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Department of Obstetrics and Gynecology, School of Medicine (J.F.R.), and Departments of Epidemiology (MF.S., I.V.B., S.D.H.) and Biostatistics (R.J.L.), School of Public Health, University of Michigan, Ann Arbor, Michigan 48109; and Department of Obstetrics and Gynecology (J.L.L.), Rush University Medical Center, Chicago, Illinois 60612
Address all correspondence and requests for reprints to: John F. Randolph, Jr., M.D., L4228 Women’s Hospital, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0276. E-mail: jfrandol{at}med.umich.edu.
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Abstract |
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At the baseline visit, 46.2% of the women were classified as being early perimenopausal, with the remaining being premenopausal. By the second follow-up visit, 5.5% of the women in that cohort were postmenopausal, 66.8% were early perimenopausal, 8.3% were late perimenopausal, and 19.4% remained premenopausal.
Serum E2 concentrations decreased significantly with age, with a steeper decline at higher ages. FSH concentrations increased significantly with age, with a steeper increase at higher ages. Similar patterns in the decline of E2 and the increase in FSH with age were found across ethnic groups, but the levels of these hormones differed by race/ethnicity. Specifically, over time, Chinese and Japanese women had lower E2 concentrations but similar FSH levels, compared with Caucasian women, and African American women had higher FSH concentrations but comparable E2 levels with those of Caucasian women. These ethnic differences in E2 and FSH were independent of menopausal status. The effect of BMI on serum E2 and FSH levels varied by menopausal status. Increasing BMI was associated with decreasing concentrations of E2 among premenopausal and early perimenopausal women but was associated with increasing concentrations of E2 among late perimenopausal and postmenopausal women. Increasing BMI was associated with decreasing concentrations of FSH, with the effect of BMI becoming larger as women transitioned through menopause.
We conclude that serum E2 levels decrease and FSH concentrations increase with increasing age in midlife women, that ethnic differences in E2 over time differ from ethnic differences in FSH and suggest ethnic differences in the pituitary-ovarian relationship, and that the effect of BMI on E2 and FSH concentrations varies by menopausal status.
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Introduction |
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Few studies, whether cross-sectional (2, 3, 4, 5, 7, 8, 10, 11) or longitudinal (1, 6, 9), have investigated ethnic differences in reproductive hormones in midlife women. Lower serum E2 concentrations have been observed in postmenopausal Chinese women than in postmenopausal Caucasian women (12). Likewise, lower levels of serum E2 (13) were observed in African-American women than in Caucasian women approaching menopause as well as differences in urinary gonadotropins and sex steroids (14). A cross-sectional analysis of baseline serum E2 and FSH concentrations in early perimenopausal women in the Study of Women’s Health Across the Nation (SWAN) reported higher serum FSH levels in African American and Hispanic women compared with Caucasian women, but no ethnic differences in E2 levels after adjustment for BMI and other host characteristics (15). However, unadjusted E2 concentrations were significantly lower in Chinese women than Caucasian women despite comparable FSH levels and were still 13% lower in Chinese and Japanese women after adjustment for age and body size, although this difference was no longer statistically significant. FSH differences in ethnicities with comparable E2 concentrations, and possible E2 differences in ethnic groups with comparable FSH levels, suggest the possibility of ethnic differences in the pituitary-gonadal relationship during the menopausal transition. Moreover, other factors such as body mass index (BMI), age, and lifestyle factors have been associated with variations in serum concentrations of E2 and FSH in both longitudinal (1) and cross-sectional studies (12, 15) and may contribute to observed ethnic differences in reproductive hormone levels and patterns of change during the perimenopause.
SWAN is a longitudinal, multiethnic, multidisciplinary study of the natural history of the menopausal transition (16). Participants were recruited from five self-designated groups: African-American, Caucasian, Chinese, Japanese, and Hispanic women. The purpose of this report was to assess whether patterns of change in serum E2 and FSH concentrations with age differ by race/ethnicity in women traversing the menopausal transition. We also assess whether ethnic differences persist after accounting for individual host factors including BMI, menopausal status, socioeconomic status, parity, smoking, alcohol use, and an initial diagnosis of diabetes.
