Advances in Growth Hormone and Growth Factor Research

Advances in Growth Hormone and

Growth Factor Research

EDITED BY

EUGENIO E. MULLER DANIELA COCCHI VITTORIO LOCATELLI Department of Phannacology, Chemotherapy and Toxicology, University of Milan School of Medicine, 20129 Milan, Italy

~ ~-VerlagBerlin ~ Heidelberg GmbH

Eugenio E. Mtiller Daniela Cocchi Vittorio Locatelli

Department of Pharmacology, Chemotherapy and Toxicology, University of Milan School of Medicine, Via Vanvitelli, 32 20129 Milan, Italy

ISBN 978-3-662-11056-0 ISBN 978-3-662-11054-6 (eBook) DOI 10.1007/978-3-662-11054-6

TIris work is subject to copyright AlI rights are reserved, whether the whole or part of the material is concemed, specificalIy the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, repnxluction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and copyright fee must always be paid. Violations falI under the prosecution act of the German Copyright Law.

© Springer-Verlag Berlin Heidelberg 1989

The use of registered names, trademruks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

FOREWORD

In all experimental sciences, but perhaps in none to the extent as in the biological sciences, is it true that fields dealing with different phenomena and problems suddenly merge into a unique area of endeavour. A typical instance of such a unified approach is the study of hormones, somatomedins and specific growth factors in the past decade. Although in recent years the common features of polypeptides listed in one of the categories of biologically active macromole­cules have been stressed at an ever-increasing number of symposia, a major merit of this volume is to have brought to the fore the similarity in the control mechanisms in cell proliferation, differentiation, and function elicited by all of the peptides. Anoth~r equally important contribution is that such a remarkably extensive number of essays, produced by highly competent investigators in each one of these areas of reseach, have been collected.

The first section of the volume deals with recent developments in the study of the growth hormone which, ever since its discovery, has been the model of choice for the study of hormone production, mechanisms of action, and spectrum of activity. The exploitation of the powerful recombinant DNA and monoclonal antibody techniques has unveiled additional most important aspects of its evolu­tionary origin, regulatory mechanisms at the level of its coding gene, and modu­latory effect on the proliferative activity of different cells.

The second and third sections dealing respectively with recent advances in the exploration of the somatomedins and of the ever-lengthening list of specific growth factors, shed light on the manifold properties of these substances as revealed in normal and experimentally manipulated animal models or exemplified by rigorous measurements of blood serum of humans suffering from different endocrine dysfunctions.

The fourth section is almost entirely devoted to a thorough analysis of the neural regulation of growth hormone secretion, a topic of utmost interest. This raises the question of to what extent the opposite is also true: Is the developing and fully differentiated nervous system in turn dependent on growth hormone and other factors belonging to the second and third categories listed above? It is all too well known that steroid hormones play a most important role in modulating the formation of some brain centers and of their functional properties. To what extent,

VI

if any, does growth hormone modulate the formation and function of the same or of other brain centers and of their connecting circuits? The fmdings (not reported in this volume) that NGF is endowed with a most important role in the regulation and function of brain cholinergic neurons1 and that its depletion through the injection of NGF-specific antibodies during fetal life impairs the normal differ­entiation of the neuroendocrine axis2 suggest extending to other hormones, somatomedins, and growth factors the study of their possible role in the formation of that immensely complex network which forms the central nervous system.

The fifth and sixth sections bring to light a new and most needed change in the criteria guiding the selection of speakers in biological symposia and the inclusion of their reports in the proceedings. In this volume they supplement studies reported in the previous sections with others dealing with the aberrant functions in the synthesis and secretion of the most extensively investigated hormone: the growth hormone. Thus, the time-honored concept that basic and clinical (or applied) science belong to two distinct categories is timely defeated. There is only one sound criterium which ought to direct the selection of speakers by conference organizers and the acceptance of their reports in the proceedings: that is, that there exist only two main classes of scientific contribution: one consists of excellently acquired and meaningful data, the other fails to meet these prerequisites. Obvi­ously, only the former should be included in the proceedings. The present volume honors this unwritten, and not always followed, guiding rule.

1-Thoenen H, Bandtlow C, Heumann R ( 1987) The physiological function of nerve growth factor in the central nervous system: comparison with the periphery. Rev Physiol Biochem Pharmaco/109: 145-178 2- Aloe L, Cozzari C, Calissano P, Levi-Montalcini R (1981) Somatic and behavioural postnatal effects of fetal injections of nerve growth factor antibodies in the rat. Nature 2 91: 413-415

Rome, August 1988 Rita Levi-Montalcini

PREFACE

A series of international symposia held in Milan in the last 20 years under the chairmanship of Dr. C.H. Lion growth, growth hormones, and related fields, testify to major advances made in this important area of biology and medicine. In the first meeting "Growth Hormone" (1967), the major events were the reports of the final determination of the chemical structure of human growth hormone (hGH) and the official recognition and introduction into clinical practice of GH radioimmunoas­say. The second meeting, "Growth and Growth Hormone" in 1971, focused on the newly discovered human chorionic mammosomatotropin (hCS) and heralded the recognition of prolactin as a chemical and biologic entity separate from GH. Four years later, the third symposium, "Growth Hormone and Related Peptides," was the appropriate forum to discuss the manifold properties of the newcomer somatostatin and to report progress on the chemical and biological study of somatomedins. In 1979, the last symposium, "Growth Hormone and Other Bio­logically Active Peptides" dealt mainly with somatomedins and a new family of pituitary hormones, the endorphins.

