Huiyong Zheng

Change in Follicle-Stimulating Hormone and Estradiol Across the Menopausal Transition: Effect of Age at the Final Menstrual Period

BACKGROUND AND OBJECTIVE To determine whether patterns of change in serum estradiol (E2) and FSH across the menopausal transition were associated with age at the final menstrual period (FMP). DESIGN AND SETTING The Study of Womens Health Across the Nation (SWAN) is a seven-site, multiethnic, longitudinal study of the menopausal transition being conducted in 3302 menstruating women who were aged 42-52 yr at the 1996 study baseline. MEASUREMENTS Annually collected serum was assayed for E2 and FSH levels. Patterns of hormone change were evaluated in the 1215 women with a documented natural FMP by follow-up visit 9 (2006) using semiparametric stochastic and piecewise linear mixed modeling. RESULTS The FSH pattern across the menopausal transition began with an increase 6.10 yr before the FMP, an acceleration 2.05 yr before the FMP, deceleration beginning 0.20 yr before the FMP, and attainment of stable levels 2.00 yr after the FMP, independent of age at the FMP, race/ethnicity, or smoking status. Obesity attenuated the FSH rise and delayed the initial increase to 5.45 yr before the FMP. The mean E2 concentration did not change until 2.03 yr before the FMP when it began decreasing, achieving maximal rate of change at the FMP, then decelerating to achieve stability 2.17 yr after the FMP. Obesity, smoking behavior, and being Chinese or Japanese were associated with some variation in E2 levels but not the pattern of E2 change. CONCLUSIONS Time spans and overall patterns of change in serum FSH and E2 across the menopausal transition were not related to age at FMP or smoking, whereas time spans but not overall patterns were related to obesity and race/ethnicity.

Estradiol Rates of Change in Relation to the Final Menstrual Period in a Population-Based Cohort of Women

CONTEXT/OBJECTIVE The aim was to characterize rates of change in serum estradiol (E2) levels across the menopausal transition and into early postmenopause. SETTING/PARTICIPANTS We studied the Michigan Bone Health and Metabolism Study cohort of 629 women with median age of 38 yr (interquartile range, 7) at the 1992-1993 baseline with annual assessment of E2 levels over the subsequent 15-yr period. DESIGN/MAIN OUTCOME MEASURES: The purpose was to describe patterns of acceleration/deceleration in (log)E2 rates of change before and after the final menstrual period (FMP) using nonparametric and piecewise regression modeling. RESULTS Between -10 to -2 yr to the FMP, mean fitted serum E2 population values were relatively stable. The 95% confidence bands around the slight increase in E2 rate of change 5 yr prior to the FMP included the value of no change. The fitted population mean E2 value declined 67% from 64.5 pg/ml (se = 3.6) to 21 pg/ml (se = 1.2) in the 4 yr between -2 < FMP < +2. A second significant mean E2 rate of change was identified from 6-8 yr after FMP. Fitted population mean E2 values declined 18% from 18.1 pg/ml (se = 1.3) at FMP = 6 to 14.8 pg/ml (se = 1.3) at FMP = 8. In nonobese women, the mean E2 percent decline was 42% from FMP = 6 to FMP = 8, whereas in obese women, the mean E2 percent decline over this time was 31%. CONCLUSIONS Population mean serum E2 levels were sustained until approximately 2 yr prior to the FMP. In the ensuing 4-yr period, E2 levels declined 67%. A secondary E2 decline, commencing about 6 yr after the FMP, was observed in nonobese but not obese women.

Follicle Stimulating Hormone and Its Rate of Change in Defining Menopause Transition Stages

CONTEXT/OBJECTIVE The objective of the study was to identify menopause transition stages using acceleration or deceleration patterns of FSH rates of change from the late reproductive years to postmenopause. SETTING/PARTICIPANTS Participants were the Michigan Bone Health and Metabolism Study cohort of 629 women, aged 24-44 yr (in 1992/3), with 5757 annual FSH data points over a 14-yr period. DESIGN/MAIN OUTCOME MEASURES: The study was designed to relate acceleration/deceleration patterns in FSH rate of change to time to final menstrual period (FMP) and chronological age using nonparametric and piecewise regression modeling. RESULTS Four major FSH stages, based on rate of FSH change patterns, were identifiable in relation to the FMP. In FSH stage 1, the rate of FSH change increased modestly up to -7 yr prior to the FMP; in FSH stage 2 (-7 to -2 yr prior to FMP), there was a major acceleration in FSH rate of change. FSH stage 3 had an acute increase in FSH rate of change (-2 to +1 yr around the FMP), with average FSH level of 34 mIU/ml. The fourth, or plateau, FSH stage began at 1 yr after FMP when the average FSH level was 54 mIU/ml. During the yr 28-60, there were eight age-specific epochs defined by significant changes of FSH trajectory accelerations or decelerations and rate of change. CONCLUSIONS Four menopause transition stages bounding the FMP and eight epochs in chronological aging from age 28 to 60 yr were defined by changes of FSH trajectory accelerations/decelerations and rates of change. This timing information, combined with knowledge of FSH levels and menstrual cycle characteristics, can help discern the likely status of women with respect to their reproductive viability and menopause transition stage.