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Subjects and Methods |
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SWAN is a multisite, longitudinal cohort study being conducted in community-based groups of women. At baseline, 3302 women who belonged to one of five ethnic/racial groups were recruited: Caucasian (n = 1550), African-American (n = 935), Japanese (n = 281), Chinese (n = 250), and Hispanic (n = 286). Eligibility criteria for entry into the SWAN longitudinal cohort were: age 42 to 52 yr; intact uterus and at least one ovary; no current use of estrogens or other medications known to affect ovarian function; at least one menstrual period in the 3 months before screening; and self-identification as a member of one of the five eligible ethnic groups. Cohort recruitment and enrollment have been described in detail (16). In brief, participants were enrolled at seven clinical sites in the following geographic areas: Boston, Massachusetts; Chicago, Illinois; Detroit, Michigan; Los Angeles, California; Hudson County, New Jersey; Oakland, California; and Pittsburgh, Pennsylvania. Recruitment techniques were designed to generate a community-based sample of women at each of the seven sites. Each site enrolled Caucasian women as well as women belonging to one prespecified minority ethnic group. African-American women were enrolled in Boston, Chicago, the Detroit area, and Pittsburgh, whereas Japanese, Chinese, and Hispanic women were enrolled in Los Angeles, Oakland, and Hudson County, New Jersey, respectively. Institutional review board approval was obtained at each study site.
This analysis includes data from 3257 women with a serum E2 or FSH value from at least one longitudinal visit: baseline, first annual follow-up, or second annual follow-up. Participants with reported hysterectomy, pregnancy, or hormone replacement therapy use in the course of the study were censored from analysis at the corresponding visit. Two observations with E2 levels greater than 1000 pg/ml were excluded from analysis.
Measures
Common assessment protocols were observed across the seven clinical sites, supported by a written manual of operations, common training, and standardization of research staff. Height (centimeters) and weight (kilograms) were measured using a stadiometer and calibrated scales. BMI was calculated as weight (kilograms)/height (meters)2. Age, educational achievement, difficulty in paying for basics, smoking history, parity, and the diagnosis of diabetes at the baseline visit were self-reported. Seven smoking questions were adapted from the American Thoracic Society standards (17). Cigarette smoking was categorized as never, former, or current smoker.
Menopausal status was based on self-report of decreased predictability in the time between menses in the prior 3 months (early perimenopausal) or no decreased predictability in the same time period (premenopausal), no menses for 3–11 months (late perimenopausal), or no menses for 12 or more months (postmenopausal) (18).
Phlebotomy was performed in the morning after an overnight fast. Women were scheduled for venipuncture on d 2–7 of a spontaneous menstrual cycle occurring within 60 d of recruitment at the baseline visit and annually thereafter. Two attempts were made to obtain the d 2–7 sample. If a timed sample could not be obtained, a random fasting sample was taken within a 90-d window. Blood was refrigerated 1–2 h after phlebotomy and then, after centrifugation, the serum was aliquotted, frozen, and batched for shipment to the central laboratory. At the central laboratory, samples were catalogued and assayed continuously upon arrival.
FSH assays were conducted in singlicate and E2 assays in duplicate using an ACS-180 automated analyzer (Bayer Diagnostics Corp., Norwood, MA). Serum E2 concentrations were measured with a modified, off-line ACS-180 (E2–6) immunoassay. Inter- and intraassay coefficients of variation averaged 10.6 and 6.4%, respectively, over the assay range (12.5% at < 10 pg/ml) and the lower limit of detection was 1 pg/ml with a cross-reactivity of less than 1% (19). Serum FSH concentrations were measured with a two-site chemiluminometric immunoassay using constant amounts of two monoclonal antibodies provided by Bayer Diagnostics. Each antibody is directed to different regions on the ß-subunit (one coupled to paramagnetic particles and the other labeled with dimethyl-acridinium ester) with specificity for intact FSH. Inter- and intraassay coefficients of variation were 12.0 and 6.0%, respectively, and the lower limit of detection was 1.1 IU/liter.
Data analysis
We first used several exploratory techniques, including plots of individual profiles and smoothed average trends, to understand differences in age-related trends in hormone concentrations among relevant subpopulations and to identify possible interactions. We then used linear mixed models appropriate for repeated-measures data (SAS Proc Mixed, release 8.1, SAS Institute, Cary, NC) to assess whether decreases in E2 and increases in FSH concentrations during the menopausal transition (ages 42–55 yr) were associated with ethnicity or BMI. In the regression analyses, serum E2 and FSH concentrations and BMI were logarithmically transformed to reduce skewedness, with values back-transformed to present the results.
