A few years ago, the use of hormone replacement therapy (HRT) looked like a medical mess. For decades, women were told that HRT -- usually a combination of estrogen and progestin -- was good for them during and after menopause. Then the 2002 results of the Women's Health Initiative study seemed to show just the opposite: hormone replacement therapy actually had life-threatening risks such as heart attacks, strokes, and cancer.

"Women felt betrayed," says Isaac Schiff, MD, chief of obstetrics and gynecology at Massachusetts General Hospital in Boston. "They were calling their doctors, saying, 'How could you put me on this drug which causes heart attacks, strokes, and cancer?'"

Almost overnight, standard medical practice changed. Doctors stopped prescribing hormone replacement therapy and 65% of women on HRT quit, according to Schiff.

But some experts say hormone replacement therapy may be coming back. All along HRT remained an important treatment for menopause symptoms like hot flashes. And now, a number of recent studies show that hormone replacement therapy may have protective benefits for women who are early in menopause.

"I think we swung too positive on hormone therapy in the past and then we went too negative," says Schiff, who is also chair of the American College of Obstetricians and Gynecologists Task Force on Hormone Therapy. "Now we're trying to find a balance in between."

"We're definitely in a gray zone of uncertainty about hormone therapy," says Jacques Rossouw, MD, project officer for the federal Women's Health Initiative (WHI). "But when you're uncertain, you have to err on the side of safety."

While Rossouw concedes that new studies show some preventative benefit for younger women, he says any potential benefit is very slight. And, he notes, there is no evidence that any benefit would last if women kept taking hormones as they got older.

But increasing numbers of researchers say there should be a place for hormone replacement therapy as a preventive treatment for limited periods as it may help prevent disease in younger women around the age of menopause.

"We have evidence that hormone therapy can prevent heart disease, hip fractures, and osteoporosis, and that it cuts the risk of developing diabetes by 30% in younger women," says Shelley R. Salpeter, MD, a clinical professor of medicine at Stanford University's School of Medicine.

In one recent study, Salpeter and her colleagues found that HRT reduced the number of heart attacks and cardiac deaths by 32% in women who were 60 or younger (or women who had been through menopause less than 10 years ago). In older women, hormone replacement therapy seemed to increase cardiac events in the first year, and then began to reduce them after two years.

The 32% drop is significant, but perhaps not as dramatic as it sounds. In hard numbers, Salpeter estimates that of women aged 50 to 59 who don't get hormone replacement therapy, about 7 out of 4,800 will have a cardiac event in one year. With HRT, 3 out of 4,800 will have a cardiac event.

Salpeter's study indicates something crucial: The age at which a woman starts HRT may make a big difference.

Salpeter argues that when a person first starts hormone replacement therapy, her risk of blood clots increases slightly. In healthy women who are in their 50s -- and close to the age of menopause -- this increase is very unlikely to cause problems. The higher risk subsides after a couple of years, she says, although other experts disagree.

But women in their 60s may be more likely to already have early heart disease or hardening of the arteries (arteriosclerosis). In these cases, the risk of blood clots becomes more serious. So if a woman first starts hormone replacement therapy in her 60s, the initial risks are more dangerous, Salpeter says.

This is what Salpeter says affected the results of the Women's Health Initiative trial. The average age of a woman in that trial was 63, with a range of ages between 50 and 79. She and other critics argue that the researchers were looking at many women who might already have been sick.

"I was surprised when I first heard the [WHI] results," says Lynne T. Shuster, MD, director of the Women's Health Clinic at the Mayo Clinic in Rochester, Minn. "But, once I saw the details, I wasn't surprised anymore. They gave women who were older and possibly had underlying arteriosclerosis a pill that increased the risk of blood clotting. Of course it increased the risk of heart problems."

Shuster and Salpeter argue that those results have no bearing on whether younger, healthy women in their 50s would benefit from HRT.

"Basically, [the WHI researchers] were looking at the wrong group of people," Salpeter tells WebMD.

Rossouw defends the WHI study design. "We were specifically testing the hypothesis that hormone therapy would help protect older women against disease," Rossouw tells WebMD, "The results were absolutely clear: They do not."

Media reports on the WHI results may have given people inflated fears of hormone replacement therapy's risks, the doctors say.

For example, the Women's Health Initiative results showed that combined hormone replacement therapy seems to increase the risk of breast cancer by 33%, Schiff says. That's a serious increase. Still, the risk to any one woman is not as high as it sounds, Schiff says.

"According to the WHI, without hormone therapy, 3 of every 1,200 women aged 55 to 59 will develop breast cancer this year," says Schiff. "With hormone therapy, 4 out of 1,200 will. It's a 33% increase, but the absolute risk is still very, very small."

