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INTRODUCTION — Natural menopause is defined as the permanent cessation of menstrual periods, determined retrospectively after a woman has experienced 12 months of amenorrhea without any other obvious pathological or physiological cause. It occurs at a median age of 51.4 years in normal women, and is a reflection of complete, or near complete, ovarian follicular depletion, with resulting hypoestrogenemia and high FSH concentrations (figure 1). Menopause before age 40 is considered to be abnormal and is referred to as primary ovarian insufficiency (premature ovarian failure). The menopausal transition, or perimenopause, occurs after the reproductive years, but before menopause, and is characterized by irregular menstrual cycles, endocrine changes, and symptoms such as hot flashes.
This topic will review the clinical features and diagnosis of the menopausal transition and menopause. The physiology and epidemiology of menopause, postmenopausal hormone therapy, and primary ovarian insufficiency are reviewed separately. (See "Ovarian development and failure (menopause) in normal women" and "Postmenopausal hormone therapy: Benefits and risks" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
CLINICAL MANIFESTATIONS — The menopausal transition, or perimenopause, begins on average four years before the final menstrual period, and includes a number of physiologic changes that may affect a woman’s quality of life. It is characterized by irregular menstrual cycles and marked hormonal fluctuations, often accompanied by hot flashes, sleep disturbances, mood symptoms, and vaginal dryness [1-6]. (See 'Symptoms' below.) In addition, changes in lipids and bone loss begin to occur, both of which have implications for long-term health.
Virtually all women experience the menstrual irregularity and hormonal fluctuations prior to clinical menopause, up to 80 percent develop hot flashes (the most common menopausal symptom), but only 20 to 30 percent seek medical attention for treatment. (See 'Hot flashes' below.)
Much of the available information about the endocrine and clinical manifestations of the menopausal transition comes from a number of longitudinal cohort studies of midlife women [7-19], the largest of which, the Study of Women’s Health Across the Nation (SWAN), has followed a multiethnic, community-based cohort of over 3000 women ages 42 to 52 years for 15 years [7,12-14,16,17,20-29]. Based upon data from the cohort studies, a staging system was developed that is now considered to be the gold standard for characterizing reproductive aging from the reproductive years through menopause. The STRAW staging system (Stages of Reproductive Aging Workshop) includes definitions for the late reproductive years, the menopausal transition, perimenopause, menopause, and postmenopause (figure 2) . Although the STRAW system has been used primarily for women’s health research, it is helpful in the clinical setting for patients and clinicians for assessing fertility potential, contraceptive needs, and potential need for hormone therapy.
Menstrual cycle and endocrine changes — The typical menstrual cycle and hormonal changes that women experience as they traverse from the premenopausal or reproductive years through the postmenopausal years include the following (figure 2):
Late reproductive years — In the late reproductive years before the onset of the menopausal transition, serum inhibin B begins to decrease , serum FSH increases slightly, estradiol levels are preserved, but luteal phase progesterone levels decrease as fertility potential begins to decline (figure 3). Menstrual cycles are ovulatory, but the follicular phase (the first half of the menstrual cycle before ovulation occurs) begins to shorten (eg, 10 versus 14 days) (figure 4) . Women who are having difficulty conceiving often seek advice about their menopausal status during this stage. Although there is variability in age at any given stage of reproductive aging, women are typically in their 40s when cycles begin to shorten. (See "Evaluation of female infertility", section on 'Assessment of ovarian reserve'.)
Menopausal transition/perimenopause — As the process of ovarian follicular depletion continues in midlife (figure 1), women eventually experience a change in intermenstrual interval. The change in bleeding pattern, which is accompanied by hormonal fluctuations and a variety of symptoms, is referred to as the menopausal transition (MT), or perimenopause, and occurs on average at age 47 years .
Women typically first notice a lengthening in the intermenstrual interval (in contrast to the shortening that occurs in the late reproductive years). Normal intermenstrual interval during the reproductive years is 25 to 35 days; during the menopausal transition, this may increase to 40 to 50 days. Early follicular phase FSH levels are high but variable (figure 5). The initial stage of the MT is referred to as the “early transition” in the STRAW staging system, which is described below (figure 2). (See 'The STRAW staging system' below.)
