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Clin Obstet Gynecol. Author manuscript; available in PMC 2019 September 01.
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Published in final edited form as:

Clin Obstet Gynecol. 2018 September ; 61(3): 419–432. doi:10.1097/GRF.0000000000000389.

Management of the Perimenopause

Lara Delamater, MD and Nanette Santoro, MD*
University of Colorado School of Medicine Department of Obstetrics and Gynecology, 12631 E
17th Avenue, Mail Stop B-198, Aurora, Colorado 80045

Abstract
Perimenopause, or the menopausal transition, represents a period of time during which newly
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arising symptoms can present complex management decisions for providers. Many women present
to care with complaints of hot flashes, vaginal and sexual changes, altered mood and sleep, and
changing bleeding patterns. The effect of these symptoms on quality of life, even before a woman
enters menopause, can be significant. The appropriate evaluation and evidence-based management
of women in this transition is reviewed in this article. Two case vignettes are used to highlight
certain evaluation and treatment challenges.

Keywords
Perimenopause; menopause transition; hot flashes; abnormal uterine bleeding
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Introduction and Case Vignettes

Perimenopause, or the menopausal transition, encompasses that period of time during which
physiologic changes mark progression toward a woman’s final menstrual period (FMP).
This phase begins with the onset of menstrual irregularities and continues until a woman
reaches menopause, or one year after amenorrhea has occurred1. Perimenopause, then, can
last for a variable amount of time, the median of which is four years. Changing hormone
levels manifest in varying symptoms that can present complex clinical management
situations for providers. As many as 90% of women will present to health care providers for
advice on how to cope with menopausal symptoms, demonstrating the importance of this
issue worldwide2.

Understanding the physiology of the decline in ovarian function, which results in systemic
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hormonal changes and ultimately, symptoms, can help guide management. Traditionally,
perimenopause includes an early and a late stage: the early stage is defined by occasional
skipped cycles. The second stage is characterized by greater menstrual irregularity, with
periods of amenorrhea lasting over 60 days and up to 12 months. Twelve or more months of
amenorrhea defines the FMP, after which future menses are very unlikely3. The purpose of
this review is to explore these stages of the menopausal transition and associated hormonal

*
Corresponding author: Phone 303-724-2041, FAX: 303-724-2061, [email protected].
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events, review common symptoms that characterize this period, and provide in depth
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evidence-based recommendations for evaluation and treatment.

Case #1
Ms. M is a 45 year old woman who has been using oral contraceptives since the birth of her
second child 10 years ago. She has noted progressively heavier menses during the pill free
week over the past 9 months, with menstrual cramping that is only partially relieved by
ibuprofen 600-800mg tid, and hot flashes during her menstrual periods. She also reports a
feeling of pelvic heaviness. On bimanual examination, her uterus is about 8-10 weeks’ size
with an irregular contour. She requests an endometrial ablation, because her friend reported
complete cessation of menses from this procedure. She does not believe she needs
contraception any longer, because she is now ‘close to menopause.’
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Case #2
Ms. Y is a 50 year old woman who had her last menstrual period 4 months ago, and reports
having moderate- to-severe hot flashes that are particularly bothersome at night. She is the
CEO of a regional pharmaceutical company, and has noted that her frequent travel related to
her work has become ‘exhausting’ due to the chronic sleep disruption. She also reports
experiencing anxiety when she speaks publicly for fear of having a hot flash mid-speech.
She has a BMI of 22 kg/m2 and reports taking 12.5mg of hydrochlorthiaziide daily for
‘borderline’ elevated blood pressure. In the office, her BP is 150/90, which she attributes to a
stressful drive with ‘too much traffic’.

Questions
- What additional information on history and physical exam would be helpful in
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assessing this patient?

- What evaluation is indicated at this time?

- How would you counsel this patient about the natural history of menopause and
how it may impact her symptoms and treatment options?

- What treatment options would you recommend?

- How do you plan to follow her through her menopausal transition?

