Women who take a commonly prescribed combination of the hormones estrogen and progesterone after menopause may increase their risk of breast cancer much more than previously suspected, according to a major study released yesterday.
The new findings affect millions of American women, many of whom may now re-evaluate whether the benefits of taking the hormones outweigh the risks, experts said. Some experts urged women to consult their doctors in light of the new findings to determine whether long-term hormone treatment makes sense for them.
"This clearly shifts the equations rather seriously in doing the risk/benefit analysis," said Walter Willett of the Harvard School of Public Health, who wrote an editorial accompanying the findings in today's Journal of the American Medical Association. "It definitely makes life more complicated."
About 8.6 million American women take estrogen and progesterone, according to Wyeth-Ayerst Laboratories, a drug company that makes Premarin and other hormone products. Another 12 million women who have had hysterectomies take estrogen alone, according to the company.
The new research found that breast cancer rates were higher in women taking both estrogen and progesterone than in those who took only estrogen. For instance, for each year women take the combination, their risk of breast cancer rose by 8 percent compared with that of nonusers. After 10 years of treatment, the risk would thus be 80 percent higher than that of non-users, or almost double. In contrast, the risk of breast cancer for women taking estrogen alone rose by only 1 percent per year.
At least two other recent studies have raised similar concerns, but the magnitude of the effect of combination therapy in the latest report surprised researchers, Willett said. "Everyone is perhaps stunned by how big the increased risk seems to be," he said.
The possible pros and cons of taking hormones after menopause have long made the decision of whether to take them difficult for women.
Hormones do reduce the frequency of fractures caused by the bone-thinning condition osteoporosis, and alleviate symptoms such as hot flashes, vaginal dryness and insomnia.
Several studies have also found that women who take such treatment for up to 10 years have a lower overall death rate, perhaps in part because of a reduced risk of heart disease, the No. 1 killer of both sexes. But Willett said he thought the potential beneficial effect of hormones on heart disease had been "overpromoted." He added that the recent findings cast doubt on whether combination therapy will turn out to reduce women's overall death rate, since most of the mortality data have come from studies of women taking estrogen alone.
Previous studies, which had suggested a moderate increase in breast cancer rates in long-term hormone users, almost exclusively evaluated women who took estrogen alone. However, because taking estrogen without progesterone promotes development of cancer of the uterus, the regimen now recommended for women who have not had a hysterectomy is "combination therapy" with both estrogen and progesterone. Only recently have researchers been able to study sufficient numbers of women taking the combination to gauge its impact on breast cancer risk.
The new study, by researchers at the National Cancer Institute (NCI) and the University of Massachusetts, examined the relationship between hormone therapy and the incidence of breast cancer in 46,355 post-menopausal women who participated in a large study of mammography between 1980 and 1995. Among those who took hormones, the use of estrogen alone was more common than combination therapy. Women were followed for an average of 10 years, and a total of 2,082 cases of breast cancer were identified.
Hormones increased breast cancer risk only in current or recent users, the researchers found. In women who had taken combination therapy within the previous four years, the risk of breast cancer was 1.4 times that of non-users; in those who had taken estrogen alone within the previous four years, it was 1.2 times that of nonusers. In women who had been off hormones for more than four years, the risk was not significantly elevated.
"I think these results should not discourage a woman from using hormones on a short-term basis for treatment of menopausal symptoms," said Catherine Schairer of the NCI, the study's principal author. "Long-term use is more questionable."
Other researchers said additional information is needed on the impact of combination hormone therapy on breast cancer risk.
"I think the totality of the evidence on the benefit and risk has become less certain," said Andrea Z. LaCroix of Seattle's Fred Hutchinson Cancer Research Center and a key researcher in the Women's Health Initiative, a large government-funded study of hormone therapy after menopause that is due to be completed in 2005. "We don't really know anything about mortality" among women on combination therapy, either from breast cancer or from heart disease.
She noted that a 1998 study in women with heart disease found that combination therapy did not reduce the likelihood of heart attacks or cardiac death.
William Andrews of Eastern Virginia Medical School, who has been paid by Wyeth-Ayerst for lecturing at conferences, noted that several other studies have failed to detect an increased risk of breast cancer among women taking hormones. "Studies with breast cancer are not as overwhelming and not as clear" as the research supporting a link between estrogen and cancer of the uterus, he said. "We don't have the final answer."
In light of the new findings, Willett said he urged postmenopausal women to ask themselves, "Why am I on hormones?" In his commentary accompanying the study, he suggested that fear of cancer should not discourage women from using such therapy for two to three years for menopausal symptoms.
However, Willett suggested that women contemplating long-term treatment for protection against osteoporosis or heart disease should consider alternatives. For instance, osteoporosis can be prevented by exercise, calcium supplements and prescription drugs such as bisphosphates and raloxifene. The risk of heart disease can be reduced by exercise, avoidance of smoking, reducing fat in the diet and treating high blood pressure and cholesterol.