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Polycystic Ovary Syndrome (PCOS)

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OC Fertility
OC Fertility

This document discusses polycystic ovary syndrome (PCOS), including its objectives, epidemiology, etiology, pathophysiology, clinical presentation, diagnostic criteria, differential diagnosis, evaluation, and physical exam findings. PCOS is a common endocrine disorder in reproductive-aged women characterized by hyperandrogenism, ovarian dysfunction, and chronic anovulation. It has a heterogeneous presentation and no single diagnostic test, with diagnosis typically made based on meeting criteria from the NIH, Rotterdam, or AE-PCOS Society guidelines. Evaluation involves assessing hirsutism, menstrual irregularities, polycystic ovaries on ultrasound, and hormonal abnormalities.

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Polycystic Ovary Syndrome  (PCOS) Sharon E. Moayeri, M.D., M.P.H., M.S. FACOG, Reproductive Endocrinology & Infertility www.ocfertility.com University of California, Irvine Department of Obstetrics & Gynecology 34rd Annual Review Course in Clinical Obstetrics/Gynecology October 2011
Objectives 1. Describe PCOS and associated pathophysiology 2. Identify risk factors of and conditions related to PCOS 3. Diagnose and evaluate comorbidities relevant to PCOS 4. Characterize goal specific therapy options PCOS 2
Polycystic Ovary SYNDROME • 1800s: polycystic ovaries – “cystic oophoritis”; “sclerocystic” • Stein & Leventhal (1953) – Enlarged ovaries, hirsutism, obesity,  and chronic anovulation • “Syndrome O” – Ovarian confusion – Ovulation disruption – Over‐nourishment – Overproduction of insulin 3 PCOS
PCOS • Collection of signs and symptoms • May be difficult to diagnose – Heterogeneous presentation – Features change with age • NO single test or feature is diagnostic PCOS 4
PCOS: Clinical Presentation Signs and Symptoms PCOS 5
Epidemiology • Most common endocrine abnormality in reproductive  aged women • 5‐15% women affected – with ethnic predilection – Caucasians:  4.8% – Latina/hispanics: 13% – African americans: 8.0% • Hereditary:  – Affected mother 35% – Affected sister 40% PCOS 6
Polycystic Ovary Syndrome (PCOS) ETIOLOGY & PATHOPHYSIOLOGY PCOS 7
PCOS: Etiology • Neuroendocrine derangement: ↑LH relative  to FSH • Hyperinsulinemia: defect in insulin action or  secretion • Androgen excess: ovarian and adrenal PCOS 8
Normal Menstrual Cycle PCOS LH FSH Cycle day Cycle day PCOS 9
Effects of Hyperinsulinemia • Decrease binding proteins (ie., SHBG, IGFBP‐I) • Increase unbound androgens • Reduce HDL [good] cholesterol • Risk for PCOS (Legro et al.,1999; Dunaif, et al. 1997) – Insulin resistance: ~50% – NIDDM: 8% • Acanthosis nigricans PCOS 10
PCOS: Androgen Excess • Worse with hyperinsulinemia • Hirsutism:  80% PCOS • Acne: 20% PCOS • Androgenic alopecia: 10% PCOS PCOS 11
PCOS Etiology: Unifying theory? PCOS 12
PCOS: Phenotypic & Genetic Variation Susceptibility  Genes Modifier  Environment Genes PCOS 13
Gene Polymorphism Phenotype IGF-2 Apal PCOS IGF-IR Trinucleotide repeat Increased fasting glucose and insulin resistance PPAR-У2 Pro12Ala Body mass index Lower insulin resistance PCOS Obesity Lower insulin resistance and hirsutism score Paraoxonase (PON-1) -108C/T PCOS Leu55Met Obesity and insulin resistance SORBS1 Thr228Ala Obesity Calpain-10 UCSNP-43,-19,-63 PCOS and insulin levels UCSNP-43,-45 Hirsutism score and idiopathic hirsutism UCSNP-44 PCOS Adiponectin 45 T/G Androstenedione PCOS Insulin resistance 276 G/I Obesity and insulin resistance Lower adiponectin levels PCOS 14 Adapted from Luque-Ramirez et al, Clinica Chimica Acta, 2006.
