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Flashes: Exploring the Mystery of Women's Thermal ChaosBy DENISE GRADY
There comes a time in many a woman's life when she must cast off her garments, fling open windows, toss back blankets and ask repeatedly, Is it hot in here? Even her fondest friends and relatives may find it hard not to laugh.
Hot flashes are pretty funny, as long as they are happening to someone else.
Of the many little adventures that accompany menopause, hot flashes are the most common affecting as many as 80 percent of women The rush of heat, the drenching sweat and the telltale flushed face last only a few minutes, but they can recur 10 times a day and several times a night. And the pattern can drag on for years. Is this nature's idea of a joke?
The causes of such thermal chaos are only partly understood. A hot flash is a sudden, intense version of what the body normally does to cool down when it is overheated: blood vessels near the skin dilate to dissipate heat, and the person breaks into a sweat. The tactic works so well that after a hot flash, many women feel chilled.
But why, when a woman is sitting at her desk or driving down Main Street, does her body suddenly think it is overheated? The answer is not clear. One basic fact has been known for decades: hot flashes are linked to declining estrogen levels. In women who have their ovaries removed surgically, the effect can be almost immediate. Some actually begin having hot flashes in the recovery room. And regardless of whether flashes are brought on by surgery or natural menopause, estrogen replacement therapy quickly stops them in most women.
Hot flashes are common in the United States, Australia and Western Europe, but are said to occur less often in Asian women. But no knows whether Asians really have fewer flashes, or just report them less. If they do have fewer, whether the difference is due to diet, genetics or both is not known.
In fundamental ways, hot flashes remain a mystery. They must originate in the brain. Body temperature is regulated there, in a region called the hypothalamus. But no one knows exactly how estrogen, or the lack of it, acts on that region. Nor is it known why one woman sweats through a dozen flashes a day while another, with the same flagging estrogen levels, stays cool. Similarly, doctors do not know why, in most women, the symptoms eventually go away on their own. And if hot flashes have a purpose or a health benefit, scientists have yet to figure out what it might be.
The unanswered questions have become more important recently, as mounting evidence has cast doubt on the safety of hormone replacement, especially for long-term use. Hormones are the most effective treatment for hot flashes, but many doctors and patients have begun to question whether taking them just to relieve symptoms is worth the risks, which include slightly increased odds of heart attack, stroke, breast cancer, blood clots and gallbladder disease. Women want safer alternatives, and although a better understanding of hot flashes may lead to better treatments, so far no great breakthroughs have occurred.
Dr. Robert R. Freedman has been studying hot flashes for about 20 years at Wayne State University in Detroit, where he is a professor of psychiatry and obstetrics and gynecology. The National Institutes of Health has supported his work, he said, but not many other scientists have taken up the cause, and he wishes more would.
"Science gets better with more people working on it," he said.
Before he became interested in hot flashes, Dr. Freedman was trying to find out whether biofeedback could help people with Raynaud's disease, which causes very cold hands and feet. One of his students, whose mother had severe hot flashes from the breast cancer drug tamoxifen, which blocks the action of estrogen, said, "I know you can make cold people warm, but can you take hot women and make them cold?" Dr. Freedman was intrigued.
Most of his studies have been in humans, he said, noting that "rats are a lousy model of menopause." Rats reproduce until they die and do not have menopause. An artificial menopause can be induced with drugs or surgery, but even then it is not clear whether the rats have hot flashes, he said.
"People have measured changes in tail temperature that they assume are flashes, but I don't buy it at all," Dr. Freedman said. Researchers, he added, do not know whether other animals have hot flashes, including female monkeys and apes, though he hopes to study them.
Dr. Freedman and his colleagues study menopausal women, often comparing those who have flashes with those who do not, though, he said, it is hard to find menopausal women who do not have hot flashes.
In the laboratory, the women are hooked up to equipment that measures their skin temperature, sweating and other skin changes that mark the start of a hot flash. In addition, the women swallow radiotelemetry pills, which measure their core body temperature every 30 seconds or so as they travel through the digestive tract. In some experiments the women are given drugs that bring on hot flashes or stop them, and some women stay in the laboratory overnight so the researchers can measure hot flashes during sleep.
