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Abstract Context Several statistical models were introduced for the prediction of age at menopause using a single measurement of anti-müllerian hormone (AMH); however, individual prediction is challenging and needs to be improved. Objective The objective of this study was to determine whether multiple AMH measurements can improve the prediction of age at menopause. Design All eligible reproductive-age women (n = 959) were selected from the Tehran Lipid and Glucose Study. The serum concentration of AMH was measured at the time of recruitment and twice after that at an average of 6-year intervals. An accelerated failure-time model with Weibull distribution was used to predict age at menopause, using a single AMH value vs a model that included the annual AMH decline rate. The adequacy of these models was assessed using C statistics. Results The median follow-up period was 14 years, and 529 women reached menopause. Adding the annual decline rate to the model that included single AMH improved the model’s discrimination adequacy from 70% (95% CI: 67% to 71%) to 78% (95% CI: 75% to 80%) in terms of C statistics. The median of differences between actual and predicted age at menopause for the first model was –0.48 years and decreased to –0.21 in the model that included the decline rate. The predicted age at menopause for women with the same amount of age-specific AMH but an annual AMH decline rate of 95 percentiles was about one decade lower than in those with a decline rate of 5 percentiles. Conclusion Prediction of age at menopause could be improved by multiple AMH measurements; it will be useful in identifying women at risk of early menopause.

Abstract Background Experimental and epidemiological studies have linked metals with women's reproductive aging, but the mechanisms are not well understood. Disrupted ovarian folliculogenesis and diminished ovarian reserve could be a pathway through which metals impact reproductive hormones and outcomes. Objective The study aimed to evaluate the associations of heavy metals with anti-Müllerian hormone (AMH), a marker of ovarian reserve. Methods The study included 549 women from the Study of Women's Health Across the Nation with 2252 repeated AMH measurements from 10 to 0 years before the final menstrual period (FMP). Serum AMH concentrations were measured using picoAMH ELISA. Urinary concentrations of arsenic, cadmium, mercury, and lead were measured using high-resolution inductively coupled plasma mass spectrometry. Multivariable linear mixed regressions modeled AMH as a function of time before the FMP interaction terms between metals and time to the FMP were also included. Results Adjusting for confounders, compared with those in the lowest tertile, women in the highest tertile of urinary arsenic or mercury concentrations had lower AMH concentrations at the FMP (percent change: −32.1%; 95% CI, −52.9 to −2.2, P-trend = .03 for arsenic; percent change: −40.7%; 95% CI, −58.9 to −14.5, P-trend = .005 for mercury). Higher cadmium and mercury were also associated with accelerated rates of decline in AMH over time (percent change per year: −9.0%; 95% CI, −15.5 to −1.9, P-trend = .01 for cadmium; −7.3%; 95% CI, −14.0 to −0.1, P-trend = .04 for mercury). Conclusion Heavy metals including arsenic, cadmium, and mercury may act as ovarian toxicants by diminishing ovarian reserve in women approaching the FMP.

Abstract Context Per- and polyfluoroalkyl substances (PFAS) are widespread chemicals that may affect sex hormones and accelerate reproductive aging in midlife women. Objective To examine associations between serum PFAS concentrations at baseline (1999-2000) and longitudinal serum concentrations of follicle-stimulating hormone (FSH), estradiol, testosterone, and sex hormone-binding globulin (SHBG) at baseline and through 2015-2016. Design Prospective cohort. Setting General community. Participants 1371 midlife women 45 to 56 years of age at baseline in the Study of Women’s Health Across the Nation (SWAN). Main Outcome Measure(s) FSH, estradiol, testosterone, SHBG. Results In linear mixed models fitted with log-transformed hormones and log-transformed PFAS adjusting for age, site, race/ethnicity, smoking status, menopausal status, parity, and body mass index, FSH was positively associated with linear perfluorooctanoate [n-PFOA; 3.12% (95% CI 0.37%, 5.95%) increase for a doubling in serum concentration), linear perfluorooctane sulfonate [PFOS; 2.88% (0.21%, 5.63%)], branched perfluorooctane sulfonate [2.25% (0.02%, 4.54%)], total PFOS (3.03% (0.37%, 5.76%)), and 2-(N-ethyl-perfluorooctane sulfonamido) acetate [EtFOSAA; 1.70% (0.01%, 3.42%)]. Estradiol was inversely associated with perfluorononanoate [PFNA; −2.47% (−4.82%, −0.05%)) and n-PFOA (−2.43% (−4.97%, 0.18%)]. Significant linear trends were observed in the associations between PFOS and EtFOSAA with SHBG across parity (Ps trend ≤ 0.01), with generally inverse associations among nulliparous women but positive associations among women with 3+ births. No significant associations were observed between PFAS and testosterone. Conclusions This study observed positive associations of PFOA and PFOS with FSH and inverse associations of PFNA and PFOA with estradiol in midlife women during the menopausal transition, consistent with findings that PFAS affect reproductive aging.