PCOS 15
PCOS: Diagnostic Criteria • NIH/NICHD: USA, 1990  • ESHRE/ASRM: Rotterdam, 2004 • Androgen Excess‐PCOS Intl Society: 2006 PCOS 16
PCOS Criteria NICHD/NIH Definition, 1990 Rotterdam Definition, 2004 Less inclusive More inclusive 1 and 2 needs to be met: 2 of 3 need to be met: 1. Hyperandrogenism 1. Hyperandrogenism – clinical (hirsutism, acne,  – Clinical or biochemical frontal balding)  – biochemical (high serum  androgen concentrations) 2. Menstrual irregularity 2. Menstrual irregularity 3. **Polycystic ovaries **      – Chronic anovulation (Key difference from NIH) – Oligomenorrhea, > 35d FOR BOTH: Exclude other causes (hyperprolactinemia, NC- congenital adrenal hyperplasia, thyroid disorder, etc.) PCOS 17
AE‐PCOS Society, 2006 • Hyperandrogenism**: Hirsutism and/or  hyperandrogenemia AND • Ovarian Dysfunction: Oligo‐anovulation  and/or polycystic ovaries • Exclusion of other androgen excess or related  disorders PCOS 18
Number 108, October 2009(Replaces Practice Bulletin Number 41, December 2002)
Polycystic Ovary Syndrome (PCOS) EVALUATION PCOS 20
Differential Diagnosis • Hypothalamic amenorrhea • Neoplasm: rapid onset  symptoms?  • Premature ovarian failure – Ovarian (sertoli‐leydig,  granulosa‐theca, hilus‐cell) • Idiopathic hirsutism – Adrenal – Pituitary/hypothalamic • Other endocrinopathies:  thyroid disorder,  • Drugs (i.e.,  steroids) hyperprolactinemia, NC‐CAH,  Cushing syndrome, etc.  • HAIR‐AN syndrome  – HyperAndrogenism,  • Severe IR Syndromes (i.e.,  – Insulin Resistance,  Syndrome X/Metabolic  – Acanthosis Nigricans Syndrome) PCOS 21
PCOS: Menstrual Dysfunction • 25‐30% of women with oligo‐anovulation have PCOS – ≥35 day intervals or <10 bleeds per year • 2/3 of patients with PCOS have oligo‐anovulation • PCOS patients may describe “normal” menses, but further  investigation reveals chronic anovulation in ~25%  • Consequences: – Menstrual Dysfunction – Infertility – Endometrial hyperplasia/cancer PCOS 22
Polycystic ovaries ≠ PCO syndrome • Transvaginal sono is best • Incidence decreases with age • Sonogram Morphology: – >12 follicles/ovary @ 2–9 mm diameter – Volume: >10mL – +/‐ “string of pearls” • Rule of 20%: – 20% of women with PCO have PCOS – PCO absent in ~20% with PCOS – Present ~20% without PCOS • Hypothalamic amenorrhea • Adolescents • Hyperprolactinemia PCOS 23
Assessing Hirsutism • Hirsutism vs virilization: rapidly developing virilization or certain virilizing symptoms (i.e., clitoromegaly, voice  deepening) warrants further evaluation • Modified Ferrimen‐Gallwey – 9 body parts, scored 0‐4 each – Score >6 hirsutism PCOS 24
PCOS: Physical Exam • Blood pressure • Body mass index (kg/m2) >25 overweight >30 obese • Waist circumference > 35 inches, abnormal • Acanthosis nigricans: insulin resistant • Acne/alopecia: androgen excess • Galactorrhea: hyperprolactinemia • Thyroid • Stigmata of Cushings? (striae, moon facies, etc…) PCOS 25
PCOS: Basic Work‐up • FSH & estradiol (E2) +/‐ LH:  – premature ovarian failure (low E2; high FSH) – hypothalamic amenorrhea (low/normal E2; low FSH) – In [lean] PCOS, LH/FSH > 2 • Free testosterone, normally <0.8% free • Prolactin & TSH  – Mild elevations of prolactin more common in PCOS – Hypothyroidsim  hyperprolactinemia – NOTE: both conditions can produce PCO morphology on sonogram • Progesterone in luteal phase to confirm ovulation  – >3 ng/mL – Can corroborate with sonogram monitoring of follicular development PCOS 26
Hyperandrogenemia in PCOS • A. Huang, et al., F&S, April 2010, N= 720 (NIH criteria) • Hyperandrogenemia present 75% Hormone [Reference] [>88 ng/dL] [>275 mcg/dL] [0.66 ng/dL, >0.8%] PCOS 27
