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New studies fail to change ‘unfavorable balance’ of risks/benefits of testosterone supplements

With the results of the new studies, “the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed,” writes endocrinologist David Handelsman.

Sales of testosterone supplements for “Low T” skyrocketed, increasing tenfold in the United States between 2000 and 2011.

The only male medical condition that testosterone supplements have been shown to clearly help is hypogonadism — abnormally low levels of the hormone that result from a disorder of the hypothalamus, pituitary gland or testes.

But that’s a relatively small market for such drugs. Hypogonadism affects only 0.1 percent of men in their 40s and just 5.1 percent of men in their 70s. So, about two decades ago, pharmaceutical companies hit upon a grand idea: They would get doctors to expand the definition of “low testosterone” to include any middle-aged or older man with somewhat lower testosterone levels (a drop that occurs naturally with age) as well as common age-related complaints, such as fatigue, sleep problems, weight gain, and decreased libido or physical abilities.

This medicalization of male aging, which began about a decade ago, worked. Sales of testosterone supplements for “Low T” skyrocketed, increasing tenfold in the United States between 2000 and 2011.

Researchers have been playing catch-up ever since, trying to figure out if testosterone supplements — whether gels, patches, pills or other products — really live up to all the marketing hype. In 2003, the National Academy of Medicine (then the National Institute of Medicine)  called for more rigorous research to look at both the positive and negative health effects of testosterone replacement therapy in older men.

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So far, concerns about the drugs have tended to heavily outweigh any claims of benefits. Indeed, in 2015, the U.S. Food and Drug Administration required the products’ labels to carry warnings that their use is associated with an increased risk of heart disease and stroke. 

Randomized trials

A series of new studies is unlikely to ease those concerns. The studies examined the effect of testosterone supplements on the bone health, anemia status, memory skills and cardiovascular health of older men. 

Four of the studies used data from the Testosterone Trials (TTrials), which involved 790 men aged 65 and older. Half of the men were randomly assigned to take a daily dose of testosterone in the form of a gel for a year, while the others took a placebo for the same period of time. (The gel raised the men’s testosterone to levels that tend to occur in healthy, younger men.)

The results were published Tuesday in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine:

  • One of the studies found that the testosterone gel improved bone density in some men. But, as the authors of the study point, the clinical significance of this finding is unknown as it’s not clear that increased bone density reduces fractures.
  • A second study found that the gel was associated with an increase in the percentage of men who recovered from mild anemia, both when the source of the condition was known (an iron deficiency) and unknown. (Note: This study has been criticized for an ethical lapse. The participants with anemia were not told they had the condition when it was detected at the start of the study — an oversight, according to the study’s authors.)
  • A third study found no association between testosterone supplementation and memory improvement. At the start of the study, 493 of the participants had age-associated memory impairments (defined by both the men’s own reports and by the results of memory tests). Half received the testosterone gel, and half received the placebo. Tests conducted at the end of the 12 months found no difference between the two groups in memory improvement or other cognitive functions.

Findings for the heart

Those three studies could be viewed as neutral or even mildly promising for testosterone supplements. But the same can’t be said of the fourth study — the one on cardiovascular health.

Its findings suggest that testosterone supplementation may raise the risk of heart disease. The men in the study who were using the testosterone gel experienced a significantly greater buildup of plaque in their arteries compared to the men who were taking the placebo. Arterial plaque is considered an early sign of heart disease.

The study was small, however, and followed the men for only a year. A larger, longer study would be needed to confirm the findings.

A fifth study, which was also published Tuesday in JAMA Internal Medicine but which was not part of the TTrials, also looked at the association between testosterone supplementation and cardiovascular outcomes, this time in more than 8,000 men aged 40 or older with “low T” levels of the hormone. It found that the supplementation was associated with a lower risk of stroke, angina and other heart-related outcomes.

But that study was an observational one, which means its findings do not prove that the testosterone treatments were related to the better heart outcomes. Many associations that emerge from observational studies vanish once they are tested in clinical trials.

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Still an unfavorable balance

Overall, the findings from these studies “do not materially change the unfavorable balance of safety and efficacy to initiate testosterone treatment for age-related” declines in the hormone, writes David Handelsman, a reproductive endocrinologist at the University of Sydney, in an editorial that accompanies the study. “Rather, low testosterone levels due to obesity and other aging comorbidities are better addressed by lifestyle measures directed at those comorbidities.”

Handelsman then takes the medical profession to task, noting that “testosterone overprescribing has been propelled not only by direct-to-consumer advertising, but also with the complicity of some professional organizations and physicians that have supported redefinition of the term hypogonadism through permissive guidelines appearing to minimize the fundamental distinction between pathological hypogonadism and age-related, low circulating testosterone.”

Those guidelines need to be revised, he stressed, to remove their “tacit, uncritical endorsement” of testosterone supplements “as a panacea for male aging.”

“Hopes for hormonal rejuvenation appear periodically throughout history,” he writes, but with the results of the studies published on Tuesday, “the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed.”

FMI: You’ll find all the studies mentioned — and the editorial — in the Feb. 21, 2017, issues of JAMA and JAMA Internal Medicine