CAUSE FOR CONCERN
Physicians wrote more than two million prescriptions for HRT in 2003. Many were for off-label use, intended to revive testosterone levels that wane with age.
"Fatigued? Depressed mood? Low sex drive? Could be your testosterone is running on empty." This Web sales pitch1 comes not from one of the myriad disreputable companies peddling 21st-century snake oils such as "Libido Enhancement Cream." Rather, the site belongs to Solvay Pharmaceuticals, Marietta, Ga., which produces Androgel, a prescription testosterone-laced gel that received approval from the Food and Drug Administration three years ago.
The drug is at the forefront of a campaign to convince men that they must replace the steroid hormones that ebb as they age. But some expert groups fear that the campaign for male hormone replacement therapy is running way ahead of the data, and they have launched a counter-effort to slow it down. Potential...
CLINICAL RESEARCH DEBATES
Instead of costly large-scale clinical trials to assess long-term benefits and risks, the report recommends small clinical trials, confined to men older than 65 with low testosterone levels who are not at high risk for prostate cancer, and who have at least one symptom that testosterone might improve. The aim, the IOM says, should be to find out whether testosterone replacement really does offer benefits suggested by small published studies and anecdotal evidence. This smaller-scale strategy would involve several hundred men instead of several thousand and would take only a year or two instead of 10 or more. If testosterone offers clear benefits, then larger clinical trials to assess risks might make sense, the report concludes.
John E. Morley, who directs the Division of Geriatric Medicine at St. Louis University, says he thinks that's the wrong approach. He advocates a men's version of the government's Women's Health Initiative (WHI), which includes massive, long-term, double-blind clinical trials.3 The National Institutes of Health shut down one arm of the WHI in July 2001 after it reported small increases in breast cancer and cardiovascular disease for women taking Prempro, a popular hormone replacement therapy for menopausal symptoms.
Morley argues, "We waited forever to find out in women whether or not giving estrogen long-term is good for them. While the study didn't quite answer that, certainly it didn't give us the answers we thought it would. What IOM has suggested ... won't answer the question of whether or not testosterone might have side effects."
In fact, the turmoil accompanying the bad news about women's hormones4 was very much on the testosterone committee's collective mind. Hormone replacement for women charged ahead beginning in the 1980s, because observational studies were showing not only that it cured immediate menopausal symptoms such as hot flashes, but also that it protected against future ills, including heart disease and mental decline. But observational studies are not controlled and may suffer from selection biases. The IOM committee does not want to repeat that mistake, hence the call for short-term double-blind trials to see whether testosterone performs as advertised.
BACK TO BASICS
The committee also called for more basic research, especially on physiologic regulation of endogenous testosterone levels, the hormone's mechanism of action, and age-related changes in testosterone. Neal Simon, chair of the Department of Behavioral Sciences at Lehigh University in Bethlehem, Pa., agrees. "My own bias is that we really need an investment in work that helps characterize the mechanism of action of these compounds," especially in the brain. "When people take testosterone supplements," he says, "they report feeling energized, but they also report irritability. ... Those are psychological attributes, and the question is, what is the underlying physiological mechanism mediating that?"
Simon's work focuses on a different hormone, dehydroepiandrosterone. DHEA, produced in the adrenal glands, is the most abundant steroid in the human body, an essential precursor to androgens and estrogens, and also a potent neurosteroid. DHEA is an unregulated food supplement, and an unknown number of men and women consume it in hopes of slowing down aging.
"You often see reports of improvement in well-being, but studies on cognitive enhancement produce very mixed results. Our interpretation of that literature is that, for individuals who have an adrenal insufficiency, DHEA replacement appears to have benefits, but for the normal population, it's really not clear," Simon says. He and his colleagues study the hormone's brain effects, and have recently shown in mice that DHEA itself is directly androgenic and exerts genomic effects in the central nervous system.5 Previously, DHEA was believed to act only at the cell surface. "The discovery that the compound is directly androgenic would lead to changes in how you might think about it as a therapeutic agent, or how you think about its role in promoting general functions in the CNS."
Simon says DHEA may have potential as a selective androgen receptor modulator (SARM). The IOM report mentioned this infant research area, analogous to the selective estrogen modulators (SERMs), the drug company darlings that are now moving into clinical use.6 The idea is to find molecules that will restrain hormonal action just enough to reduce risks while retaining benefits. SARM research is at a much earlier stage than SERM research. Simon says, "Now the question is how to design compounds that avoid as a primary target, prostatic problems, and secondarily, the cardiovascular problems that are associated with androgens."
DHEA is much weaker than testosterone in peripheral tissues. "You may be able to get some androgenic benefits of DHEA without as high a risk profile as one might get from testosterone. Of course, we need to understand the dose-response relationship," Simon says.
TRUTH AND AN INDUSTRY BONANZA
The National Institute on Aging and the National Cancer Institute, which wanted guidance on clinical testosterone research, requested the IOM study. Evan Hadley, NIA associate director for geriatrics and clinical gerontology, says the agency is likely to launch some small, short-term studies based on the IOM recommendations, but decisions probably won't happen before spring. A WHI-type initiative for men, he says, is not likely soon.
"It's extraordinarily important to know what the truth is, and the truth is not going to come out until we have something equivalent to the WHI," Morley argues. He says he believes testosterone is a very good short-term treatment for men, but the need for long-term data is urgent. "I have no idea if I treat [men] for 10 or 15 years, or even for five years, whether we would be killing a subset of them off."
While emphasizing his financial ties to the pharmaceutical industry, including testosterone products, Morley predicts that the IOM report is likely to be an industry bonanza, providing at least a 15-year window of opportunity for testosterone to become another blockbuster drug. It may take a company four or five years to get a new testosterone product over regulatory hurdles, but that still leaves 10 years on the market before unpleasant data emerging from large, lengthy clinical trials might spoil profits, he says.
"It means that anyone developing a drug now can put it on the market, get into a billion-dollar industry, and by the time these studies are done they'll have made their money," says Morley. He believes that testosterone is probably relatively good for men. "It's just that I would like to see the equivalent of the WHI, even though I stand to gain so much more from what the report said, that I should just shut up."
Tabitha M. Powledge
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