PCOS: Evaluation • DHEA‐S  – Mildly elevated in 30‐40% PCOS – adrenal tumors >700 mcg/dL  Pelvic/Adrenal contrast CT – Dexamethasone suppression test • 17‐hydroxyprogesterone (17‐OHP):  – Ashkenazi Jews, Latina, Mediterraneans, Inuits, Yugoslavians – Nonclassical CAH: AR, ~5% of presumed PCOS – Measure a.m. during follicular phase – Nonclassical CAH >4 ng/mL – Borderline: 2‐4 ng/mL  Cortrosyn stimulation test  PCOS 28
PCOS: Optional Evaluation • Total testosterone  – Ovarian tumors >200ng/dL  get imaging – PCOS: upper limit of normal female, <80ng/dL – Use to calculate free testosterone • 24‐hr urinary cortisol  – Screen Cushing’s syndrome >50mcg/24h  need  further testing PCOS 29
PCOS: Obesity • NOT part of diagnostic criteria • Common in PCOS, affects between 50 to 80% • Waist‐to‐hip ratio >0.85 predicts insulin  resistance better than BMI • Worsens phenotype PCOS 30
PCOS: Overweight? • Screen impaired glucose tolerance or Diabetes – oral GTT: Fasting glucose  drink 75 gram glucola  repeat 2‐hour glucose; can also test insulin • Fasting: <100 normal; 100‐125 impaired; >126 DM‐II • 2‐hour: <140 normal; 140‐199 impaired; >200 DM‐II – Fasting glucose/insulin < 4.5  (+/‐) • 20% annual risk of developing glucose intolerance • Fasting lipid panel: elevated in nearly 70% of PCOS – HDL < 50 abnormal; TG > 150 abnormal PCOS 31
Metabolic Syndrome • 15% of U.S. population  • 33% of PCOS!! • Adult Treatment Panel III (others exist): – Elevated blood pressure ≥ 130/85 – Increased waist circumference ≥ 35 in – Elevated fasting glucose ≥ 100 mg/dL – Reduced high‐density lipoprotein cholesterol  (HDL) ≤50 mg/dL – Elevated triglycerides ≥ 150 mg/dL
Polycystic Ovary Syndrome (PCOS) TREATMENT: GOAL SPECIFIC PCOS 33
PCOS: Goal Specific Therapy • Screen and manage comorbidities  • Hirsutism/acne/hair loss • Protect/monitor endometrium  – Ultrasound +/‐ endometrial sampling – HRT/OCP (+/‐ insulin sensitizing agents) for endometrial  protection and menstrual regulation • Incidentally may reduce hyperandrogenism (hirsutism, acne, etc.) • Fertility PCOS 34
PCOS: Co‐morbidities! • Insulin resistance, ~30% • Type‐II DM,  ~10% (3‐5x) • Gestational diabetes (2.5x) • Endometrial hyperplasia/ atypia/cancer • Metabolic syndrome/syndrome X • Sleep apnea/disordered breathing (Ehrmann, 2006) • related to IR NOT weight/BMI or androgens (30‐40x) • Depression • Sexual dysfunction PCOS 35
PCOS: Probable Links • Coronary artery disease • Dyslipidemia • Hypertension • Ovarian cancer (?) • Miscarriage (?) • Pregnancy induced hypertension/PIH (?) PCOS 36
Prevention of CVD and DM • Lifestyle: weightloss and exercise!! • Metformin 1500‐2000 mg daily if documented  impaired glucose tolerance or metabolic  syndrome, otherwise limited evidence for use. • Statins: beneficial in long‐term for prevention,  but must avoid pregnancy, since category X PCOS 37
PCOS: Endometrial CA • 56 obese PCOS women (Cheung,2001) – 36% hyperplasia  2% cancer without tx – 9% atypia  23% cancer without tx • Women >50 yrs with endometrial cancer, PCOS  present in 62.5% PCOS 38
Summary: Sequelae of  biochemical aberrations Biochemical  Signs / Symptoms Consequences abnormality High androgens &  Hirsutism; acne; Anovulation; Low SHBG Alopecia Infertility Chronic estrogen excess  Irregular menstrual  Endometrial  cycles, menorrhaghia,  hyperplasia/cancer; dysfunctional menstrual  Ovarian cancer (?); bleeding Breast cancer (?) Impaired glucose  Acanthosis nigricans Diabetes; tolerance/Insulin  Obesity/central  Gestational diabetes; resistance/ diabetes adiposity Hypertension; PIH/preeclampsia (?) Dyslipidemia Abnormal lipid panel CAD PCOS 39
