PROJECT 4: ANDROGEN EXCESS IN ADIPOGENIC DYSFUNCTION IN PCOS WOMEN

对象摘要(请参阅说明)： 多囊卵巢综合征(PCOS)是一种常见的高雄激素血症、排卵功能障碍和多囊卵巢的异质性综合征。大多数多囊卵巢综合征女性的胰岛素抵抗(IR)也超过了体重指数(BMI)的预测，增加了患糖尿病的风险。尽管许多PCOS女性超重，但在非肥胖的PCOS女性中，皮下(SC)腹部脂肪细胞(脂肪细胞)的脂类分解(脂解)减少，导致SC腹部脂肪细胞增大，其大小与IR相关。这一发现可能是由于雄激素过多，因为雄激素减少脂肪分解并抑制SC腹部脂肪生成，从而脂肪干细胞成为前脂肪细胞并分化为脂肪细胞。因此，PCOS中过多的雄激素可能会减少SC腹部脂肪中的脂肪细胞数量，并降低该脂肪安全储存脂肪的能力。当能量摄入超过这一能力时，SC腹部脂肪细胞可能会充满脂肪，将游离脂肪酸动员到异位位置(脂毒性)，促进IR和卵巢功能障碍。我们假设瘦削的PCOS妇女雄激素过多降低了成脂分化，增加了受限的SC腹部脂肪储备中脂肪细胞的脂肪含量，导致脂肪毒性、IR和卵巢功能障碍。如果是这样的话，对瘦身的PCOS妇女进行6个月的氟他胺抗雄激素治疗，可以改善SC腹部脂肪生成、胰岛素敏感性以及卵巢功能和形态。我们将1)比较瘦型PCOS女性与年龄和体重指数匹配的对照组在SC腹部脂肪生成方面的差异；2)检测瘦型PCOS女性6个月的Fiutamine治疗对SC腹部脂肪生成、体内脂肪分布、代谢功能和卵巢卵泡生成的影响；3)确定雄激素抑制脂肪生成的潜在机制。了解瘦削的PCOS妇女体内的雄激素过多是否会破坏SC的腹部脂肪生成从而损害卵巢功能，这将在造脂和卵巢功能障碍之间建立一个关键的联系，从而有助于开发新的临床策略，改善PCOS妇女的生殖能力，并在不孕不育治疗期间提高促排卵药物的安全性。

ROJECT SUMMARY (See instructions): Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous syndrome of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Most PCOS women also have insulin resistance (IR) beyond that predicted by body mass index (BMI), increasing the risk for diabetes. Although many PCOS women are overweight, in nonobese PCOS women, breakdown of lipids (lipolysis) is decreased in subcutaneous (SC) abdominal fat cells (adipocytes), causing enlarged SC abdominal adipocytes that correlate in size with IR. This finding may be due to androgen excess, since androgen decreases lipolysis and inhibits SC abdominal adipogenesis, whereby adipose stem cells become preadipocytes and differentiate to adipocytes. Thus, androgen excess in PCOS may decrease numbers of adipocytes in SC abdominal adipose and reduce capacity of this adipose to safely store fat. When energy intake exceeds this capacity, SC abdominal adipocytes may overfill with lipid, mobilizing free fatty acids to ectopic locations (lipotoxicity), promoting IR and ovarian dysfunction. We hypothesize that androgen excess in lean PCOS women decreases adipogenic differentiation and increases adipocyte lipid content in a constrained SC abdominal adipose store, inducing lipotoxicity, IR and ovarian dysfunction. If so, antiandrogen therapy with flutamide for 6 months to lean PCOS women should improve SC abdominal adipogenesis, insulin sensitivity and ovarian function and morphology. We will 1) compare differences in SC abdominal adipogenesis in lean PCOS women vs. age- and BMI matched controls; 2) examine the effect of 6-month fiutamide therapy in lean PCOS women on SC abdominal adipogenesis, body fat distribution, metabolic function and ovarian folliculogenesis; and 3) determine the underlying mechanisms whereby androgen inhibits adipogenesis. Understanding if androgen excess in lean PCOS women disrupts SC abdominal adipogenesis to impair ovarian function will establish a crucial link between adipogenic and ovarian dysfunction, allowing development of new clinical strategies that improve reproduction in PCOS women and enhance safety of ovulation-inducing agents during infertility therapy.