title: Hormone replacement therapy and vascular protection - The influence of oestrogen on the endothelium
Creators: name: Duncan, Ann Carolyn
Publisher: name: University of Glasgow
Year: 2001
Subjects: subject: Endocrinology, menopause, vascular endothelium.

description: Cardiovascular disease is the leading cause of death and an important cause of morbidity in postmenopausal women, the incidence being particularly high in the West of Scotland. Retrospective studies strongly suggest an aetiological link between oestrogen deficiency and cardiovascular risk, and moreover have suggested that mortality can be reduced by up to 50% by the administration of hormone replacement therapy. However, recently reported randomised controlled studies have challenged this view (Hulley et al, 1998). The mechanism by which the apparent cardioprotective benefit occurs is multi-factorial and incompletely understood. Direct effects on the vessel wall particularly at the level of the endothelium, as well as indirect effects on metabolic risk factors such as lipid and carbohydrate metabolism, may play an important role in any underlying protective mechanism. The aim of this project was to study the effect of oestrogen on the vessel wall, more specifically by examining its effect on vascular reactivity and its influence on nitric oxide synthesis and release from the vascular endothelium. In vivo studies using forearm venous occlusion plethysmography were used to assess the effect of oestrogen on forearm vasodilator responses, and on the release of nitric oxide from the intact endothelium. To compliment this work, the effect of sex steroids on the growth and function of endothelial cells, and on the synthesis and release of nitric oxide from vascular endothelial cells, was studied in vitro using cultured human aortic endothelial cells. The effect of short and longterm oestrogen on endothelial nitric oxide synthase (eNOS) gene expression was studied in cultured cells using northern analysis. No change in forearm blood flow was observed following intra-arterial infusion of 17beta-oestradiol, suggesting that oestrogen is not an acute vasodilator in the forearm vasculature. Forearm blood flow responses to NG-monomethyl-L-arginine, a stereospecific inhibitor of nitric oxide which provides an index of basal nitric oxide synthesis, were unchanged following 4 weeks' of transdermal 17beta-oestradiol treatment, suggesting that oestrogen supplementation did not enhance basal nitric oxide release in the forearm vascular bed. In cultured endothelial cells, a significant increase cell number was observed following long term oestradiol treatment. The underlying mechanism for this observation is unclear. Expression of messenger RNA for the eNOS gene was confirmed by northern analysis, however the results of these studies did not demonstrate any change in eNOS mRNA expression following oestrogen treatment, supporting the findings of the in-vivo study. With the exception of the growth studies which yielded interesting results requiring further evaluation, the negative results of the remaining carefully designed and well executed studies, while at variance with the results of other investigators, nevertheless generate interesting new data which appears to be in broad agreement with the albeit limited results of the randomised control studies currently available. From our present knowledge base, there remain many unanswered questions about the true risks and benefits of hormone replacement therapy, and a better understanding of the mechanisms contributing to any beneficial effects will lead to better prescribing practices and may ultimately lead to improvements in womens' health.