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Estrogen and Hormone Replacement in Menopause

By Robin Arnette
March 2009

Mendelsohn is the first recipient of the Elisa Kent Mendelsohn Professorship of Molecular Cardiology and Medicine at Tufts University School of Medicine and executive director of the Molecular Cardiology Research Institute at the New England Medical Center. (Photo courtesy of Steve McCaw)

Korach, who monitored the question-and-answer session, was one of the investigators who developed animal models and, in collaboration with Mendelsohn, helped resolve the issue regarding estrogen and its therapeutic effects in the development of cardiovascular disease. (Photo by Steve McCaw)

The use of estrogen and hormone replacement therapy (HRT) to treat menopausal symptoms in women has caused confusion in the general public and cardiology research circles. By the early 90s, the concept that estrogen and other hormones had a beneficial effect on the heart and its blood vessels was widely appreciated, based on two decades of animal and pre-clinical data. However, in 2003, the Women's Health Initiative (WHI) ( Exit NIEHS study of a large cohort of older women declared that estrogen was bad for women who were postmenopausal. Now, the pendulum has swung back to the idea that hormone therapy is beneficial to the heart, depending on when the therapy is administered.

Distinguished Lecturer Michael E. Mendelsohn, M.D., a specialist in Cardiovascular Disease (CVD) at Tufts University and the New England Medical Center says, "The 2006 WHI analysis showed that older women were at increased risk for heart disease following HRT, whereas younger women were, in fact, protected." Mendelsohn presented a seminar February 10 at NIEHS titled "Estrogen Action in the Cardiovascular System." In his seminar, Mendelsohn explained why he and others in the field believe that current data support the hypothesis that women who are going through menopause or recently postmenopausal receive a protective effect with HRT. The talk was hosted by Mendelsohn's friend and collaborator Kenneth Korach, Ph.D., chief of the NIEHS Laboratory of Reproductive and Developmental Toxicology.

When all of the published data on the topic were reviewed in 1992, the results consistently showed a 30-35 percent reduction in the relative risk of cardiovascular events and cardiovascular morbidity and mortality in menopausal women who took estrogen. A decade later, however, the WHI study completely changed this paradigm. "It reported that the postmenopausal women in the study experienced a substantially increased risk of coronary heart disease," Mendelsohn recalled. "There was an absolute uproar in the lay press, and NHLBI stopped the estrogen-only arm of the trial early."

Mendelsohn explained that the women in the WHI were mostly well past menopause (greater than 10 years) and had not taken HRT previously. Work from his lab and others, especially that of Thomas B. Clarkson, D.V.M., of Wake Forest University, led to the development of the "timing hypothesis," which likely explains the inconsistency. It states that normal blood vessels retain beneficial hormone responses such as vasodilatation, decreased inflammatory activation and decreased lesion progression, while vessels with advanced atherosclerosis do not.

Estrogen receptors, alpha (ERα) and beta (ERβ), exist in most cells, but Mendelsohn focused his talk on their role in vascular endothelial and smooth muscle cells, the cells that line blood vessels. The binding of estrogen to estrogen receptors in the endothelial cell causes the cell to generate nitric oxide, which activates a signaling system in the adjacent smooth muscle cell. "There are two classes of effects for estrogen on the blood vessel - rapid and longer-term," Mendelsohn said. "The rapid effects dilate the blood vessel, while the longer-term effects decrease the response to vascular injury and the rate at which atherosclerosis accrues."

Although estrogen took a beating in the press early-on, Mendelsohn said that a recent article published in the Wall Street Journal was one of several signs that things were changing. He said, "Melinda Beck's 'The Seven Things You Should Know About Hormones' ( Exit NIEHS reflects a growing consensus that the risks and benefits of HRT are different for younger and older women. This news is heartening for those of us who have been watching this evolve since the early 90s."

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