Most women who have flashes average six a night, Dr. Freedman said, but, he added, "I saw a woman recently who had 17."
The overnight studies showed something surprising about the sleep problems that many women have after menopause.
"The common thinking is that the hot flashes wake you up and disturb your sleep, and you feel crummy in the morning," Dr. Freedman said. "But we found that half the flashes don't have wake-ups, and half the wake-ups don't have flashes. The insomnia is not necessarily a product of the flashes."
He is conducting more sleep studies to try to decipher the connection.
Dr. Freedman's experiments have found a major difference between menopausal women who have hot flashes and those who do not. Women without flashes have a "neutral" zone of about 0.7 degrees Fahrenheit, and their core body temperatures can rise or fall in that zone without making them shiver or sweat. The upper limit of the zone is the threshold for sweating, and the lower limit the threshold for shivering.
But in women who do suffer from flashes, the zone has shrunk so much that it is almost nonexistent, meaning that even a tiny rise in core temperature will cause a hot flash, and a tiny drop can cause shivering.
But why is the neutral zone compressed to nothing? Dr. Freedman and his colleagues theorize women who suffer from hot flashes, compared with those who do not, have higher brain levels of a hormone called norepinephrine, which can shrink the neutral zone. The norepinephrine changes may be related to dropping levels of estrogen, or to aging, or both, Dr. Freedman said.
In any case, too much norepinephrine seems to play a major role in hot flashes. Studies in animals have shown that increased norepinephrine shrinks the neutral zone, and experiments in people show that a drug called clonidine, which lowers norepinephrine, can expand the zone.
But for most women, clonidine has too many side effects to be a good treatment for hot flashes, Dr. Freedman said, noting that it can cause tiredness, dry mouth and low blood pressure. Some women get relief from antidepressants like Paxil and Effexor that can affect the hypothalamus. But so far, nothing works as well as estrogen.
For women bothered by hot flashes who do not want to use drugs, Dr. Freedman recommends using air-conditioning, wearing light clothing in layers and keeping room temperatures low, because warm environments can definitely bring on hot flashes. Cold drinks can help ward off flashes. In addition, he has done studies showing that the kind of deep breathing techniques taught in yoga classes can reduce the rate of hot flashes by about half. The techniques require training and practice, and he advises patients to take a yoga class to learn them.
He has also tried, unsuccessfully, to get a grant to help a small company make cooling sheets, similar to the ones used in hospitals to treat fever. The cooling sheet would go on the mattress, under a regular sheet, and the woman would lie on top of it.
"You could just stick it on your half of the bed, and you wouldn't freeze your spouse," Dr. Freedman said. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Sorting Through the Confusion Over EstrogenBy JANE E. BRODY
Susan McGee of Bethesda, Md., and Jane Quinn of Brooklyn were not planning to take hormones at menopause. But after many months of sleep disrupted nightly by drenching sweats and changes of bedclothes, they gave in.
Ms. McGee said she became so sleep deprived that she could hardly do her job and feared falling asleep while driving. Ms. Quinn found it increasingly difficult to concentrate on her work, became uncharacteristically irritable and began to think she was losing her mind. The hormones quickly restored their sleep and their sanity.
These two are among millions of American women near, at or beyond menopause who are asking why so much remains unknown about a drug that has been on the market for 60 years, and what they should make of new findings that are surprising and disappointing proponents of hormone replacement therapy, or H.R.T.
Estrogen sold today in myriad forms with and without a companion hormone progesterone was originally marketed to counter the annoying and sometimes disruptive symptoms of menopause.
But in the decades since its initial approval by the Food and Drug Administration in 1942, estrogen had acquired a reputation as an antidote to many of the illnesses and afflictions of aging. Scores of observational and case studies supported this view, and drug makers and their advertising agencies embraced it with enthusiasm. By 2000, the therapy had become a $2.75 billion business.
The benefits of temporary use of estrogen to weather disruptive menopausal symptoms have not been challenged. Nor is there concern about vaginal applications of estrogen to counter the atrophy that can destroy the joy of lovemaking.
