Sex Steroids Program Premature Ovarian Failure

性类固醇计划卵巢早衰

• 批准号: 6867612
• 负责人: VASANTHA PADMANABHAN
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867612
• 关键词: androgen receptor; behavior test; behavioral /social science research tag; blood tests; cell differentiation; cell growth regulation; data collection methodology /evaluation; embryo /fetus; estrogen receptors; female; fertility; gene expression; graafian follicles; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; mature animal; neuroendocrine system; ovary disorder; polycystic ovary syndrome; reproductive development; sex behavior; sex hormones; sheep; terminal nick end labeling; testosterone; ultrasonography

Each woman is endowed with a finite number of primordial follicles at birth. Most of this initial endowment is depleted during normal reproductive life, mainly through atresia. The length of reproductive life is largely defined by the rate of follicular depletion. The variability in the length of reproductive life suggests variability in the initial endowment of primordial follicles and/or rate of follicle loss. Reproductive life span can be shortened by factors that reduce primordial follicular endowment, accelerate the rate of recruitment/atresia of follicles, and/or induce follicular deficiencies leading to developmental arrest of follicles. Increasing evidence suggests that the environment to which the fetus is exposed can alter the path of reproductive organ differentiation. The use of animal models offers exciting potential for delineating the mechanisms by which human fertility disorders can be programmed in fetal life. Our studies found that prenatal exposure of sheep to testosterone results in altered neuroendocrine feedback, hyperandrogenism, multifollicular ovarian morphology, increased follicular atresia and reproductive cycle defects culminating in early reproductive failure. The objective of this proposal is to delineate the ovarian programming that occurs as a consequence of in utero sex steroid exposure that is responsible for reproductive failure later in life. The working hypothesis is as follows: Exposure of fetuses to excess testosterone during critical stages of ovarian follicular development alters normal developmental trajectories by changing the expression patterns of key growth factors, androgen/estrogen receptors, and ratio of anti- to proapoptotic Bcl-2 members, resulting in accelerated recruitment of primordial to primary follicles, accelerated growth of primary follicles to antral stage and enhanced incidences of atresia or arrest of antral follicles. These alterations eventually, lead to premature depletion of ovarian follicular reserve and ovarian failure. The deleterious effects of testosterone are mediated either by its androgenic action, estrogenic action due to its conversion to estradiol, or both. Further, prenatal exposure to steroids alters ovarian follicular susceptibility to postnatal steroids leading to premature ovarian failure. The outcome of these studies is of relevance to 3 of the targeted NIH missions, fetal antecedents of disease, developmental biology and reproductive health for the 21st century.

每个妇女在出生时都被赋予有限数量的原始卵泡。在正常的生殖生活中，这种最初的禀赋大部分被耗尽，主要是通过闭锁。生殖寿命的长短很大程度上取决于卵泡消耗的速度。生殖寿命长短的变化表明原始卵泡的初始禀赋和/或卵泡损失率的变化。生殖寿命可因降低原始卵泡禀赋、加速卵泡募集/闭锁速率和/或诱导卵泡缺陷导致卵泡发育停滞的因素而缩短。越来越多的证据表明，胎儿所处的环境可以改变生殖器官的路径， 分化动物模型的使用提供了令人兴奋的潜力，描绘的机制，人类生育障碍可以编程在胎儿的生活。我们的研究发现，绵羊产前暴露于睾酮导致神经内分泌反馈改变、高雄激素血症、多卵泡卵巢形态、卵泡闭锁增加和生殖周期缺陷，最终导致早期生殖失败。这项建议的目的是描绘卵巢编程发生的结果，在子宫内性类固醇暴露，是负责生殖失败以后的生活。工作假设 如下所示：在卵泡发育的关键阶段，胎儿暴露于过量的睾酮，通过改变关键生长因子、雄激素/雌激素受体的表达模式以及抗凋亡与促凋亡Bcl-2成员的比例，改变了正常的发育轨迹，导致原始卵泡向初级卵泡的加速募集，促进初级卵泡向有腔卵泡生长，增加有腔卵泡闭锁或停滞的发生率。这些改变最终导致卵巢卵泡储备过早耗尽和卵巢功能衰竭。睾酮的有害作用是通过其雄激素作用、由于其转化为雌二醇而引起的雌激素作用或两者来介导的。此外，产前暴露于类固醇改变卵巢卵泡对出生后类固醇的敏感性，导致卵巢早衰。这些研究的结果与NIH的3个目标任务有关， 21世纪的疾病、发育生物学和生殖健康的胎儿前因。