The Mediating Role of Follicle-Stimulating Hormone in the Associations between Exposure to Perfluoroalkyl Substances and Incident Natural Menopause

Abstract

Exposure to perfluoroalkyl substances (PFAS) has been associated with earlier natural menopause, possibly through depletion of ovarian reserve and disturbance of hormone homeostasis. We aimed to investigate and quantify the degree to which follicle-stimulating hormone (FSH) could mediate the associations between PFAS exposure and natural menopause among 1120 premenopausal women aged 45-56 years in 1999-2000 from the Study of Women’s Health Across the Nation (SWAN). Serum concentrations of linear- and branched-chain perfluorooctane sulfonic acid (n-PFOS and sm-PFOS), linear-chain perfluorooctanoic acid (n-PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) were measured in 1999-2000 and included in the analyses because their detection frequency was larger than 70%. Accelerated failure time models were utilized to evaluate time to incident natural menopause. 578 women reached natural menopause, with a median survival time of 6.5 (95% CI: 6.1, 6.8) years. The proportion of the effect mediated through FSH was 8.5% (95% CI: -11.7%, 24.0%) for n-PFOS, 13.2% (95% CI: 0.0%, 24.5%) for sm-PFOS, 26.9% (95% CI: 15.6%, 38.4%) for n-PFOA, and 21.7% (6.8%, 37.0%) for PFNA. No significant associations were observed for PFHxS. PFAS are associated with an earlier age at natural menopause. The effect of PFAS on natural menopause may be partially explained by variation in FSH concentrations.