Identification of new biomarkers of low-dose GH replacement therapy in GH-deficient patients.

CONTEXT GH secretion peaks at puberty and continues to be secreted in adulthood, albeit at a declining rate. Profound GH deficiency (GHD) in adults with pituitary disease is associated with symptoms that improve with GH substitution, but it is important to tailor the GH dose to avoid overtreatment. Measurement of serum IGF-I levels is an important clinical tool in this regard, but it is well recognized that some patients receiving GH treatment do not show an increase in IGF-I. OBJECTIVE The objective of the study was to identify novel serum biomarkers of GH treatment in adults with GHD. DESIGN AND PATIENTS Eight patients with profound GHD as a consequence of a pituitary adenoma or its treatment were evaluated before and 3 months after GH replacement therapy (0.2-0.4 mg/d). MAIN OUTCOME MEASURES Serum proteomic changes were studied using two-dimensional gel electrophoresis and mass spectrometry. Protein profiles were analyzed and compared in serum samples obtained before and after GH treatment. RESULTS The levels of six serum protein spots were significantly altered after GH substitution. These proteins were identified as five isoforms of haptoglobin (decreased in posttreatment samples) and one isoform of apolipoprotein A-I (increased in posttreatment samples). Importantly, changes in the levels of the identified proteins were associated with decreases in fat mass and increases in lean mass in all patients. These results were independent of serum IGF-I levels. CONCLUSIONS Evaluation of the identified proteins provides a novel alternative to traditional markers of GH status, such as serum IGF-I levels, to assess GH therapy in GH deficient adults.

[1]  J. Kopchick,et al.  Serum proteome changes in acromegalic patients following transsphenoidal surgery: novel biomarkers of disease activity. , 2011, European journal of endocrinology.

[2]  A. Klibanski,et al.  Effects of recombinant human growth hormone in anorexia nervosa: a randomized, placebo-controlled study. , 2010, The Journal of clinical endocrinology and metabolism.

[3]  M. Powell,et al.  Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes. , 2010, American journal of physiology. Heart and circulatory physiology.

[4]  L. Frohman,et al.  Activation of the GH/IGF-1 axis by CJC-1295, a long-acting GHRH analog, results in serum protein profile changes in normal adult subjects. , 2009, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[5]  J. Kopchick,et al.  Perspective: proteomic approach to detect biomarkers of human growth hormone. , 2009, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[6]  D. Goulis,et al.  Amelioration of cardiovascular risk factors with partial biochemical control of acromegaly , 2008, Clinical endocrinology.

[7]  J. Kopchick,et al.  Analysis of mouse skin reveals proteins that are altered in a diet‐induced diabetic state: A new method for detection of type 2 diabetes , 2007, Proteomics.

[8]  M. Paoli,et al.  Growth hormone deficiency, low levels of adiponectin, and unfavorable plasma lipid and lipoproteins. , 2006, The Journal of pediatrics.

[9]  Michael Buckley,et al.  Novel biomarkers of human growth hormone action from serum proteomic profiling using protein chip mass spectrometry. , 2006, The Journal of clinical endocrinology and metabolism.

[10]  B. Zetter,et al.  Cancer biomarkers: knowing the present and predicting the future. , 2005, Future oncology.

[11]  J. Frystyk,et al.  Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. , 2005, The Journal of clinical endocrinology and metabolism.

[12]  J. Kopchick,et al.  Differentially Expressed Proteins in the Pancreas of Diet-induced Diabetic Mice* , 2005, Molecular & Cellular Proteomics.

[13]  H. Van Vlierberghe,et al.  Haptoglobin polymorphisms and iron homeostasis in health and in disease. , 2004, Clinica chimica acta; international journal of clinical chemistry.

[14]  P. Chanson,et al.  Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials. , 2004, The Journal of clinical endocrinology and metabolism.

[15]  A. Klibanski,et al.  Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. , 2003, The Journal of clinical endocrinology and metabolism.

[16]  S. Grottoli,et al.  Occurrence of GH deficiency in adult patients who underwent neurosurgery in the hypothalamus-pituitary area for non-functioning tumour masses. , 2003, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[17]  A. Kastrati,et al.  Genotyping of the common haptoglobin Hp 1/2 polymorphism based on PCR. , 2002, Clinical chemistry.

[18]  Maliha S. Nash,et al.  Handbook of Parametric and Nonparametric Statistical Procedures , 2001, Technometrics.

[19]  J. Jørgensen,et al.  The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults. , 2000, The Journal of clinical endocrinology and metabolism.

[20]  N. Yıldız,et al.  Effects of growth hormone replacement therapy on lipids, lipoproteins and apolipoproteins: Is the increased apolipoprotein A‐1/B ratio the only benefit? , 2000, Pediatrics international : official journal of the Japan Pediatric Society.

[21]  J. Jørgensen,et al.  Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition , 1996, Clinical Endocrinology.

[22]  L. Mosekilde,et al.  Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. , 1996, The Journal of clinical endocrinology and metabolism.

[23]  R. Clayton,et al.  The effect of hypopituitarism on life expectancy. , 1996, The Journal of clinical endocrinology and metabolism.

[24]  H. Orskov,et al.  Non-competitive time-resolved immunofluorometric assays for determination of human insulin-like growth factor I and II. , 1995, Growth regulation.

[25]  G. B. Schaefer,et al.  Lipids and apolipoproteins in growth hormone-deficient children during treatment. , 1994, Metabolism: clinical and experimental.

[26]  N. Skakkebaek,et al.  Three years of growth hormone treatment in growth hormone-deficient adults: near normalization of body composition and physical performance. , 1994, European journal of endocrinology.

[27]  P. Sönksen,et al.  The growth hormone deficiency syndrome in adults , 1992, Clinical endocrinology.

[28]  J. Hardy,et al.  The clinical and endocrine outcome to trans‐sphenoidal microsurgery of nonsecreting pituitary adenomas , 1991, Cancer.

[29]  N. Skakkebaek,et al.  Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. , 1989, The Journal of clinical endocrinology and metabolism.

[30]  N. Skakkebaek,et al.  BENEFICIAL EFFECTS OF GROWTH HORMONE TREATMENT IN GH-DEFICIENT ADULTS , 1989, The Lancet.

[31]  R. Campbell,et al.  Inhibition of Growth Hormone-Stimulated Lipolysis by Somatostatin, Insulin, and Insulin-like Growth Factors (Somatomedins) in Vitro , 1988, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[32]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[33]  P. Blackett,et al.  Growth hormone in the regulation of hyperlipidemia. , 1982, Metabolism: clinical and experimental.

[34]  C. Lundby,et al.  Novel serum biomarkers for erythropoietin use in humans: a proteomic approach. , 2011, Journal of applied physiology.

[35]  Shu Zheng,et al.  Identification of novel serum biomarkers in child nephroblastoma using proteomics technology , 2010, Molecular Biology Reports.

[36]  Michaela Scigelova,et al.  Multidimensional protein identification technology for clinical proteomic analysis , 2009, Clinical chemistry and laboratory medicine.

[37]  K. Ho,et al.  Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II : a statement of the GH Research Society in association with the European Society for Pediatric , 2007 .

[38]  D. Dunger,et al.  Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetes. , 2004, The Journal of clinical endocrinology and metabolism.

[39]  A. Klibanski,et al.  Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. , 2003, The Journal of clinical endocrinology and metabolism.