Project 1 - Steroidal and Metabolic Mediation of Ovarian Function and fertility

怀孕期间异常的激素、营养、代谢或环境条件会改变 胎儿的发育轨迹最终导致成人疾病。绵羊暴露于过量 睾丸激素（T）在胎儿期导致神经内分泌，卵巢和代谢缺陷，平行 多囊卵巢综合征伴产后肥胖妇女的生殖和代谢表型 放大了这些缺陷。卵巢缺陷涉及卵泡募集增加和卵泡持续存在。 卵巢破坏在胎儿期是明显的，包括雄激素受体表达增加， 雌激素受体α和β的比例失衡，以及胰岛素信号的改变。代谢缺陷， 由T的雄激素作用介导，在胎儿早期也很明显，最终导致胰岛素抵抗。 青春期后使用胰岛素增敏剂治疗可改善胰岛素敏感性并预防进一步的 生殖轴的恶化暗示胰岛素的作用。我们最近的研究结果表明， 与雄激素拮抗剂的联合治疗克服了产前T对神经内分泌的破坏作用， 卵巢水平。拟议的研究将确定产前雄激素在妊娠中的作用。 产前T诱导的生殖病理学的规划，并描绘出生后的相对作用， 高胰岛素血症和功能性卵巢高雄激素血症促进周期性卵巢 干扰具体而言，研究将探讨高胰岛素血症状态是否在 青春期使用胰岛素增敏剂或卵巢高雄激素症使用雄激素拮抗剂将克服 产前T处理绵羊的卵泡持续性和拯救周期功能以及雄激素的预防作用 在胎儿期与雄激素拮抗剂联合治疗的作用将阻止代谢程序化， 和生殖病理学这些干预性研究的卵巢将用于1）解决以下作用： 卵巢内类固醇和胰岛素受体信号传导，2）鉴定介导产前T诱导的 卵巢功能障碍; 3）描述表观遗传修饰在介导差异蛋白中的作用 表情这些研究的结果将与人类不孕症相关。

Abnormal hormonal, nutritional, metabolic or environmental conditions during pregnancy alter the developmental trajectory of the fetus culminating in adult diseases. Exposure of sheep to excess testosterone (T) during fetal life leads to neuroendocrine, ovarian and metabolic defects that parallel the reproductive and metabolic phenotype of women with polycystic ovary syndrome, with postnatal obesity amplifying these defects. Ovarian defects involve increased follicular recruitment and follicular persistence. Ovarian disruptions are evident during fetal life and include increased androgen receptor expression, imbalance in the ratio of estrogen receptor alpha and beta, and altered insulin signaling. Metabolic defects, mediated by androgenic actions ofT, are also evident eariy in fetal life culminating in insulin resistance. Postpubertal treatment with an insulin sensitizer improves insulin sensitivity and prevents further deterioration of reproductive axis implicating a role for insulin. Our recent findings suggest that gestational co-treatment with an androgen antagonist overcomes disruptive effects of prenatal T at the neuroendocrine and ovarian level. Proposed studies will determine the contributing role of prenatal androgen in the programming of prenatal T-induced reproductive pathology and delineate the relative role of postnatal hyperinsulinemia and functional ovarian hyperandrogenism in facilitating the expression of cyclic ovarian disruptions. Specifically, studies will address if attenuation of hyperinsulinemic status beginning before puberty with insulin sensitizers or ovarian hyperandrogenism with an androgen antagonist would overcome follicular persistence and rescue cyclic function in prenatal T-treated sheep and if prevention of androgen action by co-treatment with androgen antagonist during fetal life would prevent programming of metabolic and reproductive pathologies. Ovaries from these interventional studies will be used to 1) address the role of intraovarian steroid and insulin receptor signaling, 2) identify protein clusters mediating prenatal T-induced ovarian dysfunction; and 3) delineate the role of epigenetic modifications in mediating differential protein expressions. Findings from these studies would be of translational relevance to human infertility disorders.