Treatment of Hirsutism Multi‐step approach is most‐effective: • Hair removal: wax, laser, eflornithine, etc. • OCPs for at least 3 months, (>18 months is best) • Metformin (+/‐) • Continuous progestin therapy • GnRH agonist (lupron): <6m use; many side‐effects • Anti‐androgens (USE with contraceptive!):  – Spironolactone (100‐200mg/d): binds DHT intracellular  receptor; in‐utero risk: incomplete virilization of male fetus – Finasteride (2.5mg q 3 d to 5mg/d): inhibits 5‐alpha‐ reductase (blocks T  DHT); in‐utero risk: male fetus  hypospadias  • Steroids: many SE, reduces androgens, ok short‐term PCOS 40
Treating PCOS anovulatory infertility Intervention Cost Risk of multiples Lifestyle/  Low  No increase weight‐loss Clomid/ Femara Low  Modest increase (<10%) FSH injections High Marked increase (20‐30%) Ovarian surgery High No increase, but limited efficacy In vitro  Marked increase, but modifiable by  High fertilization limiting the number of embryos  transferred. Modified from Barbieri, Up‐To‐Date PCOS 41
PCOS: Weight Loss • Frequency of obesity in women with anovulation and PCO:   30%‐75% ‐‐ most before puberty • 5‐10% weight loss restores ovulation >55%  < 6months (Kiddy, 1992) • Weight‐loss program for anovulatory obese women: – Lost 6.3 kg (13.9 lbs) on average – Decreased fasting insulin and testosterone levels – Increased SHBG concentrations – 92% resumed ovulation (12/13) – 85% became pregnant (11/13) PCOS 42
PCOS and Infertility: Metformin? • Metformin (biguanide ): improves insulin resistance  – reduce hepatic glucose production & intestinal absorption – Increase peripheral glucose uptake – increase SHBG  reduce androgen levels • Major side effect of metformin is GI (n/v/d) – Metformin 500mg qD for 1 week  2000mg daily  – Can use extend release dosing, qd @ dinner • Risks/Contraindications – Renally excreted (Cr<1.4) – Hepatotoxic ‐‐ avoid with elevated transaminase – Lactic acidosis (RARE!) – Stop 1 day before IV contrast dye study or surgery PCOS 43
PCOS and Infertility: Metformin? • MC‐RCT, 6 months • No screening for IR • Medications started concomitantly • No difference in SAB rates N=626 CC + Plac Met + Plac CC + Met N=209 N=208 N=209 LBR, % 22.5 7.2 26.8 Preg/ovul, % 39.5 21.7 46 MGR, % 6 0 3 PCOS 44 Legro et al., NEJM 2007
PCOS Fertility Options: Ovulation  Induction (OI)/Superovulation (SO) • Clomiphene Citrate: non‐steroidal weak estrogen related  to diethystilbestrol, SERM • Clomid:  – start cycle‐day 2, 3, 4, or 5 – take for 5 days  (less common protocols exist)   – Dose 50mg/day to 200 mg/day  (take pills once per day, not  bid/tid/etc… • Ovulate ~80%  60% pregnant < 6m for OI patients • Consider letrozole/femara: aromatase inhibitor, may have  less negative impact on endometrial thickness PCOS 45
PCOS Fertility Options: OI/SO (2) • Gonadotropins: HMG, FSH – 60% live‐birth 12‐18 mo – Need careful monitoring (follicle scans,  estradiol levels) • OHSS (~1‐2%)  • Multiple gestation risk (~20‐30%) • Risk of multiples may be hard to modify – Combine with clomid to reduce risks and  costs of treatment (i.e., start with clomid cycle day 3‐7, then add gonadotropins) PCOS 46
PCOS Fertility Options: ART • Assisted Reproductive Technologies (ie, IVF/ICSI)  PROS – Highly successful in PCOS: >60% OPR/cycle in <35 yo – Efficient: Usually have supernumery embryos that can be  cryopreserved for future use (~70%) – Can modify risk of multiples (i.e., elective single embryo  transfer) CONS – [Relatively] expensive  (per cycle)  though increasing  evidence that this is more cost‐effective per live born…  – Risk hyperstimulation PCOS 47
PCOS Fertility Options: Surgery • Laparoscopic wedge resection or ovarian drilling  PROS – May avoid fertility treatment risks (i.e., multiples, OHSS) – May identify and treat other comorbidities (i.e.,  endometriosis, pain, adhesions) – Intraoperative findings may alter treatment decisions CONS – Relatively invasive – Doesn’t universally restore ovulation ~50:50 – Postoperative adhesions  – Iatrogenic compromise to ovarian function/reserve – Limited data support its efficacy  – Gonadotropins likely to be successful (70% vs. 60%) PCOS 48