Age 42 yr, the youngest age in the study population, was defined as the reference age and centered by subtracting 42 from each woman’s chronological age. A status variable was created combining information on a woman’s menopausal status (pre-, early peri-, late peri-, and postmenopausal) and whether phlebotomy was performed within d 2–7 of a spontaneous menstrual cycle (in/out the window). Models were run including ethnicity as a covariate and stratifying by ethnicity. A variable for site is included in all models as a covariate to account for sampling design.
The initial model included age and status. We evaluated potential interactions between status and age. Potential interactions between age and ethnicity were examined for the whole study population and within each site. Next, log (BMI) was added to the model as a time-varying covariate and interactions with menopausal status were evaluated. Finally, other potential confounders including smoking, diabetes, parity, alcohol intake within 24 h before the blood draw, and socioeconomic status were evaluated. Final models account for age-related changes in the variance of both E2 and FSH and for differences in the variance structure for hormones measured in and out the d 2–7 window. We assumed conditional independence of the residual covariance structure conditional on the random effects, as suggested by the scatter plot matrix and adequate model fit, as assessed by the Akaike information criteria.
We conducted two informal checks of the robustness of the estimates. First, we restricted the analysis to participants with all three observations available. Second, using the method and the macro suggested by Verbeke and Molenberghs (20), we excluded influential observations. In both cases, the resulting estimates were very close to the original estimates.
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Results |
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. Notably, 10.9% had never been pregnant, 7.3% reported having diabetes at the baseline visit, 9.0% noted significant difficulty in paying for basic necessities, and 17.3% reported current smoking on at least one annual visit.
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. At the baseline visit, 46.2% of the women were classified as being early perimenopausal, with the remaining being premenopausal. By the second follow-up visit, 5.5% of the women in that cohort were postmenopausal, 66.7% were early perimenopausal, 8.4% were late perimenopausal, and 19.5% remained premenopausal. Both E2 and FSH concentrations were significantly higher in women who had phlebotomy outside the target window at all three visits. Consistently, E2 levels decreased over the three visits, whereas FSH concentrations increased, with the FSH increase being smaller for women assessed within the d 2–7 window than for women assessed outside of this window.
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. Consistent with the resulting longitudinal model, serum E2 concentrations within each status group declined with each visit in the overall cohort and when serum was obtained within the d 2–7 window. However, mean serum concentrations were higher at the follow-up visits than at baseline when serum was obtained outside the window. Serum FSH levels in the premenopausal and early perimenopausal groups in the entire cohort and when serum was obtained within the window increased minimally over the three visits and were lower at the first follow-up visit when serum was obtained outside the window. Serum FSH increased with each visit in the late perimenopause and postmenopause except in the group of late perimenopausal subjects able to have phlebotomy within the d 2–7 window. These may be compared with listed basal normal ranges for reproductive aged women of 20–60 pg/ml for E2 and 5–20 IU/liter for FSH (21).
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. The fitted average serum concentrations of E2 and FSH over age and stratified by ethnicity are shown in Fig. 1, A and B, respectively. Note that the hormone values in these plots are not equally spaced because models were fitted on the logarithmic scale. Serum E2 concentrations decreased significantly with age, with a steeper decline at higher ages (Fig. 1A). FSH concentrations increased significantly with age, with a steeper slope at higher ages (Fig. 1B). We found similar patterns in the decline of E2 and the increase in FSH with age across ethnic groups, but the levels of these hormones differed by race/ethnicity. Specifically, both Chinese and Japanese women had lower E2 concentrations, compared with Caucasians, whereas E2 concentrations of African-American and Hispanic women did not differ from those in Caucasian women. In contrast, African-American women demonstrated higher FSH concentrations, compared with Caucasian women, whereas FSH concentrations of Chinese, Hispanic, and Japanese women did not differ from those of Caucasians. The decline of E2 concentration with age was greater for early and late perimenopausal women assayed outside the d 2–7 window than for premenopausal women with samples within the window. The increase in FSH concentrations with age was largest for early perimenopausal and late perimenopausal women.
