The role of reproductive hormones and anovulation in moderating the relationship of phthalates with fecundability

Abstract

BACKGROUND AND AIM: Phthalates are endocrine disruptors that may inhibit folliculogenesis and we previously observed a relationship of metabolites of DEHP, DEP and BzBP with reduced fecundability. Estrogen supplementation may additionally mitigate phthalate-associated follicular atresia. Thus, we aimed to evaluate whether the impact of phthalates on achieving pregnancy was modified by their relationship with endogenous reproductive hormones and anovulation. METHODS: The EAGeR trial (2007-2011) enrolled 1,228 women attempting pregnancy with a history of pregnancy loss and followed them for up to 6 menstrual cycles or throughout pregnancy if they became pregnant. Twenty phthalate metabolites were measured in a 3-day pooled urine sample at the beginning of the first menstrual cycle of follow-up. Hormone levels were assessed during the follicular phase, ovulation and the luteal phase in the first two cycles. Cycles were considered anovulatory in the absence of a surge in luteinizing hormone (LH). Generalized estimating equations assessed risk of anovulation and generalized linear models change in hormone levels, adjusting for urinary creatinine and individual characteristics. Modification of the relationship of DEHP, DEP, and BzBP with fecundability by quartiles of estradiol was evaluated using discrete-time Cox proportional hazards models, incorporating interaction terms. RESULTS:We observed no clear relationship between phthalates and anovulation. Phthalates were associated with lower levels of estradiol and higher levels of follicle-stimulating hormone across the menstrual cycle, and higher pregnanediol and LH in the luteal phase. We observed the strongest association of metabolites of DEHP and DEP with fecundability among women in the lowest quartile of estradiol during the follicular phase (e.g. DEP fecundability odds ratio [FOR] 0.70, 95% CI 0.55, 0.91 for quartile 1 vs. FOR 0.95, 95% CI 0.76, 1.18 for quartile 4, p-interaction = 0.036). CONCLUSIONS:Reproductive hormones may play a role in the relationship of phthalates with fecundability among couples trying to conceive. KEYWORDS: Phthalates, Female reproductive outcomes