Abstract
Recombinant human (rh) insulin-like growth factor I (IGF-I) is being developed as a therapy for short stature caused by IGF deficiency (IGFD) and also for diabetes mellitus. To complement the human efficacy and safety data, a large amount of information is available regarding the pharmacology and toxicology of rhIGF-I in animals. This review summarizes the risks and benefits of normalizing blood IGF-I concentrations in IGFD, especially with regard to carcinogenicity, and compares and contrasts safety data for rhIGF-I, recombinant human growth hormone (rhGH), and insulin. A major difference between rhIGF-I and rhGH is that rhIGF-I (like insulin) has hypoglycaemic activity, whereas rhGH opposes insulin action and is diabetogenic. In most of their actions, GH and IGF-I are similar. IGF-I mediates most of the actions of GH, so the safety of rhGH and that of rhIGF-I also share many common features. In animals, the transgenic expression of hGH has been shown to act directly, by activating the prolactin receptor, to increase the incidence of mammary and prostate tumours. In comparison, the over-expression of IGF-I in animals or the administration of rhIGF-I does not have a carcinogenic effect. In formal toxicology and carcinogenicity studies, rhIGF-I has similar effects to insulin in that it can increase food intake, body size, and the growth rate of existing tumours. In animals and humans, IGFD has many long-term detrimental effects besides short stature: it increases the risk of diabetes, cardiovascular disease, and low bone mineral density. Therefore, a case can be made for replacement therapy with rhIGF-I to normalize blood IGF-I levels and reverse the detrimental effects of IGFD.
References
1.
Clark RG, Robinson IC: Up and down the growth hormone cascade. Cytokine Growth Factor Rev 1996;7:65–80.
[PubMed]
2.
Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A: Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 2002;277:39684–39695.
[PubMed]
3.
Le Roith D, Bondy C, Yakar S, Liu JL, Butler A: The somatomedin hypothesis: 2001. Endocr Rev 2001;22:53–74.
[PubMed]
4.
Laron Z: The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome. J Clin Endocrinol Metab 1999;84:4397–4404.
5.
Rosenfeld RG, Hwa V: Toward a molecular basis for idiopathic short stature. J Clin Endocrinol Metab 2004;89:1066–1067.
[PubMed]
6.
Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A: Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 2001;229:141–162.
7.
Giovannucci E, Pollak M, Liu Y, Platz EA, Majeed N, Rimm EB, Willett WC: Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men. Cancer Epidemiol Biomarkers Prev 2003;12:84–89.
[PubMed]
8.
Woodson K, Tangrea JA, Pollak M, Copeland TD, Taylor PR, Virtamo J, Albanes D: Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Cancer Res 2003;63:3991–3994.
[PubMed]
9.
Juul A: Determination of insulin-like growth factor I in children: normal values and clinical use. Horm Res 2001;55(suppl 2):94–99.
[PubMed]
10.
Cronin MJ: Pioneering recombinant growth hormone manufacturing: pounds produced per mile of height. J Pediatr 1997;131:S5–S7.
[PubMed]
11.
Growth Hormone Research Society: Critical evaluation of the safety of recombinant human growth hormone administration: Statement from the Growth Hormone Research Society. J Clin Endocrinol Metab 2001;86:1868–1870.
12.
Root AW, Kemp SF, Rundle AC, Dana K, Attie KM: Effect of long-term recombinant growth hormone therapy in children – the National Cooperative Growth Study, USA, 1985–1994. J Pediatr Endocrinol Metab 1998;11:403–412.
[PubMed]
13.
Wilton P: Safety in growth hormone replacement therapy: a matter of varied responsiveness? Horm Res 200;55(suppl 2):61–64.
14.
Sperling MA, Saenger PH, Hintz R, Wilson T, Rose SR; Lawson Wilkins Pediatric Endocrine Society. LWPES Executive Committee and the LWPES Drug and Therapeutics Committee: Growth hormone treatment and neoplasia – coincidence or consequence? J Clin Endocrinol Metab 2002;87:5351–5352.
15.
FDA approves growth hormone for short children (editorial). Child Health Alert 2003;21:4.
16.
Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ: Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785–792.
17.
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367.
[PubMed]
18.
Hatton J, Rapp RP, Kudsk KA, Brown RO, Luer MS, Bukar JG, Chen SA, McClain CJ, Gesundheit N, Dempsey RJ, Young B: Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: A phase II safety and efficacy trial. J Neurosurg 1997;86:779–786.
[PubMed]
19.
Rosen T, Bengtsson BA: Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285–288.
[PubMed]
20.
Renehan AG, O’Connell J, O’Halloran D, Shanahan F, Potten CS, O’Dwyer ST, Shalet SM: Acromegaly and colorectal cancer: A comprehensive review of epidemiology, biological mechanisms, and clinical implications. Horm Metab Res 2003;35:712–725.
21.
Orme SM, McNally RJ, Cartwright RA, Belchetz PE: Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 1998;83:2730–2734.
[PubMed]
22.
Melmed S: Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 2001;86:2929–2934.
23.
Jenkins PJ, Besser M: Clinical perspective: acromegaly and cancer: A problem. J Clin Endocrinol Metab 2001;86:2935–2941.
[PubMed]
24.
Mukherjee A, Monson JP, Jonsson PJ, Trainer PJ, Shalet SM; KIMS International Board: Seeking the optimal target range for insulin-like growth factor I during the treatment of adult growth hormone disorders. J Clin Endocrinol Metab 2003;88:5865–5870.
[PubMed]
25.
