Studies in female monkeys helped raise important questions about hormone therapy that were addressed in a Women's Health Initiative study reported recently in the New England Journal of Medicine. The animal research, conducted at the Wake Forest University Primate Center, also suggests the role that stress can play in heart disease development and point to the need for early prevention of heart disease.
"Our research in monkeys suggests that stress can affect estrogen levels and may set the stage for heart disease later in life," according to Jay Kaplan, Ph.D., professor of comparative medicine and director of the primate center. "It also suggests women need to start thinking about heart disease prevention before menopause. We found that the five years before menopause are when heart vessel disease begins to accelerate."
Kaplan and Thomas Clarkson, D.V.M., have published numerous articles from their monkey research on the effects of hormone therapy on heart vessel disease. Their findings, along with research in humans, were a driving force behind the hypothesis that there is a "window of opportunity" during which hormone therapy can help prevent atherosclerosis. The theory was explored in the Women's Health Initiative Coronary Artery Calcium Study (WHI-CAC).
WHI-CAC showed that younger postmenopausal women who take estrogen-alone hormone therapy have significantly less building of calcium plaque in their arteries compared to their peers who did not take hormone therapy. The plaque is considered a marker for future risk of atherosclerosis, the buildup of fatty deposits that can lead to heart attacks and strokes.
Clarkson began a study in 1988 funded by the National, Heart Lung and Blood Institute to study how hormone therapy affects heart disease risk in monkeys. He found that estrogen replacement administered to monkeys as soon as they were made surgically menopausal resulted in about a 70 percent inhibition in the progression of coronary artery atherosclerosis.
When treatment with estrogen or estrogen plus progestin was delayed for an equivalent of six years in women, however, there was no benefit. The work led to the hypothesis that estrogen inhibits the development of vessel disease, but may be ineffective, and even harmful, if the disease already exists.
"Clearly hormone therapy isn't a drug for preventing or treating heart disease," said Clarkson. "The question is whether, when hormone therapy is used for the treatment of menopausal symptoms, there are benefits associated with the cardiovascular system that might offset any documented risks."
In addition to raising this important question about hormone therapy, the animal studies also have other important health implications for women. Women have traditionally been considered immune from heart disease until after menopause, when their estrogen levels dramatically drop. But the monkey studies suggest that stress can actually reduce estrogen levels much earlier in life and hasten the development of atherosclerosis, thus increasing the postmenopausal burden of coronary disease risk.
These effects may apply to up to half of premenopausal women, Kaplan said, emphasizing the need for young women to be educated about the relationship between reproductive health and chronic disease risk.
"Our research adds to the growing body of evidence that cardiovascular health after menopause is influenced by hormone levels many years earlier," said Kaplan. "The message for women is that anything that reduces estrogen levels in young adulthood - whether it be stress or exercise and diet habits - may put women on a high-risk course for heart disease."
Clarkson said that because cardiovascular disease is the leading cause of death among women over age 55 -- and because studies show that declines in estrogen in perimenopause can lead to its development -- it is imperative to identify risk factors and promote early prevention.
"The evidence that levels of atherosclerosis present at the time of menopause are determined by premenopausal estrogen exposure is underappreciated," he said.
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