. Raloxifene is a SERM which has
counseling estrogenic effects on the bones, but antiestrogen effects
C. Refer her for genetic counseling on breast and uterine tissue. Raloxifene increases the risk
D. Start mammograms with supplemental breast MRIs of thrombosis. Raloxifene does not increase the risk of
annually when she turns 40 ovarian cancer or uterine cancer. Raloxifene is approved
The correct answer is C. This woman should be referred for the prevention and treatment of osteoporosis.
now for genetic counseling given the age of her aunt at Raloxifene is only approved for use in postmenopausal
time of her breast cancer diagnosis. Per the NCCN guide- women [51–53].
lines, any first-, second-, or third-degree relative with 4. A 31-year-old female with a history of Hodgkin’s lym-
breast cancer diagnosed at age 45 or younger qualifies for phoma at age 11 had treatment with chemotherapy and
a genetic counseling referral to evaluate for high- radiation therapy to her chest. She was not aware of her
penetration genetic mutations [13]. This is the next step increased risk of breast cancer. What is the recommended
because the results of her genetic testing will determine prevention plan for women with her history?
A. Start mammograms with possible tomosynthesis at References

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Breast Cancer Screening
18
Anna Golob, Traci A. Takahashi, and Kay M. Johnson
Learning Objectives LuAnn is a 44-year-old African American woman who

1. Assess breast cancer risk to determine whether presents to her primary care provider for a routine
women are of average, moderate, or high risk for health care visit. She has several questions about
breast cancer over the next 5 years and in their breast cancer screening. She is worried because her
lifetimes. mother was recently diagnosed with breast cancer at
2. Discuss screening and diagnostic imaging tools the age of 68. Also, LuAnn had a mammogram at age
including mammography types (2D conventional 40 and received a letter stating that her mammogram
vs 3D tomosynthesis), MRI, and ultrasound, includ- was normal but that she had “heterogeneously dense
ing the risks and benefits for patients. breasts.” The letter advised that she discuss further
3. Discuss the recommended ages and screening inter- screening options with her primary care provider. She
vals for mammography for average-risk women underwent menarche at age 10, is nulliparous and is
according to the US Preventive Services Task Force still menstruating. Today she asks whether she needs a
(USPSTF) and American Cancer Society (ACS) breast MRI and whether she should get a genetic test,
guidelines. because of her dense breasts, and because of her moth-
4. Describe the categories of mammographic breast er’s recent breast cancer diagnosis.
density, the implications for breast cancer risk, and
imaging options for dense breasts.
5. Identify women at increased risk for breast cancer
who may benefit from earlier initiation of mam-
mography screening, MRI imaging, referral for Introduction
genetic testing, and referral to a breast specialist for
prophylactic treatment recommendations. Breast cancer is the most common invasive cancer in women
6. Perform a clinical breast exam when indicated and worldwide and is responsible for more deaths than any other
list clinical scenarios in which it is most likely to cancer in women. In the USA, cancers are the leading cause
add benefit. of death in women aged 35–65 [1]. Over their lifetime, one
7. Interpret mammography results and initiate appro- out of eight women in the USA will be diagnosed with breast
priate follow-up. cancer [2]. Although breast cancer incidence has increased in
8. Describe initial patient counseling issues in women the USA since the 1970s, breast cancer mortality has steadily
with suspected breast cancer who are being referred decreased at a rate of approximately 2.2% per year since the
for further evaluation and treatment by breast 1990s. This decrease in mortality is attributed to improve-
oncologists. ments in breast cancer treatment in addition to earlier detec-
tion with more widespread screening with mammography.
While there is good evidence that mammography reduces
mortality from breast cancer in women at average-risk ages
50–69, optimal screening protocols for younger women and
A. Golob (*) · T. A. Takahashi · K. M. Johnson women at intermediate risk are debated among professional
Department of Medicine, University of Washington and VA Puget organizations. Values placed by patients and physicians upon
Sound Healthcare System, Seattle, WA, USA

298 A. Golob et al.
early detection versus the burden of false-positive findings, Breast Cancer Risk Assessment
with the resulting unnecessary diagnostic and treatment
modalities, inform shared decision-making in such cases. The identification of risk factors for individual patients allows
Newer imaging technologies, such as 3D breast tomosynthe- for risk assessments which categorize women into average-,
sis, may augment conventional 2D mammography for breast moderate-, and high-risk categories. The risk assessments
cancer screening, particularly for women with dense breasts. inform several decision points (see Table 18.1):
Women at moderate and high risk (referred to in the litera-
ture as “increased risk”) should be identified and referred for 1. Which imaging modalities should be employed, starting
appropriate genetic testing and discussion of prophylactic at what age and how often?
treatments. Breast MRI in addition to mammography has 2. Which women should be offered chemoprophylaxis or
become a standard screening modality for women at high prophylactic mastectomy?
risk for breast cancer. This chapter will address breast can- 3. Which women should be referred for genetic counseling
cer risk assessment, screening recommendations, shared and possible genetic testing?
decision-making, and patient counseling issues in women
with suspected breast cancer who are being referred for fur- Some women are easily identified to be at average risk
ther evaluation and treatment by breast specialists. due to the absence of risk factors, and others are clearly at
high risk based on the presence of strong predisposing fac-
tors: chest radiation and known genetic mutation. Women
reast Cancer Risk Factors and Risk
B with one or more risk factors or a positive family history for
Assessment cancer, however, may require more detailed risk assessment
and calculation to determine risk category. Risk assessment
Breast cancer screening guidelines depend foremost on tools are useful to determine 5- or 10-year risk and life-
breast cancer risk category. Current screening guidelines time risk of developing invasive breast cancer in individual
for mammography are applicable to the majority of women patients. These tools are widely available to the public and to
patients who are at average or moderate risk for the develop- clinicians on the Internet. A woman is at average risk if her
ment of breast cancer. Women who are at high risk of breast lifetime risk of developing breast cancer is 15% or less, at
cancer are screened according to separate protocols utilizing moderate risk if her lifetime risk is 15–20%, and at high risk
MRI in addition to mammography beginning in the third and if her lifetime risk exceeds 20–25% [5]. Women at moderate
fourth decades of life. risk are screened according to the same guidelines as aver-
age risk women. All women should be assessed annually to
determine if new information places the patient into a higher
Risk Factors risk category.
Breast cancer risk assessment should be part of the health

care maintenance of all adult women, starting at age 18. (See Table 18.1 Breast cancer risk categories for screening
Chap. 17 on The Primary Prevention of Breast Cancer.) Risk Lifetime risk
factors are identified through history-taking and by reviewing Risk of developing
diagnostic imaging and testing, if any, related to the breast. category breast cancer Screening recommendations
The major risk factor categories for breast cancer risk Average <15% Offer routine mammography per
average risk screening guidelines by the
include:
ACS or USPSTF (see Table 18.3)
Moderate 15–20% Offer routine mammography per
1. History of chest radiation prior to age 30 (usually for average risk screening guidelines by the
Hodgkin’s disease) ACS or USPSTF (see Table 18.3)
2. Genetics: family history of cancer or known genetic syn- Consider 3D tomosynthesis rather than
conventional 2D mammography when
drome, race available for women with dense breasts
3. Personal breast characteristics: lumps, pain, discharge, High >20% Offer annual mammography and breast
prior biopsies and result, density MRI starting at age 30 or as
4. Reproductive and hormonal factors: age of menarche, recommended by breast specialist
Consider annual breast exam
parity, age of first birth, menstrual status, age at meno-
(recommended by NCCN but not ACS)
pause (if postmenopausal), history of breastfeeding, past
ACS American Cancer Society, USPSTF US Preventative Services Task
or current exogenous hormone use Force, NCCN National Comprehensive Cancer Network
18 Breast Cancer Screening 299
Average Risk Women with a personal history of dense breasts or abnor-

Women with an average risk of breast cancer have a <15% mal breast biopsies need closer evaluation. Patients with a
lifetime risk of developing invasive breast cancer and are history of ductal carcinoma in situ (DCIS) or a previous his-
screened per USPTF guidelines. Per American Cancer tory of breast cancer are excluded from most risk assess-
Society guidelines, a woman may be presumed to be of aver- ment tools and should be managed in consultation with a
age risk for screening purposes if she has none of the follow- breast specialist. Women with biopsy-proven atypical lobu-
ing risk factors: lar (ALH) and atypical ductal hyperplasia (ADH) or lobular
carcinoma in situ (LCIS) should be offered chemoprevention
• Personal history of breast cancer or abnormal breast and be evaluated for lifetime breast cancer risk. Patients with
biopsy dense breasts should be evaluated for risk in conjunction
• Strong family history of breast cancer or a genetic muta- with other risk factors. Consultations from breast health spe-
tion known to increase the risk of breast cancer (such as a cialists will assist in decisions regarding appropriate genetic
BRCA gene mutation) testing, prophylactic therapies, and screening regimens for
• Chest radiation therapy before the age of 30 [6] women at higher than average or unclear risk status. (See
Chap. 17 on Primary Prevention of Breast Cancer.)
Most women who develop breast cancer are considered
average risk, with no additional strong risk factors beyond
age and sex. se of Risk Assessment Tools in Women
U
at Possible Increased Risk
High Risk
Some women are known to be high risk without the use Risk assessments may be performed using one of several risk
of risk assessment tools and should be referred to a breast assessment tools. For breast cancer screening purposes, the
health specialist for evaluation and counseling. These include goal is to identify women with a greater than 20% lifetime
women with: risk who should be offered annual MRI screening in addi-
tion to mammography. The most commonly used tool is the
• Known BRCA1 or 2 mutation carriers or known genetic National Cancer Institute’s “Breast Cancer Risk Assessment
mutation with increased risk Tool (BCRAT)” also called the Gail Model that is available
• Untested first-degree relatives of a known BRCA muta- on the National Cancer Institute website: https://bcrisktool.
tion carrier cancer.gov/ [7, 8].
• History of chest irradiation between 10 and 30 years of The Gail Model is valid for use in women aged 35–85,
age with no history of breast cancer, DCIS, or LCIS. Other tools
• >20% lifetime risk of cancer based on a risk assessment should be used for women with known mutations in BRCA1,
tool BRACA2, and other hereditary syndromes associated with
breast cancer and in patients with a strong family history of
These patients often begin screening with annual mam- breast or ovarian cancer.
mography and MRI prior to age 40, and options of prophy- The Gail Model calculator can be used for 35- to 85-year-
lactic mastectomy, oophorectomy, or chemoprophylaxis old women, and asks for:
should be discussed with the patient. (See Chap. 17 on
Primary Prevention of Breast Cancer.) • Age
Breast cancer risk assessment is highly dependent on • Age of menarche
an accurate and up-to-date family history. The USPSTF • Age at first live birth (or nulliparity)
recommends that all women be screened at 18, and then • Number of first-degree female relatives with breast cancer
periodically every 3–5 years as family history changes, (mother, sisters, and daughters only)
to determine who should be tested for inheritable cancer • Number of previous breast biopsies and results (with or
genes. Women with a family history of premenopausal without atypical hyperplasia)
breast cancer, male breast cancer or ovarian cancer in • Race/ethnicity (White, Hispanic, Asian American (with
first-degree relatives, or multiple cases of cancers in the subcategories), or American-Indian/Alaskan Native
immediate or extended family should be considered for
genetic counseling and testing. (See Chap. 17 on Primary Five-year and lifetime risks of developing invasive breast
Prevention of Breast Cancer.) cancer are then calculated. According to the Gail Model, a
300 A. Golob et al.
5-year risk >1.7% is interpreted as increased risk (includ- • Age at first live birth (or nulliparity)
ing both moderate- and high-risk women). Women in this • Number of first-degree female relatives with breast cancer
risk category are candidates for chemoprevention with selec- • Number of previous breast biopsies and results (with or
tive estrogen receptor modulators or aromatase inhibitors or without atypical hyperplasia)
consideration of surgical prophylactic options. (See Chap. • Height and weight
17 on Primary Prevention of Breast Cancer.) Patients with a • Hormone therapy use
lifetime risk over 20% are offered screening MRI in addition • Breast density category
to mammography. • Ashkenazi grandparent
The Gail Model’s strengths include validation in three • BRCA or another genetic syndrome
large population databases [9] and ease of use during an • History of LCIS
office visit. Limitations of the Gail Model include (1) a • Family history that includes breast and ovarian cancer in
relatively low sensitivity (28–44%) and moderate specific- first- and second-degree relatives on both sides of the
ity (66–88%) for predicting breast cancer diagnosis in all family including age of diagnosis
women and (2) worsened performance characteristics in • Male breast cancer in first-degree relative
women with a strong family history of breast cancer (e.g., • Bilateral breast cancer
more than one first-degree relative or multiple non-first- • Breast cancer in half-sisters, female cousins, and nieces is
degree relatives or male relatives) or family history of other also considered
cancers such as ovarian cancer [9–11]. The Gail Model is not
well validated among women of Hispanic or Asian descent The IBIS calculator can be downloaded without charge
and may underestimate breast cancer risk in women of some from http://www.ems-trials.org/riskevaluator/ [12].
races and ethnic backgrounds including African American There are numerous other risk calculators that are not as
and Jewish women. Many women are of mixed racial decent, widely known, the discussion of which is beyond the scope
so while the Gail Model makes an attempt to incorporate of this chapter. These tools may be used by breast health
data on race, these are significant limitations which the cre- specialists, researchers, or genetic counselors and can give
ators acknowledge. Lastly, breast density is not included in more detailed risk information for risk of 5- or 10-year and
the Gail Model calculation. lifetime breast cancer risk.
For women in whom an inherited breast cancer syndrome
is suspected based on strong family history of breast, ovar-
ian, tubal, or peritoneal cancer, the USPSTF recommends Case Resolution
the use of other clinical risk prediction tools with better
predictive accuracy than the Gail Model to determine which
patients should be referred for genetic counseling/testing or Per the Gail Model (BCRAT), LuAnn has a 5-year risk
undergo other preventive strategies [11]. (See Chap. 17 on of 1.9% and a 14.5% lifetime risk of breast cancer. The
Primary Prevention of Breast Cancer.) 5-year risk is such that she should consider chemopre-
vention and would warrant referral to a breast special-
ist. Her lifetime risk, however, is in the average-risk
he Tyrer-Cuzick or International Breast Cancer
T category (<15% lifetime risk).
Intervention Study (IBIS) Model Knowing that the Gail Model underestimates risk in
African American women and does not account for
The Tyrer-Cuzick or International Breast Cancer Intervention breast density, a second risk calculation was per-
Study (IBIS model) is considered superior to other online formed for LuAnn. Per the Tyrer-Cuzick (IBIS) tool,
screening tools, in that it does not underestimate risk, con- she has a 26% lifetime risk of breast cancer which puts
siders both clinical and family history data in depth, and her into the high-risk category (>20–25% lifetime
includes breast density in risk calculations. The calculator risk). Given this risk prediction from a more appropri-
estimates probability of BRCA1 and 2 mutations, lifetime ate tool, she should be referred to a breast health spe-
risk of breast cancer, and 5- or 10-year risk. cialist for consideration of genetic testing, begin
The International Breast Cancer Intervention Study (IBIS: annual imaging with breast MRI in addition to annual
version 8 released Sept 2017) calculator asks for [12]: screening mammography, and also consider preven-
tive strategies such as chemoprevention to reduce her
• Age of patient risk of future breast cancer.
• Age at menarche
Breast Cancer Screening Modalities its effect on false positives. One large prospective trial of
12,631 exams interpreted either with conventional digital
Mammography mammography alone or with tomosynthesis combined with
conventional mammography found cancer (invasive and in
Conventional digital mammography has essentially situ) in 6.1 per 1000 exams with conventional mammog-
replaced film mammography in the US. Digital breast raphy alone vs 8.0 per 1000 exams with added 3D tomo-
tomosynthesis (DBT), sometimes referred to as “3D mam- synthesis, resulting in a 27% increased detection rate with
mography”, is a newer technology that has been approved the addition of tomosynthesis. There were 15% fewer false
by the FDA as an adjunct to conventional digital mam- positives with the addition of tomosynthesis: 61.1 per 1000
mography, and is now routinely built into newer-generation exams with mammography alone vs 53.1 per 1000 exams
mammography units [13]. Using the same breast compres- with added tomosynthesis [15]. In another prospective study
sion required for standard 2D digital mammography, DBT of 9672 exams using conventional digital mammography
images are obtained using a moving x-ray source that arcs alone vs tomosynthesis combined with conventional digital
over the breast (See Fig. 18.1). These images from multiple mammography, there was a similar increase in cancer detec-
angles are then processed into thin “slices.” The radiologist tion rate but also an increased rate of false positives with
can scroll through the different projections slice by slice, tomosynthesis views (4.0–4.5%) vs conventional mammog-
as in other cross-sectional imaging examinations, compar- raphy alone (3.4%) [16]. In this study, the increased cancer
ing them to the standard 2D images. The main advantage detection rate was particularly notable in women with dense
of DBT is that it can mitigate the problem of focal asym- breasts.
metry due to overlapping breast tissue. On standard digital The downsides of 3D tomosynthesis include increased
projections, overlapping tissue can create the appearance radiation exposure, longer duration of exam, and increased
of a tumor that isn’t there or can make it hard to see small radiologist reading time, in addition to higher costs of
cancers that are present. these studies. Newer tomosynthesis technology that allows
Potential benefits of using tomosynthesis with conven- reconstruction of standard 2D images from the tomosyn-
tional digital mammography compared to conventional digi- thesis data aims to reduce radiation exposure and duration
tal mammography alone include increased cancer detection of exam.
(better sensitivity) and decreased rates of false positives There are not yet clear consensus guidelines regarding the
(better specificity). Though no randomized trials have been appropriate use of 3D tomosynthesis as a primary screening
done, prospective studies evaluating this technology have modality. The USPSTF 2016 guidelines give it an “I” grade:
confirmed increased cancer detection rates with the addi- insufficient evidence to assess harms and benefits for tomo-
tion of tomosynthesis but have conflicting results regarding synthesis as a primary screening modality [17].
X-ray Tube
Breast MRI
Women at high risk for breast cancer should be offered gado-

linium contrast-enhanced breast MRI in combination with
mammography to screen for breast cancer (See Table 18.1).
While breast MRI has not yet been shown to reduce breast
cancer mortality, it has been shown to detect smaller breast
cancers and cancers at an earlier stage in high-risk women.
Since half of all abnormal breast lesions seen on MRI are
not seen on other imaging modalities, facilities performing
Pivot breast MRIs should be capable of performing MRI-guided
breast biopsies. Breast MRIs have a significantly lower spec-
Breast
ificity compared to mammography, resulting in higher call
back rates and biopsies. Glandular enhancement by gado-
linium can occur in the lactating breast and during certain
Detector days of the menstrual cycle [18]. Despite the clear benefits of
breast MRI as an adjunct to mammography to screen high-
Fig. 18.1 Schematic representation of image acquisition in breast risk women, it remains greatly underutilized in the high-risk
tomosynthesis [14]. (Reprinted from Yaffe MJ. Measurement of mam-
mographic density. Breast Cancer Res. 2008;10:209) population [19].
302 A. Golob et al.
Benefits of Screening Mammography among women who start screening at age 50 years, 9% of
women with annual screening and 6% of women with bien-
The goal of screening mammography (whether 2D or 3D) nial screening will have a false-positive mammogram and
is early detection of clinically important breast cancer to biopsy recommendation [22].
allow earlier treatment and therefore decrease breast can-
cer mortality. Though the effectiveness of mammography
in detecting only clinically important breast cancer is still Risk of Overdiagnosis and Overtreatment
debated, the evidence supports that screening mammography
programs do decrease breast cancer mortality by 12–33% It is not currently possible to determine the exact propor-
[5, 17]. Not surprisingly, since breast cancer risk increases tion of mammogram-detected breast cancer that represents
with age, the benefit of screening also increases with age. A overdiagnosis since available diagnostic studies cannot dif-
2016 meta-analysis of mammography breast cancer screen- ferentiate clinically important from clinically unimportant
ing trials found that for every 10,000 women screened with cancers. However, estimates from randomized controlled tri-
repeat mammography for 10 years, 3 deaths were avoided in als (RCTs) suggest an overdiagnosis rate of 1 in 5 women
women aged 39–49 years, 8 deaths were avoided in women who are diagnosed with breast cancer via mammography
aged 50–59 years, 21 deaths were avoided in women aged over a 10-year period [23]. A 2016 USPSTF-commissioned
60–69 years, and 13 deaths were avoided in women aged modeling study found a median overdiagnosis risk of 1 in 8
70–74 years [20]. women who are diagnosed with breast cancer with biennial
screening from ages 50–75 [24]. The task force concludes
that with this conservative estimate of breast cancer over-
Harms of Screening Mammography diagnosis risk of 1 in 8, two to three women will be treated
unnecessarily for every breast cancer death avoided.
Identified harms of screening mammography include (1)
false-positive results that lead to unnecessary further testing,
including diagnostic imaging and biopsies, and (2) overdi- reast Cancer Screening Guidelines
B
agnosis and overtreatment of breast cancer, defined as the in Average-Risk Women
detection or treatment of a cancer that would never have been
detected or threatened health in the absence of screening. Increasing age is the most important risk factor for most
For example, a small DCIS lesion that might never have pro- women, which is why screening guidelines, including the
gressed to invasive breast cancer would currently be treated USPSTF, publish recommendations which are based upon
similarly to invasive cancer. The natural history of DCIS is the age of the patient. A woman in her 70s has a relative
not fully understood, and it is possible that this treatment will risk of 18 compared to a woman in her 30s [25]. Similarly,
not benefit the patient as compared to no treatment. the 2017 US cancer statistics summary data from the
Surveillance, Epidemiology, and End Results (SEER) data-
base reports that the odds of developing invasive breast can-
isk of False Positives and Biopsy
R cer increases from 1 in 52 for women under 50 years of age
Recommendations to 1 in 15 for women 70 years of age and over [26].
Several professional organizations, societies, and national
False-positive mammograms are extremely common. health care systems have created breast cancer screening
Based on observational study data from the Breast Cancer guidelines based upon their own interpretations of the litera-
Surveillance Consortium (BCSC), a large population-based ture, particularly their assessment of the balance of benefits
database of mammogram and tumor registries in the USA, if and potential harms of mammography. These are summa-
a woman starts annual screening at age 40, her risk of having rized in Table 18.2.
a false positive in the first decade is 61%; if she has biennial To highlight key differences, the US Preventive Services
screening starting at 40, her risk over the first decade is 42% Task Force (USPSTF) recommends biennial mammography
[21]. The rates of false positives were similar in women who screening starting at age 50, whereas the American Cancer
began screening at age 50 compared to women who began Society (ACS) recommends annual mammography screen-
at age 40. ing starting at 45 with transition to biennial screening start-
A significant number of false-positive mammograms lead ing at age 55. Both guidelines generally do not recommend
to breast biopsy. Among women who start screening at age screening younger average-risk women (40–49 for USPSTF
40 years, 7% of those with annual screening and 5% of those and 40–44 for ACS) but rather that providers use individual
with biennial screening will have a false-positive screening shared decision-making regarding screening in these age
mammogram leading to a biopsy recommendation. Similarly, groups.
Table 18.2 Comparison of breast cancer screening guidelines for average-risk women from multiple organizations [5, 14, 27–31]
Frequency/duration
Organization Year Start screening mammography of screening mammography
US Preventative Services Task Force 2016 Start routine screening at age 50 Biennial
(USPSTF) [14] Women may choose to start screening Insufficient evidence to recommend for or against
between ages 40 and 49 screening >75 years old
American Cancer Society (ACS) [5] 2015 Start routine screening at age 45 Annual for women ages 45–54
Women may choose to start at age 40 Biennial for women aged ≥55 (Women may
choose to continue annual screening after age 54)
Continue screening if overall good health and life
expectancy ≥10 years
American College of Obstetrics and 2017 Offer starting at age 40 Annual or biennial
Gynecology (ACOG) [27] Initiate no later than age 50 Continue until age 75; women may choose to
continue longer
American Academy of Family 2013 Start at age 50 Annual or biennial
Physicians (AAFP) [28] Women may choose to start screening Continue until age 75; consider longer with
between ages 40 and 49 shared decision-making
American College of Radiology 2017 Start at age 40 Screen annually
(ACR) [29] Consider stopping when life expectancy is
<5–7 years
Canadian Task Force [30] 2011 Start at age 50 Screen every 2–3 years for women ages 50–74
National Health Service (UK) [31] 2010 Start at age 50 Screen every 3 years from ages 50–70
The USPSTF acknowledges that the evidence suggests earlier screening after a risk versus benefit discussion. By
women aged 40–49 do have a net benefit from screening contrast, other women may prefer to start later and screen
mammography, but this is small (3 deaths avoided per 10,000 every other year.
women screened for 10 years, compared to 8–21 deaths
avoided for women aged 50–75) and may not be acceptable
to some women when potential harms are considered. reast Cancer Screening for Women
B
The ACS argues that women aged 45–49 are more similar with Dense Breasts
in risk of breast cancer, with a 5-year absolute breast cancer
risk of 0.9%, compared to women aged 50–54, whose 5-year Breasts with a high proportion of glandular and fibrous con-
absolute risk is 1.1% than they are to women aged 40–44 nective tissue compared to fat appear dense on mammogra-
who have a 5-year risk of 0.6%. The risk of false positives phy. The American College of Radiology’s Breast Imaging
is similar whether screening begins at 40 or 50, hence their Reporting and Data System (BI-RADS) classification of
recommendation to start screening at 45 [5]. Regarding their breast density is shown in Table 18.3.
recommendation to screen women annually from 45 to 54, “Dense breasts” (BI-RADS C or D) are common, occur-
the ACS acknowledges that direct evidence comparing breast ring in approximately 43% of women aged 40–74 years. A
cancer mortality by screening interval is limited. However, woman’s BI-RADS density category may vary from one
they cite observational data, meta-analyses, and modeling year to the next, due to both biological reasons (primarily
studies that show greater mortality benefit for annual screen- body weight and hormonal status) and variation in readings
ing in younger women as compared to older women, likely by radiologists [32].
due to a combination of more aggressive tumor characteris- Dense breasts are at an increased risk of developing
tics and decreased sensitivity of mammography in younger breast cancer, estimated to be about 20–30% higher risk
premenopausal women. The ACS does note that annual than women with normal breast density [17, 33] and may
screening also increases risks of false positives [5]. obscure breast tumors on mammography. The sensitivity of
The above discordance in guideline recommendations mammography to detect breast cancer ranges from 87% in
highlights the need for individual shared decision-making women with BI-RADS A to 63% in women with BI-RADS
between clinicians and patients. In summary, all women at D density [34]. This raises the question of whether supple-
average risk for breast cancer are recommended to begin mental screening (with ultrasound, MRI, or other modality)
screening no later than age 50. Clinicians should discuss should be done when a mammogram is negative in women
screening with average-risk women starting in their 40s. with dense breasts. There are no published randomized tri-
Women who are strongly interested in screening mammog- als to answer this question. The USPSTF funded a system-
raphy between 40 and 50 years of age and who are willing to atic review of the literature and concluded in its 2016 Breast
accept an increased risk of false positives should be offered Cancer Screening guidelines that there is insufficient evi-
304 A. Golob et al.
Table 18.3 Breast density classification [3] and prevalence of each reast Cancer Screening in Women
B
category among US women age 40–74 [4] at Increased Risk for Breast Cancer:
Breast Moderate and High Risk
composition Description of breast tissue Prevalence
category appearance (%)
A Almost entirely fat 13.3
Moderate Risk
B Scattered areas of fibroglandular 43.4
density For women at moderately increased risk for breast cancer
C Heterogeneously dense, which 35.9 (15–20% lifetime risk) but no identified genetic mutation,
may obscure small masses there is currently no data from randomized trials to show that
D Extremely dense, which lowers the 7.4 early mammography prior to age 50 or adjunctive imaging
sensitivity of mammography
studies including breast ultrasound or MRI reduce mortality.
This group includes many women in the 40–49 age group
dence to assess the balance of benefits and harms of adjunc- with one first-degree relative with postmenopausal breast
tive screening using digital breast tomosynthesis, breast cancer, but no other risk factors. The ACS and USPSTF
ultrasound, MRI, or other methods in women identified to guidelines state that the current evidence is insufficient to
have dense breasts on an otherwise negative mammogram recommend for or against adjunctive MRI in women at mod-
[17]. Digital 3D breast tomosynthesis may increase sensi- erate risk [35]. Clinicians may discuss uncertain benefits
tivity and decrease recalls in patients with dense breasts; with individual patients in this moderate-risk category and
however randomized trials are lacking to confirm this with consider individual risks/benefits/preferences, availability,
direct evidence. Ultrasound is limited by a very high rate of cost, and insurance coverage factors when deciding about
false positives. MRI is limited by cost, lack of widespread adjunctive imaging. Alternately, primary care clinicians
availability, and potential for adverse events related to the may consider referral to a breast health specialist for advice
use of gadolinium contrast, especially if used annually for regarding appropriate screening.
decades.
No major guidelines recommend supplemental screening
for women with dense breasts; however, due to grassroots High Risk
efforts, more than half of US states require mammogra-
phy result letters to include information on breast density. Women who are assessed as having high risk to develop
Mammography result letters are required to include the breast cancer, defined as a lifetime risk >20–25% based
woman’s breast density in the report or to include a com- on a risk prediction tool such as the Gail Model (BCRAT)
ment stating that breast density decreases the sensitivity or Tyrer-Cuzick (IBIS) model, known BRCA carrier state,
of mammography screening. Some statements encourage untested first-degree relative of BRCA carrier, history of
women to discuss supplemental screening with ultrasound chest radiation between 10 and 30 years of age, or another
or MRI with their health care provider. This can cause stress high-risk genetic syndrome, should be referred to a breast
and confusion for patients whose providers may not always health specialist as soon as possible for evaluation and coun-
agree and whose insurance may not pay for supplemental seling. The breast health specialist will make recommen-
screening. Providers should be prepared to assess a wom- dations regarding appropriate genetic testing, prophylactic
an’s overall risk. therapies, and screening regimens. (See Chap. 17 on The
For women with dense breasts and a high risk of breast Primary Prevention of Breast Cancer.) In general, for women
cancer, the clinician should discuss the potential risks and at high risk of developing breast cancer (see Table 18.4),
benefits of additional screening with MRI or referral to a the American Cancer Society recommends adjunct annual
breast specialist. As mentioned above, the IBIS tool does MRI screening in addition to annual mammography starting
include breast density in its risk assessment. At this time, at age 30; however, they note that this recommendation is
decisions for supplemental screening with MRI are based on based on data from nonrandomized screening trials, obser-
estimates of breast cancer risk as described in the section vational studies, and expert opinion [35]. The MRI and the
above and are only recommended for women with high risk. mammogram should be scheduled approximately 6 months
Women should be reassured that they will be followed clini- apart to effectively screen twice yearly.
cally, and their risk will be assessed annually. As emerging Ultrasounds should be considered in lieu of MRI in
technologies and future studies improve screening modali- women who are unable to undergo MRI examinations. The
ties and inform care, providers will notify patients and advise age to start screening should be individualized, with consid-
them accordingly. eration of patient-specific risk factors and the age of diagno-
Table 18.4 American Cancer Society recommendations for or against Table 18.5 BI-RADS mammography categories and management
adjunctive breast MRI for breast cancer screening in women [35]. recommendations. (Reprinted by permission of the American College
(Adapted with permission from Saslow D, Boetes C, Burke W, Harms of Radiology. ACR BIRADS Atlas Mammography; Table 6: https://
S, Leach MO, Lehman CD, et al. American Cancer Society guidelines www.acr.org/-/media/ACR/Files/RADS/BIRADS/Mammography-
for breast screening with MRI as an adjunct to mammography. CA Reporting.pdf. All rights reserved. The most current version of the ACR
Cancer J Clin. 2007;57(2):75–89) BI-RADS® Atlas can be found at http://www.acr.org/Quality-Safety/
Resources/BIRADS [36])
Insufficient evidence to Recommend
Recommend annual recommend for or against against MRI BIRADS category Appropriate management
MRI screening MRI screening screening 0: Incomplete Recall for additional imaging and/or
Women at high risk: Women at moderate risk: Women at assessment – need comparison with prior examination(s)
Lifetime risk Lifetime risk 15–20% average risk: additional imaging
>20–25% based on based on risk prediction Women <15% evaluation and/or prior
risk prediction model models lifetime risk mammograms for
BRCA1 or BRCA2 Lobular carcinoma in comparison
mutation situ (LCIS) or atypical 1: Negative Return to routine mammography
lobular hyperplasia screening
(ALH) 2: Benign Return to routine mammography
Untested first-degree Atypical ductal screening
relative of BRCA hyperplasia (ADH) 3: Probably benign Short interval (every 6 months)
carrier follow-up with diagnostic mammogram
Radiation to chest Heterogeneously or and/or ultrasound × 1–2 years; return to
between 10 and 30 extremely dense breast routine screen when determined benign
years of age on mammography 4: Suspicious Refer for tissue diagnosis
(BIRADS C and D) 4A: Low suspicion for
Li-Fraumeni, Women with a personal malignancy
Cowden, or PTEN history of breast cancer 4B: Moderate
hamartoma tumor including ductal suspicion for
syndromes and carcinoma in situ (DCIS) malignancy
first-degree relatives 4C: High suspicion for
malignancy
5: Highly suggestive of Refer for tissue diagnosis
sis of affected relatives. (The use of ultrasounds in women malignancy (95–100%)
6: Known biopsy-proven Oncology referral for comprehensive
with breast complaints, mammographic abnormalities,
malignancy cancer treatment evaluation
or palpable masses is discussed separately in Chap. 16 on
Benign Breast Conditions.)
herself. CBEs are essential when evaluating and following
a woman with a breast mass, pain, or discharge (see Chap.
Mammography Interpretation 16 on Benign Breast Conditions) and for evaluating and
and Appropriate Follow-Up following women at high risk of breast cancer. The CBE
is also used by breast specialists for patients in the evalu-
The American College of Radiology has developed standard- ation of known breast abnormalities, increased breast risk,
ized guidelines by which the FDA mandates all mammo- and malignancies. The CBE is also used by many clinicians
grams, breast ultrasounds, and breast MRIs be interpreted. to screen for breast cancer, both in the US and worldwide.
These are called the “Breast Imaging Reporting and Data Like mammography, CBEs can help with the early detec-
System,” referred to as “BI-RADS” [36]. The BI-RADS tion of breast cancer but also can result in harms associated
manual specifies that mammogram reports must include an with false-positive results. It is not known whether screen-
indication, an assessment of breast density, a description of ing CBEs decrease breast cancer mortality either in addition
abnormalities, and a summary that includes the most impor- to imaging or as the only screening modality. An ongoing
tant findings and specification of a final BI-RADS assess- randomized trial comparing CBE to no screening in India
ment category, of which there are seven (see Table 18.5). should answer part of this question in the next several years
[37]. The Canadian National Breast Screening Study-2 pro-
vides some evidence for the effectiveness of CBE [38]. All
The Clinical Breast Exam the women in the study received CBE, and half the women
were also screened by mammography. The mammography
The clinical breast exam (CBE) described in this chapter is a group had no reduction in breast cancer mortality compared
physical exam which is performed by a clinician, in contrast to CBE alone. CBE detected most of the invasive breast can-
to a self-breast exam (SBE), which is done by the patient cers but did not detect cancer as early as mammography;
306 A. Golob et al.
however, the percent of women whose cancer was diag- One limitation of the CBE is that it has not been fully stan-
nosed prior to lymph node spread was the same whether dardized. When a clinician performs a CBE, the exam should
detected by mammography or CBE. The sensitivity of CBE be careful and systematic [18, 41], particularly when assess-
to detect breast cancer appears to be 40–69% and specificity ing a breast complaint, evaluating a woman at increased risk,
88–99% [39]. or when examining a woman who is not receiving screen-
There are no randomized trials evaluating the effective- ing mammography. Gloves should not be used. Inspection
ness of adding CBE to the assessment of average-risk women of breast contour (looking for puckering, dimpling, nipple
already being screened by mammography. The USPSTF last retraction, or asymmetry) and palpation of axillary and supra-
addressed CBE in its 2009 guidelines, stating that the cur- clavicular lymph nodes is done while the patient is sitting up
rent evidence is insufficient to assess the additional benefits or standing. Though there are no adequate data to support
and harms of clinical breast exam (CBE) beyond screening specific positioning of the patient for inspection [41], some
mammography in women 40 years or older. The latest ACS clinicians inspect while the woman raises her arms above
Breast Cancer Screening Guidelines do not recommend her head, as she puts her hands on her hips and contracts her
CBE for average-risk, asymptomatic women given lack of pectoralis muscles or leans slightly forward. After the patient
demonstrated benefit and an increase in false positives [5]. is supine, breast palpation should be performed with the pads
Based on consensus and expert opinion, ACOG’s view is of the fingers using circular motions (not “walking” of the
that screening CBE may be offered “in the context of an finger tips). Each area should be palpated using three dif-
informed, shared decision-making approach that recognizes ferent pressures (light, medium, and deep) to detect a mass
the uncertainty of additional benefits and the possibility of at any of these levels. The best coverage of breast tissue is
adverse consequences of clinical breast examination beyond accomplished by examining tissue in vertical strips begin-
screening mammography. If performed for screening, inter- ning at the axilla and extending down the midaxillary line to
vals of every 1–3 years for women aged 25–39 years and the bra line, then back up to the clavicle, moving medially in
annually for women aged 40 years and older are reason- rows to the center of the chest. This is sometimes referred to
able” [27]. Reflecting the diversity of opinion in the medical as the lawnmower method and is more thorough than a circu-
community, some authors of this textbook do not routinely lar or wheel-and-spoke method [41, 42]. The nipples should
offer CBE to asymptomatic women who are getting regular be inspected for skin changes, discharge, or asymmetry. It
screening via mammography, but others feel strongly that a has been suggested by some authors that truly careful palpa-
CBE (albeit shortened) should be offered to all women as tion should take about 3 minutes per breast.
part of an annual complete physical exam and breast health
education.
There are multiple scenarios in which a CBE is espe- he Self-Breast Examination and Breast
T
cially useful in clinical practice. A thorough and skilled Awareness
breast exam is essential for patients who present to clinic
with breast lumps and other breast complaints. When order- Clinicians in the USA used to routinely teach SBE to
ing diagnostic mammograms or other imaging, clinicians patients, but after a randomized trial in Shanghai showed no
must locate and confirm a breast mass and perform a lymph benefit and increased harms (false positives, extra biopsies,
node exam (see Chap. 16 on Benign Breast Conditions). complications of treatment) [43], this practice has fallen out
Mammography, in addition, misses 13–15% of breast of favor. In 2003, the ACS stopped recommending SBE, and
cancers that are palpable on exam and is less sensitive in the USPSTF also recommends against teaching women how
women with dense breasts. Although uncommon, a breast to perform SBE [40].
cancer can present first as an axillary node with no detect- In lieu of teaching patients SBE, there is a newer concept
able primary tumor in the breast. Some women may not of teaching patients breast self- awareness. Unlike breast
mention a breast or axillary mass to their clinician due to self-examination, which entails women examining their
high anxiety or denial, leading to a delay in medical atten- breasts in a systematic way on a routine basis, breast self-
tion if a routine exam is not performed. Not all women want awareness empowers a woman to notice a change or poten-
mammograms; some of them may accept a CBE for screen- tial problem with her breasts and to take action. Women
ing, and this may be beneficial in age groups at highest risk should be educated about the signs and symptoms of breast
for breast cancer (e.g., ages 50–75). Some elderly women cancer and advised to notify their health care provider as
forego mammography, but the detection and treatment of soon as they notice a change such as pain, a mass, new onset
palpable cancers may reduce morbidity and mortality. As of nipple discharge, or redness in their breasts [44]. Teaching
mentioned previously, CBE may detect a substantial pro- points include the fact that most masses are found by women
portion of cases of cancer if it is the only screening test during normal activities such as bathing and dressing, the
available [40]. underlying structures of normal breast architecture, and the
feel of normal glandular tissues. Given the strong public cer, with an estimated overall breast cancer-specific mortal-
awareness, fear and attention given to the subject of breast ity rate of 3.3% at 20 years [50]. Having DCIS increases the
cancer, and the perceived importance of SBE, it is critical risk of developing a subsequent invasive breast cancer and
that providers arm patients with accurate up-to-date informa- thus, the goal of treating DCIS is to reduce the risk of inva-
tion, to encourage appropriate screening and awareness and sive breast cancer and the associated increase in mortality.
to educate women about the prevention and early detection Lobular carcinoma in situ is commonly found incidentally in
of breast cancer. breast biopsy specimens and is discussed in Chaps. 16 and
17 on Benign Breast Conditions and The Primary Prevention
of Breast Cancer respectively.
The Palpable Breast Lump Invasive cancer, in contrast, shows infiltration of tumor
cells through the ductal or lobar basement membrane on
It is critical that any patient who presents with a concerning histology. (See Chap. 19 on Breast Cancer Diagnosis and
breast lump on physical exam should have a full diagnostic Management.) There are several different histologic types of
workup with ultrasound, possible biopsy, and/or referral to invasive breast cancer.
a breast specialist even if initial mammography is normal Ductal carcinoma is the most common histologic type,
(BI-RADS 1–3). Not all cancers are apparent on mammo- accounting for approximately 74% of invasive breast can-
graphic images, and the rate of false negatives for screen- cer. Lobular carcinoma and mixed lobular/ductal carcinomas
ing mammography is reported between 10% and 30% and is comprise 8%, and 7% of invasive carcinomas. Lobular can-
highest in women with very dense breast tissue [45]. Lobular cer may be invisible on mammogram and thus may present
cancer in particular may not show on mammogram as it can with a breast mass not seen on mammogram or at later stages
have a very low density and grow in a fishnet-type pattern with adenopathy in the neck, supraclavicular fossa, or axilla.
rather than forming masses with calcifications [46]. From Other rarer types of breast cancers comprise the remaining
a risk management standpoint, all palpable lesions must cases.
be well documented and followed through to resolution.
(See Chap. 16 on Benign Breast Conditions for a detailed
discussion.) he Initial Evaluation of Newly Diagnosed
T
Breast Cancer
ounseling Women with Suspected Breast

C Once a woman has biopsy-proven invasive breast cancer, the
Cancer following important steps will be taken by the oncologist:
Over 90% of breast cancers in the USA are initially detected 1. Staging or extent of disease (size, lymph node involve-
by mammography and the remainder by physical exam alone ment, metastatic disease)
(i.e., a palpable lump) [47]. When a suspicious lesion has 2. Hormone receptor and tumor marker analysis
been identified, tissue should be obtained with a percutane- 3. Surgical staging and treatment planning
ous needle biopsy, which has been shown to be as accurate as 4. Genetic counseling +/− genetic testing if high risk for
an open surgical biopsy [48]. A core needle biopsy can con- hereditary breast cancer
firm malignancy and provide information of breast cancer
histology. (See section on breast mass evaluation in Chap. 16 In general, the tumor size, lymph node involvement, and
on Benign Breast Conditions.) the presence of metastatic disease are all important prognos-
tic determinants. The size of the tumor will be determined
by imaging (mammography, ultrasound, or MRI) and clini-
Malignant Findings on Breast Biopsy cal findings. Axillary lymph node involvement significantly
impacts prognosis and removal of involved lymph nodes can
Ductal carcinoma in situ (DCIS, stage 0 breast cancer) is a reduce local recurrence. If patients have clinical evidence
noninvasive carcinoma of the breast that is confined to the of lymph node involvement such as a palpable, enlarged
breast ducts and lobules and is a distinct entity from invasive node or evidence of nodal involvement on imaging, they
breast cancer. The diagnosis of DCIS has increased signifi- will undergo an axillary lymph node dissection (ALND).
cantly in the 1980s and 1990s as a result of increased breast Patients who have early-stage breast cancer without clinical
cancer screening with mammography [2]. An estimated evidence of lymph node involvement will undergo sentinel
20–25% of all breast cancers detected by mammography are lymph node biopsy to confirm the presence or absence of
proven to be DCIS upon biopsy [49]. In general, DCIS has lymph node involvement [51]. Women with symptoms or
a more favorable prognosis compared to invasive breast can-
308 A. Golob et al.
signs of metastatic disease will undergo appropriate imaging survival. For low-risk DCIS, XRT may not provide a clini-
to define the extent of disease. cally significant benefit [55]. Debate currently exists about
whether some women with low-grade DCIS can undergo
umor Biology and Receptor Testing
T close active surveillance in lieu of immediate surgical treat-
Invasive breast cancers are tested for hormone receptor sta- ment. The results of the low-risk DCIS (LORIS) trial com-
tus to determine the expression of estrogen receptors (ER) paring surgery with active monitoring for low-risk DCIS in
and progesterone receptors (PR). Approximately 80% of the UK will provide important information to help solve this
invasive breast cancers are ER and/or PR positive and tumors question, and information can be found on the LORIS web-
that express these hormone receptors generally have a more site: www.birmingham.ac.uk/research/activity/mds/trials/
favorable prognosis [52]. The presence of estrogen recep- crctu/trials/loris/index.aspx [56].
tors and progesterone receptors also predicts responsiveness
to endocrine-based therapies [53]. Expression of human
epidermal growth factor 2 (HER2) is measured in all inva- Invasive Breast Cancer
sive breast cancers at the time of diagnosis or recurrence.
Approximately 20% of invasive breast cancers overex- The treatment of invasive breast cancer is broadly determined
press HER2 and in general, HER2 overexpression is asso- by type and size of tumor, lymph node involvement, specific
ciated with more aggressive tumors. Patients with HER2+ hormone receptors and tumor markers, and the presence or
breast cancers may benefit from HER2-directed therapies. absence of metastatic disease. Most women with early-stage
Breast cancers can be subtyped according to the presence invasive breast cancer (stage I or stage II) can be offered
or absence of ER, PR, and HER2. Approximately 13% of breast-conserving therapy (lumpectomy followed by whole
breast cancers are ER, PR, and HER2 negative, also known breast radiation therapy) which has been shown to have
as triple-negative disease which tends to be more aggressive equivalent survival rates to mastectomy [57]. Women with
than ER+ tumors. early-stage breast cancer who are at increased risk of recur-
rence may also be offered adjuvant systemic chemotherapy.
Staging Women with stage III breast cancer may be offered surgical
The formal staging of breast cancer has been standardized resection with radiation therapy and adjuvant or neoadjuvant
using the American Joint Committee on Cancer and the chemotherapy. Women with non-operable breast cancer are
International Union for Cancer Control (AJCC-UICC) clas- offered systemic chemotherapy with consideration of spe-
sification system for tumor, nodes, and metastases (TNM). cific hormone receptor status and tumor markers [54]. A
Initially, patients are assigned a TNM stage clinically more detailed discussion of breast cancer and management
(cTNM) and then they are restaged after surgery (pTNM). can be found in Chap. 19 on Breast Cancer Diagnosis and
Tumor stage is the most important prognostic factor for Management.
women with breast cancer. For women with nonmetastatic
breast cancer, the number of axillary lymph nodes involved
is the strongest predictor of recurrent, distant disease [54]. sychosocial Impact of Breast Cancer
P
All patients diagnosed with invasive breast cancer should Diagnosis and Treatment
undergo a detailed family history to determine if they are at
high risk for hereditary breast cancer and undergo genetic A diagnosis of breast cancer can have a negative impact on
testing if indicated (see Chap. 17 on The Primary Prevention a woman’s sense of well-being and mental health and can
of Breast Cancer). cause significant distress. Nearly half of women newly diag-
nosed with breast cancer screen positive for distress or a psy-
chiatric disorder [58]. Younger women diagnosed with breast
Treatment Planning for Breast Cancer cancer have more distress compared to their older counter-
parts and both the diagnosis of cancer and the effects of
Ductal Carcinoma In Situ surgical and medical treatment may negatively affect qual-
ity of life and self-image [59]. The National Comprehensive
DCIS accounts for approximately 20% of all breast cancer Cancer Network (NCCN) recommends screening all patients
diagnoses. DCIS is not an invasive cancer but increases the diagnosed with breast cancer for distress at the time of diag-
risk of invasive breast cancer. DCIS lesions are treated by nosis and ideally at every subsequent visit. At a minimum,
lumpectomy followed by whole breast radiation therapy, women should be screened at clinically appropriate intervals
mastectomy, or lumpectomy with clinical observation. and particularly when there is a change in disease status.
Whole breast radiation therapy has been shown to reduce The NCCN Distress Thermometer Screening Tool may be
local recurrence but does not improve breast cancer-specific used to determine severity of distress. Patients should also
be screened for depression and anxiety, if indicated. A treat- 6. A careful and systematic breast exam should include pal-
ment plan should be developed to provide appropriate psy- pation performed with the pads of the fingers using circu-
chosocial support and care via the oncologic team, mental lar motions using the vertical strip (lawnmower) method
health professionals, social workers, and spiritual and/or for breast tissue coverage. CBE is essential when
chaplaincy care with periodic reassessments and modifica- evaluating breast symptoms, such as a breast mass noticed
tions of the treatment plan as needed [60]. For further discus- by a patient. CBE is often used for breast cancer screen-
sion, see Chap. 20 on Care of the Breast Cancer Survivor. ing, though its additional benefit in women getting mam-
mography is not known.
Summary Points
1. Breast cancer risk categories include average (lifetime Review Questions

risk of <15%), moderate (lifetime risk 15–20%), and high
(lifetime risk >20%). Women with any of the following
conditions are considered to have high risk for breast can- 1. A 40-year-old woman who is at average risk for breast
cer: known BRCA1 or 2 mutations, untested first-degree cancer presents for a routine visit. After a thorough dis-
relatives of a BRCA mutation carrier, a history of chest cussion of the risks and benefits of screening mammogra-
irradiation between 10 and 30 years of age, or another phy, she says that she truly has no preference about when
high-risk genetic syndrome. To assess risk in women who to start screening. She wants to know your recommenda-
do not have high-risk conditions, we advise clinicians to tion. Based on recent guidelines, which screening strat-
use a risk assessment tool. The Gail Model (BCRAT) risk egy is most appropriate?
assessment tool is most appropriate for women without A. Biennial screening mammography starting at age 55
risk factors for a familial breast cancer syndrome and the B. Annual screening mammography starting at age 40
Tyrer-Cuzick (IBIS) tool should be used for women with C. Annual screening mammography from 45 to 54, then
risk factors. biennial screening, or biennial screening starting at
2. Tomosynthesis “3D” mammography has been approved age 50
by the FDA as an adjunct to conventional “2D” mammog- D. Annual screening with mammography and breast
raphy. It has been shown to increase sensitivity of screen- MRI starting at age 40
ing mammography, especially in women with dense The correct answer is C. Answer C describes the recom-
breasts, but has an unclear impact on rates of false posi- mended screening strategy for average-risk women per
tives and breast cancer clinical outcomes. ACS and USPSTF, respectively. Answer A is incorrect
3. The ACS recommends screening women at average risk because no organizations advise waiting until 55 to start
annually from ages 45–54 and then biennially from age screening. Answer B is incorrect because most organi-
55 until their life expectancy is <10 years. The ACS rec- zations (except for the American College of Radiology)
ommends using shared decision-making for women aged do not advise starting screening at age 40 for average-
40–44. risk women, although it is an option. Answer D is incor-
4. The American College of Radiology’s Breast Imaging rect because MRI is not indicated for average-risk
Reporting and Data System (BI-RADS) classifies breast women [5, 17].
density on mammography as ranging from A to D, where 2. A 50-year-old patient with an average risk for breast cancer
A is almost entirely fatty and D is extremely dense based on careful review of personal and family history had
breast tissues. High breast density (BI-RADS C and D) her screening mammogram two weeks ago. She received a
increases the risk of developing breast cancer by about letter stating that, though the mammogram was normal, she
20–30% and can also make it harder to see tumors on has extremely dense breasts. It further states women with
mammography. dense breasts have a higher risk of breast cancer than aver-
5. At this time, additional imaging such as MRI is not rec- age, and she should talk with her doctor about possible
ommended for women at moderate risk, but clinicians supplemental screening. What is recommended?
should consider referral to a breast health specialist for A. Order a breast MRI.
further evaluation and screening recommendations on an B. Order a breast ultrasound.
individual basis. Women in the high-risk category (>20– C. Refer to a breast health specialist for genetic counsel-
25% lifetime risk) should be referred to a breast specialist ing and testing.
whenever possible and should have annual screening D. Tell her it’s unknown whether supplemental imaging
breast MRI in addition to annual screening improves survival in average-risk women with dense
mammography. breasts and is not recommended.
310 A. Golob et al.
The correct answer is D. Explanation: The USPSTF con- sufficient to screen women at high risk for breast cancer;
cluded in its 2016 Breast Cancer Screening guidelines and referral directly to a surgeon without genetic testing
that there is insufficient evidence to assess the balance of and consultation with a breast specialist would be prema-
benefits and harms of adjunctive screening using digital ture [35].
breast tomosynthesis, breast ultrasound, MRI, or other 5. A 39-year-old woman presents to her primary care pro-
methods in women identified to have dense breasts on an vider with concerns for a new dime-sized lump in her
otherwise negative mammogram. The other answer right breast that she discovered incidentally while show-
choices are incorrect because she is at average risk other- ering. The lump is not painful. She denies associated red-
wise and so is not recommended to have supplemental ness, fevers, or nipple discharge; she is not breastfeeding.
screening with ultrasound and MRI or see a breast spe- She has never had a mammogram; no family history of
cialist [17]. breast or other cancers. On exam, her provider palpates a
3. A 42-year-old woman presents to establish care. Her fam- firm nontender nodule in the upper outer quadrant of her
ily history is notable for breast cancer diagnosed in her right breast without associated skin changes, nipple dis-
mother at age 50 and her older sister at age 46 and ovarian charge, or lymphadenopathy. She is referred for a diag-
cancer in a maternal aunt at age 55. She has never had a nostic mammogram, which is normal (BIRADS-1). What
mammogram or other breast cancer screenings. As far as is the next step?
she knows, her family members have not had genetic test- A. Reassure her based on the normal diagnostic mam-
ing for their cancers. What is the most appropriate tool to mogram; no other testing is indicated.
estimate her breast cancer risk? B. Advise her that she should have a repeat diagnostic
A. Tyrer-Cuzick (IBIS) tool. mammogram in 6 months.
B. Gail Model (BCRAT). C. Refer her to a breast surgeon for prophylactic
C. Atherosclerotic cardiovascular disease (ASCVD risk mastectomy.
calculator). D. Despite a negative mammogram, she should also have
D. No tool is needed; proceed with average-risk a diagnostic ultrasound with consideration of image-
screening. guided biopsy and referral to a breast health
The correct answer is A. Explanation: This patient is specialist.
clearly at high risk for a familial breast cancer syndrome; The correct answer is D. Explanation: Not all cancers are
hence, the IBIS tool should be used as this has better risk apparent on mammographic images. The rate of false
prediction in patients with inherited breast cancer risk negatives for screening mammography is reported
factors. The Gail Model (BRCAT) is not recommended between 10% and 30% and is highest in women with very
when a familial breast cancer syndrome is strongly sus- dense breast tissue [45]. Palpable lumps must be fully
pected. The ASCVD tool is not relevant, and it would be evaluated with diagnostic mammogram, diagnostic ultra-
inappropriate to proceed with average-risk screening sound, consideration of image-guided biopsy, and referral
given her concerning family history [11]. to a breast health specialist. Answer choices A and B are
4. A 42-year-old patient has an estimated lifetime risk of incorrect because she needs further evaluation with diag-
breast cancer of over 20% using the IBIS calculator. What nostic US and consideration of biopsy. Answer choice C
is the next step regarding breast cancer screening? is incorrect because a tissue diagnosis must be obtained to
A. Annual 3D tomosynthesis mammography starting guide treatment decisions.
now 6. A 52-year-old patient with an average risk of breast can-
B. Annual breast MRI in addition to annual mammogra- cer reports having a mammogram 2 years ago which was
phy, genetic risk evaluation, and referral to a breast negative. She shares that having the mammogram was
health specialist for consideration of prophylactic extremely uncomfortable and despite a detailed discus-
therapies sion about the benefits of mammography to screen for
C. Referral to a surgeon for consideration of prophylac- breast cancer and potential options to lessen discomfort,
tic mastectomy and oophorectomy she is adamant about avoiding another. What other option,
D. Biennial mammography starting at age 50 if any, could be offered to her?
The correct answer is B. Explanation: A patient with a A. Breast MRI.
lifetime risk of cancer which is >20% should be referred B. Breast ultrasound.
to a breast specialist and be considered for: annual MRI in C. Clinical breast exam (CBE).
addition to mammography screening (staggered by D. No other options should be offered.
6-month intervals), evaluation of genetic risk, and consid- The correct answer is C. Explanation: Currently, mam-
eration for prophylactic therapies. The other answer mography is the only recommended breast cancer screen-
choices are incorrect because mammography alone is not ing modality for average-risk women. Breast MRIs and
ultrasounds are used as adjunctive imaging to mammog- 16. Bernardi D, Macaskill P, Pellegrini M, Valentini M, Fanto C, Ostillio
L, et al. Breast cancer screening with tomosynthesis (3D mammog-
raphy for diagnostic purposes and breast MRI is recom-
raphy) with acquired or synthetic 2D mammography compared
mended for women at high risk for breast cancer with 2D mammography alone (STORM-2): a population-based
screening. Patients can be offered a well-performed, sys- prospective study. Lancet Oncol. 2016;17(8):1105–13.
tematic clinical breast exam (CBE) to assist with screen- 17. Siu AL, Force USPST. Screening for breast cancer: U.S. Preventive
Services Task force recommendation statement. Ann Intern Med.
ing. While there is no evidence at this time that clinical
2016;164(4):279–96.
breast exams reduce breast cancer mortality, a random- 18. Saslow D, Hannan J, Osuch J, Alciati MH, Baines C, Barton M,
ized trial comparing CBE to no screening in India will et al. Clinical breast examination: practical recommendations
hopefully answer this question in the next several years for optimizing performance and reporting. CA Cancer J Clin.
2004;54(6):327–44.
[37]. There is some evidence that CBE can detect a sub-
19. Miles R, Wan F, Onega TL, Lenderink-Carpenter A, O’Meara ES,
stantial proportion of cases of cancer if it is the only Zhu W, et al. Underutilization of supplemental magnetic resonance
screening test available [40]. imaging screening among patients at high breast cancer risk. J
Womens Health (Larchmt). 2018;27(6):748–54.
20. Nelson HD, Fu R, Cantor A, Pappas M, Daeges M, Humphrey
L. Effectiveness of breast cancer screening: systematic review and
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Breast Cancer Diagnosis
and Management 19
Mita Sanghavi Goel and Aarati Didwania
to date and to advocate for timely follow-up of any remain-

Learning Objectives ing diagnostic testing. Furthermore, primary care providers
1. Classify the stage of breast cancer based on data may be involved in breast cancer treatment decisions. In a
from imaging and biopsy in the preoperative survey of women recently diagnosed with breast cancer,
setting. nearly one third reported involving their PCP, and higher lev-
2. Discuss how treatment modalities are chosen based els of PCP engagement were associated with higher decision
on the preoperative classification of breast cancer. satisfaction [2]. These findings suggest that PCPs are able to
3. Anticipate and counsel patient about adverse effects draw upon an established relationship to prepare patients for
related to possible treatment modalities. their initial oncology visit and that they may also enhance
4. Prepare patients for the initial and subsequent meet- communication between the patient and their oncology team.
ings with the oncology team. When a patient has an abnormal mammogram requiring
5. Describe clinical factors that influence the progno- biopsy, the PCP is often notified and given the opportunity to
sis of patients with breast cancer. let the patient know that a biopsy is recommended. The PCP
can then inform the patient and make a referral. The primary
care office should arrange timely consultation with a surgeon
or breast specialist, ideally within 3–7 days, to evaluate the
Khadijah is a premenopausal 40-year-old woman with patient, perform a biopsy, review biopsy results, and begin
an abnormal screening mammogram (BI-RADS-5) the initial evaluation and treatment of any breast abnormal-
showing a 3 cm area with calcifications in her left ity. If the diagnosis of cancer is confirmed, the primary care
breast. She returns to discuss her results and wants to provider or the surgeon can refer to a medical oncologist and
know what to expect going forward. possibly a radiation oncologist to plan treatment.
he Primary Care Provider in the Care

T Khadijah is referred to the breast clinic, and biopsy
of Patients with Breast Cancer reveals infiltrating ductal carcinoma that is estrogen
receptor negative (ER-), progesterone receptor nega-
The primary care provider (PCP) has a variety of different tive (PR-), and HER-2/neu receptor negative. She
roles to assume in caring for a patient with breast cancer, comes to the office and wants to know what these
throughout the continuum of breast cancer care. Traditionally, results mean and what type of treatment will be recom-
PCPs bear responsibility for managing preventive health and mended. She understands that her results are consis-
screening exams in their patient population; however, most tent with “triple-negative” breast cancer in a
patients also see their PCPs while they are undergoing diag- premenopausal patient, and she is very worried.
nostic testing for breast cancer [1]. During these visits, PCPs
have opportunities to educate patients about the test findings
Recommending a course of treatment in a newly diagnosed
M. S. Goel (*) · A. Didwania
breast cancer patient depends on a number of factors: tumor
Northwestern University, Feinberg School of Medicine, Division characteristics, tumor biology, and patient characteristics.
of General Medicine & Geriatrics, Chicago, IL, USA Tumor characteristics and biology predict how aggressive the
e-mail: [email protected]; [email protected]

314 M. S. Goel and A. Didwania
cancer may be, how probable the cancer is to spread or recur, (LORIS) trial comparing surgery with active monitoring for
and how effective a treatment may be. Patient characteristics low-risk DCIS in the United Kingdom will provide impor-
such as menopausal status, genetic mutations which confer a tant information to help solve this question: information can
high risk of breast cancer, and comorbid conditions also influ- be found on the LORIS website www.birmingham.ac.uk/
ence the likelihood of recurrence and determine the risk-bene- research/activity/mds/trials/crctu/trials/loris/index.aspx [3].
fit ratio. Patient preferences may also influence treatment
decisions, especially when considering surgical treatments
such as mastectomy vs. lumpectomy and reconstruction. Invasive Ductal Carcinoma (IDC)
Invasive ductal carcinoma consists of cancerous cells that

Histopathology line breast ducts and have invaded beyond the original tissue
layer. IDC represents 75% of invasive breast cancers and
Most cases of breast cancer arise from epithelial breast cells typically requires treatment with surgery. Chemotherapy or
and are classified as carcinomas. Rarely, lymphomas, sarco- radiation therapy may also be recommended depending on
mas, and melanomas occur in the breast. the stage of the cancer.
The most common histopathologic types of carcinomas Invasive Lobular Carcinoma (ILC) and Mixed Lobular/
on biopsy are the following. Ductal Carcinoma. Lobular carcinoma consists of invasive,
cancerous cells that originate in the breast lobules, where
milk is produced. Lobular cancer may be invisible on mam-
Lobular Carcinoma In Situ (LCIS) mogram and thus present at later stages with axillary or
supraclavicular adenopathy. ILC constitutes fewer than 15%
LCIS is a unique entity which is not cancerous, but which of all breast cancers. Similar to IDC, treatment typically
increases the risk of breast cancer. LCIS consists of non- requires surgery and possibly chemotherapy and/or radiation
cancerous, abnormal cells that are found in the lobules of therapy.
breast tissue, where milk is produced. LCIS is often mul- Rarer breast carcinomas include:
ticentric. Women with LCIS should be followed closely Mucinous or colloid carcinoma accounts for 2.3% of
and offered chemoprevention (see Chaps. 16 and 17 on invasive carcinoma. It is more common in older women and
“Benign Breast Conditions”, and “The Primary Prevention is notable for producing mucus. These tumors can grow large
of Breast Cancer”). and have a soft texture.
Tubular carcinoma (TC) is a subtype of IDC which tends
to be small, full of tubules, and not aggressive. TC is often
Ductal Carcinoma In Situ (DCIS) detected by mammography before there is a palpable mass.
Papillary carcinoma is usually small, ER/PR+ HER2-
DCIS is a noninvasive or preinvasive breast cancer. DCIS is and has a good prognosis. Papillary tumors should be
diagnosed when abnormal cells replace the normal cells lin- resected whole and sent to pathology to clarify whether or
ing the breast ducts but have not extended beyond their origi- not invasive cancer is present.
nal tissue layer. DCIS is most commonly identified on Metaplastic carcinoma contains two or more cell types
mammography as a cluster of microcalcifications and and is treated similarly to IDC.
accounts for approximately 25% of cancers found on mam- Phyllodes tumors are rapidly growing tumors which arise
mography. DCIS, by definition, does not spread to other in connective tissues, are classified as sarcomas, and occur in
organs; however, it is estimated that 20–30% of DCIS lesions premenopausal women. Phyllodes tumors do not respond to
progress to invasive cancer. Intermediate- and high-grade hormone therapy and can be resistant to XRT and chemo-
DCIS are generally treated with excision and XRT, and che- therapies. Women with Li-Fraumeni syndrome are at
moprevention is offered to reduce the risk of the develop- increased risk of phyllodes tumors. Malignancy is seen in
ment of invasive breast cancer (see Chap. 17 on “The Primary 10–25% of cases.
Prevention of Breast Cancer”). The full discussion of DCIS Mammary Paget’s disease presents as changes in the nip-
treatment algorithms is beyond the scope of this chapter. ple and areola, and DCIS or invasive cancer is often con-
Debate currently exists about whether some women with comitantly present in the ipsilateral breast.
low-grade DCIS can undergo close active surveillance in lieu Inflammatory breast cancer (IBC), less than 5% of newly
of immediate surgical treatment. Whichever treatment is diagnosed breast cancers, is an extremely aggressive, locally
offered, it is critical that women with DCIS understand that advanced cancer. Most women develop diffuse erythema and
continued close follow-up and monitoring are essential to edema of the breast itself, and many have distant, metastatic
prevent and detect invasive cancer. The low-risk DCIS disease on presentation.
19 Breast Cancer Diagnosis and Management 315
A full discussion of treatment strategies for each of these Gene Profile Testing
cancer types is beyond the scope of this volume. Examining patterns of gene activity, also referred to as gene
expression tests, genomic testing, or microarray testing, in
breast cancer can help determine the risk of recurrence,
Tumor Grade thereby informing discussions regarding the benefits of treat-
ment with chemotherapy. Additionally, specific genetic pro-
Grading is a scoring system to describe how abnormal tumor files can inform oncologists and patients when targeted
cells appear, compared with normal cells. For breast cancer, therapies or clinical trials may be applicable to the individual
grading is typically determined by reviewing tubule forma- patient based upon tumor biology.
tion, the size and shape of the nucleus, and the mitotic rate Oncologists choose to order a gene profile test based on
and then assigning a score for each characteristic. Tumors the patient characteristics, availability and familiarity of a
are then categorized as grade 1 (low grade or well differenti- certain test, and insurance coverage. Multiple assays should
ated), grade 2 (intermediate grade or moderately differenti- not be used on the same patient, because their results may be
ated), or grade 3 (high grade or poorly differentiated). discordant. Some examples are as follows:
Tumors that have higher grades are considered more aggres-
sive and tend to grow faster and spread more rapidly than • The recurrence score (Oncotype Dx®) is a validated
lower grades [4]. assay to assess the risk of recurrence in node-negative,
ER+, and HER2- disease. The calculations assume that
women would complete 5 years of hormonal therapy and
Tissue Markers and Molecular Profiling thus estimate the additive benefit of adjuvant chemother-
apy for an individual woman. Results are reported as
Specific molecular profiles of breast carcinomas provide recurrence scores ranging from 0 to 100 to indicate high
additional insight into a tumor’s potential for metastasis and (score > 30), intermediate (score 18–30), and low
recurrence and help oncologists determine the appropriate, (score < 18) likelihood of recurrence. Chemotherapy is
effective treatments for each patient. A full discussion of generally indicated for women at high risk of recurrence
microarray and molecular profiling tests is beyond the scope and may be of limited benefit in women with both low and
of this chapter. Common current molecular profiles that intermediate scores [6, 7].
strongly influence treatment choice include the following. • Amsterdam 70-gene profile (MammaPrint®) also esti-
mates risk of recurrence in ER+ and HER2- disease.
strogen Receptor and Progesterone Receptor
E Although it may be used in select patients with ER-/PR+
(ER/PR) Status disease, it is not recommended in women with triple-
Hormone receptor status describes whether, and how many, negative disease or HER2+ tumors. Testing is designed to
receptors for estrogen and progesterone are present on or in help determine which patients might benefit from adju-
the tumor cells. The presence of these receptors is important vant chemotherapy. Testing is indicated in women
to identify because when hormones attach to their receptors, younger than 61 years old with:
they can fuel tumor growth. Approximately two-thirds of all –– Tumors 5 cm or smaller
breast cancers have at least one hormone receptor positive. –– No lymph node involvement (although some trials
Negative hormone status is conferred when less than 1% of indicate benefit when up to three lymph nodes are
cells tested have the receptor in question. Tumors that are involved)
ER-negative and PR-negative tend to grow more rapidly than
hormone receptor positive tumors, are more likely to recur Results are reported as “low risk” and “high risk” of dis-
within the first few years of treatment, and are more common tant recurrence, thereby indicating those who are more likely
among premenopausal women [5]. to benefit from chemotherapy.
Additional profile tests are presented at: https://www.
Human Epidermal Growth Factor Type 2 Receptor asco.org/sites/new-www.asco.org/files/content-files/prac-
(HER2/neu or Simply HER2) tice-and-guidelines/documents/2017-adjuvant-biomarkers-
The HER2 receptor allows for the binding of a growth- summary-table.pdf [8].
promoting protein; thus its presence indicates a more aggres-
sive tumor type and one that may be less responsive to hormonal
therapy. While all breast cancer cells have some HER2 recep- Staging
tors, those with an overexpression are considered positive. At
times, initial testing is equivocal, requiring additional testing to “Stage” is a summative method for describing the extent of
conclusively determine HER2 receptor status. cancer. There are two types of stages: clinical stage (assigned
prior to surgery using clinical information such as physical Table 19.1 Breast cancer staging, treatment options, and 5-year sur-
exam, imaging, and biopsy results or when surgery is not an vival rates for primary care provider counseling purposes [10]
option) or anatomic or pathologic stage (using surgical spec- General treatments 5-year
imens). Stage is often assigned using the American Joint Stage offered survival
Stage 0: DCIS Primary tumor Nearly
Commission on Cancer (JCC) TNM System [9] that incorpo-
Stage 1: Tumor ≤20 mm, no resection 100%
rates the following different data points. nodes, no metastatic lesions Consider radiation
(mets) therapy (RT)
umor Size (T)
T Consider hormonal
chemoprevention
Higher numbers following the T indicate a larger, more
therapy
advanced tumor. Typical categories include: Less likely adjuvant
chemotherapy
• T1 – tumor is ≤20 mm across its widest point. Stage 2A: Tumor >20 mm to Primary tumor 93%
• T2 – tumor is >20 mm and ≤50 mm across. ≤50 mm, no nodes, no mets resection
Stage 2B: Tumor >20 mm to Likely RT
• T3 – tumor is >50 mm across. ≤50 mm, 1–3 nodes, or Likely adjuvant
• T4 – tumor of any size growing into the chest wall or skin, >50 mm, no nodes, no mets chemotherapy and/or
including inflammatory breast cancer. hormonal therapy
• Tx – unable to assess tumor. Stage 3A: Tumor of any size, Primary tumor 72%
• T0 – no evidence of primary tumor. with up to nine nodes, no mets resection
Stage 3B: Tumor of any size Likely RT
• Tis – ductal carcinoma in situ (DCIS) and Paget’s disease with growth into chest wall or Likely chemotherapy
of the breast, with no associated mass, that are not inva- skin, including inflammatory and/or hormonal
sive cancers. cancer, with up to nine nodes, therapy
no mets
Stage 3C: Any size tumor, more
odal Involvement (N)
N than ten nodes, no mets
The N categories indicate how many and which lymph Stage 4: Any T, any N, one met Primary tumor 22%
nodes are affected. With improving technology, smaller or more resection
areas of nodal involvement can be detected; current cutoffs Consider RT for local
control or mets
to change nodal status require at least 200 cancerous cells
Curative intent
measuring at least 0.2 mm detected in a node. Categories unlikely
include: Systemic therapies
Hormonal therapy if
ER+: SERM or AI
• N0 – no cancer in nearby lymph nodes
Palliative and
• N1 – cancer found in 1–3 lymph nodes in the axilla or end-of-life care
cancer found in internal mammary lymph nodes on senti- Adapted from Breast Cancer Survival Rates [10]
nel node examination
• N2 – cancer found in 4–9 axillary lymph nodes or internal
mammary lymph nodes enlarged by imaging The classifications are described in detail on the American
• N3 – cancer involving 10 or more axillary lymph nodes or Joint Committee on Cancer (AJCC) website in their cancer
cancer found in both axillary lymph nodes and internal staging manual [9]. Staging categories include early stage
mammary nodes or cancer in the infra- or supraclavicular (IA, IB, IIA, IIB, IIIA) and advanced stage (IIIB, IIIC, and
lymph nodes IV). These categories provide a method to allow comparison
• Nx – nodal status could not be determined of average survivorship (Table 19.1). For example, 5-year
survivorship for stage I breast cancer is 95.3% compared
Metastases (M) with 79.8% for stage IIB.
The M designation indicates whether the cancer has distant
spread. Categories include:
ereditary Breast and Ovarian Cancer
H
• M0 – no distant spread (HBOC) Syndromes and Gene Mutations
• M1 – distant spread present, most often to bone, brain, in Breast Cancer Patients
lung, or liver
• Mx – metastatic spread could not be assessed Genetic Mutations
The summative staging category is determined by the spe- Certain genetic mutations, if present in the breast cancer
cific TNM results. patient, confer an increased risk of future breast cancer in the
contralateral breast and an increased risk of other cancers. ther Genetic Mutations Which Increase Breast
O
Patients with personal or family history characteristics suspi- Cancer Risk
cious for a genetic syndrome should be screened and man- Other high-penetrance mutations that increase the risk of
aged accordingly. The presence of a genetic mutation has breast cancer include the following:
implications for surgical treatment, chemoprevention, and Li-Fraumeni syndrome (p53). This syndrome increases
cancer screening with mammography, clinical breast exams, the risk of premenopausal breast cancer, and the breast can-
and annual breast MRI. A full discussion of testing for cer risk in these patients is 49% by age 60.
genetic syndromes in cancer patients is found in Chap. 20 on PTEN Hamartoma Tumor Syndromes, Including Cowden
the “Care of the Breast Cancer Survivor”. A discussion of Syndrome. The lifetime breast cancer risk in these patients is
genetic syndromes and the recommended screening sched- up to 50%. Diagnostic criteria can be found at: https://www.
ules for affected patients is found in Chap. 17 on “The nature.com/articles/gim2014147/tables/4 [15].
Primary Prevention of Breast Cancer”. Diffuse Gastric and Lobular Breast Cancer Syndrome.
Pathogenic variations in the CDH1 gene increase the risk of
poorly differentiated invasive adenocarcinoma of the stom-
BRCA 1/BRCA 2 ach and lobular breast cancer. The lifetime risk of breast can-
cer is 39% to over 50% in these patients.
Mutations in the BRCA 1 and 2 genes are present in 2% of all Peutz-Jeghers Syndrome and PALB2 also greatly increase
women with breast cancer, with the prevalence increasing to the risk of breast cancer.
10% among women diagnosed with breast cancer younger
than 40 years. Identifying patients with these mutations is Lynch Syndrome Also known as hereditary nonpolyposis
important because it has implications for breast cancer screen- colorectal cancer (HNPCC), this syndrome does not increase
ing, prophylaxis, and treatment, such as prophylactic mastec- lifetime risk of breast cancer to the level that prophylactic
tomy and salpingo-oophorectomy (see Chap. 17 on “The mastectomy should be considered; the risk is approximately
Primary Prevention of Breast Cancer”). Women with breast 18%, but has a high risk of right-sided colon cancer, endo-
cancer who are positive for BRCA 1 or 2 should consider con- metrial cancer (second most common), and less commonly
tralateral prophylactic mastectomy, which reduces the future ovarian cancer [16, 17]. See Chap. 17 on “The Primary
risk of breast cancer, through shared decision-making with Prevention of Breast Cancer” for a full discussion of genetic
the surgical oncologist. It is unclear whether prophylactic syndromes with recommendations for screening and preven-
mastectomy reduces breast cancer associated mortality in tion in these patients.
women who already have breast cancer [11]. Similarly, risk-
reducing salpingo-oophorectomy decreases risk of ovarian/
peritoneal/fallopian cancers in patients with BRCA genes [12] Patient Characteristics
(see Chap. 15 on “Gynecologic Malignancies”).
Personal and family history factors, beyond age at diagnoses, Patient characteristics influence the efficacy of recommended
that increase likelihood of a deleterious gene mutations include: therapies and the choice of treatment therapies based on their
a personal history of ovarian cancer, a history of bilateral breast side effects.
cancer, breast cancer in a male relative, triple negative (i.e., ER/ Menopausal status informs the choice of antiestrogen
PR negative, HER2 negative) breast cancers diagnosed agents in women with ER/PR-positive tumors. Selective
at younger than 60 years, and Ashkenazi or Sephardic Jewish estrogen receptor modulators (SERMs) block estrogen recep-
heritage. Only 1 in 40 Ashkenazi Jews has a BRCA gene muta- tors on breast tissue, and tamoxifen is first-line hormonal
tion compared to 1 in 300–500 individuals in the general US treatment in premenopausal women. Aromatase inhibitors
population. Though exact estimates vary, BRCA 1 and 2 muta- (AIs) prevent the conversion of peripheral androgens into
tions confer a lifetime breast cancer risk of approximately 72% estrogen, are first line in postmenopausal women, and are
and 69%, respectively, and a lifetime ovarian cancer risk of 44% generally not used in premenopausal women. Postmenopausal
and 17%, respectively [13]. BRCA mutations also increase the women generally benefit more from AIs than from SERMs in
risk of prostate and pancreatic cancers. cancer treatment, which is different from how these agents
Risk models such as Breast and Ovarian Analysis of are used for breast cancer prevention. (See Chap. 17 on “The
Disease Incidence and Carrier Estimation Algorithm Primary Prevention of Breast Cancer”.)
(BOADICEA) and BRCAPRO help genetic counselors and Cardiovascular disease may impact the choice of chemo-
oncologists identify women with breast cancer who may therapy: there is an increased risk of heart failure with
require genetic testing for BRCA 1 and 2 gene mutations, anthracyclines, an increased risk of coronary artery disease
although a recent study suggests that all breast cancer with left-sided radiation therapy, and an increased risk of
patients should be tested [14]. heart failure with trastuzumab for adjuvant therapy. The
presence and severity of osteoporosis may limit use of treat- may be an option. In breast-conserving surgery, only a por-
ment of aromatase inhibitors or dictate that bisphosphonate tion of the breast is removed, and surgery is often followed
treatment be given concomitantly. by external beam radiation (XRT). Cancers that are multi-
Lastly, numerous studies describe disparities in breast centric or large may require a mastectomy, which removes
cancer stage at diagnosis, and mortality, by race/ethnicity, all the breast tissue on the affected side(s) of the body. Shared
physical ability, and socioeconomic status [18–21]. For decision-making is used in the selection of mastectomy over
example, Black women have similar screening rates as White breast conservation therapy, since there is no difference in
women, but they are more likely to be diagnosed with overall survival between these two treatments [25–27].
advanced cancers and have higher mortality [18]. Primary Support from the patient’s PCP and oncologists for informed
care clinicians are well positioned to promote equitable, decision-making is critical and may reduce decisional con-
high-quality care by identifying barriers affecting their indi- flict [28]. As a corollary, women undergoing mastectomy
vidual patients, such as barriers to accessing recommended face myriad reconstruction options and demonstrate
follow-up care and barriers to adhering to optimal therapy. improved decisional satisfaction from the use of decision
aids [28].
Treatment Options
Radiation Therapy
Treatment for breast cancer consists of a range of options.
Treatment for stages I–III breast cancer includes surgical Many women require additional treatment with radiation,
excision, radiation therapy (RT), and often chemotherapy. based on the type of surgery, the involvement of lymph
Additional agents may be employed, depending on the status nodes, the size and location of the breast cancer, and the
of molecular markers, such as ER/PR and HER2 receptors. presence of metastatic lesions in the brain or bones. Radiation
The American Society of Clinical Oncology recommends therapy is administered from an external source using exter-
integrating palliative and end of-life care into standard oncol- nal beam radiation (XRT) or via brachytherapy: implanting a
ogy care for patients with advanced malignancies [22]. radiation source into the affected area using seeds or pellets
Advanced or metastatic breast cancer is incurable, although to deliver radiation locally.
some patients will live many years after diagnosis. In women Typical indications for radiation therapy to the breast
with ER+/PR+ tumors especially, hormonal therapies with include:
AIs have extended life expectancy expectations, even in
stage 4 cases. Palliative care specialists assist patients and • Breast conservation surgery
families by addressing spiritual and emotional issues, assist- • Removal of breast cancers that are 5 cm or larger (which
ing with decision-making, transitioning to end-of-life (hos- may not have adequate margins)
pice care), and providing grief counseling. Early referral in • Breast cancers with positive lymph nodes (lymph nodes
cases of metastatic breast cancer also decreases depression are then included in the radiation field)
and improves survival [23]. • Metastatic disease to the brain or bones (targeted radia-
Palliative care and hospice care are underutilized, as evi- tion is then directed to the metastatic lesions)
denced by the relatively short time between referral and
death [24]. Primary care clinicians are well positioned to
mitigate this gap by explaining to patients that the goal of Chemotherapy
palliative care is to reduce pain and discomfort and increase
quality of life. PCPs may want to reinforce the message that The need for chemotherapy is determined based on stage and
the goal of palliative care is not to abandon treatment or has- tumor characteristics. Chemotherapy is administered as
ten death, when providing referrals for patients. adjuvant chemotherapy after surgery or prior to surgery as
neoadjuvant chemotherapy. Neoadjuvant chemotherapy is
given prior to surgery in the hopes of reducing tumor size
Surgical Resection of the Primary Tumor and thus reducing the extent of surgery needed.
Common chemotherapeutic agents used in locally
The mainstay of cancer treatment is removal of the primary advanced breast cancers include: anthracyclines, taxanes,
tumor. Surgery is usually performed prior to chemotherapy; 5-FU, cyclophosphamide, and carboplatin. The frequency
however, some women with large tumors benefit from neo- and duration of chemotherapies vary greatly depending on
adjuvant chemotherapy to reduce the size of the tumor prior the chemotherapy agents selected, patient comorbidities, and
to surgery. Depending on the size of the tumor, its location, tolerability of the chemotherapy. Most recommended regi-
and likely cosmetic outcome, breast conservation surgery mens include two or more drugs that act on cells during dif-
ferent phases of the cell cycle. Adverse effects of specific menopause or that are in menopause induced by ovarian sup-
chemotherapeutic agents vary and are listed in the following pression or ablation. The absolute benefit is greatest in those
section. The discussion of specific chemotherapeutic regi- receiving systemic therapy and in those at higher risk of
mens is beyond the scope of this chapter. recurrence. The guidelines state:
“It is recommended that, if available, zoledronic acid or
clodronate be considered as adjuvant therapy for postmeno-
Hormonal Therapies in ER-/PR-Positive Cancers pausal patients with breast cancer who are deemed candi-
dates for adjuvant systemic therapy. Further research
Hormonal therapies (HT) are active against breast cancer comparing different bone-modifying agents, doses, dosing
because they act as an antiestrogen in the breast tissue or by intervals, and durations is required. Risk factors for osteone-
reducing levels of estrogen in the circulation. Hormonal ther- crosis of the jaw and renal impairment should be assessed,
apies are recommended in the treatment of ER/PR-positive and any pending dental or oral health problems should be
tumors, most commonly as a 5- to 10-year course of tamoxi- dealt with prior to starting treatment” [33].
fen for premenopausal women or an aromatase inhibitor in A full discussion of bisphosphonates in breast cancer patients
postmenopausal women. These medications have been found is beyond the scope of this chapter. Additional information may
to reduce both disease-free survival and breast cancer-related be found at www.asco.org/breast-cancer-adjuvant-bisphospho-
mortality [29]. Additional research is currently underway to natesguideline, www.asco.org/guidelineswiki, and https://www.
determine the effects of transitioning between tamoxifen and cancercareontario.ca/guidelines-advice/types-of-cancer/breast
aromatase inhibitors. Ovarian suppression or ablation may [34–36].
be considered for some women, especially those younger
than 35 years at the time of diagnosis who also received che-
motherapy [30]. Patients with BRCA mutations often undergo Metastatic Disease Treatment
salpingo-oophorectomy for the additional benefit of prevent-
ing ovarian cancer. A diagnosis of metastatic disease was once considered
untreatable, but currently, women diagnosed with metastatic
breast cancer live a median of 2 years, with some living
Anti-HER2/neu Antibody much longer. Given the advancements in the treatment of
metastatic disease, particularly ER-positive cancers, some
Numerous studies demonstrate the benefit of using the anti- consider metastatic breast cancer to be a chronic illness that
HER2 antibody, trastuzumab, on disease-free survival and can be managed to support a good quality of life for many
overall survival when given following chemotherapy with years. Thus, PCPs have a critical role in the care of breast
either anthracycline- or non-anthracycline-containing regi- cancer patients, even in those with advanced disease (see
mens, for patients who are HER2 positive [31, 32]. Chap. 20 on “Care of the Breast Cancer Survivor”).
Trastuzumab is typically administered for 1 year in those The treatment of metastatic disease is generally deter-
with early-stage, HER2-positive breast cancer. Additional mined based on three different tumor characteristics: (a)
antibodies are currently being evaluated for their additive ER-positive status, (b) HER2-positive status (regardless of
benefit to trastuzumab. ER status), and (c) triple-negative status. Of note, approxi-
mately 15% of metastatic tumors have discordant estrogen
status compared with the primary tumor due to cell line
Bisphosphonates mutations. For this reason, biopsy is recommended for recur-
rent, metastatic disease to confirm tumor characteristics, to
Adjuvant bisphosphonates have many uses in breast cancer see if they differ from the original tumor and inform treat-
patients. Bisphosphonates are used in patients with osteopo- ment decisions.
rosis and in those on AI therapy who are at increased risk of Metastatic ER-positive tumors are treated primarily with
bone loss. In breast cancer patients with metastatic disease to antiestrogen hormonal therapy agents: tamoxifen or aroma-
the bone, bisphosphonates have long been used to prevent tase inhibitors. In stage 4 cancer, the primary tumor may or
fractures, spinal cord compression, pain, and hypercalcemia. may not be resected, and XRT is given to control local
More recently, bisphosphonates have found an additional growth and treat selected metastatic lesions to bone or brain.
indication: to reduce bony recurrence and improve survival Recently, two additional classes of agents have been shown
in postmenopausal patients with nonmetastatic breast cancer. promise in treating ER-positive metastatic disease: CDK4/6
Based on a review of the literature, ASCO guidelines recom- inhibitors, which include medications such as abemaciclib,
mend using bisphosphonates, particularly intravenous zole- palbociclib, and ribociclib, and mTOR inhibitors, such as
dronic acid or oral clodronate in patients with natural everolimus. These medications increase progression-free
survival, but have not yet demonstrated improvements in participation before counseling them about their involve-
overall survival. In general, the CDK4/6 inhibitors seem bet- ment. PCPs can refer patients to the following website to
ter tolerated than mTOR inhibitors. enhance their understanding of clinical trials: https://www.
HER2-positive metastatic tumors in patients who are cancer.org/treatment/treatments-and-side-effects/clinical-tri-
treatment naive are generally treated with a combination als/what-you-need-to-know.html [39].
therapy of HER2-directed therapy with trastuzumab, and
chemotherapy with a taxane. For select patients, additional
targeted therapy has shown substantial increases in overall Complications of Treatment
survival.
Triple-negative metastatic breast cancers are particularly Treatment options for breast cancer depend on the underlying
aggressive and are typically treated with chemotherapy in histology and extent of disease. The oncologist will also con-
either a sequential manner or in combination. sider the patient’s comorbidities and general health in terms
of tolerance of treatment. All treatment options can be associ-
Novel and Emerging Therapies ated with immediate and late effects. For breast surgery and
Reviewing all trials examining breast cancer treatment is local radiation therapy, most complications are mild.
beyond the scope of this chapter; the following websites pro- Immediate side effects from XRT are dose and field depen-
vide updated information on treatment advances: dent and may include fatigue and mucositis in addition to
local pain and erythema. Patients do cite some degree of
• National Institutes of Health: https://www.cancer.gov/ interference with their normal functioning or quality of life
types/breast/hp/breast-treatment-pdq [37] after surgery and radiation [40]. The greater the extent of sur-
• Susan G. Komen: https://ww5.komen.org/BreastCancer/ gery or the higher amount of radiation received increases the
EmergingAreasInTreatment.html [38] local effects. Table 19.2 lists commonly (>10% of patients)
encountered local complications after treatment with surgery
and/or radiation. Less than 10% of patients report developing
cellulitis or pneumonitis from radiation therapy [41].
Khadija would like to discuss potential side effects
The surgical oncologist will likely refer the patient to a
from the various treatment options that she has
plastic surgeon to discuss breast reconstruction if mastectomy
researched. She wants to know, if she is given options
is performed. If reconstruction is undertaken, the optimal type
for management by the oncologist, how much the treat-
of procedure will depend on the patient’s preference and anat-
ment side effects should weigh into her decision. She
omy. Since these decisions have emotional components, PCPs
has also been asked if she would like to enroll in a
with a good doctor-patient relationship are well positioned to
clinical trial and wants advice with this decision.
assist in decision-making. There is no evidence suggesting
that immediate or delayed reconstruction alters the long-term
outcome of breast cancer or that it impedes or delays the
Participation in Clinical Trials detection of local or regional recurrence [42, 43]. Radiation
therapy can contribute to complications and impair cosmetic
During the course of evaluation and treatment, patients may results after reconstruction. According to Victor et al., the risk
be offered participation in clinical trials. Patients may seek of cosmetic failure may be related to the higher percentage of
counsel from their PCPs about the risks and benefits of trial
participation. Clinical trials test the safety and outcomes of
evolving treatments, diagnostics methods, and screening Table 19.2 Common local complications after surgery and/or radia-
tests. The goal of these trials is to determine whether a new tion [41]
therapy or test should be a part of standard treatment. While Complicationa Treatment-related risk factor
participation in these trials is voluntary, participation can Pain or numbness in breast, chest Greater extent of surgery
wall, or axilla (15–75%)
make the patient feel like they are helping to advance medi-
Arm swelling or lymphedema Greater extent of axillary
cal care and potentially improve their outcomes by gaining (10–25%) surgery
exposure to experimental treatments. On the other hand, par- Restricted arm motion or Greater extent of surgery,
ticipation may introduce adverse effects and increase the weakness (8–70%) radiation therapy, recent
amount of testing beyond that which is needed for standard surgery
of care. There are four phases of clinical trials, and patients Reoperation after breast implant Radiation therapy
or reconstruction (20–34%)
will be offered enrollment based on whether they fit the
Adapted from Burstein and Winer [41]
enrollment criteria. It is important for primary care physi- a
Percentage of patients reporting symptoms via patient survey or chart
cians to be cognizant of what the patient hopes to gain from review
patients with advanced disease, those who received bolus Table 19.3 Immediate adverse effects from common chemotherapeu-
application (a rubberlike disc placed on the skin to increase the tic agents in breast cancer
dose of radiation to the tissue beneath), and those who received Medication or medication
earlier delivery of radiation therapy after the cosmetic proce- class (with examples) Common adverse effects
Anthracyclines Pancytopenia, nausea, vomiting and
dure in reconstructed breasts [44–46].
(doxorubicin or mucositis, complete alopecia
Lymphedema is one of the most concerning and well- epirubicin)
known side effects for patients treated with lymph node dis- Taxanes (paclitaxel, Pancytopenia, alopecia, arthralgias,
section, surgery, and/or radiation. Symptoms can arise docetaxel) peripheral neuropathy, nausea,
immediately after specific treatment type and persist. Most vomiting, diarrhea, mucositis
cases of lymphedema are mild and the cumulative incidence 5-Fluoruracil Nausea, diarrhea, mucositis, decreased
appetite, photophobia, taste changes,
of breast cancer-related lymphedema within five years of sur- pancytopenia
gery, as assessed in the Olmsted County Rochester Cyclophosphamide Pancytopenia, hair thinning, nausea,
Epidemiology Project Breast Cancer Cohort, was 9.1% [47]. vomiting, decreased appetite
The risk of lymphedema is directly related to the extent of Platinum-based agents Pancytopenia, nausea, vomiting, taste
axillary surgery and radiation treatment [48]. Sentinel lymph (carboplatin or cisplatin) changes, alopecia, weakness
Vinorelbine Nausea, vomiting, muscle weakness,
node biopsy requires less extensive axillary surgery than axil- constipation, peripheral neuropathy,
lary dissection and is associated with a lower risk of lymph- diarrhea, alopecia, thrombocytopenia
edema [49]. Additional risk factors for development of Capecitabine Neutropenia, anemia, hand-foot
lymphedema include obesity, weight gain, and infection in the syndrome, diarrhea, elevated liver
ipsilateral arm. Often patients will ask if there is anything they enzymes, fatigue, nausea, vomiting,
rash, abdominal pain
can do to minimize the risk of developing lymphedema. It is Gemcitabine Flu-like symptoms, fever, fatigue, hair
reasonable to protect the ipsilateral arm from infection, com- thinning, nausea, vomiting, poor
pression, venipuncture, and exposure to intense heat and abra- appetite, rash, pancytopenia
sion. Although these measures can be suggested, the clinical Ixabepilone Peripheral neuropathy, weakness,
effect of any or all of these measures has not been well studied muscle and joint pains, alopecia,
nausea, vomiting, neutropenia
[50]. Many comprehensive cancer centers have lymphedema
Eribulin Pancytopenia, fatigue, alopecia, nausea,
clinics, volunteer networks, and gifts shops with experts to peripheral neuropathy
assist patients with these troubling issues. The full discussion
of lymphedema is beyond the scope of this chapter.
high, patients should prepare by determining how they would
like to handle the loss. Patients often order wigs and shave their
Systemic Therapy heads in advance to ease the transition. Women will find hair
coverings besides wigs that are more comfortable for everyday
Most chemotherapeutic regimens are associated with toxic use. Hair tends to grow back after treatment, and many women
adverse effects. The common immediate side effects from report thicker or curlier hair texture with the new growth.
these agents are listed in Table 19.3. Options for mitigating the hair loss associated with chemother-
The likelihood of developing adverse effects is based on apy are being developed. Scalp hypothermia during chemother-
the duration and total dose of therapy, but also varies by the apy administration, either by an automated continuous cooling
individual. Primary care physicians can discuss management device or by cold packs designed for the scalp, is one such
and possible side effects with patients once their regimen has option. There are theoretical but not proven concerns with this
been determined by the oncologist. option, for example, if the chemotherapy does not reach the
scalp, and insurance generally does not cover these systems,
Alopecia which can be expensive. Nonetheless, in patients who value the
Anthracyclines and taxanes usually cause complete hair loss on avoidance of alopecia, a scalp hypothermia device may be con-
the scalp within 2–3 weeks of the first chemotherapy treatment sidered. Most comprehensive cancer centers have volunteer net-
with possible loss of eyebrows, eyelashes, and pubic hair. Hair works and gifts shops with experts to assist patients with these
on the extremities and in the axilla tends to be spared. troubling issues. The full discussion of hair loss is beyond the
Cyclophosphamides and gemcitabine cause some degree of hair scope of this chapter.
thinning of head hair for most patients over the course of treat-
ment. The hair thinning is gradual over the course of treatment. Nausea and Vomiting
Some patients will experience hair loss significant enough to Nausea and vomiting are feared adverse effects for patients
warrant a wig or head covering. If the likelihood of hair loss is and often occur with chemotherapy and pain medications
[51]. Three classes of antiemetics are currently recom- premenopausal women with breast cancer reports that the
mended for management of chemotherapy-induced nausea odds ratio of chemotherapy-induced amenorrhea is 10.1 in
and vomiting because of their efficacy specifically in this set- 35- to 39-year-olds and 39.5 in 40- to 44-year-olds compared
ting: serotonin receptor antagonists, neurokinin-1 receptor with women younger than 35 years [55]. In premenopausal
antagonists, and corticosteroids. Alternatives are combina- women, menstruation returned in 28% within 6 months after
tion products or olanzapine when used with other antiemet- completion of systemic therapy, within 6–12 months for
ics. Directing patients to resources [52] to understand adverse 14%, and after 1 year in 3% of patients. Fifty-five percent of
effects and management can be helpful for their discussion women had amenorrhea at the end of 33 months of follow-up
with the oncology team. [55]. Breast cancer patients become menopausal at a younger
age compared to the general population. One study found the
median age of menopause to be 44 years after adjuvant ther-
Antiestrogen and Anti-HER2 Therapies apy with cyclophosphamide/methotrexate/5-FU compared
with the national average of 52 years [54].
Common adverse effects in patients taking tamoxifen include Pre-chemotherapy anti-Mullerian hormone (AMH) and
hot flashes, vaginal discharge, swelling, and loss of libido. follicle-stimulating hormone (FSH) levels can predict the
Less commonly (<30%), patients can experience nausea, return of ovarian function and are used in prognostic scoring,
menstrual irregularities, vaginal bleeding, weight loss, along with age and body size, to estimate ovarian recovery.
thrombosis, and mood changes. Tamoxifen also increases the The assessment of ovarian reserve can help determine the
risk of uterine cancer. probability of future pregnancies after the end of treatment.
Aromatase inhibitors are commonly associated with hot AMH and age can reliably estimate ovarian reserve and aid
flashes, muscle and joint pain, and stomach upset. Less com- patients in fertility options prior to and after treatment. These
monly, patients taking AIs experience decreased energy, discussions should be initiated by the oncologist [56, 57].
mood disturbances, sore throat, high blood pressure, depres-
sion, nausea, and vomiting. AIs may increase the risk of onadotoxic Chemotherapy Agents
G
osteoporosis. See Chap. 17 on “The Primary Prevention of In terms of specific chemotherapy agents, cyclophosphamide
Breast Cancer” for more discussion on managing adverse is gonadotoxic. Chemotherapy regimens with reduced lower
effects from tamoxifen and AIs. cumulative dosing of cyclophosphamide have lower rates of
Patients taking trastuzumab may experience chills and/or amenorrhea. Studies of docetaxel, doxorubicin, and cyclo-
fever during the initial infusion [53]. Other common adverse phosphamide have found a greater than 80% risk of perma-
effects include body pain, weakness, and nausea. Less com- nent amenorrhea in women 40 years and older and a less than
monly, patients may experience headache, diarrhea, abdomi- 20% risk of permanent amenorrhea in women 30 years and
nal pain, back pain, flu-like symptoms, vomiting, cough, younger [58, 59]. Data are limited with regard to taxanes,
shortness of breath, insomnia, rash, dizziness, or swelling. with mixed evidence as to whether adding a taxane to a regi-
men confers additional gonadotoxicity [60]. Selective estro-
gen receptor modulators, such as tamoxifen, have indirect
effects on fertility and increase the risk of amenorrhea [58].
Khadijah has a significant other that she has been with
Pregnancy is contraindicated during treatment with endo-
for some time and although they have discussed having
crine therapy because of the risk of teratogenicity [61].
children they are not ready to have children immedi-
Trastuzumab has not been shown to definitely increase the
ately. Khadijah wants to know how she can optimize
likelihood of infertility [55].
her chances of having children after breast cancer
therapy.
ounseling Patients on Fertility Concerns
C
The responsibility for addressing fertility concerns falls on
all providers caring for breast cancer patients. Often, it is
Infertility Risk in Breast Cancer Patients the primary care physician who has a long-standing, thera-
peutic relationship with the patient and can address the
Concerns for future childbearing potential are increasingly issues early in the course of treatment. Counseling on fer-
common among younger women with breast cancer. tility preservation includes discussion on risks and preser-
Systemic therapy for breast cancer is directly harmful to vation strategies. Multiple guidelines state that preservation
ovarian follicles and increases the risk of amenorrhea. options should be discussed with all women of reproduc-
Systemic therapy such as chemotherapy is the most well- tive age, even if the threat of infertility is low, and the pos-
defined risk factor for infertility in premenopausal cancer sibility of infertility should be discussed as part of patient
patients, followed by advanced maternal age [54]. A study of education and informed consent, before initiating cancer
therapy in patients of reproductive age [62]. Patients should he Psychological Impact of Breast Cancer
T
be referred to reproductive specialists if they are interested Diagnosis and Treatment
or unsure about preservation, and referrals to psychosocial
care providers should be offered if the possibility of infer- The diagnosis and treatments of any cancer are life-changing
tility could cause distress [62]. events, having a significant psychological impact on patients,
Primary care physicians may assist the patient by introduc- their extended families, and friends. Primary care providers
ing this important topic as some oncologists, although aware of have a therapeutic relationship with their patients and, there-
these issues, lack knowledge of fertility preservation resources fore, the ability to detect emotional distress as it arises.
and are concerned about delaying treatment if a patient chooses During the first year after diagnosis and therapy, breast can-
to undergo preservation [63]. A survey of physicians in the cer patients may demonstrate intense psychosocial distress
United States found that fewer than half of all oncologists rou- and problems with adjustment, which tends to improve over
tinely refer cancer patients of childbearing age to fertility spe- time [67]. In 2008, the Institute of Medicine report, “Cancer
cialists [64]. Primary care physicians, through early intervention Care for the Whole Patient: Meeting Psychosocial Health
with counseling and referrals, can greatly improve patient anxi- Needs,” described that the psychological needs of patients
ety and effect fertility outcomes. A patient who has an increased with cancer were not being addressed, posing a serious prob-
understanding of the management options for female infertility lem for the health care system [68].
will be better able to participate in shared decision-making The American Society of Clinical Oncology (ASCO) has
with their oncologist and fertility specialist. adapted guidelines for the screening, assessment, and care of
Options for future motherhood include: preserving fertil- anxiety and depressive symptoms in adults with cancer.
ized eggs, freezing ovarian tissue, egg or embryo donation, These guidelines recommend evaluating for depression and
surrogacy, and adoption. Fertility preservation techniques anxiety at periodic times, across the trajectory of care, via a
include [65]: validated, published measure and procedure [69]. Primary
• Embryo cryopreservation: Embryo cryopreservation care physicians, who are familiar with patients at the time of
occurs following in vitro fertilization. Hyperstimulation their diagnosis, should perform screening for anxiety and
of the ovary may require a slight delay in initiating cancer depression. Validated screening measures, such as the PHQ-9
treatment. and GAD-7, for anxiety and depression, respectively, are not
• Oocyte cryopreservation: Hormone-induced hyperstimu- 100% sensitive and physicians should inquire about the
lation can also be used in the absence of a sperm donor for patient’s coping, anxiety, and depression throughout their
oocyte cryopreservation. Improved technological pro- treatment.
cesses have increased the egg survival rates after thaw to The diagnosis of cancer is a distressing, sometimes trau-
close to 90%. matic experience. Nearly half of newly diagnosed breast can-
• Ovarian tissue cryopreservation: An investigational tech- cer patients experienced distress, depression, and anxiety, or
nique, either an entire ovary or a portion of an ovary, is post-traumatic stress disorder (PTSD) is common in this
removed and cryopreserved. population [70, 71]. For a full discussion, please see Chap.
• Ovarian transposition: The ovaries and fallopian tubes 20 on “Care of the Breast Cancer Survivor” and Chap. 33 on
are surgically moved within the body out of the field of “Depressive and Anxiety Disorders”.
radiation exposure.
• GnRH agonist treatment: In investigational method, hor-
mone agonists may prevent the iatrogenic loss of ovarian
Khadijah would like to know when she should be seen
reserve but the precise mechanism of these drugs is
next in the office and what specifics she should discuss
unknown.
with her oncologist at their visit.
Education and resources are invaluable for the patient.
Primary care physicians can refer patients to sites such as:
http://www.breastcancer.org/treatment/side_effects/fertility_
issues for further understanding of management options [66]. The relationship between patient and primary care pro-
vider should not end or be put on hold at the time of diagno-
sis with breast cancer. Consistent attention to health
Khadijah appears distraught, but will not admit to maintenance needs and management of chronic disease pro-
anxiety or depression. Her primary care doctor, how- cesses should continue. The management of high blood pres-
ever, has developed a therapeutic relationship with her sure, diabetes, and hyperlipidemia throughout the treatment
and recognizes the need to address her emotional process can affect long-term morbidity and mortality unre-
needs. lated to the cancer diagnosis. Patients often express concerns
over the number of physician or health care-related appoint-
ments which are required during the time of active treatment. addressed by an oncologist. Furthermore, given their longi-
If management of their chronic diseases can be managed in tudinal relationship with patients, PCPs are well positioned
conjunction with the oncology office, then lab work and to promote their patient’s adherence to recommended fol-
adjustments to medications can be done at the time of their low-up and adjuvant therapies and to help insure that patients
oncology visits. Open lines of communication, and the use of are not lost to follow-up.
medical records, facilitate the flow of information between
the patient, primary care physician, and oncologist.
The primary care clinician may further assist the breast Conclusion
cancer patient by helping her anticipate and frame questions
that she would like answered when meeting with the oncolo- The care of breast cancer patients typically relies most heav-
gist. The oncology visit should readdress many of these con- ily on surgical, medical, and radiation oncologists, but pri-
cerns or questions. The authors suggest the following list of mary care providers are often well positioned to engage in
suggested questions that can be given to the patient to address discussions regarding diagnostic and treatment modalities,
with the oncologist: prepare patients for their initial oncology visits, and support
patient adherence to recommended testing and treatment. In
• What is the stage of my cancer and the prognosis associ- addition, understanding long-term implications of breast
ated with this stage and histology? cancer and its treatment, especially as it relates to fertility,
• What are my treatment options and common immediate psychosocial adjustments, and prognosis, will position PCPs
and late effects from this treatment? to provide longitudinal care for patients throughout the
• Can we address the diagnosis and treatment risk on my breast cancer care spectrum.
fertility?
• What else can I do to optimize my tolerance of the treat-
ment and minimize side effects? Summary Points
1. Breast cancer is staged based on results from imaging and

biopsy. The four most commons types of histopathology
Khadijah has one final question before leaving the are LCIS, DCIS, invasive lobular carcinoma, and invasive
office. She knows that cancer has yet to be “cured” ductal carcinoma.
and wants to know her prognosis. 2. Treatment modalities for patients are chosen based on the
classification of breast cancer and the extent of this dis-
ease process. Treatment modalities include surgical
Breast Cancer Prognosis resection, chemotherapy, and radiation.
3. Primary care physicians should be familiar with adverse
Breast cancer prognosis is complicated and is best discussed effects of the common treatment modalities so as to coun-
with the oncologist. The stage of cancer and pathologic char- sel patients on what to anticipate during the course of
acteristics are needed to provide accurate prognostic infor- treatment and potentially aid patients in their decision-
mation to patients. Principles of the cancer staging system, making process.
which requires information obtained by imaging and lymph 4. Primary care providers should prepare patients for the
node assessment, could be explained to the patient to help initial and subsequent meetings with the oncology team
guide her understanding of prognosis. The PCP can reinforce by reviewing common treatments, adverse effects of
and educate the patient in general terms and defer more treatment, prognosis, and questions related to these
detailed discussions to the oncologist. To help with a frame- categories.
work for discussion, the expected 5-year relative survival by 5. Clinical factors that influence the prognosis of patients
stage at diagnosis is shown in Table 19.1. with breast cancer include: age of patient, existence of
The oncologist will provide the patient with the most cur- comorbid conditions, and presence of genetic markers.
rent prognostic statistics based on the stage, pathology, and
treatment regimen, but this information may need to be pro-
cessed with the patient several times and with different pro- Review Questions
viders. With the information in this chapter, PCPs can
communicate in general terms about prognosis and treatment 1. A premenopausal 39-year-old woman with a normal clin-
options, with the knowledge that the specific information ical breast and axillary exam had an abnormal screening
regarding prognosis and treatment depends upon a number mammogram. Subsequent workup of the 3 cm area with
of specific clinical and tumor characteristics that are best calcifications in her left breast showed infiltrating ductal
carcinoma that was estrogen receptor negative, progester- breast cancers are typically treated with surgery and che-
one receptor negative, and HER-2 receptor negative. She motherapy +/− XRT, but those who are found to have
calls to review her biopsy results and prepare for her BRCA gene mutations may also elect prophylactic bilat-
upcoming appointment with a medical oncologist. What eral mastectomy and bilateral salpingo-oophorectomy
stage of breast cancer does she have? [72, 73].
A. She hasn’t had surgery; therefore, she cannot be 3. A 40-year-old premenopausal breast cancer patient is
staged without pathology from her sentinel lymph tested for the BRCA gene mutation and is found to be neg-
node biopsy. ative. She is interested in a future pregnancy and would
B. T1, cN0, pM0. like to undergo fertility preservation. After completion of
C. Clinical stage IIA. fertility preservation with cryopreservation of oocytes, she
D. Staging based on TNM classifications is no longer undergoes neoadjuvant chemotherapy followed by a mas-
done, as it is not predictive of overall survival. tectomy. Lymph node sampling revealed two positive
lymph nodes. She subsequently undergoes additional che-
The correct answer is C. There are two types of stages: motherapy and XRT. Which statement is true regarding
clinical stage which is assigned prior to surgery, or when the likely adverse effects of her treatment regimen?
surgery is not an option, and anatomic/pathologic stage A. She is not a candidate for immediate reconstruction
which uses pathologic and surgical specimens. This with her mastectomy because of her need for XRT.
patient has not yet had surgery, and her staging is consid- B. As a result of axillary node dissection and radiation
ered clinical. Stage is assigned using the American Joint therapy, she is at risk of developing lymphedema.
Commission on Cancer (JCC) TNM System that incorpo- C. Radiation treatment is well tolerated and will not con-
rates information on tumor size (T), involvement of tribute to worsening fatigue.
lymph nodes (N), and presence of metastases (M). Her D. Given her young age at diagnosis, she is unlikely to
tumor is between 2 and 5 centimeters and is considered develop amenorrhea during chemotherapy and does
T2, and her nodal status is clinically negative given her not need to be concerned about fertility preservation.
normal axillary exam; however this may change after sur- The correct answer is B. The risk of lymphedema is
gery is completed. While clinical stage may not provide directly related to the extent of axillary surgery and radi-
as accurate overall survival predictions as surgical stag- ation treatment, and thus she is at risk for lymphedema.
ing, it is still used to guide patient expectations of treat- She would be eligible for immediate reconstruction,
ment prior to surgery [9]. because there is no evidence that immediate or delayed
2. Which statement regarding a 39-year-old premenopausal, reconstruction alters the long-term outcome of breast
stage II, triple-negative cancer patient is true? cancer or that it impedes or delays the detection of local
or regional recurrence. Radiation is generally well toler-
A. Because of her age and triple negative status, she ated, but fatigue is a common side effect. Lastly, all pre-
should undergo genetic counseling and possible test- menopausal women should consider the desire for
ing for BRCA gene mutations. fertility preservation into their treatment plans. A study
B. She will require ovarian suppression treatment; there- of premenopausal women with breast cancer reports
fore, she should discuss fertility preservation options. that the odds ratio of chemotherapy-induced amenor-
C. She will probably require treatment with tamoxifen, rhea is 10.1 in 35- to 39-year-olds and 39.5 in 40- to
which can lead to increased risk of endometrial 44-year-olds compared with women younger than
cancer. 35 years of age. This patient, at age 40, has a significant
D. She should have a bilateral mastectomy regardless of risk of amenorrhea after chemotherapy [42, 43, 48, 55].
BRCA status.
4. Which of the following statements regarding a premeno-
The correct answer is A. Her tumor is estrogen and pro- pausal triple-negative, BRCA-negative patient’s breast
gesterone receptor negative, and therefore hormonal cancer prognosis is most accurate?
therapies such as tamoxifen or ovarian suppression are A. Her prognosis would depend upon the recurrence
unlikely to provide survival benefit. Given her triple- score as calculated by the Oncotype Dx.
negative status and her age (<40) at diagnosis, she is at B. Her prognosis is better than if her HER-2 receptor
higher risk of having a BRCA gene mutation. Offering status of her tumor was positive.
genetic counseling and testing is an important first step C. Despite having no identified BRCA gene mutations,
to identifying a mutation and is ideally completed before her risk of developing a contralateral breast cancer is
selecting a treatment course. Women with triple-negative still triple that of the average population.
D. Triple-negative breast cancer has about a 15% higher her initial presentation with metastatic disease. She
5-year mortality than women with other forms of may consider the risks and benefits of participating in
breast cancer. a clinical trial if offered by her oncologist [75–77].
The correct answer is D. The recurrence score
(Oncotype Dx) can only be completed among women
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Care of the Breast Cancer Survivor
20
Sarah Merriam and Deborah DiNardo
Excluding skin cancers, breast cancer is the most commonly

Learning Objectives diagnosed malignancy among US women, representing 15%
of all new cancer cases in the USA. It accounts for nearly one
1. Apply current practice guidelines for the care of in three cancers in women and is the second leading cause of
breast cancer survivors in the primary care setting. cancer death among women. The lifetime risk for diagnosis
2. List the goals and components of a survivorship of female breast cancer is 12%, or one in eight women, and
care plan. approximately 266,120 new cases of breast cancer were
3. Employ appropriate screening strategies for sur- expected among US women in 2018 [1]. Because of early
veillance for breast cancer recurrence. detection and advances in treatment, long-term survival is
4. Assess and manage the physical and psychological common, with 89.7% of all women diagnosed with breast
sequelae of breast cancer treatment including vaso- cancer surviving 5 years. Survival over the same time frame
motor symptoms, sexual dysfunction, depression, for women with localized breast cancer (stage 1) is even
anxiety, PTSD, and bone health. higher at 98.9%. Accordingly, the number of women living
5. Evaluate and treat common sexual problems in with breast cancer in the USA is large and ever-growing,
breast cancer survivors, incorporating appropriate estimated at around 3.4 million in 2015 [1].
physical exam skills and evidence-based communi- A cancer survivor is defined as “any person with a history
cation techniques. of cancer, from the time of diagnosis through the remainder
6. Counsel breast cancer survivors regarding strate- of their life” [2]. Importantly, survivorship is a distinct phase
gies for overall health promotion, including weight, of cancer care which involves the surveillance for and the
physical activity, nutrition, alcohol intake, and assessment and management of mental, physical, spiritual,
smoking cessation which in turn may reduce future and social aspects of cancer diagnosis and treatment [3].
breast cancer risk. Unfortunately, major gaps in the care provided to survivors
have been described.
In 2006, the Institute of Medicine (IOM) report entitled
“From Cancer Patient to Cancer Survivor: Lost in Transition”
Rachel is a 48-year-old perimenopausal woman with a underscored the quality gaps which exist in cancer survivor-
past medical history of mild depression in remission. ship care, including inadequate support for physical and
She was diagnosed with breast cancer last week, after emotional difficulties associated with cancer and its treat-
feeling a left breast lump and being referred for a diag- ment, and poor communication and coordination between
nostic mammogram and biopsy. oncologists and primary care providers [3]. Breast cancer
survivors also describe a feeling of uncertainty as they transi-
tion from the intensive and active phase of breast cancer
treatment to primary care follow-up [4]. Primary care pro-
viders themselves report feeling ill-equipped to provide
S. Merriam · D. DiNardo (*) optimal care for breast cancer survivors, in part due to insuf-
VA Pittsburgh Healthcare System, Department of Medicine,
Pittsburgh, PA, USA

330 S. Merriam and D. DiNardo
ficient knowledge of the consequences of cancer treatment physical function, emotional function, and depressive symp-
[5]. Recognizing the importance of survivorship care, multi- tom burden over a 3-month follow-up [15]. Cancer survivors
ple organizaions, including the IOM, American Society of themselves endorse high levels of patient satisfaction with
Clinical Oncology (ASCO), American Cancer Society SCPs and report using the materials provided to make health
(ACS), and the Commission on Cancer, have highlighted the behavior choices and to improve communication with pro-
importance of addressing the needs of breast cancer survi- viders [16, 17]. Additional research, to provide evidence
vors following active treatment. Survivorship care plans about the optimal way to deliver survivorship care to the
(SCPs) have been recommended as one way to improve sur- large and growing population of women with breast cancer,
vivorship care [3, 6–8]. is needed. Meanwhile, given the large number of survivors,
The goal of a SCP is to decrease fragmentation of survi- the unique role of PCPs in building a long-term relationship,
vorship care and to assign responsibility for managing differ- the recommendations of the IOM, and the cited data regard-
ent aspects of survivorship care to various providers in the ing patient satisfaction with SCPs, we endorse SCPs as a
healthcare team. The role of the SCP has become increas- valuable tool to assist PCPs in taking care of cancer
ingly important due to increasing numbers of breast cancer survivors.
survivors and longer durations of treatment with endocrine-
based therapies. The logistical challenges that result from
caring for this population are quickly outpacing the ability of One year later, Rachel, now 49 years old, presents for
oncologists to provide all follow-up care needed. Thus, the her first visit following completion of combined che-
role of the primary care provider in providing posttreatment motherapy and radiation for stage II, hormone
follow-up, timely and appropriate surveillance, and manage- receptor-positive invasive ductal carcinoma. She
ment of late and long-term effects of therapy is critical. A underwent breast-conserving surgery with axillary
2015 joint guideline from ASCO and ACS recommends that lymph node dissection, chemotherapy (anthracycline
SCPs should discuss the following elements [9]: and taxane containing), and whole breast radiation.
Her tumor was estrogen and progesterone receptor
• Surveillance for breast cancer recurrence.
positive, HER2/neu negative. She has just started tak-
• Screening for second primary cancers.
ing tamoxifen. She feels well and has no physical com-
• Assessment and management of both physical and psy-
plaints. She brings her SCP with her to the visit.
chosocial long-term and late effects of breast cancer and
treatment.
• Health promotion.
• Care coordination and practice implications. The aim of surveillance after curative treatment for breast
Despite patient and provider receptivity toward SCPs, cancer is the early detection of local or regional recurrences
implementation has been limited, with fewer than half of and of second primary cancers. Because breast cancer is a
cancer programs using SCPs and less than one-third of pri- heterogeneous disease, the incidence of recurrence is influ-
mary care providers routinely receiving SCPs as patients enced by numerous factors, including age, tumor grade,
complete active treatment [10]. Barriers to SCP implementa- stage at diagnosis, nodal involvement, hormone receptor sta-
tion are well documented. A major challenge is the shortage tus, and treatment of the primary tumor.
of staffing and resources [11]. Although calls to implement In general, the risk for breast cancer recurrence peaks
SCPs have been made by multiple medical societies, there is around 4% approximately 2 years after the primary tumor in
no agreed-upon standardized model. Ideally, a SCP would be women with stage I–III invasive breast cancer [18]. However,
provided by the patient’s oncology team to the patient, which patients remain at risk for recurrence for as long as they live.
can then be shared with the PCPs and other providers Breast cancer survivors are also at increased risk for new pri-
throughout life. mary breast cancers and for local tumor recurrences. The risk
Evidence regarding the efficacy of SCPs in improving of a contralateral breast cancer has been estimated to be
patient outcomes (quality of life, functional status), patient between 0.5% and 1.0% per year [19], though this may be an
satisfaction, or continuity and coordination of care is mixed. overestimate given these studies were performed during an
Interventions focusing solely upon the delivery of a SCP era of less effective systemic treatments and prior to the use
have failed to impact the aforementioned outcomes [12–14]. of extended hormonal therapy treatments.
However, an intervention which utilized a SCP in conjunc- Surveillance for breast cancer recurrence includes three
tion with a single coaching encounter utilizing motivational components: the history and physical exam, screening for
interviewing techniques to engage breast cancer survivors local recurrence or a new primary breast cancer, and labora-
appeared to have a positive impact on self-reported health, tory tests and additional imaging. Before considering each of
20 Care of the Breast Cancer Survivor 331
these aspects of screening individually, it is important to erated cancer screening and prevention program for affected
make clear that the decision to perform surveillance should individuals. (See Chap. 17 on Primary Prevention of Breast
consider the patient’s functional status and personal Cancer.) A referral to a genetic counselor for consideration
preferences. of testing for gene mutations should be made in breast cancer
survivors with any of the following characteristics [21]:
• Age <50 years at the time of diagnosis OR age <60 years
The History and Physical Exam
at the time of diagnosis of triple-negative breast cancer.
• A personal history of bilateral breast cancer.
The frequency of follow-up for breast cancer survivors
• A personal history of ovarian cancer at any age.
should be determined in conjunction with the patient’s
• A history of ovarian cancer in any first-degree or second-
oncologist and consider the patient’s age, her diagnosis, and
degree relative.
her treatment protocol. In general, the patient should have a
• A first-degree relative with breast cancer diagnosed
detailed history and physical exam every 3–6 months for the
<50 years.
first 3 years after primary therapy, every 6–12 months for the
• Two or more first-degree or second-degree relatives diag-
next 2 years, and annually thereafter (Table 20.1) [9]. The
nosed with breast cancer at any age.
surveillance physical exam should include a clinical breast
• A history of breast cancer in a male relative.
exam and regular gynecologic follow-up [20].
• Having at least one grandparent of Ashkenazi Jewish
Postmenopausal women on selective estrogen receptor mod-
heritage.
ulator (SERM) therapies, like tamoxifen, are at increased
risk for endometrial hyperplasia and endometrial cancer.
Therefore, guidelines recommend that patients taking
Surveillance
SERMs be counseled to report any vaginal spotting or bleed-
ing to their provider. Of note, in the absence of abnormal
Mammography is recommended annually for all breast can-
uterine bleeding, screening with pelvic exam, endometrial
cer survivors to screen for local recurrence or a new primary
biopsy, or transvaginal ultrasound is not routinely recom-
breast cancer. For women who have received a unilateral
mended, even in patients taking SERMS (see chapter on
mastectomy, mammography should be performed on the
gynecologic cancer).
intact breast; the reconstructed breast does not require imag-
Follow-up visits should include a detailed cancer-related
ing [9]. For women who have received lumpectomies, mam-
review of systems [9]. The signs and symptoms of local or
mography should be performed on both breasts. More
regional cancer recurrence and of metastatic disease should
frequent follow-up may be warranted if an abnormality is
be reviewed (e.g., new lumps in the underarm or neck,
found.
changes in the contour/shape/size of the breast, swelling of
There is no evidence to suggest that screening MRI
the breast or arm, bone pain, persistent headaches, chest or
improves outcomes in asymptomatic patients with a history
abdominal pain). The patient should be instructed to contact
of breast cancer. Of significant import, the use of breast MRI
her provider if any of these symptoms occur between follow-
for screening is restricted to women who meet the high-risk
up visits.
criteria, defined as women with a lifetime risk of a second
Primary care physicians should also continually review
primary breast cancer greater than 20%, as would be the case
and update the patient’s cancer family history, with a goal of
for a woman with a BRCA1/BRCA2 mutation or a very
identifying women who are at increased risk for a second
strong family history of breast cancer [9, 20, 22]. (See Chap.
primary breast cancer and/or genetic syndromes [9]. The
18 on Breast Cancer Screening.) Additionally, there is a sig-
presence of a genetic mutation increases the risk of future
nificant increased risk of false-positive findings on breast
breast, ovarian, or other malignancies and dictates an accel-
MRI, which may lead to unnecessary additional imaging and
unnecessary breast biopsies.
Table 20.1 Frequency of clinical follow-up, including cancer-related
history and physical exam, for breast cancer survivors after curative
therapy
Laboratory Tests and Additional Imaging
Years after primary History and exam frequency by oncologist
curative therapy or primary care clinician
Primary care providers should NOT offer routine lab tests,
1–3 Every 3–6 months
4–5 Every 6–12 months
tumor markers, or imaging studies (e.g., bone scan, chest
>5 Annually X-ray, PET scan, MRI scan) for the detection of disease
recurrence as a part of routine screening of breast cancer sur- placebo- controlled, double-blinded, randomized clinical
vivors who have completed therapy for early-stage disease trials [9, 25].
[9]. None of these have been demonstrated to improve sur-
vival or quality of life in asymptomatic women when com-
pared to standard clinical follow-up. Nonhormonal Treatments for Vasomotor
Symptoms
SSRIs/SNRIs
Rachel comes back to clinic 1 year later and wants to
discuss management of her hot flashes. She notes that The SNRIs venlafaxine (75 mg daily) and desvenlafaxine
over the past year, her hot flashes have become more (100 mg daily) have been shown to reduce hot flash fre-
frequent and severe, and she now finds them disabling. quency and severity by 50–67% when compared to placebo
She is waking multiple times per night with drenching and are generally well-tolerated [25]. The SSRIs citalopram
sweats, having to change her sheets and her clothes. (10 mg daily) and escitalopram (10 and 20 mg daily) have
She also reports some sexual problems with her hus- also been shown to reduce hot flash burden by 50–55% com-
band. Vaginal dryness has caused sex to become pared to 20–30% with placebo and are similarly well-
uncomfortable and her libido is decreased. tolerated [25]. It is important to note that the SSRI paroxetine
is a potent inhibitor of the cytochrome P450 2D6 (CYP2D6)
enzyme pathway, which may reduce the conversion of
tamoxifen to active metabolites. Though the clinical impor-
Vasomotor Symptoms tance of this interaction remains controversial, paroxetine is
not recommended for use in women taking tamoxifen [9].
Breast cancer survivors may experience vasomotor symp- Fluoxetine, duloxetine, and bupropion also inhibit CYP2D6,
toms as a result of therapy-induced menopause (premature but to a lesser degree, and are thus avoided by many experts.
cessation of ovarian function from chemotherapy or as a side Sertraline, citalopram, escitalopram, and venlafaxine are
effect of hormonal therapies), surgical menopause from thought to be the safest choices among the SSRI/SNRI class
oophorectomy, or natural menopause. Breast cancer patients for women on tamoxifen.
with therapy-induced menopause experience more frequent
and more severe hot flashes than do women undergoing natu-
ral menopause. For example, between 50% and 70% of Anticonvulsants
young women treated with tamoxifen will experience severe
hot flashes [23]. Though vasomotor symptoms are not life- Gabapentin at a dose of 900 mg/day in three divided doses has
threatening, they can greatly impact quality of life and can been demonstrated to decrease hot flashes by 35–50% com-
result in early discontinuation of breast cancer treatment pared to placebo [25]. Gabapentin may also be used as a single
[24]. Hot flashes are thought to result from thermoregulatory nighttime dose for nocturnal hot flashes. In one randomized
dysfunction at the level of the hypothalamus precipitated by crossover trial, gabapentin was as effective as venlafaxine in
estrogen withdrawal, caused by menopause or by medica- reducing hot flashes, but venlafaxine was preferred by patients
tions such as aromatase inhibitors (AIs) or SERMs. While [25]. Pregabalin (75 mg or 150 mg twice daily) has also been
the pathophysiology and management of vasomotor symp- demonstrated to reduce hot flashes to a similar degree as gaba-
toms in this population are similar to those described in the pentin, though the side effect burden (e.g., dizziness, lower
general population (see Chap. 8 on Menopause), some fac- extremity edema, weight gain) and increased cost compared to
tors specific to breast cancer survivors warrant further gabapentin makes this regimen less attractive [25].
discussion.
Though hormone replacement therapy is the most effec-
tive treatment for control of menopausal symptoms, its use Clonidine
is relatively contraindicated in patients with breast cancer
[9]. Selective serotonin reuptake inhibitors (SSRIs), sero- Though the antihypertensive agent clonidine has been dem-
tonin and norepinephrine reuptake inhibitors (SNRIs), and onstrated in older trials to decrease hot flashes more than
anticonvulsants (e.g., gabapentin) are three classes of placebo, the efficacy of this medication is less than the afore-
drugs which have been found to be safe and efficacious in mentioned classes. This, along with its significant side effect
treating vasomotor symptoms in breast cancer survivors in profile, limits clonidine’s utility.
Complementary and Alternative Therapies Diagnosis
Complementary and alternative medications including black Unfortunately, primary care providers report feeling both
cohosh, isoflavones, other phytoestrogens, evening primrose uncomfortable and inadequately prepared to discuss sexual
oil, flaxseed, ginseng, and dong quai have been found to be function with female cancer survivors [31]. The 5 As is an
minimally effective in treating hot flashes [9]. Several recent evidence-based framework for communicating about health
studies have examined the effect of acupuncture on the behaviors that has been adapted to guide communication
reduction of menopausal symptoms in patients with breast about sexual dysfunction in female cancer survivors [32].
cancer [26–28]. Overall, data indicate that acupuncture has a This counseling model underscores five core components of
small but positive effect in reducing the frequency and sever- communication about sexual health (Fig. 20.1). Sexual dif-
ity of hot flashes and burden of menopausal symptoms. Other ficulties may be reported as a temporary condition or may
non-pharmacological interventions including cognitive become a more serious disorder.
behavioral therapy, yoga, paced breathing, and hypnosis The physical exam remains an essential component of
have been purported to have a beneficial effect on hot flashes, evaluation of sexual dysfunction. In addition to looking for
though high-quality evidence supporting their effectiveness signs of contributing general medical conditions, the gyne-
is currently lacking [29]. cologic exam is important to determine the etiology of any
pain complaints. Specifically, the primary care provider
should look for signs of vulvovaginal atrophy, vaginismus (a
exual Dysfunction and Vulvovaginal
S painful spasmodic contraction of the vaginal walls in
Symptoms response to pressure), postoperative or postradiation changes
(e.g., vaginal stenosis or atrophy), evidence of primary gyne-
Sexual dysfunction is defined as “a heterogeneous group of cologic disease (e.g., endometriosis or vaginitis), or evidence
disorders that are typically characterized by a clinically sig- of organ prolapse. (See Chap. 9 on Female Sexual Function
nificant disturbance in a person’s ability to respond sexually and Dysfunction for further information.)
or experience sexual pleasure” [30]; See Chap. 9 on Female
Sexual Function and Dysfunction. Sexual concerns are com-
mon among breast cancer survivors. Management
Between one- and two-thirds of breast cancer survivors
experience sexual concerns, including decreased libido, Treatment of sexual dysfunction is dictated by the type of
arousal and/or lubrication concerns, orgasmic concerns, and sexual dysfunction and by the suspected underlying cause(s).
dyspareunia [9]. (Please refer to Chap. 9 on Female Sexual Function and
Dysfunction for a detailed review of the management of sex-
ual dysfunction.) Just like in non-survivors, often treatment
Epidemiology and Risk Factors will be multimodal, including psychoeducational support,
pharmacotherapy, sexual or marital counseling, and physical
The etiology of sexual complaints in survivors, similar to therapy [9]. Patient education is an essential component of
non-survivors, is often multifactorial and may include bio- any treatment plan, including a discussion of normal sexual
logical, interpersonal, and psychological facets. Hormonal function and treatment options.
alterations, as a result of chemotherapy or hormonal therapy, Nonhormonal treatments remain the mainstay of pharma-
can lead to vaginal atrophy, dryness, and pain. Over time, cotherapy for vaginal dryness in breast cancer survivors.
these changes may lead to dyspareunia and subsequent low Combining as-needed use of water-based lubricants with
libido and arousal difficulties. Breast cancer survivors may consistent (3–5×/week) use of a vaginal moisturizer may
also have a negative perception of body image because of provide more benefit than either agent alone [9]. Due to con-
treatment (e.g., the loss of part or all of a breast, postopera- cerns regarding the possibility of systemic absorption, topi-
tive scarring or lymphedema, therapy-induced early meno- cal estrogens should be reserved for patients who are not
pause and hair loss, and others). Accordingly, these body responsive to nonhormonal treatments [9]. Low-dose estra-
image issues can significantly impact sexual function as diol 10 mcg vaginal tablets or the low-dose 2 mg
related to poorer self-esteem and mental health. Anxiety, dis- (7.5 mcg/24 hrs) estradiol vaginal ring is preferred to estro-
tress, or depression as a result of a diagnosis of breast cancer gen creams, which have more variable absorption. Although
or fear of recurrence can also impact survivors’ sexual func- low-dose vaginal estrogens do not result in sustained serum
tion. Further, problems with sexual intimacy may be estrogen levels exceeding the menopausal range, the deci-
impacted by relationship discord, lack of communication, or sion to utilize these therapies should be made in coordination
other relationship challenges. with the patient’s oncologist with a discussion of the risks
Fig. 20.1 The 5 As

• Use non-judgmental, normalizing language with open-ended questions
framework for evaluating
• "Sexual problems after cancer are very common. How has treatment affected your
sexual dysfunction in female Ask sex life?"
cancer survivors [32]
• Use validating language

• Let patients know that these problems are expected and normal and that help is available
Advise
• Identify and explore symptoms

• "Are you experiencing pain with sexual activity or do you avoid sexual activity because of
Assess pain?"
• Recommend and counsel regarding indicated treatments

• This may include referrals as indicated
Assist
• Schedule a follow-up visit to check in with the patient

