A large clinical trial designed to learn the true benefits and risks of hormone replacement therapy (HRT) was stopped early after U.S. government health officials found that study participants on one type of HRT were more significantly more likely to develop invasive breast cancer and other health problems compared to women who did not take the hormones. While the HRT regimen that consisted of combined amounts of estrogen and progesterone (progestin) was associated with the health risks, the women in the study who took estrogen alone faced an unchanged risk of health problems. Therefore, the estrogen-only leg of the study will continue. However, experts say the findings are alarming and should prompt women on HRT to seriously discuss the therapy with their physicians to determine whether it is an appropriate option for them.

Hormone replacement therapy (HRT) is synthetic estrogen and progesterone (called progestin), designed to "replace" a woman’s depleting hormone levels as she reaches menopause. Decreased levels of estrogen may cause hot flashes, vaginal dryness, sleep disturbances, or other bothersome side effects. HRT has been found to be highly effective at treating menopausal symptoms.

An estimated 6 million women who take HRT take a combined regimen of estrogen and progestin. Other women take estrogen alone. However, taking estrogen alone (without progestin) may   lead to an increased risk of endometrial cancer—cancer of the uterine lining. Since progestin counteracts this risk, women who have not had their uteruses removed with a hysterectomy are advised to take the combined estrogen/progestin HRT regimen.

The benefits and risk of HRT have been heatedly debated in recent years as studies have emerged contradicting the once-believed advantages of HRT. While no research denies the benefits of HRT in relieving menopausal symptoms, studies have been challenging prior data that suggested HRT could help prevent heart disease and the bone-thinning disease, osteoporosis. Emerging studies have also found that long-term use of HRT (over five years) may increase the risk of breast cancer. The uncertainty of contradictory findings has caused confusion in the medical community and alarm among many women taking or considering HRT.

The HRT arm of the Women’s Health Initiative (WHI) was supposed to settle the debate on HRT. Over 16,000 women with intact uteruses had been recruited to study whether estrogen plus progestin helped prevent heart disease and hip fractures, and whether the therapy caused any increased risks in breast cancer or colon cancer. The trial, run by the National Heart, Lung, and Blood Institute (NHLBI), was scheduled to continue to 2005. However, surprisingly negative results have caused researchers to stop the study early, with participants being followed for an average of 5.2 years. Findings were announced by the NHLBI a week prior to their publishing in the July 17, 2002 issue of the Journal of the American Medical Association.

The findings that led to the halt of the combined estrogen/progestin arm of the study consisted of an increased risk of invasive breast cancer and increased risks of coronary artery disease, stroke, and pulmonary embolism (blood clots in the lungs). Specifically, the study shows that during one year among 10,000 post-menopausal women with a uterus who are taking estrogen plus progestin, 8 more will develop invasive breast cancer, 7 more will have a heart attack, 8 more will have a stroke, and 18 more will have blood clots, including 8 with blood clots in the lungs, compared with a similar group of 10,000 women who are not taking HRT. The study did find benefits to HRT, including fewer hip fractures (often a sign of osteoporosis) and a decreased risk of colon cancer.

"We have long sought the answer to the question: Does postmenopausal hormone therapy prevent heart disease and, if it does, what are the risks?" said NHLBI Director Claude Lenfant, MD, in an NIH press statement. "The bottom-line answer from WHI is that this combined form of hormone therapy is unlikely to benefit the heart. The cardiovascular and cancer risks of estrogen plus progestin outweigh any benefits — and a 26 percent increase in breast cancer risk is too high a price to pay, even if there were a heart benefit. Similarly, the risks outweigh the benefits of fewer hip fractures," said Dr. Lenfant. Dr. Lenfant noted that there are other, safer methods of reducing heart decrease risk, including dietary modifications and cholesterol-lowering drugs.

The study did not find an increased risk of death from health problems among women taking both estrogen and progestin. Furthermore, the women who had had their uteruses removed and were taking only estrogen were not found to be at higher risk for breast cancer or other health problems. Researchers will continue the estrogen-only arm of the study to learn more about potential benefits and risks for this group.

The following data from the NIH show study findings for women taking combined estrogen/progestin, compared to a similar group of women who did not take HRT:

• 41% increase in strokes
• 29% increase in heart attacks
• A doubling of rates of venous thromboembolism (blood clots)
• 22% increase in total cardiovascular disease
• 26% increase in breast cancer
• 37% reduction in cases of colorectal cancer
• A one-third reduction in hip fracture rates
• 24% reduction in total fractures
• No difference in total mortality (of all causes)

Government officials urge women on combined estrogen/progestin regimens of HRT to discuss the benefits and risks of the therapy with their physicians. "If they are taking this hormone combination for short-term relief of symptoms, it may be reasonable to continue since the benefits are likely to outweigh the risks. Longer term use or use for disease prevention must be re-evaluated given the multiple adverse effects noted in WHI," said Jacques Rossouw, MD, acting director of the WHI, in an NIH press statement.

Additional Resources and References

• The July 9, 2002 Nationals Institutes of Health (NIH) news release, "NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit," is available at http://www.nih.gov/
• The National Heart, Lung, and Blood Institute (NHLBI) provides information on the study findings at http://www.nhlbi.nih.gov/
• Further information about the Women’s Health Initiative findings is available at http://www.whi.org/
• To learn more about hormone replacement therapy, please visit http://www.imaginis.com/breasthealth/hrt.asp

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