The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency

Abstract

Objectives: Controversy persists with regard to the atherogenic risk associated with adult growth hormone deficiency (GHD). Endothelial dysfunction and enhanced oxidative stress are early features of atherogenesis. Therefore, we have studied the effect of three months of low dose GH replacement therapy (0.03 IU/kg/day) on these parameters in GHD adults. Subjects and Methods: Eight hypopituitary GHD adults (4 male, 4 female), who were receiving conventional hormone replacement therapy, were studied before and after 3 months of GH replacement (0.03 IU/kg/day). All observations obtained were compared with similar measurements made in 8 matched control subjects. All study subjects were non-smokers, normotensive and gave no personal or family history of premature vascular disease. Endothelial function was assessed using a specialised vessel wall tracking system to measure endothelium-dependent, flow-mediated, brachial artery dilatation (FMD). Measurements were repeated following glyceryl-trinitrate (GTN) (endotheliumindependent dilatation). Oxidative stress was assessed by directly measuring lipid-derived free radicals in venous blood by electron paramagnetic resonance spectroscopy. Fasting lipids, insulin, plasma glucose and IGF-I were also measured at baseline and following GH replacement. Results: FMD, expressed as a percentage change from resting base-line diameter, was significantly impaired in the pre-treatment GHD patients compared with controls (3.1 Ϯ 2.1% vs 6.1 Ϯ 0.9%, P < 0.001; means Ϯ S.D.) indicating endothelial dysfunction. Significant increase in FMD was noted following GH therapy (3.1 Ϯ 2.1% vs 6.5 Ϯ 1.9%, P < 0.001). Free radicals (arbitrary units) were elevated in the pre-treatment GHD patients compared with controls (0.36 Ϯ 0.09 vs 0.11 Ϯ 0.12, P < 0.05) and fell significantly following GH therapy (0.23 Ϯ 0.03 vs 0.36 Ϯ 0.09, P < 0.05), although they remained elevated compared with controls. Fasting insulin was significantly higher (25.9 Ϯ 18.8 vs 13.9 Ϯ 6.7 mu/l, P < 0.05) and IGF-I concentrations lower (10.8 Ϯ 4.7 vs 20.2 Ϯ 6.3 nmol/l, P < 0.05) in the pre-treatment GHD subjects. After treatment there were no changes in insulin concentration, although IGF-I levels were normalised (10.8 Ϯ 2.3 vs 23.6 Ϯ 11.4 nmol/l, P < 0.05). Conclusions: Endothelial dysfunction and enhanced oxidative stress are features of adult GHD. This study suggests plausible mechanisms underlying any proatherogenic tendency in adult GHD and demonstrates improvement of these factors following GH replacement.

Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel

“…Oxidative stress, measured as lipid-derived free radicals, was elevated in a cohort of GH deficient patients but fell significantly during GH replacement therapy, paralleled by improvement of endothelial function (Evans et al 2000). In the present study, we found that the alpha type of glutathione S-transferase was up-regulated by GH.…”

“…Besides affecting cardiac structure and contractility (Fazio et al 1997, Longobardi et al 2000, Barreto-Filho et al 2002, both experimental and clinical GH deficiency has been associated with increased systemic vascular resistance (Fazio et al 1997, Longobardi et al 2000 and abnormal vascular reactivity (Rossoni et al 1999, Evans et al 2000, Capaldo et al 2001. Accordingly, an increased prevalence of hypertension (Barreto-Filho et al 2002) and atherosclerotic disease (Pfeifer et al 1999) has been reported among patients with GH deficiency, and hypopituitary patients show increased cardiovascular morbidity and mortality (Rosen & Bengtsson 1990).…”

“…Accordingly, an increased prevalence of hypertension (Barreto-Filho et al 2002) and atherosclerotic disease (Pfeifer et al 1999) has been reported among patients with GH deficiency, and hypopituitary patients show increased cardiovascular morbidity and mortality (Rosen & Bengtsson 1990). GH treatment in GH deficient states has been shown to normalize systemic vascular resistance (Boger et al 1996, Longobardi et al 2000, arterial stiffness (Smith et al 2002), endothelial and/or endothelium-independent vasodilation (Rossoni et al 1999, Evans et al 2000, Capaldo et al 2001, and may reverse markers of early atherosclerosis (Pfeifer et al 1999).…”

Antioxidation improves in puberty in normal weight and obese boys, in positive association with exercise-stimulated growth hormone secretion

“…Indeed, children with GH deficiency and decreased IGF1 concentrations demonstrate substantially increased oxidative stress that decreases after GH replacement therapy (10). Furthermore, in GH-deficient adults, the presence of endothelial dysfunction is associated with enhanced oxidative stress that diminishes following GH replacement (11).…”

“…Children with GH deficiency demonstrate decreased production of antioxidation markers, which increase upon GH replacement therapy (10). In addition, in adults with GH deficiency, endothelial dysfunction is common and associated with the increased levels of prooxidation markers, which decrease following GH replacement therapy (11). Furthermore, physiological concentrations of testosterone have been shown in vitro to suppress neutrophil prooxidative capability (12).…”