Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep.
Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep.
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DOI：
10.1210/en.2015-1235
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发表时间：
2015-04
期刊：
影响因子：
4.8
通讯作者：
V. Padmanabhan;A. Veiga-Lopez;Carol Herkimer;B. Abi Salloum;Jacob Moeller;Evan M. Beckett;Rohit Sreedharan-Ro
中科院分区：
文献类型：
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作者：
V. Padmanabhan;A. Veiga-Lopez;Carol Herkimer;B. Abi Salloum;Jacob Moeller;Evan M. Beckett;Rohit Sreedharan-Ro
与多囊卵巢综合征患者相似，产前T过量可导致母体高胰岛素血症、青春期提前和女性生殖/代谢缺陷。本研究探讨了雄激素和胰岛素在青春期提前和排卵期LH峰缺陷中的组织/激活作用。治疗组包括以下：1）对照组; 2）产前T组; 3）产前T+产前雄激素拮抗剂氟替卡松组; 4）产前T+产前胰岛素增敏剂罗格列酮组; 5）产前T+产后氟替卡松组; 6）产前T+产后罗格列酮组; 7）产前T+产后二甲双胍组。产前处理跨越妊娠30-90天，产后处理在约8周龄时开始并持续整个过程。从大约12周龄开始至青春期，每周采集两次血样。在与前列腺素F2α同步化后2小时采集样本，持续120小时，以表征7月龄和19月龄时的LH峰动力学。产前T女性进入青春期早于对照组，所有干预措施阻止了这一进展。产前T降低了LH峰动物的百分比，并且呈现LH峰的雌性动物表现出LH峰的时间延迟和振幅减弱。产前雄激素拮抗剂，而不是其他干预措施，恢复LH峰没有正常化的时间高峰。产前/产后雄激素拮抗剂和胰岛素增敏剂干预的青春期时间正常化表明，青春期提前是由T的雄激素作用，包括胰岛素作为媒介。通过与雄激素拮抗剂联合治疗恢复LH峰支持组织水平的雄激素规划。
Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30-90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level.