PROJECT 2 - Reproductive Hormonal Alterations in Obesity

女性BMI增加与下丘脑-垂体-卵巢轴功能恶化有关， 繁殖性能我们观察到LH脉冲性分泌幅度降低， 雌二醇和雌二醇环境中FSH分泌降低，孕酮代谢产物显著减少 在病态肥胖的女性中的排泄。手术减肥后，这些变化只是部分 相反，这表明要么肥胖重置生殖轴，要么体重减轻到正常范围， 这对于大多数肥胖个体来说是无法实现的，即使是在采取手术措施之后。根据我们初步的 有证据表明，下丘脑、垂体和卵巢水平都受到肥胖的不利影响， 计划进行一系列实验，以阐明肥胖诱导生殖轴的机制 功能障碍提出了以下具体目标：1。为了验证垂体减少 对GnRH诱导的LH和FSH分泌的敏感性导致相对低促性腺激素性性腺功能减退， 肥胖，我们将静脉注射GnRH，观察内源性LH和FSH反应， 促性腺激素清除（目标1a），并将在GnRH拮抗剂阻断后给予外源性LH， 当给予相同的分子种类时，观察LH清除率（目的1b）; 2.为了检验这一假设 下丘脑-垂体轴对雌二醇负反馈异常敏感，我们将给予 来曲唑对正常体重和肥胖妇女进行治疗，观察垂体（LH脉动、GnRH敏感性和 FSH反应，Aim 2a）和卵巢反应（雌二醇、卵泡抑素A和B以及苗勒管抑制物质- - 错误目标2b）; 3.为了验证肥胖症中观察到的黄体功能不全是由于 在对LH的反应性缺陷中，我们将检查孕酮的产生对内源性 和外源性LH（Aim 3a），检测一种独特的黑长尾猴的黄体基因表达谱 在暴露于肥胖诱导饮食（目标3b）之前和之后的菌落，并检查新的潜在缺陷 在LH受体mRNA加工中的作用。

Increasing BMI in women is related to worsening hypothalamic-pituitary-ovarian axis function and impaired reproductive performance. We have observed a reduced amplitude of pulsatile LH secretion, inappropriately low FSH secretion for the estradiol and inhibin milieu, and dramatically reduced progesterone metabolite excretion in morbidly obese women. After surgically induced weight loss, these changes only partially reverse, indicating that either obesity resets the reproductive axis or that weight loss into the normal range is not achievable for most obese individuals, even after surgical measures are taken. Based on our preliminary evidence that hypothalamic, pituitary and ovarian levels are all adversely affected by obesity, we have planned a series of experiments to elucidate the mechanisms underlying obesity-induced reproductive axis dysfunction. The following specific aims are proposed: 1. To test the hypothesis that reduced pituitary sensitivity to GnRH-induced LH and FSH secretion causes the relative hypogonadotropic hypogonadism of obesity, we will administer intravenous GnRH and observe endogenous LH and FSH response and gonadotropin clearance (Aim 1a), and will administer exogenous LH after GnRH antagonist blockade to observe LH clearance (Aim 1b) when identical molecular species are administered; 2. To test the hypothesis that the hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback, we will administer letrozole to normal weight and obese women and observe the pituitary (LH pulsatillty, GnRH sensitivity and FSH response, Aim 2a) and ovarian response (estradiol, inhibin A and B and Mullerian Inhibiting Substance- -MIS-Aim 2b); 3. To test the hypothesis that the corpus luteum insufficiency observed in obesity is due to a defect in responsiveness to LH, we will examine progesterone production in response to both endogenous and exogenous LH (Aim 3a), examine corpus luteum gene expression profiles in a unique vervet monkey colony before and after exposure to an obesity-inducing diet (Aim 3b) and examine a novel potential defect in LH receptor mRNA processing via mevalonate kinase.