Urinary metals and metal mixtures and timing of natural menopause in midlife women: The Study of Women’s Health Across the Nation

•Urinary arsenic was associated with earlier age at natural menopause.•Urinary lead was associated with earlier age at natural menopause.•Metal mixtures may play a role in accelerated ovarian aging. Exposure to metals and metal mixtures may influence ovarian aging. However, epidemiologic evidence of their potential impact is lacking. We prospectively examined the associations of 15 urinary metal concentrations and their mixtures with natural menopause in the Study of Women’s Health Across the Nation Multi-Pollutant Study. The study population consisted of 1082 premenopausal women from multiple racial/ethnic groups, aged 45–56 years at baseline (1999–2000), with the median follow-up of 4.1 years. Urinary concentrations of 15 metals, including arsenic, barium, cadmium, cobalt, cesium, copper, mercury, manganese, molybdenum, nickel, lead, antimony, tin, thallium, and zinc, were measured at baseline. Natural menopause was defined as the final bleeding episode prior to at least 12 months of amenorrhea, not due to surgery or hormone therapy. Cox proportional hazards models were used to examine associations between individual metal concentrations and timing of natural menopause. The associations between metal mixtures and natural menopause were evaluated using elastic net penalized Cox regression, and an environmental risk score (ERS) was computed to represent individual risks of natural menopause related to metal mixtures. The median age at natural menopause was 53.2 years. Using the Cox proportional hazards models, the adjusted hazard ratio (HR) (and its 95% confidence interval (CI)) for natural menopause was 1.32 (1.03, 1.67) for arsenic and 1.36 (1.05, 1.76) for lead, comparing the highest with the lowest quartiles of metal concentrations. The predicted ages at natural menopause in the highest and lowest quartiles were 52.7 and 53.5 years for arsenic; and 52.9 and 53.8 years for lead. A significant association between ERS and menopause was also observed. Women in the highest vs. the lowest quartiles of ERS had an HR of 1.71 (1.36, 2.15), equivalent to a 1.6 year earlier median time to natural menopause. This study suggests that arsenic, lead, and metal mixtures are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life.