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Sex differences in vascular aging in response to testosterone

Moreau KL1,2Babcock MC3Hildreth KL3.

Biol Sex Differ. 2020 Apr 15;11(1):18. doi: 10.1186/s13293-020-00294-8.

 

Abstract

Large elastic arterial stiffening and endothelial dysfunction are phenotypic characteristics of vascular aging, a major risk factor for age-associated cardiovascular diseases. Compared to men, vascular aging in women appears to be slowed until menopause, whereafter vascular aging accelerates to match that seen in men. These sex differences in vascular aging have been attributed to changes in sex hormones that occur with aging. Although the role of estradiol in vascular aging in women has been highlighted in recent aging research, little is known about the impact of declining testosterone concentrations in both sexes. Importantly, while androgen concentrations generally decline with age in men, there are data that indicate reductions in androgen concentrations in women as well. Evidence suggests that low testosterone is associated with impaired endothelial function and increased arterial stiffness in men, although the effect of androgens on vascular aging in women remains unclear. Testosterone may modulate vascular aging by mitigating the effects of oxidative stress and inflammation, although there is sex specificity to this effect. The purpose of this review is to present and summarize the research regarding sex differences in vascular aging in response to androgens, specifically testosterone. Because exercise is a potent lifestyle factor for slowing and reversing vascular aging, we briefly summarize the available literature regarding the regulatory function of testosterone on vascular adaptations to exercise training.

Summary

Vascular aging, featuring large elastic arterial stiffening and endothelial dysfunction, is thought to provide the milieu in which vascular diseases can flourish by combining with other pathophysiological CVD risk factors, creating a potentially lethal age-disease interaction. As such, elucidating mechanisms contributing to increased risk are needed for further development of strategies that attenuate or prevent the age-related changes in vascular function. Sex differences in vascular aging have been attributed to sex differences in gonadal aging and sex hormones. Although most of the literature on sex differences in vascular aging has focused on the effects of estrogen deficiency associated with menopause, little attention has been paid to the modulatory influence that declines in testosterone may contribute to vascular aging in women and men. Overall, available data support an association between lower levels of testosterone and endothelial function and increased arterial stiffness in men . However, any effect of testosterone on vascular aging may be dependent on multiple factors including age, disease status, degree of testosterone deficiency, and form of testosterone supplementation, as well as effects from changes in other vasoactive hormones, such as estrogens. In contrast, the available data investigating the association of testosterone and vascular aging in women are more variable . Moreover, the safety of long-term testosterone therapy on cardiovascular health has not been established. Thus, other strategies such as regular exercise are promoted as antiaging interventions to target vascular aging in older adults. However, declines in gonadal function may also diminish beneficial endothelial adaptations to exercise training. The very limited data on the role of androgens in vascular adaptations to exercise suggest that testosterone may enhance improvements in endothelial function with exercise training in men with low levels of testosterone. Additional research is needed to further explore the effects of androgens on vascular adaptations to exercise in both men and women, as well as to explore underlying mechanisms for potential androgenic effects. Collectively, an improved understanding of the impact of declines in sex hormones, including androgens, on the aging vasculature at the cellular and systemic levels is needed to inform future sex-specific therapies for the prevention of CVD.