Since then, after an initial slow down, the last few years have witnessed a renaissance of interest and accomplishments in this field.

Among them are the availability of synthetic GH obtained by recombinant DNA technology, allowing more extensive clinical use in GH-deficiency states and extrasomatotropic pathologies; the isolation and characterization of GHRH, coupled with a better understanding of the neurohumoral control of GH secretion; new knowledge on the chemical and biological nature and potential clinical applications of somatomedins; and the recognition of their belonging to a large family of hormone-like molecules, the growth factors. Finally, the clinical con­sequences of these discoveries which will allow a more precise diagnosis and discrete approach to therapy of growth disorders and other disease states.

This volume is devoted to the proceedings of a congress held in Milan during the fall of 1987, "Advances in Growth Hormone and Growth Factor Research," where outstanding speakers discussed the aforementioned problems. In the first section on Native and Biosynthetic Growth Homones, Parks and coworkers discuss the mechanisms responsible for the extent and tissue specificity of hGH and hCS gene expression, Tripputi et a!. deal particularly with the regulation of GH gene expression, Bennett et a!. recapitulate the steps involved in the biosynthesis and

VIII

the properties of the recombinant hGH expressed in E. coli, Kawauchi and Yasuda characterize the structural similarities between GH and prolactin at many phylo­genetic levels, Baumann reports on the properties and possible function of the newly discovered binding protein for hGH, and Schwartz and colleagues discuss direct and independent metabolic effects of GH and insulin-like growth factors (IGFs) on adipocytes.

In the section Somatomedins, Hynes et al. apply hybridization analysis to study biosynthesis of IGF-I and IGF-II and their tissue regulation, Povoa et al. focus on the somatomedin binding protein throughout life, pregnancy and in some disease states, Rosenfeld describes the structure and physiologic roles of IGF-I and IGF­II receptors in mediating a wide variety of anabolic and mitogenic actions, Zapf et al. describe the metabolic and growth-promoting effects of recombinant human IGF-I in rats and humans.

The important topic of Growth Factors is addressed by Donaldson eta/., who summarize recent developments of epidermal growth factor and its receptor related research, while Betsholtz et al. discuss the structure, biological functions, and relatedness to oncogene products of human platelet-derived growth factors, Moses eta/. extensively review the biological effects of transforming growth factors and their putative role in several disease states involving abnormal proliferation.

The contribution of maternal and neonatal compartments to the regulation of growth in the fetus and neonate is dealt with by Wehrenberg and Gaillard, in the section Neural Regulation of Growth Hormone Secretion. Here Mayo reports on studies of eDNA GHRH cloning, isolation, and characterization of the rat GHRH gene and its expression in transgenic mice, Berthelier et al. review the neurotrans­mitter and neuropeptide regulation of GH secretion and postreceptor coupling mechanisms, Frohman and coworkers examine the complex neuroendocrine regulation of GH secretion and its derangement under pathologic conditions, and Camanni and colleagues focus on noradrenergic and cholinergic control in animals and humans and the implications of these findings for the diagnosis and therapy of GH deficiency.

In a major clinical section Blizzard reviews the etiology and characteristics of GH deficiency and GH-like deficiency states, Bierich and colleagues analyze the contribution of GH provocative tests or spontaneous GH secretion to the diagnosis of GH deficiency, Rappaport et al. report on the GH secretory dysfunc­tion in children after hypothalamic and pituitary irradiation. After a critical state of the art review by Milner, Takano, Ross, Pintor and their colleagues describe advantages and drawbacks of the diversified approaches to therapy of GH defi­ciency, by way of recombinant hGH, GHRH, and CNS-acting compounds. The discussion generated from these contributions adds a great deal to the appeal of the book.

Finally, in the section Growth Hormone Hypersecretory States, Shibasaki, Spada, Chiodini and their colleagues deal with aspects of the neural regulation,

IX

morphology, and function of the hypersecreting somatotroph and the medical therapy of acromegaly, del Pozo et al. describe the effect of a long-acting somatostatin analog on glucose homeostasis in normal subjects, and Reichlin reviews a number of pathological states (diabetes, anorexia nervosa, hepatic cirrhosis, etc.) in which excess secretion of GH occurs.

A subtle analysis of past research, present knowledge, and future perspectives in this exciting field is finally presented by Friesen.

In all, the book provides an invaluable forum where important aspects of the biological nature of growth and development, and the pathophysiology, diagnosis, and therapy of growth hormone deficiency and excess states are addressed and critically evaluated. It should therefore be of particular interest not only to basic and clinical endocrinologists, neuroendocrinologists, and pediatric endocrinolo­gists, but also to the increasing number of students of cell biology.

