The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has stopped early a major clinical trial of the risks and benefits of combined estrogen and progestin in healthy menopausal women due to an increased risk of invasive breast cancer.

The large multi-center trial, a component of the Women's Health Initiative (WHI), also found increases in coronary heart disease, stroke, and pulmonary embolism in study participants on estrogen plus progestin compared to women taking placebo pills. There were noteworthy benefits of estrogen plus progestin, including fewer cases of hip fractures and colon cancer, but on balance the harm was greater than the benefit. The study, which was scheduled to run until 2005, was stopped after an average follow-up of 5.2 years.

Participants in this component of WHI, like most women with a uterus who take hormone therapy, were given progestin in combination with estrogen. This practice is known to prevent endometrial cancer.

A separate WHI study of estrogen alone in women who had a hysterectomy before joining the WHI hormone program continues unchanged because, at this point, the balance of risks and benefits of estrogen alone is still uncertain.

"We have long sought the answer to the question: Does postmenopausal hormone therapy prevent heart disease and, if it does, what are the risks? 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 per cent 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 NHLBI Director Claude Lenfant.

"Menopausal women who might have been candidates for estrogen plus progestin should now focus on well-proven treatments to reduce the risk of cardiovascular disease, including measures to prevent and control high blood pressure, high blood cholesterol, and obesity. This effort could not be more important: heart disease remains the number one killer of American women," added Lenfant.

The estrogen plus progestin trial of the WHI involved 16,608 women ages 50 to 79 years with an intact uterus. An important objective of the trial was to examine the effect of estrogen plus progestin on the prevention of heart disease and hip fractures, and any associated change in risk for breast and colon cancer. The study did not address the short-term risks and benefits of hormones for the treatment of menopausal symptoms. About 6 million women in the U.S. are taking estrogen plus progestin for a variety of reasons, including symptom relief, because their doctors advised it, or for long-term health.

Women enrolled in the estrogen plus progestin study were randomly assigned to a daily dose of estrogen plus progestin (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate) or to a placebo. Participants were enrolled in the study between 1993 and 1998 at over 40 clinical sites across the country.

In 2000 and again in 2001, WHI investigators complied with a recommendation from the study's Data and Safety Monitoring Board (DSMB) to inform participants of a small increase in heart attacks, strokes, and blood clots in women taking hormones. The DSMB, an independent advisory committee charged with reviewing results and ensuring participant safety, found that the actual number of women having any one of these events was small and it did not cross the statistical boundary established to ensure participant safety. Therefore, the group recommended continuing the trial due to the still uncertain balance of risks and benefits.

Then, at the DSMB's regularly scheduled meeting on May 31, 2002, the data review revealed for the first time that the number of cases of invasive breastcancer in the estrogen plus progestin group had crossed the boundary established as a signal of increased risk.

The DSMB's May 31 recommendation to stop the trial was based on the finding of increased breast cancer risk, supported by the evidence of overall health risks exceeding any benefits. Following the NHLBI's decision to stop the study, the Institute and the investigators have worked intensively to develop information materials for participants. On July 8, participants started receiving letters informing them about the results and telling them that they should stop study medications. Participants will be contacted by their clinical centers for further counseling and will continue to have clinic visits so that their health outcomes can be followed.

All WHI participants, including those in the other study components, are also receiving a newsletter with a summary of the findings and an explanation of risks and benefits.