Unproven elixir: hormone therapy tempts aging men, but its risks haven't yet been reckoned.

With each passing birthday, Mr. Y feels increasingly frail. His bones have grown fragile, his strength has slipped, and his muscles have given way to fat. His sex drive has waned, and his once-keen mind seems perpetually fogged. He often feels gloomy. Vigor has turned to fatigue, zest to melancholy. In body and in mind, he has grown old. While advanced age naturally brings certain declines, a growing number of men who might identify with the fictive Mr. Y are looking to hormone-replacement therapy to stave off the advance of the characteristic signs. Specifically, they're taking prescribed, synthetic forms of testosterone.

Declining concentrations of natural androgens, which include testosterone and related male sex hormones, may be at least partially responsible for physical and mental signs of aging in some men. Accumulating research suggests that supplemental testosterone can stall or counteract some aspects of these declines, but the specifics are far from resolved. What's more, it will take years to determine whether the treatment is doing most men more harm than good.

As the first substantial studies are concluding, some doctors are optimistic. Testosterone therapy "can make the process of aging more tolerable;' says Alvaro Morales, a urologist at Queen's University in Kingston, Ontario. "I'm all in favor of giving [certain aging men] therapy, but they have to be followed closely"

Other scientists urge more restraint until the benefits and risks of the therapy are better understood. "What we need now is more information," says Peter J. Snyder of the University of Pennsylvania in Philadelphia. "We don't need willy-nilly treatment."

This much is known: A few percent of men younger than 40 suffer from a failure to maintain sufficient androgen in their blood, usually as a result of cancer or an injury to the testes or pituitary gland. Many such men experience bone and muscle weakness, lack of energy, sexual dysfunction and diminished sex drive, cognitive deficits, and depression. Because supplemental testosterone frequently alleviates these symptoms, many hormone researchers hypothesize that supplements could benefit generally healthy men--the Mr. Ys of the world--who show similar, if often less severe, symptoms stemming from ebbing natural hormone concentrations.

The rough physiological analogy between age-related testosterone decline in men and changes in sex hormones that women experience at menopause has led many people to adopt the term "andropause" for a midlife change in men. Many researchers point out that the term is technically inaccurate, since the production of sex hormones doesn't drop precipitously in men as it does in menopausal women. Some researchers prefer alternative names, such as androgen deficiency in aging males, or ADAM.

SIZING UP A SYNDROME Part of the challenge for a medical approach to middle-age androgen decline is that the condition lacks clear diagnostic criteria. To identify patients who might benefit from testosterone therapy, many doctors use a two-pronged approach that weighs both symptoms and biochemistry.

John Morley of St. Louis University and his colleagues have developed a quiz, called the ADAM questionnaire, designed to help men spot signs of aging that may be associated with insufficient testosterone. These include lack of vigor and falling sex drive. Once a man has determined that he has certain signs of decline, blood tests can reveal whether his testosterone concentrations are low. Commonly cited thresholds for treatment are 200 and 300 nanograms per deciliter (ng/dl) of blood. In contrast, the typical blood-testosterone concentration for a 40-year-old man is about 500 ng/dl, according to some recent studies.

A 2001 study defined low testosterone as a blood concentration below 325 ng/dl. The prevalence of the condition among 890 men was less than 10 percent among those under 50, but 49 percent of those in their 80s, reported S. Mitchell Harman, now at the Kronos Longevity Research Institute in Phoenix, and his colleagues at the National Institutes of Health in Bethesda, Md. They calculated an average drop of about 3.2 ng/dl, or about 1 percent, per year.

According to another study, men's average blood-testosterone concentrations decline 0.8 to 1.6 percent per year between the ages of 40 and 80. John B. McKinlay of the New England Research Institutes in Watertown, Mass., and his colleagues reported their findings in the February 2002 Journal of Clinical Endocrinology and Metabolism.

If anything, these numbers may underestimate the effect of age-related decline in testosterone. Certain proteins in blood bind to testosterone and keep most of the hormone from interacting with cells. What remains, so-called bioavailable testosterone, drops more rapidly with age than total testosterone does because the blood of older men contains more testosterone-binding proteins, both Harman and McKinlay have found.

