PROJECT 4: ANDROGEN EXCESS IN ADIPOGENIC DYSFUNCTION IN PCOS WOMEN

项目 4：多囊卵巢综合征女性脂肪生成功能障碍中雄激素过多

基本信息

批准号：
8510090
负责人：
Daniel A Dumesic
金额：
$ 21.45万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510090
关键词：
Abdomen Adipocytes Adipose tissue Age Androgen Antagonists Androgens Antiandrogen Therapy Antral BMP4 Blood Vessels Body fat Body mass index Cells Clinical Coculture Techniques Culture Techniques Development Diet Dose Energy Intake Fatty Acids Fatty acid glycerol esters Female Flutamide Frequencies Functional disorder Gene Expression Glucuronides Gonadal Steroid Hormones Human Follicle Stimulating Hormone Hyperandrogenism In Vitro Individual Infertility Instruction Insulin Insulin Resistance Link Lipids Lipolysis Location Measures Metabolic Metabolism Morphology Non obese Nonesterified Fatty Acids Outcome Measure Ovarian Ovarian Follicle Overweight Ovulation Ovulation Prediction Polycystic Ovary Syndrome Pregnanediol Recombinants Reproduction Reproductive Health Safety Serum Signal Transduction Signaling Protein Stem cells Structure Syndrome Tissues Visceral Woman abdominal fat adiponectin diabetes risk folliculogenesis glucose metabolism improved in vivo insulin sensitivity lipid biosynthesis mullerian-inhibiting hormone paracrine response subcutaneous urinary

项目摘要

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.

摘要（请参阅说明）：多囊卵巢综合征（PCOS）是一种普遍的异质生成，排卵功能障碍和多囊卵巢的异质综合征。大多数PCOS女性还具有超出体重指数（BMI）预测的胰岛素抵抗（IR），从而增加了糖尿病的风险。尽管许多PCOS女性超重，但在非肥胖PCOS妇女中，皮下（SC）腹部脂肪细胞（脂肪细胞）的脂质分解（脂解）降低，从而导致SC肿瘤肿瘤肿瘤脂肪细胞的扩大，与大小相关。这一发现可能是由于雄激素过量引起的，因为雄激素会降低脂解并抑制SC腹部脂肪生成，从而使脂肪干细胞成为前脂肪细胞并与脂肪细胞区分开。因此，PCOS中的雄激素过量可能会减少腹部脂肪中脂肪细胞的数量，并降低该脂肪安全储存脂肪的能力。当能量摄入超过这种能力时，SC腹部脂肪细胞可能会用脂质过度填充，将游离脂肪酸动员到异位位置（脂肪毒性），从而促进IR和卵巢功能障碍。我们假设瘦PCOS女性中的雄激素过量会降低脂肪生成分化，并在受约束的SC腹部脂肪储存中增加脂肪细胞脂质含量，从而诱导脂肪毒性，IR和卵巢功能障碍。如果是这样，则用氟丁二酰胺治疗6个月，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）比较精益PCOS女性与年龄和BMI匹配的对照中SC腹部脂肪形成的差异； 2）检查6个月的富丁酰胺治疗对瘦PCOS女性对SC腹部脂肪生成，体内脂肪分布，代谢功能和卵巢卵泡发生的影响； 3）确定雄激素抑制脂肪形成的基本机制。了解精益PCOS女性中的雄激素过量是否会破坏SC腹部脂肪生成以损害卵巢功能会在脂肪生成和卵巢功能障碍之间建立关键联系，从而允许开发新的临床策略，从而改善PCOS女性的繁殖并增强在不育治疗期间诱导排卵剂的安全性。