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DOI: 10.1055/s-2006-925402
Evaluation of the Components of the Insulin-like Growth Factors System in GH-deficient Adults: Effects of Twelve-month rhGH Treatment
Publication History
Received 8 August 2005
Accepted after revision 6 December 2005
Publication Date:
23 May 2006 (online)
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Abstract
The impact of GH deficiency and rhGH replacement therapy on IGF-I, IGFBP-3 and ALS levels has been widely studied. There is less information available on IGF-II levels, the component of the ternary complex poorly dependent on GH. We investigate the components of IGFs system in 36 GHD adults (28M, 8F, age 45 ± 14 yrs) before and after 12 months of rhGH therapy (mean dose 0.3 ± 0.1 mg/day). One-hundred healthy sex- and age-matched subjects were studied for comparison. At baseline, GHD patients showed IGF-I and IGF-II levels and IGFs to IGFBP-3 molar ratios that were lower than controls. During therapy, IGF-I levels increased (p < 0.01) to normal range. IGF-II levels, though higher than at baseline (p < 0.01), remained lower than in controls (p < 0.01). ALS and IGFBP-3 significantly increased (p < 0.001). These modifications resulted in normalization in IGF-I to IGFBP-3 ratio, while no change in IGF-II to IGFBP-3 ratio was observed. In conclusion, the increase of serum IGF-II levels during rhGH treatment in GHD patients probably reflects the increase in the other components of ternary complex (ALS and IGFBP-3). However, serum IGF-II levels as well as IGF-II to IGFBP-3 ratio, although increased, were definitely lower than in controls. This last result, given the increasing evidences of a direct implication of IGF-II in cancer, may further confirm the safety of rhGH replacement in adults with severe GHD as diagnosed by appropriate stimulation tests.
Key words
IGFs - IGFBPs - GH deficiency - GH therapy
References
- 1 Daughaday W H, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989; 10 68-91
- 2 Barreca A, Ponzani P, Arvigo A, Voci A, Giordano G, Minuto F. Functions and regulation of the acid-labile subunit of the 150 K complex. Prog Growth Factor Res. 1995; 6 231-239
- 3 Twigg S M, Baxter R C. Insulin-like growth factor (IGF-)binding protein 5 forms an alternative ternary complex with IGFs and Acid-labile subunit. J Biol Chem. 1998; 273 6074-6079
- 4 Baxter R C. Inhibition of the insulin-like growth factor (IGF-)IGF-binding protein interaction. Horm Res. 2001; 55 (Suppl 2) 68-72
- 5 De Boer H, Block G J, Popp-Snijders C, Stuurman L, Baxter R C, van der Veen E. Monitoring of growth hormone replacement therapy in adults, based on measurements of serum markers. J Clin Endocrinol Metab. 1996; 81 1371-1377
- 6 Juul A, Møller S, Mosfeldt-Laursen E, Højby Rasmussen M, Scheike T, Pedersen S A, Kastrup K W, Yu H, Mistry J, Rasmussen S, Müller J, Henrisken J, Skakkebaek N E. The acid-labile subunit of human tenary insulin-like growth factor binding complex in serum: hepatosplacnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency. J Clin Endocrinol Metab. 1998; 81 4408-4415
- 7 Yu H, Mistry J, Nikar M J, Khosravi M J, Diamandis A, van Doorn J, Juul A. Insulin-like growth factors (IGF-I, free IGF and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6 and ALS) in blood circulation. J Clin Lab Anal. 1999; 13 166-172
- 8 Shimatsu A, Nakamura Y, Ihara C, Mizuta H, Murabe H. Serum Insulin-like growth factor-II (IGF-II) levels in patients with acromegaly and growth hormone deficiency: correlation with IGF-I and IGF binding protein-3. Endocr J. 1996; 43 (Suppl) S71-73