While the Food and Drug Administration has approved several forms of testosterone supplements for men with low testosterone from medical conditions, it hasn't specifically given a green light to the therapy as a treatment for aging. Nevertheless, physicians can legally prescribe testosterone to whomever they judge to require it, including aging men with signs of androgen deficiency.

Injections, typically given every few weeks, are the cheapest method and have been available for decades. However, a single injection delivering such a large amount of testosterone creates unnaturally high spikes in hormone concentrations, which may increase the potential for side effects.

Daily pills, skin patches, and rub-on gels maintain more consistent concentrations of testosterone. The oral form currently available in the United States, however, has limited effectiveness and is toxic to the liver, and patches can irritate the skin. In 2000, Unimed Pharmaceuticals of Marietta, Ga., began marketing Andro-Gel, an androgen preparation absorbed through the skin. The gel's ease of application has expanded the potential market for testosterone therapy.

According to pharmaceutical-industry estimates, testosterone use among men rose almost 30 percent just between 2001 and 2002. It's not clear how much of this increased use is to counter low testosterone from aging rather than illness.

GOSPEL OF YOUTH Research on testosterone therapy has risen along with the upsurge in the treatment's use. Nevertheless, studies of testosterone treatments for aging men have generally been small and of short duration. They've yielded fragmentary and contradictory data.

Among the most ambitious studies have been two separate trials that each lasted 3 years. In one, sponsored by NIH, data on 70 men--beginning with testosterone concentrations below 350 ng/dl--suggest that supplemental testosterone increases bone density of men over age 65 by about 10 percent in the lower spines and at least 2 percent in the hips. J. Lisa Tenover of Emory University in Atlanta and her colleagues reported these findings on March 31 in Phoenix at the meeting of the American Society of Andrology.

Whether this change in bone density would translate into reduced risk of fractures isn't clear, says gerontologist Alvin Matsumoto of the University of Washington in Seattle, who worked on the study.

The other 3-year study followed 108 men who were over 65 years old. Long-term use of testosterone patches provided by the manufacturer increased spinal-bone density by 8 percent among men who had blood-testosterone concentrations of 200 ng/dl at the start of the study. However, treatment had minimal effect on the participants who began with at least 400 ng/dl of natural blood testosterone, says Snyder of the University of Pennsylvania.

In the same study, Snyder and his colleagues also found that regardless of initial testosterone concentration, men on the therapy, on average, lost 3 kilograms of body fat and gained 2 kilograms of muscle mass. The team, however, measured no significant increase in muscle strength.

Such findings suggest that testosterone therapy might someday be useful not only to reverse the signs of aging in men but also to preemptively "delay physical frailty," says geriatrician Anne M. Kenny of the University of Connecticut in Farmington. She found in a 1-year study that testosterone therapy helps men over 65 maintain bone mass at certain fracture-prone points in their thighs. Despite the promising finding, Kenny says, testosterone shouldn't be used preventively until its side effects are better understood.

Matsumoto and David Gruenewald of Veterans Affairs Puget Sound Health Care System in Seattle recently assembled a jigsaw of data from 29 studies, including those of Tenover, Snyder, and Kenny. In the January Journal of the American Geriatrics Society, the Seattle researchers identified improvements in bone, muscle, and body fat as the most likely benefits of testosterone supplementation.

Some of the reports also suggest that testosterone therapy can combat declines in energy, libido and sexual function, cognitive capabilities, and mood, but other studies found no such advantages, says Matsumoto.

For example, some researchers have tried without success to use synthetic testosterone to treat depressed, low-testosterone men who hadn't responded to standard antidepressants. Recent research by Harrison G. Pope Jr. of McLean Hospital in Belmont, Mass., and his colleagues, however, did show a benefit. In the January American Journal of Psychiatry, the researchers report observations on 30-to-65-year-old men with low testosterone and severe depression who continued to receive antidepressants. After 8 weeks, the 10 middle-aged men given testosterone-gel treatments improved significantly more on two of three indexes of mental health than did 9 men given a hormone-free gel.

