E-Poster Presentation ESA-SRB-ANZBMS 2021

Androgen receptor signaling in GABA neurons is not necessary for the development of PCOS traits in a peripubertal PCOS mouse model (#573)

Irene E Sucquart 1 , Chris Coyle 2 , Valentina Rodriguez Paris 1 , Denovan P Begg 3 , Robert B Gilchrist 1 , Rebecca E Campbell 2 , Kirsty A Walters 1
  1. Fertility and Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
  2. Centre of Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
  3. Department of Behavioural Neuroscience, School of Psychology, University of New South Wales, Sydney, NSW, Australia

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting reproductively aged women. Hyperandrogenism is a key characteristic of PCOS and many women with PCOS also experience luteinizing hormone hypersecretion. Although the origins of PCOS are unknown, evidence in animal models strongly implicates androgen signalling in the brain. Gamma-aminobutyric acid (GABA) expressing neurons have a role in stimulating gonadotrophin releasing hormone (GnRH) secretion. Circuit remodeling of GABA neurons has been observed in hyperandrogenic PCOS animal models, with studies reporting an increase in GABAergic innervation and activation of GnRH neurons. This suggests that AR-mediated disruption of GnRH neuron activity may occur primarily via GABA neurons.

To investigate the role of androgen actions in GABAergic neurons in PCOS pathogenesis, we combined a dihydrotestosterone (DHT)-induced PCOS mouse model with a GABA specific AR knock out (GABARKO) mouse model and assessed the development of PCOS-like traits after 12 weeks of DHT exposure.

DHT exposure in both WT and GABARKO females induced key reproductive and metabolic PCOS traits. DHT exposed WT and GABARKO mice both exhibited anovulation and acyclicity. Moreover, DHT treatment, but not genotype, had a significant main effect on total body weight and retroperitoneal fat pad weight in WT and GABARKO mice (2-way ANOVA P<0.05). DHT treatment had significant main effects on adipocyte size in retroperitoneal fat (P<0.05), with no significant difference observed between GABARKO and WT mice. Lastly, DHT exposure had significant main effects over blood glucose IAUC (P<0.05), but no difference was observed between GABARKO and WT PCOS mice.

Overall, these data show that impeding AR signaling in GABA neurons does not change the development of PCOS-like traits in mice chronically exposed to DHT. Therefore, these findings suggest that primary androgen actions in the female brain driving the pathogenesis of PCOS are likely mediated via non-GABAergic neurons or non-neuronal cells.