|WHI Follow up Study Confirms Health Risks of
Long-Term Combination Hormone Therapy Outweigh Benefits for Postmenopausal
New results from the Women's Health Initiative (WHI) confirm that
the health risks of long-term use of combination (estrogen plus
progestin) hormone therapy in healthy, postmenopausal women persist
even a few years after stopping the drugs and clearly outweigh
the benefits. Researchers report that about three years after women
stopped taking combination hormone therapy, many of the health
effects of hormones such as increased risk of heart disease are
diminished, but overall risks, including risks of stroke, blood
clots, and cancer, remain high. The WHI is sponsored by the National
Heart, Lung, and Blood Institute (NHLBI) of the National Institutes
of Health (NIH).
Results of the WHI three-year follow-up study of the estrogen
plus progestin clinical trial are published in the March 5, 2008,
issue of the Journal of the American Medical Association.
"The good news is that after women stop taking combination hormone
therapy, their risk of heart disease appears to decrease," noted
Elizabeth G. Nabel, M.D., NHLBI director. "However, these findings
also indicate that women who take estrogen plus progestin continue
to be at increased risk of breast cancer, even years after stopping
therapy. Today's report confirms the study's primary conclusion
that combination hormone therapy should not be used to prevent
disease in healthy, postmenopausal women."
The FDA recommends that hormone therapy never be used to prevent
heart disease, and, when hormone therapy is used for menopausal
symptoms, it should only be taken at the smallest dose and for
the shortest time possible.
The new findings are from a follow-up study of 15,730 postmenopausal
women with an intact uterus, ages 50 to 79 years (average age of
63) at enrollment, who participated in the WHI estrogen-plus-progestin
clinical trial. Participants were randomly assigned to receive
a combination of estrogen (0.625 milligrams of conjugated equine
estrogens per day) plus progestin (2.5 mg of medroxyprogesterone
acetate) or placebo (inactive pill). The main estrogen-plus-progestin
study was stopped in 2002 after an average of 5.6 years of treatment
due to an increase in breast cancer. Women on combination hormone
therapy were also at increased risk of stroke, blood clots, and
heart disease, while their risk of colorectal cancer and hip fractures
was lower, compared to women who did not take hormone therapy.
The follow-up study began in July 2002 after women in the study
were instructed to stop taking combination hormone therapy, and
continued through March 2005, with participants followed for an
average of 2.4 years. All study participants were examined at least
once a year by a WHI clinician and received an annual breast examination
and mammogram, with biopsies performed as needed. During the follow-up
study, the numbers of heart attacks, strokes, and blood clots were
not significantly different between the two groups (overall, 343
cardiovascular events among those who initially received hormone
therapy versus 323 among those who did not). In addition, the number
of deaths was not significantly different (233 women who had been
in the hormone therapy group died, versus 196 women who had been
in the placebo group).
"After being on combination hormone therapy for several years,
the women's risk of cardiovascular disease was significantly higher — from
a 29 percent increase in heart attacks to a 41 percent increase
in strokes and nearly twice the risk of serious blood clots — compared
to the women who did not take hormones," said Michael S. Lauer,
M.D., director of the NHLBI Division of Prevention and Population
Sciences. "While it is reassuring that heart attack risk decreased
and that the risks for stroke and blood clots did not grow after
the women stopped taking hormones, this study provides further
evidence that five years
of combination hormone therapy is harmful. All the accumulated
risks do not simply disappear."
The study also found that other effects of combination hormones,
such as decreased risk of colorectal cancer and hip fractures,
also stopped when therapy ended.
"We continue to encourage women to use hormones only if needed
for menopausal symptoms, and for the shortest time possible, and
to adopt and maintain a healthy lifestyle, that is, engage in regular
physical activity, maintain a healthy body weight, consume a diet
low in saturated fat, and to not smoke, to reduce their risks of
cardiovascular and other chronic diseases," said Marcia Stefanick,
Ph.D., professor of medicine at Stanford University, Stanford, Calif.,
and a coauthor of the paper, as well as chair of the WHI Steering
Committee. She added that women should know their cholesterol and
blood pressure levels and other health risks and take preventative
measures, as needed.
In contrast to the other effects, the risk of breast cancer continued
at a rate similar to that seen during treatment. Women who had
stopped taking estrogen plus progestin were about 27 percent more
likely to develop breast cancer than the women who didn't take
hormones during the study, with 79 women in the post-treatment
group developing breast cancer during the three-year follow-up
study, compared to 60 women in the non-treatment group.
"The hormones' effects on breast cancer appear to linger," noted
Leslie Ford, M.D., associate director for clinical research in
the Division of Cancer Prevention of the NIH's National Cancer
Institute. "These findings reinforce the importance of women getting
regular breast exams and mammograms, even after they stop hormone
Researchers also report a 24 percent increased risk of
developing any form of cancer among women who had been in the treatment
group. Overall, there were 63 more diagnoses of cancer during the
follow-up study, or three per 1,000 participants
per year, among women who had taken combination hormone therapy
compared to women who did not take hormones during the study (281
diagnoses compared to 218). A more detailed analysis on the cancer
findings is underway.
"The continued increased risk of breast cancer clearly plays a
role in the increased overall risk of cancer years after stopping
long-term estrogen plus progestin therapy, and it is important
that we continue to follow these women," added Stefanick, noting
that the new results provide further evidence that the health risks
of long-term combination hormone therapy outweigh the benefits.
The WHI is a major, 15-year research program designed to address
the most frequent causes of death, disability, and poor quality
of life in postmenopausal women: cardiovascular disease, cancer,
and osteoporosis. The principal findings from the two WHI hormone
therapy trials, which studied 27,347 postmenopausal women on estrogen
plus progestin, estrogen-alone, or placebo, found that the overall
risks of long-term use of hormone therapy outweigh the benefits.
Both of these trials were stopped early because of increased health
risks and failure to prevent heart disease, a key question of the
In addition to NCI, NHLBI collaborates on the WHI with the National
Institute of Arthritis and Musculoskeletal and Skin Diseases, the
National Institute on Aging, and the Office of Research on Women's
Health, all parts of the NIH. Wyeth-Ayerst Research provided the
medication and placebo for the hormone study.
To interview Dr. Lauer, call the NHLBI Communications Office at
(301) 496-4236. To speak with Dr. Ford, please contact the NCI
Office of Media Relations at (301) 496-6641. To speak with Dr.
Stefanick, please contact Susan Ipaktchian at 650-725-5375.
For more information:
Part of the National Institutes of Health, the National Heart,
Lung, and Blood Institute (NHLBI) plans, conducts, and supports
research related to the causes, prevention, diagnosis, and treatment
of heart, blood vessel, lung, and blood diseases; and sleep disorders.
The Institute also administers national health education campaigns
on women and heart disease, healthy weight for children, and other
topics. NHLBI press releases and other materials are available
online at: www.nhlbi.nih.gov.
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Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
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