Original Paper
HORMONE RESEARCH
Horm Res 2008;70:230–235 DOI: 10.1159/000151595
Received: May 15, 2007 Accepted after revision: December 21, 2007 Published online: September 5, 2008
Circulating Levels of High-Sensitivity C-Reactive Protein and Soluble Markers of Vascular Endothelial Cell Activation in Growth Hormone-Deficient Adolescents Roberto Lanes a Henry Marcano b Omar Villaroel a Peter Gunczler a Edgar Morillo d Mariela Paoli e Marvelys Perez b Nora Maulino b Anselmo Palacios c a
Pediatric Endocrine Unit, Hospital de Clinicas Caracas, b Division of Endocrinology, Hospital de Niños JM de los Rios, and c Division of Endocrinology, Clinica Avila, Caracas, d Division of Endocrinology, Hospital Pediatrico Universitario Dr. Agustin Zubillaga, Barquisimeto, and e Division of Endocrinology, Hospital Central de Los Andes, Merida, Venezuela
Key Words Growth hormone deficiency ⴢ Intercellular adhesion molecule-1 ⴢ Vascular cell adhesion molecule-1 ⴢ E-selectin ⴢ P-selectin ⴢ C-reactive protein
Abstract Background/Aims: Significant endothelial dysfunction as determined by lower flow-mediated vasodilation of the brachial artery was recently reported by us in growth hormonedeficient (GHD) adolescents. The circulating concentrations of markers of vascular endothelial cell and platelet activation and their relationship to inflammatory markers have not been previously evaluated in this group of patients. Objective: To assess the relationship between circulating levels of high-sensitivity C-reactive protein (CRP) and soluble markers of vascular endothelial cell activation in GHD adolescents. Design/Methods: Twenty-eight GHD children on GH treatment with a chronological age of 15.7 8 2.6 years and 16 untreated GHD adolescents with a chronological age of 16.6 8 3.3 years were studied. Concentrations of CRP, as an inflammatory marker, were measured in all patients and the association between CRP and the fasting soluble markers of
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vascular endothelial cell activation intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin levels was evaluated. Sixteen healthy adolescents with a mean chronological age of 15.1 8 2.2 years served as controls. Results: CRP and P-selectin levels were significantly higher in untreated GHD adolescents than in treated GHD subjects or in healthy controls (p ! 0.02), while VCAM-1 concentrations were increased in both untreated and treated GHD adolescents when compared to controls (p ! 0.007). E-selectin and ICAM-1 levels were similar in all three groups. CRP was found to be associated with BMI (r: 0.62; p ! 0.001), P-selectin (r: 0.43; p ! 0.01), E-selectin (r: 0.27; p ! 0.03), ICAM-1 (r: 0.23; p ! 0.05) and VCAM-1 (r: 0.40; p ! 0.001) concentrations in untreated GHD adolescents and with P-selectin (r: 0.88; p ! 0.001) and E-selectin (r: 0.29; p ! 0.01) in treated GHD subjects. A weak inverse association was observed in a subgroup of patients between brachial artery endothelium-dependent dilation and P-selectin (r: –0.56; p ! 0.07). Conclusions: Low-grade inflammation as manifested by increased circulating levels of CRP seems to be associated with the early activation of vascular endothelial cells in GHD adolescents Copyright © 2008 S. Karger AG, Basel
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Hypopituitarism in adults has been associated with increased cerebrovascular and cardiovascular morbidity and mortality and growth hormone deficiency (GHD) may contribute to these findings [1, 2]. Increased visceral adiposity [3, 4], disturbances in lipoprotein metabolism [4, 5], premature atherosclerosis [6, 7], impaired fibrinolytic activity [8, 9], increased peripheral insulin resistance [10], hypoadiponectinemia [11], abnormal cardiac structure and impaired cardiac performance [12–15] have been reported in GHD adults and adolescents. Inflammation plays an important role in the atherosclerotic process of the arterial wall and peripheral markers of inflammatory activity such as C-reactive protein (CRP), TNF-␣ and interleukin-6 have been shown to correlate with the risk of atherosclerosis in adults [16] and adolescents with GHD [9] and to be independently associated with the degree of common carotid artery intimamedia thickness (IMT) in GHD adults [17]. In two recent studies in GHD adolescents, Colao et al. [18] and ourselves [14] were unable to find a significant increase in the IMT of the carotid arteries in untreated GHD adolescents, although a tendency towards such an increase was noted in both these studies, while Kostro et al. [19] found carotid artery IMT values to be significantly higher in GHD versus healthy children. Studies of endothelial function in GHD adults using both biochemical (ICAM-1, E-selectin, P-selectin, PAI-1 antigen, thrombomodulin and von Willebrand factor) and biophysical methods [flow-mediated endotheliumdependent dilation (EDD) of the brachial artery] revealed significant endothelial dysfunction and a good correlation between both these parameters [20]. In adults 12 months of GH replacement led to a decrease in the concentrations of soluble adhesion molecules reaching levels similar to those of healthy controls in one study [21] and to no improvement in biochemical endothelial markers in another [22]. Upregulation of endothelial adhesion molecules allows for leukocyte and monocyte adhesion to the endothelial cell surface and their migration to the subendothelial space, where they facilitate the atherogenic process [23]. We have recently demonstrated that GHD adolescents present with vascular abnormalities as manifested by lower flow-mediated EDD; an improvement in endothelial function and a reduction in arterial stiffness appear to occur following GH replacement [14]. Low-grade inflammation may contribute to the early activation of vascular endothelial cells and platelets and GH may play an important role in the modulation of both the systemic inflammatory and the local vascular endothelial response in GHD patients, as early as in adolesMarkers of Inflammation and Endothelial Cell Activation in GHD Adolescents
cence. In order to assess the relationship between circulating levels of high-sensitivity CRP and soluble markers of vascular endothelial cell activation in GHD, we have measured these parameters in a group of GH-treated GHD adolescents, in a group of untreated GHD adolescents and in a healthy control group. In addition we have correlated previously obtained results of flow-mediated EDD of the brachial artery with those of soluble markers of vascular endothelial cell activation in a subgroup of patients.
