Cardiometabolic Consequences of the Loss of Ovarian Function

Menopause accelerates cardiovascular disease (CVD) risk due to adverse changes in risk factors (e.g., increased body fat) and vascular health, related to changes in the hormone environment. The investigators showed that measures of vascular health progressively worsen across the menopause transition, related to increased oxidative stress. The oxidative stress-mediated vascular dysfunction was related to the loss of estrogen. The loss of estrogen with menopause also causes an increase in percent body fat levels, particularly in the abdominal region. However, it is unknown if the increase in abdominal body fat worsens vascular dysfunction with the loss of estrogen. Thus Aim 1 of Project 1 will investigate the impact of increased abdominal adiposity superimposed on the direct effects of estrogen deficiency on vascular function in women. In collaboration with SCORE Projects 2 and 3, Aim 2 and an Exploratory aim will investigate the underlying causes for the increase in abdominal body fat and vascular dysfunction. There is emerging evidence that links the tryptophan-kynurenine (TRP-KYN) pathway as a regulator of vascular function, body fat and the aging process. TRP is an essential amino acid that is metabolized to KYN and various metabolites. KYN and some of its breakdown products have been associated with an increase in body fat and an impairment in vascular function. It is unknown if estrogen regulates this pathway. Thus, Aim 2 and the Exploratory aim will investigate if the TRP-KYN pathway is dysregulated with the loss of estrogen, and if this is associated with an increase in abdominal body fat and an impairment in endothelial function. The Aims of Project 1 will be accomplished by conducting an intervention trial in premenopausal women randomized to a low estrogen condition (gonadotropin releasing hormone antagonist, GnRHant, plus a placebo patch) or a high estrogen condition (GnRHant plus an estrogen patch) to isolate the actions of estrogen. Women will wear a patch daily that will be switched out weekly. At weeks 9 and 17, women will receive 5 mg of medroxyprogesterone acetate (MPA) for 12 days to prevent endometrial hyperplasia. Outcomes will be assessed before the intervention and after 2 and 20 weeks of the intervention, except where indicated. All women will continue their intervention until testing has been completed. Initially, women interested in the study will undergo a phone or e-mail screening to assess likelihood for eligibility.