"It is reassuring that breast cancer risk begins to return to normal six months after women stop combined dose estrogen-progestin therapy," said Duane Alexander, M.D., of the National Institutes of Health. "Women, in consultation with their physicians, need to make the most informed decision possible. The study authors have provided them with one more piece of important information."

The Women's Health Initiative trial was the first large clinical trial to assess the risks and benefits of continuous combined hormone therapy. In July 2002, researchers stopped the trial because the risk of breast cancer and heart disease from combined hormone replacement therapy outweighed its potential benefits.

In combined therapy, women take both estrogen and progestin. Estrogen relieves vasomotor symptoms of menopause, as well as sleeplessness and vaginal dryness. In women with an intact uterus, estrogen increases the risk for endometrial cancer. Thus, combination therapy was developed to eliminate the risk for endometrial cancer.

"In planning the [National Institutes of Health] study, we sought to learn as much as
we could about the risks associated with the various kinds of hormone therapy," said Robert Spirtas, DrPH, senior author of the study. "At the time, little information existed on whether combined hormone therapy posed the same risks as estrogen therapy alone."

In the earlier study, the Women’s Health Initiative trial, women used continuous combined hormone therapy and researchers monitored their health during the course of the study. When it became clear that the women were developing breast cancer at higher than normal rates, the researchers stopped the trial. Because the study was stopped only recently, this group of researchers cannot tell yet whether the women in the study face any increased risk of after discontinuation of hormone therapy.

In contrast, researchers for the current study began by questioning women who had been diagnosed with breast cancer about their hormone use and other potential risk factors for breast cancer. These women were then compared with a similar group of women who had not developed breast cancer.

The researchers enrolled women who had been diagnosed with breast cancer between July 1, 1994 and April 30, 1998 at treatment centers in a number of U.S. cities. A total of 3823 postmenopausal white and black women were analyzed for the study. In all, the medical histories of 1870 women who had developed breast cancer were compared with the histories of 1953 women who did not have breast cancer.

The researchers found that women on continuous combined therapy for 5 years or more were 1.54 times more likely to develop breast cancer than other women their age not on
this form of therapy. The risk of breast cancer increased the longer the women used hormone replacement therapy. However, six months after women discontinued the combined therapy, their risk of breast cancer began to return to normal. This held true for women who took hormones for 5 years or longer before stopping, as well as for women who took the hormones for only about 6 months.

"Our data suggest a positive association between continuous combined hormone replacement therapy and breast cancer risk among current, longer term users," the authors concluded. "Progestin administered in an uninterrupted regimen may be a contributing factor."

"The [current] study also included former users, and our data indicate that the increased risk associated with use of continuous combined hormone therapy began returning to normal about 6 months after the women stopped using them," Dr. Spirtas said.

The analysis also found that an alternate form of hormone therapy, in which hormones are taken separately on different days of the month, may not increase breast cancer
risk for this group of women. The alternate form of therapy, sequential estrogen-progestin therapy, includes a number of regimens in which patients take the hormone progestin only for 5 to 14 days per month. Earlier studies have indicated, however, that sequential estrogen-progestin therapy may increase the risk for endometrial cancer, although the increase in endometrial cancer from sequential estrogen-progestin therapy is thought to be less than the risk from taking estrogen alone.

Researchers also evaluated risks for women who took estrogen only as hormone replacement therapy after hysterectomy. There was no evidence of any additional risk of breast cancer in these women. However, a recent study by the National Cancer Institute found that women taking estrogen alone may be at increased risk for ovarian cancer.