Epidemiology
Ongoing research has enhanced our understanding of the epidemiology of the menopausal
transition4. With the goal of establishing nomenclature and standardized reporting for
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clinical and research purposes, the first Stages of Reproductive Aging Workshop (STRAW)
in 2001 developed a map of both hormonal and clinical changes preceding and following the
FMP to define perimenopausal stages.5 This paradigm was reevaluated by a
multidisciplinary team in 2011 (ReSTAGE), with a follow up workshop, including support
of further data from multiple cohorts, incorporating the interval information on hormonal
changes1. Classifications from this workshop confirmed the division of the menopausal
transition into an early and a late stage. Figure 1 details the criteria and important

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characteristics of these stages. The early menopausal transition is defined as either a

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persistent difference of 7 days or more in the length of consecutive cycles, or one more
skipped cycles (persistence, in this case, is demonstrated by a recurrence in this cycle length
difference that occurs within the subsequent 10 cycles). This irregularity progresses to
longer periods of amenorrhea; when they last 60 days or longer, the patient has moved to the
late menopausal transition, marked by increasing duration of amenorrhea, and more
dramatic fluctuations in hormones. This late stage is more likely to be associated with
vasomotor symptoms (VMS), although the highest VMS prevalence is found after the FMP.
An individual patient’s menopausal transition may not always follow this staging precisely.
For example, some women, particularly those who transition at a later age, may skip the
early menopause transition stage entirely; others, particularly those who transition at earlier
ages, may spend many years in the early stage6. Traversal through the STRAW stages are
also influenced by racial and ethnic differences, BMI, and lifestyle choices1. While many
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hormonal markers have been observed to change across the menopausal transition, none are
presently useful for diagnostic purposes and staging remains best performed using menstrual
history alone7. For women with irregular menses or amenorrhea (e.g., polycystic ovary
syndrome), tracking the transition stages is not currently possible.

As women traverse menopause, symptoms and other health markers have been more closely
evaluated through a number of studies. The Study of Women’s Health Across the Nation
(SWAN) represents an ethnically diverse cohort of North American Women, addressing a
lack of diversity in previous studies. Through this cohort, the Melbourne Women’s Health
Study, and the Penn Ovarian Aging Study among others, we have come to better understand
both the hormonal changes as well as the symptoms that constitute the transition. The
menopausal transition encompasses a median of four or more years, with median onset at
age 47, progression to late menopausal transition at a median age of 49 and arrival at the
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FMP at age 51-528. This progression varies according to the age at onset of the menopausal
transition, with a cohort of earliest onset symptoms translating to a longer median time of
transition (8.6 years), as compared to a late onset symptoms cohort demonstrating a shorter
median time of transition (4.3 years). SWAN has demonstrated that transit time to
menopause can be impacted by other factors; for instance, African American women had a
longer duration than white women, and greater body mass index was associated with a later
onset menopausal transition.

Hormonal changes
The physiologic changes of the menopausal transition stem primarily from the decline in
ovarian function. Various markers of ovarian aging have emerged to determine transitions
within the perimenopause. Traditionally, FSH has been utilized as a measure of ovarian
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aging, but assessing this gonadotrophin has its limitations given its indirect correlation with
ovarian functional decline. Although determining perimenopausal status relates to the
patient’s age, menstrual history and experience of VMS, further evaluation in the
menopausal transition can also include other laboratory information such as estradiol, and
Anti-mullerian hormone. Here we review briefly the timing of hormonal events throughout
the menopausal transition, and the factors that influence them.

