Doctors change course again on estrogen therapy

Times Staff Writer

Nearly five years after government scientists told women that estrogen replacement therapy increased their risks of heart attack and stroke, researchers have largely reversed their position, concluding that the drugs are beneficial for many after all.

Continuing analysis of the original data indicates that the researchers raised a false alarm for most women and that, if women begin taking the hormones shortly after menopause, the drugs do not raise the risk of heart disease and might even lower it.

The latest findings, published in today's New England Journal of Medicine, show that taking estrogen for seven years or more after menopause reduces calcification of the arteries -- a key indicator of atherosclerosis -- by as much as 60%. High levels of calcification are generally considered a predictor of increased heart attack risk.

The only group of women at significant risk from the drugs are those who delay taking them for at least 10 years after menopause, experts said.

The findings "provide some additional reassurance for women who have been denying themselves relief" from hot flashes and other symptoms of menopause, said Dr. JoAnn Manson of Brigham and Women's Hospital in Boston, who led both the original and the latest research.

The research is based on the Women's Health Initiative, a vast federal study launched in the 1990s.

Virtually all researchers agree that women should not fear using estrogen replacement therapy to mitigate menopausal symptoms. The debate is over how long they may safely continue to do so.

Dr. Elizabeth G. Nabel, director of the National Heart, Lung and Blood Institute, which sponsored the research, said the new findings "do not alter the current recommendations that when hormone therapy is used for menopausal symptoms, it should only be taken at the smallest dose and for the shortest time possible, and hormone therapy should never be used to prevent heart disease."

Dr. Howard N. Hodis, director of USC's Atherosclerosis Research Unit, countered: "There is absolutely no evidence, none, zero, that if you start a woman on estrogen at menopause and continue until she is 80, the risk goes up as she gets older."

There is an increased risk of breast cancer with age for estrogen when combined with progestin, Hodis said at a news conference Tuesday sponsored by Wyeth Pharmaceuticals, and it is not clear whether the risk outweighs the benefits.

"We will never know when we should stop hormones," said Dr. Michelle Warren of the Columbia University College of Physicians and Surgeons, who spoke at the news conference and urged the shortest use possible. But "if you have been on the hormone since the time of menopause, I am not worried anymore."

Dr. Jacques Rossouw, who heads the heart institute's Women's Health Initiative branch, said it was virtually impossible to conduct a study on long-term hormone use because the risks are so low that the number of women required would be prohibitive.

Long-term use of hormone replacement therapy was popularized in 1966 by Dr. Robert A. Wilson's book "Feminine Forever," which touted the treatment as a panacea for menopausal ills. Subsequent animal and small human studies suggested the hormones could help ward off heart attacks and increase bone density.

By the end of the century, an estimated 40% of menopausal women were taking the drugs.

It came as a shock in 2002 when researchers from the Women's Health Initiative reported that the drugs actually increased risks of heart attack and stroke.

Within a year of the report, the number of new prescriptions for estrogen fell by 68% as both physicians and patients shied away from the drugs.

The new study involved a subset of 1,064 women in the Women's Health Initiative study who were ages 50 to 59 and had undergone surgically induced menopause through a hysterectomy. Half were randomized to receive a Wyeth-produced estrogen called Premarin and half a placebo.

The women were on the drugs for an average of 7 1/2 years. About a year after the study was stopped, physicians used CT scans to measure the buildup of calcium deposits, or atherosclerotic plaque, in their blood vessels.

Overall, they found, women taking estrogen had 42% less calcification of their arteries. Women who had taken at least 80% of their daily doses of the drug had 61% less calcification.

The results were "clear and striking," wrote Dr. Michael E. Mendelsohn and Dr. Richard H. Karas of the Tufts University School of Medicine in an editorial accompanying the study. "Now, some clarity about hormone replacement therapy and heart disease is emerging."

Another analysis by Manson and Rossouw, published in the Journal of the American Medical Assn. in April, found a 30% decrease in the number of deaths from any cause among women receiving estrogen during the course of the research.

They concluded that the use of estrogen by women in their 50s would reduce the number of heart attacks per 10,000 women to 17 from 27, and the number of strokes to 15 from 17.

The newest findings probably will not drastically change clinical practices, said Dr. Robert Greenfield, a cardiologist at Orange Coast Memorial Medical Center in Fountain Valley. "Women who are thinking about taking them should do so because they have peri-menopausal symptoms," and not to prevent heart disease, he said. "Using them in modest doses for symptoms is the way to go."

For younger women, there seems to be little downside, added Dr. Suzanne R. Steinbaum of Lenox Hill Hospital in New York City. "With a much younger and healthier population, we can easily go forward in reassuring women that HRT will not be the cause of future heart attacks," she said.

The change in attitudes about hormone replacement therapy is an outgrowth of the development of what is known as the "timing hypothesis," Mendelsohn and Karas said.

Researchers believe the benefits of estrogen replacement occur only if it is started before atherosclerosis begins to develop. Once the hardening of the arteries has set in, estrogen is known to produce damaging effects.

The initial negative findings in the Women's Health Initiative resulted because the investigators included a substantial number of older women in the study in the hopes of observing enough heart attacks to be able to draw conclusions. But those women are rarely considered for hormone replacement therapy.

"Unfortunately, [those results] were unfairly generalized, creating widespread concern that hormone replacement therapy is neutral or even harmful, with respect to heart disease, in all women," they wrote.

Dr. Robert W. Rebar, executive director of the American Society for Reproductive Medicine, concluded: "We are clearly learning that the benefits of estrogen in young, healthy, symptomatic post-menopausal women outweigh the risks."

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thomas.maugh@latimes.com

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Hormone guidelines

The Food and Drug Administration recommends the following:

* Hormone therapy should be used at the lowest doses for the shortest duration needed to alleviate acute symptoms of menopause.

* It should not be used to prevent heart disease.

* It should be used to treat osteoporosis only in women who are at significant risk and cannot take non-estrogen medications.

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Source: Food and Drug Administration

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Shifting advice

Here is a look at how hormone advice has changed over time as the federal Women's Health Initiative has been analyzed in more detail. Researchers now think health risks are far greater for women who take hormones years after menopause than for women in their 50s.

July 2002: Officials halt a phase of the study after doctors find higher rates of breast cancer, heart attack and stroke in women taking estrogen with progestin.

May 2003: A study of the federal data finds that in women 65 and older, taking hormones for years raises the risk of Alzheimer's.

September 2003: A study finds estrogen-progestin pills do not reduce -- and might increase -- the risk of ovarian cancer.

March 2004: Federal officials stop a phase of the women's health study that looks at estrogen alone after finding that women taking it have an increased risk of stroke, and possibly a higher risk of dementia.

April 2007: A review of data from the federal women's study shows hormones did not raise heart attack risks for women in their 50s, but did raise breast cancer and stroke risks.

May 2007: A new review of the data concludes that those who took hormones before age 65 reduced risk of dementia by half.

June 2007: A review of the data shows a lower risk for hardening of the arteries for women who took hormones in their 50s.

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Source: Associated Press

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