MON-LB037 The Impact of Maternal Testosterone and Western-Style Diet on the Fetal Hypothalamic-Pituitary-Gonadal Axis

Abstract

Polycystic ovary syndrome (PCOS) is a common fertility disorder affecting 5-10% of reproductive-age women. PCOS is associated with elevated androgens, obesity, and increased risk for diabetes. Evidence from animal models indicates that elevated androgens during pregnancy programs PCOS-like characteristics in female offspring, suggesting an early developmental origin of the disease whereby predisposition to PCOS may be transmitted from mother to daughter. However, many of the findings in animal models are associated with maternal levels of androgens that are much higher than those found in PCOS women and that can result in virilization of female offspring. To address this, our group previously developed a more translational model in which peripubertal female rhesus macaques were chronically treated with testosterone (T) implants to achieve modestly elevated serum androgen levels (1.35 ng/mL) in the presence and absence of an obesogenic western-style diet (WSD). After 3 years of treatment, animals were mated and fetal tissue was collected from pregnancies at gestational day 135 (GD 135, early third trimester). At GD135 the hypothalamic-pituitary-gonadal (HPG) axis is active during the so-called “mini-puberty,” and several adult disorders of the HPG axis are often preceded by evidence of a dysfunction during “mini-puberty.” Therefore, alterations in fetal HPG axis function could indicate a predisposition for future HPG dysfunction in adulthood. The current study examined the HPG axis in these fetuses to determine whether T, WSD, or the combination (T+WSD) predisposes offspring to reproductive dysfunction. Although the impact of maternal factors on the HPG axis may be greater in female offspring, there was insufficient sample size to separate by sex; therefore, offspring of both sexes were included in the initial analysis. The infundibular nucleus of the hypothalamus was dissected and assessed for expression of key reproductive neuroendocrine hormones by quantitative PCR. Several hypothalamic neuropeptides showed differential expression with maternal androgen exposure, including TAC3, KISS1R, and PDYN which are all critical components of the GnRH pulse generator. Examination of pituitary function through assessment of circulating gonadotropins revealed a modest decrease in the LH:FSH ratio with T treatment, regardless of diet. Preliminary examination of the testes found variation in histology. Control ovaries also had wide variability in follicle cohorts, making it difficult to draw conclusions about T and/or WSD effects on the gonads. These findings suggest that prenatal T exposure may result early changes in the HPG axis that begin in the hypothalamus and are reflected in a reduced ratio of LH to FSH secreted from the pituitary. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.