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Early to Late Changes

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Hormone changes mark the progression through the menopausal transition, but can be
highly variable and not always correlative with clinical symptoms. For instance, FSH is
often, but not always, elevated even prior to onset of menstrual cycle irregularity, sometimes
even 10 years before onset of the menopausal transition. A popular but incorrect belief is
that the dwindling supply of ovarian follicles that leads to menopause manifests during the
transition as a progressive decrease in estradiol. The earliest detectable event in the
menopausal transition, as identified by Burger, et al, is a decrease in inhibin9. Inhibin is a
peptide of the transforming growth factor-beta (TGF-B) family, produced by the granulosa/
luteal cells of the ovary. The physiologic role of inhibin (which exists in two forms, A and
B) is to reduce pituitary FSH secretion via negative feedback inhibition10. In the early
transition, when the follicle cohort decreases, inhibin B declines, leading to a loss of
pituitary inhibition, and FSH secretion is increased, albeit intermittently. Thus, the rise in
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FSH in the early transition is not due to decreased estradiol11,12. Falls in estradiol are more
characteristic of the late menopausal transition, as the number of anovulatory cycles
increase. Increases in FSH and decreases in inhibin B generally represent early changes, and
are followed by decreases in both estradiol and inhibin A in the late stage of menopausal
transition; however, significant variability is emphasized in all such reviews13. Given this
variability, although commonly performed, assessing FSH levels is not recommended as a
test to determine if a patient is perimenopausal.

Anti-mullerian Hormone
Anti-mullerian hormone (AMH), like inhibin, is a TGF-B family peptide that is produced by
the small, growing follicles of the ovary and is a biologically plausible marker of ovarian
reserve 14. AMH has been found to decrease over the reproductive life span and to directly
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reflect ovarian follicular reserve15. As women approach menopause, AMH decreases, and
two AMH determinations, used to determine the rate of change, have been found to predict
the age at menopause within about 4 years16, only slightly better than what can be
determined using menstrual cyclicity alone. When more sensitive AMH assays have been
used, the predictive value of AMH increases, but such measurements are not currently
available for clinical practice 17. Another recent analysis of a population based cohort from
the US indicated that an AMH ≥200 pg/ml provided very strong predictive value that the
FMP would NOT occur within the next 5 years18. AMH has been demonstrated to be more
accurate in predicting time to the FMP than FSH, estradiol, or inhibin and is largely
independent of the patient’s BMI, race or ethnicity17. While it remains a promising marker,
AMH is not currently recommended as a routine diagnostic test for perimenopause.
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Other Markers
Longitudinal studies of menstrual cycle hormones using measurement of urinary metabolites
reveals a progressive decline in urinary progesterone metabolites across the menopausal
transition19,20. However, the degree of decline is relatively small and again, not helpful for
diagnostic purposes. The proportion of cycles with low or anovulatory progesterone
production appears to increase slightly as women traverse the menopause, but anovulatory
cycles do not become markedly more prevalent until the 2 years before the final menses20. A

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common misconception about the menopausal transition is that androgens decline

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precipitously over this time period. Multiple longitudinal cohort studies do not confirm this
notion. Although testosterone secretion drops with menopause, a concomitant decline in
SHBG leads to either maintenance or even an increase in the free androgen index21.
Declines of SHBG of 43% and increases in free androgen index of 80% have been
reported21. Adrenal androgens decline throughout adulthood, and continue this decline
throughout the transition22,23. However, there is a transient rise in DHEAS in the latter
transition in a majority of women who have been followed longitudinally24. Taken together,
the available data do not favor the notion that androgen deficiency is a common feature of
the menopause transition.

Factors Influencing Hormone Levels

BMI and race impact hormones. Obesity is associated with lower LH, FSH, estradiol and
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progesterone secretion, as well as marked decreases in urinary hormone metabolite

excretion11. Women with obesity have a lower rise in FSH and a less steep decline in
estradiol as they traverse the FMP25. African American and Hispanic women had higher
FSH and lower testosterone compared to other ethnic groups based on an analysis of 2930
women from the SWAN Study26.

