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THE MENOPAUSE TRANSITION
MENOPAUSE AND HORMONE REPLACEMENT THERAPY
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THE MENOPAUSE TRANSITION Gail A. Greendale, MD, and MaryFran Sowers, MD
DEFINITIONS The definitions of menopause, postmenopause, and perimenopause used herein are those proposed by the World Health Organization in 1981.Il9 The menopause is defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. After 1 year of amenorrhea, the final menstrual period is retrospectively designated as the time of menopause. The postmenopause is defined as commencing from the time of the final menstrual period (menopause). Termination of ovarian function and menses is not an acute physiologic event. Rather, the physiologic antecedents associated with the transition from premenopausal to postmenopausal follicular function are believed to occur in the perimcnopause. The perimenopause comprises the period of time (2 to 8 years in duration) preceding the menopause and 1 year following the final menses. The term pcrimcnoynzrse is used interchangeably with the climacteric and is also often called the menopause transition. Figure 1 schematically summarizes these definitions and their timing related to menopause. As currently conceived, these categories of the female reproductive life span overlap (e.g., the last year of the perimenopause coincides with the first year of the postmenopause). This work was supported in part by the Iris-Cantor-UCLA Women’s Center and by grants NR.04061 and AR.40888.
From the Department of Obstetrics and Gynecology, Division of Geriatrics, UCLA School of Medicine, University of California at Los Angeles, Los Angeles, California (GAG); and Departments of Epidemiology and Obstetrics and Gynecology, School of Public Health, University of Michigan, Detroit, Michigan (MS)
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA
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VOLUME 26 NUMBER 2 JUNE 1997
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Premenopause
Menarche
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Menopause
Figure 1. Categories of the reproductive life span (pre-, peri-, and postmenopause). Idealized ages at menarche and menopause used for simplicity.
PHYSIOLOGY AND CHARACTERISTICS OF THE MENOPAUSAL TRANSITION
Inferred in the concept of the menopausal transition or perimenopause is a period of gradual transition during which the ovarian follicles and their associated hormonal feedback loops undergo a series of changes which can be distinguished from the normal follicular function of earlier reproductive life. However, the inceptions of the menopausal transition and its phases are neither well-defined nor universally agreed upon. One theoretical model based on available evidence is described in the next section and awaits further elucidation by ongoing studies of the menopause transition.
Early Perimenopause In the earliest phase of the menopause transition, cycle lengths may appear normal or slightly shortened while clinically imperceptible alterations in the systems controlling ovulation occur. In the decade before the final menses, cycle length shortening occurs as a result of a shortened follicular phase.5oLevels of follicle-stimulatinghormone (FSH) increase in comparison with those of younger w0men.4~* 57, 90 The increase in FSH can be interpreted as compensation for a decreased number of ovarian follicles67or a consequence of decreased secretion of ir~hibin.'~, 78 One recent study of a series of patients undergoing oophorectomy"' found that serum FSH and luteinizing hormone (LH) levels were inversely related to the presence of ovarian FSH and LH receptors,
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whereas in postmenopausal patients, no ovarian gonadotropin receptors were detectable. Middle Perimenopause
Middle perimenopause is defined as the time when an overtly altered menstrual cycle pattern occurs.63Classically, this transitional pattern is described as long intermenstrual intervals interspersed with very short cycles.1o5 Erratic maturation of the remaining ovarian follicles may be responsible for this transitional Some menstrual cycles may be ovulatory (i.e., characterized by a midcycle estrogen surge followed by luteal phase progesterone secretion), whereas others are anovulatory (i.e., a rise and fall of estrogen levels but no progesterone ~ecretion).~~ Physiologic characteristics of middle perimenopause cycles may include elevated early follicular phase FSH (>25 mIU/mL)14 and decreased progesterone in the luteal phase in comparison with the levels at younger ages.&Some perimenopausal cycles may be characterized by relatively low estrogen levels13and others by relatively highsz,91 levels. The clinical correlates of the middle perimenopause in addition to the erratic cycle length may include hot flashes, breast engorgement and tenderness, endometrial hyperplasia, and menorrhagia.lDJPerimenopausal dysfunctional uterine bleeding is postulated to result from anovulatory cycles and long follicular phases (leading to prolonged estrogen stimulation of the endometrium followed by a large amount of sloughing after the estrogen levels fall). Scant information is available on the proportion of women who experience overt changes in cycle length, on the relation of changes in cycle length to hormonal characteristics, and on the association of symptoms with cycle pattern. In one cross-sectional study of perimenopausal women, Ballinger and colleagues4reported an association between luteal phase hormone profiles and menorrhagia. Late Perimenopause In the late perimenopause (i.e., the year after the final menstrual flow) and postmenopause, follicles no longer ovulate under the influence of gonadotropins. Estradiol levels decline to the postmenopausal range (about 20 pg/mL); estradiol is no longer produced by the follicle but is primarily generated by the peripheral conversion of estrone and testosterone.%A small amount of progesterone is made by the adrenal giand.39
Postmenopause
After menopause, the average estrone production is 40 Fg/day and that of estradiol approximately 6 pg/day, derived from the aromatiza-
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tion of androstenedione and testoster~ne.~~? 54 Studies indicate that in the early postmenopause (up to 3 years after the final menses), levels of androstenedione, testosterone, dihydrotestosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate remain stable.%Testosterone production continues in the ovarian hilar and luteinized stromal cells; levels do not change dramatically when compared with those of premenopausal w0men.3~ AGEATMENOPAUSE
In population studies, the age at menopause has been ascertained by each woman's recall of her age at menopause or, less frequently, by longitudinal observation of the participant's menstrual patterns. Inconsistent estimates of the median or mean age at menopause have resulted. A frequently cited estimate emanates from a longitudinal cohort in which menstrual patterns were recorded; the median age at menopause was estimated to be 51 years with a range of 35 to 58 years.@Other studies have reported mean ages at menopause of between 48 and 52 years.44.56 The variation in the reported age at menopause is caused in large part by inconsistency and lack of clarity in the definition of menopause across studies. It is difficult to determine whether menopause was defined as the age when the last menses occurred or the age at cessation of menses plus 1 year. Some studies of the age at menopause have included women with surgical and natural menopause. Factors that may contribute to an earlier or later age at menopause remain poorly characterized. Most of the possible influences on the timing of menopause (e.g./ medical, reproductive, behavioral) have been studied as sole exposures and may not be independent. Proposed contributors to the timing of natural menopause include cancer chemotherapy, cigarette smoking, menstrual and reproductive history, use of oral contraceptives, and surgical trauma to ovarian blood supply. Consistent evidence suggests that some forms of cancer chemotherapy induce early menopause. Early ovarian failure occurs in 40% to 85% of women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) and in similar proportions in women treated with cyclophosphamide, doxorubicin, and fluorouracil.8,83 The alkylating agents, in particular, may be directly toxic to ovarian follicles. Age is a major cofactor of early ovarian failure as a result of chemotherapy. Permanent amenorrhea will develop as a result of chemotherapy for cancer in 40% to 50% of women aged less than 40 years versus 90% of women aged more than 40 Cigarette use is the most consistently reported characteristic associated with (earlier) age at menopause.', 3, 5,10,51,62 On average, smokers are 1 to 2 years younger at menopause than nonsmokers. Multiple plausible hypotheses have been offered to explain the association between cigarette smoking and younger age at menopause. Estrogen metabolism is increased in smokers when compared with nonsmokers,68compounds
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contained in cigarettes are directly toxic to oocytes in animal models,27 follicle aging is accelerated by aromatic hydrocarbon^,^^ and estrogen receptor binding is decreased by Early age at m e n a r ~ h ehas ~ ~ been associated with a later age at have been menopause, whereas menstrual cycles shorter than 26 correlated with earlier menopause. Some", 75, loo but not all6*,114 studies suggest that higher parity and later menopause are associated. The reported relationship of prior oral contraceptive use to age at menopause also remains uncertain. Some studies have found that users of oral contraceptives have later menopause,Q loowhereas others have reported FSH influences the rate of follicular depletion in no ass~ciation.~~ humans.%,117 It is postulated that an effect of parity or oral contraceptive use on the timing of menopause could be mediated through an FSHsuppressing pathway. Gynecologic surgery, particularly hysterectomy (without oophorectomy), may lead to early menopause by traumatizing the limited blood supply to the ovaries and reducing ovarian function. This hypothesis has not been upheld with minimal investigation to date.8u SYMPTOMS OF MENOPAUSE
The Challenge of Defining Menopause Symptoms
