Mary Fran Sowers

Anti-Mullerian Hormone and Inhibin B in the Definition of Ovarian Aging and the Menopause Transition

CONTEXT/OBJECTIVE The objective of the study was to determine whether anti-Mullerian hormone (AMH) and inhibin B are viable endocrine biomarkers for framing the menopause transition from initiation to the final menstrual period (FMP). DESIGN We assayed AMH, inhibin B, and FSH in 300 archival follicular phase specimens from 50 women with six consecutive annual visits commencing in 1993 when all women were in the pre- and perimenopausal menopause stages. Subsequently each woman had a documented FMP. The assay results were fitted as individual-woman profiles and then related to time to FMP and age at FMP as outcomes. RESULTS Based on annual values from six time points prior to the FMP, (log)AMH longitudinal profiles declined and were highly associated with a time point 5 yr prior to FMP [including both observed and values below detection (P < 0.0001 and P = 0.0001, respectively)]. Baseline AMH profiles were also associated with age at FMP (P = 0.035). Models of declining (log)inhibin B profiles (including both observed and values below detection) were associated with time to FMP (P < 0.0001 and P = 0.0003, respectively). There was no significant association of (log)inhibin B profiles with age at FMP. CONCLUSIONS AMH, an endocrine marker that reflects the transition of resting primordial follicles to growing follicles, declined to a time point 5 yr prior to the FMP; this may represent a critical biological juncture in the menopause transition. Low and nondetectable levels inhibin B levels also were observed 4-5 yr prior to the FMP but were less predictive of time to FMP or age at FMP.

Sex Hormone–Binding Globulin and the Free Androgen Index Are Related to Cardiovascular Risk Factors in Multiethnic Premenopausal and Perimenopausal Women Enrolled in the Study of Women Across the Nation (SWAN)

Background—Recent clinical trials have shifted attention away from estrogens and toward androgens and sex hormone–binding globulin (SHBG) as potential mediators of increasing cardiovascular (CV) risk in women at midlife. Methods and Results—The correlation between reproductive hormones and CV risk factors was evaluated in a multiethnic (white, black, Hispanic, Chinese, and Japanese) sample of 3297 premenopausal and perimenopausal women. Testosterone and estradiol (E2) were evaluated along with SHBG and the free androgen index (FAI), the amount of testosterone not bound by SHBG. Low SHBG and high FAI were strongly and consistently related to elevated CV risk factors (higher insulin, glucose, and hemostatic and inflammatory markers and adverse lipids) even after controlling for body mass index (P<0.001 for all). Low levels of E2 were associated with elevated CV risk factors to a lesser degree. These observations were consistent across the 5 ethnic groups. Compared with whites, blacks had higher levels of SHBG and lower levels of FAI, and Chinese had lower levels of SHBG and higher levels of FAI. Conclusions—Low SHBG and high FAI are strongly associated with CV risk factors in racially diverse women, and thus, androgens likely play a role in the CV risk profile of perimenopausal women.

Are Changes in Cardiovascular Disease Risk Factors in Midlife Women due to Chronological Aging or to the Menopausal Transition

OBJECTIVES This prospective study examined whether changes in traditional and novel coronary heart disease (CHD) risk factors are greater within a year of the final menstrual period (FMP), relative to changes that occur before or after that interval, in a multiethnic cohort. BACKGROUND Understanding the influence of menopause on CHD risk remains elusive and has been evaluated primarily in Caucasian samples. METHODS SWAN (Study of Womens Health Across the Nation) is a prospective study of the menopausal transition in 3,302 minority (African American, Hispanic, Japanese, or Chinese) and Caucasian women. After 10 annual examinations, 1,054 women had achieved an FMP not due to surgery and without hormone therapy use before FMP. Measured CHD risk factors included lipids and lipoproteins, glucose, insulin, blood pressure, fibrinogen, and C-reactive protein. We assessed which of 2 models provided a better fit with the observed risk factor changes over time in relation to the FMP: a linear model, consistent with chronological aging, or a piecewise linear model, consistent with ovarian aging. RESULTS Only total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B demonstrated substantial increases within the 1-year interval before and after the FMP, consistent with menopause-induced changes. This pattern was similar across ethnic groups. The other risk factors were consistent with a linear model, indicative of chronological aging. CONCLUSIONS Women experience a unique increase in lipids at the time of the FMP. Monitoring lipids in perimenopausal women should enhance primary prevention of CHD.

