Urinary Metals and Metal Mixtures and Incident Natural Menopause in Midlife Women: the Study of Women’s Health Across the Nation

Abstract

BACKGROUND AND AIM: Exposure to metals and metal mixtures may have long-term effects on ovarian aging. However, limited data have reported the possible effects of metals on the timing of natural menopause. We prospectively examined the associations of 15 urinary metal concentrations and their mixtures with incident natural menopause in the Study of Women’s Health Across the Nation Multi-Pollutant Study. METHODS: The study population consisted of 1082 premenopausal women from multiple racial/ethnic groups, aged 45-56 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. Natural menopause was defined as the bleeding episode prior to at least 12 months of amenorrhea, not due to surgery or hormone therapy. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for individual metals. The associations between metal mixtures and natural menopause were evaluated using elastic net (ENET) penalized Cox regression. An environmental risk score (ERS) was computed to represent individual risks of natural menopause related to metal mixtures. RESULTS:The median age at natural menopause was 50.5 years. The adjusted HR (95% CI) for natural menopause was 1.36 (1.06-1.72) for arsenic and 1.39 (1.08-1.80) for lead, comparing the highest with the lowest quartiles of metal concentrations in Cox models. Women in the highest vs. the lowest quartiles of ERS had an HR of 1.69 (1.35-2.12), which is equivalent to a 1.4 year earlier median time to natural menopause. This estimate was roughly equivalent to or even larger than an effect estimate of 1.1 years comparing current smokers versus never smokers in our study. CONCLUSIONS: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. KEYWORDS: Metals, mixtures, menopause, women, cohort study.