Current research in menopause focuses on several areas of investigation. Do certain physical and emotional experiences occur in conjunction with the menopause (i.e., "symptoms" of menopause)? Are these symptoms attributable solely to menopause or are they age-related or both? Does a woman's prior medical and life history influence her menopause experience and is this influence exerted biologically, socially, or both? What are the ethnic/cultural determinants of the menopause experience and are these mediated by social or biological factors? Approach to Epidemiology of Potentially Menopause-related Events
The ideal method of cataloging experiences that are truly menopause-related would be nonbiased. Major sources of bias include the selection of the population studied (e.g., clinical versus nonclinical samples) and the method of ascertaining the data (e.g., self-report versus direct observation and the content of the data collection instruments). Much of the literature on menopause symptoms suffers from self-selection bias. Symptoms of menopause have been studied based on the observations made on women seeking clinical care. Such women are more likely than the general population to be symptomatic and to attribute potentially unrelated problems to menopause. Careful attention must be given to how the symptoms of menopause are surveyed, as
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different data collection instruments will yield varied results. Unless respondents are given an opportunity to express both positive and negative events, the experience of the menopause may be inaccurately reflected.61
Estrogen-related Events and Menopause Utian108proposed a model to discriminate between the health conditions associated with aging versus those associated with menopause. The Utian model posits that characteristics associated with estrogen deficiency should be considered unique to menopause.1o8The major characteristics that are regarded as related to menopause using this model are hot flashes, epithelial atrophy, and bone loss. However, it is now recognized that the estrogen deficiency model may be too limited to explain all of the potential alterations in health status around the menopausal transition. Evolving models consider a broader range of hormone activity, including the potential role of androgens as well as estrogens. Furthermore, newer models attempt to account for the pattern and frequency of changes in hormone levels. Nevertheless, the estrogen deficiency model has stimulated a body of work to address the physiologic and psychologic phenomena of the menopause. Emerging issues in menopause research include the following: Definitions Concept of gradual transition from premenopause to perimenopause to postmenopause Increased attention to the need for a standard terminology to describe the phases of menopause to enhance between-study comparability Need to address whether a hormone-based or vaginal bleedingbased definition of menopause status is preferable New assays More sensitive and reliable assays for sex steroids More robust assays for key compounds such as inhibin Broadened theoretical models Inclusion of both transitory and persistent events Consideration of sex steroids other than estrogen as potentially etiologic to some menopause events Accounting for multiple potential confounders and effect modifiers Use of sophisticated analytic strategies to account for complex patterns of hormone levels Hot Flashes
A hot flash is the increase in perception of heat within or on the body. This is often accompanied by sudden skin flushing and perspira-
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tion. Some women report rapid heart beat and lightheadedness in association with the hot flash. The range of hot flash frequency varies (from less than daily to several per hour)lo6,113 as well as the duration (from 112, 113 seconds to an hour).106, In a longitudinal follow-up study of a US community-based sample, 40% to 58% of women reported hot flashes in the 2-year period surrounding the final menses.63Thus, hot flashes occur in the perimenopause as well as postmenopause. The estimated prevalence of hot flashes ranges between 50% and 85%.@,lo4 Hot flashes decrease (without treatment) as the time from menopause increase^.^^ The relationship between hot flashes and estrogen status is complex and has been reviewed by GreendaleZ9and Kronenberp47and their colleagues. Although the etiology of hot flashes remains speculative, one working hypothesis is that the loss of ovarian function leads to decreased hypothalamic opioid tone and thermoregulatory instability. Thus, although it is not accurate to say that hot flashes are caused by low estrogen levels, changing estrogen levels may be the source of the dysregulation of the hypothalamic thermoregulatory axis. The relation of hot flashes to changing estrogen levels is a good example of the need to update the estrogen-deficiency model to account for more complex relations. Consistent evidence suggests that administration of postmenopausal estrogen diminishes hot flush frequency in a dose-dependent manner."%94,101 Although the potential for hot flashes to disrupt daily activity and sleep quality is well-known, few studies have produced quantitative estimates of the quality-of-life impact of hot flashes.46Recent investigations have suggested that hot flashes might have metabolic consequences, such as hyperglycemia, hypertriglyceridemia, and glucocortihowever, these findings have not been corroborated coid excess19,26, ffi; by others1" and remain speculative. Other possible metabolic correlates of hot flashes include premenstrual syndromeN and greater bone loss than in women without hot flashes,'l although the latter finding has not been confirmed in subsequent evaluation^.^^ One cross-sectional study found that women with osteoporosis were more likely to report more frequent and more intense premenstrual symptoms, oligomenorrhea, and a history of vasomotor symptoms when compared with controls of a similar age (average of 64 years).48 The sources of between-population variations in the occurrence of hot flashes may offer insight into the symptoms of menopause. In comparison with Western Caucasian cultures, Japanese, Indonesian, and Mayan women7,53 report a markedly lower prevalence (OYOto loo/,) of hot flashes at menopause. In contrast, the rate of hot flashes among perimenopausal women in seven Southeast Asian countries is between 20% and 6O%, much closer to estimates of hot flashes in women in Western samples? Population and geographic variability in the occurrence of hot flashes may be related to several factors, including the lack of similar meaning of the concept of hot flash, the different incidence in hotter climates, the interpretation of hot flashes as fever, differences in
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reporting due to cultural norms, environmental modifiers (e.g., dietary estrogens), or genetic differences in the biology of menopause. The crosscultural difference in the hot flash experience is an area of active biologic and epidemiologic research. Factors that might be associated with, provoke, or intensify hot flashes have received little attention. In two studies, no association between the occurrence of hot flashes and employment status, social class, age, marital status, parity, menarcheal age, and age of menopause has been evident.", 89 Recent investigations have reported that stressful situations can provoke hot flashes.lo3This is concordant with Ballinger's thesis that stress may lead to falls in estrogen and thereby precipitate menopausal symptom^.^
MENOPAUSE AND THE EPITHELIUM: DERMATOLOGIC AND GENITOURINARY IMPACT Epidermis
Substantial evidence suggests that estrogen influences the dermis and epidermis, but its clinical impact on skin integrity has received limited investigation. Collagen synthesis and maturation are stimulated 40, y3 Nonrandomized studies of estrogen administration by suggest that estrogen preserves collagen content", l 2 and benefits the mechanical properties of skin.76Small randomized clinical trials have reported that estrogen maintains both skin collagen content and 58 To date, two large population-based, cross-sectional studthi~kness.'~, ies of the effects of estrogen on skin have found discordant results. One found that the skin of estrogen users was thinner on the basis of caliper assessment of skin thickness," whereas the other reported that estrogen use was associated with a substantially lower prevalence of skin wrinkles and dry skin on the basis of a clinical dermatologic exarnination.*l
Vaginal Epithelium
Clinically, the genital changes seen in postmenopausal women include subepithelial and epithelial alterations that lead to shortening of the vaginal canal, loss of rugae, and a pale sometimes friable epithelial surface. Although it is generally agreed that this is a postmenopausal phenomenon, these observed vaginal changes have not been well-quantified, and thus their response to supplemental estrogen has not been evaluated using quantitative methods. The vaginal smear maturation index (the proportion of basal, parabasal, and superficial cells) is a biologic assay of estrogen's effect on vaginal tissue, however, the maturation index does not correlate with vaginal symptoms.102
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Lower Urinary Tract Estrogen receptors are located on the urethra and bladder triAfter menopause, the urethra can become thinner due to regression of its squamous epithelial layer.1z1It is postulated that postmenopausal estrogen-related changes in the lower urinary tract lead to dysuria (caused by a thinned urethra), urinary frequency (caused by atrophic trigonitis), stress incontinence (caused by a loss of urethral back-pressure and less sphincter tone), and urge incontinence (caused by to atrophic trigonitis). Although these are plausible hypotheses, concordant epidemiologic evidence of a relation between menopause and urinary consequences is limited. Epidemiologic studies are contradictory as to whether the prevalence of incontinence increases in the menopause.33,37, 69, Placebo-controlled intervention studies of oral estrogen for stress incontinence have been few in number; some have reported no effect, but small sample sizes limit the ability to detect effe~ts.8~1 118 One trial of estrogen in combination with phenylpropanolamine for stress urinary incontinence found a 50% reduction in incontinent episode~.~* A 40% reduction in the symptoms of urge incontinence was reported in a clinical trial of estradiol and estriol for urge urinary in~ontinence."~ Although a recent meta-analysis of estrogen trials for incontinence concluded that the effect of estrogen on incontinence is small, the limitations of the trials to date must be considered (e.g., small samples, varied forms of incontinence, and the use of relatively weak e~trogens).~~ Bone Density and Calcium Metabolism
