Associations ofPerfluoroalkyl Substances withIncident Natural Menopause: the Study of Women’s Health Across the Nation

Abstract

Context: Previous epidemiologic studies of per- and polyfluoroalkyl substances (PFAS) 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 PFAS serum concentrations and incident natural menopause.Design and Setting: A prospective cohort of midlife women, the Study of Women’s Health Across the Nation, from 1999 to 2017.Participants: 1120 multi-racial/ethnic premenopausal women (White, Black, Chinese and Japanese) aged 45-56 years in 1999-2000.Methods: Serum PFAS concentrations were measured using an online solid phase extraction-high performance liquid chromatography-isotope dilution-tandem mass spectrometry. The final menstrual period was determined during the annual follow-up visits. 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 to 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=0.03), 1.27 (95%CI: 1.01-1.59) for branched-PFOS (Ptrend=0.03), and 1.31 (95%CI: 1.04-1.65) for n-perfluorooctanoic acid (Ptrend=0.01). Women were classified into four clusters based on their overall PFAS concentrations as mixtures: low, low-medium, medium-high, and high. Compared to the low cluster, the high cluster had a HR of 1.63 (95% CI: 1.44-1.84), which is interpreted as 2.0 years earlier experience of 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.