Rethinking HRT

Risks Small; Benefits Depend on Individual

From the WebMD Archives

Feb. 12, 2003 -- Nanette K. Wenger, MD, tells this story: A woman who'd just had bypass surgery came into her office in tears. Because it increases risk of heart disease, her doctor had taken her off hormone replacement therapy. "My life is not worth living," she said. "My menopausal symptoms are worse than my angina."

Wenger knows a lot about heart disease. She's chief of cardiology at Atlanta's Grady Memorial Hospital. She also knows a lot about hormone replacement therapy (HRT). An Emory University professor of medicine, she's been a part of most major HRT studies -- including the Women's Health Initiative (WHI).

It was the sudden closing of the WHI that started the current furor over HRT. The trial was stopped when it found that the small but serious risks from HRT outweighed its even smaller benefits. Risks and benefits, that is, for women who'd already passed through menopause without serious trouble.

"The women in these trials are not the women with the worst symptoms. Such women would never participate in a trial where they might get a placebo," Wenger tells WebMD. "Those trials do not apply to severely symptomatic women."

Wenger isn't the only expert who's seriously rethinking HRT. It's the topic of two papers in the Feb. 13 issue of The New England Journal of Medicine. Both agree that the WHI and other trials don't tell the whole story. And they note that many crucial questions remain open.

Francine Grodstein, ScD, and colleagues at Brigham and Women's Hospital look at why the WHI findings came as such a surprise. One reason, they suggest, is that women who volunteer for clinical trials are different from women who take HRT because they have symptoms -- exactly the point that Wenger makes.

"People don't like to hear this, but good studies often produce more questions than answers," Grodstein tells WebMD. "There are a lot more questions to ask than we used to think. We used to think we should give all women hormones. Now we know that isn't going to work. The thing a lot of people don't appreciate is how complex health is. No single study can tell us the answer. We just learn as we go along. We are now trying to learn what the right questions are."


The shocking thing about WHI wasn't its finding that women on HRT have an increased risk of breast cancer. The surprise was that HRT -- which earlier studies suggested would decrease risk of heart disease and stroke -- actually increased these risks. Moreover, there was a less-than-expected improvement in osteoporosis. It wasn't the size of these risks that stopped the trial, but the fact that the risks outweighed the benefit.

WHI was a clinical trial -- that is, women who entered the trial agreed to take the pills they were given, knowing that they had a 50-50 chance of getting HRT or placebo do-nothing pills. Earlier studies were observational -- they followed women already on HRT and looked at what happened.

"I think there is a lot of evidence that the observational studies of HRT are generally getting the right answers," Grodstein says. "Generally the risks seen for stroke, breast cancer, colon cancer, and pulmonary embolism are identical to those seen in clinical trials. Why the findings on heart disease were so different -- there are not a whole lot of answers right now. It may be that the women in the clinical trials were older. In terms of heart disease, there is some suspicion that if the disease process has gone a certain distance, it is hard to help it. Early intervention could work, but starting later in the disease process may make that same product have harm instead of benefits."

Caren Solomon, MD, MPH, deputy editor of TheNew England Journal of Medicine and a physician at Brigham and Women's Hospital, is co-author of the other NEJM paper.

"I think Dr. Grodstein's goal was to make sense of why randomized clinical trials looked so different from observational data," Solomon tells WebMD. "What we tried to do is say OK, given everything that is out there, what do we do? When should women use HRT, and if they should not use it, how should they stop it? We wanted to offer clinicians some very practical information."

Here's Solomon's advice to women:


These steps, she says, are much more likely to preserve health than HRT. Both she and Grodstein say HRT should be used only to get over symptoms of menopause, and that long-term use -- five years or more -- isn't advised for prevention of heart or bone disease.

"People shouldn't forget there is value to HRT in some women," Solomon says. "This was ignored at first when WHI came out and there was this widespread panic. It has been a good medicine for years for some women with menopausal symptoms. It is reasonable for symptomatic women who are in the early stages of menopause and who don't have risk factors for the drug. The risks are real, but on an absolute basis they are quite small for young women without other risks of complications. Estrogen helps symptoms enormously."

However, Solomon says there is no convincing evidence that estrogen keeps a woman looking younger, or that it prevents mental decline.

"Women think that they will look better if they're on estrogen," she says. "But if you look for good data to support that contention -- for women to take estrogen with the purpose of looking younger -- there really aren't any. And the other benefit a lot of women hope for is preventing dementia.... I advise my patients that those cannot be considered justifications for taking estrogen."

And what about Wenger's patient with heart disease and terrible menopausal symptoms? After advising her of the risks, Wenger put her back on HRT. She's doing fine now.

"This medicine is for quality of life," Wenger says. "Nothing we do in medicine is riskfree. As long as a woman knows the risks, there is nothing else in our armamentarium to control menopausal symptoms."

Grodstein thinks there are better alternatives than HRT. But she says women have to make up their own minds.

"People have a right to make their own decisions. It is not up to us to tell them right or wrong," she says. "The important thing is to make the decision with the best information available. I think a lot of the problem with HRT it is that we still don't know a lot. This is not a very satisfying answer, but that's where we are."

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SOURCES: The New England Journal of Medicine, Feb. 13, 2003 • Fran Grodstein, ScD, assistant professor of medicine, Brigham and Women's Hospital and Harvard University, Boston • Caren Solomon, MD, MPH, deputy editor, The New England Journal of Medicine and physician, Brigham and Women's Hospital, Boston • Nanette K. Wenger, MD, chief of cardiology, Grady Memorial Hospital and professor of medicine, Emory University, Atlanta.
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