Results from a recently published set of coordinated trials indicate that raising testosterone concentrations offers moderate benefits in sexual function and some benefit on mood and depressive symptoms.
In the largest randomized, controlled trial to investigate the benefits of testosterone therapy in men 65 years of age and older, researchers report raising testosterone concentrations offers moderate benefits in sexual function and some benefit on mood and depressive symptoms.
The New England Journal of Medicine published results of three of seven of the Testosterone Trials (TTrials) (2016; 374:611-24). The TTrials are a coordinated group of seven trials testing the effect of a testosterone gel compared with a placebo gel. The NEJM study includes the results of the three primary trials-sexual function, physical function, and vitality.
The authors, led by Peter J. Snyder, MD, of University of Pennsylvania Perelman School of Medicine, Philadelphia, studied 790 men 65 years of age and older. Subjects, who had serum testosterone concentrations of less than 275 ng/dL and symptoms suggesting hypoandrogenism, received either testosterone gel or placebo gel for 1 year.
“The results of the TTrials show for the first time that testosterone treatment of older men who have unequivocally low testosterone levels does have some benefit. However, decisions about testosterone treatment for these men also will depend on the results of the other four trials-cognitive function, bone, cardiovascular, and anemia-and the risks of testosterone treatment,” Dr. Snyder said in a Penn press release.
Results from the three trials include:
Reaction from experts Urology Times spoke with was largely positive, although one thought leader pointed out that the use of testosterone therapy was short term, as was follow-up.
“Although there was already level 1 evidence that T therapy improved sexual desire and erection quality, as well as reducing fat mass and increasing lean mass, these results ‘seal the deal’ that T therapy has significant benefits for men, including mood and physical activity,” said Abraham Morgentaler, MD, of Men’s Health Boston, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston. “Whereas testosterone critics have attempted to undermine the benefits of T therapy by claiming that prior studies were too small, or of poor quality, or unduly influenced by pharmaceutical funding, this multi-center, NIH-funded study eliminates those concerns. In the face of these results, it can no longer be claimed that ‘the benefits of testosterone therapy are unproven.’ ”
Urology Times Editorial Council member Arthur L. Burnett, II, MD, MBA, also praised the study.
“This is a solid study with respect to its well-defined study population, high-caliber study design, rigor, and execution, and excellent choice of endpoints. It affirms the understanding that testosterone therapy (in the form of topical therapy administered to eugonadal therapeutic levels) significantly benefits sexual function (sexual activity, sexual desire, and erectile function) and modestly improves physical function and depressive symptoms. The findings also show that this therapy affords safety with regard to cardiovascular risk, prostate health risk and urinary symptoms,” said Dr. Burnett, of Johns Hopkins University, Baltimore.
Dr. Burnett included a caveat with his comments, however.
“These positive conclusions must be tempered, however, by the constraints of this study that enrolled fairly healthy older but not elderly men and the relatively short-term use of therapy and (12 months) and follow-up (12 months),” Dr. Burnett added.
Ranjith Ramasamy, MD, of the University of Miami, told Urology Times these are important findings, statistically and clinically.
“The results are significant because the results of the study are in contrast to the results of the TEAAM trial (JAMA 2015; 314:570-81) [and] because this is the first randomized trial that showed beneficial effects in elderly men who received testosterone therapy,” Dr. Ramasamy said.
The results observed in this new study are what prospective studies have demonstrated previously (including Eur Urol 2015; 67:167-7), according to Dr. Ramasamy.
Much of the controversy over testosterone replacement therapy for the last 3 years has been anchored by cardiovascular concerns based primarily on intense media coverage of two retrospective studies (JAMA 2013; 310:1829-36; PLOS One 2014; 9:e85805). The JAMA study initially reported that absolute rate of cardiovascular events was higher among testosterone-deficient men treated with testosterone compared with untreated men, according to Dr. Morgentaler.
