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HRT Trial Halted, Health Risks Cited

Kate Traynor

A National Institutes of Health (NIH) study examining the use of combined estrogen and progestin was halted three years early because the treatment puts postmenopausal women at increased risk for breast cancer, stroke, and myocardial infarction.1

Study participants were told in June to stop taking their medication after a planned safety analysis revealed that long-term use of the therapy increased a woman’s chance of having invasive breast cancer by 26%. This increase is equivalent to 37 women, instead of 30, in 10,000 having invasive breast cancer per year. Compared with placebo users, women treated with the hormone replacement regimen were 41% more likely to have a stroke and 29% more likely to have a myocardial infarction.

Previous epidemiologic and case–control studies had suggested that hormone replacement therapy (HRT) reduces women’s risk of cardiovascular disease. The current prospective study, which was sponsored by NIH’s National Heart, Lung, and Blood Institute (NHLBI) and involved 16,608 women, was conducted to determine whether HRT offers cardiovascular benefits to postmenopausal women with no history of heart disease.

The study results were published in the July 17 issue of the Journal of the American Medical Association (JAMA) but released online one week early because of the report’s clinical significance.

In an editorial accompanying the research article, two Harvard researchers described the study results as "unexpected and disquieting," noting that "the whole purpose of healthy women taking long-term estrogen–progestin therapy is to preserve health and prevent disease. The results of this study provide strong evidence that the opposite is happening."

Guidelines released last year by NHLBI indicated that estrogen–progestin therapy offers no cardiovascular benefit to postmenopausal women with heart disease. The guidelines also noted that postmenopausal women with heart disease who take long-term HRT may increase their risk of breast cancer, thromboembolism, and gallbladder disease.

In the current study, safety analyses conducted during the past two years had linked estrogen–progestin therapy with a slight increase in users’ risk for cardiovascular events. But the combined risks of the therapy did not reach statistical significance until the breast-cancer cases came to light.

Women who participated in the double-blind multicenter study were 50–79 years old at enrollment and had an intact uterus. Each woman was randomly assigned to receive either a placebo or a single tablet containing 0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate (Prempro, Wyeth Ayerst) daily for at least three years.

The study participants were contacted for follow-up information every six months during the trial, and they also visited a study site once each year. On average, the researchers collected 5.2 years of follow-up data for each woman in the study. At the time the study was halted, data were available for 8199 women in the HRT group and 7826 women who had been assigned to the placebo group.

The hormone replacement regimen offered some health benefits along with the risks. Women who used the combination therapy were 33% less likely than placebo users to have a hip fracture and 37% less likely to have colorectal cancer during the study.

The current product labeling for Prempro, the estrogen–progestin tablet used in the study, states that the product is indicated for the treatment of menopausal symptoms and vaginal atrophy and the prevention of osteoporosis. Wyeth noted in a press release that HRT remains critical for the treatment of menopausal symptoms.

But Jacques Rossouw, acting director of NHLBI’s Women’s Health Initiative (WHI), which orchestrated the study, said in a statement that all women who use HRT need to consider the study’s results. "Women with a uterus who are currently taking estrogen plus progesterone should have a serious talk with their doctor to see if they should continue it," he said. "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 reevaluated given the multiple adverse effects noted in WHI."

NHLBI confirmed in a statement that the current findings do not affect an ongoing WHI study on the effects of estrogen monotherapy in women who have had a hysterectomy. "At this point," NHLBI noted, "the balance of risks and benefits of estrogen alone is still uncertain."

  1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33.