10-Year Anniversary of Landmark Paper From the Women's Health Initiative: What the Findings Mean for You Today
In July 2002, a landmark research paper from the National Institutes of Health (NIH)-supported Women’s Health Initiative (WHI) on hormone therapy was published; “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” This study found that estrogen plus progestin therapy (EPT) increased rather than decreased the risk of heart attack and stroke, as well as blood clots and breast cancer, in healthy postmenopausal women. The study showed that postmenopausal hormone therapy should not be used for prevention of heart disease.
The study findings had far-reaching aftereffects on the use of postmenopausal hormone therapy and on women’s health outcomes. The results led to a U.S. Food and Drug Administration (FDA) “black box” warning against the use of postmenopausal hormone therapy for prevention of heart disease. Many professional societies changed their previous recommendations to caution against using postmenopausal hormone therapy for prevention of chronic diseases, such as heart disease.
On the 10-year anniversary of this landmark paper, Jacques Rossouw, M.D., chief of the WHI Branch at the National Heart, Lung, and Blood Institute (NHLBI), reflects on the outcomes of the study and what lies ahead for the WHI. In the answers below, he discusses the implications for health care providers and for the millions of menopausal women who are trying to determine whether they should use hormone therapy.
Why was the WHI established?
The WHI was established in 1991 to study strategies to prevent the most common causes of death, disability, and poor quality of life in postmenopausal women—heart disease, breast and colorectal cancer, and osteoporosis. This multiyear project, led by the NHLBI, involved more than 161,800 women aged 50–79 years. The WHI Extension Studies program continues to follow 93,500 participants.
What were the key findings of the 2002 WHI research?
The study results showed that healthy postmenopausal women with a uterus who received combined hormone therapy (estrogen-progestin therapy, or EPT) had higher risk of invasive breast cancer, stroke, coronary heart disease (CHD), and pulmonary embolism, compared with women who received placebo pills. Although EPT was found to have noteworthy benefits, including fewer cases of hip fractures and colorectal cancer, on balance the harm was greater than the benefit. Thus this WHI research study, which was scheduled to run until 2005, was stopped after an average followup of 5.6 years. In 2004, the companion trial of estrogen therapy alone (ET) in hysterectomized women (women who had had their uterus surgically removed) also was stopped early because of an increased risk of stroke.
In summary, the large multicenter WHI trials found that both EPT and ET increased risk of stroke, problems with memory and dementia, blood clots in the legs or lungs, urinary incontinence, and gallbladder disease. Both EPT and ET reduced the risk of fractures and of diabetes, compared with women taking placebo pills. However, in contrast to the EPT trial, ET did not increase the risk of CHD and breast cancer, and there was no effect on colorectal cancer.
Why are the findings of this study so important, and how have they changed physician practices since 2002?
Despite decades of data showing a beneficial association of postmenopausal hormone use with heart disease, the WHI trial of EPT demonstrated increased risk of CHD, especially in the first few years. The WHI trial also showed increased risk of stroke, pulmonary embolism, and breast cancer. The overall health risks exceeded the benefits from reduced rates of hip fracture and colorectal cancer and led to the early termination of the trial.
The findings potentially affect all women reaching menopause, two-thirds of whom would have used hormone therapy in the past mainly for the relief of menopausal symptoms. The findings are particularly relevant to older women who use hormone therapy for disease prevention; when the WHI began, 40 percent of prescriptions were for older women.
Since 2002, the prescriptions for postmenopausal hormone therapy have decreased by about two-thirds, with a slightly greater decrease in women older than 60 years. The declines in prescriptions were most noticeable in the first 12 months after the 2002 study results were released, but prescriptions have continued to decline (the latest published data go up to 2009). Standard-dose therapy (conjugated equine estrogen 0.625 mg plus medroxyprogesterone 2.5 mg daily) as tested in the WHI has decreased markedly but remains higher than that of lower dose preparations. In parallel with these changes, the rate of breast cancer has declined in the United States, and data are emerging that rates of CHD and stroke also decreased after 2002.
What important questions surrounding hormone therapy still need to be addressed?
The major research questions relate to finding the biological mechanisms (such as blood factors or changes in the walls of the arteries) underlying increased risk of CHD in the first few years after starting hormone therapy, and why older women are at higher risk than younger women. The most promising leads are that women with high blood cholesterol are at particularly high risk from taking hormone therapy, and so are older women with hot flashes and night sweats.
It is possible that hot flashes and night sweats in older women are signals of abnormally functioning blood vessels. On the other hand, there are questions about whether younger women may reduce their risk of CHD if they initiate hormone therapy close to menopause and continue for many decades. The WHI has provided information that coronary artery calcium (CAC) is reduced in women ages 50–59 who received ET, consistent with a reduction in risk of CHD in that age group. Other studies are looking at whether hormone therapy will reduce CAC or carotid artery intima-media thickness. However, none of these studies is able to answer the question of whether long-term therapy will reduce the eventual risk of CHD as women grow older, and it is not feasible to conduct the very large and very long-term study that would be needed to answer this question. Therefore, it is likely that the WHI data, which include both younger and older women, will remain the most relevant source of reliable information.
