Associations between Repeated Measures of Urinary Phthalate Metabolites with Hormones and Timing of Natural Menopause: The Study of Women's Health Across the Nation

Abstract

Background and Aim: Studies on phthalate metabolites and sex hormones during the menopausal transition are limited and have yielded conflicting results. We aimed to examine the associations of phthalate metabolites with hormones including estradiol, testosterone, follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), anti-Müllerian hormone (AMH), and the timing of natural menopause. Methods: We examined 1,189 midlife women from the Study of Women’s Health Across the Nation aged 45-56 years in 1999-2000 who had complete information on phthalate metabolites and hormones while not receiving hormone therapy. Urinary concentrations of 12 phthalate metabolites were repeatedly measured in 1999-2000 and 2002-2003. Hormones were measured at the same time points. Linear mixed-effect models were used to calculate percent differences (%D) and 95% confidence intervals (CIs) in serum concentrations of estradiol, testosterone, FSH, SHBG, and AMH per doubling in urinary phthalate metabolites. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of natural menopause per doubling increase in urinary phthalate metabolites. Results: We observed significant associations of phthalate metabolites with lower testosterone concentrations: mono (7-carboxy-2-methyloctyl) phthalate (MCOP) (%D: -2.08%, 95% CI: -3.66, -0.47), and mono-n-butyl phthalate (MnBP) (%D: -1.99%, 95% CI: -3.82, -0.13), after adjusting for multiple comparisons with false discovery rates < 5%. Lower AMH concentrations were also found with higher MECPP (%D: -14.26%, 95% CI: -24.10, -3.14), MEHHP (%D: -15.58%, 95% CI: -24.59, -5.50), and MEOHP (%D: -13.50%, 95% CI: -22.93, -2.90). No associations were observed for other hormones or timing of natural menopause. Conclusions: These results suggest that exposure to phthalates may affect circulating levels of testosterone in midlife women. Exposure to phthalates may also dimmish the ovarian reserve. Given the endocrine-disrupting role of phthalates, future studies are warranted to evaluate their impact on health outcomes among midlife women. Keywords: Phthalates; endocrine-disrupting chemicals; hormones; midlife women; menopause