Amount of bone loss in relation to time around the final menstrual period and follicle-stimulating hormone staging of the transmenopause.

BACKGROUND AND OBJECTIVE The objective of the study was to describe bone loss rates across the transmenopause related to FSH staging and the final menstrual period (FMP). DESIGN AND SETTING This was a population-based cohort of 629 women (baseline age 24-44 yr) with annual data points over 15 yr. MEASUREMENTS Measures were bone mineral density (BMD), FSH to define four FSH stages, and menstrual bleeding cessation to define the FMP. Bone loss rates were reported by obesity status. RESULTS Annualized rates of lumbar spine bone loss began in FSH stage 3, which occurs approximately 2 yr prior to the FMP (1.67%/yr); bone loss continued into FSH stage 4 (1.21%/yr). Mean spine BMD in FSH stage 4 was 6.4% less than spine BMD value in FSH stage 1. Annualized rates of femoral neck (FN) bone loss began in FSH stage 3 (0.55%/yr) and continued into FSH stage 4 (0.72%/yr). The FN difference between mean values in FSH stage 1 and FSH stage 4 was 5%. Annualized rates of spine bone loss in the 2 yr prior to the FMP were 1.7%/yr, 3.3%/yr in the 2 yr after the FMP, and 1.1%/yr in the 2- to 7-yr period after the FMP. Nonobese women had lower BMD levels and greater bone loss rates. CONCLUSIONS Spine and FN bone loss accelerates in FSH stage 3. Bone loss also began to accelerate 2 yr before the FMP with the greatest loss occurring in the 2 yr after the FMP. Bone loss rates in both spine and FN BMD were greater in nonobese women than obese women.

Trajectory Clustering of Estradiol and Follicle-Stimulating Hormone during the Menopausal Transition among Women in the Study of Women's Health across the Nation (SWAN)

CONTEXT Variability in the pattern of change in estradiol (E2) and FSH levels over the menopause transition has not been well defined. OBJECTIVE The current study aimed to determine whether different trajectories of E2 and FSH could be identified and whether race/ethnicity and body mass index were related to the different trajectories. DESIGN The Study of Womens Health Across the Nation is a longitudinal observational study of the menopausal transition. SETTING Women aged 42-52 yr from seven participating sites were recruited and underwent up to 11 annual visits. PARTICIPANTS Postmenopausal women with 12 or more months of amenorrhea that was not due to hysterectomy/oophorectomy and who were not using hormone therapy before the final menstrual period participated in the study. MAIN OUTCOME MEASURES Annual serum E2 and FSH levels anchored to final menstrual period were measured. RESULTS Four distinct E2 trajectories and three distinct FSH trajectories were identified. The E2 trajectories were: slow decline (26.9%), flat (28.6%), rise/slow decline (13.1%), and rise/steep decline (31.5%). The FSH trajectories were: low (10.6%), medium (48.7%), and high (41.7%) rising patterns. Obesity increased the likelihood of a flat E2 and low FSH trajectory for all race/ethnic groups. Normal-weight Caucasian and African-American women tended to follow the rise/steep decline E2 and high FSH trajectories. Normal-weight Chinese/Japanese women tended to follow the slow decline E2 and the high/medium FSH trajectories. CONCLUSIONS E2 and FSH trajectories over the menopausal transition are not uniform across the population of women. Race/ethnicity and body mass index affect the trajectory of both E2 and FSH change over the menopausal transition.

Changes in Bone Resorption Across the Menopause Transition: Effects of Reproductive Hormones, Body Size, and Ethnicity

OBJECTIVE Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity. METHODS Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women. RESULTS Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m² and smallest in women with BMI >30 kg/m². Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. SUMMARY During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.

Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging

BACKGROUND In this study, levels and rates of change in total testosterone (T), sex hormone-binding globulin (SHBG) and free androgen index (FAI) were related to chronological age and to the final menstrual period (FMP) as an indicator of ovarian aging. METHODS Data were annually acquired over a 15-year period in 629 women of the Michigan Bone Health and Metabolism Study cohort. Data were censored for hormone therapy use. Endogenous androgen patterns over time were described with stochastic processes and bootstrapping. RESULTS With ovarian aging, T levels rose from a mean of 18 ng/dl commencing 10 years prior to the FMP to 27 ng/dl at the FMP. Over the 20-year period encompassing the FMP, modeled mean SHBG levels changed from 58 to 34 nM and the FAI ratio increased from 1.6 to 2.9 in a non-linear manner. With chronological aging, total T levels increased (P < 0.0001) from 43 to 50 years, but not thereafter. SHBG declined steadily with age with a modestly greater rate of change between 49 and 54 years. The FAI increased from 1.3 to 2.5 from 34 to 58 years. CONCLUSIONS T increased from approximately age 40 until the FMP whereas SHBG had rate of change patterns reflecting both chronological and ovarian aging components. These data provide new insight into the endogenous androgen patterns at mid-life.