The mechanisms underlying the even greater risk of stroke (which occurs irrespective of years since menopause) remain elusive. In regards to breast cancer, there does not appear to be an increased risk in the first few years of EPT, and no increased risk in women on estrogen alone for the duration studied in the WHI (3.5 years of adherent therapy). Other studies indicate that longer exposure to ET is needed to increase breast cancer risk.
How do you decide whether the risks outweigh the benefits of hormone therapy?
As with all trial findings, health care providers need to consider the overall findings and apply them carefully for each woman. It is clear that the risks are greater in older women than in younger women, especially older women who experience hot flashes and night sweats.
On the other hand, the risks are lower in younger women, and so short-term use (for 3–4 years at most, since that was the duration of adherent exposure in the WHI) is a reasonable option for relief of moderate to severe hot flashes and night sweats. For many women, the benefit of relief of symptoms may outweigh any risks.
At all ages, measuring blood cholesterol helps to determine coronary risk. Women with high blood cholesterol have an increased risk of heart attack when they take hormone therapy. Women with high blood pressure have an increased risk for stroke, and this risk is increased further when they take hormone therapy. A family or personal history of blood clots would be a contraindication for hormone therapy, as would a family or personal history of breast cancer.
In 2007, the WHI investigators published a secondary analysis of the trial data and showed that the risk of heart attack was most marked in women who were 20 or more years removed from menopause, with some increase in risk in women more than 10 years past menopause. The risk was highest in older women who had hot flashes and night sweats. The risk of heart attack was not elevated in women on EPT who were less than 10 years past menopause (irrespective of whether they had hot flashes or night sweats), though there remained some small risks of stroke, blood clots, and breast cancer even in these women. These findings make it extremely clear that hormone therapy should not be used for any indication in older women, especially women who experience hot flashes and night sweats.
What are some of the other significant findings from the WHI?
Other key findings from the WHI include:
- Hormone therapy increased the risk of memory problems and dementia, urinary incontinence, and gallstones, but decreased the risk of diabetes.
- Deaths from breast cancer did not increase during the trial, but 8 years after the stopping of EPT, the risk of dying from breast cancer and total cancer had increased significantly.
- EPT increased the risk of lung cancer.
What should women who are reaching menopause know about hormone therapy?
The current recommendation from the American College of Obstetricians and Gynecologists and the North American Menopause Society is that recently postmenopausal women (within 10 years of menopause) can use hormone therapy short-term for relief of moderate to severe symptoms of menopause. According to WHI researchers, the best definition of short-term is 3–4 years, since this is the period on which the WHI has the most information. Consistent with FDA guidance, WHI researchers and the American Heart Association state that postmenopausal hormone therapy should not be used for the long-term prevention of chronic diseases (such as heart disease).
Current knowledge indicates that physicians considering prescribing hormone therapy for hot flashes and night sweats in recently postmenopausal women should consider whether a woman has a family history of breast cancer or heart disease. In addition, the presence of any of the following risk factors for heart disease should be determined before prescribing hormone therapy:
- High blood pressure
- High blood cholesterol
Do a woman’s options for hormone therapy depend on whether she has had a hysterectomy (surgical removal of the uterus)?
Yes. For women who have had a hysterectomy at a young age, estrogen alone is usually prescribed to treat hot flashes or night sweats and prevent osteoporosis. This can be continued until the usual age of menopause (around age 52). The WHI data include women who had had a hysterectomy at a young age and the findings from the WHI apply, i.e., if these women have menopausal symptoms when not on therapy, a short-term course of hormone therapy can be considered.
The WHI found that estrogen alone did not increase the risk of heart attack or of breast cancer; therefore, it is safer than EPT. Estrogen alone did increase the risk of blood clots (less so than EPT) and of stroke. Like EPT, it decreased the risk of hip fractures. Women who have an intact uterus would need EPT to protect against endometrial cancer, and from WHI data it is clear that EPT has more risks than benefits. In particular, the risk of breast cancer increases steeply after 3–5 years. Therefore, more caution is appropriate for EPT than ET.
How long can a woman safely be on hormone therapy?
There is no safe period of time, because the risks of heart attack, stroke, and blood clots occur immediately, and are highest for heart attacks and blood clots in the first few years. The risk of breast cancer may be delayed to later years, and for EPT the risk of breast cancer accelerates after 3–5 years. The risk of breast cancer for women on EPT is highest in those who start therapy within 5 years of menopause.
