Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency

Adult hypopituitarisin is known to be associated with reduced life expectan cy related to excess vascular events, and endothelial dysfunction is presen t in patients with this condition. We studied the relationship between biop hysical and biochemical markers of endothelial dysfunction, including E-sel ectin, intercellular cell adhesion molecule-1, von Willebrand factor, and t hrombomodulin in 52 adult patients with hypopituitarism and severe GH defic iency (<2 ng/ml on provocative testing) compared with 54 age-, sex-, and sm oking-matched normal controls. We also examined endothelium-dependent dilat ation of the brachial artery to postischemic occlusion and carotid artery m orphology (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<plus/minus>3 vs. 49 +/-2 ng/ml (mean +/- SEM)] (P<0.043), intercellular cell adhesion molecule-1 (308<plus/minus>11 vs. 266 +/- 10 ng/ml) (P<0.001), thrombomodulin (49<plus/minus>3 vs. 35 +/- 2 ng/ml) (P<0.001), and von Willebrand factor (132<plus/minus>7% vs. 105 +/ -5%) (P<0.004) were significantly higher in patients than in controls. Brac hial artery endothelium-dependent dilatation was significantly lower in pat ients than in controls [4.7% (0.00-9.77) vs. 10.5% (6.4-16.2) (median, inte rquartile range)] (P<0.001). This difference in endothelium-dependent dilat ation was more marked in female patients than in controls (P<0.003), althou gh it disappeared when estrogen-sufficient female patients were compared wi th controls (P=0.31). However, the female patients who were not replaced wi th estrogen continued to show a striking difference compared with estrogen- deficient control females (P<0.004). There was no difference in carotid int ima-media thickness between patients of either sex and controls. On univari ate analysis, brachial artery endothelium-dependent dilatation correlated i nversely with intercellular cell adhesion molecule-1 (r = -0.225, P<0.033). Intercellular cell adhesion molecule-1 correlated positively with E-select in (r=0.466, P<0.0001) and negatively with IGF-l (r = -0.238, P<0.016). E-s electin correlated with thrombomodulin (r=0.215, P<0.034) and von Willebran d factor (r=0.218, P<0.03) and negatively with IGF-I (r = -0.255, P<009). T hrombomodulin 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 pe rsisted after correction for age, sex, body mass index, and waist to hip ra tio, with the exception of IGF-I, which now correlated with thrombomodulin only. These results confirm significant endothelial dysfunction in hypopitu itarism. and provide insight into the relationship of biochemical and bioph ysical markers of early atherosclerosis in hypopituitary GH-deficient adult s. The negative correlation of IGF-I with some biochemical markers of endot helial dysfunction and the predictive nature of GH deficiency in stepwise r egression analysis in this study supports the hypothesis that GH deficiency may play a role in these abnormalities. Future studies will determine whet her GH treatment can reverse these abnormalities. Furthermore, the more sig nificant endothelium-dependent dilatation abnormality in the female estroge n-deficient subjects compared with those who were estrogen replete suggests that estrogen replacement in these patients is a crucial element in protec ting against vascular disease.