Marcia L. Stefanick, Ph.D.
Committee, and Principal Investigator
Associate Professor of Medicine
for Research in Disease Prevention
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
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. The
results in general were positive, showing that each of the various hormone
regimens reduced "bad" cholesterol levels and raised "good" cholesterol levels,
did not increase blood pressure, and slowed bone loss. However, the picture was
complicated by some unfavorable changes and by differences in the effects of
the hormone regimens. Estrogen alone appeared to have stronger
cardio-protective effects than the combination therapies. On the other hand, a
large percentage of the participants who took estrogen alone had a high rate of
overgrowth of the lining of the uterus, which can lead to cancer. This result
had an immediate effect on the WHI study, which was already under way when the
PEPI results were reported in 1995. All the women with a uterus who entered the
WHI were thereafter assigned to receive estrogen plus progestin. Only the women
who had had a hysterectomy were given estrogen alone.
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.