A Cloud of Confusion Lingers Over Hormone Therapy Use

Hormone therapy is often prescribed for women going through menopause for its benefits in relieving the uncomfortable symptoms of hot flashes and night sweats, as well as preventing osteoporosis.

Until recently, observational studies comparing women who used hormone therapy to women who did not indicated that the therapy could lower the incidence of cardiovascular disease in postmenopausal women. In search of better answers to this and related questions, the National Institutes of Health launched the Women’s Health Initiative (WHI) in 1991. It was an ambitious 15-year research program, including a set of clinical trials to test the effects of postmenopausal hormone therapy on heart disease, fractures, and breast and colorectal cancer.

“Randomized, controlled clinical trials are the most rigorous and reliable research tests available,” said Phyllis Greenberger, president and CEO of the Society for Women’s Health Research in Washington, D.C. “When you give one group of research subjects the same specific treatment and another group of research subjects a placebo, which is an inactive substance containing no medication, you can determine more precisely the effectiveness of the treatment.”

In contrast, observational studies merely document an individual’s health or progress by asking questions and sometimes inviting them to participate in a clinical examination, Greenberger said. Researchers in an observational study do not intervene or interfere in a patient’s care by mandating that they follow a specific course of action. They only note the patient’s reported activities and outcomes.

The WHI included two studies of hormone therapy. Both were large, randomized, placebo-controlled clinical trials. One trial examined a combination pill containing estrogens and progestin, which is a synthetic form of the hormone progesterone. The second trial included women who had had a hysterectomy, and compared the same estrogen preparation without progesterone to placebo.

At the start of the estrogen-plus-progestin trial, concerns were raised that the women given the inactive placebo would be at a much higher risk for developing cardiovascular disease than the women given active hormones or that women taking hormones would be at higher risk for developing breast cancer than those taking placebo. As a result, the researchers agreed to stop the study if differences between the treatment and control groups reached a predetermined threshold on these or other serious health conditions.

In 2002, three years before the study was complete, the threshold for increased incidence of breast cancer in the treatment group compared to the control group was reached. Investigators stopped the study because they found that “overall health risks of coronary heart disease events, strokes, and breast cancer exceed the benefits of the treatment, which include lower rates of fractures and reduced risk of colon cancer.”

In 2004, the estrogen-only study was stopped when researchers found that the increased risk of stroke and blood clots exceeded the benefits of treatment.

The decision to stop the estrogen-plus-progestin study received a great deal of attention from the news media, women, and health care providers. Media coverage offered messages that ranged from “hormone therapy isn’t as helpful as we thought” to “hormone therapy is dangerous for women.” Women who were taking hormone therapy feared for their health and overwhelmed their health care providers with calls, emails, and office visits asking for help in deciding what to do. Health care providers were often as confused as their patients.

In response to the results of this and other hormone therapy trials, the Food and Drug Administration (FDA) added a warning to the label to all hormone therapy products stating that hormone therapy should be taken at the lowest effective dose for the shortest time and only for relief of menopausal symptoms and prevention of bone loss.

Gradually the attention given the initial announcement died down. Researchers, health care providers, and women’s health advocates continued analyzing the results, which has led to more complete and rational conclusions about the risks and benefits of hormone therapy.

Among the issues raised in subsequent discussion of the WHI results were the following:

1. An individual woman’s risk for heart disease or breast cancer was very low.
2. All of the women in the study were past menopause. Only one-third of the women in the study were between the ages of 50-59. Most women who use hormone therapy are under 60, and most start taking hormones early in the menopausal transition.
3. The estrogen plus progesterone trial was stopped because of an apparent increased risk of breast cancer in women taking hormones, but the estrogen only study did not show an increase in risk of breast cancer in women taking estrogen. More analysis on hormone therapy’s impact on breast cancer will soon be published.
4. The average age of the WHI participants was 63 years old and many of them had at least one other risk factor for cardiovascular disease, so it is likely that many of the participants had already developed some vascular damage before taking hormones. Therefore, the WHI study did not answer the question of whether taking hormones before vascular disease develops can prevent it from developing.
5. An increased risk of blood clots and stroke in response to estrogen has been recognized and was part of the information provided to prescribers well before the WHI studies were begun.
6. The studies looked at only one type of estrogen and one progesterone drug – both high-dose regimens delivered via a pill. Since then, many forms of estrogen and natural and synthetic progesterone have been approved by the FDA. The choice of products allows women and their health care providers to carefully tailor the treatment to the individual woman.

Unfortunately, the WHI did not provide the most complete answers to questions about hormone therapy because of how the study was designed and the health of the study’s participants.

“One could argue that the study population, described by WHI as ‘generally healthy postmenopausal women,’ was in fact anything but,” said Dr. Wulf Utian, M.D., Ph.D., executive director of the North American Menopause Society. Utian points out that 40 percent of the study’s participants had high blood pressure, more than seven percent had diabetes, 15 percent had high cholesterol, and just over three percent had previously suffered a heart attack. These pre-existing conditions could have had an impact on the study’s results.

Other research on hormone therapy is continuing in new clinical trials comparing low doses of hormones and various delivery systems (pills, creams, patches) to placebo. More studies of hormone therapy are planned or ongoing, and the results should further clarify the appropriate role of hormone therapy in symptom relief and in prevention of disease.

Additional reports from the WHI are also being published, including one in the Feb. 14 issue of The Archives of Internal Medicine. It suggests that taking estrogen alone does not increase the risk of heart disease in women who have had a hysterectomy. In women age 50-59, when the investigators compared the total occurrence of heart attack, bypass surgery, angioplasty and treatment for angina, the women receiving estrogen were less likely to need treatment than those receiving a placebo.

These results only apply to women who have had hysterectomies, which is important to note because women who have had a hysterectomy receive estrogen without progesterone. Further research is needed to better understand the risks and benefits of beginning hormone treatment early in menopause.

So how should women view the evidence collected on hormone therapy?

The results so far indicate that hormone therapy should not be prescribed for the single and specific purpose of protecting against heart disease. Some observers believe that emerging, further analysis of the WHI indicates that the overall risks do not outweigh the benefits for all women.

“In my own opinion,” Utian said, “these results should be extraordinarily reassuring for average aged symptomatic women considering” starting hormone therapy before the age of 60.

The choice to use hormone therapy should not be made without careful consideration. Women who experience menopausal symptoms such as hot flushes, night sweats or vaginal dryness, or who are at risk of osteoporosis, should consult their health care providers, weigh the evidence, evaluate the advantages and disadvantages and make informed decisions.

Sherry Marts, Ph.D.