The Trouble With Testosterone

Hoping to revive sluggish libidos and boost their energy levels, middle-aged men are replenishing their waning testosterone concentrations. But researchers worry that men seeking this treatment are doing so without knowing whether it has any benefits or, more importantly, any risks to their health.

For years, menopausal women have opted to receive hormone replacement therapy (HRT) to cope with hot flashes and night sweats. In 2002, the Women's Health Initiative (WHI)--a set of clinical trials designed to test HRT and other interventions in more than 161,000 postmenopausal women--revealed that long-term use of a certain combination of hormones increased the risk for breast cancer, stroke, and heart attack. The results surprised the research community and the public, and prompted the National Institutes of Health (NIH) to shut down the study (see "Hormone Replacement Therapy: The Last Waltz or a New Step?").

Now some researchers say that a large number of men will experience a similar fate--receiving a treatment that has not been adequately tested--unless NIH conducts large-scale studies to look at the long-term effects of testosterone replacement therapy (TRT). But administrators at NIH's National Institute on Aging (NIA) have put the brakes on any plans to fund such a project. "We don't think it is feasible to involve [that] many men in a trial that would look at testosterone replacement therapy when there is no conclusive evidence of safety or benefit at this time," says Sergei V. Romashkan, health science administrator of clinical trials at NIA. NIA officials based their decision on a report issued by the Institute of Medicine (IOM), Testosterone and Aging: Clinical Research Directions. It declared that not enough information on the safety and effectiveness of TRT exists to warrant a large-scale trial right now.

Unlike estrogen concentrations, which plunge as women go through menopause, male testosterone production decreases gradually. As men age, their testes tend to churn out less testosterone than they did during the hormonal heyday of adolescence and early adulthood. For many older men, testosterone concentrations stay well within what is considered the "normal" range. But for 19% of men in their sixties, testosterone concentrations dip below this value.

Although the debate over TRT is only now heating up, the treatment itself is not new. For more than 60 years, doctors have been giving testosterone to men who produce little or no hormone--individuals whose testes have been damaged or whose pituitary glands, which stimulate testosterone synthesis, have been destroyed by infections or tumors. In these relatively rare cases, testosterone patches, injections, or topical gels help these men maintain strong muscles and bones, and boost their energy and sex drive. What is not clear is whether TRT would do the same for the one in five middle-aged or elderly men whose testosterone supplies fall below youthful concentrations.

Several small studies have shown that TRT provides some benefits to these men, improving their strength and cognitive function and generally addressing their most common complaints about aging. But the IOM task force stated that the data were inconclusive, because the studies "are generally short of duration, are conducted in a variety of populations and often do not include adequate controls."

To beef up the data, the IOM report recommends carrying out carefully designed, short-term studies with a limited number of participants. If these abbreviated studies show significant benefits--with no serious side effects--IOM endorses proceeding with a study the size of WHI. "It could be that a large-scale trial will be funded as early as 5 years [from now]," says NIA's Romashkan. "But I should stress that safety is the number one priority."

Those safety concerns prompted NIA officials to shelve plans for the first long-term study of TRT--the Efficacy and Safety of Testosterone in Elderly Men (ESTEEM) trial. Among other things, researchers worried that the treatment might put participants at risk for prostate cancer. Scientists have long known that eliminating testosterone slows the growth of existing prostate tumors, suggesting that the hormone might somehow induce or support cancer.

But that's exactly why NIA should support trials such as ESTEEM, says Alvin Matsumoto, an endocrinologist at the University of Washington, Seattle, and one of the study's principal investigators. "The risk of prostate cancer cannot be addressed in a short-term trial"--the type that IOM favors.

What's more, he says, comprehensive studies are needed sooner rather than later, because a growing number of men are already undergoing treatment. More than 800,000 people--most of them men over the age of 46--received testosterone in 2002, 29% more than the previous year. "In the last 5 to 6 years there has been a wave of testosterone prescriptions," says Matsumoto.

Until TRT's safety and efficacy have been established, its use, writes the IOM task force, should be limited to indications approved by the U.S. Food and Drug Administration--mainly, to treat men with extreme hormone deficiencies. Right now, the IOM report states, TRT is "inappropriate for wide-scale use to prevent possible future disease or for enhancing strength or mood in otherwise healthy males." These recommendations, however, are unlikely to have any effect on what clinicians are doing. "Testosterone replacement therapy is going on and will continue to go on," says Matsumoto. "More people are using testosterone each year without knowing its risks and benefits. I think it is unfortunate, but I don't know that it is unjustified," considering the promising results of the short-term studies conducted thus far.

NIA is planning to issue a request for proposals for studies of the benefits and risks of TRT in aging men to meet the recommendations of the report. In the meantime, men considering whether to undergo TRT will have to rely on scanty and sometimes contradictory information--the same issues that menopausal women have been grappling with for years.

Laura Bonetta writes from the suburbs of Washington, D.C. She hopes not to have to think about HRT for a long time.