Healthy Skepticism Library item: 6361

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Publication type: news

Parker-pope T.
A Safer Prescription for Menopause?
The Wall Street Journal 2006 Oct 21
http://online.wsj.com/article/SB116077063606692229.html

Full text:

A Safer Prescription for Menopause?
Scared away from hormones, millions of women are turning to other drugs to
cope with hot flashes and other symptoms. But they may be taking on a whole
new set of risks.
By TARA PARKER-POPE
October 21, 2006; Page R1
Wall Street Journal

After a major government study four years ago raised questions about the
safety of hormone drugs, many women stopped taking the pills.

But that doesn’t mean they stopped taking drugs.

Today, women are using a litany of drug regimens to cope with many symptoms
of menopause that in the past were treated by hormones alone.
Antidepressants are prescribed to calm hot flashes and mood changes. Bone
drugs are offered to prevent osteoporosis. Sleep aids help with the restless
nights that often afflict middle-aged women. Prescription anti-inflammatory
pills help ease the aches and pains common in menopause.

Now, with the menopausal medicine cabinet overflowing with more drugs than
ever before, many doctors and women’s health advocates are starting to
worry. At a time when we finally know more than ever about the full range of
risks and benefits of hormone drugs, women instead are gobbling down a
different set of pills backed by very little science and long-term safety
data. After years of fighting for more research into the real risks and
benefits of menopause hormones, many doctors, researchers and women’s groups
now wonder whether women are really any better off. Has the shift away from
hormones made women safer, or has it just subjected them to a whole new set
of drug risks?

“It’s horrible what they’re trying to give to women now,” says Barbara
Seaman, who in 1975 helped found the National Women’s Health Network, a
group that has battled for more research on women’s health issues, including
the risks and benefits of menopause hormones.

RISK REASSESSMENT

The Debate on Compounded Hormones7Ms. Seaman remembers sitting at a
government health conference last year and listening to doctors describe the
various drugs used now to treat menopause. She says the shift from hormones
to other drug treatments reminded her of an old folk song where a young man
traded his first wife for an abusive second wife.

“That’s how I feel now,” says Ms. Seaman. “Give me my old wife back.”

The new prescription for menopause was spurred by the Women’s Health
Initiative, a study of more than 27,000 women who used menopause hormones or
a placebo. In July 2002, the first part of the hormone study was stopped
because women using estrogen and progestin appeared to be at higher risk for
heart attacks and breast cancer. In the years since the WHI results were
first announced, a closer look at the study data shows that it was primarily
older women who started taking the hormones long past menopause who had
health problems from hormones. Younger women who began taking the drugs at
the time of menopause appeared to have far fewer risks, and in some cases
hormones appeared to protect women from heart problems and other health
worries, though the data aren’t conclusive.

But that hasn’t stopped women from abandoning hormones in droves. Sales of
menopause hormones dropped 33% from 2001 to an estimated $1.9 billion last
year. And the decline hasn’t stopped. Sales of estrogen and progestin
combination drugs dropped 8% in the first six months of this year from the
year-earlier period, and estrogen sales fell 4%, according to IMS Health, a
pharmaceutical information and consulting company in Plymouth Meeting, Pa.

THROUGH THE YEARS

Selected developments in the history of drug treatments for menopause 1898
Berlin doctors feed fresh cow ovaries to a woman for hot flashes after
ovarian surgery
1929 Scientists isolate estrogen as a compound
1938 The first synthetic estrogen, diethylstilbestrol, or DES, is developed
1942 FDA approves Premarin, an estrogen drug made from the urine of pregnant
mares
1966 Estrogen use surges after book promises women they can stay “Feminine
Forever”
1968 Scientists report bisphosphonates inhibit bone resorption
1975 New England Journal of Medicine studies link estrogen with endometrial
cancer
1980s Doctors start combining progestin with estrogen to lower risk for
endometrial cancer
1987 Prozac, the first serotonin-altering antidepressant, is approved by the
FDA
1995 FDA approves Fosamax for treatment of osteoporosis in women.
2002 National Institutes of Health halts the Women’s Health Initiative,
linking hormones with higher risk for heart attack and breast cancer
2003 JAMA study shows Paxil, a serotonin-altering antidepressant, provides
some relief for hot flashes
2005 NIH “State of the Science” conference lists antidepressants and
bisphosphonates as options for menopause treatment
Source: WSJ reportingTreating Hot Flashes

One of the biggest shifts in menopause treatment in recent years has been
the prescribing of antidepressant drugs to treat hot flashes. The drugs
aren’t approved by the Food and Drug Administration as a hot-flash remedy,
but doctors now prescribe them “off label” for the purpose.

