The menopausal transition
Practice Committee of the American Society for Reproductive Medicine
The American Society for Reproductive Medicine, Birmingham, Alabama
This Committee Opinion outlines the stages of the menopausal transition, as defined by the July 2001 Stages of Reproductive Aging Workshop (STRAW). (Fertil Steril2008;90:S61–5.2008 by American Society for Repro-ductive Medicine.)
DEFINITIONS
As defined by the Stages of Reproductive Aging Workshop (STRAW) held in July 2001, the menopausal transition (MT) begins with variations in menstrual cycle length and a monotropic rise in follicle-stimulating hormone (FSH; no associated increase in luteinizing hormone [LH]), and ends with the final menstrual period, classically confirmed only when followed by 12 months of amenorrhea(1). The perime-nopause, which literally means ‘‘about or around the meno-pause,’’ begins at the same time as the MT and ends 1 year after the final menstrual period (Fig. 1). The median age at the final menstrual period is 51.4 years(2).
The STRAW report, based on the proceedings of a consen-sus conference, further classifies reproductive and postrepro-ductive life into seven stages, with the MT accounting for two of those stages(1). The anchor for the staging system is the final menstrual period, and the age range and duration for each of the stages varies. Five stages precede (–), and two fol-low (þ), the final menstrual period. A modified menopausal staging system (PENN-5) has attempted to refine the STRAW staging system by adding an eighth stage that further subdi-vides the early MT(3).
In the early MT (stage –2), previously regular menstrual cycles become more variable and cycle length (intermenst-rual interval) changes by 7 days or more. The late MT (stage –1) is characterized by two or more missed menstrual periods, at least one intermenstrual interval of 60 days or more, and an FSH level greater than 40 IU/L (4). Meno-pause is determined in retrospect after a year of amenorrhea
(1, 5). For women with at least one intermenstrual interval of 60 days or more, the median time to menopause is 2.6 to 3.3 years (6). For women over the age of 45 having a year of amenorrhea, there is a 90% probability that they will not have another spontaneous menstrual period (7). Cigarette smoking may alter the ovarian aging process and advances the age of menopause by as much as 2 years (8).
ENDOCRINE CHANGES IN THE MENOPAUSAL TRANSITION
Secretion of reproductive hormones during the MT previ-ously was thought to decline progressively in a linear fashion,
but hormone levels have since been shown to fluctuate widely. Studies in large cohorts of women have demonstrated that circulating FSH concentrations rise progressively during the MT(9–11). The monotropic rise in FSH is attributed to a decrease in ovarian inhibin secretion rather than to a de-crease in estradiol production (11–13). In perimenopausal women, estradiol production fluctuates with FSH levels and can reach higher concentrations than those observed in young women under age 35(14, 15). Estradiol levels generally do not decrease significantly until late in the MT (15, 16). Despite continuing regular cyclic menstruation, progesterone levels during the early MT are lower than in women of mid-reproductive age and vary inversely with body mass index
(11). Women in the late MT exhibit impaired folliculogenesis and an increasing incidence of anovulation, compared to midreproductive-aged women (13). Testosterone levels do not vary appreciably during the MT(10).
Inhibin and activin are proteins produced by the granulosa cells and have been shown to play major roles during the MT. The inhibin molecule consists of a covalently-bound dimer having anasubunit and one of two differentbsubunits, des-ignated asbAandbB; the resulting heterodimers are known as
inhibin A and inhibin B. Inhibin A is secreted by the corpus luteum and inhibin B by antral and dominant follicles. Con-sequently, inhibin A levels increase during the luteal phase, and inhibin B concentrations rise during the follicular phase. Both inhibins inhibit pituitary FSH secretion. Activins are a related class of proteins thatstimulatepituitary FSH release and derive from the combination of two inhibinbsubunits. The activin molecule is a homodimer composed of two cova-lently linked inhibin b subunits, designated as activin A (bAbA)and activin B (bBbB).
Antim€ullerian hormone (AMH) is secreted by the granu-losa cells of secondary and preantral follicles. Circulating concentrations remain relatively stable across the menstrual cycle and correlate with the number of early antral follicles. Levels of AMH decrease markedly and progressively across the MT(17).
During the late reproductive stage (stage –3), follicular phase inhibin B levels decrease as FSH concentrations rise
(9, 12, 18). As the MT progresses, luteal phase inhibin A levels also decline (13). Activin A concentrations also are elevated in perimenopausal women(19, 20). Whereas activins clearly play a local role in regulating pituitary FSH secretion, Committee Opinion
Revised January 2008.
No reprints will be available.
their ability to act as endocrine factors to influence the pro-duction of FSH has not been established. Thus, a decrease in secretion of inhibin A and inhibin B, and a corresponding increase in activin production may favor increased FSH secretion in the absence of any decrease (and perhaps an increase) in estradiol production.