Osteoporosis is considered to be the classic estrogen-deficiency disease, yet studies of possible bone loss at the time of menopause have not been concordant. This lack of consistency may be the result of several methodological constraints, including the following: 1. Measurements of diverse bone sites and markers of bone status are likely to vary in their ability to demonstrate detectable changes with time. 2. The study may fail to account for characteristics of women (in addition to menopause status) that may predispose to more or less change in bone?' 3. Age may be used as an index for menopause rather than the actual measurement of menstrual status. 4. Imprecise or conflicting definitions of premenopause, perimenopause, and postmenopause may be used. This is particularly problematic when cross-sectional data are used to make inferences about events across the menopausal transition. Heightened attention to the onset of subtle changes in the hypothalamic pituitary axis in the early and mid perimenopause has led to
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investigations to determine whether some corresponding bone loss occurs during perimenopause. Hernandez and co-workers31using peripheral CT of the distal radius reported that there was lower trabecular bone mass in the perimenopause period (women had missed three to six menstrual cycles in the previous year) and that older perimenopausal women had lower bone mass in comparison with younger perimenopausal women. By grouping women according to their menstrual pattern, Nilas and Christiansen" found increasing rates of bone loss from forearm sites and the spine as the frequency of menses declined. From early to late perimenopause, the forearm loss increased from 0.5% to 1% annually with a trend toward higher rates at the distal forearm site 98 and throughout the transition. Other studies both ~ross-sectional~~~ 10ngitudinal~~ in design have found evidence of bone loss in perimenopausal women, albeit, the perimenopausal status is typically defined by chronologic age as opposed to the measurement of hormones, concurrent 95 presentation with menopausal symptoms, or menstrual bleeding.22, Other cross-sectional studies have not found significant losses of bone mass before the menopause.", *l Slemenda and c o - w ~ r k e r sfound ~~ no forearm bone loss in early perimenopausal women but identical rates of 1%per year in both late perimenopausal and postmenopausal women. The changes at two forearm sites were similar and showed no acceleration immediately after menopause. In one of the rare longitudinal studies, a 12-year investigation encompassing 160 women, there was no change in bone mineral density (BMD) of the forearm in the 2 years prior to menopause, but there was a 16% loss in BMD in the 8 years following menopause.79 Lower axial BMD measured in women between the ages of 47 and 59 years predicted fracture risk within the subsequent 2-year period.& Women in the lowest quartile of spine BMD (by dual x-ray absorptiometry) had a 2.9 times greater risk of fracture than women in the highest quartile of spine BMD.45The effect of menopause on fracture incidence was stronger than the effect of a 5-year age increase.'07 In most studies using fracture rather than BMD as the endpoint, there has been no difference in the average age at menopause in cases versus controlsG or in the proportion with earlier age of menopause. A case-control study and a prospective cohort study have shown that menopause after age 55 years is protective for fracture. This has led some investigators to suggest that the inappropriate prolongation of menopausal levels of bone remodeling accounts for the increased frequency of vertebral fracture.lI6 If the menopause is indeed an initiating event for higher rates of bone loss, women with early natural menopause (before age 45 years) who spend a longer time in the postmenopause (adjusted for chronologic age) should have more bone loss and higher subsequent fracture risk than women who experience menopause at a later age. Some investigations have concluded that low BMD occurs with early menopause.25,52 However, others have reported no significant association between BMD
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and early menopause, albeit, early menopause was defined as before age 50 years.% Biochemical markers of bone turnover may be a more sensitive indicator of incipient changes in bone metabolism in the perimenopause and early postmenopause. Studies have shown that osteocalcin (a higher level of which is commonly thought of as a ”marker of formation” but which can represent higher bone turnover) increases with menopause.72,92 Some studies have correlated the timing of estrogen decline in the postmenopause with evidence of increased turnover by bone markers.20,72 However, a clear increase in osteocalcin at the time of the menopause has not been confirmed in all instances.41,74 Some evidence suggests that this rise may be a phenomenon of aging or a reflection of more long-term estrogen deficiency. In a cross-sectional study, Del Pino and co-workersZ0observed a rise in osteocalcin in women who were at least 2 years postmenopause but not in premenopausal women and women who had 2 years of menopausal amenorrhea. Other reported patterns of osteocalcin levels include a continuous increase from premenopause to postmen0pause,7~or a decline before menopause, a rise at menopause, and a fall in the seventh and eighth decades.41Osteocalcin levels have decreased in postmenopausal women treated with hormone replacement therapy? Hydroxyproline, a marker of bone resorption (and therefore turnover), has similarly been noted to rise at the time of the 73 menopause.6o* Few studies have evaluated the impact of a therapeutic regimen to minimize bone mineral loss during the perimenopause. Gambacciani and co-workersZ4evaluated the effect of a low-dose oral contraceptive containing 30 kg of ethinyl estradiol and 75 FLg of gestodene in a 2-year nonrandomized clinical trial of 32 women; all of the subjects were offered a calcium supplement. There was a significant decrease in bone turnover markers and a maintenance of BMD in the treated group, whereas the control group showed an increase in biochemical markers of bone remodeling and a significant decline of BMD. Vitamin D levels, although increasingly appreciated as an important component of bone health in the elderly, are rarely addressed with respect to menopause. In a cross-sectional design, Sowers and co-worke r reported ~ ~ ~an intriguing decline in vitamin D levels with menopause and the prevention of such decline in hormone users-highly suggestive evidence of an estrogen-related phenomenon that deserves further study. Several issues remain to be resolved, including whether there are ”fast” and ”slow” bone losers in the menopausal periodI8 and whether biochemical markers of bone turnover can be used to discriminate between such groups. Further information is also needed as to the duration of accelerated bone loss in the menopausal period. Pouilles and colleaguesT suggest that the accelerated phase of bone loss occurs early in the first year after menopause and lasts only a few years.
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Menopause and Other Chronic Diseases and Syndromes
The relation between menopause and cardiovascular disease is complex. Although numerous cohort studies have found that exogenous estrogens afford cardiovascular protection (reviewed by Wren)'*O and that several biomarkers of heart disease risk are negatively impacted on by menopause (reviewed by Sowers and LaI3et1-a):~there is not an abrupt increase in the rate of heart disease in women after the menopause.I5This topic is beyond the scope of this article, and the reader is referred to the previously mentioned reviews and to discussions elsewhere in this issue. Another complex question that is not addressed herein is the relationship among menopause, sexuality, and sexual function. Recent reviews and articles by Sarrells6ss7and Greendale and colleagues28discuss this issue in detail. The potential associations among menopause, postmenopausal estrogen use, and other chronic diseases and conditions have been the focus of new explorations in the field of menopause research. These have included studies of rheumatoid arthritis, osteoarthritis, and obesity. The findings of these investigations have been summarized by Sowers and LaPietra.97
SUMMARY
New paradigms for the study of menopause will increase our understanding of whether symptoms, syndromes, and chronic diseases are associated with menopause. Rather than considering menopause as a discrete event, it has become clear that the menopause transition takes place over many years. Although this realization is central to our understanding of menopause, it is difficult to measure the temporal pattern of changes in hormones and their relation to concurrent or subsequent health-related events. The model of hormonal changes at the time of the transition has been expanded to include not only declines in estrogen but changes in a broader range of hormones, including the potential role of androgens. New models are attempting to account for the pattern and frequency of changes in hormone levels. Another level of complexity is contributed by the expansion of the menopause model to include comorbid medical and psychiatric conditions, environmental influences, and behaviors as covariates that influence the expression of menopauserelated events. Although this more complicated paradigm makes the conduct of menopause research more challenging, it is also likely to elucidate previously confusing data, as the proper understanding of potentially complex exposures, effect modifiers, and confounders is more likely to provide clearer answers to critical research questions.
