Role of Antioxidants in Ovarian Thecal Hyperplasiar

该提议旨在检验以下假设：（i）氧化剂增加和抗氧化剂降低卵巢卵泡膜-间质（T-I）区室的大小和类固醇生成能力，以及（ii）胰岛素、胰岛素样生长因子I（IGF-I）和肿瘤坏死因子α（TNF-α）通过诱导氧化应激刺激T-I细胞的生长。 我们认为，在病理条件下，T-I细胞的过度氧化应激可能有助于多囊卵巢综合征（PCOS）的发展。这一假说是基于证据表明，与胰岛素抵抗和高胰岛素血症相关的其他疾病，如X综合征，其特征是氧化应激增加和自由基捕获，抗氧化能力降低。 我们认为胰岛素和胰岛素样生长因子（IGFs）增加了氧化应激，从而导致维生素E等抗氧化剂的相对消耗。 与高胰岛素血症和/或增加的生物可利用IGF相关的病症的特征还在于几种间充质组织（包括血管平滑肌和皮肤成纤维细胞）的增殖增加。 同样，PCOS妇女也有胰岛素抵抗、代偿性高胰岛素血症和游离IGF-I水平升高. 我们的研究表明，胰岛素和IGFs促进增殖和减少T-I细胞的凋亡;这些作用可能有助于T-I细胞的增生，这是PCOS的一个特征。 我们的初步数据表明，在体外给予维生素E琥珀酸酯和其他抗氧化剂抑制增殖的T-I细胞的剂量依赖性的方式。相反，诱导适度的氧化应激刺激增殖。该提案的具体目的是：（i）研究氧化剂和抗氧化剂对T-I增殖、类固醇生成和凋亡的影响;以及（ii）评价胰岛素、IGF-I和TNF-α在T-I细胞培养物中产生活性氧的作用。 这些目标将通过对大鼠T-I细胞培养物的实验来解决。 将测试关键发现与人类卵巢的相关性。这些研究的结果将为氧化应激和抗氧化剂，特别是维生素E对卵巢间质生长和功能的作用提供新的见解。 最终，这项研究可能会揭示PCOS的病理生理学，从而为开发新的诊断和治疗方法提供动力，包括抗氧化剂的可能治疗用途。

This proposal is designed to test the hypothesis that (i) oxidants increase and antioxidants decrease the size and steroidogenic capability of the ovarian thecal-interstitial (T-I) compartment and (ii) insulin, insulin-like growth factor I (IGF- I) and tumor necrosis factor alpha (TNF-alpha) stimulate growth of T-I cells by inducing oxidative stress. We propose that, under pathological conditions, excessive oxidative stress on T-I cells may contribute to the development of polycystic ovary syndrome (PCOS). This hypothesis is based on evidence indicating that other disorders associated with insulin resistance and hyperinsulinemia, such as syndrome X, are characterized by increased oxidative stress and reduced radical-trapping, antioxidant capacity. We propose that insulin and insulin-like growth factors (IGFs) increase oxidative stress and thus cause relative depletion of antioxidants such as vitamin E. Conditions associated with hyperinsulinemia and/or increased bioavailable IGFs are also characterized by increased proliferation of several mesenchymal tissues including vascular smooth muscle and skin fibroblasts. Similarly, women with PCOS have insulin resistance, compensatory hyperinsulinemia, and increased levels of free IGF- I. Our studies have shown that insulin and IGFs promote proliferation and decrease apoptosis of T-I cells; these effects likely contribute to hyperplasia of T-I cells, a characteristic feature of PCOS. Our preliminary data demonstrate that in vitro administration of vitamin E succinate and other antioxidants inhibit proliferation of T-I cells in a dose-dependent fashion. In contrast, induction of modest oxidative stress stimulates proliferation. The specific aims of this proposal are: (i) to study the effects of oxidants and antioxidants on T-I proliferation, steroidogenesis, and apoptosis; and (ii) to evaluate the role of insulin, IGF-I and TNF-alpha in the generation of reactive oxygen species in cultures of T-I cells. These aims will be addressed by experiments on rat T-I cell cultures. The relevance of the key findings to the human ovary will be tested. The results of these studies will provide a new insight into the role of oxidative stress and antioxidants, especially vitamin E, on the growth and function of ovarian mesenchyme. Ultimately, this study may shed new light on the pathophysiology of PCOS and thus provide an impetus towards development of new diagnostic and therapeutic approaches, including the possible therapeutic use of antioxidants.