Exposure to per- and polyfluoroalkyl substances (PFAS) and timing of menarche: A systematic review and meta-analysis

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals with potential endocrine-disrupting properties. Exposure to PFAS may influence pubertal development, particularly the timing of menarche, a key marker of reproductive health. However, existing studies report conflicting results, limiting clear synthesis. This systematic review and meta-analysis evaluated the association between PFAS exposure and age at menarche, applying statistical models to address study heterogeneity. Methods: Following PRISMA guidelines, we included 14 observational studies from PubMed, Embase, and Scopus, examining exposures to PFOA, PFOS, PFHxS, and PFNA. Standardized regression coefficients (b) harmonize different effect measures and quantify the direction and strength of association. Mixed-effect models were employed to explore heterogeneity, with the timing of exposure and study design as a moderator variable. Results: A positive association was observed between PFOA and PFOS exposure and delayed menarche, especially in longitudinal studies with postnatal exposure (PFOA: b = 0.180, 95 % CI: 0.070, 0.289; PFOS: b = 0.122, 95 % CI: 0.063, 0.180). No associations were found in cross-sectional and prenatal exposure studies. Moderator analyses confirmed the influence of study design and exposure timing on effect sizes (p < 0.001). No associations were found for PFHxS and PFNA. Conclusions: These findings suggest a potential role of PFAS, particularly PFOA and PFOS, in delaying menarche, with stronger effects in postnatal exposure studies. Standardization of exposure and statistical methods is needed in future research to improve comparability and clarify this relationship.