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What the Generalist Should Know About REI

What Every Gynecologist Should Know About Perimenopause

VERRILLI, LAUREN MD*; BERGA, SARAH L. MD

Author Information
Clinical Obstetrics and Gynecology: December 2020 - Volume 63 - Issue 4 - p 720-734
doi: 10.1097/GRF.0000000000000578
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Abstract

Introduction

Perimenopause is one of many terms that refer to the transition from regular ovulatory menstrual cycles to irregular menstrual cycles that result from ovarian aging and the accompanying decline in oocyte quantity and quality. Other common nomenclature is climacteric and menopausal transition. The clinical presentation of the perimenopause includes infertility, irregular menstrual cycles, menorrhagia, and new onset of or worsening of mood disorders. Unlike menopause, which is characterized by low levels of estradiol and progesterone, the hallmark of perimenopause is highly variable levels of estradiol and progesterone with abrupt increases and decreases that are often described as a “hormonal roller coaster” or “hormonal chaos.” Perimenopause is often contrasted with puberty in that both processes are transitions, the former largely a reflection of ovarian reserve and the latter largely attributable to maturation of gonadotropin-releasing hormone. Both transitions are characterized by menstrual cycle irregularity. While the menstrual irregularities of perimenopause and puberty and the cessation of ovarian cyclicity at menopause respond to appropriate hormonal management, the management of the perimenopausal transition is more complicated because low-dose regimens prescribed for menopause hormone therapy are often fail to control or buffer the woman from the often large magnitude fluctuations characteristic of perimenopausal ovarian function.

Menopause is defined as 1 year of amenorrhea accompanied by biochemical evidence of hypergonadotropic hypogonadism. While neither perimenopause nor menopause are diseases per se, both reflect ovarian aging and may exacerbate or elicit a variety of physical, cognitive, and psychosocial ailments. Gynecologists have the opportunity to usher women through the perimenopausal transition by offering an explanation of the process and management options while reinforcing preventative care measures. The table below based on US census data, illustrates the demographics that inform the practice of gynecology (Table 1). A recent editorial called attention to the lack of training in the area of perimenopausal and menopausal medicine.1

TABLE 1 - The Growing Menopausal Population
Year Population of Postmenopausal Women in the United States
1990 10.8 million
2000 12.1 million
2010 17.1 million
2020 19.3 million
Adapted from US census data, 2018. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

TABLE 2 - Hormonal Assay Interpretations in the Menopause Transition
Hormone Perimenopause Postmenopausal Important to Know
Follicle-stimulating hormone (FSH) Normal to intermittently elevated Persistently elevated (≥25 IU/mL) In perimenopause, decreased inhibin allows for tonic increases in FSH that initiate folliculogenesis during the luteal phase of the prior cycle (LOOP cycles)
Luteinizing hormone (LH) Normal, with appropriate surge values midcycle but earlier timing of LH surge relative to LMP Elevated (≥50 IU/mL) Time from LMP to midcycle LH surge shorter because of initiation of folliculogenesis during the prior luteal phase
Estradiol (E2) Generally elevated in LOOP and lag cycles but there may be “spells” of low estradiol during lag cycles when there is not a responsive follicle for FSH to recruit. In lag cycles, estradiol may exceed 500 pg/mL Low, 10-30 pg/mL Menopausal symptoms initially triggered by dramatic increase and abrupt declines in estradiol levels from follicles that respond aberrantly to FSH stimulation
Estrone (E1) Normal to elevated depending on estradiol levels Slightly reduced, 30-70 pg/mL Circulating levels of estrone and estrone sulfate reflect peripheral conversion of androstenedione to estrone
Progesterone (P4) Normal or low, may vary from cycle to cycle Undetectable Following cessation of ovulation, progesterone is not produced
Total testosterone Normal Normal The adrenal glands and ovaries continue produce androgens including testosterone. Elevated LH drives theca cell production of androstenedione which is converted to testosterone
Free testosterone Normal Normal to elevated When SHBG drops, free testosterone levels rise. Obesity and insulin suppress SHBG and estrogens increase SHBG, so after menopause, free testosterone levels may increase
Androstenedione Normal Normal After menopause LH drives ovarian thecal cell production of androstenedione
Dehydroepiandrosterone sulfate Normal Normal The adrenal glands undergo adrenarche and adrenopause due to the ontogeny of hypothalamic CRH and pituitary drive coupled with adrenal responsiveness to CRH and ACTH but the adrenal lifespan does not appear to be linked to the ovarian lifecycle
Anti-Mullerian hormone (AMH) Low to undetectable Undetectable AMH levels decline progressively across the reproductive lifespan and reflect the oocyte-follicular pool. The lower the AMH, the greater the variability in oocyte quality and the quantity of follicles recruited by FSH
Inhibin B Low Lower Inhibin B is produced by the granulosa cells of the follicles and reflects ovarian reserve. A decrease in inhibin B is one of the hallmarks of early ovarian aging
ACTH indicates adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; LMH, last menstrual period; SHBG, sex hormone binding globulin.

