According to Essential Science Indicators
fromClarivate, the paper,
"Risks and benefits of estrogen plus progestin in
healthy postmenopausal women—principal results
from the Women's Health Initiative randomized
controlled trial" (Rossouw JE, et al., JAMA
288: 321-33, 17 July 2002), ranks at #4 among
Highly Cited Papers in Clinical Medicine, garnering
4,123 cites from the time of its publication to
February 29, 2008.
Dr. Jacques Rossouw is the lead author of this
paper. Dr. Rossouw's record in Essential Science
Indicators includes 28 papers cited a total of
12,977 times in the field of Clinical Medicine.
Dr. Rossouw is the chief of the Women's Health Initiative, which was
established in 1991 by the National Heart, Lung, and Blood Institute at the
National Institutes of Health "to address the most common causes of death,
disability and poor quality of life in postmenopausal women
—cardiovascular disease, cancer, and osteoporosis."
This month, ScienceWatch.com talks
with Dr. Rossouw about this groundbreaking
Please tell us about the aims and design of the
trial described in the paper.
The Women's Health Initiative (WHI) randomized trial of estrogen plus
progestin versus placebo was designed to answer the question of whether
hormone therapy given to postmenopausal women aged
50-79 years and with an intact uterus would prevent coronary heart
disease. Breast cancer
was monitored as a major potential adverse outcome, and we also
monitored several other important conditions to assess whether the
overall benefits of hormone therapy outweighed the risks.
The hormones selected for study were conjugated equine estrogen at a dose
of 0.625 mg/day plus medroxyprogesterone acetate at a dose of 2.5 mg/day,
since these are the most widely used postmenopausal hormones in the US, and
prior data from non-randomized observational studies had suggested that
they might reduce risk of coronary heart disease. The trial was conducted
in 40 clinical centers across the US, and the published report was on
behalf of the entire WHI investigator group. The WHI is funded by the
National Heart, Lung, and Blood Institute.
What were the findings of this study?
publication of these findings
gained widespread attention in the
media and in scientific
The trial was stopped early—after 5.2 years of data had accumulated
rather than the planned 8.5 years—on the recommendation of the
independent Data and Safety Monitoring Board. The immediate reason for
stopping was that the risk of breast cancer on estrogen plus progestin
became significantly elevated, and crossed the pre-specified monitoring
boundary for safety. Additionally, the risks of coronary heart disease,
stroke, and venous thromboembolism were significantly elevated,
and these risks were not counterbalanced by the reduced risks of hip
fracture and colorectal cancer.
Hence, the primary hypothesis—that hormone therapy would reduce the
risk of coronary heart disease—was not borne out and in fact the
result was opposite to what was anticipated. Also, the balance of benefits
and risks was in an unfavorable direction.
The implications of these findings were that this hormone therapy should
not be used for prevention of coronary heart disease, and indeed, in view
of the many adverse effects, it was not suitable for prevention of chronic
How were these results received by the
The publication of these findings gained widespread attention in the media
and in scientific circles. This resulted in a marked shift in attitudes
towards this hormone therapy, with prescriptions dropping by some
two-thirds in the months following publication (and remaining at those or
lower levels since then). The Food and Drug Administration changed the
package insert of all hormone therapies to include warnings about not using
them for prevention of coronary heart disease, and relegating them to
second-line treatment status for prevention of
osteoporosis. The major indication for oral hormone
therapy is now for the short term, at the lowest doses possible, for the
relief of hot flashes and night sweats.
Cardiologists and internists who deal with long-term prevention of chronic
diseases readily accepted the findings, and now focus on proven and
effective non-hormonal strategies for prevention. Gynecologists had more
difficulty with dealing with the findings because there are few effective
alternatives for the treatment of hot flashes and night sweats.
Has the balance of the risks and benefits of hormone use
in postmenopausal women been explored further since the publication of
this paper? If so, have the findings differed from those in this
The original paper has withstood the test of time, and indeed a parallel
study in the UK (stopped within a few years of starting after WHI published
its findings) using the same estrogen and progestin has published data that
are very consistent with our findings.