• This indicates that the PCP takes the issue seriously and reassures the patient that
Arrange continued symptoms will be addressed in future visits
and benefits. Regardless of the type of treatment pursued, Distress, Depression, and Anxiety
patients should be counseled that improvement in dryness
might require 6–12 weeks of therapy. Epidemiology and Risk Factors
Referral to pelvic floor physical therapy may be of addi-
tional benefit to breast cancer survivors with sexual dysfunc- Breast cancer survivors are at risk for a range of mental
tion for relaxation techniques and to improve pelvic muscle health problems including distress, depression, anxiety, and
floor strength, tone, and vaginal elasticity [9]. Patients with post-traumatic stress disorder (PTSD). Distress in this con-
vaginal fibrosis or stenosis as a result of pelvic radiation may text is defined as “a multifactorial unpleasant experience of a
benefit from vaginal dilators, foreplay, the use of erotica, psychological, social, and/or spiritual nature,” while depres-
and/or dilation with lubrication prior to insertion. Many can- sion and anxiety are defined as they are in the general popu-
cer centers have clinicians specializing in sexual health for lation [9]. According to a 2013 systematic review of
cancer patients or may provide referrals for patients who observational studies, the median prevalence of depression
experience sexual difficulties during or after cancer and anxiety in the breast cancer survivor population ranged
treatment. from 10% to 22% (with broad range of estimates across stud-
Finally, it is essential to attend to psychological and ies) depending on the measurement scale being used [33].
interpersonal factors affecting sexual function in cancer Importantly, these problems can occur at any time across the
survivors. Referral to a sexual counselor, marital counselor, survivorship continuum, not only during the time surrounding
or psychotherapist should be offered to all patients to diagnosis and treatment but also at any time during the phase
address underlying body image, anxiety, stress, and mood of survivorship following treatment completion.
changes, all of which can affect sexual function [9]. While many of the predisposing factors for depression
Specialized clinics and clinicians who are skilled in and anxiety in this population are similar to those described
addressing sexual issues for cancer survivors are available in the general population (see Chap. 33 on Depressive and
in some medical centers. Anxiety Disorders), some factors specific to cancer survivors
warrant further discussion. First, fear of recurrence (FOR)
can be a significant contributor and has been documented at
higher levels in those whose cancer diagnosis is more recent,
While exploring the impact of her sexual dysfunction
in those receiving chemotherapy, and in those experiencing
and hot flashes on her quality of life, Rachel becomes
more symptoms [34]. The risk of depression in breast cancer
tearful. On further questioning, she relates that she’s
survivors is increased and has been associated with younger
unsure where to go with her life now that she has “beat
age at the time of cancer diagnosis, lower socioeconomic sta-
cancer.” She constantly worries she will have a recur-
tus, and prior history of psychiatric disease [35]. PTSD,
rence, is hopeless about the future, and feels guilty that
which can develop after experiencing a frightening or life-
she is not doing “more with her life.”
threatening situation, is also common in cancer survivors and
can persist or worsen over time. Estimates suggest that ety, the traditional cutoff score of ≥10 on the GAD-7 is
between 20% and over 80% of breast cancer patients experi- used to identify at least moderate symptomatology, as in
ence symptoms of PTSD. the general population [41]. Despite the usefulness of
screening tools, providers should have a high index of sus-
picion and employ expert interviewing skills to detect
Diagnosis depression of anxiety that the patient may not have dis-
closed on the questionnaires. (Please refer to Chap. 33 on
The primary care provider, whose contact with survivors Depressive and Anxiety Disorders for a more detailed dis-
spans the continuum from diagnosis through treatment and cussion of the general principles of screening for depres-
beyond, is ideally positioned to play a key role in the identi- sion and anxiety.)
fication and appropriate management of distress, depression,
and anxiety in breast cancer survivors. Per the American
Cancer Society/American Society of Clinical Oncology Management
(ACS/ASCO) Breast Cancer Survivorship Guidelines,
primary care providers should screen for the presence of psy- When screening is positive, further assessment and/or
chological distress in all survivors while probing more management is indicated. Treatment should be individual-
deeply in those who are at higher risk based on the factors ized, considering severity of symptoms and functional
discussed above [9]. The 2014 ASCO anxiety and depression impact of those symptoms as well as patient preferences.
guideline adaptation recommends screening at the time of The 2014 ASCO anxiety and depression guideline adapta-
cancer diagnosis and “at appropriate intervals, and as clini- tion includes care maps for adults with cancer and depres-
cally indicated, especially with changes in disease or treat- sion or anxiety, respectively [41]. Pharmacological,
ment status (i.e., post-treatment, recurrence, progression) psychological, and psychosocial therapies are the main-
and transition to palliative and end-of-life care” [36]. stays of treatment just as they are in patients without a can-
Use of the National Comprehensive Cancer Network cer history. Primary care providers should become familiar
(NCCN) Distress Thermometer and Problem List for with the resources available within their individual prac-
Patients is recommended for the initial screening and moni- tice settings, including awareness of any psycho-oncology
toring of distress. Scores on this scale range from 0 (no dis- or mental health resources geared toward cancer survivors.
tress) to 10 (extreme distress); in completing the screen, Pharmacologic treatments are essentially the same as for
patients are asked to circle the number that best describes the general population. As discussed in the section on
how much distress they have been experiencing in the last vasomotor symptoms, the use of the certain SSRIs, espe-
week. A score of 4 or higher indicates the presence of clini- cially paroxetine, should be avoided in women taking
cally significant distress [37]. There is also a checklist to tamoxifen due to the potential for interaction leading to
question which activities and situations cause the most dis- reduced tamoxifen active metabolites [9]. Care should also
tress for patients. The tool is freely accessible and down- be taken in women with sexual dysfunction when prescrib-
loadable for use in patient care, but cannot be used in ing SSRIs which have frequent sexual side effects includ-
publications. Please refer to the NCCN.org website for more ing low libido, lack of arousal, or delayed orgasm.
info and free download [38].
For depression and anxiety, screening can be performed
using validated screening tools available for use in the gen- Rachel comes back in follow-up a few months later.
eral population, such as the Patient Health Questionairre-9 She is now engaged with an individual therapist and
(PHQ-9) for depression and the Generalized Anxiety reports that both her mood and hot flashes are much
Disorder-7 (GAD-7) for anxiety [39, 40]. improved having started treatment with venlafaxine
For depression, ASCO recommends, as outlined in an for combined benefit. She is doing well, with no other
algorithm specific to adults with cancer, starting with two complaints today, and would like to discuss recommen-
specific questions from the PHQ-9 to assess for the classic dations for overall health promotion and cancer
symptoms of anhedonia and low mood. Providers should prevention.
administer the remaining seven questions to those with a
positive screen, with the expectation that 25–30% of
patients will require this step [36]. Importantly, a cutoff Health Promotion
score of ≥8 for the PHQ-9 is recommended (as opposed to Health promotion is critical to the well-being of breast can-
the more traditional ≥9 cutoff) as this is the threshold for cer survivors, most of whom will experience long-term sur-
at least moderate depression based on a study of this tool’s vival [42]. Pursuit of a healthy lifestyle can not only reduce
diagnostic accuracy in cancer outpatients [41]. For anxi- the risk of cancer recurrence and second cancers but also
have a positive impact on cancer-related symptoms and on Table 20.2 ACS/ASCO health promotion guideline for breast cancer
overall mortality [43–50]. The ACS/ASCO Breast Cancer survivors, adapted from ACS/ASCO Breast Cancer Survivorship
Guidelines [9]
Survivorship Guidelines make recommendations regarding
weight, physical activity, nutrition (including recommenda- Lifestyle
category Counseling recommendations
tions regarding alcohol consumption), and smoking cessa-
Weight and Achieve and maintain a healthy weight
tion for breast cancer survivors (Table 20.2) [9]. These obesity If overweight or obese, limit consumption of
recommendations provide a framework that primary care high-calorie foods and beverages and increase
providers can use for counseling and to answer important physical activity to promote and maintain weight loss
questions breast cancer survivors may have about healthy Physical Engage in regular physical activity consistent with the
activity ACS guideline and specifically:
behaviors and their potential impact on health and disease Avoid inactivity and return to normal daily
prevention. Each category is discussed briefly below. activities as soon as possible following diagnosis
Aim for at least 150 min of moderate or 75 min of
Weight vigorous aerobic exercise per week
Include strength training exercises at least 2 days
Counseling regarding maintenance of a healthy weight is per week; emphasize strength training for women
particularly important for breast cancer survivors. Many sur- treated with adjuvant chemotherapy or hormone
vivors, like the rest of the population, are overweight or therapy
obese. Obesity is an established risk factor for breast cancer Nutrition Achieve a dietary pattern that is high in vegetables,
recurrence, second cancer recurrence, and a multitude of fruits, whole grains, and legumes; low in saturated
fats; and limited in alcohol consumption
other medical comorbidities [51]. Additionally, weight loss
Smoking Avoid smoking
has been associated with improvements in symptoms and in If smoking, refer to cessation counseling and
quality of life in cancer survivors. Primary care providers resources
should, therefore, counsel breast cancer survivors to achieve
or maintain a healthy weight [52]. ciated with smoking at the time of breast cancer diagnosis
[61]. As such, primary care providers should work to motivate
Physical Activity and encourage smoking cessation and provide support with
A minority of cancer survivors meet the ACS guidelines for pharmacotherapy and/or multimodal tobacco cessation pro-
physical activity. High-quality data suggests that physical grams according to local availability and patient preference.
activity improves quality of life and physical functioning,
and observational data supports a connection between physi-
cal activity and reduced breast cancer-specific and all-cause
During her next visit, Rachel states that her oncologist
mortality [53, 54]. For these reasons, primary care providers
has stopped the tamoxifen and started anastrozole
should communicate physical activity guidelines with all
because she is now definitively postmenopausal and
survivors, as outlined in Table 20.2.
did not tolerate raloxifene. She asks for advice regard-
ing guidelines for bone health assessment and man-
Nutrition and Alcohol
agement in survivors who are receiving aromatase
Breast cancer survivors should be advised to consume a diet
inhibitor therapy.
rich in vegetables, fruits, whole grains, and legumes due to
the association of good nutrition with reduced all-cause mor-
tality [55–57]. Importantly, achievement of weight loss as a
result of dietary change may be required in order for breast Bone Health
cancer survivors to experience benefits in terms of breast
cancer recurrence and prognosis [58, 59]. Regarding alcohol Epidemiology and Risk Factors
consumption, the ACS recommends that breast cancer survi-
vors should limit intake to no more than one drink per day Breast cancer survivors often possess additional risk factors
[9]. Other organizations site recent data that alcohol con- for bone loss beyond the well-established risk factors for
sumption of any amount increases cancer risk; therefore, women in general: age, personal fracture history, family his-
some survivors may choose to limit intake even more or tory of fracture or osteoporosis, and lifestyle factors such as
abstain from all alcoholic beverages [60]. smoking, alcohol intake, insufficient exercise, etc. (please
refer to Chap. 25 on Osteoporosis for a detailed discussion of
Smoking Cessation osteoporosis risk factors in the general population). Potential
Observational data suggests that, in addition to the other well- specific risk factors for breast cancer survivors include the
established health consequences associated with smoking, following treatments: chemotherapy (and consequent risk
increased breast cancer-specific and overall mortality are asso- for chemotherapy-induced premature menopause), drugs
that suppress gonadal function, oophorectomy causing pre- based algorithm for both fracture risk assessment and the
mature menopause, glucocorticoids, and/or antiestrogen treatment of bone loss in this high-risk population; see
therapies such as aromatase inhibitors [62]. Existing reports Table 20.3 [65]. Notably, these guidelines highlight the
estimate that up to 80% of breast cancer survivors experience important role that the primary care provider plays in provid-
some degree of bone loss [63, 64]. Furthermore, according to ing counseling about modifiable risk factors for bone loss.
a recent review, aromatase inhibitor therapy leads to a two- Specifically, providers should counsel all survivors about
to fourfold increase in bone loss compared to expected post- engaging in physical activity including weight-bearing exer-
menopausal bone loss [65]. Breast cancer survivors receiv- cise, to avoid tobacco products, to limit alcohol intake, and to
ing aromatase inhibitors are thus at increased risk for fracture ensure adequate calcium and vitamin D supplementation (if
and experience increased morbidity and mortality [66–70]. dietary intake is inadequate) [9, 65]. The recommendations
As aromatase inhibitor therapy and other therapies which differ slightly from general bone health advice because sur-
cause bone loss continue to proliferate (see Chap. 19 on vivors may be at increased risk for rapid bone loss.
Breast Cancer Diagnosis and Management), a further If a breast cancer survivor meets criteria for treatment
increase in fracture risk for breast cancer survivors must be with antiresorptive therapy, either based on DXA t-score or
anticipated. based on risk factors as indicated in Table 20.3, treatment
with a bisphosphonate or denosumab is recommended.
While the 2015 ACS/ASCO guidelines do not recommend
Diagnosis one agent over another, more recent consensus guidelines
suggest that intravenous zoledronic acid, administered once
Current guidelines recommend that all postmenopausal every 6 months, is first line. This recommendation is made
breast cancer survivors being treated with aromatase inhibi- based on available efficacy data in this specific patient popu-
tors be referred for a baseline DXA scan, regardless of age, lation as well as on tolerability. Cost and availability, how-
for assessment of bone mineral density [9]. Additionally, all ever, may limit its use. Oral bisphosphonates (which are
women (regardless of menopausal status) who have received limited by issues with compliance and by lack of efficacy
treatments that can suppress ovarian function should undergo data for aromatase inhibitor-induced bone loss) and deno-
assessment with DXA. DXA scans should be repeated every sumab (which is limited by cost, a paucity of efficacy data,
2 years, with consideration of shortening the interval to and rebound effect after treatment termination) are alterna-
1 year if major risk factors change such as use of glucocorti- tive treatment options.
coids or continued aromatase inhibitor use [9]. Importantly, recent consensus guidelines recommend
continuation of antiresorptive therapy for as long as a survi-
vor is receiving aromatase inhibitor therapy (up to 5 years)
Management
Table 20.3 Guidelines for management of bone loss in breast cancer
Once bone mineral density has been assessed with DXA, survivors receiving treatments known to accelerate bone loss, according
primary care providers should consider the results in the to the joint position statement of the IOF, CABS, ECTS, IEG, ESCEO,
IMS, and SIOG, 2017 [65]
context of other risk factors for bone loss to direct treat-
ment. While many risk factors for bone loss exist in this Risk category Recommendation
T-score > −2.0 and no Exercise
population, it remains unclear how best to account for them additional risk factors Calcium and vitamin D if not
in the context of treatment decisions. The World Health present adequately in diet
Organization Fracture Risk Assessment Tool (FRAX, Check BMD and risk factors every
http://www.sheffield.ac.uk/FRAX) [71] is a widely used 2 years or every 1 year if risk
changes
tool for fracture risk assessment in the general population,
T-score ≤ −2.0 OR any two Exercise
but its value for use in the breast cancer survivor population of the following risk factors: Calcium and vitamin D
has been questioned. The FRAX tool has not been validated Age >65 Bisphosphonate or denosumab
to assess fracture risk in breast cancer survivors and may T-score <1.5 therapy
Check BMD every 2 years
underestimate risk in this population, at least in part because Smoking (current or
history of)
the “secondary osteoporosis” option in the tool does not BMI <20
adequately account for aromatase inhibitor-associated bone Family history of hip
loss [65]. fracture
Personal history of
Several guidelines make recommendations regarding the
fragility fracture at
management of bone loss in breast cancer survivors. A joint age ≥50 years
position statement from several interdisciplinary cancer and Oral glucocorticoid use
bone societies was released in 2017, to update an evidence- ≥6 months
[65]. Providers should also be aware that some survivors be used to treat osteoporosis in survivors who are receiving
may be receiving intravenous bisphosphonates as a compo- an aromatase inhibitor [9].
nent of adjuvant breast cancer therapy or as a component of
management for metastatic bone disease. (See Chap. 19 on
Breast Cancer Diagnosis and Management for more infor- Other Late and Long-Term Complications
mation regarding adjuvant use of bisphosphonates in breast
cancer treatment.) Finally, while SERMs such as raloxifene Additional late and long-term effects of breast cancer treat-
are approved for treatment of postmenopausal osteoporosis ment including lymphedema, cardiotoxicity, fatigue, cogni-
in the general population, combining SERMs with aromatase tive dysfunction, and neuropathy may occur and should be
inhibitor therapy has been shown to impair the effectiveness considered as part of a comprehensive SCP. Evaluation and
of the aromatase inhibitor [72]. As such, SERMs should not treatment options are presented in Table 20.4.
Table 20.4 Additional recommendations for breast cancer survivorship care, from the American Cancer Society/American Society of Clinical
Oncology [9, 73, 74]
Description and epidemiology Management
Lymphedema Arm, breast, or chest wall swelling as a result of blockage of Counsel how to prevent or reduce the risk of
lymphatic fluid from the arm and/or breast lymphedema, including weight loss (if overweight or
Can range in severity from mild to severe obese)
Incidence varies widely, estimated over 40% Refer patients with clinical symptoms or swelling
Risk factors: Lymph node dissection (axillary > sentinel), suggestive of lymphedema to a knowledgeable therapist
breast surgery, radiation therapy, obesity (e.g., a physical or occupational therapist or lymphedema
specialist)
Cardiotoxicity Postmenopausal women are at increased risk of mortality Monitor and treat other nontreatment-related CVD risk
attributed to CVD (risk is increased due to radiation therapy), factors (HTN, DM, dyslipidemia, and lifestyle)
which manifests ~7 years after diagnosis of breast cancer aggressively
Patients at elevated risk of left ventricular (LV) dysfunction Counsel breast cancer survivors on healthy lifestyle
include patients treated with: modifications, potential cardiac risk factors, and when to
Doxorubicin ≥250 mg/m2 report concerning symptoms
Radiation ≥30 Gy Routine screening in asymptomatic patients at low risk
Lower-dose anthracycline with lower-dose radiation for CVD beyond history and physical exam is not
(<30Gy) warranted
Treatment with lower-dose anthracycline or trastuzumab Asymptomatic patients at elevated risk of LV dysfunction
AND any of the following: may undergo imaging 6–12 months following completion
Multiple CV risk factors of cancer therapy
Age ≥ 60 years at cancer treatment
Compromised cardiac function (e.g., diminished LV Symptomatic patients should be assessed with
ejection fraction, history of myocardial infarction, echocardiography
moderate to severe valvular heart disease) before or
during treatment
Cognitive Includes symptoms such as difficulty with concentration, Ask patients about cognitive difficulties, and assess for
impairment executive function, and memory reversible contributing factors
Reported by 75% of patients during treatment and 35% Refer patients with signs of cognitive impairment for
after treatment neurocognitive evaluation
Cause is multifactorial Refer patients with cognitive problems for rehabilitation
including cognitive therapy or cognitive training
Data regarding pharmaceuticals are inconsistent
Fatigue One of the most prevalent (30–90%) and distressing long-term Assess for fatigue and treat any secondary causes
effects of cancer treatment, which can significantly impact Counsel patients to engage in regular physical activity
quality of life and refer for cognitive behavioral therapy if no
May last long after treatment ends and can significantly identifiable cause of fatigue is determined
interfere with quality of life
Musculoskeletal Difficulties with ipsilateral upper extremity (e.g., rotator cuff Assess for musculoskeletal symptoms
health injury, adhesive capsulitis, and axillary web syndrome) are Treat musculoskeletal pain and aromatase inhibitor-
common after surgery and can impact quality of life and function associated pain as indicated, considering physical therapy
Up to 50% of women receiving aromatase inhibitor therapy and acupuncture
report arthralgias and myalgias, which can be severe enough
that 20% discontinue treatment and are often nonresponsive to
NSAID therapy

Description and epidemiology Management
Neuropathy Neuropathy is common (30–40%) following surgery and after Comprehensively assess the patient’s pain history to
treatment with taxane- or platinum-based chemotherapeutic determine the most likely underlying cause, with
agents dedicated inquiry regarding presence of the characteristic
symptoms of peripheral neuropathy (numbness and
tingling in the hands or feet)
Offer a combination of physical activity and
pharmacologic therapy, as indicated, for patients with
neuropathic pain
Infertility Especially important to consider in breast cancer survivors of Premenopausal women who desire pregnancy and have
childbearing age been unable to conceive for ≥6 months should be referred
Risk of infertility varies according to age and treatments to a fertility specialist
received Future fertility concerns are ideally addressed prior to
treatments
Summary Points A. A patient whose cancer has been in remission for

5 years or more is a survivor.
1. Key components of a breast cancer survivorship plan B. A patient who has been diagnosed with breast cancer
include defining a surveillance plan for recurrence or new is a survivor.
primary breast cancers, addressing and managing late and C. A patient whose cancer is in remission is a survivor if
long-term complications of treatment, providing psycho- she remains cancer-free.
social support, and counseling regarding lifestyle modifi- D. A patient whose cancer is in remission is a survivor
cations and strategies for overall health promotion. for the rest of her life.
2. In addition to annual mammograms, patients should be The correct answer is B. The American Cancer Society
followed to assess for signs and symptoms of recurrence defines a cancer survivor as “Any person with a history of
with a periodic history and physical exam. Routine blood cancer, from the time of diagnosis through the remainder
tests, advanced imaging, and tumor markers are NOT rec- of their life.” Survivorship is a distinct phase of cancer
ommended for surveillance testing in asymptomatic care, involving the surveillance for and assessment/man-
patients. agement of mental, physical, spiritual, and social aspects
3. Breast cancer survivors face many potential late and of cancer diagnosis and treatment [2].
long-term complications of therapy, including lymph- 2. A 64-year-old woman with stage I, hormone receptor-
edema, cardiotoxicity, premature menopause, fatigue, negative invasive ductal carcinoma s/p lumpectomy with
cognitive dysfunction, depression, anxiety, neuropathy, sentinel node biopsy, XRT, and chemotherapy 1 year ago.
vasomotor symptoms, and loss of bone mineral density. Her most recent mammogram was negative 2 months ago
4. Sexual dysfunction is common in breast cancer survivors and there was no sign of clinical disease at her oncology
and is often multifactorial. In conjunction with a gyneco- appointment that same day. She presents to primary care
logical exam, the “5 As” framework can be employed to for her first follow-up appointment after curative therapy
identify and explore symptoms of female sexual dysfunc- to transition to cancer survivorship care. She feels well
tion and to provide counseling regarding treatment and has no physical complaints. Which of the following
options. best describes your breast cancer surveillance plan for
5. Women with breast cancer are likely to have long-term this asymptomatic patient during the first 3 years after
survival and thus it is important for the primary care pro- primary curative therapy?
vider to assess and make recommendations related to A. A clinic visit to assess for signs and symptoms of
healthy behaviors including weight, activity, nutrition, recurrence with clinician breast exam every
smoking cessation, and alcohol use. 3–6 months, mammogram every 6 months, and annual
CT of the chest, abdomen, and pelvis.
B. A clinic visit to assess for signs and symptoms of
Review Questions recurrence with clinician breast exam every
3–6 months with annual mammography.
1. Many breast cancer patients become “permanent survi- C. A clinic visit to assess for signs and symptoms of
vors” and have at least some component of their care tran- recurrence with clinician breast exam every 3–6 months
sitioned back to primary care. Which of the following with annual breast MRI, annual FDG-PET scan, and
accurately defines a breast cancer survivor? annual bloodwork for CEA and CA 15–3.
D. An annual clinic visit to assess for signs and symp- more short-lived and less severe than in postmeno-
toms of recurrence with clinician breast exam, annual pausal women without breast cancer.
mammography, and annual CT of the chest, abdo- D. Gabapentin at bedtime may be an option, especially if
men, and pelvis. her symptoms are most bothersome at night.
The correct answer is B. In general, the patient should The correct answer is D. Breast cancer patients experi-
have a detailed history and physical exam every ence more frequent and more severe hot flashes than do
3–6 months for the first 3 years after primary therapy, women undergoing natural menopause. Because her hot
every 6–12 months for the next 2 years, and annually flashes are disabling, they warrant treatment now [9].
thereafter (Table 20.1) [9]. The surveillance physical Systemic hormone therapy is contraindicated in this
exam should include a clinical breast exam and regular patient with hormone receptor-positive breast cancer.
gynecologic follow-up. Because postmenopausal women Paroxetine is a potent inhibitor of the cytochrome P450
on SERM therapies, like tamoxifen, are at increased risk 2D6 enzyme pathway, which may reduce the conversion
for endometrial hyperplasia and endometrial cancer, of tamoxifen to active metabolites and is not recom-
guidelines recommend that these patients be counseled to mended for use in women taking tamoxifen. Other
report any vaginal spotting or bleeding. Of note, in the SSRI/SNRI treatments such as venlafaxine may be
absence of abnormal uterine bleeding, routine pelvic effective. Gabapentin has been demonstrated to decrease
exams (more than the usual recommendation guidelines) hot flashes when compared to placebo and would be an
and transvaginal ultrasounds are not recommended and appropriate way to treat the patient’s hot flashes at this
may lead to unwarranted biopsies. Follow-up visits time [25].
should also update any family history of cancer and 4. A 35-year-old woman with a history of early-stage node-
include a detailed cancer-related review of systems positive breast cancer, who completed lumpectomy with
including signs and symptoms of local or regional cancer adjuvant chemotherapy and XRT 6 months ago. She is
recurrence (e.g., new lumps in the underarm or neck, now on tamoxifen. She reports some sexual problems
changes in the contour/shape/size of the breast, swelling with her husband. Sex has become painful. She also
of the breast or arm, bone pain, persistent headaches, notices a feeling of vaginal dryness most of the time.
chest or abdominal pain) [9]. Prior to her diagnosis and treatment, she was satisfied
Mammography is recommended on an annual basis to with her sex life. Which of the following is TRUE regard-
screen for local recurrence or a new primary breast cancer. ing treatment of vaginal dryness and pain with
Primary care providers should NOT offer routine lab tests, intercourse?
tumor markers, or imaging studies (e.g., bone scan, chest A. Vaginal estrogen preparations are considered first line
X-ray, PET scan, MRI scan) for the detection of disease for treatment of these symptoms in breast cancer
recurrence as a part of routine screening of breast cancer survivors.
survivors [9]. None of these have been demonstrated to B. In patients who report painful intercourse, vaginal
improve survival or quality of life in asymptomatic women lubricants should be applied as needed before
when compared to standard clinical follow-up. intercourse.
3. A 40 year-old woman with a history of early stage hor- C. Vaginal dryness in breast cancer survivors is often
mone receptor-positive breast cancer treated with lumpec- self-limited and thus may not require
tomy and XRT followed by adjuvant chemotherapy. She pharmacotherapy.
is currently in year 3 of tamoxifen therapy. She wants to D. Vaginal lubricants should not be used in patients who
discuss management of her hot flashes. She notes that her are already using a vaginal moisturizer.
hot flashes have become worse over the last year, and she The correct answer is B. Systemic hormone therapy is
now finds them disabling. She is waking multiple times contraindicated in this patient with hormone receptor-
per night with drenching sweats, having to change her positive breast cancer. Due to concerns regarding the
sheets and her clothes. How would you counsel her possibility of systemic absorption, topical estrogens
regarding her treatment options? should be reserved for patients who are not responsive
A. Systemic hormone therapy is a safe and effective to nonhormonal treatments [9]. Combining as-needed
treatment for hot flashes in breast cancer survivors. use of water-based lubricants prior to intercourse with
B. Paroxetine is an option, especially if she also has consistent (3–5×/week) use of a vaginal moisturizer
symptoms of anxiety or depression. may provide more benefit than either agent alone, to
C. Pharmacologic treatment may not be needed – vaso- improve vaginal dryness and resultant pain with
motor symptoms in breast cancer survivors tend to be intercourse.
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Part IV
Common Medical Conditions
Cardiovascular Disease in Women
Part 1: Sex and Gender Differences 21
in Cardiovascular Conditions and Risk
Factors
Alexandra M. Goodwin, Agnes Koczo, Sarah A. Jones,

Melissa A. McNeil, and Brigid M. Dolan
Introduction
Learning Objectives
1. Discuss the impact of cardiovascular disease on
Physicians caring for women patients must consider CVD
women including disease burden and costs of care.
risk assessment during the course of routine primary care
2. Identify CVD risk factors unique to female patients,
due to the high morbidity and mortality conferred by cardio-
including those related to menstrual and reproduc-
vascular diseases. CVD affects about 47.8 million women in
tive health history.
the United States and is the number one cause of death over-
all for American women [1]. Though mortality rates for
CVD have decreased, overall CVD in women accounts for
about 1 in 3.3 deaths; coronary artery disease specifically
accounts for 1 in 8.3 deaths [1, 2]. Direct annual medical
Angela is a 65-year-old woman who is presenting to costs in the United States attributable to CVD in women are
establish care after her previous physician retired. Her approximately $272.5 billion and rising [3].
best friend recently had a heart attack, prompting her The scope of the problem is broad and extends outside of
to read about heart disease in women. She was sur- the physician’s office. Women are more likely than men to
prised to learn that women die of heart disease more die from myocardial infarction (MI) outside of the hospital.
than they die of other causes and wants to learn more. More women have died of ischemic heart disease since
1984 in comparison with their male counterparts [4]. While
still low, women’s recognition that CVD is the predominant
cause death for women has doubled since 1997. Significantly,
awareness remains lower in African American and Hispanic
populations when compared to White women [5].
A. M. Goodwin (*) Importantly, physicians themselves may have falsely low
New York University, Bellevue Hospital Center, Department of perception of women’s cardiovascular risk, impacting down-
General Internal Medicine and Clinical Innovation, stream treatment choices and management of CVD risk fac-
New York, NY, USA
tors [2, 6, 7]. Part of this misperception may lie in the
differential presentation of cardiovascular conditions in
A. Koczo
University of Pittsburgh Medical Center Montefiore, Department
women. The incidence and clinical presentations of a num-
of Internal Medicine, Pittsburgh, PA, USA ber of cardiovascular diseases prevalent in women are briefly
e-mail: [email protected] discussed in the following paragraph.
S. A. Jones · M. A. McNeil For many of the cardiovascular diseases noted below, it is
University of Pittsburgh Medical Center, Department of Medicine, important to recognize that disparities exist within groups of
Pittsburgh, PA, USA women. For example, Black women in the United States
have a higher prevalence of ischemic heart disease when
B. M. Dolan compared to Hispanic and White women (7%, 5.9%, 4.6%,
Northwestern University Feinberg School of Medicine, Division of
General Internal Medicine and Geriatrics, Department of
respectively) [8]. A combination of factors including social
Medicine, Chicago, IL, USA and environmental factors, clinician implicit bias, and health
e-mail: [email protected] care system factors all have been hypothesized to play a role

348 A. M. Goodwin et al.
in contributing to said health disparities [9]; further work is protective effects of estrogen against catecholamine
needed to address these factors and improve cardiovascular effects on the myocardium.
health equity.
pontaneous Coronary Artery Dissection

S
Ischemic Heart Disease (SCAD)
Cardiovascular disease encompasses a range of disease pro- Women are also differentially impacted by spontaneous cor-
cesses affecting the coronary and peripheral arterial vessels. onary artery dissection, with estimates in some case series
The most common form of CVD in women is ischemic heart showing that over 90% of those diagnosed are women [15,
disease, which includes coronary artery disease and coronary 16]. In one long-term study of 87 patients diagnosed with
vasospasm, among others. Microvascular dysfunction and SCAD—one of the most robust available retrospective
microvascular ischemia are also more common in women cohort studies—SCAD presented as a life-threatening condi-
and may lead to delayed diagnosis of cardiac ischemia [10]. tion in greater than 50% of cases. Percutaneous coronary
“Cardiac syndrome X”—the combination of typical exer- intervention (PCI) in these patients is associated with higher
tional chest pain, normal coronary angiography, and positive rates of complication, and although long-term survival is bet-
response to stress testing—is more common in pre- and post- ter than in those with typical ACS, these patients still have
menopausal women than their age-matched male counter- high rates of major adverse cardiac events [17].
parts. Women, especially young women, may have poorer Non-atherosclerotic coronary artery disease (NACAD) is
outcomes after MI [11] and delayed recognition of anginal an important cause of MI in women under 50, accounting for
symptoms. 30% of MI; in this group, SCAD is the most common etiol-
ogy, accounting for 24% of MI [16]. Although classically
thought of as a disease of younger women, multiple studies
Heart Failure have shown the highest prevalence of disease to be in the
fifth and sixth decades of life. SCAD should be considered in
Chronic heart failure impacts women and men differently. In the differential for ACS and MI [18].
comparison to men, women are more likely to develop con-
gestive heart failure symptoms later in life and are also more
likely to have heart failure with preserved ejection fraction. Cerebrovascular Disease
The etiology of heart failure in women is less likely to be
from ischemic cardiomyopathy than it is in men, with diabe- As the fourth leading cause of death for US women, cerebro-
tes mellitus and hypertension as predominant comorbid con- vascular disease bears particular mention [1]. While stroke is
ditions [12]. more prevalent in men earlier in life, women over 85 have a
higher incidence of stroke and are more likely to be institu-
tionalized or have lasting disability after a stroke than their
Takotsubo Cardiomyopathy age-matched male counterparts [19]. An important risk fac-
tor for ischemic stroke in women is migraine headache as
Gender differences in cardiovascular disease are not lim- women with migraine headaches—particularly migraines
ited to the common, widespread conditions discussed with aura—have greater risk than those without [20].
above. Takotsubo cardiomyopathy (TC), while accounting Women are less likely than men to receive standard diag-
for only 2–3% of cases of all patients presenting with nostic workup for possible ischemic CVA upon arrival to an
symptoms of acute coronary syndrome (ACS), preferen- Emergency Department [21]. Similar to differences in MI
tially impacts women. In the United States, women are presentation, women may be less likely than men to present
almost nine times as likely as men to develop Takotsubo with “typical” stroke symptoms such as gait disturbance and/
cardiomyopathy. Postmenopausal women with cardiac or imbalance, sensory abnormalities, dysarthria, or aphasia,
risk factors such as diabetes, dyslipidemia, and hyperten- leading to possible delays in treatment [22]. Women are
sion were more likely than younger women to develop more likely than men to initially come to medical attention
TC. Age alone conferred an almost fourfold increased risk with nontraditional symptoms of stroke such as pain, unclas-
of the development of this disorder in women over 55 in sifiable neurologic symptoms, disorientation, or nonspecific
comparison with controls younger than 55 [13, 14]. This symptoms [23]. There is also some evidence to suggest that
gender-specific impact is not fully understood, but it is women with acute stroke will present to the ED later in their
posited that postmenopausal women have lost some of the course of symptoms [24].
21 Cardiovascular Disease in Women Part 1: Sex and Gender Differences in Cardiovascular Conditions and Risk Factors 349
Asymptomatic carotid stenosis—a potential precursor to Traditional Cardiovascular Risk Factors

ischemic stroke—is less common in women than in men,
with a prevalence of about 2.2%, although this value
increases with age [25]. Cerebral aneurysms, however, have
As you take her history, you find that Angela has a BMI
a higher incidence in women with 22.5 per 100,000 people,
of 32 and is a former cigarette smoker. She used to
according to one large study; women 75–84 years of age
exercise regularly but after moving recently, she has
have the highest incidence [26]. In comparison with men,
been unable to get into a routine.
women with unruptured or asymptomatic cerebral aneu-
rysms are more likely to present with subarachnoid hemor-
rhage and are more likely to have multiple aneurysms that
present later in life [27]. In this section, we review traditional risk factors and rel-
evant gender differences. The next sections discuss female-
specific risk factors. These risk factors are summarized at the
Peripheral Arterial Disease end of this chapter.
Peripheral arterial disease (PAD) was classically thought to

have a higher prevalence in men, but recent studies using the Age and Family History of CHD
ankle-brachial index, a highly sensitive and specific test,
demonstrates that women may in fact have higher rates of Like men, women have increased risk of CHD and stroke as
PAD than men (15.6% vs. 13.4%) [28]. PAD disproportion- they become older. Family history of premature CHD—
ately impacts the elderly where women comprise an increas- defined as a first-degree male relative under age 50 or a
ing sector of the elderly population, so rates of PAD in female under age 60—is also an important consideration
women are expected to increase [27, 28–30]. PAD confers a [33, 34].
two- to fourfold increase in the rates of cardiovascular mor-
bidity and mortality; thus, it is important to identify and
treat [31]. Hypertension
Women are more likely than men to have asymptomatic
disease—estimated at about 50% of female patients with Hypertension is a well-established risk factor for cardio-
PAD—which can lead to delayed diagnosis and treatment. vascular disease. There are not well-described sex differ-
Additionally, it is estimated that only 10% of women with ences in how hypertension manifests in men and women
PAD have “classic” anginal symptoms. Their symptoms are outside of hypertensive disorders of pregnancy (see Risk
more likely to be misinterpreted as arthritis or spinal steno- Factors Associated with the Reproductive Life Cycle
sis. Women have similar rates of traditional risk factors for below). However, women are more likely to develop hyper-
PAD development such as obesity, tobacco use, hyperten- tension later in life and have poorer blood pressure control
sion, and dyslipidemia. However, women may have comor- than men [35].
bid conditions like depression, osteoporosis, and
hypothyroidism that are under-recognized as being associ-
ated with an elevated risk of developing PAD, as discussed in Dyslipidemia
a 2014 systematic review. For example, women diagnosed
with PAD may have a fourfold increase in their odds of hav- Postmenopausal women are disproportionately impacted by
ing baseline depression in comparison with men. Rates of dyslipidemia and are less likely to be prescribed lipid-
PAD may also be increased in patients with subclinical hypo- lowering therapy. This discrepancy may be attributed to pro-
thyroidism, which is more likely to impact women than men. vider bias as well as underestimation of women’s CVD risk
Women with a history of hypertension during pregnancy had [36]. One cohort study identified several independent vari-
an adjusted OR of 1.6 (95% CI 1.04–2.49) in comparison ables associated with decreased statin use: increased age,
with women with normotensive pregnancies, which further history of smoking, decreased referrals to cardiologists, and
underscores the need for inclusion of a reproductive and increased reports of adverse events [37]. These findings were
obstetric history in the assessment of cardiovascular risk supported by the USAGE (Understanding Statin Use in
[28]. Data from the RATIO (Risk of Arterial Thrombosis in America and Gaps in Patient Education) study, which found
Relation to Oral Contraceptives) study showed an increased that in comparison with man, women are more likely to stop
risk of PAD development in women aged 18–49 years using taking a statin or switch agents because of muscle symp-
oral contraceptives in comparison with no contraceptive use toms. Importantly, more women in the USAGE study
(OR 3.8 [95% CI 2.4–5.8]) [32]. reported that their physician did not explain their CVD risk
in relation to their LDL cholesterol levels in comparison with on overall mortality and on the development of CHF:
men prescribed statins (36% vs. 24%; p < 0.0001). Among women with severe obesity (BMI 40 or greater) had an 88%
current statin users in the USAGE study, women were also increased risk of all-cause mortality. Additionally, their risk
less likely to be prescribed adjunctive therapies such as nia- of developing CHF was five times higher than normal BMI
cin, fibrates, or fish oil [38]. These pervasive discrepancies— cohorts. This study also suggests a synergistic effect of
from counseling and medication use to adherence—in the obesity and traditional cardiac risk factors such as hyper-
provision and use of statins in women are important targets tension, smoking, and diabetes mellitus, finding a 15-fold
for advocacy for and adequate treatment of female patients increase in coronary heart disease in severely obese women
with hyperlipidemia. with multiple risk factors (smoking, hypertension, diabetes
mellitus) in comparison with their normal-weight, low-risk
female counterparts [47]. Further, the Framingham Heart
Diabetes Mellitus and Metabolic Syndrome Study suggests that being obese increased women’s coro-
nary artery disease risk by 64% in comparison to 46% in
Diabetes mellitus (DM) and metabolic syndrome are key men [43].
risk factors for cardiovascular disease in women. Overall, Sedentary lifestyle is also an important risk factor to con-
men suffer more cardiovascular deaths attributable to dia- sider in women patients, as sitting for ≥10 hours each day
betes than women. However, women with DM have was associated with greater CVD risk than sitting for
between three and six times the risk of death from CAD <5 hours per day [48]. This may be of particular concern as
than women without DM. Additionally, female diabetics there is evidence to suggest that women are less physically
have a higher risk of death attributable to CAD in compari- active than men [8] and thus more vulnerable to the impact
son with men with DM and fatal MI [39]. This difference of the added CVD conferred by inactivity.
may be attenuated when controlling for other traditional
risk factors such as obesity, smoking status, and hyperlipid-
emia [40–42]. The presence of DM may also increase risk isk Factors Throughout the Reproductive
R
of the development of heart failure and PAD in affected Life Cycle
women. The exact mechanism of the increased risk of CVD
found in diabetic women is not fully understood, but may
be related to the impact of DM and metabolic disorder on
You ask about Angela’s pregnancy history. She is sur-
increased central adiposity, endothelial dysfunction, and
prised that you ask, as she had her last child at age 32
inflammation [43].
and she doesn’t recall physicians asking her about
pregnancy since then. She had preeclampsia with her
last pregnancy and had to deliver the baby at 37 weeks
Smoking
gestational age.
A 2011 meta-analysis showed that when adjusted for other
CVD risk factors, women who smoked had a 25% increased
risk of the development of coronary artery disease compared When evaluating a patient’s cardiovascular risk, a repro-
to men, with the exception of the youngest cohort of women ductive and pregnancy history is a crucial, though often
included in the study (age 30–44). This risk increased by 2% overlooked, aspect of data gathering. Data show that inter-
yearly [44]. Identifying female smokers for early interven- nists are less likely to obtain a pregnancy history than gyne-
tion is a critical strategy to reduce future CVD risk. cologists, though they are more likely to order appropriate
follow-up testing once that history is obtained [49]. Recent
data indicate that both internists and obstetrician/gynecolo-
Obesity and Sedentary Lifestyle gists miss opportunities to identify pregnancy-related risk
factors and pursue appropriate risk stratification testing for
Overweight and obesity remain important risk factors in the patients. There are multiple factors in a woman’s pregnancy
development of CVD for both women and men [45]. Data history that may impact their cardiovascular risk [50]. As
from the year 2015 to 2016 from the NHANES survey in with traditional risk factors, disparities in reproductive risk
the United States show that in comparison with Hispanic factors exist between groups of women; non-Hispanic
men and with non-Hispanic Black and non-Hispanic Asian Black women have a greater likelihood of preterm delivery,
men, women in these cohorts had a higher prevalence of any hypertensive disorder of pregnancy, or small for gesta-
obesity [46]. Analysis of a large, multiethnic cohort of tional age birth when compared to non-Black women in the
postmenopausal women shows a “dose effect” of obesity United States [51].
Risk Factors Associated with Pregnancy terolemia, and weight gain are taken into account, though
according to a major cohort study, these risks only account
ypertensive Disorders of Pregnancy
H for <25% of the association between preterm first births and
A personal history of preeclampsia occurring with any preg- the subsequent development of CVD [58, 59].
nancy has been linked to an increased risk of major adverse Small for gestational age births (SGA) have been shown
cardiac events and the development of hypertension later in to increase the risk of subsequent cardiovascular events such
life. Women with one lifetime birth with preeclampsia are as congestive heart failure and hypertensive heart disease.
almost twice as likely to develop a major coronary event later SGA delivery is an independent risk factor for CVD mortal-
in life than women who did not have preeclampsia (HR 2.1 ity even when controlling for factors such as obesity, diabe-
[95% CI 1.73–2.65]). When preeclampsia is combined with tes, and the presence of preeclampsia [60].
a small-for-gestational-age infant or preterm delivery, the
likelihood of a subsequent major coronary event is further pontaneous Pregnancy Loss
S
increased (HR 3.3 [95% CI 2.37–4.57]) [52]. The time of Eliciting a history of spontaneous pregnancy loss is also
preeclampsia diagnosis may impact future disease risk as an important component of cardiovascular risk assess-
well. One study found that a diagnosis of preeclampsia ment in your female patients. History of recurrent miscar-
before 37 weeks is associated with an eightfold increase in riage (in one study, defined as over three spontaneous
the risk of subsequent ischemic heart disease in comparison pregnancy losses) conferred an almost fivefold increased
with women diagnosed after 37 weeks and may increase the risk of later MI in comparison with no spontaneous preg-
risk of stroke later in life twofold [53]. Preeclampsia itself nancy loss when adjusted for age, hypertension, BMI, use
may increase the subsequent risk of diabetes mellitus later in of tobacco and alcohol, amount of physical activity, and
life; one study found a threefold increase in subsequent type presence of metabolic risk factors. The risk of MI
2 diabetes mellitus in mothers with preeclampsia in compari- increased by about 40% for each miscarriage. Notably,
son with mothers without preeclampsia, even when induced abortion does not confer added risk of MI, nor
controlling for multiple factors such as preterm delivery and does miscarriage increase risk of CVA. Having a stillbirth
small for gestational age births [54]. was also associated with an approximately 3.5 times
increased risk of MI [55].
Gestational Diabetes
Gestational diabetes mellitus (GDM) is defined as the onset eight Gain and Pregnancy
W
or recognition of impaired glucose tolerance during preg- Obesity and overweight are known risk factors for the devel-
nancy. Although the exact mechanisms for the development opment of CVD, as discussed above. In one study, women
of GDM are unknown, it creates a state of chronic inflamma- who retain postpartum weight after 1 year were found to
tion and cytokine release. Most clinicians recognize that the have increased body weight after 15 years, which in turn
diagnosis of GDM is a risk factor for the subsequent devel- may confer increased cardiovascular risk [61]. Additionally,
opment of DM [55]. Clinicians also must recognize that the multiple studies have shown that increased weight gain in
presence of GDM is an independent risk factor for future pregnancy and retention of weight even 3 months after preg-
CVD, even if a patient does not develop non-gestational dia- nancy have adverse effects on BMI, blood pressure, and lipid
betes. This risk is compounded in a woman with a family profiles, which may persist for years [62, 63].
history of type 2 diabetes and is attenuated when adjusted for
weight gain in pregnancy [56, 57].
ther Risk Factors Related to the Reproductive
O
reterm Delivery and Small for Gestational Age
P Cycle
Births
Even in the absence of preeclampsia, preterm delivery is enarche and Premenstrual Syndrome
M
associated with an increased risk of maternal cardiovascular Data are mixed on whether early menarche—defined as
disease. Ten percent of pregnancies in the United States menarche occurring over two standard deviations earlier
result in preterm delivery each year. Women who give birth than the mean for other girls of the same race and geographic
to a preterm infant have a 20–40% increased risk of future location—increases subsequent risk of CVD. It may increase
CVD events in comparison with women who did not experi- the risk of having metabolic syndrome earlier in life, which
ence a preterm delivery. This risk almost doubles for women is itself a risk factor for the development of CVD. In one
who deliver before 32 weeks of gestation. The risk is slightly meta-analysis, with early menarche defined as <12, early
decreased when pre- and post-pregnancy cardiovascular risk menarche was associated with increased risk of overall mor-
factors such as hypertension, diabetes mellitus, hypercholes- tality [64].
ombined Oral Contraceptives

C [75–77]. Subsequently, two large randomized clinical trials,
The use of combined oral contraceptive pills (COCs) that the Heart and Estrogen/Progestin Replacement Study
contain both estrogen and progesterone not only increases (HERS) and the Women’s Health Initiative (WHI), both
the risk of arterial and venous thromboembolism but also failed to show an overall benefit to HT in either primary or
may increase the risk of unwanted cardiovascular outcomes, secondary prevention of CVD [78, 79]. Amidst concerns of
especially in women with preexisting risk factors for CVD several individual disease outcomes from these large trials
such as uncontrolled hypertension, obesity, or active tobacco including CVD, endometrial cancer, breast cancer, and
use [65]. Women over 35 who are active smokers may have thromboembolic disease, there was an overall decline in the
up to ten times greater risk of MI than nonsmoking woman use of HT in the 2000s.
who take COCs. Similarly, this group has an increased risk Closer analysis of subgroups within the WHI found
of both hemorrhagic and ischemic stroke. In women with that women in younger age cohorts had more favorable
hypertension, the use of combined oral contraceptive pills CVD outcomes giving rise to the timing hypothesis. In the
may increase the risk of MI twofold [66]. For these reasons, timing hypothesis, HT given within 5–10 years of meno-
the Centers for Disease Control Medical Eligibility Criteria pause has different effects than when initiated later into
for Contraceptive Use (MEC) and other guidelines discour- menopause. Age-stratified analysis of the WHI demon-
age the use of COCs for women with these CVD risk factors strated statistically significant hazard ratio reduction for
[67]. CHD mortality at 0.76 for women within 10 years of
menopause, 1.10 for women within 10–20 years of meno-
Menopause pause, and 1.28 for women more than 20 years since
Estrogen pays a role in lowering lipids, especially LDL, and menopause [80]. This was further supported by a large
also improves endothelial function [68]. The decrease in the meta-analysis looking at 23 HT clinical trials encompass-
amount of circulating estrogen after menopause may miti- ing nearly 40,000 women [81, 82]. More recent studies
gate some of these protective effects and contribute to the have sought to look at subclinical end points of estrogen’s
higher rates of heart disease seen in postmenopausal women. effect on CVD, including carotid intimal thickness
Postmenopausal women, those most at risk for CVD, have a (CIMT), and have noted a decrease in progression of
high incidence of obesity, about 40% [69]. Even if a woman CIMT as compared to age-matched cohorts when HT is
does not gain weight after menopause, menopause is associ- given within 6 years of menopause as compared to when
ated with redistributed body fat, increasing abdominal fat given to women >10 years into menopause, further sup-
waist circumference, which is linked to cardiometabolic dis- porting the timing hypothesis [83].
ease [8]. Long-term outcomes using 18 years of cumulative
follow-up data from the WHI trials provided reassuring
Hormone Therapy data for providers who are still unsure about recommend-
Hormone therapy (HT) in postmenopausal women has long ing HT. It found no difference in all-cause mortality
been a controversial topic in women’s health. The proposed between hormone users (including both the combination
beneficial effects of estrogen on the vasculature in vitro and of estrogen plus progesterone and the estrogen alone
in premenopausal women are discordant with the clinical cohort) and nonusers (27.1% vs. 27.6%; hazard ratio
CVD outcomes observed in postmenopausal women on HT. [HR], 0.99 [95% CI, 0.94–1.03]). Similarly, no differ-
An evolving understanding distinguishes the beneficial ence in CVD mortality, CHD mortality, or stroke mortal-
effects of endogenous estrogen in the premenopausal endo- ity was found with the CVD-specific death rate in the
thelium versus that of exogenous estrogen in postmeno- pooled cohort at 8.9% in the hormone therapy group vs.
pausal women. Epidemiologic evidence demonstrated a 9.0% in the nonuser group with HR 1.00 [95% CI, 0.92–
tenfold increase in CVD in postmenopausal women, com- 1.08], CHD mortality with HR 0.97 [95% CI, 0.86–1.09],
pared to about a fivefold increase in age-matched men [70]. and stroke mortality with HR 1.06 [95% CI, 0.9–1.25].
Early interest in the cardioprotective effect of estrogen On age-stratified analysis, younger women (aged 50–59)
comes from data in animal models, showing estrogen had did not exhibit significant differences with respect to all-
numerous positive effects on both the cellular and molecular cause mortality in the pooled cohort on cumulative fol-
levels [71, 72]. Proposed mechanisms include increasing low-up (HR 0.89 [95% CI 0.79–1.01]) as compared to
nitric oxide synthesis and availability, propagating degrada- older women both in the 60–69 age group (HR 0.98 [95%
tion of oxygen free radicals, and altering the expression of CI 0.91–1.05]) and in the 70–79 age group (HR 1.03
enzymes responsible for the creation of free radial species, [95% CI, 0.96–1.10], p value for the trend = 0.06) [84].
thereby functioning as an antioxidant [73, 74]. Current guidelines do not recommend using estrogen
The beneficial estrogen effect in animal models was fur- for the primary or secondary prevention of CVD. The use
ther supported by early retrospective observational studies of HT at the lowest effective dose remains appropriate to
treat early menopausal symptoms in women who do not Hypertension

have contraindications [85, 86] and, reassuringly, does not
appear to negatively impact long-term CVD mortality and Several retrospective and prospective studies have found
may be beneficial if started early in menopause [84]. breastfeeding to have a dose-response relationship (longer total
Refer to the menopause chapter for additional duration of breastfeeding confers the lowest risk) with lower-
recommendations. ing risk for developing hypertension [92, 93]. Of note, this cor-
relation was not true for women over 64 years of age, in which
the risk for hypertension due to aging again seems to outweigh
Lactation and CVD Risk Reduction in Women any risk reduction that comes from lactation [94, 95]. While
gestational hypertension and preeclampsia increase the risk for
Lactation following pregnancy is thought to reset maladap- hypertension in later adult life, no risk factor schema including
tive metabolic changes occurring during pregnancy. The lactation histories has been validated; it is unknown whether
relationship between lactation and subclinical and clinical lactation reduces risk for these high-risk groups.
CVD and cardiovascular risk factors such as hypertension
and diabetes has been examined in several studies [87]. Less
data exist related to the association of lactation on postpar- Diabetes
tum weight and dyslipidemia.
Women with gestational diabetes (GDM) have a tenfold
higher risk of developing diabetes in later life [96, 97]. While
Cardiovascular Disease a dearth of longitudinal studies in this area exists, emerging
data suggest that lactation may be protective against the
Markers of subclinical and clinical atherosclerosis, including development of diabetes and cardiometabolic disease [69].
atherosclerosis and carotid intima-media thickness (CIMT), Normal pregnancy confers a state of increased insulin resis-
decrease with lactation. One prospective study examined 846 tance in order to divert nutrition to the fetus by impeding the
women without heart disease prior to pregnancy and found a use and storage of glucose in maternal tissues [98]. Lactation
graded inverse association between duration of breastfeeding counteracts this by redirecting glucose for milk production
and CIMT for 20 years postpartum [88]. Another study dem- [99]. One meta-analysis found that breastfeeding duration
onstrated that women with no breastfeeding history had and diabetes risk was protective with a hazard ratio 0.89
increased odds of developing aortic calcifications (OR 3.85 (95% CI 0.82–0.97), though this was no longer significant
[95% CI 1.47–10.00]) and coronary calcifications (OR 2.78 when controlling for factors including baseline BMI [100].
[95% CI 1.05–7.14]), of which aortic calcifications remained Another meta-analysis found a significant dose-dependent
significant even after controlling for BMI and other cardio- nonlinear (1–3 months vs. 6–10 months) decrease in diabetes
vascular risk factors [89]. with lactation, including one study with GDM patients,
In addition, the Nurses’ Health Study found women where improved risk attributed to lactation remained signifi-
with a lifetime breastfeeding duration of >23 months were cant even after controlling for BMI [101]. Favorable glucose
less likely to experience an acute coronary event compared metabolism has been positively associated with lactation,
to their counterparts who never breastfed (HR 0.63 [95% and insulin resistance has been associated with impaired lac-
CI 0.51–0.77]). This remained significant after controlling togenesis. These associations confound the results such that
for a number of cardiovascular risk factors [90]. Another the relationship could be women with good glucose metabo-
large, prospective study with nearly 22,000 Norwegian lism breastfeed more easily rather than breastfeeding is pro-
women found that over 15 years of follow-up, women tective for improving glucose metabolism [102].
without heart disease prior to pregnancy had an increased
risk of cardiovascular mortality if they never breastfed as
compared to women with cumulative lifetime lactation Stroke
more than 24 months (HR 2.86 [95% CI 1.51–5.39]), but
the trend of breastfeeding and mortality benefit was not Several studies have examined the impact of breastfeeding on
statistically significant in women who breastfed for a total future stroke risk. In a prospective cohort study of 300,000
of 7–12 months [91]. The beneficial associations between Chinese women, women who breastfed had a decreased risk
lifetime lactation duration with clinical cardiovascular dis- of stroke, hemorrhagic or ischemic, when compared to
ease and mortality lose significance for women over age women who had never breastfed (HR, 0.83; 0.79–0.87). Each
65. This suggests that the risks of age and menopause out- additional 6 months of breastfeeding was associated with fur-
weigh the benefits from lactation for women in their later ther reduced risk [103]. A recent analysis of the Women’s
adult years. Health Initiative (WHI) Observation Study sought to examine
Table 21.1 Summary of observed effects of lifetime lactation on cardiovascular disease and its risk factors
Lifetime duration of breastfeeding
<3 months 3–12 months 12–23 months >23 months
Cardiovascular disease Calcification aorta ↓
Calcification coronary artery ↓
Myocardial infarction ↓
Stroke ↓ ↓
Mortality ↓ X ↓
Hypertension ↓ ↓ ↓
↓ Decrease in risk
X No association. Insufficient evidence to observe trend. See text
Cumulative lifetime breastfeeding for at least 3–12 months is recommended
whether breastfeeding has an impact on the risk of developing developing ischemic heart disease in a dose-dependent fash-
stroke in later life. It found that of the 80,191 parous women ion that is proportional to the mean amount of radiation
in the study, about 58% (46,699) reported some history of delivered, with a 7.4% increase in coronary events for each
breastfeeding. The study showed that women who reported 1 Gy of radiation delivered. This risk remains increased for
any breastfeeding as compared to those who had never breast- about 30 years after the radiation is administered [105].
fed had a 23% lower risk of stroke (adjusted HR 0.77; 95% CI Women who receive left-sided radiation have a higher risk of
0.70–0.83) even after adjusting for non-modifiable confound- developing CVD in comparison to women with right-sided
ers. A subgroup analysis across races noted that the protective breast cancers [106].
effect of breastfeeding on risk of stroke was strongest for
Black women (adjusted HR 0.52; 95% CI 0.37–0.71). A fur-
ther, graded, inverse relationship was also noted between risk Other Cancer Therapy
of stroke and duration of breastfeeding among both White
and Black women. Specifically, the association was stronger Radiation is not the only cancer therapy that confers an
with women who reported longer breastfeeding durations and increased risk of developing CVD. Anthracyclines and
among non-Hispanic White and non-Hispanic Black women HER2 receptor antagonists are both associated with macro-
(test for trend P < 0.01). This study both supports the protec- vascular and microvascular cardiotoxicity, risks that may be
tive effect of breastfeeding on stroke risk while highlighting potentiated by co-administration with radiation therapy. A
disparities in risk for Hispanic and Black women who have recent longitudinal prospective cohort study demonstrated
lower rates of breastfeeding and increased rates of stroke rela- steady decline in left ventricular ejection fraction (LVEF)
tive to their White counterparts [104]. with both doxorubicin and trastuzumab, which showed a
Table 21.1 summarizes the protective effects of lactation 3.8% decline and 2.8% decline in LVEF after 3 years, respec-
on ASCVD and hypertension. We propose counseling repro- tively. Those patients who received both agents had an aver-
ductive age women that 3–12 months of lifetime lactation can age decline in their EF of 6.6% [107]. A number of factors
protect against ASCVD and hypertension at least until age 65. are considered to confer additional risk for the development
of cardiovascular complications from breast cancer thera-
pies: age greater than 60, presence of two or more CVD risk
Emerging Risk CVD Risk Factors in Women factors, preexisting valvular dysfunction, history of MI, and
preexisting mildly depressed EF (55%) [108]. While the use
of aromatase inhibitors has not been found to increase risk of
Angela comes back to see you 4 years later. Just after subsequent ischemic heart disease, it does increase the risk
her visit with you, she began exercising regularly and of subsequent dysrhythmia, pericarditis, and valvular dys-
lost 10 pounds. She was then diagnosed with breast function (HR 1.29 [1.11–1.50] [109].
cancer and did not come back to see you due to the
many visits she needed for surgery, chemotherapy, and
radiation. She is now 1-year status-post completion of Depression
those therapies and in remission on anastrozole.
Depression is an emerging risk factor for the development of
CAD and is increasingly being recognized as a prognostic
History of Radiation Therapy factor in recovery from major cardiovascular adverse events
such as MI [110]. The presence of depression and anxiety
A history of previous mantle field radiation therapy or radia- may be a stronger risk factor in women than in men [111],
tion therapy to the chest wall or breasts increases the risk of and early treatment is warranted.
Table 21.2 Summary of cardiovascular risk factors in women 2. Women and men are both at increased risk for cardiovas-
Risk factors associated cular disease from diabetes, smoking, and sedentary life-
Traditional CVD with pregnancy, estrogens, styles, but women face unique risks: cardiometabolic
risk factors and the reproductive cycle Emerging risk factors complications of pregnancy and greater incidence of
Obesity Pregnancy associated: Depression [110, autoimmune and inflammatory disease, depression, and
[43–47] Hypertensive disorders 111]
Hypertension of pregnancy [52–54] Autoimmune disease cancer treatments that confer additional risk. A thorough
[35] Small for gestational [43, 112, 113] pregnancy history is critical to assessing cardiovascular
Smoking status age births [58–60] Inflammatory risk for women patients.
[44] Spontaneous conditions [112,
Family history pregnancy loss [55] 113]
[33, 34] Preterm delivery [58, Atrial fibrillation
Age [33, 34] 59] [114–116] Review Questions
Sedentary Weight retention after Provider bias [9–11,
lifestyle [48] pregnancy [61–63] 38] 1. Jane is a 58-year-old woman who presents for annual
Diabetes Gestational DM Cancer therapy:
mellitus (DM) [55–57] Aromatase PE. She endorses a healthy diet and regular exercise. She
[39] Lactation (negative risk inhibitors [109] is a nonsmoker and has two healthy adult children. Her
Metabolic factor) [87–104] Anthracyclines past medical history is negative for a history of hyperten-
syndrome [43] Reproductive cycle: [107, 108] sion, diabetes, stroke, or heart attack. However, her run-
Dyslipidemia Use of COCs [65–67] HER2 receptor
[36–38] Early menopause antagonists [107, ning buddy recently had a heart attack and she is worried
[68–70] 108] that she might as well. On exam, her BMI is 24 and her
Early menarche [64] Radiation therapy blood pressure is 118/70.
Hormone therapy: to chest [105, You assess her cardiovascular disease risk as:
Extended use 10 years 106]
after the menopausal A. Low risk
transition [78–83] B. Moderate risk
C. High risk
D. Not enough data to calculate risk
Autoimmune and Inflammatory Diseases The correct answer is D. While Jane appears to be in good
health, she notes at least two prior pregnancies and we do
Both men and women with autoimmune and inflammatory dis- not know her pregnancy history. In addition to checking
orders have increased CVD mortality. This is thought to stem her lipids, in order to fully determine a patient’s cardio-
from antigen response causing damage to tissues and endothe- vascular disease risk, one must ask a patient if she had
lium [112, 113]. Patients with rheumatoid arthritis (RA) have a any history of preterm delivery, small-for-gestational age
50% higher risk of CVA and a two- to threefold increase in MI delivery, and GDM or hypertensive disorders of preg-
when compared to those without autoimmune disease. Patients nancy, including preeclampsia [4, 114].
with systemic lupus erythematosus (SLE) also carry increased 2. Miriam is a 48-year-old woman who presents to establish
risk of MI. The prevalence of autoimmune diseases like RA care. She reports a history of severe preeclampsia during
and SLE is higher in women, and thus women bear the higher her first pregnancy in her mid-30s. Her labor was other-
burden of this increased CVD risk [43]. wise without incident and her baby was born healthy and
at term. Her health history is otherwise unremarkable.
She had not mentioned this to her prior internist, but
Presence of Atrial Fibrillation heard about an increase in US maternal morbidity on the
radio and now is concerned. She asks if her history of
While atrial fibrillation is more prevalent in men than in preeclampsia confers any risk to her health now.
women, women have increased morbidity and all-cause mor- You tell her that compared to a woman with otherwise
tality from the condition [114, 115]. Of note, women have similar CVD risk factors, her history of preeclampsia
increased risk of CVA and MI related to their atrial fibrilla- increases her risk of developing ischemic heart disease in
tion in comparison to age-matched men [116]. Table 21.2 the next 12 years by roughly how much?
provides a summary of cardiovascular risk factors in women. A. No change
B. Risk is decreased
C. Twofold increase
Summary Points D. Fourfold increase
The correct answer is C. A preeclampsia history is a sig-
1. Women in the United States have high rates of cardiovas- nificant risk factor for the development of future CVD. In
cular disease which may be under-recognized and two separate trials, risk was found to be greater than
undertreated. 50%. Riise et al. found a 60% increased risk of subse-
quent major adverse cardiac event in women with pre- Circ Cardiovasc Qual Outcomes. 2010;3(2):120–7. https://doi.
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6. Mosca L, Linfante AH, Benjamin EJ, et al. National study of phy-
with other women without preeclampsia while control- sician awareness and adherence to cardiovascular disease preven-
ling for other CVD risk factors. Lykke et al. found an tion guidelines. Circulation. 2005;111(4):499.
80% increase in risk of ischemic heart disease in women 7. Gu Q, Burt VL, Paulose-Ram R, Dillon CF. Gender differences in
with preeclampsia during their first delivery, which was hypertension treatment, drug utilization patterns, and blood pres-
sure control among US adults with hypertension: data from the
corroborated by a meta-analysis showing a RR of 1.81 National Health and Nutrition Examination Survey 1999–2004.
for preeclamptic women in developing ischemic heart Am J Hypertens. 2008;21(7):789–98.
disease after 12 years, which overall shows a roughly 8. McSweeney JC, Rosenfeld AG, Abel WM, et al. Preventing and
twofold increase in risk of IHD development of pre- experiencing ischemic heart disease as a woman: state of the sci-
ence: a scientific statement from the American Heart Association.
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3. One of your long-term patients presents for a routine fol- 9. Green AR, Carney DR, Pallin DJ, Ngo LH, Raymond KL, Iezzoni
low-up visit. She is 65 years old, Caucasian, and generally LI, Banaji MR. Implicit bias among physicians and its predic-
feels well. Her past medical history includes rate-con- tion of thrombolysis decisions for black and white patients. J Gen
Intern Med. 2007;22(9):1231–8.
trolled non-valvular atrial fibrillation, for which she also 10. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary micro-
takes rivaroxaban. She is of a normal weight. She has vascular dysfunction is highly prevalent in women with chest pain
hypertension well controlled on medication. in the absence of coronary artery disease: results from the NHLBI
All else being similar, which of these aspects of her WISE study. Am Heart J. 2001;141(5):735–41.
11. Ford ES, Capewell S. Coronary heart disease mortality among
medical history increases her ASCVD risk in comparison young adults in the U.S. from 1980 through 2002: concealed lev-
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A. Her age chronic heart failure. Int J Cardiol. 2018;255:145–51.
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B. Her atrial fibrillation JL. Prevalence of Takotsubo cardiomyopathy in the United States.
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15. Saw J, Ricci D, Starovoytov A, Fox R, Buller CE. Spontaneous
hypertension both increase her risk of cardiovascular dis- coronary artery dissection: prevalence of predisposing conditions
ease, atrial fibrillation in women has been shown to including fibromuscular dysplasia in a tertiary center cohort. JACC
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Cardiovascular Disease in Women Part
2: Prevention, Identification, 22
and Treatment of Cardiovascular
Disease
Agnes Koczo, Alexandra M. Goodwin, Melissa A. McNeil,

and Sarah A. Jones
programs like the American Heart Association’s Go Red

Learning Objectives for Women initiative, both patients and physicians often
1. Counsel women that atherosclerotic cardiovascular fail to recognize opportunities for better ASCVD preven-
disease (ASCVD) is preventable with lifestyle tion, diagnosis, and management [3]. Primary care provid-
modification. ers meet at-risk women decades before they meet a
2. Identify and treat eligible women with lipid man- cardiologist or neurologist so the opportunities for preven-
agement and aspirin for primary prevention of tion belong to us in primary care.
ASCVD. In Chap. 21, Part 1 of Cardiovascular Disease in
3. Assess cardiovascular risk, including appropriate Women, we discussed the range of cardiovascular condi-
use of coronary artery calcium (CAC) to improve tions and their impact on women, as well as detailed both
ASCVD risk assessment. sex and gender differences in traditional risk factors and
4. Recognize sex and gender disparities in prevention, female-specific risk factors. In this chapter, Part 2, we
diagnosis, and treatment of ASCVD among women. discuss how to address these risk factors in prevention
and use them to assess risk. Additionally, we review
approaches to pharmacologic prevention, diagnosis, and
Introduction management.
Cardiovascular disease (CVD) is the leading cause of

death for both women and men in the United States [1], Ann is a 55-year-old woman presenting to establish
killing more women than all forms of cancer combined care in your clinic. Unfortunately, her mother died last
[2]. In 2013, this was 400,000 deaths or one death per min- year from her second myocardial infarction at the age
ute with an estimated 44 million women in the United of 78. Ann helped to care for her mother in the last few
States living with or at risk of heart disease [2]. CVD is years and wants to know how she can reduce her risk
also costly; estimated indirect and direct costs totaled over of a heart attack. Ann does not smoke. Her BMI is 28,
$100 billion (USD) in 2010 for ischemic heart disease and a busy work schedule keeps her from regular
(IHD) alone [3]. Strokes and cerebrovascular accidents exercise.
(CVAs) are also costly and life-altering events with risks
for lost independence and permanent disability. Despite
Prevention of Atherosclerotic Vascular

A. Koczo · M. A. McNeil · S. A. Jones (*)
Disease
University of Pittsburgh Medical Center, Department of Internal
Medicine, Pittsburgh, PA, USA Given that 80% of ASCVD is preventable, it is incumbent on
e-mail: [email protected]; [email protected]; primary care to counsel women on risk reduction through
[email protected]
lifestyle modification and pharmacologic prevention.
A. M. Goodwin Focusing first on risk reduction, the American Heart
New York University, Bellevue Hospital Center, Department of
Association (AHA)/American College of Cardiology (ACC)
General Internal Medicine and Clinical Innovation,
New York, NY, USA provides a framework through “Life’s Simple 7” [4]. These
e-mail: [email protected] include the following:

362 A. Koczo et al.
1. Not smoking (quit >12 months). lower mortality risk [7]. This improvement with a small
2. Healthy diet pattern. change is particularly important for women, who, compared
3. Sufficient physical activity (>150 min/week moderate to men, are less likely to have healthcare provider
or >75 min/week vigorous intensity). encouragement to exercise and have less experience in team
4. Normal body weight (BMI <25). activities and group exercise [3].
5. Normal total cholesterol (initially <200 with an updated Blood pressure (BP) guidelines have changed rapidly in the
goal <178). last few years and remain controversial. The initial Life’s
6. Normal blood pressure (<120/80). Simple 7 called for goal blood pressure <120/80 [4]. In 2014,
7. Normal fasting blood glucose (<100). the Eighth Joint National Committee (JNC 8) proposed less
restrictive hypertension management goals [10]. For hyperten-
A woman can calculate her score using the AHA online sive adults <60 years of age, regardless of comorbid diabetes
tool, MyLifeCheck [5], and track her progress toward these or chronic kidney disease, goal BP is <140/90 [10]. For adults
goals [6]. over the age of 60, goal BP is <150/90 [10]. In 2017, the AHA/
Almost half of US deaths from heart disease, stroke, and ACC recommended a systolic BP target <130 as their meta-
type 2 diabetes can be attributed to poor dietary habits such analysis showed less cardiovascular events with this goal [11],
as high sodium intake, high consumption of processed meats and we suggest using this goal whenever possible.
and sugar-sweetened beverages, as well as low intake of nuts Both JNC 8 and AHA/ACC BP recommendations are the
and seeds or omega-3 fats in seafood, vegetables, and fruits same for women and men. However, disparities in hyperten-
[7]. In 2015–2016, rates of US adult obesity approached sion management exist between women and men. More than
40%, with 44.7% of women aged 40–59 and 43.1% of 75% of women over age 60 have hypertension, and meno-
women aged 60 and over being obese [8]. While there was pause is a risk factor for hypertension [3]. Yet, hypertension
not a statistically significant difference, these rates are higher is not diagnosed in women as often as men and is not as well
than aged-matched men at 40.8% and 38.5%, respectively controlled in women when compared to men [12]. Also,
[8]. In the Framingham Heart Study, obesity increased the hypertension is more difficult to control in women who are
risk of CAD in women by 64%, compared to 46% in men obese, an important comorbid risk for ASCVD, when com-
[9]. Conversely, in good news, the benefit of even small pared to women with a normal BMI [13].
exchanges of sedentary behaviors can be marked. For The counseling for behavioral changes as well as the
instance, exchanging 10 minutes of sedentary time for diagnosis and treatment of cardiometabolic disease should
10 minutes of light-intensity activity is associated with 9% continue over the lifetime of her primary care. See Fig. 22.1.
Fig. 22.1 Atherosclerotic

cardiovascular disease
prevention across the adult
lifespan
22 Cardiovascular Disease in Women Part 2: Prevention, Identification, and Treatment of Cardiovascular Disease 363
Since you last saw Ann, she has started walking four You calculate Ann’s risk using the Pooled Cohort
mornings per week for 30 to 45 minutes and stopped Equation. With normal blood pressure, total choles-
eating an after-work snack, and her BMI improved to terol 236, and HDL 45, her 10-year ASCVD risk is
26. She wishes to understand more clearly her risk for 8.1%. She wants to know what more she can do to
a heart attack. reduce her risk.
Risk Assessment Pharmacologic Primary Prevention of ASCVD
In 2013, the American College of Cardiology (ACC) and Low-dose aspirin and high-intensity statin use are recom-
American Heart Association (AHA) proposed calculating risk mended for secondary prevention of ASCVD events in
based on the ASCVD Pooled Cohort Equations (referred to as patients with a history of clinical ASCVD such as acute cor-
the PCE risk estimator in this chapter), which has largely onary syndrome (ACS), angina, myocardial infarction (MI),
replaced the Framingham risk score (FRS). The PCE estima- stroke, transient ischemic attack (TIA), and atherosclerotic
tor uses data derived from the Coronary Artery Risk peripheral vascular disease (PVD) in both women and men
Development in Young Adults (CARDIA), Framingham, [22–24]. This discussion focuses on pharmacologic primary
Atherosclerosis Risk in Communities (ARIC), and prevention of ASCVD in patients with increased risk of
Cardiovascular Health Study (CHS) databases in the United ASCVD or subclinical CVD and summarizes significant
States and has been validated, including in women [14]. It is guideline changes as of late 2018.
available at http://tools.acc.org/ascvd-risk-estimator-plus [15].
The PCE risk estimator also broadened the risk categori-
zation from coronary artery disease (CAD) risk to ASCVD Aspirin
risk, which includes stroke and other vascular diseases. It
calculates the 10-year risk of hard CVD-related endpoints In 2016, the United States Preventive Services Task Force
such as myocardial infarction (MI), CAD, and nonfatal CVA (USPSTF) updated their recommendations on the use of
in patients without known CVD [16]. aspirin for the primary prevention of cardiovascular disease
An alternative risk calculator is the Reynolds risk calcula- (CVD) [25]. Previously, USPSTF recommendations for
tor [17], available at http://www.reynoldsriskscore.org [18]. aspirin as primary prevention were stratified by gender.
This calculator generates a 10-year CVD risk score, using Aspirin use was limited to ischemic stroke prevention for
the additional variables of a high sensitivity C-reactive pro- women, and aspirin for primary prophylaxis has previously
tein (hsCRP) and a family history of heart disease. For adults been shown to be underutilized in women [26, 27]. The cur-
with diabetes, a hemoglobin A1C is included. Recognizing rent recommendation is based on a 17–22% reduction in
that inflammation is a central component of atherosclerosis nonfatal MI and CVA and no sex differences in outcomes
pathogenesis, the Reynolds calculator incorporates a hsCRP [25]. CVD risk is calculated using the PCE risk estimator.
result. High-sensitivity CRP is an inflammatory biomarker • For adults aged 50–59 years, daily low-dose aspirin use
test that is not routinely completed and is controversial as a (typically 81 mg in the United States) is recommended for
screening test. those with ≥10% CVD risk, without increased risk of
This model was derived from a cohort of more than bleeding, with a life expectancy ≥10 years, and with a
24,000 healthy US women over the age of 45, who were fol- willingness to take aspirin for at least 10 years (grade B
lowed for 10 years, and was applied to recategorizing women recommendation) [25].
of intermediate risk according to Adult Treatment Panel III, • For adults aged 60–69 years, USPSTF recommends
a previous cholesterol management model [19]. The shared decision-making with consideration of daily
Reynolds risk calculator can be used in conjunction with the low-dose aspirin use for those with ≥10% CVD risk,
PCE risk estimator to add nuance to risk prediction and without increased risk of bleeding, with a life expec-
shared decision-making between patients in this population tancy ≥10 years, with a willingness to take aspirin for at
and their providers, as it was found to reclassify intermediate- least 10 years, and with patients who value the possible
risk women into higher- or lower-risk subgroups [20]. When benefits over the possible harms (grade C recommenda-
compared with the Framingham risk score (FRS), approxi- tion) [25].
mately 14% of women were elevated in risk category using • For adults <50 years of age or >70 years of age, USPSTF
Reynolds, while 2% were de-escalated [21]. To our knowl- finds insufficient data to recommend for or against aspirin
edge, the Reynolds risk score has not been compared to the use in the primary prevention of CVD and colorectal can-
PCE risk estimator. cer (CRC) [25].
364 A. Koczo et al.
The 2016 recommendation updates include consider- Statins and Non-Statin Adjuvant Therapies
ations of a life expectancy ≥10 years and a willingness to
take aspirin for at least 10 years, reflecting the finding that Guidelines for the recommended use of statins as primary pre-
CRC prevention is a latent effect with benefit after vention of ASCVD events have also been rapidly changing in
5–20 years use [25]. Of note, lose-dose aspirin is typically the past few years. In 2013, the AHA/ACC suggested evalua-
considered 81 mg in the United States although studied tion of ASCVD risk every 4–6 years and use of the PCE risk
“low-dose aspirin” ranges from 75 mg daily to 325 mg every estimator to identify at-risk patients likely to benefit from
other day. Lose-dose aspirin remains preferred over higher- statin therapy [22]. In late 2018, the AHA/ACC proposed new
dose aspirin, such as 325 mg daily, since risks of bleeding Cholesterol Clinical Practice Guidelines with the three most
are lower [23]. notable changes of (1) defining “risk enhancers” which are
USPSTF’s strongest recommendations focus on similar to risks identified in Chap. 21 and, (2) formalizing the
ASCVD prevention during a patient’s sixth decade while improvement target for low- density lipoprotein-cholesterol
onset of ASCVD events is typically one to two decades (LDL-C) while on statins (i.e., decrease LDL-C by 30–50%
later for women. The 2016 updated recommendation for those on moderate intensity therapy and by ≥50% for those
changes largely reflect that the benefit of ASCVD risk on high-intensity therapy), and (3) recommending non-statin
reduction is attenuated by increased bleeding risks, par- therapies such as ezetimibe, bile acid sequestrants, or propro-
ticularly in the setting of improved overall ASCVD risk tein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,
reduction with increased statin use and decreased tobacco when LDL-C targets are not met despite maximum statin dos-
use. We did not identify studies assessing gender-specific ing [24]. A free smartphone app “American Heart Association
implementation of the USPSTF’s 2016 recommendations On-The-Go” is available with updated 2018 algorithms under
above. Chol Update > Chol Primary Prevention.
Interestingly, the benefit of aspirin for primary preven- Statins are the first-line therapy because of their effective-
tion of ASCVD events continues to be questioned. Recently, ness and availability. Statins limit cholesterol biosynthesis.
the ASCEND trial showed a slight benefit of aspirin for pri- Ezetimibe decreases cholesterol absorption from the small
mary prevention of ASCVD events in patients with diabetes intestine. Bile acid sequestrants prevent bile acid reabsorp-
although bleeding event risks increased [28], the ARRIVE tion causing fecal loss of LDL-C. PCSK9 inhibitors are
trial showed that aspirin did not prevent ASCVD events in monoclonal antibodies that bind to the hepatic enzyme
patients with risk factors for ASCVD disease [29], and the PCSK9. PCSK9 causes LDL-C receptor degradation on
ASPREE trial showed that aspirin did not confer a protec- hepatocytes, increasing LDL-C levels, and PCSK9 inhibitors
tive effect for ASCVD event prevention among healthy allow for more LDL-C receptors and thus less LCL-C in
patients aged 70 years or older [30]. Furthermore, a recent circulation.
meta-analysis found the number needed to treat to prevent Summarized treatment recommendations based on the
ASCVD events as 265 and the number needed to harm from 2018 AHA/ACC Cholesterol Clinical Practice Guidelines
bleeding events as 210 [31]. We anticipate adjustment to the are as follows:
guidelines with this new data. Recent expert review of these
studies prompted Dr. Ridker to conclude, “Thus, beyond • For adults ≥21 years of age with LDL-C ≥190, there is no
diet maintenance, exercise, and smoking cessation, the best need to use the PCE risk estimator. Initiate high-intensity
strategy for the use of aspirin in the primary prevention of statin therapy (class I recommendation). If LDL-C per-
cardiovascular disease may simply be to prescribe a statin sists at ≥100 mg/dL, consider ezetimibe (class IIa recom-
instead” [32]. mendation). If, despite treatment with statin and ezetimibe,
Reviewing the data, we endorse the 2016 USPSTF rec- LDL-C remains ≥100 mg/dL, consider a bile acid seques-
ommendation. We recognize 50–59 year-old women who trant and/or PCSK9 inhibitor (class IIb recommendation)
cross the CVD risk threshold of ≥10% as high risk, although [24]. Given the expense of PCSK9 inhibitors and limited
this relatively young age for women would generally be pro- safety data for long-term use, primary care providers may
tective in the PCE risk estimator. The elevated risk likely consider referral to cardiology when considering PCSK9
reflects many CVD risk factors. For the 60–69 year-old inhibitor prescriptions in this population.
women and women over the age of 70, we endorse the shared • For adults aged 40–75 years with diabetes and with
decision- making that favors protecting women from the LDL-C 70–189, moderate-intensity statins are recom-
harms of bleeding risks by reserving aspirin for primary pre- mended, with consideration of high-intensity statin in
vention to only those recognized as very high risk in light of higher-risk patients (i.e., multiple risk factors or aged
the recent ARRIVE, ASCEND, and ASPREE trials. For the 50–75 years of age) (class IIa recommendation). If
same reasons, we recommend stopping aspirin for women in ASCVD PCE risk is ≥20%, ezetimibe can be added to
these age ranges who have taken as aspirin for primary pre- maximally tolerated statin therapy to achieve at least 50%
vention but who are lower risk. reduction of LDL-C (class IIb recommendation) [24].
• For adults aged 20–39 years with long-standing diabetes or Early studies of statins for primary prevention did not
significant micro- or macrovascular complications, statin show benefit of statin therapy for women but the trials
therapy may be reasonable (class IIb recommendation) [24]. included limited numbers of younger women who experi-
• For adults aged 40–75 years without diabetes and with enced fewer ASCVD events. Subsequent meta-analysis of
LDL-C 70–189, the updated 2018 recommendation is to only trials including women demonstrated protective effects
pursue shared decision-making. If patients favor treatment of statins for primary prevention of coronary heart disease
and the PCE risk is estimated at 7.5–20%, the recommen- events (RR = 0.78, CI 0.64–0.96) and CVD events
dation is to initiate moderate-intensity statin therapy (class (RR = 0.63, CI 0.49–0.82) [33, 34]. However, in a Spanish
IIb and class I recommendations, respectively). For those cross-sectional study, lower-dose statins were prescribed to
with uncertain risk, coronary artery calcium (CAC) may women, and dyslipidemia was less controlled [35]. Reduced
improve the understanding of risk (class IIa recommenda- statin prescribing and use for secondary prevention of
tion). For individuals with 10-year PCE risk ≥20%, the ASCVD events in women has been shown in the United
goal is to reduce LDL-C by more than 50% with maxi- States [36, 37]. While statins are safe in women, women
mally tolerated statins and addition of non-statin adjuvant report more myalgias, trial more statin medications (>3), and
therapies as needed (class I recommendation) [24]. express less satisfaction with communication about statins
• For adults 75 years of age or older, the PCE risk estimator than men [38, 39]. These are proposed reasons for this sex
cannot calculate 10-year risk. Therefore, it may be rea- disparity and provide an actionable remedy with improved
sonable to initiate moderate-intensity statin therapy or to healthcare communication.
continue well-tolerated statin therapy in patients with risk Additionally, it is worth noting that a woman is unlikely
factors (class IIb recommendation). With functional to satisfy the recommendations for statin initiation for pri-
decline or limited life expectancy, it may be reasonable to mary prevention during her reproductive years unless she
stop statin therapy (class IIb recommendation). has diabetes due to the significant contribution of age to
• In general, repeat lipid measurement after 4–12 weeks of the PCE. Since many women of childbearing age have dia-
statin therapy can guide dosing with an expectation that betes and women are having children later in life, it is
moderate-intensity statins will decrease LDL-C by important to remember that statins are category X and
30–50% and high-intensity statins will decrease LDL-C should be avoided in pregnancy. The AHA/ACC 2018
by more than 50%. For high-risk patients who do not Cholesterol Clinical Practice Guidelines recommend that
achieve LDL-C ≤70 mg/dL on maximal statin therapy, women of childbearing age on statin therapy should be
consider adding ezetimibe, bile acid sequestrants, or counseled on reliable contraception and that statins should
PCSK9 inhibitors (class I recommendation) [24]. be stopped 1–2 months before trying to conceive (class I
recommendation) [24]. Statins should be discontinued
The USPSTF developed a recommendation for initiation
immediately upon discovery of unintended pregnancy
of statin therapy in 2016. USPSTF also adapted its guide-
(class I recommendation) [24].
lines for initiation of lipid screening to starting at age 40 uni-
In summary, a woman’s risk may be underestimated by
versally rather than following prior sex-stratified initiation
the PCE risk estimator as it does not include risk enhancers,
for men at age 35 and women at age 45 [1]. Overall, both
and we will suggest strategies to stratify her risk more appro-
AHA/ACC and USPSTF recommend statin therapy for pri-
priately in the next section. With better identification of at-
mary prevention in those individuals with an ASCVD PCE
risk women, primary care can utilize primary prevention
risk ≥10%, but AHA/ACC recommends higher-intensity
pharmacotherapy to reduce her risk of ASCVD events.
statin therapy than USPSTF does. Additionally, AHA/ACC
considers a lower threshold to favor statin therapy in shared
decision-making at ASCVD PCE risk of 7.5%. Please see
You discuss options for ASCVD prevention with Ann
Fig. 22.2 for a summary of these differences.
and review the pros and cons of statin therapy. Ann
• For adults aged 40–75 years without known CVD, with at prefers continued lifestyle changes to medication “but
least one CVD risk factor, and with a 10-year ASCVD only if that is what is best for her health.” Since she is
PCE risk >10%, USPSTF recommends low- to moderate- at intermediate risk, you review her risk factors more
dose statin therapy for primary prevention of ASCVD completely. You inquire about her pregnancies and
(grade B recommendation) [1]. learn that she had high blood pressure with both of her
• For adults aged 40–75 years without known CVD, with at pregnancies and was on medication. She exclusively
least one CVD risk factor, and with a 10-year ASCVD breastfed each of her children for 3 months before
PCE risk between 7.5% and 10%, clinicians may choose returning to work. She went through menopause
to offer statin therapy (grade C recommendation) [1]. 5 years ago. Her LDL is 167. Ann wants to know how
• For adults >75 years of age without known CVD, USPSTF this matters for her health.
finds insufficient evidence to recommend for or against
statins for primary prevention [1].
366 A. Koczo et al.
SCVD Prevention in Asymptomatic Women

A the next 2–5 years is 0.1% per year [42]. Adding risk calcula-
of Intermediate Risk tion to CAC, a CAC = 0 with FRS of low to intermediate risk
demonstrated low mortality risk for 15 years while a CAC = 0
As outlined in Chap. 21, women have unique risk factors for with high FRS risk was associated with low mortality risk for
ASCVD such as pregnancy complications like preeclampsia 5 years [43]. However, AHA/ACC cautions that for individu-
and gestational hypertension as well as a higher prevalence als with diabetes, if a strong family history of premature
of autoimmune disease. Furthermore, both women and men ASCVD or cigarette use exists, statin therapy should not be
have risk factors not incorporated into the PCE risk estimator withheld or delayed even if the CAC score is 0 [24]. A CAC
such as LDL-C >160 and a family history of premature score of 1–99 is considered intermediate risk although the
ASCVD [22]. When discussing overall risk with a patient AHA/ACC recently recommended favoring statin therapy in
who has additional risk(s) absent from the PCE risk estima- those over age 55 years [24, 42]. A score of ≥100 is consid-
tor or who has a calculated risk in the discrepant zone ered high risk for a cardiac event within the next 2–5 years,
between the AHA/ACC and USPSTF guidelines, further risk an annual risk of >2%, and initiation of statin therapy is rec-
stratification and shared decision-making are needed. See ommended [24, 42]. Compared to a score of 0, a CAC score
Chap. 2 on High-Value Health Care for discussion on shared of ≥100 conferred a ninefold increased risk of CHD events
decision-making. and sixfold increased risk of CVD events [44].
Asymptomatic ASCVD can be evaluated using modalities In the Multi-Ethnic Study of Atherosclerosis (MESA),
such as coronary artery calcium (CAC), carotid intimal wall CAC identified candidates for aspirin and statin primary pro-
thickness (CIMT), and arterial-brachial index (ABI). For phylaxis better than risk calculators. When aspirin was used
brevity, we will focus on CIMT and CAC. CIMT is an ultra- in individuals with CAC = 0, net harm from bleeding events
sound technique evaluating the thickness of the carotid artery was observed [44]. Aspirin showed net benefit for individu-
intima and media. It has performed well in research studies als with CAC ≥100 with a number needed to treat around
with well-trained technicians but has been more difficult to 125 for prevention of ASCVD events and number needed to
operationalize in clinical settings [40]. Increases in CIMT harm of 512 for bleeding events [44]. In those with
from 0.1 mm to 1 mm have been shown to increase the risk CAC ≥100, statin use resulted in a reduction of CV events
of MI and stroke in both men and women [40]. While similar to the rates when statins were used for secondary
increased rates of annual progression may increase the risk rather than primary prevention [45]. Additionally, the use of
of CV events, serial evaluation is currently not recommended CAC may demonstrate cost savings compared to the PCE
[40]. In its 2010 Guidelines on Assessment of Cardiovascular risk estimator when statins are no longer prescribed for
Risk in Asymptomatic Individuals, the American College of CAC = 0 but are initiated when CAC ≥1 and especially with
Cardiology Foundation (ACCF)/AHA recommends consid- CAC ≥100 [46].
eration of CIMT for further risk stratification in intermediate- The ACCF/AHA currently recommends against serial
risk individuals but cautions there are practical challenges, CAC scanning. Although an accelerated rate of CAC progres-
such as the availability of a skilled technician and insurance sion is associated with increased rates of CV events, serial
coverage (grade B recommendation) [40]. scanning has not improved outcomes or altered therapy [40].
In the 2018 Cholesterol Clinical Practice Guidelines, the As the prognostic protection conferred by a CAC score of 0
AHA recommends consideration of CAC for those in the lasts 2–5 years, repeat risk stratification with CAC could be
“intermediate-risk” population with ASCVD PCE risk considered after 5 years if it would change pharmacologic
≥7.5% to <20% for whom the risk decision to start a statin prevention. CAC may become more widespread in the future
was uncertain [24]. For those in the “borderline risk” popula- as the American College of Radiology recommends reporting
tion with ASCVD PCE risk 5% to <7.5% with risk enhanc- moderate to severe CAC identified on low-dose lung cancer
ers, CAC may be considered if the risk decision is uncertain screening CT, and the Society of Cardiovascular Computed
[24]. The AHA cautions against the use of CAC in popula- Tomography with the Society of Thoracic Radiology is advo-
tions with low prevalence of detectable CAC, namely, cating for CAC to be reported on all non-contrasted CT chest
women <50 years old or men <40 years old since the CT to increase identification of subclinical ASCVD for which
scan requires exposure to radiation, albeit a low dose [40]. interventions could be initiated [41].
CAC has been shown to be superior for risk stratification Another emerging indicator of subclinical ASCVD dis-
compared to FRS, CIMT, hsCRP, and the ACC/AHA ASCVD ease is breast arterial calcification (BAC), which is variably
Pooled Cohort Equation risk estimator [40, 41]. The scoring reported on mammography. BAC was shown to correlate
has performed consistently for women and men [40]. with CAC; particularly, no BAC was found to have 81% neg-
With a negative CAC test (score = 0), the presence of ath- ative predictive value for CAC [15]. We recommend further
erosclerotic plaque or significant luminal obstructive disease evaluation of CVD risk when a mammography report does
is highly unlikely, and the risk of a cardiovascular event in make mention of calcifications of the breast arteries.
Using these current tools, we recommend using the A CAC score of 0 provides strong reassurance of low risk. A
Reynolds score and CAC to stratify women of borderline and CAC score of 1–99 prompts shared decision-making about pri-
intermediate risk for whom you are concerned that her mary prevention with aspirin and statin therapy. A CAC score of
ASCVD risk is not accurately captured in the PCE risk esti- 100 or greater reclassifies as high risk; these women likely ben-
mator (Fig. 22.3). Specifically, we would recommend further efit from low-dose aspirin and statin therapy (Fig. 22.3). On a
risk assessment for women with several risk enhancers (see practical note, often insurance will cover the hsCRP needed for
Chap. 21). For a woman of low risk (<5%), counsel on life- the Reynolds risk score but may not cover the CAC (estimated
style changes and continue to reassess her risk approximately cost $100–$400). With addition of CAC to the 2018 Cholesterol
every 5 years. For a woman of high risk (≥20%), she is rec- Clinical Practice Guidelines, insurance coverage for this test
ommended high-intensity statin therapy. Although the 2018 may improve. Therefore, patient preference, the degree of risk
guidelines increased the risk score threshold in the definition uncertainty, cost and availability of CAC, as well as likelihood
of the intermediate group and decreased the intensity of statin of changing management are important in considering use of
therapy to moderate intensity, this group of high intermediate this additional risk assessment tool.
risk (ASCVD PCE risk of 10–19.9%) is high enough risk for
a strong recommendation of moderate-intensity statin ther-
apy. If the woman remains uncertain after discussion, CAC Ann undergoes CT chest, and her CAC score is 110.
could be considered, consistent with the 2018 Cholesterol You recommend high-intensity statin therapy and aspi-
Clinical Practice Guidelines [24]. rin given her CAC ≥ 100. Her CAC ≥ 100 reclassifies
For women of borderline risk and low intermediate risk her as high risk despite her intermediate 10-year
(ASCVD PCE risk of 5–9.9%), we recommend CAC as a tool ASCVD risk from the PCE risk estimator. She agrees to
to enhance your shared decision-making. CAC has performed take these medications to reduce her risk of heart
better than many risk calculators including the PCE, performs attack and stroke.
as well in women as in men, has been shown to increase med-
ication adherence and lifestyle change, and is cost-effective
[40, 41, 44–49]. Since women are more likely to have issues
Several years later, at age 59, Ann presents to the clinic
with statin use, we believe this additional risk assessment can
with increasing difficulty completing her morning
better inform shared decision-making with women.
walks. She feels that she needs to rest once or twice
As outlined in Fig. 22.3, for a woman of borderline risk
during the walk. She has not regained any weight. She
(ASCVD PCE risk of 5–7.%) who does not have additional
does not have chest pain or trouble breathing. A sense
risk enhancers, Reynolds risk score could be used to further
of fatigue prompts her to rest.
assess her risk, noting than CRP ≥ 2 mg/L is considered a
risk enhancer. If her risk does not increase, she can be man-
aged similarly as a woman of low risk. If it does increase,
CAC can be used to stratify her risk. For women of high iagnosis and Treatment of ASCVD
D
intermediate risk (ASCVD PCE risk of 7.5–9.9%), we rec- in Symptomatic Women
ommend CAC to stratify when no additional risk enhancers
exist. If the risk enhancers are present, these increase her risk Ischemic Heart Disease
enough to strengthen the recommendation for moderate-
intensity statin therapy. If a patient remains uncertain after Although most patients with acute myocardial infarction pres-
discussion, CAC could be considered, consistent with the ent with chest pain, women are more likely to present with vari-
2018 Cholesterol Clinical Practice Guidelines [24]. able features. A symptom prodrome with shortness of breath,
Fig. 22.2 Statins for primary

prevention: comparing AHA/
ACC and USPSTF
recommendations [1, 24].
(Adapted from data in US
Preventive Services Task
Force et al. [1] and Grundy
et al. [24])
368 A. Koczo et al.
unusual fatigue, discomfort in the jaw/teeth, or discomfort in Guideline-directed medical therapy (GDMT) remains the
the arms may develop weeks to months before a major cardiac same for women and women [55]. However, women with
event [50]. During the acute event, similar symptoms often CAD are less likely to initiate statin therapy and to persist
recur, and over 25% of women never report chest pain or dis- with statin therapy for at least a year. Lacking an evaluation
comfort [51]. Symptoms also are likely to occur at rest or with by cardiology, reporting more adverse reactions, being older
stress rather than with exertion [5, 17]. When presenting at event onset, and not smoking were the factors linked to
acutely, women are more likely to have acute coronary syn- women’s discontinuation of statin therapy [36]. Between
drome (ACS) with atypical symptoms and lack EKG findings 2014 and 2015, 47% of women filled a statin prescription
[3]. In contrast to obstructive lesions which are candidates for upon 30 days after hospital discharge for MI compared to
revascularization, women have nonobstructive CAD more 56% of men [37]. Additionally, in a recent meta-analysis,
often and the resulting vascular dysfunction and myocardial women are less likely to be referred to cardiac rehabilitation
IHD that results is less well understood [3, 52]. This may, in after MI that men (0.68, 95% CI 0.62–0.74) [56].
part, explain why women’s early and late morbidity and mor-
tality after CV events are worse than that of men [3, 52].
While presentation with acute myocardial ischemia is Although Ann’s atypical symptoms and age would
more likely to occur in the emergency department, the pri- have made her a low-risk candidate, suitable for reas-
mary care clinician is more likely to encounter women with surance, her elevated CAC score escalated her risk
the symptom prodrome or stable ischemic heart disease such that she undergoes exercise myocardial perfusion
(SIHD) of nonobstructive CAD. In women who have non- imaging with abnormalities that prompt left heart
acute symptoms, the AHA recently published a consensus catheterization. She has an area with 50% stenosis of
statement for noninvasive imaging for women based upon her left anterior descending artery (LAD) but no
four levels of risk [52, 53]: obstructing lesions. Her cardiologist recommends
GDMT including secondary prevention with continued
• A low-risk woman is premenopausal, less than age 60 low-dose aspirin and high-intensity statin for preven-
with atypical angina, and without diabetes mellitus. She tion of an acute ASCVD event. She is thankful that she
can be offered reassurance about her low risk, and imag- did not have a heart attack like her mother.
ing may be deferred.
• A low intermediate-risk woman is in her 50s with a func-
tional limitation to her activities of daily living (ADLs) or
is 60–69 years old. Exercise treadmill testing (ETT) is merging Diagnostics in IHD
E
appropriate if she has a normal baseline EKG and can be In addition to the risk-stratified diagnostic recommendations
expected to achieve the exercise requirements. identified above, there are several emerging imaging modali-
• A high intermediate-risk woman is in her 60s with func- ties for patients who are at least intermediate risk for isch-
tional limitation of her ADLs. Similar to a high-risk emic heart disease, particularly if they have indeterminate or
woman, stress imaging is appropriate. inability to exercise precluding exercise treadmill testing.
• A high-risk woman either has peripheral artery disease, has Stress cardiac MRI, positron emission tomography (PET),
poorly controlled diabetes, or is greater than 70 years old. and coronary CT angiography (CCTA) have emerged as
effective diagnostic modalities for ischemic heart disease
Extensive comorbidities elevate a woman’s categorization
including for nonobstructive coronary and microvascular
by one level [52, 53].
disease, both of which disproportionately affect women [57–
We endorse additional high-risk features as ASCVD risk 59]. Research to assess the prognostic (and thus manage-
≥20% (by PCE risk estimator) or CAC ≥100. The sensitivity ment) value of both the ischemic burden by perfusion
and specificity for detecting obstructive CAD on ETT are modalities and the extent of plaque in CCTA continues to
decreased for women given a higher likelihood of not achiev- evolve [47]. Decision-making on which imaging modality to
ing maximal exercise requirements and lower baseline QRS select also depends on several factors including type of
voltage, yet the negative predictive value remains high [3, imaging available at an institution, exposure to ionizing radi-
54]. When stress imaging is planned for high intermediate- ation, and expertise in imaging interpretation (Fig. 22.4).
to high-risk women, we recommend exercise myocardial
perfusion imaging, exercise stress echocardiography, or car-
diac MRI, with a preference for exercise stress imaging Stroke
given the prognostic benefit of evaluating her exercise toler-
ance [52, 53]. Figure 22.4 illustrates risk-stratified diagnostic For both women and men, control of hypertension is an
recommendations for women presenting with SIHD. important modifiable risk factor to reduce the risk of stroke.
Fig. 22.3 Additional

ASCVD risk stratification of
asymptomatic women for
initiation of statin therapy
[24]. (Adapted from Grundy
et al. [24])
While conditions of blood pressure dysregulation during tive use and an increased risk for migraine with aura. These
pregnancy, such as pregnancy-induced hypertension, pre- observations prompted the Centers for Disease Control to
eclampsia, and eclampsia, increase the risk of acute stroke recommend against combined hormonal contraceptives in
during pregnancy, we will focus on the long-term risk con- women with a history of migraine with aura [60, 62].
ferred by these conditions. Pregnancy-induced hypertension Hormone therapy in menopausal women should not be
and preeclampsia are associated with two- to tenfold used for stroke prevention but may be considered for vaso-
increased risk of hypertension in the 5–30 years after the motor symptom management. A recent evaluation of the
complicated pregnancy [60]. Similarly, the risk of CVD Women’s Health Initiative showed no increase in stroke
event in 10 years after pregnancy had an odds ratio of 13 mortality [60, 63].
when comparing women with preeclampsia to those with an Stroke diagnosis and treatment guidelines remain the
uncomplicated pregnancy in a 2012 study [61]. Thus, we same for women and men [64]. Of note, women are less
again emphasize the importance of taking an obstetric his- likely to undergo carotid endarterectomy (CEA) which is
tory to identify women with an elevated risk for hypertension thought to be related to the smaller diameter of women’s
and stroke. internal carotid arteries and shorter segments of stenosis as
Women have unique risk factors for stroke including a well as less frequent high-grade stenosis [60]. For those that
small increased risk with combined hormonal contracep- qualify for CEA with symptomatic stenosis, women have
370 A. Koczo et al.
Fig. 22.4 Strategy for the

diagnosis of ischemic heart
disease in women [52].
(Adapted from Mieres et al.
[53])
been shown to undergo CEA less often and experience a ology of ASCVD is different in women. These disparities are
delay in time to surgery compared to men [60]. opportunities.
In reading this book, clearly you are interested in excel-
lent primary care for women. We would empower you to
Addressing Disparities remedy these disparities in cardiovascular care for women
with the following ideas:
Throughout these two chapters on cardiovascular disease,
the leading cause of death for women in the United States, 1. Rewrite the illness script.
we highlighted distinguishing features of ASCVD in women. CVD is the leading cause of death for women in the United
This includes identifying unique risk factors related to preg- States [1]. Use the rewrite to prioritize risk reduction for
nancy and menopause as well as risk factors more prevalent women. Also, use the rewrite to hear atypical symptoms in
in women, like autoimmune disease. It recognizes that our your patient’s history and diagnose her disease. Consider
risk assessment tools underestimate risk in women, that we that women of color face even greater disparities in cardio-
are not optimizing our primary or secondary risk reduction vascular care and rewrite the illness script again.
strategies for women, that we are less likely to recognize the 2. Identify that traditional risk assessment may not fit your
presentation of ASCVD in women, and that the pathophysi- patient.
Offer additional risk stratification as outlined in this 4. When women present with acute coronary syndrome (ACS),
chapter to help identify women with underestimated risk they are more likely than men to have nonobstructive isch-
and then to prescribe appropriate pharmacotherapies for emic heart disease (IHD) leading to atypical symptoms
primary prevention and to motivate lifestyle changes. which can delay diagnosis and treatment of acute myocar-
3. Recognize opportunities for patient education. dial infarction (MI). Women are typically 10 years older than
Lack of physician encouragement to exercise and men when presenting with first stroke or MI. Women have
inadequate communication about statin medications are worse short- and long-term mortality after these events, and
two opportunities identified for primary care to engage treatment is less likely to follow guidelines.
women for ASCVD risk reduction [3, 39]. Likely there
are more. Celebrate Go Red for Women month in your
clinic each February. Review Questions
4. Get with the guidelines.
This campaign is being applied to help us checklist 1. A non-Hispanic Caucasian 50-year-old woman presents
various disease management strategies and can be a quick to establish care. She is healthy, takes no medications,
reminder to review your patient’s ASCVD event manage- and has two healthy children delivered in her late 20s
ment and secondary prevention strategies. without complications. She reports no history of MI in
5. Recruit and research. either of her parents. She recently had her HDL measured
When trials are recruiting patients to address questions at 80 and her LDL at 140. In addition to learning more
about ASCVD, encourage your eligible female patients to about her risk of cardiovascular events including MI and
enroll, improving our evidence to guide better outcomes CHD death, she also wants to know her risk of stroke/
for women. Consider being active in ongoing research or death from stroke. Which is most appropriate risk calcu-
developing new research questions for ASCVD in lator to apply in this setting to use to calculate her 10-year
women. ASCVD risk?
A. Framingham
B. Reynolds risk
Summary Points C. Pooled cohort equation
D. Ellington cardiac index
1. Eighty percent of cardiovascular disease (CVD) is The correct answer is C. As a general risk calculator for
thought to be preventable. The American Heart all-comers, the pooled cohort equation risk estimator
Association’s Life’s Simple 7 outlines smoking, diet, (which uses data derived from the CARDIA, Framingham,
BMI, activity, blood pressure, cholesterol, and blood ARIC, CHS databases in the United States) has the high-
sugar as targets for reducing risk of ASCVD. est level of evidence and is the strongest recommendation
2. The USPSTF recommends low-dose aspirin for primary from the ACC and AHA. The ACC/Framingham risk cal-
prevention of ASCVD in women who are aged culator does not predict risk of CVA or CVA death. The
50–59 years with ≥10% CVD risk, without increased risk Reynolds risk calculator could be an option for this
of bleeding, with a life expectancy ≥10 years, and with a patient if an hsCRP were available and/or more data
willingness to take aspirin for at least 10 years. The points about risk could help with clinical decision-
USPSTF recommends low- to moderate-dose statin ther- making. Of note, this patient is a candidate for risk assess-
apy for primary prevention of ASCVD in women aged ment using the pooled cohort equation as she has no
40–75 years without known CVD but with a 10-year known ASCVD and has no prior major cardiac events.
ASCVD PCE risk ≥10% and with at least one CVD risk 2. A 64-year-old African-American woman is establishing care
factor. AHA/ACC recommends high-intensity statin ther- and wants to improve her health and is interested in choles-
apy for women aged 40–75 without diabetes and with a terol-lowering medications. She has a history of an upper
10-year ASCVD PCE risk ≥20% and shared decision- gastrointestinal bleed (UGIB) from overuse of non-steroidal
making about moderate-intensity statin when the 10-year anti-inflammatories (NSAIDs). She smokes ½ pack of ciga-
ASCVD PCE risk is 7.5–19.9%. rettes per day. She has high blood pressure, which is well
3. Women’s risk of ASCVD is underestimated by com- controlled on two medications. Her BMI is 26. She wants to
monly used risk calculators, and guidelines vary on sug- reduce her risk for heart attack and stroke. She has no symp-
gested thresholds to initiate statin therapy. Coronary toms of heart disease. You calculate her ASCVD risk as 14%
artery calcium (CAC) is a noninvasive strategy to iden- over the next 10 years using the Pooled Cohort Equation. In
tify women with subclinical ASCVD or at risk for addition to lifestyle changes, what pharmacologic strategy do
ASCVD who may benefit from aspirin and statin you recommend to reduce her risk, since she does not plan to
therapy. stop smoking?
372 A. Koczo et al.
A. A moderate-intensity statin and aspirin 325 mg D. If it is >400, indicating severe disease, recommend
B. A moderate-intensity statin and aspirin 81 mg aspirin and statin and send her for left heart
C. No statin but a daily aspirin catheterization.
D. A moderate-intensity statin but no aspirin The correct answer is A. Her risk of a cardiovascular
The correct answer is D. According to the USPSTF rec- event in the next 2–5 years is <0.1% with a score of 0. For
ommendations for primary prevention of ASCVD, she choice B, shared decision-making is appropriate for CAC
would not qualify for aspirin 81 mg given that she’s in score of 1–99, and for choice C, recommendation of aspi-
her 60s and has an increased risk of bleeding with her rin and statin therapy is appropriate as long as she does
history of UGIB. Both USPSTF and AHA/ACC would not have increased risks for bleeding or a contraindication
recommend at least a moderate-intensity statin given to statin therapy. For both choices B and C, the AHA does
ASCVD PCE risk >10% if shared decision-making not recommend serial CAC-CT as it has not been shown
favors the statin [22, 24, 25] which we would encourage to change outcomes or decision-making [40, 42]. For
given she intends to keep smoking. choice D, primary prophylaxis recommendations are
3. At this visit, she also tells you that her concern for her appropriate. However, given that she is asymptomatic, the
heart attack and stroke risk is because a good friend AHA does not recommend using CAC to guide plans for
recently had a heart attack. Her friend was only a few revascularization [42].
years older than she is and had similar health issues. She
noticed her friend was increasingly tired in the weeks pre-
ceding her heart attack but that she never had any chest
pain, even when she drove to the emergency department. References
Her friend had felt tired, weak, and nauseated. She wants
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Urinary Incontinence
23
Katherine E. Twist and Halle G. Sobel
Risk factors include increasing age, obesity, and tobacco

Learning Objectives use. Conditions unique to women that also increase the risk
1. Describe the impact of urinary incontinence on of urinary incontinence include pregnancy, pelvic floor
daily life. trauma such as vaginal delivery, menopause, and hysterec-
2. Define the types of urinary incontinence in women. tomy. Other contributors to incontinence include urinary
3. Evaluate a woman with symptoms of urinary tract infections (UTIs), functional or cognitive impairment,
incontinence. chronic cough, and constipation [2].
4. Manage urinary incontinence. Urinary incontinence is associated with a high societal
5. Appropriately seek specialty consultation for uri- cost as it is estimated at exceeding $82 billion in the year
nary incontinence. 2020 [2]. The impaired quality of life can take the form of
falls, fractures, sleep disturbances, depression, and UTIs.
Older women with lower urinary tract symptoms are about
twice as likely to experience falls as those without symptoms
[3–5].
Preeti is a 65-year-old female who has type 2 diabetes,
Though it can be easily screened for and often managed
obesity, hypertension, and hyperlipidemia. She pres-
in a primary care setting, urinary incontinence is frequently
ents for an annual exam. On reviewing her pre-visit
underreported and underdiagnosed. Women often do not
questionnaire, you note in the review of systems that
volunteer symptoms because of embarrassment, lack of
she checked off urinary incontinence and she has
understanding about the disease, or misconceptions about
gained 10 pounds over the last 5 years.
treatment, so it is important to ask about urinary leakage
[6, 7].
Background and Epidemiology

Normal Anatomy and Physiology
Urinary incontinence is a common condition defined as an
involuntary loss of urine. It is frequently underdiagnosed but The lower urinary tract consists of a urinary bladder and the
can negatively affect the quality of life in psychological, urethra. Normal urinary function depends on functioning
social, and sexual aspects. Nearly half of all women will anatomy, muscular supports in the pelvic floor, and neural
experience urinary incontinence at some point during their communications from the central nervous system and periph-
lifetime, but only 25% of women with the condition will eral ganglia.
seek treatment [1]. Functional anatomy of the urinary system includes the
bladder and urethra. The bladder is composed of a muscular
layer called the detrusor muscle. The detrusor in the bladder
K. E. Twist (*)
University of Kentucky, Department of Internal Medicine, dome is innervated by both sympathetic beta-adrenergic
Lexington, KY, USA receptors and parasympathetic muscarinic receptors. When
e-mail: [email protected] the parasympathetic system is stimulated, muscarinic recep-
H. G. Sobel tors are activated causing detrusor contraction and bladder
Robert Larner MD, College of Medicine at The University of emptying. The urethra consists of an internal sphincter which
Vermont, Department of General Internal Medicine,
Burlington, VT, USA

376 K. E. Twist and H. G. Sobel
is made up of smooth muscle and an external sphincter which impaired urethral function. Patients have a combination of
is under external/voluntary control. symptoms with this condition and may be affected by stress
The bladder and surrounding pelvic structures are held in and urgency to varying degrees.
place by a group of muscles that support the pelvic viscera,
including the coccygeus and layers of the levator ani.
Collectively, these muscles are referred to as the “pelvic floor.” Overflow Incontinence
Complex neural pathways between the central nervous
system (CNS) and peripheral ganglia maintain urethral clo- Overflow incontinence occurs due to incomplete bladder
sure and affect detrusor muscle function for the storage and emptying from either impaired detrusor contractility or blad-
release of urine. Bladder storage is primarily mediated in the der outlet obstruction. Symptoms can be similar to stress and
spinal cord, whereas micturition is controlled by reflex urge incontinence but may also be associated with incom-
mechanisms in the brain [8]. plete emptying of the bladder. In females, this condition typi-
cally occurs with underlying systemic neurologic disease or
anatomic abnormalities like urethral obstruction [16].
Preeti acknowledges urinary leakage before she can
make it to the bathroom and also urinary leakage with
coughing and sneezing. Functional Incontinence
Patients with functional incontinence have a normal voiding

system, but they have a physical or psychological impair-
Pathophysiology of Urinary Incontinence ment to mobilizing to a toilet, such as patients with limited
mobility or dementia.
Urinary incontinence is classified based on a combination of
clinical manifestations and the underlying abnormal mecha-
nism. However, the distinction between the different types is Preeti’s leakage is intermittent and has been present
not always clear [2]. for years after the birth of her two children but notes
she has had worsening symptoms over the past 2 years.
Not only does it occur with coughing and sneezing, but
Stress Incontinence occasionally, she will note a sudden urge to urinate
that seems almost uncontrollable and is associated
Stress incontinence occurs when increased intra-abdominal with leakage. As you proceed with your evaluation, you
pressure puts enough force on the urinary bladder that the note she has symptoms of both stress and urgency
urethra can no longer resist the flow of urine. It is typically incontinence.
caused by urethral hypermobility, which is often due to
impaired pelvic floor support. Risk factors include vaginal
delivery, obesity, and conditions that increase intra-
abdominal pressure such as chronic constipation, heavy lift- Differential Diagnosis and Contributing
ing, and high impact exercise [9–14]. Factors
Though the diagnosis of urinary incontinence specifically

Urgency Incontinence refers to involuntary urine loss, there are a number of condi-
tions that can result in similar lower urinary tract symptoms.
Urgency incontinence is characterized by a sudden desire to Urinary tract infections are frequent causes of incontinence
pass urine that is difficult to hold. It is caused by detrusor over- and should be ruled out in a primary care setting. (See Chap.
activity [15]. While usually idiopathic, it can be associated 24 on Urinary Tract Infections.) Other conditions that cause
with systemic neurologic conditions like Parkinson’s disease, inflammation in the lower urinary tract and nearby structures
multiple sclerosis, or pelvic or spinal nerve injury [16]. can also result in similar symptoms, such as interstitial cysti-
tis and vaginitis [17]. (See Chap. 12 Vaginitis and Vulvar
Problems.)
Mixed Incontinence Urinary frequency and urgency can also be precipitated
by systemic diseases including uncontrolled diabetes melli-
Mixed incontinence is a combination of stress and urge tus as the osmotic effect of glucosuria results in polyuria and
symptoms due to detrusor overactivity combined with polydipsia. Many commonly prescribed medications can
23 Urinary Incontinence 377
cause urinary symptoms by interfering with the bladder or Diagnostic Strategies

sphincter function, increasing pressure within the bladder, or
impairing mobilization. Such classes include diuretics, ACE History
inhibitors, sedatives-hypnotics, antidepressants, antipsychot-
ics, and antihistamines. The urethral sphincter tone can be The first step to evaluating urinary incontinence occurs with
reduced with alpha-blocking medications and can result in a detailed patient history. Many women do not report symp-
stress urinary incontinence [18]. The genitourinary syn- toms or think symptoms are due to normal aging. Thus, a
drome of menopause, previously called vulvovaginal atro- proactive approach to questioning patients, especially
phy, can cause urinary frequency, urgency, and urgency women, is imperative [19].
incontinence [19]. (See Chap. 8 on Menopause.) The two most common urinary incontinence types, stress
Neurologic impairment in the spinal cord can also result and urgency, can be determined by a brief validated ques-
in incontinence and, though rare, should not be missed. tionnaire which takes little time in an office visit. Additional
Spinal cord trauma as well as a neoplasm or abscess would questions should include a review of voiding habits as well
result in overflow incontinence and usually other neurologic as the amount and type of fluid intake [20].
symptoms. If a patient has difficulty describing symptoms or the
diagnosis is unclear, encourage the patient to keep a voiding
elvic Organ Prolapse
P diary. The patient should be instructed to record the quantity
Pelvic organs can prolapse or descend into the vagina or and timing of fluid intake for 1–3 days. This will assist in
beyond its walls. A cystocele is the prolapse of the bladder and determining if there are fluid modifications that can be rec-
can be seen on a speculum exam when using only the posterior ommended to the patient.
blade as anterior descent of the wall on Valsalva maneuver. A
rectocele is the prolapse of the rectum, which is seen on a
speculum exam when using only the anterior bladder as a pos- Exam
terior descent of the wall on Valsalva. The prevalence of pelvic
organ prolapse is highly dependent on age and parity. Obesity, The pelvic exam can provide additional information as to the
history of hysterectomy, White or Latina groups, and occupa- cause and/or contributing factors to the incontinence. In
tions with heavy lifting are also risk factors for symptomatic postmenopausal women, it is useful to evaluate for atrophy
prolapse. See Chap. 3 on the Sex and Gender Specific History and consider treatment with local estrogen to improve ure-
and Examination for details on diagnosing and documenting thral hypermobility. Pelvic organ prolapse beyond the vagina
the severity of pelvic organ prolapse. is associated with a higher risk of urinary retention, and
Pelvic organ prolapse is associated with a weakened pelvic referral to a specialist may be warranted. Pelvic floor integ-
floor which can increase urethral mobility and thus the risk for rity can be evaluated during the bimanual pelvic exam by
incontinence. Prolapse can also potentially restrict urine flow asking a patient to contract her pelvic floor muscles. If the
and result in overflow incontinence symptoms as well. Women patient has a difficult time isolating these muscles or she can
with pelvic organ prolapse may present with the sensation of only achieve a poor contraction, she may benefit from a for-
something falling out of the vagina or a bulge. mal pelvic floor therapy program [21, 22].
Management of pelvic organ prolapse depends on the
presence of symptoms. If prolapse is discovered on exam but
is asymptomatic, no specific therapy is necessary. If prolapse Laboratory Studies
is symptomatic (i.e., urinary dysfunction, bowel dysfunction,
or the pressure sensation), conservative therapy includes pes- A urinalysis should be used as an initial diagnostic test to
saries and pelvic floor muscle exercises, both discussed evaluate for a urinary tract infection. Additionally, a urinaly-
below. Women who have symptoms of prolapse that persist sis can detect hematuria, pyuria, and glucosuria which often
despite conservative therapy are surgical candidates. represent comorbid conditions that may need to be treated
separately [23].
Preeti urinates about every 4 hours during the day and

gets up once per night. She denies any dysuria, pelvic Other Diagnostic Strategies
pain, pressure, or other vaginal symptoms. She reports
her last hemoglobin A1c was 7.5%. Her current medi- In the authors’ experience, the large majority of patients can
cations include metformin, lisinopril-be managed based on history, exam, and urinalysis without
hydrochlorothiazide, simvastatin, and aspirin. consultation. When diagnosis is still unclear, other diagnos-
tic studies can be used and are often in conjunction with an
incontinence specialist. A simple urinary stress test can be Strengthening the pelvic floor provides a support system
done in the office: a woman with a comfortably full bladder against which the urethra may close. For stress urinary
strains or coughs while in a standing or lithotomic position. incontinence, muscle strengthening helps compensate for
Leakage during this maneuver highly suggests stress incon- anatomic weakness and defects. For urgency incontinence, it
tinence [24]. intensifies the pelvic floor muscle contractions to improve
Other special diagnostic testing like urodynamic studies continence when the bladder detrusor muscle is contracting.
are often performed by urologists and are not recommended Kegel exercises are a low-cost, low-risk intervention, but
for the uncomplicated disease. They can be used in patients they do require personal engagement from the patient. To
with unclear diagnosis, with suboptimal response to standard perform, the patient consciously contracts the levator ani
treatments, or before undergoing significant and irreversible muscles as if trying to stop the flow of urine. It is recom-
invasive treatments [23, 25]. mended to gradually build up to performing three sets of 10
A post-void residual (PVR) test should be obtained if contractions which are held for 10 seconds each. The patient
symptoms point toward incomplete emptying or exam should not interrupt urine stream while doing the exercises.
findings demonstrate a distended bladder. Within 10 min- The addition of weighted vaginal cones, biofeedback, or
utes of a measured void, the PVR is obtained either by other feedback with a trained physiotherapist can potentially
ultrasound or catheterization. While definitions vary, improve cure rates because a patient has greater awareness of
experts typically consider normal residual as either muscular activity [26, 27].
<100 mL left in the bladder when the patient has voided For anticipated events that may result in stress inconti-
>200 mL or one-third of the total voided volume with nence such as coughing or sneezing, patients can perform
lesser voids [23]. a Knack maneuver. This maneuver consists of a patient
preemptively contracting the pelvic floor and holding the
contraction through the episode of increased abdominal
pressure [19].
Preeti’s vital signs are significant for a BMI of 37,
blood pressure 137/79, pulse 68. She is neurologically
intact. Pelvic exam reveals pale, thin vaginal mucosa, Bladder Training and Scheduled Voiding
and poor muscle tone with Kegel contraction. A uri-
nalysis is normal. She completes a brief questionnaire Most patients are recommended to perform bladder training
in the office, which indicates she has stress-predominant and scheduled voiding as it is a simple, low-cost intervention.
mixed urinary incontinence. Bladder training can be offered as first-line therapy for
urgency incontinence, and these include timed voiding and
urge suppression. Patients should schedule voiding every
2–3 hours or as needed for fluid intake to reduce the risk of
Treatment Strategies incontinence episodes. Urge suppression helps reduce the
urge to urinate and improve bladder control. When the urge to
The goal of treatment in patients with urinary incontinence is urinate occurs, the patient is recommended to become still, sit
to achieve or improve continence. General strategies for any down and breathe deeply to relax, and then contract the pelvic
type of incontinence include conservative management as a floor muscles quickly and strongly 5–10 times. Once the urge
reasonable initial approach and include pelvic floor strength- to urinate goes away, the patient can either walk calmly to the
ening as well as behavior and lifestyle modifications. We rec- bathroom or wait until the urge returns again.
ommend these therapies because they are low-cost strategies
that address the underlying condition and are often without
adverse effects. Dietary and Other Lifestyle Changes
For most patients, dietary changes should be recommended

Pelvic Floor Therapy and include avoiding excess fluid intake and reducing caf-
feine and alcohol [23, 28]. Fluid intake should occur in small
Pelvic floor muscle strengthening exercises, including amounts of 4–5 ounces per hour for up to 2 liters per day of
Kegels, are recommended as first-line treatment for stress predominantly water. Modest weight loss (>5% reduction in
and mixed urinary incontinence [2]. Pelvic floor muscle body weight) should be recommended in obese patients, as
training can also offer modest benefit in urgency this has been shown to reduce the incidence of incontinence
incontinence. episodes [23, 29].
Other General Treatments Injection of bulking agents can also potentially reduce
symptoms of stress incontinence. This is usually an in-office
Using absorbent products can be beneficial in social situa- procedure using local anesthesia and a cystoscope and entails
tions and is recommended for light urinary incontinence; if injecting bulking material under the urethral mucosal layer
contact dermatitis develops, topical zinc oxide can be used as to increase outflow resistance. Success rates are lower with
a barrier. Patients should also be evaluated and treated for bulking agents compared to sling procedures [34].
underlying problems that contribute to increased intra-
abdominal pressure, including tobacco abuse/chronic cough
and constipation. Treatments for Urgency Incontinence
Topical estrogen is recommended in patients with the
genitourinary syndrome of menopause who have urinary Medications
incontinence. The topical estrogen is thought to increase ure- For patients in whom bladder training is unsuccessful, medi-
thral blood flow and potentially collagen deposition to cations can be used as second-line therapy for urgency
improve urethral coaptation [19, 30]. Systemic estrogens do incontinence [35]. There are six FDA-approved anticholiner-
not have a role in the treatment of urinary incontinence; gic medications that block muscarinic receptors in the
some studies indicate a worsening of incontinence with sys- smooth muscle of the bladder to inhibit detrusor contrac-
temic estrogen. See Chap. 8 on Menopause for details on tions, and these include darifenacin, fesoterodine, oxybu-
topical and systemic estrogen. tynin, solifenacin, tolterodine, and trospium. The only
contraindications to these medications are untreated narrow-
angle glaucoma, urinary retention, and gastric retention,
Treatments for Stress Incontinence although some evidence suggests these medications may
aggravate existing cardiac arrhythmias and be associated
Medications with dementia. Use caution in starting the medication in
There are currently no FDA-approved medications for stress older adults because of side effects such as drowsiness, hal-
incontinence, and the American College of Physicians rec- lucinations, cognitive impairment, and dementia [23].
ommends against its use [2]. Dry mouth is the most common side effect due to anticho-
linergic effects and can affect 20–50% of patients [36]. In
Pessaries addition, constipation, abdominal pain, dyspepsia, fatigue,
Pessaries are commonly used to treat pelvic organ prolapse dry eye, and dry skin can also occur. Due to bothersome side
but can also help support the bladder neck so the urethrove- effects, less than 50% of patients continue taking the medica-
sicular junction is stabilized [19]. Data are limited regarding tion beyond 6 months [37].
the value of pessaries for incontinence, but they may be pref- Most efficacy data have been limited to short-term
erable for patients who only have stress incontinence during industry-supported studies, but all appear to have similar
specific situations such as exercise [31]. When referring for efficacy. The choice of agent relies on the side-effect profile,
pessary placement, look for a gynecology or urology col- insurance formulary, or patient cost. Oxybutynin and toltero-
league that regularly fits pessaries. dine are generic anticholinergics that typically have lower
cost. When available, extended-release formulations typi-
Surgery/Invasive Options cally have more favorable side-effect profiles [23].
For patients with persistent symptoms despite conservative A newer agent, mirabegron, is a beta-3 agonist that stimu-
measures, surgical procedures and injection of bulking lates beta-3 adrenergic receptors through the sympathetic
agents can often improve incontinence symptoms. Selection nervous system to promote smooth muscle relaxation of the
of appropriate candidates is critical because, while surgery is bladder. It has not been shown to be more effective than anti-
often efficacious for stress incontinence, its effects may be cholinergics, but it does result in less dry mouth and consti-
time-limited in some women, and these procedures put pation [16], and we recommend its use as second-line therapy
women at risk for postoperative voiding difficulty or urge when anticholinergics are not tolerated. Recent evidence
incontinence [32]. suggests that mirabegron with anticholinergics may be syn-
Surgical intervention with mid-urethral slings or other ergistic in women who have insufficient response with
similar procedures can be highly effective but more inva- monotherapy alone [38]. Adverse effects associated with
sive than other measures. A mid-urethral sling is the most mirabegron are less common and can include hypertension,
studied anti-incontinent operation and consists of the nasopharyngitis, headache, and UTI [19]. As this is a newer
insertion of a synthetic mesh sling in a 30-minute outpa- agent, potential long-term effects and adverse reactions in
tient procedure and has documented short- and long-term patients with other significant comorbidities are less well
efficacy [33]. understood.
Other Options hen to Refer and Other Team Members

W
Other treatment options when lifestyle and medication ther- Who Can Help
apy fail include percutaneous tibial nerve stimulation, botox
injection, and sacral neuromodulation. (See below on when The vast majority of urinary incontinence can be evaluated
to refer.) and managed in the primary care setting. As mentioned, many
Percutaneous tibial nerve stimulation is an office procedure women benefit from a referral to a physical therapist if they are
involving electrical stimulation via an acupuncture needle deliv- having trouble with pelvic floor exercises. A rare urgent evalu-
ered in twelve 30-minute weekly sessions followed by monthly ation should occur if there are signs of an acute neurosurgical
maintenance therapy. It has similar efficacy to anticholinergic emergency occurring with the urinary incontinence. Cauda
medications and low rates of transient local adverse events [39]. equina syndrome, acute trauma, suspected abscess, or other
OnabotulinumtoxinA can also be injected into the bladder causes of spinal cord compression would necessitate immedi-
to block the presynaptic release of acetylcholine to decrease ate evaluation and management by a specialist.
muscarinic receptor activation involved in detrusor contraction. Urology or urogynecology referral should be considered
This is inserted through a cystoscope with local anesthetic in a for patients who have persistent symptoms despite appropri-
provider’s office. It is usually as effective as anticholinergic ate treatments and who are considering more invasive treat-
medication and lasts for 6–12 months. Risks of this procedure ments. Patients who may have a suspected bladder neoplasm
include urinary retention and urinary tract infections [40]. or otherwise unexplained hematuria should also be evaluated
Sacral neuromodulation is an outpatient surgical proce- outside of the primary care domain. Patients with a history of
dure involving an implanted electrode placed along the third prior radical pelvic surgery or radiation or prior pelvic incon-
sacral nerve root to deliver nerve stimulation. A short-term tinence surgery are more likely to fail conservative measures
test will determine whether this procedure is successful and and may benefit from earlier specialist referral.
tolerable to the patient, and if so, a permanent stimulator can Finally, in cases of significant pelvic organ prolapse or
be implanted and last up to 5 years. symptomatic prolapse that persists despite a trial of pessaries
and pelvic floor therapy, patients should be referred for sur-
gical evaluation. The risk of urinary retention is elevated in
Strategies for Mixed Incontinence severe prolapse, and these patients typically have limited
benefit with conservative treatments.
The initial management of mixed incontinence should focus
on the predominant component, either stress or urgency, and
should be conservative in nature [41]. Though there are no Summary Points
randomized controlled trials to evaluate patients with mixed
incontinence, combined pelvic floor muscle therapy with 1. Urinary incontinence is common in women, affecting up
bladder training is recommended as a low-cost and low-risk, to half of all women at some point in their lifetime, yet it
noninvasive therapy [2, 36, 42]. remains underreported with only a quarter of those
As second-line therapy, anticholinergic medications can affected seeking treatment.
also be useful when managing mixed incontinence; how- 2. The most common types of incontinence are diagnosed
ever, this treatment tends to be more useful for urgency primarily by history and are stress, urge, mixed, and
symptoms [42]. More invasive procedures and surgeries overflow.
include urethral bulking, retropubic urethropexies, pubo- 3. To evaluate urinary incontinence, first collect a detailed
vaginal slings, and mid-urethral slings. These typically history of the amount and circumstances of the episodes.
have mixed results and are considered if conservative man- Order a UA, to rule out secondary causes.
agement fails [42]. The overactive bladder aspect may not 4. Pelvic floor muscle exercises are recommended as initial
improve with surgery [41]. treatment for stress and mixed incontinence. For urgency
incontinence, bladder training is first-line therapy fol-
lowed by medication therapy with anticholinergics or
Preeti is treated with pelvic floor muscle strengthening beta-3 agonists.
by referring to a pelvic physical therapist and a recom- 5. Refer if a spinal cord problem is suspected or if symp-
mendation to void every 2 hours during the day, as well toms persist despite appropriate treatments.
as avoiding excessive fluid intake. Her hydrochlorothia-
zide is discontinued, and lisinopril was titrated to man-
age her blood pressure. She denies cough or constipation. Review Questions
She is referred to a dietician to assist in weight manage-
ment. After completing physical therapy, she reported a 1. A 50-year-old woman with a BMI of 41.0 presents to
75% decrease in incontinent episodes. your office with a 3-day history of urinary leakage with
coughing and sneezing. She has not noted any blood in
her urine but does have mild dysuria. She has had three References
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Urinary Tract Infections
24
Jane S. Sillman and Michael P. Carson
Epidemiology
Learning Objectives
1. Diagnose and treat cystitis. Urethritis and cystitis are both common in sexually active
2. Diagnose and treat pyelonephritis. women. The incidence of cystitis in a study of 796 young
3. Evaluate and treat recurrent urinary tract women was 0.5–0.7 per person-year [1] and was 0.07 per
infections. person-year in a 2-year study of 1017 postmenopausal
women [2]. Pyelonephritis is less common, and at most, only
3% of cystitis cases progress to pyelonephritis [3].
Definitions
Microbiology
Complicated urinary tract infection (UTI): an infection
occurring in patients with conditions that increase the risk of Cystitis and Pyelonephritis
failing therapy, as outlined in Table 24.1 Seventy-five percent to ninety-five percent of uncomplicated
Cystitis: infection of the bladder cystitis and pyelonephritis in women are due to Escherichia
Pyelonephritis: infection of the kidney coli. Less common causes include other Enterobacteriaceae
Recurrent urinary tract infections: ≥2 infections in such as Proteus mirabilis, Klebsiella pneumoniae, and
6 months or ≥3 infections in 1 year Staphylococcus saprophyticus.
Urethritis: inflammation of the urethra.
ecurrent Urinary Tract Infection
R
Table 24.1 Conditions that qualify urinary tract infections as Most are thought to be due to reinfection rather than relapse.
complicated Recurrent uncomplicated episodes of cystitis are common in
Pregnancy young healthy women and in older women, while recurrent
Poorly controlled diabetes pyelonephritis is not. Women whose first UTI is caused by E.
Hospital-acquired infection coli are more likely to have a second episode within 6 months
Acute kidney injury or chronic kidney disease than those with a first urinary tract infection due to other
Suspected or known urinary tract obstruction organisms [4]. A Finnish study of women ages 17 to 82 who
Presence of an indwelling urethral catheter, stent, nephrostomy
had E. coli cystitis showed that 44% had a recurrence within
tube, or urinary diversion
Functional or anatomic abnormality of the urinary tract 1 year [5].
Renal transplant
Immunocompromise related to other condition or medical therapy
Clinical Manifestations of UTIs
J. S. Sillman (*)
Brigham and Women’s Hospital, Department of Medicine, Urethritis
Boston, MA, USA
e-mail: [email protected] This is a common cause of dysuria in sexually active women.
M. P. Carson The presence of a urethral discharge suggests that the patient
Hackensack Meridian School of Medicine at Seton Hall, Jersey may have a sexually transmitted infection. Causes include
Shore University Medical Center, Department of Medicine,
chlamydia, gonorrhea, trichomonas, candidiasis, and herpes
Neptune, NJ, USA

