Millions of women have taken hormone replacement therapy (HRT), most to relieve menopausal symptoms (i.e., hot flashes, vaginal dryness) and prevent bone loss . In the past, some observational research indicated HRT could help prevent other chronic conditions, such as heart disease .

But in July 2002, two large trials—the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study follow-up (HERS II)—indicated that an estrogen plus progestin regimen of HRT (combination HRT) was associated with an increased risk of heart disease, breast cancer , stroke , blood clots, and other adverse effects. The estrogen-progestin arm of the WHI was stopped early because of these safety concerns.

Another arm of the WHI study, however, was following women taking estrogen alone. It wasn’t yet clear whether taking estrogen alone was associated with adverse effects, so the WHI estrogen-alone trial was continued under careful supervision.

The results of this study, published in the April 14, 2004 issue of the Journal of the American Medical Association , indicate that estrogen alone increases the risk of stroke, decreases the risk of hip fracture , and does not protect against heart disease in postmenopausal women. Because of these findings, the study was halted two years early.

About the Study

This study included 10,739 healthy postmenopausal women, ages 50-79, who had undergone a hysterectomy (estrogen alone is not recommended for women with a uterus because it is associated with an increased risk of endometrial cancer ). The women were randomly assigned to receive a daily dose of either 0.625 milligrams of conjugated equine estrogen (Premarin) or a placebo.

Every six months, the women were followed-up by telephone or clinic visit (clinic visits were required annually), during which researchers determined whether the women had developed:

  • Coronary heart disease (CHD, defined as heart attack or death due to CHD)
  • Stroke
  • Blood clots
  • Cancer (other than non-melanoma skin cancer )
  • Osteoporotic fractures

Electrocardiograms were taken before the study began, and were scheduled for three, six, and nine years thereafter. In addition, the researchers measured 8.6% of the women’s blood lipid levels before the study began and after one year. All women were required to attend annual mammograms and clinical breast examinations.

The researchers also developed a “global index” to compare the overall risks versus benefits associated with taking estrogen. An independent safety board monitored the study closely, and was prepared to stop it if the data indicated the risks associated with estrogen outweighed the benefits.

The Findings

After almost seven years of followup, the National Institutes of Health stopped the intervention phase of the study, citing safety concerns, and all participants were advised to discontinue their study medication.

In the group of women with blood lipid measurements, estrogen was associated with a greater reduction in low-density lipoprotein (LDL, or “bad”) cholesterol and a larger increase in high-density lipoprotein (HDL, or “good”) cholesterol than the group taking the placebo. But the estrogen group experienced larger increases in triglyceride levels and had slightly higher blood pressure readings.

Estrogen did not significantly affect the women’s risk for coronary heart disease. The risk of stroke, however, was significantly increased (by 39%) in the women taking estrogen, as was the risk of having deep vein thrombosis (DVT, a serious type of blood clot occurring in the veins of the pelvis or legs). Overall, the women taking estrogen were 12% more likely to have a cardiovascular event than the women taking the placebo.

Women taking estrogen were 30% to 39% less likely to have osteoporotic fractures. And, interestingly, the women taking estrogen were 23% less likely to be diagnosed with invasive breast cancer, but this reduction in risk narrowly missed statistical significance.

The global index of health risks and benefits indicated a balance between the estrogen and placebo groups (estrogen was not associated with more deaths than the placebo).

While these results are certainly valuable, they have certain limitations:

  • A single estrogen regimen was tested, so these results may not apply to other brands, doses, or methods of administration (i.e., estrogen patches).
  • Over half of the women stopped taking the study medication, which could have affected the results. But further analyses indicated that while poor adherence may have diluted the estrogen effects, it did not distort the balance between the estrogen and placebo groups.
  • The trial was stopped two years early; a longer intervention period may have yielded different results.

How Does This Affect You?

These findings add to the building evidence that HRT is not in the best interest of post-menopausal women. Most health professionals now agree that the risks of estrogen-progestin therapy outweigh the benefits for most women, and this study reveals that although estrogen decreases the risk of osteoporotic fractures, it significantly increases the risk of stroke in postmenopausal women and does not protect against cardiovascular disease.

The possibility that estrogen may protect postmenopausal women against breast cancer requires further study, since these findings were non-significant and past research demonstrates the opposite: that estrogen increases the risk of developing breast cancer.

In addition to the findings of increased risk of stroke, the NIH has indicated that more results will soon be released from this study suggesting “a trend toward increased risk of probable dementia and/or mild cognitive impairment ” associated with estrogen. At this point, it seems that the long-term benefits of HRT do not outweigh its risk. However, since estrogen alone appears (for now) to be associated with fewer long-term risks than estrogen-progestin combinations, some women who have had a hysterectomy may still consider taking estrogen to manage serious, debilitating menopausal symptoms. But these women and their physicians should aim to use the smallest effective dose of estrogen for the shortest duration possible.