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Menopause
Definition
Menopause is defined as the permanent cessation of menses and is the culmination of a process of reproductive aging that typically occurs in the fifth to sixth decades of life, with a median age of 52.5 years.
Epidemiology
Menopause is a universal phenomenon among women, and its lived experience varies by individual. The advent of menopause and the coincident loss of gonadal steroids significantly affect multiple organ systems in affected women, thereby resulting in an increased risk for osteoporosis ( Chapter 225 ), dementia ( Chapter 371 ), and heart disease ( Chapter 40 ).
Many factors influence the timing of the final menstrual period for any given woman ( Table 222-1 ). Knowing one’s mother’s age at her final menstrual period is a strong predictor of when a woman is likely to have her own.
TABLE 222-1
SOME KNOWN FACTORS THAT INFLUENCE THE AGE AT MENOPAUSE
| FACTOR | DIRECTION | DEGREE/COMMENT |
|---|---|---|
| GENETIC/FAMILIAL | ||
| CYP3A4 and CYP1B1 | Earlier menopause | Interaction with smoking |
| MSH6 | Earlier menopause | Detected by GWAS |
| MCM8 | Earlier menopause | Detected by GWAS |
| PvuII ER polymorphism | Earlier menopause, hysterectomy | 6 mo |
| Mosaic Turner syndrome | Earlier menopause | Variable |
| Fragile X | Earlier menopause | Variable |
| ENVIRONMENTAL | ||
| EDCs | Earlier menopause | 1.8-3.8 yrs |
| High altitude | Earlier menopause | 1-1.5 yrs |
| LIFESTYLE | ||
| Smoking | Earlier menopause | 1-2 yrs |
| Low socioeconomic status | Earlier menopause | 1-2 yrs |
| Oral contraceptive use | Later menopause | 6 mo |
| RACIAL/ETHNIC | ||
| African American race | Earlier menopause ∗ | 2 yrs |
| Hispanic ethnicity | Earlier menopause ∗ | 2 yrs |
| Asian ethnicity | Later menopause | 1-2 yrs |
| MENSTRUAL CHARACTERISTICS | ||
| Shorter cycles (<26 days) | Earlier menopause | 1.4 yrs |
| Higher parity | Later menopause | Variable |
CYP1B1 = cytochrome P450 family 1 subfamily B; CYP3A4 = cytochrome P450 3A4 enzyme; EDCs = endocrine-disrupting chemicals; ER = estrogen receptor; GWAS = genome-wide association study; MCM8 = minichromosome maintenance 8 gene, involved in recombination factor repair; MSH6 = mutS homolog 6 gene, involved in DNA mismatch repair.
The menopausal transition refers to the processes of reproductive aging ( Table 222-2 ) that involve menstrual cycle change, irregularity, and a breakdown of typical reproductive hormonal patterns and feedback mechanisms that characterize the fertile cycles of midreproductive-age women. Patterns of the production of gonadal hormones are altered, such that cycles become shorter and more sporadic and display less progesterone production. Follicle-stimulating hormone (FSH) increases sporadically as the remaining ovarian follicular pool (ovarian reserve) requires more and more stimulation to produce a preovulatory follicle. Eventually, FSH cannot sustain folliculogenesis, so menses begin to skip. Because ovarian folliculogenesis waxes and wanes over the course of the transition, cycles do not stop abruptly. Instead, ovulatory and anovulatory cycles alternate in an apparently random fashion. The resulting hormonal fluctuations trigger the onset of bothersome and sometimes debilitating symptoms for many women.
TABLE 222-2
STAGING REPRODUCTIVE AGING
| STAGE | REPRODUCTIVE (−5 to −3) | MENOPAUSAL TRANSITION (−2 to −1) | POSTMENOPAUSE (+1 to +2) | |
|---|---|---|---|---|
| Subdivisions | Early, peak, late | Early (−2) | Late (−1) | Early, late |
| Age ranges (approximate) | 13-47 | 47-49 | 49-52 | 50+ |
| Menses | Mostly regular | Minor irregularity | ≥60-364 days amenorrhea | Amenorrhea |
| Hormonal hallmarks | FSH—low (rises sporadically at stage −3) AMH—high |
FSH sporadically elevated AMH—normal to low |
FSH more consistently elevated AMH—low |
FSH consistently elevated (>25 IU/L) AMH—undetectable |
The diagram distills the evidence from the STRAW paradigm (Harlow SD, Gass M, Hall JE, et al. J Clin Endocrinol Metab . 2012;97:1159-1168) into a brief referable item to help “place” a woman along the menopause transition. Stage 0 is the final menstrual period. Clinically helpful milestones are mostly related to menstrual regularity. FSH or AMH can be used as confirmatory tests when clinical context is unclear. AMH = antimüllerian hormone; FSH = follicle-stimulating hormone.
