Androgen signaling pathways driving reproductive and metabolic phenotypes in a PCOS mouse model

in Journal of Endocrinology
Authors:
Ali Aflatounian Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia

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Melissa C Edwards Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia

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Valentina Rodriguez Paris Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia

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Michael J Bertoldo Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia
Laboratory for Ageing Research, School of Medical Sciences, University of New South Wales Sydney, New South Wales, Australia

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Reena Desai Andrology Laboratory, ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia

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Robert B Gilchrist Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia

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William L Ledger Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia

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David J Handelsman Andrology Laboratory, ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia

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Kirsty A Walters Fertility and Research Centre, School of Women’s & Children’s Health, University of New South Wales Sydney, New South Wales, Australia
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia

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Correspondence should be addressed to K A Walters: k.walters@unsw.edu.au
DOI:
https://doi.org/10.1530/JOE-19-0530
Volume/Issue:
Volume 245: Issue 3
Article Type:
Research Article
Page Range:
381–395
Online Publication Date:
Jun 2020
Copyright:
© 2020 Society for Endocrinology 2020
Restricted access
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As the mechanistic basis of polycystic ovary syndrome (PCOS) remains unknown, current management relies on symptomatic treatment. Hyperandrogenism is a major PCOS characteristic and evidence supports it playing a key role in PCOS pathogenesis. Classically, androgens can act directly through the androgen receptor (AR) or, indirectly, following aromatization, via the estrogen receptor (ER). We investigated the mechanism of androgenic actions driving PCOS by comparing the capacity of non-aromatizable dihydrotestosterone (DHT) and aromatizable testosterone to induce PCOS traits in WT and Ar-knockout (ARKO) mice. DHT and testosterone induced the reproductive PCOS-like features of acyclicity and anovulation in WT females. In ARKO mice, DHT did not cause reproductive dysfunction; however, testosterone treatment induced irregular cycles and ovulatory disruption. These findings indicate that direct AR actions and indirect, likely ER, actions of androgens are important mediators of PCOS reproductive traits. DHT, but not testosterone, induced an increase in body weight, body fat, serum cholesterol and adipocyte hypertrophy in WT mice, but neither androgen induced these metabolic features in ARKO mice. These data infer that direct AR-driven mechanisms are key in driving the development of PCOS metabolic traits. Overall, these findings demonstrate that differing PCOS traits can be mediated via different steroid signaling pathways and indicate that a phenotype-based treatment approach would ensure effective targeting of the underlying mechanisms.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
15
Article Type:
Research Article
Received Date:
23 Mar 2020
Accepted Date:
25 Mar 2020
Print Publication Date:
01 Jun 2020
Online Publication Date:
Jun 2020
Keywords:
polycystic ovary syndrome; hyperandrogenism; androgen receptor; estrogen receptor

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