We wish to thank Kabi Vitrum, Pierre[, and Sandoz for generous financial support, and the Italian Council of Research (CNR, Rome).

Milan, January 1989 The Editors

CHOH HAO LI

1913 - 1987

Choh Hao Li- CH-is no longer amongst us. He was the last of the large group of biochemists who between 1940 - 1970 put pituitary hormones into the limelight in endocrine research. He was in my opinion one of the best. The door to his laboratory has been closed and the name plate taken down.

As a scientist, CH belongs to an exclusive group of great men in his area; PHILIP E. SMITH, who introduced hypophysectomizing rats as a working method (1926-30) and was the first to demonstrate the effects of the operation; HERBERT M. EvANs, who produced the first purified hormone extract from the pituitary; BERNARDO A. HoussAY, who shed light on the pituitary's importance for experimental diabetes; RosALYN S. Y ALOW and SoLOMON A. BERSON who introduced the RIA method in order to measure peptide hormones in the blood.

Within the space of a short obituary it is difficult to give an account of a research achievement which is distinguished by more than 1,000 scientific publications. Neither is it made any easier because CH worked within an area which during his life time underwent an explosive development and which was highly competitive. I shall therefore restrict myself to those achievements that I myself regard as milestones in CH's scientific career.

His earlier achievements, together with Evans, in the purification of ACTH and GH were in themselves milestones in research on peptide hormones even if the hormones produced later on -when new techniques became available - showed to be far from "pure".

CH was one of the few - may be the only one - who consistently studied pituitary peptides from the first stage, that is the purification, to structural analysis and synthesis. This concerned ACTH and MSA. He found himself at the forefront of every stage, from the beginning to the end, even if other researchers with the unlimited resources of drug companies could contend his success. He remained the central figure within the area.

CH was the first one to discover, isolate, purify and structurally analyze a pituitary hormone, LPH, an achievement which can be described as innovative.

XII

CH's early discoveries concerning the prtmtary hormone's structure and analysis of the biological effect of certain amino acid sequences opened a new field within the peptide hormone area at that time. This made it possible to explain overlapping effects of different peptides isolated from the pituitary. The latest example of many other discoveries was that sequences within the ~-LPH molecule were identical with endorphins.

One can summarize his achievements chronologically in this way: 1940 purification of LH; 1944 isolation of bovine GH; 1949 isolation of FSH; 1956 isolation of MSA and also isolation of monkey and human GH; 1964 isolation of lipotropin; 1976 isolation of human ~-lipotropin, LPH; in later years total synthesis of IGF-I and II.

Something which has always fascinated me was CH's obstinacy in his work -he "pursued" his peptides year after year, even when the odds were not especially propitious. This is illustrated with LPH. He isolated it together with Birk in 1964, really as a byproduct during the purification of ACTH. They found that the peptide consisted of 59 amino acid residues and had evident but not especially high lipolytic activity. Their continued work resulted in the isolation of ~-LPH in 1965 with al least 90 amino acid residues (later on 91) and 1966 in y-LPH (58 residues) where the sequencing of the 18 C-terminal amino acids was identical with the sequence in ~-MSH. That opened up the possibility that ~-LPH could be a large molecule, a "prohormone", which by cleaving could be changed to y-LPH and ~-MSH: ~­LPH (91 amino acid residues) ---+ y-LPH (58) ---+ ~-melanotropin (39)

This was the first time one could see ~-LPH as a precursor for other peptides. CH continued to work his favourite object in recent years, that is LPH. The

area exploded again in 1975, when Hughes and other scientists showed that enkephalin, the ligand for the recently discovered opiate receptors in the brain, consisted of two pentapeptides, of which one has a sequence which corresponds with the 61-65 sequence of the ~-LPH which CH had isolated. This discovery instigated a stream of studies in different parts of the world. CH participated in such studies and found, together with A. Goldstein and B.M. Cox, that the ~-LPH sequence 61-91 had opiate receptor-binding capacities, and with Guillemin et al. that the sequences 61-77 (y-endorphin) and 61-76 (a-endorphin) had similar capacities. The field now lay wide open, which the literature bears witness to.

It is quite clear today that if CH had not discovered ~-LPH, determined its sequences and attached weight to these different fragments after cleaving, it would have been a long time before the endorphins would had been discovered.

CH was born in Canton in China 1913. He came to the University of California in Berkeley 1935, and was awarded a Ph.D. in physico-organic chemistry 1938. After this he began his career with the legendary Herbert M. Evans and stayed there until 1950, when he then organized his own domain in Berkeley, The Hormone Research Laboratory. This was moved in 1967 to the San Francisco campus of the University of California. He remained there till his death, as active,

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innovative and stimulating as ever before. Our thoughts go to his wife Annie, her support and stimulation during their long life together, and his children.

