Women's Health Initiative: Not over yet

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Women's Health Initiative: Not over yet

The largest study of women's health has raised at least as many questions as it has answered. Stay tuned.

In December 1993, the federally funded Women's Health Initiative (WHI) set out to enroll one out of every 200 women in the United States, ages 50–79, in a 12-year study to fill gaps in medical knowledge about postmenopausal women's health and chronic disease prevention. This prodigious undertaking involved 40 clinical centers, 1,000 investigators and staff, and 161,808 women — the largest study of its kind and the most comprehensive look to date at several women's health problems.

The goal was daunting: to find out if hormone therapy, a low-fat diet, and calcium supplements reduced the risk for major diseases affecting older women, including cardiovascular disease (heart attack and stroke), breast cancer, colon cancer, and osteoporosis. The WHI's ambitious aims reflected the somewhat limited state of knowledge about women's health at the time. Much was assumed, but little had been tested — and a "one size fits all" approach predominated. For example, many clinicians routinely prescribed estrogen with or without a progestin to women after menopause, even though the practice had never been proved safe or effective. The same was true for advice about a low-fat diet to prevent breast cancer and calcium supplements to protect bones.

By 1998, more than 68,000 women had signed up for the WHI's randomized clinical trials of hormone therapy, dietary modification, and supplemental calcium plus vitamin D. Some were in a secondary study (the Women's Health Initiative Memory Study, or WHIMS) looking at hormone therapy and dementia in women ages 65 and over. Women ineligible for or not interested in the clinical trials could enroll in an observational study that kept track of their health habits and medical records. Nearly 94,000 women became part of that study.

From the beginning, the WHI had plenty of critics. Some researchers complained that it was trying to accomplish too much and that the trials wouldn't be long enough to assess the impact of hormones, diet, and supplements on chronic illness. Others argued that participants wouldn't be able to stick with their assigned interventions or wouldn't accurately report what they were doing. And some researchers believed so strongly in estrogen's benefits that they deemed it unethical to give anyone a placebo instead. Critics of the critics speculated that the WHI's opponents were mainly worried that accepted wisdom about women's health might be overturned.

By the study's formal conclusion in 2005, certain assumptions indeed appeared to have been toppled — most notably, that postmenopausal hormone therapy wards off cardiovascular disease. The hope that estrogen would preserve cognitive function was also dashed.

But the WHI didn't settle all the questions it set out to answer. For one thing, women able to participate in such a demanding study are likely to be healthy to begin with, so the findings may not apply to all women. Other factors may have skewed the results. For example, the hormone study couldn't include women whose hot flashes were so severe that they wouldn't chance taking a placebo. And some women may have had undetected atherosclerosis when they entered the trial (average age at the start of the study was 63). Still, the WHI had many things going for it, including size, diversity, and the devotion of its subjects and investigators.

In February 2006, WHI participants and researchers, scientists, and sponsors gathered at the National Institutes of Health (NIH) in Bethesda, Md., to review the findings, discuss the study's implications, and talk about the future. The National Heart, Lung, and Blood Institute said it will fund the WHI Extension Study, which will follow the women who took part in the original hormone therapy, diet, and calcium trials until 2010.

Moreover, the NIH, with the okay of WHI participants, will make the study's enormous store of data and blood and DNA samples available to outside researchers. Combined with advanced technologies in genetic, biomarker, and molecular science, this information will likely provide years of research possibilities and new insights into women's susceptibility to certain diseases, which treatments are best for which women, and how to individually tailor preventive care. In this way, the WHI may have hastened the day when "one size fits all" truly becomes medical history.

Hormone therapy: Greater risk than benefit

The hormone therapy trials tested estrogen plus a progestin (Prempro) against a placebo in 16,608 women who had an intact uterus at the start of the study and estrogen alone (Premarin) versus a placebo in 10,739 women who'd had a hysterectomy. The Prempro trial ended in 2002 after it became clear that it was causing more harm than good, especially in relation to heart disease — the very thing it was supposed to prevent. The Premarin trial also ended early, in 2004, after the risk of stroke rose by 40% in the estrogen-takers. Estrogen showed some benefit in both trials, but it wasn't enough to outweigh the risks (see chart). Prempro and Premarin were the only hormone preparations tested.