PCOS: Pharmacotherapy summary PCOS 49
PCOS: Conclusions (1) • Multifaceted condition with varying presentation • No clearly accepted basis for diagnosis • Significantly associated health consequences – Genetic and pre‐natal implications – Metabolic disorder with risk of long term health  complications: DM, cardiovascular, obesity, etc. – Reproductive repercussions: Endometrial hyperplasia   cancer;   menstrual irregularities; infertility PCOS 50
PCOS: Conclusions (2) • Treatment goals – Educate – Identify and monitor co‐morbidities • i.e., hyperlipidemia, diabetes, endometrial hyperplasia  – Modify associated long term health risks  • i.e., diet, exercise, induce cyclic bleeding, medications – Treat patient concerns: effective therapies exist! • i.e., Hirsutism; infertility; cycle regulation PCOS 51
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Polycystic Ovary Syndrome (PCOS)

  • 1. Polycystic Ovary Syndrome  (PCOS) Sharon E. Moayeri, M.D., M.P.H., M.S. FACOG, Reproductive Endocrinology & Infertility www.ocfertility.com University of California, Irvine Department of Obstetrics & Gynecology 34rd Annual Review Course in Clinical Obstetrics/Gynecology October 2011
  • 2. Objectives 1. Describe PCOS and associated pathophysiology 2. Identify risk factors of and conditions related to PCOS 3. Diagnose and evaluate comorbidities relevant to PCOS 4. Characterize goal specific therapy options PCOS 2
  • 3. Polycystic Ovary SYNDROME • 1800s: polycystic ovaries – “cystic oophoritis”; “sclerocystic” • Stein & Leventhal (1953) – Enlarged ovaries, hirsutism, obesity,  and chronic anovulation • “Syndrome O” – Ovarian confusion – Ovulation disruption – Over‐nourishment – Overproduction of insulin 3 PCOS
  • 4. PCOS • Collection of signs and symptoms • May be difficult to diagnose – Heterogeneous presentation – Features change with age • NO single test or feature is diagnostic PCOS 4
  • 6. Epidemiology • Most common endocrine abnormality in reproductive  aged women • 5‐15% women affected – with ethnic predilection – Caucasians:  4.8% – Latina/hispanics: 13% – African americans: 8.0% • Hereditary:  – Affected mother 35% – Affected sister 40% PCOS 6
  • 8. PCOS: Etiology • Neuroendocrine derangement: ↑LH relative  to FSH • Hyperinsulinemia: defect in insulin action or  secretion • Androgen excess: ovarian and adrenal PCOS 8
  • 9. Normal Menstrual Cycle PCOS LH FSH Cycle day Cycle day PCOS 9
  • 10. Effects of Hyperinsulinemia • Decrease binding proteins (ie., SHBG, IGFBP‐I) • Increase unbound androgens • Reduce HDL [good] cholesterol • Risk for PCOS (Legro et al.,1999; Dunaif, et al. 1997) – Insulin resistance: ~50% – NIDDM: 8% • Acanthosis nigricans PCOS 10
  • 11. PCOS: Androgen Excess • Worse with hyperinsulinemia • Hirsutism:  80% PCOS • Acne: 20% PCOS • Androgenic alopecia: 10% PCOS PCOS 11
  • 12. PCOS Etiology: Unifying theory? PCOS 12
  • 13. PCOS: Phenotypic & Genetic Variation Susceptibility  Genes Modifier  Environment Genes PCOS 13
  • 14. Gene Polymorphism Phenotype IGF-2 Apal PCOS IGF-IR Trinucleotide repeat Increased fasting glucose and insulin resistance PPAR-У2 Pro12Ala Body mass index Lower insulin resistance PCOS Obesity Lower insulin resistance and hirsutism score Paraoxonase (PON-1) -108C/T PCOS Leu55Met Obesity and insulin resistance SORBS1 Thr228Ala Obesity Calpain-10 UCSNP-43,-19,-63 PCOS and insulin levels UCSNP-43,-45 Hirsutism score and idiopathic hirsutism UCSNP-44 PCOS Adiponectin 45 T/G Androstenedione PCOS Insulin resistance 276 G/I Obesity and insulin resistance Lower adiponectin levels PCOS 14 Adapted from Luque-Ramirez et al, Clinica Chimica Acta, 2006.
