CLINICAL STUDY The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency L M Evans, J S Davies, R A Anderson 1 , G R Ellis 1 , S K Jackson 1 , M J Lewis 1 , M P Frenneaux 1 , A Rees and M F Scanlon Section of Endocrinology, Diabetes and Metabolism and 1 Cardiovascular Sciences Research Group, University Hospital of Wales, Cardiff, UK (Correspondence should be addressed to L M Evans, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Wales, Heath Park, Cardiff CF4 4XW, UK; Fax: +44 2920 744581) 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 replace- ment (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) (endothelium- independent 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  2.1% vs 6.1  0.9%, P < 0.001; means  S.D.) indicating endothelial dysfunction. Significant increase in FMD was noted following GH therapy (3.1  2.1% vs 6.5  1.9%, P < 0.001). Free radicals (arbitrary units) were elevated in the pre-treatment GHD patients compared with controls (0.36  0.09 vs 0.11  0.12, P < 0.05) and fell significantly following GH therapy (0.23  0.03 vs 0.36  0.09, P < 0.05), although they remained elevated compared with controls. Fasting insulin was significantly higher (25.9  18.8 vs 13.9  6.7 mu/l, P < 0.05) and IGF-I concentrations lower (10.8  4.7 vs 20.2  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  2.3 vs 23.6  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. European Journal of Endocrinology 142 254–262 Introduction Adult growth hormone deficiency (GHD) may be associated with an increased risk of premature cardio- vascular disease (1), although the precise nature and magnitude of any risk remain contentious (2). Adult GHD is associated with several cardiovascular risk factors including altered body composition (3), reduced exercise capacity (4), insulin resistance (5) and dyslipidaemia characterised by small, dense low-density lipoprotein (LDL) particles, decreased high-density lipoprotein (HDL) cholesterol and increased triglyceride levels (6, 7). Recently, abnormal post-prandial lipid profiles (a factor implicated in the pathogenesis of atherosclerosis) have also been described in adult GHD patients (8). However, the mechanisms underlying vascular injury in GHD remain unclear, with some authors suggesting that non- physiological hormone replacement may be of greater significance than GH deficiency per se (9). Intervention studies with recombinant human growth hormone (rhGH) appear to show physical, biochemical and psychological benefits (9) but any effects of rhGH replacement on cardiovascular mortality are hitherto unknown. European Journal of Endocrinology (2000) 142 254–262 ISSN 0804-4643  2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 11/02/2021 08:57:41AM via free access