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SELECTED SCIENTIFIC ASPECTS OF THE 8TH IMS WORKSHOP« AGEING , MENOPAUSE, CARDIOVASCULAR DISEASE AND HRT »Ulysse GASPARD This small, hyperspecialized workshop superbly organized by the « maestro » chairman of the meeting Andrea Genazzani, was a joint venture between the International Menopause Society and the European Society of Cardiology, ESC Task Force on gender. Twenty-eight invited presentations were made by opinion leaders on fundamental, epidemiological and clinical aspects of age, CVD and HRT-a particularly « HOT » topic. These will be soon published, and you will be informed about it.
It is impossible to briefly sum up these briliant contributions, and I propose to highlight one important aspect of CVD and HRT on which particularly new insights have been brought during the Workshop : After much debate, it has been hypothesized, when reviewing the data of the large american randomized clinical trials and observational studies ,that there might be in 50 to 59 years-old women a « WINDOW OF OPPORTUNITY » for a potential benefit in CVD, and more specifically coronary heart disease (CHD) when HRT is administered early in the menopause, whereas an increased CHD risk is observed when HRT is initiated late (i.e.> 60 years of age) after the onset of menopause. In endothelial cells, receptors ER, ER, PRA, PRB and A(androgen)R are present as well as the aromatase enzyme complex. About 300 coregulators are found to enhance or inhibit the ligand-receptor complexes of sex steroids in the endothelium. Through different mechanisms relying on nuclear as well as extra-nuclear activation, E-dependent actions are now well demonstrated, such as reendothelization of traumatized vessels, remodelling with inhibition of excess proliferation of vascular smooth muscle cells, neoangiogenesis and functional modulation (Simoncini). Vasodilation is enhanced by increased e-NOS activity and increased availability of endothelial NO, and also of PGI2 under the influence of E.An atheroprotective activity of E is exerted through inhibition of subendothlial deposition of LDL, ox-LDL and formation of fatty streaks (Mendelsohn).The latter observations can also be made in intact mice. By contrast,in ERa complete KO mice, there is a full abrogation of E-dependent atheroprotection and the atheroprotective effect of E is also abolished in mice specifically deficient in endothelial ERa (Arnal). On the other hand, as is also observed in the human and in animal models (monkey,mouse), chronic exposition to E elicits a direct proinflammatory action on various cell populations of the inflammatory/immune system and concurs to lymphocyte/macrophage migration in atheromatous plaques and secretion of proinflammatory cytokines such as IFN, Accordingly, E behaves like a two-faced « Janus »,in animal models in vivo :E protects the vessel mainly through NO enhancement, but promotes altogether proinflammatory changes.If atheromatous plaques are present in the subendothelium, they can be destabilized and the clinical situation deteriorates.These biological data fit very well with the « window of opportunity » hypothesis and reinforce the epidemiological data, which seem to indicate that in the early postmenopausl women, the protective role of HRT will prevail if atherogenic lesions are scarce, and deterioration will prevail in older postmenopausal women presenting with atheromatous lesions. The « timing hypothesis » was introduced by Clarkson with the oophorectomized monkey model, which shows a close correlation with clinical observations. All these arguments (and many others, related to Flow Mediated Dilation in postmenopausal women,etc...) concur to establish not only the epidemiological but also the biological plausibility of a protective effect of E on the cardiovascular system, provided HRT is initiated early after the menopause.
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| Last Updated ( Monday, 31 August 2009 09:28 ) |