With ET, there is no increased risk of breast cancer in women who start within 5 years of menopause. There is a reduced risk if they start more than 5 years after menopause, continue for about 3.5 years, and then stop.
The WHI data cover 3–4 years of adherence to therapy, and then stopping. Because the most data exist on that period of use, WHI investigators recommend no more than 3–4 years of postmenopausal hormone therapy. There are no trial data on cardiovascular effects of longer term use. Specifically, even though younger women may not have an increased risk of heart attack with short-term use, scientists do not know whether continuing therapy will lead to reduced or increased risk of heart attack in later years as women (and their arteries) grow older. The WHI data are quite clear that it’s not a good idea to start hormone therapy in older women.
Are certain doses or preparations of hormone therapy safer than others?
The WHI trials have no data on lower doses or other preparations. However, it seems prudent to use lower doses, as recommended by the FDA. The lower doses are effective for prevention of osteoporosis. Transdermal estrogen (a patch that is applied to the skin) does not appear to increase the risk of blood clots, so may be a safer option.
What happens to a woman’s health risks and benefits after she stops hormone therapy?
The WHI investigators have published followup papers showing what happened to the health of women in the trials after stopping postmenopausal hormone therapy—an important question, as so many women in the United States have indeed stopped. In short, for EPT the risk of heart attack, stroke, and blood clots disappeared. The risk of breast cancer declined more slowly, and in fact the risk of dying from breast cancer (and all cancers) became significant. So it remains important for women to continue getting screened for cancer even after stopping hormone therapy. The benefits of a reduction in risk of fractures and colorectal cancer also disappeared after stopping hormone therapy.
In women receiving estrogen alone (women with a hysterectomy), the risk of breast cancer was slightly decreased during the trial, and this decreased risk continued after stopping ET. There was no effect on heart attacks during or after the trial, while the previously elevated risks of stroke and blood clots went away. The reduction in risk of fractures also went away after stopping.
Are new findings from the WHI being published?
Yes; the overall WHI is publishing more than 100 papers a year from its various components, including the hormone trials. (View a list of WHI publications.)
Is it possible that new results will be published that lead to a change in the current recommendations?
It is unlikely that any new data from the WHI or elsewhere will change current recommendations. However, research using WHI and other data continues in an effort to better identify women who are at risk when they receive hormone therapy, and this will help tailor treatment to lower risk. The followup of these women continues, and there is little doubt that the WHI will keep providing important information in the future.
Key WHI Publications and Accompanying News Releases
Risks and Benefits of Estrogen Plus Progestin Therapy (July 2002)
Risks and Benefits of Estrogen Alone Therapy (April 2004)
- Publication: Anderson, G.L., Limacher, M., Assaf, A.R., Bassford, T., Beresford, S.A., Black, H., … and the Women’s Health Initiative Steering Committee. (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA, 291(14):1701-12.
- News release: WHI Study Finds No Heart Disease Benefit, Increased Stroke Risk With Estrogen Alone.
Effects of Age and Years Since Menopause (April 2007)
- Publication: Rossouw, J.E., Prentice, R.L., Manson, J.E., Wu, L., Barad, D., Barnabei, V.M., … and Stefanick, M.L. (2007). Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA, 297(13):1465-77.
- News release: NHLBI Media Availability: Effect of Hormone Therapy on Risk of Heart Disease May Vary by Age and Years Since Menopause.
Health Risks After Stopping Combination Therapy (March 2008)
- Publication: Heiss, G., Wallace, R., Anderson, G.L., Aragaki, A., Beresford, S.A., Brzyski, R., … and the WHI Investigators. (2008). Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA, 299(9):1036-45.
- News release: WHI Follow-up Study Confirms Health Risks of Long-Term Combination Hormone Therapy Outweigh Benefits for Postmenopausal Women.
Combination Therapy and Heart Disease Risks (February 2010)
- Publication: Toh, S., Hernández-Díaz, S., Logan, R., Rossouw, J.E., Hernán, M.A. (2010). Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear? A randomized trial. Ann Intern Med, 152(4):211-7.
- February 15, 2010 WHI Study Data Confirm Short-Term Heart Disease Risks of Combination Hormone Therapy for Postmenopausal Women.
Breast Cancer Risks After Stopping Combination Therapy (October 2010)
- Publication: Chlebowski, R.T., Anderson, G.L., Gass, M., Lane, D.S., Aragaki, A.K., Kuller, L.H., … and the WHI Investigators. (2010). Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA, 304(15):1684-92.
Health Risks After Stopping Estrogen Alone Therapy (April 2011)
- Publication: LaCroix, A.Z., Chlebowski, R.T., Manson, J.E., Aragaki, A.K., Johnson, K.C., Martin, L., … and the WHI Investigators. (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA, 305(13):1305-14.
For more key findings, please see The Estrogen-Plus-Progestin Study (Selected Findings)