The step from the material world to the world of memory is short, infinitely short. CH was in our material world a rich source of common research and friendship. In our memories, he will be as rich a source for inspiration and happiness.

Stockholm, August 1988 Rolf Luft

Foreword Preface Choh Hao Li - Obituary Contributors List of abbreviations

Contents

Native and Biosynthetic Growth Hormones

v VII XI

XIX XXIX

Evolution and structure of the growth hormone gene cluster 3 J.S. Parks, M. Kassels, M.C. McKean, J.T. Parks, C. Johnson, and L. Meacham

Cell-type-specific regulation of growth hormone gene expression 19 P. Tripputi, S. Guerin, and D.D. Moore

Characterization of natural-sequence recombinant human growth hormone 29 W.F. Bennett, R. Chloupek, R. Harris, E. Canova-Davis, R. Keck, J. Chakel, W.S. Hancock, P. Gellefors, and B. Pavlu

Evolutionary aspects of growth hormones from nonmammalian species 51 H. Kawauchi, and A. Yasuda

Circulating binding proteins for human growth hormone 69 G. Baumann

Direct actions of growth hormone and insulin-like growth factor in cultured adipocites 85 J. Schwartz, C. Carter-Su, C.M. Foster, and JA. Shafer

Somatomedins

Localization and regulation of IGF-I and IGF-11 mRNA 103 M.A. Hynes, P.J. Brooks, J. English, J.J. Van Wyk, and P.K. Lund

XVI CONTENTS

Studies on somatomedin-binding protein G. Povoa, K. Hall, and V.P. Collins

Receptors for insulin-like growth factors I and II R.G. Rosenfeld

In vivo actions of insulin-like growth factor-I J. Zapf, H.P. Guier, C. Schmid, A. Kurtz, and E.R. Froesch

Growth Factors

121

133

145

The structure and physiology of epidermal growth factor and its receptor 165 R.W. Donaldson, S. Nishibe, and G. Carpenter

Platelet-derived growth factor - Structural and functional aspects of the A -chain gene 181 C. Betsholtz, F. Rorsman, M. Bywater, C.-H. Heldin, and B. Westermark

Biological effects of transforming growth factors 191 H.L. Moses, J. Keski-Oja, R.M. Lyons, N.J. Sipes, C.C. Bascom, and RJ. Coffey, Jr.

Neural Regulation of Growth Hormone Secretion

Ontogeny of growth hormone-releasing factor and its role in fetal and neonatal growth 203 W.B. Wehrenberg and R.C. Gaillard

Structure and expression of growth hormone-releasing hormone (GHRH) genes 217 K.E. Mayo

Multifactorial regulation of growth hormone 231 C. Berthelier, P. Bertrand, M.T. Bluet-Pajot, H. Clauser, D. Durand, A. Enjalbert, J. Epelbaum, E. Rerat, and C. Kordon

Growth hormone-releasing hormone and somatostatin in the physiology and pathophysiology of growth hormone secretion 247 L.A. Frohman, P. Chomczynski, T.R. Downs, H. Katakami, and J.-0. Jansson

Aspects of neurotransmitter control of GH secretion: basic and clinical studies 263 F. Camanni, E. Ghigo, E. Mazza. E. Imperiale, S. Goffi, V. Martina, V. De Gennaro Colonna, S.G. Cella, D. Cocchi, V. Locatelli, F. Massara, and E.E. Muller

CONTENTS XVII

Growth Hormone Deficiency States

Growth hormone deficiency (GHD) and GHD-like syndromes 285 R.M. Blizzard

Use of provocative tests and measurement of spontaneous GH secretion to diagnose GH deficiency 299 J.R. Bierich, G. Brugmann, and E. Kiessling

Growth hormone secretory dysfunction after hypothalamic and pituitary irradiation 321 R. Rappaport, M. Fontoura, and R. Brauner

Round Table-Approach to Therapy

A critical overview of the state of the art 341 R.D.G. Milner

Human growth hormone therapy in children with growth hormone deficiency 353 K. Takano, K. Shizume, N. Hizuka, K. Asakawa, I. Sukegawa, R. Horikawa, and the members of the Study Committee for hGH

Growth hormone-releasing hormone: a new treatment for growth hormone deficiency 365 R.J.M. Ross, M.A. Preece, G.M. Besser, and M.O. Savage

Growth hormone deficiency states: approach by CNS-acting compounds 375 C. Pintor, S. Loche, R. Puggioni, S.G. Cella, V. Locatelli, A. Lampis, and E.E. Muller

Discussion by Bierich, Blizzard, Cattaneo, Cavallo, Costin, Ghigo, Heinrich, Marek, Milner, Muller, Pintor, Rappaport, Rosenfeld, Ross, Savage, Smith, Takano 389

Growth Hormone Hypersecretory States

Growth hormone-releasing factor in acromegaly 401 T. Shibasaki, A. Masuda, M. Hotta, T. Imaki, N. Hizuka, K. Takano, and K. Shizume

The hypersecreting somatotroph: functional and morphological aspects 411 A. Spada, M. Bassetti, M. Arosio, L. Vallar, F.R. Elahi, and G. Giannattasio

