Healthy Hormones

Study Finds New Risks in Hormone Therapy

By Denise Grady — New York Times
June 25, 2003

One year after a major study linked postmenopausal hormone therapy to an increased risk of breast cancer, new findings from the same study paint an even more ominous picture of the hormones’ role in the disease.

In addition to stimulating the growth of breast cancer, the combination of hormones used in a common type of therapy also makes tumors harder to detect, leading to dangerous delays in diagnosis, researchers are reporting today in The Journal of the American Medical Association.

The new results deal with a widely used type of hormone therapy that combines estrogen and progestin; the most popular brand is Prempro, made by Wyeth. The results do not apply to the use of estrogen alone, although a second study, also published in the journal today, found that estrogen alone did not increase the risk of breast cancer.

Women who take the combination are also more likely to have changes in their breast tissue that lead to abnormal mammograms, problems that can show up as soon as the first year of hormone use. Many of the abnormalities turn out to be harmless, but they can be nerve-racking and risky, since they require further tests that may include biopsies.

Of the estimated three million women in the United States who now take combined hormones, about 120,000 a year may have abnormal mammograms solely because of their hormone treatment, the researchers said.

The total number of women taking these hormones reflects a decline of more than 50 percent after the study last year that cautioned against long-term use of the combined hormones. But because breast abnormalities can develop so soon after a woman starts taking hormones, the new findings are now raising questions about the safety of even short-term use, which is commonly recommended to treat severe hot flashes and other menopausal symptoms.

The hormone combination is now approved in the United States only to treat menopausal symptoms and to prevent the bone-thinning disease osteoporosis. Because the hormones have risks, women are advised to use the lowest dose for the shortest time possible and to consult their doctors about other ways to prevent osteoporosis.

A sharply worded editorial accompanying the new report said it provided “further compelling evidence against the use of combination estrogen plus progestin hormone therapy.”

Natalie de Vane, a spokeswoman for Wyeth, said yesterday that the new data about hormone therapy is “clearly important for women to know.”

But she said that hormones like Prempro are still necessary because they are currently the only products that have been approved to treat moderate to severe menopausal symptoms, including hot flashes and night sweats.

“They should be taken for the shortest duration of time at the lowest dose,” Ms. de Vane said. “Hormone therapy is not a lifetime commitment.”

Bad news has been piling up about hormones, which were once promoted as every woman’s key to lasting youth, health and femininity. Recent studies have found that many of the expected benefits never materialized and, indeed, that hormones raise the risk of several serious diseases, including some they were supposed to prevent. The increased risks are small, but many doctors say even a small risk is not worth taking if there is no benefit to counterbalance it.

For example, another study, published last month in The Journal of the American Medical Association, found that combined hormones doubled the risk of Alzheimer’s disease and other types of dementia in women who began the treatment at age 65 or older. That result was an especially hard blow because many doctors and patients had hoped for the opposite result — that hormone therapy would prevent dementia.

Researchers had also once thought hormones might prevent heart attacks and strokes, but the latest findings — from the Women’s Health Initiative, a large federal study of the combination therapy that was stopped ahead of schedule a year ago because the hormones caused a small but significant increase in the risk of breast cancer — also found that hormones increased those risks. Hormones also increased the likelihood of blood clots.

The Women’s Health Institute study included 16,000 women and is widely considered to be the most reliable and scientificially rigorous of the many studies on hormone therapy because it was the largest experiment to compare women on hormones with a group taking placebos.

Many women gave up hormone therapy after the first report came out last July. Before it was published, about six million women were taking combination therapy; now the figure is less than half that.

Today’s report is based on a further analysis of the data from the Women’s Health Initiative. The first report predicted that, in a group of 10,000 women taking hormones, 41 per year would develop breast cancer, compared with 33 in a group of 10,000 women not on hormones. The latest report found a similar increase in risk after 5.6 years of follow-up.

What is new in today’s report is the finding that, compared with women not on hormones, those who take estrogen and progestin tend to develop tumors that are discovered at a more advanced stage and are harder to cure.

Of the 8,506 women on hormones in the study, 199 developed invasive breast cancers, compared with 150 cases in the 8,102 women taking placebos. In the women using hormones, 25.4 percent had cancers that had begun to spread either to nearby tissue or distant parts of the body, compared with only 16 percent in the placebo group. All the women in the study had yearly mammograms.

It is not known why women on hormones were more likely to have advanced tumors. One reason may be that tissue changes caused by the hormones made their mammograms harder to read and hid the tumors until they grew large. It is also possible that the hormones made tumors grow faster.

In addition, after one year of treatment, 9.4 percent of women in the hormone group had abnormal mammograms, as opposed to only 5.4 percent in the placebo group. The risk, therefore, of an abnormal mammogram linked to hormone therapy translates into 1 in 25 treated women per year.

“This reinforces the breast cancer data and, for the first time, raises a new concern regarding the risk-benefit ratio of short term use,” said Dr. Rowan T. Chlebowski, the lead investigator in the study and a medical oncologist at the Research and Education Institute at Harbor-U.C.L.A. Medical Center in Torrance, Calif. “This will give women something to think about. Do you want to take an intervention like estrogen plus progestin that will reduce hot flashes 90 percent, probably, at the cost of having a 1 in 25 chance of having this abnormal mammogram, which might be more significant? I think a lot of women with modest symptoms will now say, `Wait a minute.’ “

Dr. Clifford Hudis, chief of breast cancer medicine at Memorial Sloan-Kettering Cancer Center in New York, said, “The whole health benefit story for hormones has really unraveled.”

Dr. Chlebowski said that earlier studies had suggested that women on hormones who got breast cancer tended to develop less aggressive types of cancer that were detected early and relatively easy to treat. But, he said, the new study contradicts that theory.

“We saw cancers which didn’t have favorable characteristics, and were found in higher numbers at a higher stage,” he said.

Dr. Peter H. Gann, a cancer epidemiologist at Northwestern University and an author of the editorial in the journal, said: “It’s unique to have an agent that does this, both delays the diagnosis while accelerating growth. I think the bottom line is that this is further compelling evidence against using it.”

A second report in the same issue of the journal found that combined hormones increased breast cancer risk even when the progestin was given in a sequential manner, meaning on only certain days of the month, as opposed to every day, as with Prempro. Some advocates of hormone therapy had suggested that sequential therapy might be safer.

The second study, directed by Dr. Christopher I. Li of the Fred Hutchinson Cancer Research Center in Seattle, also found that women who took estrogen only, without progestin, had no increased risk of breast cancer, even if they took the hormone for 25 years or more. Estrogen alone can cause cancer of the uterus and so is prescribed only for women who have had hysterectomies. Women who have not had hysterectomies are given combination treatment because progestin can protect the uterus from the harmful effects of estrogen.

But progestin can also stimulate the growth of breast cells, and it is widely believed to be the culprit in causing breast cancers that occur in women who are on hormone treatment.

Women who take estrogen alone are still being studied as part of the Women’s Health Initiative, with results expected in 2005. That this arm of the study has not yet been stopped indicates that, so far, estrogen has caused neither significant harm nor significant benefit.

The Food and Drug Administration recently approved two lower-dose formulations of Prempro, said Ms. de Vane, of Wyeth. One of those will become available in the next couple of weeks, she said, while the lowest-dose pill will be in drugstores by the end of the year.

Wyeth projects that sales of its hormone replacement products will total about $1.5 billion this year, she said. The company does not expect that projection to change because of the new findings.

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