  • 15. PCOS 15
  • 17. PCOS Criteria NICHD/NIH Definition, 1990 Rotterdam Definition, 2004 Less inclusive More inclusive 1 and 2 needs to be met: 2 of 3 need to be met: 1. Hyperandrogenism 1. Hyperandrogenism – clinical (hirsutism, acne,  – Clinical or biochemical frontal balding)  – biochemical (high serum  androgen concentrations) 2. Menstrual irregularity 2. Menstrual irregularity 3. **Polycystic ovaries **      – Chronic anovulation (Key difference from NIH) – Oligomenorrhea, > 35d FOR BOTH: Exclude other causes (hyperprolactinemia, NC- congenital adrenal hyperplasia, thyroid disorder, etc.) PCOS 17
  • 18. AE‐PCOS Society, 2006 • Hyperandrogenism**: Hirsutism and/or  hyperandrogenemia AND • Ovarian Dysfunction: Oligo‐anovulation  and/or polycystic ovaries • Exclusion of other androgen excess or related  disorders PCOS 18
  • 19. Number 108, October 2009(Replaces Practice Bulletin Number 41, December 2002)
  • 21. Differential Diagnosis • Hypothalamic amenorrhea • Neoplasm: rapid onset  symptoms?  • Premature ovarian failure – Ovarian (sertoli‐leydig,  granulosa‐theca, hilus‐cell) • Idiopathic hirsutism – Adrenal – Pituitary/hypothalamic • Other endocrinopathies:  thyroid disorder,  • Drugs (i.e.,  steroids) hyperprolactinemia, NC‐CAH,  Cushing syndrome, etc.  • HAIR‐AN syndrome  – HyperAndrogenism,  • Severe IR Syndromes (i.e.,  – Insulin Resistance,  Syndrome X/Metabolic  – Acanthosis Nigricans Syndrome) PCOS 21
  • 22. PCOS: Menstrual Dysfunction • 25‐30% of women with oligo‐anovulation have PCOS – ≥35 day intervals or <10 bleeds per year • 2/3 of patients with PCOS have oligo‐anovulation • PCOS patients may describe “normal” menses, but further  investigation reveals chronic anovulation in ~25%  • Consequences: – Menstrual Dysfunction – Infertility – Endometrial hyperplasia/cancer PCOS 22
  • 23. Polycystic ovaries ≠ PCO syndrome • Transvaginal sono is best • Incidence decreases with age • Sonogram Morphology: – >12 follicles/ovary @ 2–9 mm diameter – Volume: >10mL – +/‐ “string of pearls” • Rule of 20%: – 20% of women with PCO have PCOS – PCO absent in ~20% with PCOS – Present ~20% without PCOS • Hypothalamic amenorrhea • Adolescents • Hyperprolactinemia PCOS 23
  • 24. Assessing Hirsutism • Hirsutism vs virilization: rapidly developing virilization or certain virilizing symptoms (i.e., clitoromegaly, voice  deepening) warrants further evaluation • Modified Ferrimen‐Gallwey – 9 body parts, scored 0‐4 each – Score >6 hirsutism PCOS 24
  • 25. PCOS: Physical Exam • Blood pressure • Body mass index (kg/m2) >25 overweight >30 obese • Waist circumference > 35 inches, abnormal • Acanthosis nigricans: insulin resistant • Acne/alopecia: androgen excess • Galactorrhea: hyperprolactinemia • Thyroid • Stigmata of Cushings? (striae, moon facies, etc…) PCOS 25
  • 26. PCOS: Basic Work‐up • FSH & estradiol (E2) +/‐ LH:  – premature ovarian failure (low E2; high FSH) – hypothalamic amenorrhea (low/normal E2; low FSH) – In [lean] PCOS, LH/FSH > 2 • Free testosterone, normally <0.8% free • Prolactin & TSH  – Mild elevations of prolactin more common in PCOS – Hypothyroidsim  hyperprolactinemia – NOTE: both conditions can produce PCO morphology on sonogram • Progesterone in luteal phase to confirm ovulation  – >3 ng/mL – Can corroborate with sonogram monitoring of follicular development PCOS 26
  • 27. Hyperandrogenemia in PCOS • A. Huang, et al., F&S, April 2010, N= 720 (NIH criteria) • Hyperandrogenemia present 75% Hormone [Reference] [>88 ng/dL] [>275 mcg/dL] [0.66 ng/dL, >0.8%] PCOS 27
  • 28. PCOS: Evaluation • DHEA‐S  – Mildly elevated in 30‐40% PCOS – adrenal tumors >700 mcg/dL  Pelvic/Adrenal contrast CT – Dexamethasone suppression test • 17‐hydroxyprogesterone (17‐OHP):  – Ashkenazi Jews, Latina, Mediterraneans, Inuits, Yugoslavians – Nonclassical CAH: AR, ~5% of presumed PCOS – Measure a.m. during follicular phase – Nonclassical CAH >4 ng/mL – Borderline: 2‐4 ng/mL  Cortrosyn stimulation test  PCOS 28
