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Biochemical and Biophysical Markers of Endothelial Dysfunction in Adults with Hypopituitarism and Severe GH Deficiency

Department of Medicine (T.A.E., T.A.A., R.N.C.), School of Postgraduate Medicine, Keele University, Staffordshire, United Kingdom; Departments of Nuclear Medicine (J.O.) and Clinical Biochemistry (R.N.), North Staffordshire Hospital, Stoke-on-Trent, United Kingdom; and Section of Vascular Biology and Medicine (G.K., M.M., J.J.F.B.), University Department of Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom

Address all correspondence and requests for reprints to: Prof. R. N. Clayton, Department of Medicine, School of Postgraduate Medicine, University of Keele, Thornborow Drive, Stoke-on-Trent ST4 6QJ, United Kingdom. E-mail: r.n.clayton{at}keele.ac.uk

Abstract

Adult hypopituitarism is known to be associated with reduced life expectancy related to excess vascular events, and endothelial dysfunction is present in patients with this condition. We studied the relationship between biophysical and biochemical markers of endothelial dysfunction, including E-selectin, intercellular cell adhesion molecule-1, von Willebrand factor, and thrombomodulin in 52 adult patients with hypopituitarism and severe GH deficiency (<2 ng/ml on provocative testing) compared with 54 age-, sex-, and smoking-matched normal controls. We also examined endothelium-dependent dilatation of the brachial artery to postischemic occlusion and carotid artery morphology (intima-media thickness) by high-resolution ultrasonography. The patients were stable on conventional hormone replacement therapy but not on GH therapy, and none of the subjects had a known risk factor for vascular disease. Levels of E-selectin [57 ± 3 vs. 49 ± 2 ng/ml (mean ± SEM)] (P < 0.043), intercellular cell adhesion molecule-1 (308 ± 11 vs. 266 ± 10 ng/ml) (P < 0.001), thrombomodulin (49 ± 3 vs. 35 ± 2 ng/ml) (P < 0.001), and von Willebrand factor (132 ± 7% vs. 105 ± 5%) (P < 0.004) were significantly higher in patients than in controls. Brachial artery endothelium-dependent dilatation was significantly lower in patients than in controls [4.7% (0.00–9.77) vs. 10.5% (6.4–16.2) (median, interquartile range)] (P < 0.001). This difference in endothelium-dependent dilatation was more marked in female patients than in controls (P < 0.003), although it disappeared when estrogen-sufficient female patients were compared with controls (P = 0.31). However, the female patients who were not replaced with estrogen continued to show a striking difference compared with estrogen-deficient control females (P < 0.004). There was no difference in carotid intima-media thickness between patients of either sex and controls. On univariate analysis, brachial artery endothelium-dependent dilatation correlated inversely with intercellular cell adhesion molecule-1 (r = -0.225, P < 0.033). Intercellular cell adhesion molecule-1 correlated positively with E-selectin (r = 0.466, P < 0.0001) and negatively with IGF-I (r = -0.238, P < 0.016). E-selectin correlated with thrombomodulin (r = 0.215, P < 0.034) and von Willebrand factor (r = 0.218, P < 0.03) and negatively with IGF-I (r = -0.255, P < 009). Thrombomodulin correlated positively with von Willebrand factor (r = 0.422, P < 0.0001) and inversely with IGF-I (r = -0.266, P < 0.008). These correlations persisted after correction for age, sex, body mass index, and waist to hip ratio, with the exception of IGF-I, which now correlated with thrombomodulin only. These results confirm significant endothelial dysfunction in hypopituitarism and provide insight into the relationship of biochemical and biophysical markers of early atherosclerosis in hypopituitary GH-deficient adults. The negative correlation of IGF-I with some biochemical markers of endothelial dysfunction and the predictive nature of GH deficiency in stepwise regression analysis in this study supports the hypothesis that GH deficiency may play a role in these abnormalities. Future studies will determine whether GH treatment can reverse these abnormalities. Furthermore, the more significant endothelium-dependent dilatation abnormality in the female estrogen-deficient subjects compared with those who were estrogen replete suggests that estrogen replacement in these patients is a crucial element in protecting against vascular disease.

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