Influence of menopause and sex hormone deficiency on autonomic and vascular determinants of blood pressure - Project Summary/Abstract Cardiovascular disease (CVD) risk poses a considerable concern in menopausal females; however, sex-specific risk factors for CVD remain under-recognized and incompletely understood. Hypertension (HTN) often precedes CVD and HTN prevalence increases with age. Indeed, autonomic and vascular determinants of blood pressure are often impaired with aging. Because menopause is both a consequence and a facilitator of aging, the impact of menopause, independent of age, on autonomic and vascular function, has yet to be discovered. Long-term objectives of this proposal are to delineate the influence of the menopausal transition on sympathetic activity, baroreflex function, vascular conductance and endothelial function (autonomic and vascular function) in females (Aim 1). In addition, Aim 2 will determine how ovarian suppression with a gonadotropin-releasing hormone antagonist (GnRHANT) alters autonomic and vascular function (Aim 2A) and if the impairment in autonomic and vascular function with ovarian suppression is related to estradiol (E2; Aim 2B). Dr. Manda L. Keller-Ross, PhD, DPT, an early-stage investigator in the Department of Family Medicine and Community Health at the University of Minnesota, is the PI of the Cardiovascular Research and Rehabilitation Laboratory, where the proposed R01 study will take place. To accomplish the research objectives outlined in this R01, the PI Keller-Ross and her Co-Is (Drs. Anne Blaes, Benjamin Langworthy, Jason Carter, and Kerrie Moreau) will employ gold-standard measures and novel methodological approaches to evaluate autonomic and vascular function in females. For both Aims, participants will complete autonomic testing: muscle sympathetic nerve activity (MSNA) via microneurography, baroreflex sensitivity, and venous occlusion plethysmography to quantify vascular conductance. Further, endothelial function will be measured with flow-mediated dilation and nitroglycerin to determine endothelium-dependent and -independent vasodilation. In Aim 1, females (45-55 yrs old) will complete this testing in perimenopause and up to one year post-final menstrual period. We hypothesize that during the menopause transition, a shift in autonomic and vascular function will emerge, such that MSNA will increase and baroreflex sensitivity, vascular conductance and endothelial function will become impaired. In Aim 2, premenopausal females (40-50 yrs old) will be randomized to a subcutaneous injection of degarelix, a GnRHANT, to reversibly suppress ovarian hormone production or to a placebo injection. Those who receive GnRHANT will then be randomized to E2 or placebo and will complete autonomic and vascular testing before, during and after treatment. We hypothesize that treatment with GnRHANT will increase MSNA and impair baroreflex sensitivity, vascular conductance and endothelial function. We further hypothesize that E2 add-back, but not placebo, will normalize these measures. By identifying the menopause-associated alterations in autonomic and vascular function, vital determinants of blood pressure, we will have a clearer understanding of the impact of E2 on cardiovascular health and establish the groundwork for prophylactic strategies to mitigate CVD risk in females.
