HORMONE-EWL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 具体目标 超过一半的美国成年人超重或肥胖，超过5%的美国医疗支出用于与肥胖相关的医疗费用。我们最近报道，在842名年龄在43-55岁的女性队列中，排卵性超重和肥胖女性的生殖激素模式与体重指数低于25公斤/平方米的女性相比存在显著差异。这些变化包括更长和更不规则的周期，以及整个月经周期中尿中黄体生成素、卵泡刺激素和黄体酮代谢物排泄的减少。我们假设这些荷尔蒙变化与体重有关，它们在超重和肥胖女性的发病率增加中发挥了作用。在此，我们建议进行一项研究，以检验肥胖女性体重减轻将导致生殖激素正常化的假设，并确定这种有益效果的潜在机制。我们提出以下具体目标： 目的：确定30名年龄在35-50岁、计划接受胃旁路手术的病态肥胖女性的大幅减重(至少是平均开始体重的25%)对每日生殖激素模式、卵泡生成、中枢神经促性腺激素释放激素驱动和脂肪因子的急性和慢性影响。 假设1：病态肥胖女性体重至少减少25%的急性和慢性减重将导致整体、全周期孕二醇(PDG)、黄体生成素和卵泡刺激素水平从基线水平上升。 结果：在三个时间点评估了全周期生殖激素模式： 在胃旁路手术前， 二、在“急性”减肥阶段，以及 三、在手术后的“平台期”。 假设2：病态肥胖女性体重下降至少25%是慢性的，但不是剧烈的，这将改变中枢神经下丘脑-垂体的驱动力。 结果：评估卵泡期促黄体生成素的搏动性分泌模式： 在胃旁路手术前， 二、在“急性”减肥阶段，以及 三、在手术后的“平台期”。 假设3：病态肥胖女性体重下降至少25%是慢性的，但不是剧烈的，这将导致更合适的卵泡发生和卵泡生长模式。 结果：连续经阴道超声检查一个周期，或在三个时间点评估最多25天： 在胃旁路手术前， 二、在“急性”减肥阶段，以及 三、在手术后的“平台期”。 假设4：脂联素图谱的改善以及瘦素和肿瘤坏死因子-α的降低将预测生殖激素正常化。 结果：定期检测脂联素、瘦素和肿瘤坏死因子-α与体重减少率和生殖激素的关系。 肥胖相关改变对月经周期的可逆性的证明将为进行更大规模的随机临床试验提供支持，在减肥过程中对卵泡生长和下丘脑-垂体轴功能的详细监测可以为肥胖的急性和慢性逆转对女性生殖产生积极影响的机制提供重要线索。因此，这一初步探索，如果成功，将为PI研究生殖与新陈代谢之间的相互作用提供新的基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SPECIFIC AIMS More than half of all US adults are overweight or obese, and over 5% of US health expenditures are directed at medical costs associated with obesity. We have recently reported, in a cohort of 842 women aged 43-55, dramatic differences in reproductive hormone patterns in ovulatory overweight and obese women, compared to women with a body mass index less than 25 kg/m2. These changes include longer and more irregular cycles, and decreased LH, FSH, and luteal progesterone metabolite excretion in urine over the course of an entire menstrual cycle. We hypothesize that these hormonal alterations are weight related, and that they play a role in the increased morbidity that overweight and obese women experience. We propose herein to perform a study to test the hypothesis that weight loss in obese women will result in normalization of reproductive hormones and to determine potential mechanisms for this salutary effect. We propose the following specific aim: To determine the acute and chronic effects of a large weight reduction (at least 25% from mean starting weight) in 30 morbidly obese women aged 35-50, who are scheduled to undergo gastric bypass surgery, on daily reproductive hormone patterns, folliculogenesis, central neural GnRH drive and adipokines. Hypothesis #1: Acute and chronic reduction in body weight of at least 25% in morbidly obese women will result in overall increases in integrated, whole-cycle pregnanediol (Pdg), LH and FSH from baseline. Outcome: whole cycle reproductive hormone patterns assessed at three time points: i. before gastric bypass surgery, ii. during the 'acute' weight loss phase, and iii. during the 'plateau' phase after surgery. Hypothesis #2: Chronic, but not acute reductions in body weight of at least 25% in morbidly obese women will alter central neural hypothalamic-pituitary drive. Outcome: follicular phase pulsatile LH secretory patterns assessed: i. before gastric bypass surgery, ii. during the 'acute' weight loss phase, and iii. during the 'plateau' phase after surgery. Hypothesis #3: Chronic, but not acute reductions in body weight of at least 25% in morbidly obese women will result in a more appropriate pattern of folliculogenesis and follicle growth. Outcome: serial transvaginal ultrasounds for one cycle or up to 25 days assessed at three time points: i. before gastric bypass surgery, ii. during the 'acute' weight loss phase, and iii. during the 'plateau' phase after surgery. Hypothesis #4: Improved adiponectin profiles and reductions in leptin and TNF-alpha will predict reproductive hormone normalization. Outcome: Adiponectin, leptin, and TNF-alpha will be examined periodically in relation to rate of weight loss and reproductive hormones. Demonstration of the reversibility of obesity related changes on menstrual cyclicity would provide support for the conduct of a larger randomized, clinical trial, and the detailed monitoring of follicle growth and hypothalamic-pituitary-axis function over the course of weight loss can be used to provide important clues to the mechanisms by which the acute and chronic reversal of obesity impacts positively upon female reproduction. Thus, this initial exploration, if successful, would provide the basis for a new line of investigation for the PI into the interactions between reproduction and metabolism.