Rather, the focus is on how long a woman can safely stay on hormone replacement that is taken orally or by skin patch and what effects, good or bad, the long-term therapy may have on her health.
Most of the data on the presumed benefits of hormone replacement come from observational studies of women who chose to take it or not. Although in analyzing their findings, researchers tried to account for differences between these groups of women, there is always a chance that factors not considered could have influenced the results, especially since women who choose to use hormones tend to have healthier habits over all and are likely to be followed more closely by their physicians.
To establish facts required a large clinical trial in which women were randomly assigned to take hormones or a look-alike placebo, with neither the women nor their doctors knowing who was on what regimen until the study was completed. Major new findings from such clinical trials have seriously challenged estrogen's image as a preventive of chronic disease, raising doubts about the benefits of lifelong hormone replacement.
First, the Heart and Estrogen/Progestin Replacement Study, known as HERS, found that the hormone combination did not prevent heart attacks and cardiac deaths in women who already had heart disease. Initially, in fact, women who took the combination actually had slightly more heart problems than women given dummy pills.
In July, the Women's Health Initiative, or W.H.I., abruptly ended a study of the same drug combination, marketed as Prempro, in younger and initially healthy postmenopausal women. This well-designed clinical trial found small but statistically significant increases in health risks including breast cancer, heart attacks, strokes and blood clots that outweighed the benefits, a lower risk of hip fractures and colon cancer.
"W.H.I. changed the way we think about estrogen; this is not a drug to be used for prevention," said Dr. Bruce Ettinger, a longtime researcher on hormone replacement at the Kaiser Permanente Medical Care Program in Oakland, Calif. "Giving the drug to a lot of healthy women is not the right thing to do."
He and others suggest that women taking it to relieve severe menopausal symptoms should use the lowest possible dose and taper off as soon as possible.
These findings are of grave concern to the more than 40 million women in the United States at menopause or beyond it and 20 million others who will reach it in the next decade.
Hormone replacement therapy has soared in popularity in recent decades after observational studies reported that it might greatly reduce the risk of heart disease and osteoporosis and might even protect against Alzheimer's disease and the mental decline associated with aging.
When added to the widely held belief that estrogen could prevent wrinkles, preserve sexual vigor and maintain a youthful distribution of body fat, the claims made the therapy hard to resist for women willing to take a pill every day or apply a skin patch every week.
Now, as the more precise studies begin producing data, claims for estrogen are being scaled back to the only two approved indications for treatment: preservation of bone density and the original reason for marketing this hormone, to relieve the hot flashes, night sweats and vaginal dryness and atrophy that disturb about half of American women to varying degrees when ovarian function slows to a near halt.
These, in fact, are the only benefits manufacturers are permitted to claim in advertising their estrogen products.
If the findings concerned only the therapy's benefits, the 20 million women already on hormone replacement and the 1.4 million who reach menopause each year would face a relatively simple choice. But the recent findings that the therapy may bring risks vastly complicate things for women who must now decide whether these risks outweigh benefits already known and those yet to be established.
The pioneering Women's Health Initiative was not begun until 1993, amid rising concern about the relative lack of studies of women's health problems and pressure from Dr. Bernadine Healy, who was then the director of the National Institutes of Health. Today many women wonder why this kind of research did not take place much earlier.
"These studies are incredibly expensive," noted Dr. Wulf Utian, executive director of the North American Menopause Society. "The government-sponsored W.H.I. study cost $600 million so far. Why would drug companies go to such an expense when their products were already on the market and being widely used for reasons not even listed on the label?"
Dr. Isaac Schiff, director of obstetrics and gynecology at the Massachusetts General Hospital in Boston, said, "Drug companies would not underwrite studies that might find something wrong with their products." Wyeth-Ayerst Laboratories financed the HERS study because it hoped to be able to advertise its drug Prempro as a preventive and treatment for heart disease.
To be sure, the studies completed to date are not the final word on the risks and benefits of hormone replacement. Nor can they be used to determine which, if any, kind or combination of hormones may tip the balance in favor of benefits over risks and for which women.
The American College of Obstetricians and Gynecologists noted those limits in a long advisory to doctors and specified that the Women's Health Initiative findings applied only to the Prempro formulation. But it added, "Caution is warranted for different preparations, and their safety should not be assumed in the absence of conclusive data."
