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Unraveling Estrogen's Effect in Older Women

Researchers think they know why HRT raises cardiovascular risk after menopause

TUESDAY, Feb. 22, 2005 (HealthDayNews) -- Researchers believe they now know how estrogen turns from friend to foe as a woman ages. The finding could explain why hormone replacement therapy raises the risk of coronary artery disease after menopause.

In younger women, estrogen relaxes coronary blood vessels, but because of chemical changes that occur during menopause, the same hormone can suddenly do the opposite, claim scientists from the Medical College of Georgia. They hope that by tinkering with those chemical changes, they can make it safe once again for women to use hormone replacement therapy (HRT).

"Many clinical and experimental studies to date have shown that estrogen preserved cardiovascular function in postmenopausal women. So, when the Women's Health Initiative released its findings indicating that it could actually increase CAD [coronary artery disease] and stroke risk, we couldn't believe it," said study author Richard E. White, an associate professor of pharmacology and toxicology. "It didn't make any sense because we knew that estrogen was a vasodilator and did so many good things, so we wanted to know how it could be harmful," he said.

The National Heart, Lung, and Blood Institute was intrigued enough by White's research to award him a $1.2 million, four-year grant to definitively answer that question. White presented his findings last week at the Second International Conference on Women, Heart Disease and Stroke in Orlando, Fla.

By studying estrogen's effects on coronary blood vessel walls in pig heart tissue, White and his colleagues determined that, in young women, estrogen acts as a vasodilator, stimulating nitric oxide synthase (NOS) to produce nitric oxide (NO). That's a good thing for the heart, since nitric oxide regulates dilation of blood vessels.

They already knew that estrogen could relax blood vessels, but finding out that estrogen might be equally capable of constricting blood vessels after a certain age was a surprise.

"We thought it was a mistake," White said. What they found upon closer examination is that when estrogen stimulates NOS in the arteries in the absence of two chemical helpers (tetrahydrobiopterin and L-arginine), which are found in younger women but less so in postmenopausal women, superoxide is formed instead, and that's when trouble starts. Superoxide enhances oxidation and promotes aging, White explained.

The effect of estrogen seems to be dose-dependent, too. "The more estrogen we had, the bigger the effect," White said, explaining that estrogen is an antioxidant and, like other antioxidants, it has the potential to do harm at higher doses.

But don't blame estrogen, White said; blame the aging process, since that's what causes a natural decrease in some of those vital molecules that are needed to make nitric oxide. For estrogen, it's just a matter of being in the right place at the wrong time, he noted.

"We know of two molecules [tetrahydrobiopterin and L-arginine] that are involved for sure, and there may be others," he said.

The jury is still out on estrogen, suggested Dr. Frederick Naftolin, director of the Center for Research in Reproductive Biology at Yale University School of Medicine. "The advent of the WHI, HERS and ERAS trials has led to a rash of misinterpretation and concern that estrogen is 'bad for the blood vessels.'" In fact, he says, it's the "lack of estrogen, plus aging, [that] are associated with deterioration of blood vessels."

"What this study does do is help us better understand vascular biology, but it needs to be tested in more lifelike circumstances," Naftolin said. "More than half of people die of vascular disease, and estrogen is important in vascular health. We need this and other research to continue and even increase."

White's team will be scrutinizing the estrogen-NOS relationship, and trying to find out what other signaling molecules may affect their interaction. Like going through a fuse box one at a time to find the blown fuse, the researchers will be knocking out or overexpressing certain molecules to see which ones are involved.

White estimates it will be at least two years down the road, after completing a number of clinical trials, before their findings can be translated into something clinically useful, such as changing hormone therapy.

More information

For more on the dangers of hormone replacement therapy, visit the National Library of Medicine.

SOURCES: Richard E. White, Ph.D., associate professor, pharmacology and toxicology, Medical College of Georgia, Augusta, Ga.; Frederick Naftolin, M.D., Ph.D., emeritus chairman and professor, departments of obstetrics, gynecology and reproductive sciences, and director, Center for Research in Reproductive Biology, Yae University School of Medicine, New Haven, Conn.; presentation, Second International Conference on Women, Heart Disease and Stroke, Orlando, Fla.
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