Dallas TX - Researchers have identified a compound that effectively inhibits the function of estrogen in the vascular tissue by antagonizing the estrogen-receptor blockers. The compound, known as 27-hydroxycholesterol (27HC), an endogenous metabolite of cholesterol, binds to the estrogen receptors, taking away the cardioprotective effects of the hormone, primarily by inhibiting the production of nitric oxide.

The findings, say investigators, could help explain why hormone replacement therapy failed to protect some postmenopausal women from heart disease in the Women's Health Initiative (WHI) study.

"It's basically a protection thing," senior author Dr David Mangelsdorf (University of Texas Southwestern Medical Center, Dallas) told heartwire. "Estrogen protects the artery from injury. If the artery is injured or the state of the artery is compromised, there is a greater risk of oxidized LDL to be recruited by macrophages into the artery wall to start the process of atherosclerosis. Once that process is started, that protective effect of estrogen no longer works and might make the situation worse. This is why we think the WHI failed, in part, to show any protective effect."

Women in the WHI, he said, had been without estrogen for approximately 12 years. It is important to start estrogen therapy very early after menopause, because if the women were at risk, even at a subclinical level, giving estrogen would not make a difference; the hormone must be present before the initiation of disease, said Mangelsdorf. During the dozen or so years the WHI postmenopausal women were without estrogen, 27HC could have bound to the estrogen receptors, setting in motion the cardiovascular disease process.

In the study, published in the October 2007 issue of Nature Medicine with lead investigator Dr Michihisa Umetani (Howard Hughes Medical Institute, Chevy Chase, MD), the researchers first showed that 27HC, elevated in hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of the estrogen receptor in the vasculature, inhibiting estrogen-dependent nitric-oxide production by vascular cells. This resulted in reduced estrogen-induced vasorelaxation of the rat aorta.

"27-hydroxycholesterol is an intermediate in the process of getting rid of cholesterol and converting it into a bile acid," explained Mangelsdorf. "It's a necessary component, but the problem is in the periphery; when the concentration of cholesterol starts to rise, the concentration of this compound also starts to rise."

In normal premenopausal women, the amount of 27HC generated from cholesterol is low compared with the level of estrogen circulating in the blood. When the level of 27HC is higher relative to estrogen, however, such as after menopause or in women with hypercholesterolemia, 27HC blocks the function of the estrogen receptors and results in a loss of cardiovascular protection. Mangelsdorf told heartwire that this could help explain why men, who also produce estrogen but in much lower amounts than women, are at greater risk of cardiovascular disease than women until women reach menopause.

The investigators say these findings might help explain the repeated observations showing that estrogen replacement therapy is less likely to benefit women who have existing vascular disease. In addition, in the WHI, although the women were free of known cardiovascular disease, subclinical disease was not defined, and it is possible that many of the women had atherosclerosis and the resulting high levels of 27HC.

Another study published this week in Molecular Endocrinology also showed 27HC to act in a deleterious manner in breast tissue [2]. In that study, 27HC activated estrogen receptors to promote tumor growth. The findings, said Mangelsdorf, suggest that estrogen-responsive breast cancers might also be responsive to 27HC.