Age and Timing of Menopause

In 1994, the Study of Women’s Health Across the Nations (SWAN) began recording the health of American women as they transition through perimenopause (www.swanstudy.org). The results of the SWAN study augmented evidence from other longitudinal studies including the Melbourne Women’s Health Study and the Penn Ovarian Aging study that have helped us to better understand the nuances of ovarian function and the resulting hormonal milieu during the menopausal transition. Collectively, these data have demonstrated that the perimenopausal period begins 4 to 8 years before the final menstrual period (FMP) and that the median arrival at menopause is age 51.3.2 According to the SWAN data, late menopause was defined as the FMP occurring after 54 years of age and early menopause as the FMP between age 40 to 45.3 Each of these conditions encompass ∼5% of the population, whereas 1% of women will experience primary ovarian insufficiency, or their FMP before age 40.4

Genetics and lifestyle modify the age of menopause. Chromosomal deletions on the X chromosome (such as POF 1 and POF 2) have been shown to decrease the age at menopause5 and fragile X premutations are associated with early menopause as well as primary ovarian insufficiency.6 The SWAN study, among other longitudinal studies, has underscored the importance of lifestyle factors in influencing the age of the FMP. For instance, nonsmokers had a significantly longer time until the FMP as did those with better health at baseline, higher level of education, higher body mass index, and prior use of oral contraceptive pills.3

Age of menopause has an important genetic underpinning. Multigenerational genetic studies have demonstrated a strong familial relationship between age of natural menopause between mothers and daughters. In particular, early and late menopause tend to aggregate within families, with one study noting a 6-fold increased incidence of early or late menopause in offspring of women with either of these findings.7

Clinical Vignette #1

Chandra, a 39-year-old healthy G3P2012 woman, comes to see you after she obtained an online anti-Mullerian hormone (AMH) test result. Her AMH was ≤0.001 ng/mL and she is concerned she is headed into menopause very soon. She reports regular menstrual cycles every 29 days with 5 days of bleeding. She is ambivalent about future childbearing. She spontaneously conceived in the past but despite not using contraception she has not conceived for 5 years. She endorses occasional hot flashes and headaches but no night sweats, dyspareunia, or significant mood changes. She does not feel depressed. She currently takes a multivitamin and occasional ibuprofen. What counseling can you tell her about AMH and age of menopause? Does she need to use contraception?

