In 2002, the Women’s Health Initiative (WHI), a research program begun in 1991 by the National Heart, Lung, and Blood Institute to address common health issues in postmenopausal women, issued an explosive report. Women who had had hormone replacement therapy (HRT)—a popular and highly recommended method of reducing the discomforts of menopause—were at greater risk of having heart attacks. This news—which was at odds with previous research—rocked the medical and lay communities and prompted many women and their doctors to abandon HRT.

But some researchers had doubts about the study; could limitations in the data analysis have skewed the results? Noting that the WHI studied older women, these researchers questioned whether HRT might provide a higher degree of protection for younger women who had recently entered menopause.

The Kronos Early Estrogen Prevention Study (KEEPS), coordinated by the Kronos Longevity Research Institute in Phoenix, is an effort to answer this question. Nine sites around the country, including the School of Medicine, are participating in a five-year study of 720 women to determine whether beginning hormone therapy in recently menopausal women (ages 42 to 58) protects against atherosclerosis, the major cause of heart attacks.

The principal investigator of the Yale portion of the study is Hugh S. Taylor, M.D., professor of obstetrics, gynecology and reproductive sciences and of molecular, cellular and developmental biology, and director of the department’s division of reproductive endocrinology and infertility. Ninety menopausal women who are within three years of their last period will receive one of three regimens—progestin plus an estrogen patch; oral estrogen; or progestin plus a placebo. Researchers will monitor the effects of estrogen on the subjects’ cardiovascular systems over four years, studying such markers as coronary calcium levels and the thickness of the walls of the carotid artery.

“We want to look at women from the beginning, before atherosclerosis has already started to develop,” Taylor said. The problem with the WHI study, he said, is that researchers looked at women who were already more than a decade past their last period. “It was too late. Those women had already started showing signs of heart disease.”

KEEPS will also look at cholesterol levels and other markers to explore which hormone delivery system is better: transdermal or oral. Transdermal estrogen is thought to be safer because it isn’t processed by the liver in high concentrations.

In addition to these two studies, each KEEPS site is conducting its own ancillary studies. Yale researchers plan to look at estrogen’s effects on skin integrity, bone density, moods, cognition (including memory) and heart rhythms.

Last spring the WHI followed up on its initial research with a study of younger women. Its findings suggest that the KEEPS study may yield encouraging news for women. WHI found a 24 percent reduction in risk of coronary heart disease in women starting HRT less than 10 years after menopause and a 30 percent reduction in overall deaths among women ages 50 to 59 using HRT. And in June, a report by WHI researchers published in The New England Journal of Medicine found that women who take estrogen for seven years after menopause had a lower risk of calcification of the arteries.