Symptoms of menopause do not simply appear with the final menstrual period; rather, they are usually present throughout the transition, although they tend to intensify as women progress through the transition. For many women, symptoms begin in the early menopausal transition and worsen by the late transition through the early postmenopausal period.
Determining a woman’s proximity to her final menstrual period has implications that are important for her health. Women with an early final menstrual period will spend a greater proportion of their lifetime in a state of relative hypogonadism, which has consequences on bone health and cognition as well as on cardiovascular health. Women whose transition is later are more prone to estrogen-related diseases, such as breast cancer ( Chapter 183 ) and endometrial cancer ( Chapter 184 ). Additionally, women who have not yet undergone 12 months of amenorrhea may wish to know when they can safely discontinue the use of contraception. Finally, many women who are symptomatic may want to predict how long their symptoms are likely to last.
Pathobiology
Both menopause and advancing age impose adverse effects on central nervous system (CNS) function ( Chapter 371 ). The brain is enriched with estrogen receptors, and estrogen receptor signaling is hypothesized to mediate multiple key processes in the CNS, including but not limited to neurotrophic effects and neuroprotection. Menopause and advancing age both impose adverse effects on CNS function.
Sex differences in the structure and function of the hippocampus and the temporal lobe are hypothesized to relate to differences in the activational and organizational effects of estradiol on memory performance. Estrogen-mediated structural differences in the hypothalamic cytoarchitecture translate into higher executive functioning in women. Consequently, anxiety and mood changes are more common in perimenopausal and recently menopausal women, especially in women who have a history of mood dysfunction or adverse childhood experiences. Hypogonadism of menopause may explain why perimenopausal and early postmenopausal women frequently complain of memory loss and inability to focus. However, studies of hormone therapy in menopausal women provide conflicting results regarding its benefit on attention and executive functions such as nonspatial and spatial working memory, as well as verbal memory. Moreover, many of these executive functions spontaneously recover within a few years of the final menstrual period.
Bone health is significantly affected by gonadal steroids, and women who have undergone bilateral oophorectomy have a nearly 3-fold increased risk of bone fractures. Over the menopausal transition, serum estradiol and estrone concentrations decrease by as much as 90%. This decline closely parallels a period of accelerated and progressive bone loss ( Chapter 225 ). Reduced estrogen signaling in menopause disrupts the balance of receptor activator nuclear factor-κβ ligand (increased) and osteoprotegerin (decreased) concentrations, with the end effect being increased osteoclast activity, accelerated bone resorption, and attenuated bone remodeling. All of these changes result in significant increases in urinary and serum markers of bone resorption, as well as accelerated changes in bone mineral density in the late menopause transition. Annual rates of bone loss approximate 1.8 to 2.3% in the spine and 1.0 to 1.4% in the hip. As much as 30% loss of trabecular and 10% loss of cortical bone occurs over the 6 to 10 years spanning the perimenopausal and early menopausal period. Menopause-driven changes in bone physiology result in an increased risk for osteoporosis ( Chapter 225 ) and a 50 to 100% higher fracture rate.
Increased weight gain and altered fat distribution are common complaints in perimenopausal and menopausal women regardless of race, ethnicity, or socioeconomic status. Midlife women gain approximately 2 to 5 pounds on average, though with wide variation, and exhibit significant changes in their body composition. Postmenopausal weight gain and increased central adiposity may in part reflect an effect of hypogonadism on the gut microbiota. Hypogonadism may affect adipose tissue, which is an endocrine organ that expresses estrogen receptors, by disrupting adipocyte lipolysis and adipogenesis. Increased central adiposity is characterized by chronic low-grade inflammation, metabolic syndrome, and more than a four-fold increased risk in cardiovascular death. Additionally, obese perimenopausal and early menopausal women experience more frequent and severe hot flashes as well as sexual dysfunction.
Clinical Manifestations
Menopause is a universal phenomenon among women, and its lived experience varies from person to person. The advent of menopause and the coincident loss of gonadal steroids affect multiple organ systems and can result in increased risk for morbidity related to osteoporosis, dementia, and heart disease.
Symptoms that women report as they traverse menopause may be difficult to disentangle from those related to aging itself. Four cardinal symptoms are considered to be directly related to menopause, based on their association with the transition and their ability to be treated with hormones. These include vasomotor symptoms/hot flashes, vaginal dryness, sleep disturbances, and mood/cognition problems.
