Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnor-malities. As the origins of PCOS remain unknown, mechanism- based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was requiredfor the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. AR-driven mechanisms that initiate PCOS strategy for the development of novel treatments for PCOS. findings suggest neuroendocrine AR signaling as a key target for the development of novel mechanism-based PCOS treatments. Our data show, by combining a DHT-induced PCOS mouse model with global and tissue- and cell-specific ARKO mouse models, that the induction of the PCOS traits of acyclicity and anovulation requires AR signaling. These findings are in agreement with clinical evidence supporting a direct role for androgen actions in the development of dysfunctional menstrual cycling and ovulation in PCOS, as prolonged treatment with the AR flutamide is reported to restore menstrual-cycle reg-ularity and ovulation in some with PCOS In-terestingly, by contrast, the treatment of women with PCOS with estrogen blockage, either by antiestrogen (clomiphene citrate) or an aromatase inhibitor (letrozole) that increases FSH secretion, is rapidly effective at inducing ovulation This implies that the hypothalamic – pituitary feedback response in PCOS women is functional but that the longer time to effective treatment by androgen blockade may involve more complex, possibly multistep underlying mechanisms of androgen-mediated effects, compared with the more direct mode of action of estrogen blockade. Impor-tantly, our findings highlight the importance of extraovarian AR actions in the pathogenesis of ovulatory dysfunction in PCOS. We show that females treated with DHT display aberrant ovulatory function when they have fully functional AR actions (intact WT females and ovariectomized WT females bearing WT ovary transplants) or a loss of AR signaling in the ovary only (GCARKO females and ovariectomized WT females bearing ARKO ovary transplants). However, females with an extraovarian loss of AR actions (NeurARKO females and ovariectomized ARKO females bearing WT ovary transplants) are protected against DHT-induced reduction in ovulation, indicated by reduced numbers of corpora lutea. This suggests that hyperandrogenism-induced PCOS requires AR actions in neurons and that the