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. When stratified by menopausal status, the effect of BMI on E2 was negative and did not differ between premenopausal and early perimenopausal women, but among late perimenopausal and postmenopausal women, increasing BMI was associated with increasing concentrations of E2. Increasing BMI was associated with decreasing concentrations of FSH, with the effect of BMI becoming more pronounced as women transitioned through menopause. Diabetes at baseline was negatively associated with FSH levels. Current smoking was positively associated with serum FSH concentrations. Parity, socioeconomic status, alcohol intake, and physical activity were not significantly associated with either E2 or FSH and were not included in the models. |
Discussion |
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The consistently lower E2 concentrations in both Chinese and Japanese women, compared with Caucasian women, in the absence of a comparable difference in serum FSH concentrations, suggests either a difference in the feedback regulation of the pituitary or an ethnic-specific difference in pituitary sensitivity to gonadal-negative feedback. Feedback differences potentially could arise from the greater exposure to dietary estrogens reported in Asian populations (22, 23, 24). Although we documented that, among these SWAN enrollees, intake of the isoflavones daidzein and genistein was 2 times greater in Japanese women than in Chinese women (25), the average E2 and FSH levels of Chinese and Japanese women were not different, suggesting that dose-dependent negative feedback is an insufficient explanation of these observations. It is also possible that there is an ethnic-specific difference in the secretion of a nonestrogen regulator such as inhibin B (26, 27, 28).
The SWAN finding that E2 concentrations in Asian women are about 20% lower than Caucasian women over the entire midlife age range is consistent with studies reporting lower serum E2 levels in postmenopausal Chinese women than in postmenopausal Caucasian women (12). This phenomenon may be related to observations of reduced symptom reporting in Asian women (22, 23, 29, 30, 31, 32, 33), which has also been reported among perimenopausal Chinese and Japanese women in SWAN (24). The differences in the ethnic differentials in the E2 and FSH concentrations raise the possibility that symptom differences could have a central origin associated with decreased pituitary sensitivity to negative feedback rather than an ovarian source.
Although the magnitude of the difference is much more modest, the higher serum FSH levels in African-American women, compared with Caucasian women, despite comparable E2 concentrations, also suggests potential ethnic-specific differences in pituitary-ovarian communication. This finding, with longitudinal data, supports the baseline cross-sectional observation (15). These higher FSH concentrations may be related to an earlier menopause in African-American women (34, 35, 36) reported in other studies; however, SWAN has observed too few final menstrual periods in African-American women to appropriately test this relationship. The absence of significant differences in FSH levels in Asian or Hispanic women, compared with Caucasian women, must be viewed as preliminary because the observed difference in African-American women is quite modest and the power to discern such small differences is more limited in the Asian groups whose cohort size is smaller than the African-American and Caucasian cohorts.
The difference in the effect of BMI on E2 concentration by menopausal status has not been previously reported in cross-sectional (2, 3, 4, 5, 7, 8, 10, 11, 15) or longitudinal (1, 6, 9) studies. Ethnic differences in the relationship of BMI and reproductive hormones have been reported in cross-sectional studies (13, 14). For example, African-American but not Caucasian women had decreased levels of E2 with increasing BMI (13). Burger et al. (1) reported no significant BMI effect on E2 levels either as a function of age or with respect to a documented final menstrual period in what was the largest longitudinal study of the menopausal transition reported before the organization of SWAN. The failure to report this finding from the Melbourne Women’s Midlife Health Study may have arisen because the age range of their enrollees was 45–55 yr, compared with 42–52 yr among the SWAN enrollees. Thus, SWAN may have been able to detect differences in the early perimenopausal period that would not have readily been apparent in the Melbourne Women’s Midlife Health Study. Conversely, in SWAN the numbers of women classified as late perimenopausal (8.36%) or postmenopausal (5.48%) at the second follow-up visit are still relatively few and preclude undertaking a parallel retrospective analysis synchronized to the final menstrual period similar to the report from the Melbourne study. The shift in the BMI effect from early perimenopause to late perimenopause is statistically significant and consistent with a shift in estrogen metabolism associated with the decrease in ovarian E2 secretion at the menopausal transition. The decrease in FSH with increasing BMI is consistent with that observed in the baseline cross-sectional SWAN analysis (15) and with the retrospective analysis reported from the Melbourne Women’s Midlife Health Study (1).