Estrogen alone (without a progestin) has a somewhat more favorable profile.
In 2004 the WHI investigators published the results of the trial of
estrogen alone. This, too, was stopped early (after 6.8 years) but in this
instance because of an increased risk of stroke, with no benefit for heart
disease. Like estrogen plus progestin, estrogen alone also increased the
risk of venous thromboembolism and decreased hip fractures, but unlike
estrogen plus progestin, it did not have any effect on breast cancer or
colorectal cancer. The increased risk of stroke and venous thromboembolism
makes estrogen alone unsuitable for long-term prevention.
safe to predict that hormone
therapy for prevention of coronary
heart disease will not regain
Since the publication of the primary results of the hormone trials, several
secondary papers from both trials have explored the data in more detail,
but the overall conclusions and recommendations have not changed. The risk
of coronary heart disease due to hormones may be modified by age or years
since menopause at time of initiation, such that there is no increased risk
in women closer to the menopause compared to the clearly increased risk in
women more distant from the menopause. On the other hand, the increased
risk of stroke due to hormones does not depend on years since menopause,
and neither does the increased risk of breast cancer on estrogen plus
The findings of no increased risk of coronary heart disease in women
initiating hormones within 10 years of the menopause are somewhat
reassuring for those women considering short-term hormone therapy for the
relief of hot flashes and night sweats. In any case, at those younger ages
women are at very low risk of coronary heart disease. However, the data
provide no reassurance that initiation at a younger age, if continued for
decades into older ages, will result in continued freedom of risk from
coronary heart disease. Given this uncertainty, and together with the many
off-target effects of long-term hormone therapy (such as breast cancer,
stroke, venous thromboembolism), it is safe to predict that hormone therapy
for prevention of coronary heart disease will not regain favor.
We have recently published the results of the first three years of
follow-up after stopping estrogen plus progestin, and the results show that
there was no increased risk of coronary heart disease, stroke, or venous
thromboembolism after stopping. There was still some increased risk of
breast cancer in the three-year period, but the trend towards
ever-increasing risk towards the end of the original trial period was no
Overall cancer risk appeared to increase after stopping hormones, perhaps
due to a carry-over effect of the trial exposure. The in-trial benefits for
hip fracture and colorectal cancer did not carry over into the first three
years after stopping.
What other research questions are the Women's Health
Initiative working on?
We will continue to follow the study cohorts to gain further insights into
what happens when the hormone therapy is stopped. We are doing several
laboratory-based studies of risk markers, genomics, and proteomics to see
if we can identify women who might be at increased risk if they take
hormone therapy. One such study suggests that it might be useful to measure
the blood cholesterol levels prior to hormone therapy—elevated
cholesterol levels themselves confer risk of coronary heart disease, and
that risk appears to be amplified further by hormone therapy.
Where do you see this work going in five to ten
The WHI has several other components, including trials of low-fat dietary
pattern and calcium and vitamin D, together with a large observational
study of women who were not enrolled in the trials. We would like to follow
the entire cohort of more than 100,000 women for decades to study the
long-term effects of the interventions. More importantly, many of these
women are now entering their 80s and 90s and form an extremely valuable
resource for studying the predictors of healthy aging, or on the other hand
predictors of frailty, loss of cognitive function, and congestive heart
failure. These and other conditions affecting aging women will consume an
increasing proportion of the nation's health budget, and it would be
important to identify factors that might help us avoid them.
Jacques Rossouw, M.D.
Women's Health Initiative Branch
Division of Prevention and Population Studies
Bethesda, MD, USA
's most-cited paper with 5,821 cites to
Cleeman JI, et al., "Executive summary of the
third report of the National Cholesterol Education Program
(NCEP) expert panel on detection, evaluation, and treatment
of high blood cholesterol in adults (Adult Treatment Panel
III)," JAMA 285(19): 2486-97, 16 May 2001. Source:
Essential Science Indicators from
Keywords: Jacques Rossouw, women's health initiative, whi,
hormone therapy, estrogen, progestin, healthy postmenopausal women,
randomized controlled trial, risks, benefits, elevated breast cancer
risk, coronary heart disease, stroke, venous