After the initial lengthening of intermenstrual interval, women then develop more dramatic menstrual cycle changes with skipped cycles, episodes of amenorrhea, and an increasing frequency of anovulatory cycles (figure 5). This stage is referred to as the “late transition” in the STRAW staging system, and typically lasts for one to three years before the final menstrual period (FMP) (figure 2) . (See 'The STRAW staging system' below.) Of note, not all women follow a “typical” bleeding pattern. Some will have episodes of amenorrhea interspersed with short ovulatory cycles that resemble those of the late reproductive stage.
The more irregular cycles are accompanied by more dramatic fluctuations in serum FSH and estradiol concentrations (figure 5). A random serum sample may demonstrate high FSH and low estradiol concentrations consistent with menopause, but soon thereafter FSH and estradiol may return to the normal premenopausal range (figure 5) . One study reported that a random serum FSH >25 IU/L is characteristic of the late menopausal transition , but measurements of serum FSH during the late MT are not routinely recommended because of their variability. (See 'Evaluation' below.)
Other endocrine changes across the menopausal transition include a progressive decrease in serum inhibin B, as well as a decrease in antimüllerian hormone (AMH), another product of the granulosa cell. In addition, ovarian antral follicle count (AFC), defined as follicles measuring 2 to 10 mm in diameter on transvaginal ultrasound, declines steadily from the reproductive years though postmenopause. Inhibin B, AMH, and AFC have all been used to assess ovarian reserve in the setting of assisted reproductive techniques, but none are validated for the evaluation of menopausal status . (See "Evaluation of female infertility", section on 'Assessment of ovarian reserve'.)
In general, the transition is characterized by a gradual decrease in menstrual bleeding . However, some women do experience heavy or prolonged bleeding, which has always been assumed to be due to anovulatory cycles and prolonged exposure to unopposed estrogen. However, in one report, the heaviest bleeding occurred in women in the late transition during ovulatory cycles, which were more likely than anovulatory cycles to be associated with high serum estradiol concentrations . Women with obesity and uterine fibroids are also more likely to experience heavy bleeding . The evaluation and management of heavy (>80 mL) and prolonged bleeding (>7 days) is reviewed separately. (See "Chronic menorrhagia or anovulatory uterine bleeding", section on 'Menopausal transition'.)
Menopause — After the years of menstrual irregularity, women eventually experience permanent cessation of menses. Twelve months of amenorrhea is considered to represent clinical menopause and is termed “postmenopause” in the STRAW system. The final menstrual period (FMP) is determined retrospectively. Although the median age at natural menopause is 51.4 years, the timing of menopause is affected by a number of factors including genetics and smoking, which are reviewed separately. (See "Ovarian development and failure (menopause) in normal women", section on 'Epidemiology'.)
The increase in serum FSH becomes sustained near the final menstrual period, then increases over several years to levels in the 70 to 100 IU/L range, followed by a decline with increasing age [35,36].
There are no validated predictors of the final menstrual period. Women who have experienced at least three months of amenorrhea are highly likely (about 95 percent) to become postmenopausal within the next four years . Other factors associated with a shorter time to FMP included older age, current smoking, higher serum FSH concentration, and more variable menstrual cycles .
Symptoms — The hallmark symptom of the menopausal transition/perimenopause and early postmenopausal years is the hot flash. Women may experience a number of other symptoms whose association with the menopausal transition is well established, including vaginal dryness, sleep disturbances, and new-onset depression . For other symptoms such as joint pain and memory loss, the association with menopause is less clear.
Hot flashes — The most common symptom during the menopausal transition and menopause are hot flashes (also referred to as vasomotor symptoms or hot flushes), which occur in up to 80 percent of women in some cultures [21,37-39]. However, only about 20 to 30 percent of women seek medical attention for treatment [22,40,41]. Some women first develop hot flashes that cluster around menses during their late reproductive years, but symptoms are typically mild and do not require treatment. Symptoms become far more common during the menopausal transition, with a frequency of approximately 40 percent in the early transition, increasing to 60 to 80 percent in the late menopausal transition and early postmenopausal periods (figure 2) [22,23,32,38,42]. When hot flashes occur at night, women typically describe them as “night sweats.”
