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http://www.nytimes.com/2002/07/16/health/16HORM.html

Hormone Therapy: One Size, Clearly, No Longer Fits All

By MARY DUENWALD

enopause is not a disease, as doctors often point out, only an inevitability of middle age. But for most women, it does come with symptoms, as the body is weaned from its customary diet of estrogen. Some of these can be more than a little annoying: sudden spikes in temperature that make the face flush and the sweat flow; soaked sheets at 3 a.m.; vaginal dryness that causes incessant pain and itching.

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An estimated 20 million American women have been treating these problems and also trying to preserve the strength of their bones and hearts by taking daily doses of estrogen to replace what their ovaries no longer provide. But then came last week's announcement that hormone replacement therapy caused small but significant increases in breast cancer, heart attack, stroke and blood clots in a nationwide study of postmenopausal women. And now many women are wondering if they may want to try something else.

Many doctors say that for women to turn their backs on hormone replacement therapy would be a gross overreaction.

"I don't think we should throw out the baby with the bath water just because of this one study," said Dr. Daniel R. Mishell, chairman of obstetrics and gynecology at the University of Southern California's Keck School of Medicine.

Dr. Mishell and others point out that the increased risk of breast cancer and cardiovascular problems for a woman in the federal study was small. Many doctors still say that taking hormones for two to four years, to treat temporary symptoms of menopause, is probably safe for most women. And the fact is, nothing else works as well as estrogen to relieve hot flashes and vaginal dryness.

Still, the news from the Women's Health Initiative study is prompting a reassessment of the standard regimen of hormone replacement therapy. It seems likely that in the months ahead, many doctors will be prescribing formulations of estrogen and progestin that are tailored to each woman's health and personal preferences. Some women will opt for lower doses, and some will forgo hormones altogether in favor of other remedies.

"More than ever, one needs to individualize treatments to determine if there really is a need for hormones and to find out what regimen works best for each woman," said Dr. Roger A. Lobo of Columbia-Presbyterian Medical Center in New York.

Selecting the right treatment is bound to be challenging and confusing because the scientific data behind most menopausal remedies remain sketchy. The study reported last week is the only randomized clinical trial of hormone replacement therapy in healthy women.

Women in the study were given Prempro, a combined estrogen-progestin pill that has been the most widely used form of hormone replacement therapy in the United States. (Progestin is added to estrogen because women who take estrogen alone stand a significant risk of developing uterine cancer.)

The estrogen in Prempro is derived from the urine of pregnant mares. Other estrogen supplements are made of estradiol, a synthetic copy of the kind produced by human ovaries. Theoretically, the action of estradiol in the body may be different from that of equine estrogen, but there is no evidence to show that it would be any safer for breast tissue or cardiovascular health.

Similarly, progestins that are chemically different from the kind in Prempro theoretically may not have the same effect as was found in the trial.

"We can't generalize our finding to the other estrogens and other progestins, or other doses or ways of taking hormones like pills versus patches," said Dr. Marcia Stefanick, the principal investigator of the Women's Health Initiative trial. "But if pharmaceutical companies or anyone else starts to claim that these other kinds are safer, they really need to prove that."

The Women's Health Initiative is continuing to study the use of estrogen supplements alone in women who have had hysterectomies. That part of the trial was not halted, but will go on as planned until 2005 because there is no evidence that the estrogen alone is causing an increased risk of breast cancer.

Lower doses of estrogen and progestin have been found to be effective against hot flashes and vaginal dryness in studies done by Dr. Lobo. Lower doses, about half as strong as the standard dose, have the added benefit of reducing the chance of breakthrough bleeding, Dr. Lobo said.

Dr. Lobo said he had been moving toward lower doses of estrogen over the last several years. It is logical to assume that lower doses will pose less risk to breast and heart health, he said, though no studies have proved that.

Dr. Lobo also sometimes prescribes lower doses of progestin. Some women, he has found in his own practice, can take it for just 10 to 12 days every two or three months.

Estrogen can be given in the form of patches, too, which are typically placed on the abdomen. The patches deliver a steady stream of estrogen or estrogen plus progestin directly to the bloodstream for a few days or a week at a time. Some believe that patches may be safer because the estrogen does not go directly through the liver. "This is also effective for menopause symptoms," said Dr. Deborah Grady, director of the Mount Zion Women's Health Clinical Research Center at the University of California in San Francisco. "But has anyone ever tested transdermal estrogen to see if it's more safe? Well, no."

For women who want or need even more finely tuned regimens, doctors can turn to so-called compounding pharmacies, which are scattered around the country and will prepare made-to-order hormone replacement therapy in the form of pills, pellets that can be placed under the skin, or creams that can be rubbed on the skin. "This is a niche market," said Dr. Joanna Cain, director of the Center for Women's Health at Oregon Health and Science University in Portland. "But it's one more way to individualize treatment."