XVIII CONTENTS

Medical treatment of acromegaly- Dopaminergic agonists and long-acting somatostatin 423 P.G. Chiodini, R. Cozzi, D. Dallabonzana, G. Oppizzi, G. Verde, M.M. Petroncini, A. Liuzzi, E. Boccardi, and I. Lancranjan

Effect of Sandostatin on glucose metabolism and counterregulatory mechanisms: studies in normal volunteers 437 E. del Pozo, C. Sieber, M. Neufeld, H. Berthold, and P.H. Althoff

Neuroregulatory abnormalities of growth hormone secretion 445 S. Reichlin

Perspectives on growth hormone and growth factor research -Post-congress reflections 465 H.G. Friesen

Author Index 471 Subject Index 473

Contributors

Althoff P.H. University Medical Clinic Frankfurt am Main Federal Republic of Germany

Arosio M. Department of Endocrinology School of Medicine University of Milan Via F. Sforza, 35 20122 Milan, Italy

Asakawa K. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 10 Kawada-Cho Shinkjuku-ku, Tokyo, Japan

Bascom C.C. Department of Cell Biology Vanderbilt University School of Medicine Nashville, TN 37232, U.S.A.

Bassetti M. CNR Center of Cytopharmacology Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

Baumann G. Center for Endocrinology Metabolism and Nutrition Department of Medicine Northwestern University 303 East Chicago Avenue Chicago, IU 60611, U.S.A.

Bennett B. Genentech Inc., 460 Point San Bruno Boulevard South San Francisco CA 94080, U.S.A.

Berthelier C. Unite de Neuroendocrinologie Institut National de la Sante et de la Recherche Medicale INSERM U 159 Centre Paul Broca 2 ter, rue d' Alesia 75014 Paris, France

Berthold H. Experimental Therapeutics Department Clinical Research Sandoz Ltd. CH-4002 Basel, Switzerland

Bertrand P. Unite de Neuroendocrinologie Institut National de la Sante et de la Recherche M edicale INSERM U 159 Centre Paul Broca 2 ter, rue d' Alesia 75014 Paris, France

Besser G.M. Department of Endocrinology St. Bartholomew's Hospital West Smithfield London ECIA 7BE United Kingdom

Betsholtz C. Department of Pathology University Hospital S- 75I 85 Uppsala, Sweden

Bierich J.R. Department of Pediatrics University of Tubing en D-74 Tubingen Federal Republic of Germany

Blizzard R.M. Department of Pediatrics University of Virginia Medical School Box 386 Charlottesville, VA 22901, U.S.A.

XX

Bluet-Pajot M.T. Unite de Neuroendocrinologie Institut National de la Sante et de la Recherche Medicale INSERM U 159 Centre Paul Broca 2 ter, rue d' Alesia 75014 Paris, France

Boccardi E. Servizio di Neuroradiologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20162 Milan, Italy

Brauner R. Hopital des Enfants Malades 149 Rue de Sevres F-75015 Paris, France

Brooks P.J. Department of Physiology and Curriculum on Neurobiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27514. U.S.A.

Briigmann G. Department of Pediatrics University of Tiibingen D-74 Tiibingen, Federal Republic of Germany

Bywater M. Department of Pathology University Hospital S-751 85 Uppsala, Sweden

Camanni F. Dipartimento di Biochimica Endocrino-Metabolica e Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, 14 10126 Turin, Italy

Canova-Davis E. Genentech Inc.,

CONTRIBUTORS

460 Point San Bruno Boulevard South San Francisco CA 94080, U.S.A.

Carpenter G. Department of Biochemistry Vanderbilt University School of Medicine Nashville, TN 37232, U.S.A.

Carter-So C. Department of Physiology, Pediatrics and Biochemistry University of Michigan Medical School Ann Arbor, MI 48109, U.S.A.

Cella S.G. Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

Chakel J. Genentech Inc., 460 Point San Bruno Boulevard South San Francisco CA 94080, U.S.A.

Chiodini P.G. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20162 Milan, Italy

Chloubek R. Genentech Inc., 460 Point San Bruno Boulevard South San Francisco CA 94080, U.S.A.

Chomczynski P. Division of Endocrinology and Metabolism University of Cincinnati 231 Bethesda Avenue Cincinnati, OH, 45267, U.S.A.

CONTRIBUTORS XXI

Clauser H. Unite de Neuroendocrinologie Institut National de la Sante et de Ia Recherche M edicale INSERM U 159 Centre Paul Broca 2 ter, rue d'Alesia 75014 Paris, France

Cocchi D. Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

Coffey Jr. R.J. Department of Biochemistry Vanderbilt University School of Medicine Nashville, TN 37232, U.S.A.

Collins V.P. Ludwig Institute for Cancer Research, Stockholm Branch Stockholm, Sweden

Cozzi R. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20162 Milan, Italy

Dallabonzana D. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20162 Milan, Italy

De Gennaro Colonna V. Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

del Pozo E. Sandoz Research Institute Monbijoustrasse 115 3001 Bern, Switzerland

Donaldson R.W. Department of Biochemistry Vanderbilt University School of Medicine Nashville, TN 37232, U.S.A.

