Objective: Low levels of testosterone in men have been shown to be associated with type 2 diabetes, visceral adiposity, dyslipidaemia and metabolic syndrome. We investigated the effect of testosterone treatment on insulin resistance and glycaemic control in hypogonadal men with type 2 diabetes. Design: This was a double-blind placebo-controlled crossover study in 24 hypogonadal men (10 treated with insulin) over the age of 30 years with type 2 diabetes. Methods: Patients were treated with i.m. testosterone 200 mg every 2 weeks or placebo for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostatic model index (HOMA) in those not on insulin), fasting blood glucose and glycated haemoglobin. The secondary outcomes were changes in body composition, fasting lipids and blood pressure. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared against the treatment effect of testosterone.

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.

Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.

Objective: Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone. Research design and methods: A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.8G1.3 S.D. years. Mortality rates were compared between total testosterone O10.4 nmol/l (300 ng/dl; nZ343) and testosterone %10.4 nmol/l (nZ238). The effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group. Results: Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; PZ0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (PZ0.009, 95% CI 1.2-3.4). TRT (mean duration 41.6G20.7 months; nZ64) was associated with a reduced mortality of 8.4% compared with 19.2% (PZ0.002) in the untreated group (nZ174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3-3.9, PZ0.004). Conclusions: Low testosterone levels predict an increase in all-cause mortality during long-term followup. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.

Testosterone is a key hormone in the pathology of metabolic diseases such as obesity. Low testosterone levels are associated with increased fat mass (particularly central adiposity) and reduced lean mass in males. These morphological features are linked to metabolic dysfunction, and testosterone deficiency is associated with energy imbalance, impaired glucose control, reduced insulin sensitivity and dyslipidaemia. A bidirectional relationship between testosterone and obesity underpins this association indicated by the hypogonadal-obesity cycle and evidence weight loss can lead to increased testosterone levels. Androgenic effects on enzymatic pathways of fatty acid metabolism, glucose control and energy utilization are apparent and often tissue specific with differential effects noted in different regional fat depots, muscle and liver to potentially explain the mechanisms of testosterone action. Testosterone replacement therapy demonstrates beneficial effects on measures of obesity that are partially explained by both direct metabolic actions on adipose and muscle and also potentially by increasing motivation, vigour and energy allowing obese individuals to engage in more active lifestyles. The degree of these beneficial effects may be dependent on the treatment modality with longer term administration often achieving greater improvements. Testosterone replacement may therefore potentially be an effective adjunctive treatment for weight management in obese men with concomitant hypogonadism.

Obesity, type 2 diabetes mellitus and the metabolic syndrome are major risk factors for cardiovascular disease. Studies have demonstrated an association between low levels of testosterone and the above insulin-resistant states, with a prevalence of hypogonadism of up to 50% in men with type 2 diabetes mellitus. Low levels of testosterone are also associated with an increased risk of all-cause and cardiovascular mortality. Hypogonadism and obesity share a bidirectional relationship as a result of the complex interplay between adipocytokines, proinflammatory cytokines and hypothalamic hormones that control the pituitary-testicular axis. Interventional studies have shown beneficial effects of testosterone on components of the metabolic syndrome, type 2 diabetes mellitus and other cardiovascular risk factors, including insulin resistance and high levels of cholesterol. Biochemical evidence indicates that testosterone is involved in promoting glucose utilization by stimulating glucose uptake, glycolysis and mitochondrial oxidative phosphorylation. Testosterone is also involved in lipid homeostasis in major insulin-responsive target tissues, such as liver, adipose tissue and skeletal muscle.

Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms.