Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes

M en with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone–binding globulin (SHBG). Conversely, the presence of low testosterone and/or SHBG predicts the development of metabolic syndrome and type 2 diabetes. Visceral adiposity present in men with low testosterone, the metabolic syndrome, and/or type 2 diabetes acts through proinflammatory factors. These inflammatory markers contribute to vascular endothelial dysfunction with adverse sequelae such as increased cardiovascular disease (CVD) risk and erectile dysfunction. This review focuses on the multidirectional impact of low testosterone associated with obesity and the metabolic syndrome and its effects on erectile dysfunction and CVD risk in men with type 2 diabetes. Whenever possible in this review, we will cite recent reports (after 2005) and meta-analyses. Epidemiological studies of low testosterone, obesity, metabolic status, and erectile dysfunction Epidemiological studies support a bidirectional relationship between serum testosterone and obesity as well as between testosterone and the metabolic syndrome. Low serum total testosterone predicts the development of central obesity and accumulation of intra-abdominal fat (1–3). Also, low total and free testosterone and SHBG levels are associated with an increased risk of developing the metabolic syndrome, independent of age and obesity (1–3). Lowering serum T levels in older men with prostate cancer treated with androgen deprivation therapy increases body fat mass (4). Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels (1–3,5). Because obesity suppresses SHBG and as a result total testosterone concentrations, alterations in SHBG confound the relationship between testosterone and obesity. Low total testosterone or SHBG levels are associated with type 2 diabetes, independent of age, race, obesity, and criteria for diagnosis of diabetes (6,7). In longitudinal studies, low serum total and free testosterone and SHBG levels were independent predictors of type 2 diabetes (6,8). In these studies, SHBG levels were stronger predictors of diabetes than total or free testosterone. Because type 2 diabetes is often associated with obesity, which suppresses SHBG and in turn total testosterone levels, both obesity and SHBG levels represent important confounding factors in the relationship between testosterone and type 2 diabetes. The prevalence of low free testosterone levels is higher in diabetic men compared with nondiabetic men (6). However, a recent longitudinal study found that free testosterone did not predict the development of type 2 diabetes. In this study, the association of total testosterone and of SHBG with diabetes was not significant after adjusting for waist circumference or central obesity (9). Also, low SHBG was found to be a strong independent predictor of type 2 diabetes (10,11). Finally, in prospective studies, androgen deprivation therapy either using bilateral orchidectomy or gonadotropin-releasing hormone agonist in older men with prostate cancer is associated with an increased risk of diabetes and CVD (12). A number of epidemiological studies support associations of obesity (13,14), the metabolic syndrome (15,16), type 2 diabetes (17), and low serum testosterone (18) with sexual dysfunction including erectile dysfunction (ED) (19). These studies highlight the complex often multidirectional relationships among obesity, metabolic status, low testosterone, and ED in men. c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c