384 J. S. Sillman and M. P. Carson
simplex. Use of irritating substances like contraceptive gel in an increase in vaginal pH. These changes lead to the over-
can also cause noninfectious urethritis. growth of nonacidophilic coliforms and the disappearance of
lactobacilli, predisposing to infection [6]. In a case-control
study of 149 healthy postmenopausal women with a history
Cystitis of recurrent UTI and 53 controls, the following factors were
found to be strongly associated with recurrent UTIs: urinary
Symptoms of bladder inflammation/infection may include incontinence (OR 5.0), history of UTI before menopause
urinary frequency, urgency, and suprapubic pain. Patients (OR 4.85), and ABO blood group antigen nonsecretor status
may note hematuria, and suprapubic tenderness may be (OR 2.9) [7].
noted on an exam. Risk factors for pyelonephritis are similar to cystitis and
include sexual activity, factors that impede urine flow such as
pregnancy or mechanical obstruction, genetic predisposition,
Pyelonephritis high microbial load, pathogen virulence characteristics such
as adhesion factors, and possibly diabetes mellitus [3].
Fever is a defining feature of pyelonephritis. Patients may Inherited factors can also predispose to UTI. For example,
also have chills and malaise, unilateral costovertebral angle being a nonsecretor of ABO blood group antigens (associ-
tenderness, nausea, and vomiting with or without typical ated with enhanced adherence of uropathogenic E. coli com-
symptoms of dysuria/cystitis. pared with secretors [8], having a first UTI before or at age
Urinalysis shows significant pyuria, and an elevated white 15, and a mother with a history of UTIs [9] increase UTI
blood cell count is supportive of the diagnosis, but not risk. In one case-control study of 213 women, the mean dis-
required. tance from the urethra to anus was significantly shorter in
recurrent UTI cases than in controls (4.8 versus 5.0 cm,
p = 0.03) [10].
Recurrent Urinary Tract Infection
Alice is a 25-year-old woman who telephones you
The symptoms are the same as those of a first episode of
because of pain on urination.
cystitis. A postmenopausal patient may also have symptoms
of vaginal dryness, burning, and dyspareunia due to estrogen
deficiency. The physical exam in a postmenopausal patient
may reveal atrophy of the external genitalia, loss of normal Differential Diagnosis of Dysuria
rugae in the vagina, and foreshortening of the cervix.
Dysuria often represents cystitis or UTI, but not always.
Other diagnoses to consider, with differentiating features,
Pathophysiology are as follows:
The basic pathogenesis of all UTIs is thought to be the same: • Urethritis: Symptoms may include dysuria and frequency
uropathogens from the fecal flora colonize the vaginal introi- in a sexually active woman. The physical exam may
tus, ascend from the urethra to the bladder, and cause cystitis. reveal a urethral discharge. A urinalysis may show pyuria
The pathogens may also ascend from the ureters to the kid- but no bacteriuria.
neys, resulting in pyelonephritis. Seeding of the kidneys • Vaginitis: Symptoms include vaginal discharge, odor or
from bacteremia can also cause pyelonephritis. itching, or pain on intercourse. The physical exam will
While UTIs often occur in women without risk factors, reveal a vaginal discharge and the findings associated
certain factors such as sexual behaviors, genetic predisposi- with candidiasis, trichomonas, or bacterial vaginosis on
tion, and postmenopausal atrophy increase risk. In young normal saline wet mount and KOH prep.
women, risk factors for cystitis include sexual intercourse, • Subclinical pyelonephritis: Suspect subclinical pyelone-
new sex partner, spermicide use, and history of urinary tract phritis in patients with symptoms of cystitis for more than
infections. 5 days. Subclinical pyelonephritis is more common in
In postmenopausal women, estrogen deficiency increases pregnant women and in patients with recurrent UTIs, dia-
the risk of urinary tract infections. Hypoestrogenic changes betes, immunosuppression, renal tract pathology, or pre-
include thinning of the vaginal, urethral, and bladder epithe- vious UTI before age 12.
lium, making them more vulnerable to infection. The low • Pyelonephritis: Symptoms include fever, chills, and flank
glycogen content of the thin vaginal epithelium leads to a pain. The physical exam will reveal costovertebral angle
reduction in lactic acid production by lactobacilli, resulting tenderness. Urinalysis shows pyuria and bacteriuria.
24 Urinary Tract Infections 385
• Nephrolithiasis: Patients typically present with abdomi- However, all tests should be used only as a complement to
nal or flank pain and hematuria without fever. the clinical diagnosis as a negative dipstick does not reliably
• Pelvic inflammatory disease: Symptoms include abdomi- rule out infection in a patient with classic symptoms.
nal pain, purulent cervical discharge, and cervical motion
tenderness in sexually active women. Microscopic urinalysis Urinalysis is often not needed in
• Structural urethral abnormalities: These, including ure- women with typical symptoms of acute uncomplicated cysti-
thral diverticula or strictures, can cause frequency or tis but can be helpful when a patient’s clinical presentation is
urgency and hematuria, with persistent sterile pyuria. atypical. In the lab, an unspun voided midstream urine is
• Painful bladder syndrome: It is a diagnosis of exclusion in examined for pyuria and hematuria. Greater than 10 leuko-
women with ongoing dysuria, frequency, or urgency with cytes per high-power field is consistent with cystitis or pyelo-
no evidence of an identifiable cause. nephritis and absence suggests an alternative diagnosis [13].
Hematuria is common in urinary tract infections but not in
urethritis or vaginitis. However, hematuria does not indicate
Alice reports that she has had pain on urination and that the patient has a complicated infection or requires
urinary frequency for 1 day. She has never had this extended therapy.
before. She denies fever, back pain, or vaginal dis-
charge and is sure that she is not pregnant. She has a Urine culture In women with uncomplicated cystitis,
new boyfriend and has been having intercourse about empiric treatment of common organisms is typically ade-
once a week. They are using a condom and spermicide quate, and urine culture is often not necessary. Obtaining a
consistently for contraception. urine culture prior to therapy is recommended if the patient’s
symptoms are not typical of a urinary tract infection, if
symptoms persist or recur within 3 months of treatment, or if
there is concern about a resistant organism or complicated
Alice asks if you need her to come in and submit a
infection [14]. Colony counts as low as 100 colonies/mL can
urine sample for testing.
be associated with infection. Organisms typically considered
to be contaminants may be considered causal when identi-
fied as the sole organism on culture and in high counts such
Diagnostic Strategies as 105 colonies/mL in a voided midstream urine.
Cystitis: Outpatient via Phone Suspected pyelonephritis always requires an office evalu-
ation to check vital signs, assess for suprapubic and costo-
If the patient calls with classic symptoms of cystitis, no vertebral angle tenderness, and obtain a urine dipstick and/or
symptoms to suggest pyelonephritis, is not pregnant, and has urinalysis. In pyelonephritis, the urinalysis will typically be
no other known risk factors for a complicated UTI, it is rea- positive for leukocyte esterase and nitrites. In a patient with
sonable to treat her empirically over the phone without symptoms suggestive of pyelonephritis, the absence of
obtaining a urinalysis or urine culture. pyuria suggests the need to evaluate for an obstructing lesion,
while white cell casts indicate the presence of an upper tract
infection [15]. The urine culture is the most important con-
Cystitis: In the Office firmatory test. It typically will show >10,000 colonies of a
uropathogen/mL. Lower counts may be present if the patient
The office affords the opportunity of a physical exam. Check received prior antibiotics, has extreme urine acidification, or
for suprapubic or costovertebral angle tenderness. has urinary tract obstruction. Blood cultures may be helpful
An office urine dipstick can be performed to identify the in making the diagnosis in ambiguous cases: e.g., a patient
presence of leukocyte esterase, an enzyme released by white who received prior antimicrobial therapy. In this situation,
blood cells. A dipstick positive for leukocyte esterase corre- the blood culture may still be positive though the urine cul-
lates with >10 leukocytes per high-power field. Nitrite posi- ture has become negative. Though blood cultures can be
tivity indicates the presence of Enterobacteriaceae which helpful diagnostically, the presence of bacteremia rarely
convert urinary nitrate to nitrite and is sensitive and specific changes the management of acute pyelonephritis.
for detecting ≥100,000 colonies/ml on urine culture [11].
Recent ingestion of beets can turn the urine red resulting in a Recurrent urinary tract infection Obtain a urinalysis and
false-positive nitrite result. A dipstick positive for either leu- culture to confirm the diagnosis of a recurrent infection. In a
kocyte esterase or nitrite has a sensitivity of 75% and a speci- postmenopausal patient with symptoms suggestive of vulvo-
ficity of 82% for making the diagnosis of a UTI [12]. vaginal atrophy, it is reasonable to do a pelvic exam, look for
evidence of vaginal atrophy, and consider appropriate is an option, although its efficacy is inferior to TMP-SMX
therapy. and nitrofurantoin. The recommended dose of fosfomycin is
3 grams single dose. A recent randomized clinical trial com-
Complicated UTIs Always obtain a urinalysis and urine paring nitrofurantoin 100 mg three times a day for 5 days to
culture (Table 24.1). a single 3 gm dose of oral fosfomycin showed that 5-day
nitrofurantoin resulted in a significantly greater likelihood
of clinical and microbiologic resolution at 28 days after
You tell Alice that you think she has a bladder infection
therapy completion [23]. In a previous evaluation, fosfomy-
and that you would like to treat her with an antibiotic.
cin’s efficacy was also considered to be inferior to the other
You ask if she has received any antibiotics recently and
first-line drugs [24]. Fosfomycin should not be given if
if she has any drug allergies.
pyelonephritis is suspected because it does not achieve ade-
quate renal levels [3].
Treatment Strategies Second-Line Therapy

Second-line therapy is indicated if there is allergy or intoler-
Cystitis ance to first-line therapy and includes oral beta-lactams.
Appropriate beta-lactams include amoxicillin-clavulanate,
Duration of Antibiotic Therapy cefpodoxime, cefdinir, and cefadroxil for a 7-day course.
A systematic review of the treatment of cystitis in adults Ampicillin and amoxicillin should not be used for empiric
≥65 years of age demonstrated that the optimal regimens treatment as they have poor efficacy and high rates of resis-
were the same as those given to younger adults and 3–6 days tance [20].
were as efficacious as 7–14-day courses [16].
Non-Recommended Therapies
First-Line Therapy
First-line therapy includes trimethoprim-sulfamethoxazole Fluoroquinolones
(TMP-SMX), nitrofurantoin, or fosfomycin. Fluoroquinolones should not be used for the treatment of
cystitis as widespread use leads to an increase in resistance to
TMP-SMX fluoroquinolones and other options are available. In addition,
The recommended dose is one double-strength tablet the FDA has concluded that the risks of the fluoroquinolones
(160/800 mg) twice a day for 3 days. Randomized trials (such as tendonitis, tendon rupture, peripheral neuropathy,
demonstrate clinical efficacy of 86–100% with a 3–7-day and CNS effects) outweigh their benefits for uncomplicated
regimen [17]. Empiric treatment with TMP-SMX is not rec- acute cystitis [25].
ommended if local resistance is greater than 20% [18, 19].
However, even if local resistance rates are high, if a past Ibuprofen
urine culture showed a susceptible organism, TMP-SMX can Ibuprofen was studied but found to be inferior to antibiotics
be used. In some locales, trimethoprim 100 mg twice daily for the treatment of uncomplicated cystitis. In this recent
for 3 days is used instead of TMP-SMX, with similar effi- noninferiority study, 400 women with symptoms of uncom-
cacy [20]. plicated UTI were randomized to 3 days of either ibuprofen
or pivmecillinam, an antibiotic not approved in the United
Nitrofurantoin Monohydrate Macrocrystals States. The outcome of self-report of feeling cured by day 4
The recommended dose is 100 mg orally twice a day for was reported in 38.7% of the patients in the ibuprofen group
5 days. Randomized trials demonstrate clinical efficacy of and 72.6% in the pivmecillinam group. The adjusted risk dif-
90–95% with a 5–7-day regimen [21]. Nitrofurantoin should ference was 35% (27–43%) in favor of pivmecillinam, which
not be given if pyelonephritis is suspected as it does not crossed the noninferiority margin [26].
achieve adequate renal tissue levels [3]. It should also not be
given if the creatinine clearance is <30 mL/minute.
Observational studies show that nitrofurantoin is safe in Pyelonephritis
patients with milder renal dysfunction and that it can be used
safely in older women [22]. Outpatient management is appropriate for patients with mild
to moderate illness who can be treated initially with hydra-
Fosfomycin tion and antibiotics in an outpatient facility and discharged
If a single-dose regimen is needed, such as in situations on antibiotics under close supervision. The duration of ther-
where follow-up or adherence may be difficult, fosfomycin apy does not need to be extended if bacteremia is present.
There is no evidence that bacteremia is associated with a can take oral fluids can be transitioned to oral antibiotics.
worse prognosis. Fluoroquinolone serum levels and clinical efficacy are the
same with oral and intravenous therapy; therefore, if a patient
First-Line Therapy is able to tolerate food or liquids, she may receive oral
Fluoroquinolones are the only oral antibiotics recommended therapy.
for outpatient empiric treatment of acute uncomplicated
pyelonephritis and are an appropriate choice if the likelihood
of resistance is expected to be <10% [27]. The following Pyelonephritis During Pregnancy
suggest a higher resistance level: antibiograms in the com-
munity documenting resistance >10%, if the patient recently Pyelonephritis can progress rapidly and be life-threatening
traveled to an area with known resistance >10%, and if the to the mother and the fetus [3]. Most pregnant women with
patient has taken a fluoroquinolone in the last 3–6 months. pyelonephritis, especially in the third trimester, should be
Without these risk factors, treatment options include admitted to the hospital and treated with intravenous antibi-
ciprofloxacin 500 mg orally twice daily for 7 days, cipro- otics. Ten percent of pregnant women may develop non-
floxacin 1000 mg extended release once daily for 7 days, or cardiogenic pulmonary edema related to the lower oncotic
levofloxacin 750 mg orally once daily for 5 days [27]. These pressure of pregnancy and increased risk for capillary leak of
can be given with or without an initial intravenous dose of a water into the interstitium. A healthy fetus depends on a
long-acting parenteral antibiotic. Women who are initially healthy mother, so the consequences of not treating an infec-
evaluated in an emergency department may receive initial IV tion should be considered, and when indicated, any antibiotic
ceftriaxone or a 24-hour dose of an aminoglycoside [27]. can be used. While aminoglycosides are typically avoided in
the first trimester and fluoroquinolones are generally avoided
Second-Line Therapy throughout pregnancy, they should be used when indicated in
Second-line therapy is appropriate when there is an allergy patients with intolerance, allergy, or a resistant organism.
to first-line therapy or anticipated resistance to fluoroquino- TMP/SMX is used throughout pregnancy in patients who
lones of greater than 10%. Best choices for second-line ther- require it for prophylaxis related to acquired immunodefi-
apy are as follows: ciency syndrome (AIDS); therefore, the potential concern
about a theoretical risk to the fetus should not outweigh the
• Trimethoprim-sulfamethoxazole 160/800 mg (one clear clinical benefit. Cephalosporins and broad-spectrum
double-strength tablet) twice daily if the organism is sus- beta-lactams cover the common organisms and are reason-
ceptible. The FDA recommends 14-day duration of treatable first-line choices.
ment [3].
• Oral beta-lactam, if the pathogen is susceptible, for
10–14 days [3]. Recurrent Infections in Premenopausal Women
• If either of these drugs are used before susceptibility data
is available, an initial intravenous dose of a long-acting The following strategies can be used:
parenteral antibiotic such as ceftriaxone 1 gm or an ami-
noglycoside, gentamicin or tobramycin, 5 mg per kg Non-Pharmacologic Strategies
should be given. Change of contraceptive method can be considered in pre-
menopausal women who use spermicides, especially with
Extended care in the emergency department or observa- diaphragms. Decreased use or elimination of spermicide
tion unit for more extensive fluid therapy and initial intrave- should decrease the risk of UTI [28]. See Chap. 4 on Patient-
nous antibiotics is appropriate for patients initially unable or Centered Contraceptive Counseling.
unwilling to swallow an oral antibiotic, too ill to go home Postcoital voiding and liberal fluid intake to increase the
immediately, or with clinically significant hypovolemia. frequency of urination might be helpful in reducing the risk
Inpatient care is indicated if the patient has severe illness of recurrent UTI; however, there are no controlled studies.
with high fever, pain, debility, inability to maintain hydration
or take oral medications, pregnancy, or concerns about Pharmacologic Strategies
patient compliance. Recommended initial treatment for an
inpatient is an intravenous antibiotic such as a fluoroquino- Prophylactic Antibiotics
lone, an aminoglycoside, an extended-spectrum cephalospo- Strategies include postcoital, self-treatment, and continuous
rin, extended-spectrum penicillin, or a carbapenem [3]. The regimens. Antimicrobial prophylaxis is highly effective in
decision should be based on local resistance data and adjusted reducing the risk of recurrent UTI but may be associated
according to susceptibility results. Patients who improve and with the development of resistance so it is reserved for
selected patients [29]. Postcoital prophylaxis, intermittent to be well-tolerated and effective [35]. Patients need to be
self-treatment, and continuous prophylaxis have all been warned that long-term use of nitrofurantoin has been asso-
demonstrated to be effective. A single low postcoital dose ciated with pulmonary reactions, hepatitis, and neuropathy.
may be more efficient and acceptable than continuous pro- For these reasons, we recommend TMP-SMX if continuous
phylaxis to women whose UTIs seem to be related to sexual antibiotic treatment is initiated, unless there is a sulfa
intercourse. In the one placebo-controlled trial, postcoital allergy.
trimethoprim-sulfamethoxazole 40 mg/200 mg was associ- Antimicrobial resistance to the agent being used for pro-
ated with a lower infection rate compared with placebo (0.3 phylaxis is an increasing problem.
versus 3.6 per patient-year) [30]. Uncontrolled studies show
a similar reduction in infection rates with a single low dose
of nitrofurantoin, cephalexin, or a fluoroquinolone. Postcoital ecurrent Infections in Postmenopausal
R
prophylaxis can also be used during pregnancy. The p referred Women
treatment during pregnancy is cephalexin 250 mg or nitrofu-
rantoin 50 mg [31]. Treatment with topical low-dose estrogen is effective in
decreasing recurrent UTIs as it normalizes the vaginal, ure-
Intermittent Self-Treatment thral, and bladder epithelium, as well as the vaginal flora. In
Three studies have shown that the presence of a UTI can be a randomized placebo-controlled trial of 93 postmenopausal
accurately diagnosed by women 85–95% of the time and that women with history of recurrent UTI, intravaginal estradiol
short-course treatment with trimethoprim-sulfamethoxazole cream (50 mcg estradiol nightly for 2 weeks, then twice
or a fluoroquinolone is highly effective [32]. This strategy weekly for 8 months) significantly reduced the recurrence of
should be limited to women who have clearly documented UTI from 5.9 episodes per patient-year to 0.5 [36]. The treat-
recurrent infections and are motivated and compliant with ment increased vaginal lactobacilli and decreased E. coli
instructions. They should be told to call their clinician if their vaginal colonization. Topical estrogen is more effective than
symptoms do not completely resolve by 48 hours. systemic estrogen in decreasing recurrent urinary tract infec-
tions and alleviating the symptoms of genitourinary atrophy.
Continuous Antibiotic Treatment A 2008 Cochrane review evaluated estrogens for preventing
Continuous antibiotic treatment significantly reduces recur- recurrent UTIs in postmenopausal women [37]. In 4 studies
rences. A meta-analysis from the Cochrane database evalu- with a total of 2798 women, oral estrogens did not reduce
ated 10 trials involving 430 healthy nonpregnant women UTI compared to placebo. Treatment with vaginal estrogens
with 2 or more UTIs in the past 12 months who were treated did reduce the number of women with UTIs in two studies
with continuous or postcoital antibiotics for 6–12 months with reported RR of 0.25 (95% CI 0.13–0.50) and 0.64 (95%
and noted the following: clinical recurrences were signifi- CI 0.47–0.86).
cantly decreased with RR 0.15, (95% CI 0.08–0.28) and Topical estrogen can be given as a cream, tablet, or
NNT 1.85. The RR for side effects which included vaginal estrogen-containing ring. Low-dose therapy with a vaginal
and oral candidiasis and gastrointestinal symptoms was 1.58 cream consists of 50 mcg estradiol/0.5 g cream or 0.3 mg
(95% CI 0.47–5.28). There was no significant difference conjugated estrogen/0.5 g cream inserted into the vagina
between continuous daily and postcoital ciprofloxacin. No daily for 2 weeks, followed by treatment twice a week. Low-
conclusions could be made regarding the best antibiotic dose therapy with an estrogen tablet involves inserting a
choice or optimal duration of prophylaxis [33]. 10-mcg estradiol tablet into the vagina daily for 2 weeks, fol-
Regimens for continuous antibiotic treatment include lowed by the insertion of the tablet twice a week. The
trimethoprim-sulfamethoxazole 40 mg/200 mg once a day, estrogen-containing ring releases 7.5 mcg of estradiol daily
nitrofurantoin 50 mg once a day, cephalexin 125–250 mg into the vagina for 90 days. A new ring is inserted every
once a day, and ciprofloxacin 125 mg once a day. One trial 90 days. It typically requires 6 weeks of treatment with low-
evaluated the efficacy of fosfomycin 3 gm every 10 days for dose vaginal estrogen for vaginal, urethral, and bladder atro-
6 months in 317 nonpregnant women with recurrent UTIs phy to improve and for patients to begin to note improvement
and was associated with a decrease in the number of UTIs in their symptoms. See Chap. 8 on Menopause, Sect. on
from 2.97 to 0.14/patient-year. The time to first recurrence of Genitourinary Syndrome.
a UTI was longer in the fosfomycin group (38 versus 6 days), Postmenopausal women who are unable or reluctant to
and the drug was well tolerated [34]. use topical estrogen can use antibiotic prophylaxis as recom-
When indicated, a 6-month trial of antibiotics given at mended for premenopausal women. Postcoital prophylaxis
night should be considered, but some patients might require or self-treatment at the onset of symptoms of a UTI has the
treatment for 2 or more years [29]. Use of trimethoprim- advantage of leading to less antibiotic exposure than contin-
sulfamethoxazole for as long as 5 years has been reported uous daily antibiotic use.
ecurrent UTIs: Other Strategies

R expected clinical improvement with resolution of all symp-
Cranberry products are not recommended as there are no toms, a follow-up urine culture is not needed.
data showing efficacy. Similarly, more data are needed before
recommending probiotics.
hen to Refer and Other Team Members
W
Who Can Help
You treat Alice with trimethoprim-sulfamethoxazole,
one double-strength tablet twice a day for 3 days, and • Co-manage pregnant women with their obstetricians. The
her symptoms resolve completely. She calls to say that obstetricians will determine what kind of fetal monitoring
she is feeling fine and asks if she needs any follow-up is required, if any.
for this episode of cystitis. • Urology should be consulted if hydronephrosis is
detected.
• Consult urology and interventional radiology for women
Follow-Up with an abscess.
• Women with recurrent urinary tract infections who do not
Cystitis respond to treatment may be candidates for referral to a
urologist.
Symptoms should respond to antibiotic treatment within • Patients with persistent hematuria after their infection has
48 hours. Women with severe dysuria may benefit from a been eradicated require imaging of their upper and lower
urinary analgesic such as over-the-counter phenazopyridine urinary tracts and referral to a urologist for a cystoscopy.
three times a day as needed for a 2-day course but should be • Postmenopausal women on topical low-dose estrogen
counseled that it can turn tears and urine orange and poten- who develop vaginal bleeding should be referred for an
tially stain contact lenses. Follow-up urinalysis and/or cul- endometrial biopsy.
tures are not needed if her symptoms resolved. • Further evaluation of the urinary tract is recommended if
Patients whose symptoms persist after 48–72 hours of any suspicions arise about possible structural or func-
appropriate antibiotics or who have recurrent symptoms tional abnormalities of the urinary tract. Possible indica-
within a few weeks of treatment should be evaluated for the tions for evaluation include a UTI due to Proteus species
possibility of a complicated infection. Urine culture should as it is often associated with the presence of stones, or two
be obtained or repeated, and while it is pending, empiric recurrences of pyelonephritis. Evaluation should start
treatment should be given with a different antibiotic. with a renal ultrasound or CT urogram to rule out nephro-
Advise patients to phone right away if symptoms of cysti- lithiasis or obstructive uropathy.
tis recur and teach them the symptoms of pyelonephritis.
Consider the interventions above for women with docu-
mented recurrent infections. Summary Points
1. Women with the classic symptoms of cystitis such as pain

Pyelonephritis on urination, urinary frequency, and urgency can be
empirically treated with a short course of antibiotics. First
If the patient shows clinical worsening or the lack of improve- line is 3 days of TMP/sulfa double-strength twice daily.
ment after 1–2 days of antibiotic therapy, she requires a 2. Women with the classic symptoms of pyelonephritis such
repeat urine culture and imaging to identify if a stone, as fever, chills, and costovertebral angle tenderness must
obstruction, or other anatomical complication is the reason be evaluated with a urinalysis and urine culture and will
for the lack of improvement. An ultrasound is more sensitive require treatment with a 7–14 days of an appropriate
than computerized tomography (CT) for diagnosis of hydro- antibiotic.
nephrosis, is less expensive, and is available at the bedside. A 3. Young women with recurrent urinary tract infections can
contrast-enhanced CT is more sensitive for the diagnosis of self-treat with one dose of postcoital antibiotics. Other
an abscess, gas formation, and inflammation but should be options are to self-treat when they diagnose themselves
used with caution in patients with renal dysfunction and with a UTI or to take a continuous nightly low dose of an
impairs the detection of stones. An unenhanced CT is pre- appropriate antibiotic.
ferred for the detection of stones. 4. Recurrent urinary tract infections in postmenopausal
Among women treated as outpatients, schedule reassess- women are often due to genitourinary atrophy from estro-
ment to assess response to therapy and the need for broad- gen deficiency. Treatment with low-dose topical estrogen
spectrum antibiotics or intravenous therapy [3]. If she shows is often effective.
Review Questions done to prevent these recurrent episodes. She became

menopausal at age 51 and has had a hysterectomy for
fibroids. She notes vaginal dryness and her pelvic exam
1. Which factor is the biggest risk for cystitis in young reveals vaginal atrophy. The next best step is:
women? A. To prescribe that she use a vaginal moisturizer every
A. Wearing spandex night
B. Sexual intercourse B. To suggest that she use a vaginal lubricant before sex-
C. Oral contraceptives ual intercourse
D. Use of an IUD C. To recommend a trial of low-dose vaginal estrogen
The correct answer is B. Of the choices above, sexual D. To recommend a trial of systemic estrogen
intercourse is the biggest risk factor for cystitis in young The correct answer is C. To recommend a trial of low-
women. Sexual intercourse expedites the ascension of dose vaginal estrogen. Low-dose vaginal estrogen is
uropathogens from the fecal flora to the vaginal introitus highly effective in reducing the frequency of recurrent
and then from the urethra to the bladder. UTIs in postmenopausal women.
2. Ellen is a 23-year-old woman who calls your office to
report urinary frequency, fever, chills, and right flank pain
for 2 days. The most appropriate next step is:
A. To empirically treat her with a 3-day course of TMP/
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14. Fihn SD. Clinical practice. Acute uncomplicated urinary tract
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Bone Health and Osteoporosis
25
Jordana Friedman, Aletia Farmer,
and Jacqueline Carey Fister
Learning Objectives
steoporosis: Epidemiology and Public
O
1. Describe the public health impact of osteoporosis
Health Impact
with regard to cost, mortality, and quality of life.
Osteoporosis is a skeletal disorder characterized by a
2. Screen appropriately for osteoporosis based on age
decrease in bone strength predisposing to an increased risk
and risk.
of fracture. Because of the large number of older adults
3. Diagnose primary and secondary osteoporosis.
impacted by osteoporosis and the morbidity and mortality
4. Utilize a risk assessment tool to calculate fracture
associated with fragility fracture, osteoporosis has both a
risk.
significant clinical impact and a large socioeconomic impact.
5. Recommend non-pharmacologic measures for frac-
According to data from the National Health and Nutrition
ture prevention.
Examination Survey (NHANES), 10.2 million older
6. Identify candidates for pharmacologic treatment
Americans were estimated to have osteoporosis in 2010, and
and appropriately recommend pharmacologic treat-
43.4 million additional older Americans were estimated to
ment for patients at risk for fracture.
have low bone mass [1]. There are approximately two mil-
lion osteoporotic fractures annually in the United States, and
70% of those fractures occur in women [1, 2]. The annual
cost associated with osteoporotic fractures exceeds the com-
Marianne is a 64-year-old Caucasian woman who bined cost of caring for breast cancer, myocardial infarction,
comes in for her annual exam. She has a history of and stroke in women 55 years or older [3]. It is estimated that
hypertension and hyperthyroidism status-post radio- the costs of osteoporotic fractures will exceed 25.3 billion
active iodine therapy. She takes hydrochlorothiazide (United States dollars) by 2025 [2, 4]. There is also substan-
and an over-the-counter multivitamin. Her social his- tial morbidity and mortality associated with fragility frac-
tory is notable for a 30-pack-year smoking history and tures. While mortality can reach 20–24% in the first year
a sedentary lifestyle due to caring for her chronically after a hip fracture [5], associated morbidity rates are higher
ill husband. On exam, she is 5 feet 9 inches tall and and include fracture-related pain, deformity, reduced mobil-
weighs 134 lbs. She asks you if she should have a bone ity, and loss of function and independence. Up to 40% of
density scan for osteoporosis screening. those experiencing hip fracture are unable to walk indepen-
dently, and up to 33% are totally dependent or living in a
nursing home in the year following the fracture [6–8]. Up to
10–20% of community-dwelling patients will require long-
term nursing home care after a hip fracture [9].
J. Friedman
Northwestern University, Feinberg School of Medicine, hysiology of Bone Formation
P
Department of Internal Medicine, Chicago, IL, USA and Remodeling
A. Farmer (*) · J. C. Fister Bone strength is based on both bone density and bone qual-
University of Kentucky, Department of Internal Medicine/ ity. Bone density is the measurement of bone quantity. Bone
Women’s Health, Lexington, KY, USA
quality is determined by factors that influence how well bone

394 J. Friedman et al.
can resist fractures including microarchitecture, microscopic Impact of Age and Hormonal Fluctuations
damage, quality of bone material, size of mineral crystals,
and the rate of bone turnover [10]. Given the impact of estrogen on bone remodeling, age-
related bone loss in women begins in the fifth decade at an
average rate of 0.5–1% per year as women begin to approach
Normal Bone Remodeling perimenopause [12, 13]. Menopausal related bone loss
begins in the menopause transition 3–5 years before the last
In the normal bone remodeling process, bone continues to menstrual period (LMP) and continues for 3–5 years after
regenerate through remodeling even after the bone skeleton the LMP. During menopause, bone loss accelerates as estro-
has reached maturity and linear growth is complete. gen levels significantly decrease. The loss of estrogen leads
Remodeling refers to the process by which older bone is to increased osteoclast activity and increased bone resorption
removed and replaced by new bone and has three phases: [12, 13]. During this time, the average rate of bone loss is
resorption, reversal, and formation. The remodeling cycle 1–2% per year, which can lead to a 10–20% loss over
starts with resorption, which is the removal of old bone by 10 years [12, 13]. Age-related osteoporosis after the sixth
osteoclasts. When resorption is complete, there is a reversal decade affects both men and women. During this time,
phase in which a glycoprotein rich substance is deposited on resorption exceeds formation resulting in net bone loss.
the bone surface to which osteoblasts can adhere. In the for-
mation phase, these adherent osteoblasts produce a new bone
structure that subsequently begins to mineralize. The remod- Marianne’s mother fractured her hip at age 62. She is
eling process has a role in maintaining bone health by repair- very concerned today regarding her own risk of frac-
ing microscopic damage and minimizing the effects of aging ture and how to prevent fracture.
on bone (Fig. 25.1).
Estrogens and androgens play a role in regulating bone
remodeling. Estrogen inhibits bone resorption through cell
signaling factors including cytokines and growth factors, I dentification of Osteoporosis: Risk Factors
which induce osteoclast apoptosis and inhibit osteoclast and Indications for Screening
activity. Testosterone increases cytokines and growth factors
that stimulate osteoblast proliferation, inhibit osteoclast Osteoporosis can be defined as low bone mass with changes
activity, and induce osteoclast apoptosis. In women, estrogen in skeletal microarchitecture that lead to fragility fractures.
is the primary sex steroid involved in the regulation of bone. This definition incorporates pathophysiology and clinical
In premenopausal women, the primary source of estrogens is manifestations, providing the rationale for identification and
the ovaries. In postmenopausal women, the primary source treatment of affected individuals. In practice, osteoporosis is
of estrogens is adrenal androgens that are peripherally con- often defined by bone mass alone [14, 15] because bone
verted to estrogens by aromatase. mass is easily measurable and correlates with fracture risk.
Fig. 25.1 Three-dimensional

reconstruction of the
remodeling sequence in
human trabecular bone. (1).
Early bone resorption with
osteoclasts (OCL); (2). late
bone resorption with
6
mononuclear cells (MON);
(3). reversal phase with
5
preosteoblasts (POB); (4).
early matrix formation by 4
osteoblasts (OB); (5). late 3
bone formation with 2 Lining cells
mineralization; (6). completed 1
remodeling cycle with Time 0
OB.
reversion to lining cells
(Reprinted from Eriksen [11], OB.
by permission of Oxford
University) POB.
MON.
OCL.
25 Bone Health and Osteoporosis 395
However, clinicians caring for women must remember the younger postmenopausal women who have elevated risk of
more complex definition to minimize overidentification and osteoporosis, as identified by a clinical assessment or a tool
overtreatment and focus on the goal of preventing fractures such as FRAX. The primary screening tool for BMD mea-
and their sequelae. surement is the dual-energy x-ray absorption (DXA) test.
As noted above, osteoporosis is a common condition with DXA is an ionizing radiation test that uses photon beams of
significant clinical impact when it leads to fractures. Because two different energies (“dual energy”). A computerized sys-
low bone mass is identified with a simple imaging test—the tem, specific to the manufacturer, calculates the difference in
DXA (dual-energy X-ray absorption)—and because effec- energies, yielding a density measurement. Because DXA
tive, low cost therapies with minimal adverse effects exist to results are specific to the machine and the manufacturer, the
mitigate fracture risk, osteoporosis is well suited for popula- T-scores are generally comparable only over time on the
tion-based screening [16]. As with all screening strategies, it same machine, and are not standard across institutions.
is useful to target individuals who are at risk so that interven- Central BMD, that is, DXA at hip and spine, is the stan-
tions are appropriately applied. dard screening test [16, 20], because most studies of osteo-
To screen for osteoporosis, clinicians first perform a porotic therapies enrolled women based on central BMD
risk factor assessment. This is often done as part of an measurement. Peripheral measurement, such as at the wrist,
annual prevention visit. The most important risk factor for is needed only in unusual circumstances when there are
fracture is age, followed by previous fracture; other structural abnormalities at the standard central sites. The spi-
important factors are glucocorticoid use, parental history nal BMD may be difficult to interpret in older adults with
of fracture, low body weight, and active tobacco or alco- significant spinal osteophyte formation; in these cases, the
hol use [17]. Since fragility fractures often occur in con- hip BMD is frequently adequate. Ultrasound of the heel can-
junction with falls, osteoporotic risk assessment includes not reliably identify appropriate candidates for osteoporotic
history-taking on previous falls, neurologic conditions, therapies [21] and is therefore not recommended.
and gait assessment. During the physical exam, an accu- Many medical conditions and medications are associated
rate height measurement should be completed and com- with bone loss because they alter the balance between bone
pared to previous measurements, particularly in older resorption and formation. Secondary osteoporosis describes
women. situations in which bone loss can be attributed to identifiable
FRAX is a widely accepted risk assessment tool that factors other than aging and menopause. Up to 30% of post-
incorporates multiple clinical risk factors with or without menopausal women with osteoporosis have such an underly-
bone density results to help predict fracture risk [18]. The ing cause [22].
FRAX algorithm estimates the 10-year probability of hip
fracture as well as the 10-year probability of a major osteo-
porotic fracture; this composite includes the hip, spine, I nterpretation of BMD Tests and Diagnosis
shoulder, and wrist. The validated clinical risk factors used in of Osteoporosis
the FRAX algorithm are predictive of osteoporotic fracture
independent of bone mineral density (BMD) and include Osteoporosis can be diagnosed either clinically or based on
age, body mass index (BMI), previous fracture, a parent with bone mineral density criteria. A clinical diagnosis of osteo-
hip fracture, current smoking, glucocorticoids, rheumatoid porosis is based on the presence of a fragility fracture. A
arthritis, secondary osteoporosis (see below), and consump- patient experiences a fragility fracture when the bone frac-
tion of three or more alcoholic units per day. tures with less force than would be expected to result in a
There are limitations to FRAX. The FRAX algorithm can fracture; fragility fractures may occur either spontaneously
underestimate fracture risk by only evaluating the risk at the or from minimal trauma, such as the force from a fall from a
hip and at the major fracture sites that comprise half of all standing height or less. In the absence of other metabolic
fragility fractures. The algorithm also does not consider the diseases, a fragility fracture is diagnostic of osteoporosis,
number of fragility fractures and does not directly capture independent of BMD [14]. Traumatic fractures, on the other
fall risk. In addition, the conditions associated with second- hand, are not a risk factor for osteoporosis.
ary osteoporosis are not well defined. Finally, the FRAX tool The World Health Organization (WHO) has established
was originally created as a cost-effectiveness model; some definitions for osteoporosis and osteopenia based on central
analyses suggest that its utility for predicting which patients DXA measurements. The WHO definitions are based on
will fracture may be limited [19]. T-scores in postmenopausal women. The T-score represents
The United States Preventive Service Task Force the number of standard deviations from the mean of a stan-
(USPSTF) guidelines recommend screening for osteoporosis dardized healthy young adult population. Osteoporosis is
with BMD measurement for all women 65 years and older defined as a T-score ≤−2.5. Osteopenia is defined as a
[16]. The USPSTF also recommends BMD measurement in T-score between −1.0 and −2.5 [15].
In some patients, the results of a DXA scan will indicate Additional laboratory testing, guided by history or exami-
that the patient may have a secondary cause for low bone den- nation, may include celiac antibodies, serum and protein
sity. Whereas T-scores compare a patient’s BMD to a healthy, electrophoresis, measurement of urinary or salivary corti-
young population (that is, the mean density in 25–35 year sol, and other specialized tests to evaluate suspected condi-
olds), the Z-score compares a patient’s BMD to age- and sex- tions [14].
matched controls. The Z-score thus represents the number of
standard deviations from the mean for age- and sex-matched
subjects. For example, a patient with a Z-score of −2.0 has a Screening Interval
BMD two standard deviations below the average of others
who are in her same age group [23]. A Z-score of ≤−2.0 is There is limited data to help determine optimal rescreening
“below the expected range for age,” and this should prompt a intervals between BMD testing. The National Osteoporosis
work-up for conditions or medications which are leading to Foundation (NOF) advises rescreening every 2 years for
this profound degree of low bone mass [14]. most individuals but notes that in some patients who have
bone density in the normal or “upper limit of low” range, it
is reasonable to lengthen intervals [4]. This recommendation
valuation of Underlying Causes
E is guided in part by the Study of Osteoporotic Fractures
of Osteoporosis (SOF) which prospectively followed women 67 years and
older with no history of hip or clinical vertebral fracture and
A careful history and physical examination often yield no prior treatment for osteoporosis. SOF sought to determine
important findings when evaluating a patient for secondary the estimated interval during which osteoporosis developed
causes of osteoporosis. Patients who consistently drink more in 10% of the participants prior to fracture. The data showed
than 2 units of alcohol daily are at increased risk of fracture. that the key determinants of screening intervals are baseline
A patient with lifelong irregular menses and GI distress may T-score and age:
have celiac disease leading to malabsorption. Symptoms of
bone pain and abdominal discomfort may suggest hypercal- • In study participants with normal BMD or mild osteope-
cemia and undiagnosed hyperparathyroidism. nia (T-score between −1.01 and −1.49), osteoporosis
Based on one’s history and exam, laboratory evaluation developed in less than 10% of women during a rescreen-
can exclude or diagnose secondary causes of osteoporosis ing interval of approximately 15 years.
such as renal disease, hyperthyroidism, hyperparathyroid- • In women with moderate osteopenia (T-score between
ism, Cushing’s syndrome, celiac disease or other forms of −1.50 and −1.99), the screening interval was found to be
malabsorption, or idiopathic hypercalciuria (Table 25.1). approximately 5 years.
For patients with osteoporosis (based on T-score at or lower • For women with advanced osteopenia (T-score between
than −2.5 or history of fragility fracture), the basic labora- −2.00 and −2.49), the screening interval was 1 year.
tory evaluation includes comprehensive chemistry panel,
25-hydroxyvitamin D, and on occasion serum thyrotropin The authors suggest using these data to guide interval for
(TSH). If the clinical scenario suggests secondary osteopo- rescreening, particularly for patients with mild-to-moderate
rosis or if the Z-score is less than −2, the laboratory evalu- osteopenia where screening intervals can be lengthened from
ation should be expanded, with consideration of parathyroid the commonly used 2-year interval. The study did not take
hormone and 24-hour urine calcium and urine creatinine. into account risks and benefits of screening or cost-
effectiveness [24].
Table 25.1 Laboratory evaluation for secondary osteoporosis Since the estimated time to the development of osteoporo-
Suspected condition Suggested evaluation
sis decreases with increasing age, one may consider shorten-
Vitamin D deficiency Serum 25-OH vitamin D level ing screening intervals for older patients with moderate
Primary Serum calcium, serum 25-OH vitamin D osteopenia. Although screening intervals were found to be
hyperparathyroidism level and parathyroid hormone level appropriate even after controlling for major risk factors, cli-
Hyperthyroidism Serum TSH and free T4 nicians may choose to shorten the screening intervals for
Hypercalciuria 24-hour urine calcium and creatinine patients with risk factors not included in the analysis includ-
Multiple myeloma Serum and urine protein electrophoresis ing decreased activity, decreased mobility, or weight loss,
and serum free light chains
particularly if these factors have significantly changed since
Cushing’s syndrome 24-hour urinary cortisol or late-evening
salivary cortisol the original normal BMD was obtained. Patients who are
Celiac disease Serum anti-tissue transglutaminase taking steroids or aromatase inhibitors may benefit from
antibodies (anti-TTG), anti-endomysial more frequent screening or other prevention strategies given
antibodies, and total IgA the accelerated bone loss experienced by these patients.
diovascular events [28], nephrolithiasis, and constipation, for

Marianne’s history of smoking, parental history of hip those who wish to increase calcium intake, dietary calcium is
fracture, and low body weight put her at risk for osteo- recommended preferentially over calcium supplements.
porosis, and screening is indicated although she is not Vitamin D supplementation is similarly controversial.
quite 65 years old. Marianne’s bone density scan The USPSTF recommends against daily vitamin D and cal-
shows a T-score at the femoral neck of −2.2 (moder- cium supplementation for the primary prevention of frac-
ately low BMD). Her FRAX score shows a 10-year risk tures in noninstitutionalized postmenopausal women [29]
for any major fracture of 19% and hip fracture risk of given the lack of data for clinical efficacy. Despite these data,
3.2%. You discuss the next steps. many societies including the NOF, AACE, and AGE con-
tinue to recommend that adults aged 65 or older consume
800–1000 IU of vitamin D daily for the prevention of falls
and fractures [14].
on-Pharmacologic Strategies for Fracture
N
Prevention
Fall Prevention
A “bone healthy” lifestyle includes adequate intake of cal-
cium and vitamin D, lifelong participation in regular weight- Older or frail patients are vulnerable to falls, particularly if
bearing and resistance exercise, the avoidance of tobacco recently hospitalized, with musculoskeletal or neurologic
and excessive use of alcohol, and elimination of potential disorders including prior stroke, receiving multiple medica-
risk factors for falling. Unfortunately, there is variable evi- tions that decrease mental alertness, or cognitively impaired.
dence demonstrating the positive impact of these interven- Patients can be referred to physical therapy for gait training
tions, as noted below. when balance or strength is impaired. It is imperative to min-
imize the use of medications that impair balance. Appropriate
correction of visual impairment and walking aids should be
Exercise encouraged. Home assessments should be performed to
reduce the risk of falls [30].
Regular weight-bearing exercise (for example, walking at
least 30 minutes at least three times per week) is recom-
mended for osteoporosis prevention and fracture reduction Smoking and Alcohol
among women with osteoporosis. Additionally, non-weight-
bearing exercise (such as progressive resistance strength Given the impact of tobacco and alcohol use on bone remod-
training) or a combination of weight-bearing and strength eling, addressing these habits during a clinical encounter
training exercises may be helpful to improve BMD and pre- focused on bone health is appropriate. Patients who consume
vent falls. Studies of early postmenopausal women have alcohol in excess of 2 units/day can be counseled that this
shown that strength training leads to small yet significant use increases risk of fragility fracture. Any tobacco use can
changes in BMD [25], and evidence suggests a relatively be discouraged.
small but possibly important effect of exercise on bone den-
sity in postmenopausal women [25]. Exercise should be con-
sidered as a preferred intervention for osteoporosis in clinical Osteoporosis Treatment
practice [25] because of these effects and other health bene-
fits unrelated to bone health. Once a diagnosis of osteoporosis is made, either clinically
or using BMD measurements, pharmacologic treatment
should be offered. Additionally, guidelines recommend
Calcium and Vitamin D pharmacologic treatment for postmenopausal women with
have low bone mass (T-score between −1.0 and −2.5 at the
Many societies recommend that women aged 51 and older femoral neck or lumbar spine) and significantly elevated
consume 1200 mg of calcium per day [26]. However, large FRAX risk, defined as a 10-year probability of a hip fracture
meta-analyses note that increasing calcium intake either by ≥3% and/or a 10-year probability of major osteoporotic
dietary sources or supplements has minimal effect on bone fracture ≥20% [4].
density within the first year and does not lead to clinically The FDA has approved both antiresorptive and anabolic
meaningful reductions in fractures [27]. Additionally, based medications for the treatment of osteoporosis. Unless contra-
on potential adverse effects associated with calcium supple- indications exist, oral bisphosphonates are considered first-
ments including small but significant increased risk of car- line treatment for osteoporosis based on their efficacy and
Table 25.2 Osteoporosis treatments

Reduces hip Number needed to treat to
fracture prevent fracture: vertebral Contraindications (see text for more
Class Drug name Dose rate? (v) and hip (h) discussion)
Bisphosphonate Alendronate 70 mg orally Yes 15 (v) GFR <35,
(Fosamax) weekly 9 (h) GI disordersa, neurologic or
Risedronate 150 mg orally Yes cognitive impairment that impact
(Actonel) monthly swallowing function
Ibandronate 150 mg orally No
(Boniva) monthly
Zoledronic acid 5 mg IV once per Yes 14 (v) CKD with GFR <35
(Reclast) year 9 (h)
Monoclonal Denosumab 60 mg SQ every Yes 21 (v) None
antibody (Prolia) 6 months 200 (h)
Selective estrogen Raloxifene 60 mg orally No 16–46 (v) Prior DVT or PE
receptor modulator (Evista) daily a
NNT decreases as risk
increases
Anabolic PTH Teriparitide 20 mcg SQ daily No 11 (v) Hyperparathyroidism
analog (Forteo) (limited to 33 (nonvertebral fracture)
2 years total)
Abaloparatide 3120 mcg SQ No Limited data exist None
(Tymlos) daily (limited to
2 years total)
Antisclerostin Romosozumab 210 mg SQ once Yes 18–77 (v) [35] Uncorrected hypocalcemia
antibody (Evenity) monthly (limited 83 to NS (h) [36]
to 12 doses)
a
GI (gastrointestinal) disorders: active peptic ulcer disease, uncontrolled reflux, esophageal dysmotility, dysphagia
GFR is glomerular filtration rate, CKD is chronic kidney disease, DVT is deep venous thrombosis, PE is pulmonary embolism, PTH is parathyroid
hormone, NS is non-significant, IV is intravenous, SQ is subcutaneous
relatively long-term safety data [31–34]. Intravenous bisphos- postmenopausal women with at least one vertebral fracture,
phonates, other antiresorptive agents, and anabolic agents are risedronate was shown to decrease the incidence of vertebral
often reserved for patients who have contraindications to oral fractures by 41–49% and nonvertebral fractures by 36% over
bisphosphonates, patients who fracture while on oral bisphos- 3 years [38, 39]. On the other hand, ibandronate reduced the
phonates, patients with multiple fractures, or those with very risk of vertebral fracture, but hip fracture risk reduction was
low T-scores (≤−3.0) who are at highest risk of fracture [14]. not demonstrated in clinical trials; the use of other available
The authors note that the field of osteoporosis treatment con- bisphosphonates is preferred.
tinues to change as new therapies emerge (Table 25.2). Alendronate is approved in daily and weekly doses for the
prevention and treatment of osteoporosis. Risedronate can be
prescribed in daily, weekly, or monthly formulations for the
Bisphosphonates prevention or treatment of osteoporosis.
Gastrointestinal (GI) adverse effects of oral bisphospho-
Bisphosphonates prevent bone resorption by binding to nates such as reflux esophagitis can limit tolerance of the
hydroxyapatite in bone and inhibiting osteoclast function medications. Oral bisphosphonates are thought to cause
[32]. Bisphosphonates have high binding affinities for bone upper GI symptoms due to local effects of the medication on
and are associated with antiresorptive effects and anti- the gastric and esophageal mucosa. The incidence of GI
fracture protection for years, even after discontinuation [37]. adverse effects is low [40] and can be reduced with proper
The Fracture Intervention Trial (FIT) was a landmark study administration: patients should be counseled to take oral
of alendronate that demonstrated that alendronate decreases bisphosphonates first thing in the morning with an empty
the risk of both vertebral and nonvertebral fractures [31, 32]. stomach, ingest with 8 ounces of water, and remain upright
In postmenopausal women with low bone density, alendro- for 30 minutes afterward. Some patients may have difficulty
nate decreased the risk of radiographic hip fracture by 44%, with one oral agent but be able to tolerate others, so it is rea-
and in the subgroup with osteoporosis, alendronate reduced sonable to try switching from alendronate to risedronate if
the risk of all clinical fractures by 36% and hip fractures by needed. Oral bisphosphonates should be avoided in patients
56%. Since this trial, studies have shown that alendronate, with impaired swallowing, those with esophageal disorders,
risedronate, and zoledronic acid decrease both vertebral and or those who are unable to follow the dosing instructions.
nonvertebral fractures. For example, in the VERT trial of Bisphosphonates are poorly absorbed if taken with food.
Zoledronic acid is administered by yearly IV infusion for fracture associated with bisphosphonate use, 100 hip frac-
the treatment of osteoporosis [33]. When compared with pla- tures were prevented [44]. Clinical decision support tools
cebo, treatment with zoledronic acid reduces the risk of ver- have been developed to help discuss the benefit and side
tebral fracture by 70%, reduces the risk of hip fracture by effect profiles of bisphosphonates with patients, such as the
41%, and reduces the risk of nonvertebral fractures by 25% tool provided at https://www.healthdecision.org/tool#/tool/
over 3 years in patients with osteoporosis. Yearly infusion of osteoporosis [45].
zoledronic acid may be considered for patients who have dif- Because of the safety concerns with long-term use of
ficulty with medication adherence, impaired swallowing, or bisphosphonates, the FDA recommends drug holidays for
gastrointestinal effects with oral bisphosphonates. Post- appropriate patients to reduce potential cumulative adverse
infusion symptoms can include fever, flu-like symptoms, effects of bisphosphonates. The Fracture Intervention Trial
myalgias, arthralgias, and headaches. The symptoms occur Long-Term Extension (FLEX) compared 10 years versus
most commonly occur after the first infusion and typically 5 years of alendronate therapy and found no significant dif-
resolve within 3 days. ference in cumulative risk for nonvertebral fractures at
Other adverse effects associated with both oral and intra- 10 years of follow-up but a lower risk for radiographic ver-
venous bisphosphonates are uncommon but include hypocal- tebral fractures in patients treated for 10 years (2.4% vs.
cemia, impairment of renal function, musculoskeletal pain, 5.3%) [46]; however, patients at high risk for fracture were
eye inflammation, osteonecrosis of the jaw, and atypical excluded from this trial. The subset of patients with T-scores
femur fractures. Hypocalcemia is usually transient and is ≤−2.5 had increased risk for all fractures when bisphos-
more common with intravenous bisphosphonates. All phonates were discontinued at 5 years versus 10 years. In
bisphosphonates can affect renal function and are contraindi- patients treated with zoledronic acid for 3 years, treating
cated in patients with GFR below 30–35 ml/min. with an additional 3 years lowered the risk of radiographic
Osteonecrosis of the jaw (ONJ) and atypical femur frac- vertebral fractures by 52% compared with 3 years of treat-
tures are rare but serious adverse effects in patients treated ment followed by 3 years of placebo [47]. There was no
with oral and intravenous bisphosphonates. ONJ is defined difference in the rates of other fractures. The decision to
as the exposure of maxillofacial bone that remains unhealed initiate a drug holiday should be individualized based on
over 8 weeks in a patient with bisphosphonate exposure and each patient’s fracture risk. Patients should be considered
without radiation exposure [33]. Patients with poor oral for bisphosphonate holiday after 5 years of bisphospho-
hygiene, glucocorticoid therapy, and chemotherapy are at nates. Patients at high risk of vertebral fractures, low
higher risk of developing ONJ. ONJ is mostly seen with IV T-scores (≤−2.5), or ongoing or new risk factors for bone
bisphosphonates especially when used in higher doses in loss might benefit from continuing bisphosphonates for up
cancer patients for hypercalcemia of malignancy [41]. It is to 10 years.
estimated that the risk of ONJ in patients on chronic oral
bisphosphonates is between 1 in 1000 and 1 in 263,000
patient-years. It is still unclear whether the risk of ONJ Denosumab
increases with increased duration of exposure to bisphospho-
nates. Some providers discontinue bisphosphonates prior to Denosumab is biologic agent approved for the treatment of
invasive dental procedures, but there is limited evidence that osteoporosis in postmenopausal women at high risk of frac-
discontinuing bisphosphonates prior to invasive dental pro- ture and is given as a twice-yearly subcutaneous injection.
cedures will reduce the risk of ONJ [33, 42]. Denosumab is a human monoclonal antibody that prevents
Atypical femur fractures are transverse or short oblique the receptor activation of nuclear factor-kappa B ligand
fractures located in the subtrochanteric region into the fem- (RANKL) which is essential in the formation, activation, and
oral shaft that occur spontaneously or with minimal trauma survival of osteoclasts [48]. Inhibition of the RANK receptor
[43]. The evidence on the incidence and risk factors for prevents osteoclast maturation, activation, and survival,
atypical femur fractures is inconsistent, but the risk appears thereby decreasing resorption of cortical and trabecular bone
to correlate with the duration of bisphosphonate therapy. [48]. The FREEDOM Trial showed that denosumab given
However, the risk is low even with bisphosphonate use twice yearly for 3 years was associated with a reduction in
beyond 5 years. In one study, the risk increased from 1.78 the risk of vertebral, nonvertebral, and hip fractures in
atypical femur fractures per 100,000 patient-years in women with osteoporosis [34]. Denosumab reduced the inci-
patients treated for 2 years to 113.1 atypical femur frac- dence of vertebral fractures by 68%, nonvertebral fractures
tures per 100,000 patient-years in patients treated for by 20%, and hip fractures by 40% [34]. Adverse effects with
8–10 years [43]. Evidence supporting the use of bisphos- denosumab include cellulitis, rash, hypocalcemia, and rare
phonates to reduce fracture risk shows that benefits out- cases of ONJ and atypical femur fractures. There is a rapid
weigh the risk of atypical fractures: for every subtrochanteric decline in bone density and increased risk of vertebral frac-
ture with discontinuation of denosumab [34, 49]. Thus, if fracture, patients who fail bisphosphonates, or patients who
denosumab is discontinued, alternative therapy (such as have contraindications to bisphosphonates.
bisphosphonate) is recommended to maintain BMD and pre-
vent fractures.
PTH Analogs
Selective Estrogen Receptor Modulator Two PTH analogs are approved for osteoporosis therapy.
Teriparatide is a recombinant human parathyroid hormone,
Raloxifene is a selective estrogen receptor modulator and abaloparatide is a synthetic analog of parathyroid
(SERM) that binds to the estrogen receptor and acts as an hormone-related protein (PTHrP). Both teriparatide and aba-
estrogen agonist on bone. This leads to decreased bone turn- loparatide stimulate bone remodeling and, when given as
over, decreased bone loss, increased bone mineral density once-daily injections, increase bone formation more than
(BMD), and decreased risk of vertebral fractures [50]. The bone resorption [52]. Teriparatide reduces the risk of verte-
MORE trial showed that treatment with raloxifene over bral fractures by 65% and nonvertebral fractures by 53%
3 years reduced the risk of new vertebral fractures by 55% in with no reduction in hip fractures in postmenopausal women
women without prevalent baseline fractures. Raloxifene did with prior vertebral fracture after an average of 18 months of
not reduce hip or nonvertebral fractures and is therefore not treatment. Abaloparatide showed similar improvement in
considered first-line treatment. Raloxifene increases risk of bone density and reduction in fracture rates, but the use of
thromboembolic events threefold and is contraindicated in teriparatide is preferred due to limited experience and long-
patients with a history of the thromboembolic disease [50]. term safety data with abaloparatide [53].
Other adverse effects include leg cramps and worsening When teriparatide is discontinued, significant loss of BMD
vasomotor symptoms such as hot flashes and night sweats occurs; thus, an antiresorptive agent (i.e., a bisphosphonate)
that can limit use in postmenopausal women. Raloxifene is may be prescribed to preserve the gains in BMD [54].
also contraindicated in lactating women and women who are Treatment with teriparatide is recommended for a maximum
or may become pregnant [50]. As a result of its efficacy and of 2 years due to a theoretical risk of osteosarcoma, which
contraindications, raloxifene’s role in the treatment of osteo- was demonstrated in rodent models [52]. The relationship
porosis is limited to those who cannot tolerate other thera- between osteosarcoma and teriparatide in humans is unclear;
pies or have other indications for its use (See Chap. 17 on only three cases of osteosarcoma have been reported out of
The Primary Prevention of Breast Cancer). more than one million patients treated with teriparatide [55].
Potential adverse effects of teriparatide include nausea,
headache, orthostatic hypotension, leg cramps, hypercalce-
Estrogen Therapy mia, hypercalciuria, and gout [52]. Teriparatide should not
be used in patients with Paget’s disease, hyperparathyroid-
Estrogen inhibits bone resorption and has been shown to ism, bone metastasis or history of bone malignancies, or a
lower the risk of both vertebral and nonvertebral fractures in history of nephrolithiasis. In addition to adverse effects, bar-
postmenopausal women [51]. However, estrogens are FDA- riers to the use of teriparatide include the need for daily sub-
approved for prevention but not treatment of osteoporosis cutaneous injections and cost.
given current evidence favoring only early, short-term use of
hormone therapy in peri- and postmenopausal women.
During the time patients are on estrogen for menopausal Anti-Sclerostin Antibodies
symptoms or in patients who are on estrogen therapy for pre-
mature ovarian failure, estrogen therapy prevents the rapid Romosozumab is a monoclonal antibody that binds to
bone loss that is associated with loss of estrogen. Once estro- sclerostin and inhibits its activity. Sclerostin is a glycopro-
gen therapy is discontinued, however, bone loss occurs rap- tein produced by osteocytes that inhibits osteoblast activity
idly; thus, providers should consider starting alternative and bone formation, thus inhibiting sclerostin will enhance
treatment to maintain BMD. osteoblast function [56]. Romosozumab has been shown to
stimulate bone formation, decrease bone resorption, and
increase BMD. In addition, there is trial evidence of a frac-
Anabolic Therapy ture benefit. In one trial, the romosozumab group reduced
absolute vertebral fracture rate by 1.3% (0.5% vs. 1.8% after
Two classes of anabolic therapy are currently FDA-approved 12 months of placebo) [35]. In another, romosozumab
for the treatment of osteoporosis: PTH analogs and anti- decreased the incidence of vertebral and nonvertebral frac-
sclerostin antibodies. Candidates for anabolic therapy tures compared with alendronate [36]. Patients treated with
include patients with severe osteoporosis at high risk for 12 months of romosozumab followed by 12 months of alen-
dronate had a 48% lower risk of new vertebral fractures and several assays that measure biochemical markers of bone
19% lower risk of nonvertebral fractures compared with turnover. The tests measure products released from osteo-
women treated with 24 months of alendronate. Adverse reac- clasts and osteoblasts during bone remodeling. Studies show
tions with romosozumab include ONJ, atypical femoral frac- that bone biomarkers can be predictive of the rate of bone
tures, and an increase in cardiovascular events (2.5% in the loss and may be predictive of fracture risk [57–59]. Markers
group treated with romosozumab versus 1.9% in the group of bone formation include bone-specific alkaline phospha-
treated only with alendronate). In 2019, the FDA granted tase (BSAP), N-terminal propeptide of type I procollagen
approval to romosozumab after initial concern with cardio- (PINP), and less so osteocalcin. Markers of resorption
vascular events in patients treated with romosozumab during include N-telopeptide cross-link (NTX) and C-terminal telo-
clinical trials though it remains in limited clinical use at the peptide cross-link (CTX). The use of biochemical markers of
time of publication. bone turnover in individual patients has so far been limited
by biologic variability and differences in assays [60, 61].
Biochemical markers of bone turnover may have a future
Marianne agrees to start alendronate 70 mg, once a role in fracture risk prediction and monitoring medication
week for osteoporosis. You counsel her on properly compliance and efficacy [62].
taking the medication and adverse effects and recom-
mend repeating her BMD test in 2 years.
Referrals
Treatment Monitoring Referral to a bone health specialist should be considered in

situations where the clinical presentation and data are incon-
Treatment monitoring recommendations vary. While several sistent, for example, when a patient presents with a fragility
organizations recommend repeat BMD testing 1–2 years fracture with normal BMD. Referral should also be consid-
after the initiation of therapy [4, 14, 20], the USPSTF recom- ered in patients with complex management needs including
mends a minimum of 2 years between DXA scans to reliably patients with osteoporosis who have chronic conditions com-
measure changes in BMD [16], and the American College of plicating management (e.g., chronic kidney disease) and
Physicians (ACP) practice guidelines recommend against patients with recurrent fractures or bone loss while on ther-
monitoring BMD during the initial 5 years of treatment. The apy when secondary causes have been excluded. Generally,
ACP recommendations are based on data demonstrating a bone biopsy is not recommended but may be indicated for a
decrease in fractures with bisphosphonates, raloxifene, and small subset of patients to distinguish between osteoporosis
teriparatide treatment regardless of changes in BMD [42]. and other bone diseases such as renal osteodystrophy or
The authors of this chapter recommend screening no earlier osteomalacia.
than 2 years after initiating therapy and then extending the
interval when BMD is stable or improving. A decline in
BMD while on treatment should prompt an investigation into Summary Points
the causes of bone loss including medication nonadherence
or underlying conditions that could be contributing, such as 1. Osteoporosis affects about ten million Americans; hip
celiac disease or other malabsorptive disorders. BMD moni- fracture significantly impacts disability (about 40% lose
toring should occur at the same facility and on the same the ability to walk) and mortality (up to 20% within a
machine, when possible, for valid comparison between tests. year of fracture).
More frequent screening may be considered in patients at 2. Screening for osteoporosis with a DXA scan is recom-
risk for rapid bone loss, including patients taking high-dose mended for all women aged 65 and older; follow-up scans
steroids or aromatase inhibitors. are indicated 2–10 years after the first screening depend-
ing on fracture risk and initial results. Women younger
than 65 years should be screened when significant risk
pecialized Testing and Referral to a Bone
S factors are present, such as current smoking, parental hip
Health Specialist fracture, personal history of nontraumatic fracture, pred-
nisone use, or malabsorption.
Markers of Bone Turnover 3. Osteoporosis is diagnosed clinically after a fragility frac-
ture occurs or when the DXA T-score lies at or below
The use of biochemical markers of bone turnover has been −2.5. Low bone mass or osteopenia is defined as a T-score
proposed as a tool for evaluating patients with osteoporosis between −1 and −2.5. Most women have primary osteo-
and guiding decisions on screening and treatment. There are porosis, occurring after menopause and more common
with increasing age. Secondary osteoporosis occurs due 2. Which of the following scenarios best prompts an order
to endocrine, GI, hematologic, or nutritional conditions for a screening DXA scan for osteoporosis?
that affect bone mass. A. A 63-year-old with a history of 5 pack-years of smok-
4. FRAX is an online risk assessment tool to predict the ing and sedentary lifestyle
10-year risk of hip and other major osteoporotic fractures. B. A 66-year-old with a DXA last year showing a T-score
The inputs in FRAX are race/ethnicity, sex, BMI, smok- of −2.0
ing status, alcohol or prednisone use, rheumatoid arthritis C. A 69-year-old with no risk factors but no previous
or other secondary osteoporosis conditions, and personal DXA scans
or family history of fracture. D. A 72-year-old started on alendronate last year for a
5. A healthy lifestyle supports bone health, although evi- high-risk FRAX score
dence is insufficient to show these measures prevent E. A 75-year-old with treated hyperthyroidism and nor-
osteoporotic fractures: exercise, dietary calcium and vita- mal DXA 5 years ago
min D, and avoidance of tobacco or excessive alcohol. The correct answer is C. The USPSTF recommends DXA
6. Osteoporosis is generally treated with bisphosphonates, for osteoporosis screening in women aged 65 or older,
such as once-weekly oral alendronate. Bisphosphonates with a screening interval of at least 2 years, longer inter-
may also be considered in patients with 10-year hip risk vals for normal low-risk patients [16]. DXA may be
of 3% or greater or 10-year osteoporotic fracture risk of ordered earlier if with significant risk factors such as
20% or greater, according to FRAX. parental hip fracture, prednisone use, or current smoking.
7. If bisphosphonates are contraindicated, not tolerated, or if Once started on therapy, DXA scans may be ordered for
BMD declines on therapy, newer or anabolic agents may treatment surveillance, but no more frequent than every
be tried, often in consultation with a specialist. 2 years [42].
3. Patriece is a 68-year-old whose mom had a hip fracture
when she was in her 80s. Her past medical history is
Review Questions significant only for hypertension and a history of blad-
der surgery. On DXA, her T-score is −2.2. The best next
1. Tammy is a 78-year-old White woman without medical step is:
history but with significant alcohol use. She is 5′2″ and A. After confirming no contraindications such as
50 kg. She suffered a hip fracture at home slipping on the active ulcers or chronic kidney disease, prescribe a
stairs. She was hospitalized and required surgical weekly bisphosphonate such as alendronate or
intervention and physical therapy. Which of the following risedronate.
best represents her prognosis? B. Calculate her risk of a 10-year osteoporotic fracture
A. After rehabilitation therapy, she has a 30% likelihood using FRAX.
of requiring long-term nursing facility care. C. Complete her social history and ask a review of sys-
B. Changing lifestyle (walking most days of the week tems questions for conditions that cause secondary
and avoiding alcohol and tobacco) and adding a cal- osteoporosis such as malabsorption.
cium/vitamin D supplement daily will halt further D. Order a complete chemistry profile, complete blood
loss of bone mass. count, 25-hydroxy vitamin D, and urinary
C. Prescribing daily alendronate for a year will increase N-telopeptide.
her bone mass by 50%. The correct answer is C. Once a low BMD is found, the
D. Using FRAX, her 10-year risk of major osteoporotic first step is to assess for risk factors for osteoporosis and
fracture is 27%. behaviors that contribute to risk in order to understand
The correct answer is D. This woman has significant what part of the bone loss is modifiable (by treating celiac
osteoporotic fracture risk based on her age and alcohol disease, for example) and to use in FRAX calculators to
use. Her previous fracture does not qualify for osteoporo- predict future risk. Part of this assessment includes labo-
sis, since it was traumatic, and a DXA would further ratory evaluation, including chemistry, blood counts, and
clarify risk. Among women with osteoporosis, alendro- vitamin D, but would not include markers of bone turn-
nate can improve fracture risk by 40–50%, but the BMD over such as N-telopeptide, as the clinical utility of these
only improves <10% [31]. Lifestyle changes have not tests has not yet been defined. FRAX can be used but only
been shown to significantly improve age-related BMD after completing the clinical assessment. Alendronate is
decline. Hip fracture significantly contributes to mortality not indicated at this BMD level without a FRAX predict-
and morbidity, but community-dwelling adults have only ing high risk [42].
about a 10% chance of requiring long-term care after a 4. Lana has been on alendronate therapy for 5 years for low
fracture. bone mass. She has tolerated it well. Repeat DXA shows
a T-score of −2.6. Five years ago, the score was −2.4. sequence in normals and in metabolic bone disease. Endocr Rev.
1986;7(4):379–408.
Which of the following is the best next step? 12. Greenspan SL, Maitland LA, Myers ER, Krasnow MB, Kido
A. Continue alendronate for another 5 years and recheck TH. Femoral bone loss progresses with age: a longitudinal study in
DXA then. women over age 65. J Bone Miner Res. 1994;9:1959–65.
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MR, Ettinger B, et al. Bone mineral density changes during the
vitamin D and calcium intake, and adherence to menopause transition in a multiethnic cohort of women. J Clin
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phonate failure. DL, et al. American Association of Clinical Endocrinologists and
American College of Endocrinology clinical practice guidelines
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et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and 53. Miller PD, Hattersley G, Riis BJ, et al. Effect of abalopara-
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Part V
Chronic Pain Disorders
General Approach to Chronic Pain
26
Andrea E. Carter and Melissa A. McNeil
Learning Objectives
Definition and Epidemiology of Chronic Pain
1. Review the definition and epidemiology of chronic Chronic pain has been defined as “an unpleasant sensory and
pain. emotional experience associated with actual or potential dam-
2. Assess the biological and psychosocial reasons for age” that persists for longer than 3–6 months [1]. Chronic
gender differences in chronic pain. pain has a significant impact on patients’ health and quality of
3. Describe the evaluation of a patient with chronic life. Patients with chronic pain have higher rates of depres-
pain. sion and anxiety disorders, are more likely to have significant
4. Formulate an approach to chronic pain involving activity limitations, and have more unfavorable perceptions
collaborative care models and non-pharmacologic of their health [2]. The cost of chronic pain to society is sub-
therapy. stantial, accounting for 20% of outpatient visits [3], 12% of
5. Identify classes of non-opioid medications to use as all prescriptions [4], and up to $600 billion in annual expenses
first-line pharmacotherapy therapy for chronic pain. from healthcare costs and lost productivity [5].
6. Determine when to initiate or continue opioids for Chronic pain is common, affecting more than 100 million
chronic pain, and assess risk and address harms of adults in the United States [6, 7]. Data derived from the 2002
opioid use. National Health and Nutrition Examination Survey (NHANES)
7. Discuss the importance of the patient-provider rela- showed that chronic pain prevalence estimates were 10% for
tionship in the treatment of chronic pain. back pain, 7% for pain in the legs and feet, 4% for pain in the
arms and hands, 4% for headache, and 1% for abdominal pain.
Women had higher odds than men for headache and abdomi-
nal pain [8]. Specific common etiologies of chronic pain in
Kim is a 42-year-old female patient with a history of women, including fibromyalgia, chronic pelvic pain, head-
depression who is presenting to your office to establish aches, irritable bowel syndrome, and interstitial cystitis are
care and wants to discuss her total body pain. This pain discussed in detail in separate chapters in this book.
started at least 10 years ago and has waxed and waned The perception of pain in individual patients is complex.
but has been worse in the past year since she started Given this, the approach to evaluating and treating chronic
having more stress at work. This pain was diagnosed by pain must be comprehensive and individualized.
her prior primary care provider as fibromyalgia. She is
very frustrated by her pain and wants to know how
common it is for someone to suffer from chronic pain. Classification of Chronic Pain
Chronic pain can be classified in many ways, but unfortu-

nately, no single classification system can adequately catego-
rize all types of chronic pain. Often chronic pain is classified
based on perceived location (e.g., low back pain, abdominal
pain). However, some diagnoses such as fibromyalgia cause
A. E. Carter (*) · M. A. McNeil widespread pain so categorization based on location alone is
not adequate. Chronic pain can also be classified based on
e-mail: [email protected] the suspected etiology of pain (e.g., postsurgical pain, osteo-

408 A. E. Carter and M. A. McNeil
arthritis), but many types of chronic pain are idiopathic. To

F
address the need for an improved classification system for
chronic pain, the International Association for the Study of C
Pain has suggested a classification system for the upcoming

11th version of the International Classification of Diseases.
SS
Their classification system incorporates both perceived loca-
Thalamus
tion and suspected etiology of pain and includes seven cate-
gories: (1) chronic primary pain (e.g. fibromyalgia, irritable
bowel syndrome), (2) chronic cancer pain, (3) chronic post-
traumatic and postsurgical pain, (4) chronic neuropathic
pain, (5) chronic headache and orofacial pain, (6) chronic
visceral pain, and (7) chronic musculoskeletal pain [9]. It is
important to note that patients often experience more than Spinothalamic
tract
one type of chronic pain.
Another way to classify chronic pain is to categorize into
nociceptive versus neuropathic pain. This classification sys- Injury
tem is useful in guiding treatment options. Nociceptive pain is
caused by damaged tissue and is often due to mechanical or
compressive etiologies, musculoskeletal conditions, or
inflammation. Patients often describe nociceptive pain as dull
or aching. Alternatively, neuropathic pain is caused by dam-
age to the nervous system. Neuropathic pain can be central or
peripheral and causes include diabetes mellitus, post-herpetic
neuralgia, and spinal stenosis. Patients often describe neuro-
pathic pain as burning, tingling, or electrical [10]. Fig. 26.1 The pain processing pathway. (Reprinted from Rathmell and
Fields [11], with permission from McGraw-Hill Education)
Kim goes on to tell you that she feels her husband does Sensitization is an important process contributing to chronic
not understand her pain. She wonders if men and pain [11].
women experience pain differently. In addition, the experience of chronic pain is very depen-
dent on the patient’s individual circumstances. It is important
to consider the patient’s psychologic, behavioral, emotional,
social, economic, and cognitive factors as well as the prior
Pathophysiology of Chronic Pain history of pain, coping mechanisms, and support system. All
of these factors interact to moderate the patient’s experience
The processing and interpretation of pain is a complex proof chronic pain.
cess. During acute pain, tissue injury results in the stimula-
tion of sensory nerve cells called nociceptors. As seen in
Fig. 26.1, nociceptors produce a signal at the site of the Gender Differences in Chronic Pain
injury that travels along pain fibers that enter the spinal cord
at the dorsal root ganglia and terminate in the dorsal horn. There are significant gender differences in chronic pain.
Second-order neurons travel up the contralateral spinotha- Chronic pain is more common in women than men [6, 7]. In
lamic tract and terminate in the thalamus. Third-order neu- addition, evidence suggests that women experience more
rons travel from the thalamus to the anterior cingulate (C), severe clinical pain than men [12–14]. The underlying rea-
frontal insular (F), and somatosensory cortex (SS) where sons for these gender differences are an area of active research,
pain is perceived. See Fig. 26.1. and the mechanisms have not been fully elucidated.
Usually, the nociceptive sensory system returns to a nor- There are several biological mechanisms that may account
mal state once healing is complete after an episode of acute for the gender differences. First, the sex hormones have a
pain. However, chronic pain develops when pain persists complex effect on pain sensitivity, and in particular, testos-
long past the expected time of healing due a maladaptive terone may have a modulatory effect on pain [15]. In addi-
response of this system. When persistent or repeated stimuli tion, there are gender differences in the cortical processing of
are applied to damaged tissues, the threshold for activating pain [16, 17]. There may also be gender differences in the
nociceptors is lowered, which is called sensitization. activation of the opioid receptor system [18].
26 General Approach to Chronic Pain 409
There are also several psychosocial mechanisms that may The features of a psychosocial assessment can be recalled
account for the gender differences. In particular, there may using the mnemonic ACT-UP (Activity, Coping, Think,
be gender differences in self-efficacy related to pain and in Upset, People’s responses) [22]. Example questions are pre-
pain catastrophizing, which is a pain response involving sented in Table 26.2. It is also important to screen for inti-
rumination, magnification, and helplessness [19]. Also, mate partner violence and sexual abuse, as women
sociocultural beliefs may be important as pain expression is experiencing abuse are more likely to experience headaches,
generally more socially acceptable among women, which back pain, abdominal pain, and pelvic pain [21].
could lead to biased reporting of pain. In addition, women There are several validated multidimensional scales that
who have experienced childhood abuse [20] or intimate part- can be used to evaluate chronic pain. These scales are espe-
ner violence [21] are more likely to experience chronic pain. cially useful to track pain over time and to judge if the pain
is improving with treatment. The Brief Pain Inventory is a
short, validated questionnaire that measures pain severity
You discuss with Kim that there are indeed significant
and interference with daily activities [23]. The McGill Pain
gender differences in chronic pain. You would like to
Questionnaire measures pain quality and intensity [24].
obtain more information from Kim about her pain.
These scales can easily be found online and incorporated
into a clinic visit for a patient with chronic pain.
Clinical History
Physical Exam
A thorough history is imperative in the evaluation of a patient
with chronic pain. The history should include all the typical A complete physical examination should be performed in
components of a medical history with particular attention to patients with chronic pain. The examination should include a
details of the characteristics of the pain symptoms, impact of detailed evaluation of the symptomatic areas. It is also
pain on function, and psychosocial factors that could be con- important to assess mood during the physical exam. Relevant
tributing to chronic pain. components of the physical exam for specific types of
Open-ended questions should be used to determine the chronic pain syndromes are described in other chapters.
nature of the pain. The features of pain in the history of pres-
ent illness can be recalled using the mnemonic OLD CARTS
(Onset, Location/radiation, Duration, Characteristics, Diagnostic Workup
Aggravating factors, Relieving factors, Timing, and
Severity). Example questions are presented in Table 26.1 Pain is a subjective experience of the patient, and there is no
In addition to this standard history of present illness, it is diagnostic test that can confirm the presence of pain. The
critical to understand the impact of the pain on function and goal of the diagnostic workup in patients with chronic pain is
psychosocial factors that could be contributing to the pain. to identify treatable primary medical conditions causing sec-
ondary pain, such as inflammatory bowel disease causing
Table 26.1 OLD CARTS mnemonic: History-taking tool to elicit chronic abdominal pain. It is essential to consider “red flag”
characteristics of pain symptoms in every patient that may reflect pain related to
Pain features in the history
of present illness Example question(s)
Onset When did the pain start? Was there an Table 26.2 ACT-UP mnemonic: History-taking tool to elicit psycho-
inciting event? social aspects of pain [22]
Location Where is the pain located? Does it Psychosocial
radiate anywhere? assessment Example question(s)
Duration How long has the pain lasted? Are there Activity How is your pain affecting the activities in your
discrete episodes or is the pain life such as sleeping, eating, exercising, working,
continuous? and having fun?
Characteristics What does the pain feel like? Is this Coping How are you coping with your pain? Do you have
pain similar to prior events? any strategies that help you to manage your pain?
Aggravating factors What makes the pain worse? Think Do you think your pain will get better or worse in
Relieving factors What makes the pain better? the future?
Timing How often does the pain occur? Is it Upset Does your pain upset your mood? Have you been
temporally related to anything? feeling depressed or anxious?
Severity On a scale of 0 to 10, how severe is the People’s How do other people around you respond when
pain? Is the pain getting better or responses you have pain? Is your pain affecting your
worse? relationships?
malignancy, organ dysfunction, infection, or another emer-

gent condition. For example, ask about fever in patients with After discussing some non-pharmacologic treatment
chronic back to evaluate for osteomyelitis. options for Kim, she wants to pursue cognitive behav-
Keep in mind that many causes of chronic pain are idio- ioral therapy. She is also interested in trying a medica-
pathic and will not have laboratory or imaging abnormalities. tion for her chronic pain and is wondering what types
The ordering of tests in chronic pain should be judicious and of medications are available.
targeted, and there are times when no tests are indicated.
Unfortunately, unnecessary tests are often ordered in chronic
pain syndromes. For example, about 12% of outpatients with
migraine headaches undergo magnetic resonance imaging of Non-opioid Pharmacologic Therapies
the brain despite clear guidelines from the American College for Chronic Pain
of Radiology recommending against neuroimaging in
patients with uncomplicated headache [25]. Pharmacologic therapies are often used to treat chronic pain.
Suggested diagnostic workup for specific types of chronic The major classes of medications used are non-opioid anal-
pain syndromes is described in other chapters. gesics, opioids, antidepressants, anticonvulsants, and topical
agents. Using a combination of medications is often more
effective than a single medication.
Kim’s pain is widespread but is usually worst in her
neck and shoulders. The pain is predominantly
throughout her muscles, but she occasionally has joint Non-opioid Analgesics
pain as well. Most days, she would rate her pain as a 6
out of 10. The pain is worse when she feels stressed Non-opioid analgesics include acetaminophen and nonste-
out, and she has been having increasing stress at work. roidal anti-inflammatory (NSAID) medications. When pre-
She feels that her pain affects her relationship with her scribing these medications, it is useful to tailor the
husband and also makes her abstain from social activi- prescription to the patient’s complaints. For patients with
ties. She experienced childhood sexual abuse but cur- constant pain, advise taking the analgesic at set intervals
rently feels safe in her relationship. Although she has a throughout the day. For patients who experience situational
history of depression, she currently feels that her mood pain, advise taking the analgesic prior to the activity that
is good. When her pain is well controlled, she can walk causes pain (such as exercise).
for exercise, and she would like to get back to doing Acetaminophen is available over the counter and is very
that. You agree that Kim most likely has fibromyalgia. commonly prescribed for many types of chronic pain. The
Kim asks you if there is anything you can do to help her mechanism of acetaminophen is not well established. The
with her pain that doesn’t involve taking a pill. efficacy of acetaminophen is uncertain and has been shown
to have very small or no benefit in the treatment of knee
osteoarthritis and low back pain [28]. Acetaminophen over-
dose can lead to irreversible, devastating acute liver failure.
Non-pharmacologic Therapies Patients can approach toxic levels of acetaminophen inges-
for Chronic Pain tion unintentionally and should be counseled extensively
about use. The Food and Drug Administration (FDA) lists
There are many non-pharmacologic treatments for chronic the maximum safe dose as 4 grams per day, although in
pain, including exercise, physical therapy, behavioral ther- 2012, the FDA suggested but did not mandate decreasing the
apy, complementary or alternative medicine (such as chiro- maximum daily dose to 3 grams. Clinically, most providers
practor therapy and acupuncture), interventional techniques follow the 3 grams maximum recommendation, and it is
(such as steroid injections and nerve blocks), and surgical thought that the maximum dose should not exceed 2 grams
approaches. Given the complex nature of chronic pain, the per day in patients with chronic liver disease or heavy alco-
most successful treatments are often multifaceted. hol use.
Collaborative care interventions in primary care, including Many types of NSAID medications are also available over
provider education, care managers, patient workshops, the counter and commonly prescribed for many types of
development of individualized functional goals, and symp- chronic pain. NSAIDs act to decrease inflammation by inhib-
tom monitoring via telephone visits, have been shown to iting the enzyme cyclooxygenase (COX). COX catalyzes the
improve patient outcomes such as pain intensity and pain- formation of prostaglandin, which is a key messenger mole-
related disability [26, 27]. cule in the process of inflammation. NSAIDs are more effec-
tive than placebo in treating low back pain [29]. NSAIDs can that there are rising concerns for gabapentin misuse, abuse,
have adverse gastrointestinal side effects including dyspep- and diversion [34].
sia and gastric ulceration and should be avoided in patients
with history of ulcers. For patients with risk factors for gas-
troduodenal toxicity (older than 60 years of age, concurrent Topical Agents
aspirin or glucocorticoid use, dyspepsia, or reflux symp-
toms), use a COX-2 selective NSAID (e.g., celecoxib) and Topical agents are frequently used for chronic pain. They are
consider prescribing a concurrent proton-pump inhibitor. advantageous in that they avoid systemic side effects and can
NSAIDs can also cause nephrotoxicity due to renal vasocon- be delivered directly at the site of pain. Frequently prescribed
striction and should be avoided in patients with chronic renal topical agents include capsaicin, salicylate, lidocaine, and
insufficiency. In addition, the use of both nonselective topical NSAIDs.
NSAIDs and COX-2 selective NSAIDs has been associated
with an increased risk of adverse cardiovascular events
After discussing the medication options with Kim, you
including myocardial infarction, heart failure, and stroke
decide to prescribe duloxetine in addition to the cogni-
[30]. This risk varies depending on if the patient has baseline
tive behavioral therapy. Kim returns to see you 6 weeks
cardiovascular disease and on the specific NSAID chosen.
later. She says her pain is markedly improved overall,
and she is now back to walking her dog daily. However,
her pain is not completely gone. Kim says that about
Antidepressants
5 years ago, she was prescribed oxycodone for her
chronic pain, and she asks you if you can write her a
Antidepressants have analgesic effects related to their effects
new prescription for oxycodone.
on the serotonin, norepinephrine, and opioid receptor sys-
tems. Antidepressants have been shown to be efficacious in
the treatment of neuropathic pain, fibromyalgia, low back
pain, and headaches [31–33]. Although they do not have an
approved indication for pain, tricyclic antidepressants Opioids for Chronic Pain
(TCAs) such as amitriptyline and nortriptyline have long
been used to treat chronic pain. TCAs are generally pre- The use of opioids to treat chronic pain has increased despite
scribed at lower doses than those used in depression. Adverse the lack of convincing evidence that they are effective. About
effects include sedation, anticholinergic effects (such as dry 20% of patients presenting to physician offices with chronic
mouth, constipation, and mental clouding), and cardiac pain receive an opioid prescription [35]; however, a system-
effects (such as prolonged interventricular conduction and atic review examining the effectiveness of long-term opioid
prolonged QT interval). Serotonin-norepinephrine reuptake therapy for chronic pain found no controlled studies that
inhibitors (SNRIs), such as duloxetine and venlafaxine, are evaluated long-term outcomes related to pain, function, or
also frequently used in the treatment of chronic pain. The quality of life [36]. Additionally, the widespread use of pre-
most frequent adverse effects are nausea, dry mouth, scription opioids has led to a sharp increase in diversion and
insomnia, constipation, and fatigue. Patients should be coun- improper use and ultimately a national epidemic of opioid
seled that although they may experience side effects immedi- use disorder and overdose-related deaths—between 2000
ately, antidepressants may take several weeks to obtain full and 2014, there was a 200% increase in the deaths from an
benefit in the treatment of pain. opioid overdose [37]. To help address this, there is an imper-
ative need for providers to safely prescribe opioids for
chronic pain only in patients in whom the benefits outweigh
Anticonvulsants the risks.
In 2016, the Centers for Disease Control and Prevention
Three anticonvulsant medications (gabapentin, pregabalin, (CDC) released a guideline for prescribing opioids for
and carbamazepine) are approved by the FDA for the treat- chronic pain with the goal of improving communication
ment of neuropathic pain. Gabapentin and pregabalin bind to between providers and patients and reducing the risks associ-
voltage-gated calcium channels and inhibit neurotransmitter ated with long-term opioid therapy [38]. The guidelines
release. These medications can cause dose-dependent seda- recommend preferentially using non-pharmacologic and

tion; thus, it is important to start at a low dose and titrate up non-opioid pharmacologic therapy for chronic pain instead
if needed. Like the antidepressants, the anticonvulsants take of opioids. If opioids are used, they should be combined with
several weeks to obtain full benefit. It is important to note these other treatments. Before initiating opioids for chronic
pain, providers should explain risks of therapy, discuss side subsequently developing opioid use disorder [42]. More
effects, and set realistic treatment goals with patients. Women research is needed to understand the risks and benefits of
who have certain psychiatric disorders (depression, bipolar, medical marijuana use in chronic pain disorders.
schizophrenia, attention deficit disorder, or obsessive-com- Depending on the state, providers can become licensed to
pulsive disorder), a personal or family history of drug or provide certification exams for patients to enable them to
alcohol misuse, or a history of preadolescent sexual abuse purchase cannabis products from a dispensary. Providers
are more likely to develop opioid misuse [39]. If initiating themselves do not prescribe these products. It is important to
opioid therapy, always use short-acting opioids at the lowest counsel patients that medical cannabis should not be used in
effective dose, and use an “as needed” dosing regimen as women who are pregnant or lactating, and caution is indi-
opposed to a fixed dosing schedule such as “every 6 hours.” cated in patients under 24 years old. It is illegal to drive
For women with children, it is important to advise storing under the influence of marijuana. The increasing legalization
opioids in a locked medicine cabinet. Patients should be of recreational marijuana use means that patients will be able
reevaluated within 1–4 weeks of initiating opioid therapy to legally obtain marijuana without the input of their provid-
and then at least every 3 months subsequently. If the benefits ers in many instances. A full discussion of marijuana use is
of pain control are not outweighing the harms of opioid ther- beyond the scope of this chapter. The editors recommend
apy, opioids should be tapered or discontinued. Providers that providers become familiar with the uses and effects of
should use caution when prescribing more than 50 morphine medical marijuana. A comprehensive resource guide distrib-
milligram equivalents (MME) of opioid daily, and doses uted by the Canadian Government is available online
higher than 90 MME daily should be avoided as these doses “Information for Health Care Professionals: Cannabis (mari-
significantly increase the risk of an opioid overdose. To huana, marijuana) and the cannabinoids” at https://www.
reduce the risk of death from an opioid overdose, consider canada.ca/en/health-canada/services/drugs-medication/can-
prescribing naloxone to patients receiving more than 50 nabis/information-medical-practitioners/information-health-
MME daily, to patients who are prescribed any other sedat- care-professionals-cannabis-cannabinoids.html [43].
ing medications such as benzodiazepines, and to patients who
have a history of substance use disorder or drug overdose.
Providers should also check state prescription drug monitor-
You congratulate Kim for reaching her goal of being
ing programs (PDMP) to identify controlled medications pre-
able to walk her dog due to the improvement in her
scribed by other providers and check urine drug testing to
pain with the duloxetine and cognitive behavioral ther-
identify undisclosed substance use. Patients found to have
apy. You discuss that unfortunately, complete pain
aberrant behaviors including lost or stolen medications, docu-
relief may not be a realistic expectation and that you
mented use of multiple physicians, and requests for multiple
are worried about her risk of developing harm from
early refills should be screened for opioid use disorder (see
opioids given her risk factors for developing opioid
Chap. 32 on Opioid Use Disorder for more information).
misuse (her age, history of depression, and childhood
sexual abuse). After discussing the risks and benefits of
opioid therapy, Kim decides against treatment with
Medical Marijuana opioids. You talk about other possible treatments for
her fibromyalgia, and Kim decides to try acupuncture.
The use of medical marijuana is growing in momentum; at
the time of this writing, it is legalized in the majority of the
United States and in many countries. The indications for
medical marijuana use are debated, but its use in cancer
patients and in debilitating illnesses are the most widely I mportance of Patient-Provider Relationship
accepted. The use of medical marijuana in chronic pain for in Chronic Pain Management
those without a life-limiting or debilitating illness is a sub-
ject of investigation by physicians and is desired by many The patient-provider relationship is key in successful treat-
patients. There is data suggesting that Medicare patients ment of chronic pain. The patient-provider relationship can
filled fewer opioid prescriptions in states with medical can- help promote patient resilience in chronic pain, especially
nabis laws [40] and that the legalization of marijuana has when the provider provides psychologic support and promotes
been linked to fewer opioid-related deaths [41]. However, health literacy related to chronic pain and its treatment [44].
the long-term medical and psychosocial implications of It is also important to note that providers often feel an
medical marijuana use for chronic pain patients are unknown. emotional toll when caring for patients with chronic pain
Traditionally known as the “gateway drug,” recent data sug- [45]. Setting realistic expectations with patients with chronic
gests that medical marijuana use may increase the risk of pain is critical. Being completely pain-free is usually not a
realistic goal—a reduction in pain by 30% is considered clin- brile, and vital signs are within the normal range. She has
ically meaningful [46]. It is often helpful to focus on func- several tender trigger points and has decreased range of
tional goals, such as returning to work or participating in motion due to pain. She has no active arthritis on exam.
recreational activities, rather than numeric pain score goals. What is the next appropriate step in management?
Frequent visits can be helpful in monitoring pain symptoms, A. Ask about psychosocial stressors.
assessing progress toward functional goals, and coordinating B. Initiate a trial of oxycodone.
multiple treatment approaches. C. Order a serum antinuclear antibody test.
D. Refer to a rheumatologist.
The correct answer is A. It is important to assess the
Summary Points biopsychosocial factors that may be contributing to
chronic pain. Prior to obtaining a full comprehensive his-
1. Chronic pain persists for longer than 3 months and is tory, it would not be appropriate to initiate opioid therapy,
extremely common, affecting more than 50 million adults order additional testing, or refer to a specialist.
in the United States. Chronic pain is more common in
women than in men, especially headaches, abdominal 2. A 65-year-old female patient presents to your office with
pain, and widespread pain. worsening lower back pain to discuss getting an early
2. The perception of pain depends on many biological and refill and increase in the dose of her oxycodone. She has
psychosocial factors that are different in women and men, had back pain due to facet joint arthropathy for the past
including differences in cortical processing of pain, the 10 years and is currently taking oxycodone 10 mg every
endogenous opioid system, catastrophizing, and 6 hours as needed for pain. You prescribed a 4-week sup-
self-efficacy. ply of oxycodone 3 weeks ago, but she has run out of her
3. Chronic pain should be evaluated with a thorough clinical medications early. On exam, she is afebrile, and vital
history including tools to measure pain intensity and signs are within the normal range. She has some tender-
impact of pain on function, a thorough physical exam, ness to deep palpation of the lumbar vertebrae with other-
and additional testing only when indicated. wise normal back and lower extremity neurologic exam.
4. Outcomes in chronic pain are improved by using multi- What is the next appropriate step in management?
faceted approaches including non-pharmacologic thera- A. Prescribe an increased dose of oxycodone.
pies such as physical therapy, behavioral therapy, B. Order MRI of the lower back.
complementary or alternative medicine, interventional C. Screen for signs of opioid use disorder.
techniques, and surgical approaches. D. Refer to a pain specialist.
5. Many classes of medication can be used to treat chronic The correct answer is C. It is important to screen for
pain including non-opioid analgesics, topical agents, anti- signs of opioid use disorder in patients requesting early
spasmodics, opioids, TCAs, SNRIs, and anticonvulsants. refills or increase in the dose of opioid medications. If
6. The benefits and risks of opioid therapy for chronic pain patients are not displaying signs or symptoms of opioid
should be considered carefully in each patient. If opioid misuse, it may be appropriate to consider dose escalation,
therapy is appropriate, methods to reduce the risk of harm additional diagnostic testing, or referral to a specialist. It
should be used including checking urine drug screens and is important to discuss anticipatory guidance with all
prescription drug monitoring programs, prescribing nal- patients on opioids so that they have an action plan should
oxone when indicated, and tapering or discontinuing opi- their chronic pain increase between visits. Most of these
oids when needed. patients will be tempted to increase the dose of their opi-
7. The patient-provider relationship is key in treating chronic oids independently without consultation from a provider
pain. It is important to set realistic expectations, focus on which can be dangerous and lead to overdose and the lack
functional goals, and arrange for frequent follow-up of trust and stigmatization from the healthcare system.
visits.
3. A 35-year-old female patient presents to your office for
the evaluation of chronic abdominal pain. She has crampy
Review Questions abdominal pain most days of the week, and it is associ-
ated with constipation. A colonoscopy was performed a
1. A 45-year-old female patient presents to your office with year ago which was normal, and she has no family history
widespread musculoskeletal pain involving her ankles, of gastrointestinal diseases. On exam, she is afebrile, and
knees, hips, lower back, shoulders, and arms. She has pre- vital signs are within the normal range. She has mild dif-
viously been diagnosed with fibromyalgia. Her pain is fuse tenderness throughout her abdomen without rebound
worse over the past several weeks. On exam, she is afe- tenderness or guarding.
In addition to starting a trial of lubiprostone, what is ability in osteoarthritis patients: the role of catastrophizing. Pain.
2000;87(3):325–34.
the next appropriate step in management? 15. Craft RM. Modulation of pain by estrogens. Pain. 2007;132(Suppl
A. Refer to a gastroenterologist. 1):S3–12.
B. Recommend dietary manipulation and exercise. 16. Berman SM, Naliboff BD, Suyenobu B, Labus JS, Stains J, Bueller
C. Prescribe oxycodone. JA, et al. Sex differences in regional brain response to aversive
pelvic visceral stimuli. Am J Physiol Regul Integr Comp Physiol.
D. Order repeat colonoscopy. 2006;291(2):R268–76.
The correct answer is B. In patients with chronic pain 17. Derbyshire SW, Nichols TE, Firestone L, Townsend DW,
syndromes, non-pharmacologic treatment strategies are Jones AK. Gender differences in patterns of cerebral activa-
often effective. As this patient is not displaying any con- tion during equal experience of painful laser stimulation. J Pain.
2002;3(5):401–11.
cerns for opioid use disorder, it would be appropriate to 18. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM,
try non-pharmacologic treatment such as dietary manipu- et al. Mu-opioid receptor-mediated antinociceptive responses differ
lation and exercise prior to prescribing opioids, ordering in men and women. J Neurosci. 2002;22(12):5100–7.
additional testing, or referring to a specialist [26, 27]. 19. Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis
G, Choiniere M. A systematic literature review of 10 years of
research on sex/gender and experimental pain perception – part
1: are there really differences between women and men? Pain.
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Irritable Bowel Syndrome
27
Rachel Vanderberg, Amy D. Lu, and Jana G. Hashash
Epidemiology
Learning Objectives
1. Review the epidemiology and pathophysiology of Irritable bowel syndrome (IBS) is a symptom-based condi-
irritable bowel syndrome (IBS). tion defined by abdominal pain with altered bowel habits in
2. Diagnose IBS using the Rome IV criteria. the absence of demonstrable organic disease. The prevalence
3. Utilize targeted diagnostic testing in patients pre- is between 10% and 15% in North America and is equally
senting with symptoms consistent with IBS. distributed between subtypes: constipation predominant
4. Manage IBS utilizing evidence-based nonpharma- (IBS-C), diarrhea predominant (IBS-D), mixed type (IBS-
cological and pharmacological therapies in a step- M), and un-subtyped [1]. Women are 1.5–2 times more likely
wise approach. to be affected than males, and the prevalence of IBS decreases
5. Design an appropriate interdisciplinary manage- with age [2]. IBS is commonly encountered in the primary
ment plan or care team for patients with IBS. care setting and accounts for 25–50% of all referrals to gas-
troenterology. The burden of disease accounts for 3.1 million
ambulatory care visits and up to 5.9 million dollars in pre-
scriptions annually [3, 4].
Sloane is a 32-year-old gender-nonconforming natal
female (uses they/them/their pronouns) who presents
to establish care. They report a 5-year history of inter- Pathophysiology
mittent abdominal pain and diarrhea. Five years ago,
they had a bout of traveler’s diarrhea while on a trip to The pathophysiology of IBS remains elusive. Traditionally,
Mexico. After the initial resolution of symptoms, they IBS has been theorized as being a gastrointestinal tract (GI)
began experiencing episodic diarrhea and abdominal manifestation of primary brain dysfunction. However, newer
cramping. epidemiologic studies have noted that GI symptoms may
precede mood symptoms, which suggests a dual directional-
ity of gut-brain axis dysfunction. Serotonin (5-HT) is an
important and ubiquitous neurotransmitter in the central as
well as enteric nervous systems, playing an integral role in
GI motility and communication with the brain. Studies have
R. Vanderberg (*) found reduced postprandial 5-HT release in patients with
Division of General Internal Medicine, University of Pittsburgh, IBS-C compared with those patients with postinfectious IBS
Pittsburgh, PA, USA
and healthy individuals [5]. However, others have shown that
alterations in 5-HT metabolism in patients with IBS did not
A. D. Lu
San Francisco VA Medical Center, University of San Francisco
have associations with GI or mood symptoms [6].
Medical Center, San Francisco, CA, USA Acute enteric infections often precede the onset of IBS,
J. G. Hashash
especially IBS-D, and may serve as a trigger for immune
Department of Internal Medicine, Division of Gastroenterology, activation that is mechanistically different from that of non-
Hepatology, and Nutrition, University of Pittsburgh, infectious IBS. A prospective controlled cohort study of
Pittsburgh, PA, USA 19,000 individuals exposed to drinking water contaminated
American University of Beirut, Beirut, Lebanon with known GI pathogens such as Norovirus, Giardia, and

418 R. Vanderberg et al.
Campylobacter jejuni showed increased risk of developing 3 months with symptom onset of more than 6 months prior
IBS-D symptoms in those with preexisting anxiety mediated to diagnosis [12].
by T-cell immune activation [7]. Separately, studies have Classification of a patient’s predominant bowel complaint
shown increased concentration of cytokines in colonic plays an important role in determining further diagnostic
mucosa as well as peripheral blood of patients with IBS-D testing as well as treatment. As described previously, IBS is
[8]. This increased concentration of proinflammatory cyto- classified into four subtypes: IBS-D, IBS-C, IBS-M, or un-
kines was also associated with mood disorders such as anxi- subtyped IBS based on stool consistency as assessed by the
ety and depression [9]. Bristol Stool Form Scale (BSFS), a validated tool that cate-
Many patients with IBS also report diet triggers that initi- gorizes stool appearance from a score of 1 (hard and lumpy)
ate or exacerbate their symptoms. Though these are not usu- to 7 (entirely liquid). This tool can easily be accessed for free
ally reproducible when rechallenged in a double-blinded on the internet.
manner, certain foods seem to be implicated in the alteration It is important to note that the Rome IV updated subtype
of the gut microbiome and generation of IBS symptoms. criteria is explicitly based on predominant bowel habits on
Fermentable oligosaccharides, disaccharides, monosaccha- days with abnormal bowel movements, and not an average of
rides, and polyols (FODMAPs) have been reported to exac- all days. For example, a patient who experiences >25% of
erbate symptoms in a subgroup of patients due to proposed abnormal bowel movements consistent with BSFS 6 or 7 can
fermentation and osmotic effects [10]. In fact, follow-up be considered to have IBS-D, while another patient who
studies have shown increased small bowel distension and experiences 25% of abnormal bowel movements consistent
increased water content on MRI when FODMAPs are admin- with BSFS 1 or 2 has IBS-C. Moreover, another subset of
istered to healthy individuals [11]. patients may have alternating constipation and diarrheal
symptoms (IBS-M) or symptoms that do not fit into any of
the other three categories (IBS-un-subtyped). Many IBS-M
Sloane describes experiencing watery bowel move- patients may report extended periods of constipation fol-
ments up to three times a day on at least 3 out of 7 days lowed by multiple watery bowel movements only later to be
of the week. They do have occasional normal stools. diagnosed with IBS-C with progressive stool accumulation
The diarrhea is accompanied by crampy diffuse then resulting in eventual bowel purging. A stool diary in
abdominal pain that is improved with defecation. They these cases can be particularly helpful to elucidate patterns
believe intake of certain foods may correlate to timing within the chaotic bowel habits these patients may experi-
of their symptoms and have been trialing elimination ence [13].
of dairy products and gluten with limited improvement.
Their symptoms have been getting slightly worse over
the past year. Sloane denies any nocturnal stools, weight loss, rectal
bleeding, or family history of gastrointestinal issues.
They state they were previously diagnosed with IBS-
D. They are wondering if any additional testing should
linical Manifestations and Diagnostic
C be done at this point.
Criteria
Clinical manifestations of IBS encompass a wide range of

symptoms including abdominal cramping, bloating, and ifferential Diagnosis and Diagnostic
D
changes in bowel habits from loose/frequent stools to con- Strategies
stipation. Symptoms often change over time and can mimic
other disorders. Therefore, diagnosis is usually based on a For patients who present to primary care with symptoms of
combination of characteristic symptoms over time and the abdominal pain, constipation, and/or diarrhea, a detailed his-
exclusion of organic diseases. The current diagnostic stan- tory and physical exam play a key role in the diagnostic pro-
dard, the Rome IV criteria, describes IBS as recurrent cess; oftentimes, no further testing is needed to confidently
abdominal pain associated with two or more of the follow- make a diagnosis of IBS. The differential diagnosis and sub-
ing characteristics: abdominal pain related to defecation, sequent diagnostic strategies for IBS are largely dictated by
abdominal pain associated with changes from baseline the predominant symptom subtype; however, it is important
stool frequency, and/or abdominal pain associated with a to keep in mind that conditions can sometimes fall into more
change from baseline stool appearance or form. These cri- than one category. The presence of any alarm features in a
teria should be fulfilled at least 1 day a week for at least patient’s medical history including symptom onset after age
27 Irritable Bowel Syndrome 419
50, severe and progressive symptoms, unexplained weight Diarrhea-Predominant Symptoms

loss, vomiting, nocturnal diarrhea, rectal bleeding, unex-
plained iron deficiency anemia, or family history of colon Table 27.1 outlines the major categories to consider when
cancer, celiac disease, or inflammatory bowel disease indi- evaluating a patient with IBS-D [17, 18]. Categorizing diar-
cate the need to exclude organic disease. For patients who fit rhea as inflammatory, malabsorptive/fatty, or watery is a use-
the Rome IV criteria for IBS without any alarm features, ful framework to navigate the lengthy differential diagnosis
guidelines recommend no further diagnostic workup as it is for chronic diarrhea and guide additional workup. The first
low yield and unlikely to uncover a new diagnosis [14–16]. step is to assess for features of inflammatory diarrhea, which
However, even in the absence of alarm features, a limited include constitutional symptoms, fever, weight loss, and
evaluation may still be appropriate to exclude the presence of bloody diarrhea. Inflammatory bowel disease, invasive infec-
illnesses that may cause similar symptoms. tions, and malignancy all fit into this category. Inflammatory
Table 27.1 Differential diagnosis of IBS-D [17, 18]

Differential diagnoses Distinguishing features from IBS-D
1. Inflammatory diarrhea – characterized by constitutional symptoms (fever, weight loss) and bloody diarrhea
Inflammatory bowel disease Family history of IBD
(IBD) Progressive symptoms
Extraintestinal manifestations
Nutritional deficiencies (iron, vitamin B12, folate, zinc, vitamin D)
Elevated inflammatory markers (CRP, ESR)
Elevated fecal calprotectin and lactoferrin
Invasive Infections Historical risk factors: immunocompromised state, travel, animal contact, contaminated food or water
(i.e., Campylobacter, ingestion
Salmonella, Shigella,
enterohemorrhagic E. coli)
Malignancy Older age (but young age does not exclude!)
Family history of cancer or familial cancer syndrome
2. Malabsorptive diarrhea – characterized by foul-smelling, fatty, floating, pale, large volume stools; weight loss, + fecal fat, and nutritional
deficiencies (iron, vitamin B12, folate, zinc, vitamin D)
Celiac disease Dermatitis herpetiformis
Responsive to gluten avoidance
Diet-induced Diet history: symptoms exacerbated by consumption of lactose, high-fructose corn syrup, sugar alcohol
additives – sorbitol, mannitol, and xylitol – which are frequently found in sugar-free products such as gum,
candy, or soda
Chronic pancreatitis Historical risk factors: alcohol use, history of recurrent acute pancreatitis
Bile acid malabsorption Postcholecystectomy
Responsive to bile acid sequestrants
Difficult to test for outside of research settings; consider empiric treatment
Small bowel bacterial Historical risk factors: anatomic or functional abnormalities including strictures, surgically altered anatomy,
overgrowth (SIBO) motility disorders (DM, scleroderma), systemic disorders (immunocompromised state, chronic pancreatitis,
cirrhosis, ESRD)
3. Watery diarrhea – characterized by frequent liquid stools, nocturnal stools, systemic symptoms depending on etiology
Infectious (i.e., C. difficile, Historical risk factors: antibiotic use, daycare centers, immunocompromised state/HIV, extremes of age
Giardia, enterotoxigenic E.
coli, Cryptosporidium,
Listeria, viral)
Drug-induced Common culprit medications: laxatives, proton pump inhibitors, antibiotics, nonsteroidal anti-inflammatory
drugs (NSAIDs), antineoplastic agents, immunosuppression agents, metformin
Metabolic Systemic symptoms related to the metabolic abnormality (i.e., flushing, palpitations, weight loss)
Hyperthyroidism
Adrenal insufficiency
Neuroendocrine tumors
(VIPoma, carcinoid
syndrome)
Microscopic colitis Middle-aged to older patients
Can present with large stool volumes (up to 2 L/day) and nocturnal diarrhea
May be associated with medication use (i.e., NSAIDs, SSRIs, PPIs)
bowel disease (IBD) may initially present with subtle symp- cosyntropin (ACTH) stimulation test. Stool studies for bacte-
toms such as IBS-D with more than a third of IBD patients rial culture, parasites, C. difficile, leukocytes, and fecal lacto-
also fulfilling Rome criteria for IBS [19]. However, patients ferrin can be helpful if there is clinical suspicion for infectious
with IBD usually experience symptom progression over time diarrhea. Microscopic colitis might be considered in older
underscoring the importance of follow-up and reassessment. patients with nocturnal stools and comorbid autoimmune dis-
Fecal calprotectin is a noninvasive marker of intestinal ease [23]. Testing for metabolically active tumors such as a
inflammation that can be used to monitor disease activity in VIPoma or carcinoid tumor is most often done under the
patients with IBD and help differentiate IBD from IBS-D. A direction of a specialist. As always, a full medication recon-
complete blood count (CBC) and iron studies can be used to ciliation is key to determining any GI medication side effects.
look for subacute blood loss from the GI tract commonly In general, if there is any concern for an underlying IBD,
seen in IBD. Serum C-reactive protein (CRP) and erythro- microscopic colitis, or gastrointestinal malignancy, an imme-
cyte sedimentation rate (ESR) should also be considered to diate referral to a gastroenterologist for an endoscopy and/or
evaluate for underlying inflammation; these markers are colonoscopy should be placed as these diseases are most
nonspecific but can indicate underlying inflammation that readily diagnosed under direct visualization and biopsy.
needs further attention. The probability of active IBD is <1%
with fecal calprotectin levels <40 ug/g or with a CRP level
<0.5 mg/L [20]. Patients with an invasive infection may have Constipation-Predominant Symptoms
an exposure or travel history. To evaluate for infection, stool
studies for bacterial culture, parasites, Clostridium difficile, The differential diagnosis for patients suffering from IBS-C
leukocytes, and fecal lactoferrin should be sent. Patients with differs from those who have primary diarrhea symptoms, but
a strong family history of colon or rectal cancers or cancer the diagnostic strategy is similar. Table 27.2 provides a
syndromes who present with bloody diarrhea/stools should
be evaluated early for malignancy regardless of age or
Table 27.2 Differential diagnosis of IBS-C [24, 25]
accompanying symptoms.
Celiac disease, pancreatic insufficiency, diet-induced bile Differential diagnoses Distinguishing features from IBS-C
acid malabsorption, and small bowel bacterial overgrowth 1. Primary constipation (also known as chronic idiopathic
constipation or functional constipation) – abdominal pain is NOT a
(SIBO) are the main causes of malabsorptive diarrhea. prominent complaint
Malabsorptive diarrhea can present with foul-smelling “float- Normal transit constipation Regular bowel movements, but
ing” or “greasy” stools, weight loss, and vitamin deficiencies. subjective complaints of hard stools,
Checking a fecal fat can help identify malabsorptive diarrhea difficult evacuation
due to chronic pancreatitis. Celiac disease shares a significant Slow transit constipation Defecation may be dramatically
infrequent (≤1 bowel movement
overlap with IBS-D. A recent meta-analysis of 36 studies (BM)/week)
with 15,256 individuals found an increased likelihood of May be associated with a pelvic floor
biopsy-proven celiac disease in patients with IBS with a injury – childbirth, pelvic surgery
pooled odds ratio of near 4.5 compared to non-IBS controls Rectal evacuation disorder Straining even with soft stools, digital
Dyssynergic defecation manipulation to pass BM
[21]. Given its prevalence, serum testing for tissue transgluta-
Structural abnormality
minase (tTG) antibodies and total IgA levels for celiac dis- Functional defecation
ease should be considered in all IBS-D patients. Total IgA disorders
deficiency may affect the validity of antibody testing as tTG 2. Secondary constipation
antibodies are IgA antibodies. There may also be an overlap Metabolic Associated signs/symptoms of
Hypothyroidism hypothyroidism, diabetes mellitus
between IBS-D and bile acid diarrhea as a systematic review
Diabetes mellitus Review basic screening lab work:
and meta-analysis found positive SeHCAT (23-seleno-25-ho- Electrolyte imbalances TSH, BMP, Ca
motaurocholic acid) testing, which measures radiolabeled Drug-induced Common culprit medications:
bile acid retention, to be present in up to 25% of individuals opioids, antihypertensives,
with IBS-D [22]. Additional testing for lactose intolerance, antidepressants, antihistamines, and
anticholinergics
pancreatic insufficiency, small bacterial overgrowth, tumor
Neurologic disorders Associated neurologic symptoms
syndromes, and bile acid diarrhea is usually carried out after Neuropathy
consultation with a gastroenterologist. Parkinson’s disease
Patients presenting with frequent, watery diarrhea should Spinal cord injury
Multiple sclerosis
be evaluated for noninvasive infectious causes, microscopic
Malignancy Family history
colitis, thyroid disease, endocrinopathies, metabolically Weight loss
active tumors, and medication side effects. A TSH and free Bloody stools
T4 level can be checked to evaluate for thyroid disease; if Change in stool caliber related to
adrenal insufficiency is entertained, the patient can undergo a structuring
framework of differential diagnoses and distinguishing fea- skills and empathy [28, 29]. It is important to set realistic
tures to consider in the evaluation of a patient with suspected patient expectations and treatment goals, specifically that
IBS-C [24, 25]. Again, taking a detailed history assessing for IBS is not curable, but rather a chronic condition that can be
any alarm features as well as performing an appropriate well managed through individualized lifestyle modifications
physical exam will help guide whether any additional workup and, at times, medication. Patients should be made aware
is necessary. that although IBS may have a negative impact on their qual-
Constipation may be a result of primary, or chronic idio- ity of life, this illness is not life-threatening and will not
pathic constipation, or secondary to metabolic, drug-induced, transform into a malignant condition. Continued reassurance
neurologic, or malignant etiologies. If a rectal evacuation provides positive reframing for patients to help patients cope
disorder is suspected such as dyssynergic defecation, we with their symptoms.
suggest referral to a gastroenterologist for more specialized There are several nonpharmacological and pharmacologi-
diagnostic testing. Checking a TSH, free T4, and electrolytes cal therapies available for IBS. Treatment recommendations
is reasonable to ensure there is not a secondary metabolic should be based on IBS subtype, comorbid conditions,
condition contributing to constipation. A full medication rec- patient preference, and provider expertise/comfort. Given
onciliation should be performed looking for offending medi- the heterogeneity of IBS, it is important to tailor therapy rec-
cations as constipation is a common, but often overlooked, ommendations to each individual patient through shared
side effect of many medications, including many over-the- decision-making.
counter preparations.
While colonic malignancy remains a common concern,
meta-analyses of several cross-sectional studies and limited Nonpharmacological Interventions
prospective studies have found no increased colon cancer
risk in patients with typical IBS-C symptoms when com- Diet and Exercise
pared to healthy controls [26]. Nevertheless, all patients In patients with IBS, true food allergies are rare; however,
should be up-to-date with age-appropriate colorectal cancer many patients, regardless of subtype, have food sensitivities
screening. or intolerances and benefit from dietary modification. Some
patients may independently identify food intolerances.
Patients should be asked about dietary triggers and any
You order bloodwork and a stool sample given Sloane’s
dietary modifications they have already instituted. For oth-
report of slightly worsening diarrhea. CBC, CRP, thy-
ers, maintaining a food/symptom diary can help identify
roid testing, and fecal parasite testing all return within
intolerances. Traditional dietary advice includes increasing
normal limits. You call Sloane on the phone to update
dietary fiber, taking probiotics, as well as limiting caffeine,
them about the results. Sloane is relieved to hear that
alcohol, spicy foods, fatty foods, carbonated drinks, chewing
their tests were normal. They would like to avoid tak-
gum, and artificial sweeteners. Fiber can provide relief of
ing a medication if possible and asks what you would
diarrhea but is most effective at treating constipation. Soluble
recommend.
(psyllium) fiber should be recommended as insoluble (bran)
fiber may exacerbate bloating and gas [34]. A meta-analysis
suggests probiotics are beneficial in the treatment of IBS;
Treatment Strategies however, study heterogeneity makes it difficult to give a spe-
cific recommendation regarding preparations, species, or
General Considerations strains [35]. Although traditional dietary advice does provide
symptom improvement, specialized diets, such as a diet low
IBS patients frequently report dissatisfaction with their in FODMAPs, appear to be more effective at reducing gas-
healthcare, particularly in relation to a delay in diagnosis, trointestinal symptoms [36].
inadequate education, being perceived by physicians as Systematic reviews and meta-analyses demonstrate a
problematic patients, and a lack of validation of their symp- low-FODMAP diet is effective in reducing gastrointestinal
toms or suffering. A positive patient-physician relationship symptoms in most patients with IBS [36, 37]. FODMAPs
improves both IBS symptoms as well as patient satisfaction exacerbate IBS symptoms as they are poorly absorbed by the
[27–29]. Establishing a firm, prompt diagnosis of IBS and gastrointestinal tract leading to increased luminal water con-
educating the patient regarding etiology, diagnosis, and tent, increased fermentation by gut bacteria, and excess gas
prognosis is an important first step in establishing a working production. Examples of foods high in FODMAPs can be
relationship [30–33]. Providers should be aware of patients’ seen in Table 27.3. A low-FODMAP diet should be initiated
potentially prior negative interactions with the healthcare with the help of an experienced dietician. Initially, patients
system, validate their symptoms, and display active listening are instructed to eliminate all foods high in FODMAPs.
Table 27.3 Examples of high-FODMAP foods versus low-FODMAP foods [35–42]

High-FODMAP foods Low-FODMAP foods
Fruits Avocados, apples, apricots, dates, cherries, figs, Bananas, blueberries, cantaloupe, grapefruit, grapes, kiwi, lemon, lime,
mango, pears, peaches, plums, watermelon mandarin, oranges, passion fruit, pineapple, tangerine
Vegetables Artichokes, asparagus, beets, broccoli, cabbage, Bell peppers, carrots, corn, cucumbers, eggplant, lettuce, leafy greens,
cauliflower, mushrooms, okra, onions, peas potatoes, pumpkin, tomatoes, zucchini
Grains Wheat/rye/barley-based breads, cereal, pasta, Gluten-free or spelt products, oats, quinoas
crackers, cookies
Protein Cashews, legumes, baked beans, kidney beans, Almonds, eggs, tofu, plain cooked meats, and seafood
lentils
Dairy Cow’s milk, soft cheese, margarine Lactose-free products, hard cheeses
Sweeteners Honey, high-fructose corn syrup, sorbitol Maple syrup, table sugar (sucrose), dark chocolate
Symptom improvement is generally seen around 3–4 weeks, three [34, 46]. CBT is a highly structured psychotherapy that
although individual response times may be variable. After focuses on identifying and correcting maladaptive
4–6 weeks, the patient can reintroduce one high-FODMAP information processes and behavioral response patterns.

subgroup at a time while monitoring symptoms. Most Despite positive treatment outcomes with CBT, access to a
patients will be able to tolerate some high-FODMAP sub- psychologist may be difficult or limited for many patients.
groups and can follow a modified low-FODMAP diet based Thus, researchers are currently investigating the efficacy of
on individual tolerances. The rechallenge phase and relax- psychological care delivered through minimal-contact meth-
ation of dietary restrictions are important as there are con- ods utilizing technology (internet, phones, smartphone apps)
cerns about the long-term impact of a low-FODMAP diet on and self-help strategies [47].
the gut microbiome, nutritional adequacy, and patient com- Two systematic reviews found that CBT-based minimal-
pliance [38, 39]. contact treatment strategies significantly reduce IBS symp-
Several randomized double-blind placebo-controlled tri- toms as compared to usual care, waitlists, online discussion
als implicate wheat in exacerbating IBS symptoms. Most forums, and symptom monitoring [48, 49]. It is unclear,
patients with IBS, even without evidence of celiac disease, however, how CBT-based minimal-contact treatment strate-
experience improvement in gastrointestinal symptoms while gies compare to traditional CBT. Data remain limited with
on a gluten-free diet [40]. Wheat contains both gluten and regard to relaxation therapy, stress management, and mind-
high levels of fructans raising the possibility that the improve- fulness training [34, 46]. Chinese herbs and other homeo-
ment achieved on a gluten-free diet may be due to the elimi- pathic regimens are frequently advertised as treatment for
nation of high-FODMAP foods rather than the elimination IBS; however, they have not been rigorously studied and
of gluten itself [41]. There is currently stronger evidence to cannot yet be recommended as effective treatments for
support the efficacy of a low-FODMAP diet; however, a IBS. In several randomized controlled trials, acupuncture
gluten-free diet is also a reasonable recommendation and compared to sham acupuncture did not improve IBS symp-
may be easier for some patients to follow given the availabil- toms [50–52].
ity of products and the clear packaging of gluten-free foods In summary, we first recommend nonpharmacological
[40, 42]. Moreover, patients should be instructed to avoid interventions including dietary modification, particularly a
gas-producing foods, and in some, avoidance of lactose-rich low-FODMAP diet, exercise, and, if appropriate, psycho-
foods may be needed. logical therapy, as first-line treatment to all patients with IBS
In addition to dietary modifications, exercise is another (Table 27.4). Most patients will achieve satisfactory and
component of lifestyle modification for patients with adequate relief of symptoms with the nonpharmacological
IBS. There is limited data that low- to moderate-intensity interventions provided.
exercise can be beneficial for IBS symptoms [43–45].
Psychological and Alternative/Complementary Sloane decides to try a low-FODMAP diet and start
Therapies exercising regularly. They return to your office in
Underlying gut-brain axis dysfunction can respond to psy- 3 months and state that these interventions have not
chological and alternative/complementary therapies. helped with symptoms. Sloane is ready to try a medica-
Cognitive behavioral therapy (CBT), hypnotherapy, interper- tion as they are tired of dealing with frequent diarrhea.
sonal therapy, multicomponent therapy, and dynamic psy- At this appointment, Sloane also discloses that they
chotherapy all appear to be effective treatments for IBS [34, have been struggling with mood symptoms over the
46]. The strongest evidence exists for CBT, and a meta- past 6 months. They report low energy, difficulty con-
analysis demonstrated a number needed to treat (NNT) of centrating at work, and difficulty falling asleep.
Table 27.4 Stepwise approach to treatment of IBS [13, 16, 34, 46]
Nonpharmacological Interventions
Establish a trusting patient-physician relationship
Set realistic patient expectations and treatment goals
Dietary Modification(Low FODMAP Diet)
Exercise
Psychological (Cognitive Behavioral Therapy)
Pharmacological Management
IBS-C IBS-D Pain
Loperamide
Antispasmodics
Medications Initial: 4 mg, followed Hyoscyamine 0.125-0.25 mg q4 hrs
that improve Polyethylene by 2 mg after each PRN; max: 1.5 mg/day
stool Glycol loose stool; Dicyclomine 20 mg QID x 7 days;
frequency/ Maintenance 4 to then ↑ to 40 mg QID
consistency 17gm daily - TID 8 mg/day single dose
or divided doses;
max 16 mg/day
Peppermint Oil 187-225 mgTID
Lubiprostone* Rifaximine*
8 mcg BID 550 mg TID × 14 days; TCAs
may be retreated 2
Amitriptyline 10-25 mg QPM;
FDA approved Linaclotide* times with the same
medications dosing regimen may ↑ up to 75 mg
that improve 290 mcg daily Nortriptyline 10 mg daily
global IBS
SSRIs
symptoms Eluxadoline*
Citalopram 40 mg daily
75-100mg BID Fluoxetine 20 mg daily
Paroxetine 40 mg daily
*FDA approved for females 18 years or older; Pharmacological management: green = first-line;
yellow = second-line; purple = third-line
these studies failed to show improvement in abdominal dis-

Pharmacological Interventions comfort and pain symptoms in the polyethylene glycol arm,
and the sample sizes were not clearly adequate [53, 54].
Pharmacological management should be based on the sub- Polyethylene glycol is readily available over the counter, can
type of IBS and the presence of other prominent symptoms be easily titrated based on the patient’s symptoms, and is
such as pain, gas, and bloating, as well as comorbid generally well-tolerated. There is minimal systemic absorp-
conditions. tion, and the most frequent side effects associated with its
use include abdominal discomfort, bloating, nausea, and
IBS-C diarrhea. The role of polyethylene glycol in the treatment of
Along with nonpharmacological therapies, we recommend a IBS-C has been questioned by some; however, there is a pau-
trial of polyethylene glycol as first-line treatment for IBS-C city of evidence that recommends against its use [55]. Other
given its availability and excellent safety profile. Polyethylene laxatives, especially bowel stimulants, should be avoided as
glycol 3350, an osmotic laxative, is frequently used to treat these will likely exacerbate abdominal pain and have a higher
constipation. Two small randomized controlled trials in risk of leading to dependence.
IBS-C patients found that polyethylene glycol improved We recommend intestinal secretagogues as second-line
stool consistency and the number of spontaneous bowel treatment for patients with IBS-C who have failed lifestyle
movements per week as compared to placebo; however, interventions and polyethylene glycol. Intestinal secreta-
gogues, lubiprostone and linaclotide, are FDA approved for ment course. Presumably, rifaximin alters the gut microbi-
the treatment of IBS-C. Both lubiprostone and linaclotide ome to decrease the symptoms of IBS. Compared to placebo,
stimulate receptors in the intestinal mucosa that lead to an rifaximin provides significant relief of global IBS symptoms;
influx of water into the gut lumen promoting transit. Several however, approximately two-thirds of patients experience a
randomized clinical trials demonstrate that both drugs sig- relapse of symptoms after drug discontinuation [65–67].
nificantly improve IBS symptoms compared to placebo with Retreatment with another course of rifaximin appears to be
an NNT of 12.5 and 6, respectively [34]. Many of the pri- both safe and effective, and the FDA has approved up to two
mary end points of the clinical trials reflect partial improve- repeat courses of rifaximin [67].
ment in overall IBS symptoms rather than complete We reserve eluxadoline as a third-line agent given the
resolution of symptoms, so it is important to counsel patients safety concerns. Eluxadoline is an opioid receptor agonist; it
that these medications will not “cure” IBS, but rather miti- acts to decrease intestinal motility and the visceral pain
gate the symptoms. In addition, it is essential to counsel response. Compared to placebo, it is also effective at improv-
patients about potential side effects related to the use of these ing global IBS symptoms; however, sphincter of Oddi dys-
secretagogues including nausea and diarrhea. Approximately function and pancreatitis can rarely occur (0.5% and 0.4%,
twice as many patients taking lubiprostone report nausea respectively) with the use of this drug and have resulted in
when compared to placebo [56, 57]. Diarrhea is common hospitalization in some patients, specifically those with prior
with both lubiprostone and linaclotide with a number needed cholecystectomy [68, 69]. Eluxadoline is currently contrain-
to harm (NNH) of 10 and 6, respectively [34]. Apart from the dicated in patients with prior cholecystectomy, those with
abovementioned side effects, lubiprostone and linaclotide other structural biliary or pancreatic disease, and those with
are generally well-tolerated and have a favorable safety pro- heavy alcohol use.
file; the occurrence of serious adverse events are rare
[56–59]. Pain
In addition to considering subtype-specific therapies, there
IBS-D are several medications that target abdominal pain associated
Along with nonpharmacological therapies, we recommend a with IBS. Selection of an appropriate agent should be made
trial of loperamide as first-line treatment for IBS-D. A trial by considering patient comorbidities and individual patient
of ondansetron and a trial of bile acid sequestrants are also preferences and by engaging the patient in shared
reasonable alternatives for symptom control in patients with decision-making.
IBS-D. Medications such as ondansetron (a selective 5-HT3 Antispasmodics, peppermint oil, and antidepressants
receptor antagonist), loperamide (a gut-directed opioid- including tricyclic antidepressants (TCAs) and selective
receptor agonist), and bile acid sequestrants are frequently serotonin reuptake inhibitor (SSRIs) are effective at reducing
recommended for IBS-D given their antidiarrheal properties, both pain and overall IBS symptoms compared to placebo A
availability, and tolerability; however, the evidence base sup- meta-analysis found that antispasmodics, as a class, are
porting their use in IBS-D is weak. One randomized con- effective at improving IBS symptoms when compared to pla-
trolled trial demonstrated that ondansetron as compared to cebo [33]. However, there was significant heterogeneity
placebo improves stool frequency and consistency, but does among the studies regarding individual antispasmodics. Of
not improve pain scores [60]. Two small randomized con- all the drugs evaluated, hyoscyamine and dicyclomine are
trolled trials (n = 20 and n = 90) and one prospective trial the only agents available in the United States. This meta-
examining loperamide compared to placebo found improve- analysis included three trials evaluating hyoscyamine with
ment in stool frequency and consistency with mixed effects an NNT of 3, while only one trial evaluated dicyclomine
on pain scores [61–63]. The data is not overwhelming, but with an NNT of 4. Unfortunately, antispasmodics as com-
loperamide is a reasonable first-line option. Bile acid seques- pared to placebo also have a higher rate of adverse events.
trants may be beneficial in IBS-D as there appears to be an There were no serious adverse events; however, anticholiner-
overlap between IBS-D and bile acid malabsorption; how- gic side effects including dry mouth, dizziness, and blurred
ever, formal evidence supporting the uses of bile acid seques- vision were frequent with the use of antispasmodics [34].
trants in the treatment of IBS-D is currently limited [64]. Peppermint oil is an attractive alternative to antispasmod-
We recommend rifaximin as second-line therapy in ics for treating the pain associated with IBS as it is effective
patients with IBS-D who fail nonpharmacological therapy (NNT = 3) and has minimal side effects. Heartburn is the
and a trial of symptomatic management with loperamide. most common side effect reported; however, sustained
There are two FDA-approved treatments for IBS-D: rifaxi- released preparations and enteric-coated preparations of pep-
min, a gut-specific minimally absorbed antibiotic, and elux- permint oil may reduce the frequency of heartburn [34, 70,
adoline, a mixed μ-opioid receptor agonist and δ-receptor 71]. In patients with comorbid anxiety or depression, the use
antagonist. Rifaximin is FDA-approved as a 14-day treat- of either TCAs or SSRIs may improve both IBS symptoms
and mood symptoms. A meta-analysis demonstrated that apies and agents aimed at symptom management such as
TCAs and SSRIs are effective at reducing abdominal pain polyethylene glycol 3350 for IBS-C and loperamide for
and overall IBS symptoms as compared to placebo, but these IBS-D. Several other pharmacological agents are available
medications were more likely to produce adverse events, for second-line therapy including linaclotide or lubipros-
particularly dry mouth and drowsiness with the use of TCAs tone for IBS-C and rifaximin for IBS-D. Antispasmodics,
[34, 46]. Some gastroenterologists suggest preferentially antidepressants, and peppermint oil are helpful in mitigat-
starting TCAs for IBS-D and SSRIs for IBS-C because con- ing pain associated with IBS. Patients with refractory IBS
stipation and diarrhea are respective class side effects; how- or those who develop alarm features should be referred to
ever, this is not supported by the IBS-specific literature [13]. gastroenterology for additional evaluation.
Serotonin norepinephrine reuptake inhibitors (SNRIs) have a 5. Interdisciplinary support including a dietician and mental
place in some chronic pain conditions but have not been health provider should be considered in the management
thoroughly studied in patients with IBS. of patients with IBS.
When to Refer
You recommend a trial of a tricyclic antidepressant
IBS tends to be a chronic illness, and patients should be edu- and close follow-up. Sloane reports an improvement in
cated that there will be periods of time with varying control both their mood and gastrointestinal symptoms at their
of symptoms. Most patients treated with the nonpharmaco- 6-week follow-up appointment. You recommend con-
logical and pharmacological strategies tend to do well and tinuing the medication for the next several months.
are happy with their symptom control, but for those who fail Sloane asks you, however, if irritable bowel syndrome
to improve despite adherence to diet and medications, refer- can be cured by the medication.
ral to a specialist should be considered. Specialists may try
different treatment options and often conduct a more exten-
sive evaluation including endoscopy, cross-sectional imag-
ing, and/or more comprehensive laboratory blood testing to Review Questions
exclude other organic diagnoses. In tertiary care centers, IBS
patients are often seen in conjunction with a dietician and if 1. A 25-year-old female presents to your clinic with com-
need be a psychotherapist. Patients who remain refractory to plaints of intermittent abdominal pain associated with
the treatments prescribed by their primary care physician and diarrhea for the past 6 months. She states she has abdom-
the gastroenterologist often benefit from referral to a inal pain and loose stools multiple times a day about
psychiatrist. twice a week. She denies any GI bleeding, nocturnal
symptoms, weight loss, or family history of inflamma-
tory bowel disease but notes that her symptoms seem to
Summary Points be worse during times of increased stress. On physical
exam, she is afebrile, HR: 70 beats/min, BP:
1. IBS is a common clinical condition characterized by 110/65 mmHg. Abdominal exam reveals normoactive
abdominal pain associated with altered bowel habits. IBS bowel sounds, diffuse mild tenderness, no rebound or
has four clinical subtypes: IBS-D, IBS-C, IBS-M, and guarding, and no masses. Which of the following is the
IBS un-subtyped or unclassified. The pathophysiology of next best diagnostic step?
IBS is likely multifactorial and is an area of ongoing A. Colonoscopy
research. B. Fecal leukocytes
2. In patients presenting with typical IBS symptoms, no C. CT abdomen and pelvis
alarm features, and a normal physical exam other than D. Apply Rome IV criteria
abdominal tenderness, Rome IV criteria can be used to E. Watchful waiting
diagnose IBS without additional diagnostic testing. The correct answer is D. This patient displays no “red
3. The need for additional diagnostic testing should be tai- flag” features that would indicate underlying GI tract or sys-
lored to the individual patient based on patient character- temic pathology. The Rome IV criteria can be applied to this
istics, IBS subtype, and physician discretion. Red flag patient to facilitate a clinical diagnosis without additional
symptoms should prompt further evaluation for systemic diagnostics as she is presenting with complaints consistent
disease. with irritable bowel syndrome without alarm features [16].
4. A stepwise approach is recommended for the treatment of Early diagnosis helps accelerate a treatment plan and
IBS. First-line therapies include nonpharmacological ther- increases patient satisfaction. Should this patient not respond
to first-line treatment or her symptoms progress, additional 3. Everhart JE, Ruhl CE. Burden of digestive diseases in the United
States, part II: lower gastrointestinal diseases. Gastroenterology.
workup should be pursued. 2009;136(3):741–54.
4. Agarwal N, Spiegel BM. The effect of irritable bowel syndrome
2. A 51-year-old Caucasian female presents to the clinic to on health-related quality of life and health care expenditures.
establish care. She reports intermittent abdominal pain Gastroentol Clin North Am. 2011;40(1):11–9.
5. Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of
and bloating associated with diarrhea. The symptoms 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin
have been present for several years, and she denies rectal Gastroenterol Hepatol. 2005;3:349–57.
bleeding, weight loss, and nocturnal symptoms. On aver- 6. Thijssen AY, Mujagic Z, Jonkers DM, et al. Alterations in serotonin
age, the symptoms occur once a week. She has a copy of metabolism in the irritable bowel syndrome. Aliment Pharmacol
Ther. 2016;43:272–82.
prior medical evaluations which reveal normal thyroid 7. Wouters MM, Van Wanrooy S, Nguyen A, et al. Psychological
function tests, normal IgA levels, negative celiac disease comorbidity increases the risk of postinfectious IBS partly by
panel, and normal fecal calprotectin level. She has never enhanced susceptibility to develop infectious gastroenteritis. Gut.
had a colonoscopy. She uses loperamide as needed, and 2016;65:1279–88.
8. Liebregts T, Adam B, Bredack C, et al. Immune activation
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randomized placebo-controlled evidence. Clin Gastroenterol
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Headaches
28
Rachel Brook and Deborah Kwolek
Learning Objectives Introduction

