Prenatal Exposure of the Ovine Fetus to Androgens Sexually Differentiates the Steroid Feedback Mechanisms That Control Gonadotropin Releasing Hormone Secretion and Disrupts Ovarian Cycles

Abstract

Exposure of the female sheep fetus to exogenous testosterone in early pregnancy permanently masculinizes the reproductive neuroendocrine axis. Specifically, in utero androgens given to female lambs from day 30 to 90 of a 147 day pregnancy dramatically altered the response of the gonadotropin releasing hormone (GnRH) neuronal network in the hypothalamus to both estrogen (E) and progesterone (P) feedback. Elevated concentrations of estrogen stimulated a massive release of GnRH in gonadectomized female sheep; however, male and androgenized female lambs were unable to respond to high E concentrations by producing this preovulatory-like “surge” of GnRH. Further, the inhibitory actions of progesterone (P) were also sexually differentiated and adult males and androgenized females were much less responsive to P-negative feedback than normal ewes. The consequences of these abnormal steroid feedback mechanisms were reflected in the fact that only 72% of ovary-intact androgenized ewes exhibited normal estrous cycles in their first breeding season whereas none had a single estrous cycle during the second breeding season. In contrast, 100% of the control animals exhibited repeated reproductive cycles in both seasons. These data indicate that a relatively short exposure to male hormones during in utero life permanently alters the neural mechanisms that control reproduction and leads progressively to a state of infertility.