Estradiol Regulation of In Vivo Adipose Tissue Glucocorticoid Metabolism

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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.