A number of prominent experts have issued similar warnings.
After the HERS findings were announced for women with heart disease, for example, two physicians wrote that doctors should tell women about new doubts over the therapy's benefits and evidence of its risks. The message from Dr. Sally E. McNagny, a former principal health initiative investigator now working in Wellesley, Mass., and Dr. Nanette K. Wenger, a cardiologist at Emory's medical school appeared in a letter to The New England Journal of Medicine.
"We've learned a lesson the hard way," Dr. McNagny said. "Until a medication is studied long term, it should not be prescribed long term for healthy women."
But not every expert, and certainly not every physician, is willing to abandon hormone replacement based on the new studies. "Clinical trials are not the end of the story," said Dr. Roger Lobo, professor of obstetrics and gynecology at Columbia-Presbyterian Medical Center in New York. "There are still big gaps in our knowledge as to which regimens are safer than others. We need to look at all the available data and not discount the observational studies. Women are different, the regimens are different and the times are different."
Even the new studies have their weaknesses. For example, the best-designed new studies involved only one or two forms of hormone replacement, either conjugated equine estrogens alone or a combination of these estrogens and a synthetic progesterone (progestin). Some experts believe that other formulations may yield different results, but they have yet to be tested in large randomized clinical trials, and until they are there is no way to know.
But Dr. Ettinger and some other experts say further studies will be hard to do. Given the hazards found, new studies are unlikely to be approved by review committees. Getting women to enroll and agree to be randomly assigned to take either a hormone or a placebo for many years may also be hard. So women and their physicians are left to review the best available evidence about the various alternatives.
Factored into a woman's decision should be her ability to tolerate menopause, her personal and family health risks and her willingness to adopt other established protective measures like diet and exercise.
As Dr. Utian put it, "We're not paying enough attention to talking about healthy living as a treatment for menopause." He added, "We have to get away from the silver bullet mentality. What's good for one woman is not necessarily good for another."
Possible RisksHEART DISEASE It is the leading killer of American women, and physicians had many good reasons for assuming that estrogen would help protect against it.
Women develop heart disease 10 to 15 years later than men do, and a woman's risk of heart disease does not start rising until after menopause.
Estrogen is known to maintain elasticity of arterial walls, improve blood flow, raise H.D.L. (the good cholesterol) and lower L.D.L. (the bad), reduce levels of the clotting factor fibrinogen and raise levels of clot inhibitors, all of which should help to keep the heart and its blood vessels healthy.
In addition, several long-term observational studies involving tens of thousands of women found that those taking hormone replacement experienced a reduction of as much as 50 percent in their risk of developing heart disease.
Most convincing were the results of the Nurses' Health Study, an observational study involving 121,700 female nurses presumed to be reasonably uniform in health consciousness, who have been followed since 1976. Among the 42,000 who reached menopause, those who chose to take hormones experienced 40 percent fewer "major coronary events," including heart attacks and sudden cardiac death.
But HERS, a clinical trial conducted among 2,763 postmenopausal women (average age 67) who already had heart disease, found that the hormone combination did nothing to prevent future attacks. In fact, for the first year or two, women receiving the hormones had more heart attacks than those on a placebo. For a few years after that, those taking the hormones did better, but the benefit did not last, and after seven years the study showed no overall protection from the drugs.
Perhaps for these older women it was too late for estrogen to be protective. Perhaps it helps only those whose hearts and blood vessels are initially healthy. The Women's Health Initiative study of 27,000 women, nearly all of them healthy at the start, tested this hypothesis using either estrogen alone or the hormone combination marketed as Prempro.
The part of the study involving 16,000 women randomly assigned to take Prempro or a placebo was abruptly halted in July when those on the hormone combination were found to suffer more breast cancers, heart attacks, strokes and blood clots than women on the placebo.
The arm of the health initiative study involving estrogen alone is continuing among 11,000 participants who have had hysterectomies and thus do not need progestin to protect the uterus. For now, the researchers cannot say whether estrogen taken alone prevents heart disease.