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ACKNOWLEDGMENT The authors thank Ellen L. Whaling for manuscript preparation and editorial assistance.
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23. Fantyl JA, Cardozo L, McClish DK: Estrogen therapy in the management of urinary incontinence in postmenopausal women: A meta-analysis. Obstet Gynecol 831249, 1994 24. Gambacciani M, Spinetti A, Cappagli B, et al: Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: Effects on bone mineral density and metabolism. Maturitas 19125-131, 1994 25. Gardsell P, Johnell 0, Nilsson BE: The impact of menopausal age on future fragility fracture risk. J Bone Miner Res 6:429-433, 1991 26. Gennazani AR, Peyraglia F, Faccinetti V, et al: Increase of propiomelanocortin-related peptides during subjective menopausal flushes. Am J Obstet Gynecol149775,1984 27. Ginsburg J: What determines the age at menopause? BMJ 302:128&1289, 1991 28. Greendale GA, Hogan P, Shumaker S Sexual functioning in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Women's Health 5:445-455,1996 29. Greendale GA, Judd HL The menopause: Health implications and clinical management. J Am Geriatr Soc k426-436, 1993 30. Henneman DH: Effect of estrogen on in vivo and in vitro collagen biosynthesis and maturation in old and young female guinea pigs. Endocrinology 83678490,1968 31. Hernandez ER, Seco-Durban C, Revilla M, et a1 Evaluation of bone density with peripheral quantitative computed tomography in healthy premenopausal, perimenopausal and postmenopausal women. Age Aging 24447450,1995 32. Hinton P, Tweddell AL, Mayne C: Oral and intravaginal estrogens alone and in combination with alpha adrenergic stimulation in genuine stress incontinence. Int Urogynecol J 1:80-86,1990 33. Hording U, Pedersen KH, Sidenius K, et a1 Urinary incontinence in 45-year-old women: An epidemiologicalsurvey. Scand J Urol Nephrol20183-186,1986 34. Hunter M The southeast England longitudinal study of the climacteric and postmenopause. Maturitas 14117-126, 1992 35. Ingelman-Sundberg A, Rosen J, Gustaffsson SA, et al: Cytosol estrogen receptors in the urogenital tissues in stress-incontinent women. Ada Obstet Gynecol Scand 60585-586, 1981 36. Iosif CS, Batra S, Sek A, et ak Estrogen receRtors in the human female lower urinary tract. Am J Obstet Gynecol 141:817-820,1981 37. Iosif S, Henriksson L, Ulmsten U The frequency of disorders of the lower urinary tract, urinary incontinence in particular, as evaluated by a questionnaire survey in a gynaecological health control population. Acta Obstet Gynecol %and 6071-76, 1981 38. Judd HL, Judd GE, Lucas WE, et a1 Endocrine function of the postmenopausal ovary: Concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 391020, 1974 39. Judd HL: Menopause. In Hacker N, Moore JG (eds): Essentials of Obstetrics and Gynecology. Philadelphia, WB Saunders, 1986, pp 436-443 40. Kao KY, H i t t WE, McGavack W. Effect of estradiol benzoate upon collagen synthesis by sponge biopsy connective tissue. Proc Soc Exp Biol Med 119:364,1965 41. Kelly PJ, Pocock NA, Sambrook PN, et a1 Age and menopause-related changes in indices of bone turnover. J Clin Endocrinol Metab 691160-1165, 1989 42. Khaw K-T Epidemiology of the menopause. BMJ 48:249-261, 1992 43. Kiel DP, Felson DT, Anderson JJ, et al: Hip fracture and the use of estrogens in postmenopausal women. N Engl J Med 3171169-1174,1987 44. Krailo MD, Pike MC Estimation of the distribution of age at natural menopause from prevalence data. Am J Epidemiol 117356-361, 1983 45. Kroger H, Huopio J, Honkanen R, et al: Prediction of fracture risk using axial bone mineral density in a perimenopausal population: A prospective study. J Bone Miner Res 10302-306,1995 46. Kronenberg F, Downey J A Thennoregulatory physiology of menopausal hot flashes: A review. Can J Physiol Pharmacol651312-1324,1987 47. Kronenberg F: Hot flashes: Epidemiology and physiology. Ann NY Acad Sci 5925286, discussion 123-133,1990
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48. Lee SJ, Kanis JA: An association between osteoporosis and premenstrual symptoms and postmenopausal symptoms. J Bone Miner Res 24:127-134, 1994 49. Lee SJ, Lenton EA, Sexton L, et al: The effect of age on the cyclical patterns of plasma LH, FSH, oestradiol and progesterone in women with regular menstrual cycles. Hum Reprod 3:851-855, 1988 50. Lenton EA, Landgren BH, Sexton L, et a 1 Normal variation in the length of the follicular phase of the menstrual cycle: Effect of chronological age? Br J Obstet Gynaecol 91:681484, 1984 51. Lindquist 0, Bengtsson C: The effect of smoking on menopausal age. Maturitas 1:191-199, 1979 52. Lindquist 0 Influence of the menopause on ischaemic heart disease and its risk factors and on bone mineral content. Acta Obstet Gynecol Scand 11O:l-32, 1982 53. Lock M, Kaufert P, Gilbert P: Cultural construction of the menopausal syndrome: The Japanese case. Maturitas 10:317-332, 1988 54. Longcope C, Franz C, Morello C, et a1 Steroid and gonadotropin levels in women during the perimenopausal years. Maturitas 8:189-196, 1986 55. Longcope C, Johnston CC: Androgen and estrogen dynamics in pre- and postmenopausal women: A comparison between smokers and nonsmokers. J Clin Endocrinol Metab 67:379-383, 1988 56. MacMahon B, Worcester J: Age at menopause: United States 1960-1962. US Vital Statistics I1 19:l-19, 1966 57. MacNaughton J, Bangah M, McCloud P, et al: Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol34339-345, 1992 58. Maheux R, Naud F, Rioux M, et al: A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. J Obstet Gynecol 170:642449, 1994 59. Mattison DR, Thorgeirsson SS: Smoking and industrial pollution, and their effects on menopause and ovarian cancer. Lancet 1:187-188,1978 60. Mazzuoli G, Minisola S, Valtorta C, et al: Changes in mineral content and biochemical bone markers at the menopause. Isr J Med Sci 21i875-877, 1985 61. McKinlay JB, McKinlay SM, Brambilla D: The relative contributions of endocrine changes and social circumstances to depression in mid-aged women. J Health SOC Behav 28345-363, 1987 62. McKinlay SM, Bifano NL, McKinlay J B Smoking and age at menopause in women. Ann Intern Med 103:350-356, 1985 63. McKinlay SM, Brambilla PJ, Posner JG; The normal menopause transition. Maturitas 14:103-115, 1992 61. McKinlay SM, Jefferys M; The menopausal syndrome. Br J Prev SOCMed 28108115, 1974 65. Meldrum DR, Tataryn IV, Frumar AM, et al: Gonadotropins, estrogens and adrenal steroids during the menopausal hot flash. J Clin Endocrinol Metab 50:685489, 1980 66. Metcalf MG, Donald RA, Livesey JH: Pituitary-ovarian function before, during and after the menopause: A longitudinal study. Clin Endocrinol 17:489494, 1982 67. Metcalf MG, Livesey JG: Gonadotrophin excretion in fertile women: Effect of age and the onset of the menopausal transition. J Endocrinol 104:357-362, 1985 68. Michnovicz JJ, Hershcopf RJ, Naganuma H, et al: Increased 2-hydroxlation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 315:1151-1154, 1986 69. Milsom I, Ekelund P, Molander U,et al: The influence of age, parity, oral contraception, hysterectomy, and menopause on the prevalence of urinary incontinence in women. J Urol 149:1459-1462, 1993 70. Munk-Nielsen N, Overgaard K, Nilas L: Postmenopausal bone loss and response to hormone replacement therapy independent of clinical macteric symptoms. J North Am Meno SOC2:35-41, 1995 71. Naessen T, et al: Women with climacteric symptoms: A target group for prevention of rapid bone loss and osteoporosis. Osteoporosis Int 2225-1, 1992 I
