Women's Midlife Health Project Research Articles

ADHERENCE TO THE MEDITERRANEAN DIET IS NOT RELATED TO BETA-AMYLOID DEPOSITION: DATA FROM THE WOMEN’S HEALTHY AGEING PROJECT

Research has indicated the neuroprotective potential of the Mediterranean diet. Adherence to the Mediterranean diet has shown preventative potential for Alzheimer's disease incidence and prevalence, yet few studies have investigated the impact of Mediterranean diet adherence on the hallmark protein; beta-amyloid. To investigate the association between Mediterranean diet adherence and beta-amyloid deposition in a cohort of healthy older Australian women. This study was a cross-sectional investigation of participants from the longitudinal, epidemiologically sourced Women's Healthy Ageing Project which is a follow-up of the Melbourne Women's Midlife Health Project. Assessments were conducted at the Centre for Medical Research, Royal Melbourne Hospital in Melbourne, Australia. F-18 Florbetaben positron emission tomography scanning was conducted at the Austin Centre for PET in Victoria, Australia. One hundred and eleven Women's Healthy Ageing Project participants were included in the study. Mediterranean diet adherence scores for all participants were calculated from the administration of a validated food frequency questionnaire constructed by the Cancer Council of Victoria. Beta-amyloid deposition was measured using positron emission tomography standardised uptake value ratios. Gamma regression analysis displayed no association between Mediterranean diet adherence and beta-amyloid deposition. This result was consistent across APOE-ε4 +/- cohorts and with the inclusion of covariates such as age, education, body mass index and cognition. This study found no association between adherence to the Mediterranean diet and beta-amyloid deposition in a cohort of healthy Australian women.

Hormone levels and cognitive function in postmenopausal midlife women

Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.

Gonadal hormones and cognitive aging: a midlife perspective.

Gonadal steroids affect a variety of brain processes. Cognitive consequences of hormonal changes associated with menopause are of scientific interest and of relevance to public health. Natural menopause is a normal physiological process that can only be directly studied through observational research. Similarly, surgical menopause in humans is rarely directly amenable to experimental research. Causality with respect to cognitive outcomes is, therefore, difficult to infer. Cross-sectional and longitudinal findings from the Melbourne Women's Midlife Health Project, the Study of Women's Health Across the Nation and other midlife cohorts suggest that cognitive consequences of the natural menopausal transition are probably small, at least during midlife and at least for episodic memory, which is a key cognitive domain. The data for episodic memory are the most robust. Midlife episodic memory performance is similar both shortly before and after natural menopause, and serum estradiol concentration in midlife is not associated with episodic memory performance. Effects of natural menopause on other cognitive domains, cognitive consequences of surgical menopause and late-life cognitive consequences of midlife hormonal exposures are less well understood and merit continued study.

Perimenopausal use of hormone therapy is associated with enhanced memory and hippocampal function later in life

Evidence suggests that initiation of some forms of hormone therapy (HT) early in the perimenopausal or postmenopausal stage might confer benefit to verbal memory and the neural systems underlying memory, whereas late-life initiation confers no benefit or harm. This “critical window hypothesis” remains a topic of debate. Using functional magnetic resonance imaging (fMRI), we examined the long-term impact of perimenopausal HT use on brain function during performance of verbal and figural memory tasks. Participants were 34 postmenopausal women (mean age 60 years) from the Melbourne Women's Midlife Health Project and included 17 early (perimenopausal) and continuous users of HT and 17 never users matched on age, education, and verbal knowledge. Continuous HT use from the perimenopausal stage versus no use was validated with prospective daily diary records and study visit data. The primary outcome was patterns of brain activation in an a priori region of interest in the medial temporal lobe during verbal encoding and recognition of words. Results indicated that perimenopausal HT users performed better than nonusers on the imaging verbal memory task (p < .05). During verbal recognition, perimenopausal HT users showed increased activation in the left hippocampus and decreased activation in the parahippocampal gyrus bilaterally compared with never users. Each of these patterns of activation was associated with better memory performance on the imaging memory task. These results suggest that perimenopausal use of HT might confer long-term benefits to verbal memory and the brain systems underlying verbal memory. More generally, the results support the critical window hypothesis.