As Dr. McNagny put it, "The apparent cardioprotection reported in observational and case-control studies may not be caused by H.R.T. but may instead be a result of fundamental differences between women who choose to take H.R.T. and those who do not."
STROKE Findings on stroke prevention have been contradictory, tempering an initial enthusiasm for estrogen's ability to protect the brain against clots.
Although, for example, a large study of retirees in 1991 showed a 70 percent reduction in the risk of stroke among women who were using estrogen (compared with those who never did), the Nurses' Health Study found no decrease in strokes among hormone users, and the best designed study the Women's Health Initiative showed a small hormone-related increase in strokes.
Again, the presumed protection seen in some observational studies may be related to the kind of woman who chooses hormones, rather than the hormones themselves.
BLOOD CLOTS Hormone therapy can increase a woman's risk of developing clots deep in her leg veins and life-threatening clots that lodge in the lungs. Data from the health initiative indicated that if 10,000 women took Prempro for a year, 18 more would develop blood clots than would have occurred if none took it. This risk appears to be highest in the first year of hormone use and declines greatly thereafter.
Nonetheless, researchers recommend that certain women at increased risk of developing clots should think twice about taking estrogen. They include women who are obese, who smoke, who have high blood pressure or a history of blood clots, as well as those who must remain relatively immobile for a prolonged period. Each of these factors also increases the risk of clots.
CANCER After a study more than a decade ago showed that taking estrogen alone after menopause increased by 14-fold the risk of developing cancer of the uterine lining, the endometrium, women who had not had a hysterectomy were advised to take a natural or synthetic progesterone with estrogen.
But this protective measure, which had never been tested for long-term safety, may have had a more dire adverse effect than the one it prevented.
Based on the Women's Health Initiative, among 10,000 women taking the estrogen-progestin product Prempro for one year, 8 additional cases of invasive breast cancer would be expected to occur, with the risk increasing slightly with each year of use. It was mainly this finding that led to the abrupt halt in the study.
Estrogen has long been known to promote the growth of breast cancer, a fact that has prompted the use of estrogen-blocking drugs like tamoxifen to prevent this disease in high-risk women. But there are several indications that progesterone, which causes breast cells to proliferate, may play an even greater role in fostering breast cancer.
A large study published two years ago in The Journal of the National Cancer Institute indicated that progesterone greatly increased the breast cancer risk associated with estrogen alone. For each five years of hormone therapy, continuous use of a combined product like Prempro increased the risk of breast cancer by 24 percent, whereas those taking estrogen alone had only a 9 percent increase in risk. When the two hormones were used sequentially, the risk was even greater than it was with continuous use.
In a review published last year in The Journal of Midwifery & Women's Health, Mary Ellen Rousseau, a nurse-midwife in Hamden, Conn., concluded that these "results showed strong evidence that adding progestins to replacement regimens substantially increased the small increase in the risk of breast cancer" associated with estrogen alone.
She continued, "If the main purpose for adding progestins is to protect the endometrium from cancer, then this study may well tip the balance because the adverse effect on the breast may outweigh the beneficial effects on the endometrium."
Overall, hormone replacement studies have found that the risk of breast cancer increases by 2.3 percent for each year of hormone use, but that after 10 years of therapy there is about a 30 percent to 40 percent increase in breast cancer cases.
Since most studies involved Prempro or a similar drug, it is not known whether a comparable risk would accompany other hormone products. After five years, the arm of the health initiative that involves estrogen alone has not yet found an increase in breast cancer risk. That study is continuing.
But there is something of a silver lining: women who develop breast cancer while on hormone replacement have higher survival rates than nonusers, even though the hormones make breast tissue denser and mammographic detection of tiny cancers more difficult. Also, once hormone use is stopped, the risk declines to that of nonusers.
For ovarian cancer, the data are limited and the results mixed. Women who took birth control pills, with similar hormones, are less likely than nonusers to develop ovarian cancer, probably because the hormones suppress ovulation. But postmenopausal women do not ovulate and among them, a study of more than 200,000 women found that those who took estrogen replacement for 10 or more years starting in the 1970's or early 1980's (when doses were much higher than they are today) were 2.2 times as likely to die of ovarian cancer as nonusers. This risk gradually declined when hormones were discontinued.
