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Putting the 'T'rouble in Testosterone Therapy?

06 februari 2014.

Introduction (Medscape)

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. 


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.

Does Testosterone Therapy Put Men at Risk?

Does the surge in enthusiasm for the diagnosis and treatment of "low T" have consequences? A new study suggests that it may be putting men's lives at risk. [16] 

Study Synopsis

Study patients were male veterans who underwent coronary angiography between 2005 and 2011 in one of 76 Veterans Affairs (VA) medical centers. All patients had a serum total testosterone level examined, but patients who initiated testosterone therapy before coronary angiography were excluded from evaluation. Researchers also excluded patients who were prescribed testosterone therapy after having recently had a myocardial infarction (MI). 

Patient data were obtained from the VA Clinical Assessment Reporting and Tracking Program, a database with high fidelity to actual clinical outcomes. Researchers recorded angiography results as well as demographic and disease data. The main study outcome was the relationship between testosterone therapy and the incidence of MI, stroke, or mortality. Researchers used stabilized inverse probability of treatment weighting to adjust for a wide variety of possible confounders. 

A total of 8709 men had a total testosterone level less than 300 ng/dL. The mean age of patients was 63 years, and there was a high rate of comorbidity. More than 80% had evidence of coronary artery disease on angiography. 

Testosterone therapy was initiated in 1223 of these 8709 men a median of 531 days after angiography. The transdermal patch was used in nearly two thirds of treated cases. Men who were treated with testosterone were likely to be healthier than untreated men with regard to coronary anatomy and comorbid illness. Testosterone therapy was effective in significantly increasing serum testosterone levels in the 60% of men who had follow-up laboratory testing. 

The average follow-up period for study outcomes was 27.5 months. Over 3 years, the cumulative rates of the combined outcome of MI, stroke, and overall mortality in the testosterone treatment and untreated groups were 25.7% and 19.9%, respectively. The relative risk for these events increased with time in comparing the 2 groups. 

In fully adjusted analyses, the hazard ratio for the combined outcome of MI, stroke, and mortality was 1.29 in the testosterone therapy group compared with the untreated group. The presence of coronary artery disease or prior revascularization disorders failed to alter this outcome. 

All testosterone formulations appeared to increase risk for the composite outcome. Further analyses revealed that differences in blood pressure, low-density lipoprotein cholesterol levels, or treatment with beta-blockers or statins did not explain the difference in outcomes between the testosterone and untreated groups.  

Putting It All Together

The VA study is limited by its observational nature, which leaves the analysis open to unknown confounding variables. However, other randomized clinical trials also suggest that testosterone therapy may be dangerous, particularly for older men with multiple cardiovascular risk factors. Specifically, a trial of 209 men with an average age of 74 years was halted early after 23 cardiovascular events were recorded in the testosterone treatment group -- a much higher number than the 5 that occurred in the placebo group. [17] 

A systematic review and meta-analysis of placebo-controlled randomized trials found an odds ratio of 1.54 for cardiovascular events associated with testosterone therapy. [18] There was evidence that pharmaceutical funding of trials exerted an influence. The effect of therapy varied with the source of funding, but not with baseline testosterone levels. A higher risk for cardiovascular events was found in trials not funded by the pharmaceutical industry. 

These results stand in contrast to some other data that focused on men with cardiovascular risk factors. In a study of 581 men with type 2 diabetes, TD was associated with a 2-fold increase in the risk for mortality. [19] However, testosterone therapy reduced the risk for mortality. Untreated TD was associated with a hazard ratio of 2.3 for mortality compared with testosterone treatment. 

What is the practicing clinician to do with this conflicting and highly concerning data? The Endocrine Society produced a practice guideline for the use of testosterone treatment in 2010. [20] This guideline is designed in large part to curb the overuse of exogenous testosterone. Only symptomatic men should be evaluated for possible TD, and TD should not be diagnosed without 2 morning testosterone levels that are unequivocally low. Serum testosterone levels should be reevaluated 3-6 months after the initiation of testosterone treatment, with the goal of achieving serum testosterone levels in the mid-normal range. 

These guidelines make sense. They emphasize clinical rigor and personalized care when recommending a medication that still has many questions to answer about its safety. There is certainly a role for testosterone therapy among men with TD. For these men, treatment can improve symptoms as well as metabolic outcomes, and perhaps even mortality. 

But the current study, particularly in the context of previous research, makes it clear that testosterone therapy should not be used for every man who is a little tired and not feeling himself. Supraphysiologic levels of testosterone appear to promote a higher risk for death, and patients should understand the potential cardiovascular and mortality risks associated with testosterone therapy as part of pretreatment counseling. In particular, caution is warranted before recommending testosterone therapy to any man at high risk for cardiovascular events. It is our job as physicians to make the "T" about "thinking" and weighing options in this important clinical decision. 

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