Marcia L. Stefanick, Ph.D.
Chair, Steering Committee, and Principal Investigator
Women's Health Initiative
Associate Professor of Medicine
Stanford Center for Research in Disease Prevention
Stanford University

July 9, 2002

Press Conference Remarks

Release of the Results of the Estrogen Plus Progestin Trial of the Women's Health Initiative:
Study Rationale and Design

Thank you, Dr. Lenfant.

The Women's Health Initiative was designed to study strategies for preventing diseases that are the major causes of death, disability, and frailty in women as they age, namely, heart disease, breast and colon cancer, and osteoporosis. Today, we are talking about the results of the one component of the WHI that has been stopped--the clinical trial to examine the effect of estrogen plus progestin. A separate clinical trial of estrogen alone is continuing.

Like most women with a uterus who take hormone therapy, the women who had not had a hysterectomy before joining the WHI trial were given estrogen in combination with progestin. This hormone combination is known to help prevent endometrial cancer. About 6 million women in the United States take it.

The objective of the trial was to examine the effect of estrogen plus progestin on the prevention of heart disease and hip fractures, and any associated change in the risk for breast and colon cancer.

The 16,608 participants in the study were healthy, active postmenopausal women ages 50 to 79 who had an intact uterus. These volunteers were recruited at 40 clinical centers across the country. They came from a wide variety of backgrounds and circumstances; about 16 percent were minorities.

The study design called for the women to be randomly assigned to two similar groups. One group received estrogen plus progestin, and the other received a placebo. During the trial, neither the women nor the clinic staff were told which type of pills the participants were taking, unless safety concerns arose. Participants were contacted every 6 months to assess their health status. In addition, the women had a mammogram and clinical breast exam every year. Originally, the study was planned to continue for 8.5 years, but was stopped after 5.2 years of follow-up.

The WHI estrogen plus progestin trial was designed in light of previous studies that suggested that hormone therapy reduces heart disease. Earlier studies also suggested other effects of hormone use, both positive and negative, and the women in the WHI were informed about the known risks and benefits as they enrolled in the study. These included possible lower rates of fractures due to osteoporosis, but higher rates of breast cancer and blood clots in the legs and lungs among users of estrogen. Much less was known about progestin or the estrogen plus progestin combination. For example, progestins appear to counter estrogen's effects in certain tissues such as the uterus, but may enhance the effects in other tissues such as the breast and bone. The bottom line is that none of these earlier studies was able to provide the definitive answers about the overall balance of risks and benefits that we now have in the WHI study.

Among the various studies that influenced the WHI's design, two stand out as particularly important. The first is an NHLBI-funded study begun in the late 1980's, the Postmenopausal Estrogen and Progestin Intervention Study--or PEPI. This study tested the effects of different types of hormone regimens--estrogen alone and three different progestin regimens--on heart disease risk factors (not heart disease itself) and on bone mass.

Another major study of relevance to WHI is the Heart and Estrogen-Progestin Replacement Study, or HERS, which was reported in 1998. In contrast to the WHI trial, HERS was conducted in women who already had heart disease. It tested whether estrogen plus progestin would prevent a second coronary event. Surprisingly, HERS showed no benefit in reducing fatal or non-fatal heart attack. In fact, there was actually a greater coronary risk among hormone users in the first year. Over time, the excess risk disappeared and, by the end of the study, there was no overall difference in heart attacks between the treatment and the placebo groups. Like other studies, HERS also showed an increase in blood clots in the legs and lungs. The women in the WHI study were informed about the HERS findings, but the trial continued because at that time it was unclear whether the HERS results in women with heart disease applied to the healthy women in the WHI.

HERS is continuing to provide relevant results. Just last week, JAMA published findings from the HERS Follow-Up Study that showed no benefit of continuing estrogen and progestin. The investigators recommended that women on this combination therapy should not continue for the purpose of preventing another coronary event.

Today, as we report the results of the WHI, we do so in light of previous research that pointed to a complicated picture of hormone therapy's overall risks and benefits. The WHI results which you will hear shortly give us an answer using the "gold standard" of research--the randomized clinical trial. They will help inform medical practice and guide millions of women in making critical decisions about their health as they grow older.

Dr. Anderson.