1. Diagnose and treat common primary headache dis-
orders, including migraine, tension-type, and clus- Headache is one of the most common complaints in both the
ter headaches. primary care and emergency room settings worldwide. Per
2. Identify abortive and preventative treatment options the Global Burden of Disease study, approximately 3 billion
for migraine headaches. people were diagnosed with either a tension-type headache
3. Discuss the features of a menstrually associated (TTH) or migraine headache in 2016 [1]. Additionally, head-
migraine. aches were deemed the second highest cause of years lived
4. Describe the association between migraine and with disability worldwide [2]. Given the absence of objective
stroke risk in patients with and without aura. diagnostic findings on exam or imaging for most headaches,
5. Identify the risks and benefits of hormonal contra- the diagnosis of the type of headache is often based on clini-
ception use in women with migraines with and cal criteria. Headaches are generally classified as either
without aura. primary or secondary according to the International

6. Distinguish primary from secondary headache Classification of Headache Disorders third edition (ICHD-3)
disorders. [3]. Primary headaches are defined as those without any
underlying causative disorder. Common primary headache
disorders include tension-type, cluster, and migraine.
Importantly, many patients may have more than one type of
headache disorder. Recognizing “red flag” symptoms which
require further evaluation and possible imaging and recog-
Jennifer, a 22-year-old woman, presents with a new
nizing the characteristics of secondary headaches are essen-
complaint of headache. Her mother and maternal aunt
tial. Frequent, severe, or persistent headaches can become a
have migraines. Her headache is unilateral, lasts for
chronic syndrome requiring a multimodal treatment strategy.
2–3 days, and has occurred twice per month over the
Components of chronic headache can include lifestyle modi-
past year. Her headaches are associated with sensitiv-
fications, dietary changes, physical therapy, treatment of
ity to light and sound, and with nausea, but not vomit-
underlying mental health disorders, and medications. Due to
ing. She has tried ibuprofen without relief. The severity
the complexity and broad range of headache disorders, this
of her headaches has caused her to miss at least 1 day
chapter will primarily focus on migraine headaches in the
of work per month.
primary care practice.
R. Brook (*)
David Geffen School of Medicine, UCLA, Department of Internal
Medicine, Los Angeles, CA, USA
D. Kwolek

430 R. Brook and D. Kwolek
he Clinical Evaluation and Differential

T between TTH and mild migraine headaches without aura,
Diagnosis of Headaches and TTH and migraine headaches are often present in the
same patient [3, 4].
The evaluation of headaches in the primary care setting The pathophysiology of TTH is multifactorial. Episodic
begins with a thorough headache history. The history of tension-type headaches likely involve increased activation
prior headaches, the onset and duration of the current head- and/or sensitization of peripheral pain nociceptors. Over
ache, the frequency of headaches, and any recent changes are time, patients with chronic TTH may additionally develop
noted. Focused questions in which the patient “walks you altered central pain modulatory mechanisms which then con-
through” a typical headache episode include frequency, pain tribute to chronic pain symptoms [3].
(location, quality, severity), pattern (where the pain begins,
radiates, and time between those changes), associated symp- Clinical presentation and diagnostic criteria Tension-
toms (photophobia, phonophobia, nausea/vomiting, aura), type headache typically presents as a bilateral headache,
and exacerbating or ameliorating factors. Medication history and is often described by patients as a “band-like pres-
and use of over-the-counter substances are reviewed, includ- sure” or tightness of mild to moderate intensity, surround-
ing medications that have been tried previously for headache ing their entire head lasting minutes to days [3, 5]. TTH
relief. A family history of headache disorders, new or does not typically include nausea and vomiting or sensory
changed medications, recent trauma or infection, and associ- hypersensitivity, although photophobia or phonophobia
ated neurologic symptoms are noted. A patient’s sleep hab- may be present. TTH is not aggravated by routine physical
its, substance use, psychosocial stressors, and mental health activity such as walking or climbing stairs. Physical
screens are reviewed. examination may be unremarkable; however, patients
Physical examination includes blood pressure measure- with TTH may have increased tenderness to palpation of
ment, fundoscopic exam for jugular venous pulsations or the pericranial muscles or associated trigger points. A
papilledema, and neurologic examination. Musculoskeletal cephalic muscle group consisting of the frontal, temporal,
examination should include palpation of pericranial and cer- lateral pterygoid, and masseter muscles and a neck muscle
vical muscles to evaluate for myofascial tenderness or allo- group including the insertions at the mastoid processes,
dynia, temporal arteries that could suggest temporal arteritis, the sternocleidomastoid and trapezius muscles, and the
and auscultation for carotid bruits. neck insertions of these muscles are often tender or in
“Red flags” which require urgent evaluation include spasm. The differential diagnosis of TTH includes cluster
markedly elevated blood pressure, papilledema, nuchal headaches, migraine headaches, medication overuse head-
rigidity, fever, chills, head trauma, thunderclap (reaches aches, temporomandibular joint disorders (TMJ), sinus
maximum severity within a few minutes of onset), or worst disease, eye disease, chronic post-traumatic headache,
headache of the patient’s life. Although migraines often have and disorders of the cervical spine and cervical muscles
neurologic symptoms in the form of an aura, symptoms [3, 6–8].
which come on suddenly, last more than 60 minutes, involve
hemiplegia, or are associated with a decreased level of The International headache Society (IHS) has pub-
consciousness require imaging to exclude stroke. Additional lished classification guidelines for the diagnoses of head-
symptoms which require further investigation include headaches. The IHS classifies TTH into three major categories,
aches that are positional, that get worse with exertion or sex, infrequent, frequent and chronic depending upon the fre-
that occur after head trauma, that are new after the age of 50, quency of at least 10 episodes of headache over time.
that change in pattern, or that never go away. Infrequent episodic tension type headache occurs less
than one day per month on average, Frequent episodic
tension type headache occurs 1-14 days per month on
Primary Headaches average for >3 months and Chronic tension type head-
ache occurs more than 15 days per month on average for
Tension Headaches >3 months. Chronic tension type headache can last hours
to days, or be unremitting, and evolves from Frequent epi-
Tension-type headache (TTH) is the most common cause of sodic tension type headache. TTH are further subclassi-
headaches in the United States (65%), and women tend to fied by the presence or absence of pericranial tenderness.
have a slightly higher prevalence than men. TTH is often The diagnostic criteria for Infrequent episodic tension
associated with forward posture, eye strain, increased stress, type headache is outlined in Box 28.1, and differs from
fatigue, or lack of sleep. It can be difficult to distinguish Frequent and Chronic TTH as described above.
28 Headaches 431
are considered second-line therapy if the before-mentioned

Box 28.1 Diagnostic Criteria for Infrequent medications are not effective. Triptans are not indicated for the
Episodic Tension-Type Headaches: International abortive treatment of TTH, although triptans are used in
Classification of Headache Disorders ICHD-3 [3] patients with concomitant migraine headaches. Providers
should be cautious of overly frequent use of analgesic medica-
A. At least 10 episodes of headache occurring on <1 tions for TTH in order to prevent medication overuse head-
day/ month on average (<12 days/year) and fulfill- aches. In general, analgesics should not be used daily for
ing criteria B-D prolonged periods of time. Opioids and butalbital should be
B. Lasting from 30 minutes to seven days avoided in the treatment of TTH [11].
C. At least two of the following four characteristics: For patients with frequent or chronic TTH, adjunctive
1. bilateral location treatment options are needed to avoid medication overuse
2. pressing or tightening (non-pulsating) quality headaches. Cognitive behavioral therapy, relaxation tech-
3. mild or moderate intensity niques, stress reduction, attention to posture, and physical
4. not aggravated by routine physical activity such therapy of the neck and shoulder region may be beneficial.
as walking or climbing stairs Lack of sleep, lack of exercise, poor posture, and tension
D. Both of the following: from prolonged stooping, or computer work are addressed
1. no nausea or vomiting. and corrected as necessary. Massage, myofascial release,
2. no more than one of photobia or phonophobia spinal manipulation, and acupuncture may be beneficial, but
E. Not better accounted for by another efficacy data is limited. Low-dose amitriptyline, a tricyclic
ICHD-3 diagnosis antidepressant, is considered the first-line option for the pre-
vention of chronic or frequent episodic TTH [12]. Mirtazapine
Headache Classification Committee of the and venlafaxine have been used in the preventive treatment
International Headache Society (IHS). The of TTH with some reported success. Providers should care-
International Classification of Headache Disorders, fully assess patients for response to therapy and side effects
3rd edition. Cephalalgia 38(1), pp. 1–211. Copyright © with each intervention or medication trial [11].
2018 by International Headache Society. Reprinted by
permission of SAGE Publications, Ltd.
Cluster Headaches
Treatment of tension-type headaches Despite its prevalence, Cluster headaches are a rare type of headache which belongs
most patients do not seek medical attention for TTH. In gen- to the Trigeminal autonomic cephalgia category. In contrast
eral, episodic TTHs are of mild severity, do not interfere with to tension-type headaches, the prevalence of cluster head-
activities of daily living, and are infrequent in nature [9]. For aches in the general population is less than 1%. Cluster head-
patients who seek medical attention, there is a paucity of aches are one of the few primary headache disorders that
evidence-based studies to guide abortive and preventative occur more commonly in men than in women, but this ratio
therapy. First-line therapy for abortive treatment includes has decreased in recent years. Traditionally, the prevalence in
over-the-counter pain medications: aspirin, acetaminophen, men vs. women was cited as 6:1; however, data in the 1990s
nonsteroidal anti-inflammatory agents (NSAIDs), and com- found a ratio closer to 2.1:1 [13]. Despite the low prevalence,
bination preparations including caffeine. In evaluating the cluster headaches are important to diagnose because of spe-
efficacy of each treatment, an assessment is made of the cific and effective treatment options and because of the high
patients’ pain 2–4 hours after medication use [10, 11]. burden of disease impact on quality of life, including
increased suicide ideation [14]. The pathogenesis of cluster
A systematic literature review of abortive treatment options headaches is not well understood. Recent evidence has
for TTH using the International Headache Society (IHS) defi- shown that abnormal functioning of the hypothalamus; the
nitions of effective treatment was conducted and found that a trigeminal nerve, parasympathetic pathways, and cerebral
single dose of acetaminophen (also known as paracetamol) vasculature all likely contribute to the development of cluster
1000 mg, ibuprofen 400 mg, or ketoprofen 25 mg were more headaches [15].
effective than placebo in achieving pain-free intervals after
2 hours [10]. In general, a large initial dose is more effective Clinical presentation Cluster Headache is defined by the
than repeating small doses, and medication is most effective if International Classification of Headache Disorders (ICHD) as
given at the onset of the headache. Analgesics using caffeine descibed in Box 28.2. The pain intensity in Cluster headache is
severe, and the location is unilateral, typically focused in the Treatment of Cluster headache Treatment goals for patients
retro-orbital, periorbital, and temporal region. The quality of the with cluster headaches include decreasing both the individual
pain is often described as stabbing, boring, or ice pick-like in attacks and the duration of the cluster headache episode. Abortive
nature, and classically, attacks are associated with ipsilateral treatments for cluster headaches help resolve individual attacks,
conjunctival lacrimation, conjunctival injection, rhinorrhea, or but do not alter the length of cluster headache episode.
nasal congestion. Cluster headache can be associated with an Prophylactic therapies help shorten the episode length and
aura similar to those in migraine headaches, and auras associ- should be started as soon as the cluster headache is diagnosed.
ated with Cluster headache are more common in women than in
men. Cluster headache characteristically has both a circadian First-line abortive treatment of cluster headaches includes
and seasonal rhythm occurring at the same time of day, most 100% oxygen administration or treatment with triptans.
frequently at night, and around the same time of year, most fre- Oxygen therapy is generally well tolerated with minimal side
quently in spring and autumn. As the name suggests, attacks effects; recommended delivery is via a non-rebreather mask
tend to come in clusters, occurring at least every other day, up to or nasal cannula at 6–7 liters per minute. Triptans are also
eight times daily, for weeks to months at a time [3, 8]. Differential used for abortive treatment of cluster headaches.
diagnoses for Cluster headache includes paroxysmal hemicra- Subcutaneous sumatriptan has the fastest onset of action and
nias, trigeminal neuralgia, primary stabbing (ice pick) head- is dosed at 6 mg. Intranasal sumatriptan 20 mg or zolmitrip-
ache, and unilateral neuralgiform headache [3] which fall under tan 5 mg are also effective with a slightly slower onset of
the group category of Trigeminal autonomic cephalgias. Cluster- action but fewer side effects. Intranasal medications are
like headaches may occur in the presence of intracranial pathol- sprayed in the nostril on the contralateral side to the head-
ogy, and therefore, one non-contrast CT or MRI is recommended ache. In resistant cases, steroids and IV lidocaine have been
as part of the evaluation of suspected Cluster headache [16]. used although efficacy data is limited [13, 17].
Prophylactic treatments for cluster headaches are started
The ICHD-3 diagnostic criteria for Cluster headache is together with abortive treatments. The only evidence-based
listed below: Box 28.2 prophylactic treatment for reducing the duration of cluster
headache episodes is verapamil 360 mg oral daily; however,
care must be taken concerning blood pressure and bradyar-
Box 28.2 Diagnostic Criteria for Cluster Headache: rhythmias. Lithium 800 mg daily is considered to be an alter-
International Classification of Headache native treatment if patients have contraindications or adverse
Disorders ICHD-3 [3] reactions to verapamil. Lithium use requires the monitoring
of drug levels and renal function, and cannot be used in preg-
A. At least five attacks fulfilling criteria B-D:
nancy. Additional therapies for resistant or severe cases
B. Severe or very severe unilateral orbital, supraor-
should be comanaged with a neurologist. Topiramate, gaba-
bital, and/or temporal pain lasting 15-180 minutes
pentin, lamotrigene, melatonin, prostaglandin, testosterone,
(when untreated)
and surgical or transcranial stimulation treatments have been
C. Either or both of the following:
tried but have limited data for efficacy [13, 17].
1. At least one of the following symptoms or signs,
ipsilateral to the headache:
a) conjunctival injection and/or lacrimation
Migraine Headaches
b) nasal congestion and/or rhinorrhoea
c) eyelid oedema
Migraine is the most disabling primary headache disorder,
d) forehead and facial sweating
ranking as the third-highest cause of disability worldwide in
e) miosis and/or ptosis
the 2017 Global Burden of Disease Study [2]. Migraines
2. A sense of restlessness or agitation
may begin as early as childhood, peak around ages 35–39,
D. Occuring with a frequency between one every other
and tend to decrease among women after menopause [18].
day and eight per day
Migraines are two to three times more common in women
E. Not better accounted for by another ICHD-3
than in men [19] and affect approximately 20% of women [1,
diagnosis.
20]. Studies have shown a genetic predisposition in up to
Headache Classification Committee of the 50–90% of patients with migraine [20, 21]. Migraines can be
International Headache Society (IHS). The episodic or chronic and are divided into two main subtypes:
International Classification of Headache Disorders, migraine without aura (MWOA) and migraine with aura
3rd edition. Cephalalgia 38(1), pp. 1–211. Copyright (MWA). Migraine with aura is defined as transient neuro-
© 2018 by International Headache Society. Reprinted logic symptoms that precede or accompany the onset of
by permission of SAGE Publications, Ltd. headache, last no more than 60 minutes, and occur in 20–35%
of patients with migraine. Typical aura symptoms involve
28 Headaches 433
bilateral visual changes, but auras also manifest as distur- or occurring with the headache. The headache itself is the third
bances in sensation, motor function, cognitive abilities, con- phase of a migraine attack. Cephalic pain in migraine attacks
centration, or speech and language [20]. is typically unilateral, throbbing, of moderate to severe inten-
Treatment strategies for migraines include abortive medica- sity and lasting 4–72 hours in duration [23].
tions, preventive treatments, lifestyle and trigger avoidance
strategies; most patients will benefit from a combination of sev- The phenomenon of cutaneous allodynia is a sensation of
eral or all categories of treatment. MWA and MWOA respond pain, numbness, tingling, burning, or hypersensitivity of
to the same treatments. The primary difference clinically is the cutaneous nerves on the scalp or elsewhere on the trunk or
safety of estrogen-containing contraceptives, which are of con- extremities. Cutaneous allodynia is part of the neurologic
cern for patients with an aura, as the risk of stroke may be manifestations which accompany many migraine
increased. The management of migraines associated with men- headaches.
ses (MAM) which are discussed below includes strategies with After the resolution of the headache phase, there is the
hormonal manipulations and choice of triptans which add a postdrome phase, which can last up to days after a migraine
layer of complexity to treatment planning. attack, during which symptoms of fatigue, mood changes,
weakness, and cognitive delay may be present [23] (Box 28.3).
The pathophysiology of migraines The pathophysiology of
migraine involves multiple mechanisms including inflamma-
tion of the meninges resulting in increased sensitization of Box 28.3 Diagnostic Criteria for Migraine Without Aura:
meningeal nerve fibers, abnormalities in cortical activity International Classification of Headache
resulting in a hyperexcitable cortical state, and altered brain- Disorders ICHD-3 [3]
stem modulation of the ascending nociceptive pathway [21].
The hyperexcitable cortical state may render genetically pre- A. At least five attacks fulfilling the criteria B-D
disposed individuals susceptible to the development of a cor- B. Headache attacks lasting 4–72 hours (when
tical spreading depression. A cortical spreading depression is untreated or unsuccessfully treated)
a wave of neuronal and glial depolarization and subsequent C. Headache has at least two of the following four
hyperpolarization that incites a cascade of downstream characteristics:
events including vasodilation and altered permeability of the 1. unilateral location
meningeal vessels and the release of pro-inflammatory neu- 2. pulsating quality
ropeptides [20, 21]. Neuropeptides, including calcitonin 3. moderate or severe pain intensity
gene-related peptide (CGRP), substance P, and neurokinin A, 4. aggravation by or causing avoidance of routine
contribute to the activation of the trigeminal afferents, which physical activity (e.g., walking or climbing
then relay these nociceptive signals to the second- and third- stairs)
order neurons in the thalamus and cortical pain centers, pro- D. During headache, at least one of the following:
ducing pain. Cortical spreading depression has been most 1. nausea and/or vomiting
clearly correlated with the aura phase of migraine in patients 2. photophobia and phonophobia
suffering from migraines with aura [3]. While the etiology of E. Not better accounted for by another ICHD-3
migraines remains complex, a large body of evidence has diagnosis
refuted the vascular theory of migraine which had attributed
migraine headaches to the dilation of cranial vessels [22]. Headache Classification Committee of the
International Headache Society (IHS). The
International Classification of Headache Disorders,
Clinical presentation of migraines Migraine attacks have third edition. Cephalalgia 38(1), pp. 1–211. Copyright
been described as an evolution of four phases: a premonitory © 2018 by International Headache Society. Reprinted
or prodrome phase, an aura (if present), a headache phase, and by permission of SAGE Publications, Ltd.
a postdrome phase’, however, not all patients experience all
four stages. The premonitory phase can occur hours prior to
the onset of aura or headache. The most common symptoms The differential diagnoses for migraine headaches include
reported in this phase are fatigue, irritability, difficulty concen- tension-type headaches, trigeminal autonomic cephalgias
trating, mood changes, neck pain, nausea, and sensitivity to including cluster headaches, and secondary headache disorders
light or sound. The presence of these symptoms may alert a including sinus headaches, intracranial lesions, central nervous
patient to the development of a migraine prior to the onset of system (CNS) infections, face or head trauma, or cerebrovascu-
cephalic pain. The second phase is the aura which includes tran- lar disorders. In contrast to tension-type and cluster headaches,
sient, reversible neurologic symptoms immediately preceding migraine headaches are more often associated with
p hotophobia, phonophobia, sensitivity to smells, nausea/vom- According to the International Classification of Headache
iting, worsening with exertion or physical activity, and interfer- Disorders, third edition (ICHD-3) [3], the most common
ence with daily functioning [3]. Migraines are often incorrectly auras in migraine manifest clinically as bilateral visual dis-
labeled as sinus headaches by patients and physicians due to turbances including scintillations of light, fortification spec-
the periorbital and sometimes maxillary location of pain. tra, or a central scotoma. Fortification spectra are defined as
zigzag light bands, and a central scotoma is defined as a
gray/black or blind spot in the center of one’s vision. The
Migraines with Aura second most common type of aura is sensory disturbance,
which manifests as unilateral tingling and/or numbness
Migraine with aura is diagnosed by the same criteria as affecting the body, face, or tongue. The third most frequent
Migraine without aura (MWOA), but with the additional type of aura involves speech and/or language and may pres-
presence of transient neurologic symptoms (Box 28.4). ent as partial or complete aphasia.
Less frequent manifestations of auras include motor,
brainstem, or monocular retinal presentations. Auras involv-
ing motor weakness are classified as hemiplegic migraine
Box 28.4 Diagnostic Criteria for Migraine with Aura: and involve unilateral weakness. Brainstem auras present
International Classification of Headache with at least two of the following symptoms: dysarthria, tin-
Disorders ICHD-3 [3] nitus, vertigo, diplopia, ataxia (not caused by sensory or
Headache meeting the criteria for Migraine without motor deficits), decreased level of consciousness (i.e., a
aura, with the following additions: Glasgow Coma Score of <13), and/or hearing loss. Retinal
migraines present as repeated episodes of monocular visual
A. At least two attacks fulfilling criteria B and C disturbances, often with unilateral transient blindness or
B. One or more of the following fully reversible aura flashing lights [3]. The first time that patients present with
symptoms: sensory disturbances, brainstem, or hemiplegic auras, imag-
1. visual ing should be considered. Repeated episodes of auras with
2. sensory migraines, especially the brainstem and hemiplegic auras,
3. speech and/or language are an indication for migraine prophylaxis [24].
4. motor Auras typically last 5–60 minutes in duration and precede or
5. brainstem occur at the beginning of the onset of cephalic pain. Some
6. retinal patients have symptoms of aura without accompanying head-
C. At least three of the following six characteristics: ache (within 60 minutes of the start of aura symptoms).
1. at least one aura symptom spreads gradually over Occurences of neurologic symptoms without headache, espe-
>5 minutes cially when new in onset, changing, or different from a typical
2. two or more aura symptoms occur in succession. aura, should be carefully evaluated for underlying neurologic
3. each individual aura symptom lasts pathology or transient ischemic attacks (TIAs) [3].
5–60 minutes.
4. at least one aura symptom is unilateral (note:
aphasia is always regarded as a unilateral symp- Jennifer is diagnosed with migraine headache without
tom, dysarthria may or may not be). aura based on the character of her headaches. She is
5. at least one aura symptom is positive (scintilla- told that migraines often run in families. The natural
tions and pins and needs are positive signs of history and pathophysiology of her condition are dis-
aura). cussed. Jennifer inquires about treatment options,
6. the aura is accompanied, or followed within especially for nausea, and for the debilitating pain
60 minutes, by headache. which causes her to miss work. She currently suffers
D. Not better accounted for by another ICHD-3 approximately two migraines per month.
diagnosis.
Headache Classification Committee of the
International Headache Society (IHS). The reatment of Migraine by the Primary Care
T
International Classification of Headache Disorders, Provider
third edition. Cephalalgia 38(1), pp. 1–211. Copyright
© 2018 by International Headache Society. Reprinted Migraine treatment depends on the severity and chronicity of
by permission of SAGE Publications, Ltd. headache attacks. All patients benefit from stress reduction,
attention to sleeping and eating patterns, and the identification
28 Headaches 435
of possible triggers. Those with mild to moderate episodic migraine management to patients. Similar to the seizure
migraines are often successfully managed with abortive ther- threshold, patients are vulnerable to headaches when one
apy alone. Acetaminophen or nonsteroidal anti-inflammatory event, or a combination of factors, increases brain stimula-
treatments (NSAIDs) are taken in anticipation of, or at the tion toward the migraine threshold for that individual. An
beginning of each migraine headache. Patients who do not individual’s threshold and vulnerability to migraines may
respond to acetaminophen or NSAIDs alone may be given be genetically determined, and migraineurs have a lower
triptans, either alone or in combination with NSAIDs. threshold to develop a headache due to hyperexcitability
Patients with frequent and/or moderate to severe migraines and h ypersensitivity. Preventive medication and treatments
benefit from the addition of preventive medications and would increase the threshold, making migraines less com-
increased attention to lifestyle changes. Amitriptyline in low mon and less severe. An example would be that for a certain
doses is first-line treatment for prevention and is generally individual, drinking wine and skipping a meal together are
well tolerated [12, 18, 23]. enough to cause a migraine. The patient can abstain from
Patients with chronic or severe migraines require a global wine and eat regularly which will decrease migraine fre-
approach and should be co-managed with a neurologist. quency. The addition of a preventive treatment or medica-
Elimination diets, botox therapy, biologics, identification of tion might raise the threshold so that minor disturbances in
individualized migraine threshold and triggers, lifestyle sleep or an occasional glass of wine will no longer cause a
changes, abortive therapies, and prevention treatments are headache, whereas a sleepless night will still trigger a
combined and used in management. Patients with severe migraine [27].
chronic migraines may need psychosocial support, psycho-
logic care, work accommodations, or disability to manage
the burden of chronic pain and distress. Adjuvant non-pharmacologic treatments In addition to
avoiding known triggers for migraine headaches, the
American Academy of Neurology recommends various non-
Migraine Triggers pharmacologic treatment options for the prevention of
migraine headaches. Behavioral treatments with the best evi-
Migraine triggers Although there are no randomized con- dence include acupuncture, aerobic exercise, cognitive
trolled trials that support specific lifestyle changes for the behavioral therapies, thermal or electromyographic biofeed-
prevention of migraine, behavioral modifications and reduc- back, and relaxation techniques [28]. Physical therapy and
tion of migraine triggers can be a cornerstone in the success- acupuncture can be particularly helpful if myofascial pain is
ful management of migraine headaches. Migraine triggers associated with a patient’s migraines [29]. Insufficient evi-
have been shown to include increased stress, menstrua- dence was found for transcutaneous electrical nerve stimula-
tion, caffeine, odors, sleeping late, missed meals, hormone tion and acupuncture, although these therapies may still be
treatment, smoke, alcohol (especially wine), certain foods, used for the preventative treatment of migraine headaches
nitrates, exercise, weather, and neck pain. Stress is the most [28]. Most importantly, behavioral and pharmacologic thera-
frequently noted trigger [24, 25]. Maintaining regular sleep, pies need to be combined to achieve success in preventing
consistent caffeine intake (or reducing/eliminating caffeine migraine headaches.
altogether), consistent meals, regular aerobic exercise rou-
tine, and decreasing stress levels should be emphasized to
patients to help reduce migraine headache attacks [25, 26]. Abortive Treatments for Migraine Headaches
The use of opioids and combination analgesic combination
medications (barbiturate-based and over-the-counter) should Several abortive agents have been validated as effective in
be minimized, as they can increase migraine frequency and the acute treatment of migraines; the treatment is the same
severity, even when taken only once or twice a week [18]. whether the migraine is with or without aura (see Table 28.1).
Patients are encouraged to keep a headache log or symptom The most commonly used agents include acetaminophen,
diary to help them and their provider identify possible trig- nonsteroidal anti-inflammatory drugs (NSAIDs), the triptans
gers. Triggers, once identified, should be vigorously avoided (agonists of the 5-HT1BD receptor), dopamine-agonist
by the patient to help reduce the frequency and severity of based anti-emetics, and less commonly ergotamine-
migraine headache attacks. derivative compounds. The role of newer agents is currently
being defined. Ditans, which have a high affinity for 5HT1F
receptors, and agents which inhibit Calcitonin gene-related
Migraine threshold theory The concept of a migraine peptide (CGRP) activity are newly approved and have some
threshold is embraced by migraine experts, is popular in the use as abortive and preventive therapies. The first approved
lay public literature, and is a helpful way to explain ditan is lasmiditan, an oral agent approved for use in the
Table 28.1 Selected therapies for acute migraine [18, 30–43]

Reported mean therapeutic Common or serious
Class Specific treatments effectsb adverse effects Comments
Triptans [30] Almotriptan, Pain relief by 2 hr, 16–51%; Chest or facial muscle Response to and side-effect
eletriptan, frovatriptan, pain-free by 2 hr, 9–32%; free tightness, profile of different triptans
naratriptan, rizatriptan, of headache for 24 hr, 9–27% lightheadedness; varies in individual patients;
sumatriptan, contraindicated in nasal or subcutaneous delivery
zolmitriptan patients with coronary may be more effective than oral
artery disease delivery in patients with nausea
or vomiting
Ergots [31, 32] DHE nasal spray, Pain relief by 2 hr, 20–40% Nausea, dizziness; Intravenous DHE is commonly
DHE injection (for DHE nasal spray; limited contraindicated in used for refractory migraine
evidence) patients with peripheral
vascular disease or
coronary artery disease
Acetaminophen [33] Pain relief by 2 hr, 19%; Minimal with May be more effective in
pain-free by 2 hr, 9% intermittent use combination with antiemetic
agent
NSAIDs [34] Aspirin, diclofenac, Pain relief by 2 hr, 17–29%; Gastric irritation, May be effective individually or
ibuprofen, ketorolac, pain-free by 2 hr, 7–20% excessive bleeding have additive benefit when
naproxen taken with triptan; different oral
preparations (effervescent or
powder) may have improved
efficacy
Combinations [35, Acetaminophen- Pain relief by 2 hr, 10–17% Same as with NSAIDs Caffeine-containing
36] aspirin-caffeine, (limited evidence); pain-free and triptans preparations may have
sumatriptan-naproxen by 2 hr, 20–30% increased potential for overuse;
combination therapy is more
effective than individual agents
in some patients
AntiemeticAgents Chlorpromazine, Pain relief by 2 hr with oral Sedation, restlessness Phenothiazines plus
[30, 33, 37] metoclopramide, metoclopramide (plus aspirin (akathisia), dystonic metoclopramide have benefit
prochlorperazine or acetaminophen), 23%; pain reactions for headache as well as nausea;
relief by 1–2 hr with ondansetron is commonly used
intravenous delivery in the for nausea, but evidence is
emergency department, lacking
24–67%
Single-pulse TMS SpringTMS Pain-free by 2 hr, 17% No clinically significant Handheld device for patient-
[38] adverse effects delivered therapy; currently
FDA-approved for treatment of
acute migraine with aura
CGRP receptor Rimegepant, Pain-free by 2 hr, 14–18% None reported; safety Phase 2 studies have been
antagonists [39, 40] ubrogepant studies are ongoing completed
(under investigation)
From New England Journal of Medicine, Charles [18] © 2017, Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society
a
Shown are therapies that have high-quality supporting evidence or are highly recommended in guidelines from the American Headache Society
[37, 41], the Canadian Headache Society [42], and the European Federation of Neurological Societies [43], as well as other Food and Drug
Administration (FDA)—approved or emerging therapies. Citations are for primary trial data within guidelines except as noted; trials were of vari-
able quality. All approaches are FDA-approved for the treatment of acute migraine except antiemetics and calcitonin gene-related peptide (CGRP)
receptor antagonists. DHE denotes dihydroergotamine, NSAIDs nonsteroidal anti-inflammatory drugs, and TMS transcranial magnetic
stimulation
b
Values are the percentage of patients with pain relief or freedom from pain after a single dose of the treatment minus the percentage with pain
relief or freedom from pain after placebo administration. In most cases, therapy was administered when pain was already moderate or severe
treatment of acute migraine. Oral, short acting CGRP medi- safety. The number of pharmacologic interventions available
cations, such as rimegepant and ubrogepant, can also be used for migraine treatments is rapidly increasing, and readers are
as abortive migraine treatments. Long acting CGRP paren- advised to check the most current prescribing informa-
teral agents can be used as preventive migraine treatments, tion when making treatment decisions. The following table
and examples include erenumab, fremanezumab, galcane- summarizing traditional abortive treatments for migraines
zumab and eptinezumab. Both classes of agents are mildly was published in 2017 in the New England Journal of
effective, and there is little data on pregnancy or long-term Medicine, and is reprinted here with permission.
28 Headaches 437
Acetaminophen and NSAIDs For patients with mild stricting agents and 5HT 1b/1d agonists, DHE has been
migraine headaches, acetaminophen and NSAIDs are con- shown to be more effective then ergotamine, with fewer
sidered the first-line therapy given both their efficacy and adverse effects, and is available as a nasal spray [49]. Ergots
decreased adverse side effects [33, 44]. are effective and can be given for refractory migraines in an
emergency department setting, particularly in headaches
Triptans For patients with more severe or refractory lasting greater than 72 hours [49]. Such treatment is usually
migraine attacks, triptans are commonly prescribed as followed by steroid administration to prevent the rapid
first-line abortive migraine treatments. Triptans are sero- return of headache.
tonin 1b/1d agonists that are considered to be “specific
treatments” for headaches by blocking pain pathways in Ergot medications are contraindicated in patients with
the brainstem and increasing vasoconstriction [45]. There CAD, peripheral vascular disease, cerebrovascular/ischemic
are triptans with a shorter half-life which provide more stroke disease, hypertension, and hepatic or renal impair-
immediate relief but may have more side effects. ment and have been associated with clinically significant
Subcutaneous and intranasal preparations are helpful vasospasms. Ergot medications are not recommended for
when rapid onset is needed or when there is significant elderly or pregnant patients [18].
nausea and vomiting. Triptans with a longer half-life are
slower in onset but are better tolerated. Longer-acting Antiemetics Patients with nausea as a prominent feature are pre-
triptans are often used in the treatment of migraine associ- scribed an antiemetic agent, such as chlorpromazine or metoclo-
ated with menses (MAM) starting 1–3 days before the pramide which treat nausea, and may also contribute to headache
onset of menses and continuing 3–5 days into the men- relief. Ondansetron is commonly used in the treatment of acute
strual period. migraine, but it has not been significantly evaluated [18]. When
nausea or vomiting limits the use of oral medications, non-oral
Studies have shown that many patients treated with preparations are used: intranasal, intramuscular, intravenous, or
triptans are not satisfied with their treatment and experi- per rectum. In the emergency room, IV or IM antiemetics are
ence persistence of headache symptoms despite medica- used as monotherapy for severe migraines. Diphenhydramine is
tion compliance [46]. The reasons for the lack of symptom usually given concomitantly to prevent dystonic reactions.
improvement may include the fact that many patients Parenteral dexamethasone (10–25 mg) is given as adjunctive
delay the use of triptans until the pain is moderate to treatment to prevent headache recurrence.
severe in intensity, whereas early treatment with triptans
has been shown to be crucial to successful treatment of Opioids and butalbital should not be prescribed as treat-
migraine headache [18, 47]. Migraine treatment often ments for acute migraine, per the American Headache
requires a global and multimodal approach to treatment, Society, due to a lack of studies showing positive efficacy,
and expectations regarding pain relief should be managed. potential side effects of treatment, and potential for misuse
In difficult cases, the goal of treatment should be increased [28]. The doses of commonly used medications are listed in
daily functioning rather than total relief from pain. Table 28.2.
A combination of naproxen with a triptan, given at the The early administration of abortive medications,
beginning of the headache, is an effective choice for many before the migraine attack becomes severe, will increase
patients [41]. There is evidence that the addition of treatment efficacy. Medication can be taken prior to the
NSAIDs to triptan use may have a synergistic effect, headache or with the onset of the prodrome. If the patient
increasing the efficacy of the triptan and resulting in has an aura, abortive treatments should be given at the
improved control of headache symptoms (40% vs. 17%). onset [41, 64] Patients often delay the use of abortive med-
While there is limited evidence, triptans remain contrain- ications in hopes that the headache will not progress into a
dicated in patients with coronary artery disease (CAD), migraine attack or in an attempt to conserve their medica-
hemiplegic migraines, history of ischemic stroke, uncon- tion supply of triptans: insurance coverage may limit the
trolled hypertension, pregnancy, or peripheral vascular number of triptan pills that will be covered per month.
disease (PVD). Frequent triptan use has the potential to cause medication
Triptans, however, are considered safer to use than ergot- overuse headache and can be safely used only 10 days per
derived medications in the conditions listed above [48]. month in chronic migraine patients [18]. The limitations
on the use of abortive treatments underscore the impor-
Ergot medications Ergotamine and dihydroergotamine tance of trigger avoidance and lifestyle changes in the
(DHE) are infrequently used in the treatment of acute management of headaches and the use of preventive medi-
migraines due to a lack of efficacy, side effects, rebound cations for frequent headaches.
headaches, and contraindications. While both are vasocon-
Referral to a Neurologist
Jennifer is prescribed a triptan medication. She is
encouraged to identify the premonitory phase charac- Referral to a neurologist should be considered when pre-
teristics of her migraine attacks so that she can take viously diagnosed tension-type, cluster, or migraine
her triptan medication as an abortive treatment. She is headaches do not respond to initial therapies, worsen
told to take NSAIDs as needed with her triptan to help despite treatment, have features that do not allow for
with her migraine pain. Chlorpromazine is prescribed clear classification, or d isplay neurologic deficits which
to help with her nausea. Additionally, she was differ from the patient’s typical aura or prior
instructed on the importance of cutting out caffeine presentations.
and starting stress reduction strategies to help manage
her migraine triggers.
Table 28.2 Doses of medications used for selected abortive treatment in acute migraine [33, 34, 36, 47, 50–63]
Abortive medications Recommended dosing

Acetaminophen 1000 mg PO x once [33]
NSAIDs Ibuprofen 400 mg PO once [50]
Aspirin 1000 mg PO once [34]
Naproxen 500 mg or 825 mg PO once (the 825 mg dose is most effective as a single agent) [51]
Ketorolac 30 or 60 mg IV/IM once [52]
Acetaminophen-aspirin-caffeine Acetaminophen 250 mg/aspirin 250 mg/caffeine 65 mg, 1–2 tablets PO once [53]
Triptans Sumatriptan tablet: 25/50/100 mg PO once. Repeat in 2 hours later if treatment ineffective. (100 mg
(fast onset at 2 hours) dose most effective, but 50 mg dose better tolerated with fewer side effects). Maximum dose is 200 mg
per 24H [47, 54, 55]
Sumatriptan nasal spray: 20 mg intranasal in single nostril once on the contralateral side from the
headache pain. Repeat in 2 hours if treatment ineffective. Maximum dose is 40 mg intranasal per 24H
[47]
Sumatriptan subcutaneous injection: 4 mg or 6 mg (6 mg more effective). Repeat in 1 hour if treatment
ineffective. Maximum dose is 12 mg per 24H [47].
Nasal powder sumatriptan: 22 mg dose. An 11 mg capsule is placed in each nostril. Repeat in 2 hours if
treatment ineffective. Maximum dose is 44 mg per 24H [47]
Rizatriptan tablet: 5 or 10 mg PO once (10 mg dose being more effective). Repeat dose after 2 hours if
treatment ineffective [54, 56]
Zolmitriptan tablet: 1/2.5/5/10 mg PO once. Repeat dose in 2 hours if treatment ineffective. Maximum
dose is 10 mg per 24H. 2.5 mg is recommended starting dose as side effects correlate with increased
dose [54, 57]
Sumatriptan-naproxen combination Sumatriptan 85 mg and naproxen 500 mg. Take together in a combination pill once. Repeat in 2 hours if
treatment ineffective. May also take components separately [36]
Triptans (slower onset) Frovatriptan tablet: 2.5 mg PO once. Repeat dose in 2 hours if treatment ineffective. Maximum dose is
7.5 mg PO per 24H [54]
Naratriptan: 1 mg or 2.5 mg PO once. Repeat dose in 4 hours if treatment ineffective. Maximum daily
dose is 5 mg per 24H
For short-term prevention of menstrual migraines: use 2.5 mg of frovatriptan, 1 mg of naratriptan, or
2.5 mg zolmitriptan PO BID. Start 1–3 days prior to the onset of menses/symptoms, and continue for
4–7 days [58]
Ergots DHE nasal spray: 2 mg intranasal once [59]
DHE injection: 1 mg subcutaneous injection or 1 mg intravenous injection [60]
Antiemetic agents Chlorpromazine: 0.1 mg/kg IV once [61, 62]
Metoclopramide: 20 mg IV once [63]
Prochlorperazine: 10 mg IV once [63]
NSAIDS nonsteroidal anti-inflammatory agents, PO per oral, IV intravenous, IM intramuscular
28 Headaches 439
Beta-blockers, including metoprolol, propranolol, and

Jennifer returns 10 months later with increased migraines timolol, have been shown to be effective for migraine pre-
after stressful changes in her job and home life. Initially, vention. Patients are educated that beneficial effects may not
the triptans plus NSAID combination effectively aborted be seen for at least 2 weeks, and medications should be tri-
her migraines. However, as the headaches increased in aled for 3 months before being deemed ineffective [77].
frequency, she began using the medications more fre- Beta-blockers are used with caution in elderly patients,
quently than advised. For the past 4 months, Jennifer has smokers, and patients with low blood pressure or bradycar-
been having headaches and using her abortive medica- dia, asthma, erectile dysfunction, or depression.
tion for more than 15 days per month. She says her insur- Anticonvulsants, particularly topiramate and valproate,
ance will not give her more than 9 tablets of triptan per have been shown to reduce migraine headache frequency
month, and she needs medication for the remainder of [78]. Topiramate doses of 100 mg are typically needed for
the headache days. Jennifer has a BMI of 32, but no patients to see a reduction in migraine headache frequency.
other medical conditions. She asks what can be done to Side effects of topiramate include fatigue, decreased appe-
decrease her headache burden. tite, weight loss, nausea, diarrhea, stomach pain, and diffi-
culty concentrating. Valproate can cause severe weight gain
and should be used with caution.
Angiotensin-converting enzyme (ACE) inhibitors and
Preventive Treatments for Migraines angiotensin II receptor blockers (ARB) can be effective in
migraine prevention. There is some evidence that lisinopril
Chronic migraineurs and those with frequent or severe epi-
(20 mg/day) and candesartan (16 mg/day) can be effective,
sodic headaches are candidates for preventive medication.
but sample sizes were small, and use in general practice is
Chronic migraine refers to migraine headaches lasting
limited [79, 80].
>4 hours per day, occurring >15 days per month for more
Calcium channel blockers are commonly used for
than 3 months at a time, with at least 8 of those days meeting
migraine prevention; however, there is minimal data, and
criteria for migraine [3]. Patients with frequent or severe epi-
patients may develop tolerance. Verapamil is the most com-
sodic migraine attacks at least once weekly, or greater than
monly used calcium channel blocker based on both its effi-
4 days per month, whose migraines are having a negative
cacy and minimal side effects, but is not considered a
impact on their quality of life or work, are candidates for
first-line medication for migraine prophylaxis [81].
preventative treatments [18]. Migraines with severe neuro-
Flunarizine is used outside of the United States.
logic symptoms or hemiplegia are also treated with preven-
When selecting an ideal preventive pharmacologic treat-
tive medication.
ment, a patient’s comorbidities, medication side effects,
Prescription medications used to prevent frequent
efficacy of medication for the prevention of migraines, spe-
migraines include tricyclic antidepressants, anticonvul-
cific headache characteristics, and a patient’s goal for treat-
sants, beta-blockers, serotonin-reuptake inhibitors, angio-
ment outcomes are taken into consideration [18, 76].
tension receptor blockers (i.e., candesartan), NMDA
Beta-blockers may be beneficial for patients with anxiety,
antagonists, botulinum toxin, and calcitonin gene-related
palpitations, or hypertension. Amitriptyline may be used
peptide (CGRP) antagonists. Tricyclic antidepressants (i.e.,
with concomitant insomnia, depression, irritable bowel syn-
amitriptyline), anticonvulsants (i.e., topiramate), and beta-
drome, chronic pain, or mood disorders. Patients with obe-
blockers (metoprolol or propranolol) are the most com-
sity may consider topiramate. Patients with hypertension
monly used agents for prevention [18, 65] (Table 28.3).
might be considered for preventive treatment with calcium
channel blockers [76].
Antidepressants Tricyclic antidepressants (TCA) and selec-
tive norepinephrine and serotonin reuptake inhibitors (SNRI)
Herbal remedies There is data to support the use of select
are recommended by the American Academy of Neurology
supplements for migraine prevention: riboflavin (200 mg PO
guidelines for use in migraine prevention [28]. Amitriptyline
BID), co-Q10 (300–500 mg PO daily), magnesium (400 mg
is the only evidence-proven TCA for migraine prevention,
PO daily), and melatonin (3–10 mg PO daily) [71]. Riboflavin
and side effects are minimal at low doses. With higher doses,
benefits are seen after 3 months of therapy [82].
sedation, dry mouth, constipation, palpitations, weight gain,
orthostatic hypotension, and urinary retention may occur.
Butterbur is effective at doses of 75 mg PO BID, but hep-
Avoidance of TCAs should be considered in elderly adults
atotoxicity was reported with higher doses [83]. Although
[76]. Venlafaxine, an SNRI, is useful for migraine prophy-
patients may consider nonprescription herbal therapies to be
laxis, attention deficit hyperactivity disorder (ADHD),
non-pharmacologic and safe, there is a small risk of toxicity
menopausal hot flashes, and depression.
or drug interactions with use [84] (Table 28.4).
Table 28.3 Selected preventive therapies for migrainea [17, 18, 28, 66–75]
Reported mean therapeutic Common or serious
Class Specific treatments effectsb adverse effects Comments
Tricyclic Amitriptyline, Data not available Dry mouth, Low doses are typically used
antidepressant [66] nortriptyline sedation, weight (10–50 mg); may be useful in
gain, urinary patients with insomnia
retention
Beta-blockers [67, Metoprolol, nadolol, Headache days, −0.4 Hypotension, May be useful in patients with
68] propranololc, timololc (meta-analysis for exercise hypertension, tachycardia, or
propranolol) intolerance, anxiety
sexual
dysfunction
Anticonvulsant agent Topiramatec Episodic migraine days, −1.1 Paresthesias, Also used for weight loss;
[69] to −1.3; chronic migraine weight loss, preparations with various half-lives
days, −1.5 to −3.3 cognitive are available
dysfunction,
depression
Anticonvulsant agent Divalproex sodiumc Migraine days, −2.6; migraine Tremor, weight May be efficacious, but adverse
[70] attacks, −0.6 to −3.4 gain, hair loss, effects limit its use
fetal neural-tube
defects
Candesartan [68] Headache days, −0.7 to −1.7; Dizziness Side effects generally acceptable
migraine days, −0.6 to −1.1
Flunarizine [66] Migraine attacks, −1.2 to −1.8 Sedation, weight Not available in the United States
gain, depression
Nonprescription Coenzyme Q10, Migraine attacks: −1.1 with Diarrhea with Side effects are generally
therapies [71] magnesium, melatonin, coenzyme Q10, −0.5 to −0.9 magnesium acceptable, but current evidence of
petasites, riboflavin with magnesium, −0.8 with efficacy is poor
petasites or riboflavin
Botulinum toxins OnabotulinumtoxinAc Chronic migraine headache Muscle weakness, Delivered by subcutaneous
[72] days, −1.4 to −2.3; migraine headache injection at multiple sites;
days, −1.5 to −2.4 approved for chronic migraine only
Supraorbital nerve Cefaly devicec Migraine days, −2.1 Local discomfort, Headband with forehead
stimulation [73] skin irritation simulation; applied for 20 min
daily
Monoclonal Eptinezumab, erenumab, Episodic migraine headache Injection-site Multiple phase 3 trials have been
antibodies targeting fremanezumab, days, −1.0 to −1.2; high- reactions; safety completed; administered
CGRP or its receptor galcanezumab frequency episodic migraine studies are subcutaneously or intravenously
[74, 75] days, −2.8; days with chronic ongoing every 1–3 mo; rapid onset of
(under investigation) migraine headache, −2.5; hr efficacy; rates of response of 75%
with chronic migraine and in some cases 100% have been
headache, −30.4 reported
From New England Journal of Medicine, Charles [18], © 2017, Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society
a
Shown are therapies that have high-quality supporting evidence or are highly recommended in guidelines from the American Academy of
Neurology and the American Headache Society [17, 28], the Canadian Headache Society [66], and the European Federation of Neurological
Societies [67], as well as other FDA-approved or emerging therapies. Citations for the primary clinical-trial data are included in these guidelines
except where noted. All studies were of episodic migraine unless otherwise specified. Episodic migraine is defined as less than 15 headache days
per month, chronic migraine is defined as 15 days or more headache days per month, with migraine features on at least 8 of those days
b
Values are the number of migraine attacks or number of days or hours with symptoms, per month with the treatment minus the number with pla-
cebo; negative values indicated a benefit with the treatment. The mean monthly effect (typically after 3 months of treatment) is summarized
c
These therapies have been approved by the FDA as preventative therapies for migraine
Guidelines recommend starting the chosen preventative patient does not respond to or cannot tolerate a particular
medication at the lowest dose and increasing until beneficial medication, then a different class of preventives can be pre-
effects are seen or when side effects are no longer tolerable scribed, but one should also continue to assess for other fac-
[28]. It is of paramount importance to counsel patients that tors that can impede response to preventives, such as the
while side effects can begin immediately, improvement in development of medication overuse headache or lifestyle
headaches is not noted until at least 4–6 weeks after initia- habits which contribute to migraine.
tion of preventive therapy. Medications should be maintained Preventative therapies can effect a 50% reduction in
for 12 weeks before treatment failure is diagnosed [28]. If a migraine frequency, particularly amitriptyline, but the
28 Headaches 441
Table 28.4 Medications and doses for the prevention of recurrent exert positive effects in primary headache disorders by the
migraine [28, 43, 69, 70, 82, 83, 85–89] relaxation of spasmed muscles in the head and neck region,
Preventative category Medication and dosing botox has no beneficial effect on tension-type headaches.
Tricyclic Amitriptyline 10–50 mg PO QHS [28] BoNT-A may directly inhibit peripheral sensitization,
antidepressants Nortriptyline 10–50 mg PO QHS [28] thereby indirectly reducing central sensitization, which is
Beta-blockers Propanolol 40–80 mg PO BID [85]
Metoprolol 50–100 mg PO BID [85]
central to chronic migraine. The effectiveness of BoNT-A
Nadolol 20–240 mg PO daily [85] in chronic migraine, as opposed to negative findings in epi-
Anticonvulsants Topiramate 25–50 mg PO BID daily [69] sodic migraine, may relate to the fact that sensitization phe-
Zonisamide (not yet FDA approved) [69] nomena play a more important role in chronic versus
Valproic acid 500–1500 mg PO daily [70, episodic migraine [65]. Common side effects of botox may
85]
include elevated blood pressure, headache, facial paresis,
Calcium channel Flunarizine 5–10 mg PO daily (not
blockers available in the United States) [85] and neck pain/stiffness [91].
Verapamil 80 mg PO QID [43, 86]
Angiotension II Candesartan 16 mg PO daily [87] Biologic agents Erenumab, galcanezumab fremanezumab,
receptor blocker and eptinezumab are human monoclonal antibodies (mAbs)
SNRI Venlafaxine 37.5 mg150 mg PO daily
that inhibit calcitonin gene-related peptide (CGRP) recep-
[28, 85]
Nonprescription Magnesium 600 mg PO daily [88] tor activity, which is involved in the etiology of migraine.
therapies Riboflavin 400 mg PO daily [82] Erenumab binds to and inhibits the CGRP receptor, and
Butterbur (petasite) 75 mg PO BID [83] is given by monthly subcutaneous (SQ) injection.
NSAIDs Naproxen 550 mg PO BID [89] Galcanezumab and fremanzumab bind to and inhibit the
SNRI Selective serotonin reuptake inhibitor, NSAIDs nonsteroidal anti- CGRP ligand, and are given subcutaneously monthy (galca-
inflammatory drugs, PO per oral, BID two times daily, QID four times nezumab) or quarterly (fremanezumab). Eptinezumab binds
daily, QHS at nighttime
the CGRP ligand and is given as an IV infusion every
3 months. Monoclonal antibodies seem to act faster than
response is variable [28, 85]. Adherence to preventative other preventative medications for chronic migraine.
treatment tends to be low: one study involving almost 9000 Fremanezumab reached a significant difference from pla-
patients found an adherence rate between 26% and 29% at cebo after only 3 days for daily headache hours. Migraine
6 months [90]. Finding the lowest effective dose, a medica- headache days were clearly reduced and separated from pla-
tion with a beneficial side-effect profile for each individual cebo in week two. MAbs have been shown to reduce migraine
patient, and counseling about appropriate expectations for frequency, the use of abortive medications, and the effects of
time frame of improvement can help increase adherence to migraines on daily activities for a 6-month period [92]. In
therapy. addition to rapid onset and proven efficacy, titration is not
needed. Antibodies may also be an alternative for patients
who do not tolerate available medication due to substance-
Botox and Monoclonal Antibodies specific adverse events [93]. Low-frequency administration
of mAbs compared with current oral medication could
When prophylactic medication is ineffective, patients should improve therapy adherence, a problematic issue in migraine
be referred to a neurologist for consideration of botox or bio- prevention [94]. Doses of subcutaneous medications can be
logic therapy injections. self-administered. Given that there is little to no data at pres-
ent regarding safety with pregnancy and lactation, or con-
Botox Multiple reviews have found that botulinum toxin A cerning long term effects, caution may be indicated in the
(onabotulinum toxin A or BoNT-A) injections have efficacy use of these medications in young women.
in the preventive treatment of chronic, but not episodic,
migraine headaches. Studies have revealed a significant
reduction in headache and migraine days, moderate to severe Dietary intervention and elimination diets There is growing
headache days, cumulative headache hours on headache evidence in favor of food elimination diets to help with
days, and psychological distress and an increase in patients’ migraine prevention and the elimination of migraine trig-
functioning, vitality, and overall health-related quality of life gers. Dietary intervention and simple measures such as the
with the use of botox [65]. elimination of caffeine can sometimes render patients
headache-free. In other cases, the frequency and severity of
The exact mechanism by which BoNT-A reduces headaches are lessened, as is the need for preventive and
migraine days in chronic migraineurs is not yet fully under- abortive therapies [94]. Alcohol, chocolate, aged cheeses,
stood. While it was initially thought that BoNT-A may caffeine, nuts, nitrites/nitrates, aspartame, and monosodium
glutamate have all been associated with migraines; therefore, treatment of menstrual migraines, the safe use of contraceptives in
educating patients about these foods is imperative [25]. women with migraines with aura (MWA) and migraines without
There is some evidence that keto diets or vegan diets help a aura (MWOA), and the risk of stroke in migraineurs both with
subset of patients. and without the use of hormonal contraception.
Elimination diets have the goal of looking for specific

triggers which vary from person to person. Elimination diets Estrogen-Withdrawal Headaches
work by eliminating a long list of potential offenders from
the diet and gradually adding each food back one at a time as Migraines that worsen in response to estrogen withdrawal
tolerated. The elimination is best attempted with the support can occur either at the start of a woman’s natural menstrual
and guidance of professionals: patients with frequent, cycle or with withdrawal from exogenous estrogen products,
chronic, or severe migraine attacks may benefit from referral such as the placebo week, during which the birth control pills
to a neurologist and nutritionist as appropriate [95]. Many lack active hormones [101]. In patients taking combined hor-
resources for patient education are available through the monal contraceptives (COC) containing at least 20–25 mcg
National Headache Foundation https://headaches.org/ [96], of estrogen, the placebo week is physiologically equivalent
the American Migraine Foundation https://americanmi- to the withdrawal of estrogen seen in naturally occurring
grainefoundation.org/ [97], and the Migraine Research menses [100, 102]. In the case of exogenous estrogen with-
Foundation https://migraineresearchfoundation.org/ [98]. drawal, an estrogen-associated or menstrual migraine would
be defined as occurring within 5 days of cessation of exoge-
nous estrogen which had been taken for ≥3 weeks, with the
Jennifer is counseled on options for preventive therapy headache lasting no more than 3 days.
and guidelines for the use of abortive medication. She
is instructed that abortive medications should be used
for less than 10 days per month. Given her current Menstrually Associated Migraines (MAM)
headache frequency and her desire to lose weight (BMI
32), topiramate is prescribed for preventative therapy. Menstrually associated migraines (MAM) MAMs are
migraines which specifically occur prior to the beginning of
menses. MAMs are not associated with aura, and can be
more severe, more difficult to treat, longer in duration, and
more strongly associated with functional disability than
After 6 months, Jennifer returns for a follow-up. The topi-
other migraines [101, 103]. Migraines often increase in fre-
ramate initially helped reduce her migraine frequency to
quency and/or severity in the perimenopausal period, possi-
only once or twice a month, but she has recently noticed
bly due to fluctuating estrogen levels [104]. Migraines tend
that the most severe headaches consistently occur right
to improve during pregnancy and after menopause. Some
before the onset of her menses. She has been taking a tri-
studies have shown an improvement in migraine frequency
phasic combined oral contraceptive for 3 months and is
after natural menopause more so than with surgical meno-
concerned that migraines can be associated with menses.
pause, but this is not definitive [105].
She is concerned about overusing her triptan and NSAIDs
based on your previous counseling and wants to know if
MAMs occur within the 2 days prior to menses and 3 days
she should come off her birth control pill.
after the onset of menses, in at least 2 out of 3 menses cycles.
Patients with MAM can have migraines with or without aura
at other times of the menstrual cycle. Less commonly, some
women have pure menstrual migraines, and only have head-
igraines: Hormones, Contraceptives,
M aches in association with menses [106].
and Risk of Stroke Treatment strategies for MAMs include both abortive and
preventive measures. Abortive treatment options for
Migraines in most women are affected by hormones: the wom- estrogen-associated migraines are similar to non-estrogen-
an’s intrinsic hormonal cycles and externally given hormones. Up associated migraines, including the use of triptans and
to two-thirds of women with migraine headaches report worsen- NSAIDs (Tables 28.1, 28.2, 28.3, and 28.4). A strategy used
ing of headaches in association with menses [99, 100], and head- in patients with MAMs is to use a long-acting triptan for
aches associated with the onset of menses can be more severe and short-term prophylaxis. Frovatriptan, naratriptan, or zolmi-
more refractory to treatment than migraines not associated with triptan can be used twice a day starting 1–3 days prior to
menses. Important issues in patient care include the diagnosis and menses and continued for a total of 5–7 days. Studies have
28 Headaches 443
shown that administering frovatriptan 1 day prior to the onset ontraceptives in Women with Migraines
C
of a patient’s typical estrogen-associated migraine at a dose With and Without Aura and Risk of Stroke
of 2.5 mg daily for 5–6 days increased the headache-free
duration for patients [28]. Preventative strategies for MAM
should include both pharmacologic and non-pharmacologic Rena is a healthy 35-year-old woman who has chronic
interventions, as are used in the management of non- migraines without aura. Her migraines have been well
estrogen-associated migraines. Hormonal treatments which controlled on daily amitriptyline and botox injections
stabilize and prevent declines in estrogen levels can also be every 3 months. She does not use tobacco products and
used to combat MAM in selected patients. has no history of vascular disease. She now has a part-
Hormonal treatments in menstrually associated migraines ner and would like to be started on contraception. She
(MAMs). The goal of hormone treatments in MAM is to pre- read that birth control pills can cause strokes in women
vent the withdrawal of estrogen that precipitates MAM [101, with migraines and wants to discuss options.
107]. It should be noted that MAM is most often not associ-
ated with aura, and thus, hormonal contraceptives can be
used without concern for increased stroke risk if women
have pure menstrual migraines, or have MWOA at other Migraine with and without aura may be an independent
times during the cycle. Women who have migraines with risk factor for stroke (with or without contraception use), and
aura at other times of the month are discussed below. To pre- assessing women for the presence of comorbidities that
vent MAM, the placebo days for most combined oral contra- increase ischemic stroke risk must be done prior to starting an
ceptive (COC) options should be minimized in order to estrogen-containing contraceptive or combined oral contra-
reduce migraine frequency. Interventions that can be benefi- ceptive (COC) [109]. Given the efficacy of long-acting revers-
cial include: ible contraception and the lack of estrogen in their preparations,
• Use of low-dose (10–20 mg ethinyl estradiol (EE)) com- the contraceptive of choice for many migraine patients is a
bined monophasic contraceptives instead of triphasic copper or levonorgestrel IUD [100, 110, 111]. (See Chap. 4 on
formulations Patient-Centered Contraceptive Counseling.) In migraine
• Add back estrogen during the menstrual phase so that the patients taking anticonvulsants for prophylaxis, including
patient has only 2 days of placebo pills topiramate, primidone, oxcarbazepine, barbiturate, and phe-
• Use of continuous low-dose combined monophasic con- nytoin, the metabolism of estrogen can be increased, reducing
traceptives with a placebo week every 12 weeks the efficacy of oral combined hormonal contraception. IUDs
• Use of a vaginal ring for contraception that is changed or other progesterone-based contraceptives do not have a
every 3 weeks to avoid a hormone-free week reduction in efficacy with the addition of anticonvulsants and
For example, if using a COC as preventative therapy for should be encouraged [111, 112].
hormone-associated migraines, continuous use of a mono-
phasic COC and skipping the placebo week will prevent the
withdrawal of estrogen, which would ordinarily trigger Quantifying the Risk of Migraine and Stroke
headaches in women with MAM. Progestin does not control
estrogen level fluctuations or reliably suppress ovulation; The data associating migraines with an increased risk of stroke
thus, progestin-only treatment options (including oral, inject- suggests that migraine with aura (MWA) carries a higher risk
able, and intrauterine devices) are not an effective method than migraines without aura (MWOA). Quantifying the risk of
for preventing MAM [108]. using estrogen-containing contraceptives in women with
migraine has been problematic: studies have not reliably dif-
ferentiated between those taking high-dose estrogen prepara-
tions (50 or greater micrograms of EE) from those taking the
low-dose formulations commonly in use today (35 micro-
grams or less EE). Overall, the respective odds ratios (OR) of
Jennifer is diagnosed with menstrually associated
ischemic stroke varies by study population and is reported as
migraines, and does not have an aura. She is instructed
OR of 2.89, 95% CI 2.42–3.45 in patients with any type of
to discuss with her gynecologist changing from a tri-
migraine [3, 113, 114]; OR 1.29, 95% CI 0.81–2.06 in
phasic to a continuous low-dose monophasic com-
MWOA; and OR 2.51, 95% CI 1.52–4.14 in those who have
bined oral contraceptive, with a placebo week every
MWA [113, 114]. For comparison sake, the odds ratio of
12 weeks. She has a significant reduction in her
stroke is approximately 2 in those who smoke cigarettes. The
migraine frequency at 6 months follow-up after chang-
absolute rate of stroke in patients with migraines, however, is
ing her contraceptive to the suggested regimen.
very low at 17–19 per 100,000 woman years [113].
Importantly, while the relative risk for ischemic stroke in stroke and to discuss alternative contraceptive options with
all patients with migraines who use COCs is reported as patients [110]. ACOG similarly permits COC use in patients
increased [115], most studies in the past involved patients with migraines without aura but emphasizes that all patients
taking higher doses of estrogen than are present in the COC should be individually assessed for stroke risk. All guidelines
preparations used today. A meta-analysis that reviewed stud- agree that patients over 35 years of age should be individu-
ies from 1960 to 1999 demonstrated an increased relative ally assessed for risk. Women found to have risk factors for
risk of ischemic stroke of 1.6 (95% CI 1.4–1.8), in female stroke should generally avoid estrogen-containing contra-
patients (without migraines) using COC regimens with ceptives. The major risk factors include hypertension, obe-
higher doses of estrogen (50 micrograms or more of ethinyl sity (BMI > 30), diabetes, hyperlipidemia, cigarette smokers,
estradiol). Subgroup analysis from this same study showed history of CAD, and history of DVT/PE, sickle cell disease,
no increased risk of stroke in patients taking progestin-only and connective tissue disorders [118–120].
forms of contraception [116]. Current COCs use lower doses
of estrogen, between 10 and 30 micrograms of ethinyl estra-
diol; therefore, further data is needed to assess the risk of Zoe is a 39-year-old woman who presents to your
dose with modern COC formulations. Recent studies per- clinic to establish care. She does not use tobacco, has
formed with lower-estrogen-dose COC preparations, includ- no personal or family history of vascular disease or
ing hormonal contraceptive patches, vaginal rings, or COC hypercoagulable disorder, and exercises regularly. Her
pills, have shown lower odds ratios than those previously past medical history is significant for migraines with
published [116]. aura. She has no complaints today and is requesting a
Specifically, the 2015 Cochrane Review found that in refill of her COC pills. The pills were prescribed
female patients without stroke, the use of COCs containing 5 years ago by her gynecologist, and she is asking if
20mcg of ethinyl estrogen was associated with a more mod- the pills are the safest form of contraception for her
erate increased risk of ischemic stroke (RR 1.6, 95% CI 1.4–
1.8) [117]. However, given the potential devastating effects
of stroke, prior to starting a patient on combined hormonal Contraception in Migraines with Aura
contraceptives, one should assess additional risk factors for
stroke, which include, but are not limited to, age > 35 years, Systematic reviews have shown that patients with
known ischemic heart disease, dyslipidemia, hypertension, migraines with aura (MWA), without hormone use, have
obesity (BMI > 30), and systemic diseases associated with approximately a twofold increased risk for ischemic stroke
increased stroke incidence, cigarette smoking, a family his- [122, 123]. A case-control study analyzing a large health-
tory of arterial disease at <45 years of age, and diabetes mel- care claims database of women aged 15–49 who had suf-
litus. Patients with migraines with or without aura who have fered a stroke between 2006 and 2012 found a cumulative
risk factors for stroke should preferentially be prescribed incidence of stroke to be 11/100,000 females. The respec-
nonhormonal or progestin-only contraceptives [118]. tive odds ratios (OR) of ischemic stroke were migraine
with aura using combined oral contraceptives COC,
OR = 6.1 (95% CI 3.1–12.1); migraine with aura without
Contraception in Migraines without Aura COC, OR = 2.7 (95% CI 1.9–3.7); migraine without aura
using COC, OR = 1.9 (95% CI 1.1–2.9); and migraine
The Centers for Disease Control (CDC) Contraception 2016 without aura and without COC, OR = 2.2 (95% CI 1.9–
Medical Eligibility Criteria state that patients with migraine 2.7). The study concluded that compared to the general
without aura are eligible for all types of contraception, population, all migraine patients had a slightly increased
including copper IUD, levonorgestrel IUD, progestin risk of stroke. The risk of stroke was slightly increased in
implants, progestin injections, progestin-only contraception patients who had migraine with aura and in patients who
pills, or combined hormonal contraception (with no limita- had migraine without aura but were taking COCs. The risk
tions based on patient age) [110]. In patients with aura, the of stroke was highest among patients who had migraines
safety of contraception use is more controversial with the with aura and who were also taking COCs [123]. For this
CDC recommending progestin-only contraception options. reason, it has been recommended that COCs should con-
Table 28.5 lists recommendations for COC use in patients tinue to be avoided in patients with MWA.
with migraines without aura based on various societal guide- The Women’s Health Study found that aura frequency was
lines. For example, the CDC recommends COC in migraine associated with stroke risk: aura <1/month had a twofold
without aura patients who are <35 and without stroke risk increase in stroke risk, versus frequency 1/week which had a
factors. However, for patients >35 years old and with stroke fourfold increase in stroke incidence. It has been suggested that
risk factors, their recommendation is to weigh the risks of excellent preventive care with a decreased incidence of
28 Headaches 445
Table 28.5 Summary table of society recommendations for combined hormonal contraceptive use in patients with Migraine without aura
[110–112, 118, 120, 121]
European
World Health Headache
Patient ACOG 2019 Centers for Disease International Headache American Headache Organization 2018 Federation 2017
characteristics [118] Control 2016 [110] Society 2000 [112] Society 2019 [121] [111] [120]
<35 years No No No contraindication No contraindication No Can use COC
No risk contraindication contraindication to COC use to COC use contraindication to with <35mcg of
factors for to COC useb for COC use COC use EE. Benefits and
ischemic risks of
stroke contraception
must be
considered
≥35 years Individually Risks and benefits No contraindication Individually assess Individually Can use COC
No risk assess risk of of COC use for COC use risk of stroke assess risk of with <35mcg of
factors for stroke should be weighed stroke . Consider EE. Benefits and
ischemic against stroke risk non-estrogen- risks of
stroke factors containing options contraception
must be
considered
Patients with Individually Risks and benefits Individually assess Individually assess Individually Suggest
risk factors assess risk of of COC use risk of stroke . risk of stroke . assess risk of nonhormonal or
for strokea stroke should be weighed Consider use of Low-dose stroke Consider progestin-only
against stroke risk progestin-only formulations of non-estrogen- methods of
factors methods in patients COCs containing options contraception
with uncontrolled risk (EE < 50mcg) can
factors for stroke or be considered
who are current
smokers
a
Risk factors for stroke: hypertension, obesity (BMI > 30), diabetes, hyperlipidemia, cigarette smoking, history of coronary artery disease, history
of deep venous thrombosis or pulmonary embolism, sickle cell disease, and connective tissue disorders
b
COC combined oral contraceptives, ACOG American College of Obstetricians and Gynecologists
migraines with aura could also decrease a patient’s risk for isch- an individualized assessment of risks and benefits, including
emic stroke, but no clinical data yet supports that theory [107]. the frequency of migraine with aura attacks, the relation of
Ultimately, given the evidence that migraines with aura migraines to menses, and the presence of additional risk fac-
independently increase the risk of stroke, the use of COCs tors for stroke. Arguments in favor of the safety of COC in
remains controversial in this population. Table 28.6 summa- MWA include that risk of stroke with combined contracep-
rizes society guidelines for the use of COC in patients with tive use is lower than the risk of stroke with pregnancy, which
migraines with auras. All of the societies discourage the use increases to 34 strokes per 100,000 deliveries [116], and that
of estrogen-containing contraceptive preparations in all there is a paucity of data regarding the risk of stroke in
women who have migraine with aura. The International patients with MWA taking COCs with low-dose estrogen
Headache Society might seem the most permissive; however, content. Until more safety data are available, given that there
their recommendation is that all women be individually are effective non-estrogen contraceptive options, estrogen
assessed for risk of stroke. use must be used with caution in women with MWA.
The use of estrogen-containing contraception in women
with migraines with aura is currently not recommended by
the major societies listed in Table 6. More research on the
use of low-dose COC (<35 mcg of EE) in women with MWA
Zoe returns with a severe headache which she describes
is needed to define risks of harm and benefit [124]. This topic
as “the worst headache of her life.” She is in the third
is controversial, and some experts suggest that in a healthy
trimester of her first pregnancy. She lost her balance,
patient without additional stroke risk factors, low-dose
fell, and hit her head on the cement this morning, but
estrogen-containing contraceptive options (i.e., < 20 mcg)
was not concerned at the time. Vital signs include HR
could be considered. If the patient’s migraines are associated
of 93 and BP of 168/102. She has no fever, papill-
with menses, the benefit from the suppression of ovulation
edema, or rash, but she feels unsteady on her feet. She
and stabilization of estrogen levels might outweigh any addi-
is sent to the emergency room for urgent evaluation
tional risk [125]. Other experts suggest that the use of
and treatment.
estrogen-containing oral contraceptives should be based on
Table 28.6 Summary of society recommendations for combined oral contraceptive use in patients with Migraine with aura [110–112, 118, 120,
121]
American European
International Headache World Health Headache
Patient Centers for Disease Headache Society Society 2019 Organization 2018 Federation 2017
characteristics ACOG 2019 [118] Control 2016 [110] 2000 [112] [121] [111] [120]
Patients less Consider progestin- Use of COC Low-dose estrogen- Individually Use of COC Suggest
than 35 years only or contraindicated. containing assess risk of contraindicated. nonhormonal or
of age nonhormonal forms Progestin-only or contraception may stroke Progestin-only or progestin-only
of contraception in nonhormonal be prescribed in nonhormonal methods of
women with focal options approved women who have options approved contraception
neurologic signs or simple visual aura
symptoms
Patients Consider progestin- Use of COC Low-dose estrogen- Individually Use of COC Suggest
35 years of only or contraindicated. containing assess risk of contraindicated. nonhormonal or
age or older nonhormonal forms Progestin-only or contraception may stroke Progestin-only or progestin-only
of contraception in nonhormonal be prescribed in nonhormonal methods of
women with focal options approved women who have options approved contraception
neurologic signs or simple visual aura
symptoms
Patients with Consider progestin- Use of COC Use of COC Individually Use of COC Suggest
risk factors only or contraindicated. contraindicated assess risk of contraindicated. nonhormonal or
for strokea nonhormonal forms Progestin-only or stroke Progestin-only or progestin-only
of contraception nonhormonal nonhormonal methods of
options approved options approved contraception.
a
Risk factors for stroke: hypertension, obesity (BMI > 30), diabetes, hyperlipidemia, cigarette smoking, history of coronary artery disease, history
of deep venous thrombosis or pulmonary embolism, sickle cell disease, and connective tissue disorders
COC combined oral contraceptives, ACOG American College of Obstetricians and Gynecologists
Secondary Headaches Box 28.5 Secondary Headache Subtypes and

Differential Diagnosis: International Classification of
In contrast to primary headaches, secondary headaches are
Headache Disorders (ICHD-3) [3]
those caused by separate underlying conditions. The most
common etiologies listed include trauma, vascular pathol- • Headache attributed to trauma or injury to the head
ogy, intracranial abnormalities, and medication overuse and/or neck (e.g. whiplash, traumatic brain injury.)
headaches. • Headache attributed to cranial and/or cervical vas-
cular disorder (e.g. AVM, non-traumatic intracere-
bral hemorrhage, giant cell arteritis, sinus venous
Medication Overuse Headache Disorder thrombosis, cervical artery dissection.)
• Headache attributed to nonvascular intracranial dis-
Medication overuse headache refers to headaches that occur order (e.g. neoplasm, idiopathic intracranial
more than 15 days per month, for at least 3 months consecu- hypertension.)
tively, in a person with a preexisting primary headache disor- • Headache attributed to a substance or its withdrawal
der, in conjunction with overuse of an acute symptomatic • Headache attributed to infection (e.g. intracranial
headache medication on between 10 and 15 days per month infection such as meningitis or encephalitis, or sys-
depending on the medication. The headache usually resolves temic infection)
with the withdrawal of the offending agent, although it may • Headache attributed to disorder of homeosta-
take months to see improvement. When acetaminophen or sis (e.g. high altitude headache, sleep apnea head-
NSAIDS are used >15 days/month, this diagnosis is likely. ache, arterial hypertension)
Combination pain relievers containing acetaminophen/butal- • Headache or facial pain attributed to disorder of the cra-
bital/caffeine can lead to caffeine withdrawal headaches if nium, neck, eyes, ears, nose, sinuses, teeth, mouth, or
used >10 days/month. High caffeine intake can lead to caf- other facial or cranial structure (e.g. temporomandibu-
feine withdrawal headaches, and this is a common cause of lar joint disease, acute angle closure glaucoma, acute or
first trimester headaches in newly pregnant women who dis- chronic rhinosinusitis, cervical strain)
continue coffee consumption. (Box 28.5).
28 Headaches 447
reveals a clinically significant intracranial lesion in only

• Headache attributed to psychiatric disorder 0.18% of cases without concerning features [86].
• Headache Classification Committee of the When imaging is indicated, MRI of the brain with con-
International Headache Society (IHS). The trast remains the preferred brain imaging modality as it is
International Classification of Headache Disorders, more sensitive at detecting edema, vascular lesions, or other
3rd edition. Cephalalgia 38(1), pp. 1–211. Copyright intracranial pathology than CT scans. CT imaging is used
© 2018 by International Headache Society. Reprinted more frequently in the acute setting, such as the emergency
and revised by permission of SAGE Publications, Ltd. department, as it has higher sensitivity to detect acute blood
or bony trauma [129].
Evaluation of Secondary Headaches

Zoe is taken to the emergency room, and an emergent
In the evaluation of headaches, signs and symptoms may sug- noncontrast CT scan is performed. Blood pressure is
gest that an underlying disorder is responsible for the head- controlled with intravenous medication, and the fetus
ache. Assessment is made as to whether imaging, lumbar is monitored. The CT shows a subdural hematoma
pucture, blood cultures, blood tests, or urgent treatment is which is evacuated by neurosurgery. The mother and
required. “Red flags” for all headaches include age > 45 with fetus tolerate surgery well and are discharged after
no prior history of headaches, headache onset with sexual several days without complication. One month later,
activity, altered mental status, recent trauma, focal abnor- Zoe delivers a healthy baby girl.
mality on neurologic exam, findings associated with
increased intracranial pressure (i.e., papilledema, pulsatile
tinnitus, pain worsening with supine position), first or worst
headache of life, pain reaching maximal intensity within sec- Summary Points
onds to minutes, or systemic symptoms such as fever, abnor-
mal vital signs, or weight loss [126]. Patients who are 1. Tension-type headaches typically present as bilateral
immunosuppressed or HIV positive have an increased risk of headaches that are mild to moderate in intensity and
intracranial infection. Papilledema can be a sign of benign are often described by patients as having a “band-like
intracranial hypertension which is more common in preg- pressure or tightness.” Cluster headaches usually present
nancy or of increased intracranial pressure from a mass or with severe “stabbing” pain that is unilateral, and typi-
cerebral venous thrombosis. cally focused in the retro-orbital and periorbital regions.
Cluster Headaches classically have associated ipsilateral
lacrimation. Most recurring headaches in the primary
When Should Imaging Be Performed? care setting are migraine headaches.
2. Lifestyle modifications and abortive therapy with triptans
Most headaches can be diagnosed and treated based on his- and NSAIDS are first-line treatments in acute migraines.
tory and clinical exam alone. However, imaging should be NSAIDs with triptans may have a synergistic component
considered for patients with any “red flag” signs or symp- and are often used together. Preventative treatments
toms to evaluate for underlying secondary causes. should be considered with >4 migraines/month. First-line
Neuroimaging is 98.6% sensitive for diagnosing intracranial agents include tricyclic antidepressants, anticonvulsants,
pathology in patients with focal neurologic findings on phys- and beta-blockers. The identification and avoidance of
ical examination, the onset of headaches > age 45, or sudden triggers are important in the management of migraines.
onset of headache [127]. Imaging with CT or MRI is indi- Multimodal management is needed for patients with fre-
cated in the following settings: patients who are unrespon- quent, severe, or chronic migraines.
sive to adequate headache treatment, concern for meningitis 3. Menstrual or estrogen-associated migraines refer to
(prior to lumbar puncture), positional headaches, symptoms migraine attacks that occur in the absence of or decline
suggestive of cluster headaches or other trigeminal auto- of estrogen, after having been previously exposed to
nomic cephalgias, and headaches located in the temporal higher levels of estrogen. Preventative strategies may
region in older adults (in addition to ESR and biopsy). include an evaluation of the patient’s current method of
Patients who are pregnant, are immunocompromised, or contraception and consideration of hormone treatment
have a systemic illness including a hypercoagulable disorder options.
should also be imaged [128]. Patients who lack “red flag” 4. Migraines with aura are associated with an increased risk
signs or symptoms rarely require imaging: neuroimaging of stroke, but the absolute risk is very low.
5. The use of combined oral contraceptives (COCs) should Her BMI is 23, and she is normotensive on physical
be carefully considered in patients with migraines, espe- exam. She denies smoking, or any personal or family his-
cially migraines with auras. Current guidelines recom- tory of stroke, cardiovascular disease, blood clots, or dia-
mend against using COCs in patients with migraines who betes. What is her best contraceptive option?
have risks for stoke and in any patient with migraines A. Recommend stopping combined hormonal contra-
with aura. ceptive pill due to increased stroke risk in women
6. Secondary headache disorders are caused by underlying who take combined hormonal contraceptives.
conditions such as allergic rhinitis, trauma, vascular B. Refill her combined hormonal contraceptive pill.
pathology, and other intracranial abnormalities. Imaging C. Inform her that due to increased stroke risk with
should be considered for patients with “red flag” symp- migraines, she can only use progestin-only or barrier
toms, focal neurologic findings, age > 45–50 with new method contraception options.
onset headache, or sudden/worst headache of life. D. Consider continuing her oral contraceptive, but coun-
sel the patient on stroke risk factors and the impor-
tance of letting you know if she develops aura with
Review Questions her migraines.
The correct answer is D. Recent evidence has demon-
1. A 45-year-old woman presents for worsening headaches. strated that patients with migraines without auras do not
The headaches are pulsating in quality, unilateral, and have an increased risk of stroke and can receive combined
associated with photophobia. She denies any symptoms hormonal contraceptive pills if there are no other contra-
of aura. She notices the headaches most commonly indications or increased stroke risk. She should be
around her menses, but the headaches occur at other screened for additional stroke risk factors and counseled
times, especially when she has increased stress. She had on the importance of letting her provider know if she
infrequent migraines in the past which were successfully develops auras with her migraines which carry an
treated with naproxen. Her current migraines occur 1–2 increased risk of stroke [122, 123].
times per month. She does not smoke. In addition to 3. A 51-year-old woman with a past medical history of
counsel regarding stress, triggers, and musculoskeletal essential hypertension, dyslipidemia, and hypothyroid-
components of head pain, which intervention is the best ism presents for her annual well-woman exam. You
next step to help her headaches? notice on her intake worksheet that she checked the box
A. Placement of copper IUD for headaches. She states that she has recently noticed
B. Prescription of long-acting triptans in the perimen- intermittent headaches with sexual activity. She
strual period describes the headaches as intense, throbbing pain,
C. Initiation of a triphasic combined hormonal contra- located in the back of her head, with a rapid onset of
ceptive (COC) pill minutes after sexual activity. The headaches last for a
D. Behavioral modifications including help with stress half-hour and then resolve spontaneously. She becomes
management nauseous with the headaches and has to lie very still
The correct answer is B. The patient has a diagnosis of when they occur. The headaches have only occurred
menstrually associated migraine (or MAM). Treatment three times, so she didn’t know if it was necessary to
options for MAM include both standard abortive and pre- discuss. Physical exam is notable for a blood pressure of
ventative treatments for migraines: triptans and lifestyle 163/92 and BMI of 31. Neurologic exam is unremark-
modifications, and prevention of the estrogen withdrawal able. What is the next best step in her care?
that occurs during menses. Placement of copper IUD will A. Monitor her symptoms and pursue further evaluation
not improve her migraines which are partly related to hor- if her headaches worsen in frequency or quality.
monal changes. She has already attempted interventions B. Order neuroimaging to evaluate for underlying intra-
to reduce stress, so behavioral modification for stress cranial pathology.
management is not the correct next step. A monophasic C. Discuss that her uncontrolled hypertension is likely
COC is preferred over triphasic COCs in estrogen- the cause of her headaches.
associated or pure menstrual migraines, in order to main- D. Refer her for a neurology consult.
tain a steady dose of estrogen [106, 107]. The correct answer is B. The patient has new onset of
2. A 24-year-old woman presents to clinic to establish care. headaches at >50 years of age, with intense pain, rapid
Her past medical history is notable only for migraine onset, and association with sexual activity (i.e., exertion).
headaches without aura, with no recent change in fre- She should undergo neuroimaging to rule out an underly-
quency or severity. Her only medication is a combined ing intracranial cause of her headaches, given her “red
oral contraceptive, for which she is requesting a refill. flag” “symptoms. Her uncontrolled hypertension could
28 Headaches 449
be the cause of her symptoms, but intracranial patholo- ter headache and other trigeminal‐autonomic cephalalgias. Eur J
gies, including intracranial bleed, must be excluded. Neurol. 2006;13(10):1066–77.
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Neurol. 2017;16(1):76–87.
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Fibromyalgia
29
Anita Leon-Jhong and Sarah A. Tilstra
Learning Objectives
Epidemiology
1. Describe current theories on pathogenesis of Fibromyalgia is a chronic pain syndrome that affects an esti-
fibromyalgia. mated 2–6% of the population [1–3]. It is characterized by
2. Diagnose fibromyalgia using clinical criteria. widespread musculoskeletal pain and fatigue without the
3. Review appropriate, cost-conscious evaluations for presence of abnormalities on physical exam, laboratory tests,
musculoskeletal pain. or biopsy. It is frequently comorbid with other functional
4. Describe an approach to patient education and pain syndromes such as irritable bowel syndrome, interstitial
expectation setting for treatment and prognosis. cystitis, and chronic migraines. The disorder shows female
5. Initiate a patient-centered treatment plan for predominance of approximately 6:1 and prevalence increases
patients with fibromyalgia. with age [1, 3]. Fibromyalgia can be challenging to diag-
nose, and patients often suffer a delay of more than two years
and an average of 3.7 specialist consults before diagnosis,
resulting in further anxiety, stress, and healthcare spending
Niteri is a 33 year-old woman who presents to your [4]. Patients also experience high rates of disability, with
office to discuss pain “everywhere” that has been over 25% of patients in one US study reporting inability to
ongoing for the past two years. She also complains of work [5]. A Dutch study estimated a societal cost of fibromy-
overwhelming fatigue, headaches, insomnia, and fre- algia of €7813 ($9600 USD) per patient per year related to
quent diarrhea. She has been to several specialists and healthcare expenditures and lost work, more than double the
has been told that her symptoms are “all in her head” cost attributable to patients with other rheumatic disease [6].
and that she needs psychotherapy. Her pain and While fibromyalgia was previously under the umbrella of
fatigue have become so severe that she has had to rheumatology, current guidelines recommend that primary
reduce her work hours and is desperate for your help. care providers manage these patients to allow for timely
diagnosis and individualized treatment [7]. Recent research
has helped to increase understanding of the pathophysiology
of fibromyalgia, dispel myths that have hindered patient
care, and provide increased options for treatment.
Pathophysiology
The pathophysiology of fibromyalgia is not well understood,

but current research suggests a biopsychosocial model,
A. Leon-Jhong (*) where environmental and psychosocial triggers compound a
University of Pittsburgh Medical Center, Division of General genetic predisposition toward heightened pain responses [7].
This genetic basis is supported by observations that family
members of patients with fibromyalgia have an eightfold
S. A. Tilstra
greater risk of having fibromyalgia and other chronic pain
Internal Medicine, Department of Medicine, Pittsburgh, PA, USA syndromes compared with the general population [8].

454 A. Leon-Jhong and S. A. Tilstra
The brain of a patient with fibromyalgia appears to be waxes and wanes over time and may migrate to different
primed to detect and magnify even minor discomfort, a state areas of the body. Patients may experience paresthetic sensa-
referred to as “central sensitization” [9]. Studies using functions and be bothered by light touch or tight-fitting clothing
tional MRI show that fibromyalgia patients demonstrate [22]. While pain can sometimes start after a trauma or injury,
increased activity in brain regions responsible for pain pro- more commonly there is no clear inciting event. Fibromyalgia
cessing in response to mild pressure or heat stimuli [10, 11]. pain does not localize to a specific joint or muscle and is not
Fibromyalgia patients also undergo pain “catastrophizing,” associated with signs of inflammation such as joint swelling,
experiencing minor pain as extreme or unbearable, with effusion, or erythema.
observed activation of brain areas responsible for attention, Chronic fatigue is present in a majority of patients with
anticipation, and emotion [12]. A “hypervigilance” model has fibromyalgia [1]. “I’m always tired” and “I feel like I
been proposed as a means of explaining patients’ increased haven’t slept” may be clues to the diagnosis. Sleep quality
sensitivity to stimuli [13]. Patients also demonstrate reduced is poor and non-restorative and may contribute to low func-
ability to modulate pain, possibly due to a deficit in endoge- tion and mood [23, 24]. Patients fatigue easily and may
nous pain inhibition systems [14, 15]. Brain connectivity may have poor tolerance for even low levels of exertion.
also play a role, with research demonstrating elevated resting Cognitive disturbance, often referred to as “fibro fog,” is
brain activity in regions dedicated to pain processing [16]. also common, with patients reporting inability to focus and
Environmental and psychosocial triggers have also been memory impairment. Mood disturbances are prevalent,
identified as important in fibromyalgia pathogenesis. with up to 75% of patients experiencing symptoms of
Infections including Lyme disease, HIV, and hepatitis C have depression and anxiety in their lifetime [25]. All patients
been temporally associated with fibromyalgia development with fibromyalgia should be screened and treated for coex-
[17]. Adverse childhood events and psychosocial distress isting mood disorders. However, fibromyalgia is not a pri-
have also been associated with subsequent development of mary psychiatric condition, and a substantial subset of
chronic widespread pain [18, 19]. Female patients with fibro- patients do not meet criteria for a mental health diagnosis,
myalgia are more likely to report history of physical and sex- though they may feel frustrated or upset by their symptoms.
ual abuse, as well as drug use, compared with their Sexual dysfunction is present in greater than 90% of women
counterparts with other rheumatic diseases [20]. Patients with with fibromyalgia and may be associated with a spectrum
fibromyalgia have high rates of depression and insomnia, of depressive symptoms [26].
conditions which themselves have been linked to decreased In addition to the core symptoms of pain, fatigue, non-
pain tolerance [21]. While there are many unknowns regard- restorative sleep, cognitive dysfunction, and poor mood,
ing the pathogenesis of fibromyalgia, it is helpful for both patients with fibromyalgia may have other “functional” or
provider and patient to recognize that research supports a bio- “central sensitivity” syndromes, several of which are listed
logic basis for disease with environmental influences. in Table 29.1 [16, 27]. Patients are often noted to have a
“pan-positive” review of systems, as they may report abdom-
inal pain and diarrhea suggestive of irritable bowel syn-
Upon further questioning, Niteri reports that her drome, bladder pain and urinary frequency indicating
symptoms started about two years ago and have grad- interstitial cystitis, or sensitivity to lights and sounds in the
ually worsened. She cannot think of any particular setting of chronic headaches. Physicians should strongly
injury or illness that triggered them. She has an achy consider a diagnosis of fibromyalgia in patients with other
pain in her whole body that gets worse after any exer- central sensitivity syndromes who report chronic, wide-
cise, so she has cut down her activity. She always feels spread pain. In addition, identifying these comorbid condi-
tired, even upon waking in the morning, and feels she
cannot think straight, like her brain is in a “fog.” She
frequently gets diarrhea and crampy abdominal pain.
Table 29.1 Conditions frequently comorbid with fibromyalgia
She describes feeling sad and anxious because of her
medical problems. Chronic fatigue syndrome (CFS)
Irritable bowel syndrome (IBS)
Interstitial cystitis (IC)
Chronic tension-type headache
Migraine
Clinical Manifestations Temporomandibular disorder (TMD)
Chronic pelvic pain
The hallmark of fibromyalgia is widespread, chronic muscu- Sexual dysfunction
loskeletal pain. Patients may use phrases like “I hurt all over” Insomnia
or “everything hurts” when describing their symptoms. Pain Multiple chemical sensitivity (MCS)
29 Fibromyalgia 455
tions as they arise may help to prevent unnecessary testing The Widespread Pain Index (WPI) measures pain location:
and guide therapy. patients should endorse pain in at least 7 of 19 body regions.
The Symptom Severity Scale (SSS), scored from 0 to 12,
asks patients to consider how often they experience fatigue,
On physical exam, you appreciate increased tender- waking unrefreshed, and cognitive symptoms [29]. Providers
ness to palpation over Niteri’s abdomen, posterior should be aware of the WPI and SSS as they may be helpful
neck, shoulders, arms, and hips bilaterally. There is no when the diagnosis of fibromyalgia is unclear or when the
joint swelling or deformity and no peripheral edema. patient desires objective evidence of diagnosis. Most patients
She has normal thyroid and neurologic exams. She who describe symptoms suggestive of fibromyalgia can be
appears mildly anxious, but further screening for readily diagnosed based on clinical presentation alone.
depression and anxiety disorders is negative. She won- The clinical evaluation for fibromyalgia starts with taking
ders what tests you plan to order. She is worried about a careful history of the patient’s symptoms. Pain should be
her brain fogginess and inquires about an ongoing for at least 3 months and present in a majority of
MRI. Reviewing her previous workup, you note that body quadrants (i.e., right, left, upper, lower) plus the axial
extensive laboratory testing, X-rays, abdominal CT skeleton. Localized pain suggests a regional pain syndrome.
scan, and EMGs have been normal. As previously discussed, patients will often endorse addi-
tional symptoms such as fatigue, non-restorative sleep, brain
fog, mood changes, and other somatic symptoms. Patients
should be asked about family history of fibromyalgia and
Evaluation and Diagnosis other medical conditions, like autoimmune disease, which
may suggest another diagnosis. The physical exam should
Establishing the diagnosis of fibromyalgia can be very chal- focus on identifying any musculoskeletal abnormalities
lenging, as there are no specific abnormalities on physical which would suggest alternative causes of pain, for example,
exam or laboratory testing that confirm the disorder. joint effusions or warmth suggesting inflammatory arthritis.
Furthermore, as noted previously, patients often have a vari- The exam in fibromyalgia patients is generally normal aside
ety of divergent symptoms which may lead to unnecessary from diffuse tenderness of soft tissues. If fibromyalgia is
referrals and testing if not identified as part of the fibromyal- suggested by history and physical exam, no further labora-
gia syndrome. Providers should therefore have a high index tory or imaging exams are required to make the diagnosis.
of suspicion for fibromyalgia in any patient who describes Patients wait an average of 2–3 years to receive a fibromy-
chronic, widespread pain. algia diagnosis and have often have been told that they are
The American College of Rheumatology (ACR) has “normal” by prior medical providers despite their severe
developed diagnostic criteria for fibromyalgia; the most debility [4]. Diagnosing fibromyalgia helps these patients to
updated version is found in Table 29.2. The criteria are useful avoid unnecessary testing and allows them to focus on treat-
for research and may be helpful, though not required, for ment. There is some evidence that healthcare use decreases
diagnosis in the clinical setting. The original criteria released after fibromyalgia diagnosis, though not all studies have
in 1990 required the presence of “tender points” – specific demonstrated a clear economic benefit [30, 31].
areas of soft tissue where pain could be elicited by applying
modest pressure [28]. However, tender points were not par-
ticularly sensitive or specific and are, therefore, no longer Differential Diagnosis
recommended for diagnosis or monitoring [7]. The updated
ACR criteria focus instead on patient-reported symptoms. When evaluating a patient for suspected fibromyalgia, it is
helpful to exclude common conditions such as thyroid dis-
Table 29.2 American College of Rheumatology Diagnostic Criteria ease, anemia, severe vitamin deficiency, and primary psy-
for Fibromyalgia 2016 Revisions to 2010/2011 Guidelines [29] chiatric disorders like depression or anxiety. This can be
1. Generalized pain present in at least four of five body regions done by taking a careful history and ordering a basic labora-
(four body quadrants and axial skeleton) tory evaluation. The 2012 Canadian Guidelines for the
2. Symptoms present at a similar level for at least 3 months Diagnosis and Management of Fibromyalgia Syndrome
3. Widespread Pain Index (WPI) ≥ 7 and Symptom Severity Scale suggest obtaining a complete blood count (CBC), thyroid-
(SSS) ≥ 5 or WPI = 4–6 and SSS ≥ 9
stimulating hormone (TSH), creatinine kinase (CK), eryth-
4. “A diagnosis of fibromyalgia is valid irrespective of other
diagnoses. A diagnosis of fibromyalgia does not exclude the rocyte sedimentation rate (ESR), and C-reactive protein
presence of other clinically important illnesses” (CRP) [7]. Caution should be exercised when ordering an
Reprinted from Seminars in Arthritis and Rheumatism, Wolfe et al. ESR, CRP, or CK without a specific diagnosis in mind, as
[29], © 2016, with permission from Elsevier elevated results are nonspecific and could lead to additional
unnecessary workup. Similarly, routine testing for antinu- symptoms and provide reassurance that the pain is not a
clear antibody (ANA) is not recommended as it is positive result of tissue damage [7]. The 2012 Canadian Guidelines
in approximately 10% of both the general population and recommend that patients be encouraged to live as normal a
those with fibromyalgia [32]. Iron studies and vitamin B12 life as possible, to remain in the workforce, and to develop
levels can be considered as these deficiencies can mimic the self-efficacy in coping with their symptoms [7]. It is also
fatigue of fibromyalgia. Lyme disease can also have nonspe- important to frame patient expectations on treatment suc-
cific symptoms and should be considered when history and cess. Fibromyalgia is generally a chronic condition that may
physical are suggestive. wax and wane over time, but which will likely affect patients
Rheumatologic disorders can generally be distinguished throughout their lifetime. The goal of all treatment strategies
based on history and physical exam. Rheumatoid arthritis, is an improvement in function and quality of life, rather than
psoriatic arthritis, Sjogren’s syndrome, and systemic lupus a complete elimination of symptoms.
erythematosus cause pain which is localized to the joints
rather than distributed throughout the soft tissue. Joint
inflammation or destruction on exam is suggestive of an Non-pharmacologic Therapies
inflammatory arthritis. Spondyloarthritis presents with pain
and stiffness primarily in the axial skeleton. Polymyalgia Exercise is a cornerstone of fibromyalgia treatment.
rheumatica may mimic fibromyalgia pain but is generally Numerous studies have demonstrated that exercise training
localized to proximal muscle groups and has an elevated is effective in improving fibromyalgia symptoms [36, 37]. A
ESR. Polymyositis can be distinguished from fibromyalgia Cochrane review found high-quality evidence that super-
by the presence of muscle weakness and elevated CK level. vised aerobic exercise training increases physical function
As noted in Table 29.2, the presence of another disease and well-being and may decrease pain. Strength and flexibil-
state does not exclude the diagnosis of fibromyalgia. In ity training require further study to evaluate their effective-
fact, as many as 10–30% of patients with rheumatologic ness [38]. Another Cochrane review found that aquatic
diseases like rheumatoid arthritis and lupus also have fibro- exercise training is equivalent to land-based programs and
myalgia [33]. may be more tolerable to some patients [39]. Unfortunately,
many patients will have difficulty exercising due to chronic
fatigue and easy fatigability. Patients with fibromyalgia tend
Based on her history and exam, you diagnose Niteri to perceive higher exertion than fitness-matched controls
with fibromyalgia and tell her she does not need any when completing the same activity [40]. Patients may also
more testing. You explain that although there is no cure experience an increase in pain initially when starting an exer-
for fibromyalgia, you will work together to improve her cise program and should be encouraged to “start low, go
quality of life. She is relieved to finally have a diagno- slow.” For patients who are having difficulty exercising on
sis. You ask her what symptoms are bothering her the their own, it may be helpful to prescribe physical therapy or
most currently. She reports pain and difficulty sleep- a structured exercise program to get started [7, 41].
ing, so you prescribe a low dose of pregabalin to take Complementary and alternative therapies are used by an
at night. You also recommend that she start an exercise estimated 90% of fibromyalgia patients and have some evi-
program, advising her to start slowly as her symptoms dence for their efficacy [42]. The European League Against
may flare at first. You ask her to see you again in a Rheumatism (EULAR) gives a weak recommendation for
month to see how she is feeling. meditation, mindfulness, cognitive behavioral therapy
(CBT), and acupuncture [41]. A randomized trial of tai chi
vs. education and stretching found improved quality of life
with tai chi that was sustained at 24 weeks [43]. A meta-
Management analysis of six trials of mindfulness-based stress reduction
showed short-term improvements in quality of life [44].
The treatment of fibromyalgia requires a multimodal Cognitive behavioral therapy was evaluated in a Cochrane
approach that includes both pharmacologic and non- review and found to reduce pain, low mood, and disability,
pharmacologic strategies [34]. One of the most important with results sustained at 6 months [45]. Another Cochrane
components of treatment is patient education. Patients may review found that acupuncture is safe and reduces pain and
feel uncertain about the diagnosis or have experienced stigma stiffness in fibromyalgia patients, but does not perform better
from healthcare providers who implied their symptoms were than sham acupuncture and has no sustained effect at
exaggerated or purely psychological [35]. It can be helpful to 6 months [46]. Therapies which are not recommended by
frame fibromyalgia as a common condition, likely based in EULAR due to lack of evidence for benefit include biofeed-
aberrant pain processing. Physicians should validate patients’ back, hypnotherapy, massage, chiropractic, and homeopathy
29 Fibromyalgia 457
Table 29.3 Medications recommended for treatment of fibromyalgia by the European League Against Rheumatism (EULAR) [41]
Treatment considerations and
Medication (drug class) Recommended dose Summary of study results common side effects (SE)
Amitriptyline (TCA) 10–25 mg/day at NNT 4.1 for 50% pain reduction. No additional benefit to doses
bedtime Very poor quality evidence available [51] >25 mg. Useful for insomnia.
SE: dry mouth, sedation, dizziness,
weight gain
Pregabalin 300–600 mg/day NNT 7.2 for 30% pain reduction. NNT 11 to feel Useful for insomnia and anxiety.
(gabapentinoid) “much or very much improved” [52] SE: dizziness, sedation, weight
gain, edema
Cyclobenzaprine 10 mg/day at bedtime NNT 4.8 to feel “improved.” Some sleep benefit. High rate of side effects (85%) and
(muscle relaxant) or 10 mg TID No effect on pain [53] trial dropout.
SE: sedation, dry mouth
Duloxetine (SNRI) 60–120 mg/day in NNT 10 for 30% pain reduction. Improved Consider in patients with
morning patients’ “global impression.” depression or anxiety.
Milnacipran (SNRI) 100–200 mg/day in No effect on fatigue, sleep, or QOL [54] SE: nausea, headache, dry mouth,
divided doses constipation
Tramadol (opioid) 37.5 mg QID 25% reduction in pain scores when combined Weak opioid with potential for
with acetaminophen 325 mg [55] abuse and diversion.
SE: nausea, dizziness, constipation
Adapted and updated from Macfarlane et al. [41]
NNT number needed to treat, QOL quality of life, TCA tricyclic antidepressant, SNRI serotonin norepinephrine reuptake inhibitor
[41]. In general, complementary and alternative therapies are should try a tricyclic antidepressant (TCA) or gabapentinoid.
well tolerated with minimal side effects, so there is little In general, all medications have only a modest effect on pain
harm to trying them, though they may not be available to all and do not produce sustained results once discontinued. In
patients. addition, fibromyalgia patients often experience high rates of
side effects. It is prudent, therefore, to start at the lowest dose
possible and slowly increase as tolerated. A combination of
Pharmacologic Therapies several low-dose medications may be helpful.
Several medications have been studied for the treatment of

fibromyalgia and should be considered an adjunct to educa- Follow-Up and When to Refer
tion and exercise. Medications recommended by EULAR are
listed in Table 29.3 along with common doses and side In general, patients with fibromyalgia should receive care
effects. Only pregabalin, duloxetine, and milnacipran have from their primary care provider, as referral to a specialist
FDA indications for fibromyalgia, but others, including ven- has not been demonstrated to improve outcomes [50].
lafaxine and gabapentin, may be considered for off-label use. Patients with an unclear diagnosis and those who are not
EULAR recommends against nonsteroidal anti-inflammatory improving may benefit from seeing a specialist. A multidis-
drugs (NSAIDs), selective serotonin reuptake inhibitors ciplinary team that includes physical therapy, nursing, and
(SSRIs), and monoamine oxidase inhibitors (MAOIs) due to psychology may be the best option for management, but may
lack of evidence for benefit. Low-dose naltrexone (4.5 mg not be available to many patients. Recognizing that fibromy-
per day) is an emerging therapy which has shown promise algia is a lifelong condition, providers should maintain a
for pain relief and is well-tolerated [47]. Synthetic cannabi- close relationship with their patients through regular appoint-
noids have also demonstrated benefit and may be a future ments. This allows for management of new symptoms,
option [48]. Both the EULAR and Canadian Guidelines identification and care of comorbidities, and support for

strongly recommend against opioids, citing their unclear patients to live the fullest life possible.
benefit and high risk for adverse effects including addiction
and hyperalgesia. Despite this, more than 30% of patients
with a fibromyalgia diagnosis receive opioids [49]. Summary Points
When choosing an initial medication, it may be helpful to
ask the patient what symptom is most bothersome (i.e., 1. Fibromyalgia is understood to be a disorder of central
fatigue, sleep, pain, mood) and choose a medication with pain processing whose pathogenesis involves both genetic
added benefit for that symptom. Patients with anxiety or and environmental factors.
depression should consider a serotonin norepinephrine reup- 2. Diagnosis of fibromyalgia is based on patient history of
take inhibitor (SNRI), while those with sleep disturbances widespread musculoskeletal pain lasting greater than
3 months which is not explained by another condition. A. Diagnose fibromyalgia and recommend no further
Evaluation of tender points is not required for diagnosis. testing.
3. Diagnostic workup in patients suspected of having fibro- B. Check ANA, rheumatoid factor.
myalgia should be limited. Delay in diagnosis of fibromy- C. Order cervical spine and elbow X-rays.
algia leads to unnecessary testing and patient distress. D. Order Lyme serology.
4. Treatment aims to improve function and quality of life; The correct answer is A. This patient has a classic pre-
patients should be counseled to anticipate modest reduc- sentation of fibromyalgia with chronic, widespread myal-
tions in pain, but not to expect full resolution of gias and tender points without evidence of joint or muscle
symptoms. inflammation. Diagnosis is based on history and exam
5. Initial management of fibromyalgia includes patient edu- alone and does not require any specific laboratory testing
cation, initiation of an exercise regimen, and pharmaco- [29]. Additional testing should be reserved for patients
logic treatment using TCAs, SNRIs, gabapentinoids, with signs and symptoms suggestive of alternative condi-
cyclobenzaprine, or tramadol. Opioids are not tions such as inflammatory arthritis, osteoarthritis, or thy-
recommended. roid disease. It is important to establish the diagnosis of
fibromyalgia as early as possible to help patients avoid
unnecessary testing and to initiate treatment.
Review Questions
3. A 36-year-old woman with irritable bowel syndrome and
1. A 32-year-old woman with a history of depression pres- generalized anxiety disorder presents to your office with
ents to your office with chief complaint of “hurting all debilitating body pain and fatigue for the past year. Based
over.” On further questioning, she reports pain and swell- on her history and unremarkable physical exam, you sus-
ing in bilateral knees, hips, and wrists which has been pect fibromyalgia. You order a CBC, TSH, and B12 level
ongoing for at least 4 months. She also feels tired easily. which are within normal limits. What is your initial
Physical exam reveals moderate effusions at her knees approach to management?
and wrists and is otherwise unremarkable. What is the A. Refer to a rheumatologist.
next most appropriate step in management? B. Start oxycodone.
A. Screen for depression symptoms. C. Start duloxetine.
B. Provide a prescription for duloxetine. D. Begin an intensive exercise program.
C. Recommend an exercise regimen. The correct answer is C. The three medications cur-
D. Test for rheumatoid factor and anti-CCP. rently approved by the FDA for treatment of fibromyalgia
The correct answer is D. This patient does have several are duloxetine, milnacipran, and pregabalin. TCAs, gaba-
risk factors for fibromyalgia (female sex, history of mood pentin, and cyclobenzaprine have also been studied as
disorder) and has some suggestive symptoms (wide- first-line therapy. Opioids are not recommended due to
spread, chronic pain and fatigue). However, her exam is lack of efficacy and risk of side effects and addiction.
not consistent with diagnosis of fibromyalgia as she has While exercise is a crucial part of treatment, patients
evidence of joint inflammation. Patients with fibromyal- should generally start slowly as pain symptoms may flare
gia have a normal physical exam aside from soft-tissue with overexertion. Referral to specialist can be considered
tenderness and have normal lab findings. Therefore, it is if a patient does not respond to initial therapy.
most appropriate to work up other causes of her joint
inflammation at this time, including rheumatoid arthritis. 4. Edith is a 49-year-old woman who has been suffering
from generalized body pain for several years. She has
2. A 42-year-old woman presents to your office for a follow- seen several providers and undergone many tests which
up visit. She reports feeling “constantly achy” for the past have been unrevealing. You see her in the office today and
6 months and being tired all the time despite sleeping suspect fibromyalgia. She is skeptical (“are you saying
9 hours per day. Her depression screen is negative. On nothing is wrong with me?”) but agrees to start dulox-
physical exam, she has significant pain with applied pres- etine. She wants to know how soon she can expect to feel
sure to bilateral occiput, trapezius, sternocleidomastoid, better. How do you counsel her?
lateral epicondyle, and greater trochanter. Physical exam A. “We will continue to work together until we find a
is otherwise normal. She had a CBC and TSH checked treatment that fully relieves your pain.”
earlier this year for fatigue which were normal. She B. “Because fibromyalgia is a psychiatric condition, you
looked up her symptoms online and is concerned for may benefit from cognitive behavioral therapy.”
lupus and Lyme disease. What is next best step in C. “I expect you will start to feel much better once you
management? begin an exercise program.”
29 Fibromyalgia 459
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Interstitial Cystitis/Bladder Pain
Syndrome 30
Sumana Koduri
Learning Objectives Background
1. Define interstitial cystitis/bladder pain syndrome Interstitial cystitis (IC) or bladder pain syndrome (BPS) is a
(IC/BPS) and describe the typical patient female predominant, debilitating disorder characterized by
presentation. pain with bladder filling that is partially relieved by emptying,
2. Discuss the differential diagnosis of a patient with urinary frequency, and urgency. The American Urological
irritative voiding symptoms. Association defines IC/BPS as “an unpleasant sensation
3. List the common comorbidities associated with IC/ (pain, pressure or discomfort) perceived to be related to the
BPS. urinary bladder, associated with lower urinary tract symp-
4. Review the initial diagnostic strategy and manage- toms of more than six weeks duration, in the absence of infec-
ment of a woman with symptoms consistent with tion or other identifiable causes” [1]. Other common
suspected IC/BPS. symptoms include nocturia, pain with intercourse, chronic
pelvic pain, and occasionally hematuria. The terms IC and
BPS are interchangeably used in the literature; therefore, the
combined abbreviation IC/BPS will be used in this chapter.
Ingrid is a 42-year-old woman who presents with com-
plaints of urinary urgency, frequency, and burning. She
has pain unless she empties her bladder and voids Epidemiology
about every ½–1 hour in order to relieve her symp-
toms. She wakes up five to eight times a night to uri- The prevalence of IC/BPS has increased over the years,
nate. Her symptoms have progressed over the past which corresponds to less stringent criteria for the diagnosis
2 years. She has been treated for six UTIs and several over time. Roughly 2.7–6.5% of Americans suffer from IC/
yeast infections in that time period. She has been going BPS based on a population-based study of the US Census
to an urgent care clinic whenever she is symptomatic. data in 2011 [2]. The ratio of women to men has consistently
been ~9:1 in many studies with no racial predilection noted
[3]. Most women are diagnosed in their 30s–40s with a mean
of 10 years from symptom onset to diagnosis. One study also
showed that only 9.7% of patients meeting criteria for IC/
BPS were actually given a diagnosis of IC/BPS, exposing the
large potential for underdiagnosis [2].
Physiology and Pathophysiology
The pathophysiology of IC/BPS is not well understood. The

S. Koduri (*)
condition of interstitial cystitis was initially recognized by
Medical College of Wisconsin, Froedtert Memorial Lutheran
Hospital, Department of Obstetrics and Gynecology, Hunner in 1915 who described an ulceration noted in the blad-
Milwaukee, WI, USA der during distension via cystoscope [4]. Later authors found
e-mail: [email protected] that glomerulations (petechial hemorrhages) in the bladder

462 S. Koduri
wall were more commonly seen than an ulceration when the agnosed with urinary tract infections, vaginitis, or sexually
bladder was distended [4].The etiology for the abnormal find- transmitted infections for months or years before IC/BPS is
ings was thought to be from a defective glycosaminoglycan considered in the differential. Patients are often frustrated with
(GAG) protective layer in the bladder mucosa [5]; this causes the lack of effective treatment for their symptoms and are
a “leaky epithelium” in which toxins or substances in the urine eventually referred to a urologist or urogynecologist for per-
could penetrate the mucosa and induce inflammation and sistently negative urinalyses, negative urine cultures, and the
symptoms. Subsequent studies, however, have shown that lack of response to antibiotics or antifungal therapy.
even asymptomatic women can have glomerulations when the The development of IC/BPS may coincide with trauma or
bladder is hydrodistended, which has brought this theory into instrumentation to the pelvic area [18, 19], which patients
question [6]. Other mediators recognized in IC/BPS include may not associate with the start of symptoms, including hys-
histamine, a defect in the urinary Tamm-Horsfall protein, the terectomy, hysteroscopy, bladder catheterization, cystos-
peptide inhibitor antiproliferative factor, and inflammation copy, kidney stones, colonoscopy, pregnancy, and other
caused by a urinary tract infection [7, 8]. pelvic or abdominal procedures. IC/BPS may also be associ-
Chronic pelvic pain conditions are frequently present con- ated with a history of adverse childhood experiences and
comitantly in IC/BPS patients, including endometriosis, irri- sexual trauma/abuse [20]. Commonly, women with IC/BPS
table bowel syndrome, and vulvodynia. For this reason, it has have been treated for other known pelvic pain conditions
been theorized that a systemic process, central sensitization, such as endometriosis, dysmenorrhea, or irritable bowel syn-
may facilitate the development of IC/BPS [9–11]. According drome. Pelvic floor dysfunction, coccydynia, piriformis syn-
to this theory, other conditions that cause pelvic pain upregu- drome, and anismus share a common pathophysiology with
late the dorsal horns in the lower spinal cord, particularly at IC/BPS, visceral sensitization, and therefore may be seen
the T10–T12 levels. The visceral convergence of the neurons concomitantly in these patients [18, 21, 22].
in this area allows the nociceptive input from the bladder to be The lag from onset of symptoms to appropriate evaluation
amplified, causing increased bladder pain with even normal and diagnosis of IC/BPS can be as long as 5–10 years [2, 15].
distension. Once the process of central sensitization has Delays in diagnosis are caused by the insidious onset of
started, it is very difficult to normalize pain processing, and a symptoms, overlapping symptoms of IC/BPS with other dis-
state of chronic pain perception is maintained. The propensity eases, the natural waxing and waning trajectory of IC/BPS,
for developing a chronic pain condition such as IC/BPS is also and the lack of provider familiarity with the diagnostic crite-
seen with a tendency to develop chronic pain elsewhere in the ria for IC/BPS. A patient’s quality of life can be greatly
body [10, 12]. Studies show that the periaqueductal gray improved with proper diagnosis and control of the predomi-
region in the brain is a threat monitor for pain, and it is theo- nant symptoms: pain, frequent urination, and nocturia [23].
rized that dysfunction in this area of the brain may be impli-
cated in development of multiple comorbid pain conditions
[13, 14]. The pathophysiology of IC/BPS is complex, and the Differential Diagnosis
understanding of the mechanisms involved is still evolving.
The differential diagnosis of IC/BPS is broad due to the com-
plexity of the anatomy in the abdomen and pelvis and
Clinical Manifestations includes recurrent urinary tract infections, chronic urethritis,
overactive bladder, genitourinary syndrome of menopause,
The hallmark symptoms of IC/BPS are bladder pain, urinary vulvodynia, endometriosis, irritable bowel syndrome, pelvic
frequency, dysuria, and nocturia [15, 16]. The pain tends to be floor dysfunction, and neuropathic pain. The history and uri-
relieved with voiding and felt mostly in the bladder and supra- nalysis are helpful in differentiating these conditions from
pubic region, but can be referred to other areas within the pel- IC/ BPS, although many of these conditions can coexist with
vis including the lower quadrants of the abdomen, the IC/BPS (see Table 30.1).
gynecologic organs, or the vulva. Urinary frequency is more
often seen in women <30 years old, while nocturia increases Urinary tract infection The symptoms of IC/BPS are very
as patients age [7]. Typically, symptoms wax and wane over similar to those of a urinary tract infection. An uncompli-
time, lasting for hours to days or weeks. Ninety percent of cated urinary tract infection is often empirically treated, but
women describe diet sensitivity to certain foods that can exac- once the symptoms become recurrent, the diagnosis should
erbate their pain – most commonly caffeine, alcohol, soda, be questioned. A negative urinalysis and urine culture can
artificial sweeteners, spicy foods, and citrus fruits [17]. Flares rule out recurrent urinary tract infections.
tend to last hours to days and can be triggered by menstrual
cycles, intercourse, stressful situations, and increased physical Urethritis An undiagnosed urethritis caused by N. gonor-
activity. During pregnancy symptoms can worsen, improve, or rhoeae, C. trachomatis, or atypical bacteria such as myco-
remain the same. Women with IC/BPS are commonly misdi- plasma (M. hominis, M.genitalium) and ureaplasma (U.
30 Interstitial Cystitis/Bladder Pain Syndrome 463
Table 30.1 Differential diagnosis of interstitial cystitis/bladder pain syndrome and overlapping clinical features [1, 7, 12, 13, 15, 17, 18, 22,
24–30]
Pelvic Urinary
pain Dysuria frequency Pyuria Hematuria Nocturia Dyspareunia Pearls
Interstitial cystitis/ + + + +/− +/− + + Negative urine culture
bladder pain Pain relived with voiding
syndrome
Urinary tract + + + + +/− +/− + Positive urine culture
infection Pain worse with voiding
Chronic urethritis/ + + + + +/− +/− + Infectious, immunosuppressed,
cystitis radiation induced
Sexual transmitted + +/− +/− +/− +/− − + GC/CH, trichomoniasis, NGU, myco-/
infection(s) uroplasma
Irritable bowel + − +/− − − − +/− GI > GU symptoms
syndrome
Overactive − − + − − +/− − Usually painless
bladder
Genitourinary + + + +/− +/− + + Atrophy on exam
syndrome of
menopause
Vulvodynia + − − − − − + Pain without urinary symptoms
Endometriosis + − − − +/− − + Concomitant in 50% of patients
Rare bladder/urethral endometrial
implants
Pelvic floor + +/− +/− − − − + Spasm can cause dysuria/frequency
dysfunction
Neuropathic pain + − − − − − + Central sensitization
Can be induced post-procedure
Genitourinary + +/− +/− +/− +/− +/− +/− Consider malignancy in any patient
malignancy with hematuria
NGU non-gonococcal urethritis, GI gastrointestinal, GU genitourinary
urealyticum) may mimic symptoms of IC/BPS. Chlamydia differentiating the two, as uninhibited detrusor contractions
and other STIs can be excluded by polymerase chain reac- will be observed in overactive bladder [30].
tion (specific for organism) in patients at risk [1].
Genitourinary syndrome of menopause Genitourinary syn-
Nephrolithiasis and malignancy A urinalysis is important in drome of menopause (GSM) is a syndrome encompassing
detecting microscopic hematuria and screening for urinary vaginal dryness, dyspareunia, urinary frequency, urgency,
tract pathologies. Hematuria should trigger a workup for nocturia, and dysuria. Vaginal estrogen therapy is found to be
nephrolithiasis or malignancy which can both present with 80–90% effective in treating the symptoms of GSM [28];
pain, dysuria, and frequency. Patients with a cancer history therefore, IC/BPS is entertained as a diagnosis in postmeno-
should be asked about prior chemotherapy and radiation, as pausal women only if symptoms persist after appropriate
cystitis can cause similar symptoms. Any patient with unex- treatment of GSM.
plained hematuria should be evaluated with cystoscopy and
upper urinary tract imaging to help differentiate among Painful pelvic and gastrointestinal conditions Endo
benign and malignant etiologies [1]. metriosis, vulvodynia, irritable bowel syndrome, and pelvic
floor dysfunction may cause bladder pain through central
Overactive bladder In the absence of any obvious urinary sensitization [18, 22]. When pelvic or abdominal conditions
tract pathology, overactive bladder (OAB) is the most com- are identified, treatment is initiated in conjunction with the
mon diagnosis that can be confused with IC/BPS [15]. treatment of IC/BPS. The following features are helpful in
Urinary frequency is seen in both conditions as are urgency distinguishing diagnoses:
and nocturia. The differentiating symptoms are (1) pain,
which is more common in IC/BPS, and (2) incontinence, • Vulvodynia typically manifests with burning/pain in the
which can be seen in OAB but not typically in IC/ BPS. The vulva that may be associated with tampon insertion or
motivation to void for patients with OAB is the strong with insertion during intercourse.
urgency to void and fear of an incontinent episode, while • Endometriosis is typically associated with dysmenorrhea,
patients with IC/BPS void frequently to eliminate bladder dyspareunia (more with deeper thrusting rather than with
pain or discomfort [1, 30]. Urodynamics can be helpful in insertion), mittelschmerz (ovulation pain), and sensitivity
464 S. Koduri
to hormonal changes during a menstrual cycle. Hormonal Diagnostic Strategies

treatments aimed at suppressing ovulation are very effec-
tive in endometriosis and may help differentiate endome- The diagnosis of IC/BPS is challenging and anchors on a
triosis from IC/BPS. Laparoscopy may be helpful to careful history and physical. IC/BPS is a clinical diagnosis
diagnose endometriosis, but its presence does not rule out and largely a diagnosis of exclusion. The evaluation should
IC/BPS. Up to 50% of patients with endometriosis also target conditions that also cause pelvic pain and overlap with
have IC/BPS, and hence these two conditions have been the symptomatology of IC/BPS. Occasionally, other diag-
termed the “evil twins” [29]. nostic studies or even empiric treatment of comorbid condi-
• Irritable bowel syndrome typically causes crampy abdom- tions are needed to help narrow the diagnosis.
inal pain associated with either constipation and/or diar-
rhea, fecal urgency, and, rarely, fecal incontinence.
• Pelvic floor dysfunction caused by triggering myofascial History
points within the pelvic floor muscles may be a result of
sensitization from these visceral pain conditions and is Elements of the history should include a complete urologic,
present in up to 85% of patients with IC/BPS [24]. gynecologic, gastrointestinal, and psychiatric history and
Hypertonic pelvic floor dysfunction should be considered review of systems. The patient should be asked about a his-
in the differential diagnosis of IC/BPS or as a coexisting tory of urinary tract infections, kidney stones, and the pres-
condition with IC/BPS that will also need treatment. ence of gross hematuria; a gynecologic history includes
• Pudendal neuropathy is commonly seen in patients with questions regarding STIs, pelvic inflammatory disease, dys-
IC/BPS and pelvic floor dysfunction; it can be challeng- pareunia, endometriosis, structural conditions, and gyneco-
ing to diagnose and to manage. The pain associated with logic or urologic instrumentation. A history of symptoms of
pudendal neuropathy usually worsens with sitting and is IBS should be noted. Questions about comorbid medical and
relieved with standing [27]. chronic pain conditions and abdominal/pelvic surgeries
• Somatoform disorder is commonly seen in IC/BPS and should be noted. A mental health history including known
should be explored in the differential diagnosis of IC/ diagnoses, history of PTSD, history of sexual abuse or
BPS. These patients tend to have allodynia upon exami- trauma, and a history of catastrophizing tendencies should be
nation. Catastrophizing tendencies are seen commonly in obtained. A questionnaire including these elements can be
IC/BPS patients and can be a clue that a somatoform dis- completed by the patient and reviewed with the patient at the
order may be at play. time of initial presentation [31].
• Psychiatric conditions including depression, anxiety, post- In review of systems, urinary urgency, frequency, signifi-
traumatic stress disorder, panic disorder, and intimate part- cant nocturia, and dysuria should be noted. Pain with a full
ner violence are seen more commonly in women with IC/ bladder that is relieved with emptying is indicative of IC/
BPS and may manifest as IC/BPS symptomatology [9, BPS, whereas a feeling of urgency that, if not relieved, may
21]. cause an incontinence episode implies an overactive bladder
component. Questions about dietary triggers of pain or
Further reading on these topics can be found in these urgency/frequency and diuretic use, particularly in the eve-
chapters: Chap. 10 on Fibroids, Endometriosis, Ovarian ning hours, are important. A 24–48-hour voiding diary
Cysts, Chap. 12 on Vaginitis and Vulvar Conditions, Chap. including dietary/liquid input and voiding times with output
13 on Sexually Transmitted Infections, Chap. 24 on Urinary can be particularly helpful. Elements that can cause a flare of
Tract Infections, Chap. 27 on Irritable Bowel Syndrome, symptoms should be elicited if possible, such as stress, the
Chap. 31 on Chronic Pelvic Pain, and Chap. 33 on Depressive menstrual cycle, sexual activity, or certain activities.
and Anxiety Disorders.
Ingrid has a long-standing history of anxiety that is Physical Examination

well controlled despite a recent divorce. On exam, she
has suprapubic tenderness; pelvic examination shows The goal of the physical exam is to evaluate for comorbid
normal external genitalia and vaginal mucosa and illness and other primary causes of pain that may refer to the
hypertonic pelvic floor muscles, with tenderness of the pelvis and/or bladder. It is helpful to start with a general
bladder and pelvic floor muscles. The uterus, cervix, physical exam including evaluation of posture, a musculo-
and adnexa are nontender. A urine culture and STI skeletal examination evaluating the back, and a neurologic
screen are obtained as a test of cure for the last UTI exam. Arthritis of the hip can refer pain to the pelvis and can
and to screen for sexually transmitted infections. be evaluated with provocative maneuvers in the standing and
supine positions.
Thorough abdominal and pelvic exams are essential.