Executive functions in recently postmenopausal women: Absence of strong association with serum gonadal steroids

It is controversial to what extent endogenous gonadal hormone exposures influence executive functions in midlife women. Participants in the population-based Melbourne Women's Midlife Health Project were administered a battery of neuropsychological tests on two occasions 2 years apart. Tests of executive functions were the Trail Making Test (Part B), Tower of London (administered at baseline only), Symbol Digit Modalities Test, Digit Span Backward, and Letter–Number Sequencing. Estrone, free estradiol, and free testosterone levels were measured at the time of the first testing, and analyses were restricted to 147 women aged 56–64 years who had recently undergone natural menopause (mean age of menopause 53 years) and were not using hormone therapy. In multiple linear regression analyses, 2 of 20 baseline associations were significant at an alpha level of 0.05. Estrone concentrations were positively associated with Tower of London performance ( p = 0.02), and the ratio of free testosterone to free estradiol was positively associated with scores on the Symbol Digit Modalities Test score ( p = 0.04). No hormone measure was significantly predictive of 2-year change in executive functions performance. Significance levels in these exploratory analyses were unadjusted for multiple comparisons, and observed associations could be due to unique psychometric properties of these particular tasks or due to chance. Sex hormone binding globulin concentrations were unrelated to executive function scores. In recently postmenopausal women not receiving hormone therapy, serum concentrations of estrone, estradiol and testosterone, and the testosterone/estradiol ratio are not strongly associated with executive functions.

Hormone levels and cognitive function in postmenopausal midlife women

Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.

Duration of vasomotor symptoms in middle-aged women

Vasomotor symptoms adversely affect the quality of life and functional status of most women during the menopausal transition, but little is known about how long these symptoms last. The most effective treatment, hormone therapy (HT), carries risks and benefits that depend on the timing and duration of use. In this study we sought to estimate the duration of vasomotor symptoms in a longitudinal study. We reanalyzed primary data from 438 women in the longitudinal cohort of the population-based Melbourne Women's Midlife Health Project. Two hundred and five women who had completed 13 years of follow-up were included in the analyses. The onset and cessation of vasomotor symptoms were reported, stratifying analyses according to ever use of HT. Symptom duration was calculated as the time between the first and last bothersome hot flush reported. The mean (SD) duration of bothersome menopausal symptoms for women who completed 13 years of follow-up and who never used HT was estimated to be 5.2 (3.8) years (median, 4 years). If women who used HT were included, the mean (SD) duration was 5.5 (4.0) years (median, 4 years). The estimated duration of symptoms varied according to the duration of longitudinal follow-up, with a mean estimate of 3.4 years (median, 3 years) when only 8 years of follow-up data were analyzed. The only factor associated with duration of hot flushes was regular exercise-more exercise was associated with shorter symptom duration. The average duration of vasomotor symptoms in this sample is more than 5 years, substantially longer than had been previously reported.

A prospective study of the association between endogenous hormones and depressive symptoms in postmenopausal women

Across a woman's lifetime, variations in hormone levels are known to influence mood and well-being. Whether absolute or changes in hormone levels over time are associated with depression among postmenopausal women remains unclear. The Melbourne Women's Midlife Health Project is a longitudinal population-based study of women who were followed through the menopausal transition. This analysis is based on data collected from 138 postmenopausal women in years 11 and 13 of the study, who were assessed for the presence of depressive symptoms using the Center for Epidemiological Studies Depression Scale. Logistic regression models were developed to determine whether absolute or changes in hormone levels were associated with depression. No significant associations were found between depressive symptoms and the absolute levels of sex hormone-binding globulin, testosterone, free androgen index, estradiol, free estradiol, or follicle-stimulating hormone (FSH). On the other hand, women with a decline in total serum estradiol over the 2-year period had a more than threefold increased risk of depressive symptoms (odds ratio, 3.5; 95% CI, 1.2-9.9). A large increase in FSH levels over this period was also associated with depressive symptoms (odds ratio, 2.6; 95% CI, 1.0-6.7). These associations remained even after adjustment for initial depression score, as well as a range of potential confounding factors. Changes in estradiol and, to a lesser extent, in FSH levels are associated with an increased risk of depressive symptoms in postmenopausal women. These results further support a role for fluctuating rather than absolute hormone levels in depression in later life.

