Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Granulosa cell targeted androgen receptor inactivation fails to rescue Polycystic Ovary Syndrome (PCOS) features in a mouse model (#135)

Aimee S L Caldwell 1 , Charles M Allan 1 , David J Handelsman 1 , Kirsty A Walters 1
  1. Andrology Laboratory, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, NSW 2139, Australia
Polycystic Ovary Syndrome is a frequent cause of female infertility and is associated with a range of metabolic disorders. Hyperandrogenism is a key feature of PCOS, but the role of androgen actions via the androgen receptor (AR) in its development is unclear. To investigate their role, we combined our optimal PCOS mouse model [1] with our global and granulosa cell-specific AR knockout models (ARKO & GCARKO, respectively), as granulosa cells are a major site for AR-mediated actions in the follicle. DHT treated wild-type (WT) mice from both lines exhibited disrupted (fewer) estrous cycles (0±0 vs 2.6±0.2cycles/14days and 0.3±0.2 vs 2.8±0.2cycles/14days, respectively, p<0.01) and reduced corpora lutea (CL) numbers (1±1 vs 9.7±3 and 0±0 vs 9.3±1.8, p<0.05) compared to non-DHT treated controls, while also exhibiting increased body weight over 13 weeks (151.4±21.3% vs 124.6±21.8%, p<0.01 and 202.1±10.9% vs 167.7±11.2%, p=0.05), and fat pad weights (intra-abdominal: 4.53±0.42 vs 2.71±0.34 mg/BW and 6.18±0.86 vs 3.77±0.50 mg/BW, p<0.01; subcutaneous: 12.29±0.83 vs 8.79±0.73 mg/BW and 11.9±0.56 vs 9.6±0.47 mg/BW, p<0.01). Globally inactivated AR (ARKO) rescued the DHT induced effects, however, when AR inactivation was confined to the granulosa cells (GCARKO) mice displayed persistent DHT effects of reduced number of estrous cycles in 14 days (1.0±0.2 vs 2.7±0.2, p<0.001), a trend to reduced CL numbers (1.7±1.7 vs 5.7±0.7, p=0.09), increased body weight (187.0±14.5% vs 159.1±11.4%, p<0.05) and increased fat pad weights (intra-abdominal: 5.80±0.80 vs 3.05±0.37 mg/BW, p<0.01; subcutaneous: 10.58±0.49 vs 8.82±0.40 mg/BW, p<0.01). There was no difference in fasting glucose levels, glucose tolerance or blood pressure in any groups. Our results support a role for hyperandrogenism in the development of PCOS features, and indicate that these effects are not mediated via the granulosa cells but rather via other cells within the ovary or via extra-ovarian (neuroendocrine) sites.
  1. Caldwell A.S.L, Middleton L.J, Jimenez M, Desai R, McMahon A.C, Allan C.M, Handelsman D.J, and Walters K.A. Characterization of reproductive, metabolic and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology DOI: 10.1210/en.2014-1196 (In Press)