Researchers have finished designing the privately funded randomized clinical trial intended to explore the now-contrarian notion of hormone replacement: that it can, after all, thwart development of cardiovascular disease if women begin using it soon after menopause and use less of it. The study is moving forward despite recent disheartening research results that have led millions of women to abandon hormone replacement.

Beginning in September, the Kronos Early Estrogen Prevention Study (KEEPS) will enroll 90 women between 40 and 55 at each of eight participating US medical centers. KEEPS will compare a .45-mg oral dose of Premarin (conjugated horse estrogens) or a skin patch containing synthetic estradiol—said to be identical to the human ovarian estrogen—with placebo. For 10 days a month, women taking estrogen who still have a uterus will also use Prochieve, a vaginal gel containing 4% progesterone that is believed to have few systemic effects.

KEEPS' surrogate endpoints will include ultrasound imaging of the carotid and coronary artery walls and computed tomography scans of coronary calcium, as well as regular blood monitoring of inflammatory markers, cholesterol, and hormones.

“Believe it or not, even the Women's Health Initiative suggests that the results may be more favorable in more recently menopausal women,” JoAnn Manson, a principal investigator in both the new study and the Women's Health Initiative (WHI), told The Scientist.

The National Institutes of Health terminated the two arms of its massive clinical trials of hormone replacement therapy (HRT) that were part of the WHI. One study, of a popular HRT combining estrogen and progestin, was stopped in 2002 after it showed small increases in breast cancer, coronary heart disease, stroke, and pulmonary embolism in the treatment group. Earlier this year, because of a slight increase in stroke risk, the agency also shut down a trial of estrogen replacement in women who had undergone hysterectomy.

Manson, of Brigham and Women's Hospital, cited in particular the estrogen-only study, which the Journal of the American Medical Association published April 14. It showed that women ages 50 to 59 at study entry had a relative risk of coronary heart disease of 0.56 after 7 years on estrogen compared with women not taking the hormone, although this reduction was not statistically significant.

Organizers said that KEEPS is only a pilot study. If results suggest benefit from estrogen in newly menopausal women, a large and longer-term clinical trial—involving as many as 30,000 women—might be warranted, they said.

Wulf H. Utian, executive director of the North American Menopause Society, praised KEEPS for recognizing that the WHI itself shows that HRT affects younger women differently. But even if the KEEPS results suggest HRT benefits these women, he told The Scientist, the information will be too little, too late.

One of his concerns is the use of surrogate endpoints, rather than frank heart disease, although the organizers say such a strategy is warranted because most of the women in the study will be healthy. A large post-KEEPS study designed to demonstrate fewer actual heart attacks in younger healthy women on HRT would be impractical because it would require hundreds of thousands of study subjects, Utian said.

And by the time KEEPS concludes in 2009, Utian predicted, researchers will be armed with a new understanding of cardiovascular pathogenesis that will lead to new forms of intervention, and physicians will be recommending other preventive measures: existing drugs such as statins, new drugs such as selective estrogen receptor modulators, and even nonpharmacologic interventions such as exercise and smoking cessation.

KEEPS is being organized by the Kronos Longevity Research Institute in Phoenix, Ariz., and funded by the Aurora Foundation, headed by billionaire John G. Sperling, who founded the University of Phoenix. According to Kronos director Mitchell Harman, neither the foundation nor Sperling have any pharmaceutical interests. “There is no drug company money involved in this trial at all,” Harman said.

Correction (posted April 23): Due to an editing error, the original version of this story did not correctly describe the results of the April 14 JAMA study cited. The Scientist regrets the error.