The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 10 No. 3 • November 2007

A Possible Mechanism Contributing to Loss of Estrogen Cardioprotection in Late Postmenopausal Women

Recent clinical trials have indicated that estrogen replacement appears to be protective against cardiovascular disease if taken by postmenopausal women at or shortly after the start of menopause, but that estrogen replacement fails to protect (or even worsens) cardiovascular status for postmenopausal women who begin its use starting several years after menopause. Not surprisingly, there has been much concern, speculation, and data analysis concerning the reasons for this.

One possible mechanism is reported in a new paper.1 Estrogen mediates its hormonal cardioprotective effects via estrogen receptors in vascular cells. The authors show here that “. . . 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature.” They found that “27HC inhibited both the transcription-mediated and the non-transcription-mediated production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia . . . decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization [restoration of damaged endothelium].” Thus, they propose, increases in 27HC (the level of which correlates well with cholesterol) “suggest a mechanism whereby decreased circulating levels of estrogens in the presence of hypercholesterolemia, atherosclerosis, or both may lead to increased risk of heart disease, a condition that may be particularly relevant in postmenopausal women.”

As the authors explain, oxysterols such as 27HC are metabolites of cholesterol produced in peripheral tissues to help in eliminating cholesterol. The accumulation by macrophages of excess oxysterols and cholesterol is a diagnostic feature of human developing atherosclerotic lesions.

Premenopausal women have a much lower risk of cardiovascular disease as compared to postmenopausal women. As described in this paper, the development of atherosclerosis after menopause for several years may lead to conditions that greatly reduce the cardioprotective effect of supplemental estrogen. “Whereas most US women have only fatty streaks and minimal atherosclerotic plaques in their coronary arteries at age 35, there is progression of lesion formation between ages 45 and 55, and more complex lesions are present by age 65.”


  1. Umetani et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nature Med 13(10):1185-92 (2007).

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