Vasomotor Symptoms
Vasomotor symptoms are experienced by up to 80% of women, at an average of 4.5 years after their final menstrual period and with a median duration of 7.4 years. Vasomotor symptoms are caused by aberrant activation of the tachykinin system. Women whose symptoms begin at an earlier age and who are earlier in their transition at onset have a longer duration of symptoms, with some women experiencing vasomotor symptoms for more than a decade. About 50% of women whose vasomotor symptoms precede entry into the menopausal transition often have persistent vasomotor symptoms for 10 years or longer after their final menstrual period. Black women are also more likely to have persistent vasomotor symptoms compared with other racial/ethnic groups; approximately 40% will report post–final menstrual period persistence of 10 years or longer. Additional factors that may result in a longer duration of vasomotor symptoms include lower educational level, greater perceived stress, more depressive symptoms, and anxiety at the time of the first report of vasomotor symptoms. Whereas a higher body mass index (BMI) at the time of early menopause is associated with more vasomotor symptoms, a higher BMI at the time of late menopause is associated with fewer vasomotor symptoms.
Genitourinary Symptoms
Vaginal dryness, dyspareunia, and urogenital symptoms are less common than vasomotor symptoms but still prevalent in about 25 to 50% of menopausal women. Women may report dryness, chronic irritation, or burning of both the vagina and vulva. Among those who are sexually active, lack of lubrication with attempted intercourse, pain during intercourse, or bleeding after intercourse may be present. Urinary frequency, urethritis, and frequent urinary tract infections ( Chapter 263 ) may also occur. All of these symptoms are believed to reflect hypogonadism and the absence of estrogen exposure to the vaginal and urinary tract epithelium. Unlike vasomotor symptoms, symptoms of the genitourinary syndrome of menopause do not spontaneously resolve over time.
Sleep Disturbances
Sleep disturbances ( Chapter 374 ) are more common in women but also worsen with age, so it can be challenging to differentiate between age-related changes compared with menopause. Sleep architecture in menopausal women demonstrates greater sleep disturbances in the second half of the night, in association with compromise of rapid eye movement (REM) sleep. Whereas some epidemiologic studies indicate that the menopausal transition worsens preexisting sleep problems and is associated with worse sleep, others report little independent effect of ovarian failure on sleep, except for a small, vulnerable subset of women with relatively poor sleep at baseline. Studies of premenopausal women given a gonadotropin-releasing hormone (GnRH) agonist to produce abrupt estrogen withdrawal indicate significant alterations in sleep, largely related to subjective nighttime hot flashes that prompt nighttime awakenings.
An additional complexity in attributing sleep disturbances to menopause is the possibility that concomitant independent sleep disorders (e.g., insomnia, sleep apnea, and restless legs syndrome; Chapter 374 ) are present. Sleep apnea is suspected based on a history of snoring, daytime sleepiness, and less perceived restfulness of sleep, and it is diagnosed by an overnight sleep assessment. Diagnostic criteria for restless legs syndrome ( Chapter 374 ) include irresistible urges to move one’s legs; symptoms present at rest; urge relieved by movement; and peak symptoms at night or in the evening. Insomnia (see Table 374-5 and Fig. 374-6 ) may appear at the time of the menopausal transition, but it may also be long-standing in duration. Women age 35 years or over with insomnia have the highest rates of persistence of sleep disorders in menopause.
Mood Disorders
Adverse mood is associated with traversal of menopause in a complex manner. Abrupt estrogen withdrawal using a GnRH agonist in premenopausal women results in a deterioration of mood. Depressive symptoms are associated with nighttime hot flashes and sleep disruption, thereby indicating the intimate relationship between sleep and mood. Multiple cohort studies have identified the late transition as a period of vulnerability for depression in midlife women. Women are two- to four-fold more likely to experience new onset of major depression ( Chapter 362 ) during the menopausal transition than they are before they become perimenopausal or after their final menstrual period. Concomitant anxiety and hot flashes are predictors of major depression during this time of life. Although absolute levels of hormones are not clearly associated with major depression or depressive symptoms, greater variability in FSH, luteinizing hormone, and estradiol have been linked to depressive symptoms.
Diagnosis
Menopause is a clinical diagnosis typically based on amenorrhea for at least 12 months. However, this definition relies on a woman having menstrual cycles with some degree of regularity. Women who are age 45 or older have a 90% probability of never having another menstrual period once they attain the milestone of 12 months’ amenorrhea. In contrast, younger women have a substantially greater probability of experiencing subsequent menses. The final menstrual period is most often preceded by several years of instability in menstrual cyclicity and hormone secretion. This process, which is called the menopausal transition, usually persists for about 4 years, but with wide variation around this median. Women who enter the transition at a younger age tend to have more symptoms and a longer transition, whereas women who enter it later in life are more likely to have a rapid transition to their final menstrual period.
No diagnostic test can definitively predict when a woman will have her final menstrual period. Nonetheless, the serum level of antimüllerian hormone, which is a transforming growth factor beta family peptide synthesized by granulosa cells, is a reliable proxy of ovarian reserve (remaining follicle volume) and can be used to help approximate the timing of the final menstrual period. Other measures, such as levels of FSH or the inhibins, are generally not recommended for this purpose, in part because—unlike antimüllerian hormone—they fluctuate throughout the menstrual cycle.
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