氧化应激在多囊卵巢综合征高雄发生中的作用及其机制探讨

Recent studies have suggested that extensive oxidative stress, an important factor to start the chronic inflammation of the body, may play important roles in hyperandrogenism (HA), insulin resistance, and reproductive dysfunction. Polycystic ovarian syndrome (PCOS) is a complex disease and has a variety of clinical phenotypes. We recently found that the gene variants and low activities of antioxidant enzyme in high density lipoprotein (HDL) were associated with PCOS, and patients with hyperandrogenism (HA+OA+PCO, HA+OA, HA+PCO) had a relatively lower incidence of dyslipidemia and metabolic syndrome, but higher serum malondialdehyde levels when compared with the PCOS patients without hyperandrogenism (OA+PCO), suggesting that the increased oxidative stress may play an important role in the occurrence of hyperandrogenism in PCOS. However, the relationships between the key circulating markers of oxidative stress and PCOS phenotypes as well as the effect of oxidative stress on hyperandrogenism and its mechanism are unknown. The present study is to investigate the relationships between serum/plasma oxidative stress markers such as total oxidant status (TOS), total lipid peroxides, oxidized low density lipoprotein (OxLDL) and the Rotterdam PCOS phenotypes, and explore the effects of OxLDL on synthesis and secretion of sex hormone-binding globulin (SHBG) in HepG2 cells and on proliferation and androgen synthesis of rat ovarian theca-interstitial cells and their mechanism. Our results will provide the theoretical basis for the elucidation of the pathogenesis of PCOS, and prevention and treatment of PCOS and future cardiovascular and cerebrovascular diseases.

氧化应激是启动机体慢性炎症的重要因素，可能促进胰岛素抵抗、刺激雄激素分泌、影响生殖功能。研究发现PCOS患者存在氧化应激增加和抗氧化功能减弱，增加氧化应激与PCOS高雄的发生密切相关。高雄已经被表明促进氧化应激的发生，然而氧化应激是否促进PCOS高雄的发生及其机制仍未阐明，PCOS呈高度异质性，但迄今仍然缺乏重要氧化应激指标与鹿特丹不同PCOS表型关系的报道。本研究拟测定不同PCOS表型患者循环TOS、总氧化脂质和OxLDL水平，以明确氧化应激与PCOS雄激素水平的相关程度；探讨氧化应激（OxLDL）对大鼠卵泡膜间质细胞增殖和睾酮合成的影响及可能的途径，探究OxLDL对HepG2细胞SHBG合成、分泌的影响及其机制。较全面地从卵巢睾酮产生和循环睾酮转运的角度，揭示氧化应激在PCOS高雄发生中的作用，为PCOS发病机制的阐明、PCOS的预防、治疗及远期心血管疾病的防治提供理论依据和新的思路。

研究背景：多囊卵巢综合征（PCOS）是一种病因未明、临床表现呈高度异质性的常见女性内分泌代谢紊乱性疾病,以稀发排卵或无排卵（OA）、临床和/或生化高雄激素血症（HA）、卵巢多囊样改变（PCO）为特征。PCOS患者常伴氧化应激（OS）增加，然而不同鹿特丹PCOS表型（HA+OA+PCO、HA+OA、HA+PCO，OA+PCO）的OS水平尚未见报道，增加OS是否促进PCOS高雄的发生及其机制仍未阐明。.研究内容：测定了PCOS患者及对照妇女血清总氧化状态（TOS）、总抗氧化能力（T-AOC）、OS指数（OSI：TOS/T-AOC比值）、氧化修饰低密度脂蛋白（ox-LDL）、性激素结合球蛋白（SHBG）浓度和OS相关基因变异，分析了OS与PCOS临床、激素、SHBG和代谢指标的关系。以原代大鼠卵巢卵泡膜间质细胞（T-I细胞）为模型，探讨了ox-LDL、ox-HDL对T-I细胞增殖和睾酮合成的影响及其机制。.主要结果：（1）不同PCOS临床表型均存在循环绝对（TOS）和相对（OSI）OS水平的增加，其中HA-PCOS表型高于非HA-PCOS表型；不同PCOS表型也降低SHBG水平；HA+OA+PCO表型明显增加血清ox-LDL水平。（2）增加OS与PCOS HA状态、增加血糖和血脂水平以及机体抗氧化能力相对不足有关；肥胖也是影响血清ox-LDL与SHBG水平的重要因素之一；血清ox-LDL水平与SHBG水平成负相关。（3）大鼠卵巢T-I细胞实验证明：脂蛋白（HDL、LDL）与轻度氧化修饰的脂蛋白（ox-HDL、ox-LDL）明显增加细胞的增殖，以LDL的作用最强；与脂蛋白处理细胞比较，氧化修饰脂蛋白处理细胞增加培养上清睾酮浓度、细胞睾酮合成关键酶（CYP11A1、CYP17A1、3β-HSD）与类固醇合成快速调节蛋白（StAR）基因表达的作用更强。（4）对OS相关基因变异的研究发现：超氧化物歧化酶2基因A16V变异与我国HA-PCOS的发生相关联，A等位基因是PCOS发生的遗传危险因子。.结论：HA-PCOS表型有更高的循环绝对和相对OS水平。增加OS或/和血浆脂蛋白水平能够促进卵巢T-I细胞增殖、通过增加睾酮合成关键酶等的表达刺激睾酮的合成与分泌，加重PCOS HA状态。本研究结果为PCOS防治、发病机制的阐明提供了新的思路和理论依据。