Over 6 million U.S. women take hormone replacement therapy (HRT) for various reasons, including relief of uncomfortable symptoms of menopause, reduced risk of osteoporosis, and the possibility of lowering their risk of heart disease and stroke. However, some research has suggested HRT may not provide protection against heart disease and stroke, and may, in fact, increase the risk of breast cancer.

In May 2002, the Women’s Health Initiative study of HRT in postmenopausal women was stopped three years early due to evidence that HRT may increase the risk of breast cancer, heart disease, stroke, and blood clots in the leg veins and the lungs. The research will be published in the July 17, 2002 issue of the Journal of the American Medical Association (JAMA) ; however, advance copy of the article is available on the JAMA website (http://jama.ama-assn.org).

About the study

The Women’s Health Initiative (WHI) is a large nationwide study of 161,809 postmenopausal women who were between the ages of 50 and 79 when they entered the study between 1993 and 1998. WHI is actually composed of four studies, one of which was examining the effects of a combined estrogen and progestin HRT on 16,608 women with an intact uterus, meaning they had not had surgery to remove their uterus. Women were excluded from this study if they had a history of any type of cancer, other than nonmelanoma skin cancer.

At the start of the study, the women were randomly assigned to take either a placebo (inactive) pill or combined HRT in the form of one Prempro tablet (0.625 mg of estrogen plus 2.5 mg medroxyprogesterone acetate) daily. Every six months, researchers contacted the women to ask about their menopause symptoms, side effects, and any new medical conditions. In addition, the women underwent clinical exams yearly. The study was intended to follow each woman for 8.5 years, but was stopped prematurely after only 5 years.

The study’s data and safety monitoring board reviewed the study data each year to determine if the data showed any increased or decreased risk of heart attack, stroke, breast cancer, blood clots, colorectal cancer, and osteoporosis.

The findings

The study was stopped early when the data and safety monitoring board determined that the risks associated with taking HRT clearly outweighed any benefit gained from the therapy.

Compared with women taking placebo, women taking HRT were:

  • 41% more likely to have a stroke
  • 29% more likely to have a heart attack
  • 26% more likely to develop breast cancer
  • Two times more likely to develop blood clots

On the positive side, the women taking HRT were:

  • 37% less likely to develop colorectal cancer
  • 33% less likely to have a hip fracture (an indicator of osteoporosis)

Although these results sound alarming, it's important to put these numbers in perspective. The findings of the study suggest that for every 10,000 women who take HRT, only 7 will develop heart disease, 8 will have a stroke, 8 will have a blood clot in the lungs, and 8 will develop invasive breast cancer attributed to their hormone use. On the other hand, there will be 6 fewer cases of colorectal cancer and 5 fewer hip fractures. Overall, the risks of taking HRT appear to outweigh the benefits, but the vast majority of women taking HRT will apparently not develop serious complications within the first five years.

Even though this study was well designed and meticulously executed, it has its limitations. The HRT used in this study was a specific dosage of combined estrogen and progestin given only to women with an intact uterus. It’s possible that a lower dosage or an estrogen-only hormone therapy would produce different results (only women who have had a hysterectomy can take estrogen alone over the long term without increasing their risk of endometrial cancer). In addition, because the estrogen and progestin were given in combined form, there’s no way to know at this time if one or both hormones are responsible for the increased risk detected in this study. Finally, although stopping the trial early was necessary to ensure the safety of the participants, discontinuing the trial before completion reduced the precision of the long-term estimates of risk.

How does this affect you?

Should you rethink your decision to take HRT? Yes. According to Dr. Jacques Rossouw, acting director of the WHI, “Women [who still have their] uterus who are currently taking estrogen plus progestin should have a serious talk with their doctors to see if they should continue it.” The findings of the WHI study add to growing evidence that HRT may not be effective at preventing heart disease and may even present additional risks, such as increased risk of breast cancer, stroke, and blood clots. While many of these risks were known for some time, it was assumed that the overall benefits of HRT outweighed its risks. This study strongly suggests otherwise.

Dr. Rossouw explains that the risk for an individual woman who has been taking HRT is fairly low, but that even a small individual risk can add up to many adverse events when considered on a population-wide basis.

What about taking HRT to relieve hot flashes, insomnia and vaginal dryness associated with menopause? Dr. Rossouw explains that it may be reasonable for women taking combined HRT for short-term relief of menopause symptoms to continue, since the benefits are likely to outweigh the risks. However, he explains that longer-term use of HRT for disease prevention must be re-evaluated in light of the multiple adverse events identified in this study.