Testosterone Replacement Therapy: Is It Safe?

Researchers Worry That Testosterone Use Is Way Ahead of Evidence

From the WebMD Archives

Feb. 23, 2004 (Orlando) -- Just as American women once clamored for estrogen as a panacea for aging -- hoping to keep their hearts young and their minds sharp -- middle-aged men are looking at testosterone as a possible fountain of youth, sending testosterone sales through the roof and medical experts scrambling to avoid an estrogen-like disaster.

Douglas B. Kamerow, MD, MPH, chief scientist at RTI International in Washington, D.C., says testosterone is being marketed as a cure for "middle-aged blues, fatigue, or declining sexual desire," and men are clearly receptive to the sales pitch: Prescriptions for testosterone increased "170% from 1999 to 2002, and sales increased from $18 million in 1988 to $400 million in 2003."

The growth market in testosterone caught the attention of the National Institutes of Health, which is concerned about the potential for another "hormone disaster," Kamerow tells WebMD. He presented his testosterone study at the annual meeting of the American College of Preventive Medicine (ACPM).

Women used to be routinely put on hormone replacement therapy at menopause because observational studies suggested that menopausal women on HRT had lower rates of heart disease and stroke -- diseases that typically increase in postmenopausal women. Tens of thousands of women were prescribed hormone therapy without careful clinical studies to prove the therapy worked. When the NIH studied therapy with the hormones estrogen and progestin in healthy menopausal women, it discovered that the therapy could increase the risk for stroke, blood clots, and breast cancer without offering any protection for the heart. The results were so compelling that the NIH actually halted the study early.

The FDA says testosterone replacement should only be used to treat a condition called male hypogonadism, which means that the testes aren't producing sufficient amounts of testosterone. Kamerow says there are about 4 million to 5 million American men with this condition but only about 5% are receiving testosterone replacement therapy. "So clearly the bulk of prescriptions are for off-label use," he says.

"The concern is that we could have the same situation with testosterone, only the problem would be prostate cancer," Kamerow says. Testosterone increases levels of prostate specific antigen, or PSA. Increased levels of PSA are a marker for prostate cancer, although some PSA increases are caused by a noncancerous enlargement of the prostate, which is called benign prostatic hyperplasia.

The problem, says Kamerow, is that men -- especially middle-aged men -- are eager to try the hormone, which is hyped as a cure-all for everything from lack of strength to lack of libido. Advertising also suggests testosterone can cure the blues, says Kamerow. But when the Institute of Medicine asked him to find some evidence of this, he came up empty handed.

Kamerow and colleagues identified 48 publications describing the results of 39 testosterone studies, most of which were "poorly designed, with small sample size -- ranging from 6 to 108 men -- and brief duration. Only 31 of the trials were placebo-controlled," he says. Perhaps even more important: All the studies were in men who had testosterone injections. There are no studies of the newer -- and best-selling -- testosterone products: patches and gels. -->

He says the studies offered "no clear evidence" of benefit from testosterone for the treatment of depression although some studies reported improvement in "quality of life and functional status." There was evidence for increased muscle mass but not for improved bone density. There was a trend toward improvement in spatial memory. And only men with a confirmed diagnosis of hypogonadism reported improved sexual desire.

In terms of risk, Kamerow says prostate specific antigen "will go up. But we don't really know if that is significant." Additionally, some studies found reported slight increases in LDL cholesterol (bad cholesterol).

In November 2003, the Institute of Medicine recommended that the NIH study testosterone replacement in small, placebo-controlled studies of men aged 65 or older.

Kamerow agrees studies are needed, but he says it would be more useful to include younger men in the studies. He notes that his research indicates that the bulk of testosterone prescriptions are "written for men aged 46 to 65."

Another difficulty, he says, will be identifying men with "low" testosterone. Women stop producing sex hormones at menopause, but men simply slow down with age. "Testosterone levels are actually highest at about age 17 and then begin to decline at a rate of about 1.2% a year," he says. Currently, a testosterone level of 300-1,000 ng/dL is considered normal.

Robert G. Harmon, MD, MPH, president of ACPM, tells WebMD that the overuse of testosterone is a concern for his organization. He advises against off-label use of testosterone replacement until "we know the true risks and benefits."

Harmon, who wasn't involved in Kamerow's study, says, "This is just another search for the fountain of youth, similar to the use of steroids or growth hormones. It is alarming."

He says that "exercise is a much better 'fountain of youth' than any pill or injection we could offer."

But while Kamerow says there is no evidence that backs up many of the testosterone marketing claims, he says he would prescribe it for men who "want to try it as a cure for the middle-aged blues." That said, he adds that prescribing testosterone would mean that he would closely follow the man with PSA levels as frequent as every six months.

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SOURCES: American College of Preventive Medicine 2004 annual meeting. Douglas Kamerow, MD, MPH, Washington, D.C. Robert G.Harmon, MD, MPH, Washington, D.C.
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