A nationwide Swedish study found an elevated risk of ovarian cancer among hormone replacement users, especially when the therapy involved sequential use of estrogen and progestin for 10 or more years.
OTHER HEALTH RISKS Several studies have found that hormone replacement increases a woman's risk of gallbladder disease. In HERS, the women assigned to take Prempro had a 38 percent increase in the need for gallbladder surgery. Those who stayed on the hormones for three more years were nearly 50 percent more likely to need the surgery. In another finding from HERS, daily hormone use was associated with a worsening of urinary incontinence.
Possible BenefitsOSTEOPOROSIS By their early 30's, women start to lose more bone than their bodies replace, but the rate of bone loss accelerates greatly at menopause. The only health claim manufacturers can make about hormone replacement is that it prevents the loss of bone that occurs when women stop producing premenopausal levels of estrogen. Estrogen can also increase bone density in women who have suffered some bone loss. Thus, estrogen replacement can reduce the risk of osteoporosis and, it has been assumed, the fractures that accompany this density loss.
But to achieve maximum protection, hormone therapy should be started within five years of menopause and may need to be continued indefinitely. The longer after menopause that therapy is delayed, the more bone is likely to be lost and the less effective the hormones are in stabilizing bones. In older women who did not have osteoporosis and were receiving the hormones, the HERS results indicated no reduction in incidence of fracture after four years, and similarly, no reduction in height loss from vertebral bone loss.
While any duration of hormone therapy can delay the risk of osteoporosis and fractures, once estrogen is stopped, considerable bone loss can occur rapidly. In addition, there appears to be a limit to how much bone mineral can be increased with hormone replacement. A randomized clinical trial of 495 women found last spring that beyond three years of therapy no further gains were seen in bone density.
The F.D.A. lets manufacturers say that hormone therapy prevents osteoporosis, but they cannot claim it is an effective treatment. Although hormone therapy can increase bone density at any age, the hormones' effectiveness appears to diminish when started later in life.
Experts like Dr. Ettinger, now wary of long-term hormone therapy, say bones can be protected in other ways, including the drug raloxifene (or Evista), which prevents bone loss and breast cancer and may protect the heart.
BRAIN The possibility that estrogen benefits the aging brain is biologically plausible. The brain is loaded with receptors for estrogen, strongly suggesting that it is directly or indirectly vital to brain function. Estrogen affects the survival of brain cells, and it influences chemicals that send messages between brain cells, or neurotransmitters.
It also affects the formation of synapses that connect brain neurons and protects against oxygen deprivation. Estrogen increases blood flow, removes cell-damaging compounds called free radicals and increases the dendritic spines needed for nerve cell interactions.
Clinically, higher blood levels of estradiol, the most prominent premenopausal estrogen, are associated with better mental performance, and in women with menopausal symptoms, estrogen has improved verbal memory, vigilance, reasoning and the speed of motor responses. But this could be from estrogen-induced improvements in sleep patterns, rather than the direct effects on the brain.
Observational studies like the Baltimore Longitudinal Study of Aging found a halving of the risk of Alzheimer's disease in women using estrogen, and the large Leisure World study of a retirement community in Southern California found that women who had ever used postmenopausal estrogen were a third less likely to develop Alzheimer's than those who had never taken the therapy. In addition in the Leisure World study, the risk of Alzheimer's dropped sharply as the dosage and duration of estrogen use increased.
But even short-term estrogen therapy may be beneficial. In a five-year study of 1,124 elderly women, those who took estrogen for less than one year at the time of menopause were half as likely to develop Alzheimer's, suggesting that neurons may be especially susceptible to damage at the onset of menopause.
Still lacking, however, is proof from randomized clinical trials that estrogen can delay Alzheimer's or improve mental performance in women in the early stages of this disease. Well-designed studies have produced conflicting results.
OTHER BENEFITS Estrogen may help to prevent Parkinson's disease. In a study of 72 women who developed Parkinson's disease from 1976 to 1995, researchers at the Mayo Clinic found that those whose ovaries were surgically removed before menopause faced a threefold increased risk of developing this disease, but the risk was reduced by 50 percent in women who took estrogen after menopause.
