Cholesterol-Related Compound Can Block Estrogen From Helping To Prevent Heart Disease In Some Women, Study Says

Main Category: Heart Disease
Also Included In: Cholesterol;  Menopause;  Women's Health / Gynecology
Article Date: 19 Sep 2007 - 8:00 PDT

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A molecule related to cholesterol can block the hormone estrogen from performing functions in blood vessels that keep them healthy and protected against heart disease, according to a study published Sunday online in the October issue of the journal Nature Medicine, the Wall Street Journal reports.

For the study, David Mangelsdorf and colleagues at the University of Texas-Southwestern Medical Center identified the molecule 27-hydroxycholesterol, or 27HC, which is a by-product created as the body processes cholesterol. The researchers found in experiments in mice that 27HC and estrogen target the same receptors in blood vessels. According to the findings, estrogen attaches to the receptors when it is present in normal amounts and 27HC is low, which triggers functions that protect the heart. When estrogen levels decrease -- as is typical during menopause -- 27HC can reach the receptors before the estrogen and interrupt its ability to protect the heart, the researchers found.

Application to Women's Health Initiative Findings, Reaction
According to the Journal, the findings could help explain why hormone replacement therapy failed to prevent heart disease in some participants of the NIH-sponsored Women's Health Initiative study (Winslow, Wall Street Journal, 9/17).

NIH researchers in July 2002 ended the WHI study on combination HRT three years early because they determined that the treatment might increase the risk for heart disease, invasive breast cancer and other health problems. A later WHI analysis, published in the April 4 issue of the Journal of the American Medical Association, found that HRT use among women in their 50s does not increase their risk for heart attack (Kaiser Daily Women's Health Policy Report, 7/24).

Women in the WHI started on estrogen at an average of 13 years after the onset of menopause, the Journal reports. Mangelsdorf said his findings indicate that during that period, 27HC had taken over the estrogen receptors, prompting processes that increased the risk of heart disease. "Estrogen is a protector, it's not therapeutic," Mangelsdorf said, adding, "You can't give it to cure something that's started."

Donald McDonell of Duke University's School of Medicine, who was not involved in the study, said the report "brings a new perspective" to the findings of the WHI study and a "very plausible (scenario) that has been tested out in the best (animal) models we have available." It is also consistent with recent closer examination of that study, he added.

JoAnn Manson, a principal investigator of WHI, said Mangelsdorf's study provides "intriguing" insight into results of WHI. Manson said she questioned a finding from the WHI study in which women with high cholesterol tended to have worse outcomes on HRT than those with low cholesterol. Since high levels of 27HC reflect high levels of cholesterol in the blood, the new study supports that result, she said. "Their overall finding ties together very nicely with the clinical-trial results," Manson, who is chief of preventive medicine at Brigham and Women's Hospital, said, adding, "This could help fit pieces of the puzzle together" (Wall Street Journal, 9/17).

The study's abstract is available online.

New York Times Magazine Examines History of HRT Research
In related news, the New York Times Magazine on Sunday examined the history of research on the effects of HRT -- and how the "simplest" explanation for the "here-today-gone-tomorrow nature of medical wisdom" is that "it is the natural rhythm of science." According to the Times Magazine, the center of the different outcomes in HRT research is the "science of epidemiology itself," particularly the difference in observational or cohort studies, such as the 1985 Nurses Health Study, and randomized-controlled clinical trials, such as WHI. The Nurses Health Study found that women taking estrogen HRT had about one-third as many heart attacks as women who had never taken the drug. The history of public health research shows that it is "never a bad idea to remain skeptical" of a finding until it is not refuted by a randomized trial, the Times Magazine reports (Taubes, New York Times Magazine, 9/16).

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