MOLECULAR BIOLOGY OF POLYCYSTIC OVARY SYNDROME

描述：多囊卵巢综合征(PCOS)是最常见的 育龄妇女的生殖内分泌疾病。许多严肃的人 健康问题与多囊卵巢综合征有关，包括不孕不育、多毛症、 妊娠丢失增加，患心血管疾病的风险显著增加 和年轻时的子宫内膜癌。尽管多囊卵巢综合征和 这种疾病的高患病率，多囊卵巢综合征的病因仍然是 神秘感。多囊卵巢综合征患者的代谢特征是异质性的， 甚至引发了关于多囊卵巢综合征的定义的争议，但共同的 PCOS所有亚型的生理联系是卵泡发育不足 超过了早期的胃窦阶段。因此，为了了解原因， 为了开发有效的治疗方法，关键是要了解 正常女性优势卵泡选择的调控机制 以及这些机制在患有多囊卵巢综合征的女性中是如何改变的。这些研究 到目前为止所做的工作导致了这样的结论：存在内生的 多囊卵巢综合征中不存在的芳香酶抑制物(P450AROM) 毛囊。在初步研究中，我们表明， 竞争性P450AROM活性抑制剂5-α-雄烷-3，17-二酮 在人的GC中，在PCOS中显著高于正常卵泡。 有趣的是，5-α-A的产量似乎在 优势卵泡，增加了5-α调节的可能性 还原酶活性可能在优势卵泡的选择中起作用 以及多囊卵巢的发生。这项提案的总体目标是 是评估5-αA在多囊卵巢综合征发生中的作用，并了解 5-α还原酶基因表达和酶活性的调节 卵巢。具体目标是确定以下影响的大小 5-αA对PCOS卵泡中P450AROM活性的影响 在PCOS中表达被阻止，或者如果P450AROM表达但其活性 并确定P45017α和P45017α是否存在异常 P450scc在PCOS中的表达。两种5-α-还原酶的表达 MRNAs与两种5-α-还原酶的定位和活性 我们将检查正常卵巢和PCOS卵巢中的同工酶。最后， 卵巢中5α-还原酶基因表达的调节 学习。这些研究的结果将提供大量重要的 关于正常卵泡发育的分子生物学信息 以及多囊卵巢综合征中出现的异常。有很大的可能性 这一新知识可以直接导致新的治疗方法， 恢复生殖周期，消除许多增加的风险 多囊卵巢综合征妇女的心血管和恶性疾病。

DESCRIPTION: Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease in women of reproductive age. Many serious health problems are associated with PCOS, including infertility, hirsutism, increased pregnancy loss, markedly increased risk for cardiovascular disease and endometrial cancer at a young age. Despite the seriousness of PCOS and the high prevalence of this disorder, the etiology of PCOS remains a mystery. The metabolic profile of the PCOS patient is heterogenous and has led to controversy regarding even the definition of PCOS but the common physiological link in all subtypes of PCOS is a lack of follicle development beyond the early antral stage. Therefore, in order to understand the causes of PCOS and to develop an effective treatment it is critical to understand the mechanisms regulating selection of the dominant follicle in normal women and how these mechanisms are altered in women with PCOS. The studies performed to date lead to the conclusion that there is an endogenous inhibitor of aromatase (P450AROM) in PCOS that is not present in normal follicles. In preliminary studies, we showed that the concentration of 5-alpha-androstane-3,17-dione, a competitive inhibitor of P450AROM activity in human GC, is significantly higher in PCOS than normal follicles. Interestingly, it appears that 5-alpha-A production decreases markedly in dominant follicles, raising the possibility that regulation of 5-alpha reductase activity may play a role in selection of the dominant follicles and the genesis of polycystic ovaries. The overall goals of this proposal are to assess the role of 5-alpha A in the genesis of PCOS and to understand the regulation of 5-alpha reductase mRNA expression and enzyme activity in the ovary. Specific goals are to determine the magnitude of the effects of 5-alpha A on P450AROM activity in PCOS follicles, to determine if P450AROM expression is blocked in PCOS or if P450AROM is expressed but its activity is inhibited, and to determine if there are abnormalities in P45017alpha and P450scc expression in PCOS. The expression of the two 5-alpha-reductase mRNAs and the localization and activities of the two 5-alpha-reductase isoenzymes in normal and PCOS ovaries will be examined. Finally, the regulation of 5 alpha-reductase gene expression in the ovary will be studied. The results of these studies will provide a wealth of important information regarding the molecular biology of normal follicle development and the abnormalities that occur in PCOS. There is a strong probability that this new knowledge could lead directly to novel therapies that may restore reproductive cyclicity and eliminate many of the increased risks for cardiovascular and malignant disease in women with PCOS.