An estimated three million postmenopausal women are taking hormone replacement therapy (HRT) to relieve menopausal symptoms and prevent osteoporosis . In the past, some physicians prescribed HRT to postmenopausal women because it was thought to decrease the risk of heart disease . But more recently, studies have warned that HRT may increase the risk of breast cancer , heart disease, stroke , and blood clots, so physicians now carefully weigh the risks versus benefits (reducing the risk of colorectal cancer and preventing fractures ) before prescribing HRT to their patients.

Most of the well-designed, placebo-controlled trials that have investigated the risks of HRT involved a certain regimen—estrogen plus continuous progestin. So some researchers have questioned whether other hormone regimens—estrogen alone or estrogen plus sequential progestin—could protect the heart. Early observational studies suggested that estrogen alone and estrogen plus sequential progestin may be protective against heart disease.

Two studies in the August 7, 2003 issue of the New England Journal of Medicine addressthe controversy surrounding HRT. The first study reported the final results of the Women’s Health Initiative (WHI), which indicated that HRT might actually increase the risk of coronary heart disease (CHD) in postmenopausal women initially free of heart disease, especially during the first year of taking it. The second study looked at the effects of estrogen alone or estrogen with sequential progestin in post-menopausal women who already had atherosclerotic heart disease and found that neither HRT regimen slowed the progression of their atherosclerosis.

About the Studies

The first study included data obtained up through the termination of the Estrogen and Progestin trial of the WHI, in July 2002 (previous studies have reported results through April 2002). This study included 16,608 postmenopausal women between the ages of 50 and 79 who had a uterus. The women were randomly assigned to receive either a daily dose of Prempro™ (a combination of estrogen and progestin) or a placebo.

For the next five years, the researchers kept track of how many women developed CHD, defined as a heart attack requiring overnight hospitalization, death caused by CHD, or a “silent” heart attack identified by electrocardiograms . On July 7, 2002, the Estrogen and Progestin trial of the WHI was stopped early because researchers determined that the harmful effects of HRT outweighed the benefits.

The second study, called the Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), looked at 169 postmenopausal women age 75 or younger who had evidence of atherosclerosis in at least one coronary artery supplying the heart muscle. The women were randomly assigned to one of three groups:

  • Estrogen-progestin group—received a daily dose of Estrace™ (an estrogen pill) and Provera™ (a progestin pill) for 12 consecutive days every month
  • Estrogen group—received a daily dose of Estrace™ and a placebo pill for 12 consecutive days every month
  • Placebo group—received a daily placebo tablet and another placebo tablet taken for 12 consecutive days every month

The women also modified their diets (to 25% of calories from fat, 7% from saturated fats, and less than 200 milligrams of dietary cholesterol per day) and took a cholesterol-lowering medication to reduce their LDL cholesterol to less than 130 milligrams per deciliter (mg/dL [3.4 mmol/L]).

The researchers followed the women for about three years. In addition to monitoring the diets and bloodwork of the participants, coronary angiograms were conducted every year to look for changes in the buildup of atherosclerotic deposits in the coronary arteries. The researchers also tracked the occurrence of cardiovascular events.

The Findings

During the first year of the WHI study, the women taking HRT were significantly more likely to develop CHD than the women taking the placebo. After the first year, there was a significant trend toward a decreasing risk of CHD in the women taking HRT. The women who had higher LDL cholesterol levels at the start of the study had an even greater increased risk of CHD associated with HRT. Severity of menopausal symptoms, age, time since menopause, weight, and a number of other risk factors for heart disease were not related to the risk of CHD associated with HRT.

All of the women in the WELL-HART study successfully reduced their LDL cholesterol to less than 130 mg/dL (3.4 mmol/L). Although most of the women showed progression of atherosclerosis, this progression did not differ significantly among the three groups. The women in the estrogen and estrogen-progestin groups did, however, have significantly greater increases in their HDL (good) cholesterol levels, and greater decreases in their LDL (bad) cholesterol levels. In this study, there was no significant difference among the groups in the number of cardiovascular events that occurred in the first year.

How Does This Affect You?

Does this mean that physicians will stop prescribing HRT? These studies add to the building evidence that the risks of taking HRT for CHD outweigh the benefits. While previous research has suggested that the increased risk of CHD does not arise until after five years of taking HRT, the WHI study suggests that the first year of HRT use is actually the most dangerous, in terms of CHD risk. According to the authors, their study indicates that women should not begin taking HRT for the prevention of heart disease. If, however, you have or continue to take HRT, don’t panic. Although this study found an increased risk of CHD, your individual risk is still extremely low.

The WELL-HART study indicates that estrogen alone and estrogen plus sequential progestin do not benefit women who already have atherosclerosis, even though their cholesterol levels will probably improve. The researchers suggest that the cholesterol-lowering drugs may have prevented cardiovascular events associated with HRT in the first year of the study. It remains to be seen whether estrogen alone will be effective in preventing heart disease in women who do not already have atherosclerosis. Until then, HRT in any form should probably not be used for the treatment or prevention of CHD in post-menopausal women.