The Menopausal Transition—Endocrinology

The Melbourne Women's MidLife Health Project (MWMHP) and related studies have yielded valuable information regarding the endocrine changes of the menopausal transition, which are summarized in this review. To describe the endocrinology of the menopause transition. Includes changes in inhibins A and B, follicle stimulating hormone (FSH), and estradiol, cross-sectionally in regularly cycling volunteers, and longitudinally (including testosterone) in women passing through the menopause transition. Early follicular phase hormone concentrations were measured by well-characterized immunoassays in normal volunteers aged 20-50 years, and in 438 subjects initially recruited between ages 45 and 55 for a longitudinal study of the menopause transition, the MWMHP, in which annual blood samples were obtained. The data summarized here includes the first 6 years of follow-up. These volunteers also recorded menstrual cycle data and responded to detailed annual questionnaires. In regularly cycling female volunteers aged more than 40 years, it was established that inhibin B is a significant determinant of circulating FSH levels. From the MWMHP, the central endocrine event marking the onset of menstrual irregularity was shown to be a fall in follicular phase inhibin B concentrations, with a nonsignificant rise in FSH and no change in estradiol or inhibin A. Cross-sectional analysis of data from women in the early stages of the MWMHP showed a wide variation in circulating FSH levels, irrespective of menopausal status, indicating that single FSH measurements provide little useful information regarding menopausal status. Based on the prospective determination of the date of final menses (FMP), it was shown that estradiol levels begin to fall and FSH levels to rise about 2 years before FMP. At the time of FMP, FSH levels were approximately 50% of those ultimately reached postmenopausally, while estradiol had fallen by approximately 50% from reproductive age levels. Despite a major decline in sexual function, as women transited the menopause, there was no significant decline in circulating testosterone levels, the decline in sexual function being correlated with the decline in estradiol, not testosterone. Analysis of data from related studies showed that endocrinologically normal ovulatory cycles could be observed in women who had already experienced cycle irregularity, even more than 3 months of amenorrhea, and could occur close to or at the time of FMP. An extensive database on the endocrinology of the menopause transition, including both cross-sectional and longitudinal information, has been obtained.

Physician diagnosed arthritis, reported arthritis and radiological non-axial osteoarthritis

To determine the question that best predicts radiographic evidence of non-axial osteoarthritis (OA). The Melbourne Women's Mid-life Health Project (MWMHP), commenced in 1991, is a population-based prospective study of 438 Australian-born. Two hundred and fifty-seven (57%) women remained in longitudinal assessment in 2002 and 224 (87%) women agreed to undergo X-rays of their hands and knees between 2002 and 2003. Annually participants were asked about aches and stiff joints and arthritis or rheumatism. In the eleventh year of follow-up X-rays were scored for evidence of OA using a validated scale, by two investigators who were blinded to questionnaire results. Information on hormone therapy use, physical activity, mood, smoking, body mass index (BMI) and age were obtained by both self-administered and face-to-face questionnaires. Patient reported physician diagnosed arthritis was the best predictor of radiological OA (ROA). The question had a specificity of 64%, a positive predictive value of 57% and a negative predictive value of 71%. Even the most reliable question about arthritis still had a relatively low specificity for radiologically diagnosed OA. Reporting symptoms were significantly more common in participants who were depressed, those who had a higher negative affect and those with a higher BMI. In large epidemiological studies where questionnaire assessment of OA is required, the greatest accuracy is achieved by asking about physician diagnosed arthritis. Concurrent application of a validated scale for mood is important.

The relationship of reports of aches and joint pains to the menopausal transition: a longitudinal study

Objectives Part I: To determine factors associated with reported joint symptoms across the menopausal transition. Part II: To investigate the relationship between symptom reporting and radiological arthritis in postmenopausal women.Design Part I: The Melbourne Women's Mid-life Health Project, commenced in 1991, is a population-based prospective study of 438 Australian-born women, aged 45–55 years and menstruating at baseline; they were interviewed annually over 8 years. The retention rate was 88% (n = 387). Part II: After 12 years of follow-up, 257 (57%) women returned for assessment and 224 agreed to undergo X-rays of their hands and knees.Methods Part I: Annual fasting blood collection, physical measurements, and interviews including questions about bothersome aches or stiff joints in the previous 2 weeks. A score for this symptom was calculated from the product of the severity and frequency data. These data were analyzed using random-effects time-series regression models. Part II: X-rays were scored for evidence of osteoarthritis using a validated scale, by two investigators who were blinded to questionnaire results.Results Part I: ‘Aches and stiff joints’ were the most commonly reported symptom and reporting increased over time in the longitudinal study. Variables significantly associated with reporting bothersome aches and stiff joints were high body mass index (BMI) (p < 0.001), high negative mood (p < 0.01), not being employed (p < 0.001), and experiencing the menopausal transition (p < 0.05). A higher severity and frequency of this symptom were associated with BMI (p < 0.01), not being employed (p < 0.05) and high negative mood (p < 0.005). Part II: The relationship between radiological osteoarthritis and symptom reports approached statistical significance (p = 0.06). Knee osteoarthritis was significantly associated with symptom reports (p = 0.008) but not hand osteoarthritis (p = 0.2).Conclusion Menopausal status, BMI, employment status and depressed mood were all associated with the experience of bothersome aches and stiff joints. Aches and stiff joints, common in postmenopausal women, are not necessarily indicative of radiological osteoarthritis.

