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Concerns
rise as more men use hormone therapy
By
Sally Lehrman, The Los Angeles Times
November 3, 2003
Testosterone
replacement has become popular as a way to restore vigor, but experts
worry about long-term risks.
Many men, as they move into
middle age, yearn for the same muscular strength, sexual energy and sense
of well-being they had in their youth.
That's why millions of American males are asking their doctors for
testosterone replacement therapy, or TRT, to treat a collection of
symptoms that some doctors and drug companies have dubbed andropause, or
male menopause.
The popularity of TRT is creating concern among scientists, who can't
agree on whether andropause is a real phenomenon or not. Some believe that
the complaints of older men, such as decreased libido, depression and
fatigue, are more likely explained by poor habits in diet, sleep and
exercise.
Even as the debate continues, many family physicians and specialists are
prescribing the drug.
U.S.
sales of testosterone replacement drugs have
jumped more than fourfold in the last three years, to an estimated $425
million in 2003, according to Wells Fargo Securities. And industry experts
predict that the market will continue to climb, perhaps by more than a
third, in 2004.
Many men's health specialists, however, worry that testosterone
replacement may offer little benefit and may lead to more severe medical
problems in the future. Their concerns are heightened by the experience of
millions of women, who for years took hormone replacement therapy, or HRT,
in the belief that it would protect against age-related disease. Recent
studies have shown that HRT actually increases women's risk of heart
disease and breast cancer, and many doctors no longer advise it.
A report in 2000 by the American Assn. of Clinical Endocrinologists found
that nine out of 10 endocrinologists surveyed were worried about possible
misuse of TRT. Doctors interviewed for this story said they were
especially concerned by evidence suggesting that testosterone might
stimulate prostate cancer and raise the risk of heart disease and strokes.
Dr. Shalender Bhasin, an endocrinologist at the Charles R. Drew University
of Medicine and Science in
Los Angeles
, believes it is premature for doctors to
recommend TRT to older men reporting age-related symptoms, even if their
testosterone levels are low.
Bhasin is one of four specialists who proposed a major government study on
testosterone's risks and benefits three years ago. In 2000, hormone sales
soared after the introduction of Unimed Pharmaceuticals' Androgel product,
a testosterone gel that is rubbed on the skin. "It occurred to me
this was a big tsunami … not a trivial event," Bhasin said.
A clinical trial to assess the risks and benefits of TRT was initially
endorsed by a National Institutes of Health panel, Bhasin said, but
officials decided to postpone the project until a group of experts could
further study the issue.
The NIH asked the Institute of Medicine, which advises the government and
nonprofits on health policy issues, to create a task force to review
existing data about testosterone replacement in men 65 and older and
either recommend a plan for one or more clinical trials or suggest other
options that might not include a clinical study. "One of the concerns
was the risk for prostate cancer,'' said Evan Hadley, a geriatrics expert
at the National Institute on Aging. The
Institute
of
Medicine
is scheduled to release its report next week.
Physicians sometimes recommend testosterone supplementation when a man's
hormone level falls below 350 nanograms per deciliter, or the lower range
of normal, although they don't always agree on the level at which
treatment is needed. For many years, men had to go to a doctor's office to
get regular shots. Then a skin patch became available, but it often caused
skin irritation. Androgel, which can be rubbed on the skin each day, went
on the market in February 2000. The Food and Drug Administration approved
another gel, Testi, in October 2002. And, in June, the FDA approved a
gum-like substance that can be pressed inside one's cheek to release
testosterone all day.
While some doctors believe it is likely that the benefits of TRT outweigh
the risks, others are concerned that thousands of American men already
have embarked on risky experiments reminiscent of the HRT experience with
women. Six million American women took estrogen and progestin on the
advice of doctors who were convinced by small- and medium-size studies
that the treatment could protect hearts, improve bone density and sharpen
thinking. But in July 2002, investigators suddenly halted a major clinical
trial of HRT, the Women's Health Initiative, because of an increased risk
of heart disease, strokes and breast cancer. Since then, the evidence that
HRT could do anything more than ease menopausal symptoms has steadily
unraveled.
"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."
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