"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."
