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Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3334-E3343. doi: 10.1073/pnas.1616467114. Epub 2017 Mar 20.

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome.

Author information

1
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia.
2
Discipline of Obstetrics and Gynaecology, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
3
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia; k.walters@unsw.edu.au.

Abstract

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.

KEYWORDS:

PCOS; androgen; animal model; neuroendocrine

PMID:
28320971
PMCID:
PMC5402450
DOI:
10.1073/pnas.1616467114
[Indexed for MEDLINE]
Free PMC Article

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