HORMONAL TESTING FOR EVIDENCE OF MENOPAUSAL TRANSITION
Diagnosis of the MT is based on clinical signs and symptoms. Although hormonal changes occur during the MT, hormone measurements are not useful for predicting the stage of MT or the final menstrual period. The monotropic rise in FSH as-sociated with menopause becomes evident during the early follicular phase of the menstrual cycle in many women over age 40 and has been associated with a poor prognosis for fu-ture fertility(21). However, FSH levels can vary significantly across cycles, and the utility of FSH levels for predicting menopause in individual women is therefore low (4, 14). Symptoms similar to those associated with the MT may be observed in numerous other disorders. Specific evaluation to exclude hypothyroidism or depression may be warranted be-cause these common conditions often emerge during the MT.
MANAGEMENT AND TREATMENT OF SYMPTOMS DURING THE MENOPAUSAL TRANSITION
Much of the available information about the MT derives from the ongoing Study of Women’s Health Across the Nation (SWAN), a multiethnic, community-based, longitudinal study
of perimenopausal women at seven sites throughout the United States(4, 6, 10, 11). Most women who are symptom-atic during the MT present with frequent or excessive bleeding or with hot flashes and other symptoms of estrogen deficiency. Abnormal uterine bleeding is common during the MT, par-ticularly once menses become irregular and unpredictable. Because the time interval surrounding menopause is charac-terized by relatively high, acyclic estrogen levels and rela-tively low progesterone production, women in the MT are at some increased risk for developing endometrial hyperpla-sia or carcinoma. Among premenopausal women over age 45 with abnormal uterine bleeding, the risk for endometrial hy-perplasia or cancer is increased three-fold (OR 3.1; 95% CI, 1.5–6.1) and the overall prevalence is 7.9% (22 cases out of 280 patients) (22). Abnormal bleeding may be controlled effectively with combination oral contraceptive pills, pro-vided the patient does not smoke and has no other contrain-dications. Although still frequently prescribed, a systematic review concluded that cyclic administration of medroxypro-gesterone acetate is ineffective for the treatment for bleeding during the menopausal transition(23). A progestin-contain-ing intrauterine device (IUD) is another option that offers both control over bleeding and contraception (24), but its use is not approved for this indication by the U.S. Food and Drug Administration (FDA).
Changes in hormone secretion during the MT are associ-ated with a number of symptoms, the most common being hot flashes. The prevalence of hot flashes increases as the MT progresses and reaches a high of about 63% during the
FIGURE 1
Stages/nomenclature of normal reproductive aging in women. The stages of reproductive aging in women in relation to the final menstrual period, defined as Stage 0. Stage –5: the early reproductive stage. Stage –4: the peak reproductive stage. Stage –3: the late reproductive stage. Stage –2: the early menopausal transition. Stage –1: the late menopausal transition. Stageþ1a: the first year after the final menstrual period. Stageþ1b: years 2 to 5 after menopause. Stageþ2: the later postmenopausal years. Recommendations of Stages of Reproductive Aging Workshop (STRAW), Park City, Utah, July 2001. (Reprinted with permission from the American Society for Reproductive Medicine.Fertility and Sterility,2001, Vol. 76, No. 5, page 875).
late menopausal transition (25–27). Vasomotor symptoms before or at the onset of the MT are common, affecting up to 39% of women, but they are usually well tolerated (28). Longitudinal studies have shown that hot flashes are associ-ated with low exercise levels, smoking, high FSH and low estradiol levels(29), increasing body mass, ethnicity, socio-economic status, and a history of premenstrual dysphoric disorder (PMDD) or depression(30).
Depressed mood disorders also are increased during the MT. Community-based surveys have shown that perimeno-pausal women report significantly more psychological dis-tress and have an increased risk for significant depression, compared with premenopausal or postmenopausal women
(31, 32). In an 8-year longitudinal study of premenopausal women having no prior history of depression, a depressive disorder was more likely to be diagnosed during the MT than in the premenopausal years (OR, 2.5; 95% CI, 1.25– 5.02,P¼.01)(33).
Sleep disturbances also are very common during the MT. In longitudinal studies of perimenopausal women, the preva-lence of sleep disturbances has ranged from 32% to 40% in
the early MT and from 38% to 46% in the late MT (27,
34). Other common symptoms during the MT include
decreased libido, forgetfulness, vaginal dryness, and urinary incontinence(35, 36).
