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.
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. Ms. 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.
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.
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."
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.
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."
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