  • 29. PCOS: Optional Evaluation • Total testosterone  – Ovarian tumors >200ng/dL  get imaging – PCOS: upper limit of normal female, <80ng/dL – Use to calculate free testosterone • 24‐hr urinary cortisol  – Screen Cushing’s syndrome >50mcg/24h  need  further testing PCOS 29
  • 30. PCOS: Obesity • NOT part of diagnostic criteria • Common in PCOS, affects between 50 to 80% • Waist‐to‐hip ratio >0.85 predicts insulin  resistance better than BMI • Worsens phenotype PCOS 30
  • 31. PCOS: Overweight? • Screen impaired glucose tolerance or Diabetes – oral GTT: Fasting glucose  drink 75 gram glucola  repeat 2‐hour glucose; can also test insulin • Fasting: <100 normal; 100‐125 impaired; >126 DM‐II • 2‐hour: <140 normal; 140‐199 impaired; >200 DM‐II – Fasting glucose/insulin < 4.5  (+/‐) • 20% annual risk of developing glucose intolerance • Fasting lipid panel: elevated in nearly 70% of PCOS – HDL < 50 abnormal; TG > 150 abnormal PCOS 31
  • 32. Metabolic Syndrome • 15% of U.S. population  • 33% of PCOS!! • Adult Treatment Panel III (others exist): – Elevated blood pressure ≥ 130/85 – Increased waist circumference ≥ 35 in – Elevated fasting glucose ≥ 100 mg/dL – Reduced high‐density lipoprotein cholesterol  (HDL) ≤50 mg/dL – Elevated triglycerides ≥ 150 mg/dL
  • 34. PCOS: Goal Specific Therapy • Screen and manage comorbidities  • Hirsutism/acne/hair loss • Protect/monitor endometrium  – Ultrasound +/‐ endometrial sampling – HRT/OCP (+/‐ insulin sensitizing agents) for endometrial  protection and menstrual regulation • Incidentally may reduce hyperandrogenism (hirsutism, acne, etc.) • Fertility PCOS 34
  • 35. PCOS: Co‐morbidities! • Insulin resistance, ~30% • Type‐II DM,  ~10% (3‐5x) • Gestational diabetes (2.5x) • Endometrial hyperplasia/ atypia/cancer • Metabolic syndrome/syndrome X • Sleep apnea/disordered breathing (Ehrmann, 2006) • related to IR NOT weight/BMI or androgens (30‐40x) • Depression • Sexual dysfunction PCOS 35
  • 36. PCOS: Probable Links • Coronary artery disease • Dyslipidemia • Hypertension • Ovarian cancer (?) • Miscarriage (?) • Pregnancy induced hypertension/PIH (?) PCOS 36
  • 37. Prevention of CVD and DM • Lifestyle: weightloss and exercise!! • Metformin 1500‐2000 mg daily if documented  impaired glucose tolerance or metabolic  syndrome, otherwise limited evidence for use. • Statins: beneficial in long‐term for prevention,  but must avoid pregnancy, since category X PCOS 37
  • 38. PCOS: Endometrial CA • 56 obese PCOS women (Cheung,2001) – 36% hyperplasia  2% cancer without tx – 9% atypia  23% cancer without tx • Women >50 yrs with endometrial cancer, PCOS  present in 62.5% PCOS 38
  • 39. Summary: Sequelae of  biochemical aberrations Biochemical  Signs / Symptoms Consequences abnormality High androgens &  Hirsutism; acne; Anovulation; Low SHBG Alopecia Infertility Chronic estrogen excess  Irregular menstrual  Endometrial  cycles, menorrhaghia,  hyperplasia/cancer; dysfunctional menstrual  Ovarian cancer (?); bleeding Breast cancer (?) Impaired glucose  Acanthosis nigricans Diabetes; tolerance/Insulin  Obesity/central  Gestational diabetes; resistance/ diabetes adiposity Hypertension; PIH/preeclampsia (?) Dyslipidemia Abnormal lipid panel CAD PCOS 39
  • 40. Treatment of Hirsutism Multi‐step approach is most‐effective: • Hair removal: wax, laser, eflornithine, etc. • OCPs for at least 3 months, (>18 months is best) • Metformin (+/‐) • Continuous progestin therapy • GnRH agonist (lupron): <6m use; many side‐effects • Anti‐androgens (USE with contraceptive!):  – Spironolactone (100‐200mg/d): binds DHT intracellular  receptor; in‐utero risk: incomplete virilization of male fetus – Finasteride (2.5mg q 3 d to 5mg/d): inhibits 5‐alpha‐ reductase (blocks T  DHT); in‐utero risk: male fetus  hypospadias  • Steroids: many SE, reduces androgens, ok short‐term PCOS 40
  • 41. Treating PCOS anovulatory infertility Intervention Cost Risk of multiples Lifestyle/  Low  No increase weight‐loss Clomid/ Femara Low  Modest increase (<10%) FSH injections High Marked increase (20‐30%) Ovarian surgery High No increase, but limited efficacy In vitro  Marked increase, but modifiable by  High fertilization limiting the number of embryos  transferred. Modified from Barbieri, Up‐To‐Date PCOS 41