In addition to BMI and race, which account for variability in hormones over time, there are
cycle to cycle changes that may impact the menopause and symptom experience. For
example, women who experience the cycle irregularity of the early menopause transition at a
younger age than the median of 47 are more likely to have a longer, and more symptomatic
transition than those whose onset is later in life6. Women who have more variable hormone
levels over time are also more likely to have a symptomatic menopause transition27.
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Symptoms
Vasomotor Symptoms
Vasomotor symptoms (VMS), also known as hot flashes or hot flushes, are described as
sudden onset, intense feelings of warmth often involving the face, neck or chest, sometimes
followed by a chill. The longstanding theory exists that VMS are related to the withdrawal
of estrogen, specifically estradiol. Interestingly, ambient serum estradiol does not correlate
with presence or severity of symptoms; the one marker independently associated with
increased risk of VMS was higher levels of FSH28. More clearly, VMS appear to be related
to a complex combination of genetic makeup, physical changes and other outside influences,
including culture and expectations.
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It appears that up to 80% of women experience VMS during the perimenopause, increasing
over the transition from early to late menopausal transition. The cohort of women in the
SWAN study reported a prevalence of 39% in the early transition progressing to 67%
cumulative prevalence29. Those women who were pre or perimenopausal at the onset of their
reported VMS were also demonstrated to have the longest duration of symptoms and
persistence after their FMP, with a median of 11.8 years, as compared to those who were
postmenopausal at the time of onset (median duration of 3.4 years) 30. Overall, while VMS

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previously were thought to last for under two years, these studies have more recently
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demonstrated median durations of 7 to 10 years, with African American women found to

have the longest median duration of 10.1 years compared to 8.9 years for Hispanic women,
6.5 years for non-Hispanic white women, 5.4 years for Chinese women and 4.8 years for
Japanese women30,31. Other factors that impact risk and severity include BMI, cigarette
smoking, depressive symptoms, and alcohol intake29. In the SWAN study, lower rates of hot
flash reporting were noted in Chinese and Japanese women. A protective effect in duration
among women reporting 12 or more alcoholic drinks in the previous year has also been
reported32. Finally, women with a high body-mass index noted worse VMS during the
menopausal transition, but milder symptoms after the FMP33.

Given that a significant cause of mortality in women is cardiovascular disease (CVD),

investigators have sought to determine if VMS might represent a biomarker for its risk. One
large study noted that women having frequent VMS had an increased risk of developing
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CVD over a 14 year period; this finding was demonstrated in women reporting later onset
VMS as compared to those experiencing them in the early menopausal transition34,35 The
crossover between these symptoms and cardiovascular risk highlights the importance of
assessing women for CVD risk factors early in the clinical relationship, ideally even before
onset of VMS.

Vaginal and Sexual Symptoms

Vaginal dryness, atrophy and associated symptoms such as dyspareunia and urinary
symptoms, are common in the postmenopause, affecting between 1/3 to 1/2 of women or
more36. Symptoms may also arise in the perimenopause. These symptoms, collectively, are
termed genitourinary syndrome of menopause and are associated with decreased vaginal
collagen and elastin content, thinned epithelium, and increased vaginal pH related to
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decreasing estrogen37. Vaginal dryness and its effect on quality of life, particularly its impact
on sexual function, is of significant import to patients. Cross-sectional studies have
suggested that increased pain during sexual intercourse may occur earlier in the transition,
while decreases in desire may occur later in a woman’s transition. The SWAN cohort noted a
decrease in reported sexual functioning starting at around 20 months prior to the FMP, with
the greatest rate of decline in the late transition and a slower decline in postmenopause38. Of
women reporting vulvovaginal symptoms, 40% also reported overall sexual dysfunction39.
However, the most important factors influencing sexual function were not hormonal
determinants, but rather prior, premenopause transition level of sexual function and
relationship satisfaction40. While many perimenopausal symptoms such as VMS and mood
tend to improve with time, ongoing targeted treatment is required for improvement in
vaginal symptoms (please see chapter on Genitourinary Syndrome of Menopause).
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Sleep and Mood Changes

Sleep is a very common concern among women in the menopause transition. Trouble falling
asleep, early awakening, and interrupted sleep can occur. In the Study of Women Across the
Nation, 37% of women between the ages of 40 and 55 reported difficulty sleeping, with
highest rates noted in Caucasian and Hispanic women41. Sleep disturbances are strongly
associated with vasomotor and psychological symptoms, in addition to stress- and health

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related lifestyle factors. With more severe VMS, a woman is more likely to report insomnia;
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however VMS alone do not explain all of the sleep changes during the transition. Hormone
levels are not associated with sleep disturbances. Poor sleep prior to the transition is
predictive of worsening sleep symptoms throughout menopause.41. Sleep symptoms tend to
stabilize as a woman progresses to postmenopause42.

Sleep habits and presence of problems should be routinely assessed in clinic visits, given the
significant impact on quality of life and health outcomes. A brief screen to determine the
cause of the sleep problem is indicated. Women who have difficulty falling asleep
(insomnia) can be screened with simple self-assessment tools43. Depression, which can
cause early morning awakening, restless leg syndrome, and sleep apnea should also be ruled
out prior to attributing sleep problems to estrogen deficiency.

The impact of the menopausal transition on mood is strongly related to quality of life during
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the period. Women should be routinely assessed for major depressive disorders and other
psychiatric pathology as for any other cohort, noting that the risk of adverse mood
symptoms (based on the Center for Epidemiologic Studies-Depression scale) increased from
20% to 62% by the early perimenopause as compared to premenopause. In the SWAN
cohort, prevalence of psychological distress (CES-D score ≥16) was 28.9% in the early
menopausal transition, 25.6% in the late menopausal transition, and 22% in
postmenopause44. Three robust longitudinal studies–SWAN, the Penn Ovarian Aging Study,
and the Harvard Study of Moods and cycles all demonstrated an increased risk for depressed
mood during the menopausal transition, 44–46 including increased risk of new-onset major
depressive disorder and anxiety in women with no prior history of a psychologic diagnosis.
Major depressive episodes are defined by DSM V as having 5 or more symptoms (weight
changes or change in appetite, insomnia or hypersomnia, psychomotor agitation or
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retardation, fatigue or loss of energy or interest, feelings of worthlessness or guilt, decreased

concentration, recurrent thoughts of death), one of which must include either depressed
mood or loss of interest, causing significant distress or impairment in social, occupational, or
other areas of functioning47. Using this definition, peri- and postmenopausal women were
2-4 times more likely to experience an episode, even when controlling for prior history of
major depression, medication use, VMS, and very upsetting life events44.

Bleeding
Bleeding patterns among women in the perimenopause vary, thus distinguishing between
“normal” and “abnormal” can be difficult. In the early menopause transition, short cycle
intervals (fewer than 21 days) are more common, while long cycle intervals (more than 36
days) occur later in the transition48. During the menopausal transition, women were more
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likely to experience an increased number of days of bleeding, with 77% reporting at least 3
episodes of 10+ days of bleeding49.

Abnormal uterine bleeding presents a unique challenge to the provider in the

perimenopause, as physiologic hormonal changes may mimic, or mask pathologic
diagnoses. These presentations often warrant further evaluation to rule out serious conditions
such as hyperplasia or cancer, and to guide treatment options. For perimenopausal women,

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the PALM-COEIN classification of abnormal uterine bleeding applies and should be utilized
to establish a differential diagnosis of bleeding and to guide evaluation and management50.
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Evaluation should include a thorough menstrual, medication, and family history, and
assessment for endocrine dysfunction or bleeding disorders (when indicated). Examination
should evaluate BMI, thyroid, uterus and cervix via both a speculum and bimanual
assessment. This information will help guide laboratory testing, which may include
complete blood count, iron studies, thyroid assessment, or evaluation for coagulation
disorders. Transvaginal ultrasonography is the imaging modality of choice to identify uterine
and endometrial structural abnormalities, although further assessment with saline infusion
sonohysterography (SIS) or office hysteroscopy may be warranted for evaluation of
intracavitary lesions51. Endometrial biopsy is indicated for persistent abnormal uterine
bleeding, or in the perimenopausal setting for those with risk factors, including chronic
anovulation and obesity. While endometrial biopsy is sensitive in detecting global
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endometrial pathology, it is important to keep in mind that its sensitivity decreases for focal
pathology52. Once evaluation is complete, tailored management options can be discussed.

