Cardiac Physiology
Michael A. Gropper MD, PhD, in Miller's Anesthesia, 2020
Sex Steroid Hormones and the Heart
Cardiac contractility is more intense in premenopausal women than in age-matched men, and withdrawal of hormone replacement therapy in postmenopausal women leads to a reduction in cardiac contractile function. The gender dimorphism in heart function and its adaptive responses to injury and disease states are partly mediated by sex steroid hormones. Indeed, healthy premenopausal women exhibit a lower cardiovascular risk compared to men, which suggests a mechanism for sex hormones in the modulation of cardiac function.76
The most extensively studied sex steroid hormones are estradiol-17β (E2) and its bioactive metabolites. They bind and act on the two subtypes of estrogen receptors (ERs) in the heart: ERα and ERβ. Progesterone and testosterone (two other sex steroid hormones) and the enzyme aromatase, which converts testosterone to estrogen, are much less well investigated. Progesterone and testosterone bind and act on their respective progesterone receptors and androgen receptors in the heart. Sex steroid hormones interact with their receptors to affect postsynaptic target cell responses and to influence presynaptic sympathoadrenergic function. Cardiomyocytes are not only targets for the action of sex steroid hormones, but they are also the source of synthesis and the site of metabolism of these hormones.77
E2 is derived from testosterone and is primarily metabolized in the liver to form hydroxyestradiols, catecholestradiols, and methoxyestradiols. Estradiol metabolism also takes place in vascular smooth muscle cells, cardiac fibroblasts, endothelial cells, and cardiomyocytes. Cardiomyocytes express nuclear steroid hormone receptors that modulate gene expression and nonnuclear receptors for the nongenomic effects of sex steroid hormones. They interact withmany different coregulators to confer tissue and temporal specificity in their transcriptional actions. These cell-specific coactivator and corepressor proteins are known as estrogen-related receptors.78 Sex steroid hormones can activate rapid signaling pathways without changing gene expression (Fig. 14.18). One such example is stimulation of vascular endothelial nitric oxide synthase to mediate vascular dilation. Estrogen’s vasodilatory effect might explain the lower systolic blood pressures of premenopausal women when compared with age-matched men. In men, aromatase-mediated conversion of testosterone to estrogen maintains normal vascular tone. In addition to sex steroid hormone stimulation of nuclear or nonnuclear receptors, sex steroid hormone receptors could also induce rapid signaling of growth factor pathways in the absence of ligands.
Gender differences exist in cardiac electrophysiologic function. The modulatory actions of estrogen on Ca2+ channels might be responsible for sex-based differences in repolarization of the heart, such as the faster resting heart rate of women, as well as the increased propensity of women to have prolonged QT syndrome.79 Estrogen, through the activation of ERβ, confers protection after ischemia and reperfusion in murine models of myocardial infarction. In contrast, testosterone, in the same model, has the opposite effect. Aromatase also has protective effects, probably through its action to increase estrogen and to decrease testosterone.