Role of Antioxidants in Ovarian Thecal Hyperplasiar

本研究旨在验证如下假设：(I)氧化剂增加卵巢膜-间质(T-I)室的大小，抗氧化剂降低卵巢膜-间质(T-I)室的大小和类固醇生成能力，(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。这一假说基于的证据表明，其他与胰岛素抵抗和高胰岛素血症相关的疾病，如X综合征，其特征是氧化应激增加，自由基捕获和抗氧化能力降低。我们认为，胰岛素和胰岛素样生长因子(IGF)增加氧化应激，从而导致抗氧化剂(如维生素E)的相对枯竭。与高胰岛素血症和/或生物可利用性IGF增加相关的情况还表现为几种间质组织包括血管、平滑肌和皮肤成纤维细胞的增殖增加。同样，PCOS患者存在胰岛素抵抗、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T-I细胞的增殖和减少凋亡；这些作用可能导致T-I细胞的增殖，这是PCOS的特征。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以剂量依赖的方式抑制T-I细胞的增殖。相反，适度的氧化应激刺激细胞增殖。该建议的具体目的是：(I)研究氧化剂和抗氧化剂对T-I细胞增殖、类固醇合成和细胞凋亡的影响；以及(Ii)评估胰岛素、IGF-I和肿瘤坏死因子-α在T-I细胞培养中产生活性氧的作用。这些目标将通过在大鼠T-I细胞培养上的实验来实现。这些关键发现与人类卵巢的相关性将得到检验。这些研究结果将为了解氧化应激和抗氧化剂，特别是维生素E对卵巢间充质生长和功能的作用提供新的见解。最终，这项研究可能为多囊卵巢综合征的病理生理学提供新的线索，从而为开发新的诊断和治疗方法提供动力，包括可能的抗氧化剂的治疗用途。

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.