Forebrain AR Deletion Restores PR Expression but not Reproduction in Prenatally Androgenized Female Mice.

Prenatal androgen excess (PNA), an etiologic factor for polycystic ovary syndrome (PCOS), is implicated in programming long-term reproductive deficits in females such as anovulation, subfertility, and hyperandrogenism. Impaired steroid hormone feedback is a key neuroendocrine feature suspected to underpin the development of reproductive dysfunction in both clinical PCOS and in PNA mice exposed to dihydrotestosterone during late gestation. PNA is suspected to act in the brain to program the impaired sensitivity of the GnRH neuronal network to progesterone negative feedback, centrally dysregulating the hypothalamic-pituitary-ovarian axis controlling reproduction. To test the hypothesis that androgen-sensitive neurons mediate PNA programming, we generated PNA female mice with a neuron-specific deletion of androgen receptors (AR) (NeurARKO) using Cre-lox transgenics. Following confirmation of embryonic AR deletion, PNA NeurARKO females were reproductively phenotyped and assessed for changes in progesterone receptor expression in the brain. PNA-induced reproductive traits including delayed pubertal onset, acyclicity, altered ovarian morphology, and subfertility were not different between NeurARKO and wild-type mice. In contrast, downregulation of progesterone receptor expression in PNA wild-type mice was protected against in PNA NeurARKO mice. Together, these findings suggest that although neuronal AR may contribute to PCOS-like impaired sensitivity to progesterone feedback, their deletion alone is insufficient to rescue reproductive dysfunction associated with PCOS.