Table Of ContentAdvances 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
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© Springer-Verlag Berlin Heidelberg 1989
The use of registered names, trademruks, etc. in this publication does not imply, even in the absence
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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 macromole
cules 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 evolu
tionary origin, regulatory mechanisms at the level of its coding gene, and modu
latory 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,
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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 differ
entiation 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. Obvi
ously, 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 ofD r. 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 radioimmunoas
say. 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 Bio
logically 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 con
sequences 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 phylo
genetic 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 IGF
II 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 neurotrans
mitter 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 dysfunc
tion 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 defi
ciency, 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,
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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 endocrinolo
gists, 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