Downs T.R. Division of Endocrinology and Metabolism University of Cincinnati Department of Internal Medicine 231 Bethesda Avenue Cincinnati, Ohio 45267, U.S.A.

Durand D. Unite de Neuroendocrinologie Institut National de Ia Sante et de la Recherche M edicale INSERM U 159 Centre Paul Broca 2 ter, rue d' Alesia 75014 Paris, France

Elahi F.R. CNR Center of Cytopharmacology Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

English J. Department of Physiology and Curriculum in Neurobology University of Nprth Carolina at Chapel Hill Chapel Hill 27514, NC, U.S.A.

Enjalbert A. Unite de Neuroendocrinologie Institut National de la Sante et de la Recherche M edicale INSERM U 159 Centre Paul Broca 2 ter, rue d' Alesia 75014 Paris, France

XXII CONTRIBUTORS

Epelbaum J, Unite de Neuroendocrinologie Institut National de Ia Sante et de Ia Recherche Medicate INSERM U 159 Centre Paul Broca 2 ter, rue d' Atesia 75014 Paris, France

Fontoura M. Hopital des Enfants Malades 149 Rue de Sevres F-75015 Paris, France

Foster C.M. Department of Physiology, Pediatrics and Biochemistry University of Michigan Medical School Ann Arbor, MI 48109, U.S.A.

Friesen H.G. Department of Physiology University of Manitoba Winnipeg, MB R3E OW3, Canada

Froesch E.R. Metabolic Unit Department of Medicine University Hospital Riimistrasse 100 CH-8091 Zurich, Switzerland

Frohman L.A. Division of Endocrinology andM etabolism Department of Internal Medicine University of Cincinnati 231 Bethesda Avenue Cincinnati, OH 45267, U.S.A.

Gaillard R.C. Clinique Medicate et Division d' Endocrinologie Hopital Cantonal Universitaire de Geneve Geneva, Switzerland

Gellefors P. Kabi Vitrum Peptide Hormones AB S-112 87 Stockholm, Sweden

Ghigo E. Dipartimento di Biochimica Endocrino-M etabolica e Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, 14 10126 Turin, Italy

Giannattasio G. CNR Center of Cytopharmacology Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

Goffi S. Dipartimento di Biochimica Endocrino-M etabolica e Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, 14 10126 Turin, Italy

Guerin S. Department of Molecular Biology Massachusetts General Hospital Boston, MA 02114, U.S.A.

Guier H.P. Metabolic Unit Department of Medicine University Hospital Riimistrasse 100 CH-8091 Zurich, Switzerland

Hall K. Department of Endocrinology Karolinska Institute Karolinska Hospital S-104 01 Stockholm, Sweden

Hancock W.S. Genentech Inc., 460 Point San Bruno Boulevard South San Francisco CA 94080, U.S.A.

CONTRJBUTORS XXIII

Harris R. Genentech Inc., 460 Point San Bruno Boulevard South San Francisco CA 94080, U.S.A.

Heldin C.-H. Ludwig Institute for Cancer Research Box 595, Biomedical Center S-753 23 Uppsala, Sweden

Hizuka N. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 10 Kawada-Cho Shinkjuku-ku, Tokyo 162, Japan

Hotta M. Department of Medicine Institute of Clinical Endocrinology Tokyo Wonten's Medical College 10 Kawada-Cho Shinjuku-ku, Tokyo 162, Japan

Horikawa R. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 10 Kawada-Cho Shinkjuku-ku, Tokyo 162, Japan

Hynes M.A. Howard Hughes Medical Institute Research Laboratory Neurobiology and Behavior Center Columba University New York, NY U.S.A.

Imaki T. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 10 Kawada-Cho Shinkjuku-ku, Tokyo 162, Japan

Imperiale E. Dipartimento di Biochimica Endocrino-M etabolica e

Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, 14 10126 Turin, Italy

Jansson J.-0. Division of Endocrinology and Metabolism Department of Internal Medicine University of Cincinnati 231 Bethesda Avenue, Cincinnati, OH 45267, U.S.A.

Johnson C. Department of Pediatrics Emory University School of Medicine 2040 Ridgewood Dr. Atlanta, GA 30323, U.S.A.

Kassels M. Department of Pediatrics Emory University School of Medicine 2040 Ridgewood Dr. Atlanta, GA 30323, U.S.A.

Katakami H. Division of Endocrinology and Metabolism Department of Internal Medicine University of Cincinnati 231 Bethesda Avenue Cincinnati, OH 45267, U.S.A.

Kawauchi H. Laboratory of Molecular Endocrinology School of Fisheries Sciences Kitasato University Sanriku, Iwate 02201, Japan

Keck R. Genentech Inc., 460 Point San Bruno Boulevard South San Francisco CA 94080 U.S.A.

