CLINICAL STUDY Positive effects of a physiological dose of GH on markers of atherogenesis: a placebo-controlled study in patients with adult-onset GH deficiency Jens Bollerslev 1 , Thor Ueland 1 , Anders P Jørgensen 4 , Kristian J Fougner 3 , Ragnhild Wergeland 2 , Thomas Schreiner 1 and Pia Burman 5 1 Section of Endocrinology and 2 Department of Medical Biochemistry, The National University Hospital, N-0027 Oslo, Norway, 3 Medical Department, Section of Endocrinology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, 4 Department of Endocrinology, Aker University Hospital, Oslo, Norway and 5 Global Endocrine Care, Pfizer Inc, New York, New York, USA (Correspondence should be addressed to J Bollerslev; Email: jens.bollerslev@klinmed.uio.no) (P Burman is now at Department of Endocrinology, University Hospital MAS, Malmo ¨, Sweden) Abstract Objective: GH deficiency is associated with an increased cardiovascular mortality. Fifty-five patients with adult-onset GH deficiency (AO-GHD) (24 female, 31 male, mean age 49 years) were enrolled in a placebo-controlled double-blind crossover study to investigate the effects of GH therapy on a var- iety of cardiovascular risk factors representing different aspects of atherogenesis, including apolipo- proteins (Apo A-1, Apo B), markers of subclinical inflammation (high-sensitivity C-reactive protein (CRP) and interleukin-6) and markers of endothelial function (intercellular adhesion molecule-1, von Willebrand factor and sCD40L (a pro-atherogenic factor and marker for plaque destabilization)). Methods: GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4 month washout period. Results: The final mean dose of GH was 50% higher for women and IGF-I increased to the same level in both sexes. Compared with placebo, substitution with GH showed a significant effect on Apo B (mean change 2 0.15 (2 0.22 to 2 0.08) mg/l) and CRP (2 1.8 (2 3.3 to 2 0.3) mg/l). The baseline level of and change in IGF-I during treatment with GH contributed significantly to the improvement in both markers. No effects were found on interleukin-6 or Apo A-1, or on markers of endothelial function. No gender differences were observed for any of the markers at baseline or following intervention. Conclusions: GH substitution to naı ¨ve patients with AO-GHD at a low, individually titrated dose aiming at normalizing IGF-I was followed by significant reductions in Apo B and CRP, indicating a positive effect of GH on cardiovascular risk. European Journal of Endocrinology 154 537–543 Introduction Patients with long-standing growth hormone deficiency (GHD) have significantly impaired health compared with the normal population, and long-term follow-up studies of patients with hypopituitarism have shown markedly reduced life expectancy (1–3). GHD may contribute to increased vascular morbidity and mortality (4, 5), as the syndrome is followed by central obesity, insulin resistance, unfavorable lipid alterations, early atherosclerotic changes as shown by increased intima-media thickness of the carotid arteries, reduced cardiac performance and decreased physical capacity (6). Several studies have documented positive effects of GH replacement therapy on all of these parameters (7–14), with the exception of glucose homeostasis, for which most controlled studies have found an increase in glucose and insulin levels (7, 13), at least during short-term treatment. An unfavorable lipid profile is central in the patho- genesis of atherosclerosis, and the changes in lipids typical of GHD may help to explain the increased cardi- ovascular risk in untreated GHD, especially in women (15). However, a chronic low-grade inflammation has been considered to play an important role in the ather- osclerotic process of the arterial wall (16) and serum markers of inflammation, including C-reactive protein (CRP) and interleukin-6 (IL-6) may predict the risk for European Journal of Endocrinology (2006) 154 537–543 ISSN 0804-4643 q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02125 Online version via www.eje-online.org