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72. Nilas L, Christiansen C: Rates of bone loss in normal women: Evidence of accelerated trabecular bone loss after the meno. Eur J Clin Invest 18:529-534, 1988 73. Nordin BEC, Polley KJ: Metabolic consequences of the menopause: A cross-sectional, longitudinal, and intervention study on 557 normal postmenopausal women. Calcif Tissue Int 4123-59, 1987 74. Pansini F, Bonaccorsi G, Calisesi M, et al: Evaluation of bone metabolic markers as indicators of osteopenia in climacteric women. Gynecol Obstet Invest 33231-235, 1992 75. Parazzini F, Newjri E, LaVechia C L Reproductive and general lifestyle determinants of age at menopause. Maturitas 15:141-149, 1992 76. Pierard GE, Letawe C, Dowlati A, et al: Effect of hormone replacement therapy for menopause on the mechanical properties of skin. J Am Geriatr SOC43:662-665, 1995 77. Pouilles JM, Tremollieres F, Ribot C: Spine and femur densitometry at the menopause: Are both sites necessary in the assessment of the risk of osteoporosis? Calcif Tissue Int 52344-347, 1993 78. Prior JC, Barr SI, Vigna YM: The controversial endocrinology of the menopausal transition [letter]. J Clin Endocrinol Metab 81:3127-3128, 1996 79. Rannevik G, Jeppsson S, Johnell 0, et al: A longitudinal study of the perimenopausal transition: Altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 21:103-113, 1995 80. Ravn P, Lind C, Nilas L: Lack of influence of simple premenopausal hysterectomy on bone mass and bone metabolism. Am J Obstet Gynecol 172891495, 1995 81. Recker RR, Lappe JM, Davies KM, et al: Changes in bone mass immediately before menopause. J Bone Miner Res 7:857-862, 1992 82. Reyes FI, Winter JS, Faiman C: Pituitary ovarian relationships preceding the menopause. I. A cross-sectional study of serum follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone levels. Am J Obstet Gynecol 129:557564, 1977 83. Richards MA, O’Reilly SM, Howell A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: An update of the Guy’s Manchester trial. J Clin Oncol 82032-2039, 1990 84. Richardson SJ, Nelson JF: Follicular depletion during the menopausal transition. Ann NY Acad Sci 59213-20, 1990 85. Samsioe G, Jansson I, Mellstrom D, et al: Occurrence, nature and treatment of urinary incontinence in a 70-year-old female population. Maturitas 7335-342, 1985 86. Sarrel PM, Whitehead MI: Sex and menopause: Defining the issues. Maturitas 7217, 1985 87. Sarrel PM: Sexuality in the middle years. Obstet Gynecol Clin North Am 14:49, 1987 88. Seeman E, Cooper ME, Hopper JL, et al: Effect of early menopause on bone mass in normal women and patients with osteoporosis. Am J Med 85:213-216, 1988 89. Sherman B, Wallace R, Bean J, et al: Relationship of body weight to menarcheal and menopause age: Implications for breast cancer risk. J Clin Endocrinol Metab 52:488493, 1981 90. Sherman BM, West JM, Korenman SC: The menopausal transition: Analysis of LH, FSH, estradiol and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab 42629-636, 1976 91. Shideler SE, DeVane GW, Kalra PS, et al: Ovarian-pituitary hormone interactions during the perimenopause. Maturitas 11:331-339, 1989 92. Slemenda C, Hui SL, Longcope C, et al: Sex steroids and bone mass: A study of changes about the time of menopause. J Clin Invest 80:1261-1269, 1987 93. Smith QT, Allison DJ: Changes of collagen content in skin, femur and uterus of 17 beta-estradiol benzoate-treated rats. Endocrinology 79:486, 1966 94. Sonnedecker EUW, Polakow E S Effects of conjugated equine estrogens with and without the addition of cyclical medrogestone on hot flushes, liver function, blood pressure, and endocrinological indices. S Afr Med J 77281-285, 1990 95. Sowers MFR, Clark MK, Hollis B, et al: Radial bone mineral density in pre- and perimenopausal women: A prospective study of rates and risk factors for loss. J Bone Miner Res 7647-657, 1992
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96. Sowers MFR, Kshirsagar A, Crutchfield M, et al: Body size, age and femoral bone mass of young women. Ann Epidemiol 1245-254, 1991 97. Sowers MFR, LaPietra MT: Menopause: Its epidemiology and potential association with chronic diseases. 17287-302, 1995 98. Sowers MFR, Shapiro B, Gilbraith M, et a1 Health and hormonal characteristics of premenopausal women with lower bone mass. Calcif Tissue Int 47130-135, 1990 99. Sowers MFR, Wallace RB, Hollis BW: The relationship of 1,25-dihydroxyvitamin D and radial bone mass. J Bone Miner Res 10139-148, 1990 100. Stanford JL, Hartge P, Brinton LA, et al: Factors influencing the age at natural menopause. J Chron Dis 40:995-1002,1987 101. Steingold KA, Laufer L, Chetkowski RJ, et a1 Treatment of hot flashes with transderma1 estradiol administration. J Clin Endocrinol Metab 61:627-632, 1985 102. Stone SC, Mickal A, Rye PH: Postmenopausal symptomatology, maturation index, and plasma estrogen levels. Obstet Gynecol45:625, 1975 103. Swartzman LC, Edleberg R, Kemmann E: Impact of stress on objectively recorded menopausal hot flushes and on flush report bias. Health Psycho1 pp 529-545, 1990 104. Thompson B, Hart SA, Dumo D Menopausal age and symptomatology in a general practice. J Biosoc Sci 5:71-82, 1973 105. Treloar AE, Bonton RE, Behn BG, et al: Variation of the human menstrual cycle through reproductive life. Int J Fertil 1277-127, 1967 106. Tulandi T, Samarthji L Menopausal hot flush. Obstet Gynecol Surv 40:553-563, 1985 107. Tuppurainen M, Honkanen R, Kroger H, et al; Osteoporosis risk factors, gynaecological history and fractures in perimenopausal women-the results of the baseline postal enquiry of the Kuopio Osteoporosis Risk Factor and Prevention Study. Maturitas 17:89-100, 1993 108. Utian W H The place of oestriol therapy after menopause. Acta Endocrinol Suppl (Copenh) 2335-56,1980 109. Vagenakis AG: Endwrine aspects of menopause. Clin Rheumatol8;48-51,1989 110. Versi E: Incontinence in the climacteric. Clin Obstet Gynecol33:392-398, 1990 111. Vihko P, Wagener C; Structure and genetic engineering of antigens and antibodies: Applications in immunoassays. J Int Fed Clin Chem 55G59, 1993 112. Voda AM, Feldman BM, Gronseth E; Description of the hot flash: Sensations, meaning and change in frequency across time. In The Climacteric in Perspective. Hingham, MA, MTP Press, 1984, pp 259-269 113. Voda AM: Climacteric hot flush. Maturitas 3:73-90, 1981 114. Walsh RJ: The age of the menopause of Australian women. Med J Aust 2:181-215, 2978 115. Walters S, Wolf H, Barlebo H, et al: Urinary incontinence in postmenopausal women treated with estrogens. Urol Int 33135-143, 1978 116. Wand JS, Green JR, Hesp R, et al: Bone remodeling does not decline after menopause in vertebral fracture osteoporosis. J Bone Miner Res 17361375, 1992 117. Whelan EA, Sandler DP, McConnaughey DR, et al: Menstrual and reproductive characteristics and age at natural menopause. Am J Epidemiol 131:625632, 1990 118. Wilson PD, Faragher B, Butler B, et al: Treatment with oral piperazine oestrone sulphate. Br J Obstet Gynecol94:568-574, 1987 119. World Health Organization: Report of a WHO Scientific Group: Research on the menopause. Geneva, WHO Technical Report Series 670, 1981 120. Wren BG: The effect of oestrogen on the female cardiovascular system. Med J Aust 156204-208, 1992 121. Zuckerman S Morphological and functional homologies of the male and female reproductive system. BMJ 2:264, 1936 Address reprint requests to Gail A. Greendale, MD Division of Geriatrics University of California Los Angeles 10945 Le Conte Avenue, Suite 2339 Los Angeles, CA 90095-1687
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THE MENOPAUSE TRANSITION Gail A. Greendale, MD, and MaryFran Sowers, MD
DEFINITIONS The definitions of menopause, postmenopause, and perimenopause used herein are those proposed by the World Health Organization in 1981.Il9 The menopause is defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. After 1 year of amenorrhea, the final menstrual period is retrospectively designated as the time of menopause. The postmenopause is defined as commencing from the time of the final menstrual period (menopause). Termination of ovarian function and menses is not an acute physiologic event. Rather, the physiologic antecedents associated with the transition from premenopausal to postmenopausal follicular function are believed to occur in the perimcnopause. The perimenopause comprises the period of time (2 to 8 years in duration) preceding the menopause and 1 year following the final menses. The term pcrimcnoynzrse is used interchangeably with the climacteric and is also often called the menopause transition. Figure 1 schematically summarizes these definitions and their timing related to menopause. As currently conceived, these categories of the female reproductive life span overlap (e.g., the last year of the perimenopause coincides with the first year of the postmenopause). This work was supported in part by the Iris-Cantor-UCLA Women’s Center and by grants NR.04061 and AR.40888.