DISCUSSION

AMH is produced by the granulosa cells of the preantral and antral follicles within the human ovary. AMH is one way to estimate what is often termed “ovarian reserve” and is a biochemical indicator of follicle “pool.”8AMH is made by both granulosa cells in the ovary and Sertoli cells in the testes. Because menopause ensues when there are no more oocytes that are responsive to gonadotropin stimulation,9AMH is utilized to estimate timing of menopause or stage of perimenopause. Several studies have explored the sensitivity and specificity of a single AMH and following the decline over time.10,11 These studies, however, have failed to demonstrate that AMH measured once or even longitudinally predicted time to menopause, however, available evidence suggests that AMH is a good estimate of ovarian reserve and is useful in counseling patients about outcomes related to infertility interventions. The best correlation that has been found is that an undetectable AMH has been correlated with menopause within 5 years.10,12 Because AMH assays were developed using young, healthy controls, the current assays cannot detect ovarian reserve during the final stages of perimenopause and thus we cannot utilize low or undetectable levels to accurately forecast FMP.12Also, low or undetectable levels do not exclude the possibility of spontaneous conception and our patient in the vignette should be counseled about contraceptive options if conception is not desired.

The proximate cause of perimenopause is declining oocyte quantity and quality such that follicles do not respond appropriately to gonadotropin drive. Oocyte quality may vary from cycle to cycle. The maximum number of primordial follicles, ∼10 million, are present in the female fetus at 20 weeks gestation.13 At puberty, girls have ∼2 to 500,000 total oocytes remaining and the rate of atresia remains fairly steady through the early and mid-reproductive years.14 Over 35 to 40 years of reproductive function, ∼500 oocytes will be ovulated, thus, the majority of the ovarian reserve is lost due to atresia rather than ovulation. At the time of menopause, ∼100 oocytes remain in the ovary15,16 (Fig. 1).

FIGURE 1
FIGURE 1:
The life history of oocytes.15

Using a model of stable decline, follicular depletion in women with regular menses would result in an ovary that still contains well over 2500 follicles at the average age of menopause.13 Knowing that the menopausal ovary is nearly deplete of follicles, it has been thought that there is a rapid increase in the rate of follicular atresia in the perimenopausal years.

Key Points

  • The maximum number of oocytes within the ovary occurs at 20 weeks gestation.
  • The majority of the ovarian reserve is lost to atresia rather than ovulation.
  • The perimenopausal period is defined by a rapid increase in the rate of follicular atresia.
  • Genes that control the rate of atresia are being identified. The most common genetic cause of premature atresia may well be Turner syndrome (45,X). The girls experience complete oocyte atresia before the onset of gonadotropin-releasing hormone drive at the time of puberty.

Hormonal Changes Associated With Perimenopause and Menopause

Ovarian function in the perimenopausal period is unpredictable because oocyte quality varies from cycle to cycle. The stages of menopause have been previously described using the STRAW (Stages of Reproductive Aging Workshop) acronym.17 The STRAW timeline focuses on the continuum of the menopausal transition and gives flexible guidelines when reviewing labs and cycles, particularly in the early transition.

THE MENOPAUSAL TRANSITION

The hallmark of the early premenopausal phase (stages −3 and −2) is a shortening of menstrual cycle interval. The classic sign of the menopausal transition is amenorrhea, but this is a late stage development. Several studies have documented a decrease in menstrual cycle interval across the final years of the reproductive lifespan.18 Santoro et al19 compared urinary hormone profiles of 6 women aged 47 and older with regular cycles with those of women aged 38 and younger. Surprisingly, older women had higher concentrations of urinary estrone-glucuronide, a reflection of serum estradiol, compared with women aged 19 to 38.19 Further, pregnanediol-glucuronide levels, a reflection of serum progesterone, were much lower. Chronic exposure to higher estradiol and lower progesterone levels may predispose to endometrial proliferation and hyperplasia and may explain the increased in menorrhagia and fibroid and polyp growth.19 In early perimenopause (stages −3 and −2), the corpus luteum still functions to maintain low normal levels of luteal progesterone (Fig. 2).