  • 42. PCOS: Weight Loss • Frequency of obesity in women with anovulation and PCO:   30%‐75% ‐‐ most before puberty • 5‐10% weight loss restores ovulation >55%  < 6months (Kiddy, 1992) • Weight‐loss program for anovulatory obese women: – Lost 6.3 kg (13.9 lbs) on average – Decreased fasting insulin and testosterone levels – Increased SHBG concentrations – 92% resumed ovulation (12/13) – 85% became pregnant (11/13) PCOS 42
  • 43. PCOS and Infertility: Metformin? • Metformin (biguanide ): improves insulin resistance  – reduce hepatic glucose production & intestinal absorption – Increase peripheral glucose uptake – increase SHBG  reduce androgen levels • Major side effect of metformin is GI (n/v/d) – Metformin 500mg qD for 1 week  2000mg daily  – Can use extend release dosing, qd @ dinner • Risks/Contraindications – Renally excreted (Cr<1.4) – Hepatotoxic ‐‐ avoid with elevated transaminase – Lactic acidosis (RARE!) – Stop 1 day before IV contrast dye study or surgery PCOS 43
  • 44. PCOS and Infertility: Metformin? • MC‐RCT, 6 months • No screening for IR • Medications started concomitantly • No difference in SAB rates N=626 CC + Plac Met + Plac CC + Met N=209 N=208 N=209 LBR, % 22.5 7.2 26.8 Preg/ovul, % 39.5 21.7 46 MGR, % 6 0 3 PCOS 44 Legro et al., NEJM 2007
  • 45. PCOS Fertility Options: Ovulation  Induction (OI)/Superovulation (SO) • Clomiphene Citrate: non‐steroidal weak estrogen related  to diethystilbestrol, SERM • Clomid:  – start cycle‐day 2, 3, 4, or 5 – take for 5 days  (less common protocols exist)   – Dose 50mg/day to 200 mg/day  (take pills once per day, not  bid/tid/etc… • Ovulate ~80%  60% pregnant < 6m for OI patients • Consider letrozole/femara: aromatase inhibitor, may have  less negative impact on endometrial thickness PCOS 45
  • 46. PCOS Fertility Options: OI/SO (2) • Gonadotropins: HMG, FSH – 60% live‐birth 12‐18 mo – Need careful monitoring (follicle scans,  estradiol levels) • OHSS (~1‐2%)  • Multiple gestation risk (~20‐30%) • Risk of multiples may be hard to modify – Combine with clomid to reduce risks and  costs of treatment (i.e., start with clomid cycle day 3‐7, then add gonadotropins) PCOS 46
  • 47. PCOS Fertility Options: ART • Assisted Reproductive Technologies (ie, IVF/ICSI)  PROS – Highly successful in PCOS: >60% OPR/cycle in <35 yo – Efficient: Usually have supernumery embryos that can be  cryopreserved for future use (~70%) – Can modify risk of multiples (i.e., elective single embryo  transfer) CONS – [Relatively] expensive  (per cycle)  though increasing  evidence that this is more cost‐effective per live born…  – Risk hyperstimulation PCOS 47
  • 48. PCOS Fertility Options: Surgery • Laparoscopic wedge resection or ovarian drilling  PROS – May avoid fertility treatment risks (i.e., multiples, OHSS) – May identify and treat other comorbidities (i.e.,  endometriosis, pain, adhesions) – Intraoperative findings may alter treatment decisions CONS – Relatively invasive – Doesn’t universally restore ovulation ~50:50 – Postoperative adhesions  – Iatrogenic compromise to ovarian function/reserve – Limited data support its efficacy  – Gonadotropins likely to be successful (70% vs. 60%) PCOS 48
  • 50. PCOS: Conclusions (1) • Multifaceted condition with varying presentation • No clearly accepted basis for diagnosis • Significantly associated health consequences – Genetic and pre‐natal implications – Metabolic disorder with risk of long term health  complications: DM, cardiovascular, obesity, etc. – Reproductive repercussions: Endometrial hyperplasia   cancer;   menstrual irregularities; infertility PCOS 50
  • 51. PCOS: Conclusions (2) • Treatment goals – Educate – Identify and monitor co‐morbidities • i.e., hyperlipidemia, diabetes, endometrial hyperplasia  – Modify associated long term health risks  • i.e., diet, exercise, induce cyclic bleeding, medications – Treat patient concerns: effective therapies exist! • i.e., Hirsutism; infertility; cycle regulation PCOS 51