The abdominal examination is performed in the supine
position. At this time, the bony parts of the pelvis can be
palpated particularly on the pubic bone looking for signs of
chronic suprapubic pain from osteitis pubis, pubic symphy-
sis relaxation, or rectus muscle inflammation at its insertion
to the pubis. One should check for tenderness and masses
in the various quadrants of the abdomen to evaluate for
abdominal pathology and/or for suprapubic tenderness that
is commonly seen in IC/BPS. Any rigidity, guarding, or
rebound tenderness can imply an acute process such as
diverticulitis, pelvic inflammatory disease, colitis, or an
appendicitis and signals a medical emergency. Distension,
bowel sounds, ascites, masses, vascular bruits, and superfi-
cial vs deep tenderness should be noted. Superficial tender-
ness may imply a neuropathic process or a musculoskeletal/
fascial process. Deeper palpation may help evaluate the Fig. 30.1 The technique to help isolate bladder tenderness [27].
deep visceral structures such as the bowel, bladder, and (Reprinted with permission from Wolters Kluwer, Howard [27])
gynecologic organs. The ilioinguinal and iliohypogastric
nerves should be evaluated for sensory deficits including Uterine tenderness may be present in the setting of pelvic
hyperalgesia or allodynia, which is the perception of nox- infection, endometritis, or endometriosis. Only after comple-
ious stimuli with light touch. tion of this single digit exam, the traditional bimanual exam
The pelvic exam is then performed in the lithotomy posi- with two fingers in the vagina and the second hand on the
tion. The external genitalia should be inspected for any vul- abdomen is performed (see Chap. 3 on The Female Sex and
var lesions, vestibular erythema, skin changes, perianal Gender Specific History and Examination for full details on
lesions, fissures, and fistulae. The urethral meatus should be performing the pelvic exam). Tenderness that is elicited on a
inspected for any lesions or a caruncle. A urethral caruncle is bimanual exam, but not the single digit examination, may
an inferior erythematous protrusion of the urethral mucosa mistakenly be thought to be pelvic when it is in fact abdomi-
commonly seen in atrophic menopausal women. The absence nal in origin. The bimanual exam assesses the size, contour,
of labia minora may also indicate genital atrophy or lichen and mobility of the uterus, attempts to palpate any adnexal
sclerosus. Hypersensitivity or allodynia of the thoracic and masses or tenderness, and confirms or better characterizes
lumbar nerves should be evaluated along the mons area, the tenderness felt on the single digit vaginal examination. A
groin, labia, and perirectally, as well as the thighs and lower rectal and/or rectovaginal examination is performed last in
extremities. Bulbocavernosus and anal wink reflexes should the lithotomy position to evaluate for any rectal masses or
be elicited as part of the pudendal nerve evaluation. A cotton hemorrhoids and to better palpate the adnexa or a retroverted
swab may be used to check for tenderness along the vulvar uterus. Any vaginal discharge should be sampled and evalu-
vestibule assessing for vulvar vestibulitis. ated with a wet mount, if available, and specimens can be
It is helpful to first start with a single digit examination of obtained to evaluate for sexually transmitted infections.
the vagina. First the perineal body is palpated followed by Examinations must be performed with gentleness and
the levator muscles. The various muscles that can be appreci- caution as maneuvers during the pelvic examination may
ated with the single digit vaginal examination are the trigger pelvic floor spasm and limit the remainder of the
puborectalis, obturator internus, iliococcygeus, coccygeus, examination. Care should be taken to involve the patient and
and piriformis muscles. These muscles should be evaluated keep her informed every step of the way, watching for any
for spasm, which is commonly seen in visceral pelvic pain negative reaction from the patient during the examination.
disorders [32]. The urethra and the bladder are then palpated Anxiety or prior negative experiences can trigger a post-
and evaluated for urethral diverticula, urethral tenderness, traumatic reaction, and the patient may distance herself from
trigonal tenderness, and bladder tenderness. The technique the examination. This may limit the information obtained
to help isolate bladder tenderness is shown in Fig. 30.1. during the evaluation. The presence of any hypertonicity or
Using a single digit for examination, the cervix is pal- vaginismus during the examination or at the beginning of the
pated for tenderness, which can be a sign of cervicitis or pel- examination should be documented.
vic infection. The posterior fornix is then evaluated for any Please refer to Chap. 31 on Chronic Pelvic Pain to read
uterosacral nodules that may be seen in endometriosis. more about the gynecologic exam in women with chronic pain.
466 S. Koduri
Testing Treatment Strategies
Laboratory evaluation is very limited in the diagnosis of IC/ The goal of treatment for IC/BPS is improvement of symp-
BPS, except to rule out an infectious process by urinalysis, toms and quality of life. A patient-centered approach is key
urine culture, and/or testing for sexually transmitted in management of this syndrome where symptoms can vary
infections. from mild to debilitating in the absence of correlating physi-
Urinalysis in patients with IC/BPS may be difficult to cal findings. The American Urological Association treatment
interpret as up to 40% of patients can have microscopic or guidelines (Fig. 30.2) have formalized management of IC/
gross hematuria [33] which does not necessarily correlate BPS into a step-by-step approach [1, 38] to help patients and
with disease severity or cystoscopic findings [34]. Urinalysis providers. Patient education is very important in obtaining
can also be bland or have mild pyuria, though urine cultures patient buy-in.
should always be sterile [35]. If sterile pyuria persists, other All patients should be offered first-line treatment which
etiologies for urinary symptoms, other than IC/BPS, should includes behavioral modification and self-care techniques.
be pursued [36, 37]. Urine cytology should be considered if Patient education about the disorder can help manage
microscopic or gross hematuria is present, as symptoms of expectations and allow self-assessment of her triggers to
IC/BPS can overlap with those of urinary tract malignancy. manage them appropriately. As approximately 90% of
All other laboratory evaluations should be based on symp- women with IC/BPS report a sensitivity to certain foods, an
tomatology, to evaluate for a particular diagnosis rather than elimination diet tends to be quite helpful in management
to screen for disease. Imaging studies should be conducted [39]. Significant foods to avoid include caffeine, alcohol,
with the same intention and specificity, in order to minimize soda, artificial sweeteners, and acidic and spicy foods.
incidental findings. Ultrasound, CT scan, and MRI should Acid-reducing products such as baking soda slushes, cal-
be geared toward a specific pathology, keeping in mind the cium glycerophosphates, and antacids can be helpful in tol-
sensitivity and specificity of the test for the condition that is erating certain foods. Stress management should be
being targeted. Patients should be imaged when there is encouraged due to its association with flares of symptoms.
clinical or physical concern for an abdominal or pelvic mass Cognitive behavioral therapy, meditation, and pelvic floor
and in cases of microscopic or gross hematuria. relaxation can be learned.
Focused bladder testing should include a post-void resid- Symptomatic relief during flares can be obtained from
ual to rule out overdistension of the bladder and to obtain a products such as phenazopyridine or methylene blue-
baseline as some treatments can cause retention of urine containing medications that may be obtained over the coun-
(e.g., anticholinergic medications). Cystoscopy by a urolo- ter or as a prescription. These agents act as analgesics for the
gist or urogynecologist can be helpful in evaluating for bladder and can help with the dysuria, urgency, and fre-
pathology of the urinary tract, particularly during the workup quency temporarily, but should not be used long term [1].
of hematuria, but is not always necessary in the evaluation of The second-line treatments for IC/BPS include physical
IC/BPS. Glomerulations or petechial hemorrhages of the therapy techniques and medication regimens taken either
bladder mucosa may be seen in IC/BPS when the bladder is orally or instilled in the bladder and should be offered in
hydrodistended under ~80 cm H2O pressure for a few min- conjunction with first-line treatments. The majority of
utes and should be documented, but its absence does not rule women with IC/BPS have hypertonic pelvic floor dysfunc-
out IC/BPS [1]. In a patient with bladder pain, the cystos- tion and therefore can benefit from manual physical ther-
copy should be done under anesthesia if needed. Urodynamic apy (PT) or pelvic floor physical therapy [18]. PT is geared
testing is also considered invasive; it is helpful in ruling out toward reducing the spasm of the pelvic floor muscles and
other voiding disorders of the bladder such as overactive increasing relaxation and lengthening of the pelvic mus-
bladder and urinary retention, but is not needed to rule out cles. PT may be ordered directly by the primary care pro-
IC/BPS. The classic findings in IC/BPS on urodynamic test- vider. Strengthening of the pelvic floor muscles through
ing are low bladder capacity and the absence of involuntary Kegel exercises is strongly discouraged as it can trigger
detrusor contractions [30]. spasm and pain.
Medications that have demonstrated benefit in the treat-
Based on Ingrid’s symptoms and the negative evalua- ment of IC/BPS include pentosan polysulfate (PPS), tricyclic
tion for other etiologies of her symptoms, she is diag- antidepressants, cimetidine, and hydroxyzine [1]. Pentosan
nosed with IC/BPS. She asks about the next step in polysulfate is an oral sulfated polysaccharide that replen-
management. ishes the defective glycosaminoglycan layer of the bladder
mucosa and has shown efficacy in treating the pain and
urgency of IC/BPS [40]. PPS can also be instilled intravesi-
IC/BPS
An unpleasant sensation (pain, pressure, discomfort) perceived to be related to
the urinary bladder, associated with lower urinary tract symptoms of more than six
weeks duration, in the absence of infection or other identifiable causes
Research trials
Basic assessment Confirmed or First-line treatments Patient enrollment as
– History – Urinalysis, culture Uncomplicated IC/BPS – General Relaxation/ Stress Management appropriate at any point
– Frequency/Volume Chart – Cytology if smoking hx – Pain Management in treatment process
– Post-void residual – Symptom questionnaire – Patient Education
– Physical examination – Pain evaluation – Self-care/Behavioral Modification
Signs/Symptoms of Second-line treatments

Dx Urinary Tract Infection
Complicated IC/BPS – Appropriate manual physical therapy techniques
– Oral: amitriptyline, cimetidine, hydroxyzine, PPS
– Intravesical: DMSO, Heparin, Lidocaine
– Pain Management
– Incontinence/OAB Treat & reassess
– GI signs/symptoms
Microscopic/gross
hematuria/sterile pyuria Third-line treatments
– Gynecologic signs/symptoms – Cystoscopy under anesthesia w/ hydrodistention
– Pain Management
Clinical management principles
– Tx of Hunner’s lesions if found
– Treatments are ordered from most to least conservative;
surgical treatment is appropriate only after other treatment
Consider: options have been found to be ineffective (except for
– Urine cytology treatment of Hunner’s lesions if detected) Fourth-line treatments
– Imaging – Initial treatment level depends on symptom severity,
clinician judgment, and patient preferences – Intradetrusor botulinum toxin A
– Cystoscopy – Multiple, simultaneous treatments may be considered if in – Neuromodulation
– Urodynamics best interests of patient – Pain Management
– Laparoscopy – Ineffective treatments should be stopped
– Specialist referral (urologic – Pain management should be considered throughout course
or non-urologic as of therapy with goal of maximizing function and minimizing
appropriate) pain and side effects
Fifth-line treatments
– Diagnosis should be reconsidered if no improvement within
clinically-meaningful time-frame – Cyclosporine A
– Pain Management
The evidence supporting the use of Neuromodulation, Cyclosporine A, and BTX for IC/BPS is limited
by many factors including study quality, small sample sizes, and lack of durable follow up. None of Sixth-line treatments
these therapies have been approved by the U.S. Food and Drug Administration for this indication. – Diversion w/ or w/out cystectomy
The panel believes that none of these interventions can be recommended for generalized use for this – Pain Management
disorder, but rather should be limited to practitioners with experience managing this syndrome and – Substitution cystoplasty
willingness to provide long term care of these patients post intervention.
Note: For patients with end-stage structurally small bladders, diversion
is indicated at any time clinician and patient believe appropriate.
Copyright © 2014 American Urological Association Education and Research, Inc.
Fig. 30.2 AUA treatment guidelines for bladder pain syndrome algo- Bladder Pain Syndrome Guidelines, Hanno et al. [38]. © 2015 by
rithm [1, 38]. (Reprinted with permission from the American Urological American Urological Association Education and Research, Inc)
Association, 2014 AUA Diagnosis and Treatment Interstitial Cystitis/
cally in an attempt to avoid systemic side effects: bleeding, are done at various intervals from weekly to every few
headache, hair loss, nausea, diarrhea, and stomach pain. months for initial treatment and maintenance therapy.
Tricyclic antidepressants (TCAs) are helpful in treating the A referral to a urologist or a urogynecologist should be
chronic pain of IC/BPS, as they are in other chronic pain made if patients are not responding or are responding sub-
syndromes. TCAs can improve chronic pain through a neu- optimally to first-line therapies and/or oral therapies as
romodulatory mechanism, and the anticholinergic effects care beyond these treatments becomes more complex.
can help with urinary urgency and frequency. TCAs can be Invasive therapies such as cystoscopic treatments or neuro-
quite effective when used long term to decrease frequency of stimulation can be considered in refractory cases [1].
flares, but the CNS side effects of sedation and drowsiness Intravesical botox injections and cyclosporine A have been
often limit their use. Cimetidine and hydroxyzine are antihis- used with some success. The specialist and the primary
tamines and can help episodically or chronically to reduce care provider should work together to provide symptom
the frequency of flares [1]. control and pain control. A pain management specialist
Dimethyl sulfoxide (DMSO), heparin, and lidocaine have may also become involved to manage the patient in a mul-
been used intravesically to treat IC/BPS by urologists and timodal fashion. As a clinical principle, it is best to avoid
urogynecologists. Most intravesical treatments are placed in invasive, non-reversible methods of management until the
the bladder via a catheter, and the patient is asked to hold the noninvasive options have been exhausted. Finally, cystec-
medication in the bladder for at least 30 minutes. Treatments tomy is a radical option that has been used as a last resort
468 S. Koduri
in patients with intractable pain, although with mixed post-traumatic stress disorder, panic disorder, and inti-
results [1]. mate partner violence are common coexisting conditions.
Any chronic condition that can cause central sensitization
can also coexist with IC/BPS.
4. The diagnostic strategy of a woman with symptoms of IC/
Ingrid decided to start pentosan polysulfate and
BPS includes a dedicated history and physical, urinalysis,
worked on her stress management techniques. She has
urine culture, and evaluation for STIs. Imaging and inva-
had good control of her symptoms for several years.
sive testing should be reserved to rule out diagnoses other
She is now 62-years-old and has noticed that her
than IC/BPS high on the differential, as IC/BPS is largely
symptoms are returning, specifically burning when she
a diagnosis of exclusion. Treatment starts with lifestyle
urinates. Urine cultures have been negative.
changes, pelvic floor physical therapy, and stress manage-
ment. Oral and intravesical medications should be used in
a stepwise fashion as indicated by AUA guidelines.
Prognosis
IC/BPS is known to have waxing and waning symptoms over Review Questions
time. Few studies have looked at the long-term prognosis of
women with symptoms of IC/BPS. Only 8% of women have
complete regression of their symptoms at 1 year from onset 1. A 42-year-old woman presents with bladder pain. She has
of symptoms [41]. Over 40% of women tend to have persis- been voiding frequently to avoid pain with fullness and
tent symptoms although with variable levels of pain that awakens four to six times a night to urinate for the past
occur intermittently [41, 42]. While a stable level of pain 8 weeks. She underwent knee surgery 2 months ago and
may be achieved with the above treatments, women are still had a catheter in overnight. She was last sexually active
vulnerable to individual triggers including stress, sexual 1 month ago. What test is first step in the diagnostic
activity, diet, urinary tract infection, yeast vulvovaginitis, evaluation?
and strenuous activity/exercise. Many flares are prevented or A. Complete blood count.
limited by self-care techniques including relaxation, antacid B. Urinalysis.
treatments, and medications such as phenazopyridine or pain C. Urine culture.
medications. Women should be cautioned to come in for D. Urine chlamydia.
evaluation if their “usual” techniques are not working to The correct answer is B. In the initial management
revisit the diagnosis. A thorough evaluation may need to be of a patient with bladder pain and urinary frequency,
reinitiated as these symptoms may be completely indepen- it is most important to evaluate for a urinary tract
dent of the original IC/BPS diagnosis. Treatments may fail to infection as a cause of her symptoms. A complete
be effective, but also some patients discontinue therapy inde- blood count would not aid in the diagnosis of urinary
pendently when feeling better, leading to exacerbations of tract infection. A urinalysis should be completed as a
pain and frequency. first step. If her urinalysis is unremarkable, a urine
culture in this patient is not appropriate and thus is not
the first step in this evaluation. Urine chlamydia test-
Summary Points ing would not be the first test given her risk factor of
recent catheterization [1].
1. Interstitial cystitis or bladder pain syndrome (IC/BPS) is
a female predominant, debilitating disorder of the bladder 2. A healthy 65-year-old woman presents with urinary
characterized by pain with filling that is partially relieved urgency and frequency. She complains of dysuria and has
by emptying, urinary frequency, and urgency. Patients burning in the vulvar area. She had a urinary tract infec-
often present for evaluation after treatments for UTIs and tion 4 months ago, but a recent urinalysis was negative.
STIs have failed. She is not sexually active. What is a reasonable initial
2. The differential diagnosis of IC/BPS is extensive and treatment?
includes recurrent urinary tract infections, chronic ure- A. Lifestyle changes and avoidance of trigger foods.
thritis, overactive bladder, genitourinary syndrome of B. Vaginal moisturizers or estrogen therapy.
menopause, vulvodynia, endometriosis, irritable bowel C. Antibiotic therapy.
syndrome, pelvic floor dysfunction, and neuropathic pain. D. Pentosan polysulfate.
3. Conditions included in the differential diagnosis of IC/ The correct answer is B. This patient is clearly in her
BPS can coexist with IC/BPS. Migraine headaches, tem- postmenopausal years and is likely to have genitourinary
poromandibular joint pain, fibromyalgia, depression, syndrome of menopause (GSM) based on her clinical his-
tory and the fact that GSM is much more common than 9. Chen IC, Lee MH, Lin HH, Wu SL, Chang KM, Lin HY. Somatoform
disorder as a predictor of interstitial cystitis/bladder pain syndrome:
IC/BPS. She does not have a urinary tract infection as uri- evidence from a nested case-control study and a retrospective
nalysis was negative. GSM is not triggered by certain cohort study. Medicine (Baltimore). 2017;96(18):e6304.
foods like IC/BPS. Treating GSM might completely 10. Clemens JQ. Afferent neurourology: a novel paradigm. Neurourol
resolve her symptoms and should be attempted first with Urodyn. 2010;29(Suppl 1):S29–31.
11. Lai HH, Gardner V, Ness TJ, Gereau RWT. Segmental hyperalgesia
vaginal estrogen or vaginal moisturizers. If her symptoms to mechanical stimulus in interstitial cystitis/bladder pain syndrome:
persist, then one would consider IC/BPS and could treat evidence of central sensitization. J Urol. 2014;191(5):1294–9.
empirically with pentosan polysulfate after behavioral 12. Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr
and lifestyle modifications are made [26]. LK, et al. Interstitial cystitis/painful bladder syndrome and asso-
ciated medical conditions with an emphasis on irritable bowel
syndrome, fibromyalgia and chronic fatigue syndrome. J Urol.
3. A 42-year-old woman presents with 6-month history of 2010;184(4):1358–63.
urinary frequency and urgency. She complains of pain in 13. Chelimsky G, Heller E, Buffington CA, Rackley R, Zhang D,
her bladder that is relieved with voiding. She voids fre- Chelimsky T. Co-morbidities of interstitial cystitis. Front Neurosci.
2012;6:114. https://doi.org/10.3389/fnins.2012.00114.
quently to avoid the pain. She has regular menses and finds 14. As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys
that her symptoms are worse during her menstrual cycle. A, et al. Changes in regional gray matter volume in women with
Her urinalysis and urine culture are negative. What is a chronic pelvic pain: a voxel-based morphometry study. Pain.
reasonable next treatment after behavioral techniques? 2012;153(5):1006–14.
15. Teichman JM, Parsons CL. Contemporary clinical presentation of
A. Vaginal estrogen treatment. interstitial cystitis. Urology. 2007;69(4 Suppl):41–7.
B. Antibiotic suppression. 16. Bogart LM, Berry SH, Clemens JQ. Symptoms of interstitial cys-
C. Cystoscopy with hydrodistension. titis, painful bladder syndrome and similar diseases in women: a
D. Sacral neuromodulation. systematic review. J Urol. 2007;177(2):450–6.
17. Shorter B, Lesser M, Moldwin RM, Kushner L. Effect of comestibles
E. Pelvic floor therapy. on symptoms of interstitial cystitis. J Urol. 2007;178(1):145–52.
The correct answer is E. This is a typical presentation 18. Peters KM, Carrico DJ, Kalinowski SE, Ibrahim IA, Diokno
of a woman with IC/BPS. Based on the AUA treatment AC. Prevalence of pelvic floor dysfunction in patients with intersti-
algorithm, it is recommended to start with dietary/behav- tial cystitis. Urology. 2007;70(1):16–8.
19. Warren JW, Clauw DJ, Wesselmann U, Langenberg PW, Howard
ioral techniques for symptom control and then add sec- FM, Morozov V. Sexuality and reproductive risk factors for inter-
ond-line treatments such as pelvic floor therapy. Answers stitial cystitis/painful bladder syndrome in women. Urology.
A and B are not appropriate as the presentation is not con- 2011;77(3):570–5.
sistent with genitourinary syndrome of menopause or 20. Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK,
et al. Childhood sexual trauma in women with interstitial cystitis/
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reserved for patients that fail conservative therapy [1]. 2011;5(6):410–5.
21. Nickel JC, Tripp DA. International Interstitial Cystitis Study
G. Clinical and psychological parameters associated with pain pat-
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Chronic Pelvic Pain
31
Christina I. Ramirez, Sarah A. Tilstra,
and Nicole M. Donnellan
Learning Objectives
Background
1. Define chronic pelvic pain (CPP), including its Chronic pelvic pain (CPP) is a prevalent and debilitating
complex and multifactorial dimensions. condition that impacts women worldwide. It is estimated that
2. Develop a systems-based approach for developing a CPP affects up to 15% of reproductive age women in the
differential diagnosis of CPP, recognizing that a United States [1]. Globally, the prevalence of chronic pelvic
single diagnosis is often not possible. pain ranges from 2.1% to 26.6% [2, 3]. CPP is generally
3. Describe how to perform a focused history and defined as noncyclical pain of at least 3–6 months’ duration
physical exam in a patient presenting with CPP. that appears in locations such as the pelvis, anterior abdomi-
4. Provide examples of initial tests to perform when nal wall, lower back, or buttocks and that is serious enough
evaluating a patient with CPP. to cause disability or lead to medical or surgical care [4, 5].
5. Discuss treatment options for the multidisciplinary Chronic pelvic pain places a significant burden on the
management of CPP. affected individual and on society through economic and
healthcare-related costs. In a study by Mathias et al., 15% of
women with chronic pelvic pain reported missing paid work.
In 1996, this correlated with an estimated cost of $555.3 mil-
Sally is a 35-year-old G1P1 woman who presents with lion dollars due to time lost from work [1]. Women suffering
pelvic pain. Her menses are regular and last 7–8 days. from CPP have significant associated comorbidities and a
Her pain started several months after the birth of her diminished quality of life. A large study of women with CPP
daughter 3 years ago. Initially, the pain would only found that 98% met DSM-IV criteria for at least one mental
last a couple days at a time and occurred once every health disorder, 50.5% suffered from a mood disorder, and
few months. Over the last month, the pain has been 38.6% suffered from an anxiety disorder [6]. The large per-
increasing in intensity and frequency and now is occur- centage of mental health comorbidities among women with
ring on a daily basis. She is having difficulty concen- CPP underscores the importance of accurate diagnosis and
trating at work due to her pain. multidisciplinary care of CPP patients.
There are entire chapters in this book dedicated to a few
of the most common causes of chronic pelvic pain includ-
ing Endometriosis (Chap. 10), Irritable Bowel Syndrome
(Chap. 27), Interstitial Cystitis/Bladder Pain Syndrome
(Chap. 30), Vulvar Conditions (in Chap. 12), as well as
other contributors to pelvic pain such as Depressive and
Anxiety Disorders (Chap. 33) and Intimate Partner Violence
C. I. Ramirez (*) · N. M. Donnellan and Sexual Trauma (Chap. 35). Details of the diagnosis and
Magee-Womens Hospital of University of Pittsburgh Medical
Center, Department of Obstetrics, Gynecology, and Reproductive management of these conditions are outside the scope of
Sciences, Pittsburgh, PA, USA this chapter. This chapter will provide a general approach
e-mail: [email protected] to the patient who presents with pelvic pain and focus on
S. A. Tilstra localized causes of CPP such as abdominal wall pain, pel-
University of Pittsburgh School of Medicine, Division of General vic floor dysfunction, myofascial pain syndrome, vaginis-
Internal Medicine, Department of Medicine, Pittsburgh, PA, USA mus, and adhesive disease.

472 C. I. Ramirez et al.
Neuroanatomy of the Pelvis interpret any pain stimulus in an exaggerated way, and “vis-
ceral cross sensitization,” where a healthy pelvic organ is
There are numerous potential etiologies for female chronic influenced by an adjacent diseased organ to perceive pain [6]
pelvic pain, which will be reviewed in further detail within (Fig. 31.1).
this chapter through a systems-based approach. To best
understand the sources and pathophysiology of female
chronic pelvic pain, it is imperative to become familiar with Sally states that her pain is sharp and constant in the
the neuroanatomy of visceral and somatic pain pathways lower abdomen. The pain shoots down toward her
within the abdominopelvic region. groin and is aggravated by intercourse. The pain is so
The innervation of the pelvis is complex. An intricate intense that she cannot tolerate using tampons. She
relationship exists between the somatic, sympathetic, and denies any history of pain with menses (dysmenor-
parasympathetic nervous systems to allow for appropriate rhea), bowel movements (dyschezia), or urination
sensation and coordination of dual voluntary and involun- (dysuria).
tary bodily functions, such as micturition, defecation, and
parturition.
The somatic nervous system innervates the skeletal mus-
cles of the pelvis, the abdominal wall, and the skin overlying History
the external genitalia. The anterior cutaneous branch of the
tenth intercostal nerve transmits pain at the level of the umbi- Every woman who presents with chronic pelvic pain will
licus. The skin overlying the suprapubic region is innervated describe her chief complaint and the location and quality of
by cutaneous branches of the iliohypogastric nerve, which is her pain differently. Therefore, a systematic and thorough
derived from the L1 nerve root [7]. The pelvic floor, which is history is necessary to understand the full scope of the
predominantly made up of the levator ani muscle group patient’s symptoms and concerns. When obtaining the his-
(puborectalis, pubococcygeus, and iliococcygeus), is inner- tory, it is important to keep the differential diagnoses in mind
vated by the S3–S5 nerve roots. The pudendal nerve is the in order to prevent missing a potential diagnosis. Women
primary sensory and motor nerve of the perineum, which is may have many different types of pain, and the details of
derived from the S2–S4 nerve roots. Branches of the puden- each should be recorded separately. It is important to create
dal nerve provide sensory innervation to the skin of the pos-
terior labia and the clitoris, the urethral and anal sphincters,
and the muscles that coordinate orgasm [6–8]. The anterior
cutaneous innervation to the labia is supplied by the ilioin-
guinal nerve (nerve root L1) [8]. Injury to the sacral nerve
roots or their branches can result in acute or chronic pain and
dysfunction of the innervated tissues. The somatic nervous
system most often plays a role in vulvar disease (vulvo-
dynia), vaginismus, myofascial pain syndrome, pelvic floor
spasm, and abdominal wall pain.
Visceral pain is unique in that it is poorly localized, can
occur without injury (e.g., stretching of the bladder), can be
referred to other parts of the body, and is associated with
autonomic responses such as nausea, vomiting, and sweating
[9]. Visceral pain from the uterus, bladder, and rectum is pre-
dominantly transmitted through sympathetic nervous system
fibers via the hypogastric plexus [8]. The nerves of the hypo-
gastric plexus return to the spinal cord through the lumbar Fig. 31.1 Innervation of the pelvic organs. Sensory axons innervating
splanchnics and eventually reach the processing centers in the vagina reach the spinal cord via pelvic nerves and terminate in
sacral spinal cord segments (S2–S4). Axons innervating the uterus
the brain. Conversely, pain signals from the ovary and distal travel in the hypogastric nerves and terminate in the thoracolumbar spi-
fallopian tubes, which are lateral pelvic structures, and trav- nal cord segments (T10–L2). The region surrounding the cervix repre-
els through the parasympathetic system through the ovarian sents a transitional zone and is innervated by fibers that travel in both
plexus to the vagus nerve [8]. Patients with chronic pain can nerves. Sensory axons from the clitoris and vulva follow the pudendal
nerves to sacral spinal cord. Note that sensory information from all pel-
perceive any visceral sensation as pain due to complex dys- vic organs may converge onto the same spinal cord neural circuits,
regulation of pain processing. This may include “central sen- DRG (dorsal root ganglia) [10]. (Image reprinted from Jobling et al.
sitization,” where the central nervous system is primed to [10]: article 17. Special thanks also to Kelly Smith)
31 Chronic Pelvic Pain 473
a safe, comfortable, and judgment-free space for patients structures. The Carnett’s test, in which the examiner palpates
with CPP, as with all patients. The patient should feel that the each quadrant of the abdomen at rest and then with contrac-
provider is listening and taking her symptoms seriously. tion of the abdominal wall by having the patient raise her
Whenever possible, history-taking should be performed in head off the bed without using her arms, can be performed to
the office while the patient is fully clothed. assess for abdominal wall musculoskeletal pain [11]. The
A detailed pain history is critical and should include Carnett’s test is reported to be “positive” if the patient reports
information about the pain characterization: onset, location, reproduction of her pain with palpation of a contracted
duration, timing, what the pain feels like, aggravating and abdominal wall (as opposed to the relaxed state) and has a
alleviating factors, and prior treatments of each type of pain. diagnostic accuracy of 97% for abdominal wall pain [12]. In
Care should be taken to determine the impact of the chronic contrast, this physical exam finding is positive in less than
pain on the patient’s quality of life, relationships, and 10% of patients with a visceral etiology of their chronic pain.
employability. While keeping the differential diagnosis in When palpating the abdomen at rest, each quadrant should
mind, a complete neurologic, gastrointestinal, urologic, be gently palpated at a superficial and deep level to evaluate
musculoskeletal, gynecologic, and psychiatric review of for masses, organomegaly, or focal areas of tenderness.
systems should be obtained. Past medical and surgical his- Additionally, the patient should be assessed for any signs or
tory should include any history of chronic pain disorders, symptoms of an acute surgical abdomen: involuntary guard-
psychiatric conditions, and prior abdominal or pelvic suring (tensing of abdominal wall muscles in anticipation of
geries. A detailed obstetric and gynecologic history should pain with palpation) or rebound tenderness (tenderness when
include information regarding prior pregnancies and deliv- quickly releasing pressure off of the abdominal wall).
eries, menstrual history, sexual history, and any prior diag- Patients with evidence of an acute surgical abdomen require
noses of endometriosis, fibroids, or sexually transmitted immediate evaluation in an emergency room.
diseases. Pertinent aspects of the patient’s social history The gynecologic exam begins with a visual inspection of
include occupation, employment disability, support system, the perineum and vulva while the patient is in the dorsal
screening for history of trauma, and past or present intimate lithotomy position. The external genitalia should be care-
partner violence (see Chap. 35 on Intimate Partner Violence fully examined for any signs of skin changes, trauma, exco-
and Sexual Trauma) and drug use (see Chap. 32 on Opioid riations, swelling, scarring, pelvic organ prolapse, cystic
Use Disorder in Women). Family history should focus on lesions, and unusual discharge or odor [13]. Next, a Q-tip
history of chronic pain disorders, substance use, trauma, or test should be performed to assess for vulvodynia [14]. This
psychiatric illnesses. is performed by assessing for reproduction of pain around
the introitus when lightly swabbing at the 3 o’clock, 6
o’clock, and 9 o’clock locations. The patient’s baseline pain
Physical Exam should be assessed on scale from “0” (no pain) to “10” (worst
possible pain) and can be used to assess degree of pain
The physical exam for a patient with pelvic pain can be a improvement following treatment [13].
very uncomfortable experience. Prior to beginning the phys- Assessment of the pelvic floor muscles should also pro-
ical exam, it is crucial that the provider create a safe envi- ceed from superficial to deep. The perineal body can be
ronment for the patient. All components and indications for assessed by gently depressing with a single digit just outside
the different aspects of the physical exam should be the introitus at the 6 o’clock location. The bulbospongiosus
explained and verbal consent obtained prior to proceeding muscles can be palpated just deep to the labia majora from 1
with each part of the exam. The patient should also under- o’clock to 5 o’clock on the left and 7 o’clock to 11 o’clock
stand that she is in control and that she may pause or stop on the right. Next, the deep muscles of the pelvic floor (leva-
the exam at any point. Additionally, the patient should be tor ani, obturator internus, piriformis muscles) should be
offered a chaperone and/or allowed to have a support person evaluated. The levator ani muscles can be assessed by plac-
in the room with her if that makes her feel more comfortable ing a single digit within the introitus and gently palpating
with the physical exam. from 3 to 5 o’clock and 7 to 9 o’clock toward the ischial
The focused physical exam should start with a visual spines. The obturator internus muscles can be palpated supe-
assessment of the patient’s abdomen while she is lying in the rior to the ischial spines at the 3 o’clock and 9 o’clock posi-
supine position. The abdominal wall should be assessed for tions [13]. The location of any focal areas of muscular
any visible masses, areas of asymmetry, skin changes from tenderness or tight bands should be documented as these
chronic heat pad usage, and scarring from prior surgical pro- may be indicators of pelvic muscle spasm. Muscle testing
cedures. Next, auscultation for bowel sounds should be per- should also be performed by first palpating the resting tone
formed in all four quadrants. Palpation of the abdomen of the pelvic floor digitally and then asking the patient to
should proceed from superficial structures down to deep maximally contract her pelvic floor muscles (also known as
a Kegel). The strength of the muscle contraction should be Following assessment of the pelvic floor muscles, a
rated from “0” (no palpable contraction) to “5” (strong mus- bimanual exam should be performed to assess the uterus,
cle contraction) on a modified Oxford scale [15]. The cervix, and adnexa for structural abnormalities. This portion
strength of the Kegel can be determined by the degree of of the exam may be particularly uncomfortable physically or
squeeze around the examiner’s digit as well as the degree of emotionally for women with chronic pelvic pain, and the
upward lift of the pelvic floor. A weak pelvic floor contrac- patient should again be reassured that she can stop or pause
tion may be an indication of pelvic floor laxity or uncoordi- the exam at any point. Although a speculum exam is often
nated pelvic floor muscle movement. The ability to performed before the bimanual exam in most routine gyne-
voluntarily relax the pelvic floor is important and can be cologic assessments, the speculum exam may significantly
evaluated by asking the patient to Valsalva or bear down sim- aggravate chronic pelvic pain symptoms, which can make it
ilar to a bowel movement. Pelvic floor relaxation can be more difficult to localize the patient’s pain on bimanual
determined by degree of relaxation around the examiner’s exam. Clinical judgment should be used when deciding the
digit as well as visualization of descent of the perineal body. order of performing the bimanual and speculum exam.
If the patient is unable to do this, pelvic floor dysfunction The bimanual exam is performed by placing one lubri-
may be playing a role in the patient’s symptoms (Fig. 31.2). cated, gloved digit from the dominant hand vaginally until the
Fig. 31.2 (a) Muscles of the a Bulbospongiosus m.

pelvic floor. (b) Digital Clitoris
palpation of deep pelvic floor Ischiocavernosus m. Urethra
muscles. m muscle [16]. Vagina
(Reprinted from Mayo Clinic
Proceedings, Faubion et al.
[16], © 2012, with permission
from Elsevier)
Transverse
perineal m.
lliococcygeus Levator ani
Perineal body Pubococcygeus
Puborectalis muscles
Anus
b Coccygeus m. Sacral nerve

plexus
Piriformis m.
Obturator
internus
Tip of
coccyx
Ischial spine
(under iliococcygeus m.)
lliococcygeus
Pubococcygeus Levator ani
Puborectalis
Vaginal wall
Pubic symphysis
cervix is palpated. The finger can be lubricated with water or Table 31.1 Differential diagnosis of conditions contributing to chronic
a water-based lubricant. Two vaginal digits may be needed in pelvic pain
order to adequately palpate the uterus and cervix; however, Differential diagnosis of conditions contributing
System to chronic pelvic pain
this should only be performed if it is tolerated by the patient.
Gastrointestinal Irritable bowel syndrome
Following identification of the cervix, the cervix should be Constipation
gently pushed laterally or superiorly/inferiorly to assess for Inflammatory bowel disease
cervical motion tenderness. Significant cervical tenderness Urologic Painful bladder syndrome/interstitial cystitis
with minimal palpation may be concerning for acute cervici- Cystitis and urethritis
tis. Next, while placing the nondominant hand on the patient’s Musculoskeletal Abdominal wall pain/myofascial pain
syndrome
lower abdomen, the uterine fundus should be palpated while Vaginismus
elevating the uterus out of the pelvis with the internal digit(s). Pelvic floor muscle spasm
The size, shape, mobility, and tenderness of the uterus should Levator ani muscle
be assessed. A uterus that is enlarged and irregularly shaped Piriformis muscle
Obturator internus muscle
may indicate adenomyosis or uterine fibroids. Next, the inter-
Gynecologic Endometriosis
nal digits should be moved to the anterior vaginal fornix at 10 Adhesions
o’clock. With steady pressure, the external hand should sweep Vulvovaginitis
the right adnexa into the internal hand from the right anterior Vulvodynia
superior iliac spine toward the pubic symphysis. An identical Vulvar vestibulitis
Vulvovaginal atrophy
assessment should be performed of the left adnexa at the 2 Leiyomyomas
o’clock position within the anterior vaginal fornix. The Adenomyosis
adnexa should be assessed for size, fullness, mobility, and Pelvic inflammatory disease
tenderness. In patients with symptoms concerning for possi- Adnexal masses
Psychiatric Depression and anxiety
ble endometriosis (dysmenorrhea, deep dyspareunia, infertil- Intimate partner violence and sexual abuse
ity), careful palpation retrocervically and along bilateral Trauma and post-traumatic stress disorder
uterosacral ligaments should be performed to assess for any (PTSD)
tenderness or nodularity that may represent deep infiltrating Drug dependency
Somatization
endometriosis.
Next, a vaginal speculum exam should be performed to
visually evaluate the cervix and vaginal walls. The cervix mon differential diagnoses is outlined in Table 31.1. The
should be evaluated for any masses, nodules, erythema, following section highlights some of the more common eti-
lesions, or purulent discharge. The vaginal walls should be ologies of chronic pelvic pain, but the authors acknowledge
assessed for loss of rugae, which may be consistent with that the differential is very broad and the cause is most
atrophic vaginitis. Additionally, the vaginal vault should be often multifactorial.
carefully inspected for unusual vaginal discharge. During the
speculum exam, cervical swabs for chlamydia, gonorrhea,
and trichomoniasis should be obtained routinely, as not all Gastrointestinal Contributors
patients with sexually transmitted diseases are symptomatic.
Additional samples should be obtained if unusual vaginal Gender differences in the gastrointestinal system are well
discharge is present. documented. Women exhibit delayed gastrointestinal transit
A rectal exam should not be performed routinely for all within the stomach and colon when compared to male coun-
women presenting with chronic pelvic pain. However, if the terparts [8, 9]. Gastrointestinal disorders including irritable
patient indicates a history significant for painful or bloody bowel syndrome, chronic constipation, and inflammatory
stools or if the bimanual exam is abnormal, then a rectal bowel diseases may cause chronic abdominopelvic pain.
exam may be warranted to assess for hemorrhoids, rectal Irritable bowel syndrome (IBS) is a functional bowel
lesions, or pelvic masses. disorder characterized by chronic abdominal pain related to
defecation and frequent changes in baseline stool frequency
or appearance [17, 18]. Patients experience visceral pain
Differential Diagnosis from alteration in bowels habits, abdominal distention, and
cramping. The prevalence is between 10% and 15% in
Providers must keep a broad differential in mind while North America and is equally distributed between subtypes:
evaluating for potential etiologies of chronic pelvic pain. A constipation predominant (IBS-C), diarrhea predominant
systematic approach enables the primary care provider to (IBS-D), mixed type (IBS-M), and un-subtyped [19].
more easily organize information. An overview of the com- Female sex is the best-documented risk factor for IBS;
women are twice as likely to be affected by IBS compared Musculoskeletal Contributors

to men [17]. Women often experience exacerbations of
IBS-associated abdominal pain during their menses when History and physical exam can easily lead to the diagnosis
serum estrogen levels are low, and therefore IBS may be of musculoskeletal or myofascial causes of pain and avoid-
difficult to differentiate from dysmenorrhea (see Chap. 27 ance of an expensive workup of visceral causes [12].
on Irritable Bowel Syndrome) [17]. Symptoms change over Chronic abdominal wall pain is typically characterized by
time and the diagnosis is often made by history and exclu- focal, superficial tenderness along the abdominal wall [12].
sion of other diseases. In a study of 2709 patients referred to a gastroenterologist
Chronic constipation is a characterized by infrequent, over a 5-year period, 137 patients were diagnosed with
painful passage of stools [20]. The global prevalence of con- chronic abdominal wall pain with 27% experiencing pre-
stipation is 16% with a greater predisposition among the dominantly lower abdominal tenderness [12]. Women were
elderly, women, chronic narcotic users, and individuals who four times more likely than men to present with chronic
eat low-fiber diets [20]. It is particularly important for clini- abdominal wall pain, highlighting the importance of consid-
cians to ask questions regarding regularity and consistency ering the musculoskeletal system in the differential for
of stools, chronic history of ignoring the urge to defecate, or chronic pelvic pain.
incomplete evacuation requiring digital assistance [21]. Myofascial pain syndrome is a complex pain disorder
About 3 million Americans carry a diagnosis of ulcerative where tender bands of hyperirritable skeletal muscle and fas-
colitis or Crohn’s disease, which together are referred to as cia called “trigger points” cause exquisite local pain and
inflammatory bowel disease (IBD) [22]. IBD is character- autonomic symptoms. Pain from trigger point presence or
ized by potentially severe intestinal inflammation leading to manipulation can also cause symptoms at predictable remote
diarrhea, weight loss, nausea, vomiting, and abdominal and sites called “targets” [26]. In women, myofascial pelvic pain
pelvic pain. Pain can be acute or chronic, a result of damage is often characterized by dyspareunia, dysuria, and/or dys-
to the enteric nervous system from ongoing inflammation or chezia and may be due to muscle laxity or hypertonicity [27].
from underlying structural disease, adhesions, or fistulas that Myofascial pain can be triggered by trauma, poor posture,
are characteristic of Crohn’s [23]. Patients can also display stress on the pelvic floor from obesity and pregnancy, sur-
extra-intestinal manifestations of IBD such as joint pain, gery, overuse, underuse, and atrophy [28]. It is estimated that
rashes, and ocular disease. IBD can go undiagnosed for years 13.2% of women suffer from pain associated with myofas-
when symptoms are mild and diarrhea is absent and should cial pelvic pain [28] with the prevalence as high as 58% in
be considered in all patients presenting with chronic abdomi- women who suffer from chronic pelvic pain. The most com-
nopelvic pain. monly affected pelvic floor muscles include the levator ani,
piriformis, and obturator internus [28].
Vaginismus, now known as genito-pelvic pain/penetra-
Urologic Contributors tion disorder, causes chronic pelvic pain with any form of
vaginal penetration and can be very distressing for patients
Localizing complaints of urinary dysfunction or dysuria on and their partners. It includes difficulties with one or more of
review of systems may indicate a urinary contribution to the following dimensions that are persistent or recurrent: (1)
chronic pelvic pain. Interstitial cystitis or bladder pain syn- tightening of the pelvic floor muscle when vaginal penetra-
drome is a common cause of CPP and is diagnosed in patients tion is attempted; (2) pain, burning, or tension during or
with pelvic pain for greater than 6 weeks with at least one when vaginal penetration is attempted; (3) decrease in or no
urinary symptom, such as urgency or frequency (see Chap. desire for intercourse; and (4) anxiety or fear of pain, pelvic
30 on Interstitial Cystitis/Bladder Pain Syndrome). Similar or vulvovaginal, as a result of, during penetration, or in antic-
to other chronic pain disorders, bladder pain syndrome is five ipation of penetration [29]. It has long been postulated that
times more likely to occur in women when compared to men vaginismus is caused by spasm of the pelvic floor muscles,
[24]. In patients with more acute urinary discomfort, urinary occluding the vaginal opening and preventing penetration,
tract infection (cystitis or urethritis) or urolithiasis may be a but there are few studies documenting differences in pelvic
more likely diagnosis. floor tonicity, strength, and presence of spasm between
Urinary tract infection is the most common bacterial patients diagnosed with vaginismus and those that are not
infection and is more common in women due to the shorter [30]. Risk factors for vaginismus include physical and sexual
distance between the urethral orifice and the rectum [25]. trauma, relationship issues, pelvic floor dysfunction, ana-
Patients suffering from acute or recurrent urinary tract infec- tomical congenital abnormalities, untreated vulvar disease,
tions will often complain of dysuria, hematuria, urinary vaginal atrophy, endometriosis, pelvic infections, and surgi-
urgency/frequency, and/or suprapubic pain [25]. cal intervention [30].
Gynecologic Contributors exclude and/or treat other potential causes of vulvar pain,
such as vulvovaginitis, prior to initiating treatment of
Intra-abdominal adhesions result from direct peritoneal vulvodynia.
trauma most commonly due to surgery, infections, or inflam- Further discussion on the remainder of the gynecologic
mation [31]. In normal wound healing, tissue trauma triggers differential for pelvic pain can be found in Chap. 10 on
mast cell degranulation and fibrin deposition, which is sub- Fibroids, Endometriosis, and Ovarian Cysts; Chap. 8 on
sequently degraded within 72 hours [32]. However, adhe- Menopause, Atrophic Vaginitis section; Chap. 13 on Sexually
sions form when fibrinolysis is delayed, resulting in fibroblast Transmitted Infections, PID section; and Chap. 9 on Female
infiltration and vascularization [32]. Abdominal or pelvic Sexual Function and Dysfunction.
surgery causes postoperative adhesions in up to 40% of
patients [33]. Route of surgery may increase clinical suspi-
cion as studies have demonstrated a higher rate of postopera- Psychiatric Contributors
tive adhesions with open surgery when compared to
minimally invasive approach (laparoscopic or robotic). Women who suffer from chronic pelvic pain are more likely
Adhesions are an established cause of internal hernias and to have a history of major depressive disorder, somatization
small bowel obstructions that may result in acute pain [31]. symptoms, drug use or dependence, and childhood or adult
However, the data for chronic pain is not well established. sexual abuse [40]. A survey of 1931 women within a primary
Adhesions may restrict the mobility of affected organs, but it care practice found that the prevalence of pelvic pain was
is unclear if adhesions themselves are a direct source of pel- two times higher in patients with a history of childhood
vic pain. At least one study demonstrated histologic evidence abuse [41]. Additionally, up to one in three women with pel-
of nerve fibers in pelvic adhesions in women undergoing vic pain will screen positive for post-traumatic stress disor-
gynecologic surgery; however, the prevalence of adhesion der, which further emphasizes the high risk of psychological
innervation was no different between women with and with- comorbidities in women suffering from chronic pelvic pain
out pelvic pain [34]. Additionally, a cluster analysis in 2018 [42]. Therefore, screening and treatment for psychiatric
revealed that the severity of adhesions did correlate with the comorbidities, history of abuse, drug dependency, and post-
severity of a patient’s pain score [35]. traumatic stress disorder are crucial during the evaluation
Vulvovaginitis is a group of conditions affecting 15–39% and management of women with chronic pelvic pain [43].
of women and often presents with abnormal vaginal dis-
charge and/or vulvovaginal irritation [36]. The most com-
mon causes of vulvovaginitis are bacterial vaginosis, Sally is wondering if her pain might be due to endome-
vulvovaginal candidiasis, and trichomoniasis. Bacterial vagi- triosis. She recently heard an advertisement for an
nosis results from a shift in the normal vaginal flora resulting endometriosis medication on TV, and the description
in an overgrowth of predominantly anaerobic bacteria and of the symptoms is similar to what she is experiencing.
malodorous discharge [36]. Vulvovaginal candidiasis results You explain that while endometriosis is a common
from a shift in the normal vaginal flora with an overgrowth of cause of pelvic pain, there are many other causes (both
yeast species, most commonly Candida albicans [36]. gynecologic and non-gynecologic) of pelvic pain. You
Trichomoniasis is caused by a sexually transmitted proto- will need some more information to help determine the
zoan T. vaginalis and requires treatment of the patient and etiology of her pain.
her partner in order to prevent reinfection (see Chap. 12 on
Vaginitis and Vulvar Conditions and Chap. 13 on Sexually
Transmitted Infections). Chronic reinfection and irritation of
the vaginal mucosa from vaginitis can result in an ongoing Laboratory Testing
pain syndrome.
Vulvodynia is a chronic pain disorder defined as burning There are only a few laboratory tests that should routinely be
vulvar discomfort that occurs in the absence of “relevant vis- performed during the assessment of a patient with chronic
ible findings or a specific clinically identifiable neurological pelvic pain. All premenopausal women of reproductive age
disorder” [37]. This condition commonly results in dyspa- should undergo pregnancy testing for two main reasons: (1)
reunia, while in more extreme cases, the patient may be up to 50% of pregnancies in the United States are unintended
unable to wear certain clothing owing to irritation [38]. [44] and (2) a confirmed viable pregnancy will dictate treat-
Vulvar vestibulitis is a subtype of vulvodynia specifically ment options. Next, a urinalysis or urine dip test should be
associated with localized, provoked vulvar pain or discom- performed to evaluate for a possible urinary tract infection.
fort along the vestibule [39]. It is particularly important to Testing for sexually transmitted diseases, specifically for
gonorrhea, chlamydia, and trichomoniasis, can either be per- metriosis to provide histologic diagnosis and surgical treat-
formed vaginally at the time of the speculum exam or tested ment of painful endometriotic implants. Laparoscopy for the
with a urine sample. Lastly, if microscopy is available, then evaluation and treatment of adhesive disease will be dis-
a wet mount of the patient’s vaginal discharge should be cussed in further detail below.
assessed with normal saline and potassium hydroxide to
evaluate for yeast, bacterial vaginosis, or an abundance of
white blood cells which could signal either acute or chronic Sally’s urinalysis and sexually transmitted infection
abnormal inflammation. testing are both negative. On exam it is noted that Sally
has multiple tender spots along her levator ani, and
you are concerned she may be experiencing levator
Radiographic Imaging muscle spasm. You recommend that she see a pelvic
floor physical therapist for further evaluation and
A transvaginal pelvic ultrasound is the first-line imaging treatment.
modality during the assessment of chronic pelvic pain [45].
Ultrasound provides a fast, cost-effective, and accurate
method of evaluating the reproductive organs and is the
imaging modality of choice when assessing pathology of the Treatment of Chronic Pelvic Pain
gynecologic structures [46]. Pelvic ultrasound can also facil-
itate the diagnosis of uterine leiomyoma, adenomyosis, pel- Treatment for female chronic pelvic pain can be challenging
vic inflammatory disease, and adnexal cysts/masses [47]. for both the patient and the provider. As with any other dis-
Ultrasound may have limitations due to variability of opera- ease, the treatment of chronic pelvic pain should be tailored
tor skill, patient tolerance of the exam, patient obesity, and to the etiological source. The origin of chronic pelvic pain is
obscuring bowel gas [47]. If pelvic ultrasound is not feasible often complex and multifactorial. A systems-based approach
or provides limited information, an abdominal/pelvic MRI ensures that the provider evaluates the patient in an orga-
may be useful in select patients to determine the extent of nized and thorough manner. The optimal treatment of a
disease in cases of suspected deep infiltrating endometriosis patient with chronic pelvic pain often requires simultaneous
or a large fibroid uterus [45]. Limitations of MRI include treatments across multiple specialties. For this reason, stud-
inability to perform in patients with certain metal implants or ies have shown improved patient outcomes with the utiliza-
pacemakers, high cost, and patient tolerance of a small, tion of an interdisciplinary care team, wherein a team of
enclosed space [47]. Abdominal/pelvic computed tomogra- specialists collaborate in order to achieve a common treat-
phy is commonly used during the evaluation of acute abdom- ment goal [49]. Many interdisciplinary care teams include a
inal pain; however, it has limited utility in the evaluation of primary care provider, gynecologist, chronic pain specialist,
chronic pelvic pain. Patients with a clinical history concern- psychologist, and physical therapist [50]. Depending on that
ing for possible gastrointestinal etiology of their pain may patient’s specific clinical presentation, the care team may
benefit the most from additional imaging with CT, as the also include a gastroenterologist, urologist, urogynecolo-
large and small intestines are not adequately visualized on gist, general surgeon, or psychiatrist. Additionally, it is criti-
pelvic ultrasound [45]. cal that the provider and patient understand that complete
resolution of the pain may not be realistic or a feasible treat-
ment goal [50]. Rather, the goal of chronic pelvic pain man-
Diagnostic Laparoscopy agement should be overall reduction in pain with associated
improvement in quality of life and daily functionality [51].
Diagnostic laparoscopy should not be routinely offered as a An exhaustive review of the treatment options for all poten-
first-line assessment for chronic pelvic pain. A detailed his- tial causes of chronic pelvic pain is beyond the scope of this
tory and physical exam with indicated laboratory testing and chapter as there are other chapters in this book dedicated to
radiographic imaging will often provide more diagnostic diseases that commonly cause chronic pelvic pain. Please
information without exposing the patient to an invasive sur- see Chap. 8 on Menopause, Atrophic Vaginitis section;
gical procedure [48]. Diagnostic laparoscopy is a reasonable Chap. 10 on Fibroids, Endometriosis, and Ovarian Cysts;
next step in patients when the clinical history, physical exam, Chap. 12 on Vaginitis and Vulvar Conditions; Chap. 13 on
and noninvasive testing fail to provide a diagnosis. Patients Sexually Transmitted Infections, PID section; Chap. 24 on
should be counseled that diagnostic laparoscopy fails to find Urinary Tract Infections; Chap. 27 on Irritable Bowel
a diagnosis in up to 35% of patients with CPP [48]. Diagnostic Syndrome; and Chap. 30 on Interstitial Cystitis/Bladder
laparoscopy may be offered to patients with suspected endo- Pain Syndrome.
Musculoskeletal may be treated with biofeedback training, which increases

the patient’s awareness of her pelvic floor muscles during a
Patients identified as having abdominal wall myofascial pain state of activation or relaxation [55]. Patients should be
based on a positive Carnett’s test often require a multimodal counseled that consistent follow-up and adherence with the
approach toward the management of their pain. Patients with physical therapy regimen is necessary for adequate treat-
evidence of abdominal wall scar tissue from prior trauma or ment. Studies have shown that the pelvic pain improvement
surgery may benefit from manual scar release performed by a with physical therapy is directly correlated with the number
trained physical therapist. Additionally, a significant rectus of physical therapy visits completed by the patient [56].
diastasis may occur after pregnancy, which may warrant fit- In cases refractory to medical and physical therapy, pelvic
ting for an abdominal binder to stabilize and support the floor needling or injections may be indicated, an intervention
abdominal wall muscles. Lifestyle modifications with stretch- provided by urogynecologists or gynecologists specializing
ing and exercise are critical as stretching lengthens taut mus- in chronic pelvic pain. Dry needling involves insertion of a
cles and exercise increases strength and stability. Patients needle into the affected myofascial trigger point to produce a
should be screened for repetitive tasks that may be resulting local twitch response [26]. A trigger point injection differs
in recurrent microtrauma to abdominal wall muscles. In cases such that a local anesthetic (lidocaine, bupivacaine, or ropi-
refractory to initial lifestyle modifications, patients may ben- vacaine) and a steroid (triamcinolone) are administered
efit from complementary or alternative medicine treatments together at the site of maximum tenderness, often transvagi-
with acupuncture, massage, or electrotherapy [26]. Oral and nally into the levator ani muscles [57]. Trigger point injec-
topical nonsteroidal anti-inflammatory drugs are the first-line tions often provide immediate pain relief and can help to
medical treatment options for chronic myofascial pain [26]. confirm the diagnosis of a pelvic floor spasm [57]. The deci-
Muscle relaxants such as cyclobenzaprine and tizanidine sion to perform dry needling versus trigger point injections
have been shown to be effective in the treatment of chronic requires clinical judgment as multiple studies and a Cochrane
myofascial pain [26]. There is limited data on the utility of analysis have not shown a difference in effectiveness between
topical lidocaine patches, but may be beneficial in patients the two needling options [58–60].
that demonstrate significant hypersensitivity [26]. Like patients with pelvic floor dysfunction, patients suffer-
Patients with evidence of myofascial pain syndrome of ing with vaginismus (genito-pelvic pain/penetration disorder)
the pelvis and pelvic floor muscle dysfunction often require should also be treated using a multidisciplinary approach
interdisciplinary management with a pelvic floor physical with a pelvic floor physical therapist, urogynecologist, pri-
therapist, urogynecologist, primary care physician, and psy- mary care physician, psychologist, and sex therapist. It is
chologist. In the acute setting, pharmacologic management important to advise patients to stop engaging in painful sexual
of pain with nonsteroidal anti-inflammatory drugs may be activity and seek treatment, as continued painful experiences
helpful, but is unlikely to result in long-lasting pain improve- can increase situational anxiety and result in increased pelvic
ment [52]. Other medications that have been shown to be floor tension and pain [61]. Cognitive behavioral therapy, bio-
effective for chronic pelvic pain include tricyclic antidepres- feedback, and mindfulness-based approaches have been
sants and gabapentin [53]. Muscle relaxants, such as cyclo- shown to be helpful for addressing the pain associated with
benzaprine, should be used with caution as they are sedating, vaginismus [62–68]. Additional therapies with mixed results
nonspecific for the pelvic muscles and may induce urinary include topical lidocaine [69, 70], antidepressants such as tri-
retention [14]. Although data is limited to support its use as cyclic antidepressants [71], anticonvulsants such as gabapen-
monotherapy, vaginal diazepam, 5–10 mg BID supposito- tin [72], or vestibulectomy (excision of the hymenal ring and
ries, in conjunction with pelvic floor physical therapy has superficial vulvar mucosa) [72–75], although the latter is
been suggested to benefit patients with contracted or “high- reserved for women who have failed multiple less invasive
tone” pelvic floor muscle dysfunction [54]. treatments. For refractory cases, pelvic floor injections with
Massage, myofascial release, or directed therapeutic exer- botulinum toxin have also been shown to be effective for
cise by a trained pelvic floor physical therapist is a critical management of involuntary pelvic floor spasms [76].
component of the treatment of pelvic floor dysfunction and
pain [55]. Pelvic floor physical therapy is a distinct specialty
within physical therapy that requires dedicated training and Gynecologic
certification through the Woman’s Health Section of the
American Physical Therapy Association [14]. The specific As previously discussed, numerous studies have failed to
therapeutic strategy should be tailored to the patient’s symp- find a definitive etiologic link between adhesions and chronic
toms. Hypertonicity may require stretching techniques, vagi- pelvic pain. Although there is limited data to guide manage-
nal dilators, or manual massage to relax the chronically ment options, conservative treatment with non-opioid pain
contracted pelvic muscles [55]. Inadequate muscle control medications, such as nonsteroidal anti-inflammatory drugs
or acetaminophen, should be tried first. There is insufficient debilitating to the affected patient, but can also be challenging
data to support the use of gabapentin or pregabalin specifi- for her sexual partner and overall sexual health. Therefore,
cally for adhesion-related pain [77]. Adhesive disease is not referral to a therapist specializing in sexual disorders is rec-
reliably diagnosed with any imaging modality and can only ommended for all women undergoing treatment for vulvo-
be confirmed with surgical exploration. Laparoscopy is the dynia [81]. Psychological treatment and support may actually
least invasive surgical option for the diagnosis and treatment improve pain symptoms, and in fact, at least one study dem-
of adhesions. Surgery should be reserved for patients in onstrated that cognitive behavioral therapy resulted in greater
which other causes of their chronic pain have been ruled out long-term reduction in dyspareunia caused by vestibular pain,
and are at high risk of having adhesions based on a history of when compared to vestibulectomy alone [82].
prior surgery or inflammatory/infectious processes. For pain
relief, short-term success rates for laparoscopic excision of
adhesions, or adhesiolysis, are variable between 38% and Psychiatric
87% [78]. However, at least one randomized controlled trial
revealed that laparoscopic adhesiolysis resulted in compara- Psychiatric comorbidities are prevalent in women suffering
ble success rates to simple diagnostic laparoscopy [34]. from chronic pelvic pain. Due to the inherent complexity of
Similarly, complete adhesiolysis does not necessarily corre- chronic pelvic pain, it may be difficult to determine if the
late with better pain relief when compared to incomplete psychiatric conditions are precipitating factors, conse-
excision [79]. In contrast, extensive adhesiolysis increases quences of the chronic pain, or both. When approaching the
the surgical time and may increase the risk of bleeding, psychiatric care of patients with chronic pelvic pain, it is cru-
bowel injury, or vascular injury. Patients with chronic pain cial that the provider validates that he/she believes in the
and suspected intra-abdominal adhesions should be referred patient’s pain symptoms as patients may become concerned
to a gynecologic or general surgeon for further evaluation that the provider believes “the pain is just all in her head.”
and counseling to determine if laparoscopic evaluation and Therefore, acknowledgment and treatment of the psycho-
treatment is indicated. Preoperatively, patients must be coun- logical effects of chronic pelvic pain is just one component
seled that adhesions may or may not be found at time of sur- of the overall treatment plan. It is appropriate to refer patients
gery. Additionally, although adhesiolysis may result in with concerns for depression, anxiety, PTSD, and somatiza-
short-term pain improvement, patients must also be aware tion to a behavioral health specialist for long-term manage-
that recurrence rates may be as high as 26% [78]. ment or co-management with their primary care provider.
Vulvodynia and vulvar vestibulitis are conditions charac- Patients with a history of interpersonal violence, sexual
terized by chronic vulvar pain or discomfort. Initial manage- abuse, or drug dependency may need referral to a provider
ment steps should include lifestyle modifications with who has expertise in specialized therapy and treatment (see
avoidance of vulvar irritants. Such lifestyle modifications Chap. 33 on Depressive and Anxiety Disorders and Chap. 35
include wearing 100% cotton underwear and avoiding syn- on Intimate Partner Violence and Sexual Trauma).
thetic fabrics/tight-fitting pants, using fragrance-free soaps Medications such as tricyclic antidepressants, gabapentin,
and detergents, using preservative-free emollients for barrier SSRIs, and SNRIs are commonly used in patients with con-
protection, sex counseling, and generally keeping the vulvar comitant pelvic pain and psychiatric comorbidities under the
area clean and dry [80]. If there is no improvement with ini- supervision of primary providers comfortable managing
tial conservative measures then referral to a gynecologist these medications or psychiatrists as they harbor properties
should be considered for treatment with topical agents: to treat both neuropathic pain and mood symptoms [83–86].
anesthetics, estrogen cream, or compounded tricyclic antide-
pressants [80]. Additionally, oral tricyclic antidepressants and
anticonvulsants have been shown to be effective in improving Following several months of pelvic floor physical ther-
vulvar pain; however, care should be taken to confirm the apy, Sally has some improvement in her pelvic pain
patient’s current medications to avoid potentially dangerous and is now able to tolerate the use of tampons. She still
drug interactions [80]. In patients whose symptoms are has significant pain that prevents her from having
refractory to medical management and with pain localization intercourse, and she confides in you that she has a his-
to vestibule, surgical intervention has been shown to be effec- tory of sexual abuse. After confirming that Sally is cur-
tive [81]. A vulvar vestibulectomy involves excision of the rently in a safe home situation, you gently recommend
hymenal ring and superficial vulvar mucosa from 3 to 9 that speaking with a therapist may be beneficial. She
o’clock [81]. In addition to lifestyle modification, pharmaco- plans to see a psychiatrist specializing in sexual abuse
logic treatment, and surgical intervention, the patient should patients and will continue working with the pelvic floor
also be offered treatment for the psychological effects of vul- physical therapist.
vodynia. Vulvodynia can be physically and emotionally
Summary Points counter antifungal for a presumed yeast infection. She is

married and denies new sexual partners. She does report a
1. Chronic pelvic pain is defined as noncyclical pain in the long-standing history of burning pain with intercourse.
pelvis, anterior abdomen, or lower back lasting for at least There are no lesions on her external genitalia and biman-
3–6 months’ duration. ual exam is unremarkable. She reports severe pain from 4
2. The etiology of chronic pelvic pain is often multifactorial o’clock to 7 o’clock along the posterior fourchette on cot-
and complicated. In order to avoid misdiagnosis, a ton swab testing. Wet mount with 10% KOH of the vagi-
systems-based approach should be utilized focusing on nal discharge shows no evidence of candidal vaginitis.
gastrointestinal, urologic, neurologic, musculoskeletal, What is the first-line treatment of vulvodynia?
gynecologic, and psychiatric causes which contribute to A. Nonsteroidal anti-inflammatory drugs
chronic pelvic pain. B. Vulvar care measures: wearing cotton underwear and
3. The evaluation of chronic pelvic pain includes a compre- avoiding vulvar irritants
hensive history detailing the patient’s pain symptoms and C. Vestibulectomy
the effect on her quality of life, personal and family his- D. Topical lidocaine cream
tory of chronic pain disorders or psychiatric conditions, E. Tricyclic antidepressants
surgical history, gynecologic history, sexual history, and The correct answer is B. Vulvodynia is a chronic pain
pregnancy history. Screening for a history of trauma, past disorder that is defined as burning vulvar pain in the
or present intimate partner violence, and substance use is absence of relevant visible findings or a specific clinically
imperative. identifiable neurological disorder. This is a diagnosis of
4. The physical exam of the CPP patient should include a exclusion, and treatable causes of vulvar pain, such as
full abdominal exam, testing for abdominal wall pain, candidal vaginitis, must be ruled out. Other chronic skin
careful visual and Q-tip testing along the vulva, evalua- conditions, such as lichen sclerosus, lichen planus, and
tion of the superficial and deep pelvic floor muscles, vulvovaginal atrophy, should be first ruled out by careful
bimanual exam, and a speculum examination. Particular visual examination of the vulva and perineum. Vulvar
care should be taken to create a safe, supportive environ- lesions may warrant biopsy in order to obtain a tissue
ment during the history and physical exam. diagnosis. Cotton swab testing along the perineum allows
5. Initial testing for the evaluation of chronic pelvic pain for mapping of the location and severity of the patient’s
should be guided by the patient’s symptoms, history, and vulvodynia symptoms. First-line treatment for suspected
physical exam. Office laboratory testing, as applicable, vulvodynia includes lifestyle modifications with vulvar
should include pregnancy testing, urinalysis, screening care measures that avoid vulvar irritants. Such measures
for sexually transmitted diseases, and wet mount micros- include wearing 100% cotton underwear, avoiding per-
copy of vaginal discharge. Pelvic ultrasound should be fumes/dyes in detergents or soaps, avoiding douching,
considered the first-line imaging modality for chronic cleaning the vulva with water only, keeping the vulvar
pelvic pain. Diagnostic laparoscopy should not routinely area dry throughout the day and applying a preservative-
be offered for first-line assessment. free emollient daily, and rinsing and gently drying the
6. The treatment for chronic pelvic pain should target the vulva after urination. If lifestyle modifications do not
most likely etiological source of the patient’s pain, utiliz- result in improvements, then topical local anesthetics,
ing a patient-centered multidisciplinary team approach estrogen cream, or topical tricyclic antidepressants may
which includes a primary care provider, gynecologist, provide symptomatic relief. Oral tricyclic antidepressants
chronic pain specialist, psychologist, and physical thera- or anticonvulsants may be incorporated as a third-line
pist. Realistic treatment goals should be established treatment. Nonsteroidal anti-inflammatory drugs usually
focusing on improvement in quality of life in addition to provide minimal relief for chronic pain associated with
reduction in pain symptoms. vulvodynia. Surgical resection of the vestibule, or vesti-
bulectomy, should be reserved for patients who have tried
and failed medical management options [80, 87].
Review Questions 2. A 45-year-old multiparous woman presents to your office

reporting pelvic pain since the birth of her last child
1. A 30-year-old woman comes to your office reporting pel- 7 years ago. The pain is constant and sharp and radiates to
vic pain and vulvar irritation for the last 10 years that has her lower back. Her past medical history is significant for
been worsening over the last several weeks. She chronic constipation. She has not been sexually active for
researched her symptoms online and took an over-the- multiple years due to significant dyspareunia. Pelvic
exam is limited due to discomfort. She has point tender- D. Abdominal x-ray
ness along her left and right levator ani muscles. Which of The correct answer is A. This patient’s symptoms of
the following is the most appropriate next step in the dysmenorrhea and acute worsening of her chronic pelvic
management of this patient? pain with cul-de-sac tenderness and adnexal fullness is
A. Recommend strict pelvic rest. concerning for endometriosis. The gold standard for
B. Initiation of oral muscle relaxants. diagnosis of endometriosis is histologic confirmation
C. Initiation of low-dose long-acting narcotics. with tissue biopsy. Radiographic evaluation for pelvic
D. Referral to pelvic floor physical therapy. pain should identify structural causes for patient’s pain
The correct answer is D. Pelvic floor muscle dysfunc- while minimizing unnecessary exposure to ionizing radi-
tion or myofascial pain can often be diagnosed with his- ation. Transvaginal ultrasound is the optimal initial imag-
tory and physical exam. Often, the patient will report a ing modality for the evaluation of female pelvic pain
history of painful intercourse, painful urination, and/or because ultrasonography can delineate structural abnor-
pain with defecation. Pelvic floor muscle dysfunction malities within the uterus and adnexae without exposing
may result from either increased muscle tone (muscle the patient to radiation. Specifically, ultrasound can dis-
spasms) or decreased muscle tone (myofascial laxity). tinguish the characteristics of adnexal cysts as simple,
The most commonly affected muscles are the levator ani, complex, hemorrhagic, or endometrioma or exhibits fea-
obturator, and piriformis muscles which are found deep tures concerning for malignancy. Additionally, transvagi-
within the pelvic floor. Patients with pelvic floor dysfunc- nal ultrasound can be used to detect deep infiltrating
tion may require an interdisciplinary team including a endometriosis along the rectovaginal septum. Computed
pelvic floor physical therapist, urogynecologist, primary tomography (CT) rarely adds useful additional informa-
care physician, and psychologist. The most important first tion to a pelvic ultrasound and exposes the patient to ion-
step in the management of patients with suspected pelvic izing radiation and significantly increases cost. CT may
floor muscle dysfunction is referral of the patient to a cer- be useful for further evaluation of patients with an
tified pelvic floor physical therapist for confirmation of adnexal mass with features concerning for malignancy.
the diagnosis and treatment. Directed therapeutic exercise Magnetic resonance imaging (MRI) may provide better
or myofascial release is recommended over strict pelvic imaging of deep tissue structures; however, it is signifi-
rest, which may actually worsen the pelvic floor dysfunc- cantly more expensive than transvaginal ultrasound and
tion. Oral muscle relaxants do not specifically target the unlikely to be an ideal first imaging study. None of the
pelvic floor muscles and are often associated with reproductive organs can be visualized with abdominal
increased sedation; therefore, their use should be limited. x-ray [88–90].
Narcotics in general are unlikely to be effective in treating
pelvic floor muscle dysfunction and may worsen the
patient’s chronic constipation. Patients with pelvic floor
muscle spasms, who are refractory to physical therapy,
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Opioid Use Disorder
32
Alfred Shoukry and Melissa A. McNeil
both disorders. “Dependence” most often refers to the body’s

Learning Objectives need to use opioids to avoid physical withdrawal symptoms
1. Define opioid use disorder. or the need to use more to produce the same effect, also
2. Review the epidemiology of opioid use disorder in known as “tolerance.” “Abuse” refers to the patient’s contin-
women. ued use of opioids despite negative social, medical, legal, or
3. Identify treatment strategies for opioid use disorder occupational problems [1]. Patients with opioid use disorder
including counseling, abstinence, and medication- can misuse opioid prescriptions, use diverted prescription
assisted treatment. opioid medications, or use illicit opioids such as heroin. It is
4. Appropriately prescribe medication-assisted ther- clear from evaluating changes in opioid use and death from
apy for pregnant women. opioids over time that America is facing a major opioid epi-
demic [2]. In 2015, approximately 91.8 million people in the
United States used opioids, 11.5 million people misused
them, and 1.9 million people during this period met criteria
Emily is a 32-year-old woman with history of chronic for opioid use disorder [2]. About 5.1 million people used
lower back pain who underwent lumbar fusion surgery heroin at some point during their lifetime according to a
3 years ago. She has been on long-standing opioid 2015 estimate. In the United States, opioid-related deaths are
medications prescribed through your office. In the past increasing with 33,000 deaths related to opioid overdose in
year she noticed that she has required higher doses of 2015 [3]. Most patients who use heroin report previously
opioids to manage her pain and has recently started using prescription drugs for nonmedical uses [4]. Gender has
resorting to getting additional pills from friends and been shown to play a role in opioid use disorder—women
family to manage her pain. tend to initiate illicit drug use at an earlier age, and progress
more rapidly to drug dependence than men [5]. Women with
serious mental illness or cigarette smoking are more likely to
have nonmedical use of prescription opioids [6].
Epidemiology In an effort to gain insight into the factors influencing
long-term opioid use, researchers analyzed outcomes of
Opioid use in the United States has been rising during the opioid-naive patients treated with opioids; the probability of
past two decades and has resulted in increasing rates of opi- continued opioid use at 1 year in this group was 5.3%.
oid use disorder. “Opioid use disorder” (OUD) as defined by Factors that increased the risk of continued opioid use in this
the DSM V and will be discussed in detail later in this chap- population included: prescriptions of greater than 90 mor-
ter has replaced the prior DSM IV diagnoses of opioid phine milligram equivalents, initiation of treatment with tra-
dependence and opioid abuse by accounting for features of madol, or treatment with long-acting opioids [7].
A. Shoukry (*) Physiology and Pathophysiology

UPMC, Department of Internal Medicine, Pittsburgh, PA, USA
Opioids are natural or synthetic substances that act on the
M. A. McNeil
mu, kappa, and delta receptors. They have central and periph-
University of Pittsburgh Medical Center, Department of Medicine,
Pittsburgh, PA, USA eral nervous system effects. Activation of mu receptors in the

486 A. Shoukry and M. A. McNeil
central nervous system leads to the analgesia, euphoria, and have a longer duration of action if there are active
respiratory depression. Opioid receptor activation in the metabolites.
peripheral nervous system can cause constipation and cough Patients receiving opioids chronically may wish to be
suppression. Removal of opioids from mu receptors leads to tapered to off, especially if patients are experiencing adverse
withdrawal effects including piloerection, joint pain, diapho- effects which include sedation, difficulty with concentration,
resis, mydriasis, diarrhea, and dysphoria [8]. The severity of nausea, mood changes, or constipation. One approach to this
these withdrawal symptoms is often a barrier that prevents would be to taper the opioid dose by 10% per week. In
patients who try to stop using opioids. patients who have been on long-term opioids for more than
Natural opioids, including morphine, codeine, and heroin, 2 years, the taper can be changed to decreasing the dose by
are drugs extracted directly from the opium poppy plant. 10% every month [11].
Semisynthetic opioids, including oxycodone, hydrocodone,
hydromorphone, and oxymorphone, are derived from the
opium poppy plant. Synthetic opioids, including methadone,
tramadol, and fentanyl, are drugs produced without the After discussing your concerns with Emily about her
poppy plant. Some urine drug assays do not consistently using additional pills from her friends and family, she
detect semisynthetic and synthetic opioids [9]. becomes concerned and decides to stop using opioids
Table 32.1 shows the half-lives and duration of effect of on her own without a taper. She misses her next sched-
some commonly used opioids [10–12]. These properties of uled appointment and returns 2 months later. She
opioid medications are important when considering which reports that she experienced nausea, vomiting, diapho-
drug to prescribe, how much to prescribe, and how often to resis, joint pain, and diarrhea after stopping her oxy-
prescribe it. Most opioids are “short-acting” and need to be codone. Due to the severity of her withdrawal
given several times per day in order to provide adequate pain symptoms, she started buying opioids illegally.
control for chronic pain. Opioids with a short half-life can
Table 32.1 Onset, half-life, brand names, and equianalgesic doses of commonly prescribed opioid medications [10, 12, 13]. Onset, half-life, and
potency of medication will vary by patient
Equianalgesic
Drug Onset Half-life Common brand names dose
Fentanyl (synthetic) IM: 7–15 minutes IM: 3–4 hours Duragesic, Abstral, Fentora, Sublimaze, IM: 0.125
IV: immediate IV: 2–4 hours Subsys Transdermal:
Transdermal patch: 6 hours Transdermal patch: variable
20–27 hours
Oxymorphone IM: 10–20 minutes IM: 2–3 hours Opana IM: 1
(semisynthetic) PO: Variable PO: Variable (FDA recall of extended-release PO: 10
formulation in 2017)
Hydromorphone IM: 10–20 minutes IM: 2–3 hours Dilaudid, Exalgo IM: 1.5
(semisynthetic) IV: 5 minutes PO: Variable PO: 7.5
PO: 15–30 minutes
Hydrocodone PO: 30–60 minutes PO: 4 hours Vicodin, Norco, Lorcet, Lortab, Xodol, 5–10
(semisynthetic) Verdrocet (with acetaminophen)
Oxycodone PO (short-acting PO (short-acting Percocet, Endocet, Roxicet, Primlev, 15–30
(semisynthetic) formulations): formulations): 2–3 hours Xartemis (with acetaminophen)
30–60 minutes Roxicodone, Oxaydo, Oxycontin,
Roxybond, Xtampza
Oxycodone PO (long acting): 4.5 hours PO (long acting): Oxycontin 15–30
(semisynthetic) 12 hours
Codeine PO: 10–30 minutes PO: 3 hours Tylenol #3, Tylenol #4 (with 15–30
(natural) acetaminophen)
Morphine IM/IV: 5–20 minutes IM/IV: 2 hours MS Contin, Kadian, MorphaBond, IM/IV: 10
(natural) PO: ~ 30 minutes PO: 2–4 hours Duramorph PO: 30
Tramadol PO: <60 minutes PO: 5–7 hours Ultram, Zytram, Tridural, Ralivia, 50–100
(synthetic) Durela
Methadone PO: 30–60 minutes PO: 12–190 hours Dolophine, Methadose Variable
(synthetic)
Buprenorphine PO 100 minutes PO: 24–42 hours Suboxone, Zubsolv, Bunavail (with Variable
naloxone)
Subutex (without naloxone)
32 Opioid Use Disorder 487
Diagnosis abuse, problematic medication-related behaviors, family his-

tory of substance use, and issues with the provider-patient
Opioid use disorder (OUD) is formally diagnosed using the relationship [14]. The Opioid Risk Tool (ORT) is another
Diagnostic and Statistical Manual of Mental Disorders, patient-reported questionnaire that assesses risk factors for
Fifth Edition. This definition now encompasses the previous opioid use disorder including personal and family history of
diagnoses of opioid abuse and opioid dependence from the substance abuse, age, sexual abuse, and psychological dis-
DSM IV. The DSM V defines opioid use disorder as opioid eases [15]. At the time of publication, both of these tools can
use that leads to significant impairment and distress as evi- be accessed on the Internet for free.
denced by two of the following, over a 12-month interval: For patients already on opioids, it is important to monitor
for aberrant behaviors including lost or stolen medications,
1. Patient takes medication in larger quantities than what is documented use of multiple physicians, and requests for
recommended, prescribed, or intended. early refills. Patients with more aberrant behaviors should
2. Unable to successfully stop or wean down opiates prompt further screening for opioid use disorder [15]. The
despite the desire to. Rapid Opioid Dependence Screen (RODS) is an eight-item
3. Significant efforts are made to secure, use, and recover tool for screening opioid use disorder in the clinical setting
from opioids. [16]. This tool asks about the pattern of opioid use and its
4. Uncontrollable desire to use opioids, whether or not they effect on patients’ functioning. Patients who screen positive
are prescribed. should be asked about the items in the DSM V criteria for the
5. Opioid use consistently causes problems in home, diagnosis of opioid use disorder.
school, or work life. Patients that are not prescribed opioids and are not being
6. Continued use despite social, personal, medical, or psy- evaluated for management of acute or chronic pain can still
chological problems that result directly from use (social/ have opioid use disorder. Frequent visits to the emergency
personal issues = 1, medical/psychological issues = 1). department for pain-related conditions (tooth pain, abdomi-
7. Social or work obligations are compromised due to opi- nal pain, trauma), history of mental illness, stress at home,
oid use. job loss, history of substance use, and family history of sub-
8. Ongoing use in physically hazardous situations. stance use should always raise concern for a concomitant
9. Physical tolerance to opioids—needing more opioid to substance or opioid use disorder, and patients should be
produce the same effect or having a diminished effect by screened appropriately.
consistently using the same dose.
10. Withdrawal—developing physical symptoms of pilo-
erection, joint pain, diaphoresis, mydriasis, diarrhea, History and Physical Exam
and dysphoria after stopping opioids or taking opioids to
alleviate these symptoms. When evaluating patients with opioid use disorder, the
provider should assess for the type of opioids consumed
Patients with two to three symptoms present have mild and the method of consumption. Opioids can be used
opioid use disorder; four to five symptoms have moderate through intranasal, intravenous, subcutaneous, or intra-
opioid use disorder; and six or more symptoms have severe muscular use or by smoking. Patients using needles should
opioid use disorder. also be asked about needle sharing, disposal, reuse, or
other behaviors such as licking needles. The amount of
opioid use should also be assessed along with details on
Screening the frequency of use and the time of last use. Patients
should also be asked about prior attempts at treatment
Screening for OUD is an important part of evaluating patients including inpatient rehabilitation, outpatient rehabilita-
who are prescribed chronic opioids. This can help identify tion, or prior medication-assisted treatment (MAT). Other
individuals in which the risk of starting or continuing opioids historical elements about medical or legal complications
outweighs the benefits of opioid therapy. of opioid use should be assessed. Medical complications
Several screening tools exist for identifying patients who can include infections such as cellulitis, bacteremia, diski-
are at high risk of misusing opioids and should be adminis- tis, osteomyelitis, epidural abscesses, septic joints, endo-
tered to patients prior to starting opioid medication to help carditis, sepsis, HIV, hepatitis B, or hepatitis C. Any
guide decisions about treatment and follow-up. The Screener surgeries related to orthopedic or valvular infections
and Opioid Assessment for Patients with Pain (SOAPP) is a should be documented. Legal issues can be related to pur-
14-item patient-reported questionnaire which assess several chasing or distributing opioids or operating vehicles under
domains including psychiatric issues, history of substance the influence of substances.
A thorough physical examination should be performed laboratory and discuss the results with the patient, rather
paying particular attention to the potential complications than assume use behaviors about the patient.
from opioid use. Patients who inject opioids may have track The history and physical exam should drive any further
marks on their skin, which are scars or wounds from frequent workup and testing for acute or chronic medical issues at the
intravenous injections commonly found on the upper extrem- time of patient presentation. If patients are being considered
ities but can be found anywhere there is an accessible vessel. for medication-assisted treatment (MAT), it is important to
Injection sites should be examined for infection. All joints evaluate for liver disease, since naltrexone and naloxone are
should be examined for swelling, erythema, warmth, and contraindicated in this patient population.
range of motion. A heart exam can reveal murmurs related to
endocarditis. A neurovascular exam should also be done to
assess for any neurological deficits which could be related to Emily remains motivated to discontinue using illicit
spine infections, cerebral abscesses, or mycotic aneurysms. opioids, but she feels helpless in her struggle. She has
The nasal septum should be examined in case of perforation been attending narcotics anonymous meetings but has
which can occur in patients who use intranasal drugs. Pain not been able to discontinue opioids due to intense
should be taken seriously and investigated, especially in the cravings and the severity of her withdrawal symptoms
setting of a fever as it can indicate an underlying nidus of when she discontinues them. She asks if there are any
infection. options available to help her stop using opioids.
Patients using opioids may be intoxicated or experiencing
withdrawal symptoms. Signs of intoxication can include pin-
point pupils, impaired cognition, or drowsiness. Conversely,
patients withdrawing from opioids may have lacrimation, Treatment
rhinorrhea, yawning, hyperactive bowel sounds, piloerec-
tion, and tachycardia. The approach to treatment for OUD is the same regardless of
The prescription drug monitoring program should be the severity of OUD. Long-term treatment for opioid use dis-
checked if available to identify any controlled substances order involves a multifaceted approach including addiction
that patients are being prescribed. counseling and consideration of medication-associated treat-
ment (MAT). Members of a successful treatment team usu-
ally include providers from primary care or psychiatry,
Laboratory Evaluation psychology, peer support groups, social work, and nursing.
Factors including the patient’s medical comorbidities and
Laboratory evaluation is an important component in the ini- preferences can help guide the approach to treatment.
tial evaluation of patients with opioid use disorder. Patients
who use opioids intravenously or subcutaneously are at risk
for HIV and hepatitis B and C due to sharing needles and Medically Supervised Withdrawal
drug injection equipment that are contaminated with blood.
Active substance use can facilitate disinhibited behaviors Withdrawal symptoms can be severe and a challenging barrier
such as unsafe sex practices, sex with multiple partners, and to recovery. Many patients with OUD continue to use opioids
sex for drugs placing patients at high risk for STIs [17]. only to avoid withdrawal symptoms and not to become intoxi-
Screening for hepatitis B and C, syphilis, and HIV is indicated. Medically supervised withdrawal can help to safely
cated. Gonorrhea and chlamydia screening should be offered transition patients to abstinence or long-term MAT. Managing
according to guidelines for high-risk individuals depending patients with opioid use disorder is a complicated task which
on age, sexual exposures, and HIV status [18]. Women requires motivational interviewing strategies and a willingness
should be screened for pregnancy with urine hCG and on the patient’s part to engage in treatment.
strongly encouraged to use reliable forms of contraception. There are two approaches to treating opioid withdrawal: (1)
A urine drug screen can be helpful to determine if patients by treating withdrawal with opioid receptor agonists (buprenor-
are using prescribed medications appropriately and to evalu- phine or methadone) which allows gradual taper of the drug or
ate for other illicit substances. Having patients return for ran- continuation as part of MAT and (2) by using medications to
dom drug screens can also provide helpful information about block the symptoms of opioid withdrawal, allowing the patient
use behaviors. Most labs have different choices for urine to go through withdrawal “cold turkey” from opioids. Alpha-2
drug screens; some of these may not detect semisynthetic agonists (clonidine) help block sympathetic overdrive and
opioids (such as oxycodone, hydrocodone, oxymorphone) or decrease sweating, restlessness, anxiety, and rhinorrhea; H2
synthetic opioids (such as methadone, tramadol, fentanyl). If blockers such as diphenhydramine or hydroxyzine assist with
a urine drug screen returns with unexpected results, a good treating anxiety or restlessness. Loperamide can be used to
first step is to discuss the characteristic of the test with the manage diarrhea, and antiemetics such as ondansetron can be
used to manage nausea or vomiting. NSAIDs can help with ers or at mutual support groups which often encourage
joint pain, and muscle relaxants such as cyclobenzaprine or abstinence-based treatment. This should be explored in a
baclofen can be helpful with muscle spasms. Opioid agonist supportive environment and the benefits of medication-
therapy is more effective than symptomatic management of assisted treatment should be emphasized.
withdrawal symptoms and is preferred unless the patient is in
an environment such as a prison where opioid agonist therapy
is not permitted [19]. Alpha-2 agonists should be avoided in Medication-Assisted Treatment (MAT)
patients with bradycardia or hypotension.
Withdrawal symptoms should be measured serially to All patients with OUD can be considered for MAT. The goal
assess progress and guide medication therapy. Withdrawal of MAT is to allow the patient to be free of physiologic crav-
symptoms can be assessed using the structured Clinical ings and adverse psychosocial effects of opioids in a con-
Opioid Withdrawal Scale (COWS) [20]. The COWS accounts trolled environment with a trusted provider. MAT can be
for resting heart rate, gastrointestinal upset, sweating, tremor, started in patients that want to curb cravings that are not cur-
restlessness, yawning, pupil size, anxiety, gooseflesh skin, rently using opioids and started in patients currently using
runny nose, or tearing each on a scale of 1–5. While these opioids independently or part of a medically supervised
withdrawal symptoms can sometimes be severe enough to withdrawal program. Long-term treatment of OUD with
necessitate inpatient admission for their management, they MAT can consist of opioid antagonist treatment (naltrexone)
are not life-threatening. Patients with the following should or opioid agonist treatment (methadone or buprenorphine).
be considered for admission for medically supervised with-
drawal: (1) the patient’s home environment is not safe or
conducive for patient detoxification; (2) the patient’s medical Naltrexone
problems need to be monitored during the withdrawal period
(e.g., if a patient has chronic renal insufficiency and is hav- Naltrexone is a mu-opioid receptor antagonist which helps to
ing profuse diarrhea from opioid withdrawal, volume status lower the rate of opioid use relapse by blocking the euphoric
and renal function need to be monitored); (3) there is con- effect of opioids [22]. Since this medication is an antagonist,
cern for concomitant drug use with alcohol, benzodiaze- patients should be abstinent from all opioids for at least 7 days
pines, or barbiturates—acute withdrawal from these prior to starting. Administering this medication in patients
substances can be life-threatening; or (4) the patient has who have used opioids recently can precipitate withdrawal
severe mental illness or is psychologically unstable. effects. Naltrexone does not have any analgesic effects due to
Medication-supervised withdrawal or tapering patients its antagonism of the mu-opioid receptor. When starting nal-
off opioids is often insufficient for achieving long-term trexone, a challenge dose of 0.8 mg–1.6 mg IV or IM dose can
abstinence, and patients forgoing long-term treatment have be given with monitoring over the next 15–30 minutes or a
been found to have higher mortality than ones undergoing 12.5 mg–25 mg oral dose with monitoring over the next
MAT due to higher rates of resuming opioid use [21]. 4 hours. If patients tolerate a test dose without significant
withdrawal symptoms as outlined previously, then they can be
started on the full oral or intramuscular dose. Naltrexone is
Counseling available in 50 mg tablets which can block the effect of opi-
oids for 1 day or can be administered in a 380 mg injection
Current evidence supports the use of MAT for the treatment of which can last for 1 month. Side effects include nausea,
opioid use disorder. Addiction counseling can serve as an abdominal pain, fatigue, or insomnia. Transaminases should
adjunctive tool or can be used in patients who prefer not to use be monitored as they can increase while on naltrexone. Women
MAT. Addiction counseling is a loose definition and can take using naltrexone should be counseled on reliable contracep-
many forms. It can include individual, family, group, cognitive, tion and be screened for pregnancy. In one study, 74% of
and behavioral therapies provided by trained physicians, psy- patients receiving naltrexone had urine samples negative for
chologists, counselors, or peer advocates. Patients can enroll in opioids, compared to 56% of patients receiving counseling
inpatient, intensive outpatient, or outpatient programs depend- and referral to community treatment programs [23]. Naltrexone
ing on their needs. Mutual support groups such as Alcoholics is typically used as a monthly intramuscular injection.
Anonymous and Narcotics Anonymous have played a major
role in addiction recovery across America. All of these pro-
grams can be used concomitantly with MAT. Methadone and Buprenorphine
buprenorphine programs typically require patients to partici-
pate in some form of addiction counseling. Buprenorphine is a partial mu-opioid receptor agonist which
Some patients may be hesitant to engage in MAT due to can help to reduce opioid cravings and withdrawal symp-
stigma previously encountered with other healthcare provid- toms. It can also help to block euphoric effects if opioids are
used in conjunction. Providers can undergo special training medication-assisted-treatment/physician-program-data/

to become waivered to prescribe buprenorphine in the outpa- treatment-physician-locator) [25].
tient setting. Buprenorphine is most commonly prescribed in
an outpatient setting, but increasingly patients are being
started on buprenorphine while in the hospital to facilitate Methadone
MAT when they are admitted for complications from opioid
use. The ability to take the medication in outpatient offices Methadone is a full mu-opioid receptor agonist which is
makes it more convenient than methadone, which requires restricted to specialized clinics that require daily visits.
daily clinic visits for dosing. This also means that it should Given the high degree of monitoring and participation for
be reserved for patients who do not require the frequent fol- patients, methadone can be an effective option in patients
low-up and structure of a methadone clinic. with severe opioid use disorder and has been associated with
The most commonly used formulation of buprenorphine a reduced risk of death [26]. It also serves as an effective
is a combination buprenorphine-naloxone film. The nalox- treatment for special populations including women during
one in this formulation is metabolized through first pass pregnancy. Methadone treatment typically has three phases:
metabolism and does not cause withdrawal. If injected, how- induction/early stabilization with low doses, late stabiliza-
ever, the naloxone in this formulation causes withdrawal tion with increasing doses, and maintenance. Maintenance
symptoms. This is used as a deterrent for injecting the doses between 80 mg and 100 mg are targeted to minimize
medication. cravings while avoiding euphoria and sedation. Side effects
It is optimal to start buprenorphine after patients start to include constipation and QT interval prolongation.
have withdrawal symptoms because starting buprenorphine Methadone has several drug interactions and patient medica-
in patients who are acutely intoxicated can precipitate severe tions must be monitored carefully. Because methadone is
withdrawal symptoms. Because it is a partial agonist, most often prescribed by small local clinics, providers may
patients being initiated on buprenorphine should attempt to not know that patients are taking methadone, and methadone
abstain from opioids for about 12–24 hours prior to starting will not show up on a routine pharmacy dispensing record.
the medication in order for them to develop withdrawal Opioid substitution therapy with methadone or buprenor-
symptoms. If patients are taking longer-acting opioids such phine to treat opioid use disorder can help to reduce injection
as methadone, they may need to wait for longer periods (up use, needle sharing, and therefore cases of HIV infection
to 48–72 hours) before they develop withdrawal symptoms. [27]. Patients who inject drugs should be considered for pre-
Patients can typically start with a 4 mg dose of buprenor- exposure prophylaxis (PrEP) to protect against contracting
phine and increase over the course of 1–2 days as needed to HIV [28]. Patients with history of opioid use disorder should
curb withdrawal symptoms. Side effects of buprenorphine undergo routine urine drug screening regardless of the choice
include fatigue, anxiety, nausea, or constipation. Since of therapy to ensure that medications they are prescribed are
buprenorphine is a partial mu-receptor agonist, it does have present in their urine, that medications they are not pre-
some mild analgesic effect. In a randomized, double-blind, scribed are absent, and that they are free of other illicit sub-
placebo-controlled efficacy study of buprenorphine for stances. All patients with OUD should also be provided with
patients with opioid use disorder, the proportion of urine naloxone in case of relapse or overdose. Naloxone is a short-
samples that were negative for opioids was 17.8% in patients acting opioid antagonist that can rapidly reverse the effect of
taking buprenorphine- naloxone compared to 5.8% in opioids in case of overdose. Naloxone can be provided via an
patients receiving placebo [24]. intramuscular or intranasal route.
Buprenorphine is an effective treatment for opioid use
disorder in pregnant women. In this population of patients, Emily considers methadone or buprenorphine in order
buprenorphine monotherapy should be used rather than to help with withdrawal symptoms and opioid crav-
buprenorphine-naloxone due to limited data regarding nal- ings. She opts for buprenorphine because she doesn’t
oxone safety during pregnancy. Buprenorphine monotherapy feel that she can make it to daily visits for methadone
should also be used in patients with cirrhosis due to clear- administration. You help her to find a provider waiv-
ance of naloxone by the liver. ered to prescribe buprenorphine through the SAMHSA
As with naltrexone, if prescribing buprenorphine for website who is near her home. In addition to MAT, she
women, providers should discuss effective contraception and enrolls in drug and alcohol counseling. She starts to
screen for pregnancy routinely. attend Narcotics Anonymous meetings and has been
Patients interested in buprenorphine therapy can find a successful in abstaining from opioids. During her fol-
provider authorized to prescribe it through the low-up visit, she reports that she would like to become
Buprenorphine Treatment Practitioner Locator at the pregnant and would like advice about how to manage
Substance Abuse and Mental Health Services Admin her medications.
istration (SAMHSA) website (https://www.samhsa.gov/
Opioid Use Disorder During Pregnancy 2. Opioid use disorder carries significant morbidity and
mortality; women are more likely to start using opioids at
Early universal screening for opioid use disorder with vali- a younger age and have a more rapid progression toward
dated tools is recommended in pregnant women. The 4Ps can overt substance use.
serve as a brief screening tool [29]. 3. Treating opioid use disorder is best done by a multidisci-
plinary team including primary care, psychology, social
• Parents: One or both parents with a problem with alcohol work, nursing, and peer support services. Medications
or drug use? including buprenorphine, methadone, and naltrexone can
• Partner: Partner with problems with alcohol or drug use? be used to treat opioid use disorder.
• Past: Prior difficulties in life due to alcohol or drugs 4. Buprenorphine and methadone are the preferred medica-
(including prescribed medications)? tions for treatment of opioid use disorder in pregnant or
• Present: Drug or alcohol use in the past month? nursing women.
Any questions answered with “yes” should trigger addi-

tional questions and potential intervention. Review Questions
Buprenorphine and methadone are both effective for
treating opioid use disorder during pregnancy. Less data are
available regarding use of naltrexone in pregnant women. 1. A 27-year-old woman with history of opioid use disorder
The American College of Obstetricians and Gynecologists who has been maintained on buprenorphine-naloxone
(ACOG) recommends using buprenorphine or methadone presents to your office for routine follow-up. She has
for MAT during pregnancy [30]. The use of buprenorphine been doing well with buprenorphine-naloxone and has
during pregnancy has the advantage of having lower rates of not used any illicit drugs in the past 3 months. A urine
neonatal withdrawal syndrome compared to methadone [31]. drug screen is positive for buprenorphine and negative for
For pregnant women with opioid use disorder who are other substances. A urine pregnancy test is positive.
receiving MAT, abrupt discontinuation is not recommended Which is the most appropriate option for management of
given higher relapse rates than patients who continue MAT her opioid use disorder?
[30]. If a pregnant patient wants to wean down her opioid use A. Taper and discontinue buprenorphine-naloxone.
during pregnancy, she should be closely monitored by her B. Start methadone for the duration of pregnancy.
obstetrician and/or maternal fetal medicine physician. C. Switch buprenorphine-naloxone to buprenorphine
Buprenorphine can be started in the outpatient setting. If a only.
pregnant woman is to be started on methadone for MAT, D. Switch to naltrexone intramuscular shots (Vivitrol).
most often she is admitted for methadone induction and titra- The correct answer is C. ACOG recommends against
tion given the long-acting nature of the drug and risk for discontinuing MAT in patients who are stable even during
respiratory depression. Fetal monitoring is important during pregnancy [30]. Both buprenorphine and methadone are
this time to avoid adverse outcomes. acceptable options in pregnant patients. Since naloxone
Most women that have been on MAT during pregnancy should be avoided during pregnancy, patients receiving
choose to continue MAT postpartum. Buprenorphine and buprenorphine-naloxone should be switched to buprenor-
methadone are both excreted in low doses in breast milk, phine monotherapy. In this case, since the patient has
and infants should be observed for sedation. ACOG recom- been stable on buprenorphine-naloxone, it would be rea-
mends encouraging women on MAT to breastfeed [30]. sonable to have her continue the same dose of buprenor-
Similar to pregnancy, naltrexone should be avoided in phine without naloxone [30].
breastfeeding women. However, naloxone is a short-acting
opioid antagonist which can be used for treatment of opioid 2. A 23-year-old woman presents for follow-up 1 month
overdose and should be given to pregnant or breastfeeding after right knee surgery. She was prescribed a 1-month
women in case of overdose [30]. All women in the postpar- supply of oxycodone 5 mg by mouth every 6 hours as
tum period should be followed closely as this can be a time needed for pain. She reports that she had breakthrough
associated with additional stress, depression, and relapse, pain with this dose and took double the prescribed dose
regardless of MAT use. for pain relief. What is the most appropriate next step?
A. Discuss the need to use opioids only as prescribed and
explore strategies for pain control.
Summary Points B. Inform the patient that she has opioid use disorder and
refer her for drug and alcohol counseling.
1. Opioid use disorder is defined by problematic opioid use C. Refill the patient’s oxycodone early.
leading to significant impairment over a 12-month period. D. Add extended-release oxycodone to help with pain.
The correct answer is A. The next best step in this situ- 3. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug
and opioid-involved overdose deaths - United States, 2010-2015.
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adhere to prescribed doses and frequency, and to explore doi.org/10.15585/mmwr.mm6450a3.
strategies for pain control. There is insufficient evidence 4. Jones CM. Heroin use and heroin use risk behaviors among non-
in this case to diagnose the patient with OUD [32]. Before medical users of prescription opioid pain relievers - United States,
2002-2004 and 2008-2010. Drug Alcohol Depend. 2013;132(1-
giving additional short- or long-acting opioids, other pain 2):95–100. https://doi.org/10.1016/j.drugalcdep.2013.01.007.
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5. Unger A, Jung E, Winklbaur B, Fischer G. Gender issues in
3. A 54-year-old woman with history of heroin use presents the pharmacotherapy of opioid-addicted women: buprenor-
phine. J Addict Dis. 2010;29(2):217–30. https://doi.
for consideration of medication-assisted therapy with org/10.1080/10550881003684814.
buprenorphine-naloxone. She reports injecting heroin 6. Tetrault JM, Desai RA, Becker WC, Fiellin DA, Concato J, Sullivan
1 hour prior to her appointment. Physical examination LE. Gender and non-medical use of prescription opioids: results
reveals normal vital signs. The patient is in no apparent from a national US survey. Addiction. 2008;103(2):258–68. Epub
2007 Nov 27.
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reveals regular rate and rhythm without murmurs, rubs or use among opioid naive patients: an examination of initial prescrip-
gallops. Her skin is dry. She has no tremor on neurologic tion characteristics and pain etiologies. J Pain. 2017;18(11):1374–
exam. Urine drug screen is positive for opioids. Laboratory 83. https://doi.org/10.1016/j.jpain.2017.06.010.
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A. Start buprenorphine-naloxone now by giving the first Toxicol. 2012;8(4):408–16.
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thesia: foundations and clinical application. 2nd ed. Philadelphia:
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12. DiPiro JT. Pharmacotherapy: a pathophysiologic approach. 8th ed.
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Part VI
Mental Health
Depressive and Anxiety Disorders
33
Rebecca Gitlin and Alexandra E. Mieczkowski
Learning Objectives Monica is a 27-year-old cisgender woman presenting

for a primary care appointment to address problems
1. Describe the prevalence of depressive and anxiety
with her sleep. She appears agitated during the
disorders among women in the United States,
appointment and expresses frustration because she
including gender differences in incidence, preva-
“can’t sleep” and is “at [her] wit’s end.”
lence, and presentation.
2. Differentiate among depressive disorders, bipolar
disorders, and anxiety disorders.
3. Utilize two validated screening measures, PHQ-9
and GAD-7, to assess depressive and anxiety symp- Introduction
toms in the primary care setting.
4. Formulate patient-centered inquiries to gather Depressive and anxiety disorders disproportionately affect
information about mood or anxiety symptoms, psy- women and are a significant cause of morbidity in the United
chosocial context, and goals for treatment. States and across the world. Globally, more than 300 mil-
5. Conduct a suicide risk assessment to determine the lion people are affected by depression [1]. Mental health
presence or absence of suicidal ideation, intent, and and substance use disorders are the leading global causes of
plan. disability and therefore represent an important public health
6. Contrast treatments used for depression and anxi- focus [2]. Per the 2016 National Survey on Drug Use and
ety in the primary care setting with respect to antic- Health (NSDUH), 18.3% of adults in the United States have
ipated side effects, efficacy, and safety in pregnancy at least one mental health disorder, and the prevalence is
and lactation. higher in women (21.7%) than in men (14.5%) [3]. Gender
7. Identify patients who require referral to a psychia- disparity statistics are similar for specific types of mental
trist and those who would benefit from voluntary or health issues, such as depressive episodes (8.5% prevalence
involuntary hospitalization. in women relative to 4.8% prevalence in men) and anxiety
(23.4% prevalence in women relative to 14.3% prevalence
in men). Bipolar disorders have a similar prevalence in both
men and women, estimated to be around 2.8% annually [4].
In contrast, women are less likely than men to be diagnosed
with a substance use disorder (5.7% prevalence in women
versus 10.1% prevalence in men) [3]. Co-occurring sub-
stance use and mental health disorders show a similar preva-
R. Gitlin (*) lence among men (3.6%) and women (3.2%).
Los Angeles County Department of Mental Health, The prevalence of depression and anxiety is affected by
Los Angeles, CA, USA demographic and socioeconomic factors [3]. Younger adults,
ages 18–25, are more likely to be affected by depression
A. E. Mieczkowski when compared with older patients. Individuals of American
UPMC Presbyterian Shadyside and Children’s Hospital of
Indian or Alaska Native descent and those who report two or
Pittsburgh of UPMC, Division of General Internal Medicine,
General Academic Pediatrics, Pittsburgh, PA, USA more races are more likely to be affected by depression than

498 R. Gitlin and A. E. Mieczkowski
individuals from other racial/ethnic groups [3]. Similarly, revealed that structural brain changes are variable between
younger adults in the 18–29- and 30–44-year-old age ranges the sexes. For example, depressed women had smaller amyg-
are more likely to be affected by anxiety disorder than older dalae than controls but no change in left inferior cingulate
adults (60+). Sexual minorities, those who identify as gay, gyri, but depressed men had no change in amygdala volume
lesbian, bisexual, or queer, and gender minorities, those but a decrease in cingulate gyrus volumes [13]. PET imaging
identifying as transgender, non-binary, or genderqueer, are has shown differences in serotonin synthesis between female
disproportionately affected by depression and anxiety com- and male patients with major depressive disorder (MDD)
pared with heterosexual and cisgender individuals (see Chap. [14]. These differences suggest that different causal mecha-
36 on the Care of Sexual Minority Women and Chap. 37 on nisms for MDD may exist in women and men, resulting in
Transgender Care) [5]. similar clinical syndromes, but which may benefit from dif-
Social determinants of health that likely contribute to ferent treatment strategies.
the disproportionate rates of depression and anxiety among On the microscopic level, environmental and genetic
women include the greater likelihood of women to earn less effects on targets such as the serotonin receptor are impor-
income [6], to be exposed to discrimination based on gender tant; further understanding of these mechanisms will inform
and other social identities [6, 7], and to experience marked future treatments. Microscopic changes at the level of the
interpersonal and family-related stress [8, 9]. Women often neuron synapse are implicated in the development and treat-
serve as caregivers for multiple family members of multiple ment of a variety of disorders discussed in this chapter.
generations and take on more household tasks and respon- Genetic predisposition and environmental factors such as
sibilities than men, even when employed full-time [10]. chronic stress and activation of the hypothalamic-pituitary-
Women are also at increased risk of anxiety and depression adrenal (HPA) axis throughout development may influence a
in response to life stressors caused by significant life transi- person’s tendency toward depression or anxiety by exerting
tions, including having children, starting a new job, or navi- effects on serotonin receptor signaling pathways [15]. The
gating significant changes in relationships. CNS signaling system is further complicated by the presence
of multiple different subtypes of signaling receptors.
Pathophysiology
Serotonin Receptors
Understanding the pathophysiology of depression and anxi-
ety helps one to understand the factors that may predispose a Recent research has elucidated that multiple serotonin recep-
patient toward mental health disorders and the mechanisms tor subtypes exist, and signaling may result in both positive
by which treatments work. While scientific research has and negative effects on depressive and anxiety symptoms
provided a basic understanding of neurologic macroscopic depending on which receptors are targeted [16]. Individuals’
and microscopic patterns in depression and anxiety, the bio- signaling pathways involving serotonin and norepinephrine,
logical underpinnings of these disorders continue to be elu- which affect specific CNS structural areas, are pharmaco-
cidated through animal models, human neuroimaging, and logic targets and will be discussed later in the chapter [12].
neurocognitive modeling. On a macroscopic level, several Many medications exert effects on transport within the syn-
structures within the brain are thought to be important in the apse, preventing the reuptake of serotonin or norepinephrine
development of depressive and anxiety disorders. Anxiety from the synapse. As more is understood about signaling
disorders arise in part from how perceived threats are pro- pathways, attempts are being made to more precisely target
cessed through signaling from and between the hippocam- desired treatment effects or avoid side effects with medica-
pus, amygdala, and cortex [11]. These areas are responsible tions that target specific receptor subtypes. Some of these
for multiple actions, including processing emotion and plan- agents, which may both exert effects as selective serotonin
ning responses and actions [12]. Individuals with anxiety reuptake inhibitors (SSRIs) and agonist or antagonist effects
disorders have been shown to have hyperactivity in the on 5HT1A, 5HT3, and 5HT4 receptor subtypes, will be dis-
amygdala on fMRI, an effect which can be further modulated cussed [17, 18].
by appropriate or dysfunctional processing by the prefrontal Beyond transporter and receptor signaling, patients’
cortex where thoughts help interpret a perceived threat [12]. genetics can influence the metabolism of medications (e.g.,
through the hepatic cytochrome P450 system). Individual
alleles may determine which medications are efficacious or
Sex and Gender-Based Differences may be prone to adverse effects for individual patients. For
example, individuals with CYP2C19 alleles that result in
Research studies aiming to determine the etiology behind the decreased, normal, or increased metabolism of medications
greater prevalence of depressive disorders in women have such as citalopram or escitalopram show differing blood lev-
33 Depressive and Anxiety Disorders 499
els on exposure to these medications [19]. Such differential occurring, for example, over the phases of a menstrual
metabolism and exposure may influence treatment response. cycle or for women during the menopausal transition can
Testing is currently available that can assess an individual’s significantly correlate with sleep changes; however, in the
cytochrome P450 alleles and help predict a response to spe- latter situation, this may in part be related to vasomotor
cific medications; however, this is not routinely available for symptoms as opposed to direct effects [24]. Prolactin inter-
use in primary care clinical practices at present [16]. As test- acts with both the HPA and dopaminergic systems; changes
ing becomes less expensive and covered by insurance plans, in levels may correlate with the emergence and remission
such testing may help guide medication selection. of anxiety symptoms [22].
Gamma-Aminobutyric Acid (GABA) Receptors he Importance of Psychiatric Screening

T
and Intervention in Primary Care
Gender-specific signaling through additional pathways, such
as the dopaminergic and gamma-aminobutyric acid (GABA) Although women are more likely to seek help for mental
pathways, and hormone regulation through the HPA axis are health problems compared with men [25], many will not
important to consider. GABA signaling is a critical neural seek help from mental health providers due to inadequate
(typically inhibitory) signaling pathway. GABA receptor access, cultural beliefs about mental healthcare, and/or inter-
subtypes are present throughout the brain, particularly in nalized stigma. Primary care providers may be the only point
areas known to be important in anxiety pathways: the amyg- of contact between a female patient and the healthcare sys-
dala and hippocampus, among others. Consequently, GABA tem; hence, it is crucial for primary care providers to gain
receptors serve as a potential therapeutic target in the treat- competence in the screening, diagnosis, and intervention
ment of anxiety disorders [20]. The hypothalamic-pituitary- planning for women presenting with depressive and anxiety
adrenal axis has traditionally been thought to play a role in disorders encountered in the primary care setting.
anxiety symptoms, though it is variably implicated in specific
disorders [21]. Glucocorticoid and mineralocorticoid recep-
tors are present within the areas of the brain (e.g., the hippo- Monica states that she has difficulty maintaining focus
campus) involved in anxiety, and alterations in signaling are during the day and has no energy, leading to some
implicated in both macro- and microstructural changes and recent critical feedback from her employer. She wor-
clinical symptomatology [22]. ries that her job is in jeopardy.
Sex Hormone Influences in the Brain

Differential Diagnosis
Hormonal changes associated with reproductive health
(e.g., premenstrual, perinatal/postpartum, or perimeno- Mental health diagnoses are classified into groups of disor-
pausal status) may have a significant impact on the emer- ders. Diagnostic criteria for each disorder can be found in the
gence of depressive or anxiety symptoms through the Diagnostic and Statistical Manual of Mental Disorders, Fifth
signaling pathways mentioned. Estrogen and progester- Edition (DSM-5), published by the American Psychiatric
one interact with multiple systems that may be involved in Association [26]. Depressive and bipolar disorders are con-
mood or anxiety symptoms [23]. On the macro scale, both sidered mood disorders, and the diagnostic criteria are repre-
the hippocampus and amygdala have estrogen and proges- sented in distinct classification groups in the DSM-5. Anxiety
terone receptors, which have been shown to be associated disorders, which are classified as another distinct group of
with neuron survival pathways. Additionally, estrogen and disorders, have high rates of co-occurrence with mood dis-
progesterone act on several receptors, including GABAA, orders. When the DSM-5 was published in 2013, several
N-methyl-D-aspartate (NMDA), serotonin, and dopamine changes were made in how disorders were organized and
receptors involved in mood and anxiety disorders. Times classified. Table 33.1 provides an example of how bipolar,
of hormonal change, such as increasing estrogen levels depressive, anxiety, and trauma-related disorders are classi-
during puberty and relative decreasing levels in the post- fied within the DSM-5. Note that each group of disorders is
partum period and in menopause, may predispose women distinct within the DSM-5, whereas bipolar and depressive
to changes in mood and anxiety symptoms through these disorders were grouped together within the Diagnostic and
mechanisms. For women, changes in estrogen and pro- Statistical Manual of Mental Disorder, Fourth Edition, Text
gesterone can also negatively affect sleep, which may in Revision (DSM-IV-TR), as were anxiety and trauma-related
turn influence anxiety and depressive symptoms. Changes disorders.
Table 33.1 Classification of disorder types in DSM-IV-TR and Table 33.2 Diagnostic criteria for major depressive disorder and per-
DSM-5 sistent depressive disorder (dysthymia)
Mood disorders (DSM-IV-TR) Anxiety disorders (DSM-IV-TR)a Persistent
Depressive Anxiety Trauma- and depressive
Bipolar and disorders disorders stressor-related Major depressive disorder
related disorders (DSM-5) (DSM-5) disorders disorder Both disorders (dysthymia)
(DSM-5) (DSM-5) Presence of five or Symptoms must include Presence of three
Bipolar I Major Generalized Post-traumatic more total depressed mood and/or or more total
disorder depressive anxiety stress disorder symptoms anhedonia (loss of symptoms
disorder disorder interest or pleasure in
Bipolar II Persistent Panic disorder Acute stress most activities)
disorder depressive disorder Symptoms must be Symptoms must
disorder present for 2 weeks be present for
(dysthymia) or more 2 years or more
Cyclothymic Premenstrual Agoraphobia Adjustment Additional Additional symptoms Additional
disorder dysphoric disordersb symptoms may may include: symptoms may
disorder include: Too much or too little include:
Specific Psychomotor sleep Feelings of
phobia slowing or Significant changes in hopelessness
Social anxiety agitation appetite or weight
disorder Recurrent Fatigue or low energy
(social phobia) thoughts of Difficulties
a
Within the DSM-IV-TR, anxiety disorders also included obsessive- death or concentrating or
compulsive disorder. The DSM-5 has a discreet obsessive-compulsive suicidality making decisions
and related disorders section Low self-esteem or
b
Adjustment disorders were described within a distinct section of disor- feelings of
ders within the DSM-IV-TR, separate from anxiety disorders worthlessness
No history of a manic or
hypomanic episode
Based on initial report, it appears that the patient in our Full copyrighted criteria are available from the American Psychiatric
case study may be presenting with symptoms of a depressive Association [26]. All of the criteria are required for the diagnosis of
and/or anxiety disorder, assuming that medical conditions major depressive disorder or persistent depressive disorder. The table
which might contribute to her symptoms have been excluded. text summarizes the diagnostic criteria
report an increased appetite, tearfulness, fatigue, and sleep

Depressive Disorders disturbances [27]. Historically, women have been thought
to present with more somatic symptoms of depression as
Table 33.2 outlines the diagnostic criteria for two common opposed to the “pure” mood symptoms seen in men [27].
depressive disorders: major depressive disorder (MDD) and However, the research is mixed regarding whether these dif-
persistent depressive disorder (dysthymia or PDD). Each of ferences are related to a gendered interpretation of symp-
these disorders is primarily characterized by low mood and/ toms or biological differences [27]; of note, the American
or anhedonia (decreased interest or pleasure in activities pre- Psychiatric Association has not reported any clear differ-
viously enjoyed) [26]. Note the overlap in symptoms between ences between men and women in symptom presentation or
these two diagnoses. The primary differences between the treatment response [26].
disorders are in length of time and severity. Major depressive
disorder can be diagnosed in a patient experiencing the req-
uisite symptoms for an episode spanning 2 weeks or more; Premenstrual Dysphoric Disorder
persistent depressive disorder, on the other hand, can only
be diagnosed when symptoms have been present for at least A diagnosis of premenstrual dysphoric disorder (PMDD)
2 years. Additionally, the symptoms of MDD are more likely may be considered when depressive and anxiety symptoms
to be acute and severe in nature compared with PDD. Patients are present and interfering with daily functioning. PMDD is
may describe PDD as a “cloud that’s been hanging overhead a severe form of premenstrual syndrome (PMS) that inter-
for years,” whereas MDD may be characterized by distinct feres with daily functioning. PMDD is characterized by a
“low” periods of time or shorter duration. MDD will often marked increase in mood dysregulation or subjective affec-
go into remission after 6 months to a year. PDD tends to be tive distress, during the luteal phase of the menstrual cycle,
more chronic and can be difficult to treat. days 14–28. Symptoms begin 1–2 weeks preceding the start
Gender differences may exist in the way depressive disor- of menstruation and typically subside within a few days after
ders present. Compared with men, women may be likely to menstruation begins. Common symptoms include changes
in sleep and/or appetite, irritability, tension, and difficulty Table 33.3 Diagnostic criteria for generalized anxiety disorder and
concentrating [26, 28]. Women with PMDD do not appear to panic disorder
have differing levels of hormones relative to women without Generalized anxiety disorder Panic disorder
PMDD; rather, it is hypothesized that individual differences Excessive worried thoughts or The presence of multiple
subjective feelings of anxiety, unexpected panic attacks,
in the GABAA receptor subunits may confer differing levels which are difficult to control characterized by sudden
of sensitivity toward the natural hormone fluctuations of a discomfort or fear
woman’s menstrual cycle, resulting in symptoms [23, 29]. Additional symptoms may Additional symptoms may
include: include:
Feeling restless or “on edge” Increased heart rate and/or
Difficulty concentrating chest pain
Anxiety and Panic Disorders Muscle tension Sweating
Irritability Shaking or trembling
Stress and sleeplessness may suggest the presence of an anxi- Being easily fatigued Shortness of breath
ety disorder. Anxiety and depressive disorders can occur sepa- Disturbed or decreased sleep Dizziness or light-headedness
Nausea or abdominal
rately, though many patients will meet criteria for both. The
discomfort
most common anxiety disorder is generalized anxiety disorder
Symptoms are present for At least one of the below is
(GAD), which is characterized by excessive and uncontrolla- 6 months or longer present for 1 month or longer
ble worries that interfere with daily functioning [26]. GAD following the panic attack(s):
may or may not include the presence of panic attacks, which Intense worry about future
panic attacks
are acute episodes of intense anxiety accompanied by distress-
Disruptive behavior changes
ing physical symptoms. When panic attacks are the primary in an effort to avoid future
manifestation of anxiety (without ongoing excessive worried panic attacks
thoughts), and efforts to decrease the likelihood of these Full copyrighted criteria are available from the American Psychiatric
attacks is interfering with daily life, a diagnosis of panic disor- Association [26]. All of the criteria are required for the diagnosis of
der may be appropriate. Anxiety disorders are common in generalized anxiety disorder or panic disorder. The table text summa-
rizes the diagnostic criteria
women, and research is ongoing to determine specific under-
lying mechanisms which can inform therapeutic management.
As previously discussed, neuroendocrine signaling can be Bipolar Disorder
affected by both estrogen and progesterone, and these hor-
mones’ interactions at the level of the GABAA receptor and Patients should be screened for any history of a manic or
with the HPA axis may be responsible in part for differential hypomanic episode, which would suggest a diagnosis of
presentations between women and men [22] (Table 33.3). bipolar disorder. Manic and hypomanic episodes are mood
episodes that present with abnormal and marked increases
in energy or mood, along with other symptoms associated
When asked for more information about her sleep hab- with heightened arousal (e.g., decreased sleep or appetite,
its, Monica reveals that when she goes to bed, she racing thoughts, rapid speech) [26]. Mania may also be
“can’t turn [her] brain off.” Despite her lack of sleep, manifest as excessive irritability. A patient cannot be diag-
Monica describes feeling “keyed up” and restless nosed with a primary depressive disorder if she has ever
throughout the day, and she is unable to wind down experienced manic/hypomanic episodes. Many patients
and relax at home. with bipolar disorder will experience depressive episodes
in addition to manic/hypomanic episodes within the course
of the illness.
The differentiation between bipolar disorder and a depres-
ipolar Disorder and Post-Traumatic Stress
B sive disorder has important implications for treatment. Some
Disorder medications that are used to treat depressive symptoms, such as
selective serotonin reuptake inhibitors (SSRIs, described below),
Changes in mood or increased anxious distress have a broad can potentially induce a manic/hypomanic episode. This is an
range of differential diagnoses to consider, including medi- uncommon occurrence, though women with a family history
cal conditions (thyroid disorders, cardiac disease, and respi- of bipolar disorder may be at particular risk [30]. Additionally,
ratory distress), substance use disorders, and two important depressive episodes occurring within the context of bipolar dis-
psychiatric conditions: bipolar disorder and post-traumatic order can require more complex medication management, such
stress disorder. The evaluation and ruling out of medical con- as mood stabilizers or adjunctive pharmacotherapy as compared
ditions associated with the common symptoms of depressive to PMDD. Patients reporting symptoms of bipolar disorder
and anxiety disorders is beyond the scope of this chapter. should be referred for a psychiatric consultation.
Post-Traumatic Stress Disorder • Time course of symptoms/episodes:

–– “When did you first start to notice (changes in)
Patients presenting with mood or anxiety symptoms should _________? How long have you been experiencing
also be screened for a history of trauma. Depending on the __________?”
course and characterization of psychiatric symptoms follow- • Diagnostic criteria that may not immediately be reported:
ing a traumatic event, a diagnosis of post-traumatic stress –– “Tell me about your sleep and appetite.”
disorder (PTSD) may be most appropriate. PTSD, which is –– “You mentioned having panic attacks. How would you
often comorbid with mood and/or anxiety disorders, is a syn- describe them? What are some of the changes that hap-
drome that occurs when symptoms persist following a trau- pen during the attacks?”
matic event that interferes with a patient’s everyday life [26]. • Interfering with daily functioning:
Symptoms of PTSD fall into four clusters: –– “It sounds like this has been pretty distressing for you.
Has it gotten in the way of your ability to live your life
• Re-experiencing the traumatic event through nightmares, the way you were before?”
flashbacks, or intrusive memories
• Avoiding reminders of the traumatic event through sup-
pressing memories or avoiding places or people that trig- Screening Tools for Depression and Anxiety
ger memories of the trauma
• Hyperarousal as manifested by increased startle response, In addition to clinical inquiry, symptom screening measures
decreased anger threshold, or engagement in reckless or are helpful in gathering information about a patient’s symp-
impulsive behaviors toms. These tools are useful both in the diagnosis of depres-
• Negative changes in mood or affect, including feelings of sive and anxiety disorders and in documenting response to
worthlessness, low mood, and affective numbness treatment. One of the most commonly used measures to assess
depressive symptoms is the Patient Health Questionnaire-9
Chronic exposure to stress also places women at risk, but (PHQ-9). The PHQ-9 is a validated screening tool consist-
a thorough discussion of this topic is beyond the scope of this ing of nine Likert-scale items corresponding with each of
chapter. the DSM-5 diagnostic criteria for a major depressive episode
[32, 33]. It is publicly available and widely used in primary
care settings. Scores range from 0 to 27, with higher scores
Monica clarifies that she has never experienced an indicating a greater severity in depressive symptoms. To
abnormal elevation in her mood or energy level. She diagnose a depressive disorder, one of the first two items,
reports that she was sexually assaulted at a party in anhedonia or depressed mood, must be endorsed by the
college. She denies any intrusive thoughts or memories patient. In the absence of anhedonia or depressed mood, the
of the event and has not avoided any memories or PHQ-9 can indicate the presence of other important symp-
other reminders of the assault. toms to address, such as changes in appetite, sleep, energy,
or concentration (Fig. 33.1).
Similar to the PHQ-9, the GAD-7 is a seven-item anxi-
ety symptom screening measure whose items represent each
of the diagnostic criteria for generalized anxiety disorder
Clinical Interviewing [33]. Higher scores signify increased severity of anxiety
symptoms.
Effective diagnostic interviewing uses a patient-centered Utilizing these screening measures represents an impor-
approach with open and readily understood language that tant opportunity for preventive care. The PHQ-9 and GAD-7
emphasizes a balanced dynamic in verbal exchange between allow providers to gather invaluable data about acute depres-
provider and patient. Patient-centered interviewing maxi- sive or anxiety symptoms that patients may not choose to
mizes patient satisfaction [31] and is distinct from a more self-report during a clinical interview. Endorsement of key
traditional, top-down interview. Patient-centered interview- items, especially related to low mood, anhedonia, difficulty
ing incorporates open-ended questioning (e.g., “Which con- controlling worried thoughts, and suicidal ideation, can help
cerns would you like to address today?”) along with more providers initiate a dialogue about psychiatric distress and
focused and reflective inquiries (e.g., “Tell me more about possibilities for early intervention. Open dialogue will help
feeling like you can’t get anything done these days”). It is patients gain awareness about mood and anxiety symptoms,
helpful to practice using language that the patient can relate decrease stigma toward discussing mental health concerns,
to, rather than using clinical jargon. Important information to and potentially prevent exacerbations of distress and associ-
gather includes the following: ated impairment in patients.
Fig. 33.1 Patient Health

Questionnaire-9 (PHQ-9) PATIENT HEALTH QUESTIONNAIRE-9
[32]. (Developed by Drs. (PHQ-9)
Robert L. Spitzer, Janet
B.W. Williams, Kurt Kroenke,
and colleagues, with an Over the last 2 weeks, how often have you been bothered More Nearly
educational grant from Pfizer, by any of the following problems? Several than half every
(Use “ ” to indicate your answer) Not at all days the days day
Inc)
1. Little interest or pleasure in doing things 0 1 2 3
2. Feeling down, depressed, or hopeless 0 1 2 3
3. Trouble falling or staying asleep, or sleeping too much 0 1 2 3
4. Feeling tired or having little energy 0 1 2 3
5. Poor appetite or overeating 0 1 2 3
6. Feeling bad about yourself—or that you are a failure or

0 1 2 3
have let yourseIf or your family down
7. Trouble concentrating on things, such as reading the

0 1 2 3
newspaper or watching television
8. Moving or speaking so slowly that other people could have
noticed? Or the opposite—being so fidgety or restless 0 1 2 3
that you have been moving around a lot more than usual
9. Thoughts that you would be better off dead or of hurting

0 1 2 3
yourself in some way
0
FOR OFFICE CODING + + +
=Total Score:
If you checked off any problems, how difficult have these problems made it for you to do your
work, take care of things at home, or get along with other people?
Not difficult Somewhat Very Extremely
at all difficult difficult difficult
Monica reports that she has had previous depressive Biopsychosocial Risk Factors
episodes, but none as lengthy and severe as this one.
She notes that her current episode began about In the treatment of depressive and anxiety disorders, infor-
18 months ago. Her PHQ-9 score is consistent with mation should be gathered regarding risk factors and life
moderate depression and her GAD-7 score is consis- circumstances: psychosocial stressors (recent and chronic),
tent with moderate anxiety. genetic predispositions, health-related behaviors, and access
to resources. Contextual factors can impact diagnosis,
p rognosis, and treatment. A trained medical social worker rate assessing risk for medication misuse or addiction, and
or mental health provider typically performs assessments the selection of therapies should be determined accordingly
in these domains. A therapeutic multidisciplinary team will in collaboration with patients (see Chap. 26 on General
provide the best comprehensive care for patients. In the bio- Approach to Chronic Pain and Chap. 32 on Opioid Use
psychosocial model of care, providers gather data within Disorder).
biological/genetic/medical, psychological/psychiatric, and
social/systemic/political influences on a patient’s lived expe-
rience and overall functioning. Stressors
Providers should ask about any salient stressors or other

Substance Use significant life events that may have impacted the onset or
exacerbation of psychiatric symptoms. Research suggests
Health-related behavior such as substance use can influence that women may be particularly susceptible to depressive
the onset or course of psychiatric symptoms. Substance use or anxiety symptoms in response to stressful events [35].
disorders often occur in conjunction with psychiatric disor- Depending on the stressor in question, making changes in
ders and can have a cyclical relationship with one another; a patient’s environment or other adjustment behavior may
a patient may self-medicate a mood or anxiety disorder with obviate the need for pharmacologic treatment or greatly
various substances, and heavy substance use may result speed recovery when used in conjunction with pharmaco-
in chemical and behavioral changes leading to a mood or logic or psychotherapeutic interventions. A provider might
anxiety disorder. Because substance use can be highly stig- use inquiries such as:
matized, assessment should be conducted in an open and • “You mentioned that these symptoms started about
nonjudgmental way. Examples include the following: 18 months ago. What else was happening in your life
• “Tell me a bit your alcohol and drug use.” around that time?”
• “How often do you drink?” (This is counter to an inquiry • “Thinking back, can you identify any event or major
such as “Do you drink? If so, how much?”) change that may have impacted your mood or levels of
A family history of psychiatric illness or substance use anxiety?”
should also be assessed. Genetic and environmental fac- Due to sociocultural expectations and constraints, women
tors may predispose a patient to psychiatric illness and/or often face a unique and complex intersection of stressors.
problematic substance use in adulthood, and thus an under- These may include workplace stress, unhealthy or unhappy
standing of the family history is critical for context. Bipolar romantic relationships, or perceived expectations to “have it
disorder and substance use disorders are strongly influenced all” within professional and family domains. Women may
by genetic factors. find themselves in a “sandwich generation,” wherein family
obligations include simultaneously caring for children as
well as aging parents. Social isolation, poverty, immigration-
Chronic Pain related concerns, and discrimination are other common and
highly impactful stressors that many women navigate.
The presence of chronic or recurrent pain symptoms may
serve as a significant contributor to the development or
maintenance of psychiatric symptoms. Mood and anxiety When asked about recent events that may be affecting
symptoms are common among patients who are living with her life, Monica reports that she was unfairly fired
chronic pain [34]. Patients with comorbid chronic pain, from her job shortly before her current symptoms
depression, and anxiety may have higher levels of pain emerged. She described feeling betrayed by her
intensity and lower quality of life than patients with chronic employer and socially isolated, since much of her
pain but without co-occurring psychiatric distress. Effective interpersonal interaction occurred within the context
treatment planning for these patients necessitates an integra- of employment. Though she has since started another
tion of interventions addressing pain as well as psychiatric job, she continues to feel down and detached at work.
symptoms. Thoughtful treatment planning should incorpo-
Traumatic Events in Childhood or Adult Life Trauma-informed primary care
As noted earlier in this chapter, the primary precipitating fac-

tor contributing to a patient’s psychiatric symptoms may be a
major traumatic event. Exposure to trauma occurs at high life-
time rates and has a marked impact on an individual’s over-
all functioning. The ACE (Adverse Childhood Experiences)
Study, conducted by the CDC and Kaiser Permanente [36],
examined the impact of childhood trauma on a variety of
health-related outcomes in adulthood. ACE trauma catego-
ries include (but are not limited to) physical abuse, sexual
abuse, neglect, intimate partner violence, household sub-
stance misuse, and incarceration of family members. The
study found that 64% of study participants endorsed at least
one trauma category during childhood, and one in six partici-
pants endorsed exposure to at least four trauma categories.
Women were found to be 50% more likely than men to have
experienced at least six types of trauma during childhood;
this disproportionate exposure to trauma often continues
during adulthood, as one in three women experience lifetime
intimate partner violence (see Chap. 35 on Intimate Partner
Violence and Sexual Trauma) [37]. Trauma exposure has a Fig. 33.2 Core elements of the trauma-informed primary care frame-
dose-response relationship, and a history of trauma can neg- work [39]. (Reprinted from Women’s Health Issues, Machtinger et al.
atively impact many areas of functioning. Childhood and [39], © 2015, with permission from Elsevier)
adulthood trauma are correlated with multiple poor health
outcomes, including increased rates of lung and liver dis- experiences, highlighting the standardization of such inquiry
ease, alcoholism, intravenous drug use, depression, chronic (e.g., “This is something we ask every patient”). Examples of
pain syndrome, and suicide attempts [36, 38]. trauma screening questions include the following:
• “What happens when you and your partner fight? Does

Trauma Informed Care your partner ever hit, kick, slap, or push you?”
• “Were you exposed to any violence during childhood?”
Increasing attention is being given to the cultivation of • “Have you experienced unwanted sexual attention or sex-
trauma-informed primary care, which highlights the aware- ual contact?”
ness of and responsiveness to the ways in which traumatic
experiences can affect a patient’s engagement in healthcare A patient may not want to discuss past traumatic events
and ability to effectively participate in other life domains or provide many details, and it is important for patients to be
[39]. Figure 33.2 outlines several key aspects of trauma- able to retain control over their own historical information.
informed primary care practices. Despite the high rates at Maintaining a trauma-informed approach includes an aware-
which patients are exposed to trauma and the significant ness of the possibility of retraumatizing a patient by pres-
impact it has on functioning, most primary care providers suring her to disclose more information than is necessary or
do not routinely screen for histories of abuse [40]. comfortable. If the patient has a negative reaction to ques-
Given the salient influence of trauma exposure on health- tioning, it may be sufficient to understand that she continues
care outcomes, providers should consider whether trauma to be impacted by past traumas and allow her to share more
may be a driving force behind the onset of psychiatric symp- information at another time. In the meantime, providers can
toms, even if these symptoms do not indicate the presence promote recovery by fostering a safe and responsive clinical
of post-traumatic stress disorder. Patients should be asked environment, including possible referrals for mental health
about current, recent, and childhood traumas. It may be or social services (see Chap. 35 on Intimate Partner Violence
helpful to contextualize the importance of asking about these and Sexual Trauma).
Resiliency and Coping Factors tion, intensity, outcome, and strategies used to mitigate or
stop suicidal or other self-harm behavior.
In addition to stressors that may be contributing to distress,
patients also likely have protective factors that help foster
resilience and effective coping. Resilience is fostered in intra- Protective Factors
personal (e.g., self-soothing strategies, accessing resources)
and community or interpersonal (e.g., constructive relation- Protective factors against suicide are important to include
ships, availability of necessary resources) spheres [41]. within a risk assessment. These might be treatment-related
Inquiring about support systems can serve dual purposes; it protective factors, such as displayed hope or motivation to
will demonstrate a motivation to see the patient as a whole improve symptoms by seeking help. Protective factors are
person rather than a sum of problematic symptoms, and it can also represented through important roles or relationships
also provide helpful information to the provider about factors (e.g., importance of being a mother, involvement in support-
that can contribute to treatment. Questions such as, “Who are ive relationships). Patients experiencing symptoms such as
some of the important people in your life?” and, “What, or hopelessness may have difficulty identifying these protective
who, has been helpful to you when you have felt sad or anx- factors, which can indicate elevated risk.
ious?” are non-assumptive and may open opportunities for
broader discussions around coping and resilience.
Suicidal Ideation
The first step within a present-focused suicide risk assess-

Monica notes that “it all just feels like too much” ment is determining the presence and type of suicidal ide-
sometimes, and she occasionally wonders whether it ation. Passive SI describes a desire to die without a conceived
would easier if she just “weren’t here.” plan. This can manifest as a desire to “disappear” or state-
ments such as, “It wouldn’t be so bad if I just didn’t wake
up one day.” Active SI refers to a desire to die along with a
plan of how a patient might pursue this (e.g., “I think about
Suicide Risk Assessment jumping off a bridge,” or, “I’ve thought about overdosing on
my prescription meds”). Inquiring about suicidal ideation is
Women have significantly higher rates of suicide attempts, most effective when done in a nonjudgmental and straight-
though lower rates of dying by suicide, compared with forward way. Examples include the following:
men [26, 42]. Suicide risk assessments are vital within the
broader practice of addressing psychiatric distress within • “Sometimes, when people are feeling down, they may
any healthcare setting. Conducting a suicide risk assessment have thoughts about dying or about doing something to
can evoke anxiety for many clinicians. Cultivating an under- end their life. Is this something you have experienced?”
standing of the components of these assessments, along with • “Have you ever had thoughts of suicide or of doing some-
how to interpret and respond to patients’ reports, will help thing to end your life?”
clinicians gain competence and confidence with suicide risk
assessment. It is important to remember that asking about If a patient endorses passive and/or active suicidal ide-
suicide will not make somebody suicidal, and in fact such ation, the provider should assess the intensity and frequency
inquiry may help mitigate distress associated with suicidal of these thoughts. Strategies used to navigate SI can also be
ideation [43]. Generally, the primary components within a assessed. The provider might ask, “What do you do when
comprehensive suicide risk assessment are risk and protec- you have these thoughts of suicide?” Such questions can
tive factors, current ideation, plan, means, and intent. reveal adaptive coping mechanisms and/or protective factors
against self-harm.
Suicide Risk
Plan and Means to Implement the Plan
The greatest predictor of suicide risk behavior is a history of
suicide attempts [44]. Suicide risk assessment should incor- The next component of assessing suicide risk is determining
porate inquiries about past suicidal ideation (SI) and related the presence of a plan and the means to implement it. A patient
behaviors in addition to those occurring in the present. When may reveal some of this information while describing any
discussing past risk behaviors, ask about frequency, dura- active suicidal ideation, but further probing may be required
to elicit additional specific elements to any plan(s) in place. A oluntary Hospitalization or Urgent
V
patient’s plan(s) may cover a wide range of access and feasi- Psychiatric Referral and Safety Planning
bility; this also needs to be assessed. For example, if a patient
states that she imagines ending her life by a self-inflicted gun- Patients who do not warrant involuntary hospitalization may
shot wound, she should be asked whether she owns or has be offered voluntary hospitalization and/or an urgent psy-
access to a firearm. Described plans may have different lev- chiatry referral. If suicidal ideation is still present with a
els of specificity. For instance, a patient who reports thinking plan and means, but risk is not imminent, safety planning is
about jumping off a bridge may or may not have a particular an appropriate course of action. Safety plans are completed
bridge in mind. Patients should also be asked about timelines in collaboration with a patient and are ideally written down
or dates associated with any plans, in addition to preparatory for the patient to keep with her. Drafted safety plans may
behaviors she may be engaging in to carry out the plan. include (a) reaching out for support through calling a crisis
hotline or contacting someone in the patient’s life, (b)
engaging in constructive self-soothing or distracting activi-
Intent ties, (c) engaging in ongoing mental health treatment, and/
or (d) restricting any access to available means (e.g., keep-
Finally, intent needs to be evaluated by a provider con- ing a firearm locked in a safe and giving someone else the
ducting a suicide risk assessment. Determining the level of key, having a friend or family member maintain possession
intent includes (a) asking about whether the patient antici- of medications).
pates implementing any plans she has made to end her life
or seriously harm herself and (b) exploring how lethal or
harmful a patient believes her plan(s) to be. Here, provid- Treatment
ers have a key opportunity to identify any ambivalence
expressed by a patient. For example, these discussions may
include explorations of reasons to live versus reasons to end Monica is told she may be experiencing a depressive
one’s life. disorder with concomitant anxiety. There is no evi-
dence of a prior manic episode, and bipolar disorder
has been ruled out as a possible diagnosis. She agrees
Involuntary Hospitalization and asks about available treatments.
For patients who are exhibiting suicidal ideation or intent,

the actions taken by a treatment team are determined by the Most patients who seek treatment for disorders such as
level of risk. Patients who are deemed to be at imminent risk depression and anxiety seek care through their primary care
for suicide or serious self-harm may be voluntarily or invol- provider [45], and it is therefore essential for providers to
untarily hospitalized. Regulations pertaining to the imple- understand the range of treatment modalities available to
mentation and lengths of stay of involuntary hospitalizations patients. Treatments range from psychotherapy, to medica-
vary by state. tion management, to complementary and alternative treat-
Patients may be concerned about what will happen during ments. Unfortunately, over a third of patients with major
or after involuntary hospitalization. Generally, involuntary depressive disorder receive no treatment, likely due to the
holds will last for several days. These hospitalizations are lack of identification of symptoms, further highlighting
intended to reduce risk of imminent harm, and they ensure the need for screening in the primary care setting [46]. A
that a patient is evaluated by a psychiatrist and linked to nec- large proportion of patients receives dual treatment with
essary treatment to further mitigate risk. Depending on the medication management and psychotherapy (44%), while
acuity and severity of a patient’s symptoms, there are sev- a smaller proportion receives only therapy or medication
eral possible outcomes following an involuntary hold. These (13% and 6%, respectively) [46]. Though it is difficult to
include an extension of involuntary commitment via a court quantify how many patients use complementary and alter-
order, inpatient psychiatric treatment, intensive outpatient native medicine (CAM) treatments for anxiety and depres-
programming, and outpatient treatment. Each of these out- sion specifically, over a third of adults use CAM annually
comes may involve medication management with a psychia- for treatment of issues such as pain, mood, or other symp-
trist as well as psychotherapy. toms [47].
Lifestyle Behavior Modifications Patient’s History and Family History
Mood and anxiety symptoms often present alongside sleep The initial step in determining an appropriate medication
disturbances, changes in diet or weight, and decreases in for the patient is a careful consideration of the patient’s pre-
physical activity. Screening for mood and anxiety symp- senting history to ensure that symptoms are consistent with
toms should include assessing these vital lifestyle factors. the diagnosis being considered. Prescribed medications
Psychiatric symptoms and health-related behaviors often should be appropriate for the patient’s diagnosis: depres-
show a bidirectional relationship [48]. Making lifestyle sion, anxiety, or both. If a primary care provider is unsure
changes in sleep, diet, and exercise can be an efficient and about a diagnosis, additional consultation with a psychi-
effective intervention to implement, with the potential for atric professional should be obtained prior to considering
positive outcomes, which are further maximized by ongo- medication management. Caution should be used with
ing support, adjunct psychoeducation, or behavioral inter- patients who exhibit hypomanic or manic symptoms, which
ventions [49, 50]. Sleep hygiene techniques, including can at times be difficult to differentiate from symptoms of
consistent sleep-wake schedules, can be remarkably helpful anxiety. As noted throughout this chapter, patients whose
in reducing the intensity of mood dysregulation or anxiety symptoms suggest bipolar I or bipolar II disorder will usu-
symptoms [51]. Maintaining a balanced and nutritious diet ally require consultation with a psychiatrist. Care should be
and engaging in regular physical activity can be particu- taken to exclude other diagnoses which may mimic depres-
larly valuable aspects of a patient’s treatment plan. Physical sion or anxiety symptoms, such as thyroid disorders, car-
activity has been shown to improve anxiety and depressive diac disease (e.g., a patient with arrhythmia may present
symptoms and may be particularly beneficial for those not with palpitations), or respiratory diseases such as asthma
interested trying medication or psychotherapy [52, 53]. [58]. Hazardous substance use can also co-occur or mimic
Modalities such as yoga and mindfulness meditation may these disorders; primary care providers should screen for
also be effective in mitigating depressive or anxious distress substance misuse as part of the ongoing evaluation [58, 59].
[54, 55]. These lifestyle changes are cost-effective and sus- Evidence is minimal as to whether a patient will respond
tainable strategies to integrate into an overall mental health better to a medication they have used successfully in the past
wellness plan. as opposed to another treatment [60]. For patients who are
medication naïve, but who may have family members who
have been treated with medication for depression, there is
Medication Management face validity to the idea that starting the same or a similar
agent may have a higher likelihood of response; however,
A variety of pharmacologic treatments are available for the the literature supporting this is sparse. Some studies have
treatment of depressive and anxiety symptoms in the primary attempted to elucidate whether genetic variations in recep-
care setting, depicted in Table 33.4. Of note, the medical tors can predict responses to different medications, but with-
treatment of bipolar disorder includes mood stabilizers and out clear conclusions currently to guide clinical management
atypical antipsychotics; a thorough discussion of these medi- [60, 61]. Regardless of patient and provider choice, many
cations is beyond the scope of this chapter. When a provider patients will respond to either a previously used medication
and patient have determined that a medication will be used in or a new medication within the same class, so either may
a patient’s treatment plan for depression or anxiety, second- be considered appropriate [57]. If a patient has a bias for or
generation antidepressants including SSRIs and SNRIs are against a medication based on their own, a friend’s, or a fam-
considered first line [56]. Choosing which medication to pre- ily member’s use and recommendation, a provider should
scribe requires knowledge of the patient’s current symptoms, consider this preference through shared decision-making. If
the patient’s medical and psychiatric history, the patient’s a patient has a preconceived prejudice or preference against
family history, and a working knowledge of medication indi- a medication, in most cases it is unnecessary to push for this
cations, costs, and potential side effects [57]. medication if other options are available.
Table 33.4 Medications for management of depression and anxiety
33
Class-level side effects/ Medications within Medication-specific side effects/

