Associations of Perfluoroalkyl Substances with Incident Natural Menopause: The Study of Women's Health Across the Nation

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) (P-trend =.03), 1.27 (95% CI: 1.01-1.59) for branchedPFOS (P-trend =.03), and 1.31 (95% CI: 1.04-1.65) for n-perfluorooctanoic acid (P-trend =.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.