In the United States alone, hundreds of thousands of depressed men might benefit from testosterone treatments, Pope suggests. Unimed Pharmaceuticals supported his research.

In another Unimed-supported study, Ronald S. Swerdloff of Harbor-UCLA Medical Center in Torrance, Calif., Matsumoto, and their colleagues included 227 men with initial blood-testosterone concentrations below 300 ng/dl. The group reported in 2000 that testosterone-replacement therapy decreased sexual dysfunction and improved mood and muscle strength.

WORTHY OF THE WORRY?

While some aspects of testosterone therapy appear promising, the hormone treatment may carry risks for aging men. The greatest concern among researchers is that supplemental testosterone could exacerbate prostate cancer. "Testosterone can serve as a growth factor for existing prostate cancer," which often goes undiagnosed, says Swerdloff.

Several studies have shown that in some men, testosterone therapy increases prostate size, a condition that can impede urination. The treatment also increases blood concentrations of prostate-specific antigen, or PSA, a marker associated with prostate cancer and prostate enlargement. Studies haven't yet determined whether testosterone contributes to prostate cancer deaths.

Circulatory complications are also among the potential problems of synthetic testosterone. Many men receiving testosterone develop an abnormally high volume of red blood cells, says Matsumoto. This can improve the blood's oxygen-carrying capacity and thereby increase energy, but it can also make blood excessively viscous and lead to dangerous blockages of blood vessels, especially in smokers.

On the other hand, a few studies suggest that aging men with naturally high blood testosterone have a lower-than-average risk of heart attacks from obstructed blood vessels. It's not certain whether that relationship holds among men treated with synthetic testosterone. Overall, says Swerdloff, "most of the data on cardiovascular disease suggest that the treatment might be beneficial rather than harmful."

Other complications of testosterone therapy may include reduced sperm count, enlarged breasts, and nighttime breathing problems that are associated with snoring and heart disease.

To minimize potential side effects from synthetic testosterone, researchers recommend thorough and regular follow-up of men on the therapy. Such monitoring could identify men who don't benefit from the therapy, so their doctors could suspend the testosterone supplements.

NO FORMULA YET Many men experiencing the signs of aging want a concrete recommendation on whether they should get testosterone treatments. "The field is not far enough along to make that recommendation," says Snyder. "Testosterone treatment could cause an epidemic of prostate cancer. Or it might do no such thing."

Swerdloff notes that for decades, some physicians have prescribed testosterone for some of their low-testosterone male patients. "The risk must not be horrendous, or else we wouldn't be debating this after 50 years," he says.

In the long run, only large clinical trials can rigorously demonstrate whether the benefits of testosterone therapy outweigh the risks for many aging men. The studies that last year linked hormone-replacement therapy in menopausal women with increased risks of ovarian cancer, blood clots, strokes, and heart disease followed each of more than 10,000 volunteers for at least 5 years (SN: 7/27/02, p. 61). No trial of testosterone therapy in men has approached such size or duration.

However, Glenn Cunningham of the Houston Veterans Affairs Medical Center, Matsumoto, Snyder, and other U.S. researchers have designed such a trial of testosterone therapy. For 6 years, they would monitor thousands of generally healthy men over the age of 65 who have initial total testosterone concentrations below 350 ng/dl. To detect whether the hormone substantially increases prostate cancer, the study must include at least 6,000 volunteers--half receiving synthetic testosterone. Such a study's cost would exceed $100 million.

The National Institutes of Health has provisionally approved the study but hasn't yet committed funding. It's waiting for recommendations, expected this fall, from an Institute of Medicine (IOM) committee that recently formed to review the data on testosterone therapy and consider what future tests would be most important.

"Out of one large study would come a huge amount of information that would help direct physicians all over the world," says Swerdloff, who recently testified before the IOM committee.

Assuming that research soon moves ahead, it will still be years before data on the long-term safety and efficacy of testosterone therapy become available. For doctors and patients weighing the current uncertainties about treatment, that's a long wait.