HDL is a powerful independent risk factor for atherosclerotic cardiovascular disease. HDL influences atherosclerosis, in part, by promoting the efflux of cholesterol from macrophages in the arterial wall and returning this cholesterol to the liver for excretion, a process referred to as reverse cholesterol transport (136). In observational studies, every 1-mg/dL increment in HDL cholesterol (HDL-C) is associated with a 2% decreased risk of coronary artery disease in men (137).
Most studies that have included 100 or more adult men have found a positive association between testosterone or SHBG and HDL-C levels (14,87,138-147). Although it has been less well studied, there is evidence that the age-related decline in testosterone may be associated with decreases in HDL-C in middle-aged men (148). The relationship between endogenous testosterone and HDL-C has been observed in different ethnic groups (142,143) and is linear throughout the physiologic range of testosterone concentrations, such that HDL-C increases by 1-mg/dL with every 100 ng/dL increase in total testosterone (143).
The association of testosterone with HDL-C is statistically independent of several possible confounding factors, including age, obesity, alcohol consumption, cigarette smoking, use of medications, triglyceride levels, and glucose and insulin concentrations (14,87,139,140,143,144). The mechanisms by which testosterone may influence HDLC levels are unclear. One possibility is that testosterone increases the synthesis of apolipoprotein A-I (149), the major protein component of nascent HDL particles. There is also recent evidence that testosterone regulates expression of HDL receptors (135).
Low HDL-C is often found in individual patients in association with other metabolic risk factors, including elevated very low-density lipoprotein (VLDL) and small, dense low-density lipoprotein (LDL), hypertriglyceridemia, and glucose intolerance (136). Insulin resistance may underlie this clustering of metabolic abnormalities, which has been referred to as the metabolic syndrome (150). Many of these metabolic changes promote the development of atherosclerosis and risk of cardiovascular events. All components of the metabolic syndrome have been related to low testosterone and SHBG in epidemiologic studies (14,65,87,138-140,142-144,146). Whether these relationships are truly causal or indirect must be evaluated further. An association of testosterone and SHBG with at least some components of the metabolic syndrome has been attributed to insulin resistance (65).
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