Sympathetic Consequences of the Menopausal Transition - ABSTRACT Although overall cardiovascular (CV)-related mortality has declined, there has been an alarming increase in CV mortality in women prior to menopause (i.e., perimenopause, PERI). There is a crucial gap in knowledge regarding physiological changes in CV function during the menopausal transition as follicle stimulating hormone (FSH) increases and estradiol (E2) declines. Heightened sympathetic nervous system activity (SNA) at rest and in response to acute stimuli (i.e., SNA reactivity) is implicated in the pathogenesis of various CV diseases. SNA is governed centrally by regions in the medulla oblongata and influenced by higher brain regions. In the periphery, efferent SNA and the subsequent release of the neurotransmitter norepinephrine (NE) is a major contributor to vascular tone. While the α-adrenergic receptor-mediated vasoconstrictor response predominates, concurrent β-adrenergic receptor-mediated vasodilation partially restrains excessive NE-induced vasoconstriction. Although this effect is lost in postmenopausal women (POST), it is unclear if the loss of β-mediated dilation occurs during the menopausal transition, and to what extent changes in E2 and FSH contribute. Thus, aberrant changes in sympathetic function either centrally or peripherally during the menopausal transition (PERI) may have physiological consequences that contribute to higher rates of CV disease. Therefore, the goal of this study is to examine the upstream (i.e., central) causes and downstream (i.e., peripheral) consequences of sympathetic activation in premenopausal, early peri-, late peri-, and postmenopausal women and to understand the mechanistic contribution of changing reproductive hormones (FSH and E2) during the menopausal transition. Our overall hypothesis is that the menopausal transition promotes SNA overactivation centrally (i.e., medullary and supramedullary) and peripherally (efferent SNA, vascular adrenergic function) and is driven by greater FSH and lower E2 concentrations. We will perform a comprehensive assessment of sympathetic function in women across various menopausal stages based on the STRAW+10 criteria of reproductive aging, as well as during a controlled hormone intervention to isolate the effects of FSH and E2. Aim 1 we will directly record efferent SNA (peroneal microneurography) to test the hypothesis that SNA at rest and SNA reactivity will be augmented across the menopausal transition due to greater FSH and lower E2 concentrations. Aim 2 will test the hypothesis that BOLD fMRI signal changes during sympatho-excitatory maneuvers will be augmented in the supramedullary and medullary sympathetic regions in women across the menopausal transition due to greater FSH and lower E2 concentrations. Aim 3 will test the hypothesis that NE-induced vasoconstriction will be augmented across the menopausal transition and mediated by a loss of β-mediated dilation due to greater FSH and lower E2 concentrations. These findings will help identify the optimal treatment timeframe and target for interventions to promote CV health in women.
