(SACRAMENTO, Calif.) — Replacing estrogen during the earliest stages of menopause can prevent inflammation and protect cardiac functions, according to new research by a team of UC Davis Health System investigators. Published in the April 2011 issue of Endocrinology, the study, which was conducted in rats, is believed to be the first to show that the timing of estrogen replacement therapy could be an important consideration in heart health.
“Females naturally lose many cardiac protective factors as they age, but our study shows that estrogen given soon after menopause begins can help mitigate that loss,” said Anne Knowlton, principal investigator of the study and professor of medicine and pharmacology at UC Davis. “Gaining a better understanding of the specific effects of estrogen on cardiac functions at different phases of menopause could be valuable in refining approaches to heart disease prevention.”
Knowlton, whose research focuses on the molecular foundations of heart failure, acknowledges that hormone replacement therapy following menopause is controversial, given that large clinical trials on the effects of hormone replacement therapy for postmenopausal women showed no cardiovascular benefits. The Women’s Health Initiative, for instance, brought about dramatic changes in hormone use for postmenopausal women. But because this study was conducted on women who were, on average, 10 years past menopause, some researchers believe it may not decisively capture the potential benefits of estrogen to cardiac health.
“At that point, it is likely that changes in estrogen receptors or other proteins have occurred, making the hormone no longer as effective and potentially as beneficial as it would have been soon after menopause,” said Knowlton. “In our study, prompt estrogen replacement showed benefits that we may not have seen if we waited years after the start of menopause.”
In addition to evaluating estrogen and cardiac function, the researchers sought to clarify the effects of the hormone on a specific class of proteins — called heat-shock proteins — that are induced in cells during physiological stress and play important roles in preserving cellular functions. These proteins are crucial to protecting the heart from ischemia that can occur with angina or a heart attack. Without them, the heart is much more vulnerable to permanent injury.
To conduct the study, the investigators induced menopause in rats of two age groups — adult and older — by removing their ovaries. Half of the rats in each age group was given estrogen replacement immediately afterwards, while the other half received no treatment. Heart function was evaluated using echocardiograms and measures of heart muscle activity, concentrations of inflammatory factors and cellular responses to stress. Heat-shock protein expression was measured in cardiac myocytes in vitro.
The outcomes showed that estrogen replacement preserved important heart cell responses to stress and protected cardiac function, regardless of the rats’ ages. In addition, the hormone prevented damage due to cytokines, inflammatory factors increasingly recognized as significant contributors to heart and vascular disease. Estrogen replacement perpetually reduced this inflammatory response, thereby reducing cell injury. The researchers also found that aging females lose the induction of heat-shock proteins, a change that was not prevented by estrogen replacement.
“Estrogen supported heart health in a number of ways,” said Knowlton, “but while we thought it was possible that estrogen replacement would have an impact on heat-shock protein expression, that was not the case. We have more work to do to determine what could preserve these important cardiac protectors in females as they age.”
Knowlton’s team is currently conducting additional experiments to determine the molecular interactions that could help prevent the loss of the heat-shock protein response, and she recommends additional research on the timing of hormone replacement to help refine treatment protocols for women.
“Our study does not indicate that all women should take estrogen right after menopause,” said Knowlton. “Rather, our findings add to the knowledge of the cardiovascular effects of hormones after menopause, which may one day help clinicians determine how best to treat women as they age.”
The current study, titled “17β-Estradiol, Aging, Inflammation and the Stress Response in the Female Heart,” was supported by funds from National Institutes of Health (National Institute on Aging) and the American Heart Association.
Additional authors were James P. Stice, Le Chen, Se-Chan Kim, J.S. Jung, A.L. Tran and T. T. Liu, who were at UC Davis when the study was conducted. Stice is currently at Duke University, Kim is at the University of Bonn in Germany and Jung is at UC Irvine.
The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit the UC Davis School of medicine website.