Popular antidepressants act by increasing levels of a brain chemical called
serotonin. While the drugs are effective against depression, nobody really
knows how or why altering a woman’s brain chemistry might work to stem hot
flashes. It may be that adjusting a woman’s serotonin levels affects the
part of her brain that controls body temperature. Another theory is that
serotonin influences levels of a woman’s natural estrogen. Hot flashes are
triggered by fluctuating levels of estrogen.

Studies show that antidepressants do appear to curb hot flashes, but not as
well as estrogen. And while the benefits of antidepressants in treating hot
flashes appear to be small, some of the side effects may make women feel
worse. In May, the Journal of the American Medical Association reported that
there have been only six small studies of serotonin-altering antidepressants
for the treatment of hot flashes. However, only two of them — trials of
Wyeth’s Effexor and GlaxoSmithKline PLC’s Paxil — met scientific standards
for “good quality” studies, the JAMA review said. That means most of what we
know about antidepressants and hot flashes comes from just 386 women who
took the drugs for six weeks or less.

The studies looked at whether antidepressants could reduce the number of hot
flashes a woman has each day. A woman with moderate to severe menopause
symptoms has at least seven or eight hot flashes a day, and about one-third
of women who suffer from hot flashes have more than 10 a day. But in the
Paxil trial, the antidepressants eliminated only about one more hot flash a
day than women on placebo. By comparison, estrogen reduces the frequency of
hot flashes by 77%, or about 2.5 to three hot flashes daily compared with
placebo, according to the JAMA report.

The Effexor trial looked at three different doses of the drug. At the lowest
dose, the drug reduced hot flashes by only 37%, compared with 27% for
placebo. When the dose jumped to 75 milligrams and 150 mg, the drug group
reported about 60% fewer hot flashes. But there was a downside. The women
who were taking the two largest doses also experienced the most side
effects, including loss of appetite, dry mouth, nausea and constipation.

A Vulnerable Time

Antidepressants’ side effects worry many doctors, in part because menopausal
women may be particularly vulnerable to some of them. One area of concern is
possible sexual problems, including loss of libido — problems to which
women may be susceptible anyway during the hormonal chaos of menopause.

Rutgers University anthropologist Helen Fisher has conducted brain-scan
studies that suggest antidepressants also blunt important emotions related
to love, romance and long-term attachment. They may do this by interfering
with dopamine, a brain chemical connected with emotion and feelings of
pleasure. An April 2005 mouse study in the medical journal Neuron showed
that antidepressants not only affect serotonin levels in the brain, but also
“hijack” dopamine signaling as well. That means brain transmitters that are
supposed to carry dopamine around the brain appear to end up carrying
serotonin.

The fact that antidepressants blunt emotions and interfere with sex is
particularly concerning for menopausal women, who may be especially
vulnerable to relationship problems as a result of the physiological changes
of menopause as well as other midlife issues, like kids leaving for college
or a husband’s approaching retirement.

“You are taking a chance of jeopardizing your ability to fall in love and
stay in love and feel attachment to the people around you when you take
antidepressants,” Dr. Fisher says. “And with menopause we usually aren’t
talking about giving these drugs to women who are depressed. We are talking
about normal women who enjoy caring about their families, enjoy caring about
their work, home and future plans. So you’re taking a normal brain and
blunting all these precious emotions that are the joy of living. Do you
really want to give all that up to treat hot flashes?”

Beyond the known side effects from antidepressants, nobody understands the
long-term impact of using them in women with normal brain chemistry who
aren’t depressed. It is known that taking antidepressants results in certain
changes in brain receptors. That’s why people who try to stop the
medications can sometimes develop severe withdrawal symptoms until the brain
receptors return to normal. Doctors believe antidepressants are potentially
life-saving drugs for people coping with moderate to severe depression, so
the risks and side effects likely are worth it. But they question the use of
antidepressants in menopausal women who don’t suffer from depression.