From the Department of Obstetrics and Gynecology, Division of Geriatrics, UCLA School of Medicine, University of California at Los Angeles, Los Angeles, California (GAG); and Departments of Epidemiology and Obstetrics and Gynecology, School of Public Health, University of Michigan, Detroit, Michigan (MS)
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Figure 1. Categories of the reproductive life span (pre-, peri-, and postmenopause). Idealized ages at menarche and menopause used for simplicity.
PHYSIOLOGY AND CHARACTERISTICS OF THE MENOPAUSAL TRANSITION
Inferred in the concept of the menopausal transition or perimenopause is a period of gradual transition during which the ovarian follicles and their associated hormonal feedback loops undergo a series of changes which can be distinguished from the normal follicular function of earlier reproductive life. However, the inceptions of the menopausal transition and its phases are neither well-defined nor universally agreed upon. One theoretical model based on available evidence is described in the next section and awaits further elucidation by ongoing studies of the menopause transition.
Early Perimenopause In the earliest phase of the menopause transition, cycle lengths may appear normal or slightly shortened while clinically imperceptible alterations in the systems controlling ovulation occur. In the decade before the final menses, cycle length shortening occurs as a result of a shortened follicular phase.5oLevels of follicle-stimulatinghormone (FSH) increase in comparison with those of younger w0men.4~* 57, 90 The increase in FSH can be interpreted as compensation for a decreased number of ovarian follicles67or a consequence of decreased secretion of ir~hibin.'~, 78 One recent study of a series of patients undergoing oophorectomy"' found that serum FSH and luteinizing hormone (LH) levels were inversely related to the presence of ovarian FSH and LH receptors,
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whereas in postmenopausal patients, no ovarian gonadotropin receptors were detectable. Middle Perimenopause
Middle perimenopause is defined as the time when an overtly altered menstrual cycle pattern occurs.63Classically, this transitional pattern is described as long intermenstrual intervals interspersed with very short cycles.1o5 Erratic maturation of the remaining ovarian follicles may be responsible for this transitional Some menstrual cycles may be ovulatory (i.e., characterized by a midcycle estrogen surge followed by luteal phase progesterone secretion), whereas others are anovulatory (i.e., a rise and fall of estrogen levels but no progesterone ~ecretion).~~ Physiologic characteristics of middle perimenopause cycles may include elevated early follicular phase FSH (>25 mIU/mL)14 and decreased progesterone in the luteal phase in comparison with the levels at younger ages.&Some perimenopausal cycles may be characterized by relatively low estrogen levels13and others by relatively highsz,91 levels. The clinical correlates of the middle perimenopause in addition to the erratic cycle length may include hot flashes, breast engorgement and tenderness, endometrial hyperplasia, and menorrhagia.lDJPerimenopausal dysfunctional uterine bleeding is postulated to result from anovulatory cycles and long follicular phases (leading to prolonged estrogen stimulation of the endometrium followed by a large amount of sloughing after the estrogen levels fall). Scant information is available on the proportion of women who experience overt changes in cycle length, on the relation of changes in cycle length to hormonal characteristics, and on the association of symptoms with cycle pattern. In one cross-sectional study of perimenopausal women, Ballinger and colleagues4reported an association between luteal phase hormone profiles and menorrhagia. Late Perimenopause In the late perimenopause (i.e., the year after the final menstrual flow) and postmenopause, follicles no longer ovulate under the influence of gonadotropins. Estradiol levels decline to the postmenopausal range (about 20 pg/mL); estradiol is no longer produced by the follicle but is primarily generated by the peripheral conversion of estrone and testosterone.%A small amount of progesterone is made by the adrenal giand.39
Postmenopause
After menopause, the average estrone production is 40 Fg/day and that of estradiol approximately 6 pg/day, derived from the aromatiza-
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tion of androstenedione and testoster~ne.~~? 54 Studies indicate that in the early postmenopause (up to 3 years after the final menses), levels of androstenedione, testosterone, dihydrotestosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate remain stable.%Testosterone production continues in the ovarian hilar and luteinized stromal cells; levels do not change dramatically when compared with those of premenopausal w0men.3~ AGEATMENOPAUSE
In population studies, the age at menopause has been ascertained by each woman's recall of her age at menopause or, less frequently, by longitudinal observation of the participant's menstrual patterns. Inconsistent estimates of the median or mean age at menopause have resulted. A frequently cited estimate emanates from a longitudinal cohort in which menstrual patterns were recorded; the median age at menopause was estimated to be 51 years with a range of 35 to 58 years.@Other studies have reported mean ages at menopause of between 48 and 52 years.44.56 The variation in the reported age at menopause is caused in large part by inconsistency and lack of clarity in the definition of menopause across studies. It is difficult to determine whether menopause was defined as the age when the last menses occurred or the age at cessation of menses plus 1 year. Some studies of the age at menopause have included women with surgical and natural menopause. Factors that may contribute to an earlier or later age at menopause remain poorly characterized. Most of the possible influences on the timing of menopause (e.g./ medical, reproductive, behavioral) have been studied as sole exposures and may not be independent. Proposed contributors to the timing of natural menopause include cancer chemotherapy, cigarette smoking, menstrual and reproductive history, use of oral contraceptives, and surgical trauma to ovarian blood supply. Consistent evidence suggests that some forms of cancer chemotherapy induce early menopause. Early ovarian failure occurs in 40% to 85% of women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) and in similar proportions in women treated with cyclophosphamide, doxorubicin, and fluorouracil.8,83 The alkylating agents, in particular, may be directly toxic to ovarian follicles. Age is a major cofactor of early ovarian failure as a result of chemotherapy. Permanent amenorrhea will develop as a result of chemotherapy for cancer in 40% to 50% of women aged less than 40 years versus 90% of women aged more than 40 Cigarette use is the most consistently reported characteristic associated with (earlier) age at menopause.', 3, 5,10,51,62 On average, smokers are 1 to 2 years younger at menopause than nonsmokers. Multiple plausible hypotheses have been offered to explain the association between cigarette smoking and younger age at menopause. Estrogen metabolism is increased in smokers when compared with nonsmokers,68compounds
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contained in cigarettes are directly toxic to oocytes in animal models,27 follicle aging is accelerated by aromatic hydrocarbon^,^^ and estrogen receptor binding is decreased by Early age at m e n a r ~ h ehas ~ ~ been associated with a later age at have been menopause, whereas menstrual cycles shorter than 26 correlated with earlier menopause. Some", 75, loo but not all6*,114 studies suggest that higher parity and later menopause are associated. The reported relationship of prior oral contraceptive use to age at menopause also remains uncertain. Some studies have found that users of oral contraceptives have later menopause,Q loowhereas others have reported FSH influences the rate of follicular depletion in no ass~ciation.~~ humans.%,117 It is postulated that an effect of parity or oral contraceptive use on the timing of menopause could be mediated through an FSHsuppressing pathway. Gynecologic surgery, particularly hysterectomy (without oophorectomy), may lead to early menopause by traumatizing the limited blood supply to the ovaries and reducing ovarian function. This hypothesis has not been upheld with minimal investigation to date.8u SYMPTOMS OF MENOPAUSE
The Challenge of Defining Menopause Symptoms
Current research in menopause focuses on several areas of investigation. Do certain physical and emotional experiences occur in conjunction with the menopause (i.e., "symptoms" of menopause)? Are these symptoms attributable solely to menopause or are they age-related or both? Does a woman's prior medical and life history influence her menopause experience and is this influence exerted biologically, socially, or both? What are the ethnic/cultural determinants of the menopause experience and are these mediated by social or biological factors? Approach to Epidemiology of Potentially Menopause-related Events
The ideal method of cataloging experiences that are truly menopause-related would be nonbiased. Major sources of bias include the selection of the population studied (e.g., clinical versus nonclinical samples) and the method of ascertaining the data (e.g., self-report versus direct observation and the content of the data collection instruments). Much of the literature on menopause symptoms suffers from self-selection bias. Symptoms of menopause have been studied based on the observations made on women seeking clinical care. Such women are more likely than the general population to be symptomatic and to attribute potentially unrelated problems to menopause. Careful attention must be given to how the symptoms of menopause are surveyed, as
