Effects of testosterone on vascular reactivity

An early hallmark of atherosclerosis is decreased vascular responsiveness to various physiological stimuli due either to endothelial or to endothelium-independent disturbances in the vascular smooth muscle cell (Bonetti et al. 2003). As a result, decreased vasodilation and enhanced vasoconstriction can lead to vasospasm and angina pectoris. Moreover, endothelial dysfunction also contributes to coronary events by promoting plaque rupture and thrombosis (Libby 2002; Ross

1999). Testosterone can induce vasodilation or vasoconstriction via endothelium-dependent or endothelium-independent mechanisms and by genomic or non-genomic modes of action. The diversity of these findings appears to be due to differences in species, gender, concomitant disease and, most importantly, dosage of testosterone.

Suggestive of an adverse effect of testosterone, nitrate-induced and hence endothelium-independent dilation of the brachial arteries was significantly reduced in female-to-male transsexuals taking high-dose androgens (McCredie etal. 1998). In another case-control study, castrated patients with prostate cancer had a greater flow-induced (i.e. endothelium-dependent) dilation of brachial arteries than controls, whereas the endothelium-independent vasodilation by nitroglycerin did not differ between groups (Herman et al. 1997). In another study, untreated hypo-gonadal men were found to have increased flow-mediated vasodilatation of the brachial artery compared to matched eugonadal men. Upon three months of substitution treatment with 250 mg testosterone enanthate every two weeks, flow-mediated dilatation decreased significantly (Zitzmann et al. 2002). In a group of 110 healthy men, we observed a positive association between the number of CAG repeats in exon 1 of the androgen receptor gene and endothelium-dependent as well as endothelial-independent vasodilatation. Thus, the greater the sensitivity to testosterone, the less brachial arteries dilate in response to either flow or nitrate (Zitzmann etal. 2001b).

In contrast to these observational or long-term treatment studies, acute inter-ventional studies with intravenous administration of testosterone to male patients with coronary artery disease revealed apparently beneficial vasodilatory effects of testosterone (see section 10.3.3). Likewise, in vivo studies in monkeys and dogs of both sexes as well as most in vitro studies with animal vessels suggest that testosterone exerts beneficial effects on vascular reactivity. After testosterone treatment for two years in ovariectomized female cynomolgus monkeys, intracoronary injections of acetylcholine caused significant endothelium-dependent vasodilation in treated but not in untreated animals. In contrast, endothelium-independent vasodilation occurred normally in both groups (Adams etal. 1995). In dogs, testosterone induced vasodilation of coronary arteries by endothelium-dependent and independent mechanisms (Chou etal. 1996; Costarella etal. 1996). In vitro studies with isolated rings of coronary arteries and/or aortas from rats, rabbits, and pigs also found that, in both sexes, testosterone improved both endothelium-dependent and/or endothelium-independent vascular responsiveness (Chou et al. 1996; Costarella et al. 1996; Yue et al. 1995). However, it must be emphasized that all these studies employed supraphysiological doses of testosterone in the micromolar range. Teoh et al. (2000) observed a direct vasodilatory effect of testosterone on porcine coronary artery rings at micromolar concentrations but no direct effect at nanomolar dosages. In contrast, physiological doses of testosterone inhibited the vasodila-tory effects of bradykinin and calcium ionophores. Similarly, testosterone inhibited the adenosine-mediated vasodilation of rat coronary arteries and impaired endothelium-dependent relaxation of aortic rings from rabbits which were either made hypercholesterolemic or exposed to tobacco smoke (Ceballos et al. 1999; Farhat etal. 1995; Hutchison etal. 1997).

The cellular and molecular mechanisms by which testosterone (and estra-diol) regulate the vascular tone are little understood. Evidence for and against endothelium-dependent or endothelium-independent mechanisms have been found. Results of some studies suggest the involvement of endothelial nitric oxide (Chou etal. 1996; Costarella etal. 1996; Geary etal. 2000). In dog coronary arteries, rat aorta, and rat cerebral arteries the nitric oxide synthase inhibitor L-NMMA prevented testosterone-induced vasodilation. However, in another in vitro study L-NMMA had no effect on testosterone-induced vasodilation of rabbit aortas and coronary arteries (Yue etal. 1995). In agreement with the latter, in vitro expression of nitric oxide synthase in human aortic endothelial cells was stimulated by estradiol but not by testosterone (Hishikawa etal. 1995). The involvement of prostaglandins is suggested by the observation that testosterone increases the response of coronary arteries to prostaglandin F2a (Farhat et al. 1995) and by the finding that dihy-drotestosterone increases the density of thromboxane receptors in rats and guinea pigs (Masuda etal. 1995). However, in some in vivo and in vitro animal studies, pre-treatment with the prostaglandin synthesis inhibitor indomethacin had no effect on testosterone-induced vasodilation, so that the role of eicosanoids mediating the actions of testosterone on the arterial wall is still controversial.

Several observations also suggest that testosterone, modulates vascular tone via its secondary metabolites e.g. estradiol. Neither the aromatase inhibitor aminogluthemide nor the estrogen-receptor antagonist ICI 182,780 prevented the testosterone-induced vasodilation (Chou et al. 1996), so that the vasoactive mechanisms of testosterone do not appear to involve the estrogen receptors.

Beating The Butt On Your Own

Beating The Butt On Your Own

Need To Stop Smoking? Are You Willing To Follow My Powerful Strategies To Stop Smoking And Vividly Transform Your Life Today? Proven Tips, Tools and Tactics To Stop Smoking And Live An Awesome Life You Always Wanted.

Get My Free Ebook

Post a comment