Sex Steroids Program Premature Ovarian Failure

每个女性在出生时都被赋予了有限数量的原始卵泡。在正常的生殖生活中，这种最初的天赋大部分被耗尽，主要是通过闭锁。生殖寿命的长短在很大程度上取决于卵泡的衰减率。生殖寿命的变异性表明原始卵泡的初始捐赠和/或卵泡损失率的变异性。减少原始卵泡天赋、加速卵泡招募/闭锁和/或导致卵泡缺陷导致卵泡发育停滞的因素可缩短生殖寿命。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。 差异化。动物模型的使用为描绘人类生育障碍在胎儿生活中被编程的机制提供了令人兴奋的潜力。我们的研究发现，绵羊出生前暴露于睾酮会导致神经内分泌反馈改变、雄激素过多、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由于宫内性类固醇暴露而发生的卵巢编程，这是导致以后生命中生殖失败的原因。工作假说 主要研究结果如下：在卵泡发育的关键阶段，胎儿暴露于过量的睾酮中，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/促凋亡基因bcl2的表达模式，改变正常发育轨迹，加速原始卵泡向初级卵泡的募集，加速初级卵泡向有腔卵泡的生长，增加有腔卵泡闭锁或停滞的发生率。这些改变最终会导致卵泡储备的过早耗尽和卵巢衰竭。睾酮的有害作用是通过其雄激素作用，或由于其转化为雌二醇而产生的雌激素作用，或两者兼而有之。此外，产前暴露于类固醇可改变卵泡对出生后类固醇的易感性，从而导致卵巢早衰。这些研究的结果与NIH目标任务中的三个相关， 21世纪胎儿疾病前兆、发育生物学和生殖健康。

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.