Estradiol Regulation of In Vivo Adipose Tissue Glucocorticoid Metabolism

描述（由申请人提供）：绝经前妇女防止腹部肥胖，这似乎是雌激素介导的。药物抑制性激素在绝经前妇女增加全身脂肪，与躯干脂肪不成比例的增加。随机对照试验提供了强有力的证据，表明以雌激素为基础的激素治疗可以减轻绝经后妇女的体重增加和腹部脂肪堆积；这些作用的机制尚不清楚。因此，我们的总体目标是采用一个实验模型来评估雌二醇（E2）的退出引发腹部肥胖增加的潜在生物学机制。糖皮质激素是腹部脂肪堆积的有力刺激物。在动物中，雌激素缺乏增加了无活性糖皮质激素可的松向活性糖皮质激素皮质醇的转化，从而增加了组织对皮质醇的暴露；这种作用是由酶11- β -羟基类固醇脱氢酶1型介导的。我们建议研究30名健康的绝经前妇女在接受性激素抑制（GnRH拮抗剂（GnRHant）） 5天后的全身和腹部脂肪组织特异性糖皮质激素代谢（使用一种新的体内微透析技术）。为了分离E2的影响，我们将继续GnRHant并随机分配妇女进行5天的“加回”治疗，使用低剂量或高剂量透皮E2或安慰剂。我们假设，与卵泡月经周期的早期和晚期相比，性激素抑制会增加可可松向皮质醇的全身和皮下腹部脂肪转化（预期剂量反应：GnRHant >早期卵泡>晚期卵泡）。此外，我们假设E2的添加会逆转性激素抑制的影响。我们的研究将评估一种生物学机制，我们认为这种机制是导致绝经期腹部肥胖增加及其相关代谢后遗症的原因。重要的是，我们将研究的机制，e2介导的糖皮质激素代谢调节，可能与更年期过渡后增加的其他疾病（例如骨质疏松症，认知障碍）有关。因此，该建议高度响应RFA的目标，即解决内源性下丘脑-垂体-卵巢轴激素的潜在生物学及其与非生殖器官系统的相互作用。

DESCRIPTION (provided by applicant): Premenopausal women are protected against abdominal obesity and this appears to be estrogen-mediated. Pharmacologic suppression of sex hormones in premenopausal women increases total body fat, with disproportionate increases in trunk fat. Randomized controlled trials provide strong evidence that estrogen-based hormone therapy attenuates weight gain and abdominal fat accumulation in postmenopausal women; the mechanisms for these actions remain unknown. Thus, our global aim is to employ an experimental model to evaluate a potential biological mechanism by which the withdrawal of estradiol (E2) triggers an increase in abdominal adiposity. Glucocorticoids are a potent stimulus of abdominal fat accumulation. In animals, estrogen deficiency increases conversion of the inactive glucocorticoid, cortisone, to the active glucocorticoid, cortisol, thereby amplifying tissue exposure to cortisol; this action is mediated by the enzyme 11-beta-hydroxysteroid dehydrogenase type 1. We propose to study both whole-body and abdominal adipose tissue-specific (using a novel in vivo microdialysis technique) glucocorticoid metabolism in 30 healthy, premenopausal women after 5 days of sex hormone suppression (GnRH antagonist (GnRHant)). To isolate the effect of E2, we will continue GnRHant and randomize women to 5 days of "add-back" therapy with low-or high-dose transdermal E2 or placebo. We hypothesize that sex hormone suppression will increase both whole body and subcutaneous abdominal fat conversion of cortisone to cortisol compared with the early and late follicular menstrual cycle phases (expected dose response: GnRHant > early follicular > late follicular). Further, we postulate that E2 add-back will reverse the effects of sex hormone suppression. Our studies will evaluate a biological mechanism that we believe is responsible for the menopausal increase in abdominal adiposity and its associated metabolic sequelae. Importantly, the mechanism that we will study, E2-mediated regulation of glucocorticoid metabolism, likely has relevance to other conditions that also increase after the menopause transition (e.g., osteoporosis, cognitive impairment). Therefore, this proposal is highly responsive to the RFA goal of addressing the underlying biology of endogenous hypothalamic-pituitary-ovarian axis hormones and their interactions with non-reproductive organ systems.