Blood Coagulation and Fibrinolytic Proteins

Testosterone may influence the risk of cardiovascular disease by affecting hemosta-tic function and thrombosis. Fibrinogen is the primary coagulation protein, and through conversion to fibrin, it promotes thrombus formation (151). Thrombosis is a major precipitating factor in the onset of cardiovascular events, and prospective studies have shown that increased fibrinogen levels are an independent risk factor for clinical cardiovascular disease (152). The few population studies that have examined the relationship between endogenous testosterone and hemostatic factors have produced inconsistent results. Lower levels of total testosterone were associated with higher concentrations of fibrinogen independent of obesity and other cardiovascular risk factors in one small cross-sectional study of middle-aged and elderly men (153,154) but not in another (155). Bonithon-Kopp et al. (156) examined the cross-sectional relationships between endogenous testosterone and hemostatic factors in 251 middle-aged men without ischemic heart disease who were not taking medications that influence sex steroid hormones or hemostatic function. There was no association between total testosterone and fibrinogen concentrations in multivariate analyses that controlled for body mass, cigarette smoking, alcohol consumption, and other cardiovascular risk factors. On the other hand, lower levels of total testosterone were associated with higher concentrations of another key component of the blood coagulation system factor VII. In another report of 64 healthy men aged 18 to 45 yr, lower levels of free testosterone were associated with higher concentrations of fibrinogen and factor VII, independent of age, central obesity, fasting insulin and glucose, and other cardiovascular risk factors (157).

Several studies have also reported an association between endogenous levels of testosterone and plasminogen-activator inhibitor type 1 (PAI-1), a major inhibitor of fibrinolysis. High PAI-1 plasma levels have been related to coronary atherosclerosis and myocardial infarction (158). Several cross-sectional studies (106,154,157,159), but not all (153), observed an inverse relationship between endogenous testosterone and PAI-1 in older men. Increased PAI-1 levels are closely related to obesity, body fat distribution, and insulin resistance (158), and it is unclear if endogenous testosterone levels are directly related to PAI-1 or reflect an underlying association with adiposity and insulin sensitivity. PAI activity was positively correlated with body mass, triglycerides, and fasting insulin and inversely correlated with total testosterone and SHBG in a study of 42 men with myocardial infarction and 72 healthy controls (106). However, in multivariate analyses, only triglycerides, fasting insulin, and SHBG remained significant independent correlates of PAI activity, explaining nearly 27% of variation in PAI activity. In another study of 64 otherwise healthy men aged 18 to 45 yr, lower free-testosterone and SHBG concentrations were both associated with greater PAI-I antigen, independent of age, central obesity, fasting insulin and glucose, and other cardiovascular risk factors (157). These observations must be confirmed in larger cohorts of middle-aged and elderly men, but they raise the possibility that lower levels of testosterone may be associated with a prothrombotic state.

Lipoprotein(a) [Lp(a)] is a lipoprotein complex in which apolipoprotein(a) is linked by a disulfide bridge to LDL particles (160). Lp(a) has both proatherogenic and prothrombotic properties, and high Lp(a) levels are an independent risk factor for coronary heart disease in prospective studies (161). Although serum concentrations of Lp(a) are largely under genetic control (162), there is some evidence that androgens influence circulating Lp(a). For instance, suppression of endogenous testosterone levels by a GnRH antagonist (163) or after orchidectomy (164) increased Lp(a) concentrations, whereas parenteral administration of testosterone decreased Lp(a) concentrations in men (165-167). These results are consistent with studies demonstrating that testosterone reduces apolipoprotein(a) gene expression in mice (168). On the other hand, levels of total and free testosterone within the eugonadal range and SHBG have not correlated significantly with Lp(a) (106,169,170). These population studies included fewer than 200 subjects and may have had insufficient power to detect a modest correlation between testosterone and Lp(a). Moreover, the association between endogenous testosterone and Lp(a) in the population may be nonlinear and only present at the extremes of the testosterone distribution. None of the population studies had an ade-

Fig. 3. Relationship between sex hormone-binding globulin and free testosterone levels estimated using an analog assay from Diagnostic Systems Laboratories (Webster, TX) in normal men.

quate sample size to analyze if a nonlinear relationship exists between endogenous testosterone and serum Lp(a).

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