FIGURE 2
FIGURE 2:
The climacteric transition. AMH indicates anti-Mullerian hormone; FSH, follicle-stimulating hormone. Adapted from Stages of Reproductive Aging Workshop (STRAW). Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

In stage −2, as the follicle pool declines, so does inhibin which in turn leads to tonically elevated follicle-stimulating hormone (FSH) levels.20 Higher FSH levels during the luteal phase initiate folliculogenesis even before the demise of the corpus luteum. The initiation of folliculogenesis during the luteal phase results in a shortened follicular phase because instead of sequential cycles there is overlap of cycles. When the corpus luteum dies, folliculogenesis is often so advanced that the lead follicle triggers an luteinizing hormone (LH) surge by days 7 to 10 rather than days 10 to 13. During this phase the overall luteal length is preserved but progesterone levels are lower.21 These overlapping cycles in which the follicle pool begins development during the luteal phase have been termed LOOP (luteal out of phase) cycles.22 As the follicle pool declines further, responsive follicles are often not available during the luteal or the next follicular phase and there may be a gap, lag, or a “spell” of menopause before the next responsive follicle is available. However, even in the presence of lags or gaps, when the next follicle responds, it tends to secrete high levels of estradiol and only intermittently are the cycles ovulatory. Thus, despite lags or gaps in folliculogenesis, estradiol fluctuations become more dramatic. Symptoms such as hot flashes generally reflect the rate of change, meaning that levels that fall abruptly from a higher to a much lower levels provoke acute onset of hot flashes and related symptoms. Heavy and unpredictable withdrawal bleeding (flooding) are often triggered by an abrupt decline in estradiol after prolonged endometrial stimulation by estradiol and a lack of progesterone exposure.

Only in the late perimenopause (stage −1) do estradiol levels begin to decline as the pool of responsive follicles dwindles.23 In the 2 years before the FMP, overall estradiol levels begin to decline accompanied by a sustained rise in FSH.24 During this phase, the clinician may be surprised to find that estradiol is elevated in the presence of elevated estradiol levels >200 pg/mL. This classic finding reflects the loss of feedback sensitivity to estradiol negative feedback in the setting a low inhibin and AMH levels. The ovarian theca cells continue to produce androstenedione because LH levels are also elevated and thus testosterone levels do not decline. Androstenedione can be converted to estrone, which serves as the major reservoir of estrogen in a postmenopausal woman.13

At a critical oocyte threshold (100 to 1000),9 cessation of menstruation will become permanent. For the first 1 to 2 years of menopause (stage +1), progesterone is no longer produced, however, aberrant surges of estrogen have been noted.19 In late postmenopause (stage +2), a predictable steady state of hypergonadotropic hypogonadism is noted and some of the menopausal symptoms triggered by abrupt declines in estradiol such as hot flashes and heavy withdrawal bleeding may taper somewhat. However, Weber et al25 documented a marked increase in verbal learning, verbal memory, fine motor skills, and working memory in the first few years after FMP.

Key Points

  • The earliest hormonal change noted in perimenopause is a decline in circulating inhibin levels, rise in FSH, rise in estradiol, and decline in progesterone with shortening of the menstrual interval.
  • Estradiol levels fluctuate until the FMP and only begin to decline ∼2 years before the FNP.
  • Androgen levels do not decline due to menopause because theca cells continue to produce androstenedione.
  • LOOP cycles are common in early perimenopause, whereas lag cycles are more common in the later phases of the perimenopause.
  • Lag cycles are associated with high estradiol, high FSH, and anovulatory cycles with overall lengthening of the duration between menses but heavier withdrawal bleeding episodes (Table 2).

Clinical Vignette #2

Ebony, a 47-year-old woman, presents with hot flashes, vaginal dryness, fatigue, and depressed mood for the past 6 months. She reports that her symptoms are worsening and that her menstrual interval has shortened from circa 30 to 20 to 24 days. Her menstrual flow now lasts about 7 including 4 days of extremely heavy bleeding. Her primary care doctor drew the following labs on her on day 20 of her cycle.

WHAT CAN YOU TELL HER ABOUT HER LABORATORY VALUES?

