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      Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS

      , PhD 1 , , BSc (Hons) 1 , , BSc (Hons) 1 , , PhD 2 , , PhD 3

      Journal of the Endocrine Society

      Oxford University Press

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          Abstract

          Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility in women of reproductive age, characterised by androgen excess, polycystic appearance of the ovary and irregular menstruation. PCOS is also frequently associated with metabolic abnormalities, including increased adiposity and insulin resistance. The origins of PCOS are unknown, however recent findings in animal models strongly implicate androgen signalling in the brain in the development of PCOS pathophysiology. Exposure to androgen excess, either acutely during prenatal development or chronically from a peripubertal timepoint, can drive the development of PCOS-like features in adulthood. Prenatally androgenized (PNA) mice exhibit the cardinal reproductive features of PCOS and increased luteinizing hormone (LH) pulse frequency. This phenotype is associated with increased GABAergic innervation of gonadotropin-releasing hormone (GnRH) neurons, postulated to drive elevated GnRH/LH release and downstream effects. Chronic exposure to di-hydrotestosterone (DHT) from 3 weeks of age drives both reproductive and metabolic PCOS-like features that are ameliorated by selective AR loss from the brain. Here, we aimed to determine whether chronic exposure to DHT drives a similar increase in LH pulsatility and elevated GABAergic innervation to GnRH neurons as seen following prenatal exposure to androgen excess. GnRH-green fluorescent protein (GFP) female mice received either DHT or blank capsules for 90 days from postnatal day (PND) 21 (N = 6-7/group). Serial tail tip blood sampling was used to measure pulsatile LH and fixed brains were collected and immunolabelled for vesicular GABA transporter (VGAT) to assess putative GABAergic terminals associated with GFP-labelled GnRH neurons. Chronic androgen excess from the peripubertal period resulted in acyclicity and increased body weight as expected. However, LH pulsatility was not different between DHT-treated females and controls. Similarly, the density of VGAT appositions to GnRH neurons was not different between groups. Therefore, the programmed changes in the GnRH neuronal network and hyperactive LH secretion that result from prenatal androgen excess are not affected by chronic DHT exposure initiated at 3 weeks of age. These findings suggest that unique central mechanisms are involved in the reproductive impairments driven by exposure to androgen excess at different developmental stages.

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          Author and article information

          Journal
          J Endocr Soc
          J Endocr Soc
          jes
          Journal of the Endocrine Society
          Oxford University Press (US )
          2472-1972
          03 May 2021
          03 May 2021
          03 May 2021
          : 5
          : Suppl 1 , ENDO 2021 Abstracts Annual Meeting of the Endocrine Society
          : A533-A534
          Affiliations
          [1 ] UNIVERSITY OF OTAGO, Dunedin, New Zealand
          [2 ] University of New South Wales , Sydney, Australia
          [3 ] University of Otago, Dunedin, New Zealand
          Article
          bvab048.1086
          10.1210/jendso/bvab048.1086
          8090661
          © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

          Page count
          Pages: 2
          Product
          Categories
          Neuroendocrinology and Pituitary
          Neuroendocrinology and Pituitary Basic Research Advances
          AcademicSubjects/MED00250

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