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      Haplosufficient genomic androgen receptor signaling is adequate to protect female mice from induction of polycystic ovary syndrome features by prenatal hyperandrogenization.

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          Abstract

          Polycystic ovary syndrome (PCOS) is associated with reproductive, endocrine, and metabolic abnormalities. Because hyperandrogenism is the most consistent PCOS feature, we used wild-type (WT) and androgen receptor (AR) knockout (ARKO) mice, together with a mouse model of PCOS, to investigate the contribution of genomic AR-mediated actions in the development of PCOS traits. PCOS features were induced by prenatal exposure to dihydrotestosterone (250 μg) or oil vehicle (control) on days 16-18 of gestation in WT, heterozygote, and homozygote ARKO mice. DHT treatment of WT mice induced ovarian cysts (100% vs 0%), disrupted estrous cycles (42% vs 100% cycling), and led to fewer corpora lutea (5.0±0.4 vs 9.8±1.8). However, diestrus serum LH and FSH, and estradiol-induced-negative feedback as well as hypothalamic expression of kisspeptin, neurokinin B, and dynorphin, were unaffected by DHT treatment in WT mice. DHT-treated WT mice exhibited a more than 48% increase in adipocyte area but without changes in body fat. In contrast, heterozygous and homozygous ARKO mice exposed to DHT maintained comparable ovarian (histo)morphology, estrous cycling, and corpora lutea numbers, without any increase in adipocyte size. These findings provide strong evidence that genomic AR signaling is an important mediator in the development of these PCOS traits with a dose dependency that allows even AR haplosufficiency to prevent induction by prenatal androgenization of PCOS features in adult life.

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          Author and article information

          Journal
          Endocrinology
          Endocrinology
          The Endocrine Society
          1945-7170
          0013-7227
          Apr 2015
          : 156
          : 4
          Affiliations
          [1 ] Andrology (A.S.L.C., S.E., M.J., R.D., C.M.A., D.J.H., K.A.W.) and Biogerontology (A.C.M.) Laboratories, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia; and School of Anatomy, Physiology and Human Biology (C.R.K., J.T.S.), University of Western Australia, Perth, Western Australia 6009, Australia.
          Article
          10.1210/en.2014-1887
          25643156
          9d8d45a0-4a84-446f-bd95-67ae98be4744
          History

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