Medication class Indication Mechanism of action cautions class Dosage options Compelling indications cautions
Selective serotonin Anxiety Inhibit serotonin GI upset, nausea, Citalopram 10 mg QTc prolongation especially at high
reuptake inhibitors Depression reuptake at the vomiting, sexual 20 mg doses and with polypharmacya
(SSRI) synaptic level dysfunction 40 mg
Escitalopram 5 mg QTc prolongation especially at high
10 mg doses and with polypharmacya
20 mg
Fluoxetine 10 mg OCD Drug interactions: Decreases
20 mg Eating tamoxifen levels with concomitant
30 mg Disorders use
40 mg PMDD
Depressive and Anxiety Disorders
10 mg/5 ml
solution 90 mg
(weekly)
Fluvoxamine 25 mg OCD Off label for treatment of depression/
50 mg anxiety
100 mg
150 mg
Paroxetine 10 mg OCD Weight gain, daytime somnolence
20 mg PMDD Drug interactions: Decreases
30 mg PTSD tamoxifen levels with concomitant use
40 mg Contraindicated in pregnancy
Sertraline 25 mg OCD
50 mg PMDD
100 mg
20 mg/1 ml
solution
Serotonin partial Depression Inhibit serotonin GI upset, nausea, Vilazodone 10 mg
agonist-reuptake reuptake and vomiting, low risk for 20 mg
inhibitor (SPARI) serotonin receptor sexual side effects 40 mg
and related modulation Vorioxetine 5 mg
medications 10 mg 20 mg
Serotonin Anxiety Inhibit serotonin and GI upset, nausea, Duloxetine 20 mg Diabetic nerve pain
norephinephine Depression norepinephrine vomiting, sexual 30 mg Fibromyalgia
reuptake inhibitors reuptake dysfunction 40 mg ADHD (possibly)
(SNRIs) 60 mg
Desvenlafaxine 25 mg Major depressive disorder
50 mg only
100 mg
Levomilnacipran 20 mg Major depressive disorder
40 mg only
80 mg
120 mg
Milnacipran 12.5 mg Fibromyalgia, depression
25 mg indication outside of the
50 mg United States
100 mg
Venlafaxine 37.5 mg Diabetic Neuropathy Safest choice with tamoxifen
75 mg Hot flashes
150 mg ADHD
509
225 mg
(continued)
510
Class-level side effects/ Medications within Medication-specific side effects/

Medication class Indication Mechanism of action cautions class Dosage options Compelling indications cautions
Dopamine- Depression Prevents dopamine Lower seizure Bupropion 75 mg Smoking Cessation Low Do not use in patients with seizure
norephinephrine and norepinephrine threshold 100 mg Risk of sexual side effects disorder, substance abuse, or eating
reuptake inhibitors reuptake at the 150 mg Off label for weight loss disorders
synaptic level 200 mg (combination medication) Decreases tamoxifen levels with
300 mg concomitant use
450 mg
Benzodiazepines Anxiety GABA agonist Sedation effects, risk Alprazolam 0.25 mg Rebound anxiety and potential for
for misuse and 0.5 mg misuse, given short half-life
addiction 1 mg
2 mg
3 mg
1 mg/ 1 ml
solution
Clonazepam 0.125 mg Rapid dissolving available
0.25 mg for panic disorder
0.5 mg Seizure disorder
1 mg management
2 mg
Diazepam 2 mg Acute seizure treatment
5 mg Procedural sedation
10 mg
5 mg/ 1 ml
Lorazepam 0.5 mg Use possible in patients
1 mg with renal or hepatic
2 mg impairment
2 mg/ 1 ml
solution
Temazepam 7.5 mg Insomnia
15 mg
22.5 mg
30 mg
Tetracyclic Depression Serotonin and Weight gain, sedation Mirtazapine 7.5 mg Used in insomnia
antidepressants norepinephrine 15 mg
reuptake inhibition 30 mg
45 mg
Tricyclic Pain, migraines, Serotonin and GI upset, Amitriptyline 10 mg Migraine Prophylaxis Dosages above 50 mg are rarely used
antidepressants IBS, no longer norepinephrine constipation, sedation, 25 mg Irritable bowel syndrome
(TCAs) used for reuptake inhibition overdose may cause 50 mg Chronic pain
depression fatal cardiac 75 mg
arrythmias 100 mg
150 mg
Nortriptyline 10 mg Dosages above 50 mg are rarely used
25 mg
50 mg
75 mg
10 mg / 5 ml
solution
Abbreviations: NE norepinephrine, D depressive disorders, A anxiety disorders
a
Risk factors for QTc prolongation include female sex, age over 65, high dosages of antidepressant medication, electrolyte disturbances, cardiac or other medical comorbidities, history of QTc
R. Gitlin and A. E. Mieczkowski
prolongation, family history of QTc prolongation, and polypharmacy (see text)

Medication Cost and Generic Drug Availability tion of citalopram and other SSRIs. As many as 50% of
patients may experience unwanted sexual side effects, espe-
Cost is important at both the patient and the health systems cially delayed orgasm and lack of libido, when taking citalo-
level. The American College of Preventive Medicine issued pram. Adding bupropion to citalopram can help mitigate
the recommendation to use generic equivalents to expensive sexual side effects in many patients.
brand names when available as part of the Choosing Wisely
initiative, estimating the average cost of generic medica- Citalopram has a greater tendency for QTc prolongation
tions to be 80–85% lower than brand name medications [62]. than other SSRIs, and thus an EKG should be performed
Fortunately, SSRIs, which are first line and have been used before the medication is prescribed and after significant
for over 20 years, are inexpensive, and generic versions are increases in dose. Risk factors for QTc prolongation include
widely available. female sex, age over 65, electrolyte disturbances, a history of
any cardiac abnormality, polypharmacy, and higher doses of
antidepressants [66]. It is unclear whether patient risk factors
Compelling Indications such as CYP metabolism place patients at risk or whether this
risk is intrinsic to the medication itself, but caution should be
Indications and major side effect profiles are highlighted used in patients who (1) already have QTc prolongation or
in the following sections and summarized in Table 33.4. (2) are on other QTc prolonging medications [67, 68]. Daily
Patients may have compelling indications for a given medi- dosages of citalopram of 40 mg or more pose higher risk and
cation, as certain classes may have approvals or be used off should be used with caution.
label for other diagnoses. Other patients may wish to avoid
certain side effects that will guide choice of medication. Escitalopram Escitalopram is the S-enantiomer of citalo-
pram (which is a racemic mix of the L and S enantiomers),
and the typical dose range is between 10 mg and 20 mg. It
Major Classes of Medication has similar roles in treatment of depression and anxiety and
shares the same cautions for QTc prolongation and sexual
elective Serotonin Reuptake Inhibitors (SSRIs)
S side effects [69] as citalopram.
SSRIs have been used in clinical practice for over two
decades, and numerous clinical trials have been conducted to Fluoxetine Fluoxetine has stood the test of time as one of
guide providers and patients on their efficacy and side effects the premier first line medications to treat depression and
[63]. SSRIs act at the level of the synapse, inhibiting sero- anxiety. Fluoxetine was the first SSRI to be introduced in
tonin reuptake and thereby permitting increased serotonin the United States and among the first in the world when it
action. There is significant evidence that SSRIs improve was developed in the 1970s and approved in 1987 [70]. It
depressive and anxiety symptoms compared to placebo; has been studied extensively and carries approvals not only
however, there is no evidence of significant efficacy differ- for anxiety and depressive disorders, but also for PMDD,
ences among medications in the class. Side effects and toler- obsessive compulsive disorder (OCD), and eating disor-
ability may differ among medications and therefore are used ders [71]. Fluoxetine may have a stimulating effect and, in
to guide providers and patients in the choice of initial drug some patients, may help promote weight loss. Fluoxetine
therapy [64, 65]. Individual medications within this class, is relatively safe in pregnancy. Caution should be used in
listed alphabetically, are discussed in detail below. women on tamoxifen treatment, as fluoxetine may decrease
tamoxifen levels, although it is safe with raloxifene and
Citalopram Citalopram is an excellent first line medication aromatase inhibitors (see Chaps. 16, 17, 18, 19, and 20 in
for patients with depression, especially when there is signifi- the Breast Health and Disease section of this book). Daily
cant co-occurring anxiety. It is also effective to treat anxiety dosage forms range from 10 mg to 40 mg, and a weekly
alone. Typical doses range between 20 mg and 40 mg, though 90 mg form is available. The latter may be useful for treat-
10 mg dosage forms are available for slower titration if ment of PMDD with dosing during the last 1–2 weeks of
desired. Citalopram is well tolerated in most patients, is rela- the menstrual cycle, for women who do not want to take
tively safe in pregnancy, and can be used in patients taking daily medication, or for patients in whom daily dosing is
tamoxifen for breast cancer prevention or treatment (see difficult [71, 72].
Chap. 17 on The Primary Prevention of Breast Cancer and
Chap. 19 on Breast Cancer Diagnosis and Management). Fluvoxamine Fluvoxamine is an SSRI which is used in anx-
When treating anxiety, patients may be offered lorazepam to iety disorders in the United States, especially OCD, social
be used for the first few days to counteract the temporary jit- anxiety disorder, and panic disorder. It has been in use as
teriness or increased anxiety which may occur at the initia- long as fluoxetine, has been proven safe in children to elderly
patients, and has a lower incidence of sexual dysfunction Vortioxetine Vortioxetine is a serotonin receptor antagonist
than many other SSRIs [73]. (5-HT3, 5-HT7, and 5-HT1D), partial agonist (5-HT1B) and
agonist (5-HT1A), and serotonin transporter inhibitor [80]. It
Paroxetine Paroxetine has been studied and approved for a is approved with a dosage range of 5 mg to 20 mg and acts
variety of psychiatric conditions: depression and anxiety dis- across multiple signaling pathways in the brain to improve
orders, PTSD, OCD, and PMDD, with dosage ranges symptoms of major depressive disorder and associated anxi-
between 10 mg and 60 mg depending on the indication [74]. ety. Like vilazodone, it has a similar side effect profile to
Paroxetine has lost popularity because of its numerous side SSRIs but may result in less sexual dysfunction than SSRIs.
effects and teratogenicity. Paroxetine is pregnancy class D
due to its association with heart defects and should not be erotonin Norepinephrine Reuptake Inhibitors
S
used in patients who are pregnant. It should also be avoided (SNRIs)
in patients taking tamoxifen, as it can decrease tamoxifen SNRIs are first line medications for depression, anxiety, and
drug levels (citalopram can be considered as an alternative). chronic pain. SNRIs are a class of medications that affect
Paroxetine has been shown to have more sedating effects both the serotonin and norepinephrine signaling pathways in
than other SSRIs [75]. Paroxetine may be associated with the brain and prevent synaptic reuptake of both neurotrans-
significant weight gain, fatigue, daytime somnolence, and mitters, allowing for greater activity [81]. Medications within
severe withdrawal symptoms, more than other SSRIs. the class have varying levels of selectivity for the serotonin
versus norepinephrine receptors; however, this does not
Sertraline Sertraline is a safe and well-tolerated medica- translate into differences in clinical efficacy for depressive
tion. Sertraline is approved for depressive and anxiety disor- and anxiety symptoms. Despite this approval, however, the
ders in addition to PMDD and OCD. Dosages range from benefit for anxiety may be offset by the stimulating effect
25 mg to 200 mg daily. It is available in 25 mg, 50 mg, and from the norepinephrine reuptake inhibition. SNRIs are used
100 mg dosages and comes in a solution form [76]. The for chronic pain associated with disease processes such as
availability of low-dose tablets and liquid preparations diabetic neuropathy, migraine headaches, and fibromyalgia
makes sertraline a useful medication with elderly patients. [82]. SNRIs may also be considered as alternative treatment
Sertraline is relatively safe in pregnancy and lactation and is option for the treatment of ADHD [83, 84].
not stimulating like fluoxetine. It may cause QTc prolonga-
tion, and caution is therefore advised, as with other SSRIs. Duloxetine Duloxetine is approved for depressive, anxiety,
Nausea can be a limiting side effect, especially at the initia- and multiple pain disorders including diabetic neuropathy,
tion of treatment, and bedtime dosing can sometimes miti- fibromyalgia, and chronic musculoskeletal pain. Typical
gate this symptom. doses range from 20 mg to 60 mg daily [85]. Duloxetine
seems to have similar efficacy to other SSRI and SNRI fam-
erotonin Partial Agonist-Reuptake Inhibitors
S ily members [86]. Duloxetine may be more effective, but
(SPARIs) and Related Medications may have more adverse side effects, than vortioxetine [87].
Serotonin partial agonist-reuptake inhibitors inhibit sero- The most common side effects include gastrointestinal
tonin reuptake and also have partial agonist activity on sero- symptoms: nausea, vomiting, and diarrhea.
tonin receptors. There is interest in developing classes of
medications which provide precise targeting of specific sero- Levomilnacipran and Milnacipran Levomilnacipran is the
tonin receptor targets to maximize therapeutic effects and to enantiomer of the racemic milnacipran [88]. The former is
minimize side effects. At present, these medications are sec- approved in the United States for major depressive disorder,
ond line to SSRIs and are primarily prescribed by psychia- while the latter is approved for fibromyalgia [89]. Milnacipran
trists. These medications may be helpful in patients whose is not approved for MDD in the United States, but it is
symptoms are refractory or those who cannot tolerate SSRIs. approved for depression outside of the United States. At lower
doses, these medications may be more selective for norepi-
Vilazodone Vilazodone is a selective serotonin reuptake nephrine than other medications within the SNRI class [90].
inhibitor and has additional action as a partial agonist of the
5HT1A receptor. It has been approved for depressive disorders
[77] and has activity against anxiety. It is available in 10 mg, Venlafaxine and Desvenlafaxine Desvenlafaxine is the
20 mg, and 40 mg doses. Therapy is typically started at 10 mg enantiomer of the racemic venlafaxine. Both medications are
for 7 days and titrated upward as tolerated. Safety and efficacy approved to treat depressive and anxiety disorders and have
data suggests that it has similar treatment effects and side additional uses in ADHD, migraine headache prophylaxis,
effect profiles to SSRIs [78]. Data suggests it is relatively and for menopausal hot flashes. Venlafaxine shows dose-
weight neutral and has low risk for sexual side effects [79]. dependent effects in improving symptoms that may affect
mood (such as insomnia) in menopausal women with hot prescribing or renewing these medications, and primary care
flashes, although hormone replacement is more effective physicians should weigh the risks and benefits associated
[91]. Venlafaxine may also be a useful prophylactic option in with their use [97]. Benzodiazepines vary by onset, potency,
patients with migraines [92]. Venlafaxine may be helpful in and half-life, which are important considerations in their
patients with ADHD. Venlafaxine should not be used in clinical use. Availability of additional formulations beyond
patients with uncontrolled narrow angle glaucoma. Some oral agents, such as sublingual preparations which allow for
research suggests venlafaxine may be associated with the rapid absorption, may also play into treatment decisions.
development of hypertension; however, other studies have The major side effect of benzodiazepines is sedation, and
not shown a clear association [93, 94]. Blood pressure should care should be taken in patients who use other sedatives such
be monitored, especially in doses above 300 mg/day. Side as alcohol or other prescription sedatives. Collaboration with
effects include headache, dizziness, tremor, somnolence, and a geriatric psychiatrist, or at minimum dose adjustment, is
nausea. High doses of venlafaxine may prolong QTc. strongly encouraged for elderly patients for whom benzo-
diazepines are being considered. Given the concern about
increased risk for falls and other adverse events, other medi-
Dopamine-Norephinephrine Reuptake cation options should be discussed [98].
Inhibitors Alprazolam is generally avoided in favor of other ben-
zodiazepines, as it is more addictive and is associated with
Bupropion is a medication which is widely used by PCPs marked rebound anxiety which limits its use. It is a rapid
for depression and smoking cessation. Bupropion works onset, short-acting medication with high potency, contribut-
primarily on the dopamine and NE pathways, preventing ing to the addictive potential [99].
reuptake into the synapse and allowing for increased activ- These properties may also predispose to its misuse, per-
ity of these neurotransmitters [95]. Bupropion can be used haps more so than other benzodiazepine class members [100].
first line in patients with depressive symptoms but does not Patients who have been prescribed alprazolam by another
have significant activity against anxiety. Bupropion has sev- provider may be accustomed to its therapeutic effect with its
eral compelling indications in patient care. Bupropion car- rapid onset and high potency and may find lorazepam (the
ries an indication for smoking cessation; thus, patients with first line benzodiazepine) to be less effective by comparison.
concomitant tobacco use disorder may derive both mood and
tobacco cessation benefits from use [96]. Bupropion does Clonazepam Clonazepam is a rapid-onset, intermediate-
not negatively affect sexual functioning and thus is useful duration, high-potency benzodiazepine. Because it has a rapid
as an add-on to low-dose SSRIs or alone for patients with onset, but a longer duration than alprazolam, it may be a better
sexual health concerns. Bupropion can be used (in combina- option than alprazolam due to reduced concern about rebound
tion with naltrexone) to assist with weight loss. Bupropion anxiety [99]. Beyond its role in the treatment of anxiety, it is
lowers the seizure threshold and is not be used in patients also used in patients with seizure disorders. Clonazepam is
with seizure disorders or in those at risk for development available in a rapid dissolving lingual preparation.
of seizure disorders, including women with eating disorders
or substance use disorders [57, 65]. Bupropion reduces the Diazepam Diazepam is a fast-acting, long-acting, medium
effectiveness of tamoxifen and is general avoided, along with potency benzodiazepine and is used in a variety of clinical
fluoxetine and paroxetine, in this population. situations, including procedural sedation and seizure disor-
ders. It is generally not prescribed for anxiety disorders. It has
been used for the acute management of lower back pain; how-
Benzodiazepines ever, the quality of evidence is low, and it may not be superior
to placebo for acute or chronic lower back pain [101].
Benzodiazepines, which are GABA agonists, have been used
for their anxiolytic properties for decades. Benzodiazepines Lorazepam Lorazepam is generally the first line benzodiaz-
may be used safely for panic disorder and anxiety in many epine used for anxiety and panic symptoms [102]. Lorazepam
patients; however, concerns about risk of dependence and may be useful during times of acute stress, such as bereave-
adverse effects remain. Generally, it is preferred to give an ment, and for short-term use in severe anxiety or insomnia. It
alternative treatment such as an SSRI as a first line treatment is used as an anxiolytic for airplane travel and as premedica-
for anxious depression or anxiety. Benzodiazepines may be tion prior to MRIs and other medical procedures. It is a fast-
useful at the initiation of treatment while awaiting the thera- acting, intermediate-duration, high-potency benzodiazepine.
peutic effect of SSRIs and to counter temporary increases Lorazepam, unlike other class members, is metabolized out-
in anxiety which may occur when SSRIs or other agents are side of the cytochrome P450 system and thus can more safely
started. The risk for addiction should be assessed prior to be used in patients with renal or hepatic disease [99].
Temazepam Temazepam is an intermediate-onset, intermediate- medication combinations should be considered. Bupropion

duration, low-potency benzodiazepine which has traditionally has been used successfully to augment SSRI effects and
been used for insomnia. While its pharmacology may result in to mitigate sexual side effects. Mirtazapine has been stud-
decreased risks of misuse relative to other benzodiazepines, ied in combination with venlafaxine for treatment-refrac-
class-specific side effects remain. It currently carries a recom- tory depression [106]. Antipsychotic medications such as
mendation from the American Academy of Sleep Medicine for quetiapine or aripiprazole, originally approved for bipolar
use in insomnia, with acknowledgment of the weak level of evi- disorder, may provide additional benefit for patients with
dence to support its use [5]. difficult to treat symptoms such as insomnia, severe anxi-
ety, and refractory depression [106]. Consultation with a
psychiatrist to guide the initiation of bipolar disorder medi-
Miscellaneous Agents cations and antipsychotics should be sought, although PCPs
may become knowledgeable in their use through experi-
Gabapentin and pregabalin have some effectiveness in the ence and continuing medical education. A full discussion
treatment of anxiety but are not currently approved for this of combinations of medications is beyond the scope of this
indication. These medications are discussed in Chap. 26 on chapter.
General Approach to Chronic Pain. Patients who have refractory symptoms despite treat-
ment by a PCP, patients with bipolar disorder, or patients
Mirtazapine (Tetracyclic Antidepressant) Mirtazapine is a with psychotic disorders should be evaluated by a psychi-
second line medication that acts on the serotonin and norepi- atrist to assist in treatment. Substance misuse, PTSD, and
nephrine systems and has been found to be as effective as severe psychosocial stressors may also complicate medica-
SSRI treatment. Weight gain and sedation are more common tion management and require the input of mental health pro-
with mirtazapine, and it may be useful in some patients who fessionals and social services.
have insomnia [103].
Hormone Therapy
Tricyclic Antidepressants (TCAs) Tricyclic antidepres- Given the link to a woman’s menstrual cycle, oral contracep-
sants (TCAs) are useful at low doses, alone, or in combina- tives have been studied and found overall to be an effective
tion with other medications, for migraine prophylaxis, option for PMDD [107, 108]. As noted previously, there is
chronic pain, irritable bowel syndrome, urinary inconti- clear data that hormone replacement improves hot flashes
nence, and sleep disturbances. TCAs were used to treat during the menopausal transition, which may in turn posi-
depression for decades, but they are no longer used as pri- tively affect sleep and mood. (See Chap. 8 on Menopause.)
mary antidepressants due to negative side effects at high
doses [104]. TCAs are especially discouraged for use in I nsomnia in Depression and Anxiety
older adults due to their highly anticholinergic and sedating Many patients note difficulty with sleep, which coincides with
effects [105]. TCAs prevent serotonin and/or norepineph- depressive and anxiety symptoms. Symptoms may be ade-
rine reuptake, and concomitant use with SSRIs may result quately addressed through the treatment of the primary disor-
in increased SSRI levels. TCAs cause QTc prolongation at der; however, additional medication therapy may be needed.
high doses and have severe cardiac effects when taken as an Medications useful for insomnia include trazodone, benzodi-
overdose. azepines (short term), zolpidem (5 mg in women), quetiapine,
mirtazapine, and low-dose TCAs (if there is another indication
Trazodone Trazodone is a first line treatment for insomnia such as pain). Caution should be taken with medication inter-
at low doses but is not typically used as an antidepressant actions, including serotonin syndrome [109].
due to the side effects associated with higher doses. It acts
through multiple therapeutic mechanisms, including block- Serotonin Syndrome
ing serotonin 2A receptors, histamine receptors, and alpha1 Serotonin syndrome is a set of typically iatrogenic symp-
receptors [81]. toms that can range from mildly uncomfortable to severe
and life-threatening. These symptoms occur as a result of
excess serotonin in the body. The syndrome is character-
Additional Considerations ized by neurologic (hyperreflexia, clonus), autonomic
(tachycardia, diaphoresis, diarrhea), and mental status
I nsufficient Response to One Medication changes (agitation, delirium). Prevention efforts should
Some patients may not achieve adequate improvement in include adherence to recommended prescribed doses and
their symptoms in response to a single medication, and avoidance of, or use of caution with, polypharmacy. When
introducing a new medication, the lowest dose should be ment. The most commonly known evidence-based psy-
prescribed with an upward titration. In addition, clinicians chotherapy treatment is cognitive behavioral therapy
should have a high index of suspicion for serotonin syn- (CBT). CBT employs a variety of techniques aiming to
drome when patients develop unexpected symptoms [110]. help a patient identify and modify maladaptive thoughts
A full discussion of serotonin syndrome is beyond the and behaviors. This is done within a framework of under-
scope of this chapter, but a partial list of implicated sub- standing that thoughts, feelings, and behaviors are bidirec-
stances includes SSRIs, SNRIs, MAO inhibitors, triptans, tionally interrelated; by changing one component of this
fentanyl, lithium, metoclopramide, St. John’s wort, valpro- triad, the others will alter in turn. Patients being treated
ate, carbamazepine, cyclobenzaprine, dextromethorphan, with CBT may see significant and constructive changes in
amphetamines, levodopa, cocaine, and LSD. how they interpret internal and external stimuli, the kind
of “self-talk” they engage in, and become aware of their
behavioral responses to stress-inducing situations. CBT
Follow-Up and Treatment Duration can be highly effective in reducing depressive or anxiety
symptoms.
When treating a patient for depression or anxiety, close Psychotherapeutic approaches such as dialectical
follow-up within the first weeks of initiating treatment is behavioral therapy (DBT) for higher-risk or more dys-
essential [111]. Follow-up within a week may be use- regulated patients, eye movement desensitization and
ful for patients with severe symptoms; those with milder reprocessing (EMDR) for PTSD, interpersonal therapy,
symptoms may be able to follow up in 4–6 weeks after mindfulness-based therapy, and others may also be effec-
the initial appointment, with a phone or online check-in to tive for a patient based on individual preferences, cog-
assess response and side effects within the first few weeks. nitive style, or other factors [112, 113]. The detailed
Communication regarding patient expectations of medica- discussion of these therapies is beyond the scope of this
tions is an essential part of the conversation about medica- chapter.
tion management. It is wise to “start low and go slow” and
only start one medication at a time. An exception would be
patients with significant anxiety or panic that may benefit Collaborative Care
from a benzodiazepine to be taken as needed while initiating
and adjusting to a new antidepressant. Collaborative care models show promise in addressing
While some patients may respond to treatment within a depressive symptoms within primary care settings [114].
couple of weeks, others may require 4–6 weeks, especially for These multidisciplinary and integrated treatment models
severe depression. If no improvement is seen within 12 weeks propose the utilization of multidisciplinary treatment teams
of treatment, alternative treatments or additional add-on consisting of the primary care provider, the patient, a “care
therapies should be considered [63]. The PHQ-9 and GAD- manager” (allied mental health professional), and a consult-
7 should be serially administered at follow-up appointments ing psychiatrist. Collaborative care is defined as (a) team-
to document and monitor response to treatment. Suggested driven, (b) population-focused, (c) measurement-guided,
treatment duration is a minimum of 6 months to help prevent and (d) evidence based [115]. Regular follow-up and treat-
the risk of relapse of patients’ symptoms [57]. Medications ment team meetings facilitate ongoing communication
should be tapered slowly, particularly with long-term use, as among providers so that treatment can quickly be modi-
symptoms may result from abrupt cessation. In some cases fied or enhanced to maximize treatment outcomes. Primary
of long-term use and recurrent depression, medication discon- care providers and their patients collaboratively formulate
tinuation should not be attempted. The US Preventive Services a treatment plan to address depressive symptoms, includ-
Task Force and others endorse a collaborative care model in ing medication management and/or brief psychotherapy
which PCPs work in collaboration with mental health provid- implemented within a primary care setting. The care man-
ers to treat patients (discussed below). ager works with the patient and the primary care provider
to track symptoms (often using a symptom screening mea-
sure such as the PHQ-9), implement brief psychotherapy
Psychotherapy (solution-focused, cognitive behavioral, or behavioral acti-
vation), and maintain close follow-up of treatment prog-
Psychotherapy is a practice that can be implemented in ress. Care managers may also ultimately refer patients to
multiple healthcare settings, using a variety of approaches specialty care outside the primary care setting. Consulting
and techniques. Most commonly, patients are referred to psychiatrists remain available for recommendations and
providers within specialty care for psychotherapy treat- referrals.
Treatment Planning Postpartum Care
Shared Decision-Making The American College of Obstetrics and Gynecology, the

American College of Physicians, the American Academy of
Each patient who seeks care for depression, anxiety, or other Pediatrics, and the American Academy of Family Physicians
psychiatric concerns should have a treatment plan informed all recommend and support screening and treatment for psy-
by her own preferences and values. Primary care providers chosocial aspects of health affecting mothers to provide the
are advised to both review options with patients and check in best care for the whole family [116–118]. Providers should
with patients about their thoughts and beliefs. For example, screen for symptoms of postpartum depression and mania (in
patients may have strong feelings about wanting to avoid patients with bipolar disorder) in addition to addressing other
medications, while others would prefer medications and do health concerns in the postpartum period for all women. The
not believe psychotherapy is right for them. The data Edinburgh Postpartum Depression Scale (EPDS) is a screen-
reviewed in this chapter demonstrates that a variety of treating tool which has been validated for use in the postpartum
ment modalities may be helpful for depressive and anxiety setting. The use of psychiatric medications during pregnancy
symptoms. A patient’s belief in the efficacy of her treatment and lactation is covered in Chap. 39 on Obstetric Medicine.
plan is also important, highlighting the need to ensure a plan
mutually determined by the patient and provider.
Conclusion
Monica begins taking an SSRI and engages in weekly Depressive and anxiety disorders disproportionately affect
psychotherapy. Six months later, she returns to clinic women and can be treated in the realm of primary care.
and reports an improvement in her mood and her Primary care providers should be able to recognize risk
sleep. She remarks that she and her long-term partner factors for these disorders and utilize common screening
have been talking about starting a family within the modalities. Primary care providers must carefully consider
next year. differential diagnoses, including both psychiatric and medi-
cal alternatives. If uncertain, collaboration with a psychiatrist
is encouraged. Treatment plans should be individualized,
including patients’ comorbidities, beliefs, and preferences
to arrive at mutually determined plans that may incorpo-
Preconception Considerations rate psychotherapy, medication, lifestyle modifications, or
complementary and alternative treatments. After initiation of
In women of childbearing age, it is useful to discuss plans a treatment plan, patients require close follow-up to ensure
for pregnancy during initial treatment planning, including improvement in mood or anxiety symptoms.
the risks and benefits of medication use in pregnancy. Early
discussions regarding plans for medication use and discon-
tinuation may help avert concerns and more urgent discus- S ummary Points
sions in early pregnancy. Patients will benefit from receiving
education that depression tends to worsen during pregnancy; 1. Depressive disorders and anxiety disorders are common
thus, medications should be discontinued with care. SSRIs and underreported in women seeking care in the primary
are generally safe in pregnancy, with the exception of par- care setting; annually, 8.5% of women present with
oxetine, but other medications may have a higher level of depressive disorders and 23.4% present with anxiety dis-
risk. Proactive planning in regard to medication alternatives orders. Women may be hesitant to seek out mental health-
during pregnancy is indicated, and patients should be co- care on their own; thus, the assessment and treatment of
managed with obstetricians and psychiatrists during precon- depressant and anxiety symptoms in primary care is vital.
ception planning, pregnancy, and in the postpartum period. 2. Bipolar disorder and post-traumatic stress disorder are
key differential diagnoses to consider for patients pre-
senting with depressive or anxiety symptoms; differentia-
Psychiatric Management of Mood and Anxiety tion between these disorders is critical given that treatment
Disorders During Pregnancy is pharmacologically and behaviorally distinct and usu-
ally requires psychiatric consultation.
Please see Chap. 39 on Obstetric Medicine for a discussion 3. Patient-centered inquiries are important components of a
regarding medication use and management during pregnancy. comprehensive clinical interview and diagnostic assess-
ment. These include open-ended questions, reflective C. A validated screening tool for depressive symptoms
statements, clarifying questions, and emotion-seeking D. A validated assessment measure for substance use
approaches. Screening tools such as the PHQ-9 and The correct answer is C. The Patient Health
GAD-7 are helpful adjuncts in the diagnosis and monitor- Questionnaire (PHQ) is commonly used in primary
ing of depressive and anxiety disorders. care as a screening tool for depression. There are mul-
4. Suicide risk assessments are essential to any provider- tiple versions which have been adapted for differing
patient exchange related to emotional or psychiatric dis- patient populations and situations. The PHQ-2 (two-
tress. These assessments include determining the presence question version) and PHQ-9 have been found to be
of any ideation (passive and active), intent, and/or plan. reasonable screening tools for depression; however,
Suicide risk is determined through direct and nonjudg- providers should undertake additional discussion with
mental inquiries. individual patients before making the diagnosis of a
5. The treatment of depressive and anxiety disorders is indi- depressive disorder [119].
vidualized based on symptom acuity and severity and 3. A 45-year-old woman is being evaluated for depression.
patient preference. The choice to prescribe psychotropic For a person to be diagnosed with major depressive disor-
medication, recommend behavioral and lifestyle changes, der, several symptoms should be present, but at least one
or refer for psychotherapy is made using shared decision- of two possible symptoms is required. Which of the fol-
making. Complex or severe symptoms may necessitate a lowing is one of those two required symptoms?
referral to a psychiatrist or psychotherapist. A. Recurrent thoughts of death, self-harm, or suicide
6. Referral to a psychiatrist is appropriate when patients fail B. Marked changes in sleep
to respond to standard treatment modalities or demon- C. Feelings of worthlessness or excessive guilt
strate symptoms concerning for complex psychiatric dis- D. Loss of interest or pleasure in previously enjoyed
ease including bipolar disorder or psychosis. activities or events
The correct answer is D. The DSM-5 criteria for
major depressive disorder require at least one of two
Review Questions symptoms, depressed mood or loss of interest or plea-
sure, and a total of five of nine symptoms. While
1. A 27-year-old woman presents to clinic with acute dis- thoughts of death, feelings of guilt, changes in sleep,
tress. She declares that she has been “feeling crazy” lately or feelings of worthlessness may be present, they are
and that her thoughts and emotions feel “out of control.” not required for the diagnosis. Additionally, the diag-
She mentions that her boyfriend called her “bipolar” dur- nosis requires that the episode of symptoms not be
ing their most recent argument and asks whether she attributable to substance use or symptoms of another
might have bipolar disorder. What definitively differenti- medical condition. Collaboration within a treatment
ates a bipolar disorder from a depressive disorder? team as described in the question is important [26].
A. Hospitalization or arrest 4. A 34-year-old woman is seen in follow-up in your office
B. A manic, hypomanic, or mixed episode for depressive symptoms. She notes that she sometimes
C. Markedly decreased sleep feels like it would be better if she weren’t “here any-
D. Impulsive or destructive behavior more.” What would be the most appropriate patient-
The correct answer is B. The diagnosis of bipolar centered response to this statement?
disorders requires a least one episode of hypomania or A. Begin following protocol to initiate involuntary
mania for bipolar II and bipolar I disorder, respec- hospitalization.
tively. While hospitalization, arrest, or impulsive B. Probe to gather more information about these
behavior may occur in patients with bipolar disorder; thoughts.
these history points are not required for the diagnosis C. Do not inquire further, since she did not report an
of the bipolar disorder. Markedly decreased sleep may intent to harm herself.
occur in many psychiatric disorders, including depres- D. Advise her to increase or change her medication regi-
sion or anxiety, and is not specific to bipolar disorder; men, since it probably is not optimally addressing her
the same is true with impulsive or destructive behav- depression.
ior [26]. The correct answer is B. Vague statements such
2. A 55-year-old woman presents for her routine physical as those made by this patient can have a variety of
appointment and is asked to complete a Patient Health meanings, and it is important to sensitively gather
Questionnaire-9 (PHQ-9) at check-in. The PHQ-9 is: more information about her symptoms to determine
A. A validated assessment measure for diet and exercise the most appropriate treatment plan. While some
B. A validated screening tool for anxiety symptoms patients may have active suicidal intent, not all may,
and thus involuntary hospitalization for all patients disorder: a positron emission tomography study. Psychiatry Res.
2010;183(2):157–66. Available from: https://doi.org/10.1016/j.
who make this statement is inappropriate. It is cur- pscychresns.2010.05.005.
rently unclear if she has intent to harm herself, so 15. Caspi AR, Holmes A, Uher R, Moffitt TE. Genetic sensitivity to
failing to inquire further is also inappropriate. While the environment: the case of the serotonin transporter gene and
her medication regimen may need to be changed, the its implications for studying complex diseases and traits. Am J
Psychiatry. 2010;167(5):509–27. Available from: https://doi.
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self-harm [120]. Kim YK, editor. Understanding Depression. Singapore: Springer;
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Eating Disorders and the Female
Athlete Triad 34
Brianna Rossiter and Anna K. Donovan
Learning Objectives Manual of Mental Disorders (DSM-5) [1]. These disorders are
1. Distinguish between the clinical presentations of characterized by a persistent disturbance of eating or behav-
the three most common eating disorders: anorexia ior regarding eating that results in impaired consumption or
nervosa, bulimia, and binge eating disorder. absorption of food. Importantly, these eating behaviors must
2. Identify medical complications of eating disorders co-exist with a significant impairment of physical health or
that necessitate inpatient evaluation and treatment. psychosocial functioning [1]. The most familiar EDs seen by
3. Appropriately treat eating disorders with non- providers—anorexia nervosa (AN), bulimia nervosa (BN), and
pharmacologic and pharmacologic approaches. binge eating disorder (BED)—will be discussed in this chap-
4. Describe the female athlete triad and discuss how ter. Of note, the DSM-5 no longer uses the umbrella diagnosis
this syndrome relates to disordered eating. of “not otherwise specified” (NOS); instead, EDs not meet-
ing the diagnostic criteria of a particular type are classified as
“Other Specified Feeding or Eating Disorder” (OSFED) and
“Unspecified Feeding or Eating Disorder” (UFED) [1].
Gianna is a 33-year-old female who presents to your
office as a new patient. She was previously seen in
Epidemiology
another state and moved here for work in a local law
firm. She identifies heartburn and allergies as previous
The prevalence of EDs is challenging to estimate because
medical conditions. Her only complaint today is poor
available data are based on the DSM-4 criteria, which were
sleep. Her vital signs on presentation are a heart rate
more restrictive than the current DSM-5 criteria. Additionally,
of 62, a blood pressure of 112/74, and a body mass
patients with EDs often go to great lengths to conceal their
index (BMI) of 16.
illness, leading to an underestimation of prevalence. Based
on the DSM-4 criteria, the US lifetime prevalence estimates
of anorexia nervosa, bulimia nervosa, and binge eating dis-
order are 0.9%, 1.5%, and 3.5%, respectively, among women
Background and 0.3%, 0.5%, and 2.0%, respectively, among men [2].
Both AN and BN are more common in women than in men,
Eating disorders (EDs) are classified under the category of with a median age of onset of 18-years-old.
“feeding and eating disorders” in the Diagnostic and Statistical Certain patients are at higher risk for AN and BN than oth-
ers. For example, a history of dieting is common among indi-
B. Rossiter (*) viduals who subsequently develop severe EDs. Therefore,
VA Pittsburgh Healthcare System, Pittsburgh, PA, USA activities that emphasize low weight, such as certain sports
University of Pittsburgh School of Medicine, Department of Medicine, (dancing, gymnastics, wrestling) and professions (model-
Division of General Internal Medicine, Pittsburgh, PA, USA ing), may place individuals at increased risk of an ED. There
is also evidence that genetics play a role in the development
A. K. Donovan of EDs; individuals with a family history of EDs should be
IM Residency Training Program, University of Pittsburgh Medical
considered at higher risk [3, 4]. Additionally, AN and BN
Center-Presbyterian, Department of Medicine, Division of General
Internal Medicine, Pittsburgh, PA, USA are associated with co-existing psychiatric conditions, most

524 B. Rossiter and A. K. Donovan
notably mood disorders and substance use disorders [5]. Pathophysiology

Bulimia in particular is associated with a history of sexual
abuse [5]. Despite the widespread association between AN The low population prevalence of EDs makes any prospec-
and higher socioeconomic status, this relationship has not tive study to determine their pathophysiology challenging.
been proven. However, increasing evidence suggests that A likely pathologic model for EDs is a combination of bio-
an association between BN and lower socioeconomic status logic, psychologic, and environmental factors. For example,
may exist [6]. anorexia nervosa has been linked to abnormalities in sero-
Binge eating disorder (BED) is also more common in tonin functioning, with animal models suggesting increased
women than men. Prevalence rates are similar among vari- synaptic serotonin release with inhibition of feeding [11]. A
ous demographics irrespective of race, marital status, and number of other neurotransmitters and hormones have also
employment status. The median age of onset of BED is been implicated in the development of AN, including ele-
approximately 23-years-old. Individuals with BED are more vated cortisol [12] and decreased oxytocin [13]. Most of the
likely to have a higher body mass index and obesity when studies to date examining neurochemical changes in AN rely
compared to the general population. Similar to AN and BN, on indirect measures and are therefore challenging to inter-
over 70% of patients with BED have another co-existing pret. Regardless of the proposed neurochemical changes,
psychiatric disorder [7]. a “multiple-hit hypothesis” in regard to ED pathology is
largely accepted [14], with the thought that a certain set of
genes expressed under the right sociocultural conditions
Screening creates a likely environment for an ED. Similarly to AN,
cholecystokinin [15], serotonin [16], and leptin [17] are sug-
There are currently no screening recommendations for gested neurochemicals influencing binge and purge behav-
EDs from major organizations (e.g., USPSTF), and few iors in BN. Recent data suggests a biologic basis for BED as
tools exist for use in the primary care setting [8]. While well. Neuroimaging studies have suggested that individuals
no major guidelines exist, primary care providers may opt with BED have corticostriatal circulatory alterations similar
to screen patients considered to be in higher-risk groups to those seen in substance abuse, suggesting problems with
epidemiologically; these high-risk individuals include ado- impulse control [18]. Overall, further studies are needed to
lescent females, individuals with a family history of EDs, better understand the pathophysiology of various EDs.
those with rapidly changing or low BMI, those with signifi-
cant psychiatric illness, and those with high-risk careers like
athletes and models [9]. iagnostic Criteria and Clinical
D
There are currently no recommendations for screening Manifestations
for BED. Patients that should be considered for screening
include those with rapid weight gain, high BMI, and under- Eating disorders are diagnosed by their clinical features in
lying mood disorders; however, keep in mind that all patients the DSM-5. When diagnosing EDs, medical comorbidities
with BED are not overweight. Screening tools created for (most often gastrointestinal disease) and food insecurity
use in patients with BED include the BEDS-7 [10], a patient- must be excluded.
reported screening tool designed to identify individuals in
need of referral to BED specialists. Questions of the BEDS-7
ask about episodes of excessive overeating and the character- Anorexia Nervosa
istics and emotions that tend to accompany them.
Anorexia nervosa is characterized by abnormally low body
weight, an intense fear of gaining weight, and a distorted
Gianna reports insomnia and poor sleep for the last perception of body weight and shape [1]. Patients with AN
10 years that has substantially worsened since moving will put forth significant effort to prevent weight gain even in
to the area. She denies any problems falling asleep but the setting of a dangerously low BMI. Anorexia can be fur-
awakens at night and cannot fall back to sleep. She ther categorized as restricting-type or binge eating/purging-
reports that she often gets up and does work, or she type [19]. Restricting-type includes individuals who have
will go to the kitchen to eat. She often feels guilty in the not engaged in binge eating or purging behavior, but rather
morning after eating late at night and admits to accomplish weight loss through calorie reduction, fasting,
restricting food the following day. and/or excessive exercise. The binge eating/purging subtype
encompasses individuals who engage in recurrent episodes
34 Eating Disorders and the Female Athlete Triad 525
of binge eating and purging behavior (described in the buli- feature in BED is the significant emotional and/or psycho-
mia section). The severity of AN is based on BMI, with mild logical impairment that follows a binge episode. As noted
characterized by a BMI between 17 and 18.5 kg/m2, moder- above, defining an amount of food intake that qualifies as
ate with a BMI between 16 and 16.99 kg/m2, severe with a a binge eating episode can be challenging. The DSM-5
BMI between 15 and 15.99 kg/m2, and extreme with a BMI attempts to qualify a binge episode under the BED criteria
under 15 kg/m2 [1]. The level of severity also reflects the with a binge episode having at least three of the following
clinical symptoms, the degree of functional disability, and features: (1) eating well beyond the point of satiety, (2) eat-
the need for supervision and medical intervention. ing more quickly than one would during a normal meal, (3)
Features associated with AN may also include behaviors eating large amounts of food when one is not particularly
difficult to observe or assess, including features of extreme hungry, (4) making efforts to cover up the binge or eating
preoccupation with food, preference for low-calorie foods, alone due to shame or embarrassment, and (5) feeling sad,
overestimation of calories consumed, and food-related ritu- depressed, or guilty after a binge [1]. Importantly, binge epi-
als. Food rituals can include behaviors such as cutting food sodes must cause marked mental distress, and, unlike BN,
into small pieces prior to eating or eating foods in a par- the diagnosis of BED does not include any inappropriate
ticular order. These behaviors can ultimately lead to social compensatory behaviors. The BED level of severity is based
withdrawal, excessive exercise, restlessness, dysregulation upon the number of binge eating episodes per week: mild,
of emotions, poor sleep, and low libido [20]. one to three episodes per week; moderate, four to seven per
week; severe, eight to 13 per week; and extreme, 14 or more
episodes per week [1].
Bulimia Nervosa
The DSM-5 criteria for BN include recurrent episodes of Associated Comorbidities

binge eating with an accompanying, inappropriate com-
pensatory behavior to prevent weight gain, regardless of a Psychiatric comorbidity is common among patients with
patient’s current weight [1, 19]. A binge episode can be chal- EDs, but can be challenging to distinguish as some are sec-
lenging to define as it is somewhat subjective based on an ondary to the ED itself and can resolve with treatment of the
individual’s determination of a “discrete amount of time” ED [2, 21]. Many experts believe that the development of an
and a “large amount of food” as compared to most people. ED is a way for individuals to exert control over their envi-
Regardless, an individual engages in a binge episode when ronment. It is often hard to distinguish if the ED manifests
they eat an excessive amount in a small period of time (e.g., as a pathologic coping mechanism from a primary mood
30 minutes to 2 hours). Most importantly, these episodes disorder or if the mood disorder is secondary to a primary
are defined as a total lack of eating control by the individu- ED. Ideally, the ED should be treated initially, and, follow-
als (e.g., they feel that they cannot stop eating). This cor- ing remission, the patient should be reassessed for any other
responding lack of control is essential in defining a binge persistent psychiatric comorbidities. The only exception is
episode. In BN, binge episodes are followed by inappropri- the co-existence of a severe substance use disorder, which
ate compensatory behaviors including activities such as self- should be prioritized at the time of initial treatment of the ED
induced vomiting, misuse of laxatives or diuretics, fasting, or to manage withdrawal phenomena [22].
excessive exercise. The combination of a binge episode and a Although the specific rate of comorbid disorders differs
compensatory behavior is the cornerstone feature of BN. To between epidemiologic surveys and studies in clinical set-
diagnose BN, behaviors must occur at least once per week tings, there is general agreement that patients with AN and
for 3 months [1]. Severity is based on the number of epi- BN often suffer from anxiety, mood disorders, obsessive-
sodes of compensatory behavior per week, with mild having compulsive disorder, body dysmorphic disorder, and PTSD
an average of one to three episodes per week while extreme [23]. The lifetime rates for these comorbidities in patients
averages more than 14 binge episodes per week [1]. with EDs exceed the rates in the general population. As an
example, the estimated lifetime prevalence of unipolar major
depression in the general population is 23% compared to
Binge Eating Disorder 50% in the ED population [24]. Lifetime rates of substance
use disorders are also higher in patients with EDs [22] with
Binge eating episodes are also required in the diagnosis alcohol use disorder being most common [25]. Bulimia ner-
of BED [1]. Similar to BN, individuals must feel a lack of vosa is the most common ED associated with prior child-
control during the episode. In contrast to BN, the defining hood trauma (e.g., sexual abuse) [26]. Personality disorders
associated with EDs have received increasing attention, with and Secondary Amenorrhea to learn more about secondary
the most commonly observed co-occurring personality dis- amenorrhea.
orders including histrionic, obsessive-compulsive, avoidant, Given the features of AN, patients with anorexia often
dependent, and borderline personality types [27]. However, have FHA. Importantly, amenorrhea is no longer a crite-
similar to determining prevalence data in EDs, determining rion for the diagnosis of AN in the DSM-5 [32]; however,
the prevalence of personality disorders in individuals with it can serve as a surrogate marker for the severity of an eat-
EDs is also challenging. For example, a 2005 meta-analysis ing disorder. Irregular menses or complete loss of menses
found the prevalence of personality disorders to be 0 to 58% in a patient who previously menstruated normally should be
among individuals with AN and BN, but documented that viewed as a red flag that requires additional history taking
these associations are often determined through self-reported regarding food intake, excessive exercise, and restricting or
instruments that greatly overestimate personality disorder purging behaviors.
prevalence [28].
Patients with BED are also more likely to have comorbid
psychiatric conditions; up to 79% of BED patients have at The Female Athlete Triad
least one additional psychiatric diagnosis with specific phobia
being most common. These prevalence rates are higher than The female athlete triad is a syndrome often seen in com-
in the general population [29]. Additionally, BED patients are petitive athletes and characterized by functional hypotha-
more likely to have co-existing medical diagnoses in addition lamic amenorrhea (FHA) [33]. This syndrome is defined by
to psychiatric comorbidities. Specifically, individuals with a three components: (a) low energy availability with or with-
history of BED are at increased risk of developing chronic out disordered eating, (b) menstrual dysfunction, and (c)
pain, diabetes mellitus, and hypertension [29]. low bone density [34, 35]. Patients with the female athlete
triad most often have low BMIs and participate in activities
where weight and aesthetics are important (dance, gymnas-
tics, figure skating, cross-country, marathon runners). These
You learn that Gianna lives alone and works as a law-
patients tend to present with oligomenorrhea or amenor-
yer in a new law firm. She is a never smoker, rarely
rhea in the setting of weight loss or extreme exercise. This
drinks, and denies illicit drug use. She swam competi-
causes low energy availability in turn causing dysregulation
tively until college. She has never been pregnant and
of gonadotropin-releasing hormone (GnRH) secretion, lead-
only briefly used contraceptive pills. She reports that
ing to a state of estrogen deficiency and FHA, much akin
she intermittently would not get her period throughout
to the hormonal dysregulation experienced by patients with
high school and college and that currently her periods
anorexia.
are irregular and very light.
All patients with FHA live in an estrogen deficient state
and are at increased risk for the consequences of estrogen
deficiency, notably low bone density [36, 37]. Low bone den-
Functional Hypothalamic Amenorrhea sity in an athlete can lead to stress fractures, occult fractures,
and other musculoskeletal injuries. Evidence of hypotha-
Given that EDs often result in low energy availability from lamic dysfunction manifested clinically as oligomenorrhea,
decreased caloric intake and/or excessive energy expen- amenorrhea, or a stress fracture should be a red flag and
diture, ED patients are at risk of developing functional prompt screening for an eating disorder. It is important to
hypothalamic amenorrhea (FHA). FHA is a cause of second- note that not every patient with FHA has an eating disorder,
ary amenorrhea that results from abnormalities in pulsatile and hypothalamic dysfunction is a protective response when
gonadotropin-releasing hormone (GnRH) secretion, which the body is in an energy deficient state as the body is unlikely
in turn causes less gonadotropin release (follicle-stimulating to be able to support a healthy pregnancy.
hormone and luteinizing hormone). The altered pathways Treatment of patients with the female athlete triad has
result in complex hormonal changes, most notably, profound several goals: restore normal menses, reverse and treat bone
hypoestrogenism [30]. Disruption in GnRH drive is postu- complications, treat underlying psychiatric disorders, and
lated to occur from energy deprivation by calorie restriction, evaluate for any concomitant eating disorders. Most often,
excessive exercise, and/or psychological stress, acting to pro- decreasing the number of workouts per week and increasing
voke hypothalamic disruption [31]. Importantly, as in every BMI will reinstitute the hypothalamic-pituitary-ovarian axis
woman with new-onset secondary amenorrhea, other causes and normal menses will return. If patients who are overex-
such as pregnancy, hypothyroidism, hyperprolactinemia, and ercising are unwilling to decrease their workouts and do not
polycystic ovary syndrome should first be excluded before have a sporting commitment, a provider should assess for the
diagnosing FHA [30]. Please see Chap. 5 on Menstruation presence of restrictive eating habits and other purging behaviors
such as the use of laxatives and vomiting. Psychological All patients with AN should be engaged in nutritional
evaluation, either with a sports psychologist or therapist, rehabilitation for guidance on dietary choices and caloric
is recommended if the patient has unrealistic performance management. Nutritional rehabilitation is best done at a
expectations or places undue training demands on herself. dedicated ED treatment center with knowledgeable nutri-
Combined oral contraceptives can be used to facilitate tionists. Notably, there is tension between weight restora-
regular menses, endometrial protection, and pregnancy tion and patient anxiety; most patients will be resistant to
prevention; however, as per the Endocrine Society Clinical weight recovery. Caloric requirements in patients with AN
Practice Guidelines, it is not recommended to start oral con- are high and vary between 30–40 kcal/kg/day for inpatients
traceptive pills for the sole purpose of regaining menses or and 20 kcal/kg/day for outpatients. These caloric amounts
improving bone mineral density in patients with FHA [30]. will facilitate weight gain of 1–1.5 kg/week in the inpatient
Medroxyprogesterone acetate for contraception should be setting and of 0.5 kg/week in the outpatient setting [42].
avoided if possible in patients with FHA as it has been asso- Adjunctive pharmacotherapy may help reduce symptoms
ciated with low bone mass and osteoporosis in long-term of depression and anxiety in patients who do not respond
users [38]. Other aspects of bone health in FHA will be dis- to psychotherapy and/or treat primary psychiatric disorders
cussed later in the chapter. [40, 43]. However, distorted thinking about body image and
food usually will not respond to pharmacotherapy, nor do
drugs delay or prevent subsequent episodes of anorexia ner-
vosa [44]. Patients should be seen often, sometimes weekly,
Gianna is diagnosed with anorexia nervosa and desires
for weight checks, lab monitoring, and assessment of the
treatment. She does not meet inpatient criteria for
recovery process [45]. One should consider blinding the
treatment and you refer her to an intensive outpatient
patient to weight checks in the office as weight can be a trig-
program for patients with eating disorders.
ger for restrictive behavior, especially in those with a history
of AN in remission.
Treatment
Bulimia Treatment Options
Eating disorders can be life-threatening, most often due to
medical complications but occasionally secondary to sui- Similar to AN, standard treatment for BN includes nutritional
cide [39]. Unfortunately, complications compound because rehabilitation and psychotherapy, with a slightly larger role
of patients’ frequent refusal of treatment. Similar to patients for pharmacotherapy [40, 46–48]. Notably for patients with
with substance use disorders, patients must be active and BN, management of electrolyte imbalances is essential given
willing participants in treatment to facilitate successful out- purging behaviors. Patients may require high-dose electro-
comes. Treatment of eating disorders generally involves an lyte replacement from excessive vomiting or laxative use.
interdisciplinary team including, but not limited to, a mental Patients with BN benefit from nutritional counseling to help
health provider, a dietitian, and a general medical provider. disrupt the binging and purging cycle. For patients with buli-
Consultation with a mental health provider with expertise in mia nervosa, CBT is superior to other psychotherapies [46].
eating disorders should be considered at the time of diagno- Pharmacotherapy alone appears to be less efficacious than
sis [19]. psychotherapy alone, but combining the two is the preferred
approach [46]. If nutritional rehabilitation and psychother-
apy are not available, pharmacotherapy alone is reasonable
Anorexia Treatment Options in the treatment of BN. Selective serotonin reuptake inhibi-
tors (SSRIs) are better tolerated than other medications
Treatment for AN is challenging; standard treatment con- and recommended over tricyclic antidepressants (TCAs) or
sists of nutritional rehabilitation and psychotherapy, with monoamine oxidase inhibitors (MAOIs). These medications
only occasional augmentation with pharmacotherapy [40]. also help treat a co-existing mood disorder. Bupropion is
Pharmacotherapy is not first-line treatment in AN and is contraindicated in patients with BN given the risk of seizures
never used alone [18–20]. Psychotherapy is essential, but secondary to electrolyte disturbances.
there is no compelling evidence that one therapeutic modal-
ity is clearly superior to others [20, 41]. Options include
cognitive behavioral therapy (CBT), group therapy, moti- Binge Eating Disorder Treatment Options
vational interviewing, and family therapy. Thus, the choice
is based upon availability, patient age, patient preference, Management of a patient with BED is twofold: (1) assess
and cost. for and treat comorbid psychiatric disorders, and (2) treat
underlying overweight- and obesity-related comorbidities. for patients with ED starts with the physical examination.
Exploring the patient’s attitude toward their body weight Exam findings that suggest severe malnutrition and a need
and shape and their current and future nutritional goals is for immediate medical evaluation include low body mass
important. While multiple treatment modalities exist, includ- index (<17.5 kg/m2), a core body temperature <35 °C, a heart
ing psychotherapy, self-help treatment, pharmacotherapy, rate <60 beats per minute, and/or a systolic blood pressure
and behavioral weight loss treatment, psychotherapy is pre- <90 mmHg. Additional exam findings may include hypoactive
ferred [49]. Studies have indicated that psychotherapy alone bowel sounds, xerosis, brittle hair, hair loss, and lanugo hair
is more beneficial than pharmacotherapy alone, with the pre- growth. Recommended laboratory testing for these patients
ferred first-line treatment being cognitive behavioral therapy includes serum electrolytes including calcium, potassium,
or interpersonal therapy [50]. phosphorus, and magnesium, serum albumin and pre-albumin,
Several types of medication have been studied for BED liver function tests, thyroid-stimulating hormone, and a preg-
and include SSRIs, antiepileptic drugs (e.g., topiramate), and nancy test in women. Bradycardia should prompt immediate
medications typically indicated for attention deficit hyper- electrocardiogram evaluation to assess for changes related to
activity disorder (e.g., atomoxetine and lisdexamfetamine) electrolyte abnormalities and profound malnutrition [54].
[51]. SSRIs are the preferred medication given their effi- If severe exam findings are not present, most medical
cacy and tolerability [51]. Additionally, antiepileptics and complications of anorexia nervosa are managed in outpatient
stimulants have the potential for adverse effects and poten- or residential care facilities [40]. Other treatment settings
tial for abuse or dependence. Among antiepileptic drugs, that may be available include intensive outpatient (e.g., 2 to
topiramate often reduces hunger and promotes weight loss, 3 hours per weekday) and partial hospitalization (day pro-
resulting in a significant reduction in daily binge episodes gram that provides 6 to 8 hours of outpatient care per week-
and impulsivity. Importantly, topiramate is contraindicated day). While there are no evidence-based criteria indicating
in pregnancy and can lower the efficacy of estrogen and/ which patients with anorexia nervosa need hospitalization
or progesterone-analog contraceptives. This should be taken [53], clinical practice guidelines suggest inpatient hospital-
into consideration given the prevalence of young women ization for adult patients with profound vital sign abnormali-
with eating disorders. Drugs that treat attention deficit ties, concern for cardiac dysrhythmia, and/or concern for
hyperactivity disorder facilitate function of the dopamine refeeding syndrome [54]. Profound vital sign abnormalities
and/or norepinephrine systems, which are involved in eat- include a pulse less than 40 beats per minute, a blood pres-
ing behavior and subsequent reward that manifests in binge sure <80/60 mmHg, weight <70 percent ideal body weight,
eating [52]. However, these stimulant medications are con- or BMI <15 kg/m2 or signs of marked dehydration. The most
trolled substances and contraindicated in patients with sig- concerning cardiac features include an increased PR inter-
nificant cardiovascular comorbidities. val, first-degree heart block, ST wave abnormalities, and a
QTc > 499 msec [55].
Refeeding syndrome is a potentially fatal complication of
Gianna presents for her 9-month follow-up visit. She malnutrition that occurs as a result of fluid and electrolyte
looks tired and withdrawn but does not have any spe- shifts during aggressive nutritional rehabilitation [56]. The
cific complaints. Vital signs at this visit include a heart most worrisome electrolyte abnormality in refeeding is hypo-
rate of 52 and blood pressure of 91/76. Patient is phosphatemia. AN patients are already phosphate depleted
orthostatic by HR and BP. BMI is noted to be 15.6. You from starvation. Subsequent refeeding causes insulin release
facilitate immediate admission to an inpatient pro- resulting in additional cellular uptake of phosphate and
gram for treatment of AN. worsening hypophosphatemia. This lack of phosphorylated
intermediates causes tissue hypoxia and resultant myocardial
dysfunction and potential respiratory failure [57]. While it
is difficult to determine which ED patients will experience
Criteria for Hospitalization refeeding syndrome, those with lower BMI and starvation
in the 5–10 days preceding nutritional support are most at
Anorexia nervosa is the ED most likely to require inpatient risk [56].
evaluation and stabilization based on potential laboratory and There is currently a lack of evidence regarding the deci-
cardiac abnormalities [53]. The goal of hospitalization is to sion for voluntary versus involuntary hospitalization in
restore nutrition and vital metabolic functions that are com- patients with severe presentations of AN or BN [58, 59].
promised by chronic underfeeding. Patients with BN may Assessing the patient’s intentional and unintentional risk
also require inpatient electrolyte correction given purging to self and ability to understand the consequences of their
behaviors that result in hypokalemia, hypomagnesemia, and actions and decisions is vital in assessing the need for invol-
hypophosphatemia. The evaluation for inpatient admission untary inpatient admission.
arly Medical Complications of Eating

E period of vulnerability for the onset, persistence, or relapse
Disorders of ED symptoms [63].
Women with eating disorders who consider becoming
Regardless of the treatment setting, patients with AN and pregnant should receive preconception counseling about the
BN exhibit medical complications early in their course. risks to the patient and child, as well as education about body
Early complications of anorexia, aside from those already changes and weight gain during pregnancy. Patients should
discussed, are broad in clinical scope. Complications range ideally postpone pregnancy until the disorder and medical
from arrested growth and myocardial atrophy to unplanned complications are stable. The dietary habits of patients with
pregnancy with neonatal complications to cognitive impair- eating disorders must be monitored to ensure proper weight
ment [60, 61]. gain and fetal growth, and nutritional guidance should be
Early complications of BN include xerosis, parotid gland provided. In addition, patients with ED should be asked
swelling, and erosion of dental enamel. Gastrointestinal about the use of teratogenic medications, including appetite
complications are common with possible loss of gag reflex, suppressants, diuretics, and excess use of laxatives.
ongoing abdominal pain and bloating, Mallory-Weiss syn- In women with a history of AN and BN, fertility rates
drome, gastroesophageal reflux disease (GERD), and appear to be comparable to those in the general population
colonic dysmotility. As noted above, the most common [62]. However, eating disorders appear to be associated with
renal and electrolyte complications of BN include dehydra- several adverse perinatal outcomes, to both mother and off-
tion, hypokalemia, hypochloremia, and metabolic alkalosis. spring. Maternal AN is associated with slow fetal growth,
Cardiac complications are rare in BN but can include ortho- premature contractions, and infants that are small for ges-
stasis resulting in syncope, sinus tachycardia, palpitations, tational age. Maternal BN is associated with premature
and arrhythmias. contractions and low Apgar scores. Alternatively, BED is
Early medical complications of BED can include insu- associated positively with maternal hypertension and large-
lin resistance, hypertension, hyperlipidemia, and metabolic for-gestational-age infants [64].
syndrome [2]. Should patients develop morbid obesity as a
result of BED, they are at ongoing risk for resistant hyperten-
sion, obstructive sleep apnea, and diabetes. Bone Health
Osteoporosis is a common complication of anorexia ner-

vosa. Multiple factors increase risk, including decreased
Gianna presents to your office 5 years after her hospi-
body weight and fat content, elevated cortisol levels, inad-
talization for routine follow-up. She has been doing
equate vitamin D and calcium intake, and amenorrhea and
well and has since married. She is having regular peri-
hypoestrogenism. There are both decreased bone formation
ods and her BMI is 21. She and her husband are inter-
and increased bone resorption in patients with AN. It places
ested in getting pregnant.
these patients at an increased lifetime risk for fractures. Bone
loss may never recover completely even if weight is restored.
The degree of osteopenia depends on the age of onset and
Sexuality, Fertility, and Pregnancy duration of amenorrhea.
The etiology of bone loss in the patient with anorexia ner-
A concern for patients with EDs includes future fertility vosa is multifactorial. In addition to reduced estrogen and
given the suppression of the hypothalamic-pituitary-ovar- progesterone, excess cortisol levels and low levels of insu-
ian axis resulting in hypogonadotropic hypogonadism with lin growth factor (IGF-1), a correlate for bone formation,
amenorrhea (as discussed above). Importantly, reproductive are observed. While low estradiol levels contribute to bone
function is restored in approximately 85 percent of women loss, the severity of bone loss in women with AN is greater
following weight recovery [62], so nutritional support in a than in those with normal-weight hypothalamic amenorrhea,
treatment protocol is essential. Aside from these hormonal indicating that, in addition to estradiol deficiency, there are
disturbances, eating disorders affect patients’ sexuality other factors including nutritional deficiencies and hormonal
because of body image issues and low libido. Unexpected abnormalities that contribute to bone loss [65].
pregnancy can occur given irregular menses, as patients Dual-energy X-ray absorptiometry (DXA) screening is
may nevertheless ovulate either intermittently or regularly. important to assess bone mineral density (BMD). While no
Pregnancy itself is often a time when eating disorders come guidelines exist for screening, one option is to obtain a base-
to clinical attention given that weight and eating habits are line DXA measurement with periodic follow-up in females
closely monitored at this time. This may be an opportunity with persistently low weight. Assessment of other risk fac-
for recovery in some, but for other patients, pregnancy is a tors for osteopenia, such as reproductive and family history,
smoking, excessive alcohol use, and use of medications with BED often go undiagnosed and thus untreated. Without
affecting bone metabolism, should be assessed [32]. treatment, binge eating disorder is likely to last for many
Successful treatments to reverse bone loss in those years and to cause a significant impact on weight, health,
with anorexia nervosa are lacking. Treatment includes psychiatric symptoms, and ability to function. In some cases,
weight normalization and supplemental calcium and vita- serious effects of binge eating disorder on health could result
min D. Exercise regimens must be individualized; while in death from suicide or medical complications [1].
weight-bearing exercise is generally beneficial to the bone,
overexercise in these women can perpetuate weight loss
and amenorrhea, thereby leading to bone loss. In addition, Summary Points
women with severe bone loss are at risk for exercise-related
stress fractures. Weight gain and restoration of menstrual 1. The three most common eating disorders are anorexia
cycles can independently improve BMD, and they remain nervosa, bulimia nervosa, and binge eating disorder.
the primary goal [66]. Differentiating features include the patient’s body weight/
The data for use of hormones in FHA specifically sec- BMI at presentation, presence of binge eating, and com-
ondary to AN is not known, with some studies suggesting pensatory behaviors to prevent weight gain.
modest improvement in bone mineral density and others 2. Serious complications of eating disorders include cardiac
showing a marginal, if any, effect [67]. In other states of and hypothalamic-pituitary-ovarian axis dysregulation,
estrogen deficiency, estrogen replacement therapy prevents electrolyte disturbances, osteoporosis, and gastroparesis.
further bone loss. While oral contraceptives are widely pre- Patients with poor response to outpatient treatment,
scribed for this purpose in the clinical setting, the efficacy of unstable vital signs, evidence of arrhythmia, weight
combination estrogen-progestin in the treatment of osteope- <70% of ideal body weight, and/or concern for refeeding
nia of anorexia nervosa lacks sufficient evidence, with mul- syndrome should be immediately hospitalized.
tiple studies showing no effect on BMD [68]. There is some 3. Patients with eating disorders are best cared for by an
data that physiologic transdermal estrogen dosing, which interdisciplinary team consisting of a mental health pro-
is lower than the dosing of estrogen in contraceptive pills, vider, a dietitian, and a primary care provider. Cognitive
does improve BMD in adolescent girls and adults with AN behavioral therapy and treatment of any underlying mood
[69–71]. Unfortunately, physiologic dosing of estrogen does or substance use disorder is essential for success.
not protect women from pregnancy. In women with pro- 4. Severe energy restriction or expenditure can cause
longed amenorrhea who do not need pregnancy protection, hypothalamic-pituitary-ovarian axis dysfunction, leading
transdermal physiologic estrogen with cyclic micronized to the female athlete triad, a syndrome characterized by
progesterone is a reasonable option to negate the bone loss (1) low energy availability, (2) menstrual dysfunction,
associated with FHA. Women in need of contraception have and (3) low bone density.
two options: (1) insertion of a levonorgestrel IUD combined
with transdermal physiologic estrogen or (2) combined oral
contraceptive pills. Whether these measures translate into a Review Questions
decrease in fracture risk is unclear and more data are needed.
1. A 19-year-old woman is evaluated during an office visit.
She feels the need to diet to achieve a more appropriate
Prognosis and Relapse body weight and exercises daily. Dietary history suggests
that she consumes very little food, but at least twice per
Both anorexia and bulimia are marked by a prolonged course week she eats large amounts of high-calorie desserts over
to recovery. In AN, there is an almost 18-fold increase in mor- the course of 2 hours with compensatory purging behav-
tality including a high suicide rate. Recurrent bouts of AN ior by vomiting. Her menses are irregular with 40–60 days
occur in approximately 20 percent of individuals. Mitigating between cycles. Physical exam is notable for a BMI of 23
factors include onset of the disorder during adolescence and and parotid enlargement.
longer duration of follow-up [40]. The longer-term outcome Which of the following is the most likely diagnosis?
of BN is only slightly better compared to AN; however, the A. Anorexia nervosa
rate of mortality is low. As a general guideline, it appears that B. Bulimia nervosa
a third of BN patients fully recover, a third experience per- C. Binge eating disorder
sistent symptoms without meeting the threshold for a formal D. Female athlete triad
diagnosis, and a third transition into a chronic eating disor- The correct answer is B. Bulimia nervosa is char-
der [40]. Unlike individuals with AN and BN, who may pres- acterized by frequent episodes of binge eating fol-
ent to providers with more obvious clinical signs, individuals lowed by inappropriate compensatory behaviors such
as exercise or food restriction due to fear of weight SSRI to either topiramate or a stimulant for this indi-
gain. Physical examination may reveal erosion of den- cation. Additionally, these medications have greater
tal enamel, parotid gland swelling, and Russell sign negative side-effect profiles: topiramate can cause
(scarring or calluses on the dorsum of the hand). cognitive impairment and somnolence, whereas stim-
Anorexia nervosa is characterized by persistent caloric ulants can cause anorexia, gastrointestinal distress,
intake restriction leading to significantly low body headaches, and insomnia and have a potential for
weight and a distorted body image. Subtypes include abuse. Lastly, anti-obesity medications are not recom-
restricting type (no binge eating or purging behaviors) mended because of lack of efficacy, high remission
and binge eating/purging type (purging with or with- rates, and adverse effects [72].
out binging). The differentiating factor between buli- 3. A 28-year-old woman is evaluated for infertility. She
mia nervosa and the purging subtype of anorexia reports having had normal puberty but irregular menses
nervosa is BMI. The diagnostic criteria for anorexia since her teens. She has been unable to become pregnant
require that the patient be underweight, generally with since marrying 1 year ago despite regular intercourse.
a BMI less than 18.5. Menstrual irregularities occur in During the past year, she has menstruated three times. She
both anorexia nervosa and bulimia nervosa and are was a track athlete in high school and college and still
present in approximately one half to one third of enjoys distance running. On physical examination, blood
patients with bulimia. Although amenorrhea previ- pressure is 108/72 mm Hg, pulse rate is 52/min, and BMI
ously was a requirement for the diagnosis of anorexia is 16. There is no evidence of hirsutism or acne. Genital
nervosa, it has been removed from the diagnostic cri- exam is normal. Results of laboratory studies including a
teria in the DSM-5 [1]. prolactin, TSH, LH/FSH, and beta human chorionic
2. A 31-year-old female presents to establish care. On gonadotropin are normal. Which of the following is the
review of systems, she acknowledges that she sometimes most appropriate next step in management?
eats large amounts of food and is unable to stop until she A. Clomiphene
has consumed an entire family-size bag of candy or a bag B. Pelvic ultrasonography
of potato chips. She says that this eating behavior occurs C. Referral to a reproductive endocrinologist
almost daily when she is stressed. She denies compensa- D. Weight gain and decreased exercise
tory purging behaviors. She is upset about her weight and The correct answer is D. Functional hypothalamic
would like to lose 15 lbs. Physical exam is normal with amenorrhea (FHA) is a reversible cause of infertility,
the exception of BMI, which is 29. What is the most which resolves over a period of time after energy
appropriate treatment option for her condition? availability normalizes or any underlying stress con-
A. Cognitive behavioral therapy tributing to FHA resolves [73]. Given this patient’s
B. Family therapy low body mass index and irregular menses with nor-
C. Orlistat mal labs, it is reasonable to recommend weight gain
D. Atomoxetine to regain ovulatory function and allow for pregnancy
The correct answer is A. This patient has binge eat- before pursuing alternate diagnoses.
ing disorder (BED). Psychotherapy, particularly cog-
nitive behavioral therapy, is first-line treatment for
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Part VII
Selected Populations
Intimate Partner Violence and Sexual
Trauma 35
Raquel A. Buranosky and Jennifer S. McCall-Hosenfeld
I ntimate Partner Violence Domains,

Learning Objectives
Prevalence, and Epidemiology
1. Describe the components and dynamics of IPV,
including the factors that sustain as well as interrupt
Intimate partner violence (IPV) is a pervasive public health
the cycle of violence.
problem that affects the health of a significant proportion of
2. Identify the clinical signs of IPV and other forms of
women in the United States and internationally. IPV is
violence against women (VAW) including sexual
defined by the Centers for Disease Control and Prevention
violence and human trafficking.
(CDC) as physical violence, sexual, stalking, or psychologi-
3. Recognize the biopsychosocial, physical, and sex-
cal harm perpetrated by a current or former intimate partner
ual sequelae of VAW.
or spouse [1]. There is controversy regarding the distinction
4. Using evidence-based strategies perform a patient-
of abusive relationships from dysfunctional ones. However,
centered assessment for IPV.
the presence of coercion and control of one partner over
5. Summarize the primary provider’s role in interven-
another is a key feature in distinguishing the relationships
tion, treatment, and referral for IPV.
associated with the most severe harm [2].
6. Develop a strategy for trauma-informed care of
IPV encompasses many domains, and overlaps between
people suffering the sequelae of VAW, including
those domains are common. The most recent estimates of
PTSD.
IPV prevalence are reported in the National Intimate Partner
7. Outline the key components of safety planning for
Violence and Sexual Violence Survey (NISVS) [3–5]. This
survivors of IPV.
study described five separate domains of intimate partner
violence.
Physical violence are behaviors meant to induce bodily
harm, ranging from mild to severe. Examples of these behav-
iors include slapping and shoving to severe acts such as beat-
ing and choking. This form of violence affects approximately
32.4% of US women in their lifetimes, with 3.9% reporting
We recognize that persons of all genders may be victims as well as exposure in the past year [3].
perpetrators of IPV, sexual violence, and human trafficking. As this
chapter was specifically written for a women’s health text, and to avoid Sexual violence includes rape, being made to penetrate
pronoun confusion, we primarily use the female pronoun to describe someone else, sexual coercion, unwanted sexual contact, and
victims of VAW. As most perpetrators are male, we also use male pro- non-contact unwanted sexual experiences. Over 9% of US
nouns to indicate perpetrators. We encourage healthcare providers to be women report that they have been sexually victimized by an
alert to VAW in all healthcare encounters, with persons of all genders,
including gender-fluid and non-conforming individuals. intimate partner in their lifetimes and 0.6% have been sexu-
ally victimized in the past year [4].
Stalking is defined by the National Intimate Partner and
R. A. Buranosky Sexual Violence Survey (NISVS) as “a pattern of harassing or
University of Pittsburgh Medical Center, Department of Medicine, threatening tactics used by a perpetrator that is both unwanted
Pittsburgh, PA, USA and causes fear or safety concerns in the victim” [5].
J. S. McCall-Hosenfeld (*) Approximately 15.8% of US women report that they have
The Pennsylvania State University College of Medicine, experienced stalking in their lifetimes, with 4.2% of women
Department of Medicine, Hershey, PA, USA
reporting stalking victimization in the past year [3]. Women

538 R. A. Buranosky and J. S. McCall-Hosenfeld
reporting stalking note that it is severe enough to cause the by an intimate partner, 22.4% had their first experiences
victim to be extremely fearful, feeling that she, or someone between 11 and 17 years of age and nearly half (47.1%) had
close to her, is in danger of being harmed or killed [4]. their first experience between ages 18 and 24 [4]. This fact is
The NISVS defines the experience of physical violence, particularly salient in light of the 2015 Youth Risk Behavior
sexual violence, or stalking collectively as severe forms of Survey findings showing that among girls in grades 9–12,
IPV victimization. These severe forms of abuse from an inti- 11.7% had experienced physical dating violence and 15.6%
mate partner have been experienced by more than one in had experienced sexual dating violence within the past
three US women (35.6%) in their lifetimes [4]. 12 months [10]. Additionally, young people are more likely
Psychological aggression is defined through behaviors that to experience violence than older individuals. Numerous
fall under the following two domains: expressive aggression other individual characteristics are listed by the CDC, includ-
and coercive control. Expressive aggression includes behav- ing depression, heavy alcohol and drug use, anger and hostil-
iors that humiliate the victim often through name-calling and ity, unemployment, isolation, antisocial or borderline
insults. Coercive control is exerted through “behaviors that are personality traits, and a strong belief in traditional gender
intended to monitor and control or threaten an intimate part- roles (e.g., male dominance and aggression in relationships).
ner” [5]. According to the NISVS, almost half (47.1%) of all One of the strongest predictors of perpetration is the indi-
US women had experienced psychological aggression in their vidual being a victim themselves of physical or psychologi-
lifetimes, with 39.3% reporting expressive aggression and cal abuse [8].
39.7% reporting coercive control [3]. Approximately 14% of The association of race and ethnicity with IPV has been
US women reported that they had experienced psychological questioned. While it is important to remember that IPV is
aggression during the past year [4]. highly prevalent among women of all races and ethnicities,
Control of reproductive or sexual health was defined by epidemiologic studies have shown some racial and ethnic
the CDC in 2010 as a form of intimate partner abuse [4]. A disparities. Among US women, 56.6% of multiracial, 47.5%
man can exert this type of control over his female partner by of American Indian/Alaska Native, 45.1% of non-Hispanic
trying to get her pregnant by either refusing to wear a con- Black, 37.3% of non-Hispanic White, 34.4% of Hispanic,
dom or by not allowing her access to other forms of birth and 18.3% of Asian or Pacific Islander women reported any
control. Conversely, a female abuser can attempt to control lifetime contact of sexual violence, physical violence, or
her male partner by becoming pregnant without his consent, stalking by an intimate partner [3].
such as by falsely stating that she is on birth control when Relationship factors that are associated with higher lev-
she is not. An additional form of control of reproductive or els of IPV include relationships in which there is a high level
sexual health is the removal of a condom without a partner’s of conflict, or instability, such as that caused by divorce or
consent, a practice which can transform consensual sexual economic uncertainty [8].
activity into non-consensual sexual activity (known collo- Certain communities may have unique risk factors. For
quially as “stealthing”) [6]. example, rural women are exposed to IPV at levels that are at
least as high or higher than non-rural women [11, 12].
Moreover, rural women may be particularly vulnerable to
Risk Factors for IPV IPV due to limitations in health services, social services, lack
of transportation, or long distances to travel for services [12,
The CDC’s social–ecological model is a useful framework 13]. Finally, community norms in rural areas may affect
for examining risk factors, as well as preventative factors, for women’s perceptions of IPV as a health problem and fre-
being in an abusive relationship. This model considers risk quency of screening by primary providers [14], making it
and prevention in the following domains: individual, rela- less likely that women exposed to IPV come to medical
tionship, community, and societal [7, 8]. Although there are attention.
some identified risk factors for abuse victimization, it is Another community factor that affects IPV is poverty.
important for providers to be aware that IPV is prevalent in Poverty and IPV have a complex relationship, with sequenc-
all sectors of the population, and screening should be univer- ing of poverty and IPV exposure characterized as a “down-
sally applied, rather than applied only to those who are con- ward spiral” [15]. Partner violence often follows poverty, as
sidered by the provider to be at risk [9]. poor women may be financially dependent on an abusive
Of the individual factors that predispose to both intimate partner. However, IPV likely also contributes to poverty, as
partner violence and sexual violence victimization, one of abuse can contribute to employment instability [15], which
the most consistent is exposure to violence in youth. Among in turn can lead to greater dependence on an abusive
women who experienced rape, physical violence, or stalking partner.
35 Intimate Partner Violence and Sexual Trauma 539
Communities who are marginalized also have high rates Human Trafficking: Prevalence
of IPV. For example, IPV among sexual minorities should and Epidemiology
not be dismissed. Bisexual women are 1.8 times more likely
to report IPV compared to heterosexual women [16], and Human trafficking is defined as “the recruitment and move-
IPV prevalence is also higher among lesbian women comment of individuals—most often by force, coercion, or decep-
pared to heterosexual women, although this difference is not tion—for the purpose of exploitation” [20]. Among the
statistically significant. estimated 2.5 million persons who are subjected to human
Societal factors known to impact IPV risk including tra- trafficking, 43% are trafficked for purposes of commercial
ditional gender norms in which women are expected to be sexual exploitation and 32% are trafficked for participation in
submissive to men, or where men are considered the decision forced labor [21]. Individuals who are trafficked are very often
makers, and women are expected to remain at home and out subject to severe forms of physical, sexual, and emotional
of the workforce [8]. abuse. Human trafficking disproportionately affects women.
Women and girls make up 56% of persons trafficked for the
purposes of forced labor, and 98% of the population trafficked
for commercial sexual exploitation. Due to the covert nature of
Sexual Violence: Prevalence human trafficking, epidemiologic data on trafficked individu-
and Epidemiology als is scarce. However, the United States is one of the top 10
destinations for human trafficking internationally [22].
An estimated 19.1% of US women have been raped during
their lifetimes, with 36.3% of women reporting other forms
of sexual violence (being made to penetrate, sexual coer- Pathophysiology of IPV
cion, unwanted penetration, unwanted sexual contact (e.g.,
kissing or fondling).) In addition, 32.1% reported experi- The pathophysiology of IPV is related to control and fear. For
encing non- contact unwanted sexual experiences (e.g., a batterer, control is the goal of the abuse, and fear is the tool by
being flashed) [3]. which the abuser maintains control. Fear is always present in
Risk factors for sexual violence victimization are similar abusive relationships; thus, identifying fear in the relationship
to those for IPV. Youth is a consistent correlate of rape vic- can help to differentiate between relationships that are truly
timization. Of women experiencing completed rape, 79.6% abusive versus those that are dysfunctional [23]. There are two
were less than 25 years of age at the time of the first assault. well-established models depicting the dynamics of the abusive
Of these female victims, 29.9% were between 11 and intimate partner relationship: the “Cycle of Violence” [24] and
17 years of age at time of first rape and 12.3% were at or the “Power and Control Wheel” [23] (Fig. 35.1).
younger than 10 years of age [17].
As with other forms of IPV, vulnerable populations may
be at greater risk for sexual violence victimization perpe- Cycle of Violence
trated by an intimate partner. Globally, these factors include
being married or cohabitating, consuming alcohol or drugs, The “Cycle of Violence” is comprised of three phases as fol-
involvement in sex work, and poverty. Of note, women’s lows: (1) Tension Building, (2) Crisis/Violence, and (3)
education and economic empowerment reduce vulnerability Honeymoon/Apology. Useful examples of each phase are
to intimate partner sexual violence [18]. offered by www.shelterforhelpinemergency [24]. In the ten-
Campus sexual violence has gained increased media sion building stage, which usually lasts for weeks to months,
attention recently and deserves special attention. Efforts to stress builds and communication breaks down between part-
describe the frequency of sexual assault on college cam- ners. Verbal abuse and less severe violence may occur. Victims
puses have been limited by issues with accurate data collec- may sense increasing danger and may try to anticipate the fac-
tion and reporting. However, at least 28% of college campus tors that may precipitate more severe violence. During the cri-
women report at least one incident of sexual assault, defined sis/violence phase, usually lasting for 24–72 hours, violence
as sexualized touching, or attempted or completed penetra- escalates. Significant injuries, some of which may come to
tion [19]. Factors associated with increased risk for sexual medical attention, are most likely to occur during this phase,
assault among college students included sexual minority and the victim’s actions focus on surviving the abuse. The
status, difficulty paying for basic necessities, fraternity or honeymoon phase follows the crisis phase. The honeymoon
sorority membership, participation in casual sexual encoun- phase may last from days to months and is characterized by
ters, binge drinking, and experiencing sexual assault prior to the abuser apologizing, asking for forgiveness, promising it
college [19]. will never happen again, and displaying vulnerability.
POWER AND CONTROL WHEEL
VIOLENCE
al
ysic se
ph COERCION xu
al
AND THREATS: INTIMIDATION:
Making and/or carrying Making her afraid by
out threats to do using looks, actions,
something to hurt her. and gestures. Smashing
Threatening to leave her, things. Destroying her
commit suicide, or report property. Abusing pets.
her to welfare. Making Displaying weapons.
her drop charges.
Making her do illegal
things.
EMOTIONAL ABUSE:
MALE PRIVILEGE: Putting her down. Making her
Treating her like a servant: making feel bad about herself.
all the big decisions, acting like the Calling her names. Making her
"master of the castle." Being the think she’s crazy. Playing mind
one to define men's and women's games. Humiliating her.
roles. POWER Making her feel guilty.
AND
ECONOMIC ABUSE: CONTROL ISOLATION:
Preventing her from getting Controlling what she does,
or keeping a job. Making her who she sees and talks to,
ask for money. Giving her an what she reads, and where
allowance. Taking her money. she goes. Limiting her
Not letting her know about or outside involvement.
have access to family income. Using jealously to justify
actions.
USING CHILDREN: MINIMIZING, DENYING,

Making her feel guilty AND BLAMING:
about the children. Using Making light of the abuse
the children to relay and not taking her concerns
messages. Using about it seriously. Saying
visitation to harass her. the abuse didn't happen.
Threatening to take the Shifting responsibility for
children away. abusive behavior. Saying
she caused it.
ph l
ysi ua
cal
sex
VIOLENCE
Fig. 35.1 Power and Control Wheel [23, 25]. Produced and distributed www.theduluthmodel.org/, 202 East Superior Street, Duluth, MN,
by National Center on Domestic and Sexual Violence. www.ncdsv.org, 55802. www.theduluthmodel.org)
Austin, TX. (Adapted from Domestic Abuse Intervention Project,
The cycle of violence model has several important caveats

to consider. First, over time the honeymoon period becomes Example: Mary’s husband comes home to their family
shorter and less frequent and may disappear altogether. seated at the table, trying to be on their best behavior
Despite this, fear keeps the victim in the cycle. Second, (Tension Building), until a small disagreement arises
breaking the cycle can have repercussions. When a woman between the children. The husband throws his plate
leaves a male perpetrator, there can be up to a fivefold across the table in anger and it hits the wall behind his
increase in the risk of homicide, which increases to a n inefold wife’s head, missing her by inches (Violence). He
increase in risk of homicide when the batterer is extremely exclaims, “I work hard all day and all you have to do
controlling during the relationship [26].
Stress leads to impaired immunity, autonomic dysfunction,

is keep things in order here.” The children run to their inflammatory changes, and neurochemical imbalances,
rooms. He later apologizes, “You know my job is which manifest in physical and mental health problems [30].
stressful. I need things to be calm here. If you could do Conditions such as chronic headaches, chronic abdominal
a better job of managing these kids, I wouldn’t have to pain, and chronic pelvic pain are common among IPV survi-
get so angry.” The children return to the table, as the vors [31, 32] as are mental health conditions such as anxiety,
tension is reduced (Honeymoon). depression, and post-traumatic stress disorder (PTSD). Signs
of acceleration of abuse can either present as exacerbations
of these chronic diseases or with acute symptoms such as
Power and Control Wheel diarrhea, dizziness, or insomnia [33]. When stress-related
complaints are reported, assessing for either ongoing abuse
The second model, the Power and Control Wheel, was devel- or past abuse is critical.
oped to show types of abuse and the patterns that “are used
by a batterer to establish and maintain control over his part- dverse Health Conditions
A
ner” [23]. As noted previously, violent relationships are sus- Women who survive IPV are more likely to have poorer
tained by power and control. In the Power and Control Wheel physical health status compared to non-abused women. In
model, fear of physical or sexual violence are the primary studies that assess overall physical health with standardized
agents used to maintain the batterer’s control. However, instruments, women with a lifetime history of IPV show sub-
more subtle behaviors such as undermining her self-esteem, stantial decrements in overall health regardless of whether
preventing her from getting a job, threatening to take away they were exposed to physical, sexual, or psychological
her kids, and isolating her from friends are also used to abuse. Women with a history of IPV have been shown to
maintain power and control. All these behaviors are com- have greater frequency of numerous adverse health condi-
bined in different ways to form patterns of abuse. tions ranging from cardiovascular disease to diabetes and
Because control is at the core of the batterer’s behaviors, asthma [34–39].
occurrences that decrease the batterer’s control act as trig-
gers for escalation of violence. Examples of this include a Mental Health
victim gaining financial independence through educational Depression, anxiety, somatization disorders, and eating dis-
attainment or the batterer sensing a loss of control as his vic- orders are highly prevalent among women who survive IPV
tim is perceived to place the needs of a newborn child over [40–43]. A common misconception is that PTSD is a disease
those of the batterer [26]. more commonly experienced by men; however, women are
The Power and Control Wheel is not an “all-inclusive” list approximately twice as likely to experience PTSD compared
of abusive behaviors. Certain populations experience abuse to men, due to a combination of different biological profiles
unique to their status. Among sexual minority women, a and differing trauma burden [44]. Thus, clinicians should be
powerful source of control is the threat of the abuser “out- particularly alert to symptoms of PTSD among survivors of
ing” the partner, which can bring negative social and eco- IPV [45]. Although the rate of PTSD among IPV survivors
nomic consequences. Other issues affecting sexual minorities has been difficult to characterize, it is estimated that approxi-
may include legal access to children and the dependence on mately 64% of women who survive IPV met the criteria for
a tight-knit community in which avoidance of the abuser is PTSD [46]. Moreover, PTSD in IPV survivors is often
not realistic [27]. People with disabilities also experience comorbid with other mental health disorders such as depres-
abusive behaviors unique to their situations, including sion and other anxiety disorders [47, 48].
neglect in daily care, withholding medication or over-
medicating, and control of access to healthcare professionals dverse Health Behaviors
A
or other services [28]. Adverse health behaviors such as substance abuse, obesity,
and noncompliance are elevated in survivors of IPV. In one
clinical sample, women who neither smoked nor engaged in
Clinical Clues problem drinking had a 10% probability of IPV in the pre-
ceding 12 months. In contrast, if both smoking and problem
Stress drinking were present, the risk of 12-month IPV almost tri-
Providers who are assessing patients for signs of abuse pled to 27% [49]. The association between IPV and sexual
should be alert to assault-related injuries, unusual patterns of violence and alcohol and other drugs of abuse is complex.
injury, and injury that does not match the stated mechanism Use of drugs or alcohol can create vulnerabilities which pre-
[29]. In addition to these clinical clues from direct assault, dispose women to assault, but also be used as a coping mech-
women will often present with issues resulting from stress. anism to address the adverse effects of assault and trauma
[50]. Women with a lifetime history of IPV were also more Academic abuse may be identified as behaviors that can
likely to be identified as obese by a healthcare professional reduce the potential for independence through success.
[51] suggesting a relationship between IPV and adverse Interfering with studying either through guilt (“if you loved
dietary and exercise patterns. Additionally, women exposed me, you wouldn’t study so much”), peer pressure (making
to IPV have been shown to be less likely to attend regular fun of studying) or through direct interference (frequent texts
preventive healthcare appointments [35]. One explanation or calls that deliberately interfere with study schedules) may
for this may be due to partner interference in healthcare. In impact academic performance. An abuser may take all the
one study [52], women who reported IPV were also more same classes as his partner as means of monitoring her
than seven times likely to report that their partner had inter- behaviors and interaction [60]. Some abusers harass their
fered with their healthcare, suggesting that missed clinic victims at work, making the victim an undesirable employee.
appointments or “noncompliance” may be a manifestation of Multiple job changes and lack of career advancement can
partner control tactics. result [60].
exual and Reproductive Health

S Clues to Human Trafficking
Numerous adverse reproductive health consequences follow Identification of victims of human trafficking in healthcare
IPV. Women who survive IPV are more likely to report dys- settings is particularly complicated. Human trafficking is
pareunia [53] and less likely to use their preferred form of defined by the United Nations as the “recruitment, transpor-
contraception [54]. Thus, it is not surprising that these tation, transfer, harboring or receipt of persons, by means of
women have increased risk of sexually transmitted infections threat or…coercion, …abduction, fraud, of deception, of the
(STIs), [53] cervical cancer [55], unintended pregnancy [56], abuse of power…for the purposes of exploitation” [61].
and abortion [53]. IPV is associated with reproductive Many victims of trafficking are forced to be involved in ille-
coercion and birth control sabotage, which in turn is associ- gal activities such as sex work or drug use, and some are
ated with unintended pregnancy [57]. undocumented or using false documents [62]. Thus, traf-
ficked individuals may be less likely to come to medical
attention, due to concerns regarding criminal prosecution or
Social History Clues legal status. Traffickers are likely to accompany their victims
at all times, including to healthcare appointments. Thus, it
Partner Characteristics can be challenging for healthcare providers to determine
There are partner characteristics and social behaviors that whether the trafficker is a sex partner, a parent, or an
have been linked to an increase in risk of a couple’s relation- employer [63, 64].
ship being or becoming an abusive one. Healthcare providers Common red flags for trafficked individuals presenting to
should be alert to these cues, as their patients often do not healthcare clinics include the following [65]:
identify them as abusive.
A patient may reveal that her partner has a charismatic 1. Chronic untreated medical issues
personality but is living a “double life” in which the abuser is 2. Tattoos indicating tagging or possession
kind in public and cruel in private. Because of this, when 3. Silence, difficulty speaking, or making eye contact
abusive behavior does occur, people outside the relationship 4. Mental health issues
may find it difficult to believe the woman, causing her to 5. Untreated injuries
doubt her own intuition. Abusers minimize the impact they 6. Multiple STIs or abortions
have on their partners and may exploit their partners as prop- 7. Fear or mistrust in the healthcare system
erty or sexual objects. Abusers blame the victim or external 8. Lack of knowledge of local language
factors, such as illicit substance abuse, stress due to jobs or
family finances. It is important for the provider to identify
these characteristics and to understand the potential that Evaluation and Diagnostic Strategy
these are signs of an abusive partner [8, 58, 59].
In technological abuse, the batterer controls cell phone Trauma-Informed Care
and online use. The abuser may restrict access to technology
or monitor calls, texts, and emails. An abuser may use GPS Trauma-informed healthcare service is defined as care which
to monitor location and track his partner. Cyberbullying, a is “influenced by an understanding of the impact of interper-
practice in which abusers use social media to mar personal sonal violence and victimization on an individual’s life and
and professional reputations, is a common and effective development” [66]. Unfortunately, trauma is pervasive in our
means of control [60]. society. Healthcare professionals must recognize that all
patients, as well as colleagues and co-workers, may be survi- healthcare. The CUES intervention includes Confidentiality,
vors of trauma. Providers practicing trauma-informed care Universal Education, Empowerment, and Support (www.
recognize that trauma survivors need support and understand- ipvhealth.org). This approach acknowledges that women do
ing from those around them. Healthcare providers are also not always disclose IPV to healthcare providers, but that
exposed to vicarious trauma, which is the emotional trauma there is value in making the inquiry and offering resources
that can result from working with trauma victims [27, 67]. regardless of whether the patient makes a disclosure. CUES
The Substance Abuse and Mental Health Services assists healthcare providers with this process [27].
Administration (SAMHSA) offers guidelines to organizations
on how to adopt a trauma-informed approach. In this approach,
healthcare systems and providers do the following [68]. Case with CUES Intervention
1. Realize the widespread impact of trauma and understand

potential paths for recovery.
2. Recognize the signs and symptoms of trauma in clients, Shu is a 24-year-old undergraduate student who comes
families, staff, and others involved with the system. in to see you for an urgent visit. She has recurrent diar-
3. Respond by fully integrating knowledge about trauma rhea. A chart review reveals that she has had a com-
into policies, procedures, and practices. prehensive, but negative work up by her
4. Seek to actively resist re-traumatization. gastroenterologist. She notes that it seems to happen
mostly towards the end of the week. She thinks it must
Thus, providers and healthcare systems are encouraged to be related to fatigue, as she is always more tired by
adopt universal screening, identification, and response to Friday than on Monday.
IPV while considering a trauma-informed approach.
• MD: Sometimes symptoms such as diarrhea are
signs of stress, good or bad. What is going on in
Screening for IPV: Guidelines your life over the past couple of months that may be
causing stress for you?
Recognizing the adverse health effects associated with IPV, • Shu: Well, I’ve been doing a lot of traveling because
governmental and professional organizations have called for I spend most weekends with my boyfriend who lives
better identification and response to IPV in healthcare set- in Cleveland. Also, I am having trouble in choosing
tings. These calls date back to 1992, when the American a graduate program. My boyfriend really wants me
Medical Association (AMA) recommended routine screen- to move to Cleveland, but the program here is better
ing for IPV among all women patients [29]. Despite this, for me. It is causing a lot of tension between us.
routine screening and counseling for IPV was not codified in • MD: Can you see a pattern between the diarrhea
US policy until 2011, when the Institute of Medicine (IOM) and weekends with him?
identified IPV screening and intervention as a routine pre- • Shu: Yes! I actually only get this when I am getting
ventive healthcare service for women [69]. Subsequently, ready to see him.
these guidelines were adopted as part of comprehensive pre-
ventive women’s healthcare services under the Affordable
Care Act, and in 2013, the United States Preventive Services
Task Force (USPSTF) recommended routine screening and Confidentiality
follow-up for all women of reproductive age (18–46) for life- The first step is to ensure Confidentiality. In this step, the
time exposure to IPV [9]. provider ensures that the patient is always seen alone.
Screening recommendations recognize both ongoing and The provider openly informs the patient that what she
past violence. Asking patients routinely about IPV increases discloses will be kept confidential. However, the provider
awareness, decreases isolation, and increases a patient’s trust must also note the limits of confidentiality. For example,
in the healthcare system. Screening, regardless of whether disclosure of risk of self-harm or harm to others, espe-
disclosure occurs, can help women who experience abuse. cially children, is likely to require reporting to authori-
Women who have discussed abuse with a healthcare provider ties. Providers need to be familiar with the mandated
are more likely to plan for their safety and more likely to exit reporting requirements within their state and inform
an abusive relationship [70, 71]. patients prior to inquiry of the legal or ethical bounds that
To assist providers in implementing screening guidelines, inform these discussions. For more information about
Futures Without Violence, a non-profit organization, created specifics of mandatory reporting requirements, Futures
an intervention to outline IPV screening and response in without Violence offers a compendium of reporting
requirements by state https://www.futureswithoutvio-

lence.org/compendium-of-state-statutes-and-policies- make sure that I ask all my patients about their rela-
on-domestic-violence-and-health-care/ (2013) [72]. tionships, and specifically ask about domestic vio-
lence. I like to provide all my patients with
information that they can take away which helps
them understand healthy relationships. Does this
• MD: Before we go any further, I want to let you
sound like something I can share with you?
know that anything you tell me will be kept strictly
• Shu: Okay. I understand.
confidential. This conversation is just between you
and me. However, please be aware that there may
be limits to this confidentiality. For example, if you
give me credible evidence that you are going to Empowerment
harm yourself or another person, I may be required The goal of empowerment is to allow the woman to be the
to report this to the authorities. If I must do that, I agent of change, giving her the tools to have control over her
can make sure that you are in the room and present decisions. This restores control to the patient and reverses
to hear what is being said. Does that make sense? one of the cornerstones of IPV, in which the abuser assumes
Do you have any questions before we go forward? control of her behaviors and decisions. Providers empower
• Shu: Yes, that makes sense. women through respectful communication and through
affirming their patients’ ability to make sound decisions.
Keys to empowering patients are the precepts of validation,
empathy, respect for autonomy, and education about the
Universal Education health impact of IPV [74, 75].
The next step is Universal Education. Providers should start
by normalizing the inquiry with a framing statement, so that Validation
patients understand why they are being screened and do not To validate the patient’s experiences, the healthcare provider
feel singled out or stigmatized [73]. Framing statements pro- should assure the patient that the abusive behavior is a prob-
vide education about violence. For example, the American lem that the patient did not create nor is it a problem that they
College of Obstetricians and Gynecologists recommends the deserve. IPV is sustained when the perpetrator places the
following: “We’ve started talking to all of our patients about blame on the woman, indicating that her behaviors and
safe and healthy relationships because it can have such a actions are causal for the abuse suffered. After living under
large impact on your health” [73]. these often-subtle messages, women may internalize this
Futures without Violence recommends having pocket blame, accepting some of the responsibility for the presence
cards on hand and using these to provide universal education of the abuse. By dispelling these myths, the provider empow-
about healthy and unhealthy relationships. These cards, ers the patient [74, 76].
available at www.ipv.org, outline the difference between
healthy and unhealthy relationships, how unhealthy relation- Empathy
ships may affect health, and steps that a victim can take to Women value an empathetic approach to screening, in which
assess her risks as well as resources she can utilize to improve the provider listens attentively, with compassion and kind-
her safety. ness. Women often feel ashamed or embarrassed to admit
For providers, the pocket cards provide information on that they are in an abusive relationship to a healthcare pro-
beginning a discussion about healthy and safe relationships vider. Empathy reduces this barrier to disclosure [74–76].
and exploring how relationships can adversely affect a
patient’s health. Futures Without Violence suggests giving Respect for Autonomy
two cards to each patient, so that the information can be In offering support, the clinician must respect the patient’s
shared with friends and family who may need it [27]. decisions, even if the provider does not understand or agree
with these decisions. The patient often knows what options
will be the safest and most appropriate for her [77]. For
• MD: I have found that many women in my practice example, it may be important for the provider to recognize
struggle with significant stressors in their relation- that in marginalized or vulnerable communities, the patient
ship. Some of my patients are in relationships that may prefer counseling that focuses on harm reduction rather
are controlling and even violent. Therefore, I now than separation from a partner, which may remove her con-
tact with her community [27].
Health Impact Although the discussion does not require standardized

Providers must also assess the impact of the IPV (past or language, if scripted screening questions are preferred,
present) on the patient’s health [78]. An encounter with a numerous instruments exist which are recommended by the
healthcare provider may be the first time that a patient real- USPSTF as valid and reliable screening tools for domestic
izes that some of her health issues may be attributable to violence. These include the following:
IPV. Education about the health impact of IPV also helps
patients to understand that IPV is appropriately positioned in 1. HARK: Humiliate-Afraid-Rape-Kick HITS [79].
the healthcare system (in addition to, or instead of the crimi- 2. HITS: Hurt, Insult, Threaten, Scream [80].
nal justice system) and that a healthcare provider may be an 3. OVAT: Ongoing Violence Assessment Tool [81].
important ally as both the patient and the provider are work-
ing to improve her health. Each of these is brief and has a high degree of sensitivity
and specificity, making them useful tools for primary care.
Additionally, screening can be accomplished via electronic
• MD: Stress is common during transitions, espe- media, and in many cases, this is preferred over face-to-face
cially for couples. I’d like to explore this further. I screening [82].
hear that there is tension between you, and I ask all
women this question in this situation. Has it gotten Support
to a point now that you feel that your partner is try- This final step in CUES is to provide support. Key elements of
ing to control you in a way that makes you feel support include referral to specialists and domestic violence
afraid of him? Has he done anything to make you advocacy services. Patients should be aware that the National
feel threatened either physically or emotionally? Domestic Violence Hotline [83] (1-800-799-SAFE, www.the-
• Shu: My diarrhea has just been getting worse and hotline.org) is available 24/7, across the United States, and can
worse. He has become very controlling where he connect patients with counseling and local services at any
won’t let me see my friends when he comes to visit. time. Healthcare providers should be familiar with their local
When I cancelled a trip to see him to study for a resources and know how to refer patients if needed.
test, he showed up at my apartment banging on the In addition to referring her to services, the provider should
door and yelling, until my friends threatened to call make a follow-up appointment with the patient in the medi-
the police if he didn’t leave. I guess I am afraid of cal office [78]. Women may feel safer coming to a medical
him. He hasn’t threatened to hurt me but I am just appointment versus structured domestic violence services,
not sure what he is capable of. He is acting so crazy. and in many locations, domestic violence service providers
I am afraid to stay here for graduate school as it may be able to meet the patient at her medical appointment.
will upset him, but I am afraid to live with him by
myself in Cleveland. Safety Assessment
A critical aspect of support is exploring the patient’s imme-
diate safety, including the pattern and severity of abuse, and
the safety of any children, or other household members [78].
Examples of Provider Responses If she has disclosed abuse, either the patient may feel safe to
• Validate: I am sorry this is happening to you and want you leave the office or she may not feel safe going home from the
to know that this abusive behavior is not your fault. No office. Extensive safety planning is outside the purview of
one deserves to be hurt or to feel afraid of his or her most primary care providers; however, it is reasonable to
partner. advise women of the tenets of basic safety planning. The
• Support: We will work on this together and I want you to basic components of safety planning are listed in Fig. 35.2.
know that whatever decisions you make, I will be here to Patients should know that if their safety is at immediate risk,
support you. I have information and resources to share they should call 911 or their local emergency response num-
with you. ber. Escalation in violence, use of a weapon, and threats of
• Respect: You have been living with this situation for a suicide or homicide are all indicators that the patient’s imme-
while and before I offer my thoughts, what is it that my diate safety is threatened. Having an emergency kit available
staff or I can do to help you today with this situation? including such items as money, keys, medicines, and legal
• Health Impact: All types of stress can contribute to health documentation may be useful to review with patients.
problems, including diarrhea. Do you think that this is Likewise, patients should be directly asked if they are able to
something that is happening to you? safely go home [78].
Fig. 35.2 Planning ahead for safety. (Reprinted with permission from Chang [84])
Part of safety planning is knowing what the risk factors immigrants, homeless, adolescents, and members of the
are for severe forms of violence. Risk factors that are associ- LGBTQI community.
ated with femicide [26] include the following: On-site counseling from a social worker or other trained
provider can provide immediate safety planning. When
• Abuser’s lack of employment appropriate, hospital admission can be offered to address
• Access to a firearm immediate health issues as well as to protect the patient and
• Use of illicit drugs to provide for more intensive safety planning by the inpatient
• Recent separation social work team or community resource team. In all cases,
• Having ever left or asked the partner to leave the trained professionals who can help the patient determine the
relationship safest course of immediate action, given the individual risks
• Living with a non-biologic child of the abuser and benefits of her decisions, should conduct detailed safety
• Expression of highly controlling behaviors planning and decision making with the patient. For example,
• Prior threats with a weapon Protection From Abuse orders may reduce harm in some
• Prior threats to kill his partner cases; however, at other times, these may only exacerbate the
problem without providing the expected protection [85].
Among these risks, one most important for providers to
understand is that separation leads to an increased risk of
homicide, especially when the abuser has shown controlling Feels “Unsafe” Example
behaviors. For this reason, if the woman is considering leav- • Shu: I really don’t feel safe to go back to my dorm
ing her partner, it is important that the physician tell her that today and my parents live in Cleveland. I am not
she should not confront her partner with this decision. As sure where he is or what he will do since I haven’t
abusers may retaliate, patients should be advised to leave spoken to him since this weekend when my friends
secretly and notify the abuser later, when all loved ones are chased him away. That is probably why the diar-
in safe places [26]. Trained counselors are best qualified to rhea has not gone away as it usually does on
construct the safest leaving plan for the patient and her fam- Mondays!
ily. Thus, establishing and utilizing relationships with • MD: Since you don’t feel safe to return home today,
domestic violence advocates are critical in helping patients what options, if any, have you thought about as next
to plan for their safety [85]. steps? (Further prompts may depend on her
answer). Here are a few things that I can do that
have been helpful for my other patients who have
• MD: “Now that you have brought up this fear, do had similar problems.
you feel that you would be safe to be at home or do
you think that he may do something harmful to you
in the next few weeks?”
2. What to do if she discloses IPV and IS safe to return
home
There are many reasons women may not wish to leave
1. What to do if she discloses IPV and is NOT safe to their partners. They may be economically dependent, they
return home may worry about the safety of children or pets, or they may
There are many options to offer once there is a disclosure. love their partners [86]. Providers should respect women’s
Asking what she has thought of or tried in the past empowers decisions about leaving or staying and should not look to
the patient to offer her own solution before listening to the IPV disclosure as the primary goal. Leaving is an option, but
provider’s options. A warm referral, which involves contact- doing so in the safest way possible is the ultimate goal.
ing an advocate or domestic violence specialist while the Additionally, IPV victims may define “safe” differently than
patient is in the office with you, ensures that the handoff is her healthcare providers. Women may prioritize immediate
made. Many women do not have private access to a phone, so safety, such as “we just got paid and he never hurts me at this
simply offering her the use of the phone in the office can be time of the month” or “my grandson is visiting for the week-
lifesaving. Many shelters provide not only emergency hous- end and he is not abusive when he is around” [87].
ing but also offer free legal advocacy, housing, job finding, Providers should ask the patient if she has thought about
support groups, and individual counseling. The National what she would do if her situation were to become unsafe on
Domestic Violence Hotline, 1-800-799-SAFE [83] is avail- her returning home. Written materials outlining safety plan-
able 24/7, has interpreters for most languages, and under- ning should be reviewed with the patient. She should only
stands the unique needs of subpopulations such as take these home if her abuser will not find them, as this help-
seeking behavior may escalate abuse. Basic safety planning

can be reviewed (Fig. 35.2). She should be encouraged to available if this ever happens to you or someone
trust her fear and to act accordingly. Close follow-up should you know. No one deserves to be hurt or afraid of
be planned, with an open invitation for return calls or visits his or her partner. In our practice, we like to pro-
for further discussion or for access to immediate resources vide all our patients with information about where
such as the phone, staff, or resource materials [88]. to go in the case of abuse or violence. [Provide a
safety card from www.ipvhealth.org, local resources,
and/or referral to the National Domestic Violence
Hotline.] Because domestic violence is common
Feels “Safe” Example
and we want to get the word out, we encourage all
• Shu: No, I feel safe to go home. I have good support
our patients to take two of these cards, in case you
in my friends, and if I don’t make a decision to stay
discover that a friend or a loved one may need sup-
here for school, he should be ok. He is also away for
port from domestic violence services.
the next few weeks with his family and I have told
his parents what he did. They want to talk with him
to see if they can help him with our situation.
4. What not to do
• MD: Well, I can’t tell you for sure what may happen
Many providers want to know “what NOT to do” in IPV
in the future with him and your relationship, but I
discussions. Potentially harmful medical interventions
will advise you to always trust your fear. When a
include pressuring a patient to leave, contacting legal author-
partner is concerned that he is losing control, he
ities, or obtaining a restraining order or protection from
may increase abuse in an attempt to regain that
abuse order (PFA) without the patient’s permission, as these
control. So, if you get to the point of making a sepa-
might not be the safest options for the individual woman at
rating decision, you will want to do it in a safe way.
that time in her life. Further, exposing the patient’s help-
My office will always be here as a source of support
seeking behaviors to an abusive partner could lead to an
and information, whenever you need it.
escalation of abuse. Providers should refrain from inadver-
tently showing frustration or anger toward the patient, asking
what she did to bring about the abuse or asking why she has
3. What to do if she does not disclose abuse not left the partner. These behaviors and questions suggest
In many ways, IPV “treatment” in the healthcare setting that the presence and persistence of the abuse is her fault
does not fit the traditional medical model of disease. The [88–91].
goal of screening and intervention for IPV is not to get a
disclosure but to build awareness and to provide resources Special Consideration: Forensic Sexual Exam
to help patients achieve safety and independence [74, 88]. If the patient reports to you that she has been a victim of
Women have reported that provider screening and educa- sexual assault, she should be offered referral to a facility
tion about IPV is an effective intervention, even if she says that offers forensic sexual exam. Forensic sexual assault
“no,” as it offers information and a safe place for follow-up examiners (Sexual Assault Nurse Examiners, or SANEs and
if she does need further support [88]. The patient may not Sexual Assault Forensic Examiners, or SAFEs), are health-
be ready to disclose for several reasons including embar- care professionals who are specially trained to guide sexual
rassment, denial, fear of repercussions from her abuser, assault survivors through the healthcare system. They can
fear of family separation, and fear of police involvement. also help sexual assault providers obtain advocacy and legal
Repeat screening has been shown to increase the rate of services as requested or required by the patient [92].
disclosure [85, 88]. Moreover, SANEs and SAFEs are specially trained in foren-
sic evidentiary collection as part of post-assault care, espe-
cially within 5 days of the rape. Sexual assault evidence kits
Does Not Disclose Example collected by a trained forensic examiner are more likely to
• Shu: I understand what you are saying, and be complete, produce higher quality evidence, and have
although I understand that my relationship may not fewer mistakes that can adversely affect prosecution of a
be in a good place, I don’t feel like I am being con- sexual assault case [93, 94]. Medical forensic evidence col-
trolled and I am not really scared of him. lected by the sexual assault nurse examiner has been shown
• MD: I’m glad that nothing like this is happening to to improve rates of successful prosecution of sexual assaults
you. However, IPV is common in women’s lives, [95]. Rape hotlines can identify which hospitals participate
including my own patients. There are good resources in the SANE program and link patients with legal and medi-
cal advocates.
Documentation separate problem in Assessment and Plan to limit the pos-

Documentation of IPV in the medical record may be par- sibility that the patient’s insurance is billed as “adult mal-
ticularly worrisome to providers. There are pros and cons to treatment/physical abuse” or similar billable labels.
documentation that should be reviewed with the patient [88,
96]. The healthcare record can be a powerful tool in legal
cases against abusers. Many providers may not realize the Special Consideration: Caring for Victims of Trafficking
importance of documentation for patients seeking protec- Individuals who are trafficked and present to the healthcare
tion and may even be concerned that documentation will system deserve special consideration. Although a detailed
increase the probability that they will be involved in litiga- understanding of the care of trafficked individuals is outside
tion. However, good documentation may reduce the likeli- the purview of this chapter, there are many principles in car-
hood that providers be required to testify in court cases. A ing for victims of trafficking that can reasonably be per-
factual medical record can help the patient to obtain a formed within the healthcare system. For more detail, please
Protection from Abuse (PFA) order, help the patient to refer to the World Health Organization (WHO) Ethical and
establish legal safety parameters in child custody cases, and Safety Recommendations for Interviewing Trafficked
help to make her eligible for special exceptions for health- Women https://www.unodc.org/documents/human-traffick-
care insurance [89]. ing/Toolkit-files/08-58296_tool_6-12.pdf [98]. Key points
Providers have appropriate concerns that the information of these guidelines include (but are not limited to) the fol-
in the medical record could cause the patient harm if found lowing (edited for space):
by her abuser. The abuser may have access to the records,
request “proxy” status on electronic medical records, or be 1. Treat all contact with trafficked persons as a potential
listed as an emergency contact in the healthcare records. The step toward improving their health
health insurance policy may be in the abuser’s name, in 2. Prioritize the safety of trafficked persons, self, and staff
which case the abuser could receive “explanations of bene- by assessing risks
fits” and bills that list billing codes. These potential situa- 3. Provide respectful, equitable, non-discriminatory care
tions need to be discussed with the patient prior to 4. Provide referral information to shelter, legal, counsel-
documentation and billing [97]. ing, and advocacy services
Providers’ documentation is valuable if it is accurate and 5. Collaborate care with ancillary services and referral
factual as it is only admissible in court if it is not considered services
“hearsay.” The “hearsay rule” prohibits out-of-court state- 6. Ensure privacy and confidentiality in the healthcare
ments with a few exceptions; one of which is a patient’s encounter
medical record. Admissible items from the provider as a 7. Provide information in a way that each patient can
“medical expert” include the following [88]: understand
8. Obtain voluntary, informed consent from patients
1. HPI: Providers should put in quotes what the patient 9. Respect the rights, choices, and dignity of each individual
states, including the batterer’s name if used. These are 10. Avoid calling authorities, unless the patient has given
called “excited utterances,” which are statements made in consent to do so
states of agitation or excitement that are too spontaneous
to be prefabricated, and thus are considered credible for
use in court. IPV Course Over Time
2. Physical Exam: Documentation of injuries should be
recorded by photographs, drawings, or detailed descrip- Although physical and sexual violence are usually preceded
tions. Optimally, photographs should be taken in close by more subtle controlling behaviors, this trajectory may not
range to show details of the injury as well as from a dis- be linear, and more severe harm can occur without warning
tance to show the location on her body. The distant photo behaviors [88]. IPV exposure is not a state but may change
must include her face to identify that the injury is hers. over time. Even when an abusive relationship is terminated,
Knowledge of local protocols and rules for photographic women remain at high risk for victimization by a subsequent
documentation is important. Description of her demeanor partner, as well as the ex-partner [99]. Among women with
is helpful as well and is admissible as part of a medical severe IPV exposure, 39% of women were re-victimized by
exam. their index partner within the following year, and 16% were
3. Assessment/Plan: If possible, link the abuse to a medical re-victimized by a different partner [100]. However, it is
issue to allow admittance as “medical expert witness.” important to recognize that IPV cessation is possible. In one
Document the discussion of the abuse and the resources study, approximately half of all women who reported expo-
offered to patient as part of the plan. Avoid listing IPV as sure to IPV at baseline did not report IPV exposure during
the following year [101]. The properties of IPV may be to leave safely. Providers can participate in safety planning
important in determining whether IPV persists. Women by providing basic safety tips (having an emergency bag on
exposed to psychological IPV alone were more likely to hand), assessing for recent red flags (escalation of violence,
remain in an abusive relationship compared to those exposed presence of firearms), and giving resources for additional
to both physical and psychological IPV [102]. Thus, investi- assistance by trained counselors (social work, hotline coun-
gating for IPV at periodic encounters, providing universal selors, in-person shelter counselors, some therapists.).
education and resources remain critical throughout women’s
lives.
Shu returns to your clinic 6 months later to fill out a
health form prior to graduate school. She reports that
Summary Points she broke up with her boyfriend and is not currently in
a relationship. Prior to breaking up, she contacted
1. Intimate partner violence is a pattern of coercive and/or 1-800-799-SAFE and was referred to a counselor at
forceful behaviors in which one partner controls another her local domestic violence shelter. She reports that
without regard to their health, safety, or human rights. It she worked with the counselor a few times, and eventu-
is sustained by fear and control. ally made the decision to pursue graduate school in a
2. Clinical signs of IPV and other forms of violence against different city. After breaking up with her partner, her
women (such as sexual violence, reproductive coercion, diarrhea improved. She states she feels prepared to
and human trafficking) include physical injury, signs of enter a new chapter in her life.
sexual trauma, chronic physical or mental illness, adverse
health behaviors, partner’s control over access to health-
care, and problems at work or school.
3. Intimate partner violence is multidimensional and includes Review Questions
physical violence, sexual violence, stalking, and psycho-
logical aggression. Sequelae that sustain intimate partner 1. You have been seeing Sidney in your primary care office
violence fall into these subtypes as well and are based on for 10 years. Over this time, Sidney has related challenges
persistent fear of physical harm, of sexual coercion, of being in her relationship with her partner. You are wondering
constantly watched, or of harm to professional reputation. whether Sidney’s partner could be emotionally abusing
4. A patient-centered evidence-based intervention to approach her. Which of the following questions would be most
IPV is the CUES (Confidentiality, Universal Education, helpful in distinguishing IPV from a non-abusive (but
Empowerment, and Support) intervention. Assessment of dysfunctional) relationship.
IPV includes normalizing the inquiry through a framing A. “Do you feel that you are angry at your partner?”
statement, assuring confidentiality, approaching the survi- B. “Have you ever been afraid of your partner?”
vor non-judgmentally and with compassion, validating her C. “Are you jealous of your partner?”
experiences, using guideline- informed screening tech- D. “Does your partner use illegal drugs or drink alcohol
niques, providing referrals, and providing universal infor- excessively?”
mation regardless of the outcome of screening. The correct answer is B. The pathophysiology of
5. The primary care provider’s role in IPV is to perform uni- IPV is related to control and fear. Fear is always pres-
versal education and screening. Even without disclosure, ent in abusive relationships; thus, identifying fear in
screening has been shown to increase a woman’s aware- the relationship can help to differentiate between rela-
ness with higher likelihood of future planning for safety tionships that are truly abusive versus those that are
and exiting an abusive relationship. Providers should dysfunctional [23].
understand that leaving an abusive situation may be asso- 2. Which of the following is a form of coercive control?
ciated with an increased risk for violence. Providers A. Suzanne’s partner becomes belligerent when she
should connect patients with trained professionals to drinks alcohol on the weekends.
assist with safety planning, including social workers, B. Ali’s partner insists on reviewing her cell phone use
local and national hotlines, and local shelter services. every day when she comes home from work.
6. A trauma-informed approach recognizes that trauma is C. Yolanda’s ex-partner becomes depressed and refuses
pervasive in our society and acknowledges that trauma to answer the phone or engage in conversation.
survivors can be re-traumatized by well-meaning caregiv- D. Ryan discloses that he and his partner yell at each
ers and healthcare providers. other daily.
7. Safety planning includes ways to stay safe if the patient The correct answer is B. Coercive control is a form
must currently remain in the relationship and ways to plan of psychological aggression in which behaviors are
intended to monitor and control or threaten an inti- never pressure a woman to disclose abuse or to leave
mate partner. According to the NISVS, 39.7% of US the abuser as these actions can exacerbate the abuse.
women reported that they had experienced coercive 5. Sarah is a 45-year-old woman with multiple stress-related
control during their lifetimes. The other form of psy- symptoms. She responds “no” when asked if anyone is
chological aggression is expressive aggression, such hurting her physically, emotionally, or sexually at home
as name calling, insulting, or humiliating an intimate or making her feel afraid. What do you do next?
partner. This has been reported by 39.3% of US A. Tell her you are happy that she is not in that situation
women in their lifetimes [3]. and normalize the conversation by moving on to ask-
3. Lee is new to your practice and makes an urgent appoint- ing about other stressors.
ment to see you. During this appointment, Lee’s injuries B. Tell her that you are glad this is not happening to her,
and demeanor suggest that their partner may have been reinforcing that IPV is common and there are
abusing them. Which of the following is most promising resources available—including your office—should
in promoting action-taking for Lee to safely remove she or her loved ones ever need this support.
themselves from this relationship? C. Tell her you are happy that she is not in this type of
A. Referral to services. relationship and assure her that there is no reason for
B. Counseling the partner. you to suspect that she is an abused woman.
C. Reporting the violence to law enforcement. D. Normalize this question by explaining that you are
D. Advising the patient to leave their partner. required to ask this question and just need to check
The correct answer is A. Women have identified the box on the history form and do this for all women.
increased awareness of options and increased access The correct answer is B. Women feel that screen-
to support and resources as a possible turning point to ing and universal education alone are an effective
promote action taking. Addressing the partner can intervention, regardless of disclosure. This model
lead to increase in abuse to the woman, as the disclo- offers a safe place for follow-up if she does need fur-
sure threatens the control that an abuser has in the ther support. She may not be ready to disclose for rea-
relationship. Although reporting the violence to law sons including embarrassment, denial, fear of
enforcement or counseling her to leave the partner repercussions from her abuser, fear of family separa-
seem like safe options, these may have the negative tion, and fear of police involvement. However, repeat
repercussions of escalating the violence by threaten- screening has been shown to increase the rate of dis-
ing a partner’s control. Homicide rates increase by closure. Although disclosure is not necessary to pro-
fivefold when women leave a relationship and any vide effective intervention, it does help to offer more
perceived sense of separation has been shown to be a individualized and appropriate resources for a survi-
trigger for homicide [88–90]. vor [85, 88].
4. Rochelle is a 45-year-old woman with multiple stress-
related symptoms. She answers “yes” when asked if any-
one is hurting her physically, emotionally, or sexually at References
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Care of Sexual Minority Women
36
Eloho Ufomata and Carla Spagnoletti
over the years, and the increase in self-identification as

Learning Objectives LGBT is more noticeable in women than in men. In 2012,
1. Describe healthcare disparities and challenges with 3.5% of women identified as LGBT, while in 2016, 4.4% of
access to care faced by women who identify as les- women identified as LGBT. This contrasts with 3.4% of men
bian, gay, or bisexual (LGB). in 2012 vs. 3.7% in 2016 [1]. Of note, definitions of LGB
2. Define the terms “sexual orientation,” “sexual status are varied in studies and may be based on behavioral
behavior,” “gender identity,” and “gender factors (e.g., women who have sex with women) vs. self-
expression.” identification (e.g., lesbian). This can make the data in this
3. Elicit information about a patient’s sexuality in a patient population difficult to interpret. This chapter focuses
sensitive and inclusive manner. on sexual minority women, or women who identify as les-
4. Screen and treat sexually transmitted infections in bian, bisexual, or gay. There is a separate chapter focusing on
women who have sex with women. the health of transgender individuals (See Chap. 37).
5. Apply guidelines to optimize preventive care in There are health disparities associated with LGB status.
patients who identify as LGB. Compared to heterosexual adults, LGB adults appear to
experience mood disorders at a higher rate and are more
likely to have experienced suicidal ideation and self-injurious
behaviors [2]. This might be due in part to minority stress, a
conceptual framework describing stress related to the experi-
Natalie is a 42-year-old woman who presents to estab-
ence of being a minority, which could include experienced
lish care. She has a history of depression and obesity.
prejudice, expectations of rejection or discrimination, con-
She has not seen a physician in 10 years due to prior
cealed identity, and internalized negative attitudes such as
unpleasant experiences at providers’ offices. Prior to
homophobia [3]. In addition, women who identify as LGB
the visit, she called the office staff to inquire about its
may be at higher risk for breast cancer and cardiovascular
nondiscrimination policy.
disease due to more prevalent risk factors such as obesity and
higher rates of tobacco and alcohol use [2]. Individuals who
identify as LGB are also at increased risk for discrimination,
Overview stigmatization, and violent crimes compared to their hetero-
sexual counterparts. The CDC’s National Intimate Partner
According to 2016 data from the Gallup poll, about 10 mil- and Sexual Violence Survey (NISVS): 2010 Findings on
lion adults in the United States self-identify as lesbian, gay, Victimization by Sexual Orientation found that lesbian and
bisexual, or transgender (LGBT), of which about 55% are bisexual women reported intimate partner violence and sex-
women [1]. This population has steadily been increasing ual violence over their lifetimes at rates equal to, or higher
than those of, heterosexual women. Bisexual women are
E. Ufomata (*) most likely to experience intimate partner violence [4].
University of Pittsburgh School of Medicine, Department of
C. Spagnoletti
University of Pittsburgh, Department of Medicine,
Pittsburgh, PA, USA

556 E. Ufomata and C. Spagnoletti
Establishing a Welcoming Environment not be assumed based on the perceived sex of the person or
the person’s partner(s) [11].
It is important to note that the majority of Americans have Sexual practices are defined by a person’s sexual behav-
implicit bias which favors heterosexual people over LGB iors and guide the clinical assessment of patient risk for sex-
people [5]. A study examining the implicit preferences of ually transmitted infections (STIs), which drives counseling
healthcare providers found that implicit preferences for het- on risk-reduction strategies, testing protocols, and the identi-
erosexual over lesbian and gay people were common among fication of anatomical sites from which to collect specimens
nurses, physicians, and mental health providers [5]. Lesbians testing [11]. Sexual orientation and sexual practices can
and bisexual women were also significantly more likely than change over time, and do not necessarily “align,” although
heterosexual women to have unsatisfactory care, as well as to they typically closely correlate.
have faced discrimination or disrespect from a healthcare Gender identity is a person’s innate, deeply felt identifica-
provider [6, 7]. These factors may contribute to a patient’s tion as a male person, female person, both male and female,
apprehension in establishing care with a new provider and an or neither. For patients who identify as cisgender, their gender
overall delay in medical care. LGB individuals look for identity corresponds to that person’s assigned sex at birth
favorable clues when entering healthcare facilities including (i.e., the sex listed on the birth certificate) [11]. For those who
posted non-discrimination policies, respectful interactions identify as transgender, their gender identity is different from
with staff, and gender-neutral bathrooms. They also take their assigned sex at birth (i.e., the sex listed on the birth cer-
note of whether office intake forms are inclusive [8]. tificate). For those who identify as gender fluid, their gender
Unfortunately, many offices have forms that exclude gender identity is not fixed and may be different depending on the
and sexual minority experiences which can discourage dis- context. For those who identify as agender (sometimes
closure of gender identity, sexual orientation, and sexual referred to as gender neutral), their gender identity does not
behavior. A 2013 survey study piloted a patient intake form align with male or female [11]. One question that can be used
in order to validate sexual orientation and gender identity to determine a patient’s gender identity, recommended by the
(SOGI) questions [8, 9]. A gender/sexuality diverse group of National LGBT Health Education Center is: “Many people
roughly 400 patients were asked questions about their SOGI are affected by gender issues, so I ask patients if they have
and the acceptability of the questions. Most patients believed any concerns. Is this topic relevant to you?” [12]. Another
that the SOGI questions were important, felt that they would question is: “It is common to have concerns relating to gen-
answer similar questions in the future, and believed that it der, would you like to discuss your gender identity?” [10].
was important for their physician to know the information Gender expression is the way in which a person commu-
provided [8, 9]. The patients who identified as LGB felt that nicates gender by external means such as clothing, hairstyles,
the questions allowed them to accurately report information mannerisms, or voice [11]. Many patient’s gender expression
about themselves in a comfortable manner [8, 9]. If intake does not necessarily reflect their gender identity, exemplify-
forms are not inclusive, it is critical to obtain a patient’s sex- ing the importance of asking patients, rather than assuming
ual orientation and gender identity during history taking. their identity (Table 36.1).
It is imperative that when asking about SOGI, open-ended
questions are used and nothing is assumed about the patient,
Natalie identifies as bisexual and states that she is cur- their partners, or their practices.
rently in a monogamous relationship with a woman.
She identifies as a woman and prefers to wear clothing
from the “men’s department.” ow to Ask About Sexual Orientation
H
and Gender Identity (SOGI)
Determining a patient’s sexual orientation and gender iden-