Abstract Context Ectopic fat depots are related to the deregulation of energy homeostasis, leading to diseases related to obesity and metabolic syndrome (MetS). Despite significant changes in body composition over women's lifespans, little is known about the role of breast adipose tissue (BrAT) and its possible utilization as an ectopic fat depot in women of different menopausal statuses. Objective We aimed to assess the relationship between BrAT and metabolic glycemic and lipid profiles and body composition parameters in adult women. Methods In this cross-sectional study, we enrolled adult women undergoing routine mammograms and performed history and physical examination, body composition assessment, semi-automated assessment of breast adiposity (BA) from mammograms, and fasting blood collection for biochemical analysis. Correlations and multivariate regression analysis were used to examine associations of BA with metabolic and body composition parameters. Results Of the 101 participants included in the final analysis, 76.2% were in menopause, and 23.8% were in premenopause. The BA was positively related with fasting plasma glucose, glycated hemoglobin, homeostasis model assessment of insulin resistance, body mass index, waist circumference, body fat percentage, and abdominal visceral and subcutaneous fat when adjusted for age among women in postmenopause. Also, the BA was an independent predictor of hyperglycemia and MetS. These associations were not present among women in premenopause. Conclusion The BA was related to different adverse body composition and metabolic factors in women in postmenopause. The results suggest that there might be a relevant BrAT endocrine role during menopause, with mechanisms yet to be clarified, thus opening up research perspectives on the subject and potential clinical implications.

It is unclear whether risk for major depression during the menopausal transition or immediately thereafter is increased relative to pre-menopause. We aimed to examine whether the odds of experiencing major depression were greater when women were peri- or post-menopausal compared to when they were pre-menopausal, independent of a history of major depression at study entry and annual measures of vasomotor symptoms (VMS), serum levels of, or changes in, estradiol (E2), follicular stimulating hormone (FSH) or testosterone (T) and relevant confounders. Participants included the 221 African American and Caucasian women, aged 42-52 years, who were pre-menopausal at entry into the Pittsburgh site of a community-based study of menopause, the Study of Women's Health Across the Nation (SWAN). We conducted the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) to assess diagnoses of lifetime, annual and current major depression at baseline and at annual follow-ups. Psychosocial and health factors, and blood samples for assay of reproductive hormones, were obtained annually. Women were two to four times more likely to experience a major depressive episode (MDE) when they were peri-menopausal or early post-menopausal. Repeated-measures logistic regression analyses showed that the effect of menopausal status was independent of history of major depression and annually measured upsetting life events, psychotropic medication use, VMS and serum levels of or changes in reproductive hormones. History of major depression was a strong predictor of major depression throughout the study. The risk of major depression is greater for women during and immediately after the menopausal transition than when they are pre-menopausal.

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.

Abstract Context Previous epidemiologic studies of per- and polyfluoroalkyl substances (PFASs) and menopausal timing conducted in cross-sectional settings were limited by reverse causation because PFAS serum concentrations increase after menopause. Objectives To investigate associations between perfluoroalkyl substances and incident natural menopause. Design and Setting A prospective cohort of midlife women, the Study of Women’s Health Across the Nation, 1999-2017. Participants 1120 multiracial/ethnic premenopausal women aged 45-56 years. Methods Serum concentrations of perfluoroalkyls were quantified by high-performance liquid chromatography isotope dilution tandem mass spectrometry. Natural menopause was defined as the bleeding episode prior to at least 12 months of amenorrhea not due to surgery or hormone use. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Participants contributed 5466 person-years of follow-up, and 578 had incident natural menopause. Compared with the lowest tertile, women at the highest tertile of baseline serum concentrations had adjusted HR for natural menopause of 1.26 (95% CI: 1.02-1.57) for n-perfluorooctane sulfonic acid (n-PFOS) (Ptrend = .03), 1.27 (95% CI: 1.01-1.59) for branched-PFOS (Ptrend = .03), and 1.31 (95% CI: 1.04-1.65) for n-perfluorooctanoic acid (Ptrend = .01). Women were classified into four clusters based on their overall PFAS concentrations as mixtures: low, low–medium, medium–high, and high. Compared with the low cluster, the high cluster had a HR of 1.63 (95% CI: 1.08-2.45), which is equivalent to 2.0 years earlier median time to natural menopause. Conclusion This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life.

