COMMENTARY

Putting the 'T'rouble in Testosterone Therapy?

Charles P. Vega, MD

Disclosures

January 30, 2014

In This Article

Introduction

Four in 5 men may have symptoms of testosterone deficiency, and testosterone replacement can improve body composition and metabolic outcomes related to serum glucose and cholesterol levels. In fact, some research even suggests that testosterone treatment might improve the risk for mortality among men with testosterone deficiency. However, a large new study finds a higher risk for cardiovascular disease or death associated with testosterone therapy, and it is not the first study to do so. The current review provides a balanced perspective regarding the challenging issue of testosterone deficiency and replacement among men.

Background

Testosterone is a complicated and critical hormone that plays multiple roles in vivo. It reduces fat mass and improves insulin sensitivity.[1] Circulating testosterone also helps to reduce serum low-density lipoprotein cholesterol and triglyceride levels. Higher testosterone levels correlate positively with high-density lipoprotein cholesterol levels.

The concentration of free testosterone gradually declines as men age, owing both to decreased production as well as higher concentrations of sex hormone-binding globulin. One longitudinal study of 1156 men found that the mean annual reduction in free testosterone levels was approximately 2%, although this reduction was attenuated among healthier men.[2]

The exact prevalence of testosterone deficiency (TD) is controversial. Many men have symptoms that might indicate TD. In a self-selected study that used a Web-based survey of over 10,000 men, 80% were found to have symptoms consistent with TD.[3] In a study of 2162 men at least 45 years of age who attended primary care clinics in the United States, the prevalence of a total testosterone level less than 300 ng/dL was 38.7%.[4] Less than 10% of these men were receiving testosterone treatment.

Symptoms of TD include fatigue, loss of libido, hot flashes, depression, and sleep disturbance.[5] However, there is not necessarily a linear association between testosterone levels and symptoms. A study in 3413 men failed to determine an association between testosterone levels and overall scores on a psychological health screening tool.[6] Nonetheless, men with TD had worse psychological performance, particularly for anxiety.

TD is associated with obesity and higher rates of insulin resistance, and up to 50% of older men with type 2 diabetes have been found to have TD.[7] Beyond the effect of this association on individual patients, the larger consequences of this association are staggering. In a study that assumed a highly conservative prevalence of TD of 13.4% among middle-aged and older men in the United States, the additional number of cases of diabetes attributable to TD over a 20-year period was 1.1 million.[8] The health consequences of TD were estimated to cost the US economy between $125 and $500 billion over 2 decades.

Lower testosterone levels also appear to promote a higher risk for mortality among men. In a meta-analysis of 12 studies, each decrease of 2.18 in the standard deviation of serum testosterone was associated with a 35% increase in the overall risk for mortality and a 25% increase in risk for cardiovascular mortality.[9] However, the authors of the meta-analysis note that there was significant heterogeneity among studies, and the association between lower serum testosterone levels and mortality was more pronounced among older men. A more recent study finds a U-shaped association between testosterone levels and mortality among men.[10]

Testosterone generally has positive effects on muscle power and fat mass.[11] It also improves bone mineral density while patients are on therapy. However, its effects on mood and quality of life are more mixed; not all randomized trials have supported a therapeutic benefit in this domain.[12] Similarly, although exogenous testosterone has been demonstrated to improve erectile function in some studies, a randomized trial of men with low serum testosterone levels failed to demonstrate a significant effect of testosterone when added to sildenafil for the treatment of erectile dysfunction.[13]

Testosterone therapy also has salutary metabolic effects similar to those of natural circulating testosterone, including reducing insulin resistance and ameliorating the lipid profile.[11] In a placebo-controlled randomized trial that included men with diabetes, testosterone therapy was associated with a mean decrease in glycated hemoglobin levels of 0.45%.[14]

Although there are data to support some of the health benefits of testosterone therapy, the balance of benefit and risk of treatment is far from settled. However, the growth of TD as a disease and treatment target is undeniable.

A new study found that the prevalence of testing for testosterone increased dramatically in the United States and United Kingdom between 2000 and 2010.[15] However, it was clear that testing was more targeted in the United Kingdom vs the United States, and the authors suggest that direct-to-consumer advertising in the United States could help explain this difference. Meanwhile, 4%-9% of testosterone therapy prescriptions in the United States appeared to be inappropriate because they were given to men with normal or high testosterone levels.

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