On the basis of a progesterone level >1 ng/mL, she is having an ovulatory cycle, but her progesterone level is <10 ng/mL, so progesterone levels are low. Her estradiol is also low for a luteal phase and her FSH is elevated. Ebony’s labs suggest a LOOP cycle. Let’s work through the labs sequentially using the classic graph published by Santoro et al19in 1996. This study carefully compared daily urinary hormone levels in 6 regularly cycling women aged 47 and older and 11 women aged 19 to 38. In the graph below, time 0 is represented as the onset of the LH surge.

In this study (Fig. 3) perimenopausal women demonstrated:

  • Ovulatory, albeit lower progesterone levels, in the luteal phase.
  • Elevated estradiol levels throughout the cycle with a sharp decline at the end of the luteal phase.
  • Similar LH values compared with younger ovulatory women.
  • Tonically elevated FSH levels and a sharp rise of FSH at the end of the luteal phase.

FIGURE 3
FIGURE 3:
Mean±SEM daily urinary gonadotropin and sex steroid excretion in 11 perimenopausal women with regular cycles aged 43 to 52 (○) compared with those in 11 mid-reproductive aged women (●).19 E1 indicates estrone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PDG, pregnanediol 3-glucuronide.

In short, Ebony’s labs demonstrate a LOOP cycle with low progesterone and a normal duration of the luteal phase. Ebony’s labs show an elevated FSH and low estradiol despite an elevated progesterone showing a luteal phase.

WHAT CAN YOU TELL HER ABOUT HER ADDITIONAL LABS?

Testosterone level is normal, which is typical of perimenopause in which both normal and free testosterone levels are maintained by both adrenal and ovarian supply.26

Normal TSH and free T4 indicate a normally functioning thyroid gland without evidence of hypothyroidism. Undetectable AMH is also consistent with perimenopause and unfortunately cannot predict with any precision when menopause will occur.

WHAT ADDITIONAL TESTING DO YOU RECOMMEND?

On the basis of her heavy, prolonged episodes of bleeding and fatigue, an evaluation for anemia is recommended as well as an assessment of the endometrial cavity. During perimenopause, persistently elevated levels of estradiol may provoke growth of fibroids or polyps or cause endometrial hyperplasia. In addition, if she is experiencing repetitive a lag cycles then she is at risk for developing endometrial hyperplasia and dysfunctional bleeding as a consequence of erratic estrogen withdrawal and insufficient exposure progesterone.

WHAT ARE THE NEXT STEPS?

Options for evaluating the endometrial cavity include saline infusion sonography and endometrial biopsy. There are a number of interventions to consider. Ultimately, it is important to ensure adequate and relatively constant estradiol levels and sufficient progestin exposure to protect the endometrial from overstimulation. Please see the “Hormonal treatment regimens” section for options.

Common Symptoms of Perimenopause

VASOMOTOR SYMPTOMS (VMS)

VMS are the most common symptom of menopause. Data from the SWAN study suggest that up to 70% of women will experience VMS with a median duration of 7.4 years.27 The exact mechanism of a hot flush is not well understood but is thought to be related to the precipitous fall in estradiol levels. This, in turn, generates a hypothalamic response that results in heat dissipation and an increase in peripheral temperature, decrease in skin resistance, diaphoresis, and resultant decrease in core body temperature.28 Sleep disruption as a result of VMS has been well documented using electroencephalographic monitoring.29 Aside from the bothersome side effects of VMS, recent research has demonstrated that hot flushes are associated with reduced heart rate variability and increased cardiovascular disease risk.30 It is also important to remember that not all hot flushes are related to menopause. Other conditions, such a thyroid disease, autoimmune disease, adrenal insufficiency or glucocorticoid withdrawal, and acute or chronic infection and malignancy can cause persistent VMS.