SWAN: A Multicenter, Multiethnic, Community-Based Cohort Study of Women and the Menopausal Transition

Study of Womens Health Across the Nation (SWAN) is the first national study to describe women at midlife, an understudied age group. Its multidisciplinary approach provides the opportunity to consider the contributions of both culture and biology so that one may better understand health of women. The SWAN employs a prospective design that includes sufficient pre- and postmenopausal observations to ensure the separation of menopause-related and age-related physiological changes. Other attributes include the comprehensive standardized data collection related to biological, behavioral, physiological, social, environmental, and cultural factors; specialized data collection methodologies suitable to address the monthly and yearly variation in behavioral and biological patterns; general ability to community-dwelling populations recruited from major United States population centers; sufficiently large sample size and numbers of data points to ensure reliable estimates of associations and relevant effect sizes; and inclusion of sufficient numbers of racial/ethnic minorities to provide comparative information with the non-Hispanic Caucasian population. Because of these attributes, SWAN can contribute new and substantive knowledge about womens health in general and the menopause transition in particular.

Magnetic resonance-detected subchondral bone marrow and cartilage defect characteristics associated with pain and X-ray-defined knee osteoarthritis

OBJECTIVE To assess whether the presence of subchondral bone marrow abnormalities (bone marrow edema (BME)) and cartilage defects, determined by magnetic resonance imaging (MRI), would explain the difference between painful osteoarthritis of the knee (OAK) compared with painless OAK or pain without OAK. METHOD Four groups of women (30 per group), aged 35-55 years, were recruited from the southeast Michigan Osteoarthritis cohort (group 1: painful OAK; group 2: painless OAK; group 3: knee pain without OAK; and group 4: no OAK or knee pain). OAK was defined by a Kellgren-Lawrence score of 2 or greater, while pain was based on self-report. BME and cartilage defects were identified from MRI. RESULTS BME lesions were identified in 56% of all knees. BME lesions were four times (95% CI=1.7, 8.7) more likely to occur in the painless OAK group as compared with the group with pain, but no OAK. BME lesions >1cm were more frequent (OR=5.0; 95% CI=1.4, 10.5) in the painful OAK group than all other groups. While the frequency of BME lesions was similar in the painless OAK and painful OAK groups, there were more lesions, >1cm, in the painful OAK group. About 75% of all knees had evidence of some cartilage defect, of which 35% were full-thickness defects. Full-thickness cartilage defects occurred frequently in painful OAK. One-third of knees with full-thickness defects and 47% of knees with cartilage defects involving bone had BME >1cm. Women with radiographic OA, full-thickness articular cartilage defects, and adjacent subchondral cortical bone defects were significantly more likely to have painful OAK than other groups (OR=3.2; 95% CI=1.3, 7.6). CONCLUSION The finding on MRI of subchondral BME cannot satisfactorily explain the presence or absence of knee pain. However, women with BME and full-thickness articular cartilage defects accompanied by adjacent subchondral cortical bone defects were significantly more likely to have painful OAK than painless OAK.

Disordered eating, menstrual irregularity, and Bone minéral Density in Female runners

