Hormone therapy: issues of the heart.

At the close of a woman's childbearing years, her body undergoes hormonal changes that render her more vulnerable to a number of degenerative conditions, especially heart disease and osteoporosis. Drug therapy can slow or forestall that vulnerability.

However, the recipe of hormones most commonly prescribed in the United States may not fill the bill -- at least in lowering heart risks, several new studies indicate. That's troubling, maintains veterinarian Kent Hermsmeyer, who coauthored two of the studies, because heart disease kills three out of every four postmenopausal women.

Hormone therapy delivers estrogen to make up the shortfall that occurs with menopause. To prevent the rise in breast cancer risk that typically develops when women receive estrogen alone, physicians often prescribe a combination that contains a second hormone -- usually a synthetic form of progesterone.

The new studies suggest that this duo's heart benefits depend on the form of progesterone used.

Hermsmeyer's team at the Oregon Regional Primate Research Center in Beaverton gave estrogen daily to 18 rhesus monkeys whose ovaries had been removed to simulate menopause. Six also got natural progesterone, while another six monkeys received the synthetic medroxyprogesterone acetate (MPA), the most widely prescribed progesterone for postmenopausal U.S. women.

After 4 weeks, the researchers injected the animals with two chemicals released by blood platelets, simulating a heart attack. In monkeys receiving MPA and estrogen, this injection provoked an unrelenting constriction in the coronary artery, cutting off blood flow. Unless treated within minutes, the animals would have died, says Hermsmeyer. This chemical challenge produced the same result in animals that had received no hormone therapy.

Monkeys that had been treated with estrogen alone or together with natural progesterone quickly recovered normal blood flow without drug treatment. The researchers report their findings in the March Nature Medicine and the March 1 Journal of The American College of Cardiology.

"The big surprise," Hermsmeyer says, is that "MPA poses such a huge risk. This is a really dangerous drug."

J. Koudy Williams of Wake Forest University's Bowman Gray School of Medicine in Winston-Salem, N.C., was less surprised by the findings. He says new data from his team's experiments on monkeys show that MPA can "obliterate the beneficial effect of estrogen [therapy] on the progression of coronary artery atherosclerosis."

Peter Collins of the National Heart and Lung Institute in London and his colleagues saw similar effects in 16 women with coronary artery disease. Participants in their study received two hormone replacement therapies, each for several weeks. The therapies contained estrogen plus natural progesterone or MPA.

The women exercised on a treadmill until tests showed they were experiencing reduced blood flow to the heart. They could exercise significantly longer when natural progesterone was part of the hormone therapy. "There appeared to be a negation of the beneficial effects of estrogen by MPA but not by natural progesterone," concludes Collins. He plans to present these data in a few weeks at the American College of Cardiology's annual meeting.

As far as MPA is concerned, "there's enough data accumulated to give us pause," Williams argues. In terms of heart disease protection, "it's worse than no treatment at all."

Endocrinologist JoAnn E. Manson of Harvard Medical School in Boston disagrees, arguing that the relevance of these "intriguing" studies remains uncertain. Yet they do "underscore a need for more research on different forms of progesterone," she adds.

Indeed, Williams, newest data indicate that some synthetic progesterones -- such as nomegestrol acetate, widely used in Europe -- do not erase postmenopausal estrogen's benefits.