News this month
Women’s Health Initiative study on HRT stopped

In July, the National Institutes of Health (NIH) halted a large, in-progress study examining the effects of a widely used type of hormone replacement therapy (HRT) medication called Prempro®, which combines the hormones estrogen and progestin.

The study, which is one of five major studies that comprise the large clinical trial called the Women’s Health Initiative (WHI), was discontinued because the hormones appear to increase a woman’s risk of breast cancer as well as heart disease, blood clots and stroke.

The findings were published in JAMA, the Journal of the American Medical Association.

The purpose of the study, which was scheduled to run until 2005, was to determine whether estrogen plus progestin could prevent heart disease and hip fractures in women between ages 50 and 79 with an intact uterus. A review of preliminary data found a 26 percent increase in breast cancer in women receiving the hormones compared with women receiving a placebo. In addition, instead of a heart benefit there was a 29 percent increase in heart attacks and a 22 percent increase in total cardiovascular disease among women receiving the hormones.

Risks outweigh benefit according to study
Dr. Jacques Rossouw, director of the NIH, noted, “the increased risk of breast cancer for each woman in the study who was taking the estrogen plus progestin therapy was actually very small.” It was less than one-tenth of 1 percent, he said, adding, “if you apply that increased risk to an entire population and over several years, the number of women affected increases dramatically and becomes an important public health concern.” And those risks outweigh the drugs’ actual benefits, which include a small decrease in hip fractures and a decrease in cases of colorectal cancer.

More than 16,600 U.S. women (8,506 participants in the estrogen plus progestin group and 8,102 in the placebo group) were participating in the combined estrogen-progestin portion of the trial. Neither the women nor their doctors knew who was taking the active medication. After the risks were identified among the Prempro users, they were sent letters telling them to discontinue taking those drugs.

WHI is continuing to study the effects of ERT, or estrogen-alone drugs, used by women who have had a hysterectomy. WHI has not stopped that portion of the study because the evidence shows neither an overwhelming risk nor an overwhelming benefit. Women who have had hysterectomies generally take estrogen without progestin. For others, taking estrogen alone can lead to uterine cancer.

The WHI trial with Prempro was stopped because the risk-benefit balance, as indicated by a global indicator of overall risk, was unfavorable and the breast cancer risks crossed the predetermined safety boundaries. The WHI’s Data and Safety Monitoring Board—an independent advisory committee charged with reviewing results and ensuring participant safety—set the limits of acceptable risk for breast cancer at an unusually low level of cases per thousand. When that level was reached, the trial was stopped and results were released early.

Risk ‘relatively small’ for individual women
Dr. Rossouw summarized the risk findings:
The WHI results tell us that during one year, among 10,000 postmenopausal women with a uterus [as opposed to those who have had their uterus removed] who are taking estrogen plus progestin, eight more will have invasive breast cancer, seven more will have a heart attack, eight more will have a stroke, and 18 more will have blood clots, including eight with blood clots in the lungs, than will a similar group of 10,000 women not taking these hormones. This is a relatively small annual increase in risk for an individual woman.

What patients should know
Dr. Rossouw offered this advice: Women with a uterus who are currently taking estrogen plus progestin should have a serious talk with their doctors to see if they should continue it. 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.

The WHI study is the first, long-term randomized controlled clinical trial—considered the gold standard by medical researchers—of HRT. Previously, scores of observational and case studies supported the benefits of HRT, but most of the data on the presumed benefits come from observational studies of women who chose to take it or not. Although in analyzing their findings, researchers tried to account for differences between these groups of women, there is always a chance that factors not considered could have influenced the results, especially since women who choose to use hormones tend to have healthier habits over all and are likely to be followed more closely by their physicians.

Some experts underscore the fact that this study may not be the final word on the risks and benefits of hormone replacement. This study looked only at Prempro and may not apply to other products that may tip the balance in favor of benefits over risks. Some doctors speculate that lower-dose hormones or estrogen-progestin patches and creams might avoid some of the risks associated with Prempro, but they have yet to be tested in large randomized clinical trials, and until they are, there is no definitive answer.

For the 12th year in a row, Yale-New Haven has been highly ranked by U.S. News & World Report for its programs in gynecology.