Padmanabhan Vasantha, Veiga-Lopez Almudena, Herkimer Carol, Abi Salloum Bachir, Moeller Jacob, Beckett Evan, Sreedharan Rohit
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105.
Endocrinology. 2015 Jul;156(7):2678-92. doi: 10.1210/en.2015-1235. Epub 2015 Apr 28.
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.
孕期雄激素过量会诱发母体高胰岛素血症、性早熟以及雌性动物的生殖/代谢缺陷，这些缺陷与多囊卵巢综合征女性所表现出的症状相似。本研究探讨了雄激素和胰岛素在青春期提前启动及排卵前促黄体生成素（LH）峰缺陷编程中的组织/激活作用。治疗组包括：1）对照组；2）孕期雄激素组；3）孕期雄激素加孕期雄激素拮抗剂氟他胺组；4）孕期雄激素加孕期胰岛素增敏剂罗格列酮组；5）孕期雄激素加产后氟他胺组；6）孕期雄激素加产后罗格列酮组；7）孕期雄激素加产后二甲双胍组。孕期治疗持续30至90天的妊娠期，产后治疗从约8周龄开始并持续进行。从约12周龄开始每周采集两次血样，以确定青春期时间。在与前列腺素F2α同步后，采集2小时样本，持续120小时，以表征7个月和19个月龄时LH峰的动态变化。孕期雄激素处理的雌性动物比对照组更早进入青春期，所有干预措施均阻止了这种提前。孕期雄激素降低了出现LH峰的动物百分比，出现LH峰的雌性动物LH峰的时间延迟且幅度减弱。孕期雄激素拮抗剂可恢复LH峰，但其他干预措施则不能，且无法使LH峰时间正常化。孕期/产后雄激素拮抗剂和胰岛素增敏剂干预使青春期时间正常化，这表明青春期提前是由睾酮的雄激素作用编程的，胰岛素作为中介参与其中。与雄激素拮抗剂联合治疗恢复LH峰，支持了组织水平上的雄激素编程。