Hot flashes typically begin as the sudden sensation of heat centered on the upper chest and face that rapidly becomes generalized. The sensation of heat lasts from two to four minutes, is often associated with profuse perspiration and occasionally palpitations, and is sometimes followed by chills and shivering, and a feeling of anxiety. Hot flashes usually occur several times per day, although the range may be from only one or two each day to as many as one per hour during the day and night. Hot flashes are particularly common at night. (See "Menopausal hot flashes".)
More than 80 percent of women who have hot flashes will continue to have them for more than one year. Untreated, hot flashes stop spontaneously within four to five years of onset in most women. However, some women have hot flashes that persist for many years, with 9 percent reporting persistent symptoms after age 70 years.
A more detailed discussion of the pathophysiology, risk factors for, and treatment of hot flashes is found elsewhere. (See "Menopausal hot flashes".)
Sleep disturbance — A distressing feature of hot flashes is that they are more common at night than during the day and are associated with arousal from sleep. However, women experience sleep disturbances even in the absence of hot flashes. The estimated prevalence of difficulty sleeping based upon two longitudinal cohort studies was 32 to 40 percent in the early menopausal transition, increasing to 38 to 46 percent in the late transition [39,43]. Menopausal sleep disturbances are discussed in more detail elsewhere. (See "Menopausal hot flashes".)
Depression — A number of reports indicate that there is a significant increased risk of new onset depression in women during the menopausal transition compared with their premenopausal years [24,44-50]. The risk then decreases in the early postmenopause. In a within-woman eight-year longitudinal study to determine risk factors for depressive disorders, a diagnosis of depression was 2.5 times more likely to occur in the menopausal transition compared with when the woman was premenopausal (OR 2.50; 95% CI 1.25-5.02) .
The role of estrogen in the treatment of depression in perimenopausal women is discussed separately. (See "Initial treatment of depression in adults" and "Treatment of menopausal symptoms with hormone therapy".)
Vaginal dryness — The epithelial lining of the vagina and urethra are estrogen-dependent tissues, and estrogen deficiency leads to thinning of the vaginal epithelium. This results in vaginal atrophy (atrophic vaginitis), causing symptoms of vaginal dryness, itching, and often dyspareunia. The prevalence of vaginal dryness in one longitudinal study was 3, 4, 21, and 47 percent of women in the reproductive, early menopausal transition, late menopausal transition, and three years postmenopausal stages, respectively [37,39]. Symptoms of vaginal atrophy are usually progressive and worsen as time passes and hypoestrogenism continues.
Early in the menopause transition, women may notice a slight decrease in vaginal lubrication upon sexual arousal, which is often one of the first signs of estrogen insufficiency. As the hypoestrogenic state becomes chronic, additional symptoms may be reported by the woman, including a sensation of vaginal dryness during daily activities, not necessarily during sexual activity. (See "Clinical manifestations and diagnosis of vaginal atrophy", section on 'Epidemiology'.)
On exam, the vagina typically appears pale, with lack of the normal rugae. The external genitalia may show scarce pubic hair, diminished elasticity and turgor of the vulvar skin, introital narrowing or decreased moisture, and fusion or resorption of the labia minora. (See "Clinical manifestations and diagnosis of vaginal atrophy".)
Sexual function — Estrogen deficiency leads to a decrease in blood flow to the vagina and vulva. This decrease is a major cause of decreased vaginal lubrication and sexual dysfunction in menopausal women . Vaginal dryness and dyspareunia, as described above, may also contribute to reduced sexual function. The cervix also can atrophy and become flush with the top of the vaginal vault. The elasticity of the vaginal wall may decrease and the entire vagina can become shorter or narrower. Continuing sexual activity may prevent these changes in size and shape of the vagina, even in the absence of estrogen therapy . (See "Approach to the woman with sexual pain" and "Sexual dysfunction in women: Epidemiology, risk factors, and evaluation".)
Symptoms related to genitourinary atrophy are exquisitely responsive to estrogen therapy, in particular, vaginal estrogen therapy. (See "Preparations for postmenopausal hormone therapy", section on 'Vaginal estrogen for vaginal atrophy'.)
