Many factors contribute to the current epidemic of obesity. Although estrogen (E2) status is not commonly recognized as a determinant of obesity risk in women, there is strong evidence from large randomized controlled trials that E2-based hormone therapy (HT) attenuates weight gain by about 40% in postmenopausal women. Importantly, there is also strong evidence that E2 attenuates abdominal fat accumulation, a fundamental component of the Metabolic Syndrome. The global aim of the proposed studies is to evaluate potential mechanisms by which E2 deficiency accelerates fat gain and abdominal fat accumulation in women. The first aim is to determine the effects of short-term (7 d) and chronic (5 mo) sex hormone suppression on resting energy expenditure (REE) and fat gain. It is hypothesized that a) REE will be reduced in response to short-term hormone suppression, as observed in a pilot study;b) the decrease will persist with chronic hormone suppression, promoting fat gain;and c) E2 add-back therapy will mitigate these responses. Whereas a dampened REE may cause fat gain in the E2-deficient state, it would not explain the disproportionate accumulation of abdominal fat that occurs. Altered hypothalamic-pituitary-adrenal (HPA) axis activity leading to cortisol excess causes abdominal fat accumulation (e.g., Cushing's syndrome) and there is evidence that E2 attenuates stress-induced HPA axis activity. Therefore, the second aim is to determine the effects of sex hormone suppression on stress-induced HPA axis activity and abdominal fat accumulation. It is hypothesized that stress-induced HPA axis activity will be a) amplified during sex hormone suppression;b) attenuated by E2 add-back;and c) a determinant of abdominal fat gain. These aims will be accomplished by using gonadotropin releasing hormone (GnRH) analog therapy, with placebo or E2 add-back, to determine the effects of E2 on REE, HPA axis activity, and fat gain and distribution in 100 healthy young women. Abdominal obesity purportedly accounts for 20% of coronary events in men but 48% of events in women, underscoring the value of learning the mechanisms of abdominal fat gain in women. Until menopause, women are largely protected against abdominal obesity, implicating a role for sex hormones. Recent findings that benefits of HT may not outweigh the risks in some women does not negate the importance of identifying mechanisms by which E2 attenuates fat gain and abdominal fat accumulation.

R01AG018198

2000-02-15

2014-10-31