Perfluoroalkyl Substances and Incident Natural Menopause in Midlife Women: The Mediating Role of Sex Hormones

By Ning Ding, Siobán D. Harlow, John F. Randolph Jr, Bhramar Mukherjee, Stuart Batterman, Ellen B. Gold, and Sung Kyun Park
Am. J. Epidemiol.
March 22, 2022
DOI: 10.1093/aje/kwac052

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been associated with earlier natural menopause; however, the underlying mechanisms are not well understood, particularly the extent to which this relationship is mediated by sex hormones. We analyzed data from 1120 premenopausal women from the Study of Women’s Health Across the Nation (SWAN) from 1999 to 2017. Causal mediation analysis was applied to quantify the degree to which follicle-stimulating hormone (FSH) and estradiol (E2) could mediate the associations between PFAS and incident natural menopause. Participants with higher PFAS concentrations had shorter time to natural menopause, with a relative survival of 0.82 (95% CI: 0.69, 0.96) for linear perfluorooctane sulfonate (n-PFOS), 0.84 (95% CI: 0.69, 1.00) for branched PFOS (Sm-PFOS), 0.79 (95% CI: 0.66, 0.93) for linear perfluorooctanoate (n-PFOA), and 0.84 (95% CI: 0.71, 0.97) for perfluorononanoate (PFNA), comparing the highest to the lowest tertile of concentrations. 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 mediation was observed by E2. The effect of PFAS on natural menopause may be partially explained by variations in FSH concentrations.

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