The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

We hypothesised that antenatal exposure to ubiquitous phthalates may lead to an earlier menarche and a lower prevalence of polycystic ovarian syndrome (PCOS) and polycystic ovarian morphology (PCO) in adolescence. The Western Australian Pregnancy Cohort (Raine) Study recruited 3000 women at 18 weeks of gestation in 1989-91, 1377 had antenatal serum stored without thawing at -80°C. An unselected subset was evaluated in the early follicular phase for PCO and PCOS by ultrasound and serum evaluation in adolescence. Serum was analysed for Anti-Mullerian Hormone (AMH), inhibin B, sex-hormone binding globulin (SHBG), testosterone, androstenedione and DHEAS. 400 µL of the frozen maternal serum underwent isotope diluted liquid chromatography - tandem mass spectrometry (LC-MS/MS), with preceding enzymatic deconjugation followed by solid phase extraction to determine phthalate exposure. 244 girls attended assessment and most common phthalate metabolites were detectable in the majority of the 123 samples available. Several phthalates were negatively associated with maternal SHBG, associations with maternal androgens were less consistent. The sum of the metabolites of di-(2-ethylhexyl) phthalate (DEHP) were associated with a non-significant tendency towards an earlier age at menarche (p=0.069). Uterine volume was positively associated with mono-(carboxy-iso-octyl) phthalate (MCiOP) (p=0.018). Exposure to monoethyl phthalate (MEP) and the sum of all phthalate metabolites (Σall phth.m) was protective against PCOS in adolescence (p=0.001, p=0.005, respectively). There were negative associations of MEP with PCO (p=0.022), and MEP with serum AMH (p=0.031). Consequently our data suggests that antenatal exposure to environmental phthalates may be associated with oestrogenic and/or anti-androgenic reproductive effects in adolescent girls.