Insulin signaling in theca cells from polycystic ovaries

描述（由申请人提供）：多囊卵巢综合征（PCOS）是育龄妇女最常见的生殖内分泌疾病。大约四分之三的无排卵性不孕症妇女患有PCOS，因此约占继发性闭经妇女的三分之一和约90%的月经过少妇女。多囊卵巢综合征的其他后果是多毛症，复发性早期妊娠丢失的发生率显着增加，估计50-61岁之间心肌梗死的风险增加11倍，年轻时子宫内膜癌的风险增加。在患有PCOS的女性中一致的发现是卵巢产生异常高的雄激素。有很好的证据表明，雄激素升高干扰了优势卵泡的选择，导致PCOS。更重要的是，胰岛素抵抗和PCOS雄激素过多之间存在关联。很明显，胰岛素可以刺激卵巢雄激素的产生，但存在一个悖论：胰岛素如何能过度刺激胰岛素抵抗妇女卵巢膜雄激素的产生？有两种假设可以解释这个看似矛盾的现象。胰岛素抵抗妇女的卵巢卵泡膜细胞不是胰岛素抵抗的，或者卵泡膜细胞中存在调节葡萄糖代谢和雄激素产生的不同胰岛素信号传导机制。这些研究的目的是确定胰岛素抵抗妇女的卵巢卵泡膜细胞是否具有胰岛素抵抗，探索胰岛素调节雄激素生物合成的细胞内信号传导机制，并确定多囊卵巢卵泡膜细胞中介导胰岛素作用的关键分子的浓度和/或活性是否存在差异。为了实现这些目标，我们将测量骨骼肌和卵巢卵泡膜细胞葡萄糖摄取对胰岛素的敏感性，以确定这些组织对胰岛素的相对敏感性，胰岛素敏感和胰岛素抵抗的妇女和PCOS。我们已经建立了一个人类卵泡膜细胞培养模型，我们可以检查胰岛素信号的分子细节。重要的是，体外培养的细胞中持续存在雄激素产生增加和类固醇生成酶mRNA过表达。我们建议使用这个模型来系统地确定胰岛素刺激BMP 17活性和mRNA表达的细胞内信号传导途径，然后比较定期骑自行车的控制妇女和PCOS妇女之间的信号分子的浓度和活性。这些研究的结果有望为治疗PCOS女性的新疗法提供特定的分子靶点。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease in women of reproductive age. Approximately three-quarters of women with anovulatory infertility have PCOS, thus accounting for approximately one-third of women with secondary amenorrhea and approximately 90% of women with oligomenorrhea. Other consequences of PCOS are hirsutism, markedly increased incidence of recurrent early pregnancy loss, an estimated 11-fold increased risk of myocardial infarction between the ages of 50-61 years, and an increased risk of endometrial cancer at a young age. A consistent finding in women with PCOS is that the ovaries produce abnormally high amounts of androgens. There is good evidence to conclude that elevated androgens interfere with selection of dominant follicles and cause PCOS. Importantly, there is an association between insulin resistance and the androgen excess of PCOS. It is clear that insulin can stimulate ovarian androgen production, but a paradox exists: how can insulin hyperstimulate ovarian thecal androgen production in an insulin resistant woman? One of two hypotheses could explain the seeming paradox. Either the ovarian theca cells are not insulin resistant in insulin resistant women or there are distinct insulin signaling mechanisms regulating glucose metabolism and androgen production in theca cells. The purpose of the proposed studies is to determine if ovarian theca cells are insulin resistant in insulin resistant women, to explore the intracellular signaling mechanisms by which insulin regulates androgen biosynthesis, and to determine if there are differences in the concentrations and/or activities of key molecules mediating insulin action in theca cell from polycystic ovaries. To accomplish these goals, we will measure the sensitivity of skeletal muscle and ovarian theca cell glucose uptake in response to insulin to determine the relative sensitivity of these tissues to insulin in insulin sensitive and insulin resistant women with and without PCOS. We have established a human theca cell culture model in which we can examine the molecular details of insulin signaling. Importantly, increased androgen production and steroidogenic enzyme mRNA over-expression persist in the cultured cells in vitro. We propose to use this model to systematically determine the intracellular signaling pathway for insulin stimulation of CYP 17 activities and mRNA expression and then to compare the concentrations and activities of the signaling molecules between regularly cycling control women and women with PCOS. The results of these studies are expected to yield specific molecular targets for novel therapies to treat women with PCOS.