Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome.
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.
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia.
Aimee S L
ASL
Caldwell
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia.|Discipline of Obstetrics and Gynaecology, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
Melissa C
MC
Edwards
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia.
Reena
R
Desai
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia.
Mark
M
Jimenez
Discipline of Obstetrics and Gynaecology, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
Robert B
RB
Gilchrist
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia.
David J
0000-0002-4200-7476
DJ
Handelsman
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, NSW 2139, Australia; k.walters@unsw.edu.au.|Discipline of Obstetrics and Gynaecology, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
Kirsty A
KA
Walters
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009490:Neurosecretory Systems / Q000187:drug effects*; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000502:physiology*
C000607144:AR protein, mouse; D000728:Androgens; D011944:Receptors, Androgen
PCOS; androgen; animal model; neuroendocrine