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different data collection instruments will yield varied results. Unless respondents are given an opportunity to express both positive and negative events, the experience of the menopause may be inaccurately reflected.61
Estrogen-related Events and Menopause Utian108proposed a model to discriminate between the health conditions associated with aging versus those associated with menopause. The Utian model posits that characteristics associated with estrogen deficiency should be considered unique to menopause.1o8The major characteristics that are regarded as related to menopause using this model are hot flashes, epithelial atrophy, and bone loss. However, it is now recognized that the estrogen deficiency model may be too limited to explain all of the potential alterations in health status around the menopausal transition. Evolving models consider a broader range of hormone activity, including the potential role of androgens as well as estrogens. Furthermore, newer models attempt to account for the pattern and frequency of changes in hormone levels. Nevertheless, the estrogen deficiency model has stimulated a body of work to address the physiologic and psychologic phenomena of the menopause. Emerging issues in menopause research include the following: Definitions Concept of gradual transition from premenopause to perimenopause to postmenopause Increased attention to the need for a standard terminology to describe the phases of menopause to enhance between-study comparability Need to address whether a hormone-based or vaginal bleedingbased definition of menopause status is preferable New assays More sensitive and reliable assays for sex steroids More robust assays for key compounds such as inhibin Broadened theoretical models Inclusion of both transitory and persistent events Consideration of sex steroids other than estrogen as potentially etiologic to some menopause events Accounting for multiple potential confounders and effect modifiers Use of sophisticated analytic strategies to account for complex patterns of hormone levels Hot Flashes
A hot flash is the increase in perception of heat within or on the body. This is often accompanied by sudden skin flushing and perspira-
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tion. Some women report rapid heart beat and lightheadedness in association with the hot flash. The range of hot flash frequency varies (from less than daily to several per hour)lo6,113 as well as the duration (from 112, 113 seconds to an hour).106, In a longitudinal follow-up study of a US community-based sample, 40% to 58% of women reported hot flashes in the 2-year period surrounding the final menses.63Thus, hot flashes occur in the perimenopause as well as postmenopause. The estimated prevalence of hot flashes ranges between 50% and 85%.@,lo4 Hot flashes decrease (without treatment) as the time from menopause increase^.^^ The relationship between hot flashes and estrogen status is complex and has been reviewed by GreendaleZ9and Kronenberp47and their colleagues. Although the etiology of hot flashes remains speculative, one working hypothesis is that the loss of ovarian function leads to decreased hypothalamic opioid tone and thermoregulatory instability. Thus, although it is not accurate to say that hot flashes are caused by low estrogen levels, changing estrogen levels may be the source of the dysregulation of the hypothalamic thermoregulatory axis. The relation of hot flashes to changing estrogen levels is a good example of the need to update the estrogen-deficiency model to account for more complex relations. Consistent evidence suggests that administration of postmenopausal estrogen diminishes hot flush frequency in a dose-dependent manner."%94,101 Although the potential for hot flashes to disrupt daily activity and sleep quality is well-known, few studies have produced quantitative estimates of the quality-of-life impact of hot flashes.46Recent investigations have suggested that hot flashes might have metabolic consequences, such as hyperglycemia, hypertriglyceridemia, and glucocortihowever, these findings have not been corroborated coid excess19,26, ffi; by others1" and remain speculative. Other possible metabolic correlates of hot flashes include premenstrual syndromeN and greater bone loss than in women without hot flashes,'l although the latter finding has not been confirmed in subsequent evaluation^.^^ One cross-sectional study found that women with osteoporosis were more likely to report more frequent and more intense premenstrual symptoms, oligomenorrhea, and a history of vasomotor symptoms when compared with controls of a similar age (average of 64 years).48 The sources of between-population variations in the occurrence of hot flashes may offer insight into the symptoms of menopause. In comparison with Western Caucasian cultures, Japanese, Indonesian, and Mayan women7,53 report a markedly lower prevalence (OYOto loo/,) of hot flashes at menopause. In contrast, the rate of hot flashes among perimenopausal women in seven Southeast Asian countries is between 20% and 6O%, much closer to estimates of hot flashes in women in Western samples? Population and geographic variability in the occurrence of hot flashes may be related to several factors, including the lack of similar meaning of the concept of hot flash, the different incidence in hotter climates, the interpretation of hot flashes as fever, differences in
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reporting due to cultural norms, environmental modifiers (e.g., dietary estrogens), or genetic differences in the biology of menopause. The crosscultural difference in the hot flash experience is an area of active biologic and epidemiologic research. Factors that might be associated with, provoke, or intensify hot flashes have received little attention. In two studies, no association between the occurrence of hot flashes and employment status, social class, age, marital status, parity, menarcheal age, and age of menopause has been evident.", 89 Recent investigations have reported that stressful situations can provoke hot flashes.lo3This is concordant with Ballinger's thesis that stress may lead to falls in estrogen and thereby precipitate menopausal symptom^.^
MENOPAUSE AND THE EPITHELIUM: DERMATOLOGIC AND GENITOURINARY IMPACT Epidermis
Substantial evidence suggests that estrogen influences the dermis and epidermis, but its clinical impact on skin integrity has received limited investigation. Collagen synthesis and maturation are stimulated 40, y3 Nonrandomized studies of estrogen administration by suggest that estrogen preserves collagen content", l 2 and benefits the mechanical properties of skin.76Small randomized clinical trials have reported that estrogen maintains both skin collagen content and 58 To date, two large population-based, cross-sectional studthi~kness.'~, ies of the effects of estrogen on skin have found discordant results. One found that the skin of estrogen users was thinner on the basis of caliper assessment of skin thickness," whereas the other reported that estrogen use was associated with a substantially lower prevalence of skin wrinkles and dry skin on the basis of a clinical dermatologic exarnination.*l
Vaginal Epithelium
Clinically, the genital changes seen in postmenopausal women include subepithelial and epithelial alterations that lead to shortening of the vaginal canal, loss of rugae, and a pale sometimes friable epithelial surface. Although it is generally agreed that this is a postmenopausal phenomenon, these observed vaginal changes have not been well-quantified, and thus their response to supplemental estrogen has not been evaluated using quantitative methods. The vaginal smear maturation index (the proportion of basal, parabasal, and superficial cells) is a biologic assay of estrogen's effect on vaginal tissue, however, the maturation index does not correlate with vaginal symptoms.102
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Lower Urinary Tract Estrogen receptors are located on the urethra and bladder triAfter menopause, the urethra can become thinner due to regression of its squamous epithelial layer.1z1It is postulated that postmenopausal estrogen-related changes in the lower urinary tract lead to dysuria (caused by a thinned urethra), urinary frequency (caused by atrophic trigonitis), stress incontinence (caused by a loss of urethral back-pressure and less sphincter tone), and urge incontinence (caused by to atrophic trigonitis). Although these are plausible hypotheses, concordant epidemiologic evidence of a relation between menopause and urinary consequences is limited. Epidemiologic studies are contradictory as to whether the prevalence of incontinence increases in the menopause.33,37, 69, Placebo-controlled intervention studies of oral estrogen for stress incontinence have been few in number; some have reported no effect, but small sample sizes limit the ability to detect effe~ts.8~1 118 One trial of estrogen in combination with phenylpropanolamine for stress urinary incontinence found a 50% reduction in incontinent episode~.~* A 40% reduction in the symptoms of urge incontinence was reported in a clinical trial of estradiol and estriol for urge urinary in~ontinence."~ Although a recent meta-analysis of estrogen trials for incontinence concluded that the effect of estrogen on incontinence is small, the limitations of the trials to date must be considered (e.g., small samples, varied forms of incontinence, and the use of relatively weak e~trogens).~~ Bone Density and Calcium Metabolism
