Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Androgens excess and the pathogenesis of polycystic ovary syndrome (#78)

Kirsty Walters 1
  1. University of New South Wales, Kensington, NSW, Australia

Polycystic ovary syndrome (PCOS) is a complex disorder characterised by reduced fertility, due to ovulatory disturbance and reproductive hormone dysregulation involving luteinising hormone (LH) hypersecretion and androgen excess. Women with PCOS are also predisposed to metabolic disturbances such as obesity, insulin resistance, and dyslipidemia, with an increased risk of cardiovascular disease and type 2 diabetes. The origins of PCOS remain unknown, hence mechanism-based treatments are not feasible and current management is suboptimal as it relies on the treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic, however it is unclear if androgen excess, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a hyperandrogenised PCOS mouse model with global and cell-specific AR resistant (ARKO) mice to uncover the sites of androgen action that mediate the development of the PCOS phenotype. These studies proved that global loss of AR actions (ARKO) protects females from the induction of PCOS features. Furthermore our findings highlighted the importance of non-ovarian (neuroendocrine) AR-mediated androgen actions in the origins of PCOS as a neuron-specific loss of AR signaling protected against the development of most PCOS traits. In addition, PCOS reproductive traits were ameliorated in some granulosa cell-specific ARKO females implying that additional loci of ovarian AR actions are involved in mediating the PCOS phenotype. In summary, analysis of these mouse models implies that extra-ovarian and not intra-ovarian AR actions are the key sites of androgen action in generating the PCOS phenotype.