Giovannucci E: Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res 2003;35:694–704.
26.
Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, Isaksson OG, Tornell J: Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest 1997;100:2744–2751.
[PubMed]
27.
Hovey RC, Harris J, Hadsell DL, Lee AV, Ormandy CJ, Vonderhaar BK: Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Mol Endocrinol 2003;17:460–471.
28.
Pravtcheva DD, Wise TL: Metastasizing mammary carcinomas in H19 enhancers-Igf2 transgenic mice. J Exp Zool 1998;281:43–57.
[PubMed]
29.
Moorehead RA, Sanchez OH, Baldwin RM, Khokha R: Transgenic overexpression of IGF-II induces spontaneous lung tumors: A model for human lung adenocarcinoma. Oncogene 2003;22:853–857.
30.
Chen NY, Chen WY, Striker LJ, Striker GE, Kopchick JJ: Co-expression of bovine growth hormone (GH) and human GH antagonist genes in transgenic mice. Endocrinology 1997;138:851–854.
31.
Doi T, Striker LJ, Quaife C, Conti FG, Palmiter R, Behringer R, Brinster R, Striker GE: Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulinlike growth factor-1. Am J Pathol 1988;131:398–403.
[PubMed]
32.
Clark RG, Mortensen DL, Carlsson LM, Carlsson B, Carmignac D, Robinson IC: The obese growth hormone (GH)-deficient dwarf rat: body fat responses to patterned delivery of GH and insulin-like growth factor-I. Endocrinology 1996;137:1904–1912.
33.
Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W, Le Roith D: Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes 2001;50:1110–1118.
[PubMed]
34.
Haluzik M, Yakar S, Gavrilova O, Setser J, Boisclair Y, LeRoith D: Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes 2003;52:2483–2489.
[PubMed]
35.
The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.
[PubMed]
36.
Thrailkill KM, Quattrin T, Baker L, Kuntze JE, Compton PG, Martha PM Jr: Cotherapy with recombinant human insulin-like growth factor I and insulin improves glycemic control in type 1 diabetes. RhIGF-I in IDDM Study Group. Diabetes Care 1999;22:585–592.
[PubMed]
37.
Ruberte J, Ayuso E, Navarro M, Carretero A, Nacher V, Haurigot V, George M, Llombart C, Casellas A, Costa C, Bosch A, Bosch F: Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J Clin Invest 2004;113:1149–1157.
38.
Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR: Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest 2003;111:1835–1842.
39.
Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T: Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: A population-based case-control study. Circulation 2002;106:939–944.
[PubMed]
40.
Frystyk J, Ledet T, Moller N, Flyvbjerg A, Orskov H: Cardiovascular disease and insulin-like growth factor I. Circulation 2002;106:893–895.
41.
Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM: A polymorphism in the gene for IGF-I: Functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 2001;50:637–642.
[PubMed]
42.
Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D: The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: The Rancho Bernardo Study. J Clin Endocrinol Metab 2004;89:114–120.
[PubMed]
43.
Vasan RS, Sullivan LM, D’Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, Wilson PW: Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med 2003;139:642–648.
[PubMed]
44.
Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB: Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: The Framingham Heart Study. Am J Med 2003;115:429–435.
45.
Rivadeneira F, Houwing-Duistermaat JJ, Vaessen N, Vergeer-Drop JM, Hofman A, Pols HA, Van Duijn CM, Uitterlinden AG: Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: The Rotterdam Study. J Clin Endocrinol Metab 2003;88:3878–3884.
46.
Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I: Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 2002;8:1390–1397.
47.
Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM: A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab 2000;85:4551–4555.
48.
Dik MG, Pluijm SM, Jonker C, Deeg DJ, Lomecky MZ, Lips P: Insulin-like growth factor I (IGF-I) and cognitive decline in older persons. Neurobiol Aging 2003;24:573–581.
[PubMed]
49.
Tivesten A, Bollano E, Andersson I, Fitzgerald S, Caidahl K, Sjogren K, Skott O, Liu JL, Mobini R, Isaksson OG, Jansson JO, Ohlsson C, Bergstrom G, Isgaard J: Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. Endocrinology 2002;143:4235–4242.
50.
Vickers MH, Ikenasio BA, Breier BH: IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. Endocrinology 2001;142:3964–3973.
51.
DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, Moats S, Ramirez A, Jorcano J, Conti C: Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci USA 2000;97:3455–3460.
52.
Kuo YH, Chen TT: Novel activities of pro-IGF-I E peptides: regulation of morphological differentiation and anchorage-independent growth in human neuroblastoma cells. Exp Cell Res 2002;280:75–89.
53.
Dybdal N, Elwell M, Christian B, Clark R, Fielder P, Kennedy D, Shopp D, Thakur A, Clarke J: Lifetime (104 Week) daily subcutaneous rhIGF-I treatment in the rat (abstract). 85th Annual Meeting of the Endocrine Society, Philadelphia, June 2003, 3-318.
54.
NovoLog product label. Available at http:// www.fda.gov/cder/foi/label/2000/20986lbl.pdf. Accessed April 23, 2004.
55.
Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C: Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003;424:277–283.
56.
Dupont J, Holzenberger M: Biology of insulin-like growth factors in development. Birth Defects Res Part C Embryo Today 2003;69:257–271.
57.
Cohen P, Clemmons DR, Rosenfeld RG: Does the GH-IGF axis play a role in cancer pathogenesis? Growth Horm IGF Res 2000;10:297–305.
[PubMed]
© 2004 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2005
You do not currently have access to this content.
