The Renin-Angiotensin-Aldosterone System in Postmenopausal Women: The Promise of Hormone Therapy

Estradiol (E2) plays an underrecognized role in modulating body-wide systems, including important interactions with the renin-angiotensin-aldosterone system (RAAS). The RAAS is an immunomodulating system that is critical for maintaining homeostasis across multiple organ systems. The diverse interactions between E2 and the RAAS help maintain cardiometabolic homeostasis, including successful physiologic responses to trauma and infectious pathogens. Estradiol deficiency (ie, menopause) results in impaired responses and increased susceptibility to infectious pathogens. Both immune and cardiometabolic function decline with reduced E2 production, in part because the RAAS becomes dysregulated by E2 deficiency, leaving RAAS predominantly in its proinflammatory state and predisposing to systemic low-grade inflammation. Estradiol deficiency and RAAS dysregulation contribute to impaired immune responses and increased incidence of cardiac hypertrophy, hypertension, atherosclerotic cardiovascular disease, arrhythmias, and heart failure. The RAAS consists of dual, counterbalancing pathways-proinflammatory and anti-inflammatory. Estradiol is a signaling agent that plays a major role in determining which RAAS pathway predominates. The proinflammatory pathway is activated early in response to infection or trauma, followed by up-regulation of the anti-inflammatory pathway, to resolve inflammation and to restore homeostasis. Estradiol influences activation of the "switch" to restore the anti-inflammatory state. The dysregulated RAAS is a primary target of current cardiovascular therapeutics focused on blocking portions of its proinflammatory pathway. However, RAAS-modifying pharmaceuticals often provide imperfect solutions to these physiologic disruptions and underscore the need for improved approaches to menopausal medicine. Estradiol therapy and optimal lifestyle practices combined with RAAS-modifying pharmaceuticals may be an ideal strategy to optimize postmenopausal health.