Evidence-Based Management
Management should take into account the bothersomeness of each symptom, and a holistic,
yet economical approach is recommended. For example, rather than treating multiple
symptoms with multiple medications, a single treatment is preferred. Sometimes concurrent
medical problems can be addressed, and the treatment to be deployed will allow a patient to
discontinue one of her current medications. This is another desirable approach. For example,
a patient who is taking a hypnotic for sleep but complains of night sweats that are disrupting
her sleep may benefit from a trial of gabapentin, which may simultaneously reduce her night
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sweats and promote uninterrupted sleep. This approach can allow her to discontinue the
hypnotic. A simplified approach to management of common menopausal symptoms is
provided in Figures 2 and 3.

Women who are not yet menopausal, but who have menopausal symptoms, add the
additional challenge to the clinician of assuring that treatment does not cause irregular
menstrual bleeding and that contraceptive needs are addressed. For these reasons, hormonal
management with oral contraceptives or hormonal contraceptives in patch or ring forms are
useful and FDA approved for use up to the age at menopause. There is evidence that lower
dose estrogen preparations are safer54, and for this reason, the lower dose formulations
containing 20 to 30ug of ethinyl estradiol are recommended as a starting point. Women at
high risk for cardiovascular disease should be directed to alternative treatments, as the risk
of myocardial infarction and stroke rises with age, and exposure to hormonal contraception
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increases the relative risk of an adverse cardiovascular event to 1.6 (95% CI 1.2, 2.1)54. For
these women, and for those who do not tolerate and do not wish to use systemically
administered hormonal contraception, an intrauterine device, with or without progestin, is an
effective alternative. Progestin-containing intrauterine devices (IUDs), although not
approved for use in menopausal women, appear to provide ample, local progestin, and can
allow the clinician to provide exogenous estrogen as needed to control VMS and other
symptoms55,56. The progestin-containing IUD has the added advantage of reducing or

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eliminating menstrual bleeding entirely, and has therapeutic value for common
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gynecological problems of women in their 40’s, such as adenomyosis. Additionally,

tranexamic acid offers a non-hormonal mechanism for decreasing objective quantity of
bleeding57.

Conclusions
Patients who are treated with HT with satisfactory control of symptoms often wonder when
birth control can be safely discontinued. Unfortunately for the clinician, there is at present
no foolproof way to assure a patient that she is rendered permanently infertile and is truly
menopausal other than 12 months of observed amenorrhea off of all hormones. Many
symptomatic women will not tolerate such a long period of time off HT. Others can be
switched to a non-hormonal alternative and may choose to use barrier methods of
contraception while they await the traditional 12 month definition of menopause. The
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median age at menopause in the United States is 51 years58. Therefore, half of all US
women will be menopausal by this age and this is a reasonable point of departure for shared
decision making about when to discontinue contraception. Hormonal testing to determine
definitively when a woman is truly menopausal can be misleading and is not recommended,
as current methods are not sufficiently sensitive or specific to provide confidence that they
are correct. AMH may finally provide a test that is clinically useful, but it is still in the
experimental phases17. Although the risk of conception is very low (<0.1%) for women aged
44 and older59, hormonally normal-appearing menstrual cycles have been reported up to the
end of reproductive life.20 The possibility of an unwanted conception in the late
perimenopause remains a potential, but unlikely issue.

