Bioenergetic and Metabolic Consequences of the Loss of Ovarian Function in Women

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Gonadal aging plays a distinct role in mediating some of the biological changes ascribed to the aging process. An example of this is the accelerated bone loss due to ovarian failure at the time of the menopause, which can be effectively mitigated with restoration of estrogens until other non-gonadal aging factors trigger a decline. Because it is difficult to isolate the consequences of gonadal aging from chronologic aging, it is not clear to what extent the loss of gonadal function increases risk for age-related diseases other than osteoporosis. There is compelling evidence from studies of female and male animals that the loss of gonadal function causes a dramatic decline of 30% to 80% in spontaneous physical activity. In females, but not males, this leads to accelerated weight gain, a marked increase in abdominal fat, and metabolic dysfunction. One prospective study of women followed through the menopausal transition suggests that physical activity and the maintenance of energy balance are also regulated by gonadal function in humans. In this context, the primary goal of the UCAMC SCOR clinical project is to use a controlled intervention approach to determine whether the suppression of ovarian function in women approaching the menopause causes a marked decline in physical activity. Additional goals are to assess changes in other components of energy expenditure, determine whether the disruption of energy balance is associated with changes in biomarkers of disease risk, and determine whether programmed exercise can prevent these changes. To achieve these aims, 66 women aged 45 to 50 years with normal menstrual cycle function will be randomized to receive 6 months of placebo, gonadotropin releasing hormone agonist (GnRHAc), or GnRHAG+exercise intervention. The primary outcome will be physical activity energy expenditure (PAEE), calculated from total daily energy expediture (TEE; by doubly-labeled water) with adjustment for the thermic effect of food and resting EE (REE; by indirect calorimetry). The global hypothesis is that the suppression of ovarian function with GnRHAG in women will cause a decrease in TEE due to decreased PAEE and, possibly, a decrease in REE. RELEVANCE (See instructions): A decline in PAEE secondary to the loss of gonadal function could have diverse adverse effects on health because low physical activity is associated with all-cause mortality, coronary heart disease, stroke, type 2 diabetes, certain cancers, depression, etc. Moreover, this would be expected to have a greater adverse effect in women than in men, because the loss of gonadal function occurs at an earlier age in women.