A study in monkeys published in The Journal of Neuroscience revealed that estrogen deprivation led to the death of brain cells that produce dopamine, the neurotransmitter in short supply in Parkinson's patients. In 10 days of having their ovaries removed, the monkeys lost major dopamine-producing neurons.
Estrogen may also protect against colon cancer. An American Cancer Society study in which more than 400,000 women were followed for seven years found that the longer a woman took estrogen, the less likely she was to die of colon cancer. Whereas those who took estrogen for up to one year had a 19 percent reduction in deaths from colon cancer, those on estrogen for 11 or more years were 46 percent less likely than nonusers to die of colon cancer, even if they had stopped taking the hormone. But current users of the hormone had a lower risk of dying of this cancer than those who took estrogen and then stopped.
Although this was an observational study and thus subject to bias, the randomized Women's Health Initiative study also noted nearly a 40 percent lower risk of colorectal cancer among users of the hormone combination Prempro.
But the most certain benefits of estrogen replacement involve relief of menopausal symptoms, especially hot flashes and night sweats, as well as vaginal and mucous membrane dryness. Estrogen also helps to preserve a more youthful distribution of body fat, keeping more in women's hips and thighs than around their waists. By preserving skin moisture, estrogen can also delay the appearance of wrinkles.
"Quality of life is very, very important," said Dr. Schiff of Massachusetts General. "From a heart and breast cancer point of view, the drug should be outlawed. But for hot flashes, there's nothing better." But for vaginal dryness, which can radically alter a woman's ability to enjoy sex, and for recurrent urinary tract infections, vaginal application of estrogen works well without incurring the risks associated with swallowing a pill every day.
Some women choose to stay on hormone replacement because they say it makes them feel better. But, Dr. Ettinger said: "Clinical trials are not supporting this. I think it's a strong placebo effect. When we switched women to half the estrogen dose and progestin once every six months, overall they said they felt better."
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The Search for Alternatives to Hormone Replacement TherapyBy JANE E. BRODY
Many women worried about the latest findings on the possible health risks of long-term hormone replacement are ready to abandon the therapy or have decided not to start it. But how? How can a woman stop hormones without suffering the menopausal symptoms that may have prompted her to start in the first place? What can a woman do instead to protect her bones, her heart or any other part of her that estrogen was supposed to help?
The Women's Health Initiative findings of increased risks of heart disease, breast cancer, strokes and gallbladder disease unleashed all kinds of advice about alternatives to the popular hormone combination known as Prempro. But many of the alternatives have undergone far less testing for safety and effectiveness than the drug they seek to replace.
One critical piece of advice is rarely mentioned: substituting one hormone product for another is not the answer, since there is now no way to know whether any hormone product is safer than Prempro.
For those who choose to remain on hormone replacement by mouth or patch, most experts believe that the safest approach is to use the lowest possible dose needed to relieve symptoms.
Dr. Roger Lobo, an obstetrician-gynecologist at the Columbia-Presbyterian Medical Center in New York, suggests using at most 0.3 milligrams of an estrogen-only product daily and, for women with a uterus, using progesterone (natural or synthetic) for several days two or three times a year to reduce the risk of endometrial cancer.
Getting Off Hormones
For those now using hormones to control menopausal symptoms like hot flashes, mood swings or sleep disturbances, quitting cold turkey is not the best way to become hormone-free. Dr. Sally McNagny, a former investigator for the Women's Health Initiative study of hormone replacement, suggests gradual weaning over many months.
Start by cutting out one pill during the week, then several weeks later eliminate another, then another, until you are down to one pill every other day. Then try cutting the dose in half. Finally, try eliminating each of those pills one at a time.
If at any point disruptive symptoms reappear, return to the last eliminated dose. Continue at that level for some months before trying again to cut back further. For most women, the acute symptoms of menopause are relatively short-lived, lasting only a year or two, although some women continue to experience hot flashes of varying intensity for a decade or more.
Finding SubstitutesHOT FLASHES Testimonials abound as to which products are safe and likely to do the most good in countering this common symptom of menopause. But few of these many substances have been tested in well-designed clinical trials, and virtually none have been tested for long-term safety. Also, their ability to relieve hot flashes and night sweats seems to vary greatly from woman to woman.