Terminology tity (SOGI) is an important component of history taking [10,
13]. When providers do not know a patient’s full sexual his-
An understanding of the terms used to characterize a per- tory, they may not be able to recommend appropriate health
son’s sexuality and gender is important when eliciting a his- services such as vaccinations, screening for cancers, or
tory from a woman [10]. screening for sexually transmitted infections.
Sexual orientation is a person’s attraction to another per- All providers are subject to bias and are influenced by
son, which could be a physical, romantic, emotional, and/or experiences; it is important to be cognizant of how these can
spiritual attraction. Orientation could be described as les- affect patient care. Refraining from making assumptions
bian, gay, heterosexual, bisexual, pansexual, polysexual, about a patient’s sexual orientation and gender identify is
asexual, among others. A person’s sexual orientation should critical, as gender does not imply anything about sexuality
36 Care of Sexual Minority Women 557
Table 36.1 Sexual orientation and gender identity (SOGI) terminol- 2. PRACTICES: “To better understand if you are at risk for
ogy [11] STIs, I have a few specific questions. What kind of sexual
Term Definition Keywords and pearls contact do you have or have you had? Genital (penis in
Sexual A person’s physical, Lesbian, gay, the vagina)? Anal (penis in the anus)? Oral (mouth on
orientation romantic, emotional, heterosexual, bisexual,
and/or spiritual attraction pansexual, polysexual,
penis, vagina, or anus)?”
to another person asexual, etc. Many terms 3. PROTECTION from sexually transmitted infections
used and defined by the (STIs): “Do you and your partner(s) use any protection
patient against STIs? If not, why not? If so, what kind? How
Sexual A person’s sexual Ask about partners, the often do you use protection? In what situations or with
practices behaviors type of sex they engage
in, and assess risk for whom do you use protection?”
pregnancy and STIs 4. PAST HISTORY of STIs: “Have you ever been diagnosed
Gender A person’s innate, deeply Cisgender, transgender, with an STI? What treatment did you receive? Have you
identity felt identification as a gender non-conforming, ever been tested for HIV or other STIs? Would you like to
male person, female non-binary, agender, etc.
person, both male and Many terms used and
be tested for STIs?”
female, or neither defined by the patient 5. PREGNANCY planning or prevention: “Do you have
(see Chap. 37) concerns about getting pregnant? Are you using any form
Gender The way in which a May not reflect gender of birth control (if/when sexually active with men)? Do
expression person communicates identity you want information on birth control?”
gender by external
means, such as clothing,
hairstyles, mannerisms,
or voice Natalie states that she has been with her new partner
for a few months. She notes an increase in her vaginal
discharge and that it has a “fishy odor.” She is diag-
and vice versa. Providers should reflect on phrasing of ques- nosed with bacterial vaginitis utilizing in-office test-
tions that are commonly used that can imply assumptions, ing. She wonders if her partner could be affected by
for example “Are you and your boyfriend sexually active?”, her diagnosis.
and form new habits using more inclusive phrasing. This will
allow all patient encounters to be approached in a non-
judgmental and sensitive way.
The Fenway Institute recommends the following commu- S exually Transmitted Infections (STIs)
nication techniques when obtaining a patient’s SOGI [10]: in Women Who Have Sex with Women
1. Set the stage to normalize this line of inquiry: “Next, I’d Women who have sex with women, or WSW, can acquire
like to ask you some questions about your sexuality. This sexually transmitted infections (STIs). Infected cervico-
is routine, confidential and important to your overall vaginal or anal secretions may be transmitted by digital-
health.” vaginal or digital-anal contact and by shared penetrative sex
2. Use open, inclusive language and avoid assuming gender items [15]. It is also important to note a high percentage of
of partners, monogamy, or sexual practices: “Tell me WSW have had sex with men in the past; up to one-third in
about your sexual partners.” the past 1 year [15]. Women who have sex with women are
3. Be cognizant of body language and other non-verbal twice as likely to have bacterial vaginosis (BV) compared to
cues. Maintain eye contact, be aware of facial expressions those who are not WSW. Bacterial vaginitis is not considered
or head shaking. a sexually transmitted infection per se, but it is thought to be
4. Listen to how your patients describe themselves, their sexually associated, which means the risk of BV can increase
partners, their practices, and use those same words. after sexual encounters. There is a high level of concordance
in genital lactobacillus in female sex partners and significant
The CDC’s “5 Ps” of sexual history is a framework that concordant infection rates between female partners (25–
can be used to learn more about a patient’s sexual history 50%) [16].
[14]. Although less likely than with male-to-female or male-to-
male transmission, other STIs, such as chlamydia, gonor-
1. PARTNERS: “Are you currently sexually active? Have rhea, and trichomoniasis, can be transmitted among WSW
you ever been sexually active? Are your sex partners men, [16–18]. At least one case study has described the transmis-
women, or both?” sion of HIV between females [19]. HPV infection among
lesbian women is similar to the general heterosexual popula- and lesbian women had the highest cardiovascular risk [6].
tion and can be transmitted between female partners (See In addition, a 2016 systematic review found that sexual
Chaps. 13 and 14). minority women had higher cardiovascular disease risk com-
pared to men and heterosexual women, which was associated
with lifetime tobacco use, alcohol use, illicit drug use, poor
Counseling on Safe Sex Practices mental health, and elevated body mass index [21]. Compared
to heterosexual women, lesbian women had higher rates of
Providers should share these simple tips with female patients hypertension and bisexual women had higher rates of hyper-
to help reduce their risk for acquiring STIs [20]. tension, greater use of blood pressure medication, and were
more likely to have diabetes [21]. Unfortunately, there are no
1. Use barrier protection with both male and female specific guidelines for women of sexual minority for the pre-
partners. vention of cardiovascular disease, so routine counseling of
2. Use gloves during digital-genital sex. lifestyle modification including smoking cessation and
3. Use condoms with sex toys. weight loss along with aggressive identification of cardio-
4. Use latex or plastic barriers (such as dental dams) for vascular risk factors such as diabetes and hypertension is rec-
oral-genital sex. ommended for these patients (See Chaps. 21 and 22).
5. Properly care for shared penetrative sex toys, by cleaning
with hot soapy water between use, but avoid sharing if
possible. Natalie is also interested in cancer screening as a
43-year-old woman. Her last pap test was performed
Other important preventative measures that should be 3 years ago, and she reports that it was normal. She is
taken to keep female patients healthy include the following: not sure if she was tested for HPV at that time. In addi-
(1) age-appropriate vaccination against human papilloma tion, she would like to know more about her risk for
virus (HPV) regardless of sexual practices, (2) cervical can- breast and ovarian cancer.
cer screening per established guidelines regardless of sexual
practices, and (3) STI testing per guidelines. The Center for
Disease Control (CDC) recommends chlamydia and gonor-
rhea screening for all sexually active women yearly until age Cancer Screening
25 [15]. They also recommend screening for HIV at least
once in a lifetime, regardless of sexual practices [15]. If Cervical Cancer
women are at high risk for HIV, screening at more frequent
intervals should occur and concomitant screening for hepati- Data strongly support that human papilloma virus (HPV)
tis C may be considered (See Chaps. 13 and 14). infections are common in WSW. A common misconception
among patients and some providers is that WSW have a low
risk of cervical cancer because they are unlikely to have been
Natalie presents back a year later at age 43. Her father exposed to HPV. Transmission can occur between women as
recently had a heart attack, and she is concerned that it is spread through skin-to-skin contact as well as contact
this was related to his lifestyle. Because she is obese with bodily fluids [16]. HPV has been detected in the genital
and inactive, she wants to discuss her overall health tract of 13–30% of women who have only had sex with
and strategies to prevent serious illnesses in the future. women, which is similar to rates found in the general popula-
tion [22]. As of 2018, the US Preventive Services Task Force
(USPSTF) cervical cancer screening guidelines recommend
screening with cervical cytology every 3 years for all persons
Cardiovascular Disease Risk aged 21–65 who have a cervix, regardless of sexuality or
gender identity; alternatively women ages 30–65 can be
There is some data showing that women who are sexual screened with cervical cytology and HPV co-testing or high-
minority, that is lesbian or bisexual, have an increased preva- risk HPV testing alone every 5 years (See Chap. 14) [23].
lence of cardiovascular disease. One study found that lesbian Despite this, WSW are less likely to routinely undergo cervi-
and bisexual women are significantly more likely to recall cal cancer screening, and lesbians are 87% less likely to have
being diagnosed with heart disease compared to heterosex- ever received a pap test compared to heterosexual women
ual women [6]. Within this group, bisexual women were [24]. Barriers to routine cervical screening include perceived
younger on average than heterosexual or lesbian women but low susceptibility to cervical cancer by these women and
were still at increased risk compared to heterosexual women, their providers, perceived lack of benefits to screening, and
an underestimation of the seriousness of cervical cancer 2. Sexual orientation, sexual practices, gender identity, and
[25]. These findings suggest that it is essential for providers gender expression are each unique aspects of a patient’s
to discuss sexual orientation with patients and educate them being. Each is important to elicit as part of a patient’s
on their susceptibility to HPV and the benefits of cervical history.
cancer screening. Regarding HPV vaccination, bisexual 3. The 5 Ps (Partners, Practices, Protection from STIs, Past
women were significantly more likely to have HPV vaccina- history of STIs, Pregnancy planning or prevention) frame-
tion compared to lesbian or heterosexual women, who had work is a good way to acquire a sexual history from
similar rates of vaccination [26]. The current recommenda- patients.
tion by the CDC is to routinely vaccinate adolescents/young 4. Women who have sex with women are at risk for STIs,
adults starting at age 11 regardless of sexuality [27]. The including bacterial STIs, and HPV. Bacterial vaginosis
HPV vaccination series is currently approved through age may be transmitted between female sex partners. STI
26, but the FDA just expanded their recommended coverage screening should be performed with attention to sexual
of the vaccine series to include all genders aged 9–45 (See practices. Women should receive vaccinations, cervical,
Chap. 14) [28]. and breast cancer screening based on established guide-
lines, regardless of sexual practices.
Breast Cancer
There is no data examining the prevalence of breast cancer as Review Questions

it relates to sexuality; however, the National Academy of
Medicine predicts a higher risk of breast cancer in lesbian 1. A 32-year-old woman presents to your office to establish
and bisexual women due to higher prevalence of risk factors care and for a check-up. She has no symptoms or con-
such as tobacco use, decreased parity, obesity, and alcohol cerns. As part of her routine history, you gather informa-
intake [2]. The screening recommendations are the same for tion about her sexual orientation and gender identity
average risk women regardless of sexuality and vary by (SOGI) history. You learn that she is attracted to women,
guideline, beginning at age 40. There is some data suggest- she engages in sex with her girlfriend, and they use sex
ing that lesbian and bisexual women are more likely to per- toys during sexual encounters. She has had two male sex-
ceive their risk of breast cancer as lower, to have negative ual partners in the remote past but is not interested in men
beliefs about breast cancer screening, and that trust or a posi- romantically or sexually at this time. She identifies as
tive relationship with the provider recommending the test is female. On physical exam, you note that she has long
more likely to affect intentions to follow-through with hair, is wearing make-up and earrings, and is dressed in a
screening (See Chaps. 17 and 18) [29]. blouse and skirt.
Which of the following descriptions best summarizes
this patient’s sexual orientation and gender identity?
Endometrial and Ovarian Cancer A. She is a cisgender bisexual woman.
B. She is a transgender bisexual woman.
Screening for endometrial or ovarian cancer is not recom- C. She is cisgender lesbian woman.
mended for asymptomatic women regardless of sexual orien- D. She is a cisgender polysexual woman.
tation. There are few data examining the prevalence of E. She is a gender-fluid lesbian woman.
endometrial and ovarian cancer in women who identify as The correct answer is C. Sexual orientation, sexual
lesbian or bisexual; however, the available data is conflicting practices, gender identity, and gender expression are each
[30]. Please see Chap. 15 to learn more about the prevention, unique aspects of a patient’s sexuality. Each is important
screening, and management of female cancers. to elicit as part of a patient’s history. Gathering sexual
orientation and gender identity data in a standardized way
will allow a better understanding of LGBT health dispari-
Summary Points ties. This will assist the provider in prevention, screening,
and detection of conditions that disproportionately affect
1. Women who identify as LGB have decreased access to LGBT people. This patient was assigned female sex at
quality healthcare, experience discrimination in medical birth, identifies as a female, expresses her gender in a ste-
facilities, and face healthcare disparities. These patients reotypically feminine manner, is attracted to women, and
may look for favorable clues that a healthcare environment has had sex with both men and women. Thus, she is a
is welcoming, including non-discrimination policies, cisgender woman who is lesbian, despite having had sex
inclusive intake forms, and gender-neutral bathrooms. with men in the past. Sexual orientation is defined as a
person’s enduring physical, romantic, emotional, and/or continuing through at least age 65. Annual screening of
spiritual attraction to another person and can be described all sexually active women aged <25 years for C. tracho-
as lesbian, gay, heterosexual, bisexual, pansexual, poly- matis and N. gonorrhoeae is recommended. CDC recom-
sexual, asexual, and others. A person’s sexual orientation mends HIV screening for patients aged 13–64 years at
should not be assumed based on the perceived sex of that least once as part of routine health care. Although com-
person’s partner(s), but rather based on their self-identifi- mon among WSW, routine screening for BV is not rec-
cation, as sexual practices may be fluid. Gender identity is ommended [15].
a person’s innate, deeply felt identification as a male per- 3. A 51-year-old postmenopausal woman presents to estab-
son, female person, both male and female or neither. lish care. She is requesting a pap test, and any other
Cisgender is the term used when gender identity corre- screening for gynecologic cancers available. She identi-
sponds to the person’s assigned sex at birth (i.e., the sex fies as a lesbian and has had three female sexual partners
listed on the birth certificate). Transgender is the term in the past year. She was recently tested for STIs, which
used when gender identity is different from a person’s were negative, and her last pap test was 2 years ago. Her
assigned sex at birth (i.e., the sex listed on the birth cer- pap result was atypical squamous cells of undetermined
tificate). Gender fluid is the term used for a person whose significance (ASCUS) with negative HPV testing. She is
gender identity is not fixed and may be different depend- up-to-date on breast cancer and colon cancer screening
ing on the context. Agender, sometimes referred to as per guidelines.
gender neutral, is the term used for a person whose gen- Which of the following is true regarding gynecologic
der identity does not align with male or female [31, 32]. cancer screening for this patient?
2. A 21-year-old woman presents for a routine annual exam. A. Women who identify as lesbian and bisexual should
She last saw her pediatrician at age 17. She is healthy, has be screened for cancers more frequently than women
no significant past medical history, and has no specific who identify as heterosexual.
concerns. She has had one lifetime sexual partner who is B. Women who identify as lesbian or bisexual are less
female, but has not been sexually active for the last likely to be appropriately screened for cervical cancer
6 months. She recently found out that her former partner compared to heterosexual women.
has genital herpes. Valerie has never had any lesions. C. She should have a repeat pap test and HPV testing
Which of the following should you offer to Valerie as part done now, since women who identify as lesbian are at
of routine screening for sexually transmitted infections, higher risk for cervical cancer.
per guidelines? D. Screening for endometrial cancer is warranted,
A. Screening tests for chlamydia and HIV because she is menopausal.
B. No screening tests are indicated based on her age and The correct answer is B. There is some data that
sexual history women who identify as lesbian or bisexual are less likely
C. Screening test for herpes simplex virus to have appropriate cervical cancer screening, and some
D. Screening tests for bacterial vaginosis of the barriers include perceived low susceptibility to cer-
E. Screening test for chlamydia, gonorrhea, and HIV vical cancer (by women and providers) and perceived
The correct answer is E. WSW should not be presumed lack of benefits to screening and seriousness of cervical
to be at low or no risk for sexually transmitted infections cancer [25]. Although weighted prevalence estimates
based on sexual orientation [16]. According to the Centers generated using data on 71,112 women from the California
for Disease Control (CDC), WSW are at risk for acquir- Health Interview Survey show that heterosexual women
ing bacterial (chlamydia, gonorrhea, BV), viral (HPV, have a significantly lower prevalence of cervical cancer
HSV, and HIV), and protozoal (trichomoniasis) STIs (14%) compared with lesbian women (16.5%) and bisex-
from current and prior partners, both male and female. ual women (41.2%), the guidelines are not different based
Report of same-sex-only encounters in women should not on sexual orientation, and this patient should not be
deter providers from considering and performing screen- screened more frequently [23]. The American Society for
ing for cervical cancer and STIs per current guidelines Colposcopy and Cervical Pathology recommends repeat-
[15]. There is no utility in screening for HSV based on ing cytology with HPV co-testing at 3 years for a pap test
exposure history in the absence of HSV outbreak [18]. All showing ASCUS that is HPV negative. Thus, repeating
women should receive cervical cancer screening, regard- her pap now would be inappropriate [33]. Routine screen-
less of sexual orientation (i.e., women who identify as ing for endometrial cancer in women is not recommended
lesbian, bisexual, or heterosexual), starting at age 21 and regardless of sexuality [30].
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Gender Affirming Care
37
Eloho Ufomata and Megan McNamara
Learning Objectives boy or as a man. She started seeing a therapist on the

1. Explain the concepts of sex and gender, gender advice of a friend, changed her legal name, and is
identity, gender non-conformity, gender dysphoria, dressing in clothing which is more comfortable to her.
and gender affirmation. She is seeking a provider who will be supportive of her
2. Describe the importance of using open and inclu- and understands how to help.
sive language when eliciting information about a
patient’s gender identity, transition history, and
sexual practices.
3. List strategies for optimizing patient comfort dur-
ender Identity, Gender Non-Conformity,
G
ing sensitive parts of the physical exam.
and Gender Dysphoria
4. Describe the available hormonal treatments, the
goals of hormone therapy, as well as associated
Gender is a concept that encompasses a complex relationship
risks, benefits, and contraindications for gender
between a person’s body or physical sexual characteristics,
affirmation.
their identity or a deeply held internal sense of self, and their
5. Perform appropriate screening and immunizations
gender expression or the way they present themselves to the
for transgender patients according to their natal and
world [1]. Gender is distinct from natal sex, which describes
surgical anatomy and sexual practices.
the biological make-up of the individual. People are typically
assigned a sex at birth based on the characteristic appearance
of their genitalia as male or female, and this is referred to as
“natal sex.” Sex designation is not always as simple as a male
Isis is a 45-year-old patient with depression who pres- or female binary. Intersex conditions, which may present
ents to establish care after a prolonged hiatus from with ambiguous genitalia at birth, or become evident at
medical care. She tells you that she was assigned male puberty, include persons whose chromosomal make-up or
at birth, and although she was named Isiah, she has anatomy do not fit the usual male XY and female XX binary
thought of herself as Isis since childhood and uses the pattern [1].
pronouns “she” and “hers.” She remembers wanting Over time, there is physical development into characteris-
to wear dresses as a child but her father discouraged tics that are viewed as feminine or masculine which are inter-
her from doing so. She has never felt comfortable as a preted within a cultural context as well. Gender identity is an
internal sense of self, which could be congruent with the sex
assigned at birth or “cisgender,” or could be opposite the sex
assigned at birth or “transgender” [1]. There are also people
E. Ufomata (*)
University of Pittsburgh School of Medicine, Department of who are gender non-conforming, which is an umbrella term
Internal Medicine, Pittsburgh, PA, USA for anyone whose gender identity is different from the sex
e-mail: [email protected] assigned at birth [1]. This illustrates that gender is not neces-
M. McNamara sarily on a binary spectrum, that is, male or female, and peo-
Case Western Reserve University School of Medicine, Louis ple may identify with a non-binary gender identity, meaning
Stokes Cleveland VA Medical Center, Department of Medicine,
they do not identify strictly as a boy or a girl—they could
Cleveland, OH, USA

564 E. Ufomata and M. McNamara
identify as both, neither, or as another gender entirely. Some tion into social circumstances, and social and legal services
people may not identify with having a gender at all, or as for legal transitions such as name change [3].
agender. Natal females who consider themselves to be men
are referred to as “transgender men.” Natal males who con-
sider themselves to be women are referred to as “transgender After the second visit to your clinic, Isis speaks to you
women.” Keep in mind that patients determine their own about how the office staff always calls her “Isaiah”
identity, and the best approach is to ask patients about their and uses masculine pronouns when referring to her.
gender identity and to clarify how they would like to be She is frustrated and feels that your office is not mak-
addressed. ing an effort to treat her respectfully.
Gender dysphoria is a DSM-V diagnosis which is charac-
terized by a conflict between a person’s assigned sex and
their gender identity, leading to significant distress and prob-
lems with functionality [2]. This diagnosis replaces the for-
mer DSM diagnosis of gender identity disorder to increase Creating a Welcoming Environment
access to care and negate the connotation that gender non-
conformity is a pathologic disease. The diagnostic criteria Transgender patients face barriers to accessing optimal
include a duration of at least 6 months and at least two of the healthcare, which leads to disparities in both physical and
following symptoms: mental health outcomes. A systematic review of the available
literature on primary care for transgender individuals found
• A significant difference between one’s experienced/ that there are significant disparities in HIV prevalence com-
expressed gender and physical sex characteristics pared to cisgender individuals, with significantly higher
• A desire to remove one’s primary and/or secondary sex prevalence in transgender women specifically [5]. In addi-
characteristics tion, there is increased tobacco use and lower cervical cancer
• A strong desire for the primary and/or secondary physical screening [5]. The likely causes of these disparities are mul-
attributes of the other gender tifactorial, with access to care, underinsurance, discrimina-
• A strong desire to be of the opposite gender tion, and minority stress playing a role. Data show that
• A strong desire to be treated as the opposite gender transgender individuals who delayed health care due to a fear
• A strong belief that one has the usual feelings and reac- of discrimination had worse overall health, as well as higher
tions of the opposite gender [2] odds of depression, suicidal ideation and suicide attempts in
the past year, compared to those who did not delay care [6].
The treatment for gender dysphoria includes steps toward Creating a welcoming environment is an essential first step
gender affirmation, which is a process by which a person can in establishing open and honest communication with trans-
adapt their body to their experienced gender [3, 4]. Treatment gender patients. One-third of surveyed transgender individu-
options for gender dysphoria include counseling, cross-sex als in the United States have experienced a negative encounter
hormones, puberty suppression, and gender affirming sur- with a healthcare provider, and 23% avoided seeing a doctor
gery [3]. because of concerns about mistreatment [7]. Simple changes
The World Professional Association for Transgender such as displaying signs that highlight gender diversity and
Health (WPATH) and the American Medical Association having brochures that are relevant to LGBTQ individuals can
(AMA) view treatment of gender dysphoria as medically communicate awareness and affirmation [1]. Scheduling per-
necessary and effective [3, 4]. The current standard of care is sonnel or administrative assistants should be trained to use
an individualized, multidisciplinary approach, according to open and inclusive language so that patients have a positive
the patient’s desired interventions. Primary care providers, first impression of the clinical environment. Additionally,
endocrinologists, and surgical subspecialists may provide medical intake forms that query patients about natal sex, gen-
overall health and wellness support, as well as hormonal and der identity, and sexual orientation, and which use neutral
surgical treatments. Mental health professionals may support language (“partner” as opposed to “husband”), create an
transition by performing assessment of gender dysphoria, impression of inclusivity even before the face-to-face visit
counseling on options for gender identity and expression, [1]. It is imperative that during the initial encounter, patients
management of comorbid mental illness, and assessment of should be asked about their preferred name and pronouns,
eligibility, preparation, and referral for hormone therapy or and this information should be used consistently in all verbal
surgical treatments [3, 4]. Other professionals in the team- and electronic communication among clinical personnel.
based approach may include speech and language patholo- Transgender and non-binary individuals who experience con-
gists who can assist with voice coaching, cosmetologists for sistent mis-gendering during a clinical encounter may feel
hair removal and skin care, occupational therapy for adapta- marginalized and refrain from seeking care again.
37 Gender Affirming Care 565
Obtaining the Medical History is paramount. Simple techniques such as asking the patient’s
permission, assuring confidentiality, mirroring the patient’s
A major goal of the medical history is to understand the language, and using appropriate pronouns to refer to
patient’s gender story and their overall sense of self. Although partner(s) (i.e., “they” if appropriate) can facilitate this sensi-
hormone therapy may improve psychological functioning tive conversation.
and quality of life for many transgender individuals [8], it is
important to remember that not all patients will choose to
transition with medical therapy. Similarly, gender-affirmation Performing a Physical Exam
surgery may be of interest to only certain individuals [7];
thus, providers should avoid assumptions about a patient’s The physical exam should be performed in accordance with
hormonal treatment, prior surgeries, and current anatomy. the patient’s current anatomy. Transgender men who have
Use of open-ended questions and non-judgmental language not undergone hysterectomy require routine pelvic exams for
while taking the medical history can facilitate clear and hon- cervical cancer screening according to current recommenda-
est communication about these issues. tions (see Chap. 14) [11]. Additionally, if bilateral mastec-
For patients who are currently using hormonal therapy, it tomy has not been performed, providers can consider
is important to query them about the dose and preparation performing a breast exam and screening for breast cancer
that is being used, the duration of use, any adverse effects, according to published guidelines for natal women (see
and goals and expectations of treatment. Patients should be Chaps. 17 and 18). Breast examination may be appropriate
asked about non-prescription or alternative sources of hor- for transgender women who are taking estrogen, to assess the
mone treatment, which may be obtained with little or no effects of hormone therapy on breast tissue and develop-
clinical oversight [9]. Similarly, providers should inquire ment, as well as to assess for galactorrhea. Transgender
about the use of over-the-counter herbal preparations, such women who have had gender-affirming surgery retain their
as phytoestrogens or dehydroepiandrosterone (DHEA), prostate, and screening for prostate cancer can be performed
which are frequently marketed for their hormonal effects [1]. according to recommendations for natal males [11].
It is important to perform an anatomical inventory on For some transgender patients, gender-specific aspects
every transgender patient. A thorough understanding of the of the physical exam can create anxiety. In the absence of
patient’s current anatomy (whether natal or surgical) is clear medical necessity, it is reasonable to defer aspects of
essential for providing appropriate preventive care services, the physical exam (i.e., breast, genital, and anal exams)
such as breast, cervical, and prostate cancer screening. until the patient and provider have developed a strong and
Several options are available for transgender men seeking trusting relationship [1]. Transgender men, in particular,
gender-affirmation surgery, including hysterectomy with sal- may experience emotional conflict and distress during
pingoopherectomy, vaginectomy, scrotoplasty, and phallo- gynecologic exams, due to both gender dysphoria as well
plasty. Bilateral mastectomy may also be performed. as physical discomfort related to testosterone-induced vagi-
Transgender women may undergo penectomy, orchiectomy, nal atrophy [12]. Several strategies can be used both before
vaginoplasty, vulvoplasty, and breast augmentation [10]. It and during the exam to improve the experience for the
may also be useful to assess a patient’s interest in having patient, such as using gender-neutral terms (external pelvic
gender-affirmation surgery in the future, in order to coordi- area for vulva, frontal pelvic opening for vagina), having a
nate referrals and assist with planning [1]. friend or partner present during the exam, using a small
It is important to take a thorough sexual history to accu- speculum, allowing the patient to self-insert the speculum,
rately assess a patient’s risk for sexually transmitted infec- and encouraging the patient to communicate any discom-
tions, pregnancy, and sexual dysfunction. Prior sections of fort [13]. These exam strategies are useful if a patient needs
this text have described techniques for asking sensitive and a pelvic exam due to a specific complaint such as pain or
inclusive questions while taking the sexual history, see bleeding or for cervical cancer screening. Chapter 14 dis-
Chaps. 3 and 36 for more information. For transgender cusses the use of a blind sweep HPV test as an alternative
patients, it is important to frame these questions within the for cervical cancer screening in patients who prefer not to
context of current anatomy, as well as the anatomy of their have speculum exams.
partner(s). The provider should ask patients about the num- In contrast, some transgender women find the breast exam
ber and gender identity of their partner(s), as well as types of to be gender-affirming and are comfortable during this part
sexual practices and use of barrier protection. Keep in mind of the encounter. Nonetheless, it is important for the provider
that transgender men may be at risk for pregnancy depending to explain why the exam is being done, to mirror the patient’s
on their current anatomy and sexual practices, therefore, language, and to provide draping alternatives according to
assessment of contraceptive use and interest in childbearing the patient’s preference [1].
fall off or cause skin irritation. Parenteral dosing is weekly or

Isis is interested in beginning affirming hormone ther- biweekly; weekly dosing promotes less variation between
apy. Her goal is to have an appearance which is more peak and trough concentration which may cause less side
feminine, including larger breasts, less facial and body effects but also requires more frequent injections by the
hair, and a more feminine fat distribution. Her physical patient. Patients using parenteral estradiol must be educated
exam, including her blood pressure, pulse, and body about safe needle use and disposal to prevent infection and
mass index, are entirely normal. The results of her adverse events. The efficacy between all formulations of estra-
baseline blood work, including lipids, hemoglobin diol is similar. Ethinyl estradiol, which is commonly used in
A1c, electrolytes, liver function tests, and prolactin, combined hormonal contraceptives, should not be used for
are within normal limits. Her therapist has confirmed transgender hormone therapy; it is more thrombogenic than
that she meets criteria for gender dysphoria and is 17-beta estradiol, and serum levels cannot be measured for
supportive of Isis’ plans for medical transition. She treatment titration [11]. Conjugated Equine Estrogens (CEE),
wonders if you would be willing to start her on hor- found in Premarin™ products, though used in the past, are
monal treatment. also not recommended.
During the first 3–6 months of treatment, patients will
likely notice decreased libido and spontaneous erections,
body fat redistribution, decreased muscle mass, softening of
Initiation of Hormone Therapy the skin, decreased testicular size, and breast growth. Over
the next 6–12 months, body and facial hair will thin and
Guidelines from the World Professional Association for grow more slowly. It is important to counsel that breast
Transgender Health [4] and the Endocrine Society [11] rec- growth is slow and may not fully develop until 2–3 years
ommend that individuals meet certain criteria before starting after initiation of treatment [4]. The effects of hormonal ther-
on hormone therapy. The WPATH criteria include (1) the apy on sperm production and sexual dysfunction are vari-
presence of persistent, well-documented gender dysphoria; able, so it is important that patients’ interest in child-bearing
(2) the capacity to make medical decisions and to consent to be assessed prior to initiating treatment [4].
treatment; (3) of legal adult age; and (4) reasonably well- Hormonal therapy with estradiol increases risk for venous
controlled medical or mental health conditions [4]. The thromboembolism (VTE) [14]. Lower doses of estradiol, and
Endocrine Society guidelines are almost identical, although the use of transdermal preparations, may be preferable in
they stipulate that only mental health (and not medical) con- patients who are at potentially increased risk for VTE [15].
cerns are well-controlled prior to initiating therapy [11]. To Treatment with estradiol may also be associated with hyper-
address the first criteria, both guidelines emphasize that pro- tension, increased triglycerides, and impaired glucose toler-
viders who prescribe hormone therapy should either be com- ance [4]. The effect of estradiol therapy on cardiovascular
fortable making the diagnosis of gender dysphoria or consult outcomes is unclear, although guidelines indicate that it is
with a health professional who is skilled in gender dysphoria associated with a “moderate risk” for coronary artery disease
assessment. Once the diagnosis of gender dysphoria is met, and cerebrovascular disease [11]. Prior studies that have
guidelines recommend that the patient be fully informed shown an increased risk for cardiovascular events in trans-
about the risks and benefits of hormonal treatment, including gender women on hormone therapy may have been influ-
the impact on medical, mental health, and social outcomes enced by the type of estrogen preparation (use of ethinyl
by a knowledgeable provider [11]. estradiol) as well as the subjects’ age and associated risk fac-
For transgender women, the goals of hormone therapy are tors, such as smoking [15–17]. In contrast, a more recent ret-
to reduce natal hormonal levels (testosterone) and replace with rospective cohort study of mostly non-smoking transfeminine
hormones of the affirmed gender (estrogen). In the United women, investigators noted an increased risk for ischemic
States, spironolactone is the most commonly used treatment to stroke as compared to the women in the cisgender matched
reduce testosterone levels; g onadotropin-releasing hormone cohort [14].
(GnRH) agonists can be used as well, although they are expen- Absolute contraindications to feminizing hormone ther-
sive and less convenient to administer. Feminization can be apy include an estrogen-sensitive active malignancy and
achieved with 17-beta estradiol, also referred to as E2 or end-stage liver disease. In all other instances, it is reasonable
Estradiol, which comes in a variety of preparations, including to control or reduce medical comorbidities or risk factors as
oral, transdermal, and injectable. The starting dose of estradiol much as possible before starting treatment [4, 11].
should be low and titrated up as patients tolerate. Patient pref- Patients on feminizing hormone therapy should have a
erences play a role in the route and frequency of administra- complete history, physical exam, and laboratory evaluation
tion. Oral dosing is daily. Topical estradiol patches are every 3 months. At each encounter, blood pressure and
conveniently changed only one to two times per week but can weight should be monitored, and serum electrolytes, estra-
diol, and testosterone levels should be measured. The goal of gain. Additionally, treatment can cause hyperlipidemia,
estradiol level is within the range for a reproductive age natal hypertension, impaired glucose tolerance, and severe acne.
female (100–200 pg/mL) and the testosterone level should Absolute contraindications to testosterone include the pres-
be suppressed to less than 50 ng/dL [11]. Estradiol and spi- ence of testosterone-sensitive active malignancy, pregnancy,
ronolactone doses can be titrated according to the patient’s polycythemia, and unstable coronary artery disease [4]. In all
goals for treatment (i.e., the degree of feminization that she other instances, it is reasonable to control or reduce medical
wants to achieve), as well as hormonal levels. After the first comorbidities or risk factors as much as possible before
year of therapy, and once a stable hormonal regimen is starting treatment [4, 11].
achieved, clinical and laboratory evaluation can occur every Patients on masculinizing hormone therapy should have a
6–12 months. Prolactin levels may increase in patients complete history, physical exam, and laboratory evaluation
treated with estradiol; guidelines recommend a baseline every 3 months during the first year of treatment. At each
measurement and then annual assessment during the transi- encounter, the blood pressure and weight should be moni-
tion period [11]. tored, and hemoglobin, hematocrit, and total testosterone
levels should be measured at these visits [11]. The desired
range of serum testosterone levels is between 400 and
Hormonal Therapy for Transgender Men 700 ng/dL and the peak should not exceed 1000 ng/dL [11].
The timing of testosterone measurement to assess for ade-
The main goals of hormonal therapy for transgender men are quate levels depends on which type of testosterone is being
(1) to reduce natal hormonal secretion and (2) to replace with used. For short-acting parenteral testosterone, levels should
hormones consistent with the affirmed gender [11]. For be measured mid-way between doses; alternatively, dosing
transgender males, testosterone administration is effective in can be based on peak (24-hours after dose) and trough (just
both reducing endogenous estrogen production and achiev- before next dose) measurements. For topical testosterone,
ing testosterone levels within the normal reproductive range levels can be measured after consistent daily use of testoster-
for the male gender. Testosterone can be administered as a one for 1 week, with the level drawn after 2 hours of dose
gel, a patch, or parenterally; oral testosterone is not available administration for that day [11]. Testosterone doses can be
in the United States. Like estradiol, patient preferences play titrated according to the patient’s goals for treatment (i.e., the
a role in the route and frequency of administration. Topical degree of masculinization that he wants to achieve) as well
dosing is daily, while parenteral dosing is weekly or biweekly as hormonal levels. After the first year of therapy, and once a
when starting therapy. Weekly parenteral dosing promotes stable hormonal regimen is achieved, clinical and laboratory
less variation between peak and trough concentration which evaluation can occur every 6–12 months.
may cause less side effects but also requires more frequent
injections by the patient. Patients using parenteral testoster-
one must be educated about safe needle use and disposal to Isis starts hormonal treatment with oral estradiol 1 mg
prevent infection and adverse events. Topical testosterone twice daily and spironolactone 25 mg twice daily. At
delivered in gel form can be absorbed by other people who her follow-up visit 3 months later, she reports that her
come into contact with the patient’s skin, making it impor- mood has dramatically improved, and she has noticed
tant to keep the dosing site protected from those at risk for some physical changes, including softening of her skin.
adverse effects from masculinizing hormones such as chil- She wonders if there is anything else that needs to be
dren and females. Testosterone patches can be irritating to “checked” in order to stay healthy. She is sexually
the skin and cause a local allergic reaction. Efficacy between active with her primary partner, Kelly, who is a cis
all formulations of testosterone is similar. female, and engages in oral and penile/vaginal inter-
Testosterone therapy will produce predictable changes in course. She rarely uses condoms, and her last HIV test
the physical appearance, although the time course of these was 1 year ago.
changes will vary. During the first 6 months of treatment,
patients will experience cessation of menses, acne, increased
facial and body hair growth, body fat redistribution, clitoral
enlargement, and vaginal atrophy. Increased muscle mass, Screening for Sexually Transmitted
deepening of the voice, and scalp hair loss typically occur Infections
during the first year. Some individuals will continue to expe-
rience an increase in hair growth and muscle mass for up to Several studies have shown that there is a high prevalence of
5 years [4]. HIV among transgender women. According to one system-
Testosterone can be associated with adverse effects, atic review, the pooled prevalence of HIV infection was
including polycythemia, sleep apnea, and excessive weight 19.1% among transgender women worldwide, and the odds
for being infected with HIV, as compared to reproductive age for over-diagnosis when considering screening mammogra-
adults, was 48.8 [18]. In a US study, 27.7% of transgender phy (see Chaps. 17 and 18).
women tested positive for HIV infection, and this rate was Transgender men who have not undergone mastectomy
substantially higher among those who identified as African- should be referred for mammography according to guide-
American (56.3%) [19]. The CDC recommends screening lines for natal women [11, 21]. The risk for breast cancer
for HIV and other sexually transmitted infections among among transgender men who have had mastectomy is
transgender individuals according to the patient’s sexual unclear and may depend on the amount of residual breast
practices and anatomy [20]. In patients who engage in fre- tissue that is present after surgery. Some guidelines recom-
quent unprotected intercourse, particularly anal-receptive mend performing sub- and periareolar breast examinations
intercourse, the risk for syphilis, HIV, gonorrhea, and chla- annually among transgender men who have had a mastec-
mydia is greatly increased, [21] and screening should be tomy [11], whereas other guidelines encourage providers to
offered every 3–6 months for these infections [22]. individualize the discussion about breast cancer risk accord-
Those transgender patients at high risk for acquiring HIV ing to the surgical history and the extent of persistent breast
infection may be appropriate candidates for pre-exposure tissue [21].
prophylaxis (PrEP) with daily oral tenofovir-emtricitabine to All guidelines emphasize the importance of cervical can-
prevent HIV infection. Per the CDC guidelines, patients are cer screening in transgender men who have not undergone
“clinically eligible” if they have a documented negative HIV hysterectomy. Screening should occur at intervals as recom-
test result, no signs or symptoms of active HIV infection, mended for natal women [11, 21]. Notably, as compared to
normal renal function, no co-administration of contraindi- natal women, transgender men are eight times more likely to
cated medications, and documentation of hepatitis B status have inadequate cytologic sampling during cervical cancer
(i.e., either prior infection or vaccination). Providers should screening, and this is influenced by duration of testosterone
counsel these patients about the efficacy of PrEP as well as therapy [12]. New guidelines, which emphasize the primary
risk reduction strategies, such as regular condom use and role of HPV testing (as compared to cytology), may improve
minimization of the number of sexual partners. If a patient is cervical cancer screening among transgender men and also
interested in PrEP, a daily fixed dose of tenofovir– emtric- be more acceptable to patients. Self-collection of vaginal
itabine (Truvada or Descovy) can be prescribed, with follow- HPV samples may be a good option for some patients who
up visits scheduled every 3 months for HIV testing, are opposed to or unable to tolerate a clinical examination
assessment of renal function, and discussion about adher- (see Chap. 14) [23, 24].
ence and potential side effects [20]. Transgender women should undergo prostate cancer
screening according to guidelines for natal men [11, 21]. The
prostate tissue is retained in transgender women who have
Cancer Screening undergone gender affirming surgery; depending on the type
of surgery performed, it may be located anterior to the vagi-
In all transgender individuals, screening for breast, cervical, nal wall. In these cases, if digital examination is considered,
and prostate cancer should be considered within the context it should be performed through the neovagina [21].
of the patient’s natal or surgical anatomy.
The recommendations for breast cancer screening among
transgender women vary. The Endocrine Society recom- Preventive Care
mends that routine breast cancer screening, including mam-
mography, be performed according to guidelines for natal Appropriate immunizations are an important part of trans-
women [11]. In contrast, recommendations from the gender patients’ preventive care, and the immunization
University of California San Francisco (UCSF) Transgender schedule from the Centers for Disease Control (CDC) and
Center of Excellence suggest that providers consider the Advisory Committee on Immunization Practices (ACIP)
patient’s age and duration of hormone therapy when counsel- should be followed based on age, medical comorbidity, or
ing patients about the appropriateness of mammography sexual practices. HPV vaccination is covered in Chap. 14.
[21]. Specifically, the UCSF guidelines recommend that Bone density testing is recommended for some transgen-
screening mammography be performed only in the following der individuals. According to the Endocrine Society guide-
situations: (1) the patient is over the age of 50 and (2) the lines, it is reasonable to consider screening for osteoporosis
patient has used feminizing hormone therapy for at least among transgender women starting at age 60. Similarly, in
5–10 years [21]. Furthermore, these guidelines recommend transgender men, screening should occur in the setting of
mammography biennially (not annually) in patients who treatment non-adherence, cessation of testosterone therapy,
meet these criteria and that providers discuss the individual’s or development of additional risk factors for osteoporosis
personal risk factors for breast cancer, as well as the potential (See Chap. 25) [11].
Summary Points traditional gender binary [1]. Jamie may be gender fluid,
that is, someone who identifies with different genders; or
1. Gender non-conformity is the umbrella term used when a agender, that is, someone who has a neutral gender iden-
person’s gender identity differs from that which was tity; or non-binary, that is, someone who’s gender does
assigned at birth. This can include a person who is trans- not fit into the gender binary [1]. The best way to find out
gender. Gender dysphoria is the DSM diagnosis which Jamie’s exact identity is to ask them. Jamie shows no evi-
involves a conflict between a person’s physical/assigned dence of gender dysphoria, which is a DSM diagnosis,
gender and the gender with which he/she/they identify. that involves clinically significant distress due to a con-
2. Providers should use open and inclusive language and flict between a person’s assigned gender and their gender
avoid assumptions when asking transgender patients identity [2]. In addition, Jamie is not cisgender, since they
about their gender identity, history of gender-affirming do not identify as the assigned female birth sex, or trans-
medical and surgical treatments, and sexual practices. gender, since they do not identify as male, which is the
This helps to avoid stigmatization and facilitate trust opposite of their birth sex [1].
between provider and patient. 2. A 52-year-old transgender female with a medical history
3. Providers should utilize specific strategies such as asking significant for obesity, osteoarthritis, and gastroesopha-
permission and mirroring the patients’ language to miti- geal reflux disease presents for a routine visit. She has
gate the emotional and physical discomfort that some been on hormone therapy for 7 years; her regimen
transgender individuals experience during the physical includes an estradiol patch, 0.1 mg/24 hours (changed
exam. twice weekly) and spironolactone 100 mg twice daily.
4. The goals of hormone therapy are to reduce natal hor- She has not had gender reassignment surgery. She is cur-
mone levels and to replace with hormones of the affirmed rently sexually active with one female partner and engages
gender, and there are few absolute contraindications to in oral intercourse but does not use dental dams. Her vital
the initiation of hormone therapy. Medical comorbidities signs and physical exam are entirely normal. Which of the
and plans for childbearing should be addressed prior to following is the most appropriate next step in her
starting hormone therapy. management?
5. Cancer screening in transgender patients should be indi- A. Perform a digital rectal exam for prostate cancer
vidualized according to their natal and surgical anatomy. screening
Screening for sexually transmitted infections and immu- B. Order a bone density test
nizations should be individualized according to natal and C. Refer for mammography
surgical anatomy and sexual practices. D. Perform rectal screening for Chlamydia
E. Order a complete blood count (CBC)
The correct answer is C. Cross-sex hormone therapy in
transgender women may increase the risk for breast can-
Review Questions cer. Guidelines from the Endocrine Society recommend
that transgender women of average risk for breast cancer
1. Jamie is a 45-year-old patient who presents to your office receive screening according to recommendations for natal
to establish care. Jamie was assigned a female sex at birth women [11]. The USPSTF currently recommends bien-
but does not identify as either female or male, but rather nial mammography for natal women aged 50–74 years;
as both genders. Jamie prefers the pronouns they/them/ thus, it would be appropriate to offer mammography to
their/themselves. Jamie dresses in whatever feels com- this patient [11]. The University of California San
fortable, which typically involves trousers, button down Francisco Center of Excellence for Transgender Health
shirts or polos, and has long hair which they typically offers slightly different recommendations and states that
wear in a ponytail. appropriate candidates for mammography include trans-
Which of the following best describes Jamie’s gender gender women over the age of 50 who have received
identity? 5–10 years of feminizing hormone therapy [21]. Per those
A. Non-binary guidelines, the patient in this case should be offered
B. Gender dysphoric screening mammography.
C. Transgender All transgender women, regardless of whether they
D. Cisgender have had gender-affirming surgery, will have a prostate.
E. Trans-masculine According to the Endocrine Society Guidelines, provid-
The correct answer is A. The best descriptor of Jamie’s ers should follow recommendations from the USPSTF,
gender identity is likely non-binary, which is a term to which recommends engaging in an informed consent dis-
describe a person whose gender identity falls outside the cussion about the benefits and risks of prostate-specific
antigen screening with individuals between the ages of 55 prior to initiating hormonal therapy. Transdermal estra-
and 59. Based on this patient’s age, prostate cancer diol is theoretically considered to be “safer” than oral
screening would not be currently recommended [11, 25]. estradiol with respect to VTE risk, as it avoids the “first-
Rectal screening for Chlamydia is recommended in pass” effect and so is less likely to activate hepatic coagu-
men who have sex with men and engage in receptive lation factors [14, 15].
intercourse [10] so rectal screening is not appropriate for Changes in a patient’s hormonal regimen should be
this patient. guided by their satisfaction with their appearance and
This patient is at low risk for osteoporosis and has well-being, as well as by serum hormone levels. Elevated
been compliant with her hormone therapy. She should blood levels of estrogen (exceeding guideline-recom-
start screening for osteoporosis at the age of 60, which is mended goal ranges) can increase the risk for VTE, liver
consistent with the Endocrine Society guidelines for dysfunction, and hypertension [4]. This patient is satis-
osteoporosis screening in transgender women [11]. fied with her emotional health and physical appearance,
An increase in the hemoglobin and hematocrit is com- and her serum levels are within goal range. Thus, it is not
monly seen with administration of testosterone therapy in appropriate to increase the dose of transdermal
transgender men but not in transgender women; therefore, estradiol.
routine CBC is not recommended. Several therapies can be used to decrease natal testos-
3. A 62-year-old transgender female presents to establish terone levels, including spironolactone and GnRH ago-
care. She has a medical history significant for obesity, nists [11]. Spironolactone is often used as first-line
hypertension, hyperlipidemia, impaired glucose toler- therapy due to ease of administration and cost. In this
ance, and benign prostatic hypertrophy. She has been patient, spironolactone has effectively suppressed her tes-
using hormonal therapy for 12 years, and her current regi- tosterone levels to goal range, and thus a GnRH agonist is
men includes transdermal estradiol (0.1 mg/24 hours, not indicated.
change twice weekly) and spironolactone 100 mg twice
daily. She is very satisfied with her hormonal therapy in
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Care of the Female Veteran
38
Sophia M. Reljanovic and Megan McNamara
There are approximately 2 million women veterans in the

Learning Objectives United States, and their numbers are growing rapidly [1].
1. List the key components of a military-focused history. Women veterans have served in every branch of the military
2. Summarize strategies and available resources for (Army, Navy, Air Force, Marine Corps, Coast Guard,
helping female veterans successfully reintegrate National Guard, and Reserves), and approximately 50%
from active military service. have served in either Gulf War Era I (1990–2001) or Gulf
3. Describe the rationale for screening and the screening War Era II (2001–present) [2]. There was a striking increase
procedures for mental health disorders that are preva- in the number of women on active duty in the armed services
lent among female veterans, including post-traumatic during the Gulf War Eras; 20% of the veteran population in
stress disorder, military sexual trauma, substance use the Gulf War Era II (post-September 11, 2001) are women
disorders, mood disorders, and suicidality. compared to 4% of the veteran population of the pre–Gulf
4. List medical conditions that can be influenced by War Era [2]. The care of female veterans extends across their
female veterans’ military experiences. life-span and encompasses all aspects of physical and psy-
5. Identify reproductive health issues specific to chosocial health. Two-thirds of women veterans are aged
women veterans and discuss how the approach to 35–64, with a peak around 45–54 years old reflecting Gulf
and management of reproductive health may differ War Era veterans [2].
in women veterans.
verview of Health Issues of Women

O
Veterans
Ava is a 28-year-old female who presents to establish
care. She has been experiencing back pain, bilateral knee Many female veterans receive their care in the civilian set-
pain, and insomnia for the last several months. She ting, so it is essential that all providers are aware of the
recently returned from a 2-year deployment to Afghanistan unique needs of this population [3]. As compared to non-
and has had difficulty finding employment. She is cur- veterans, women who have served in the military are more
rently living with her parents but is not sure how long she likely to be obese or overweight, have cardiovascular dis-
will be able to stay with them. Ava frequently feels “on ease, and report poor health indicators such as tobacco abuse,
guard” and suspicious, and she worries about the effect lack of exercise, and fair or poor overall health [4]. Women
that these feelings will have on her relationships. veterans who have served in recent conflicts in Iraq and
Afghanistan are also prone to developing conditions related
to their deployment, including musculoskeletal disorders
and mental health issues [3]. Approximately 20–25% of
S. M. Reljanovic (*)
female veterans report military sexual trauma (MST) as a
Case Western Reserve University School of Medicine, Louis
Stokes Cleveland VA Medical Center, Department of Women’s result of unwanted sexual attention or forced sexual encoun-
Health, Cleveland, OH, USA ters [1, 5]. Post-traumatic stress disorder (PTSD) may
e-mail: [email protected] develop because of exposure to traumatic events, including
M. McNamara prior MST [3].
Case Western Reserve University School of Medicine, Louis Providers can gain more information about women veter-
Stokes Cleveland VA Medical Center, Department of Medicine,
ans’ experiences by simply inquiring, “Are you currently
Cleveland, OH, USA

574 S. M. Reljanovic and M. McNamara
serving or have you ever served in the military?” [3]. Positive Post-traumatic Stress Disorder
responses should be followed up with additional inquiries
about when and where the individual served, the type of job Although women were not officially deployed in a combat
she performed, and the effect of military service on her life troop role until 2013, many female veterans have held posi-
[1, 3]. Screening for MST and PTSD is imperative, as dis- tions that still exposed them to combat [3]. Experiences of
cussed later in this chapter. combat-related trauma can lead to post-traumatic stress dis-
Asking additional questions about the patient’s history of order (PTSD). PTSD is a condition that can result after expo-
musculoskeletal injuries, exposures, and medical or mental sure to any traumatic event. It is characterized by
health diagnoses during the service period can provide re-experiencing the traumatic event through flashbacks or
insight into the patient’s presenting symptoms. disconcerting and intrusive thoughts [9, 10]. Individuals with
Musculoskeletal pain may be service-related; 60% of Gulf PTSD often exhibit avoidance or numbing behaviors in
War veterans have been diagnosed with musculoskeletal and which they will avoid triggers or situations associated with
connective tissue disorders [3]. Other common conditions the event or exhibit detachment or estrangement. They fre-
associated with Gulf War service include gastrointestinal, quently also have symptoms of persistently heightened
neurologic, and respiratory disorders [3]. arousal or vigilance [7, 9–11].
Chronic pain may impact ability to engage in gainful It is important to screen all female veterans for PTSD. In
employment. In 2013, nearly 100,000 women veterans were a primary care setting, a screening tool such as the Primary
unemployed, with rates higher among veterans aged 25–34 Care PTSD screen for DSM-5 (PC-PTSD-5) can be used [7,
as compared to their civilian counterparts [2]. Unemployment 12, 13]. The PC-PTSD-5 first screens for a traumatic event
has been identified as a “root cause” of homelessness among experience. If present, the patient answers a series of five
females who have served in the military; additional risk fac- questions about experiences over the last month, including
tors include trauma or substance abuse during military ser- (1) nightmares or intrusive thoughts about the event, (2)
vice, and post-military medical, mental health, and substance avoidant behaviors to suppress the event or to avoid triggers
abuse problems [6]. Women who have served in the military that may cause the patient to re-experience the event, (3)
are two to four times more likely than their civilian counter- hypervigilance, (4) the feeling of being numb or detached
parts to be homeless, and the National Coalition for Homeless from the situation at hand, and (5) guilt related to the event
Veterans reports that the number of homeless women veter- [12]. These questions mirror the diagnostic criteria for
ans has doubled in recent years [7]. PTSD. This tool has a sensitivity of 95% when using a cutoff
Fortunately, there are many programs to assist veterans, score of 3 (maximum score = 5), with one point granted for
including the Homeless Veterans Reintegration Program, each positive response to a question [12]. A preliminary
which connects homeless veterans who are reintegrating into study evaluating the use of this screening tool among a sam-
civilian life with meaningful employment. Similarly, the ple of veterans demonstrated that patients found the ques-
HUD-VA Supportive Housing Program can help veterans tionnaire to be broadly acceptable and easy to understand.
obtain vouchers for local public housing. Information about Study participants indicated a preference for having this
these programs can be found at the following website: http:// screening completed by their primary care provider rather
www.nchv.org/images/uploads/HFV%20paper.pdf [8]. than by self-report or by another member of the healthcare
team such as a nurse or medical assistant [12].
Upon further questioning, Ava reports that she served

in the Army as a supply truck driver, and that her route Military Sexual Trauma
was frequently targeted with improvised explosive
devices. Although she was never injured, she saw sev- Unfortunately, in addition to combat-related trauma, another
eral other trucks explode when they were hit. Since common cause of trauma among female veterans is military
returning home she has had frequent nightmares and sexual trauma. Military sexual trauma (MST) is defined by
feels detached from her family and friends. She has the Department of Veterans Affairs as “sexual harassment
been drinking 3–4 beers every night to help her sleep. that is threatening in character or physical assault of a sexual
nature that occurred while the victim was in the military,
regardless of geographic location of the trauma, gender of
the victim, or the relationship to the perpetrator” [3, 14, 15].
Mental Health Perpetrators are not only limited to other military personnel
but may also include civilians, friends, strangers, and inti-
Mental health disorders are common among all veterans. The mate partners [5]. As previously noted, national data from
most prevalent diagnoses include PTSD, depression, anxiety, VA screening programs for MST demonstrate that about 1 in
and substance use disorders. 4 women and 1 in 100 men reported experiencing MST [15,
38 Care of the Female Veteran 575
16]. There is concern that sexual trauma incidents may be ments of cognitive processing therapy, prolonged exposure
underreported due to concerns about confidentiality, fear of therapy, and eye movement desensitization and reprocessing
retaliation, and the belief that no action will be taken [7]. [10, 11]. Additionally, coping skills training and stress-reduc-
Risk factors for MST include: younger age, lower level of tion techniques are often a component of therapy [10, 11].
education, lower military rank, history of prior abuse, and Results from two recent meta-analyses comparing treat-
enlisting to escape an undesirable home environment [3]. ment efficacy of psychotherapy and pharmacotherapy dem-
All female veterans should be screened for MST because onstrated that trauma-focused psychotherapies led to greater
it is common, screening questions are quick and accurate, improvement in PTSD symptoms and longer duration of
and effective treatment for MST exists. Screening can be improvement compared to pharmacotherapy [10, 24, 25].
done by asking the following two questions: “When you Also, medications are typically associated with higher risk of
were in the military, did you ever receive uninvited or adverse reactions and side effects than are psychotherapies
unwanted sexual attention (i.e., touching, cornering, pressure [10]. However, in cases where individualized trauma-focused
for sexual favors, or inappropriate verbal remarks)?” and psychotherapies may not be available or may not be an
“When you were in the military, did anyone ever use force or acceptable or agreeable option to patients, medications can
the threat of force to have sex against your will?” If a patient certainly be considered as well as non-trauma focused psy-
answers “yes” to either one of these questions she should be chotherapy. Furthermore, there is currently insufficient evi-
referred to a mental health provider [1]. dence to conclude that pharmacotherapy is superior to
For women veterans, MST is one of the most significant non-trauma focused therapy or vice versa [10]. Selective
risk factors for development of PTSD [16, 17]. Unfortunately, serotonin reuptake inhibitors (SSRIs) are considered first-
many of the protective factors for PTSD, such as positive line medication options to manage PTSD. Sertraline and par-
social support and a sense of unit cohesion, are lost in oxetine are FDA approved for this indication [10].
instances of sexual trauma that occurs in the military setting Female veterans with a history of MST or a diagnosis of
[3]. MST is more predictive of PTSD than other types of PTSD are eligible for care and treatment at VA medical cen-
military trauma, such as combat-related trauma, or civilian ters. Early referrals should be made because of the availabil-
sexual trauma [3, 17]. Reports indicate that 40–60% of ity of specialized resources. Depending on the VA site,
female survivors of MST will later develop PTSD [18]. resources can include the following:
In addition to being associated with PTSD, prior MST or
other traumatic experiences are also associated with other men- • Suicide prevention coordinator
tal health problems including mood disorders and substance • MST coordinator
use disorders [7, 17, 19]. Sixty percent of women veterans with • Specialists experienced in treating patients with a history
a history of MST screen positive for depression and are twice of MST and with expertise in PSTD diagnosis and
as likely to have alcohol abuse disorder than veterans without management
MST [20]. Thus, it is important to screen for these comorbid
conditions as well. Screening for depression and anxiety can be Veterans can also be directed to other PTSD and MST
accomplished with the Patient Health Questionnaire (PHQ-2 or resources:
PHQ-9) and the Generalized Anxiety Disorder Scale (GAD-2
or GAD-7), further discussed in Chap. 33. The AUDIT-C • VA PSTD website provides information for veterans, fam-
screening tool developed by the World Health Organization can ily, friends, and providers (https://www.ptsd.va.gov/) [26]
be used to assess alcohol abuse. The Department of Veterans • VA MST website provides information about VA MST
Affairs recommends screening all veterans annually for resources and has links to helpful articles and fact sheets
unhealthy alcohol use [21]. The AUDIT-C screening tool is (https://www.mentalhealth.va.gov/msthome/index.asp) [27]
available at the following VA website: https://www.hepatitis. • Veterans crisis hotline 1-800-273-8255, press #1 [28]
va.gov/provider/tools/audit-c.asp [22].
Ava agrees to be referred to a mental health provider

Treatment and is diagnosed with PTSD. Her symptoms and mood
improve significantly with treatment, and she returns
Screening for these conditions can assist in destigmatization to primary care 3 months later to discuss her other
and earlier identification which in turn provides opportunity medical issues. She has been limiting her activities due
for earlier mental health referral and treatment [13, 23]. to her knee and back pain, and as a result has gained
Treatment for PTSD, whether due to combat-related trauma 10 pounds in the last 8 weeks. She is currently taking
or MST, can involve therapy and medication. Trauma-focused paroxetine for her PTSD and ibuprofen to manage her
cognitive behavioral therapy (CBT) is considered the most pain.
effective treatment for PTSD [10, 11]. CBT may involve ele-
Veterans have a high prevalence of certain medical condi- There is no diagnostic test for traumatic brain injury [11].
tions that can be influenced by prior military service and Rather, evaluation involves conducting a thorough history of
exposure to hostile military environments. Additionally, a the inciting incident. History for TBI should include infor-
history of trauma and PTSD can frequently have an impact mation about the mechanism of injury, course and duration
on physical wellbeing. An analysis of VA healthcare utiliza- of symptoms, and any treatment or evaluation that was com-
tion among veterans of the War in Iraq and the War in pleted at the time of the event [11]. Duration of symptoms
Afghanistan reported that 60% had diagnoses of diseases of including loss of consciousness, altered mental status, and
the musculoskeletal system and/or connective tissue disor- post-traumatic amnesia are used to classify TBI severity [13,
ders, 48.7% had diseases of the nervous system, and 37.1% 30]. Severity can range from mild to severe with mild symp-
had diseases of the digestive system [3]. toms typically improving over a short period of time.
However, in some cases, there can be residual symptoms
which can include headaches, dizziness, irritability, mood
Musculoskeletal System changes such as increased feelings of anxiety or depression,
difficulty concentrating, sleep disturbances, and persistent
All veterans are at risk for musculoskeletal injuries. Military memory problems [11, 13, 30]. Lingering symptoms are
personnel, regardless of combat experience and gender, related to the degree of brain injury sustained during the ini-
chronically expose their bodies to significant physical stress tial trauma and may be permanent; the most serious perma-
during training, drills, and daily work. Soldiers often have to nent changes can include changes in personality, executive
carry armor, weapons, and supplies for long distances [7, function, or physical health. It is important to note that the
23], which can lead to acute and overuse injuries. Compared symptoms of TBI can overlap with those of PTSD, mood
to male veterans, women veterans have higher rates of disorders, and substance use disorders [11, 30]. Thus, pro-
chronic musculoskeletal pain, physical injuries, and stress viders should maintain a high level of suspicion and assess
fractures [3]. The risk of injury can be compounded by for these conditions which may present simultaneously.
poorly fitting equipment and body armor that is often not The examination in patients with a history of TBI should
designed for the female body type [23]. include a complete neurologic exam, head and neck exam,
In addition to musculoskeletal pain resulting from physi- and neurocognitive screening [11, 13]. At present, evidence
cal injury, there is also high prevalence of functional pain does not support the use of laboratory tests or imaging
syndromes among veterans. Fibromyalgia prevalence is beyond its potential role in the acute setting immediately fol-
higher in women with a history of PTSD [3]. One study lowing injury, unless symptoms change or worsen, or the
involving patients with PTSD and fibromyalgia symptoms patient develops alarm symptoms such as acute vision
reported that in two-thirds of the cases, trauma preceded the changes, altered mental status, persistent vomiting, balance
fibromyalgia symptoms as opposed to 30% of cases in which issues, or a neurologic deficit [13, 30].
pain symptoms were followed by trauma or PTSD [29]. This Management of patients with a history of TBI is also
association illustrates that fibromyalgia and PTSD are risk based on symptoms [11, 30]. Education about sleep hygiene,
factors for each other and are often comorbid conditions [7]. referral to neurocognitive therapy, physical therapy, and use
Keeping this relationship in mind, it is important for provid- of biofeedback and relaxation therapy can often be helpful in
ers to remember to screen women with unexplained pain addressing symptoms such as sleep disturbances, headaches,
syndromes for psychiatric disorders and history of trauma irritability, and anxiety [30]. While treatment recommenda-
[3]. Please see Chap. 26 to review the General Approach to tions often include nonpharmacologic interventions, medica-
Chronic Pain and Chap. 29 to learn more about Fibromyalgia. tions for the complications of TBI can also be of benefit.
These may include analgesics for pain (NSAIDs, acetamino-
phen), treatment of acute or chronic migraine headaches
Traumatic Brain Injury (TBI) (See Chap. 28), nausea (ondansetron), mood disorders
(SSRIs, SNRIs), insomnia (sleep medications), and dizzi-
Traumatic brain injury (TBI) refers to a structural injury or ness (as needed meclizine). A general overarching guideline
physiological disruption of brain function due to a traumatic regarding medication use in persons with a history of TBI
external force and is a common injury seen among returning includes avoiding medications that lower the seizure thresh-
military personnel [30]. Operation Enduring Freedom old or cause confusion or sedation [30]. Lastly, referral to a
(2001–2014) and Operation Iraqi Freedom (2003–2011) vet- neurologist or provider that specializes in brain injury can
erans, in particular, are at risk. Ten to twenty percent of ser- always be considered if the patient has refectory symptoms
vice members report having at least one TBI as a result of that are not responding to typical treatment options. Also,
their service obligations [7, 13, 31]. referral to a mental health provider can be of benefit, particu-
larly as behavioral health conditions can often present con- port [1]. Not surprisingly, bladder dysfunction has been
currently with post-mild TBI symptoms [30]. linked to a history of trauma and mood disorders [1]. Please
see Chap. 23 to learn more.
Gastrointestinal System
Ava’s pain improves with physical therapy and weight
Functional gastrointestinal disorders such as irritable bowel loss. She returns to clinic feeling better both mentally
syndrome (IBS) and functional dyspepsia are more common and physically. She has stopped drinking alcohol, has
in women veterans compared to civilian women. It is known been adherent to the paroxetine, and has not used ibu-
that stressful events such as experiences during military ser- profen in months. She is in a new relationship with a
vice can exacerbate functional gastrointestinal disorders. In a male partner and is using condoms intermittently but
study investigating prevalence of IBS and dyspepsia among is not interested in getting pregnant. She previously
women veterans, 38% reported IBS and 21% reported dys- used oral contraceptive pills but discontinued them
pepsia [32]. This study also demonstrated a high association during deployment, because it was “too hard to
between these gastrointestinal disorders and a history of remember them.” What do you recommend for
trauma, PTSD, anxiety, and depression [32]. In another study contraception?
looking specifically at the association between trauma and
IBS in women veterans, 56% of women with IBS reported
having been forced to have sex against their will versus 42%
of women without IBS [33]. Also in the same study, 36% of Reproductive Health
patients with IBS reported attempted, forced, or unwanted
sexual contact versus 21% of patients without IBS [33]. Many women veterans experience reproductive health issues,
These studies illustrate a clear association between trauma, which may be influenced by a variety of factors, including
including MST, and functional gastrointestinal disorders. prior military exposure, medical comorbidities, and mental
Please see Chap. 27 to learn more about the diagnosis and health diagnoses and treatment [1]. In a cross-sectional VA
management of this disease. study, common reproductive health diagnoses among women
aged 18–44 included menstrual disorders, endometriosis,
sexually transmitted infections, urinary disorders, vaginitis,
Genitourinary System and pregnancy-related conditions, whereas older women vet-
erans experienced menopausal issues and osteoporosis.
Genitourinary concerns are common among women veter- Women who had a reproductive health diagnosis, as com-
ans. A review of VA healthcare utilization among War in Iraq pared to those who did not, were more likely to have a
and War in Afghanistan veterans reported that 17% had a comorbid medical or mental health condition [35].
diagnosis of diseases of the genitourinary system, which Family planning and contraceptive counseling are essen-
often include chronic pelvic pain and menstrual disorders tial for women veterans who want to avoid pregnancy or
[3]. Again, research shows that there is an association whose medical or mental health treatments expose them to
between these conditions and a history of trauma [3]. One potentially teratogenic medications. In one study, 37% of
study found that among female veterans who reported men- reproductive-age women veterans reported an unintended
strual disorders, such as premenstrual syndrome, abnormal pregnancy, and 11.5% of women at high risk for pregnancy
uterine bleeding, and dysmenorrhea, 71% had experienced were not using any form of contraception [36]. Contraceptive
MST [3, 34]. This once again illustrates the potential for far- knowledge among women veterans may be low, and differ
reaching effects of trauma. Women with a history of PTSD according to certain racial and ethnic minority groups [37].
and chronic pelvic pain have significantly lower reports of Additionally, women veterans who have been diagnosed
physical functioning and functioning without pain which can with a mental illness or substance use disorder are more
in turn impact all aspects of their lives and overall productiv- likely to be nonadherent to contraception [38].
ity [3]. Please see Chap. 31. A variety of contraceptive methods are available to
Urinary incontinence is another urogenital concern for women who receive care at VA centers, including combined
which female veterans are at higher risk. Twenty-two percent hormonal contraceptives (ring, pill, patch), a progestin-only
of women veterans report overactive bladder symptoms pill, and long-acting reversible contraceptives (LARCs:
which is higher than the prevalence seen in non-veteran injection, subdermal implant, intrauterine devices [IUDs]).
women [1]. Women may often need to participate in strenu- Providers should consider a patient’s medical and mental
ous activity and heavy lifting as part of their military service health comorbidities, as well as the likelihood of adherence,
and training which can have adverse effects on pelvic sup- when counseling about various contraceptive methods.
Among 1169 women veterans included in a cross-sectional 2. Reintegration into civilian life following military service
study, 29% had a medical contraindication to combined hor- can be challenging for many veterans. VA has many avail-
monal contraceptives, including hypertension, migraine with able resources and programs that can be helpful.
aura, and smoking over the age of 35 [39]. Similarly, women 3. Certain mental health disorders such as PTSD, MST, sub-
treated for medical or mental health disorders may be stance use disorders, mood disorders, and suicidality are
exposed to medications which are associated with adverse more prevalent among female veterans, and providers
pregnancy outcomes. Investigators who conducted a retro- should screen for these using validated screening
spective cohort study found that 12.6% of prescriptions dis- questionnaires.
pensed to female veterans were potentially teratogenic; the 4. Many medical conditions such as musculoskeletal diag-
most frequent indications for treatment included psychiatric noses, neurologic disorders, gastrointestinal symptoms,
illness, hypertension, and hyperlipidemia. Only 55.7% of and genitourinary concerns can be impacted by a wom-
women veterans who obtained prescriptions for teratogenic an’s prior military experience.
medications received any documented counseling about 5. Female veterans may have unique reproductive health
family planning [40]. needs. Providers should feel comfortable counseling
LARCs are highly effective forms of contraception which about a variety of contraceptive methods and STI preven-
are gaining in popularity among women veterans [36, 41]. tion, recognizing the medical and mental health comor-
IUDs may be an ideal choice among women with medical bidities that are more common in women veterans.
comorbidities as there are few medical contraindications to
use. LARCs’ ability to provide long-acting protection with-
out a daily, weekly, or even monthly dosing of medication
gives women on active military duty freedom to have effica- Review Questions
cious contraception without worrying about how the next
dose of medication will be obtained. In particular, LARCs 1. A 43-year-old female veteran presents for routine pri-
may be preferable for women whose history of PTSD mary care. She has a medical history significant for fibro-
increases their risk for contraceptive non-adherence and myalgia, irritable bowel syndrome, and is overweight.
whose mental health treatment may increase their risk for She was deployed to Afghanistan for 10 months and
adverse fetal outcomes. See more about contraception returned 1 year ago. For the past several months, she has
options and counseling in Chap. 4. been experiencing discomfort in her lower abdomen
As noted previously, sexually transmitted infections which is dull and constant in nature. The discomfort does
(STIs) are one of the top 5 reproductive health diagnoses not worsen with her menses, which have remained nor-
among younger women veterans [35]. Compared to their mal in flow and duration. She has been sexually abstinent
civilian counterparts, women veterans initiate sexual activity for the last 2 years. The pain has interfered with her abil-
at a younger age, have a greater number of both female and ity to work as a teacher.
male partners, are more likely to report a history of genital On exam, she is afebrile with normal vital signs; car-
warts, and to be seropositive for herpes simplex virus-2 [42]. diovascular, pulmonary, abdominal, and genitourinary
Providers should consider these factors, as well as the exams are normal.
patient’s reported sexual practices, when counseling about What is the next best step in her management?
screening for STIs. Regular condom use is the only way to A. Initiate oral contraceptive pills
protect from sexually transmitted infections. Veterans should B. Refer to gynecology for diagnostic laparoscopy
be screened for STIs according to nationally published C. Screen for sexually transmitted infections
guidelines and all women who use condoms inconsistently, D. Refer for pelvic floor physical therapy
regardless of age or partnership, should be counseled about E. Screen for military sexual trauma
screening for STIs at routine intervals [43]. The correct answer is E. This patient’s symptoms are
consistent with chronic pelvic pain. Although chronic
pelvic pain has many causes, it is important to consider an
Summary Points underlying diagnosis of trauma in patients presenting
with this syndrome [11, 14]. Mental health disorders are
1. Asking about military service is important in a primary common among female veterans, and approximately 25%
care setting. A military focused history should include a have experienced military sexual trauma [14, 15]. Military
review of the type of military service as well as screening sexual trauma (MST) is strongly associated with the
for conditions that are more common among military development of post-traumatic stress disorder (PTSD),
personnel. which, in turn, has been linked to chronic pelvic pain in
some patients. In one study, almost one-third of patients event (blast during deployment) that was potentially life-
presenting with chronic pelvic pain screened positive for threatening, she describes symptoms of re-experiencing
PTSD [3]. that event as evidenced by her reaction to loud noises; she
While endometriosis is associated with pelvic pain, exhibits avoidance behaviors and symptoms of hyper-
the discomfort is often cyclical, and associated with other arousal. It is important to note that the symptoms of TBI
symptoms, such as dyspareunia and dysmenorrhea. Oral can often overlap with and present in conjunction with
contraceptive pills are a reasonable first step in the empiric symptoms of PTSD. Thus, providers should be vigilant
treatment of endometriosis but are less appropriate here. about screening for both diagnoses which have high prev-
Diagnostic laparoscopy is recommended for evaluation of alence among veterans. The most effective treatment for
endometriosis when the diagnosis is uncertain or medical PTSD is cognitive behavioral therapy (CBT). SSRIs, such
treatments have not been helpful. as sertraline, can be considered as a medication options to
Chronic pelvic pain may be caused by untreated pelvic manage PTSD [10].
infections; thus, it is reasonable to consider testing for Options such as counseling about sleep hygiene and
sexually transmitted infections (STIs). However, this zolpidem are sometimes used to manage insomnia in
patient has been sexually abstinent for 2 years, and so patients with PTSD. However, they are not considered
STIs are less likely. Testing for STIs may be considered in first-line therapy. Neuroimaging is typically not neces-
addition to screening for military sexual trauma. sary when diagnosing TBI and has no role in diagnosing
Pelvic physical floor therapy is recommended for PTSD. Additionally, this patient is not presenting with
patients with chronic pelvic pain attributable to myofas- any “red flag” headache symptoms such as new onset,
cial syndrome or spasm of the pelvic floor muscles. thunderclap headache, awakening from sleep with head-
2. A 32-year-old female veteran presents to your primary ache, etc., that might warrant a brain MRI.
care office for follow-up. She has a diagnosis of traumatic
brain injury (TBI) following a blast injury during which
she lost consciousness for several minutes while deployed References
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2015;12(4):394–401. https://doi.org/10.1037/ser0000054. https://doi.org/10.1111/j.1365-2036.2010.04387.x.
17. Goldstein LA, Dinh J, Donalson R, Hebenstreit CL, Maguen 34. Barnard K, Frayne SM, Skinner KM, Sullivan LM. Health sta-
S. Impact of military trauma exposures on posttraumatic stress and tus among women with menstrual symptoms. J Womens Health
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https://doi.org/10.1016/j.psychres.2017.01.009. 35. Katon JG, Hoggatt KJ, Balasubramanian V, Saechao FS, Frayne
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3):S65–9. MLR.0000000000000295.
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ans, and their families: what we know now. Nurse Educ Today. et al. Unintended pregnancy and contraceptive use among women
2016;47:23–6. veterans: The ECUUN study. J Gen Intern Med. 2017;32(8):900–8.
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DR, Sullivan LM. The prevalence of military sexual assault among 37. Rosenfeld E, Callegari LS, Sileanu FE, Zhao X, Schwarz EB,
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June 2018. org/10.1016/j.contraception.2015.01.013.
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vider/tools/audit-c.asp. Accessed December 2018. traindications to estrogen and contraceptive use among women
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https://doi.org/10.1002/da.22511. long-acting reversible contraception in the United States military
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org/10.4088/JCP.12r08225. Reiber GE, Simpson TL. Sexual behaviors and sexually transmitted
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msthome/index.asp. Accessed December 2018. 43. Centers for Disease Control and Prevention. 2015 sexually trans-
28. Veterans Crisis Line website. https://www.veteranscrisisline.net/. mitted diseases treatment guidelines.
Part VIII
Pregnancy
Obstetric Medicine
39
Lisa B. Bernstein, Michael P. Carson, Meredith O. Cruz,
Rachel K. Harrison, Amanda Johnson, Anna Kho,
Beth Lewis, and Sarah A. Tilstra
Learning Objectives ection 1: Principles of Caring for

S
• Describe general principles that a provider should Pregnant Women
follow when caring for pregnant women.
• Explain preconception/interconception interven- • A healthy fetus depends on a healthy mother. The best
tions that help to minimize risk and contribute to a approach is to develop a clinical plan as if she were not
healthy pregnancy. pregnant; then obtain information to determine how the
• Describe the approach to medication utilization and plan does or does not need to be modified in the setting of
testing during pregnancy. pregnancy. Often you will be reassured that the non-
• Outline the clinical manifestations, diagnosis, and pregnant plan is best for the mother and baby. Consider
management of common medical conditions during the real benefit to the mother and fetus related to the test
pregnancy, including hypertension, asthma, venous or treatment, not just the theoretical or rare risks.
thromboembolism, diabetes mellitus, thyroid dis- • Refrain from saying “no” when you “don’t know.” Use
ease, and depression. evidence-based medicine to answer clinical questions and
• State complications that can occur in the postpar- seek out expert opinion where data is lacking or does not
tum period and what the primary care provider’s exist.
main role is in diagnosing and managing each one. • Determine if non-pharmacological therapies can be used
as first-line treatments; if medications are required, it is
important to consider the efficacy and safety profile for
pregnant women, which may vary by trimester.
• Do not consider tests, interventions, or medications as
“safe” or “unsafe”; consider the clinical setting and then
determine which ones may be “reasonable” or
“indicated.”
• Always consider the consequences and risks of NOT
obtaining the test or administering the treatment.
L. B. Bernstein (*) · A. Kho A. Johnson

Emory University School of Medicine, Department of Medicine, University of Colorado School of Medicine, Department of
Atlanta, GA, USA Obstetrics and Gynecology, Aurora, CO, USA
B. Lewis
M. P. Carson Jacobi Medical Center, Department of Obstetrics and Gynecology,
Hackensack Meridian School of Medicine at Seton Hall, Jersey Bronx, NY, USA
Shore University Medical Center, Department of Medicine,
S. A. Tilstra
Neptune, NJ, USA
M. O. Cruz Internal Medicine, Department of Medicine, Pittsburgh, PA, USA
Froedtert and the Medical College of Wisconsin, Department of
Obstetrics and Gynecology, Milwaukee, WI, USA
R. K. Harrison
Medical College of Wisconsin, Department of Obstetrics and
Gynecology, Milwaukee, WI, USA

584 L. B. Bernstein et al.
Preconception/Interconception Counseling Reproductive age women with high risk conditions such
as intestinal malabsorption, diabetes, liver disease, and those
who are taking valproic acid or carbamazepine for seizures
Aaliyah is a 32-year-old G1P1 female with a history of should take up to 1000 μg (1 mg) of folic acid for prevention
hypertension, type 2 diabetes, and intermittent asthma of poor pregnancy outcomes [8, 9]. Women with a history of
who presents to your office for an annual physical neural tube defects themselves or a first-degree relative
exam. She uses condoms for birth control and is inter- should take 4000 μg (4 mg) of folic acid daily [8, 10, 11].
ested in having more children. She takes lisinopril After the first trimester, when neural tube development is
20 mg daily for hypertension and metformin 500 mg complete, the folic acid dose can be reduced to 0.4 mg daily
twice daily for diabetes, rarely needing her rescue since high dose folic acid can lead to long-term adverse
inhaler. She smokes 2 cigarettes per day and drinks 1 effects [12]. Women should continue folic acid at 0.4 mg
glass of wine on the weekends. She had some baby daily after the first trimester through 4–6 weeks postpartum
blues after her first pregnancy but did not require any or as long as breastfeeding continues [8].
antidepressant medication. Her blood pressure is
124/78 and she is overweight with a body mass index
(BMI) of 28 kg/m2. The remainder of her exam is nor- Advanced Maternal Age
mal. What is the best way to optimize her health prior
to a pregnancy, and how would you counsel her during As women age, fertility declines and the risk of pregnancy
this preconception time period? complications increases. Advanced maternal age is defined as
maternal age ≥35 years old and is associated with increased
risk of miscarriage, preeclampsia, gestational diabetes, chro-
mosome abnormalities, congenital abnormalities, placenta
ptimal Timing of Pregnancy Based on Health
O previa, low birth weight, preterm delivery, small size for ges-
and Social Factors tational age infants, and perinatal mortality [13, 14]. As many
women are delaying childbearing until the third and fourth
In the United States, as many as half of pregnancies are unin- decade, it is important to discuss offsetting the risk of mater-
tended [1]. Primary care providers have the opportunity to nal age by optimizing modifiable risk factors.
educate women in the preconception period to help optimize
their health during pregnancy. Every clinic visit for a repro-
ductive age woman is a chance to counsel about issues that Body Mass Index (BMI)
may impact a pregnancy including the timing of pregnancy in
the setting of chronic health conditions, advanced maternal Achieving an appropriate BMI prior to pregnancy can
age, elevated BMI, family history of genetic disorders, sexu- improve obstetric outcomes. Women with a BMI ≥ 30 kg/m2
ally transmitted infections (STIs), vaccinations, folic acid are more likely to have obese infants, infants with low Apgar
supplementation, substance use, caffeine intake, environmen- scores and congenital anomalies, and higher perinatal mor-
tal exposures, and intimate partner violence (IPV) [2]. tality. Being thinner is not always better, as women with a
low BMI (<18.5 kg/m2) are at risk for preterm birth and
lower birth weight infants compared to women with a normal
Folic Acid Supplementation BMI [15–18]. However, underweight women do have a
lower rate of preeclampsia, gestational diabetes, and obstet-
Daily folic acid supplementation of 400 μg (0.4 mg) in preg- ric interventions [19]. Primary care providers should provide
nant women has been shown to reduce the risk of neural tube nutritional education and exercise recommendations for
defects, cleft lip/palate, genitourinary abnormalities, congeni- women who fall outside the range for a normal BMI.
tal heart defects, and hydrocephalus in offspring [3–5].
Because the neural tube forms quickly, between 26 and
28 days after conception, folic acid must be started before con- Family History and Genetic Counseling
ception. The CDC, National Academy of Medicine, and the
USPSTF all recommend that women of childbearing age with Obtaining a family history of inherited disorders and referral
an intact uterus, regardless of stated contraception methods, to a geneticist for further counseling and testing could be
consume 400 μg (0.4 mg) of folic acid daily [6]. Most “prena- considered for those with a personal or family history of con-
tal” or “women’s” vitamins will contain 400 μg (0.4 mg) or genital malformations, developmental disability, hemophilia,
more of folic acid and can be purchased over-the-counter [7]. hemoglobinopathy, cystic fibrosis, polycystic kidney dis-
39 Obstetric Medicine 585
ease, neurofibromatosis, or a similar inheritable condition. Influenza: All women regardless of pregnancy status, and
Counselors can help determine the need for prenatal testing who do not have a contraindication, should be vaccinated for
of the parents or the fetus to inform decisions about family influenza. Pregnant women have an exceptionally high rate
planning, observation of the fetus during pregnancy, and plan of morbidity and mortality from influenza, most often from
for any foreseeable complications upon the child’s birth. respiratory complications, secondary bacterial infections,
and sepsis [29]. Pregnant patients should not receive the live
attenuated influenza vaccine since its safety in pregnancy has
Sexually Transmitted Infection (STI) Screening not been established.
Depending on the type of infection, treatment may reduce Special populations: For patients at risk for infections with
the mother’s rate of infertility, pregnancy complications, and encapsulated organisms, compromised immunity, or high
congenital infection in the newborn [19]. For example, risk occupations, consider immunization against
women with HIV can reduce the rate of maternal-infant HIV Haemophilus influenzae, hepatitis B, meningococcus, and
transmission if maternal antiretroviral therapy is initiated pneumococcus in the preconception period.
during the antepartum or intrapartum periods and adminis-
tered to the infant during the first 6 weeks of life [20].
Women who are contemplating pregnancy should be ubstance Use (Tobacco, Alcohol, Drugs),
S
tested for chlamydia, gonorrhea, hepatitis B and C, human and Caffeine Intake
immunodeficiency virus (HIV), syphilis, and trichomonas. It
is standard of care to collect these labs at the first prenatal It may be very difficult for women who are considering preg-
visit [21]; however, if a patient is at high risk for these infec- nancy or already pregnant to admit to cigarette, alcohol, and
tions consider testing prior to and throughout pregnancy. substance use. They may fear legal consequences or perceive
that they may lose custody of their child at birth. Thus, tak-
ing the social history in a confidential and non-judgmental
Vaccinations manner is vital.
Cigarette smoking is associated with nearly every obstet-
Women should be vaccinated against vaccine-preventable ric complication including decreased fertility, placental
diseases prior to pregnancy. Live-attenuated vaccines, such abruption, preterm premature rupture of membranes
as the MMR and varicella vaccines, are contraindicated (PPROM), placenta previa, preterm labor, preterm delivery,
during pregnancy and must be given in the preconception low birth weight (LBW), ectopic pregnancy, and stillbirth
period [22, 23]. [30–32]. Smoking reduction, as assessed by maternal nico-
tine levels, has been associated with greater fetal weight
Measles, mumps, rubella (MMR), and vari- compared to women who continued smoking, and any level
cella: Congenital rubella can be devastating for the fetus of reduction up to 30 weeks gestation can have a beneficial
and is known to cause deafness, developmental disability, effect on the obstetric risk [33]. At the preconception visit,
heart defects, and eye problems [24]. Immune status, if and at every visit during her pregnancy (if needed), the
unknown, can be determined by checking MMR and vari- American College of Obstetricians and Gynecologists
cella titers prior to administration of the vaccine. If the vac- (ACOG) and the USPSTF recommend using the Five As
cine is needed, pregnancy should be avoided for at least intervention to identify smokers and facilitate cessation: Ask
1 month after each live vaccine dose for MMR and up to about her smoking status, Advise her to quit, Assess her read-
3 months after varicella vaccination [25]. iness to quit, Assist her in quitting, and Arrange follow-up
visits [34, 35]. Non-pharmacologic methods proven to help
Tetanus, diphtheria, and pertussis (Tdap): All adults pregnant women quit smoking include pamphlets, videos,
over 19 years old who have not previously received the Tdap access to a health educator, and support groups. For some
vaccination should receive one dose, followed by a tetanus patients, counseling and support by phone (1-800-QUIT-
and diphtheria (Td) booster every 10 years; Tdap should take NOW) offers a convenient and flexible way for them to com-
the place of one Td shot during adulthood to provide better municate with someone who can encourage desirable health
protection against pertussis as immunity wanes with age behaviors [36].
[26]. Additionally, pregnant women should receive Tdap When other interventions have been unsuccessful, phar-
vaccination with every pregnancy, preferably during the macotherapy may help patients in their quest to quit smok-
early part of the 27–36-week gestational range to help pro- ing. Nicotine replacement therapy (NRT), which includes
tect baby from pertussis during infancy [27, 28]. nicotine lozenges, spray, patches, gum, and an inhaler, may
be used as an adjunct to behavioral modification for smoking Much of the evidence of caffeine’s effect on humans is
cessation in the preconception period, even during preg- low quality; however, it appears that 200 mg/day or less of
nancy. The benefits of decreasing smoking with NRT are caffeine intake is not associated with increased risk of con-
thought to outweigh the risks. NRT and smoking both expose genital malformations, miscarriage, or growth restriction
the maternal/fetal unit to nicotine exposure. However, NRT [46]. Because of this, several organizations, including
use can decrease exposure to smoke and carcinogens; there- ACOG and the March of Dimes, recommend limiting caf-
fore, while long-term data may not be available, simple logic feine intake to <200 mg/day rather than restricting it entirely
dictates that NRT use is reasonable during pregnancy. NRT [47, 48].
can facilitate cessation in the non-pregnant population, it can
reduce the pulmonary effects of smoking on the mother, and
was felt to be safe enough for use in a randomized trial. Safety Assessment, Intimate Partner Violence
While the trial did not demonstrate that NRT was effective
for smoking cessation during pregnancy, it was not found to Intimate partner violence (IPV) affects millions of women
be more harmful than smoking [37–39]. regardless of age, economic status, race, religion, sexual ori-
In pregnancy, there may be a higher rate of left ventricular entation, or educational background [49]. As abuse can
outflow obstruction in infants exposed to bupropion during worsen when a woman is pregnant, it is vital to screen women
the first trimester [40]. As a result, when indicated, it is rea- for IPV and assess for characteristic features of abuse. Injury,
sonable to avoid use until after the first trimester. First tri- bruising, missed appointments, and anxiety/depression can
mester exposure to varenicline does not appear to be be objective signs that a patient may be a victim of abuse.
teratogenic, but as the safety in pregnancy has not been Please see Chap. 35 to learn more about IPV.
established, it is reasonable to recommend discontinuation of
the medicine near the time of conception [41].
Alcohol consumption during pregnancy can lead to fetal Preexisting Medical Conditions
alcohol spectrum disorder and stillbirth [42], and while
women often drink “a glass of wine here-and-there” during Women of childbearing age with chronic medical condi-
pregnancy, there is no known threshold amount of alcohol tions should be advised to seek care for optimization of their
that is proven safe to consume in pregnancy. A single-item medical issues prior to conception. These women should
screening tool is a practical way for providers to screen for use reliable contraception until their medical issues are con-
hazardous alcohol use in women: “How many times in the trolled to secure the best outcome for them and any future
past year have you had 4 or more drinks in a day?” A response pregnancy. In addition, their medications should be recon-
of ≥1 is considered positive [43]. Women who screen positive ciled and adjusted to minimize any potential harm to a
should be counseled regarding the harm that can occur when developing fetus.
alcohol is consumed in pregnancy. Patients that show signs of
alcohol use disorder should be provided information regard-
ing appropriate detoxification and treatment services includ- eneral Approach to the Management
G
ing a list of alcohol rehabilitation resources, and referrals to of the Pregnant Patient
social work, psychiatry and/or an addiction specialist.
With the legalization of marijuana in some states, both for Physiologic Changes of Pregnancy
recreation and medicinal purposes, more women are using
marijuana than ever before. Because it is legal, women may The hormonal changes of pregnancy alter maternal physiol-
not perceive that marijuana is harmful to baby. Babies born ogy as early as 5 weeks gestation and typically resolve by
to mothers who used marijuana are more likely to have lower 6 weeks postpartum. Cardiac output increases by three main
birth weights, spend time in the neonatal intensive care unit mechanisms: increase in maternal heart rate, increase in
after birth, be stillborn, and have learning and behavioral plasma volume, and decrease in systemic vascular resistance.
issues later in life [44, 45]. ACOG strongly advises against A common finding reflecting this increase in flow is a II/VI
all forms of marijuana use, including medicinal use, during systolic pulmonary artery flow murmur at the upper left ster-
pregnancy [45]. nal border. A simple maneuver to document the normal pul-
Patients who use other substances such as cocaine, meth- monic arterial flow murmur of pregnancy is that it will
amphetamines, heroin, and inhalants should be referred become quieter with a deep breath as the chest wall moves
immediately to substance use rehab programs, social work, away from the pulmonary artery. Diastolic murmurs are not
psychiatry, and/or an addiction specialist. Please see Chap. normal and should always be evaluated. The low resistance
32 for more information on how to treat opioid use during vascular beds in the uterus and placenta decrease systemic
pregnancy. vascular resistance. As plasma volume increases relative to
red cell mass, women develop physiologic anemia of preg- with worsened proteinuria in women with preexisting renal
nancy [50, 51]. disease [50, 51].
Pregnant women often feel dyspneic, even before the
uterus restricts diaphragmatic excursion. While the mecha-
nism is not entirely clear, it is likely related to how progester- Prescribing in Pregnancy
one affects the respiratory system and acid/base balance.
Maternal minute ventilation increases in the first trimester by Medications are often required for optimal control of a wom-
increasing tidal volume, while maintaining resting maternal an’s chronic medical issues in order for a successful pregnancy
respiratory rate. This causes relative hypocapnea, reflecting outcome. The US Food and Drug Administration pregnancy
the normal PCO2 of pregnancy around 30 mmHg. Pulmonary safety categories A, B, C, D, and X are no longer used to guide
mechanics and spirometry do not change, but the gravid prescribing; instead, providers should consider if a medication
uterus can restrict diaphragmatic excursion later in preg- is clinically indicated or not, and the implications for the
nancy resulting in a decreased residual volume. It is always mother and fetus if the medication is used versus withheld [53].
important to consider all causes of dyspnea in pregnant Educate patients that uncontrolled medical issues are often
women before attributing symptoms to benign dyspnea of more detrimental to a pregnancy than are the medications used
pregnancy [52]. to control them. When treating any medical illness in pregnant
Gastroesophageal reflux is common due to the women, first consider non-pharmacological interventions and
progesterone-mediated decrease in lower esophageal sphinc- try to limit medications in the first trimester. Most medications
ter tone. Progesterone also decreases intestinal motility and cross the placenta; while ample safety data may not be avail-
can lead to severe constipation. Creatinine clearance able for all medications, thankfully, few drugs are absolutely
increases by 50% during pregnancy, which can be associated contraindicated in pregnancy (Table 39.1) [53, 54].
Table 39.1 Examples of common medications that are relatively or absolutely contraindicated in pregnancy (may not be an exhaustive list of
every teratogenic medication) [53–59]
Medication Risks Clinical advice
Androgens Virilization of female fetus Avoid
Angiotensin converting enzyme Pulmonary and renal hypoplasia, renal tubular Avoid
(ACE) inhibitors and angiotensin dysgenesis, oligohydramnios, persistent patent
receptor blockers (ARB) ductus arteriosus, intrauterine growth restriction
Antiepileptics (carbamazepine, Neural tube defects, cardiac defects, limb and Use when indicated. Monitor maternal levels,
phenobarbital, phenytoin, urinary tract defects, cleft palate coordinate with obstetrician re: fetal monitoring
topiramate, valproic acid) and assessment
Antineoplastics Skeletal defects, spontaneous abortion, stillbirth. Use with caution when indicated
(cyclophosphamide, May be indicated for treatment/exacerbations of
methotrexate) autoimmune disorders
Atenolol Intrauterine growth restriction, neonatal Avoid as other options are available
bradycardia
Estrogens Feminization of male fetus Avoid
Fluconazole Abnormal facies, cleft palate, congenital heart Use with caution when indicated if other treatment
disease, thin ribs, and long bones options are not available
Isotretinoin and Tazarotene (oral) Ear, cardiovascular, and skeletal defects; central Avoid
nervous system dysfunction
Lithium Cardiovascular defects, floppy infant syndrome Avoid
Methimazole Retrospective data regarding rare risk of aplasia Drug of choice for Graves’ disease during second/
cutis associated with first trimester use third trimesters. Unless intolerant to
propylthiouracil, avoid during first trimester
Propylthiouracil (PTU) Rare risk of maternal drug induced hepatitis Drug of choice for Graves’ disease during firstt
trimester. Unless intolerant to methimazole, avoid
during second/third trimesters
Statins Central nervous system and limb abnormalities Avoid
Tetracyclines Permanent discoloration of offspring teeth; Use with caution when indicated if other treatment
maternal hepatic toxicity options are not available
Thalidomide Limb defects, eye and ear abnormalities, heart Avoid
defects, neonatal death
Warfarin Nasal and limb hypoplasia, central nervous system Avoid first trimester. First-line for women with
abnormalities, spontaneous abortion, fetal artificial heart valves during second/third trimester.
hemorrhage Use with caution
Radiologic Studies mitted” during the entire pregnancy to remain within the
safe fetal exposure range [61, 62, 64]. For additional per-
I onizing Radiation (Computed Tomography, spective, the table also lists the normal daily background
X-Ray) radiation exposure.
The clear clinical benefit of any test should not be over-
Exposure to ionizing radiation prior to conception has no shadowed by the potential rare adverse event. Fetal expo-
measurable impact on future pregnancies [60]. Except for sure >50–500 mGy poses a slight risk for failure to implant,
a nuclear medicine thyroid scan, all indicated tests can be major malformations, growth restriction, decreased IQ, as
obtained during pregnancy [52, 61, 62]. The potential well as up to 6% incidence of childhood cancer, depending
effect on the fetus is dependent on when the ionizing radia- on the dose. Radiation exposure >500 mGy is associated
tion exposure occurred, the dose of radiation, and the sta- with >20% incidence of developmental delay and >6% inci-
tus of the fetal cellular repair mechanism at the time of dence of childhood cancer. Iodinated contrast does cross the
exposure. Overall, exposure below 50 miliGray (mGy)/(5 placenta, but there are no reports of adverse obstetric or fetal
rads) over the duration of the pregnancy involves no risk of events that have been reported and therefore, when indi-
adverse obstetric or fetal outcomes, including implantation cated, should be used during pregnancy and lactation with-
failure, major malformations, restricted growth, or devel- out hesitation.
opmental delay [61–63]. In order to give providers and
patients perspective in simple language on how each test
falls well below the upper limit, Table 39.2 lists common Magnetic Resonance Imaging (MRI)
imaging studies with the number of maternal studies “per-
Magnetic resonance imaging (MRI) testing during preg-
Table 39.2 Radiologic studies and the fetal dose of ionizing radiation nancy has not been associated with adverse effects on preg-
associated with that study [62] nancy or offspring [65–67]. An expert panel concluded that
Number of maternal studies at ≤1.5 Tesla magnetic field strengths, a clinically indicated
Fetal dose of “permitted” during the entire MRI should be obtained during any trimester [68]. The risk
ionizing pregnancy to remain within for women who undergo testing at >1.5 Tesla magnetic field
radiation the safe fetal exposure range
Radiologic study (mGy) (equivalent of 50 mGy)
strengths is not clear. Gadolinium crosses the placenta, and a
Background 0.003 16,667 years retrospective study found that it may be associated with a
radiation exposure/ “broad range” of rheumatologic, inflammatory, or infiltrative
year skin disease, and stillbirth [67]. As in non-pregnant women,
7-hour airline flight 0.05 1000 7-hour flights avoid gadolinium in pregnancy unless it will significantly
(New York USA to
London UK)
improve diagnostic performance and serve to modify the
2-hour flight 0.014 3571 2-hour flights care plan [67].
Chest X-ray (2 0.0005–0.01 5000–100,000 studies
views)
CT head 0.001–0.01 5000–50,000 studies Mammography
CT chest 0.01–0.66 75–5000 studies
CT pulmonary 0.01–0.66 75–5000 studies A breast ultrasound +/− mammogram is the first indicated
angiogram
test for any breast masses detected during pregnancy, and
CT abdomen 1.3–35 1–38 studies
CT pelvis 10–50 1–5 studies
mammography with appropriate shielding should be reserved
Nuclear medicine for pregnant patients who appear to have a suspicious lesion
Ventilation 0.1–0.3 166–500 studies [69]. Evaluation for suspicious breast masses should not be
Perfusion 0.4–0.6 83–125 studies delayed during pregnancy.
Mammography 0.001–0.01 5000–50,000 studies
X-ray
Dental 0.0000001 500 million studies Thyroid Imaging Scans
Abdomen 0.1–3.0 16–500 studies
Chest (2 views) 0.0005–0.01 5000–100,000 studies
Thyroid imaging scans using radioiodine isotopes should not
Intravenous 5–10 5–10 studies
pyelography be ordered during pregnancy. The fetal thyroid absorbs
Lumbar spine 1.0–10 1–5 studies iodine 400 times more avidly than the adult gland, therefore
Extremity <0.001 50,000 studies I-123 and I-131 administered to the mother can result in fetal
Adapted with permission from RSNA, Tremblay et al. [62] thyroid ablation or thyroid cancer. In cases were a woman
CT computed tomography inadvertently received a dose, there is an “all or none” phe-
nomenon where the pregnancy either results in an early loss nosed. Pre-gestational diabetes affects 1–2% of pregnancies
or continues on without complications [62]. in the United States, and 6–15% of women will develop ges-
tational diabetes during their pregnancy [77].
Diabetes can have a major impact on the health of the
Ultrasonography mother and fetus during pregnancy. There is an increased
rate of congenital anomalies which correlate with the mater-
Ultrasonography can be used in pregnancy, and there are no nal HbA1C at the time of conception; there is a 3% rate with
long-term harmful effects to the fetus. However, it is an HbA1C ≤ 6.5%, increasing to 3.5% with HbA1C of 7%,
recommended that it be used at the lowest acoustic energy 6% with HbA1C of 8%, and nearly 11% with a HbA1C of
necessary that allows adequate diagnostic evaluation and for 10% [78]. Thus, optimizing glucose control before preg-
the shortest time possible [69]. nancy is imperative in women with preexisting diabetes, and
appropriate contraception should be recommended to women
until their disease is well controlled. The American Diabetes
ection 2: Co-management of Medical Issues
S Association (ADA) recommends targeting an HbA1C of
in Pregnancy <6.5% for diabetic women prior to conception to optimize
birth outcomes [79].
Women with chronic medical conditions, such as diabetes, Patients who are overweight or obese and have a risk
hypertension, and thyroid disorders, have better obstetric and factor for the development of gestational diabetes should be
neonatal outcomes when their condition is well controlled screened for pre-diabetes/diabetes prior to conception. Risk
[70–75]. The 35% prevalence of chronic medical conditions factors include previous gestational diabetes, delivering an
present prior to and during pregnancy often leads obstetri- infant 9 pounds or more, PCOS, metabolic syndrome,
cians to enlist primary care providers to co-manage pregnant hypertension, HbA1C >5.6%, first-degree relative with dia-
patients [52, 76]. By maintaining an open dialogue and creat- betes, and physical inactivity [80]. There is no standard on
ing a collaborative partnership, the interplay of a patient’s how to monitor patients in pregnancy if pre-diabetes is
medical and obstetric issues will be best addressed. When diagnosed. Although screening for gestational diabetes
the provider is not comfortable managing medical issues, she usually is performed at 24–28 weeks of gestation, multiple
should be referred to a maternal-fetal medicine specialist organizations, including the ADA and ACOG, advocate
and/or medical subspecialist to provide proper oversight. early screening for women in this high risk category [81].
Diabetes Pathophysiology and Clinical Manifestations
Multiple placental and maternal hormones including, but not

Aaliyah presents a year later for an annual exam. She limited to, human placental lactogen, cortisol, and several
is planning to become pregnant soon. She is on metfor- interleukins are responsible for the relative insulin resistance
min and lisinopril. Her hemoglobin A1c is 6.8%, blood of pregnancy. This physiologic effect starts early in preg-
pressure is 144/78. You change her antihypertensive nancy and continues to intensify throughout gestation.
medication, perform the indicated foot exam, and start During pregnancy, poor glucose control has been associated
a daily prenatal vitamin with 1 mg folic acid. with miscarriage, fetal growth abnormalities (mostly “large
for gestational age”), polyhydramnios, preeclampsia, neona-
A few months later, she calls to tell you that she had a tal hypoglycemia, and respiratory distress syndrome [82].
positive pregnancy test. How should you change her Pregnant women should monitor home sugars four times per
management for her medical issues now that she is day: fasting and 1 or 2 hours after each meal [83]. The goals
pregnant? What are the risks to her baby if her diabe- are fasting glucose <95 mg/dL, 1-hour postprandial glucose
tes or hypertension are uncontrolled? <140 mg/dL or a 2-hour postprandial glucose <120 mg/dL;
higher glucose levels have each been associated with poorer
fetal outcomes. Additionally, monitoring 2-hour postpran-
dial glucose values has been associated with a lower rate of
Epidemiology macrosomia and neonatal hypoglycemia compared to pre-
prandial values [83]. The HbA1c can be used to monitor gly-
Among Americans aged 18–44 years, an estimated 2.6% cemic control in women with pre-gestational diabetes
have diabetes mellitus (DM), 23.7% have pre-diabetes mellitus, but it is not useful for women with gestational dia-
(PreDM), and an additional 1.3% have not yet been diag- betes mellitus.
Treatment Table 39.3 Health maintenance for pregnant diabetic patients [81]
Pre-conception
Treatment of diabetes in pregnancy includes tight glucose Check random urine protein or microalbumin
control without hypoglycemia, keeping up with routine Refer to ophthalmology to check for diabetic retinopathy
health maintenance, and screening for diabetic Prescribe prenatal vitamin with folic acid 1 mg/day
complications. Optimize glucose control with target HgbA1c of <6.5%
As soon as pregnancy occurs
Check HbA1c
Glucose Control
Continue folic acid 1 mg/day
The mainstay of glucose control is an appropriate diet. Meals Check baseline 24-hour urine for protein/creatinine to help
should contain a small portion of low glycemic carbohy- monitor for preeclampsia
drates combined with protein to maintain glucose levels and Refer to ophthalmology to check for diabetic retinopathy
avoid gluconeogenesis. The diet should consist of three Perform foot exam or refer to podiatry
larger meals with three snacks spread out throughout the day, Monitor finger stick blood glucose at least four times per day
including a snack before bed. Long periods of fasting are not Consider changing oral diabetic regimen to insulin to optimize
glucose control
recommended, because they may cause gluconeogenesis and
Start aspirin 81 mg daily >12 weeks but <16 weeks gestation
elevated blood sugars, but if women are not hungry, it is rea-
sonable to skip snacks. Occasionally, obese women lose
weight during pregnancy as they consume an appropriate is not enough data to determine if other oral or injectable
number of calories prescribed by a clinical nutritionist/pro- medications for diabetes are safe in pregnancy.
vider causing a net negative caloric intake. Pregnant women
should be encouraged to engage in 30 minutes of physical Health Maintenance
activity daily but should not be encouraged to exceed their Table 39.3 lists the health maintenance for a diabetic patient
pre-pregnancy exercise tolerance. in anticipation of and during pregnancy. During pregnancy, a
Insulin therapy is the preferred treatment for all pregnant 24-hour urine collection for protein is a more sensitive indica-
women with diabetes [80] as it does not cross the placenta tor of preeclampsia than the spot urine protein/creatinine
and provides excellent glucose control. Insulin regimens can ratio. Because cholesterol normally goes up during preg-
vary by patient and their preferences; options include insulin nancy, and cholesterol-lowering medications are avoided in
pump therapy with continuous glucose monitoring for the absence of familial hypertriglyceridemia, there is no need
women with type 1 diabetes, multiple daily injection dosing to check lipid levels. A consensus statement suggests that low
using short-acting insulin, or a combination of short- and dose aspirin (81 mg) should be started for prevention of pre-
long-acting insulin. The most well-studied insulins include eclampsia early in pregnancy for all diabetic women, prefer-
regular insulin, lispro and aspart (short-acting), NPH (inter- ably after 12 weeks but before 16 weeks of gestation and be
mediate), and detemir (long-acting). These insulins should continued until delivery [88]. Diabetic retinopathy may
be prioritized over other insulin products due to their safety worsen in pregnancy, therefore a dilated retinal exam should
data in pregnancy. Glargine has reassuring data as well, so if be done before or during pregnancy and any diabetic retinop-
the other intermediate/long-acting ones are not available due athy should be treated per the standard of care [89].
to intolerance or logistics of the healthcare system, it can be
used. Goals for glycemic control are very strict in pregnancy:
You suggest Aaliyah continue her prenatal vitamin
fasting glucose <95 mg/dL, 1 hour post-prandial glucose
with 1 mg of folate. You tell her to start measuring her
<140 mg/dL, and 2-hour post-prandial glucose <120 mg/dL
finger stick glucose when she is fasting in the morning
[80]. Patients should be counseled about the signs and symp-
and 2 hours after each meal and reinforce the need for
toms of hypoglycemia and be prescribed glucose tablets or
good diabetic control during the pregnancy. At about
told to carry simple sugar products with them at all times.
6 weeks gestation, her finger stick log reveals fasting
Metformin has been used for many years for infertility
sugars elevated at about 120 mg/dL with three of her
related to PCOS, and there is reassuring data about its use
postprandial values elevated to about 140 mg/
throughout pregnancy. However, since it freely crosses the
dL. Although you can increase the metformin, you feel
placenta, there are concerns that there could be unknown
that she is likely to eventually need insulin and start a
long-term effects on the fetus that have yet to be studied [84,
long-acting insulin before bedtime. At 12 weeks of ges-
85]. Metformin is an acceptable alternative for women who
tation, you advise her to start aspirin 81 mg daily.
refuse insulin. Of women who used metformin as a single
agent in early pregnancy, 26–46% were eventually converted
to insulin [84, 86]. Glyburide has been used in pregnancy but
is inferior to insulin and metformin, with data showing
increased risks of macrosomia and hypoglycemia [87]. There
Hypertension uria (≥300 mg protein/24 hours or a spot protein to creatinine

ratio ≥0.3 mg/mg or 30 mg/mmol), OR hypertension, with
Epidemiology or without proteinuria, AND any one of the following exam-
ples of end-organ damage: platelet count <100 K/μL; ele-
The incidence of hypertension in the United States ranges vated liver enzymes >2× the normal level; new-onset renal
from 2.6% to 27.6% in women aged 18–54 years and varies insufficiency (creatinine >1.1 mg/dL or a doubling of the
depending on race. Chronic hypertension affects 3–5% of creatinine in the absence of other renal disease); pulmonary
pregnancies, and the risk of preeclampsia in these women is edema; new-onset cerebral symptoms (e.g., altered mental
at least 20% [52]. In 2011, the World Health Organization status, headache, weakness, stroke); or visual disturbances
(WHO) estimated that nearly 10% of all maternal deaths in (e.g., photophobia, scotomas, blurry vision, photopsia, tem-
Africa and Asia and 25% of maternal deaths in Latin America porary blindness, etc.) [91].
were associated with hypertensive disorders of pregnancy Eclampsia is defined as new-onset generalized, tonic-
[90]. Hypertension in pregnancy is defined as a systolic clonic seizures in a patient with preeclampsia. It is one of the
blood pressure of ≥140 mmHg and/or a diastolic blood pres- manifestations of severe preeclampsia and can occur before,
sure of ≥90 mmHg measured on two separate occasions at during, or after labor [91].
least 4 hours apart in previously normotensive women [91]. Preeclampsia–eclampsia superimposed upon chronic
Understanding hypertensive disorders in pregnancy and their hypertension is defined in a pregnant woman with chronic
complications can prevent unwanted adverse obstetric and hypertension who has worsening hypertension, new onset
fetal outcomes. proteinuria or features of preeclampsia–eclampsia [91].
Hemolysis, elevated liver enzymes, and low platelet count
(HELLP) syndrome shares many features of preeclampsia, but up
Classification to 20% of those with HELLP do not have hypertension [94, 95].
There are four categories of hypertension in pregnancy: (1)

chronic hypertension, (2) gestational hypertension, (3) pre- Physiology and Pathophysiology
eclampsia–eclampsia, and (4) preeclampsia–eclampsia
superimposed upon chronic hypertension. In general, the In normal pregnancy, blood pressure decreases by
risk factors for hypertension in pregnancy are similar to 5–15 mmHg in the first trimester, with a greater decrease in
those for preeclampsia [92, 93]. Table 39.4 lists the risk fac- the diastolic blood pressure than the systolic blood pressure.
tors for preeclampsia. Blood pressure reaches its nadir at approximately 20 weeks,
Chronic hypertension in pregnancy is defined as hyper- and then gradually comes back to baseline in the third tri-
tension prior to pregnancy, elevated blood pressures before mester [95, 97, 98]. Any time a previously normotensive
20 weeks gestation, or hypertension that persists beyond pregnant patient has a blood pressure ≥140/90 mmHg after
12 weeks postpartum [91]. 20 weeks gestation or has a blood pressure reading signifi-
Gestational hypertension is defined as hypertension that cantly above their baseline, an evaluation for preeclampsia
develops after 20 weeks gestation with no proteinuria or fea- should be considered [95].
tures of preeclampsia. This diagnosis is often assigned retro- Preeclampsia is a multisystem, progressive process
spectively when elevated blood pressures normalize 3 months thought to be due to a maladaptive maternal immune response
postpartum [91]. to the invading trophoblast, causing inadequate and shallow
Preeclampsia is defined as new-onset hypertension, usu- placental development. As a result, angiogenic growth fac-
ally after 20 weeks gestation, associated with new protein- tors become altered, the placenta becomes ischemic, and sys-
temic endothelial dysfunction occurs leading to the clinical
manifestations that are commonly seen in patients with pre-
Table 39.4 Risk factors for preeclampsia [91, 92, 96]
eclampsia [99].
Pre-gestational (chronic) hypertension
Pre-gestational diabetes
Body mass index of >25 kg/m2 (overweight) or >30 kg/m2 (obesity)
prior to conception Clinical Manifestations
History of preeclampsia in a previous pregnancy
Chronic kidney disease The primary clinical manifestation for the hypertensive dis-
Systemic lupus erythematosus orders in pregnancy is hypertension, which is classified as
Antiphospholipid antibody mild (140–149 mmHg systolic or a 90–99 mmHg diastolic),
First pregnancy moderate (150–159 mmHg systolic or 100–109 mmHg dia-
Multiple gestation pregnancy stolic), and severe (≥160 mmHg systolic or ≥110 mmHg
diastolic) [100]. Each office visit for these patients, whether Laboratory Studies
it is with an obstetrician or with a primary care provider for
medical management of acute or chronic conditions, should Pregnant patients with chronic hypertension should have
include an evaluation for preeclampsia by assessing for signs baseline laboratory testing early in pregnancy including
and symptoms of end-organ damage. A full review of sys- complete blood count (CBC), comprehensive metabolic pro-
tems should be conducted focusing on visual symptoms, file (CMP), and a 24-hour urine for protein excretion (normal
headache, dyspnea, chest pain, abdominal pain, swelling, is <300 mg/day during pregnancy) and creatinine clearance.
jaundice, petechiae, and paresthesias; be sure to ask family Many patients with chronic hypertension have proteinuria
members for input regarding confusion or disorientation if prior to pregnancy, so it is important to quantify the amount
appropriate. Outpatient blood pressures should be reviewed. of proteinuria in order to follow the trend during pregnancy
The physical exam should focus on manual blood pressure as worsening proteinuria can suggest progression to pre-
measurement in both arms and uncovering signs of preeclampsia. An elevated spot urine protein to creatinine ratio
eclampsia such as visual field defects, pulmonary edema, a (≥0.3 mg/mg or 30 mg/mmol) above baseline suggests sig-
cardiac gallop, hepatic tenderness, new onset edema, and nificant proteinuria; repeating a 24-hour urine collection will
abnormal neurologic findings such as altered mental status always be more accurate than a spot urine protein to creati-
and clonus. Any pregnant patient with a blood pressure nine ratio due to variability in urine concentration and the
≥160 mmHg systolic or ≥110 mmHg diastolic should be sensitivity of testing. Anemia or elevated bilirubin may sug-
immediately referred for work-up and management of pre- gest hemolysis, elevated liver enzymes and low platelets may
eclampsia or hypertension with severe features. suggest progression to preeclampsia or possible HELLP syn-
Hypertensive disorders of pregnancy can progress quickly drome. There should be a low threshold to repeat laboratory
to severe stages and the significant morbidity and mortality testing at any sign or symptom that could indicate the devel-
associated with them including preterm delivery, intrauterine opment of preeclampsia.
growth restriction, oligohydramnios, and placental abruption
[99]. Preeclampsia can occur before, during, and for up to 2
weeks after pregnancy [101, 102]; thus, women presenting Treatment
for a postpartum visit with signs of preeclampsia should be
thoroughly evaluated and treated. Treatment of hypertensive disorders of pregnancy, depend-
Women with a history of preeclampsia have a signifi- ing on their severity, can be done in collaboration with pri-
cantly elevated lifetime risk of hypertension, myocardial mary care and obstetrics. Target blood pressure prior to
infarction, congestive heart failure, stroke, peripheral arterial pregnancy should be per age-appropriate guidelines [103].
disease, and cardiovascular mortality. Thus, primary provid- Ideally, women of reproductive age with hypertension will
ers should be diligent about monitoring for and optimizing already be on a medication not known to be teratogenic in
cardiovascular risk factors in these women at young ages to the first trimester of pregnancy.
help offset their increase in cardiovascular morbidity [99]. Once women become pregnant, management changes
slightly.
In early pregnancy, there are three approaches one can
Aaliyah is at risk for preeclampsia due to a history of take in treating chronic hypertension, with a goal blood pres-
chronic hypertension, gestational diabetes, and an sure of <160/110 mmHg. The first is to stop pre-pregnancy
overweight BMI of 28 kg. She reports she had well- medication and resume it if the patient’s blood pressure rises
controlled hypertension during her first pregnancy and to ≥160/110 mmHg during pregnancy. The second option is
did not develop preeclampsia. At 28 weeks gestation, to continue the medication during pregnancy if it has a rea-
she has a blood pressure of 148/88 while taking labet- sonable safety profile, and the third option is to change the
alol 400 mg twice daily. She denies headache, visual patient’s medication to one with a larger body of data regard-
changes, shortness of breath, chest pain, or decreased ing its use during pregnancy [52]. Treating to pressures
urination. You order lab work to evaluate for pre- <150/90 mmHg decreases the risk of transient severe hyper-
eclampsia and instruct her to see her obstetrician for tension but does not reduce adverse maternal/fetal outcomes
an ultrasound to evaluate fetal growth and amniotic [104].
fluid volume, all of which are normal. You discuss Women with gestational hypertension are monitored
warning symptoms for preeclampsia with her, continue carefully for signs of end-organ damage as up to half of them
her on labetalol 400 mg twice daily and schedule a can progress to preeclampsia [105]. Because preeclampsia is
follow-up visit. a progressive disorder of placentation, tight antepartum
blood pressure control using non-pregnant goals will not
improve obstetric or fetal outcomes in patients with mild–
moderate hypertension defined as pressures <150/100 mmHg patients should be referred immediately to their obstetrical
[106, 107], and relative hypotension in these patients can be provider or to emergency services if blood pressure is well
harmful. Should women develop progressive hypertension above baseline, >160/110 mmHg, labs are abnormal, or
and concern for preeclampsia during pregnancy, delivery of symptoms are present.
the placenta is the only definitive treatment and can reverse
the course of the disease, although the time to normalization
can take days. Thyroid Disease
Women should work with their primary care providers
and obstetricians to determine the most appropriate target Hypothyroidism
blood pressure for them during pregnancy, taking into con-
sideration their baseline blood pressure on and off medica- pidemiology and Clinical Manifestations
E
tions and comorbidities. Thyroid disease, most commonly hypothyroidism, affects
about 1.5% of the population [114]. It is common for pri-
Antihypertensive Medications in Pregnancy mary providers to help manage hypothyroidism in women
Shared decision-making should be used to weigh the poten- who are thinking of getting pregnant or are currently preg-
tial concrete benefit of any medication against the potential nant. Uncontrolled thyroid disease can have major effects on
or theoretical effects on the fetus and pregnancy. First-line pregnancy as overt maternal hypothyroxinemia (0.3–0.5% of
antihypertensive agents are labetalol, nifedipine, and methyl- women) has been associated with cognitive effects in off-
dopa, because they have been well studied and are generally spring, intrauterine growth restriction, preterm labor, and
well tolerated. Labetalol is an alpha- and beta-adrenergic preeclampsia; therefore, the goal is to achieve normal thy-
blocker and considered first-line treatment with reassuring roid function prior to and during pregnancy [115, 116].
data regarding its use during pregnancy [100]. It is generally While some data are conflicting regarding the appropriate
well tolerated, but side effects may include dizziness, fatigue, management of hypothyroidism in symptomatic vs. asymp-
and rarely hepatocellular injury. Extended-release nifedipine tomatic women, the potential for adverse outcomes dictates
is also well tolerated and reasonable to use [108]. Immediate- that when a thyroid stimulating hormone (TSH) is obtained
release nifedipine could reduce blood pressure quickly and during pregnancy and is above the pregnancy-specific norm,
puts women at risk for hypotension. Children whose mothers treatment to correct it should be initiated.
had taken methyldopa in pregnancy did not show any differ- Subclinical hypothyroidism, the presence of abnormal
ences in physical capability, intelligence, sight, or hearing thyroid function tests without any overt symptoms, is more
when compared with children whose mothers were untreated, common (2.0–2.5% of women) and may be associated with
but the side effects of methyldopa (fatigue, drowsiness, drug- increased risk of placental abruption, pregnancy loss, and
induced lupus, and relative lack of potency) make it hard to preterm rupture of membranes [117]. Studies regarding the
tolerate [109]. Hydralazine, pindolol, and metoprolol are risk of cognitive effects in offspring are conflicting, and the
second-line agents, and third-line medications include cloni- relationship between subclinical hypothyroidism diagnosed
dine, diltiazem, verapamil, and thiazides. during pregnancy and pregnancy outcomes is unclear.
Antihypertensive medications that are contraindicated in Autoimmune thyroid disease, thyroid disease with high anti-
pregnancy include angiotensin converting enzyme (ACE) body titers, may have a stronger association with adverse
inhibitors, angiotensin II receptor blockers (ARBs), direct pregnancy outcomes than thyroid dysfunction itself. Not all
renin inhibitors, and mineralocorticoid receptor antagonists women have antibody positive thyroid disease; euthyroid
(such as spironolactone and eplerenone). These medicines antibody positive mothers (particularly antithyroid peroxi-
can cause fetal renal dysplasia, lung hypoplasia, fetal loss, dase or “anti-TPO” antibodies) have an increased risk of
and other adverse outcomes [110–112]. Atenolol, compared spontaneous pregnancy loss and premature delivery, and
to labetalol, was associated with lower birth weight, so is pregnancy complications increase when the TSH
avoided during pregnancy [113]. >2.5 mU/L. For anti-TPO negative women, the obstetric risk
In summary, primary care providers should be aware of remains low until the TSH is >5–10 mU/L [58]. Despite
the best medications to use in women of reproductive age, these associations, it is not clear that levothyroxine supple-
and be proactive about blood pressure monitoring and man- mentation can modify outcomes in the offspring of these
agement for those in early pregnancy. Pregnant patients with asymptomatic women [118].
known hypertension should be counseled about the signs and Many symptoms common to hypothyroidism are also
symptoms of preeclampsia and encouraged to seek care if normally experienced during pregnancy: fatigue, constipa-
concerns arise. All clinic visits should assess for end-organ tion, and weight gain. Therefore, screening for thyroid dys-
dysfunction and signs of progression to preeclampsia, and function is only indicated for the reasons listed below.
Diagnosis patient take two extra tablets of her levothyroxine per week
ACOG does not recommend routine screening for thyroid [120] until an adjustment to the daily dose is made by the
disease in asymptomatic women. Testing should be reserved provider. Women on thyroxine supplementation prior to
for high risk populations: women with appropriate symp- pregnancy should have their medication adjusted to target a
toms, history of neck/mantle radiation, a history of thyroid TSH < 2.5 mU/L during the first trimester and <3.0 during
disease or other autoimmune diseases, a strong family his- the second and third trimesters [58]. TSH levels should be
tory of thyroid disease, and women with a history of miscar- checked with the first positive pregnancy test, every 4 weeks
riage or infertility [119]. Women with a history of thyroid through mid-gestation, and once around 30 weeks if stable.
disease trying to conceive should have their TSH checked in Levels should be checked 4 weeks after each dosing change.
the preconception period to assure appropriate serum thyrox- Hypothyroxinemia (low free T4, normal TSH) is not con-
ine levels in early pregnancy. One reason to avoid indiscrimi- sidered a pathologic state and should not be treated during
nately screening during the first trimester is that the first pregnancy [58].
trimester TSH will often be normally decreased (transient Pregnant women incidentally found to have subclinical
hyperthyroidism of pregnancy) because the n-terminal por- hypothyroidism or a TSH > 2.5 mU/L should be tested for
tion of HCG (human chorionic gonadotropin) stimulates the the presence of anti-TPO antibodies, as they are a marker of
thyroid gland to secrete thyroid hormone, resulting in nega- adverse pregnancy outcomes and may drive levothyroxine
tive feedback on the pituitary, which responds with decreased supplementation [58]. Treatment of subclinical hypothyroid-
TSH output [58]. Thus, inappropriate screening may result in ism in pregnancy according to the American Thyroid
abnormal results that are clinically insignificant. Additionally, Association guidelines is outlined in Table 39.5.
prospective maternal screening for hypothyroidism in low- After delivery, levothyroxine should be adjusted to pre-
risk women and subsequent treatment did not show any ben- pregnancy doses and TSH rechecked in 6 weeks. In some
efit to the offspring [120]. women, the dosing may be confounded by postpartum auto-
Pregnancy and trimester-specific normal ranges for TSH immune thyroiditis, which is more common among TPO-
should be used for diagnosis. When pregnancy-specific TSH positive women. In women with subclinical hypothyroidism
ranges are not presented, use 0.4 mU/L less than the upper that were started on levothyroxine during pregnancy, medi-
limit of the normal value for that lab, or 4.0 mU/L as the top cation can be stopped and TSH rechecked 6 weeks after
normal value. The American Thyroid Association recom- delivery [58].
mends a target TSH of 2.5 mU/L or lower for the first trimes-
ter [58]. Total T4 and T3 levels naturally increase during
pregnancy to about 1.5 times the upper limit of the non- Hyperthyroidism
pregnant normal range. This is caused by an increase of
thyroid-binding globulin resulting in increased hormone out- Epidemiology
put by the normal thyroid in order to maintain the same Hyperthyroidism occurs in about 0.2% of the population and
amount of free thyroxine (free T4 and free T3). Free hor- is characterized by a suppressed TSH and elevated free T4.
mone levels are usually physiologically normal in preg- Hyperthyroidism complicates 0.1–0.4% of pregnancies, with
nancy; rarely free hormone assays may be falsely lower, Graves’ disease and transient gestational thyrotoxicosis
especially in the third trimester [121]. Thyroid hormone lev- being the most common causes [123]. Transient gestational
els may be assessed using either free T4 and free T3 or by
obtaining a Total T4 and T3 Resin Uptake (T3RU) to calcu-
late the Free Thyroxine Index (FTI). FTI = Total T4 Table 39.5 Treatment of subclinical hypothyroidism in pregnancy
[58]
(nmol/L) × (%T-Uptake/100).
Anti-TPOb
TSHa antibody status Management
Treatment
0.01– No medication
For women with preconception hypothyroidism, it is rea- 2.5 mU/L
sonable to titrate their thyroid hormone replacement dose 2.6– Negative No medication
to target a TSH on the lower end of the normal range as this 4.0 mU/L
will allow for the increased thyroxine demand in preg- 2.6– Positive May consider treatment with
nancy; often <2.5 mU/L is targeted as this is the recom- 4.0 mU/L 25–50 μg levothyroxine
4.1– Negative May consider treatment with
mended TSH for the first trimester of pregnancy [58, 122].
10 mU/L 25–50 μg levothyroxine
The American Thyroid Association suggests that all preg- 4.1– Positive Treat with 50 μg levothyroxine
nant women on thyroxine replacement prior to pregnancy 10 mU/L
increase their levothyroxine dose by 30% as soon as they Presumes upper limit of normal range is 4.0 mU/L
a
become pregnant. This can be accomplished by having the TPO = Anti-thyroid peroxidase antibody
b
hyperthyroidism/thyrotoxicosis is more common than TPO antibodies as they help distinguish between Graves’
Graves’ disease, occurring in 1–3% of pregnancies [58], and disease, Hashitoxicosis, and gestational transient thyrotoxi-
is a self-limited phenomenon during the first trimester. The cosis. If thyroid antibodies are negative, a watch-and-wait
n-terminal portion of HCG is similar in structure to TSH and approach for the first trimester is appropriate if the patient is
stimulates the thyroid gland resulting in elevated free T4 lev- otherwise stable without suspicion for thyroid storm.
els that will decrease as HCG levels fall during the second Antithyroid medications should not be given for hypereme-
trimester [124]. Gestational thyrotoxicosis is more likely to sis or transient gestational thyrotoxicosis, even when the free
occur in conditions associated with higher HCG levels such T4 is elevated, as hyperemesis should resolve by 14–18 weeks
as multiple gestation pregnancies, hydatidiform moles, or gestation [58].
hyperemesis gravidarum [58]. Other forms of hyperthyroid- Graves’ disease must be treated with propylthiouracil
ism, such as toxic multinodular goiter, a hormone secreting (PTU) in the first trimester which is then changed to methim-
adenoma, acute thyroiditis, and medication mismanagement azole in the second trimester to avoid the potential for apla-
for known hypothyroidism are less common causes during sia cutis rarely associated with methimazole [58]. A
pregnancy but should be considered in the differential. suppressed TSH can take months to normalize, so monitor
levels of free T4 and free T3 or total T4 1–2 weeks after dos-
Clinical Manifestations ing changes, and then at least monthly if the levels have sta-
Manifestations of hyperthyroidism mimic normal pregnancy bilized. In order to minimize fetal exposure to the antithyroid
and include heat intolerance, palpitations, fatigue, nausea, feel- medications, they should be titrated to bring the free T4 into
ings of anxiety, and mood changes. However, true hyperthy- the upper limit of normal range or just above, or until the
roidism should be suspected in women with a prior history of total T4 is 1.5 times the upper limit of normal. (Example: A
the disease, a strong family history of thyroid disease, as well woman with Graves’ disease has total T4 of 22 μg/
as in patients with weight loss, tremor, goiter, or exophthalmos/ dL. Normal range for total T4 at that lab is 5.0–12.0 μg/
lid lag on exam. Pregnancy is typically constipating, so an dL. The clinician will titrate the antithyroid medications to
increase in stool frequency (hyperdefecation) also is suggestive bring the total T4 Level to 18 μg/dL). TSI antibodies cross
of hyperthyroidism. A bruit over the thyroid gland is pathogno- the placenta and may stimulate the fetal thyroid gland.
monic of Graves’ disease. Overt maternal hyperthyroidism has Therefore, the obstetrician should obtain a fetal thyroid
been associated with poor obstetric outcomes such as fetal loss, ultrasound around 30 weeks of gestation to assess for a goi-
intrauterine growth restriction, preeclampsia, and preterm ter, and newborns should be monitored after birth by pedia-
labor. Maternal thyroid storm, which can occur in labor or with tricians for symptoms of thyroid dysfunction. In spite of
pregnancy loss, carries a 40% mortality rate [58]. thyroidectomy or radioactive iodine treatment, women with
Graves’ disease may have persistent TSI antibodies that can
Diagnosis cross the placenta and affect the fetal thyroid of any future
The TSH in patients with true hyperthyroidism will classi- pregnancies. Therefore, the fetus of subsequent pregnancies
cally be undetectable, in contrast to transient gestational thy- requires monitoring and assessment for goiter and postpar-
rotoxicosis where the TSH is below the lower limit of normal tum hyperthyroidism [126].
but still detectable. Free T4 will be elevated and the patient In summary, abnormal thyroid function affects pregnancy
will most likely have clinical signs of hyperthyroidism. A outcomes and impacts offspring. Management of hypothy-
TSH should not be routinely obtained in women with hyper- roidism prior to and during pregnancy is often the responsi-
emesis gravidarum as they often have a low but detectable bility of the woman’s primary care provider. Hyperthyroidism
TSH and/or an elevated free T4 that will resolve without is very manageable, but primary providers and obstetricians
medical intervention. When unsure, look for the classic often need to coordinate with specialists for medical man-
symptoms and findings listed above. Total thyroxine nor- agement and monitoring of the mother and the fetus.
mally increases about 10–20% during pregnancy [125] and
is not solely used to diagnose hyperthyroidism.
Nodules should be evaluated with a thyroid ultrasound, Asthma
and when indicated, fine needle aspirations can and should be
obtained during pregnancy. Thyroid radionuclide scans are
contraindicated in pregnancy as the fetal thyroid is 400 times
more avid for iodine and the fetal gland will be ablated [58]. Aaliyah had intermittent asthma prior to pregnancy.
What are the risks to her baby if her asthma is uncon-
Treatment trolled? How should you manage her asthma now that
When the diagnosis of hyperthyroidism is confirmed, obtain she is pregnant?
thyroid-stimulating antibodies/immunoglobulins (TSI) and
Epidemiology and Pathophysiology fine to rely on peak flow meter readings at subsequent visits
if a woman’s asthma is fairly well controlled. In fact, the
Asthma is present in up to 8% of pregnant women in the peak flow meter is a tool that can help patients and clinicians
United States [127]. While women with mild and well- differentiate normal symptoms of pregnancy from true air-
controlled asthma can often expect uncomplicated pregnan- flow obstruction [134].
cies, those with uncontrolled moderate or severe asthma are
at higher risk for preeclampsia, preterm delivery, and intra- Patient Education: During each visit, the provider should
uterine growth restriction [128]. Classification of asthma give anticipatory guidance about warning signs of an impend-
severity in pregnancy is the same as for non-pregnant ing exacerbation, such as worsening cough, chest tightness,
patients. Based on symptom severity, nocturnal awakenings, and wheezing, and review proper use of the patient’s peak
and frequency of use of a short-acting beta2-agonist for flow meter and metered dose inhalers [134]. Counsel regard-
symptom control, patients are classified as having (1) inter- ing avoidance or treatment of triggers, treat seasonal allergy
mittent, (2) mild persistent, (3) moderate persistent, or (4) symptoms, and advise her to rid her home of dust mites.
severe persistent asthma [129]. Warn her of the increased risk of symptoms in the setting of
During pregnancy, asthma symptoms worsen in one- a viral upper respiratory illness and discuss having a lower
third of women, improve in one-third and remain threshold to seek care should her breathing worsen. Smokers
unchanged in the remaining one-third [130, 131]. While should be counseled on cessation as the risks to the fetus
shortness of breath can be a common complaint in normal from exposure to active or passive cigarette smoke are poten-
pregnancies due to the progesterone-mediated increase in tially additive to those from uncontrolled asthma, and mater-
tidal volume, spirometry and airway mechanics do not nal smoking increases the risk of childhood asthma in the
change [132]. Asthma worsens in pregnancy for the same offspring [135, 136]. Spirometry and lung mechanics are not
reasons that asthma can worsen in non-pregnant women: altered so the standard asthma action plan should be utilized
triggers can include exposure to smoking, infection, aller- during pregnancy, where the yellow zone is identified by a
gens, changes in environment and weather, exercise, and peak flow value 50–80% of their baseline and the red zone
lack of appropriate medications. Pregnancy rhinitis is an when it is below 50%.
annoying non-pathologic state of chronic nasal congestion
that occurs during pregnancy due to changes in the nasal Pharmacologic Therapy: After education, medical ther-
mucosa and can trigger asthma symptoms [133]. Finally, apy is the mainstay of therapy and mirrors that used in non-
gastroesophageal reflux disease can also worsen during pregnant patients. Recommendations are based on the
pregnancy and induce asthma symptoms in someone who stepwise approach based on classification [134]. Patients
was previously well controlled. with mild intermittent asthma have daytime symptoms
<2 days/week or <2 nights/month and should use a short-
acting β2-agonist (SABA) as needed. Once symptoms occur
Classification/Treatment >3 days/week or >3 nights/month, then the asthma is classi-
fied as “persistent” and a low dose inhaled corticosteroid
The classification and treatment of asthma during pregnancy should be added for those with symptoms that are not daily.
is the same as for non-pregnant patients and appropriate Once symptoms become present daily or >2 nights/week,
management of asthma in pregnancy can significantly dimin- then they should be on a long-acting β2-agonist (LABA) plus
ish the increased risk of morbidity and mortality for the inhaled steroid OR placed on a medium-potency inhaled ste-
mother and fetus. The National Asthma Education and roid. Patient with persistent daily symptoms, nighttime
Prevention Program Expert Panel recommends four compo- symptoms approaching 7/week, or using SABA multiple
nents of effective asthma management: (1) assessment and times a day should be placed on high dose inhaled corticoste-
monitoring, (2) control of risk factors which may worsen roid plus LABA AND consider addition of other medications
symptoms, (3) patient education, and (4) pharmacologic or consultation.
therapy using a stepwise approach. Assessment identifies For women with more persistent asthma, monthly evalu-
triggers, symptom frequency, nocturnal awakenings, limita- ations of their asthma will allow closer monitoring of
tion of activities due to asthma, exacerbations, medication symptoms and pulmonary function as well as therapy mod-
use, and frequency of fetal movement since this can decline ifications as needed. As with other medical issues, the bet-
with worsening asthma [129]. On the physical exam, note ter controlled the asthma, the better the outcome for mother
any respiratory distress and auscultate for wheezing or pro- and child. Among inhaled corticosteroids, budesonide is
longed expiratory phase. Pulmonary function should be eval- preferred, because there is more pregnancy specific data;
uated ideally with spirometry at the first visit, though it is no data suggest that other inhaled corticosteroids are unsafe
in pregnancy, thus a provider also has the option to con- Venous Thromboembolism
tinue another inhaled corticosteroid that has been effective
based on patient preference, price, or insurance coverage
[137]. For inhaled long-acting beta2-agonists, salmeterol is Aaliyah calls you 10 days after her delivery. She tells
preferred but formoterol can also be considered based on you that while both of her legs are swollen, the left side
patient preference, cost, and response [138]. There are two is more swollen than the right and she has calf pain.
classes of oral leukotriene modifiers: leukotriene receptor She has no associated chest pain or shortness of
antagonists, such as montelukast and zafirlukast, and breath. You tell her to come to the emergency room for
5-lipoxygenase pathway inhibitors, such as zileuton. evaluation as you are concerned that she has a deep
Montelukast does not appear to be teratogenic and should vein thrombosis. What tests would you run? What tests
be used when risk factor modification and inhaled cortico- would you avoid if she was still pregnant? If she has a
steroids are not adequately controlling symptoms. The clot, how would you treat her and for how long?
adverse consequences related to uncontrolled asthma must
be considered when making management decisions; as
such, the National Asthma Education and Prevention
Program Expert Panel counsels that the benefits of asthma Epidemiology
medications used during pregnancy far outweigh their theo-
retical risks [133, 139–141]. Venous thromboembolism (VTE) encompasses deep vein
thrombosis (DVT) and pulmonary embolism (PE). In the
United States, the rate is 1–2/1000 non-pregnant person-years
Exacerbations and 2–4.7/1000 pregnant person-years [144–147]. The risk of
VTE is thought to be four to five times higher in pregnancy
Asthma exacerbations occur in up to one-third of pregnant compared to the same aged non-pregnant women, with the
asthmatic patients and the likelihood of occurrence corre- risk being even greater during the postpartum period [148,
lates with initial classification of a woman’s asthma severity 149]. In addition to the associated medical costs and neces-
[142, 143]. Develop an asthma action plan based on peak sary treatments associated with VTE, the risks to the mother
flow meter results as it can differentiate dyspnea of preg- and infant cannot be understated. Among women who died in
nancy from asthma exacerbations and give a more reliable pregnancy and postpartum from 2011 to 2013 in the United
indication of severity than her symptoms [134]. If her expira- States, 9.2% of deaths were attributed to thrombotic pulmo-
tory flow is in the yellow or red zone, she should use her nary embolism, thus a high level of suspicion is needed [150].
albuterol rescue inhaler 2–4 puffs every 20 minutes and con-
tact her provider. If in the red zone (Peak Flow <50% base-
line), she should call her provider immediately and/or go Pathophysiology
directly to the nearest emergency department. The goal of
therapy is to keep maternal oxygen saturation 95% or higher. VTE risk increases in pregnancy and the postpartum period
Short courses of oral corticosteroids are often used for severe due to many of the physiologic changes of pregnancy. The
exacerbations, as the risks of maternal hypoxemia and poorly majority of thrombogenic factors are increased in pregnancy,
control asthma outweigh the potential risks of oral cortico- including fibrinogen and factors VII and VIII [148], and anti-
steroids including pre-term birth and low birth weight [139]. coagulation factors, such as Protein S, decrease in pregnancy
[148, 151]. Increased venous stasis, particularly in the lower
extremities, results from compression of the venous vascula-
Labor, Delivery, and Postpartum Period ture and venous return by the growing uterus, and hormonal
changes lead to peripheral vasodilation [145]. Compression
About 10% of patients have an asthma attack during labor. of the left iliac vein as it passes under the right iliac artery is
Chronic asthma medications should be continued during the reason that 90% of DVTs in pregnancy occur in the left
labor and delivery. Barring a critically ill mother, cesarean leg, and the risk of VTE after cesarean section is four times
section is reserved for obstetric indications. To prevent that of vaginal delivery.
maternal adrenal crisis, any woman who received greater
than 20 mg of oral corticosteroids daily for more than 3
weeks in the 6 months prior to delivery should be given Medical Conditions Associated with VTE
stress-dose steroids during labor and for 24 hours after deliv-
ery. Management of asthma in lactating mothers is the same Those with a prior VTE outside of pregnancy are considered
as for pregnancy. at the highest risk for developing a VTE during pregnancy.
Examples of comorbidities associated with VTE include forgo a CT scan of the chest as this will prevent unnecessary
systemic lupus erythematous, sickle cell anemia, inherited radiation exposure to the fetus as treatment with systemic
thrombophilias, antiphospholipid syndrome, mechanical anticoagulation will be the same for DVT or co-existing
heart valve, obesity, tobacco use, hypertension, and cancer DVT and PE.
[148, 149]. The inherited thrombophilias include Protein C Based on the patient’s presentation and the physician’s
or S deficiency and antithrombin deficiency. Consider a level of concern for a pulmonary embolism, if chest X-ray
work-up for inherited or acquired thrombophilias in women has excluded other causes of her symptoms, it is reasonable
with a past history of VTE prior to pregnancy to quantify the to proceed to either a ventilation-perfusion (V/Q) scan or a
patient’s future VTE risk. Be aware that during pregnancy, pulmonary computed tomography (CT) angiogram if there is
Protein C levels increase and Protein S levels are universally no suggestion of an accompanying DVT [61, 62, 155].
low, which will influence the results of the thrombophilia Utilize the tests that are available and with which your radi-
screen if checked after conception [152]. While Factor V ologists have the most experience. A CT scan may actually
Leiden (FVL) and prothrombin gene mutations are more be associated with lower fetal doses of radiation than a V/Q
prevalent in patients with VTE, there is no evidence that scan (Table 39.2) [61, 62, 155]. If the suspicion for DVT/PE
prophylaxis or full anticoagulation during pregnancy can is high, and imaging is not immediately available, it is rea-
reduce the rate of recurrent events, and a prospective study sonable to initiate anticoagulation.
showed that FVL is not associated with a higher recurrence
risk [153]. Additionally, evidence does not support obtaining
homocysteine levels or testing for methylenetetrahydrofolate Acute VTE Management
reductase (MTHFR) gene mutation.
Utilizing the guidelines from the American Congress of
Obstetricians and Gynecologists as well as the American
Clinical Manifestations College of Chest Physicians, we have established recom-
mendations for acute VTE treatment as follows [148, 155]:
Bilateral lower extremity edema is common during preg-
nancy but rapidly progressive unilateral swelling, calf pain 1. If the patient is hemodynamically unstable, a large blood
or tenderness, calf redness, or warmth warrant an clot is present, the patient requires surgery, or the patient
evaluation. is nearing delivery, it is necessary for inpatient manage-
During the third trimester, healthy pregnant women will ment of an acute VTE. Some will consider hospitalization
often complain of shortness of breath due to the expanding for all pregnant women with PE for a short period at
uterus and hormonal changes and may have a resting heart diagnosis.
rate of 90–100 beats per minute (bpm) due to the increase in 2. Treatment can be initiated with intravenous unfraction-
cardiac output, but they should not have pleuritic chest pain ated heparin (IV UFH), subcutaneous UFH, or weight-
or shortness of breath that wakes them up at night [154]. based subcutaneous low molecular weight heparin
These signs, in addition to any change in dyspnea, swelling, (LMWH). A Cochrane review found that LMWH was
or heart rate from baseline are red flags and VTE should associated with lower rate of recurrent VTE, reduction in
always be considered in the evaluation. the size of thrombi, and lower rates of major hemorrhage
but no difference in mortality rates [157].
3. The indications for thrombolytic therapy for life-
Diagnostic Strategy threatening PE or large occluding DVTs that place an
affected limb at risk are the same as for non-pregnant
There are some differences that must be considered from the women. Tissue plasminogen activator does not cross the
usual diagnostic work-up of VTE in pregnant women includ- placenta, is the appropriate treatment for these women,
ing the sensitivity and safety of testing. The negative predic- and has been used during pregnancy for these indications
tive value of a d-dimer makes it useful in non-pregnant as well as stroke and myocardial infarction (prior to per-
patients; however, it is frequently elevated during pregnancy, cutaneous interventions being the standard of care) [158].
so the false-positive rate limits its utility [148, 155]. Lower 4. VTE should be treated at therapeutic doses for 3–6 months
extremity duplex ultrasounds are considered safe and are the after initial diagnosis. If the 3–6-month timeframe ends
standard of care for diagnosis of lower extremity DVT [156]. before delivery, then transition her to a prophylactic dose
In pregnant patients, if the duplex ultrasound is positive and of LMWH or UFH which will be administered until
there is also concern for a concomitant PE, it is reasonable to 6 weeks postpartum [148].
VTE Prophylaxis in Pregnancy doses of heparin during pregnancy should receive prophylac-
tic dose anticoagulation. Vitamin K antagonists such as warfa-
The treatment decisions for VTE prophylaxis throughout rin are reserved for women with mechanical heart valves.
pregnancy in women without indications for chronic antico- Warfarin is not recommended for other women who require
agulation are complex. Consensus guidelines are based on anticoagulation in pregnancy due to the risks of warfarin
theoretical risks from retrospective or cohort data, not clini- embryopathy, miscarriage, and fetal hemorrhage [152].
cal trials demonstrating efficacy or safety [159, 160]. The
known risks of heparin-induced thrombocytopenia and
osteoporosis must be considered along with the lack of pro- Labor and Delivery Considerations
spective data demonstrating that aggressive prophylaxis has
not been shown to decrease the incidence of recurrent VTE Labor and delivery present a unique challenge for anticoagu-
during pregnancy [152, 159, 160] A Cochrane review con- lated women and their providers as the onset of labor is very
cluded that “Large scale, high-quality randomised trials of unpredictable. The duration a woman will be off anticoagu-
currently used interventions are warranted” [161]. lation can be variable; thus, the medical team must strategize
Assessing if the VTE was provoked can help clinicians around epidural or spinal anesthesia placement and removal.
make treatment decisions. Specifically, assessing if a VTE Proactively refer patients for consultation with obstetric
was provoked by an estrogen-related risk factor such as anesthesiologists and maternal-fetal medicine specialists to
estrogen-containing contraceptives is a logical step, but there develop a plan. Some obstetricians will change from LMWH
is no data documenting that women with a past VTE related to UFH late in the third trimester in anticipation of delivery,
to contraceptive use have a higher in-pregnancy recurrence as the half-life is 2–4 times longer for LMWH.
risk compared to a past VTE related to another cause [152, After the last heparin injection, the following time
159, 160]. should be allowed to pass prior to placement of spinal or
American Congress of Obstetricians and Gynecologists epidural anesthesia: Therapeutic LMWH dosing: 24 hours;
Practice Bulletin #138 outlines the approach to women with prophylactic LMWH dosing: 12 hours; intravenous UFH:
prior VTE as related to inherited thrombophilias in preg- 4–6 hours [148, 163, 164]. In coordination with anesthesia
nancy, but a full discussion is beyond the scope of this chap- colleagues, after removal of epidural catheters, low-dose/
ter [152]. The following antepartum treatment scenarios are prophylactic anticoagulation is typically restarted 4–6 hours
relatively clear: after a vaginal delivery and 6–12 hours after a cesarean
delivery. As the indications are preventative and not to treat
• Scenario 1: Any indication for lifelong anticoagulation an acute clot, should full dose anticoagulation be deemed
prior to pregnancy: necessary, waiting 18–24 hours after a cesarean section is
–– Continue full-dose anticoagulation with LMWH or preferable [148].
dose-adjusted UFH
• Scenario 2: “Low risk” thrombophilia (heterozygous fac-
tor V Leiden; heterozygous prothrombin gene mutation, Depression
protein C or S deficiency) and NO prior VTE:
–– Clinical surveillance You remember that Aaliyah had some baby blues after
• Scenario 3: “High risk” thrombophilia (antithrombin defi- her first pregnancy but did not require any antidepres-
ciency; homozygous prothrombin gene mutation or factor sant medication then or during this pregnancy. She
V Leiden) and NO prior VTE: screens positive for postpartum depression at her
–– Clinical surveillance or prophylactic dose LMWH or 8-week follow-up with you.
UFH
• Scenario 4: VTE prior to pregnancy not on lifelong
anticoagulation:
–– Prophylactic dose LMWH or UFH Introduction
Prophylactic LMWH doses include enoxaparin 40 mg sub- Depression in pregnancy is common. Untreated depression
cutaneously (SC) once daily, dalteparin 4000 units SC daily, has negative effects on the mother, the developing fetus, and
or tinzaparin 4500 units SC daily. Prophylactic UFH doses the newborn if the mother’s health is not optimized. For
include 5000–10,000 units SC BID in all trimesters or 5000– patients at high risk of perinatal depression, counseling prior
7500 units BID in the first trimester, 7500–10,000 units SC to the development of depressive symptoms is an effective
BID in the second trimester, and 10,000 units BID in the third strategy to prevent the onset of depression. For patients who
trimester [152, 162]. Postpartum, all women treated with any develop perinatal depression, counseling remains an impor-
tant treatment option while many patients will also benefit weight, and preterm birth [172, 173]. There are conflicting
from pharmacologic treatment. results about the effect of antenatal depression on neurocog-
nitive development in the offspring, but a growing body of
literature has associated perinatal maternal stress, depres-
Epidemiology sion, and anxiety disorders with developmental delay [174],
behavior problems [175], and cognition [176]. There is evi-
Although it was initially believed that the “glow of preg- dence that maternal depression is associated with structural
nancy” was protective against depression, about 12% of differences in newborn gray matter structure based on MRI
women experience depression during pregnancy [165]. Risk findings, though the effect size is small [177]. Unquestionably,
factors for depression include a personal or family history of the worst possible outcome of depression on the fetus is a
depression or mood disorders, lack of social or financial sup- successful suicide or the consequences of an attempted
port, history of trauma and interpersonal violence, having suicide.
more than three children, if the current pregnancy is
unwanted, and if there have been pregnancy complications
[166, 167]. ACOG universally recommends screening for Prevention
depression and mood disorders at least once during preg-
nancy and more often in high-risk populations [167]. There For patients at risk of depression, but whose office screening
are several validated screening tools used during the perina- results do not demonstrate active depression, clinicians
tal period; the most universally accepted and most easily should discuss measures to prevent perinatal depression. In
administered tool is the Edinburgh Postnatal Depression 2019, the USPSTF recommended offering counseling to
Scale (EDPS), which is used during pregnancy as well as women at high risk for perinatal depression even before the
during the postpartum period. The Edinburgh Scale controls onset of depressive symptoms. Counseling, particularly cog-
for many of the symptoms that concomitantly occur in preg- nitive behavioral therapy or interpersonal therapy, demon-
nancy, such as changing sleep patterns, can be administered strated reduction in the rate of perinatal depression in high
in 5 minutes, and has been shown in some studies to have a risk groups in several studies. Other strategies for preventing
sensitivity of 100% [168]. depression, such as education, physical activity, or medica-
Roughly half of the women that suffer from depression tions, lacked sufficient data supporting benefits over harms
during pregnancy remain untreated [169]. Undertreated [167].
depression in pregnancy is largely due to stigma, the fear that
women will harm their babies with medication, provider dis-
comfort with treatment, and lack of local services. While Treatment: General Principles
there are concerns regarding use of psychoactive medica-
tions during pregnancy, there is data quantifying the risk and There are clear guidelines as outlined in a joint statement by
consequences of not taking them. In one study of women ACOG and the American Psychiatric Society to help with the
with depression controlled with medication who became triage and management of women with new onset or relaps-
pregnant, 26% of women who maintained their medication ing depression during pregnancy. Non-pharmacologic inter-
in pregnancy relapsed compared with 68% of those who dis- ventions such as interpersonal therapy and cognitive
continued their medication [170]. Thus, continuing medica- behavioral therapy should be considered for all women with
tions offers many women the best opportunity to maintain perinatal depression and has been shown to be effective [178,
their psychological well-being during pregnancy. 179]. Patients who fail therapy show moderate to severe
Postpartum depression is much more common; about symptoms, have a history of a mood disorder, or have sui-
80% of women suffer from postpartum blues (symptoms cidal thoughts should be referred for immediate medical sta-
<2 weeks) and about 10–16% have postpartum depression bilization [180].
(symptoms >2 weeks) [171]. Screening is recommended for In the preconception period, pregnancy should be deferred
all postpartum woman and is most often performed at the until the patient’s depression has been stable for a period of
6-week postpartum visit and at pediatrician visits for baby time, on or off medications. If the patient has been euthymic
for the first month [168]. for at least 6 months on medications and does not have a his-
tory of recurrent major depressive disorder, suicide attempt,
bipolar disorder, or psychosis, then she may be a candidate to
Clinical Outcomes wean her medications prior to conceiving. Otherwise, con-
tinuation of medications during pregnancy should be highly
Mothers with depression may have a slight increased risk of encouraged to prevent worsening of depression and its com-
poor obstetrical outcomes such as miscarriage, low birth plications [180].
Retrospective data suggests risks associated with antide- [184]; however, if a patient has failed all other antidepres-
pressant medications, but prospective data demonstrates that sants, continuation of paroxetine can be considered after a
stopping medication can cause significant decompensation risk/benefit conversation with the patient. Neonates who
in 68% of women [170]. have been exposed to an SSRI, particularly in the third tri-
mester, may have poor neonatal adaption (NAS), often char-
acterized by mild agitation and restlessness, but which can
Treatment also include gastrointestinal manifestations, respiratory dis-
tress, and in very rare cases, seizures [185]. Some patients
The goal of treatment is to use medications that have repu- have weaned or stopped their SSRIs in the third trimester to
table safety data during pregnancy and that will optimize the decrease the risk of their baby developing NAS; there is lim-
patient’s mood symptoms. Many women are best treated by ited data to support this practice, and third trimester weaning
medications that have worked for them in the past, assuming puts the mother at risk of depression relapse during a crucial
that there is an acceptable safety profile for that medication transition period [186]. Exposure to SSRIs after 20 weeks
in pregnancy. Changing a stable patient’s depression medica- gestation may be associated with persistent pulmonary
tion is not recommended unless it is highly teratogenic given hypertension of the newborn (PPHN), which may cause sig-
the risk of recurrent or worsening depressive symptoms. nificant newborn morbidity; however, in case-control stud-
When selecting a medication, it is important to identify the ies, the absolute rate of this complication was very low at
gestational age of the patient as some medications have dif- <1% (compared to 0.2% in the general population). Several
ferent effects on the fetus depending on when the medication studies have shown a small risk of postpartum hemorrhage in
is started during pregnancy. As with use of any medication in mothers on SSRIs at the time of delivery [187–189]. Possible
pregnancy, a discussion with the patient about risks and ben- associations with SSRIs and neurocognitive outcomes such
efits is warranted. as ADHD and autism have been reported [190–192]. It is
Interpreting the data regarding depression medication use important to note that these studies examining the relation-
in pregnancy is challenging. Studies are often confounded by ship between neurocognitive outcomes in children of moth-
healthy controls with the inability to account for the study ers with mental illness are likely confounded by the mother’s
group’s underlying mood disorder, the low absolute number indication for medications during pregnancy [191, 193], and
of events of poor outcomes at baseline, and hindsight bias. the magnitude of the effect of medications on outcomes rela-
The relative risk/odds ratios associating medications and tive to other variables is controversial [192]. More data is
potential adverse effects typically range from 1.3 to 1.8, and needed to tease out this relationship; in the meantime, medi-
while statistically significant, they are still subject to the cations for depression should not be withheld during preg-
biases and confounding of retrospective studies. Some asso- nancy for fear of developing ADHD or autism in offspring.
ciations may be pertinent only for women using a particular There is less readily available data about the use of sero-
medication at the time of conception or during a certain tri- tonin–norepinephrine reuptake inhibitors (SNRIs) in preg-
mester, so gestational age of the mother when a medication nancy. Most studies have included venlafaxine and duloxetine;
will be prescribed must be factored into management deci- there does not appear to be an association with congenital mal-
sions. The most important factors to consider are the more formations or cardiac defects [194]. SNRIs are associated with
obvious consequences of withholding an antidepressant a small increased risk of postpartum hemorrhage [189, 195]
medication and the risks that withholding could have on the and poor neonatal adaptation [196]. Venlafaxine has been
patient, fetus, and newborn. linked with the development of hypertensive disorders during
Most studies on bupropion (Wellbutrin) in pregnancy are pregnancy [197, 198]. Women that stay on venlafaxine during
reassuring. Bupropion has not been associated with low birth pregnancy should be educated about the signs and symptoms
weight, major congenital malformations, or premature deliv- of preeclampsia and can consider home blood pressure moni-
ery [181]. A few small studies have shown a slight increase toring should office blood pressure readings start to rise.
in cardiac anomalies, particularly ventricular septal defects Tricyclic antidepressants (TCAs) can also be considered
[182, 183]. for the treatment of depression in pregnancy. Like SSRIs and
Selective serotonin reuptake inhibitors (SSRIs) have been SNRIs, TCAs are associated with risk for postpartum hemor-
studied extensively in pregnancy and data continue to be rhage [189] and poor neonatal adaptation [199]. Unlike
refined. Sertraline is often considered the drug of choice in SSRIs, TCAs have been associated with hypertensive disor-
pregnancy; however, fluoxetine, citalopram, and escitalo- ders of pregnancy including preeclampsia [198, 200].
pram are also commonly used, particularly when a patient Nortriptyline has fewer metabolites and may be the preferred
has been stable on these medications. Paroxetine should be tricyclic to use; it is also one of the preferred drugs for breast-
avoided because of an association with cardiac anomalies feeding women [201] (Table 39.6).
Table 39.6 Antidepressants in pregnancy