Shuster points out that other behaviors -- like drinking two glasses of wine a night -- also increase breast cancer risk by a similar amount.

Women who take estrogen alone -- a treatment only available to people who have had a hysterectomy -- appear to have a lower risk of developing breast cancer than women who take progestin and estrogen together. In a 2006 JAMA article, researchers from the Women's Health Initiative found that after about seven years of treatment with estrogen, there seemed to be no increased risk of breast cancer.

However, estrogen-only therapy may have long-term risks. A May 2006 study published in the Archives of Internal Medicine found using estrogen-only therapy for 20 years or more showed increased risk of developing breast cancer.

As HRT is being re-evaluated -- and new evidence is coming in -- it's difficult to know who should get hormone replacement therapy and for how long.

The U.S. Food and Drug Administration (FDA) recommends that HRT should be used in women who have severe menopausal symptoms.

"Estrogens are the best agents we have for the relief of menopausal symptoms like hot flashes, vaginal dryness, and loss of sexuality," says Schiff. They're also a good treatment for menopausal symptoms that are often not recognized: Difficulty sleeping, stiffness, joint pain, and mood changes.

But for disease prevention -- lowering the risk of heart attacks, strokes, and most cases of osteoporosis -- the FDA still does not recommend hormone replacement therapy.

"We have other ways of cutting the risks of heart attacks and strokes," Schiff tells WebMD, including better diet, exercise, and other medicines.

Will HRT ever again be used as prevention for these serious diseases? Only time and research will tell. The experts remain divided.

"I believe that studies in the next few years will support using hormone therapy in younger women [closer to the onset of menopause] for prevention," says Shuster. "But "we don't have all the information yet."

Another big question is how long hormone replacement therapy can be used safely. It was once thought that using it for five years or less to relieve menopausal symptoms had no risks. But the WHI study seemed to show that was not the case.

There are still a lot of unknowns. Many women now take doses of hormones that are lower than the ones used in the WHI trial. Hormones are also delivered not just through pills, but in other forms, like skin patches. We don't know yet whether these lower concentrations and different forms might decrease the risks.

For now, the FDA recommends that women who take hormone replacement therapy for menopausal symptoms take the lowest effective dose and for the shortest time period to alleviate symptoms.

With all of the contradictory messages, it's hard for a woman to know what to do. There's also a lot of lingering anger about what happened in the wake of the Women's Health Initiative results.

"I lost a lot of faith in my doctors after that," says April Dawson, a 63-year-old Connecticut woman who used hormone replacement therapy for about a year. "And all of the women I know feel the same way.

"In the first place, I didn't like the idea of going on medication when I didn't have any symptoms," Dawson tells WebMD. "But I feel like my doctors ganged up on me and pushed me to take it."

Today, doctors are far more likely to tell each woman that she must make the decision herself, weighing the pros and cons of hormone replacement therapy, considering her symptoms, family history, lifestyle, and risk of disease.

If you take HRT, keep in mind that the absolute risks are low. But you should still regularly check in with your doctor. Ask if there is any new information that might cause you to rethink your decision.

"Hormone therapy is a field that continues to change rapidly," says Shuster. "Treatment has to be more individualized than ever. Women are seeking the one right answer, but for now, we just don't have one."

SOURCES: American College of Obstetricians and Gynecologists web site,"Frequently Asked Questions about Hormone Therapy, "News release: ACOG IssuesState-of-the-Art Guide to Hormone Therapy." Chen, WY et al, Archives ofInternal Medicine, May 8, 2006; vol 166: pp1027-1032. April Dawson,Milford, Conn. Jacques Rossouw, MD, project officer for the Women's HealthInitiative at the National, Heart, Lung and Blood Institute, Bethesda, MD.Salpeter, SR et al, JGIM, July 2004; vol 21: pp 363-366. Salpeter, S,Climacteric 2005; vol 8: pp307-310. Salpeter, SR et al, Diabetes,Obesity and Metabolism, in press. Salpeter, SR et al, Journal ofGeneral Internal Medicine, July 2004; vol 19: pp 791-804. Shelley R.Salpeter, MD, clinical professor of medicine at Stanford University's School ofMedicine. Isaac Schiff, MD, chief of obstetrics and gynecology at MassachusettsGeneral Hospital in Boston; chair of the American College if Obstetricians andGynecologists Task Force on Hormone Therapy. Lynne T. Shuster, MD, director ofthe Women's Health Clinic at the Mayo Clinic in Rochester, MN. Stefanick, ML etal, JAMA, April 12, 2006; vol 295: pp 1647-1657. U.S. Food and DrugAdministration web site, "Questions and Answers for Estrogen and Estrogen withProgestin Therapies for Postmenopausal Women."

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