Keski-Oja J. Department of Virology University of Helsinki, Helsinki 29, Finland

XXIV

Kiessling E. Department of Pediatrics University of Tubing en D-74 Tubingen Federal Republic ofGermany

Kordon C. Unite de Neuroendocrinologie Institut National de la Sante et de la Recherche M edicale INSERM U. 159 Centre Paul Broca 2 ter, rue d' Alesia 75014 Paris, France

Kurtz A. Institute of Physiology University of Zurich CH-8057 Zurich, Switzerland

Lampis A. Department of Pediatrics, Chair of Pediatric Endocrinology University of Cagliari Via Jenner 09100 Cagliari, Italy

Lancranjan I. Department of Neuroendocrinology Sandoz Ltd. CH-4002 Basel, Switzerland

Levi Montalcini R. Istituto di Biologia Cellulare Via G. Romagnosi, 18/A 00196 Rome, Italy

Liuzzi A. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20162 Milan, Italy

Locatelli V. Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

Loche S. Department of Pediatrics,

CONTRIBUTORS

Chair of Pediatric Endocrinology University of Cagliari Via Jenner 09100. Cagliari, Italy

Lund P.K. Department of Physiology University of North Carolina School of Medicine Medical Research Wing 206H Chapel Hill, NC 27514, U.S.A.

Lyons R.M. Department of Cell Biology School of Medicine Vanderbilt University Nashville, TN 37232, U.S.A.

Martina V. Dipartimento di Biochimica Endocrino-Metabolica e Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, 14 10126 Turin, Italy

Massara F. Dipartimento di Biochimica Endocrino-Metabolica e Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, 14 /0126 Turin, Italy

Masuda A. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 1 0-Kawada-Cho Shinljuku-Ku, Tokyo 162, Japan

Mayo K.E. Department of Biochemistry, Molecular Biology and Cell Biology Northwestern University 2153 Sheridan Road Evanston, ILL 60201, U.S.A.

CONTRIBUTORS

Mazza E. Dipartimento di Biochimica Endocrino-M etabolica e Gastroenterologica, Divisione di Endocrinologia Universita di Torino Corso Polonia, I4 IOI26 Turin, Italy

McKean M.C. Department of Pediatrics Emory University School of Medicine 2040 Ridgewood Dr. Atlanta, GA 30323, U.S.A.

Meacham L. Department of Pediatrics Emory University School of Medicine 2040 Ridgewood Dr. Atlanta, GA 30323, U.S.A.

Milner R.D.G. Department of Paedriatrics University of Sheffield Children's Hospital Sheffield SIO 2TH United Kingdom

Moore D.D. Department of Molecular Biology Massachusetts General Hospital Boston, MA 02II4, U.S.A.

Moses H.L. Department of Cell Biology Vanderbilt University School of Medicine Nashville, TN 37232, U.S.A.

Muller E.E. Department of Pharmacology University of Milan Via Vanvitelli, 32 20129 Milan, Italy

Neufeld M. Experimental Therapeutics Department

Clinical Research Sandoz Ltd. CH-4002 Basel, Switzerland

Nishibe S. Department of Biochemistry Vanderbilt University School of Medicine Nashville, TN 37232, U.S.A.

Oppizzi G. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20I62 Milan, Italy

Parks J.S. Department of Pediatrics Emory University School of Medicine 2040 Ridgewood Dr. Atlanta, GA 30323, U.S.A.

Parks J.T. Department of Pediatrics Emory University School of Medicine 2040 Ridgewood Dr. Atlanta, GA 30323, U.S.A.

Pavlu B. Kabi Vitrum Peptide Hormones AB S-I 12 87 Stockholm, Sweden

Petroncini M.M. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20I62 Milan, Italy

Pintor C. Department of Pediatrics, Chair of Pediatric Endocrinology University of Cagliari Via Jenner 09IOO Cagliari, Italy

XXV

XXVI CONTRIBUTORS

Povoa G. Centro Biomedico - UFES Caixa Postal780 29000 - Vitoria - ES Brazil

Preece M.A. Department of Growth and Development, Institute of Child Health London, United Kingdom

Puggioni R. Department of Pediatrics, Chair of Pediatric Endocrinology University of Cagliari Via Jenner 09IOO Cagliari, Italy

Rappaport R. Hopital des Enfants Malades I49 Rue de Sevres F-750I5 Paris, France

Rerat E. Unite de Neuroendocrinologie Institut National de la Sante et de la Recherche M edicale INSERM U I59 Centre Paul Broca 2 ter, rue d' Alesia 750I4 Paris, France

Reichlin S. Endocrine Division Department of Medicine New England Medical Center Tufts University School of Medicine 750 Washington Street Boston, MA 02III, U.S.A.

Rorsman R. Department of Pathology University Hospital S-75I 85 Uppsala, Sweden

Rosenfeld R.G. Department of Pediatrics Stanford University Medical Center Stanford, CA 94305, U.S.A.