Osteoporosis is considered to be the classic estrogen-deficiency disease, yet studies of possible bone loss at the time of menopause have not been concordant. This lack of consistency may be the result of several methodological constraints, including the following: 1. Measurements of diverse bone sites and markers of bone status are likely to vary in their ability to demonstrate detectable changes with time. 2. The study may fail to account for characteristics of women (in addition to menopause status) that may predispose to more or less change in bone?' 3. Age may be used as an index for menopause rather than the actual measurement of menstrual status. 4. Imprecise or conflicting definitions of premenopause, perimenopause, and postmenopause may be used. This is particularly problematic when cross-sectional data are used to make inferences about events across the menopausal transition. Heightened attention to the onset of subtle changes in the hypothalamic pituitary axis in the early and mid perimenopause has led to
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investigations to determine whether some corresponding bone loss occurs during perimenopause. Hernandez and co-workers31using peripheral CT of the distal radius reported that there was lower trabecular bone mass in the perimenopause period (women had missed three to six menstrual cycles in the previous year) and that older perimenopausal women had lower bone mass in comparison with younger perimenopausal women. By grouping women according to their menstrual pattern, Nilas and Christiansen" found increasing rates of bone loss from forearm sites and the spine as the frequency of menses declined. From early to late perimenopause, the forearm loss increased from 0.5% to 1% annually with a trend toward higher rates at the distal forearm site 98 and throughout the transition. Other studies both ~ross-sectional~~~ 10ngitudinal~~ in design have found evidence of bone loss in perimenopausal women, albeit, the perimenopausal status is typically defined by chronologic age as opposed to the measurement of hormones, concurrent 95 presentation with menopausal symptoms, or menstrual bleeding.22, Other cross-sectional studies have not found significant losses of bone mass before the menopause.", *l Slemenda and c o - w ~ r k e r sfound ~~ no forearm bone loss in early perimenopausal women but identical rates of 1%per year in both late perimenopausal and postmenopausal women. The changes at two forearm sites were similar and showed no acceleration immediately after menopause. In one of the rare longitudinal studies, a 12-year investigation encompassing 160 women, there was no change in bone mineral density (BMD) of the forearm in the 2 years prior to menopause, but there was a 16% loss in BMD in the 8 years following menopause.79 Lower axial BMD measured in women between the ages of 47 and 59 years predicted fracture risk within the subsequent 2-year period.& Women in the lowest quartile of spine BMD (by dual x-ray absorptiometry) had a 2.9 times greater risk of fracture than women in the highest quartile of spine BMD.45The effect of menopause on fracture incidence was stronger than the effect of a 5-year age increase.'07 In most studies using fracture rather than BMD as the endpoint, there has been no difference in the average age at menopause in cases versus controlsG or in the proportion with earlier age of menopause. A case-control study and a prospective cohort study have shown that menopause after age 55 years is protective for fracture. This has led some investigators to suggest that the inappropriate prolongation of menopausal levels of bone remodeling accounts for the increased frequency of vertebral fracture.lI6 If the menopause is indeed an initiating event for higher rates of bone loss, women with early natural menopause (before age 45 years) who spend a longer time in the postmenopause (adjusted for chronologic age) should have more bone loss and higher subsequent fracture risk than women who experience menopause at a later age. Some investigations have concluded that low BMD occurs with early menopause.25,52 However, others have reported no significant association between BMD
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and early menopause, albeit, early menopause was defined as before age 50 years.% Biochemical markers of bone turnover may be a more sensitive indicator of incipient changes in bone metabolism in the perimenopause and early postmenopause. Studies have shown that osteocalcin (a higher level of which is commonly thought of as a ”marker of formation” but which can represent higher bone turnover) increases with menopause.72,92 Some studies have correlated the timing of estrogen decline in the postmenopause with evidence of increased turnover by bone markers.20,72 However, a clear increase in osteocalcin at the time of the menopause has not been confirmed in all instances.41,74 Some evidence suggests that this rise may be a phenomenon of aging or a reflection of more long-term estrogen deficiency. In a cross-sectional study, Del Pino and co-workersZ0observed a rise in osteocalcin in women who were at least 2 years postmenopause but not in premenopausal women and women who had 2 years of menopausal amenorrhea. Other reported patterns of osteocalcin levels include a continuous increase from premenopause to postmen0pause,7~or a decline before menopause, a rise at menopause, and a fall in the seventh and eighth decades.41Osteocalcin levels have decreased in postmenopausal women treated with hormone replacement therapy? Hydroxyproline, a marker of bone resorption (and therefore turnover), has similarly been noted to rise at the time of the 73 menopause.6o* Few studies have evaluated the impact of a therapeutic regimen to minimize bone mineral loss during the perimenopause. Gambacciani and co-workersZ4evaluated the effect of a low-dose oral contraceptive containing 30 kg of ethinyl estradiol and 75 FLg of gestodene in a 2-year nonrandomized clinical trial of 32 women; all of the subjects were offered a calcium supplement. There was a significant decrease in bone turnover markers and a maintenance of BMD in the treated group, whereas the control group showed an increase in biochemical markers of bone remodeling and a significant decline of BMD. Vitamin D levels, although increasingly appreciated as an important component of bone health in the elderly, are rarely addressed with respect to menopause. In a cross-sectional design, Sowers and co-worke r reported ~ ~ ~an intriguing decline in vitamin D levels with menopause and the prevention of such decline in hormone users-highly suggestive evidence of an estrogen-related phenomenon that deserves further study. Several issues remain to be resolved, including whether there are ”fast” and ”slow” bone losers in the menopausal periodI8 and whether biochemical markers of bone turnover can be used to discriminate between such groups. Further information is also needed as to the duration of accelerated bone loss in the menopausal period. Pouilles and colleaguesT suggest that the accelerated phase of bone loss occurs early in the first year after menopause and lasts only a few years.
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Menopause and Other Chronic Diseases and Syndromes
The relation between menopause and cardiovascular disease is complex. Although numerous cohort studies have found that exogenous estrogens afford cardiovascular protection (reviewed by Wren)'*O and that several biomarkers of heart disease risk are negatively impacted on by menopause (reviewed by Sowers and LaI3et1-a):~there is not an abrupt increase in the rate of heart disease in women after the menopause.I5This topic is beyond the scope of this article, and the reader is referred to the previously mentioned reviews and to discussions elsewhere in this issue. Another complex question that is not addressed herein is the relationship among menopause, sexuality, and sexual function. Recent reviews and articles by Sarrells6ss7and Greendale and colleagues28discuss this issue in detail. The potential associations among menopause, postmenopausal estrogen use, and other chronic diseases and conditions have been the focus of new explorations in the field of menopause research. These have included studies of rheumatoid arthritis, osteoarthritis, and obesity. The findings of these investigations have been summarized by Sowers and LaPietra.97
SUMMARY
New paradigms for the study of menopause will increase our understanding of whether symptoms, syndromes, and chronic diseases are associated with menopause. Rather than considering menopause as a discrete event, it has become clear that the menopause transition takes place over many years. Although this realization is central to our understanding of menopause, it is difficult to measure the temporal pattern of changes in hormones and their relation to concurrent or subsequent health-related events. The model of hormonal changes at the time of the transition has been expanded to include not only declines in estrogen but changes in a broader range of hormones, including the potential role of androgens. New models are attempting to account for the pattern and frequency of changes in hormone levels. Another level of complexity is contributed by the expansion of the menopause model to include comorbid medical and psychiatric conditions, environmental influences, and behaviors as covariates that influence the expression of menopauserelated events. Although this more complicated paradigm makes the conduct of menopause research more challenging, it is also likely to elucidate previously confusing data, as the proper understanding of potentially complex exposures, effect modifiers, and confounders is more likely to provide clearer answers to critical research questions.
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ACKNOWLEDGMENT The authors thank Ellen L. Whaling for manuscript preparation and editorial assistance.
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