Abstract Context Reproductive hormones are important to the pathophysiology of cardiovascular disease (CVD) in women. However, standard estradiol (E2) and testosterone (T) assays lack sensitivity at the levels of postmenopausal women. Objective Investigate relations of mass spectrometry–assessed estrone (E1), E2, and T and SHBG and subclinical CVD in women. Design, Setting, and Participants Three hundred and four perimenopausal and postmenopausal women aged 40 to 60 years underwent subclinical CVD measurements. E1, E2, and T were assayed using liquid chromatography–tandem mass spectrometry; free T (FT) was estimated using ensemble allostery models. Regression models were adjusted for CVD risk factors. Main Outcome Measures Carotid artery intima media thickness, interadventitial diameter (IAD), and plaque; brachial flow mediated dilation (FMD). Results Higher E1 was related to higher FMD [β(SE) = 0.77 (0.37), P = 0.04], indicating better endothelial function. Higher E2 was related to lower IAD [β(SE) = −0.07 (0.02), P = 0.004], indicating less carotid remodeling. Higher SHBG was related to higher FMD [β(SE) = 1.31 (0.40), P = 0.001], yet higher IAD [β(SE) = 0.15 (0.06), P = 0.02] and plaque [OR (95% CI) = 1.84 (1.16 to 2.91), P = 0.009]; FT showed a similar yet inverse pattern of relations as SHBG. Thus, higher SHBG and lower FT were associated with better endothelial function, yet greater carotid remodeling and plaque. Conclusions Endogenous E1 levels were related to endothelial function and E2 to vascular remodeling, suggesting distinct roles of these estrogens. SHBG and FT have complex roles depending on the vessel under study. In midlife women, mass spectrometry–assessed estrone was related to endothelial function and estradiol to vascular remodeling. SHBG and free testosterone findings varied by vascular system.

Impaired kidney function and earlier menopause were associated with perfluorooctanoic acid (PFOA) serum levels in previous cross-sectional studies. Reverse causation, whereby health outcomes increase serum PFOA, may underlie these associations. We compared measured (subject to reverse causation) versus modeled (unaffected by reverse causation) serum PFOA in association with these outcomes to examine the possible role of reverse causation in these associations. In cross-sectional analyses, we analyzed PFOA in relation to self-reported menopause among women ( = 9,192) 30-65 years old and in relation to kidney function among adults > 20 years old ( = 29,499) in a highly exposed Mid-Ohio Valley cohort. Estimated glomerular filtration rate (eGFR, a marker of kidney function) and serum PFOA concentration were measured in blood samples collected during 2005-2006. Retrospective year-specific serum PFOA estimates were modeled independently of measured PFOA based on residential history and plant emissions. Using measured and modeled PFOA in 2005 or 2006 (predictor variables), cross-sectional associations were assessed for eGFR and menopause (yes/no). We also analyzed measured PFOA (dependent variable) in relation to the number of years since menopause. Menopause and eGFR were significantly associated with measured (trend tests: = 0.013, = 0.0005, respectively) but not with modeled serum PFOA ( = 0.50, = 0.76, respectively). Measured PFOA levels increased for the first 7 years after menopause (trend test, < 0.0001), providing further evidence that the observed association between measured PFOA and menopause is subject to reverse causation for this outcome. Our results support the conjecture that in previous studies, earlier menopause and reduced kidney function are the causes rather than the results of increased measured serum PFOA. These results suggest caution in using biomarkers in cross-sectional studies. Citation: Dhingra R, Winquist A, Darrow LA, Klein M, Steenland K. 2017. A study of reverse causation: examining the associations of perfluorooctanoic acid serum levels with two outcomes. Environ Health Perspect 125:416-421; http://dx.doi.org/10.1289/EHP273.

Females are at two-fold increased risk of Alzheimer's disease (AD). Leveraging naturally-occurring female biology may provide new insights into AD pathophysiology and address knowledge gaps underlying female-predominant risk. Younger age of menopause is associated with AD risk, especially tau pathology later in life. We examined plasma proteomics to identify biological targets linking menopause timing to tau. Functionally-intact postmenopausal women (n = 77) and men (n = 71) had plasma analyzed for 132 proteins via ultra-sensitive NUcleic acid Linked Immuno-Sandwich Assay. Protein levels were adjusted for age. Bivariate correlations screened associations between age at menopause and protein levels in females (bivariate p-value<0.05). Given age at menopause associated with multiple tau biomarkers, we identified proteins correlated with both menopause age and tau biomarkers at r≥0.20 and tested whether these proteins statistically mediated relationships between age of menopause and tau biomarkers. Candidate targets were then evaluated for sex-specificity in associations with tau across females and males. Seventeen proteins associated with menopause age. Older age at menopause associated with lower tau (ptau181, ptau231, MAPT), immune/inflammatory (e.g., TREM2, IL6, C1QA, IFNy, TNF), and metabolic (MDH1), and higher synaptic markers (e.g., NPTX2, BDNF, SNCA). Given high representation of tau biology, we evaluated proteomic overlap between menopause age and the identified tau markers (ptau181, ptau231, and MAPT). 11 proteins correlated with both menopause age and all three tau proteins. Of the 11 candidates, only AGRN statistically mediated the relationship between age of menopause and each tau measure (38-47% variance explained); however, all 11 factors showed significant associations with ptau181, ptau231, and MAPT in both males and females suggesting relevance to tau biology broadly. Of the 11 factors, AGRN, IL10, IL2, and CCL3 showed sex-specific interactions such that the positive association between each protein and tau biomarkers was disproportionately stronger in females versus males. Leveraging female-specific biology can uncover new insights into tau biology. In postmenopausal women, age of menopause associated with a range of biological factors relevant for brain aging, particularly immune, synaptic, and tau biology. AGRN, a secreted extracellular matrix heparin-sulfate glycoprotein, most consistently associated with menopause-related tau biomarkers and may be a candidate to explain female-specific vulnerability to tau.