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The Somatomedin Hypothesis: 2001

Clinical Endocrinology Branch (D.L., S.Y. J.-L. L.), and the Developmental Endocrinology Branch (C.B.), National Institutes of Health, Bethesda, Maryland 20892; and the Vollum Institute (A.B.), Oregon Health Sciences University, Portland, Oregon 97201

Since the original somatomedin hypothesis was conceived, a number of important discoveries have allowed investigators to modify the concept. Originally somatic growth was thought to be controlled by pituitary GH and mediated by circulating insulin-like growth factor-I (IGF-I, somatomedin C) expressed exclusively by the liver. With the discovery that IGF-I is produced by most, if not all, tissues, the role of autocrine/paracrine IGF-I vs. the circulating form has been hotly debated. Recent experiments using transgenic and gene-deletion technologies have attempted to answer these questions. In the liver-specific igf-1 gene-deleted mouse model, postnatal growth and development are normal despite the marked reduction in circulating IGF-I and IGF-binding protein levels; free IGF-I levels are normal. Thus, the normal postnatal growth and development in these animals may be due to normal free IGF-I levels (from as yet unidentified sources), although the role of autocrine/paracrine IGF-I has yet to be determined.

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				J.-L. Liu, K. T. Coschigano, K. Robertson, M. Lipsett, Y. Guo, J. J. Kopchick, U. Kumar, and Y. L. Liu Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E405 - E413. [Abstract] [Full Text] [PDF]

				P. Stattin, S. Rinaldi, C. Biessy, U.-H. Stenman, G. Hallmans, and R. Kaaks High Levels of Circulating Insulin-Like Growth Factor-I Increase Prostate Cancer Risk: A Prospective Study in a Population-Based Nonscreened Cohort J. Clin. Oncol., August 1, 2004; 22(15): 3104 - 3112. [Abstract] [Full Text] [PDF]

				A. Baez-Saldana and E. Ortega Biotin Deficiency Blocks Thymocyte Maturation, Accelerates Thymus Involution, and Decreases Nose-Rump Length in Mice J. Nutr., August 1, 2004; 134(8): 1970 - 1977. [Abstract] [Full Text] [PDF]

				T. Shavlakadze, M. Davies, J. D. White, and M. D. Grounds Early Regeneration of Whole Skeletal Muscle Grafts Is Unaffected by Overexpression of IGF-1 in MLC/mIGF-1 Transgenic Mice J. Histochem. Cytochem., July 1, 2004; 52(7): 873 - 883. [Abstract] [Full Text] [PDF]

				J. M. Fitts, R. M. Klein, and C. A. Powers Comparison of Tamoxifen and Testosterone Propionate in Male Rats: Differential Prevention of Orchidectomy Effects on Sex Organs, Bone Mass, Growth, and the Growth Hormone-IGF-I Axis J Androl, July 1, 2004; 25(4): 523 - 534. [Abstract] [Full Text] [PDF]

				R. G. Richards, D. M. Klotz, M. P. Walker, and R. P. DiAugustine Mammary Gland Branching Morphogenesis Is Diminished in Mice with a Deficiency of Insulin-like Growth Factor-I (IGF-I), But Not in Mice with a Liver-Specific Deletion of IGF-I Endocrinology, July 1, 2004; 145(7): 3106 - 3110. [Abstract] [Full Text] [PDF]

				M. Koutsilieris, C. S. Mitsiades, J. Bogdanos, T. Dimopoulos, D. Karamanolakis, C. Milathianakis, and A. Tsintavis Combination of Somatostatin Analog, Dexamethasone, and Standard Androgen Ablation Therapy in Stage D3 Prostate Cancer Patients with Bone Metastases Clin. Cancer Res., July 1, 2004; 10(13): 4398 - 4405. [Abstract] [Full Text] [PDF]

				S. I. Chisalita and H. J. Arnqvist Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E896 - E901. [Abstract] [Full Text] [PDF]

				R. P. Rhoads, J. W. Kim, B. J. Leury, L. H. Baumgard, N. Segoale, S. J. Frank, D. E. Bauman, and Y. R. Boisclair Insulin Increases the Abundance of the Growth Hormone Receptor in Liver and Adipose Tissue of Periparturient Dairy Cows J. Nutr., May 1, 2004; 134(5): 1020 - 1027. [Abstract] [Full Text] [PDF]

