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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

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 adip...

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Autores principales: Coyle, Chris, Ruddenklau, Amy, Prescott, Mel, Walters, Kirsty A, Campbell, Rebecca Elaine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090661/
http://dx.doi.org/10.1210/jendso/bvab048.1086
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author Coyle, Chris
Ruddenklau, Amy
Prescott, Mel
Walters, Kirsty A
Campbell, Rebecca Elaine
author_facet Coyle, Chris
Ruddenklau, Amy
Prescott, Mel
Walters, Kirsty A
Campbell, Rebecca Elaine
author_sort Coyle, Chris
collection PubMed
description 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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spelling pubmed-80906612021-05-12 Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS Coyle, Chris Ruddenklau, Amy Prescott, Mel Walters, Kirsty A Campbell, Rebecca Elaine J Endocr Soc Neuroendocrinology and Pituitary 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. Oxford University Press 2021-05-03 /pmc/articles/PMC8090661/ http://dx.doi.org/10.1210/jendso/bvab048.1086 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/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/ (https://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
spellingShingle Neuroendocrinology and Pituitary
Coyle, Chris
Ruddenklau, Amy
Prescott, Mel
Walters, Kirsty A
Campbell, Rebecca Elaine
Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS
title Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS
title_full Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS
title_fullStr Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS
title_full_unstemmed Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS
title_short Chronic Excess of Non-Aromatizable Androgens From Puberty Does Not Drive a Neuroendocrine Phenotype Observed in Other Preclinical Rodent Models of PCOS
title_sort chronic excess of non-aromatizable androgens from puberty does not drive a neuroendocrine phenotype observed in other preclinical rodent models of pcos
topic Neuroendocrinology and Pituitary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090661/
http://dx.doi.org/10.1210/jendso/bvab048.1086
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