The ReSTAGE Collaboration: defining optimal bleeding criteria for onset of early menopausal transition

Criteria for staging the menopausal transition are not established. This article evaluates five bleeding criteria for defining early transition and provides empirically based guidance regarding optimal criteria. Prospective menstrual calendar data from four population-based cohorts: TREMIN, Melbourne Women's Midlife Health Project (MWMHP), Seattle Midlife Women's Health Study (SMWHS), and Study of Women's Health Across the Nation (SWAN) with annual serum FSH from MWMHP and SWAN. 735 TREMIN, 279 SMWHS, 216 MWMHP, and 2270 SWAN women aged 35-57 at baseline who maintained menstrual calendars. Age at and time to menopause for: standard deviation >6 and >8 days, persistent difference in consecutive segments >6 days, irregularity, and >or=45 day segment. Serum FSH concentration. Most women experienced each of the bleeding criteria. Except for a persistent >6 day difference that occurs earlier, the criteria occur at a similar age and at approximately the same age as late transition in a large proportion of women. FSH was associated with all proposed markers. The early transition may be best described by ovarian activity consistent with the persistent >6 day difference, but further study is needed, as other proposed criterion are consistent with later menstrual changes.

A review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women's Midlife Health Project

The menopause, defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity, marks the end of natural female reproductive life. It is preceded by a period of menstrual cycle irregularity, the menopausal transition, which usually begins in the mid-40s and is conventionally divided into early and late phases. The endocrine changes, which underlie the transition, are predominantly the consequence of a marked decline in ovarian follicle numbers. The most significant changes include a decrease in early cycle inhibin B and in anti-Mullerian hormone (AMH) levels. The decline in inhibin B results in an increase in FSH, which appears to be an important factor in the maintenance of estradiol (E2) concentrations until late in reproductive life. In the post-menopause, FSH levels are markedly raised, E2 levels are low, whereas inhibin B and AMH are undetectable. The menopausal transition is a time of marked hormonal instability. The Melbourne Women's Midlife Health Project has been an extremely productive study in which it has been possible to describe longitudinal changes in hormone levels throughout the menopause transition and to separate the effects of hormone change from the effects of ageing on a number of endpoints. This review provides the background for an accompanying manuscript in which a novel approach to modelling the hormonal changes during the transition is described.

New findings from non-linear longitudinal modelling of menopausal hormone changes

Changes in FSH and estradiol (E2) across the menopausal transition are clearly not linear. The present study utilizes data from 204 women who completed the 13-year prospective Melbourne Women's Midlife Health Project. E2, FSH, symptoms, self-rated health, mood, sexual function and coronary heart disease (CHD) risk were measured longitudinally. We presumed an s-shaped curve for each hormone and estimated five parameters for each hormone curve for each woman: baseline, final value, range, slope at inflexion point and age at inflexion point. These parameters were found to adequately estimate the curve for each hormone. The median age of transition observed for E2 occurs >1 year later than the median age of transition observed for FSH. FSH parameters did not affect any of the health outcomes analysed. Hot flushes, night sweats, sleeping problems, vaginal dryness and to a lesser extent self-rated health were highly significantly associated with E2 range and slope. Sexual response and CHD risk were highly significantly associated with final E2 level (post-menopausally). These findings have clinical relevance in identifying which symptoms will be triggered by steep transitions of E2 such as sudden withdrawal and which health parameters may require a maintenance level of E2.

