Many men, as they move into middle age, yearn for the same muscular strength, sexual energy and sense of well-being they had in their youth.
That's why millions of American males are asking their doctors for testosterone replacement therapy, or TRT, to treat a collection of symptoms that some doctors and drug companies have dubbed andropause, or male menopause.
The popularity of TRT is creating concern among scientists, who can't agree on whether andropause is a real phenomenon or not. Some believe that the complaints of older men, such as decreased libido, depression and fatigue, are more likely explained by poor habits in diet, sleep and exercise.
Even as the debate continues, many family physicians and specialists are prescribing the drug. U.S. sales of testosterone replacement drugs have jumped more than fourfold in the last three years, to an estimated $425 million in 2003, according to Wells Fargo Securities. And industry experts predict that the market will continue to climb, perhaps by more than a third, in 2004.
Many men's health specialists, however, worry that testosterone replacement may offer little benefit and may lead to more severe medical problems in the future. Their concerns are heightened by the experience of millions of women, who for years took hormone replacement therapy, or HRT, in the belief that it would protect against age-related disease. Recent studies have shown that HRT actually increases women's risk of heart disease and breast cancer, and many doctors no longer advise it.
A report in 2000 by the American Assn. of Clinical Endocrinologists found that nine out of 10 endocrinologists surveyed were worried about possible misuse of TRT. Doctors interviewed for this story said they were especially concerned by evidence suggesting that testosterone might stimulate prostate cancer and raise the risk of heart disease and strokes. Dr. Shalender Bhasin, an endocrinologist at the Charles R. Drew University of Medicine and Science in Los Angeles, believes it is premature for doctors to recommend TRT to older men reporting age-related symptoms, even if their testosterone levels are low.
Bhasin is one of four specialists who proposed a major government study on testosterone's risks and benefits three years ago. In 2000, hormone sales soared after the introduction of Unimed Pharmaceuticals' Androgel product, a testosterone gel that is rubbed on the skin. "It occurred to me this was a big tsunami ... not a trivial event," Bhasin said.
A clinical trial to assess the risks and benefits of TRT was initially endorsed by a National Institutes of Health panel, Bhasin said, but officials decided to postpone the project until a group of experts could further study the issue.
The NIH asked the Institute of Medicine, which advises the government and nonprofits on health policy issues, to create a task force to review existing data about testosterone replacement in men 65 and older and either recommend a plan for one or more clinical trials or suggest other options that might not include a clinical study. "One of the concerns was the risk for prostate cancer," said Evan Hadley, a geriatrics expert at the National Institute on Aging. The Institute of Medicine is scheduled to release its report next week.
Physicians sometimes recommend testosterone supplementation when a man's hormone level falls below 350 nanograms per deciliter, or the lower range of normal, although they don't always agree on the level at which treatment is needed. For many years, men had to go to a doctor's office to get regular shots. Then a skin patch became available, but it often caused skin irritation. Androgel, which can be rubbed on the skin each day, went on the market in February 2000. The Food and Drug Administration approved another gel, Testi, in October 2002. And, in June, the FDA approved a gum-like substance that can be pressed inside one's cheek to release testosterone all day.
While some doctors believe it is likely that the benefits of TRT outweigh the risks, others are concerned that thousands of American men already have embarked on risky experiments reminiscent of the HRT experience with women. Six million American women took estrogen and progestin on the advice of doctors who were convinced by small- and medium-size studies that the treatment could protect hearts, improve bone density and sharpen thinking. But in July 2002, investigators suddenly halted a major clinical trial of HRT, the Women's Health Initiative, because of an increased risk of heart disease, strokes and breast cancer. Since then, the evidence that HRT could do anything more than ease menopausal symptoms has steadily unraveled.
"The most important thing we learned is you really need to do the [large] clinical trial" before treatments are widely prescribed for patients, says Dr. Marcia Stefanick, a Stanford University associate professor and one of the lead researchers on the Women's Health Initiative. She said there are fewer data from clinical studies on testosterone now than there were for estrogen treatment for women when it became popular.
Stefanick says family doctors get a skewed perspective on hormone replacement therapy because patients who don't find it helpful tend to discontinue its use. "They get the impression that people who are on it really love being on it," she says. And because they see limited numbers of men and women, family physicians also are likely to attribute any related heart attacks or cancer to another cause, she adds.
Unlike the sudden drop-off of estrogen in menopausal women, testosterone declines slowly in men, starting as early as age 20, and may never drop below normal.
Supporters of TRT point to findings of increased muscle strength, bone density, cognition and well-being. But most of these positive studies were extremely small and were not "blinded" or "controlled," standard research techniques to protect against the possibility that patients respond well to a drug simply because they know they are taking it. Other clinical trials -- with similar methodological weaknesses -- found no benefit from the hormone at all.
In a 1999 analysis, for example, bone density improved for all 108 men involved in the research -- including those receiving treatment and those using fake testosterone patches. This was probably because everyone also took calcium and vitamin D, the researchers said. In a small number of participants with very low levels of the hormone, lumbar spine bone density did increase a bit more.
An oft-cited study that seemed to show improved cognition among men who used a testosterone gel was too small -- involving only 19 men -- to be considered persuasive. Endocrinologists agree that the best evidence showing a benefit for TRT is increased muscle mass; a common complaint of aging men is diminished strength. Bhasin studied testosterone's effect on muscular mass in a 1996 study that he thought would dissuade athletes from using the hormone. "I was so surprised by the data," he says. "If I were a meat producer I'd be ecstatic, because it clearly increases muscle production. But it's unknown whether this translates into lower risk of falls, a better quality of life."
Clinicians mostly pin their hopes on the benefits experienced by young men who have extremely low levels of testosterone because of known disease, as well as an epidemiological study that suggested a link to declining function with age. They are encouraged by the potential to battle dementia and ease frailty in men 65 and older.
Many doctors have been impressed by patient reports of high energy and a greater sense of well-being. Dr. Lester Lee, a Huntington Beach internist, said about one-third of the male patients in his family practice are on TRT. He describes the results as "phenomenal" and says patients tell him, "I have more sparkle; my libido has gone up."
But such changes are difficult to measure, researchers said, particularly without controls to help curb the placebo response and careful analyses of mood. Testosterone has increased libido in some controlled studies, and there is some evidence that the hormone may influence erectile function. Most endocrinologists, however, have concluded that once a certain level of the hormone is present, a higher amount doesn't boost sexual interest or activity.
Data on testosterone's potential harm are just as thin, specialists say. Since the hormone is known to feed prostate tumors, physicians' biggest worry is that it may stimulate the growth of tiny existing cancers. Many older men already have microscopic tumors in their prostate that might not otherwise become dangerous.
Further, several studies have identified a slight increase in levels of PSA -- prostate specific antigen, which is used as a marker to detect cancer -- and prostate size after testosterone supplementation.
"There's reason for some optimism if you limit the treatment to men whose testosterone is really low," says Dr. Mitchell Harman, director of the Kronos Longevity Research Institute in Phoenix. But many men in their 50s and 60s are looking for an easy way to stave off tiredness, depression, loss of libido and general midlife crisis.
"People start to notice they don't have the energy they did at 25 and they want to do something about it," he says. "The best approach is good nutrition and exercise, but they want a magic bullet."