The effect of age independent of menopausal status for both E2 and FSH concentrations is consistent with the Melbourne study (1) and suggests that neither hormone is a pure marker of ovarian aging. The age effect on E2 within each status group was significant only in premenopausal and early perimenopausal women who had samples obtained outside the d 2–7 window, a not unexpected finding because these were heterogeneous groups composed of predominantly cycling women sampled later in the cycle when E2 levels are higher but more variable. The age effect on FSH was not linear and was positive within status groups for all but postmenopausal women, suggesting an upper limit on FSH levels independent of age or status.
The serum E2 concentrations in postmenopausal women were higher than previously reported (1, 5, 6, 9), although the numbers of women were relatively small, and the levels decreased by approximately 30% from the first to the second follow-up visit. This decrease is consistent with the continued decline reported in the Melbourne study until several years after the final menstrual period (1), particularly in this group of women who were still in the very early postmenopause. Higher E2 levels are also consistent with the age-related, status-independent decline reported here because the postmenopausal women are still relatively young, again consistent with the Melbourne data (1). This is the most likely reason that the mean E2 level at the first follow-up visit in the postmenopausal subjects was quite similar to the basal levels in the other status groups. We do not believe it is due to a difference in the E2 assay because the assay was validated against appropriate standards (19).
The impact of the timing of the phlebotomy within or outside the early follicular window was demonstrated in the variance functions for E2 and FSH and stratified by the timing of the serum sample and was a major factor in the final model. Women with cycles predictable enough to facilitate phlebotomy on d 2–7 are included in the within-window group, whose data demonstrated nearly stable variance over the entire 42–55 yr age range. However, the out-of-window group increasingly included late perimenopausal women with unpredictable menstrual bleeding, women who were postmenopausal, and women with irregular cycles as well as women for whom there was complicated scheduling. This group demonstrated peak variability of both E2 and FSH at about age 49 yr, which is 2–3 yr before the expected mean final menstrual period (34).
The higher serum FSH levels with current smoking is consistent with the SWAN baseline cross-sectional analysis (15) and studies linking current smoking with an earlier age at menopause (33, 34). The lower serum FSH concentrations in women who reported a diagnosis of diabetes at the baseline visit has not been reported previously, although both type 1 (37) and type 2 diabetes (38) have been associated with an earlier age at menopause. No other covariates investigated were significantly associated with either serum E2 or FSH levels.
It must be emphasized that this longitudinal analysis is limited to the first three annual measures in women still predominantly in the early menopausal transition. Moreover, relatively few women have recorded a confirmed final menstrual period to provide an anchor from which to retrospectively assess longitudinal changes.
We conclude that: 1) serum E2 concentrations are lower but serum FSH levels are not statistically different in Chinese and Japanese women, compared with Caucasian women, throughout the menopausal transition; 2) serum FSH concentrations are higher but serum E2 levels are similar in African-American women, compared with Caucasian women, throughout the menopausal transition; 3) serum E2 concentrations decrease and FSH concentrations increase with increasing age, independent of menopausal status during the menopausal transition; and 4) the effect of body size, as measured by BMI, on serum E2 and FSH concentrations differs by menopausal status.
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Footnotes |
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Clinical Centers: University of Michigan, Ann Arbor, Michigan (U01 NR04061, MaryFran Sowers, PI); Massachusetts General Hospital, Boston, Massachusetts (U01 AG12531, Joel Finkelstein, PI); Rush University, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois (U01 AG12505, Lynda Powell, PI); University of California, Davis/Kaiser, California (U01 AG12554, Ellen Gold, PI); University of California, Los Angeles, California (U01 AG12539, Gail Greendale, PI); University of Medicine and Dentistry/New Jersey Medical School, Newark, New Jersey (U01 AG12535, Gerson Weiss, PI); and the University of Pittsburgh, Pittsburgh, Pennsylvania (U01 AG12546, Karen Matthews, PI).
Laboratory: University of Michigan, Ann Arbor, Michigan (U01 AG12495, Central Ligand Assay Satellite Services, Daniel McConnell, PI) and Medical Research Laboratories, Highland Heights, Kentucky (subcontract of U01 AG12553, Evan Stein, Director).
Coordinating Center: University of Pittsburgh, Pittsburgh, Pennsylvania (Kim Sutton-Tyrrell, PI).
Project Officers: Janice Phillips, Sherry Sherman.
Steering Committee Chair: Susan Johnson.
Abbreviations: BMI, Body mass index; E2, estradiol; SWAN, Study of Women’s Health Across the Nation.
Received July 8, 2003.
Accepted December 23, 2003.
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