PURPOSE To examine the relationships between disordered eating, menstrual irregularity, and low bone mineral density (BMD) in young female runners. METHODS Subjects were 91 competitive female distance runners aged 18-26 yr. Disordered eating was measured by the Eating Disorder Inventory (EDI). Menstrual irregularity was defined as oligo/amenorrhea (0-9 menses per year). BMD was measured by dual x-ray absorptiometry. RESULTS An elevated score on the EDI (highest quartile) was associated with oligo/amenorrhea, after adjusting for percent body fat, age, miles run per week, age at menarche, and dietary fat, (OR [95% CI]: 4.6 [1.1-18.6]). Oligo/amenorrheic runners had lower BMD than eumenorrheic runners at the spine (-5%), hip (-6%), and whole body (-3%), even after accounting for weight, percent body fat, EDI score, and age at menarche. Eumenorrheic runners with elevated EDI scores had lower BMD than eumenorrheic runners with normal EDI scores at the spine (-11%), with trends at the hip (-5%), and whole body (-5%), after adjusting for differences in weight and percent body fat. Runners with both an elevated EDI score and oligo/amenorrhea had no further reduction in BMD than runners with only one of these risk factors. CONCLUSION In young competitive female distance runners, (i) disordered eating is strongly related to menstrual irregularity, (ii) menstrual irregularity is associated with low BMD, and (iii) disordered eating is associated with low BMD in the absence of menstrual irregularity.

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.

Lipid Changes During the Menopause Transition in Relation to Age and Weight The Study of Women's Health Across the Nation

Few studies have prospectively examined lipid changes across the menopause transition or in relation to menopausal changes in endogenous hormones. The relative independent contributions of menopause and age to lipid changes are unclear. Lipid changes were examined in relation to changes in menopausal status and in levels of estradiol and follicle-stimulating hormone in 2,659 women followed in the Study of Womens Health Across the Nation (1995-2004). Baseline age was 42-52 years, and all were initially pre- or perimenopausal. Women were followed annually for up to 7 years (average, 3.9 years). Lipid changes occurred primarily during the later phases of menopause, with menopause-related changes similar in magnitude to changes attributable to aging. Total cholesterol, low density lipoprotein cholesterol, triglycerides, and lipoprotein(a) peaked during late peri- and early postmenopause, while changes in the early stages of menopause were minimal. The relative odds of low density lipoprotein cholesterol (> or =130 mg/dL) for early postmenopausal, compared with premenopausal, women were 2.1 (95% confidence interval: 1.5, 2.9). High density lipoprotein cholesterol also peaked in late peri- and early postmenopause. Results for estradiol and follicle-stimulating hormone confirmed the results based on status defined by bleeding patterns. Increases in lipids were smallest in women who were heaviest at baseline.

Urinary Bisphenol A and Type-2 Diabetes in U.S. Adults: Data from NHANES 2003-2008

Objective Bisphenol A (BPA) is found in plastics and other consumer products; exposure may lead to insulin resistance and development of type-2 diabetes mellitus (T2DM) through over-activation of pancreatic β-cells. Previous studies using data from the National Health and Nutrition Examination Survey (NHANES) showed an inconsistent association between prevalence of self-reported T2DM and urinary BPA. We used a different diagnosis method of T2DM (hemoglobin A1c (HbA1c)) with a larger subset of NHANES. Methods and Findings We analyzed data from 4,389 adult participants who were part of a sub-study of environmental phenol measurements in urine from three NHANES cycles from 2003 to 2008. T2DM was defined as having a HbA1c ≥6.5% or use of diabetes medication. The weighted prevalence of T2DM was 9.2%. Analysis of the total sample revealed that a two-fold increase in urinary BPA was associated with an odds ratio (OR) of 1.08 of T2DM (95% confidence interval (CI), 1.02 to 1.16), after controlling for potential confounders. However, when we examined each NHANES cycle individually, we only found a statistically significant association in the 2003/04 cycle (n = 1,364, OR = 1.23 (95% CI, 1.07 to 1.42) for each doubling in urinary BPA). We found no association in either the NHANES cycle from 2005/06 (n = 1,363, OR = 1.05 (95% CI, 0.94 to 1.18)); or 2007/08 (n = 1,662, OR = 1.06 (95% CI, 0.91 to 1.23)). Similar patterns of associations between BPA and continuous HbA1c were also observed. Conclusions Although higher urinary BPA was associated with elevated HbA1c and T2DM in the pooled analysis, it was driven by data from only one NHANES cycle. Additional studies, especially of a longitudinal design with repeated BPA measurements, are needed to further elucidate the association between BPA and T2DM.

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 Womens Midlife Health Project, Seattle Midlife Womens Health Study, and Study of Womens Health Across the Nation) to quantitatively evaluate STRAWs 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.