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Effects of tibolone on cell adhesion molecules in postmenopausal women

Egarter, Christian MD; Sator, Michael MD; Huber, Johannes MD, PhD

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Abstract

Objective: The first step in atherosclerosis is characterized by the adherence of lymphocytes and monocytes to cell adhesion molecules expressed by endothelial cells. Therefore, we wanted to investigate the effect of tibolone on the circulating levels of various cell adhesion molecules.

Design: Thirty postmenopausal women were enrolled in a double-blind, randomized, placebo-controlled outpatient trial.

Results: Tibolone led to a significant decrease in soluble intercellular adhesion molecule-1, soluble intercellular adhesion molecule-3, and soluble vascular cell adhesion molecule-1, but had no effect on monocyte chemotactic protein-1.

Conclusions: The direct favorable effects of tibolone on endothelial cells may explain the clinical benefits of this substance in terms of anti-ischemic effects and osteoporosis prevention.

Several observational studies have suggested that postmenopausal women who receive estrogen therapy have fewer cardiovascular events over time compared with untreated women. 1,2 Although part of the antiatherogenic action of estrogen seems to be due to a beneficial effect on serum lipids, the protective mechanism of estrogen cannot be entirely explained on this basis. 3 Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the vessel wall. A prerequisite for this process is the recruitment of monocytes and lymphocytes to the artery wall. The accumulation of minimally oxidized low-density lipoproteins stimulates endothelial cells to produce a number of pro-inflammatory molecules, including cell adhesion molecules (CAMs) such as intercellular adhesion molecule (ICAM)-1 or vascular cell adhesion molecule (VCAM)-1 and chemotactic factors such as monocyte chemotactic protein (MCP)-1. 4 The firm adhesion of monocytes and T cells to endothelium is mediated by integrins on these cells, which interact with the adhesion molecules, representing the first step in atherosclerosis. 5

Decreased estrogen levels in menopause lead to an increase in cytokine concentrations, which, in turn, increases CAM expression. 6 Conversely, 17β-estradiol has been shown in endothelial cell cultures to inhibit the expression of CAMs. 7 The cytokine-induced expression of endothelial CAMs requires transcriptional activation, 8 and estrogen is known to have important gene-regulatory effects. 9 Furthermore, androgens have also been shown to suppress the production of epithelial CAMs in an animal model. 10 Tibolone (Liviel), a substance widely used in hormone replacement therapy (HRT), is characterized by a combination of estrogenic, progestogenic, and androgenic properties. 11 As a result of its androgenic property, it effects a decrease in high-density lipoprotein cholesterol, but also reduces very low-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a). 12 A number of other effects of tibolone on the cardiovascular system have also been investigated, 13,14 but the influence on the initial steps in atherosclerosis, especially on increased CAM levels in postmenopausal women, has not yet been studied. Because plasma concentrations of the soluble forms of CAMs are thought to reflect the level of cellular expression, 15 the aim of the present study was to investigate the effects of tibolone on various soluble CAMs in healthy postmenopausal women and to compare these effects with a placebo group.

©2003The North American Menopause Society

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