WHI follow-up study: Risks of long-term hormone therapy continue to outweigh benefits

March 04, 2008

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 therapy."

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 studies.
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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.

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.

The National Institutes of Health (NIH) -- The Nation's 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 its programs, visit http://www.nih.gov.

NIH/National Heart, Lung and Blood Institute

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