NEWS

IOM Report Targets Testosterone Therapy

Christine Theisen

Studies of testosterone therapy should determine the benefits of treatment before determining risks, and study participants should be limited and carefully screened, a committee of the Institute of Medicine at the National Academies has concluded.

More than 1.75 million prescriptions were written for testosterone in 2002, and a majority of them were written for off-label uses. Federally approved only to treat hypogonadism in men, a condition characterized by little or no natural production of testosterone in the testes, testosterone is popularly touted to help men gain strength, improve their sex lives, and reduce the effects of aging.

The IOM committee examined testosterone therapy at the request of the National Institute on Aging (NIA) and the National Cancer Institute. Initially, "NIA had recognized that testosterone was being used a lot more and was considering what should be done to study its use more effectively," said committee chair Dan Blazer, M.D., Ph.D., J.P. Gibbons Professor of Psychiatry at Duke University Medical Center in Durham, N.C. "NIA proposed a study that all the institutes together decided not to pursue. Having IOM review the situation was the next step."

The committee recommended that clinical trials be conducted in older men with low testosterone levels. Possible conditions older men experience that testosterone therapy may help relieve—although "none of these have been definitely proven effective," said Blazer—are frailty, difficulty functioning, cognitive impairment, and reduced sexual function. "There are other areas where it might be effective, such as depression or retarding osteoporosis, but there are other therapies currently available for those," Blazer said.

Studies should be conducted in men with low testosterone levels because there is some concern about a link between testosterone levels and prostate cancer, which is in general more common among older men. "There is no direct known connection between testosterone replacement and prostate cancer," clarified committee member Pete Nelson, M.D., assistant member of the Divisions of Human Biology and Clinical Research at the Fred Hutchinson Cancer Research Center in Seattle. However, "some epidemiological studies associate risk of prostate cancer with level of testosterone (high serum level with higher incidence of cancer), but these studies generally have shown only mild/modest associations." The issue is not clear, because "testosterone levels generally fall with age, and prostate cancer incidence rises with age," Nelson added. "Some studies have shown that prostate cancers detected in men with low testosterone levels are of a more aggressive variety."

Selecting older men for initial clinical trials who have low testosterone levels, are free of prostate cancer, and have low prostate-specific antigen values will allow researchers to focus on the other possible effects of testosterone therapy. "There is still much we don’t know about normal levels of testosterone at different ages, how decreased testosterone levels affect men’s health, and whether testosterone therapy might increase the risk of prostate cancer," Blazer said in a statement.

The IOM committee also recommended that studies should start with short-term, randomized, double-blind, placebo-controlled efficacy trials. These specifications are especially important given current off-label use of testosterone supplementation to treat a variety of symptoms. The recommended short duration of initial trials will allow for review and reconceptualization as the effects of testosterone therapy are established, the committee said.

After efficacy has been established, longer-term studies should be conducted, the committee recommended. Waiting until the benefits of testosterone therapy are established in short-term trials before beginning longer-term studies will help ensure that any risk to trial participants is balanced by proven benefits. This is particularly relevant in light of the ending, in July 2002, of the estrogen plus progestin portion of the Women’s Health Initiative study after researchers found that the supplements both increased breast cancer risk and did not provide an overall benefit for menopausal women.

The IOM committee specified that researchers should ensure the safety of patients and follow strict participant exclusion criteria and that each participant’s PSA levels be carefully monitored during testosterone therapy trials. In their final recommendation, the committee emphasized the importance of further study of testosterone’s mechanism of action and physiologic regulation of endogenous testosterone levels.

"Basically, testosterone directs a gene expression program influencing cell proliferation and prevention of apoptosis. Increased cell turnover/proliferation allows for mistakes in DNA replication leading to mutations [and possibly cancer]," said Nelson. "There is likely some sort of threshold effect for the proliferation response. However, dose–response relationships have not been established for human prostate tissues in vivo. The major point is that there are many unanswered questions to address."

Blazer emphasized the specificity of the IOM committee recommendations to learning about the effects of testosterone therapy, and possible connection with prostate cancer, only to older men. Asked about what findings in older men might mean for prostate cancer risks in younger men, Blazer said, "We don’t want to jump to conclusions. We focused on older men who had symptoms such as difficulty functioning and cognitive impairment. We believe that the drug needs to be studied in middle-aged men if it’s going to be used in middle age. I don’t believe we can translate findings from late life into midlife or the other way around."


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