Relationships between menopausal and mood symptoms and EEG sleep measures in a multi-ethnic sample of middle-aged women: the SWAN sleep study.

STUDY OBJECTIVES Examine associations of vasomotor and mood symptoms with visually scored and computer-generated measures of EEG sleep. DESIGN Cross-sectional analysis. SETTING Community-based in-home polysomnography (PSG). PARTICIPANTS 343 African American, Caucasian, and Chinese women; ages 48-58 years; pre-, peri- or post-menopausal; participating in the Study of Womens Health Across the Nation Sleep Study (SWAN Sleep Study). INTERVENTIONS None. MEASUREMENTS AND RESULTS Measures included PSG-assessed sleep duration, continuity, and architecture, delta sleep ratio (DSR) computed from automated counts of delta wave activity, daily diary-assessed vasomotor symptoms (VMS), questionnaires to collect mood (depression, anxiety) symptoms, medication, and lifestyle information, and menopausal status using bleeding criteria. Sleep outcomes were modeled using linear regression. Nocturnal VMS were associated with longer sleep time. Higher anxiety symptom scores were associated with longer sleep latency and lower sleep efficiency, but only in women reporting nocturnal VMS. Contrary to expectations, VMS and mood symptoms were unrelated to either DSR or REM latency. CONCLUSIONS Vasomotor symptoms moderated associations of anxiety with EEG sleep measures of sleep latency and sleep efficiency and was associated with longer sleep duration in this multi-ethnic sample of midlife women.

Masturbation Frequency and Sexual Function Domains Are Associated With Serum Reproductive Hormone Levels Across the Menopausal Transition

OBJECTIVE To determine whether reproductive hormones are related to sexual function during the menopausal transition. DESIGN The Study of Womens Health Across the Nation (SWAN) is a multiethnic cohort study of the menopausal transition located at seven US sites. At baseline, the 3302 community-based participants, aged 42-52, had an intact uterus and at least one ovary and were not using exogenous hormones. Participants self-identified as White, Black, Hispanic, Chinese, or Japanese. At baseline and at each of the 10 follow-up visits, sexual function was assessed by self-administered questionnaires, and blood was drawn to assay serum levels of T, estradiol, FSH, SHBG, and dehydroepiandrosterone sulfate. MAIN OUTCOME MEASURES Self-reported frequency of masturbation, sexual desire, sexual arousal, orgasm, and pain during intercourse. RESULTS Masturbation, sexual desire, and arousal were positively associated with T. Masturbation, arousal, and orgasm were negatively associated with FSH. Associations were modest. Estradiol was not related to any measured sexual function domain. Pain with intercourse was not associated with any hormone. CONCLUSIONS Reproductive hormones were associated with sexual function in midlife women. T was positively associated, supporting the role of androgens in female sexual function. FSH was negatively associated, supporting the role of menopausal status in female sexual function. The modest associations in this large study suggest that the relationships are subtle and may be of limited clinical significance.

Sources of variability in epidemiological studies of sleep using repeated nights of in-home polysomnography: SWAN Sleep Study.

STUDY OBJECTIVE To quantify sources of night-to-night variability. METHODS This project was conducted in 285 middle-aged African American, Caucasian, and Chinese women from the Study of Womens Health Across the Nation (SWAN) Sleep Study living in Chicago, the Detroit area, Oakland, and Pittsburgh. The study used 3 repeated nights of in-home polysomnography (PSG) measures. Night 1 data included assessment of sleep staging, sleep apnea, and periodic limb movements, while Nights 2 and 3 focused on sleep staging. RESULTS Mean total sleep time (TST) increased substantially from 365 minutes on Night 1 to 391 minutes and 380 minutes, respectively, on Nights 2 and 3. Mean percent sleep efficiency (SE%) for the 3 nights were 83%, 85%, and 85%, respectively. Night 1 sleep values were significantly different than Nights 2 and 3 measures except for S2 (%), S1 (min), and Delta (S3+4)%. Nights 2 and 3 differences in variability were negligible. Obesity, past smoking, and financial strain measures were associated with greater Night 1 vs. Night 2 or Night 3 differences. We concluded that there was significant Night 1 vs. Nights 2 and 3 variability and, though relatively modest, it was sufficient to bias estimates of association. Additionally, personal characteristics including smoking, obesity, and financial strain increased night-to-night variability. CONCLUSIONS This reports adds new information about between and within person sources of variation with in-home PSG and identifies elements that are essential in the design and planning of future sleep studies of multi-ethnic groups in social and physiological transition states such as the menopause.