Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.
OBJECTIVE
Type 2 diabetes (T2D) is a public health threat. Prediabetes represents a window of opportunity for intervention to prevent T2D. Men with T2D and prediabetes often have low testosterone. Since testosterone improves glycemic control in T2D, we investigated whether testosterone therapy (TTh) in men with hypogonadism and prediabetes prevents progression to T2D.
RESEARCH DESIGN AND METHODS
Three hundred and sixteen men with prediabetes (defined as HbA1c 5.7–6.4%) and total testosterone levels ≤12.1 nmol/L combined with symptoms of hypogonadism were analyzed. Two hundred and twenty-nine men received parenteral testosterone undecanoate (T-group), and 87 men with hypogonadism served as untreated control subjects. Metabolic and anthropometric parameters were measured twice yearly for 8 years.
RESULTS
HbA1c decreased by 0.39 ± 0.03% (P < 0.0001) in the T-group and increased by 0.63 ± 0.1% (P < 0.0001) in the untreated group. In the T-group, 90% achieved normal glucose regulation (HbA1c <5.7%). In the untreated group, 40.2% progressed to T2D (HbA1c >6.5%). TTh was also associated with significant improvements in fasting glucose, triglyceride:HDL ratio, triglyceride-glucose index, lipid accumulation product, total cholesterol, LDL, HDL, non-HDL, triglycerides, and Aging Males’ Symptoms (AMS) scale. Significant deterioration in all these parameters was seen in the untreated group. Mortality was 7.4% in the T-group and 16.1% in the untreated group (P < 0.05). The incidence of nonfatal myocardial infarction was 0.4% in the T-group and 5.7% in the untreated group (P < 0.005).
CONCLUSIONS
Long-term TTh completely prevents prediabetes progression to T2D in men with hypogonadism and improves glycemia, lipids, and AMS score. TTh holds tremendous potential for the large and growing population of men with prediabetes and hypogonadism.
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