A hot‐deck multiple imputation procedure for gaps in longitudinal data on recurrent events

We consider the analysis of longitudinal data sets that include times of recurrent events, where interest lies in variables that are functions of the number of events and the time intervals between events for each individual, and where some cases have gaps when the information was not recorded. Discarding cases with gaps results in a loss of the recorded information in those cases. Other strategies such as simply splicing together the intervals before and after the gap potentially lead to bias. A relatively simple imputation approach is developed that bases the number and times of events within the gap on matches to completely recorded histories. Multiple imputation is used to propagate imputation uncertainty. The procedure is developed here for menstrual calendar data, where the recurrent events are menstrual bleeds recorded longitudinally over time. The recording is somewhat onerous, leading to gaps in the calendar data. The procedure is applied to two important data sets for assessing the menopausal transition, the Melbourne Women's Midlife Health Project and the TREMIN data. A simulation study is presented to assess the statistical properties of the proposed procedure. Some possible extensions of the approach are also considered.

Recommendations from a multi-study evaluation of proposed criteria for Staging Reproductive Aging

In 2001, the Stages of Reproductive Aging Workshop (STRAW) proposed bleeding and endocrine criteria for defining the early and late menopausal transition stages. Based on expert consensus, STRAW recommended a shorter interval of amenorrhea than the commonly used 90-day amenorrhea criteria for late transition and a >7-day change in cycle length for early transition. The ReSTAGE collaboration used prospective menstrual calendar data from four cohorts (TREMIN, Melbourne Women's Midlife Health Project, Seattle Midlife Women's Health Study, and Study of Women's Health Across the Nation) to quantitatively evaluate STRAW's recommendations. This empirical assessment supported the STRAW recommendations that (1) ≥60 days of amenorrhea be used to define the late menopausal transition and (2) that early transition is consistent with a persistent 7 or more day difference in length of consecutive cycles. Serum follicle stimulating hormone (FSH) values ≥40 IU/l was an independent marker of the transition and, when occurring together with a bleeding marker, increased prediction of final menstrual period. Such a FSH criterion could be incorporated into the STRAW paradigm to facilitate prediction of proximity of the final menstrual period.

44. SEX AND SEXAGENARIANS

This paper will describe the sexual function of postmenopausal women in their seventh decade and contrast this with their sexual function some 13 years earlier when the women were premenopausal. The presentation uses data obtained in the Melbourne Women's Midlife Health project, a longitudinal population based study of women's health. Australian-born women aged 45!!55 and resident in Melbourne were eligible for the initial telephone interview. All those who were still menstruating and not taking the oral contraceptive pill were invited to take part in a longitudinal study. At follow-up, a similar proportion of the women had a sexual partner at mean ages of 51 (81%) and 63 (83%). A marked decline in sexual function was evident. The percentage of partnered women who became sexually inactive increased from 17 to 23%, the percentage who had sex less than once a week increased from 15% to 42%, while the percentage having sex more than once a week declined from 20% to 4%. The overall score on the SPEQ significantly declined but only 19% of these women were significantly distressed about this. When specific domains of sexual function were examined, women using hormone therapy at L13 have significantly higher libido and greater responsivity (Sexual Response) than postmenopausal women not using HT. There was no significant difference with respect to dyspareunia, frequency of intercourse, partner problems or partner feelings. Sexual Response was significantly affected by prior function, feelings for partner, change in partnership, estradiol level and mood as well as aging. The circulating level of estradiol is highly significantly linked to Sexual Response. Thus both chronologic and reproductive aging have negative effects on sexual function and estradiol therapy may be needed.

Factors affecting the prevalence of osteoarthritis in healthy middle-aged women: Data from the longitudinal Melbourne Women's Midlife Health Project

The prevalence of osteoarthritis (OA) is greater in women then men. Weight, a factor strongly associated with osteoarthritis, is significantly increased over the menopausal transition. Despite the high prevalence of osteoarthritis, a disabling disease with limited treatment options, there is a paucity of studies in women. The longitudinal phase of the Melbourne Women's Midlife Health Project, is a population-based prospective study of 438 Australian born women who have been followed annually over 11 years. 257 (59%) of these women remained in longitudinal assessment at 11th year of follow-up and 224 of these women agreed to undergo X-rays of their knees and hands. In this study, X-rays were scored for evidence of osteoarthritis using a validated scale, by two investigators who were blinded to questionnaire results. Information on hormone therapy use, physical activity, smoking, BMI and age were obtained by both self-administered and face-to-face questionnaires. Results showed that one hundred and twenty-eight women (56%) had evidence of radiological OA. Forty-nine (21.6%) had evidence of radiological knee OA. One hundred and one (44.5%) had evidence of radiological hand OA. Compared to baseline, at 11th year of follow-up participants had put on weight (4 kg range −14 to 25 kg) and a larger proportion (25% vs. 40%) reported exercising frequently (P = 0.005). Physical activity and BMI were associated with higher prevalence of osteoarthritis in the final year of follow-up. Smoking was associated with a lower prevalence of radiological knee OA. The prevalence was 61% among never smokers compared to only 39% among those who smoked (P < 0.05). Total OA was associated with never having used hormone therapy (odds ratio 2.7; CI 1.1–6.9). There was a trend for increasing level of physical activity at ages 20–29 to be associated with an increased risk of knee OA (P value 0.03 for trend). In conclusion increasing age, BMI and history of more frequent physical activity in younger years were risk factors for radiological knee OA. In contrast, smoking appeared to be associated with less knee OA. Never having used hormone therapy was a risk factor for radiological hand and knee OA. Further work will be needed to determine whether modification of these factors can prevent the development of OA.

Evaluation of Four Proposed Bleeding Criteria for the Onset of Late Menopausal Transition

The current criterion for onset of late menopausal transition is amenorrhea of 90 d or more. The Stages of Reproductive Aging Workshop proposed alternative criteria based on a shorter period of amenorrhea. Empirical data comparing proposed criteria are not available. This paper evaluates the several bleeding criteria that served as the basis of these recommendations. The goal was to provide empirically based guidance regarding which bleeding criterion may be optimal for widespread application in clinical and research settings. The study used prospective menstrual calendar data from four community and population-based cohort studies: TREMIN, Melbourne Women's Midlife Health Project, Seattle Midlife Women's Health Study, and Study of Women's Health Across the Nation. The study included 735 TREMIN, 279 Seattle Midlife Women's Health Study, 216 Melbourne Women's Midlife Health Project, and 2270 Study of Women's Health Across the Nation women aged 35-57 yr at baseline who contributed 10 menstrual cycles or more. The main measures were the frequency of and median age at occurrence and time from occurrence to final menstrual period (FMP) for four criteria: skipped segment, 10-segment running range, 60- and 90-d amenorrhea. A skipped segment, 10-segment running range greater than 42 d and 60-d amenorrhea identify a similar time in women's reproductive lives. The latter two identify the exact same date in two thirds of women. All three criteria occur in a greater proportion of women than the 90-d criterion and are equally predictive of the FMP, although they occur 1-2 yr earlier. These findings support the recommendation of the Stages of Reproductive Aging Workshop that 60 d of amenorrhea be used to define onset of the late menopausal transition.

The Value of Follicle-Stimulating Hormone Concentration and Clinical Findings as Markers of the Late Menopausal Transition

The Stages of Reproductive Aging Workshop proposed bleeding and hormonal criteria for the menopausal transition, but operational definitions of hormone parameters were not specified. This paper investigates the longitudinal relationship of annual serum FSH levels with four proposed bleeding criteria for the late menopausal transition in two cohort studies. The goal is to provide empirically based guidance regarding application of hormonal criteria that may be optimal for widespread application in clinical and research settings for assessing menopausal stage. Prospective menstrual calendar and annual serum FSH data were collected from two population-based cohort studies: the Melbourne Women's Midlife Health Project and the Study of Women's Health Across the Nation. Participants in the study were 193 Melbourne Women's Midlife Health Project and 2223 Study of Women's Health Across the Nation women aged 42-57 yr at baseline who contributed 10 or more menstrual cycles and at least one annual serum FSH value. Association between bleeding criteria for the late menopausal transition and FSH was a main outcome measure. Associations of bleeding criteria, FSH, and hot flashes with the final menstrual period were also measured. A single FSH measure is an independent marker of the late menopausal transition, but FSH concentrations are less predictive of menopausal stage than any of four proposed bleeding criteria. Criterion FSH values for the late transition are similar across both studies. Experience of hot flashes adds no information in the presence of hormonal and bleeding criteria. An annual serum FSH concentration of 40 IU/liter could be incorporated, in conjunction with bleeding markers, into the Stages of Reproductive Aging Workshop paradigm for markers of the late menopausal transition.