The menopausal transition

Transcription

1 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 Steril Ò 2008;90:S61 5. Ó2008 by American Society for Reproductive 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 perimenopause, which literally means about or around the menopause, 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 consensus conference, further classifies reproductive and postreproductive 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 follow (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 subdivides the early MT (3). In the early MT (stage 2), previously regular menstrual cycles become more variable and cycle length (intermenstrual 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). Menopause 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 previously was thought to decline progressively in a linear fashion, Committee Opinion Revised January No reprints will be available. 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 decrease 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 midreproductive 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 an a subunit and one of two different b subunits, designated as b A and b B ; 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. Consequently, 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 that stimulate pituitary FSH release and derive from the combination of two inhibin b subunits. The activin molecule is a homodimer composed of two covalently linked inhibin b subunits, designated as activin A (b A b A) and activin B (b B b B ). Antim ullerian hormone (AMH) is secreted by the granulosa 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, /08/$34.00 Fertility and Sterility â Vol. 90, Suppl 3, November 2008 S61 doi: /j.fertnstert Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 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. Stage þ1a: the first year after the final menstrual period. Stage þ1b: years 2 to 5 after menopause. Stage þ2: the later postmenopausal years. Recommendations of Stages of Reproductive Aging Workshop (STRAW), Park City, Utah, July (Reprinted with permission from the American Society for Reproductive Medicine. Fertility and Sterility, 2001, Vol. 76, No. 5, page 875). ASRM Practice Committee. Menopausal Transition. Fertil Steril their ability to act as endocrine factors to influence the production 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 associated 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 future 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 because 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 symptomatic 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, particularly once menses become irregular and unpredictable. Because the time interval surrounding menopause is characterized by relatively high, acyclic estrogen levels and relatively low progesterone production, women in the MT are at some increased risk for developing endometrial hyperplasia or carcinoma. Among premenopausal women over age 45 with abnormal uterine bleeding, the risk for endometrial hyperplasia or cancer is increased three-fold (OR 3.1; 95% CI, ) 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, provided the patient does not smoke and has no other contraindications. Although still frequently prescribed, a systematic review concluded that cyclic administration of medroxyprogesterone acetate is ineffective for the treatment for bleeding during the menopausal transition (23). A progestin-containing 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 associated 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 S62 ASRM Practice Committee Menopausal Transition Vol. 90, Suppl 3, November 2008

3 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 associated with low exercise levels, smoking, high FSH and low estradiol levels (29), increasing body mass, ethnicity, socioeconomic 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 perimenopausal women report significantly more psychological distress 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, , P¼.01) (33). Sleep disturbances also are very common during the MT. In longitudinal studies of perimenopausal women, the prevalence 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 compared with 30% of women receiving placebo (37). Hormone therapy also may help in the management of depression associated 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 thromboembolism, 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 equivalent) can achieve as much as a 75% reduction in vasomotor symptoms over 12 weeks, approaching the efficacy of standard-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 thoroughly investigated. The results of one observational study Fertility and Sterility â 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, ) or in combination with progestin (RR ¼ 0.72; 95% CI, ) (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 evaluate the safety and efficacy of HT during the MTand 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 â ; Enzymatic Therapy, Green Bay, WI) have been shown to have marginal or no benefit in placebo-controlled trials (37, 45). Neuroactive agents, including selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine 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 norepinephrine and serotonin appear to be involved in the TABLE 1 Nonhormonal alternatives for treatment of hot flashes. Class of drug Name Dose SSRI Citalopram Fluoxetine Sertraline Paroxetine SNRI Venlafaxine Desvenlafaxine Alphaadrenergic agents Gamma amino butyric acid succinate Clonidine 0.1 transdermally Gabapentin Note: These alternatives are not U.S. FDA approved for treatment of hot flashes. ASRM Practice Committee. Menopausal Transition. Fertil Steril S63

4 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). Clonidine (an alpha adrenergic agonist) and gabapentin also have some efficacy (46, 47). However, the effectiveness of neuroactive therapies does not equal that of HT. Given that the onset of menopause cannot be predicted precisely, 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 menstrual period varies in length, is characterized by variations in cycle length, and commonly is associated with frequent or excessive bleeding and hot flashes. The treatment of women during the menopausal transition should be based primarily on the frequency and severity of their symptoms. Hormone measurements during the menopausal transition are imprecise and cannot predict menopause. After a diagnostic evaluation has been completed, medical treatment of abnormal uterine bleeding during the menopausal transition may include the use of lowdose combination oral contraceptives, estrogens/progestogens, and progestin-containing IUDs. Overall, HT remains the most effective treatment for hot flashes. Acknowledgments: This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. 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