Cognitive changes — Women often describe problems with memory loss and difficulty concentrating during the menopausal transition and menopause, and substantial biologic evidence supports the importance of estrogen to cognitive function. A decline in cognitive function was not observed in the SWAN study, but increases in anxiety and depression had independent, unfavorable effects on cognitive performance . (See "Estrogen and cognitive function".)
Joint pain — Although the prevalence is not known, some women experience diffuse joint pain during the menopausal transition and postmenopausal period [53,54]. It is unclear if this is related to estrogen deficiency or a rheumatologic disorder, but in the Women's Health Initiative, women with joint pain or stiffness at baseline were more likely to get relief with combined estrogen-progestin therapy than with placebo . However, another study reported that neuromuscular symptoms (backache/joint pain) were stable across the menopausal transition, suggesting that an underlying medical condition was the cause of the symptoms, not the hormonal changes associated with the menopausal transition .
Long-term consequences of estrogen deficiency — Ovarian estradiol production and secretion decreases and stops altogether after menopause as a result of ovarian follicular depletion. However, the ovary continues to secrete testosterone. (See "Androgen production and therapy in women", section on 'Effect of age and menopause'.) There are a number of long-term effects of estrogen deficiency, including osteoporosis, cardiovascular disease, and dementia. Each of these is discussed in detail separately.
Bone loss — Bone loss begins during the menopausal transition. The annual rates of bone mineral density loss appear to be highest during the one year before through two years after the final menstrual period. This issue and postmenopausal osteoporosis are discussed separately. (See "Epidemiology and etiology of premenopausal osteoporosis", section on 'Perimenopausal bone loss' and "Overview of the management of osteoporosis in postmenopausal women".)
Cardiovascular disease — The risk of cardiovascular disease increases after menopause, thought to be at least in part due to estrogen deficiency. This may be mediated in part by changes in lipid profiles during perimenopause, as illustrated by longitudinal data from over 2500 subjects in the Study of Women’s Health Across the Nation (SWAN) . After adjusting for subject age, there was a small increase in serum LDL during the menopausal transition (a 6 percent increase in mean LDL from 116 mg/dL in the premenopausal years to 123 mg/dL in the early postmenopausal years). There was no change in serum HDL, but data from a later SWAN ancillary study suggested that the protective effect of HDL may decrease as women transition to menopause . (See "Determinants and management of cardiovascular risk in women", section on 'Menopause'.)
Dementia — There is limited epidemiologic support for the hypothesis that estrogen preserves overall cognitive function in non-demented women. However, in the Women’s Health Initiative, both unopposed estrogen and combined estrogen-progestin therapy had no global cognitive benefits in older, non-demented postmenopausal women. (See "Estrogen and cognitive function", section on 'Epidemiologic evidence'.)
Degenerative arthritis — Estrogen deficiency after menopause may contribute to the development of osteoarthritis, but data are limited. (See "Pathogenesis of osteoarthritis", section on 'Sex hormones'.)
Body composition — In the early postmenopausal years, women who do not take estrogen therapy typically gain fat mass and lose lean mass. Some, but not all, studies, suggest that postmenopausal hormone therapy is associated with a decrease in central fat distribution. Although women typically gain weight during midlife, it does not appear to be due to menopausal status or stage . (See "Postmenopausal hormone therapy: Benefits and risks", section on 'Weight'.)
Skin changes — The collagen content of the skin and bones is reduced by estrogen deficiency. Decreased cutaneous collagen may lead to increased aging and wrinkling of the skin. Limited data suggest that collagen changes may be minimized with estrogen. (See "Postmenopausal hormone therapy: Benefits and risks", section on 'Skin'.)
Balance — Impaired balance in postmenopausal women may be a central effect of estrogen deficiency. Problems with balance may play a role in the incidence of forearm fractures in women. The role of estrogen therapy on falls is discussed elsewhere. (See "Postmenopausal hormone therapy: Benefits and risks", section on 'Falls'.)
EVALUATION — In our experience, among women who present at midlife for evaluation of possible menopausal transition or menopause, many are interested in postmenopausal hormone therapy, while others simply want to know what to expect in the coming years: bleeding patterns, symptoms, or potential long-term consequences of estrogen deficiency (eg, osteoporosis, coronary heart disease, or dementia).
