The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Unravelling the underlying role of androgen- vs estrogen-mediated actions in development of the differing PCOS phenotypes (#131)

Ali Aflatounian 1 , Melissa C Edwards 1 2 , Valentina Rodriguez Paris 1 , Michael J Bertoldo 1 , Robert B Gilchrist 1 , William L Ledger 1 , David J Handelsman 2 , Kirsty A Walters 1 2
  1. School of Women’s & Children’s Health, University of New South Wales, Sydney, NSW, Australia
  2. ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia

Hyperandrogenism is a key defining characteristic of polycystic ovary syndrome (PCOS) and clinical and animal studies support an important role for androgen driven actions in the development of PCOS. Testosterone (T) and dihydrotestosterone (DHT) are the two bioactive forms of androgens which can act directly through androgen receptor (AR). T, unlike DHT, can also be converted to estradiol and act via the estrogen receptor (ER). Therefore, we aimed to determine if ER-mediated actions play a role in the development of PCOS, by assessing the ability of DHT vs T excess to induce PCOS traits in wild type (WT) and androgen receptor knockout (ARKO) mice. WT and ARKO prepubertal mice were implanted with a blank, T or DHT implant and examined after 12 weeks. In wild-type control mice, both T and DHT were able to induce the PCOS trait of anovulation as no corpora lutea (CL) were observed in their ovaries (CL number: WT+DHT: 0±0; WT+T: 0±0). In contrast, ARKO mice treated with DHT implants ovulated, however those treated with T exhibited ovulatory disruption (CL number: ARKO+DHT: 4±0.57; ARKO+T: 0.75 ±0.75, P<0.05). This finding implies that ER action in the absence of AR action can induce acyclicity, a key reproductive feature of PCOS. DHT, but not T, induced metabolic features of PCOS (e.g. body weight (WT+DHT: 27.1g±0.6; WT+T: 22.5g±0.67, P<0.01) in WT mice, however neither androgen had an effect in ARKO mice (Body weight, ARKO+DHT: 24.1g±0.7; ARKO+T: 23.5g±0.4). These findings demonstrate (1) the need for AR signalling for the metabolic traits of PCOS, (2) that ER-mediated actions may contribute to the reproductive features of PCOS and (3) suggest that lean PCOS patients lacking hyperandrogenism may have a distinct pathophysiology, prognosis and therapeutic approach from hyperandrogenic PCOS patients.