Patients who are satisfied with their HT can be reassured that, for the majority of women,
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VMS will eventually subside and will no longer require treatment. However, since the
median duration of VMS can exceed 10 years, women may choose to wean off hormones
sooner, or intervening health conditions may emerge that limit continued use of hormones.
In these circumstances, non-hormonal alternatives can be tried if symptoms remain severe.
For many women, it may be simple to wean off of HT. Hormones can be discontinued in a
number of different ways. Pills (and patches) can be cut in half to slowly reduce the dose. It
is important to remember that most oral HT preparations will be essentially eliminated over
24 hours; for this reason, alternate day dosing as a method of weaning is not recommended.
Similarly, extending the time interval of a weekly estradiol patch beyond 7 days or a twice-
weekly patch beyond 3.5 days in order to wean will result in an abrupt withdrawal from
estradiol, as estradiol levels will plummet beyond the recommended dosing interval. Women
should be warned that VMS are likely to return when HT is withdrawn, but they may be
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milder and will eventually subside. For the minority of women who continue to experience
severe VMS well into the postmenopause, extended duration of HT may be considered after
careful discussion of risks versus benefits60. Women who develop adverse effects from HT
or who wish to discontinue may try non-hormonal alternative medications.

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Management Considerations
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Case 1
Heavier menses are not expected to occur during a normal menopausal transition; rather,
menses tend to get lighter over time48. The report of heavier bleeding in association with the
patient’s complaint of a mass effect should prompt a search for an anatomical lesion.
Fibroids are suspected on the basis of her physical examination. Given the likelihood of
fibroids, and the fact that the patient has experienced a change in pelvic pressure and
increased bleeding, the clinician should consider the possibility that the fibroids are growing,
and that a submucosal component is present. Accordingly, assessment of the uterus with
vaginal ultrasound, saline infusion sonohystogram (SIS), or office hysteroscopy is
appropriate. Complete menstrual suppression with continuous oral contraceptive pills
(without a pill-free week) may successfully suppress menses 61. If bleeding stops, this
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strategy may be a successful one over the long term. However, if breakthrough bleeding
occurs and/or becomes heavy, a fibroid embolization may allow the clinician to temporize
the bleeding and follow the patient through menopause without surgical intervention. If
submucosal myomas are present, a hysteroscopic resection may take care of the bleeding
without need for hysterectomy. If intramural/subserosal fibroids are present, endometrial
ablation is unlikely to address the underlying problem causing the bleeding, e.g., fibroids.
Should the above strategies not prove desirable or effective for this women, one final option
for her to consider, in view of the increased pressure (bulky symptoms) as well as her
abnormal bleeding, would be hysterectomy with ovarian conservation.

Case 2
This patient would likely benefit from low dose HT. Her elevated blood pressure is a
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caution, however, and may ultimately limit its use. Her blood pressure should be normalized,
either with a second agent or by an increase in dose of her thiziade diuretic. Once her blood
pressure is within normal range, weekly or bi-weekly transdermal estradiol (25-50 mcg/day)
with nightly oral micronized progesterone(100mg) is likely to alleviate or eliminate her
symptoms and restore more restful sleep. Blood pressure should be re-checked after
hormones are initiated because estrogen can activate the renin-angiotensn-aldosterone
system (RAAS) and thereby increase blood pressure further, although transdermal estradiol
in the doses currently used for HT does not appear to activate the RAAS and may in fact
lower BP62. Alternative hormonal regimens that can be considered would be conjugated
equine estrogen or other oral estradiol or estrogen preparations, with nightly progesterone.
Conjugated equine estrogen can also be given in combination with bazedoxifene to avoid
use of progestin. This patient may also be treated with contraceptive doses of hormones,
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either oral, patch or vaginal ring, if contraception is needed. Contraceptive doses of

hormones are substantially higher than those found in typical HT regimens—even the lowest
dose options. Although they carry greater relative risk of cardiovascular complications with
age, for most low-risk women the possibility of a major complication such as a heart attack
remains small on an individual basis. For this patient under consideration, oral
contraceptives or contraceptive doses may be less desirable. Use of a progestin IUD to
provide contraception and deliver progestin to the uterus in combination with low dose

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estrogen, as described previously, if needed for treatment of hot flashes, may be a more
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desirable option. (Table)

Acknowledgments
Source of Funding: Dr. Santoro has is on the Scientific Advisory Board for Ogeda Pharmaceuticals and has stock
options for Menogenix, Inc. For the remaining authors none were declared.

