title: Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression.
abstract: Although androgen excess is considered detrimental to women's health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b, which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSH-mediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome.
authors: Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors: Aritro
authors: A
authors: Sen
authors: Hen
authors: H
authors: Prizant
authors: Allison
authors: A
authors: Light
authors: Anindita
authors: A
authors: Biswas
authors: Emily
authors: E
authors: Hayes
authors: Ho-Joon
authors: HJ
authors: Lee
authors: David
authors: D
authors: Barad
authors: Norbert
authors: N
authors: Gleicher
authors: Stephen R
authors: SR
authors: Hammes
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005260:Female; D005434:Flow Cytometry; D005496:Follicular Atresia / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006107:Granulosa Cells / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D011962:Receptors, FSH / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D051419:Paxillin; D011962:Receptors, FSH; D013739:Testosterone