WHI continues to yield data on effects of hormone therapy, calcium, low-fat diet

Extension trial will follow women for another five years, with more definitive results expected about cancer, bone fractures.

BETHESDA, Md. — Recent reports that hormone therapy could help prevent heart disease if begun during the menopausal transition are speculative and are not supported by scientific data, according to Women’s Health Initiative investigators.

Marian Limacher, MD, professor of medicine in the division of cardiovascular medicine at the University of Florida, said that the WHI results clearly show that hormone therapy should not be used as a preventive therapy for cardiovascular disease in postmenopausal women.

“American Heart Association guidelines advise that hormone therapy is not useful, is not effective and may be harmful. It should not be initiated to prevent cardiovascular disease and should not be continued to prevent CVD,” Limacher said at the WHI Conference here.

Marian Limacher, MD

A large representation of principal investigators and participants met at the National Institutes of Health recently to review results of the 12-year trial that involved 161,808 postmenopausal women aged 50 to 79.

Bernadine Healy, MD, who launched WHI when she was NIH director, said that “medicine has been humbled by our findings.”

Research data from WHI reflect reality and prove that women would participate in clinical trials, and the data will continue to narrow the gaps in information about women’s health. “Some mysterious findings from the trial will be explored further,” she said.

Elias A. Zerhouni, MD, current NIH director, said the project is being extended another five years to allow for longer follow-up. Prior to WHI, “dogma had not been questioned and had become the practice of medicine.” WHI is a reminder that medicine should learn better from its science “so that truth dominates, not dogma,” he said.

The serum, plasma, DNA and other biological information supplied by the participants now form a rich resource for subsequent research. The NIH has issued a Broad Agency Announcement inviting researchers to apply for some of the $17.5 million available in the first two-year cycle to pursue studies that will maximize the scientific value of the biologic specimens.

Trend toward lower cancer risk

Jacques Rossouw, MD, WHI project officer at the National Heart, Lung, and Blood Institute, said that 80% of the eligible participants have agreed to participate for another five years and will continue to give information on their health status.

“This will serve as a backbone for many other studies with outside funding and will look at the delayed effects of intervention. The key one is whether a low-fat diet for breast cancer will show a significant reduction in the extension trial. Don’t worry about the headlines today about a low-fat diet and cancer. They may be wrong,” he said.

A longer period of follow-up will be critical for several components of WHI, including the Dietary Modification Trial. In that trial, the difference in breast cancer rates between the dietary change group and the comparison group were not statistically significant.

Additional analyses, however, support the trend toward a lower risk of breast cancer among women in the dietary change group, with the low-fat diet reducing estrogen levels by 15%.

Longer follow-up to be provided by the WHI Extension Trial could show a significant reduction in breast cancer in coming years. Investigators said participants within the dietary change arm of the trial did not lower their fat intake as much as had been hoped.

“The current findings from the WHI [Dietary Modification] Trial are not clear enough to recommend a lower fat intake for most women to prevent breast cancer, but women who are eating a high-fat diet may benefit by reducing fat intake. Women should continue to take steps to reduce their risk of invasive breast cancer, such as having regular mammograms and breast examinations,” they said.

Longer follow-up is also needed to assess the effect of the low-fat diet on incidence of colorectal cancer. So far the results indicate that a low-fat dietary pattern probably will not prevent colorectal cancer in postmenopausal women who are followed for eight years, but investigators think the observed reduction in polyps suggests a benefit for colorectal cancer risk that could emerge over the next five years.

Dorothy Lane, MD, at the department of preventive medicine at Stony Brook University School of Medicine, said that longer follow-up is also needed to better assess the effect of estrogren and progestin on incidence of ovarian cancer and breast cancer mortality. “We recommend against the use of estrogen and progestin and the routine use of estrogen alone in women who have had a hysterectomy,” she said.

Use of estrogen and progestin therapy increased the number of abnormal mammograms and endometrial biopsies, she said.

Calcium and vitamin D

The WHI Extension Trial will continue to evaluate the long-term effects of calcium and vitamin D on the health of the participants.

Women who regularly took their assigned supplements (1000 mg calcium and 400 IU vitamin D daily) had 29% fewer hip fractures than women assigned placebo. But overall, women assigned the supplements had 12% fewer hip fractures compared with women assigned a placebo, a nonsignificant difference.

Andrea LaCroix, PhD, said there could be several explanations for the results, including an indication that the dose was too low, especially for vitamin D. Researchers now think the more suitable dose would be 600 IU daily. LaCroix, at the Fred Hutchinson Cancer Research Center, said there may be a “real but small effect but the [cohort] had too few too women and the follow-up was too short.”

Women assigned the supplements also had 17% more kidney stones, said Rebecca Jackson, MD, division of endocrinology, diabetes and metabolism at Ohio State University. More follow-up is needed to evaluate the impact of calcium and vitamin D on the incidence of colorectal cancer, she said.

Cognitive function

An ancillary study to the WHI, the Study of Cognitive Aging, overturned the assumption that hormone therapy helps prevent dementia and cognitive decline in postmenopausal women.

Sally A. Shumaker, PhD, at Wake Forest University School of Medicine, said this was the first long-term randomized trial to test the assumption. Results showed that hormone therapy does not protect and is, in fact, deleterious to cognitive function.

These results raise several questions that further research should pursue, Shumaker said.

“Do the negative effects of hormones go away once you stop taking them? Are there potential benefits? Is there a window of opportunity for younger women?” The trial underscores the need to study the effects of other agents on the brain, she said. – by Kathy Holliman

For more information:

• The WHI Legacy to Future Generations of Women: Update on Scientific Contributions. Feb. 28-March 1, 2006. Bethesda, Md.