Male Hormone Therapy Popular but Untested

GINA KOLATA / NY Times 19aug02

Last month the government halted a major study of hormone replacement therapy in healthy women, saying the treatment under study seemed to do more harm than good. But while that action generated headlines and alarm, few people noticed just a few weeks earlier when the government decided not to go ahead with a different study of hormone replacement — in older men.

The hormone is testosterone, and its use is soaring. Doctors wrote 1.5 million prescriptions for testosterone and drugs like it in 2001, up from 806,000 in 1997. The hormone has been trumpeted as a possible antidote for aging and a way to get a lean and muscular body.

But while the theory is that testosterone may help counter the effects of aging — bone and muscle loss, diminished libido — those effects have never been demonstrated in a large clinical trial. As a result, medical experts say, men taking the drug are participating in a vast, uncontrolled medical experiment.

The case for testosterone replacement rests on well-known observations: as men grow old, their testosterone levels decline; at the same time, they lose muscle and bone, their sex drive dwindles, and they may experience depression or failing memory.

In younger men with medical conditions that rob them of testosterone, such symptoms disappear when they get the drug. So, some doctors ask, why not give it to older men too?

But testosterone can fuel the growth of prostate cancer, and it increases red blood cell production, possibly increasing the risk of clots that can cause heart attacks and strokes. Those risks, with concerns about the cost, prompted the government in late June to scuttle a proposed six-year study of testosterone replacement. In the absence of such a study, answers about testosterone's risks and benefits may be a long time coming.

"The only thing we ever learn from medical history is that we never learn," said Dr. John B. McKinlay of the New England Research Institutes in Watertown, Mass. Dr. McKinlay is the director of the Massachusetts Male Aging Study, a federally supported study that follows more than 1,700 men as they age. "On the slimmest of evidence we introduced estrogen to women," he said, "and the public was whipped up to ask for it."

Referring to the large clinical trial of hormone therapy in women that was halted last month, Dr. McKinlay added: "We ended up, finally, after everyone was getting it, with 45 million prescriptions in the U.S. each year. And suddenly we find that not only does it not do what it is supposed to do but there are these untoward consequences.

"We are about to repeat that debacle. We have the slimmest evidence on testosterone replacement. Five men here, 10 men there. Six rats and a partridge in a pear tree. The physiology is not there but the industry, the industry is there."

Dr. Richard Hodis, director of the National Institute on Aging, also expressed concern. "We recognize this as a potentially important public health issue," Dr. Hodis said. "In understanding the role of testosterone replacement, we are in many ways where we were decades ago with estrogen replacement with women. It is clear that we do not know enough to inform men and their doctors on the potential advantages or risks of hormone replacement."

Nevertheless, some doctors say testosterone deficiency is a real medical condition that needs treatment. "To say it doesn't exist is to put your head in the sand," said Dr. Larry Lipshultz, a professor of urology at Baylor College of Medicine. "The question on the table is, Can we prescribe this medication enthusiastically without having good controlled studies?

"My response is that I am still going to use this drug," he went on. "There is no reason to withhold treatment from patients with symptoms and lab reports of low testosterone levels because someone has not done a placebo-controlled study."

The quest to use so-called testicular extracts as a fountain of youth began with a memorable experiment. On June 1, 1889, a 72-year-old French physiologist, Charles Édouard Brown-Séquard, reported to spellbound doctors at a medical meeting that he had injected himself with a substance extracted from the testicles of dogs and guinea pigs. The injections, he said, "had increased his physical strength and intellectual energy, relieved his constipation and even lengthened the arc of his urine," said Dr. John Hoberman, a historian of science at the University of Texas.

Instantly, a market was born. "All the hucksters jumped on that," Dr. Hoberman said.

By 1918, Dr. Leo L. Stanley, the prison doctor at San Quentin, was transplanting testicles from executed prisoners into healthy ones, asserting that the treatment restored health and potency. Soon, Dr. Stanley was substituting testicles from rams, goats and deer, and contending they were just as effective. Hundreds of patients sought him out. His papers appeared in the prestigious journal Endocrinology.

