Association between environmental pollutants and the FSH/AMH ratio as a marker of ovarian reserve

{"Background": "Ovarian reserve declines with age, but the rate of decline varies among women and cannot be fully explained by age alone\u2014over 70% of the variation in AMH and AFC remains unexplained by age. Environmental pollutants, particularly endocrine-disrupting chemicals (EDCs) such as phthalates, bisphenol A (BPA), and volatile organic compounds (VOCs), have been implicated as potential contributors to accelerated ovarian aging and premature menopause. However, most prior studies were cross-sectional comparisons between cases and controls, focused on infertile women or those in menopausal transition, and did not evaluate how pollutant exposure affects the rate of ovarian function decline with age in healthy reproductive-age women. This study aimed to assess whether exposure to 16 environmental pollutants modifies the age-related decline in ovarian reserve markers (AMH and FSH/AMH ratio) in healthy women aged 26\u201340.", "Methods": "A total of 107 healthy women aged 26\u201340 were recruited via online announcement at Korea University Anam Hospital; 98 were included after exclusions (9 excluded for missing questionnaire data, insufficient samples, or outliers). Participants completed questionnaires on reproductive history, smoking, drinking, and lifestyle. Blood samples were analyzed for FSH and AMH using electrochemiluminescence immunoassay. Urine samples were analyzed for 16 environmental pollutants: phthalate metabolites (MEHHP, MEOHP), environmental phenols (BPA, methyl paraben, ethyl paraben, propyl paraben, 2,4-DCP), VOC metabolites (tt-MA, BMA, PGA, MA, MHA, HA), PAH metabolites (1-hydroxypyrene, 2-hydroxynaphthalene), and cotinine. Pollutants were measured using HPLC-MS/MS or GC-MS, with creatinine normalization. Participants were divided into low- and high-exposure groups based on median pollutant levels. Linear regression and multivariate regression were used to assess relationships between age, hormones, and pollutants. The difference in slope of hormonal change with age between exposure groups was tested using a z-test formula comparing non-standardized regression coefficients.", "Key Results": "Mean participant age was not explicitly reported as a single value but ranged 26\u201340; mean FSH was 3.97 mIU/mL, mean AMH was 4.73 ng/mL, and mean FSH/AMH ratio was 1.18. AMH decreased by 0.37 ng/mL per year of age (p=0.001), while FSH showed no significant relationship with age. The FSH/AMH ratio increased by 0.12 per year (p=0.001). In multivariate regression, AMH decreased with increasing age and 2,4-DCP level (p=0.000, R\u00b2=45.4%), while the FSH/AMH ratio increased with age and BMA exposure (p=0.002, R\u00b2=41.7%). When comparing rate of change between exposure groups, the FSH/AMH ratio increased significantly faster in the high-exposure group for tt-MA (5.2 times faster, p<0.05) and 2-NAP (3.7 times faster, p<0.05). Non-significant but notable differences in FSH/AMH ratio change rates were observed for MEHHP (4.0\u00d7), MEOHP (3.2\u00d7), BPA (2.2\u00d7), cotinine (2.1\u00d7), MA (3.0\u00d7), and HA (2.0\u00d7). For AMH, the high-exposure groups for MEHHP, MEOHP, tt-MA, and MA showed 1.8-, 2.0-, 1.9-, and 1.7-fold faster decline, respectively, but none reached statistical significance.", "Clinical Implications": "This study provides preliminary evidence that exposure to common environmental pollutants\u2014particularly benzene metabolite tt-MA and naphthalene metabolite 2-NAP\u2014may accelerate the age-related decline in ovarian reserve, as measured by the FSH/AMH ratio. The FSH/AMH ratio appeared more sensitive than AMH alone in detecting differences in the rate of ovarian aging between exposure groups. These findings highlight the potential reproductive health risks of everyday exposures to VOCs and PAHs from sources such as smoking, automobile exhaust, and indoor/outdoor air pollution. However, the study's cross-sectional design, small sample size (n=98), and reliance on single urine measurements limit causal inference. Larger prospective cohort studies are needed to confirm these associations and to clarify exposure windows and metabolic pathways. Clinicians should be aware that environmental exposures may contribute to unexplained variability in ovarian reserve markers among reproductive-age women."}