Hypothalamic-pituitary-gonadal axis programming and disrupted ovarian-endocrine function in female offspring of the...

Children born after preeclampsia, the leading hypertensive disorder of pregnancy, are predisposed to long-term cardiometabolic and reproductive disorders that are likely associated with prenatal exposure to a dysregulated maternal endocrine milieu. We have previously described abnormal pubertal development and hyperandrogenism in female offspring from the preeclamptic-like blood pressure high subline 5 (BPH/5) mouse, recapitulating patterns observed in adolescents born after preeclampsia. Herein, our objective was to elucidate BPH/5 offspring hypothalamic-pituitary-gonadal (HPG) axis programming and the associated hormonal profile of late-gestation BPH/5 dams. Reproductive and metabolic phenotypes of BPH/5 and blood pressure normal subline 3 (BPN/3) offspring were assessed from birth to adulthood, including anogenital distance, pubertal onset, ovarian function, and adiposity. Maternal late-gestation circulating hormones and placental steroidogenic enzymes were also investigated. Anogenital distance, indicative of prenatal androgen exposure, was longer in BPH/5 male and female offspring. BPH/5 female offspring exhibited precocious pubertal onset and, during adulthood, abnormal estrous cycles, increased visceral adiposity, increased serum anti-Mullerian hormone (AMH), and ovarian morphology consistent with a polycystic ovary syndrome (PCOS)-like phenotype. Serum testosterone did not differ between late-gestation BPH/5 and BPN/3 dams. Conversely, serum AMH concentrations were threefold higher in late-gestation BPH/5 dams, a maternal endocrine disruption previously linked to abnormal female fetus HPG axis programming and PCOS-like offspring phenotype. In conclusion, BPH/5 offspring recapitulate the aberrant reproductive phenotype seen in children born after preeclampsia and major PCOS-like characteristics. Furthermore, maternal AMH excess was identified in late-gestation BPH/5 females, highlighting this as a valuable model of the interplay between PCOS and preeclampsia.NEW & NOTEWORTHY This study explored hypothalamic-pituitary-gonadal (HPG) axis development in offspring from the preeclamptic-like BPH/5 mouse model. Female BPH/5 offspring exhibited precocious pubertal development, elevated AMH, abnormal estrous cycles, abnormal ovarian histomorphology, and increased visceral adiposity. Interestingly, male and female offspring had longer anogenital distance, indicative of prenatal androgen exposure. Late-gestation BPH/5 dams exhibited a threefold higher AMH concentration, elucidating a novel developmental link between preeclampsia, offspring HPG axis programming, and postnatal ovarian and endocrine dysfunction.