Although used as a therapeutic for 50 years, it is only recently that the application of molecular techniques has provided a basis for understanding growth hormone’s (GH) clinical actions. This article reviews progress in our current knowledge of the molecular mechanism of growth hormone (GH) receptor activation based on a number of physicochemical techniques, and documents insights gained into the means used by the activated GH receptor to control the expression of genes regulating growth and metabolism. These findings are related to disorders of short stature, and the therapeutic consequences are summarized.

1.
Bengtsson BA: Growth Hormone. Norwell, Kluwer Academic Publishers, 1999.
2.
Herrington J, Carter-Su C: Signaling pathways activated by the GH receptor. Trends Endocrinol Metab 2001;12:252–257.
3.
Shapiro BH, Agrawal AK, Pampori NA: Gender differences in drug metabolism regulated by GH secretion. Int J Biochem Cell Biol 1995;27:9–20.
4.
Rudman D, Feller AG, Nagraj HS, Gergans GA, et al: Effects of hGH in men over 60 years old. N Engl J Med 1990;323:1–6.
5.
Wells JA: Binding in the GH receptor complex. Proc Natl Acad Sci USA 1996;93:1–6.
6.
Waters MJ: The growth hormone receptor; in Kostyo JL, HM Goodman (eds): Handbook of Physiology. London, Oxford Press, vol 5, sect 7, chap 13, pp 397–444.
7.
Chen CM, Brinkworth R, Waters MJ: The role of receptor dimerization domain residues in GH signalling. J Biol Chem 1997;272:5133–5140.
8.
Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV, Wells JA: Rational design of potent antagonists to the human GH receptor. Science 1992;256:1677–1680.
9.
Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ: Model for GH receptor activation based on subunit rotation within a constitutive dimer. Nat Struct Mol Biol 2005;12:814–821.
10.
Gent J, van Kerkhof P, Roza M, Bu G, Strous GJ: Ligand-independent GH receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis. Proc Natl Acad Sci USA 2002;99:9858–9863.
11.
Muller F, Kopchick JJ, Flyvbjerg A, van Der Ley AJ: Clinical review 166: GH receptor antagonists. J Clin Endocrinol Metab 2004;89:1503–1511.
12.
Rowland JE, Lichanska AM, Kerr LM, White M, D’Aniello EM, Mahler SL, Brown RJ, Teasdale R, Noakes PG, Waters MJ: In vivo analysis of GH receptor signalling domains and their associated transcripts. Mol Cell Biol 2005;25:66–77.
13.
Thompson BJL, Shang CA, Waters MJ: Identification of genes induced by GH in rat liver using cDNA arrays. Endocrinology 2000;141:4321–4324.
14.
Tollet-Egnell P, Flores-MoralesA, Stahlberg N, Malek RL, Lee N, Norstedt G: Gene expression profile of the aging process in rat liver: normalizing effects of GH replacement. Mol Endocrinol 2001;15:308–318.
15.
Flores-Morales A, Stahlberg N, Tollet-Egnell P, Lundeberg J, Malek RL, Quackenbush J, Lee NH, Norstedt G: Microarray analysis of the in vivo effects of hypophysectomy and GH treatment on gene expression in the rat. Endocrinology 2001;142:3163–3176.
16.
Gardmo C, Swerdlow H, Mode A: GH regulation of rat liver gene expression assessed by SSH and microarray. Mol Cell Endocrinol 2002;190:125–133.
17.
Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigano K, Wagner TE, Baumann G, Kopchick JJ: A mammalian model for Laron syndrome produced by targeted disruption of the mouse GH receptor. Proc Natl Acad Sci USA 1997;94:13215–13220.
18.
Miller RA, Chang Y, Galecki AT, Al-Regaiey K, Kopchick JJ, Bartke A: Gene expression patterns in calorically restricted mice: partial overlap with long-lived mutant mice. Mol Endocrinol 2002;16:2657–2666.
19.
Levy DE: Physiological significance of STAT proteins: investigations through gene disruption in vivo. Cell Mol Life Sci 1999;55:1559–1567.
20.
Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW: Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 1997;94:7239–7244.
21.
Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN: Stat5a and Stat5b have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998;93:841–850.
22.
Woelfle J, Chia DJ, Rotwein P: Mechanisms of GH action. Identification of conserved Stat5 binding sites that mediate GH-induced IGF-1 gene activation. J Biol Chem 2003;278:51261–51266.
23.
Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG: GH insensitivity associated with a STAT5b mutation. N Engl J Med 2003;349:1139–1147.
24.
Tannenbaum GS, Choi HK, Gurd W, Waxman DJ: Temporal relationship between the sexually dimorphic spontaneous GH secretory profiles and hepatic STAT5 activity. Endocrinology 2001;142:4599–4606.
25.
Clodfelter KH, Holloway MG, Hodor P, Park SH, Ray WJ, Waxman DJ: Sex-dependent liver gene expression is extensive and largely dependent upon STAT5b: STAT5b-dependent activation of male genes and repression of female genes revealed by microarray. Mol Endocrinol 2006;20:1333–1351.
26.
Shang CA, Waters MJ: Constitutively active Stat5 can replace the requirement for GH in adipogenesis of 3T3-F442A. Mol Endocrinol 2003;17:2494–2508.
27.
Berryman DE, List EO, Kohn DT, Coschigano KT, Seeley RJ, Kopchick JJ: Effect of GH on susceptibility to diet-induced obesity. Endocrinology 2006;147:2801–2808.
28.
Fain JN, Ihle JH, Bahouth SW: Stimulation of lipolysis but not of leptin release by GH is abolished in adipose tissue from Stat5a/b knockout mice. Biochem Biophys Res Commun 1999;263:201–205.
29.
Hogan JC, Stephens JM: The regulation of fatty acid synthase by STAT5A. Diabetes 2005;54:1968–1975.
30.
Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A: Roles of GH and IGF-1 in mouse postnatal growth. Dev Biol 2001;229:141–162.
31.
Tachas G, Lofthouse S, Wraight CJ, Baker BF, Sioufi NB, Jarres RA, Berdeja A, Rao AM, Kerr LM, D’Aniello EM, Waters MJ: A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-1 production and body weight gain in normal mice. J Endocrinol 2006;189:147–154.
32.
Stahlberg N, Merino R, Hernandez LH, Fernandez-Perez L, Sandelin A, Egstrom P, Tollett-Egnell P, Lenhard B, Flores-Morales A: Exploring hepatic hormone actions using a compilation of gene expression profiles. BMC Physiol 2005;5:8.
33.
Olsson B, Bohlooly M, Brusehed O, Isaksson OGP, Ahren B, Olofsson S-O, Oscarsson J, Tornell J: Bovine GH-transgenic mice have major alterations in hepatic expression of metabolic genes. Am J Physiol Endocrinol Metab 2003;285:504–511.
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.
You do not currently have access to this content.