Reviewed by Dr. Jasmine Singh
Resnick, Susan M., et al. JAMA 2017 Feb 21;317(7): 717-727
Budoff, Matthew J., et al. JAMA 2017 Feb 21;317(7): 708-716

SUMMARY
The Testosterone Trials (TTrials) were a set of 7 trials that studied the efficacy of testosterone replacement in elderly men with low testosterone secondary to aging. The trials consisted of nearly 800 men from multiple US academic medical centers over the age of 65 who had low serum testosterone (<275 ng/dL) and symptomatic hypogonadism, defined by impaired sexual function, physical function or vitality. Patients were assigned to either testosterone gel (n=394), adjusted to keep the serum testosterone within the normal range for young men, or placebo (n=394) for 12 months. Two important sub-trials studied the effect of testosterone replacement on cognitive function as well as on coronary artery non-calcified plaque volume.

The Cognitive Function Trial consisted of a subgroup of 493 men (n=246 for placebo and n=247 for testosterone) who met criteria for age-associated memory impairment (AAMI), which was based on both objective evaluation of memory performance and subjective memory complaints. The primary outcome was mean change from baseline to 6 and 12 months for delayed paragraph recall and did not show a significant difference between either group (adjusted estimated difference, −0.07 [95%CI, −0.92 to 0.79]; P = .88). Secondary outcomes included visual impairment (Benton Visual Retention Test), executive function (Trail-Making Test B minus A), and spatial ability (Card Rotation Test) and also did not show a mean change between treatment and placebo.

The Coronary Plaque Trial consisted of a sub-group of 138 men (n=65 for placebo and n=73 for testosterone). The primary outcome was non-calcified coronary artery plaque volume, measured by Coronary Computed Tomographic Angiography (CCTA), and showed a significantly greater increase in non-calcified plaque volume from baseline to 12 months after therapy (estimated difference, 41mm3; 95%CI, 14 to 67mm3; P = .003). Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score and also showed a mean difference between treatment and placebo group. There were no major adverse cardiovascular events observed in either group.

COMMENTARY
The Cognitive Function Trial showed that despite previous claims, testosterone replacement is not associated with improved cognitive function in hypogonadal men with AAMI. The Coronary Plaque trial found an increased coronary artery non-calcified plaque volume as measured by CCTA, raising concern about the cardiovascular safety of testosterone replacement in older men.

One limitation of these trials is the duration of therapy, as they only examined variables prospectively for the duration of one year. Furthermore, a longer Coronary Plaque Trial could potentially provide insight about the effect of testosterone on major cardiovascular outcomes. One limitation particular to the Coronary Artery Plaque Trial includes its small size, and larger studies are warranted to clarify its findings. Notably, the TTrials only examined the effects of testosterone replacement in elderly men with hypogonadism caused by aging, and these findings may not generalize to other populations such as men of other ages or with androgen deficiency of other etiologies. The TTrials are the largest placebo-controlled study examining the effects of testosterone replacement in elderly males and provide important insight about implications of replacement therapy.

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