HORMONE-EWL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，在一组842名43-55岁的妇女中，与体重指数小于25 kg/m2的妇女相比，排卵期超重和肥胖妇女的生殖激素模式存在显着差异。 这些变化包括更长和更不规则的周期，以及在整个月经周期过程中尿液中LH、FSH和黄体孕酮代谢产物排泄减少。 我们假设这些激素变化与体重有关，并且它们在超重和肥胖女性经历的发病率增加中发挥作用。 我们在此建议进行一项研究，以测试肥胖妇女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： 确定30名35-50岁的病态肥胖女性计划接受胃旁路手术，大幅度减重（平均起始体重至少25%）对日常生殖激素模式、卵泡生成、中枢神经GnRH驱动和脂肪因子的急性和慢性影响。 假设#1：在病态肥胖女性中，体重急性和慢性降低至少25%将导致整体、全周期妊娠结局（Pdg）、LH和FSH较基线总体增加。 结果：在三个时间点评估的整个周期生殖激素模式： I. 在胃旁路手术之前， 二. 在“急性”减肥阶段， 三. 在手术后的“平台期”。 假设#2：病态肥胖妇女体重慢性而非急性减少至少25%将改变中枢神经下丘脑-垂体驱动。 结局：评估卵泡期脉冲式LH分泌模式： I. 在胃旁路手术之前， 二. 在“急性”减肥阶段， 三. 在手术后的“平台期”。 假设#3：慢性而非急性体重下降至少25%的病态肥胖妇女将导致更适当的卵泡发生和卵泡生长模式。 结局：连续经阴道超声检查一个周期或长达25天，在三个时间点进行评估： I. 在胃旁路手术之前， 二. 在“急性”减肥阶段， 三. 在手术后的“平台期”。 假设#4：改善脂联素谱和减少瘦素和TNF-α将预测生殖激素正常化。 结果：将定期检查脂联素、瘦素和TNF-α与体重减轻率和生殖激素的关系。 证明肥胖相关的月经周期变化的可逆性将为进行更大规模的随机临床试验提供支持，并且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用于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，如果成功的话，将提供一个新的调查路线的PI到生殖和代谢之间的相互作用的基础。

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.