“This was an error, however, as the correct absolute rate of events was lower by half in the T-treated group compared with untreated men (10.1% vs. 21.2%, respectively). Twenty-nine medical societies petitioned JAMA to retract the article when it was subsequently revealed that nearly 10% of the all-male study population was comprised of women,” Dr. Morgentaler said. “Since publication of those studies, there have been more than a dozen studies demonstrating either no negative CV consequences of T therapy, or reduced CV events.
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“In the current study, there were exactly the same number of major cardiovascular events (seven) in the treatment and placebo arms. Interestingly, in the subsequent year of follow-up, there were only two events in the testosterone arm and nine in the placebo arm. Clearly, there is no hint of increased CV events with testosterone in this large prospective study,” Dr. Morgentaler added.
It is surprising that cardiovascular side effects of men treated with testosterone for 1 year was similar to men treated with placebo gel, according to Dr. Ramasamy.
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“Even though the study was not powered to detect difference in CV risks, the study results are reassuring to practitioners that follow the FDA recommendations and counsel patients about the association of T therapy with [myocardial infarction, cerebrovascular accident, and pulmonary embolism],” Dr. Ramasamy said.
According to Dr. Ramasamy, the NEJM study applies to men older than 65 years with a total testosterone (TT) of less than 275 ng/dL. But a significant proportion of men on testosterone therapy are middle-aged men-40 to 65 years-who were screened for low testosterone using a TT of less than 300 ng/dL, as recommended by Endocrine Society. The results are, therefore, difficult to extrapolate, he said.
The findings couldn’t come soon enough for Ajay K. Nangia, MBBS, of the University of Kansas Medical Center, Kansas City. Dr. Nangia holds different posts with the AUA, including one as a panel member for the AUA’s Testosterone Position Statement and as a representative of the AUA on testosterone therapy during a September 2014 FDA hearing on testosterone use.
Dr. Nangia says urologists have been caught in the cross-hairs of patients who want to be treated for symptoms, a lack of solid research, bad media coverage, and the FDA’s announcement that testosterone would be considered off-label except for treatment of specific medical conditions.
“This is like giving women HRT after menopause. The Women’s Health Initiative left that a complete mess about whether to use it or not. The pendulum went one way, then the other way; now, it’s back, trickling to the middle. So, I hope that will happen with testosterone. It was not used a lot in the ’80s and ’90s. After 2000, the use of testosterone increased very dramatically. Then, all of the sudden, the FDA came down on us like a brick after the cardiovascular papers and adding cardiovascular risk to the label, and we’ve gone the other way. I hope these trials bring us back to the mean and at least allow us to use it appropriately with short-term (and I hope one day long-term) evidence,” Dr. Nangia said.
Endocrinologist Rebecca Z. Sokol, MD, MPH, of the Keck School of Medicine of the University of Southern California, Los Angeles, called the paper “a very well-designed study.”
“I would have been interested to know how many increased sexual events actually took place. The difficulty of these studies is not being able to recruit enough men to adequately analyze risks of treatment,” Dr. Sokol told Urology Times.
The study is revealing when it comes to prescription of testosterone, according to Dr. Sokol.
“The most important finding in this study is that 51,085 men were screened, but only 14.7% met the low testosterone level inclusion criteria. If it is true that men spent $2 billion on testosterone prescriptions last year, that indicates that many more men are using testosterone than there are men with low testosterone levels, suggesting it is over-prescribed,” Dr. Sokol commented.
AbbVie provided funding as well as testosterone gel and placebo gel for the study. Dr. Snyder receives consulting fees from Watson Laboratories, and several of his co-authors have a financial or other relationship with one or more pharmaceutical companies. Dr. Ramasamy is a consultant to Beckman Coulter, and Dr. Morgentaler has received research grants and/or lecture honoraria and/or has been a consultant for AbbVie, Antares Pharma, Bayer, Clarus Therapeutics, Endo, Eli Lilly and Co., and Pfizer.
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