Research in the field of atherosclerosis and cardiovascular disease has changed substantially in recent years because of the development of noninvasive methods of measuring the extent of atherosclerosis, including ultrasound measures of carotid intima-media wall thickness, CT measures of coronary artery and aortic calcification, ankle-brachial blood pressure assessments of lower extremity peripheral arterial disease, and measures of vascular stiffness, compliance, and pulse characteristics and endothelial function (116). These newer techniques provide a means of studying the determinants of atherosclerosis in vivo and the progression of atherosclerotic vascular disease over time. Relatively few studies have examined the relationship between endogenous testosterone and these contemporary measures of atherosclerosis.
Numerous studies have shown that carotid intima-media wall thickness predicts coronary atherosclerosis and the incidence of clinical cardiovascular disease (116). Lower total testosterone levels were associated with greater carotid atherosclerosis in 297 elderly Dutch men independent of body mass index, WHR, hypertension, diabetes, cigarette smoking, and serum cholesterol levels in one recent report (117). A similar inverse association between testosterone and carotid artery wall thickness was observed in men with and without prevalent cardiovascular disease.
More recently, Hak et al. (118) demonstrated a relationship between endogenous testosterone levels and both the prevalence and the progression of atherosclerosis in a population-based study of 504 nonsmoking men aged 55 yr and older. The extent of arterial calcification in the abdominal aorta was measured with lateral radiographs at a baseline examination and after an average of 6.5 yr. Progression of aortic atherosclerosis was defined as the occurrence of new arterial calcifications or enlargement of preexisting calcifications. Aortic atherosclerosis was present in 175 men (35%), whereas severe atherosclerosis was present in 47 men (9%). Men with total testosterone levels
in the lowest tertile (<9.8 nmol/L) had 2.5-fold greater age-adjusted risk (95% confidence interval, 1.1, 5.0) of severe aortic atherosclerosis compared with men with the highest testosterone levels (>12.6 nmol/L). Men with bioavailable testosterone levels in the lowest tertile (<5.6 nmol/L) had a fivefold greater age-adjusted risk (95% confidence interval, 1.4-10.0) of severe aortic atherosclerosis compared with those with bioavailable testosterone levels in highest tertile (>7.5 nmol/L). Additional adjustments for body mass (or central adiposity), blood pressure, total and HDL cholesterol levels, diabetes (or postload insulin), history of smoking, and alcohol intake did not appreciably alter these results. Men with total and bioavailable testosterone levels in the lowest tertile were also significantly more likely to experience progression of aortic atherosclerosis compared with men with higher testosterone levels (see Fig. 2). These findings raise the possibility that relatively low total, particularly bioavailable, testosterone may be related to the development or progression of atherosclerosis in men independent of established risk factors for cardiovascular disease. Additional longitudinal studies are needed to confirm the relationship between bioavailable testosterone levels and the development and progression of atherosclerosis in different vascular beds.
Arterial endothelium dysfunction is an early manifestation of subclinical atherosclerosis and contributes to myocardial ischemia, plaque instability and rupture, and myocardial infarction during the later stages of atherosclerosis (119-121). Endothelial function can be assessed noninvasively in the brachial artery with high-resolution ultrasound (121). This technique assesses endothelial function by measuring the arterial diameter of the brachial artery at rest and during reactive hyperaemia, a flow-mediated, endothelium-dependent vasodilatory response (121). Brachial artery flow-mediated vasodilation is impaired in individuals with atherosclerosis, and these measures correlate with coronary endothelial dysfunction and atherosclerosis (120).
Studies evaluating the effects of testosterone on brachial artery endothelial function in men have been inconclusive. Some reports found improved brachial artery endothelial function after acute i.v. (122) and short-term (12 wk) oral (123) testosterone administration in men with coronary artery disease. On the other hand, brachial artery endothelial function was unchanged after 12 mo of transdermal testosterone treatment (124) or was decreased after 3 mo of intramuscular testosterone enanthate (125) in men with low testosterone levels and unknown coronary artery disease status. Interpretation of these conflicting reports is difficult because of the heterogeneous and relatively small patient populations and the different testosterone formulations and dosages that were studied. There are fewer data on the relationship between endogenous testosterone and endothelial function in men. Total testosterone levels were significantly and inversely correlated with the extent of brachial artery endothelial dysfunction in 36 hypogonadal men, whereas no association was observed in the eug-onadal range in 113 healthy men aged 20-69 yr (125). Larger population studies are needed to evaluate the relationship between total and bioavailable testosterone levels and endothelial function in men.
There have been few studies concerning the effects of testosterone on atherogenesis in animal models. An inhibitory effect of testosterone on neointimal plaque formation was reported in a rabbit aorta culture model (126). Studies in cholesterol-fed male rabbits also showed that testosterone inhibited atherosclerosis in vivo (127,128) although these findings have not been universal (129). In one placebo-controlled study of cholesterol-fed rabbits, orchidectomy produced a 100% increase in aortic atherosclerosis compared with sham operation, whereas testosterone enanthate markedly inhibited atherosclerosis in the castrated animals (128). The inhibitory effect of testosterone on atherosclerotic plaque development is at least partly independent of blood lipid changes (127,128). Castration increased the extent of fatty streak formation in the aorta of male mice fed a cholesterol-rich diet (130). Testosterone supplementation reduced atherosclerotic lesion formation in these animals, which was prevented by inhibiting the aromatization of testosterone to estradiol (130). These provocative findings raise the possibility that testosterone may inhibit early atherogenesis in males through conversion to estrogen.
The biological mechanisms by which testosterone might influence atherosclerosis in men are unclear. A direct effect of testosterone on the arterial wall is plausible, given the presence of androgen receptors in vascular smooth muscle (131) and endothelial (132) cells. The early development of atherosclerotic lesions involves the adherence of monocytes to the vascular endothelium via cellular adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), differentiation of monocytes to macrophages, and subsequent accumulation of lipids to generate foam cells and fatty streaks (133). Recent in vitro experiments indicate that testosterone decreases VCAM-1 expression in human endothelial cells, providing a cellular mechanism by which testosterone may attenuate atherogenesis (132,134). Testosterone also upregulates the expression of HDL receptors in macrophages and promotes the efflux of cholesterol from these cells (135). Thus, testosterone may directly facilitate the transport of excess cholesterol from atherosclerotic plaques of the arterial wall (135). Finally, testosterone may indirectly influence the atherosclerotic disease process by modulating cardiovascular disease risk factors, such as blood lipid and lipoproteins and coagulation and fibrinolytic proteins.
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