“People should not be taking these drugs for nonpsychiatric indications
unless there are studies to back up their effectiveness and safety,” says
Grant Mitchell, chief of psychiatry at Northern Westchester Hospital in
Mount Kisco, N.Y. “If these were harmless drugs with no side effects, we
might look at it differently. But they’re not — they are mind-altering
medications.”

A spokesman for GlaxoSmithKline, maker of Paxil, says that the company isn’t
seeking FDA approval to use the drug as a hot-flash treatment and that the
decision on whether to use Paxil for that purpose is one made between
doctors and patients. The company emphasizes that Paxil has a long track
record for safety. “Paxil’s been used safely and effectively in millions of
patients since it was first approved,” the spokesman said.

In July, Wyeth, maker of Effexor, filed for FDA approval of another type of
serotonin drug called Pristiq, to be used in the treatment of hot flashes.
The company says in its early studies, the incidence of decreased libido
wasn’t any different with Pristiq than with placebo. The Pristiq studies
also are based on healthy women who aren’t depressed.

Another concern among many doctors is that a depressed person using
antidepressants should be monitored closely because of a potentially higher
risk for suicide in the early months of antidepressant use. Psychiatrists
worry that if a gynecologist or family doctor puts a woman with undiagnosed
depression on the drugs to treat hot flashes, she won’t get the follow-up
attention she needs.

An unanswered question is whether giving antidepressants to a healthy brain
could trigger mental-health problems later on. A Wyeth spokeswoman, says
there’s no evidence of harmful brain changes from any of the serotonin
drugs, which have been safely used for decades in millions of patients.
However, doctors say more research is needed. For instance, a small
percentage of patients, such as those with a family history of bipolar
disorder or manic personality traits, may be at risk of developing severe
manic symptoms after starting antidepressants.

“Before you cavalierly place women on antidepressants for hot flashes, you
have to give them a full psychiatric evaluation,” says Shari Lusskin,
director of reproductive psychiatry at the New York University Medical
Center. “Does exposure to an antidepressant in a nondepressed patient lead
to significant changes in brain chemistry that could have a negative effect
or does it increase vulnerability to a mood disorder? I’d say we don’t
know.”

Building Bones

Another major shift in recent years has been in the treatment of
osteoporosis. The Women’s Health Initiative found that menopause hormones
boost bone density and dramatically reduce a woman’s risk for fracture. But
because of the other health worries, many women have switched to bone drugs
called bisphosphonates, which are sold under various brand names including
Merck & Co.‘s Fosamax.

Bones are in a constant state of remodeling — dissolving microscopic bits
of old bone, a process called resorption, and rebuilding new bone. After
about the age of 30, a woman’s bones start to dissolve faster than they can
be rebuilt, which is why some women eventually develop thin, brittle bones
that are easily broken. The pace of bone loss increases dramatically after
menopause.

The bisphosphonates work by slowing the bone remodeling process. Studies
show that bisphosphonates do increase a woman’s bone density and lower her
risk for bone fractures. But what’s not clear are the long-term effects of
using a drug that interrupts a key phase of the bone remodeling and renewal
cycle.

Even though short-term suppression of the dissolving process seems to
strengthen bone, questions remain about whether long-term use of
bisphosphonates has the potential to weaken bones. The worry is that every
day, tiny microscopic cracks form in bone as a result of normal wear and
tear. But with part of the bone remodeling process suppressed, those cracks
may not be repaired. Over time, the worry is that many more cracks could
accumulate, leading to a long-term weakening of the bone. A 2001 study in
the medical journal Bone studied the effect of high doses of bisphosphonates
on the bones of beagles and found an accumulation of microdamage. However,
researchers haven’t yet identified the same pattern in human subjects. Merck
notes that the beagle studies showed that the beagle bones weren’t any
weaker as a result of the microcrack accumulation.

Susan M. Ott, associate professor of medicine at the University of
Washington in Seattle, says the bone drugs are an important treatment for
older women suffering from severe osteoporosis. Her concern is that many
women in their 40s and 50s — who in the past would have been prescribed
estrogen — are now being given bisphosphonates to prevent osteoporosis.