Vasomotor symptoms during the MT can be treated with hormone therapy (HT) using estrogen or progestin alone or in combination, neuroactive agents, or other nonhormonal alternatives. Estrogen therapy provides the best treatment for severe vasomotor symptoms, reducing their frequency and severity in 80% to 85% of women over 12 weeks com-pared with 30% of women receiving placebo(37). Hormone therapy also may help in the management of depression asso-ciated with the MT. In a randomized, placebo-controlled, 12-week trial involving perimenopausal women ages 40 to 55, symptoms of depression were improved in 68% of women receiving unopposed estrogen treatment (0.1 mg transdermal estradiol patch), compared with 20% of those receiving placebo (P¼.001)(38).
Long-term use of HT in older menopausal women has been associated with increased risks for venous thrombo-embolism, coronary events, stroke, and breast cancer (39, 40). Although short-term treatment of symptomatic women during the MT likely poses significantly fewer risks, HT generally should be used in the lowest effective dose and for the shortest time required. Low-dose estrogen regimens (conjugated equine estrogens, 0.3 mg daily, or its equiva-lent) can achieve as much as a 75% reduction in vasomotor symptoms over 12 weeks, approaching the efficacy of stan-dard-dose HT regimens, and may be associated with fewer risks and side effects (41). The decision to use HT should be made only after first carefully reviewing its risks and benefits for the individual.
The relative safety of HT during the MT has not been thor-oughly investigated. The results of one observational study
have suggested that women who start HT near menopause had a decreased risk of coronary heart disease when taking estrogen alone (relative risk [RR] ¼ 0.66; 95% CI, 0.54– 0.80) or in combination with progestin (RR ¼0.72; 95% CI, 0.56–0.92)(42). A secondary analysis conducted by the investigators involved in the Women’s Health Initiative (WHI) revealed that risk for coronary heart disease was not significantly increased in women under age 60 years of age or within 10 years of menopause(43). Further studies to eval-uate the safety and efficacy of HT during the MT and the early postmenopausal years are ongoing(44).
Concerns about the risks of HT have increased interest in nonhormonal alternatives for the treatment of symptoms in the MT. In some women, vasomotor symptoms during the MT can be reduced by wearing layered clothing, avoiding caffeine and alcohol, and by keeping the ambient temperature a few degrees cooler. Herbal treatments such as black cohosh (Remifemin Menopause; Enzymatic Therapy, Green Bay, WI) have been shown to have marginal or no benefit in pla-cebo-controlled trials(37, 45). Neuroactive agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), alpha adrenergic agents, and others all have some efficacy in the treatment of vasomotor symptoms (Table 1).
Both SSRIs and SNRIs may be effective because norepi-nephrine and serotonin appear to be involved in the
TABLE 1
Nonhormonal alternatives for treatment of hot flashes.
Class of
drug Name Dose
SSRI Citalopram 10–20 mg/day Fluoxetine 10–20 mg/day Sertraline 25–50 mg/day Paroxetine 10–20 mg/day SNRI Venlafaxine 37.5–150.0 mg/day Desvenlafaxine succinate 50–100 mg/day Alpha-adrenergic agents Clonidine 0.1 mg/day transdermally Gamma amino butyric acid Gabapentin 300–900 mg/day Note:These alternatives are not U.S. FDA approved for
treatment of hot flashes.
hypothalamic regulation of temperature homeostasis and to play a role in the development of hot flashes. Randomized placebo-controlled trials have shown that SSRIs (citalopram, sertraline, paroxetine) and SSNIs (venlafaxine) can help to reduce the severity and frequency of hot flushes(46, 47). Clo-nidine (an alpha adrenergic agonist) and gabapentin also have some efficacy(46, 47). However, the effectiveness of neuro-active therapies does not equal that of HT.
Given that the onset of menopause cannot be predicted pre-cisely, that women may ovulate up until their final menses, and that prescription drugs and alternative therapies may have potential adverse effects on pregnancy, clinicians should remain sensitive to the contraceptive needs of women during the MT.
SUMMARY AND CONCLUSIONS
The menopausal transition that precedes the final men-strual period varies in length, is characterized by varia-tions in cycle length, and commonly is associated with frequent or excessive bleeding and hot flashes.
The treatment of women during the menopausal transi-tion should be based primarily on the frequency and severity of their symptoms.
Hormone measurements during the menopausal transi-tion are imprecise and cannot predict menopause.
After a diagnostic evaluation has been completed, med-ical treatment of abnormal uterine bleeding during the menopausal transition may include the use of low-dose combination oral contraceptives, estrogens/proges-togens, and progestin-containing IUDs.
Overall, HT remains the most effective treatment for hot flashes.
Acknowledgments:This report was developed under the direction of the Prac-tice Committee of the American Society for Reproductive Medicine as a ser-vice to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of man-agement may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. This committee opinion was accepted by the Practice Committee of the American Society for Reproductive Medicine and approved by the Board of Directors of the American Society for Reproductive Medicine. REFERENCES
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