Many doctors say they are determined to continue using hormone therapy, noting that the dangers discovered in the Women's Health Initiative trial were small and that no greater risk of death was found among the women taking hormones. The doctors contend the therapy offers broad benefits beyond the treatment of hot flashes. Though no hard evidence shows that hormone replacement therapy softens the skin, prevents wrinkles and tooth loss, evens out moods, or confers a generally feeling of youthfulness, women often say they experience these benefits. They also say the drugs help them think more clearly and remember things better.

Likewise, no definitive studies show that estrogen replacement can improve mental functioning, or prevent Alzheimer's disease and other forms of dementia. But some research in humans and laboratory animals has at least suggested it may. "It's one more reason why I think it's unfortunate to prematurely stop the trial of estrogen and progesterone," said Dr. Holly Thacker, head of Women's Health Center at the Cleveland Clinic.

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A subset of the participants in the Women's Health Initiative study has been undergoing tests of cognitive function to see if hormone replacement therapy affects memory. Now, only those women who have had hysterectomies and are still taking estrogen alone will continue to be tested. The results are expected in 2005.

For women who cannot take hormones, or prefer not to, doctors use a number of alternative treatments for menopause symptoms.

"As a breast cancer specialist, I've been discouraging my patients from taking H.R.T. for years, especially if their tumors have estrogen or progesterone receptors," said Dr. Larry Norton of Memorial Sloan-Kettering Cancer Center in New York. "There are many alternative ways to help them."

Progestin alone prevents hot flashes in about 70 percent of women, Dr. Norton said, as do antidepressants like Effexor, Paxil and Prozac. Women using antidepressants to treat hot flashes typically take half the dose that is used for depression. But these drugs, too, have side effects, and the effects of long-term use are unknown.

Vaginal dryness can be treated with estrogens that are placed in the vagina but not easily absorbed by the body. Estrace, a cream, and Vagifem, a solid suppository, can be used two or three times a week. Estring, a plastic ring similar to a diaphragm, releases estrogen gradually over the course of three months.

Women with osteoporosis can be given raloxifene (brand name Evista), a so-called designer estrogen, which has been shown to decrease the incidence of breast cancer. Or, they can take bisphosphonates (Actonel or Fosamax), which help maintain bone strength.

Health food and vitamin stores sell a variety of menopausal remedies, though they are backed by even less scientific data than prescription drugs are, and the existing evidence suggests they may not work. Evening primrose oil, flaxseed oil, dong quai root and vitamin E have never been shown to be more effective than placebos in reducing menopausal symptoms. Some small studies have suggested black cohosh may help quell hot flashes, Dr. Grady said, but several others have not.

The phytoestrogens, derived from plants — usually soy but also red clover — are a more complicated story. Some women find they can lessen their hot flashes by eating a diet rich in soy, and many doctors consider that a sensible strategy because the amount of phytoestrogen that can be consumed in foods is probably no more than 80 to 100 milligrams a day, a relatively low dose.

But soy supplements in pill and powder form may contain 500 to 600 milligrams of phytoestrogens. Because these estrogens attach to the same receptors that pharmaceutical hormones act on, the possibility exists that they, too, could affect breast tissue and heart health.

"Concentrated preparations concern me a lot because their biological effects are unknown," Dr. Norton said. "Just because something is natural doesn't mean it's safe."

The studies that have been done on concentrated phytoestrogens suggest that they are little better than placebos in fighting hot flashes.

Of course, many women simply try to put up with menopausal symptoms, without taking pills or supplements of any kind. They dress in layers, open windows, drink cold beverages and wait it out. For some, deep breathing techniques seem to help. "In studies, they seem to actually reduce body temperature and reduce the severity or prevent the recurrence of the hot flash," Dr. Grady said.

Many doctors point out that a woman can reduce her risk of both osteoporosis and heart disease if she gets exercise, does not smoke, limits her alcohol intake and eats a balanced diet rich in calcium and antioxidant vitamins.

"If your symptoms are mild, it's probably better to just live with them," Dr. Grady said. She added that, in her experience, many women who took hormone replacement only prolonged the time they were susceptible to symptoms.

Dr. Stefanick said many women might be surprised at how easily they could get by without treatment, based on what she observed among women who had stopped taking the pills. "As we're now bringing the women off, a lot of the those who said they felt so much better taking the pills are finding out they were actually on placebo," she said.

Still, some women have great trouble without supplemental hormones. "If a woman can't sleep and can't work, and estrogen is the only therapy that makes her feel well, it's reasonable to take some risk," Dr. Grady said. "It all depends on how much discomfort she's willing to put up with and how much risk she's willing to take."
 

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