Ross R.J.M. Department of Endocrinology St. Bartholomew's Hospital West Smithfield London ECIA 7BE United Kingdom

Savage M.O. Department of Endocrinology St. Bartholomew's Hospital West Smithfield London ECIA 7BE United Kingdom

Schmid C. Metabolic Unit Department of Medicine University Hospital Rdmistrasse 100 CH-809I Zurich, Switzerland

Schwartz J. Department of Physiology, Pediatrics and Biochemistry University of Michigan Medical School Ann Arbor, MI48I09, U.S.A.

Shafer J.A. Department of Physiology, Pediatrics and Biochemistry University of Michigan Medical School Ann Arbor, MI 48I09, U.S.A.

Shibasaki T. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College IO Kawada-Cho Shinjuku-ku, Tokyo I62, Japan

Shizume K. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College IO Kawada-Cho Shinkjuku-ku, Tokyo I62, Japan

CONTRIBUTORS XXVII

Sieber C. Experimental Therapeutics Department Clinical Research Sandoz Ltd. CH-4002 Basel, Switzerland

Sipes N.J. Department of Cell Biology School of Medicine Vanderbilt University Nashville, TN 37232, U.S.A.

Spada A. Department of Endocrinology School of Medicine University of Milan Via F. Sforza, 35 20122 Milan, Italy

Sukegawa I. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 10 Kawada-Cho Shinkjuku-ku, Tokyo 162, Japan

Takano K. Department of Medicine Institute of Clinical Endocrinology Tokyo Women's Medical College 10 Kawada-Cho Shinkjuku-ku, Tokyo 162, Japan

Tripputi P. Department of Molecular Biology Massachusetts General Hospital Boston, MA 02114, U.S.A.

Vallar L. CNR Center of Cytopharmacology

Department of Pharmacology University of Milan Via Vanvitelli, 32 20I29 Milan, Italy

VanWyk J.J. Department of Pediatrics UniversityofNorth CarolinaatChapelHill, Chapel Hill, NC 275I4, U.S.A.

Verde G. Divisione di Endocrinologia Ospedale Niguarda Piazza Ospedale Maggiore, 3 20162 Milan, Italy

Wehrenberg W .B. Department of Health Sciences University of Wisconsin-Milwaukee Milwaukee, WI 53201, U.S.A.

W estermark B. Department of Pathology University Hospital University of Uppsala S-751 85 Uppsala, Sweden

Yasuda A. Laboratory of Molecular Endocrinology School of Fisheries Sciences Kitasato University Sanriku, Iwate 02201, Japan

Zapf J. Metabolic Unit Department of Medicine University Hospital Riimistrasse 100 CH-8091 Zurich, Switzerland

List of Abbreviations

(Other abbreviations used are defined in the text.)

A

AC adenylate cyclase ACh acetycholine

AlTI arginine-insulin tolerance test ALL acute lymphoblastic leukemia

B

BP binding protein Br bromocriptine

c

CDGA constitutional delayed growth and adolescence

CI continuous infusion CLO clonidine CNS central nervous system

CS somatomammotropin CRF corticotropin-releasing factor CSF cerebrospinal fluid cr computed tomography

D

DA dopamine

E

ECP Escherichia Coli protein EGF epidermal growth factor EIA enzyme immunoassay

G

GAL galanin GH growth hormone

GHD growth hormone deficiency GHRH growth hormone-releasing

hormone GnRH gonadotropin releasing hormone

GRF growth hormone-releasing hormone or factor

GRH growth hormone releasing hormone

H

HPLC high performance liquid chro­matography

HV height velocity

I

IDDM insulin-dependent diabetes IH insulin hypoglycemia

IGF insulin-like growth factor IEF isoelectric focusing

ISHH in situ hybridization histochem­istry

M

rnf-hGH methionine free hGH m-hGH rnethyonil hGH

MI multiple injections MPO medial preoptic area

XXX ABBREVIATIONS

MSA multiplication stimulating activ­ity

N

NE norepinephrine NRS nonnal rabbit serum NSC nonnal short children

NSGHD neurosecretory growth hormone deficiency

NVSS nonnal variant short stature

0

OPI opioid neurons

p

P ill P serum procollagen ill propep­tide

Parlodel LAR long-acting repeteable bro­mocriptine

Parlodel MR modified release bromocriptine PD pyridostigmine

PDGF platelet-derived growth factor PL placental lactogen

POMC proopiomelanocortin p-hGH pituitary extracted hGH

PRL prolactin PSS psychosocial short stature

R

r-hGH recombinant hGH

s SDS-PAGE sodium dodecyl sulphate-poly­

acrylamide gel electrophoresis Sm-C somatomedin-C SMS SMS 201-995 SRIF growth hormone-inhibiting fac­

tor SS somatostatin

a-SUB a-subunit SSV simian sarcoma virus

T

TBI total body irradiation TF A trifluoroacetic acid TGF transforming growth factor TPA 12-o-tetradecanoyl-phorbol-13-

acetate TRH thyrotropin releasing hormone

u

UEP unit evolutionary period

v VIP vasoactive intestinal polypep­

tide