- 9 Aguiar-Oliveira M H, Gill M S, de Barretto E S, Alcantara M R, Miraki-Moud F, Menezes C A, Souza A H, Martinelli C E, Pereira F A, Salvatori R, Levine M A, Shalet S M, Camacho-Hubner C, Clayton P E. Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary complex formation throughout life. J Clin Endocrinol Metab. 1999; 84 4118-4126
- 10 Belgorosky A, Rivarola M A. Insulin-like growth factors binding protein (IGFBP)-3-bound IGF-I and IGF-II in growth hormone deficiency. Horm Res.. 1999; 52 60-65
- 11 Fernholm R, Bramnert M, Hagg E, Hilding A, Baylink D J, Mohan S, Thoren M. Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease. J Clin Endocrinol Metab. 2000; 85 4104-4112
- 12 Ezzat S, Fear S, Gaillard R C, Gayle C, Landy H, Marcovitz S, Mattioni T, Nussey S, Rees A, Svanberg E. Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults. J Clin Endocrinol Metab. 2002; 87 2725-2733
- 13 Tillmann V, Patel L, Gill M S, Whatmore A J, Price D A, Kibirige M S, Wales J K, Clayton P E. Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth. Clin Endocrinol. 2000; 53 329-336
- 14 Ghigo E, Aimaretti G, Giannotti L, Bellone J, Arvat E, Camanni F. New approach to the diagnosis of growth hormone deficiency in adults. Eur J Endocrinol. 1996; 134 352-356
- 15 Segal K R, Van Loan M, Fitzgerald P I, Hodgdon J A, Van Itallie T B. Lean body mass estimation by bioelectrical impedance analysis: a four-site cross validation study. Am J Clin Nutr. 1988; 47 7-14
- 16 Pichard C, Kyle U G, Bracco D, Slosman D O, Morabia A, Schutz Y. Reference values of fat-free and fat masses by bioelectrical impedance analysis in 3393 healthy subjects. Nutrition. 2000; 16 245-254
- 17 Giavoli C, Cappiello V, Porretti S, Ronchi C L, Orsi E, Beck-Peccoz P, Arosio M. Growth hormone therapy in GH-deficient adults: continuous vs. alternate-days treatment. Horm Metab Res. 2003; 35 557-561
- 18 Hankinson S E, Willett W C, Colditz G A, Hunter D J, Michaud D S, Deroo B, Rosner B, Speizer F E, Pollak M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998; 351 1393-1396
- 19 Ma J, Pollak M, Giovannucci E, Chan J M, Tao Y, Hennekens C H, Stampfer M J. Prospective study of colorectal cancer risk in men and plasma levels of insulin like growth factor (IGF)-1 and IGF binding protein-3. J Natl Cancer Inst. 1999; 91 620-625
- 20 Manousos O, Souglakos J, Bosetti C, Tzonou A, Chatzidakis V, Trichopoulos D, Adami H O, Mantzoros C. IGF-I and IGF-II in relation to colorectal cancer. Int J Cancer. 1999; 83 15-17
- 21 Li L, Yu H, Schumacher F, Casey G, Witte J S. Relation of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 to risk of prostate cancer (United States). Cancer Causes Control. 2003; 14 721-726
- 22 Renehan A G, Zwahlen M, Minder C, O’Dwyer S T, Shalet S M, Egger M. Insulin-like growth factor (IGF-)I, IGF binding protein-3 and cancer risk: systematic review and meta-regression analysis. Lancet. 2004; 363 1346-1353
- 23 Jenkins P J, Bustin S A. Evidence for a link between IGF-I and cancer. Eur J Endocrinol. 2004; 151 (Suppl 1) S17-22
- 24 Toretsky J A, Helman L J. Involvement of IGF-II in human cancer. J Endocrinol. 1996; 149 367-372
- 25 Khandawala H M, McCutcheon I E, Flyvbjerg A, Friend K E. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev. 2000; 21 215-244
- 26 LeRoith D, Roberts C T jr. The insulin-like growth factor system and cancer. Cancer Letter. 2003; 195 127-137
1 E. F. and C. G. contributed equally to this work and should both be considered first authors.
Anna Spada, M.D.
Institute of Endocrine Sciences
Ospedale Maggiore IRCCS · Pad. Granelli · Via F. Sforza 35 · 20122 Milan · Italy
Fax: +39 (02) 50 32 06 05
Email: anna.spada@unimi.it