Doctors around the world have written a surprising number of prescriptions for testosterone treatment in recent years. Nearly 3 percent of American men aged 40 and older are thought to have received such scripts in 2011—three times the percentage in 2001. (If confirmed, the 2011 ratio could mean that perhaps two million older men in the U.S. have been given prescriptions for testosterone.) Originally intended for men who have difficulty producing sex hormones because of damage or disease in their testes or other parts of the endocrine system, testosterone replacement therapy has become increasingly popular with middle-aged and older men who do not have clear deficits but who nonetheless hope to lessen some of the symptoms of aging, including fatigue, muscle wasting and lack of sex drive.

In truth, no one knows whether the hormone can offer any of the health benefits that its proponents claim for aging males. Well-designed, placebo-controlled trials of the drug in men who do not meet the standard criteria for treatment have been scant in number, and their results have been inconsistent.

As testosterone therapy becomes more widespread, a growing number of medical experts worry that it has become too easy for men to get the hormone—whether from their own physicians or stand-alone “low T” clinics—and that many users could be putting themselves at risk for worse conditions than those they are trying to counteract.

Easy Access
Testosterone, as produced by the body, is a versatile hormone. In addition to maintaining sperm production, the molecule helps many tissues to grow: it increases muscle and bone mass, as well as the production of red blood cells—all of which are vital for energy and strength. Disease or injury in the testes or pituitary gland—a part of the brain that instructs the testes to produce testosterone—can hinder the body's ability to make the hormone. When testosterone levels dip too low, men can become depressed and lethargic, lose interest in sex, and lose some of their muscle and body hair.

While the potential risks associated with taking supplemental testosterone—particularly in otherwise healthy men—are not well studied, concern has focused on whether extra amounts of the hormone might damage the prostate, heart or brain. Many prostate tumors depend on testosterone to grow, so increasing the level found in the blood might nudge normal cells to become malignant or push malignant cells to become more aggressive. In addition, two recent studies found an increase in heart attacks and strokes among older men taking testosterone—which the authors speculated might occur if the drug increased clotting risk and drove up blood pressure. Earlier this year the U.S. Food and Drug Administration announced that it is studying the matter to see whether stronger regulations are needed. In the meantime, the agency now requires all testosterone products to contain a warning label about the potential for blood clots.

As long as testosterone therapy was available only by injection, its use was largely limited to individuals with testicular injuries or other severe ailments. The treatment markedly improves mood and libido in men with these conditions, and the fda approved the drug for those situations. But fear of needles no doubt kept some men from seeking treatment.

Individuals were more willing to consider their options once pharmaceutical companies figured out how to deliver the drug more easily. A transdermal patch that delivered the medicine through the skin of the scrotum became available in 1993. (Subsequent patches could be applied to the arms, back and thighs.) But the number of men taking supplemental testosterone really began to soar in 2000, with the introduction of an even easier-to-use gel that could be rubbed on the shoulders, thighs or armpits.

Greater ease of use also led to an expansion in the number of conditions for which doctors considered testosterone therapy to be a plausible treatment in spite of any supportive data. Perhaps an extra dose of testosterone could be helpful for otherwise healthy men whose hormone levels had faded with age or because they were obese or suffered from diabetes? (It is unclear precisely why testosterone levels decline for certain individuals in these situations.) In addition, some men who did not have testicular injuries desired the sex hormone because they thought it would treat erectile dysfunction or boost their mood.

Blind Guides
Given the continuing uncertainty about the hormone, the Endocrine Society, an international organization of health care professionals focused on hormone research and endocrinology, advises doctors to perform two blood tests to confirm below-typical levels of testosterone and rule out other potential causes of their patients' symptoms before writing a prescription. Yet the most recent research suggests that between 25 and 40 percent of patients receiving testosterone replacement therapy never had a blood test to measure their testosterone before starting treatment.

Preliminary findings by Jacques Baillargeon, director of the epidemiology division in the department of preventive medicine and community health at the University of Texas Medical Branch at Galveston, and his colleagues offer clues as to why so many men get testosterone prescriptions without the recommended blood work. According to their analyses of insurance claims databases, about 70 percent of men who have tried testosterone therapy did so after seeing a primary care physician, not a urologist or endocrinologist. Although Baillargeon will not speculate about why primary care physicians are more likely to write a prescription without first ordering a blood test, Glenn Cunningham, a professor of medicine and an endocrinologist at the Baylor College of Medicine, suggests that perhaps the generalists are less familiar with the Endocrine Society's guidelines.

Other sources of testosterone include increasingly common low T clinics, many of which require men to pay for prescriptions out of pocket, prompting Baillargeon to suspect “potentially inappropriate prescribing practices.”

The clinics say their staff are trained in hormone medicine and do the appropriate blood work, but such claims are hard to verify without a data trail from insurance filings. In addition, the clinics are not reviewed or regulated by medical organizations or government groups.

New Limits?
The troubling spread of testosterone therapy in men has parallels to the early use of hormone replacement therapy in postmenopausal women. Starting in the 1990s, a series of studies suggested that many women who took a combination of estrogen and progestin as they grew older would suffer less from heart disease. But by 2004, after researchers had completed two major parts of the Women's Health Initiative—which together formed a massive study of 27,347 women that compared treatment with a placebo in a scientifically rigorous way—doctors realized hormone therapy does more harm than good in most women over the long term.

The study initially prompted a dramatic drop in the number of women taking prescription hormones. Since then, however, a more nuanced view has come into focus: the proved benefit of relieving menopausal symptoms such as hot flashes is worth the risk for some women, provided they limit treatment to the first several years after menopause. “I think we are less naive” than before the Women's Health Initiative, says Bradley Anawalt, a University of Washington professor of medicine and chair of the Endocrine Society's Hormone Health Network. “We are recognizing there is never a simple answer, and we have to discover who benefits and who gets harmed.”

For testosterone, some of those answers may soon be forthcoming. Results from a series of scientific studies detailing exactly who might gain from testosterone therapy, and under what circumstances, are expected to be published starting later this year. The series started in 2009, when the U.S. government funded a team of researchers to recruit and study participants for the Testosterone Trial—a group of seven long-term studies of how testosterone therapy affects sexual activity, energy level, memory, heart and bone health, and the ability to walk a certain distance. The trial followed 788 men, aged 65 and older, whose testosterone levels in the blood were much lower than average. Half the men (the experimental group) applied a gel with testosterone to their shoulders, abdomen or upper arms each day for a year, and the other half (the control group) used a gel containing a placebo. Researchers also monitored prostate cancer risk, based on prostate-specific antigen levels and a rectal exam, and stroke risk, based on red blood cell levels during the treatment year and for at least a year afterward.

Studies of the risks of testosterone use would likely follow only if the data on benefits were promising. Health researchers often look first at benefits of a treatment because theses studies call for fewer test subjects than risk studies do. Even though such randomized placebo-controlled trials can take years to conduct, they offer the best hope for separating truth from wishful thinking.