				J. Ayuk, R. N. Clayton, G. Holder, M. C. Sheppard, P. M. Stewart, and A. S. Bates Growth Hormone and Pituitary Radiotherapy, But Not Serum Insulin-Like Growth Factor-I Concentrations, Predict Excess Mortality in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1613 - 1617. [Abstract] [Full Text] [PDF]

				R. R. Kraemer, R. J. Durand, E. O. Acevedo, L. G. Johnson, G. R. Kraemer, E. P. Hebert, and V. D. Castracane Rigorous Running Increases Growth Hormone and Insulin-Like Growth Factor-I Without Altering Ghrelin Experimental Biology and Medicine, March 1, 2004; 229(3): 240 - 246. [Abstract] [Full Text] [PDF]

				F. Tronche, C. Opherk, R. Moriggl, C. Kellendonk, A. Reimann, L. Schwake, H. M. Reichardt, K. Stangl, D. Gau, A. Hoeflich, et al. Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth Genes & Dev., March 1, 2004; 18(5): 492 - 497. [Abstract] [Full Text] [PDF]

				J. Woelfle and P. Rotwein In vivo regulation of growth hormone-stimulated gene transcription by STAT5b Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E393 - E401. [Abstract] [Full Text] [PDF]

				H. M. Domene, S. V. Bengolea, A. S. Martinez, M. G. Ropelato, P. Pennisi, P. Scaglia, J. J. Heinrich, and H. G. Jasper Deficiency of the Circulating Insulin-like Growth Factor System Associated with Inactivation of the Acid-Labile Subunit Gene N. Engl. J. Med., February 5, 2004; 350(6): 570 - 577. [Full Text] [PDF]

				A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF]

				T. D. Etherton Somatotropic function: The somatomedin hypothesis revisited J Anim Sci, January 1, 2004; 82(13_suppl): E239 - 244. [Abstract] [Full Text] [PDF]

				J. Woelfle, D. J. Chia, and P. Rotwein Mechanisms of Growth Hormone (GH) Action: IDENTIFICATION OF CONSERVED Stat5 BINDING SITES THAT MEDIATE GH-INDUCED INSULIN-LIKE GROWTH FACTOR-I GENE ACTIVATION J. Biol. Chem., December 19, 2003; 278(51): 51261 - 51266. [Abstract] [Full Text] [PDF]

				S. R. Edmondson, S. P. Thumiger, G. A. Werther, and C. J. Wraight Epidermal Homeostasis: The Role of the Growth Hormone and Insulin-Like Growth Factor Systems Endocr. Rev., December 1, 2003; 24(6): 737 - 764. [Abstract] [Full Text] [PDF]

				B. C. J. van der Eerden, M. Karperien, and J. M. Wit Systemic and Local Regulation of the Growth Plate Endocr. Rev., December 1, 2003; 24(6): 782 - 801. [Abstract] [Full Text] [PDF]

				M.-L. Baudet, E. J. Sanders, and S. Harvey Retinal Growth Hormone in the Chick Embryo Endocrinology, December 1, 2003; 144(12): 5459 - 5468. [Abstract] [Full Text] [PDF]

				R. A. Ehrhardt, P. L. Greenwood, A. W. Bell, and Y. R. Boisclair Plasma Leptin Is Regulated Predominantly by Nutrition in Preruminant Lambs J. Nutr., December 1, 2003; 133(12): 4196 - 4201. [Abstract] [Full Text] [PDF]

				T. J. Marcell Review Article: Sarcopenia: Causes, Consequences, and Preventions J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2003; 58(10): M911 - 916. [Abstract] [Full Text] [PDF]

				M. Haluzik, S. Yakar, O. Gavrilova, J. Setser, Y. Boisclair, and D. LeRoith 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, October 1, 2003; 52(10): 2483 - 2489. [Abstract] [Full Text] [PDF]

				C. H. Lang, T. C. Vary, and R. A. Frost Acute in Vivo Elevation of Insulin-Like Growth Factor (IGF) Binding Protein-1 Decreases Plasma Free IGF-I and Muscle Protein Synthesis Endocrinology, September 1, 2003; 144(9): 3922 - 3933. [Abstract] [Full Text] [PDF]

				M. I. Lewis, H. Li, Z.-S. Huang, M. S. Biring, B. Cercek, and M. Fournier Influence of varying degrees of malnutrition on IGF-I expression in the rat diaphragm J Appl Physiol, August 1, 2003; 95(2): 555 - 562. [Abstract] [Full Text] [PDF]