By Judy Foreman, Globe Staff, 01/26/00

A provocative new study suggests that menopausal women who take both estrogen and progestin may increase their risk of breast cancer more than by taking estrogen alone.

Specifically, the study of more than 46,000 women, done by the National Cancer Institute and published in today's issue of the Journal of the American Medical Association, found that while taking estrogen alone increased a woman's risk of breast cancer by 1 percent for each year of use, taking estrogen plus progestin increased the risk by 8 percent per year. If that's true, according to an editorial accompanying the study, taking the combination therapy for 10 years could increase breast cancer risk by 80 percent.

Women take hormone supplements at menopause to combat symptoms such as hot flashes and to reduce the long-term risk of heart disease and bone fractures caused by osteoporosis.

But while some researchers not involved with the study said the new results are troubling and should cause women to reassess their use of hormone therapy, an alternate interpretation is that the NCI study is too flawed to be meaningful.

The study, led by Catherine Schairer of NCI's division of cancer epidemiology and genetics, does fit with some other data, including a report from the Nurses Health Study at Harvard, which also suggests an extra risk for combining the two hormones, as many women now do. (Doctors recommend that women take progestin with estrogen to protect against the increased risk of uterine cancer associated with estrogen alone; women who have had hysterectomies do not need to add progestin.)

In fact, though no study is definitive, the NCI study "does change the picture" of the risks of hormone therapy, said Dr. Walter C. Willett, a professor of epidemiology and nutrition at the Harvard School of Public Health, in an interview.

In an editorial accompanying the NCI research, Willett and his Harvard co-authors Drs. Graham Colditz and Meir Stampfer conclude, "The commonly held belief that aging routinely requires pharmacological management has unfortunately led to neglect of diet and lifestyle as the primary means to achieve healthy aging. Now is an appropriate time to reassess this emphasis."

But there are other ways to look at the NCI data.

"I don't think this study gives us any new information," said Dr. Nananda Col, director of the Women's Wellness Center at New England Medical Center.

For one thing, there were only 39 cases of breast cancer among women taking the combination estrogen-progestin therapy for four years or more - not enough to provide compelling conclusions.

For another, the NCI study looked mainly at women who took progestin in a cyclical fashion - taking the hormone for half the month and skipping it for the other half, a pattern that some women do not like because it induces regular bleeding. Some scientists say that regular bleeding reduces the risk of uterine cancer because potentially cancerous cells are shed along with the uterine lining.

By contrast, many women who take combination therapy today take both estrogen and progestin every day, a pattern that does not induce bleeding. It is not clear if the study's results apply to such women.

More controversially, the NCI researchers also analyzed their results by the women's weight. A woman was considered heavy if she had a body mass index of more than 24.4. (To calculate body mass index, multiply weight in pounds by 703 and divide that figure by height in inches squared.)

When analyzed this way, the results become hard to interpret. There was no increased breast cancer risk in heavier women whether they took estrogen alone or in combination with progestin, Schairer said. This may be because heavier women are already at increased risk because fat tissue makes estrogen, which can drive some breast cancers.

In leaner women who were current or recent hormone users, the increased risk of breast cancer was 3 percent per year with estrogen alone and 12 percent per year on the combination therapy. But this could merely reflect a detection bias - it's easier to find breast cancers on mammograms in thin women with small breasts.

Furthermore, the NCI data actually found that among heavier women, taking estrogen alone appeared to reduce annual breast cancer risk "which doesn't make any sense biologically,"

noted Col.

The researchers also divided up their data into unusual chunks of time. Most studies analyze results in 5-year intervals - five years or more of hormone use, or 5 to 10 years and so on. The NCI team used intervals of 2, 4, 8, and 16 years. "This makes me wonder whether they were juggling their cut points," Col said. In other words, whether the researchers were regrouping the data to make the findings appear stronger.

While the researchers' goal was to prove or disprove the hypothesis that adding progestin to estrogen therapy at menopause increases breast cancer risk, "I am not convinced that they showed this. Most of their reported findings did not reach statistical significance," Col added.

And why would adding progestin increase breast cancer risk in the first place? Some researchers think progestin may drive the proliferation of breast cells, but this is controversial.

What does seem clear is that women who take hormones for relief of menopausal symptoms like hot flashes for only two or three years "should not be influenced by fear of cancer risks," as Willett noted in the editorial.

It is also clear that women who have had a hysterectomy should not take combination therapy; in fact, it is already customary for doctors to tell women without a uterus to take estrogen alone if they want any hormone therapy at menopause.

As always, specialists say, the bottom line is that women should talk over risks and benefits of hormone therapy with their doctors.

Increasingly, there are also other options - diet and exercise to control the risks of osteoporosis and heart disease, SERMS (selective estrogen receptor modulators) such as raloxifene and tamoxifen to reduce the risk of osteoporosis and breast cancer, and other drugs to control cholesterol and strengthen bones.

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