Some women swear by one soy product or another. Soy contains weak plant-based estrogens. But to obtain enough of these estrogens to counter a severe case of hot flashes or night sweats may require doses that are as strong, or nearly so, as pharmaceutical estrogen products and may present comparable risks.
For women concerned about estrogen's effects on the breast, oncologists caution against using soy extracts like isoflavones formulated into pills or powders, since these may be no safer than Premarin or Prempro.
Others have found relief in an herbal remedy called black cohosh. German researchers who have tested this (using the product Remifemin) in placebo-controlled trials report that many women will achieve significant relief after taking the herb twice a day for at least a month, with an 80 percent reduction in hot flashes after 12 weeks. As for other herbal remedies, research evidence of their effectiveness is scarce, and some like kava kava and dong quai can be hazardous.
Another possibility is a half dose of an antidepressant in the Prozac family like Effexor or Paxil, which helps about 70 percent of women, although the long-term effects of these drugs is also unknown.
Simple changes can help, too. Avoid high necks, and dress in layers so that outer garments can be shed easily when the internal temperature rises. Install ceiling fans and use portable fans where you work and cook. Sleep in a cool room wearing as little as possible. Avoid foods that aggravate hot flashes, including caffeinated beverages, chocolate, spicy foods, alcohol and hot foods and drinks, and add soy-based foods to your daily diet.
VAGINAL DRYNESS Contrary to common belief, estrogen is not what sustains a woman's libido testosterone is. But vaginal atrophy, dryness and itching that often follows the loss of estrogen can result in painful sexual intercourse, an increase in vaginal infections and even discomfort during activities like jogging or biking.
Vaginal applications of estrogen are effective and considered safe, because little of the hormone is absorbed into the bloodstream. A popular remedy is vaginal insertion of an estrogen cream one to three times a week or use of an estrogen-containing vaginal ring. Vaginally applied estrogen can also counter recurrent urinary tract infections in postmenopausal women.
Nonhormonal options for temporary relief of vaginal dryness include gels or creams like Replens, Vagisil, Astroglide and K-Y jelly.
BONE LOSS The rapid acceleration of bone loss at menopause is most effectively countered by estrogen. One relatively new drug, raloxifene (Evista) acts like estrogen on bone but lacks estrogen's harmful effects on the breast and uterus. In fact, a large national study still in progress strongly suggests that raloxifene protects against breast cancer, much like tamoxifen. But in about 20 percent of users, raloxifene causes hot flashes, which may diminish with time.
For older women experiencing significant bone loss, tablets of biphosphonates (Fosamax or Actonel) taken weekly are effective at staving off and treating osteoporosis. Their main side effect is esophageal and gastric irritation, which may preclude their use by women with chronic reflux.
Also crucial is to provide your bones with enough building materials calcium and vitamin D and to create the mechanical stresses needed to rebuild bone through weight-bearing activities like walking or jogging or strength-training exercise like lifting weights.
HEART HEALTH The very disappointing finding that hormone replacement failed to prevent heart disease and may instead cause it has sent women back to the basics to maintain cardiovascular well-being. Start with a heart-healthy routine a diet low in saturated fats and rich in vegetables, fruits, unrefined (fiber-rich) carbohydrates and adequate calcium. Avoid cigarette smoking and engage in daily (or nearly so) moderately intense aerobic exercise like brisk walking, cycling and lap swimming.
If other measures are needed to control cardiac risks, take medicines daily to normalize blood pressure or blood sugar or lower high cholesterol, and adopt a balanced diet and exercise program that can help you achieve and maintain a normal weight.
BRAIN FUNCTION "Use it or lose it" seems to be as apt a motto for the brain as it is for muscles. Remaining intellectually and socially involved may not prevent Alzheimer's disease, but it can help to maintain a sharp mind. Experts on aging recommend doing crossword puzzles, playing bridge, attending lectures, reading books and joining discussion groups.
Women seeking more information on hormone alternatives might consult "The Truth About Hormone Replacement Therapy" by the National Women's Health Network (Prima Publishing, 2002).
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