A byproduct of cholesterol metabolism interferes with the beneficial effects that estrogen has on the cardiovascular system, according to a study conducted by researchers at the University of Texas Southwestern Medical Center in Dallas and published in the October issue of Nature Medicine.

The study results may explain why hormone replacement therapy fails to protect some postmenopausal women from heart disease, said David Mangelsdorf, MD, chairman of pharmacology and senior author of the study.

The researchers found that in rodents, a molecule called 27-hydroxycholesterol (27HC) binds to the same receptors in the heart’s blood vessels as estrogen binds. 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 functions, by inhibiting the production of nitric oxide. Reduced nitric oxide levels in blood vessels have been linked with high cholesterol and diabetes.

Animals fed a high-fat, high-cholesterol diet had elevated cholesterol and 27HC levels.

In normal premenopausal women, the amount of 27HC generated from cholesterol is relatively low compared to the level circulating in the blood, which leads to enhanced cardiovascular protection. In contrast, when the 27HC level is higher relative to estrogen, the researchers speculated that 27HC overwhelms estrogen to bind with estrogen receptors, blocking the receptors and resulting in a loss of protection.

The researchers also found that 27HC works predominantly on estrogen receptors in the cardiovascular system.