Byproduct of cholesterol interferes with the beneficial effects of estrogen on the heart

Sep 17 2007

A new study possibly offers a biological reason why hormone replacement therapy (HRT) fails to protect some postmenopausal women from heart disease.

The culprit appears to be a molecule called 27-hydroxycholesterol, or 27HC, a byproduct created as the body processes cholesterol.

The study which was carried out by researchers at the University of Texas Southwestern Medical Center in Dallas has discovered that a byproduct of the cholesterol metabolism interferes with the beneficial effects estrogen has on the cardiovascular system; the revelation could provide a better understanding of the interplay between cholesterol and estrogen in heart disease.

According to Dr. David Mangelsdorf the senior author of the paper the team found in research carried out with mice that 27HC, binds to the same receptors in the blood vessels of the heart to which estrogen binds.

The usual result of this estrogen binding is that blood vessel walls remain elastic and dilated, and damage to the vasculature is repaired, along with other heart-protective effects.

Previous research has shown that postmenopausal women who no longer produce estrogen lose this protective action and become more susceptible to heart disease.

The researchers, on the basis of the studies with animals have determined that when estrogen levels dropped relative to the amount of 27HC circulating in the blood, 27HC reacted and bound to the estrogen receptors in the cardiovascular system and blocked their protective function; this inhibited the production of nitric oxide which encourages smooth muscle relaxation in blood vessels, helps cell growth and repair, and prevents thrombosis.

High cholesterol and diabetes have previously been linked with reduced levels of nitric oxide in the blood vessels and in animals fed a high-fat, high-cholesterol diet, both cholesterol and 27HC levels were elevated.

The researchers say they found that 27HC can effectively inhibit estrogen function in vascular tissue by binding to estrogen receptors.

Dr. Mangelsdorf, says the study illustrates the damaging effects high cholesterol has on the heart but also supports the notion that the relative levels of 27HC and estrogen in the vasculature are contributing factors to the risk for cardiovascular disease.

Dr. Mangelsdorf says the study may also explain why women are better protected than men from cardiovascular disease until they reach the menopause.

Mangelsdorf says the findings may help explain why a large clinical trial that evaluated certain hormone replacement therapies (HRT) in postmenopausal women, the Women’s Health Initiative, had to be halted in 2002 when the hormones appeared to increase a woman’s risk of heart disease.

At the time the findings caused a panic and thousands of women taking hormone replacements to alleviate menopause symptoms stopped using the therapy.

Mangelsdorf says by the time the women started taking estrogen again, the damage caused by 27HC binding to the estrogen receptors in the cardiovascular system may already have occurred and once this happens it cannot be regained.

The researchers also found that when 27HC binds to estrogen receptors in other tissues, such as reproductive tissues, it has no effect on their reproduction-related functions.

They say this property makes 27HC a "selective estrogen receptor modulator," or SERM, the first such naturally occurring molecule known to exhibit such selectivity and validates the estrogen receptor as a possible drug target for manufactured SERMs.

Dr. Mangelsdorf's work was supported by the National Institutes of Health, Howard Hughes Medical Institute and a private philanthropy and is published in the October issue of the journal Nature Medicine.