Research offers clues on estrogen, heart disease

Genetic change might block hormone, Hopkins study says

August 30, 1999|By Diana K. Sugg | Diana K. Sugg,Sun Staff

Last summer, when a large study found that estrogen didn't protect women from heart disease, cardiologists were stunned. But a new report, to be released today, could explain why: A genetic change might be blocking blood vessels' ability to respond to estrogen and get its benefits.

In diseased arteries, physicians found that genes involved in letting estrogen into cells had been switched off.

Published in September's issue of the journal Cardiovascular Research, the finding links estrogen, menopause and atherosclerosis, an important and sometimes controversial connection for which the science is still evolving.

It has relevance for millions of postmenopausal American women, a third of whom will die from coronary disease.

"This is something new and potentially exciting, but we need to learn a lot more about it," said Dr. Wendy S. Post, an assistant professor of medicine at the Johns Hopkins School of Medicine, who led the research.

Some scientists call the report significant.

"In many ways this is a very exciting finding, because it goes even beyond changes in lipid levels or helping the vessel relax. It goes down to the very level of the gene," said Dr. Trudy Bush, professor of epidemiology and preventive medicine at the University of Maryland Medical School. "It gives us then a way to try to treat the problem."

Other researchers contend, however, that discovering the underlying mechanics isn't important yet, since it's still unclear whether estrogen makes a difference in protecting against heart disease. For the many women struggling to decide whether to take hormone replacement therapy, the new study does not make it any easier. Bush said about 15 percent of postmenopausal women nationwide are taking hormone therapy.

The therapy prevents osteoporosis and helps menopausal symptoms such as irritability and hot flashes. Researchers also believe hormone therapy might help decrease the risk for coolon cancer and certain types of dementia, such as Alzheimer's disease.

Its potential use in treating heart disease emerged when some studies found that estrogen can reduce cholesterol levels and cause heart vessels to relax when a person is under stress. Doctors theorized that hormone therapy might also offer a protective effect from heart disease.

But the gold standard in medicine is to perform a clinical trial, in which patients are randomly given either medicine or a dummy pill. When the first such trial was done on hormone replacement therapy and heart disease, results didn't find any benefit.

The new report offers an explanation.

Blood vessels in the heart are dotted with receptors for the hormone estrogen. The receptors are like a lock; the estrogen, a key. Together, they allow the hormone in to the cell. Post and her colleagues found that in the healthy blood vessels, about 4 percent to 5 percent of the genes that direct the production of these estrogen receptors were shut down, compared with about 11 percent of the genes in the clogged arteries.

This genetic change is called methylation. In essence, it means that a gene's bar code is taped over, or covered, so it can't do its work.

This is the first time this process has been implicated in heart disease, said Dr. Pascal Goldschmidt, director of the Heart and Lung Institute at Ohio State University in Columbus. He was part of the Hopkins team and plans to continue the research.

Some doctors interpreted the study as evidence that a woman's genes determine how she responds to estrogen.

"We should say it helps some women, and it doesn't help others, and it depends on what genes you have. But as a clinician, it's difficult because we can't identify which genes you have," said Dr. Paul Rivas, an internist at Greater Baltimore Medical Center's Mid-Life Center, which specializes in the concerns of postmenopausal women.

Dr. Jacques Rossouw, deputy director of the Women's Health Initiative at the National Heart, Lung and Blood Institute in Bethesda, described the effort as "probably not important," since it is still unclear whether estrogen confers heart benefits or not, either in older or younger women, or those with existing disease or those without.

"It may not matter at all. It may be moot," Rossouw said. "We simply don't know. The real, proper studies are only now being done, which is a sad fact, but it's true. Until they're done, we won't know."

The definitive data won't be known until about 2005, when studies are completed, said Dr. Roger S. Blumenthal, director of preventive cardiology at Johns Hopkins Hospital, one of the investigators on the clinical trial.

In the meantime, Bush said she believes that, in general, estrogen therapy is better than no therapy, because it has such good effects on bone mineral density, heart and brain function. She said there is a small risk of blood clots, breast and uterine cancer.

GBMC's Rivas said he doesn't recommend the therapy widely, but counsels patients to weigh the benefits and the risks. Every day, he deals with women who are agonizing over this decision, which for many will be a lifelong one.

But increasingly, Rivas said he finds his patients rejecting the hormone therapy -- and opting for alternatives such as herbs.

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