The Kronos trial, published in the current Annals of Internal Medicine, found that low doses of progesterone plus an estrogen pill or patch were no better than placebos at warding off buildup of fatty plaque and calcium, which are signs of heart disease.
"We were surprised, but we weren't shocked," said Nanette Santoro, chair of obstetrics-gynecology at the University of Colorado School of Medicine and one of 17 authors of the Kronos study. "Not all of the investigators believed we were necessarily going to see" a heart benefit.
On the up side, she said, therapy did not accelerate hardening of the arteries, so women need not be afraid to take hormones for several years to relieve symptoms such as hot flashes, which is what the drugs are approved for.
"It's reassuring news to women who have menopausal symptoms and may be considering taking hormones," said Santoro, who was also part of the landmark federal trial.
In a news release, Kronos Institute said "additional research on hormone treatment of newly menopausal women . . . is needed."
But other experts said it was time to give up and move on.
"We now have clear evidence that the timing hypothesis is wrong; younger women do not benefit," said Stanford University professor of medicine Marcia Stefanick, a leader of the Women's Health Initiative. "If women want to prevent heart disease, they could lose weight, change their diet, get more exercise, stop smoking."
Estrogen and progesterone, produced by the ovaries until after menopause, act on myriad tissues in the female body, so restoring these hormones has a complex, still-mysterious pattern of risks and benefits.
The Women's Health study gave 16,600 women a placebo or estrogen-progesterone for five years. Overall, the hormones reduced hip fractures and colon cancer, but increased breast cancer, endometrial cancer, and dementia - as well as heart attack and stroke.
The cardiovascular results stunned the medical world. Decades of less rigorous studies - and the fact that women rarely suffer heart attacks before menopause - suggested hormones were protective.
In the hope that timing makes a difference, the Kronos trial recruited 727 healthy women, all within three years of menopause, at nine academic medical centers, including the Mayo Clinic and Harvard Medical School; 580 women completed the four-year trial. (Nonprofit Kronos is supported by the nonprofit Aurora Foundation, created by John Sperling, the billionaire founder of the for-profit University of Phoenix.)
The study, which was too small to evaluate most risks of therapy, tracked cardiovascular changes that are strong predictors of stroke and heart attack. Neck ultrasounds evaluated the wall thickness of the main heart artery, and CT scans measured calcium deposits. Blood pressure, cholesterol and triglycerides were also checked, and overall were not significantly affected by therapy.
"Maybe we didn't look long enough, or maybe there's some delayed benefit" that would be detectable in the future, Santoro said. "Am I proposing we spend millions of dollars to do that? No. It tells us we still don't fully understand the basic science."