PFAS and menopause onset: Is it just a matter of reverse causation? Cross-sectional and longitudinal analyses in highly exposed women in the Veneto Region

Introduction: Several cross-sectional studies have linked perfluoroalkyl substances (PFAS) to prevalence of menopause. These findings might be influenced by reverse causation mechanism, making longitudinal studies more suitable. However, existing longitudinal studies are limited and present conflicting results.

Aim: This study investigates the association between PFAS and both prevalence and incidence of menopause, using longitudinal designs to limit the impact of reverse causation.

Methods: A surveillance program on a PFAS highly exposed population in the Veneto region started in 2017 with two rounds of screening, on average 3.8 years apart. Women who participated in the first screening (n = 11,046) were included in the cross-sectional analysis. Multivariate logistic regression models were used to estimate the Odds Ratios (ORs) of menopause associated with exposure to different PFAS. For incidence analysis a retrospective-prospective design used PFOA concentrations reconstructed to 2013 (n = 8536), and a prospective design involved women participating in both screenings (n = 1709), evaluating their baseline concentrations of PFOA, PFOS, and PFHxS. Cox proportional hazards models with age as the timescale were used to estimate Hazard Ratios (HRs), adjusting for sociodemographic and lifestyle factors.

Results: Increased menopause prevalence was associated with higher ln-concentrations of PFOA, PFOS, and PFHxS, with ORs of 1.31 (CI: 1.25-1.38), 1.51 (CI: 1.38-1.66), and 1.42 (CI: 1.34-1.51), respectively. The retrospective-prospective study showed increased risk of menopause in higher PFOA reconstructed quartiles, with HRs of 1.01 (CI: 0.87-1.18), 1.17 (CI: 1.02-1.37), and 1.07 (CI: 0.93-1.23) for the second, third and fourth quartiles. The prospective longitudinal study found no association between PFAS and menopause onset.

Conclusions: Our results showed a strong cross-sectional association between PFAS exposure and menopause, a weak positive association in the retrospective-prospective study, and no association in the prospective study. This suggests that cross-sectional associations may largely result from reverse causality due to early menopause on reducing PFAS excretion.