“It makes me feel a little uneasy,” says Dr. Ott, who last year wrote an
editorial in the Journal of Clinical Endocrinology & Metabolism raising
concerns about the long-term risks of the drugs. “We have 45- and
50-year-old women who don’t really have anything wrong who are on these
bisphosphonates that they are presumably going to take until they are 70?
It’s kind of scary because we don’t know what happens if you take them that
long.”

But other doctors say the evidence so far suggests the drugs are safe. Ethyl
Siris, director of the osteoporosis center at Columbia University Medical
Center in New York, notes that the drugs don’t suppress bone resorption
entirely — they simply slow the rate down to that of a young adult woman.
“There have been no alarm signals suggesting long-term safety issues in
bone,” says Dr. Siris, who says she has consulted with companies that sell
bone drugs.

Arthur Santora, executive director of clinical research and endocrinology
for Merck, says the company has 10 years of clinical-trial data looking at
bone density and turnover, and there’s no evidence that the drug’s effect on
bone turnover changes over time. “I think we can be pretty sure that there
are no apparent problems in safety and no theoretical concerns about
decreasing turnover,” says Dr. Santoro. “There is nothing that would predict
a problem beyond 10 years.”

The known side effects of bisphosphonates can include esophageal problems,
heartburn and ulcers. In rare cases a flulike illness might result. Another
rare problem is osteonecrosis of the jaw, a disease in which a patient’s
jawbone rots and dies.

Merck notes that in 10 years of study of more than 17,000 patients, there
haven’t been reports of osteonecrosis of the jaw in its own clinical trials.
The majority of patients suffering from the jaw complication are cancer
patients taking a potent intravenous form of the drug to stop cancer cells
from dissolving bone. However, a small number of other cases from noncancer
patients using oral bisphosphonates also have been reported. Doctors say
these patients typically have used the drugs for seven or eight years. It’s
simply not clear who is at risk of this complication, but some doctors
suggest that patients taking drugs like Fosamax avoid major dental or oral
surgery if they can. Such surgery may be the trigger for problems, because
the jaw bones are slower to heal and complications develop.

Sleep and Pain

Menopausal women are also candidates for a number of other drugs as
alternatives to estrogen. Sleep drugs, such as Sanofi Aventis’s Ambien and
Sepracor Inc.‘s Lunesta, are options for women suffering from sleep
disturbances related to menopause. While the drugs are considered safe, the
concern is that the sleep problems associated with menopause can last for
years. “The question is, how long do you treat them for?” says Dr. Lusskin
from NYU. “We don’t want everybody addicted to sleeping pills. People become
dependent on these drugs.”

Some menopausal women who have stopped taking hormones also have noticed an
increase in body aches, stiffness and pain. A Swedish study of nearly 4,000
women estimated the incidence of body pain to be between 50% and 70% among
menopausal women, depending on their age. It’s a little-known fact that
estrogen appears to provide relief to body pain. In the WHI, treatment with
estrogen and progestin resulted in a 25% improvement in general aches and
pains and a 43% reduction in joint pain and stiffness.

But now women with aches are more likely to be given prescription
anti-inflammatory drugs such as Celebrex, or over-the-counter drugs like
ibuprofen or naproxen, the pain reliever in Aleve. The FDA has added strong
warning labels to these and other painkillers, after some studies linked
pain drugs with an increased risk for heart attack, stroke and other
cardiovascular problems. The concerns prompted the withdrawal of Merck’s
pain drug Vioxx from the market.

Dr. Lusskin notes that her main concern about the wide range of drugs being
used during menopause is that many women have the impression that they are
safer than taking hormones. “People are saying, ‘If it’s hormones we won’t
take it, but I’ll take anything else you’ll hand me,’ “ says Dr. Lusskin.
“But there’s no medical treatment that has only benefits and no risks.
Patients have to be educated consumers and think carefully about what drugs
they’re going to take.”

—Ms. Parker-Pope, who writes The Wall Street Journal’s weekly Health
Journal column8, is the author of “The Hormone Decision,” to be published in
January by Rodale.

Write to Tara Parker-Pope at tara.parker-pope@wsj.com9

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