NIH News Release
National Cancer Institute

Friday, January 28, 2000

Contact: NCI Press Office
(301) 496-6641

Study Shows Greater Risk of Breast Cancer with Estrogen-Progestin Therapy Compared to Estrogen Alone

Researchers from the National Cancer Institute (NCI) in Bethesda, Md., have found that combined estrogen-progestin replacement therapy is associated with a greater risk of breast cancer than estrogen alone. Both groups had a higher risk than non-users. The study appears in the Jan. 26 issue of the Journal of the American Medical Association (JAMA). *

Using follow-up data from 46,000 women who participated in the Breast Cancer Detection Demonstration Project (BCDDP), a nationwide breast cancer screening program conducted between 1973 and 1980, the scientists found that compared to non-users, the relative risk for breast cancer increased by 8 percent per year for the estrogen-progestin therapy compared to 1 percent for estrogen therapy alone in women who had used hormones during the previous four years. There was no increase in risk among women who had stopped either therapy for more than four years. (Relative risk calculates the risk of developing breast cancer in the group of women taking hormones compared to that of women not on therapy.) For women who had used hormones during the previous four years, the average length of use was 3.6 years for the estrogen-progestin therapy compared to 10.3 years for estrogen alone.

When the scientists looked at subgroups of women, they found increases in risk associated with hormone replacement therapy among lean women, but not heavy women. Compared to non-users, among lean women the rate of breast cancer increased by 12 percent for each year of estrogen-progestin use compared to 3 percent for estrogen alone. (Leanness was measured by body mass index, BMI, which takes into account both height and weight. See The women at increased risk in this study had a BMI of 24.4. or less.)

For lean women, the researchers also found that the longer a woman used the hormones, the more likely she was to develop breast cancer. In contrast, short-term use was not associated with increased risks.

“These results, as well as those from other studies, suggest that women who take hormones for two to three years for relief of menopausal symptoms are not at increased risk of breast cancer,” said Catherine Schairer, Ph.D., first author of the study from NCI’s Division of Cancer Epidemiology and Genetics, Bethesda, Md.

The data for the current study was collected between 1980-1995 by follow-up telephone interviews and questionnaires of participants in the original BCDDP. The study focused on women who took hormone pills; those reporting hormone use in the form of shots, creams, or patches were excluded. Eighty-six percent of the participants were white, 5 percent black, 2 percent Hispanic, and 5 percent Asian-Americans. The increased risk was largely limited to lean women who had taken the combined therapy for longer periods of time, including the last four years of the study. Those who had stopped hormone use more than four years prior to the diagnosis of breast cancer had about the same risk as non-users.

Estrogen therapy became available for menopausal women in the 1940s, and was administered then in high doses without progestin. In the l970s, however, it became clear that women who received estrogen alone had a six to eight times higher risk of developing cancer of the endometrium (the lining of the uterus) than non-users. Since then, researchers have found that the addition of progestin to estrogen reduces the risk of endometrial cancer. As a result, it has become increasingly common to prescribe estrogen-progestin replacement therapy for women who have not had a hysterectomy (surgery to remove the uterus).

Reliable data on the effects of estrogen-progestin therapy on breast cancer risk are only recently available. Three studies – the pooled analysis of more than 90 percent of the world’s epidemiological data that appeared in 1997, a preliminary updated report in1998 from the Nurses’ Health Study, and an updated analysis from a Swedish study suggest that the estrogen-progestin regimen is associated with greater increases in breast cancer risk than estrogen alone, consistent with the current study.

The current study, however, differs in certain aspects from others. The authors found that hormone replacement therapy among lean women was associated with increases in both early and later stage invasive disease whereas in the 1997 pooled analysis increases in risk were greater for localized rather than distant or later-stage disease. However, the 1997 report did not look at the extent of disease in lean women. In addition, Schairer et al found increased risk of invasive ductal and lobular cancers whereas a report last year in JAMA found that hormone replacement therapy did not increase the occurrence of invasive ductal or lobular cancers.

Although several studies have reported beneficial effects of hormone replacement therapy on the bone and heart, Schairer’s study as well as other data suggest possible risks and uncertainties.

“An individual woman’s decision to take hormone replacement therapy depends on a analysis of the risks versus the benefits which do not easily lend themselves to simple formulas,” said Schairer. “The potential increased risk of breast cancer with hormone replacement therapy has to be weighed against the reduced risks of bone fractures and possible coronary heart disease. However, it does seem clear that if a decision is made to use hormones, that estrogen alone is recommended for women without a uterus and that hormone use for two to three years is not likely to substantially increase the risk of breast cancer.”

Several other issues are expected to be addressed in future studies. For example, it is not clear whether continuous progestin use carries the same risks as the use of progestins for 15 or fewer days per month, the most common regimen in this study. Additional studies are also needed to define the risks associated with long-term use of combined therapy.

For more information about cancer visit NCI's Web site for patients, public, and the mass media at

* The study is titled, “Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk.” The authors are Catherine Schairer, Jay Lubin, Rebecca Troisi, Susan Sturgeon, Louise Brinton, and Robert Hoover. JAMA, Jan. 26, 2000, Vol. 283, No.4.

Additional References:

1. “Breast Cancer and Hormone Replacement Therapy.” The authors are Collaborative Group on Hormonal Factors in Breast Cancer. Lancet, 1997; 350: 1047-1059.

2. “Use of Estogen Plus Progestin is Associated with Greater Increase in Breast Cancer Risk than Estrogen Alone.” The authors are Graham Colditz and B. Rosner for the Nurses’ Health Study Research Group. American Journal of Epidemiology 1998: 147(suppl):84S.

3. “Hormone Replacement Therapy and the Risk of Breast Cancer with a Favorable Histology.” The authors are Susan M. Gapstur, Monica Morrow, and Thomas A. Sellers. JAMA. 1999;281:2091-2097.

4. “Risks of Breast and Endometrial Cancer After Estrogen and Estrogen-Progestin Replacement.” The authors are I. Persson, E. Weiderpass, L. Bergvist, R. Bergstrom, C. Schairer. 1999 Cancer Causes Control 1999: 10(4):253–260.