Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome
Autor: | Melissa C Edwards, Robert B. Gilchrist, Kirsty A Walters, Reena Desai, Aimee S L Caldwell, David J. Handelsman, Mark Jimenez |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system diseases medicine.drug_class Estrous Cycle Biology Androgen Excess Mice 03 medical and health sciences Internal medicine medicine Animals Endocrine system Cells Cultured Mice Knockout Neurons Granulosa Cells Multidisciplinary Hyperandrogenism nutritional and metabolic diseases Antral follicle medicine.disease Androgen Neurosecretory Systems Polycystic ovary female genital diseases and pregnancy complications Androgen receptor Disease Models Animal 030104 developmental biology Endocrinology Receptors Androgen Dihydrotestosterone Androgens Female Polycystic Ovary Syndrome medicine.drug |
Zdroj: | Proceedings of the National Academy of Sciences. 114 |
ISSN: | 1091-6490 0027-8424 |
Popis: | 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. |
Databáze: | OpenAIRE |
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