Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/111574
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome
Author: Caldwell, A.
Edwards, M.
Desai, R.
Jimenez, M.
Gilchrist, R.
Handelsman, D.
Walters, K.
Citation: Proceedings of the National Academy of Sciences of the United States of America, 2017; 114(16):E3334-E3343
Publisher: National Academy of Sciences of the United States of America
Issue Date: 2017
ISSN: 0027-8424
1091-6490
Statement of
Responsibility: 
Aimee S. L. Caldwell, Melissa C. Edwards, Reena Desai, Mark Jimenez, Robert B. Gilchrist, David J. Handelsman and Kirsty A. Walters
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
Rights: The author(s) retains copyright to individual PNAS articles, and the National Academy of Sciences of the United States of America (NAS) holds copyright to the collective work and retains an exclusive License to Publish these articles, except for open access articles submitted beginning September 2017. For such open access articles, NAS retains a nonexclusive License to Publish, and these articles are distributed under a CC BY-NC-ND license. For volumes 106–114 (2009–September 2017), the author(s) retains copyright to individual articles, and NAS retains an exclusive License to Publish these articles and holds copyright to the collective work.
RMID: 0030083814
DOI: 10.1073/pnas.1616467114
Grant ID: http://purl.org/au-research/grants/nhmrc/1022648
Appears in Collections:Medicine publications

Files in This Item:
File Description SizeFormat 
hdl_111574.pdfPublished Version1.85 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.