MOOD AND COGNITION

Depression in menopause is also a challenging topic, as this period in a woman’s life can also be marked with major life changes, decline in physical health, and stressful transitions. Both the SWAN study and the Harvard Study of Moods and Cycles demonstrated an increased incidence of depression in the perimenopausal years.14 Depression was closely linked with VMS, sleep disturbance, and the presence underlying poor physical health, anxiety disorders, and stressful life events. In a population of nearly 6000 women aged 45 to 65 years, the incidence of depression and irritability was 57%.31

The role of estrogen fluctuations, and ultimately estrogen deprivation, has been studied as a possible exacerbating factor for depression. Estradiol and testosterone impact important brain functions including serotonin and noradrenaline neurotransmission.32 Estrogen receptors are widely distributed in the brain and in locations that mediate mood and cognition, such as the prefrontal cortex and hippocampus.13,32 For instance, administration of transdermal estradiol increased brain serotonergic function is areas serving cognition and emotion and the impact was augmented by progesterone.33,34

Given that the brain is a target tissue for hormones and that perimenopausal fluctuations in estradiol cause hot flashes and related complaints such as “cognitive fog,” mood changes, and sleep disruptions, estrogen supplementation during the menopause transition has been suggested as a way to blunt the rapid declines in estradiol associated with perimenopausal cycles and to provide sufficient “background” estradiol to mitigate symptoms. Available studies suggest that this approach provides modest improvement and no harm. In a recent placebo-controlled trial by Santoro et al,35 38 perimenopausal women (aged 38 to 52) with regular cycles who reported at least 1 symptom (hot flashes, bloating, headache, adverse mood, or poor sleep) were randomized to either a levonorgestrel intrauterine system alone or in combination with low-dose transdermal estradiol gel. Transdermal estradiol improved daytime fatigue and VMS with no significant change in mood or sleep quality.35 A retrospective observational trial comparing women who had premenopausal bilateral oophorectomy versus those who had not demonstrated that oophorectomy was associated with a significant increase in depression and anxiety.36

Two randomized controlled trials (RCTs) support the use of estradiol in the management of existing depressive disorders in perimenopause. Soares et al37 randomized 50 perimenopausal women with a preexisting depressive disorder to either weekly a transdermal estradiol patch (100 µg) versus an inert patch for 12 weeks with ongoing validated measurements of depression scores. The results of this study demonstrated a significant improvement in depressive symptoms in the group receiving estradiol therapy compared with placebo and this result showed ongoing improvement as the duration of exposure to estradiol continued.37 A study by Schmidt et al38 using a 50 µg dose of transdermal estradiol demonstrated similar results.

The cognitive decline that occurs during the menopausal transition has been linked to acute loss of estradiol immediately following the FMP.25 While postmenopausal estrogen use is unlikely to fully forestall aging, including brain aging, its use may slow age-related changes in brain function in women. A prospective observational study found that estrogen use was associated with a lower risk of all-cause dementia and the greater the duration of use, the lower the risk of dementia in postmenopausal women.39 Given that RCTs must have endpoints that are measurable within 3 years of randomization, a RCT to address the question of the longer term impact of postmenopausal estrogen use relies on other types of study designs including prospective observational population cohorts. Interestingly, brain magnetic resonance imaging of menopausal women have demonstrated fewer amyloid deposition in women treated with estrogen compared with those who were not.40 Other studies have shown that estradiol was better than conjugated equine estrogen use in augmenting brain metabolism and maintaining verbal memory and that both were better than placebo.41

GENITOURINARY SYNDROME OF MENOPAUSE (GSM)