The STRAW staging system — As noted above, the STRAW staging system was developed based upon data from multiple longitudinal cohort studies . It is considered the gold standard for characterizing reproductive aging from the reproductive years through menopause and includes criteria for the reproductive years, the menopausal transition, perimenopause, final menstrual period (FMP), and postmenopause based upon bleeding patterns, endocrine findings, and symptoms (figure 2). The menopausal transition (MT) and postmenopause are further subdivided into “early” and “late” stages.
Although the STRAW system has been used primarily for women’s health research, it may be helpful in the clinical setting for patients and clinicians to assess fertility potential, contraceptive needs, and potential need for hormone therapy. We find the bleeding and symptom criteria of STRAW to be useful when counseling patients about what to anticipate in the coming years (figure 2).
Of note, the STRAW staging criteria are not considered to represent diagnostic criteria for the MT or menopause, primarily because they include endocrine data (FSH, inhibin B, antimüllerian hormone) and pelvic ultrasound (antral follicle count) as supportive criteria when determining reproductive stage. All four criteria have been used to assess ovarian reserve in the setting of assisted reproductive technologies, but none have been validated for use in the evaluation of menopausal status. (See "Evaluation of female infertility", section on 'Assessment of ovarian reserve' and "In vitro fertilization", section on 'Adequate ovarian reserve'.)
General approach — The evaluation for women of all ages should start with an assessment of the woman’s menstrual cycle history (ideally with a menstrual calendar), and a detailed history of any menopausal symptoms (hot flashes, sleep disturbances, depression, vaginal dryness). All women with symptoms of vaginal dryness, dyspareunia, or sexual dysfunction should have a pelvic exam to evaluate for vaginal atrophy.
Women over age 45 — Although the menopausal transition (MT) begins on average at age 47 years , the age at onset of MT is variable, and women over age 45 who present with characteristic menopausal signs and symptoms are more likely to be in the menopausal transition than to have a new endocrine disorder. Therefore, for women over age 45 years who present with irregular menstrual cycles with menopausal symptoms such as hot flashes, mood changes, or sleep disturbance, we suggest no further diagnostic evaluation, as they are highly likely to be in the menopausal transition.
Although serum FSH is often measured, it is not necessary to make the diagnosis and, if normal, may be misleading. In the SWAN longitudinal cohort study described above, changes in menstrual bleeding patterns were a better predictor of menopausal stage or final menstrual period than serum FSH concentrations .
The possibility of pregnancy must always be considered and a serum hCG should be drawn in sexually active women who are not using reliable contraception.
We recommend additional endocrine testing (eg, prolactin and TSH) in this group if there are any suggestive features of hyperprolactinemia or thyroid disease (galactorrhea, goiter, tachycardia, proptosis, etc). (See "Clinical manifestations and diagnosis of hyperprolactinemia" and "Overview of the clinical manifestations of hyperthyroidism in adults" and "Clinical manifestations of hypothyroidism".)
For the occasional woman with irregular cycles and no other symptoms suggestive of the menopausal transition, we suggest the same approach. However, for asymptomatic women who want reassurance that their irregular periods are due to the menopausal transition, if they are having intervals of amenorrhea of ≥60 days (eg, in the “late transition”), a serum FSH >25 IU/L would be reassuring in this instance that this is simply the MT and nothing else . Of note, serum FSH concentrations vary widely during the transition, so a value in the normal premenopausal range does not rule out perimenopause as the cause of her symptoms. (See 'Menopausal transition/perimenopause' above.)
Ages 40 to 45 — For women between 40 and 45 years who present with irregular menstrual cycles, with or without menopausal symptoms, we suggest the same endocrine evaluation as for any woman with oligo/amenorrhea. This would include lab testing to exclude the following:
Although the presence of hot flashes with irregular menses strongly suggests the menopausal transition, we prefer to err on the side of caution and look for other possible causes of oligo/amenorrhea. (See "Etiology, diagnosis, and treatment of secondary amenorrhea", section on 'Diagnosis'.)
