From the Journals

Testosterone Trials’ cardiac, cognitive results disappoint

 

Key clinical point: Testosterone treatment may have beneficial effects on unexplained anemia or bone density in men with age-related low testosterone, but at the cost of an increase in coronary artery plaque and with no benefit for cognitive function.

Major finding: Testosterone treatment was associated with significantly greater increases in bone mineral density, hemoglobin, and noncalcified coronary artery plaque, compared with placebo, but no significant effects on cognitive function.

Data source: The Testosterone Trials in men aged 65 years or older with age-related testosterone decline.

Disclosures: The Testosterone Trials were supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Diseases and Stroke, the National Institute of Child Health and Human Development, and AbbVie, which provided the AndroGel and placebo gel. Authors from the trials declared a range of funding, consultancies, and other support from the pharmaceutical industry, including AbbVie. One author declared a pending patent for a free testosterone calculator.

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Evidence sinks testosterone-led rejuvenation

Today, 8 decades since the first clinical use of testosterone, the sole unequivocal indication for testosterone treatment is as replacement therapy for men with pathological hypogonadism (i.e., organic disorders of the reproductive system). Yet despite no proven new indications, global testosterone sales increased 100-fold over the last 3 decades, including increases of 40-fold in Canada and 10-fold in the United States from 2000 to 2011.

Overall, the findings from subtrials of the TTrials do not materially change the unfavorable balance of safety and efficacy to initiate testosterone treatment for age-related hypogonadism. With the results of the studies by Resnick et al. and by Budoff et al. in this issue of JAMA, the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed.

David J. Handelsman, MD, is from the ANZAC Research Institute, University of Sydney and Concord Hospital, Australia. These comments are taken from an editorial (JAMA 2017 Feb 21;317:699-701). Dr. Handelsman reported grants from Lawley Pharmaceuticals and Besins Healthcare and serving as a medical expert in testosterone litigation.


 

FROM JAMA AND JAMA INTERNAL MEDICINE

Testosterone treatment may have beneficial effects on unexplained anemia or bone density in men with age-related low testosterone, but at the cost of an increase in coronary artery plaque and with no benefit on cognitive function, new research suggests.

The results of four of the seven Testosterone Trials were published Feb. 21 in JAMA and JAMA Internal Medicine, adding to a growing body of research on the impact of testosterone supplementation but without finding clear evidence of an overall benefit.

In the double-blind, multicenter Anemia Trial, 788 men aged 65 years or older with average testosterone levels of less than 275 ng/dL were allocated to 12 months of testosterone gel or placebo. The group included 126 individuals with a hemoglobin level at or below 12.7 g/dL (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9540).

The study found that significantly more men who received testosterone treatment experienced increases in hemoglobin concentration of 1 g/dL or more above baseline, compared with those who received the placebo gel (54% vs. 15%; 95% CI 3.7-277.8; P = .002).

This effect was seen in men with known causes of anemia, such as myelodysplasia, iron deficiency, B12 deficiency, or chronic inflammation or disease; in men with anemia of unknown case; and in men who weren’t anemic.

After 12 months, more than half of the testosterone-treated men who started the study with unexplained anemia were no longer anemic, compared with around one-quarter of the placebo-treated men (58.3% vs. 22.2%). The men treated with placebo also had lower average hemoglobin level changes, compared with those treated with testosterone.

“Increases in hemoglobin levels were positively and significantly associated with participants’ global impression of change in overall health and energy,” wrote Cindy N. Roy, PhD, of Johns Hopkins University, Baltimore, and her coauthors.

Bone mineral density

A second trial examined the effect of 12 months of testosterone gel or placebo on bone mineral density in a group of 211 men with average testosterone concentrations less than 275 ng/L (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9539). The treatment increased median serum concentrations of total testosterone, free testosterone, and estradiol to within the normal ranges for young men.

The study showed significantly greater increases – measured by quantitative computed tomography – with testosterone treatment, compared with placebo, in spine trabecular, spine peripheral, hip trabecular, and peripheral volumetric bone mineral density, as well as in mean estimated strength of spine trabecular bone, spine peripheral bone, and hip trabecular and peripheral bone.

For the primary outcome of mean lumbar spine trabecular volumetric bone mineral density, testosterone treatment was associated with a mean increase of 7.5%, compared with a 0.8% increase with placebo.

Researchers also noted that the magnitude of the increase in spine trabecular bone mineral density from baseline was significantly associated with changes in total testosterone and estradiol.

However, there were no significant differences in fracture rate, with six fractures reported in each group during the year of treatment. In the observation year after treatment, three fractures were reported in the testosterone arm and four in the placebo arm.

“These results are unequivocal compared with prior studies of the effect of testosterone treatment on bone in older men, in spite of treatment limited to 1 year, perhaps because the mean pretreatment testosterone level was lower and the sample size larger than in prior studies, and because the primary outcome in this trial was vBMD by QCT,” wrote Peter J. Snyder, MD, of the University of Pennsylvania, Philadelphia, and his coauthors.

Coronary artery plaque

However, a third trial – this one in 170 men with low testosterone and symptoms suggestive of hypogonadism – found significantly greater increases in noncalcified plaque volume, median total plaque volume, and median coronary artery calcification score among the 88 men assigned to 12 months of testosterone gel, compared with those assigned to placebo.

The men treated with testosterone showed a mean increase in noncalcified coronary artery plaque volume of 40 mm3, compared with 4 mm3 in men given the placebo gel, and a mean increase in total plaque volume of 57 mm3 with testosterone and 21 mm3 with placebo (JAMA. 2017 Feb 21;317[7]:708-16).

There were no significant differences between the groups in change to coronary artery calcium score, and there were no adverse cardiovascular events reported in either group, despite the fact that around half the participants had severe atherosclerosis at baseline.

“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning, because any limitation of the vascular lumen could be considered deleterious,” wrote Matthew J. Budoff, MD, of the Los Angeles Biomedical Research Institute, Torrance, Calif., and his coauthors. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”

However, the investigators pointed out that the trial was neither large enough nor long enough to draw conclusions about the cardiovascular risks of testosterone treatment, and they called for larger studies to explore the association.

Cognitive function

The fourth study looked at mean change in cognitive function from baseline in 493 men with a serum testosterone level less than 275 ng/dL, impaired sexual function, physical function, or vitality, and who met the criteria for age-associated memory impairment. Half the participants were assigned to 12 months of testosterone gel, and half were assigned to placebo gel (JAMA. 2017 Feb 21;317[7]:717-27).

“The lack of association between testosterone treatment and cognition was apparent across all cognitive domains assessed among men with [age-associated memory impairment], in spite of an increase in circulating total and free testosterone concentrations in the testosterone group to levels typical of men aged 19-40 years,” wrote Susan M. Resnick, PhD, of the National Institute on Aging, and her coauthors.

The Testosterone Trials were supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Diseases and Stroke, the National Institute of Child Health and Human Development, and AbbVie, which also provided the AndroGel, and placebo gel. Authors from the trials declared a range of funding, consultancies, and other support from the pharmaceutical industry, including AbbVie. One author declared a pending patent for a free testosterone calculator.

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