GSM encompasses vulvovaginal dryness, dyspareunia, and urinary symptoms associated with estrogen deficiency.42 It is estimated that 50% of postmenopausal women suffer from GSM and these symptoms can begin in the perimenopausal period.43 Pain, sexual dysfunction, and urinary complaints are often the first signs of GSM. In the SWAN study, for instance, a decrease in sexual function and increase in vaginal dryness was noted nearly 2 years before the FNP.44 Estrogen deficiency in the vaginal mucosa manifests itself as thin and pale vaginal mucosa with elevated pH and often friable tissue. The standard treatment regimen involves both lubrication (unscented water-based lubricants) as well as local and/or systemic estrogen therapy. Estrogen treatment allows for remodeling of the vaginal mucosa. Estrogen increases blood flow to the vaginal mucosa and regenerates the superficial layer of the mucosa. In addition, estrogen decreases the vaginal pH and may improve urinary incontinence. More recently, low-dose (6.5 mg) vaginal dehydroepiandrosterone has emerged as an important adjuvant treatment for GSM although the formulation contains coconut and palm oils may provoke allergic reactions in some. Intrarosa has been shown to improve and alter vaginal cytology and aid in the treatment of symptoms associated with atrophy.45

ABNORMAL UTERINE BLEEDING

As delineated in our section “Physiology of perimenopause,” irregular uterine bleeding is a common presentation during the perimenopause. Often, women earlier in the menopause transition will present with increased frequency of bleeding episodes as the cycles shorten due to the LOOP cycle physiology.22 Because of the high likelihood that estrogen may be persistently elevated in these cycles, a thorough cavity evaluation and endometrial sampling may be indicated if irregular bleeding patterns persist. Early perimenopause represents a time at which women with existing fibroids may experience fibroid growth and increased bothersome bleeding. Younger women with obesity and abnormal bleeding, or women over the age of 40, should undergo endometrial sampling. Regardless of a woman’s stage in her menopause transition, the PALM-COEIN classification should be used to work through all possible diagnoses, acknowledging that hormonal fluctuations play a prominent role in bleeding patterns.

Evaluation of abnormal bleeding should include history and physical examination, paying close attention to the speculum and bimanual examination. In addition, transvaginal ultrasonography, with or without saline sonohysterogram, can aid in assessing for intracavitary pathology. Laboratory work should include basics such as a complete blood count and thyroid testing. Hormonal assays (as mentioned in clinical vignette 2) as well as an AMH level may aid in understanding the physiology of the current cycle as well as the overall menopause trajectory.

HORMONAL TREATMENT REGIMENS

There is no specific hormonal formulation designed for perimenopausal women. Hormone interventions used in perimenopausal women not seeking fertility fall into 2 categories: those used for contraception and those used for menopause hormone therapy. Clearly, the management of perimenopause requires an individualized approach and adapting standard formulations to nonstandard use not all estrogens or progestins have the same utility and risk:benefit profiles. An astute clinician will recognize the importance of titrating and modifying treatments on a case by case basis.

If contraception is the goal, progestin intrauterine devices (IUDs) offer long-term effectiveness against hyperplasia and provide cycle control as well as contraception. To buffer women from the symptoms of estradiol crashes and withdrawal, low-dose transdermal regimens can be utilized, especially when the endometrium is protected by a progestin IUD. An overarching goal is to moderate fluctuating levels of endogenous estradiol by providing low-dose transdermal exogenous estradiol.

The North American Menopause Society (NAMS) recommends starting with a low to moderate dose of estrogen and titrating as need to achieve desired reduction in bothersome symptoms of menopause. While some clinicians use routine laboratory monitoring to adjust dosing of estradiol during menopause, given the fluctuations of endogenous estradiol during the perimenopause, a single determination will not be indicative of ongoing estradiol exposure.46 In a normal ovulatory menstrual cycle, the mean estradiol is 100 to 110 pg/mL. However, endogenous estradiol can fluctuate as high as 700 pg/mL in the perimenopause. After menopause, when there is minimal endogenous ovarian secretion of estradiol, it may be possible to titrate circulating estradiol and common sense would dictate that levels <100 pg/mL may provide physiological replacement. Whether this approach has utility for postmenopausal women remains to be shown. Some studies suggest that circulating levels >3 to 40 pg/mL are needed for support of verbal memory and cognition more generally.47Table 3 provides options for hormone therapy in the perimenopausal period. Because of the lower side effect profile and decreased risk of venous thromboembolism, the authors of this chapter prefer transdermal estradiol as first-line estrogen therapy.