What else? In both trials, the women who took hormone therapy were more likely to develop urinary incontinence than those on placebo. Also, the WHIMS study found that among women ages 65 and over, those taking hormone therapy had a greater risk than placebo-takers of cognitive decline.

Subgroup analyses suggest that estrogen may have some heart-protective effects for women in their 50s. This idea must be tested in trials before hormone therapy can be recommended for anything other than symptoms such as hot flashes. Two trials are already under way outside the WHI.

What now? Hormone therapy should be prescribed only for symptoms such as hot flashes and vaginal dryness, at the lowest effective dose for the shortest possible time. Women who undergo surgical menopause or are at serious risk for fractures and can't take other medications may want to discuss hormone therapy with their clinicians. WHI researchers are re-examining the data to find out if younger menopausal women had better outcomes than older women or the group as a whole.

Dietary change: Marginal benefits

The dietary modification trial examined the effect of a low-fat diet high in fruits, vegetables, and grains on breast cancer, colorectal cancer, and cardiovascular disease. More than 48,000 women were assigned to either dietary change (low-fat diet) or a comparison group that followed their usual diet. The women were not asked to lose weight.

During the study, women in the dietary change group met periodically with a nutritionist for help. After eight years, their daily fat intake had dropped from 37% to 29% of calories, but this had little effect on disease outcomes.

Limitations. The women in the low-fat group never reached the study's goal of 20% of calories from fat. Further scaling back might have made a difference. Also, cancer takes many years to develop. A trend toward reduced breast cancer risk and fewer polyps (precancerous growths in the colon) suggests there might have been greater improvement over a longer period of time. And the study didn't distinguish among different types of fat. The benefits might have been greater if healthy mono- and polyunsaturated fats had replaced unhealthy saturated fat and trans fat. Finally, the women who changed their diets increased their intake of fruits and vegetables by only one serving per day, and they had some difficulty boosting grain intake.

What now? A low-fat diet is not a magic bullet against cardiovascular disease or cancer. But a diet that limits saturated fat, avoids trans fat, and includes plenty of fruits, vegetables, and whole grains should be part of an overall lifestyle approach that includes at least 30 minutes of moderate-intensity physical activity most days of the week. Regular mammograms and colon cancer screening are also important.

Supplemental calcium and vitamin D: Modest effects

Women already enrolled in the hormone or dietary trials were later invited to join the calcium and vitamin D trial, which aimed to test the effects of supplements on fractures and colorectal cancer risk. A total of 36,282 women signed up; half received a placebo, and half, supplements of 1,000 milligrams (mg) of calcium and 400 IU of vitamin D per day. After seven years, the supplement takers had 1% greater bone density at the hip than those taking a placebo. Women over age 60 who took supplements had a reduced risk of hip fractures. Calcium and vitamin D had no effect on colon cancer. Women taking the supplements had 17% more kidney stones (5 more cases per 10,000 women each year) than women taking a placebo.

Limitations. The women in this trial had normal bone density to begin with, so the results may not apply to women with low bone density or risk factors for osteoporosis and fractures. All the women in the study were allowed to take additional calcium and vitamin D on their own, and many did, so it's unlikely that many were calcium-deficient. Also, a large number were taking hormone therapy, which increases bone density. Finally, research published since the WHI began suggests that the amount of vitamin D (400 IU per day) may have been inadequate.

What now? Current guidelines recommend that women over age 50 should get 1,000–1,200 mg of calcium and 400–600 IU of vitamin D per day from food and supplements. But research suggests that at least 800 IU of vitamin D daily may be needed to reduce fractures. Few foods contain vitamin D, so consider a supplement.

Last updated:	September 05, 2008