Medication class Specific medications Reported pregnancy effects Lactation
SSRI First-line therapy Poor neonatal adaption Sertraline lowest passage to breast milk
Sertraline is first choice Postpartum hemorrhage Citalopram and fluoxetine can produce
Citalopram, escitalopram, and Conflicting data: Autism, ADHD, detectable levels in babies; less preferred
fluoxetine also reasonable PPHTN but still considered safe
If not responding to first drug, Paroxetine is safe
switch to a different SSRI
Avoid paroxetine at time of
conception and first trimester
SNRI Second-line therapy Poor neonatal adaptation Low levels detectable in infants. Monitor
Venlaxafine has more data that Postpartum hemorrhage for drowsiness, adequate weight gain and
duloxetine Hypertension disorders of milestones
Can be effective in patients pregnancy Do not stop breastfeeding if mother needs
refractory to SSRI these medications and infant is healthy
Dopamine/norepinephrine- Bupropion Conflicting data: Low teratogenic Low levels in breast milk; likely safe
reuptake inhibitor risk vs. slight increase in risk of
cardiac anomalies
Tricyclic antidepressant Nortriptyline is first choice Poor neonatal adaptation Crosses breast milk in low levels
Avoid clomipramine Postpartum hemorrhage Nortriptyline preferred agent
Hypertension disorders of
pregnancy
ADHD attention deficit hyperactivity disorder, PPHN persistent pulmonary hypertension of the newborn, SNRI serotonin-norepinephrine reuptake
inhibitors, SSRI selective serotonin reuptake inhibitors
Section 3: The Postpartum Period The postpartum period, or puerperium, is the period last-
ing from delivery of the placenta to 6–12 weeks thereafter.
During this time, many changes take place in women, as they
At the time Aaliyah presented to the hospital for deliv-
return to a non-pregnant physiology. These changes impact
ery, she was on long-acting insulin for control of her
management of chronic medical issues and introduce new
diabetes, labetalol for her chronic hypertension, and
concerns such as medication safety when breastfeeding.
albuterol as needed for control of her asthma. During
labor, she received an insulin drip for optimal control
of her glucose. She continued to receive her oral
Breastfeeding
labetalol and had an albuterol inhaler available for
use as needed.
Breastfeeding is considered the gold standard for feeding
infants in both developed and developing countries. The
Following delivery, Aaliyah’s blood pressure increased American Academy of Pediatrics (AAP) recommends exclu-
to a level that was persistently in the range of 150– sive breastfeeding during the first 6 months of an infant’s life,
155 mmHg systolic over 100–105 mmHg diastolic, with continued breastfeeding during the first year of life [202].
despite her regular dose of labetalol. She denied any
symptoms associated with preeclampsia, such as
headache, visual disturbances, or shortness of breath. Physiology of Breastfeeding
She had also been started on enoxaparin due to her
left lower extremity DVT she suffered 10 days During the latter half of pregnancy, the breast has been pre-
postpartum. paring for lactation by producing small amounts of milk and
colostrum, which is a nutrient-rich substance containing
Management issues include minerals, amino acids, and proteins, with low levels of fat
and sugar [203]. Both colostrum and breast milk contain
• Managing the increase in her blood pressure high levels of immunologic factors, in particular secretory
• Managing her diabetic medications in the postpar- IgA, which protects the infant against enteric pathogens.
tum period Other immunologic factors found in colostrum and milk
• Postpartum medical therapy for her DVT include complement, macrophages, T- and B-cell lympho-
• Counseling regarding her medications and cytes, lactoferrin, lactoperioxidase, and lysozymes [203].
breastfeeding Following delivery, progestin levels drop and there is a
high-prolactin state, stimulating changes in the breast to pro-
duce high quantities of milk. When baby nurses soon after chemotherapy stop breastfeeding while on treatment but ulti-
birth, they are only receiving the small quantity of colostrum mately depends on the regimen and duration of treatment.
and milk produced during pregnancy. Around postpartum
days 3–5, breast milk production has commenced, the breasts
become engorged, and baby becomes the driver of breast Drug Safety in Breastfeeding
milk production. The more often the breasts are stimulated
and emptied, the more milk the mother will make. If the nip- Medications are often required postpartum. Primary care
ple is not stimulated by baby (or by pumping) and prolactin providers should have a reference text in the office (elec-
and oxytocin are not released by the pituitary, milk remains tronic or paper—we suggest using the LactMed Database,
in the breast, halting further breast milk production. which is a free online resource maintained by the National
Library of Medicine [209], or the reference book Drugs in
Pregnancy and Lactation edited by Gerald G Briggs and
Benefits of Breastfeeding Roger K. Freeman published by Wolters Kluwer) [210] to
help guide medication decisions in breastfeeding women and
Breastfeeding has been shown to decrease the incidence of identify obstetric colleagues with whom they can collabo-
breast cancer and coronary artery disease and can also help rate. While many drugs are secreted into breast milk, the
decrease postpartum weight retention. Breastfeeding can important issue is how much is actually absorbed by the
have a contraceptive benefit by delaying return of ovulation; newborn and whether there is evidence of a physiological
however, definitive birth control should be used by women effect. Typically, maternal medications have no adverse
who do not desire pregnancy [203]. Neonatal benefits of effects on breastfed infants. As an example, warfarin, when
breastfeeding include decreased incidence and severity of indicated, is compatible with breastfeeding but contraindi-
gastroenteritis, lower respiratory infections, otitis media, cated in most women during pregnancy.
bacterial meningitis, urinary tract infections, and necrotizing Dr. Hale’s Lactation Risk Category is similar to the FDA’s
enterocolitis. It may protect against sudden infant death syn- former lactation categories of A, B, C, D, and X. Dr. Hale’s
drome (SIDS), type 1 diabetes mellitus, and inflammatory categories range from L1 to L5, with L1 being compatible
bowel disease, but the evidence does not support that breast- with breastfeeding referenced by controlled studies, L3
feeding reduces the risk of allergic conditions [204–207]. being probably compatible without any observed risks, and
L5 being hazardous based on observed damage to an infant.
Commonly used medications in primary care will be detailed
Complications of Breastfeeding below using Dr. Hale’s categories for reference [197].
Half of postpartum women may experience pain from breast Pain Medications
engorgement that may persist for 2 weeks in up to 10% of Acetaminophen (L1), non-steroidal anti-inflammatory drugs
patients [203]. Treatment is supportive with oral analgesics, (NSAIDs) (L1), and short-acting opioids such as oxycodone
ice packs, and use of a tight-fitting sports bra or a breast (L3) are considered safe during breastfeeding and are used
binder. Lactation mastitis, inflammation in the breast most routinely for postpartum women with no harmful effects
often from blocked milk ducts, occurs in up to 10% of breast- reported [203]. In rare cases, opioid medications may result
feeding women. It is typically unilateral and can become in infant drowsiness.
infected with Staphylococcus aureus, coagulase-negative In 2017, the Food and Drug Administration (FDA) issued
staphylococci, or Streptococcus viridans [208]. Mastitis can a Drug Safety Communication warning that breastfeeding is
cause systemic symptoms including high fevers, myalgias, not recommended while using codeine (L4) and tramadol
nausea, and weakness. Culture for the causative organism (L4) due to the risk for infant opioid overdose [211]. In
may be obtained from breast milk. Therapy typically resolves women who are “ultra-rapid metabolizers,” normal doses of
the infection within 48 hours, but up to 10% develop a breast these medications lead to high maternal serum levels of
abscess. Women should continue breastfeeding, including active metabolites, which are then present in breast milk
feeding from the inflamed breast [208]. [212]. Adverse effect reports exist for codeine, and because
tramadol has similar metabolism, the recommendation
against breastfeeding was made for both medications [212].
Contraindications to Breastfeeding
Antibiotics
Contraindications to breastfeeding are rare and include active No adverse events have been reported with use of penicillins
herpes simplex lesions of the breast, active tuberculosis, (L1), cephalosporins (L1), nitrofurantoin (L2), gentamicin
human immunodeficiency virus (HIV) infection, and active (L2), clindamycin (L2), tetracycline (L2), and macrolide
illicit drug use [208]. It is recommended that most women on (L2) antibiotics [203].
Sulfonamides are considered safe in breastfeeding, and The AAP considers lithium (L4) incompatible with
there is experience using them in patients with HIV who breastfeeding as the breast milk concentration is as high as
require prophylaxis against pneumocystis infections. one-half of the maternal serum concentration, and infant
However, these drugs should be avoided in women who serum levels may be clinically significant leading to lethargy,
have infants at risk for hyperbilirubinemia, including pre- hypotonia, hypothermia, and cyanosis [203]. Use of other
mature and ill infants, because they displace bilirubin from mood stabilizing agents, such as valproic acid (L2) and car-
binding sites on albumin leading to elevated infant bilirubin bamazepine (L2), is considered compatible with breastfeed-
levels [213]. ing [216]. Studies regarding effects of antipsychotic use in
The concentration of metronidazole (L2) in breast milk is breastfeeding women are limited. Haloperidol (L2) data is
similar to that of the maternal plasma. Discontinuation of limited with some studies showing limited effects and others
breastfeeding for 12–24 hours after single-dose (2 g) therapy demonstrating developmental delay later in life [216].
may be considered to minimize neonatal exposure to the Benzodiazepine (L3) use during breastfeeding is considered
drug through breast milk, although no adverse effects have moderately safe at low doses [216].
been reported [203]. In Utero exposure to doxycycline, (L3)
may cause staining of teeth. Anticoagulants
UFH (L1), enoxaparin (L2), and warfarin (L2) are safe to
Antihypertensive Medications take for breastfeeding mothers. Heparin does not cross into
Labetalol (L2) and propranolol (L2) have low concentrations breast milk. Warfarin is highly protein-bound, and thus it is
in breast milk, with no reported adverse effects on the infant, found in very low concentrations in breast milk [203].
so these are preferred agents for treatment in this category
[203]. Other beta-adrenergic blocking agents, such as
metoprolol (L3), can be concentrated in breast milk but Postpartum Physiology
appear reasonable when indicated.
Angiotensin-converting enzyme inhibitors [enalapril Uterus
(L2)] and calcium channel blockers [amlodipine (L3)] are
secreted into breast milk in low levels but are compatible Within 24 hours after delivery the uterus, when palpated on
with breastfeeding. the abdominal exam, should feel like a hard knot of muscle
Thiazide diuretics (L3) are low to undetectable in breast just below the umbilicus. Lochia rubra is the initial postpartum
milk and infant serum but may decrease maternal milk pro- bloody discharge, followed by 3–10 days of pale mucopuru-
duction, therefore other antihypertensive agents are preferred lent lochia serosa, then yellow–white lochia alba. Lochia typi-
if possible [197]. cally resolves by 6 weeks postpartum which coincides with
the uterus returning to its normal size and location within the
Diabetic Medications pelvis [203, 217]. Discharge beyond this, especially in the set-
Glyburide (L2) and insulin (L1) are not found in breast milk ting of fevers, chills, or uterine tenderness, should be evaluated
[214]. Metformin enters breast milk in non-clinically signifi- by the obstetrical team for retained products of conception.
cant amounts [215]. When using oral diabetic medications,
monitor infants for signs of hypoglycemia.
Ovaries
Psychiatric Medications
Most psychiatric mediations are present in breast milk at low For women who are not breastfeeding, the average time to
levels, with non-clinically relevant effects on nursing infants. return of ovulation is 70–75 days and the majority will
Testing of serum drug levels in infants is not recommended resume menstruation within 12 weeks of delivery [217]. In
[216]. women who are breastfeeding, elevated prolactin levels
SSRIs are found in breast milk at low concentrations, are result in delayed return of ovulation, which occurs on aver-
considered safe for use during breastfeeding, but irritability age 6 months after delivery [217]. The exact return of ovula-
and one case of transient apnea in an infant whose mother tion is influenced by the frequency and duration of
was taking citalopram have been reported [216]. Fluoxetine breastfeeding and the proportion of supplemental feeds in
is (L2 in older children, L3 in neonates), paroxetine (L2–no the infant’s feeding regimen.
detectable milk levels), sertraline (L2), and citalopram (L3)
may be used when indicated. Long-term studies of exposed
infants are lacking. Coagulation
Tricyclic antidepressants, such as amitriptyline (L2) are
considered compatible with breastfeeding, with the exception The hypercoaguable state of pregnancy continues into the
of doxepin (L5) due to potential respiratory depression [216]. postpartum period, with half of all thromboembolic events
occurring during this time [203, 217]. The risk for develop- nerves. They are more commonly seen in deliveries with a
ment of VTE is highest in the first week postpartum [218]. prolonged second stage or pushing in a semi-Fowler posi-
D-dimer levels may remain elevated into the postpartum tion [203]. Symptoms may include sensory deficits, motor
period, limiting their usefulness as a diagnostic test for VTE deficits, or foot drop and generally resolve by 2 months
[217]. Thrombophilia work-ups should ideally be delayed up postpartum [203].
to 12 weeks postpartum and 6 weeks post-thrombosis [152].
Body Weight
Cardiovascular System
Delivery results in an approximately 10-pound weight loss
Postpartum blood loss during delivery is balanced by the secondary to delivery of the infant, placenta, amniotic fluid,
“autotransfusion” that occurs when the uterus contracts and blood loss. Women often lose the majority of their
down to the postpartum size. Cardiac output slowly returns weight over the 6 months after delivery, women who gained
to pre-pregnancy levels after delivery, heart rate normalizes excessive weight >35 pounds are more likely to have a net
within hours after delivery, systolic and diastolic blood pres- weight gain following pregnancy, and the average woman
sure slowly increase by about 5% in the first 4 days postpar- retains about 10 pounds after the pregnancy [217]. Patients
tum [217]. Postpartum leukocytosis is common and the should be reassured that aerobic exercise does not adversely
hemoglobin typically drops 1–2 mg/dL after delivery, nor- affect breast milk production.
malizing by 6 weeks postpartum [217].
Postpartum Care of Medical Complications

Urinary System
Diabetes Mellitus
The normal pregnancy-related dilation of the renal pelvises
and ureters due to hormonal effects of progesterone will Patients with a history of type 1 and type 2 diabetes mellitus
return to their pre-pregnancy size by 6 weeks postpartum (DM) can generally be converted back to their pre-preg-
[203, 217]. nancy medication doses or started on half of their pre-deliv-
Bladder dysfunction may appear in the postpartum period ery dose [10].
as a result of labor trauma or epidural anesthesia, and urinary Following delivery, most women with gestational diabetes
retention in the first several hours after delivery is common. mellitus (GDM) will have normalization of glucose levels.
Women may also experience incontinence during pregnancy However, up to one-third of these women will demonstrate
or the postpartum period secondary to the hormonal effects glucose intolerance with postpartum screening [48]. While
of progesterone on the pelvic floor musculature or trauma to the 2-hour oral glucose tolerance test is recommended for
the perineum, which will often resolve by 6 weeks postpar- women with GDM by ADA and ACOG at 4–12 weeks post-
tum. However, parity is a risk for stress incontinence that partum because it detects both impaired fasting glucose and
typically presents later in life, affecting 3% of women under impaired glucose tolerance, compliance rates are a dismal
35 and rising to 38% of women >60 [219]. Pelvic floor phys- 35% [48, 220]. In the United Kingdom, the fasting plasma
ical therapy is a great option for young women with postpar- glucose is recommended due to the convenience factor, and
tum incontinence and will help maintain the strength of the after 12 weeks a HbA1C is recommended. A pilot study
pelvic floor as patients enter menopause. found obtaining a HbA1C at the postpartum visit, rather than
from the lab, doubled the rate of testing, although additional
data is needed to validate this approach [221].
Nervous/Musculoskeletal System Women with GDM have up to a 70% chance of develop-
ing DM later in life [48], though breastfeeding may help
Transient decreased bone mineralization occurs normally reduce the risk of developing future diabetes [222]. Patients
following delivery and resolves by 12–18 months postpar- who meet criteria for a diagnosis of DM based on postpar-
tum. Treatments such as calcium supplementation and tum screening should be referred for diabetes education and
exercise do not prevent this bone loss [217]. Muscle and management. Those who meet criteria for a diagnosis of
joint injuries associated with labor are usually transient, impaired fasting glucose or impaired glucose tolerance, life-
improved with anti-inflammatory medications and physical style modifications, nutritional therapy, and possible medical
therapy [203]. Nerve injuries complicate 1% of deliveries therapy to decrease development of DM should be consid-
such as lumbosacral plexus injury due to compression from ered [48]. For those with normal results, screening for diabe-
the fetal head, or lithotomy positioning in stirrups with tes should be repeated every 1–3 years [223]. Identifying
hyperflexion of the hips can compress the common fibular these patients at risk with a thorough pregnancy history is
important as randomized trials demonstrate that lifestyle stage renal disease [229–231]. Thus, it is critical that all
modification and use of metformin for pre-diabetic women healthcare providers inquire about a history of hypertensive
will help prevent the development of overt diabetes [224]. disorders during pregnancy so that education and lifestyle
interventions for these potential conditions become a routine
part of our long-term postpartum primary care.
Hypertensive Disorders of Pregnancy
Most preeclampsia-related hypertension normalizes by 6 Thyroid Disorders

weeks after delivery, but preeclampsia can present or flare
postpartum, so new or recurrent spikes in blood pressure After delivery, women whose dose of levothyroxine was
should prompt a clinical assessment. The diagnostic criteria increased during pregnancy should be placed on the pre-
for postpartum preeclampsia are the same. Patients who pregnancy dose and have a TSH checked around 4 weeks
meet criteria for preeclampsia with severe features in the postpartum.
postpartum period are generally admitted to the hospital for Graves’ disease tends to become less active in the third
observation, with administration of magnesium sulfate for trimester but may recur in the postpartum period. Flares are
seizure prophylaxis and initiation of antihypertensive medi- treated with antithyroid medications such as methimazole
cations as needed. (L3–no evidence of excretion into milk) or propylthiouracil
If hypertension associated with gestational hypertension (L2). Radioiodine ablation or surgery may be recommended
or preeclampsia does not resolve by 12 weeks postpartum, a for non-pregnant women with refractory disease.
diagnosis of chronic hypertension rather than pregnancy- Postpartum thyroiditis (PPT) results in transient thyroid
associated hypertension disease should be entertained [225]. dysfunction that develops in the first year after delivery in
Women with pregnancies complicated by gestational hyper- women who were previously euthyroid and may even occur
tension or preeclampsia should return to the office for blood after pregnancy termination or spontaneous loss. The preva-
pressure evaluation 7–10 days following delivery or earlier iflence ranges from 1% to 17% and women with a history of
they develop symptoms of preeclampsia at home [148]. type 1 diabetes, Graves’ disease (treated), and viral hepatitis
Antihypertensive treatment is recommended in patients are at a higher risk for developing PPT [122]. Testing in
who have persistently elevated blood pressures, ≥150 mmHg asymptomatic women found that 10% of women in early
systolic and/or ≥100 mmHg diastolic [148]. Educate patients second trimester have thyroid peroxidase antibodies and
regarding signs and symptoms of hypotension as blood pres- 50% of those women will develop postpartum thyroiditis
sure returns to pre-pregnancy levels. [232]. However, screening all pregnant women to identify
More frequent dosing (labetalol three times daily) will the 5% that may develop a self-limited syndrome is not indi-
prevent spikes in pressure. The rate of blood pressure nor- cated. PPT usually manifests first as signs and symptoms of
malization after delivery is variable, so monitoring and use hyperthyroidism. The hyperthyroid stage is due to inflamma-
of holding parameters for antihypertensives will facilitate tion of the gland with rapid release of pre-formed hormone;
proper control. It is often prudent to discharge patients withthus, initial testing may reveal an elevated free T4 and low
a home blood pressure cuff and the consider the following TSH. This is followed by a hypothyroid phase with low free
“Sliding Scale” for women discharged home on antihyper- T4 and high TSH. PPT is usually a self-limited illness, and
tensives related to persistently elevated pressures: most patients will spontaneously return to a euthyroid state.
A small subset of patients will progress to permanent hypo-
• Check pressure before each dose (three times a day) thyroidism; thus, thyroid function studies must be monitored
• Skip that dose of labetalol if the systolic pressure is every 4–6 weeks to assure normalization. Persistent hypo-
<140 mmHg thyroidism for more than 1 year following delivery ranges
from 2% to 21% [58].
Preeclampsia and gestational hypertension are major risk Treatment of PPT is largely supportive, and patients
factors for development of cardiovascular disease [226, 227]. should only be treated if they are symptomatic. Hyperthyroid
The Cardiovascular Health After Maternal Placental symptoms may be treated with a β-blocker such as proprano-
Syndromes (CHAMPS) study showed a 12-fold increased lol, which is compatible with breastfeeding [58].
risk for development of heart disease in women with a prior Hypothyroidism should be treated with levothyroxine, with a
history of preeclampsia or metabolic syndrome compared to reasonable starting dose being somewhere between 50 and
those women without these conditions [228]. This risk is 100 μg depending on the weight of the patient and degree of
especially increased for women who develop early and symptoms [58]. Subclinical hypothyroidism should be
severe preeclampsia. Additionally, preeclampsia is a marker treated according to guidelines, with initiation of thyroid
for future diabetes, subclinical hypothyroidism, and end- hormone in any patient with a TSH >10 mU/L. There is less
clear evidence that treating subclinical hypothyroidism based Postpartum psychosis is a rare complication of child birth
on a TSH > ~4.5 mU/L (or the upper limit of the reference but considered a medical emergency. Several studies have
range) and <10 mU/L provides any clinical benefits, and this quoted the incidence between 0.89 and 2.6 per 1000 births
decision must be made between the patient and the provider. across several countries [234]. Mothers present within the
Keep in mind that less thyroid hormone may be needed when first 4 weeks after childbirth, often within a few days, with
treating women with PPT in the subsequent weeks to months disorganized thinking and behaviors, hallucinations, para-
as the thyroid gland heals and PPT resolves. TSH and free T4 noia, grandiosity, mood lability, and poor judgment that can
should be checked every 4–6 weeks when adjusting medica- affect their health and the health and safety of their child.
tions or monitoring for progression/regression of PPT [122]. Risk factors include a history of mood disorder (bipolar,
Any thyroid dysfunction can affect breast milk produc- schizophrenia), a family history of a mood disorder, having a
tion. It is important to maintain a euthyroid state in women history of postpartum psychosis, major obstetrical complica-
who are planning another pregnancy. Women who have had tions, and stopping mood-stabilizing medications during
postpartum thyroiditis are at a higher risk for the develop- pregnancy [235]. Evaluation for medical causes of symp-
ment of permanent thyroid dysfunction in the future [233]. toms must be sought as the differential diagnosis includes
infection, thyroid disease, toxidromes, alcohol withdrawal,
and electrolyte disturbances. Treatment includes immedi-
Venous Thromboembolism ately psychiatric stabilization, usually in the inpatient setting
under the care of a psychiatrist for medication titration or in
For patients with a history of thromboembolism, timing of an intensive outpatient treatment program.
anticoagulation therapy in the postpartum period requires
balance between the risks of clot formation and bleeding
complications. Guidelines state that full-dose anticoagula- Summary Points
tion with unfractionated or low molecular weight heparin
(LMWH) may be restarted 4–6 hours after vaginal delivery 1. A pregnant patient’s medical and obstetric issues will be
or 6–12 hours following cesarean delivery, but one may con- best addressed by maintaining an open dialogue and cre-
sider restarting at 18–24 hours in order to avoid postopera- ating a collaborative partnership with obstetric col-
tive bleeding [148]. For those patients who require leagues and subspecialists.
anticoagulation at low dose prophylactic doses only during 2. Optimizing a mother’s health and well-being prior to
the 6-week postpartum period, LMWH is commonly used, and during pregnancy will ensure that her fetus has the
but women who need to continue therapy beyond 6 weeks best outcome.
postpartum may be bridged to warfarin or another oral agent 3. Rather than considering a medication or test to be “safe”
during this time [148]. during pregnancy, providers should consider if they are
medically indicated or reasonable, and consider the con-
sequences of not pursuing the test or prescribing the
Postpartum Depression medication.
4. Women with hypertension and risk factors for pre-
Postpartum depression, defined as an episode of major eclampsia should be educated about and monitored for
depression that occurs within the first 4–6 weeks postpartum, preeclampsia by their obstetricians and primary provid-
complicates approximately 10–16% of pregnancies [171]. ers during pregnancy and in the postpartum period.
Universal screening for postpartum depression is recom- 5. The management of asthma during pregnancy is the
mended at the postpartum visit with commonly used screen- same as for non-pregnant patients.
ing such as the Edinburgh Postnatal Depression Scale, the 6. Venous thromboembolism is an important cause of
Beck Depression Inventory, and the Postpartum Depression maternal morbidity and mortality. Providers should be
Screening Scale [216]. Most pediatrician offices also screen familiar with guidelines for prophylaxis in women with
mothers for depression when babies have visits soon after a known hypercoaguable state and maintain a high index
birth. Symptoms of depression in the postpartum period of suspicion of VTE in any pregnant patient.
mimic issues that new mothers face including poor sleep, 7. Tight glycemic control for women with pre-gestational
irritability, change in appetite, poor concentration, hopeless- diabetes mellitus can optimize pregnancy outcomes, and
ness, guilt, fatigue, amotivation, and sadness. Treatment is women with gestational diabetes require close follow-up
based on regimens for major depression in non-pregnant to screen for persistent dysglycemia.
women as discussed in the section on peripartum depression, 8. Thyroid disease is prevalent; therefore, proper precon-
with particular attention to choosing medications that are ception, pregnancy, and postpartum management of
safe during breastfeeding. hypothyroidism, and recognition of hyperthyroidism by
primary care providers can minimize the risk for for its use. However, the standard of care for glucose con-
complications trol during pregnancy is insulin. Given this patient’s
9. Depression during pregnancy is best managed with a poorly controlled diabetes, she should immediately be
multidisciplinary team and a good understanding that converted to insulin for tighter glycemic control.
medications can and should be prescribed to optimize Sitagliptin (Januvia) is a newer drug, and therefore there
outcomes and well-being for the mother and newborn is not a much safety data available on this medication in
10. Supporting lactation is important for new mothers. early pregnancy. Glipizide is not well studied in preg-
Finding medications safe for breastfeeding babies can nancy and therefore not commonly used. In women who
be accomplished through a variety of online resources were taking glipizide in pregnancy, there were not shown
and applications. to be excess anomalies though. Acarbose is not com-
11. Primary providers should be monitoring for postpartum monly used. There is no literature to support for or against
complications and for complications associated with its use; however, because most of its action is in the intes-
diseases diagnosed during pregnancy including pre- tine and it is not well systemically absorbed, it is probably
eclampsia, postpartum depression and psychosis, VTE, safe to use in pregnancy.
thyroid dysfunction, the development of diabetes, and
the progression of hypertension.
Thyroid Question
1. A 25-year-old G0 female patient was diagnosed with

Review Questions hypothyroidism 4 years ago. She has been taking levothy-
roxine 75 μg daily for the past 2 years. Her TSH last
Diabetes Questions [78, 236] month was 2.5 mU/L. She calls to tell you that she had a
positive pregnancy test. As per American Thyroid
A 32-year-old woman with a 6-year history of diabetes is on Association guidelines, you tell her to:
sitagliptin (Januvia) and metformin to control her blood sug- A. Discontinue levothyroxine
ars. She comes to your office because she missed her period. B. Continue levothyroxine at the same dose
Her last menstrual period was 6 weeks ago. A pregnancy test C. Increase levothyroxine to 100 μg daily
is positive. Her last HgA1c from a month earlier was 9.5%. D. Increase her to two tablets (150 μg) of levothyroxine
daily
1. If her diabetic control continues to be similar, her risk for The correct answer is C. As per the ATA, a woman should
a baby with a congenital anomaly will be: increase her levothyroxine dosing about 25–30% as soon
A. 3% (same as the general population) as she has a confirmed pregnancy; this would be about
B. 10% (1 per 10) 100 μg for the patient in this questions. The ATA recom-
C. 25% (1 per 4) mends that this is done empirically even before testing is
D. 50% (1 per 2) done. Although women need to increase their levothyrox-
The correct answer is B. As per the chart from the article ine dosing in pregnancy, a 200% increase empirically
by Bell, a hemoglobin A1c of 9.5% confers ~10% risk would be too aggressive in a woman who had reasonable
for a major fetal anomaly. This patient should be coun- control of her hypothyroidism just before pregnancy [58].
seled about the risk to her fetus and the need to better
control her blood glucose immediately to decrease her
future risk. Asthma Question
2. Which oral medication is commonly used early in 1. A 28-year-old G2P1 with intermittent asthma at base-
pregnancy? line in referred to you at 20 weeks gestation complain-
A. Sitagliptin (Januvia) ing of increased cough and wheezing since spring began.
B. Metformin She usually only needs her albuterol inhaler once weekly
C. Glipizide but has been using up to five times per week recently,
D. Acarbose though not at night. She has no accessory muscle use or
The correct answer is B. Because metformin is used for wheezing on exam in your office. In addition to educat-
the treatment of women with polycystic ovary syndrome ing her on avoiding triggers and giving her a peak flow
and infertility, it has been commonly used in early preg- meter, how would you address her medication regimen
nancy and there is an abundance of safety data available at this point?
A. Have her continue using her albuterol rescue inhaler associated with poor neonatal adaptation, and in very rare
but do not add another medication to minimize risks cases, persistent pulmonary hypertension of the newborn.
to the fetus. Weaning her dose does not decrease the risk of these out-
B. Start a low-dose inhaled corticosteroid as a chronic comes and puts this patient at a high risk of depression
controller relapse during pregnancy, so her dose should be contin-
C. Start a low-dose inhaled corticosteroid along with a ued at 200 mg as she is doing well. Sertraline is first line
long-acting beta2-agonist as controllers for pregnant women and has excellent safety data com-
D. Start a moderate-dose inhaled corticosteroid as a pared to other antidepressants, so changing her medica-
chronic controller tion is also not indicated. This patient should continue her
E. Start an oral leukotriene receptor antagonist current medication to optimize her mental health and
The correct answer is B. This patient is now classified as decrease the risks of depression relapse and its effect on
having mild persistent asthma due to her increased symp- her and her future pregnancy [182].
toms requiring use of her beta2-agonist multiple times per
week, though not daily (which would have bumped her up
to moderate persistent in severity). Uncontrolled asthma Anticoagulation Question
poses significant maternal and fetal risk, so while avoid-
ing triggers might help, at this point, pharmacologic con- 1. A 30-year-old woman is considering her first pregnancy.
trol is warranted. It is reasonable to start with a low-dose She has a history of bicuspid aortic valve and currently
inhaled corticosteroid as a chronic controller for mild per- has a mechanical valve in place for which she is on war-
sistent asthma. In patients with moderate persistent farin. She is otherwise healthy. She would like to breast-
asthma, involving daily symptoms or frequent nocturnal feed. She is wondering if she should continue the warfarin
symptoms, there are two options: a moderate dose of during the pregnancy and postpartum. When is warfarin
inhaled corticosteroid or a combination of a low-dose appropriate for women in pregnancy and postpartum?
inhaled corticosteroid and a long-acting beta2-agonist. If A. Warfarin is never appropriate for pregnancy or
this patient were well controlled on a leukotriene receptor breastfeeding
antagonist prior to pregnancy, it would be fine to continue B. Warfarin is never appropriate for pregnancy but is
it in pregnancy; however, these agents are not first-line to compatible with breastfeeding.
start de-novo in pregnancy [128]. C. Warfarin is appropriate in pregnancy in rare cases but
is never appropriate for breastfeeding.
D. Warfarin is appropriate in pregnancy in rare cases and
Depression Question is compatible with breastfeeding.
E. Warfarin is recommended in pregnancy and in
1. A 24-year-old woman is considering pregnancy. She has breastfeeding.
a significant history of major depression with anxiety The correct answer is D. Answers A, B, and C are incor-
since the age of 16. She was hospitalized last year for rect as there are scenarios for pregnant women at very
suicidal ideation. Although she was initially on multiple high risk of clotting, where remaining on warfarin is
medications to control her depression, she is currently appropriate, including this one. Warfarin is considered
maintained on sertraline 200 mg daily and finally doing compatible with breastfeeding. Warfarin is not recom-
well. What changes should you suggest in her medica- mended in pregnancy for most patients who require anti-
tions before pregnancy? coagulation due to its ability to cross the placenta and the
A. She should stop her sertraline because SSRIs are likely increased risks of miscarriage, warfarin embryopa-
associated with major congenital malformations and thy, and fetal hemorrhage. Warfarin embryopathy includes
poor pregnancy outcomes a constellation of symptoms identified in neonates of
B. She should wean her medication to the lowest tolera- mothers on warfarin, particularly those on more than
ble dose prior to pregnancy 5 mg/day, including nasal hypoplasia, stippled epiphyses,
C. She should change her sertraline to a less teratogenic and limb hypoplasia, as well as long term CNS sequelae.
medication However, warfarin has been shown to be the most effica-
D. She should continue her sertraline as is currently cious anticoagulant in protecting from acute valve throm-
prescribed bosis, and there have been multiple case reports of patients
The correct answer is D. SSRIs and sertraline in particular suffering from thrombosis of their mechanical valves
have not been associated with major congenital malfor- while using unfractionated heparin therapy in pregnancy.
mations or poor pregnancy outcomes. They have been Thus, weighing the risks and benefits, most pregnant
women with mechanical valves are anticoagulated with blood pressure medications if needed during pregnancy
warfarin throughout pregnancy [237, 238]. [110–112].
Hypertension Questions
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Index
A surgical management
Abdominal myomectomy, 111, 112 abdominal myomectomy, 111, 112
Abnormal uterine bleeding (AUB), 235 endometrial ablation, 111
acute, 99 hysterectomy, 112
chronic, 99 hysteroscopy, 110, 111
cost, 99 magnetic resonance-guided focused ultrasound ablation, 111
evaluation myolysis- radiofrequency thermal ablation, 111
adolescence, 104 uterine fibroid embolization, 111
history and physical examination, 104 Abnormal vaginal bleeding
laboratory testing, 106 coagulopathy, 161
mid-reproductive years, 104 diagnosis, 161
perimenopause, 104 follicle-stimulating hormone, 161
postmenopausal bleeding, 104, 105 management, 161, 162
imaging ongoing proliferation, 161
magnetic resonance imaging, 107 ovulatory dysfunction, 161
sonohysterography, 107 PALM-COEIN system, 161
ultrasonography, 106, 107 treatment, 162
intramural and submucous fibroids, 100 Academic abuse, 540
invasive testing Acetaminophen, 410, 435
diagnostic hysteroscopy, 107 Activity, Coping, Think, Upset, People’s responses (ACT-UP), 409
diagnostic laparoscopy, 107 Acupuncture, 124
endometrial biopsy, 107 Adenomas, 263
laboratory testing, 105, 106 Adenomyosis, 102
medical management Adenosis, 263
expectant management, 108 Adhesions, 477
hormonal options, 108–110 Adnexa, 475
nonhormonal options, 108 Adnexal torsion
nonstructural causes clinical manifestation, 160
coagulopathy, 103 definition, 159
endometrial causes, 103 differential diagnosis, 160
iatrogenic causes, 103 management, 160
not otherwise classified, 104 referral, 160
ovulatory disorders, 103 risk factor, 159
PALM-COEIN classification, 100 Advanced Alternate Payment Models track, 35
parameters, 99, 100 Advanced practice providers (APPs), 34
pathophysiology, 100 Adverse Childhood Experiences (ACE) Study, 505
endometrial hemostasis, 101 Adverse health behaviors, 539, 540
follicular phase, 101 Adverse health conditions, 539
luteal phase, 101 Affordable Care Act, 28, 35
menstrual bleeding patterns, 101 Alcohol consumption, 586
normal menstrual cycle, 100, 101 Allergic dermatitis, 175
ovulatory phase, 101 Allergic vulvovaginitis, 175
patterns, 99, 100 Alopecia, 321
sexual function assessment, 99 Alprazolam, 513
SF-36 scale, 99 American Academy of Family Physicians (AAFP), 12, 54
structural causes, 100 American Association of Medical Colleges (AAMC), 18
adenomyosis, 102 American Board of Internal Medicine (ABIM), 12, 13
leiomyoma, 102 American College of Obstetricians and Gynecologists (ACOG), 53
malignancies, 102 American College of Physicians (ACP), 20
polyps, 102 American Dental Education Association (ADEA), 17
premalignant lesions, 102 American Medical Women’s Association (AMWA), 7, 19
subserous fibroids, 100 Amsterdam 70-gene profile (MammaPrint®), 315

S. A. Tilstra et al. (eds.), Sex- and Gender-Based Women’s Health, https://doi.org/10.1007/978-3-030-50695-7
618 Index
Anabolic therapy, 400 intraductal papilloma, 271

Angiotensin-converting enzyme inhibitors, 604 lactational mastitis/abscess, 266
Angiotention II receptor blockers (ARB), 439 nipple discharge, 270, 271
Annual wellness visit (AWV), 28, 34 nonproliferative lesions, 262
Anorexia nervosa, 524, 525 nonpuerperal mastitis
Anovulatory bleeding, 161 central/subareolar abscesses, 266
Antibiotics, 603, 604 empiric antibiotic therapy, 267
Anticoagulants, 604 granulomatous mastitis, 268
Anticoagulation, 609 mammary duct ectasia, 266
Anticonvulsants, 411 nonpuerperal abscesses, 266
Antidepressants, 411, 602 peripheral nonpuerperal abscesses, 266
Antiemetics, 437 normal breast anatomy, 259, 260
Anti-HER2/neu antibody, 319 physiologic discharge, 270
Anti-hypertensive medications, 593, 604 proliferative lesions with atypia
Anti-mullerian hormone (AMH), 86 aromatase inhibitors, 265
Anxiety, 45 atypical ductal hyperplasia, 264, 265
Anxiety disorders. See Depression lobular neoplasia, 264
Aromatase inhibitors (AIs), 93, 265, 291, 292, 317 proliferative lesions without atypia
Asherman syndrome, 73 adenomas, 263
Assisted reproductive technology (ART), 147 adenosis, 263
Association of Academic Women’s Health Programs (AAWHP), 19 complex fibroadenoma, 263
Asthma, 608 epithelial hyperplasia, 263
classification and treatment hamartoma, 263
components, 596 intraductal papilloma, 263
patient education, 596 Phyllodes tumor, 263
pharmacologic therapy, 596, 597 radial scar, 263
epidemiology, 596 puerperal mastitis, 265, 266
exacerbations, 597 Benzodiazepines, 513
labor, delivery, and postpartum period, 597 alprazolam, 513
pathophysiology, 596 clonazepam, 513
Atherosclerotic vascular disease (ASCVD) diazepam, 513
pharmacologic primary prevention lorazepam, 513
aspirin, 363, 364 temazepam, 514
non-statin adjuvant therapies, 364, 365 Bimanual examination, 49
statins, 364, 365, 367 Binge eating disorder (BED), 524, 525
prevention of, 361, 362 Biopsychosocial model, 129
asymptomatic women of borderline risk, 366, 367 Bipolar disorder, 501
asymptomatic women of intermediate risk, 366 Bisphosphonates, 319
low intermediate risk, 367 Bladder dysfunction, 605
symptomatic women Body mass index (BMI), 73
ischemic heart disease, 367–370 Body weight, 605
stroke, 368, 369 Botox, 441
Atrophic vaginitis, 47 Breast cancer, 559, 568
Atypical ductal hyperplasia (ADH), 236, 264, 265, 299 advanced interventions
Atypical lobular hyperplasia (ALH), 264, 299 BRCA, 290
Autoimmune and inflammatory disorders, 355 clinical breast exams, 289, 290
mammography, 290
MRI screening, 290
B PALB2 mutations, 290
Bacterial vaginosis (BV), 168–170 PTEN mutation, 290
Basson model, 127, 128 breast awareness, 289
Benign breast conditions breast risk triage, 277, 279
breast imaging, 260, 261 chemoprevention
breast pain aromatase inhibitors, 292
cyclical breast pain, 268, 269 bone health, 293
extramammary pain, 269 candidates, 283, 291
history, 268 contraindications, 292
noncyclical breast pain, 268, 269 evidence of impact, 291
prevalence, 268 selective estrogen receptor modulators, 291
risk assessment, 268 vaginal bleeding, 293
treatment, 269 vaginal dryness and dyspareunia, 293
clinical breast exam, 260, 261 vasomotor symptoms, 292
comprehensive evaluation, 260 chemoprophylaxis, 293
differential diagnosis, 261, 262 comprehensive management strategies, 293
duct ectasia, 271 evaluation and management
galactorrhea, 270 DCIS/invasive cancer, 283
Index 619
dense breasts on mammography, 284 estrogen receptor and progesterone receptor status, 315
5-year and lifetime risk percentages, 284 gene profile testing, 315
history of atypical hyperplasia/lobular carcinoma in situ, 283 HER2 receptor, 315
history of breast biopsy/dense breasts, 283 treatment options
history of chest radiation, 279, 280 anti-HER2/neu antibody, 319
no radiation, no genetic or family history, and no breast history, bisphosphonates, 319
279 chemotherapy, 318, 319
non-proliferative breast lesions, 284 hormonal therapy, 319
personal or family history of cancer or genetic mutations, metastatic disease, 319, 320
279–282 radiation therapy, 318
Personalized Prevention Plan, 286, 287 surgical resection of primary tumor, 318
PPP, 285 tubular carcinoma, 314
proliferative breast lesions, 283 Breast Cancer Risk Assessment Tool (BCRAT), 284, 299
risk calculators, 284 Breast cancer screening
lifestyle counseling clinical breast exam, 305, 306
alcohol use, 288 counseling women with suspected, 307
cigarette smoking, 288 malignant findings, 307
physical activity, 285, 288 staging, 308
postmenopausal obesity, 288 tumor biology and receptor testing, 308
patient evaluation and documentation, 276–277 guidelines, in average risk women, 302, 303
primary care providers, 275 high risk, 304, 305
principles of counseling and explaining risk to patients, 285 mammography
prophylactic mastectomy, 293 benefits of, 302
reproductive and hormonal factor counseling conventional digital, 301
breastfeeding, 288 harms of, 302
hormonal contraceptive use, 288 mammography interpretation and appropriate follow-up, 305
postmenopausal hormone therapy, 289 modalities
pregnancy, 288 breast MRI, 301
risk factors, 276–277 false positive and biopsy recommendations, 302
Breast cancer diagnosis and management over-diagnosis and over-treatment, 302
adverse effects, 321 moderate risk, 304
Amsterdam 70-gene profile (MammaPrint®), 315 palpable breast lump, 307
clinical trials, 320 psychosocial impact, 308, 309
complications, 320 risk assessment
alopecia, 321 average risk, 298, 299
anti-estrogen and anti-HER2 therapies, 322 Breast Cancer Risk Assessment Tool, 299
infertility risk, 322, 323 Gail Model, 299, 300
lymphedema, 321 high risk, 298, 299
nausea and vomiting, 321, 322 IBIS model, 300
genetic mutations, 317 moderate risk, 298
histopathology risk factor, 298
ductal carcinoma in situ, 314 self breast exam, 305–307
invasive ductal carcinoma, 314 treatment planning
lobular carcinoma in situ, 314 ductal carcinoma in situ, 308
inflammatory breast cancer, 314 invasive breast cancer, 308
Li-Fraumeni syndrome, 317 women with dense breasts, 303, 304
long-term outcome, 320 Breast Cancer Surveillance Consortium (BCSC) Risk Calculator, 284
Lynch syndrome, 317 Breast cancer survivor
mammary Paget’s disease, 314 Breast cancer survivors
metaplastic carcinoma, 314 bone health
mucinous/colloid carcinoma, 314 diagnosis, 337
PALB2, 317 epidemiology and risk factors, 337
papillary carcinoma, 314 management, 337, 338
patient characteristics, 317, 318 clinical follow-up, 331
Peutz-Jeghers syndromes, 317 definition, 330
phylloides tumors, 314 distress, depression and anxiety
primary care provider, 313 diagnosis, 335
prognosis, 324 epidemiology and risk factors, 334, 335
psychological impact, 323, 324 health promotion, 336
PTEN hamartoma tumor syndromes, 317 nutrition and alcohol, 336
recurrence score (Oncotype Dx®), 315 physical activity, 336
staging smoking cessation, 336
metastases, 316 weight, 336
nodal involvement, 316 feeling of uncertainty, 330
tumor size, 316 history, 331
tissue markers and molecular profiling imaging studies, 332
620 Index
Breast cancer survivors (cont.) stroke, 368, 369

lab tests, 332 cerebrovascular disease, 348, 349
late-and long-term complications, 338–339 direct annual medical costs, 347
non-hormonal treatments emerging risk factors
anticonvulsants, 332 anthracyclines, 354
clonidine, 333 atrial fibrillation, 355
SSRIs/SNRIs, 332 autoimmune and inflammatory disorders, 355
physical examination, 331 depression, 354
recurrence peaks, 331 HER2-receptor antagonists, 354
sexual dysfunction history of radiation therapy, 354
complementary and alternative medications, 333 heart failure, 348
definition, 333 ischemic heart disease, 348
diagnosis, 333 lactation and risk reduction
epidemiology and risk factors, 333 cardiovascular disease, 353
5As framework, 334 gestational diabetes, 353
management, 333, 334 hypertension, 353
surveillance, 331, 332 stroke, 353, 354
survivorship care plans, 330 mortality rates, 347, 361
tumor markers, 332 peripheral arterial disease, 349
vasomotor symptoms, 332 pooled cohort equation, 371
Breast examination, 48 pregnancy
Breast Imaging Reporting and Data System (BI-RADS), 305 gestational diabetes mellitus, 351
Breast pain hypertensive disorders, 351
cyclical breast pain, 268, 269 preterm delivery, 351
extramammary pain, 269 spontaneous pregnancy loss, 351
history, 268 weight gain, 351
noncyclical breast pain, 268, 269 reproductive cycle
prevalence, 268 combined oral contraceptive pills, 352
risk assessment, 268 hormone therapy, 352
treatment, 269 menarche, 351
Breastfeeding menopause, 352
benefits of, 603 premenstrual syndrome, 351
complications, 603 reproductive life cycle, 350
contraindications, 603 risk assessment, 363
drug safety, 603 spontaneous coronary artery dissection, 348
antibiotics, 603, 604 Takotsubo cardiomyopathy, 348
anticoagulants, 604 traditional risk factors
antihypertensive medications, 604 age and family history, 349
diabetic medications, 604 diabetes mellitus, 350
pain medications, 603 dyslipidemia, 349, 350
physiological effect, 603 hypertension, 349
psychiatric mediations, 604 metabolic syndrome, 350
physiology, 602, 603 overweight and obesity, 350
Bristol Stool Form Scale (BSFS), 418 sedentary lifestyle, 350
Building Interdisciplinary Research Careers in Women’s Health smoking, 350
(BIRCWH) program, 7, 18 Cardiovascular Health After Maternal Placental Syndromes
Bulbospongiosus muscles, 473 (CHAMPS) study, 606
Bulimia nervosa (BN), 525, 530 Cardiovascular system, pregnancy, 605
Buprenorphine, 489, 490 Carnett’s test, 473
Bupropion, 513 Centers for Disease Control and Prevention (CDC), 53
Centers of Excellence (COEs), 7, 8
Central hypogonadism, 73
C Central/subareolar abscesses, 266
Caffeine intake, 585, 586 Cerebrovascular disease, 348, 349
Campus sexual violence, 537 Cervical cancer, 231, 558, 559, 568
Cardiac Syndrome X, 348 abnormal screening, 220, 221
Cardiovascular disease (CVD), 317 cervical neoplasia, treatment for
ASCVD conization, 222
aspirin, 363, 364 cryotherapy, 222
asymptomatic women of borderline risk, 366, 367 hysterectomy, 222
asymptomatic women of intermediate risk, 366 laser ablation, 222
asymptomatic women of low intermediate risk, 367 loop electrosurgical excision procedure, 222
ischemic heart disease, 367–370 clinical presentation, 243
non-statin adjuvant therapies, 364, 365 colposcopy and biopsy, 221, 222
prevention of, 361, 362 definitions, 220
statins, 364, 365, 367 diethylstilbestrol (DES) exposure, 243
Index 621
epidemiology, 213, 242 prevalence, 471

evaluation and diagnosis, 243 treatment
high-risk HPV, 242 gynecologic, 479, 480
incidence, 224 interdisciplinary care teams, 478
mortality, 224 musculoskeletal, 479
pap test technique, 215, 216 psychiatric, 480
prevention, 214 Cigarette smoking, 585
prognosis, 244 Citalopram, 511
screening, 215, 224, 225, 243 Clinical breast exam (CBE), 260, 261, 305, 306
screening guidelines Clinical Opioid Withdrawal Scale (COWS), 489
diethylstilbestrol exposure in utero, 219, 220 Clonazepam, 513
immunocompromised women, 219 Cluster headaches, 8
total hysterectomy with complete removal of cervix, 219 clinical presentation, 432
women 30 and older, 218 pathogenesis, 431
women age of 65, 218, 219 prevalence, 431
women under age 21, 217 treatment, 432
women under age 30, 217, 218 Coagulopathy, 103, 105, 161
staging, 243, 244 Coercive control, 536
survivorship care, 244 Cognitive behavioral therapy (CBT), 124
transformation zone, 214, 215 Collaborative care models, 515
treatment strategies, 243, 244 Combined oral contraceptive (COC), 57, 58, 64, 73, 92, 352, 442, 443
vaginal sample collection, 226 Communication, 28, 29
Cervical intraepithelial neoplastic (CIN) lesions, 42 Complementary and alternative medicine (CAM), 123
Chemoprophylaxis, 293 Complex fibroadenoma, 263
Chlamydia, 190, 191 Complicated urinary tract infection, 383
Chronic constipation, 476 Confidentiality, 541, 542
Chronic fatigue, 454 Conization, 222
Chronic hypertension, 591 Constipation predominant (IBS-C), 420, 421, 423, 424
Chronic obstructive pulmonary disease (COPD), 8 Consumerist model, 60
Chronic ovulatory dysfunction (OD), 84 Contact dermatitis, 175
Chronic pain Contact vulvovaginitis
classification, 407, 408 examination, 175
clinical history, 409 history, 175
definition, 407 management, 176
diagnostic test, 409, 410 prevalence, 175
epidemiology, 407 Continuing Medical Education (CME), 16
gender differences, 408, 409 Contraception, 64
medical marijuana, 412 Contraceptive counseling, 577
non-opioid pharmacologic therapies abortion, 62, 63
analgesics, 410, 411 consumerist model, 60
anticonvulsants, 411 contraception initiation and adherence, 61, 62
antidepressants, 411 desired pregnancy, 61
topical agents, 411 directive counseling, 60
non-pharmacologic treatments, 410 efficacy, 60
opioids, 411, 412 emergency contraception
pathophysiology, 408 copper IUD, 62
patient-provider relationship, 412, 413 levonorgestrel, 62
physical examination, 409 methods, 62
Chronic pelvic pain (CPP) ulipristal, 62
differential diagnosis, 475 Yuzpe regimen, 62
gastrointestinal contributors, 475, 476 intrauterine device
gynecologic contributors, 477 contraindications, 54
laboratory testing, 477, 478 copper, 55
laparoscopy, 478 description, 54
musculoskeletal contributors, 476 progestin, 55
psychiatric contributors, 477 requirements, 54
radiographic imaging, 478 STI screening, 55
urologic contributors, 476 trained providers, 54, 55
history, 472, 473 need for privacy, 61
neuroanatomy, 472 non-hormonal/barrier methods
physical examination, 473 diaphragm, 59
abdominal wall, 473 internal condom, 58, 59
bimanual exam, 474, 475 male condoms, 58
gynecologic exam, 473 natural family planning, 59
pelvic floor muscles, 473, 474 spermicide, 59
vaginal speculum exam, 475 sponge, 59
622 Index
Contraceptive counseling (cont.) medication management, 508–510

withdrawal method, 59 patient’s history and family history, 508, 511
non-permanent contraceptive options, 54 physical activity, 508
reproductive goals counseling, 53, 54 psychiatric symptoms and health-related
sexual activity, 61 behaviors, 508
shared decision-making, 60 MDD, 500
short-acting reversible contraceptives, 56 medication
COCs, 57, 58 benzodiazepines, 513, 514
DMPA, 56 dopamine-norephinephrine reuptake
POPs, 56, 57 inhibitors, 513
transdermal patch, 58 gabapentin and pregabalin, 514
vaginal ring, 58 insufficient response, 514
side effects, 60, 61 mirtazapine, 514
subdermal implant (Nexplanon), 55, 56 SNRIs, 512, 513
Contraceptive methods, 577 SPARIs, 512
Conventional digital mammography, 301 SSRIs, 511, 512
Council on Graduate Medical Education’s (COGME), 11 TCAs, 514
Cowden syndrome, 317 trazodone, 514
Crisis/violence phase, 537 morbidity, 497
Cultural competence, 47–48 pathophysiology, 498
Cutaneous allodynia, 433 GABA, 499
Cycle of violence model, 537, 538 serotonin receptor, 498, 499
Cyclical breast pain, 268 sex and gender-based differences, 498
Cyclooxygenase (COX), 410 sex hormone influences, 499
Cystitis, 383 PDD, 500
clinical manifestation, 384 PMDD, 500, 501
follow-up, 389 postpartum care, 516
microbiology, 383 preconception, 516
microscopic analysis, 385 pregnancy
office urine dipstick, 385 clinical outcomes, 600
outpatient via phone, 385 epidemiology, 600
suspected pyelonephritis, 385 postpartum care, 607
treatment strategies prevention, 600
duration of antibiotic therapy, 386 treatment, 600–602
fluoroquinolones, 386 prevalence, 497
fosfomycin, 386 psychiatric screening and intervention,
ibuprofen, 386 primary care in, 499
nitrofurantoin monohydrate macrocrystals, 386 psychotherapy, 515
second line therapy, 386 PTSD, 502
TMP-SMX, 386 screening tools, 502, 503
urine culture, 385 serotonin syndrome, 514, 515
suicide risk assessment, 506
components, 506
D intent, 507
Dehydroepiandrosterone (DHEA), 85 involuntary hospitalization, 507
Dehydroepiandrosterone-sulfate (DHEA-S), 86 plan and mean, 506, 507
Department of Veterans Affairs, 574, 575 protective factors, 506
Depot medroxyprogesterone acetate (DMPA), 56 safety planning, 507
Depression, 94, 354, 609 suicidal ideation, 506
anxiety and panic disorders, 501 voluntary hospitalization/urgent psychiatric
biopsychosocial risk factors, 503 referral, 507
childhood and adulthood trauma, 505 treatment planning, 516
chronic pain, 504 Dermatoses
resiliency and coping factors, 506 lichen planus, 177, 178
stressors, 504 lichen sclerosus, 176, 177
substance abuse, 504 lichen simplex chronicus, 179
trauma informed care, 505 psoriasis, 178
bipolar disorder, 501 Desquamative inflammatory vaginitis (DIV), 172, 173
clinical interviewing, 502 Desvenlafaxine, 512
collaborative care, 515 Diabetes, 350, 605, 606, 608
differential diagnosis, 499, 500 clinical manifestations, 589
follow-up and treatment duration, 515 epidemiology, 589
hormone therapy, 514 glucose control, 590
insomnia, 514 health maintenance, 590
lifestyle behavior modifications pathophysiology, 589
compelling indications, 511 Diagnostic hysteroscopy, 107
Index 623
Diagnostic laparoscopy, 107 Empowerment, 542

Diarrhea predominant (IBS-D), 419, 420, 424 Endometrial ablation, 111
Diazepam, 513 Endometrial and endocervical polyps, 102
Dietary intervention, 441, 442 Endometrial biopsy (EMB), 107, 235, 236
Diethylstilbestrol (DES), 44, 243 Endometrial cancer, 559
Diethylstilbestrol (DES) exposure in utero, 219, 220 Endometrial hemostasis, 101
Diffuse gastric and lobular breast cancer syndrome, 317 Endometrial hyperplasia, 102, 113
Digital breast tomosynthesis (DBT), 301 without atypia, 110
Dihydroergotamine (DHE), 437 Endometrial prostaglandin, 101
Dihydrotestosterone (DHT), 93 Endometriosis, 463
Dopamine-norephinephrine reuptake inhibitors, 513 chronic pelvic pain, 146, 147
Duct ectasia, 271 clinical manifestation, 145
Ductal carcinoma in situ (DCIS), 299, 307, 308, 314 diagnostic strategies, 146
Duloxetine, 512 differential diagnosis
Dyslipidemia, 349, 350 chronic pelvic pain, 146
Dysmenorrhea, 476 infertility, 146
Dyspareunia, 477, 480 epidemiology, 144, 145
infertility, 147
pathophysiology, 145
E physiology, 145
Eating disorders (EDs) Epithelial hyperplasia, 263
anorexia nervosa, 524, 525 Erenumab, 441
BED, 525 Ergot medications, 437
bone health, 529, 530 Ergotamine, 437
bulimia nervosa, 525 Escitalopram, 511
criteria for hospitalization, 528 Estrogen receptor and progesterone receptor
early medical complications, 529 status (ER/PR), 315
epidemiology, 523, 524 Estrogen replacement therapy (ERT), 6
FHA, 526, 527 Estrogen therapy, 400
pathophysiology, 524 Estrogen withdrawal headaches, 442
prognosis and relapse, 530 Executive Leadership in Academic Medicine (ELAM)
psychiatric comorbidity, 525, 526 program, 18
screening, 524 Expressive aggression, 536
sexuality, fertility, and pregnancy, 529 Extended-release nifedipine, 593
treatment External genitalia, 473
anorexia, 527 Extragenital chlamydia/gonorrhea
BED, 527, 528 infection, 192
bulimia, 527 Extramammary pain, 269
Ebola virus, 205
Eclampsia, 591
Ectopic pregnancies (Ect), 42 F
Ectopic pregnancy Family Medical Leave Act (FMLA), 17
diagnosis, 158 Family planning, 577
differential diagnosis, 157 Fat necrosis, 262
first-trimester bleeding, 157 Federated Council for Internal Medicine (FCIM)
medical management, 159 recommendations, 13
occurence, 157 Female arousal and orgasmic disorders, 133
pregnancy testing, 157 Female athlete triad. See Eating disorders (EDs)
recurrence rates, 159 Female gender-specific history
secondary amenorrhea, 157 breast health and screening history, 43
surgical management, 159 complications of pregnancy, 42
Edinburgh Postpartum Depression Scale components, 41, 42
(EPDS), 516, 600 contraception, 41
Elective termination, 62 family history, 43
Elimination diets, 442 gravidity, 41, 42
Eluxadoline, 424 gynecologic history, 42
Emergency contraception (EC) lactation, 42
copper IUD, 62 lifestyle habits, 43
levonorgestrel, 62 menstrual history, 41
methods, 62 obstetrical history, 41
ulipristal, 62 parity, 41, 42
Yuzpe regimen, 62 reproductive plans, 41
Emerging STI ROS, 43
Ebola virus, 205 sexual history, 42, 43
Zika virus, 205 social history, 43
Empathy, 542 Female Sexual Distress Scale-Revised (FSDS-R), 130
624 Index
Female sexual dysfunction (FSD) pathophysiology, 453, 454

antidepressant-associated sexual dysfunction, 131, 132 Fluoxetine, 511, 604
biopsychosocial model, 129 Fluvoxamine, 511
definition, 130 Folic acid supplementation, 584
domains, 130 Forensic sexual exam, 546
epidemiology, 128 Fremanezumab, 441
evaluation, 130, 131 Functional dyspepsia, 577
framework, 127 Functional hypothalamic amenorrhea (FHA), 526, 527
impact, 127 Functional incontinence, 376
prevalence, 128 Functional ovarian hyperandrogenism (FOH), 84, 85
screening, 129 granulosa cell dysfunction, 86
treatment normal ovarian function, 85, 86
HSDD, 133 theca cell dysfunction, 86
normative sexual behaviors, 132
sexual pain disorder, 133
sexual pain disorders, 133, 134 G
types, 131 Gabapentin, 514
Female sexual function GAD-7, 502, 515
aging and menopause, 129 Gail model, 284, 299, 300
definition, 127 Galactocele, 262
framework, 127 Galactorrhea, 270
medical and psychiatric issues, 132 Gamma-aminobutyric acid (GABA) receptor, 499
screening instruments, 130 Gastroenterological complications, 248, 249
Female Sexual Function Index (FSFI), 128, 130 Gastroenterology, 426
Female veterans Gastroesophageal reflux, 587
gastrointestinal disorders, 577 Gastrointestinal disorders, female veterans, 577
genitourinary system, 577 Gastrointestinal tract (GI), 417
health issues, 573, 574 Gender affirmation, 564
musculoskeletal system, 576 Gender dysphoria, 564
PTSD Gender expression, 556
definition, 574 Gender identity, 556
MST, 574, 575 Gender non-conformity, 564
PC-PTSD-5, 574 Gender rating, 36
treatment, 575, 576 Genital sexual pain disorders, 133
reproductive health, 578 Genital warts, 203–205
contraceptive methods, 577, 578 Genito-pelvic pain/penetration disorders, 134, 476
cross-sectional VA study, 577 Genitourinary syndrome of menopause (GSM), 118, 122–124, 129,
family planning, 577 463, 468
LARCs, 578 Genitourinary system, female veterans, 577
STIs, 578 Gestational diabetes mellitus (GDM), 351, 605
TBI, 576, 577 Gestational hypertension, 591, 592
Fermentable, oligosaccharides, disaccharides, monosaccharides and Glargine, 590
polyols (FODMAPs), 421, 422 Glomerulations, 461, 462, 466
Fibrinolysis inhibitors, 101 Gonadotoxic chemotherapy agents, 322
Fibroadenomas, 262 Gonadotropin-releasing hormone (GnRH), 72, 84, 86, 526
Fibrocystic breast disease, 261 Gonadotropin-releasing hormone (GnRH) agonist, 152
Fibrocystic changes (FCC), 261 Graduate medical education
Fibroids ABIM, 13
clinical manifestation, 142 clinical experiences, 15
diagnostic strategies, 143 competency, 12
differential diagnosis, 142, 143 fellowships, 16
epidemiology, 141 interdisciplinary educational, 13
physiology and pathophysiology, 141, 142 knowledge and clinical skills, 12
treatment patient care partnerships, 13
bleeding symptoms, 143, 144 primary care residents, 15
bulk symptoms, 144 recommendations, 13–15
Fibromyalgia, 576 WH track, 15, 16
clinical evaluation, 455 written curriculum, 15
clinical manifestations, 454 Granulomatous mastitis, 268
diagnosis, 455 Graves’ disease, 595
differential diagnosis, 455, 456 Gravidity (G), 41, 42
epidemiology, 453 Group on Women in Medicine and Science (GWIMS), 20
management Guideline directed medical therapy (GDMT), 368
follow-up, 457 Gynecologic cancers. See Gynecologic malignancies
non-pharmacologic therapies, 456, 457 Gynecologic emergencies
pharmacologic therapies, 457 abnormal vaginal bleeding
Index 625
coagulopathy, 161 survivorship care, 232

diagnosis, 161 treatment, 232
follicle-stimulating hormone, 161 uterine cancer, 231
management, 161, 162 abnormal glandular cells/atypical endometrial cells, 235
ongoing proliferation, 161 abnormal uterine bleeding, 235
ovulatory dysfunction, 161 classification, 233
PALM-COEIN system, 161 clinical presentation, 235
treatment, 162 endometrial biopsy, 235
adnexal torsion endometrial hyperplasia and precancerous lesions, 236
clinical manifestation, 160 epidemiology, 233
definition, 159 incidental pap test abnormality, 235
differential diagnosis, 160 overview, 232
management, 160 pathophysiology and risk factors, 233–234
referral, 160 post-menopausal bleeding, 235
risk factor, 159 postmenopausal women, 235
ectopic pregnancy screening, 234
diagnosis, 158 staging, 236
differential diagnosis, 157 survivorship care, 238
first-trimester bleeding, 157 treatment strategies, 237, 238
medical management, 159 vulvar and vaginal cancer
occurence, 157 clinical presentation, 245, 246
pregnancy testing, 157 diagnosis, 246
recurrence rates, 159 differential diagnosis, 246
secondary amenorrhea, 157 epidemiology, 245
surgical management, 159 evaluation, 246
Gynecologic malignancies hrHPV or lichen sclerosis, 245
cervical cancer, 231 morphology, 246
clinical presentation, 243 pathophysiology and risk factors, 245
epidemiology, 242 prognosis, 247
evaluation and diagnosis, 243 screening, 245
high-risk HPV, 242 staging, 247
prognosis, 244 suvivorship care, 248
screening, 243 treatment strategies, 247
staging, 243, 244 vulvar and vaginal intraepithelial neoplasia, 246
survivorship care, 244 vulvar and vaginal cancers, 231
treatment strategies, 243, 244
common side effects and sequelae, 248
genetic syndromes, 231 H
healthcare providers, 232 Haloperidol, 604
long-term complications Hamartoma, 263
gastroenterological complications, 248, 249 Headaches
neurologic complications, 249 clinical evaluation, 430
psychologic complications, 250 components, 429
sexual and gynecologic complications, 249, 250 definition, 429
surgical and treatment-induced menopause, 250 migraine
urologic complications, 249 abortive treatments, 435–438
ovarian cancer, 231 adjuvant non-pharmacologic treatments, 435
clinical presentation, 241 clinical presentation, 433, 434
diagnosis, 241 definition, 432, 433
epidemiology, 239 estrogen withdrawal, 442
evaluation, 241 MAM, 442, 443
highest fatality rate, 238 migraine threshold, 435
pathophysiology, 239 MWA, 434
protective factors, 240 pathophysiology, 433
risk factors, 239, 240 patient care issues, 442
screening, 240, 241 preventive treatments, 439–442
screening asymptomatic women, 238 risk of stroke, 444–446
staging, 241, 242 treatment, primary care provider, 434, 435
survivorship care, 241, 242 triggers, 435
treatment strategies, 241 primary headaches (see Primary headaches)
overview, 232 secondary headaches
prevention and early detection, 232 evaluation, 447
primary care provider, 248 imaging, 447
primary symptoms, 231 medication overuse, 446
prognosis, 231 Health promotion, 336
risk factors, 231 Health Research and Services Administration (HRSA), 16, 17
626 Index
Health-related behavior, 504 Human Papillomavirus (hrHPV or HPV), 558, 559

Healthy sexual function, 127 acquisition, 214
Hearsay rule, 547 epidemiology, 213
Heart failure, 348 high risk, 214, 216, 217
Heart Failure with preserved Ejection Fraction (HFpEF), 8 prevalence, 225
Hemolysis, elevated liver enzymes, and low platelet count (HELLP) principles, 223, 224
syndrome, 591 screening, 214
HER2-positive metastatic tumors, 320 in specific populations, 224
Hereditary breast and ovarian cancer syndromes (HBOCs), 290 vaccination, 42, 222, 223, 225, 226
Hereditary Diffuse Gastric Cancer Syndrome, 290 vaccine, 219
Hereditary nonpolyposis colorectal cancer (HNPCC), 234, 317 Human trafficking, 537
Herpes simplex virus (HSV) Hunner’s lesions, 461
counseling, 196 Hyperandrogenemia
laboratory testing, 195 acne, 87
primary infection, 195 androgenic alopecia, 87
treatment, 195, 196 clinical features, 87
High grade serous carcinoma, 239 hirsutism, 87, 88
High sensitivity C-reactive protein (hsCRP), 363 Hyperandrogenism (HA), 83, 84
High-density lipoprotein (HDL) cholesterol, 87 treatment, 93
High-risk HPV (hrHPV), 242 Hyperinsulinemia, 86
High-value care Hyperprolactinemia, 73
access to care, 27, 28 Hypertension, 349, 351, 353, 606, 610
advocacy, 37 pregnancy
breast cancer, 38 classification, 591
by cost, 29 clinical manifestation, 591, 592
cost of care for women, 35, 36 epidemiology, 591
disparities, 36 laboratory studies, 592
emergency department, 27 physiology and pathophysiology, 591
equity of care, 36 postpartum care, 606
health policy, 37 treatment, 592, 593
insurance programs, 35 Hyperthyroid symptoms, 606
interventions, 29–30 Hyperthyroidism
low-value services, 32, 38 clinical manifestations, 595
objectives, 37 diagnosis, 595
ovarian cancer, 31–32 epidemiology, 594, 595
patient-reported experience surveys, 28, 29 treatment, 595
pay-for-value programs, 35, 38 Hypnosis, 124
payment arrangements, 35 Hypoactive sexual desire disorder, 127
physicians and provider groups, 30 Hypothalamic amenorrhea, 77
precision medicine, 30, 31 Hypothalamic, pituitary, gonadal (HPG) axis, 72
prevention, 28 Hypothyroidism
primary care providers, 27 clinical manifestations, 593
process improvement, 34 diagnosis, 594
public reporting, 34, 35 epidemiology, 593
quality, affordability, and patient experience, 27 treatment, 594
shared decision-making, 33 Hysterectomy, 112, 222, 237
social determinants of health, 36, 37 Hysteroscopic myomectomy, 144, 151
systems engineering, 33, 34 Hysteroscopy
test characteristics, 32 myomectomy, 110, 111
Hirsutism, 87, 88 polypectomy, 110
Honeymoon phase, 537
Hormonal contraception
MWA, 444–446 I
MWOA, 444, 445 Immediate-release nifedipine, 593
Hormone therapy (HT), 78, 289, 319, 352 In vitro fertilization (IVF), 147
combined hormonal contraceptives, 109 Inclusive language, 564, 565
progestational agents Induced abortion, 62
danazol, 110 Infection vaginitis
depot medroxyprogesterone acetate, 110 bacterial vaginosis, 168–170
gonadotrophin-releasing hormone agonists, 110 chlamydia and gonorrhea testing, 167
levonorgestrel intrauterine device, 109, 110 clinical manifestations, 166
long-acting injectable progestin, 109 diagnosis, 166
oral progestogens, 109 differential diagnosis, 166
selective progesterone receptor modulators, 110 epidemiology, 165, 166
Human Epidermal Growth Factor Type 2 Receptor (HER2/neu, or pelvic examination, 167
simply HER2), 315 positive whiff test, 167
Index 627
saline wet mount, 167, 168 provider responses, 543

trichomoniasis, 168, 170, 171 psychological aggression, 536
urine testing, 167 respect for autonomy, 542
vaginal candidiasis, 170 risk factors
vaginal pH testing, 167 community, 536, 537
vulvovaginal candidiasis, 167, 168 individual factors, 536
Infertility, treatment, 93, 94 relationship, 536
Inflammatory breast cancer (IBC), 314 societal factors, 537
Influenza, 585 screening, 541
Inherited thrombophilias, 598 sexual violence, 535, 537
Institute of Medicine (IOM), 7 social history clues
Insulin therapy, 590 human trafficking, 540
Internal medicine (IM) residents partner characteristics, 540
ABIM, 13 stalking, 535, 536
clinical experiences, 15 support, 543–546
competency, 12 trauma-informed healthcare, 540, 541
fellowships, 16 universal education, 542
interdisciplinary educational, 13 validation, 542
knowledge and clinical skills, 12 Intraductal papilloma, 263, 271
patient care partnerships, 13 Intramural fibroids, 100
primary care residents, 15 Intraperitonal chemotherapy, 241
recommendations, 13–15 Intrauterine devices (IUDs), 49, 73, 92
WH track, 15, 16 contraindications, 54
written curriculum, 15 copper, 55
International Breast Cancer Intervention Study (IBIS), 284 description, 54
Interprofessional Education (IPE), 7, 16, 17 progestin, 55
Interstitial cystitis/bladder pain syndrome (IC/BPS) requirements, 54
clinical manifestations, 462 STI screening, 55
definition, 461 trained providers, 54, 55
diagnostic strategies Invasive cervical cancer (ICC), 214
history, 464 Invasive ductal carcinoma (IDC), 314
physical examination, 464, 465 Invasive lobular carcinoma (ILC), 314
testing, 466 Irritable bowel syndrome (IBS), 464
differential diagnosis, 462, 463 clinical manifestations, 418
nephrolithiasis and malignancy, 463 CPP, 475, 476
OAB, 463 diagnostic criteria, 418
painful pelvic and gastrointestinal conditions, 463, 464 differential diagnosis and diagnostic strategies
urethritis, 462 features, 418
urinary tract infection, 462 IBS-C, 420, 421
epidemiology, 461 IBS-D, 419, 420
pathophysiology, 461, 462 epidemiology, 417
physiology, 461, 462 female veterans, 577
prognosis, 468 nonpharmacological interventions
treatment, 466, 467 diet and exercise, 421, 422
Intimate partner violence (IPV), 43, 586 psychological and alternative/complementary therapies, 422,
caring for victims of trafficking, 547 423
clinical clues pathophysiology, 417, 418
adverse health behaviors, 539, 540 patient satisfaction, 421
adverse health conditions, 539 pharmacological interventions
mental health, 539 IBS-C, 423, 424
sexual and reproductive health, 540 IBS-D, 424
stress, 539 pain, 424, 425
confidentiality, 541, 542 Irritant contact dermatitis, 175
control of reproductive/sexual health, 536 Irritant vulvovaginitis, 175
course over time, 547, 548 Ischemic heart disease, 348
definition, 535 Ischial spines, 473
documentation, 547
empathy, 542
empowerment, 542 L
forensic sexual exam, 546 Labetalol, 604
health impact, 543 Lactational mastitis/abscess, 266
human trafficking, 537 Laser ablation, 222
pathophysiology Leiomyoma, 102
cycle of violence, 537, 538 Leiomyomas. See Fibroids
power and control wheel model, 539 Leiomyomata, 100
physical violence, 535 Lesbian, gay, bisexual, or transgender (LGBT), 555
628 Index
Levator ani muscles, 473 VTE, 119

Levomilnacipran, 512 nonhormonal medications, 122, 123
Levonorgestrel (LNg), 55 special populations, 124
Levonorgestrel intrauterine device (LNG IUD), 109, 110 Menorrhagia, 64, 65
Lichen planus (LP), 177, 178 Menstrual associated migraines (MAM), 442, 443
Lichen sclerosus (LS), 176, 177 Menstrual bleeding patterns, 101
Lichen simplex chronicus (LSC), 179 Menstruation. See Secondary amenorrhea
Li-Fraumeni syndrome, 290, 314, 317 Mental health disorders, PTSD, 574, 575
Lipoma, 262 Merit-based Incentive Payment System (MIPS), 35
Living children (LC), 42 Metabolic syndrome, 350
Lobular carcinoma in situ (LCIS), 264, 299, 314 Metaplastic carcinoma, 314
Lobular neoplasia, 264 Metastatic disease, 319, 320
Long-acting reversible contraceptives (LARCs), 54, 578 Metastatic ER positive tumors, 319
Loop endocervical excision procedure (LEEP), 222, 243 Metformin, 590, 604, 608
Loperamide, 424 Methadone, 490
Lorazepam, 513 Metronidazole, 604
Low-density lipoprotein (LDL) cholesterol, 87 Microglandular adenosis, 263
Luteinizing hormone (LH), 72 Microvascular dysfunction, 348
Lymphedema, 321 Microvascular ischemia, 348
Lynch syndrome, 234, 290 Migraine
clinical presentation, 433, 434
definition, 432, 433
M estrogen withdrawal, 442
Magnetic resonance-guided focused ultrasound MAM, 442, 443
Ablation (MRgFUS), 111 migraine threshold, 435
Major depressive disorder (MDD), 500 MWA, 434
Malabsorptive diarrhea, 420 pathophysiology, 433
Mammary duct ectasia, 266 patient care issues, 442
Mammary Paget’s disease, 314 risk of stroke
Marijuana, 586 COC preparations, 444
Mastalgia. See Breat pain Cochrane Review, 444
Masters-Johnson-Kaplan model, 127, 128 MWA, 444–446
Mature teratomas, 148 MWOA, 444, 445
Measles, mumps, rubella (MMR), 585 odds ratios, 443
Medical marijuana, 412 treatment
Medical outcomes study sexual problems index, 99 ACE, 439
Medicare Access and CHIP Reauthorization Act (MACRA), 35 acetaminophen and NSAIDs, 437
Medication Assisted Treatment (MAT), 489 acute treatment, 435, 436, 438
Medication overuse headache, 446 adjuvant non-pharmacologic treatments, 435
Menarche, 351 anticonvulsants, 439
Menopausal hormone therapy (MHT), 118 antidepressants, 439
absolute contraindications, 119 antiemetics, 437
advantages, 119, 120 ARB, 439
breast cancer, 119 beta blockers, 439
cardiovascular disease, 119 biologic agents, 441
conjugated equine estrogens with MPA, 119 botox, 441
definition, 118 calcium channel blockers, 439
history and scientific literature, 119 dietary intervention, 441, 442
prescription, 120–122 elimination diets, 442
stroke, 119 ergot medications, 437
VTE, 119 herbal remedies, 439–441
Menopausal status, 317 prescription medications, 439–441
Menopause, 352 primary care provider, 434, 435
clinical manifestation, 117, 118 strategies, 433
definition, 117 triptans, 437
genitourinary syndrome of menopause, 122–124 triggers, 435
menopausal hormone therapy Migraine threshold theory, 435
absolute contraindications, 119 Migraine triggers, 435
advantages, 119, 120 Migraine with aura (MWA), 432, 434, 443–446
algorithm, 120 Migraine without aura (MWOA), 432, 434, 443–445
breast cancer, 119 Migraines associated with menses (MAM), 433
cardiovascular disease, 119 Military service, 574, 577
definition, 118 Military sexual trauma (MST), 574, 575
history and scientific literature, 119 Milnacipran, 512
prescription, 120–122 Mirtazapine, 514
stroke, 119 Mixed incontinence, 376, 380
Index 629
Mixed Lobular/Ductal Carcinoma. Lobular carcinoma, 314 treatment

Morphine milligram equivalents (MME), 412 buprenorphine, 489, 490
Mucinous or colloid carcinoma, 314 counseling, 489
Musculoskeletal system MAT, 489
female veterans, 576 medically supervised withdrawal, 488, 489
pregnancy, 605 methadone, 490
Myofascial pain syndrome, 476, 479, 482 naltrexone, 489
Myolysis-radiofrequency thermal ablation, 111 Oral contraceptive pills (OCPs), 92
Myomectomy, 110, 111 Osteonecrosis of the jaw (ONJ), 399
Osteoporosis, 529
bone turnover, 401
N definition, 394
Naltrexone, 489 DXA, 395
National Association of Nurse Practitioners in Women’s Health epidemiology, 393
(NPWH), 20 evaluation, 396
National Board of Medical Examiners (NBME), 12 FRAX, 395
National Institutes of Health (NIH), 6 non-pharmacologic strategies
National Intimate Partner and Sexual Violence Survey (NISVS), 535, 536 calcium, 397
Natural family planning, 59 exercise, 397
Neisseria gonorrhea, 191, 192 fall prevention, 397
Nephrolithiasis, 463 smoking and alcohol, 397
Nicotine replacement therapy (NRT), 585, 586 vitamin D, 397
Nipple discharge, 270, 271 physiology
Non-atherosclerotic coronary artery disease (NACAD), 348 age and hormonal fluctuations, 394
Nonclassic congenital adrenal hyperplasia (NCCAH), 91 normal bone remodeling, 394
Non-cyclical breast pain, 268, 269 public health impact, 393
Nonhormonal therapies referrals, 401
desmopressin, 108 screening interval, 396
nonsteroidal anti-inflammatory drugs, 108 treatment, 398
tranexamic acid, 108 anabolic therapy, 400
Non-hyperandrogenic PCOS, 84 anti-sclerostin antibodies, 400–401
Non-infectious vaginitis, 172 bisphosphonates, 398, 399
Non-occupational post-exposure prophylaxis (nPEP), 200, 201 denosumab, 399, 400
Non-opioid analgesics, 410, 411 estrogen therapy, 400
Nonpuerperal abscesses, 266 monitoring, 401
Nonpuerperal mastitis PTH analogues, 400
empiric antibiotic therapy, 267 selective estrogen receptor modulator, 400
granulomatous mastitis, 268 Ovarian cancer, 231, 559
mammary duct ectasia, 266 (see Non-lactational mastitis) clinical presentation, 241
nonpuerperal abscesses, 266 diagnosis, 241
Non-steroidal anti-inflammatory treatments epidemiology, 239
(NSAIDs), 108, 152, 410, 411, 435 evaluation, 241
Normal menstrual cycle, 100, 101 highest fatality rate, 238
Nucleic acid amplification testing (NAAT), 190 pathophysiology, 239
protective factors, 240
risk factors, 239, 240
O screening, 240, 241
Obstetric medicine. See Pregnancy screening asymptomatic women, 238
Obturator internus muscles, 473 staging, 241, 242
Office for Research in Women’s Health (ORWH), 6 survivorship care, 241, 242
Oligo-anovulation (OA), 83 treatment strategies, 241
One Key QuestionTM (OKQ), 54 Ovarian cysts
Onset, Location/radiation, Duration, Characteristics, Aggravating clinical manifestation, 148
factors, Relieving factors, Timing, and Severity (OLD diagnostic strategies, 149, 150
CARTS), 409 differential diagnosis, 148, 149
Opioid dependence, 485 adenexal mass, 148, 149
Opioid Risk Tool (ORT), 487 chronic pelvic pain, 146
Opioid use disorder (OUD), 413 infertility, 146
diagnosis, 487 epidemiology, 148
epidemiology, 485 monitoring, 151
history, 487, 488 physiology and pathology, 148
laboratory evaluation, 488 treatment strategies, 150
physical examination, 487, 488 Ovaries, 604
physiology and pathophysiology, 485, 486 Overactive bladder (OAB), 463
pregnancy, 491 Overflow incontinence, 376
screening, 487 Ovulatory disorders, 103
630 Index
P granulosa cell dysfunction, 86

Pain medications, 603 normal ovarian function, 85, 86
Panic disorders, 501 theca cell dysfunction, 86
Papillary carcinoma, 314 for pregnancy, 96
Papillary uterine serous carcinoma (USC), 234 functional ovarian hyperandrogenism, 95
Papillomatosis, 263 genetics, 86
Parity (P), 41, 42 GnRH, 86
Paroxetine, 512 hirsutism, 95, 96
Patient Health Questionnaire-9 (PHQ-9), 502, 503 hyperandrogenemia
Pay-for-performance programs, 35 acne, 87
Pelvic examination, 43 androgenic alopecia, 87
accommodations clinical features, 87
adolescents, 46 hirsutism, 87, 88
atrophic vaginitis, 47 hyperinsulinemia, 86, 87, 90
older adult, 47 hypothalamic-pituitary axis factors, 84, 85
pelvic organ prolapse, 47 infertility, 90
sexual trauma, 48 insulin resistance, 87, 90
sexual/gender minority patients, 47, 48 insulin-resistant hyperinsulinemia, 85
vaginismus/vulvodynia, 47 metabolic syndrome, 87, 90
with physical/developmental disability, 46 onset of amenorrhea, 94, 95
anxiety, 45 overt dysfunction, 87
bimanual examination, 46 PCOM, 86
chaperones, 44 phenotypes, 84
discontinuation, 44 polycystic ovaries, 87
external genitalia, 45 psychosocial issues, 90
patient positioning, 44 subclinical ovulatory dysfunction, 87
screening guidelines, 43, 44 treatment
speculum examination, 45, 46 endometrial protection, 92, 93
teaching, 46 goals of, 92
Pelvic floor muscle dysfunction, 464, 482 hyperandrogenism, 93
Pelvic floor therapy, 378, 469 infertility, 93, 94
Pelvic inflammatory disease (PID), 44 menstrual regulation, 92, 93
diagnosis, 192, 193 mental health, 94
follow-up, 194 metabolic complications, 93
partner notification, 194 weight gain, 94
prevalence, 192 Polypectomy, 110
treatment, 193–195 Postmenopausal bleeding (PMB), 104
Pelvic organ prolapse, 47, 377 Postpartum depression, 600
Pelvic organs can prolapse, 377 Postpartum period/puerperium
Pentosan polysulfate (PPS), 466 breastfeeding (see Breastfeeding)
Percutaneous coronary intervention (PCI), 348 medical complications
Periductal mastitis. See Mammary duct ectasia depression, 607
Peripheral arterial disease (PAD), 349 diabetes mellitus, 605, 606
Peripheral nonpuerperal abscesses, 266 hypertension, 606
Peripheral nonpuerperal mastitis thyroid disorders, 606, 607
central or subareolar abscesses, 266 venous thromboembolism, 607
nonpuerperal abscesses, 266 physiology
Persistent depressive disorder (dysthymia or PDD), 500 body weight, 605
Personalized medicine, 18 coagulation, 604, 605
Personalized Prevention Plan (PPP), 285–287 nervous/musculoskeletal system, 605
Peutz-Jeghers syndrome, 290, 317 ovaries, 604
Phyllodes tumor, 263, 314 urinary system, 605
Physical violence, 535 uterus, 604
Physiologic discharge, 270 Postpartum thyroiditis (PPT), 606
Plasminogen activator inhibitors, 101 Post-traumatic stress disorder (PTSD), 502
Polycystic ovaries, 87 female veterans
Polycystic ovary morphology (PCOM), 86 definition, 574
Polycystic ovary syndrome (PCOS), 71, 77, 78 MST, 574, 575
AMH, 86 PC-PTSD-5, 574
androgen production, 84 treatment, 575, 576
clinical features, 87, 90 Post-void residual (PVR) test, 378
diagnostic criteria, 83, 84 Power and control wheel model, 539
diagnostic evaluation, 91 Precision medicine, 30, 31
endometrial cancer, 90 Preeclampsia, 591
epidemiology, 83 Preeclampsia-eclampsia superimposed upon chronic
FOH hypertension, 591
Index 631
Pre-exposure prophylaxis (PrEP), 201, 202, 490, 568 substance use, 585, 586
Pregabalin, 514 vaccinations, 585
Pregnancy prescribing in, 587
asthma radiologic study, 588
classification and treatment, 596, 597 ionizing radiation, 588
epidemiology, 596 magnetic resonance imaging, 588
exacerbations, 597 mammography, 588
labor, delivery, and postpartum period, 597 thyroid imaging scans, 588
pathophysiology, 596 ultrasonography, 589
breastfeeding thyroid disease (see Thyroid disease)
antibiotics, 603, 604 VTE
anticoagulants, 604 acute management, 598
antihypertensive medications, 604 clinical manifestations, 598
benefits of, 603 diagnostic strategy, 598
complications, 603 epidemiology, 597
contraindications, 603 labor and delivery, 599
diabetic medications, 604 medical conditions, 597, 598
drug safety, 603 pathophysiology, 597
pain medications, 603 prophylaxis, 599
physiological effect, 603 Premature menopause, 74
physiology, 602, 603 Premenstrual dysphoric disorder (PMDD), 500, 501
psychiatric mediations, 604 Premenstrual syndrome (PMS), 10, 351, 500
depression Prescription drug monitoring programs (PDMP), 412
clinical outcomes, 600 Primary care providers (PCPs), 248, 275, 313
epidemiology, 600 Primary Care PTSD screen for DSM-5 (PC-PTSD-5), 574
prevention, 600 Primary headaches
treatment, 600–602 cluster headaches
diabetes clinical presentation, 432
clinical manifestations, 589 pathogenesis, 431
epidemiology, 589 prevalence, 431
glucose control, 590 treatment, 432
health maintenance, 590 definition, 429
pathophysiology, 589 TTH
hypertension clinical presentation and diagnostic criteria, 430, 431
classification, 591 pathophysiology, 430
clinical manifestation, 591, 592 treatment, 431
epidemiology, 591 Primary ovarian failure, 74
laboratory studies, 592 Primary ovarian insufficiency (POI), 71, 74, 78, 80
physiology and pathophysiology, 591 Progestin therapy, 92
treatment, 592, 593 Progestin-only pills (POPs), 56, 57
OUD, 491 Proliferative lesions with atypia
physiologic changes, 586, 587 aromatase inhibitors, 265
postpartum care of medical complications atypical ductal hyperplasia, 264, 265
depression, 607 lobular neoplasia, 264
diabetes mellitus, 605, 606 Proliferative lesions without atypia
hypertensive disorders, 606 adenomas, 263
thyroid disorders, 606, 607 adenosis, 263
venous thromboembolism, 607 complex fibroadenoma, 263
postpartum physiology epithelial hyperplasia, 263
body weight, 605 hamartoma, 263
cardiovascular system, 605 intraductal papilloma, 263
coagulation, 604, 605 Phyllodes tumor, 263
nervous/musculoskeletal system, 605 radial scar, 263
ovaries, 604 Prophylactic mastectomy, 290, 293
urinary system, 605 Propylthiouracil (PTU), 595
uterus, 604 Prostate cancer, 568
preconception/interconception counseling Protection from Abuse (PFA), 547
advanced maternal age, 584 Psoriasis, 178
body mass index, 584 Psychiatric mediations, 604
family history and genetic counseling, 584, 585 Psychological aggression, 536
folic acid supplementation, 584 Psychotherapy, 515
health and social factors, 584 PTEN hamartoma tumor syndromes, 317
IPV, 586 Pudendal nerve, 472
pre-existing medical conditions, 586 Pudendal neuropathy, 464
safety assessment, 586 Puerperal mastitis, 265, 266
STI, 585 Pulmonary hypertension of the newborn (PPHN), 601
632 Index
Pyelonephritis, 383 Graves’ disease, 79, 80

clinical manifestation, 384 HPG axis, 72
follow-up, 389 imaging, 76
microbiology, 383 obesity and prediabetes, 79
during pregnancy, 387 pathophysiology, 73
treatment strategies hyperandrogenism, 74
first-line therapy, 387 hypothalamic/functional amenorrhea, 73
outpatient management, 386 pharmacologic, 73
second line therapy, 387 physiologic, 73
pituitary tumors, 73, 74
POI, 74
Q structural, 73
Q-tip test, 473 thyroid dysfunction, 74
Quality Payment Program, 35 POI, 80
primary amenorrhea, 71
progesterone withdrawal, 75, 76
R treatment
Radial scar, 263 endocrinopathies, 78
Rape, 536, 537, 546 hypothalamic amenorrhea, 77
Rapid Opioid Dependence Screen (RODS), 487 infertility, 76
Recommend dietary manipulation and exercise, 414 PCOS, 77, 78
Recurrence Score (Oncotype Dx®), 315 POI, 78
Recurrent urinary tract infection, 383 referral to specialists, 76, 77
clinical manifestation, 384 Secondary headaches
diagnostic strategies, 385 evaluation, 447
microbiology, 383 imaging, 447
non-pharmacologic strategies, 387 medication overuse, 446
pharmacologic strategies Selective estrogen-receptor modulators (SERM), 291, 400
antimicrobial resistance, 388 Selective progesterone receptor modulators (SPRMs), 110
continuous antibiotic treatment, 388 Selective serotonin reuptake inhibitors (SSRIs), 511
intermittent self-treatment, 388 citalopram, 511
prophylactic antibiotics, 387 escitalopram, 511
postmenopausal women, 388 fluoxetine, 511
Refeeding syndrome, 528 fluvoxamine, 511, 512
Reproductive health, 578 paroxetine, 512
contraceptive methods, 577, 578 sertraline, 512
cross-sectional VA study, 577 Self-breast examination (SBE), 48, 305–307
family planning, 577 Serotonin (5-HT), 417
LARCs, 578 Serotonin norepinephrine reuptake inhibitors (SNRIs), 512
STIs, 578 desvenlafaxine, 512
Resilience, 506 duloxetine, 512
Review of systems (ROS), 43 levomilnacipran, 512
Reynolds Risk Calculator, 363 milnacipran, 512
Rifaximin, 424 venlafaxine, 512, 513
Risk of ovarian malignancy algorithm (ROMA), 150 Serotonin partial agonist-reuptake inhibitors (SPARIs), 512
Rome IV criteria, 419, 425 Serotonin syndrome, 514, 515
Sertraline, 512
Sex and gender based medicine (SGBM), 7
S from 2000-2009, 7
Safety assessment, 586 from 2010 to 2020, 9
components, 543 in medical education, 12, 13
does not disclose, 546 Sex and Gender Women’s Health Collaborative (SGWHC), 9, 12, 19
risk factors, 545 Sex hormone-binding globulin (SHBG), 92
safe to return home, 545, 546 Sex is a biological variable (SABV), 4
trained counselors, 545 Sexual and gynecologic complications, 249, 250
unsafe, 545 Sexual dysfunction
what not to do, 546 definition, 333
Sclerosing adenosis, 263 diagnosis, 333
Screener and Opioid Assessment for Patients with Pain (SOAPP), 487 epidemiology and risk factors, 333
Secondary amenorrhea 5As framework, 334
androgen excess, 76 management, 333, 334
clinical evaluation, 74, 75 Sexual health, 127
clinical manifestations, 74, 75 Sexual minority women
definition, 71 breast cancer, 559
dysmenorrhea, 79 cardiovascular disease risk, 558
epidemiology, 71 cervical cancer, 558, 559
Index 633
clinical environment, 556 non-occupational post-exposure prophylaxis, 200, 201

endometrial and ovarian cancer, 559 pre-exposure prophylaxis, 201, 202
gender expression, 556 screening, 200
LGBT, 555 vertical transmission, 200
sexual practices, 556, 558 Short-acting reversible contraceptives (SARCs), 54
sexually transmitted infections, WSW, 557, 558 Sleep quality, 454
SOGI, 556, 557 Small for gestational age births (SGA), 351
Sexual orientation and gender identity (SOGI), 556, 557 Social determinants of health, 36, 37
Sexual practices, 556, 558 Society for Women’s Health Research (SWHR), 20
Sexual trauma. See Intimate partner violence (IPV) Society of General Internal Medicine (SGIM), 18, 19
Sexual violence, 535, 537 Somatic nervous system, 472
Sexually transmitted infections (STIs), 54 Somatoform disorder, 464
chlamydia, 190, 191 Spontaneous abortions (Sab), 42
emerging STI Spontaneous coronary artery dissection (SCAD), 348
Ebola virus, 205 Spontaneous pregnancy loss, 351
Zika virus, 205 Stalking, 535, 536
extragenital chlamydia/gonorrhea infection, 192 Stress incontinence, 376
herpes simplex virus treatment strategies
counseling, 196 medications, 379
laboratory testing, 195 Pessaries, 379
primary infection, 195 surgery/invasive options, 379
treatment, 195, 196 Submucosal fibroids, 100
Neisseria gonorrhea, 191, 192 Subserous fibroids, 100
pelvic inflammatory disease Substance Abuse and Mental Health Services Administration
diagnosis, 192, 193 (SAMHSA), 541
follow-up, 194 Substance use disorders, 504, 585, 586
partner notification, 194 Suicidal ideation (SI), 506
prevalence, 192 Suicide risk assessment, 506
treatment, 193–195 components, 506
pregnancy, 585 intent, 507
prevention counseling, 188 involuntary hospitalization, 507
reproductive health, 578 plan and mean, 506, 507
screening and treatment, 55 protective factors, 506
asymptomatic individuals, 188, 189 safety planning, 507
comprehensive care, 190 suicidal ideation, 506
partner services, 189 voluntary hospitalization/urgent psychiatric referral, 507
pregnancy, 189 Sulfonamides, 604
testing, 189 Survivorship care plans (SCP), 330
sexually transmitted virus Symptom Severity Scale (SSS), 455
acute HIV syndrome, 200 Syphilis
genital warts, 203–205 follow-up, 199
hepatitis B, 202, 203 incidence, 197
hepatitis C, 203 incubation period, 197
HIV, 199, 200 management, 198, 199
non-occupational post-exposure prophylaxis, 200, 201 partner management, 199
pre-exposure prophylaxis, 201, 202 primary, 197
screening, 200 screening, 199
vertical transmission, 200 stages, 197
syphilis testing, 198
follow-up, 199 Systems engineering, 33, 34
incidence, 197
incubation period, 197
management, 198, 199 T
partner management, 199 Takotsubo cardiomyopathy (TC), 348
primary, 197 Technological abuse, 540
screening, 199 Temazepam, 514
stages, 197 Tension building stage, 537
testing, 198 Tension type headache (TTH)
transgender, 567, 568 clinical presentation and diagnostic criteria, 430, 431
WSW, 557, 558 pathophysiology, 430
Sexually transmitted virus treatment, 431
acute HIV syndrome, 200 Testosterone, 567
genital warts, 203–205 Tetanus, diphtheria, and pertussis (Tdap), 585
hepatitis B, 202, 203 Texas Tech Health Sciences Center’s Laura W. Bush Institute
hepatitis C, 203 (TTUHSC LWBI), 19
HIV, 199, 200 Therapeutic abortions (Tab), 42
634 Index
Thiazide diuretics, 604 diagnostic strategies

Thyroid, 608 examination, 377
Thyroid disease history, 377
hyperthyroidism laboratory studies, 377
clinical manifestations, 595 post-void residual (PVR) test, 378
diagnosis, 595 urodynamic studies, 378
epidemiology, 594, 595 differential diagnosis, 376, 377
treatment, 595 normal anatomy and physiology, 375, 376
hypothyroidism pathophysiology
clinical manifestations, 593 functional incontinence, 376
diagnosis, 594 mixed incontinence, 376
epidemiology, 593 overflow incontinence, 376
treatment, 594 stress incontinence, 376
Thyroid disorders, postpartum care, 606, 607 urgency incontinence, 376
Thyroid stimulating hormone (TSH), 73 risk factors, 375
Tissue transglutaminase (tTG), 420 treatment strategies
Tomosynthesis, 301 bladder training and scheduled voiding, 378
Topical agents, 411 dietary changes, 378
Tranexamic acid, 108 mixed incontinence, 380
Transgender pelvic floor therapy, 378
breast cancer, 568 stress incontinence, 379
cervical cancer, 568 systemic estrogens, 379
clinical environment, 564 topical estrogen, 379
gender dysphoria, 564 urgency incontinence, 379, 380
gender identity, 563, 564 urology or urogynecology referral, 380
gender non-conformity, 564 Urinary system, pregnancy, 605
hormonal therapy Urinary tract infections (UTI), 462, 476
initiation of, 566, 567 complications, 386
transgender men, 567 cystitis
medical history, 565 clinical manifestations, 384
physical examination, 565 duration of antibiotic therapy, 386
preventive care, 568 fluoroquinolones, 386
prostate cancer, 568 follow-up, 389
sexually transmitted infections, 567, 568 fosfomycin, 386
Transient ischemic attacks (TIAs), 434 ibuprofen, 386
Transvaginal ultrasound, 482 microbiology, 383
Trauma informed care, 505 microscopic analysis, 385
Trauma-informed healthcare, 540, 541 nitrofurantoin monohydrate macrocrystals, 386
Traumatic brain injury (TBI), female veterans, 576, 577 office urine dipstick, 385
Trazodone, 514 outpatient via phone, 385
Trichomoniasis, 166, 168, 170, 171, 477 second line therapy, 386
Tricyclic antidepressants (TCAs), 439, 467, 514, 601 suspected pyelonephritis, 385
Triple-negative metastatic breast cancers, 320 TMP-SMX, 386
Triptans, 437 urine culture, 385
Tubular carcinoma (TC), 314 dysuria, differential diagnosis, 384, 385
Tyrer-Cusick calculator, 284 pathophysiology, 384
Tyrer-Cuzick or International Breast Cancer Intervention Study (IBIS pyelonephritis
model), 300 clinical manifestations, 384
during pregnancy, 387
first-line therapy, 387
U follow-up, 389
U.S. Medical Eligibility Criteria for Contraceptive microbiology, 383
Use (U.S. MEC), 54 outpatient management, 386
U.S. Selected Practices Recommendations (U.S. SPR), 54 second line therapy, 387
Uncomplicated chlamydial cervicitis, 191 recurrent
Uncomplicated cystitis, 383 antimicrobial resistance, 388
Undergraduate medical education, 11, 12 clinical manifestations, 384
United States Preventive Services Task Force (USPSTF), 28, 217 continuous antibiotic treatment, 388
Universal education, 542 diagnostic strategies, 385
University of California San Francisco (UCSF), 568 intermittent self-treatment, 388
Urethritis, 191, 383, 462 microbiology, 383
clinical manifestation, 383 non-pharmacologic strategies, 387
Urgency incontinence, 376 pharmacologic strategies, 387
Urinalysis, 462, 463, 466, 468 postmenopausal women, 388
Urinary incontinence urethritis, clinical manifestations, 383
definition, 375 Urologic complications, 249
Index 635
US Preventive Services Task Force (USPSTF), 29, 30, 558 low-value services, 32
USPSTF Cervical Cancer Screening Guidelines, 217 ovarian cancer, 31–32
Uterine cancer, 231 physicians and provider groups, 30
abnormal glandular cells, 235 precision medicine, 30, 31
abnormal uterine bleeding, 235 Varicella, 585
atypical endometrial cells, 235 Vasomotor symptoms (VMS), 117, 118
classification, 233 Venlafaxine, 512, 513, 601
clinical presentation, 235 Venous thromboembolism (VTE), 566
epidemiology, 233 acute management, 598
incidental pap test abnormality, 235 clinical manifestations, 598
overview, 232 diagnostic strategy, 598
pathophysiology and risk factors epidemiology, 597
age, 234 labor and delivery, 599
anovulation, 233 medical conditions, 597, 598
diabetes, 234 pathophysiology, 597
estrogen excess, 233 postpartum care, 607
genetics, 234 prophylaxis, 599
obesity, 233 Ventilation-perfusion (V/Q) scan, 598
oral contraceptive pills, 234 Verapamil, 439
tamoxifen, 234 Veterans Affairs (VA), 10
type I endometrial carcinoma, 233 Vilazodone, 512
type II endometrial cancers, 234 Visceral pain, 472
uterine sarcomas, 234 Visual inspection with acetic acid (VIA), 243
postmenopausal bleeding, 235 Vortioxetine, 512
postmenopausal women, 235 Vulva
screening, 234 anatomy, 173
survivorship care, 238 contact vulvovaginitis
treatment strategies, 237, 238 examination, 175
Uterine fibroid embolization, 111 history, 175
Uterine sarcomas, 102, 233, 234 management, 176
Uterus, 604 dermatoses
lichen planus, 177, 178
lichen sclerosus, 176, 177
V lichen simplex chronicus, 179
Vaginal candidiasis (VC), 170 psoriasis, 178
Vaginal intraepithelial neoplasia (VaIN), 246 general testing strategies, 174
Vaginal lubricants, 123 general therapeutic measures, 174, 175
Vaginal moisturizers, 123 history, 174
Vaginismus, 47, 476 malignant vulvar neoplasms, 179, 180
Vaginitis physical examination, 174
definition, 165 vulvodynia, 180
desquamative inflammatory vaginitis, 172, 173 Vulvar and vaginal cancer, 231
follow-up, 172 clinical presentation, 245, 246
infection diagnosis, 246
bacterial vaginosis, 168–170 differential diagnosis, 246
chlamydia and gonorrhea testing, 167 epidemiology, 245
clinical manifestations, 166 evaluation, 246
diagnosis, 166 hrHPV or lichen sclerosis, 245
differential diagnosis, 166 morphology, 246
epidemiology, 165, 166 pathophysiology and risk factors, 245
pelvic examination, 167 prognosis, 247
positive whiff test, 167 screening, 245
saline wet mount, 167, 168 staging, 247
trichomoniasis, 168, 170, 171 treatment, 247
urine testing, 167 treatment strategies, 247
vaginal candidiasis, 170 vulvar and vaginal intraepithelial neoplasia, 246
vaginal pH testing, 167 Vulvar intraepithelial neoplasia (VIN), 246
vulvovaginal candidiasis, 167, 168 Vulvar vestibulitis, 477, 480
non-infectious vaginitis, 172 Vulvodynia, 47, 180, 463, 477, 480, 481
recurrent vaginitis, 171 Vulvovaginal candidiasis, 166–168, 477
sequelae, 172 Vulvovaginitis, 477
Validation, 542
Value
by cost, 29 W
definition, 29 Warfarin, 609
interventions, 29–30 Widespread Pain Index (WPI), 455
636 Index
Women who are virginal or have sex only with women IPE, 16, 17
(WSW), 214, 557, 558 leaders and champions, 17, 18
Women’s health, 6 NIH Sex as a Biological Variable and Inclusion, 20
AAWHP, 19 from 1990-1999
ACP, 20 academic COEs, 7
addressing gaps, 18 federal action and funding, 6
advancement in, 18 in professional education, 6
AMWA, 19 industry and private sector, 6
CME, 16 from 2000-2009
community outreach, 10, 11 COE, 8
comprehensive breast centers, 9 growth in, 7
definition, 4 sex and gender differences, 8
disparities, 10, 11 SGBM, 7
faculty development, 16 NPWH, 20
fertility centers and abortion services, 9 paradigm for, 5
GWIMS, 20 priorities and values, 4, 5
health clinics, 10 protected population, 6
health equity, 10, 11 radiological services, 9
in medical education, 11–13 research, 17
internal medicine residents SGIM, 18, 19
ABIM, 13 SGWHC, 19
clinical experiences, 15 SWHR, 20
competency, 12 TTUHSC LWBI, 19
fellowships, 16 from 2010 to 2020, 9
interdisciplinary educational, 13 Veterans Affairs, 10
knowledge and clinical skills, 12 WPSI, 19, 20
patient care partnerships, 13 Women’s Health Equity Act of 1990, 6
primary care residents, 15 Women’s health initiative (WHI), 119
recommendations, 13–15 Women’s Health Track (WH track), 15, 16
WH track, 15, 16 Women’s Preventive Services Initiative (WPSI), 13, 19, 20
written curriculum, 15

Sex & Gender-Based Women's Health

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Sarah A.

Sex- and Gender-Based

Sex- and Gender-Based

Julie L. Mitchell Brigid M. Dolan

ISBN 978-3-030-50694-0 ISBN 978-3-030-50695-7 (eBook)

© Springer Nature Switzerland AG 2020

 arn up to 41.0 Continuing Medical Education (CME) AMA PRA

ABIM MOC Credit

Method of Participation and Fees

Sarah A. Tilstra Pittsburgh, PA, USA

Part I Foundations of Women’s Health and Gender Based Medicine

1 Women’s Health and Sex- and Gender-­Based Medicine: Past,

Part II Gynecologic Health and Disease

4 Patient-Centered Contraceptive Counseling ����������������������������������������������������������� 53

Part III Breast Health and Disease

Part IV Common Medical Conditions

21 Cardiovascular Disease in Women Part 1: Sex and Gender

Part V Chronic Pain Disorders

26 General Approach to Chronic Pain��������������������������������������������������������������������������� 407

30 Interstitial Cystitis/Bladder Pain Syndrome ����������������������������������������������������������� 461

Part VI Mental Health

33 Depressive and Anxiety Disorders����������������������������������������������������������������������������� 497

Part VII Selected Populations

35 Intimate Partner Violence and Sexual Trauma������������������������������������������������������� 537

Benjamin D. Beran, MD Froedtert & Medical College of Wisconsin, Department of

Deborah DiNardo, MD, MS VA Pittsburgh Healthcare System, Department of Medicine,

Kay M. Johnson, MD, MPH Department of Medicine, University of Washington and VA

Eloho Ufomata, MD, MS University of Pittsburgh School of Medicine, Department of

ACOG American College of Obstetricians and Gynecologists

HPA Hypothalamic-pituitary-adrenal axis

Deborah Kwolek and Marjorie R. Jenkins

Learning Objectives Lidia, a 42-year-old cisgender woman (pronouns she/

© Springer Nature Switzerland AG 2020 3

 he History of Women’s Health and Sex-

In the 1990s, the state of both women’s medical care and

9. Chronic obstructive pulmonary disease (COPD) is more

 he Collaboration of Women’s Health and Sex

Primary care-based women’s health clinics, staffed by

Primary Care Residents in Internal Medicine The knowl-

leave, modified responsibilities, unpaid leave opportunities, Future Directions in SGBWH

 ational Association of Nurse Practitioners

 he National Institutes of Health (NIH) Office

One component of high-value care is access to care, which is

© Springer Nature Switzerland AG 2020 27

Table 2.1 (continued)

Table 2.2 (continued)

While a provider may wish to avoid low-value services,

Shared Decision-Making ing discussions [31]. Examples of decision aids can be

Cost of Care for Women

© Springer Nature Switzerland AG 2020 41

Pelvic organ prolapse is a common condition, and a specific

© Springer Nature Switzerland AG 2020 53

believed to prevent pregnancy by causing the same foreign

is mediated via estrogen’s role in increasing sex- Nonhormonal/Barrier Methods

(usually around 2 dollars per condom). Mechanism of action, Sponge

Pattern of Sexual Activity

Ulipristal Elective termination, also known as induced abortion, is an

Contraception. 2018;97(3):198–204. https://doi.org/10.1016/j. 69. Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembo-

Secondary amenorrhea is defined as the absence of men-

arn up to 41.0 Continuing Medical Education (CME) AMA PRA

ABIM MOC Credit

Method of Participation and Fees

Sarah A. Tilstra Pittsburgh, PA, USA

Part I Foundations of Women’s Health and Gender Based Medicine

1 Women’s Health and Sex- and Gender-Based Medicine: Past,

Part II Gynecologic Health and Disease

4 Patient-Centered Contraceptive Counseling �� 53

Part III Breast Health and Disease

Part IV Common Medical Conditions

21 Cardiovascular Disease in Women Part 1: Sex and Gender

Part V Chronic Pain Disorders

26 General Approach to Chronic Pain�� 407

30 Interstitial Cystitis/Bladder Pain Syndrome �� 461

Part VI Mental Health

33 Depressive and Anxiety Disorders�� 497

Part VII Selected Populations

35 Intimate Partner Violence and Sexual Trauma�� 537

he History of Women’s Health and Sex-

he Collaboration of Women’s Health and Sex

leave, modified responsibilities, unpaid leave opportunities, Future Directions in SGBWH

ational Association of Nurse Practitioners

he National Institutes of Health (NIH) Office

Shared Decision-Making ing discussions [31]. Examples of decision aids can be

Cost of Care for Women

is mediated via estrogen’s role in increasing sex- Nonhormonal/Barrier Methods

(usually around 2 dollars per condom). Mechanism of action, Sponge

Pattern of Sexual Activity

Ulipristal Elective termination, also known as induced abortion, is an

Female HPG Axis Physiology

Pathophysiology Table 5.1 Medications associated with hyperprolactinemia [11]

Physiologic Hypothalamic/Pituitary (Low FSH/LH)

Ovarian (High FSH) Clinical Manifestations

Imaging and Procedures

The mainstay of treatment for hypothalamic amenorrhea Polycystic Ovary Syndrome

Clinical Manifestations of hirsutism can be assessed by assigning a score of 0–4

Hyperandrogenemia or hyperandrogenism: Hyperandro

Diagnostic Evaluation hyperandrogenism, including clinical features like hirsutism

PCOS Treatment enstrual Regulation and Endometrial

lassification of Causes of Abnormal Uterine

Adenomyosis Malignancies that lead to abnormal uterine bleeding include

Nonstructural Causes of AUB-COEIN Endometrial Causes

Coagulopathy Endometrial causes of AUB are based on molecular level

of images, allowing improved evaluation of the endometrium Endometrial Biopsy

Sonohysterography Hysteroscopy involves the insertion of an endoscope through

Magnetic Resonance Imaging (MRI) Diagnostic Laparoscopy

Invasive Testing Treatment

Medical Management for 5 days reduced menstrual bleeding by 54% compared to

Learning Objectives Definition

M. A. Fisher Clinical Manifestations