TABLE 3 - Estrogen Therapy Options in Perimenopause
Estrogen Route Dose Side Effects Indications Within Perimenopause Good to Know
Transdermal estradiol 0.025-0.1 mg weekly patch Itching at the site of the patch Abnormal uterine bleeding, cognitive “fog,” depression and mood swings, genitourinary syndrome of menopause, vasomotor symptoms Decreased risk of VTE compared with oral administration, does not increase SHBG, therefore, androgens remain unchanged
Oral conjugated equine estrogen 0.3-0.625 mg/d Breast tenderness, increased vaginal discharge, increased risk of VTE compared with transdermal administration Same as above Primary constituent is estrone sulfate and may not support brain as fully as estradiol
Oral micronized estradiol 0.25-1 mg/d Breast tenderness, increased vaginal discharge, increased risk of VTE compared with transdermal administration Same as above Short half-life of ∼4 h may lead to increase in symptoms. Greater conversion to estrone and estrone sulfate than transdermal estradiol
Estradiol (1%) gel 0.25-1.25 mg/daily Headaches, breast tenderness, abnormal bleeding Approved for the treatment of vasomotor symptoms Clothing cannot be worn for 15-30 min after application but minimizes skin reactions and other adherence issues with patches
Estradiol implants 25-75 mg pellets/twice yearly Breast tenderness, increased vaginal discharge, increased risk of VTE compared with transdermal administration Abnormal uterine bleeding, depression and mood swings, genitourinary syndrome of menopause, vasomotor symptoms Effects of pellets can be cumulative, leading to supratherapeutic levels over time, prone to highs and lows and may increase withdrawal symptoms
VTE indicates venous thromboembolism.

Progestogen therapy is necessary to oppose the effects of estrogen at the level of the endometrium. Side effects of systemic progestin therapies can include bloating, breast tenderness, and occasionally increase in depressed mood. Options for therapy include sequential administration or continuous. In sequential regimens, the length of exposure seems to be more important than the dose itself. A regimen that is 10 to 14 days per month is preferable to a shorter duration and decreases the risk of endometrial hyperplasia.13 Continuous administration of progestogen alongside estrogen therapy can lead to breakthrough bleeding in the first 3 to 6 months, however, many patients can achieve long-term amenorrhea.13 The most common oral progestins used in the United States are norethindrone (5 to 10 mg), medroxyprogesterone acetate (2.5 to 5 mg), or micronized progesterone (100 to 200 mg). Progestin containing IUDs appear to provide adequate localized progestin to oppose the effects of estrogen on the endometrium.23 In addition, progestin IUDs have demonstrated a dramatic reduction in bleeding days over time.48 The antiproliferative action of the IUD decreases menstrual blood loss and does not appear to significantly disrupt pituitary and ovarian function.35

Conclusions

Perimenopause often represents an era in a woman’s life that can be equally as frustrating for the patient as it can for the gynecologist. The complexities of managing abnormal uterine bleeding in concert with a constellation of other symptoms may leave patients feeling overwhelmed while practitioners lack clear guidance about the pros and cons of hormonal and other interventions. Often one treatment option, such a hysterectomy, may relieve bleeding but further exacerbate VMS and may be more therapy than is needed. Supporting a woman through perimenopause and into menopause requires a nuanced appreciation of the physiology of the perimenopause so that treatments can be tailored to the stage of the perimenopause and the patient’s symptom complex. The goal of treatment is to maximize benefit and minimize risk. While one patient may find a hysterectomy or endometrial ablation to be an as acceptable treatment option, others may still be attempting pregnancy. Perimenopause may represent a time when children move out, relationships change, retirement approaches, and parents age; these social factors may make it difficult for patients to endure the hormonal chaos and unpredictable bleeding. Taking into account these psychosocial factors can help a clinician tailor treatment using a shared decision-making model.

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Keywords:

perimenopause; menopause; abnormal uterine bleeding; hormone therapy

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