Under age 40 — For women under age 40 with irregular menses and menopausal symptoms, we suggest a complete evaluation for irregular menses. If primary ovarian insufficiency (premature ovarian failure) is confirmed, further evaluation for this disorder should be performed. (See "Etiology, diagnosis, and treatment of secondary amenorrhea", section on 'Diagnosis' and "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
Atypical hot flashes — For women of any age with atypical hot flashes or night sweats, evaluation for other disorders such as carcinoid, pheochromocytoma, or underlying malignancy is indicated. This issue is discussed in detail elsewhere. (See 'Hot flashes' above and "Approach to the patient with night sweats".)
Heavy bleeding — Women with heavy (>80 mL) or prolonged (>7 days) bleeding should undergo the same evaluation as any premenopausal woman, eg, a pregnancy test, determine if the bleeding is ovulatory or anovulatory, rule out structural abnormalities with pelvic ultrasound, and perform an endometrial biopsy if indicated. This issue is reviewed in detail separately. (See "Chronic menorrhagia or anovulatory uterine bleeding", section on 'Menopausal transition'.)
In normal, healthy women over age 45 years:
In women between the ages of 40 and 45 years:
For women under age 40 years:
Women with underlying menstrual cycle disorders — The diagnosis of menopausal transition is more difficult, and the STRAW staging system does not apply to women with underlying menstrual disorders such as polycystic ovary syndrome (PCOS) or hypothalamic amenorrhea. Little information is available about menstrual cycle and endocrine changes in either disorder, but some data suggest that women with PCOS may develop more regular cycles in their later reproductive years, for reasons that are unclear [58,59]. For women with either diagnosis who develop menopausal symptoms, we suggest measuring FSH concentration for diagnostic purposes.
Women taking oral contraceptives — Oral estrogen-progestin contraceptives are considered to be safe in nonsmokers up to the age of menopause (average age 50 to 51 years) . Women taking them want reassurance that they are postmenopausal before stopping. However, it is difficult to determine if menopause has occurred because these women do not develop the irregular bleeding or vasomotor symptoms that are typical of the menopausal transition. In addition, because their hypothalamic-pituitary axis is suppressed by the high dose of exogenous estrogen, measurement of the serum FSH level is unreliable. Some clinicians measure serum FSH concentration on the 7th day of the pill-free interval, but we do not suggest this approach, because FSH is typically still suppressed and in the premenopausal range.
We suggest stopping the pill and measuring serum FSH two to four weeks later. A level ≥25 IU/L indicates that the patient has likely entered the menopausal transition. However, there is no FSH value that would provide absolute reassurance that she is postmenopausal. We typically stop the pill by age 50 to 51 years, when the chance of conceiving is extremely low. If menopausal symptoms occur, the possibility of short-term menopausal hormone therapy for symptom relief can be discussed. (See "Treatment of menopausal symptoms with hormone therapy" and "Overview of contraception", section on 'When is it safe to stop using hormonal contraception?'.)
Post-hysterectomy or endometrial ablation — Menopause in women who have undergone hysterectomy or endometrial ablation cannot be determined using menstrual bleeding criteria. Therefore, supportive criteria, including assessment of menopausal symptoms and biochemical data are needed. In this setting, we suggest measurement of FSH concentrations (figure 5). A serum FSH >25 IU/L, particularly in the setting of hot flashes, is suggestive of the late menopausal transition . For a postmenopausal woman, FSH would be considerably higher (in the 70 to 100 IU/L range) .
DIFFERENTIAL DIAGNOSIS — Hyperthyroidism should always be considered in the differential diagnosis, as irregular menses, sweats (although different from typical hot flashes), and mood changes are all potential clinical manifestations of hyperthyroidism . (See "Overview of the clinical manifestations of hyperthyroidism in adults".)
Other etiologies for menstrual cycle changes that should be considered include pregnancy, hyperprolactinemia, and thyroid disease. (See "Etiology, diagnosis, and treatment of secondary amenorrhea", section on 'Diagnosis'.)
Atypical hot flashes and night sweats may be due to other disorders, such as medications, carcinoid, pheochromocytoma, or underlying malignancy. These are discussed in detail elsewhere. (See 'Hot flashes' above and "Approach to the patient with night sweats".)
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