By 1935, scientists had isolated testosterone itself.

"From that point on, you have the real thing," Dr. Hoberman said. It was the start of a new era, with doctors giving testosterone to women to treat breast cancer, to athletes to increase their muscle mass, to homosexuals to "cure" their sexual orientation, to trauma patients to increase their blood cell production and to healthy men to counteract aging.

On April 15, 1939, The Journal of the American Medical Association published a paper called "The Male Climacteric." The recommended treatment was testosterone therapy. "Testosterone had just come on the market," Dr. Hoberman said. "You tell me if it was an accident that we suddenly had a male menopause."

For decades, the therapy involved painful injections into muscle. A patch was introduced in the mid-1990's, but even it sometimes caused skin irritation, and some men did not like such a visible sign that they were taking testosterone.

That changed in June 2000, when Unimed Pharmaceuticals, a subsidiary of Solvay Group, a Belgian firm, began selling Androgel, a testosterone preparation that a man could simply rub on his skin. "It's like putting on sunblock if you're going to the beach," said Dr. William Crowley, a professor of medicine at Harvard Medical School.

The Food and Drug Administration approved the gel for the treatment of hypogonadism, or very low levels of testosterone, a condition that can arise from genetic disorders, chemotherapy, radiation therapy or tumors. But once a drug is on the market, doctors can prescribe it as they please. Overnight, there was a new demand for testosterone.

Dr. McKinlay called it "medicalizing normal aging." The analogy with menopause is false, he said, because men do not menstruate — they "don't have menses to pause."

At menopause, levels of estrogen drop precipitously. Healthy men, in contrast, have a slow, steady decline in testosterone, about one-half of 1 percent a year, starting about age 30. Testosterone levels are 10 to 15 percent lower in men with diabetes, heart disease, high blood pressure and obesity, among other conditions, he said.

In young men with low testosterone levels, the problem is clear. They lose muscle and gain fat. They also lose bone, have decreased stamina, are less able to maintain an erection and lose mental sharpness. Testosterone reverses these symptoms.

The effect on older men is less clear. In some studies, it increased bone density and muscle tissue. But Dr. Alvin Matsumoto a geriatrics researcher at the University of Washington and the Veterans Affairs Puget Sound Health Care System, said the studies were too small and too brief to address the treatment's potential risks — prostate cancer, heart attacks and strokes.

That, said Dr. Matsumoto, was a real problem. "The major concern for everyone who is even remotely considering treating older individuals is prostate cancer and heart disease," he said.

About three years ago, the Department of Veterans Affairs and the National Institute on Aging were inviting researchers to submit proposals to study testosterone replacement in aging men with low levels of the hormone.

Dr. Matsumoto and Dr. Glenn Cunningham of Baylor College of Medicine and the Houston V.A. Medical Center proposed a large study to determine the drug's risks and benefits: a six-year clinical trial with 6,000 men at 40 medical centers. It would cost about $110 million.

But in June, after extensive discussions among the Department of Veterans Affairs and the National Institutes of Health, a decision was made not to go ahead. The unanswered question was whether or how a clinical trial could be designed that would protect the study's subjects from the drug's potential risks and provide definitive data on its potential benefits.

In an interview last week, Dr. Andrew von Eschenbach, the director of the National Cancer Institute, said he did not favor the proposed study because he was concerned that testosterone could spur the growth of prostate cancer among some men in the study.

"I am not disagreeing that there are men out there who would desperately like to take testosterone," Dr. von Eschenbach said. But he said more research was needed to make sure any drug formula tested in a clinical trial would "minimize the likelihood of a deleterious effect."

Dr. Cunningham and Dr. Matsumoto got the news on June 27 in a conference call with administrators from the National Institutes of Health and the V.A. Their proposed clinical trial, they learned, would not take place. "We were all upset," Dr. Matsumoto said. The trial, he said, "is essentially dead at this point."

Dr. Hodis of the National Institute on Aging said he was determined to keep looking for a way to design a safe trial and was planning a major conference to discuss the matter.

