The largest randomized study ever to look at combined hormone replacement therapy (HRT) in healthy postmenopausal women was recently stopped early when researchers found an increased risk of breast cancer, according to a July 9 announcement.

Women receiving the estrogen/progesterone combination were also found to be at higher risk for coronary heart disease (CHD) and blood clots, the report said.

HRT did seem to lower the risk of colorectal cancer and bone fractures, but overall the risks outweighed the benefits, the researchers said.

The Women's Health Initiative (WHI) study report, along with an editorial recommending against the long-term use of HRT in healthy postmenopausal women, will be published in the July 17 Journal of the American Medical Association (Vol. 288:321-333, 366-368).

When hormone replacement therapy was first developed, it consisted of the female hormone estrogen given alone. It helped relieve the symptoms of menopause, and appeared to protect against heart disease and bone fractures, problems often found in older women. But doctors discovered that it also increased the risk of cancer of the endometrium (the lining of the uterus).

Doctors found that adding progesterone to estrogen (HRT) in women with an intact uterus seemed to provide protection against endometrial cancer. Whether or not this conferred the other benefits seen with ERT, however, has been unknown.

These new results are important, but they do not apply to all groups, the authors reported.

For example, they do not apply to women receiving estrogen replacement (ERT) alone, which is still commonly given to women who have had a hysterectomy. The effects of ERT on women who no longer have a uterus are being studied in a separate WHI clinical trial, with results expected in 2005, they said.

The present study also did not look at short-term use of HRT to prevent menopausal symptoms, such as hot flashes, so few conclusions about this can be drawn, the authors said.

The researchers looked at more than 16,000 healthy, postmenopausal women who were part of the WHI, a trial funded by the National Institutes of Health. All of the women were between the ages of 50 and 79, and still had a uterus. The women began taking either a combination estrogen/progesterone pill or a placebo each day, starting in the mid-1990's.

The women were supposed to be followed for an average of eight and a half years, with the researchers looking twice each year at the results. The last scheduled review (May 2002) showed the results were significant enough that the trial was stopped after just over five years.

The rate of breast cancers was 26% higher among those receiving HRT as opposed to those getting placebo. The rate for heart disease was 29% higher. Stroke rates were 41% higher, and blood clot rates were more than twice as high in those getting HRT.

HRT did have some benefits, however. The rate of colorectal cancer was 37% lower in the HRT group, and the rate of bone fractures was 24% lower. Endometrial cancer rates were about the same in both groups.

The authors gave weight to each of these factors to come up with an overall “global index,” which showed that the risks outweighed the possible benefits for these serious conditions.

In an editorial in the same issue, Suzanne Fletcher, MD, MSc, and Graham Colditz, MD, MPH, of Harvard Medical School said that 38% of postmenopausal American women now use some form of HRT.

But with this study publication, the wisdom of such use has now been called into serious question.

“Given these results, we recommend that clinicians stop prescribing this combination for long term use. Primum non nocere [First, do no harm] applies especially to preventive health care,” the editorial authors wrote.

While the increased risk of breast cancer and other conditions may make HRT unsuitable for prevention in healthy people, the overall (absolute) risk for each woman is still rather small, the authors said.

For example, the 36% increased risk of breast cancer is based on the fact that during one year, among 10,000 women receiving combination HRT there will be 38 cases of breast cancer. Among 10,000 women taking a placebo, there will be 30 cases, they said.

The same holds true for heart disease (37 cases per 10,000 women per year with HRT, versus 30 cases per 10,000 women per year with placebo) and blood clots (34 cases per 10,000 women per year with HRT, versus 16 cases per 10,000 women per year with placebo).

Still, the risk is there and it would appear to increase as the length of time taking combination HRT increased, the editorial authors said.

“The WHI provides an important answer for generations of healthy postmenopausal women to come—do not use estrogen/progesterone to prevent chronic disease,” Fletcher and Golditz said.

An American Cancer Society (ACS) expert said this study is one of the most important studies conducted on HRT.

"The findings could influence the practice of medicine for women more than almost any study done in the last 40 years," said Harmon Eyre, MD, chief medical officer for the ACS.

Dr. Eyre said, "Decisions to take hormone replacement therapy, particularly estrogen plus progestin which is widely prescribed, will be more difficult now. Women who are taking hormone replacement therapy should discuss this latest finding with their doctors."