A 53-year-old woman sits down in her physician's office. "Doctor, I haven't been feeling like myself for quite some time now, ever since I went through menopause," she says. "I've been hearing a lot about estrogen supplements and hormone therapies. Some of my friends are taking them and they feel great. They say it prevents heart disease and osteoporosis. Other women I know say they want nothing to do with them. They say they have bad side effects and may cause cancer. Should I be taking these? Will they help me feel more like my old self? How serious are the side effects? What should I do?"

Women past menopause are finding that these are some of the toughest questions to deal with when trying to decide whether to supplement the hormones no longer naturally produced by their bodies. Hormone replacement therapy (HRT) for postmenopausal women has long been the subject of much debate. Of the numerous large studies conducted to date, none has been able to resolve the difficult questions for which these women and their physicians seek definitive answers.

Adult women over the age of 50 represent 14 percent of the American population, or 37.5 million people, according to the 1990 United States census. With the average life span of both men and women increasing and with the aging "baby boomer" population, postmenopausal women not only are growing in numbers but also now live one third of their lives after the average age of natural menopause at 51.

Short-Term Use Relieves Symptoms

About 75 percent of all women experience some adverse symptoms surrounding menopause. These symptoms are believed to be caused by the loss of the hormone estrogen and its beneficial effects. While these symptoms can vary in intensity among different women, the brain, bones, heart, blood vessels, vagina and skin are typically affected at or after menopause. A woman may experience hot flashes, depression, sleep disturbances, inability to concentrate, and memory lapses. A decrease in bone density can increase the potential for fractures, and coronary heart disease may occur as a result of arteriosclerosis (hardening of the arteries). The cells in the lining of the vagina will diminish in their capacity to function causing the organ to become dry, which can result in painful intercourse. The skin will become thinner, wrinkled, and dry, and bruising and slower healing may be evident.

Estrogens are often prescribed for women on a short-term basis to treat the symptoms of menopause for their duration, typically from several months to a year or two. While some women may have adverse reactions because they are more sensitive to supplemental estrogen than most, the majority will benefit with minimal or no risk from short-term estrogen supplements if the symptoms of menopause are troublesome for them. Research has shown that in women who still have their uterus, estrogen given alone can increase the risk of endometrial (lining of the uterus) cancer. Estrogen given with progestin to these women prevents this increase in risk.

The long-term use of HRT however remains controversial. Past studies of women taking estrogen for long periods to treat menopausal symptoms led to the recognition that estrogen supplementation can help prevent bone loss in postmenopausal women and thus reduce the risk of osteoporosis. However, the long-term effects on women of taking supplemental estrogen for many years, even decades, is only beginning to be understood. Some recent observational studies have indicated that HRT may have a role in preventing heart disease in these women, while other research may suggest an increased risk of breast cancer in women taking supplemental hormones.

Prior to menopause the rates of heart disease in women are low, and they seem to be protected against the development of cardiovascular disease. However, after menopause the risk of heart disease in women rises dramatically and becomes the leading cause of death in women. This observation suggests that female hormones may exert a protective effect, reducing cardiovascular risk.

Previous Studies Suggest Benefits

There are more than 40 studies in the medical literature concerning hormone replacement therapy and its effects upon the cardiovascular system. The weight of evidence from these studies does suggest that there is about a 50 percent reduction in cardiovascular disease for women who took hormone replacement compared to those who did not.

While hundreds of women have participated in these studies, they have had limitations. These studies have been observational studies, which cannot resolve questions about the risks and benefits of HRT. In observational studies, women who choose to take hormones are compared to those who choose not to take hormones. Women who choose to take hormones may be different from those who do not. For example, women who choose to take hormones tend to be healthier, less obese, more educated, less likely to smoke, more physically active, and have access to medical care. The differences in rates of heart disease seen between the groups may be due to those differences between the women rather than the fact they are taking hormones. Only in a clinical trial where women are randomly assigned to either take hormones or not to take hormones can any differences seen in disease rates be attributed strictly to HRT and not differences between the women electing to take a medication. Observational studies can give researchers clues, but randomized clinical trials give them the proof.

The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial , a recent randomized double-blind clinical trial funded by the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH), showed estrogen to indeed be helpful in reducing certain risk factors associated with heart disease. (See previous story). However, the study did not look at actual disease outcomes, such as how many women developed heart disease or suffered strokes.

A woman's decision of whether to start HRT is further clouded by the many contradictory reports in the medical literature regarding the relationship between HRT and a potential increase in breast cancer. In June 1995 in the New England Journal of Medicine, the Harvard Nurses Health Study, a long-term observational study, reported a potential increased risk of breast cancer in women on HRT. That same summer, the Journal of the American Medical Association published a report of a case control study (a type of observational study that compares those with the disease under study with those who do not have the disease) that showed no association between HRT and breast cancer for women on hormone replacement. A review of the myriad of studies on HRT and breast cancer reveals that the data are limited and not convincing enough to draw definitive conclusions.

WHI: Providing Definitive Answers

The Women's Health Initiative (WHI), funded by NIH, is the first randomized clinical trial to examine the relationship between hormones and heart disease and breast cancer. Begun in 1991, the WHI is a 15-year study to investigate the major causes of illness and death in postmenopausal women between the ages of 50 and 79 years old. This study will involve 164,500 women, 64,500 of whom will be in the clinical trial. One of the major components of the WHI will be a hormone replacement therapy intervention that will look specifically at the effect of long-term HRT on coronary heart disease and secondarily its effects on fractures as a result of osteoporosis. Another component of the WHI will be an observational study, which will involve 100,000 women who will receive no specific intervention. These women will be followed over an extended period to discover predictors and biological markers for disease. Researchers hope that a comprehensive study like the WHI will provide the definitive answers women need to make an informed decision about HRT.

In the Meantime, What's a Woman to Do? The decision to start short-term HRT for the alleviation of menopausal symptoms is dependent on how troublesome the symptoms are for a woman. The benefits are clear and the risks are minimal. However, to make the long-term commitment to hormone replacement, a woman and her physician must discuss her risks for cardiovascular disease and osteoporosis.

Be a Part of the Answer The National Institutes of Health (NIH) is recruiting more than 164,500 women of various socioeconomic and ethnic backgrounds to participate in the Women's Health Initiative (WHI), a $628 million, 15-year project that is one of the most definitive, far-reaching clinical trials of women's health ever undertaken in the United States. Read complete article ...

The potential benefits for the cardiovascular system and a reduced risk of osteoporosis must be weighed against the potential risk of breast cancer and endometrial cancer. In addition, the contraindications and precautions of estrogen replacement therapy, such as unexplained vaginal bleeding, active liver disease, chronic impaired liver functions, or recent vascular thrombosis (blood clotting) need to be considered.

Treatments that lower the level of fats in the blood, high blood pressure medication, and low dose cfmirin are important in the prevention and management of coronary heart disease. For osteoporosis, alternative therapies may include calcium and vitamin D supplements, agents such as alendronate and calcitonin, and preventive therapies such as exercise and calcium-rich diets. Only with all the facts can a woman and her physician make an informed decision about what is best. Women who are interested in participating in the WHI should call 1-800-54-WOMEN.

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Loretta P. Finnegan, M.D., director, Community Prevention and Outreach, Women's Health Initiative.

Vivian W. Pinn, M.D., director, NIH's Office of Research on Women's Health, and a WHI study co-chair.