In the absence of a full clinical trial, patients and doctors "are left in the lurch," said Dr. William Bremner, the chairman of the department of medicine at the University of Washington. Dr. Bremner says he continues to prescribe the drug but with a caveat: "I can't sit here and tell you that it will decrease your risk of fractures. And I can't tell you it won't increase your risk of prostate cancer."

Doubts Prompt Reviews of Hormone Therapy

GINA KOLATA / NY Times 15aug02

Responding to growing doubts about the safety and value of hormone replacement therapy in women after menopause, two federal agencies are reviewing what is known about the drugs and what women and their doctors should be told about them.

The National Institutes of Health said this week that it would hold a public meeting on Oct. 23 and 24 in Bethesda, Md., to discuss questions about the therapy. The Food and Drug Administration is reviewing the labeling of hormones.

The goal of the October meeting, said Dr. Vivian Pinn, director of the institutes' Office of Women's Health, is to address confusion in the wake of a federal study last month that found increased health risks from one hormone combination taken by millions of women. Dr. Pinn said participants would also discuss whether recent findings from that study, the Women's Health Initiative, could be generalized to similar products.

Researchers, doctors and the public will be invited, she said, along with representatives from drug companies, professional groups and federal agencies.

The meeting was announced discreetly on Tuesday on the Web site of the Food and Drug Administration (www.fda.gov/cder/drug/safety/WHI_statement.htm), tucked into the end of a statement on the need to reassess the risks and benefits of hormone therapy. Yesterday, after The Washington Post published an article about the meeting, the health institutes put a notice on its Web site (www4.od.nih.gov/orwh) saying the meeting would take place but providing no details.

Increased concerns about hormone replacement therapy and the labeling of the drugs arose in July after the health institutes abruptly halted a large clinical trial of Prempro, a combination of estrogen and progestin made by Wyeth. Women taking the drug had slightly more cases of breast cancer, heart attacks and strokes than those taking a placebo, and those risks were not counterbalanced by the drug's benefits, a slight decrease in the incidence of hip fractures and colon cancer.

Another arm of the trial, involving women taking estrogen alone, is continuing because the evidence shows neither an overwhelming risk nor an overwhelming benefit. Women who have had hysterectomies generally take estrogen without progestin. For others, taking estrogen alone can lead to uterine cancer.

Prempro is approved for the prevention of osteoporosis and for the relief of symptoms of menopause, like hot flashes, but doctors had hoped it might also protect against heart disease and other diseases of aging, including Alzheimer's. Many women were advised to start taking Prempro at menopause and to continue for the rest of their lives.

But Prempro is not the only hormone replacement on the market, leaving many doctors and women with questions about whether other drugs, which are slightly different formulations, have similar risks. There are also questions about who should take Prempro and for how long.

Prempro's label was written on the basis of older studies that did not provide the sort of precise information as the new study. Those studies did indicate possible risks of heart attacks, strokes and breast cancer, however, and that is included on the drug's label.

Now, the food and drug agency is looking at the new data.

"We are going to conduct a review of the data from the Women's Health Initiative study and evaluate the product and the product labeling in light of those data," said Susan Cruzan, an agency spokeswoman.

Ms. Cruzan said the agency would also consider whether there should be changes in labeling for formulations of the hormones made by other companies. But she added that the work had just begun.

"Until we have more details, there's not a whole lot we can say," Ms. Cruzan said.

Dr. Bruce Burlington, the head of regulatory affairs at Wyeth, said the company was already planning to change Prempro's label. The company began meeting with the drug agency officials as soon as the results from the Women's Health Initiative were announced.

"We told them we needed to get warnings out and solid information out," Dr. Burlington said.

In addition to changing its label to reflect the more detailed information provided by the Women's Health Initiative study, he said, Wyeth would send letters to about half a million doctors informing them of the study's findings.

Dr. Burlington said that Wyeth expected to participate in the health institutes' meeting in October. But he added, "We don't have an agenda and we don't have an invitation as yet."