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Key Points
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- Perimenopause is defined as a period encompassing physiologic changes that

result in the onset of menstrual irregularities and other symptoms, until a
woman reaches menopause

- Commonly encountered symptoms in the perimenopausal period include hot

flashes, vaginal or sexual symptoms, sleep and mood changes, and bleeding

- Menopausal symptoms may long precede the final menstrual period, and
earlier onset may predict a longer duration of symptoms

- Evaluation and treatment of symptoms should be personalized based on type

and severity of symptoms and contraceptive need, using a shared-decision
making model
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Figure 1.
Definitions and characteristics of the Stages of Reproductive Aging, simplified from the
STRAW definitions. Progression through the perimenopause is marked by increasing
menstrual cycle variability that serves to define these stages. As will be discussed, this
correlates with trends in hormonal levels. In addition to bleeding pattern changes, symptoms
are also significant for increasingly prevalent VMS. These typically begin either during the
menopausal transition or early in the postmenopausal stage1.
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 Delamater and Santoro Page 17
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Figure 2.
Approach to evaluation and management of menopausal symptoms. Symptoms are grouped
into two main categories, from among the 4 symptom sets that are most likely related to the
menopausal transition53. Few symptoms mimic VMS, but because of their prevalence, ruling
out thyroid disease and type 2 diabetes is prudent. Vaginal dryness can sometimes be due to
conditions other than menopause (e.g. lichen sclerosus et atrophicus), and a physical
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examination is recommended. Restless leg syndrome and chronic insomnia often overlap
with menopause-related sleep concerns, and treatment will be most effective if both
problems are addressed. Primary mood disorders that are long-standing and/or severe are
less likely to respond to hormone therapy (HT) alone; a thorough history will help the
clinician determine whether single-agent therapy with hormones is indicated, or if co-
management with a mental health professional may be more effective. Hormones are likely
the most efficient path to symptom control for women with VMS or vaginal dryness; in the
latter case, topical hormones may be sufficient. Women with mood and sleep issues may
benefit from a trial of hormones; if not sufficiently improved, additional, non-hormonal
options or co-management should be considered.
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Figure 3.
Approach to management of abnormal uterine bleeding in perimenopausal patients, taking
into account appropriate evaluation, need for contraception, and management options
available. As shown, management should be targeted toward underlying pathology when
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encountered. Otherwise, decisions should incorporate a patient-centered approach after

discussion of the patient’s goals. It is important to note that, when workup has ruled out
pathology necessitating medical intervention, reassurance can be provided to the patient and
it is reasonable to pursue expectant management. Additionally, bleeding abnormalities may
be multifactorial; anovulatory bleeding concurrent with structural abnormalities is less likely
to resolve after addressing the structural component alone51. When symptoms are
bothersome to the patient, treatment can range from medical to surgical management, and

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 Delamater and Santoro Page 19

definitive surgical management (i.e. a hysterectomy) can be considered for patients who
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have failed or decline other methods.

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Table

Quality Of Evidence in Treatment of Symptoms in the Menopausal Transition

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Level III Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med 2006;355:2338-47.

Somboonporn W, Panna S, Temtanakitpaisan T, Kaewrudee S, Soontrapa S. Effects of the levonorgestrel-releasing intrauterine

system plus estrogen therapy in perimenopausal and postmenopausal women: systematic review and meta-analysis. Menopause
2011;18:1060-6.

Committee on Practice Bulletins-Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-
aged women. Obstet Gynecol 2012;120:197-206.

The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 2017;24:728-53.
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Clin Obstet Gynecol. Author manuscript; available in PMC 2019 September 01.