Prenatal Programming of Reproductive Health and Disease

项目总结（见说明）： 生殖系统对早期暴露于类固醇激素的敏感性已成为我们现代社会的一个主要问题。处于危险之中的是胎儿的母亲已经暴露于外源性类固醇的各种原因：她已经失败的避孕和持续暴露于避孕类固醇，她是合成代谢类固醇，或者她无意中暴露于环境化合物， 雌激素或雄激素活性。产前类固醇环境的实验操作为解开生殖轴编程的机制提供了一个强大的调查工具。 当前资助期的研究结果发现，产前睾酮（T）过量会扰乱胎儿的发育轨迹，最终导致生殖神经内分泌、卵巢、代谢和行为紊乱，并在病理学发展中涉及卵巢高雄激素血症和高胰岛素血症。该提案旨在利用这一最近验证的绵羊模型来测试一种新颖的、统一的关于不孕症发育起源的假设，即”高胰岛素血症和功能性高胰岛素血症“。 由代谢紊乱和/或增加的类固醇驱动胎儿神经内分泌-卵巢系统引起的高雄激素血症在产前T诱导的生殖功能障碍中起关键作用”。POI提案的具体目标是：1）在出生后使用胰岛素增敏剂以改善高胰岛素血症，并确定其是否挽救产前T治疗的绵羊的生殖功能，2）在出生后使用抗雄激素，并确定其是否挽救产前T治疗的绵羊的生殖功能，3）确定在胎儿生命期间用T和雄激素拮抗剂共同治疗是否会阻止代谢和代谢， 生殖病理从发展中的成年人和4）确定神经解剖，神经内分泌，卵巢，行为和代谢机制的功能恢复。该提案针对的是2000- 2001年国家儿童健康与发展中心举办的“从细胞到自我”讲习班所产生的战略计划的关键要素，并侧重于以下领域：胎儿疾病的先兆、21世纪世纪的生殖健康、发育生物学和生物行为发育。

PROJECT SUMMARY (See Instructions): The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. At risk is the fetus whose mother has been exposed to exogenous steroids for a variety of reasons: she has had failed contraception and continued exposure to contraceptive steroids, she is on anabolic steroids, or she is inadvertently being exposed to environmental compounds that have estrogenic or androgenic activity. Experimental manipulation of the prenatal steroid environment provides a powerful investigative tool for unraveling mechanisms that underlie programming of the reproductive axis. Findings from the current funding period found prenatal testosterone (T) excess disrupts the developmental trajectory of the fetus culminating in reproductive neuroendocrine, ovarian, metabolic and behavioral perturbations and implicates ovarian hyperandrogenism and hyperinsulinemia in the development of the pathology. This proposal aims to capitalize on this recently validated sheep model to test a novel, unifying hypothesis for the developmental origins of infertility disorders namely" Hyperinsulinemia and functional hyperandrogenism resulting from metabolic perturbations and/or increased steroid drive to the fetal neuroendocrine-ovarian system plays a key role in prenatal T-induced reproductive dysfunctions". The specific goals of the POI proposal are to 1) use an insulin-sensitizing agent postnatally to ameliorate hyperinsulinemia and determine if it rescues reproductive function in prenatal T-treated sheep, 2) use an anti-androgen postnatally and determine if it rescues reproductive function in prenatal T-treated sheep, 3) determine if co-treatment with T and an androgen antagonist during fetal life will prevent metabolic and reproductive pathology from developing in the adult and 4) determine the neuroanatomical, neuroendocrine, ovarian, behavioral and metabolic mechanisms underlying restoration of function. The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 "From Cells to Selves" and focuses on the following areas: fetal antecedents of disease, reproductive health for the 21st Century, developmental biology and biobehavioral development.