Material and Methods Twenty-eight GHD adolescents on GH treatment, 16 untreated GHD adolescents and 16 healthy controls were evaluated. All patients were in puberty (Tanner stage 3–4). Of the 28 treated GHD children 15 were males and 13 were females. These patients had a mean chronological age of 15.7 8 2.6 years, a mean bone age of 12.9 8 2.4 years and a mean height of 149.5 8 12.1 cm (height SD score of –2.1 8 0.4). Eighteen of the patients had idiopathic, isolated GHD, while 10 subjects had organic GHD deficiency (8 patients with a craniopharyngioma who had been treated with surgery and radiotherapy had multiple hormonal deficiencies, while the other 2 subjects, 1 with a hamartoma and 1 with anterior pituitary hypoplasia, had isolated GHD). These subjects were on GH treatment for the last 4.2 8 3.2 years at a dose of 0.1 IU/kg/day (0.03 mg/kg/day). Of the 16 untreated GHD adolescents there were 7 males and 9 females. They had a mean chronological age of 16.6 8 3.3 years, mean bone age of 12.3 8 2.4 years and a mean height of 147.8 8 15.8 cm (height SD score of –2.6 8 0.4). Eight of the 16 subjects had idiopathic isolated GHD and 8 had organic GHD (5 subjects with a craniopharyngioma and 1 with a macroadenoma had been treated with surgery and radiotherapy and 1 patient with histiocytosis was treated with radiotherapy and they all presented with multiple hormonal deficiencies, while 1 patient with anterior pituitary hypoplasia had isolated GHD). Untreated GHD patients were off therapy due to their inability to either obtain this medication through the social security system or to purchase it. Sixteen healthy adolescents (8 males and 8 females) with a mean chronological age of 15.1 8 2.2 years all comparable for bone age, body height, pubertal status, blood pressure and pulse participated in the study as controls. Absolute height of the controls did not differ from that of the two groups of GHD patients, but height SDS was higher in the controls than in the other two groups because the controls were somewhat younger. Baseline characteristics of all these patients can be seen in table 1. In patients with multiple pituitary hormone deficiencies the hormone they were lacking was replaced. Body mass index (BMI) was calculated by dividing body weight (kilograms) by the square of the height (meters). Initial blood samples were drawn in the morning after an overnight fast in all subjects. Serum concentrations of IGF-1 and IGFBP-3 were determined in all subjects using a two-site immunoradiometric assay (Diagnostic System Laboratories, Webster, Tex., USA) with inter- and intra-assay coefficients of variation for IGF-1 of 3.9–7 and 3.8–7.4%, respectively, and with inter- and intra-assay coef-
Horm Res 2008;70:230–235
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Table 1. Characteristics of treated and untreated adolescents with GH deficiency at the time of the study
Treated GHD (n = 28) CA, years BA, years Height, cm Height SD score BMI Waist-hip ratio Sex (m/f) Puberty GHD etiology (idiop./org.) IGF-1, ng/ml IGFBP-3, ng/ml
Untreated GHD Non-GHD (n = 16) controls (n = 16)
p
15.782.6 12.982.4 149.5812.1 –2.180.4 18.483.4 0.7680.06 15/13 all pubertal
16.683.3 12.382.4 147.8815.8 –2.680.4 21.384.8 0.8180.03 7/9 all pubertal
15.182.2 13.582.3 152.9814.4 –1.4803 19.383.2 0.7280.06 8/8 all pubertal
NS NS NS
