Hormone Resistance Syndromes

285 Pages·1999·36.444 MB·English

by  Gerhard Baumann MD, Hiralal G. Maheshwari MBBS,PhD (auth.), J. Larry Jameson MD, PhD (eds.)

HORMONE REsISTANCE
SYNDROMES
CONTEMPORARY ENDOCRINOLOGY
P. Michael Conn,
SERIES EDITOR
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HORMONE
RESISTANCE
SYNDROMES
Edited by
J.
LARRY JAMESON, MD, PHD
Northwestern University Medical School
Chicago, II
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© 1999 Springer Science+Business Media New York
Originally pub1ished by Humana Press Inc. in 1999
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Hormone resistance syndromes / edited by J. Larry Jameson.
p. cm. - (Contemporary endocrinology ; 14)
Includes index.
ISBN 978-1-4757-5418-6 ISBN 978-1-59259-698-0 (eBook)
DOI 10.1007/978-1-59259-698-0
1. Hormone resistance. 1. Jameson, J. Larry. II. Series: Contemporary endocrinology (Totowa, NJ) ; 14.
[DNLM: 1. Syndrome. 2. Hormones--physiology. 3. Mutation. 4. Drug Resistance. 5. Receptors,
Drug--physio10gy. QZ 140H812 1999]
RC649.H65 1999
616.4--dc21
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for Library of Congress 98-41146
CIP
PREFACE
In 1942, Fuller Albright proposed that pseudohypoparathyroidism resulted from end
organ resistance to parathyroid hormone (PTH). Since then, the concept of hormone
resistance has been expanded to include almost every type ofh ormone, including peptides
like GHRH, large proteins such as insulin, and the glycoprotein hormones, steroid
hormones, and even ions such as calcium.
The idea of hormone resistance builds upon thinking of hormone action in terms of an
endocrine axis that is controlled by feedback regulation. Most resistance syndromes are
characterized by elevated hormone levels because their failure to act normally results in
a lack of feedback inhibition. As an example, androgen resistance is typified by elevated
gonadotropin and testosterone levels that reflect defective androgen action. Similarly,
TSH resistance is characterized by low thyroid hormone levels that lead to reduced
feedback inhibition and the elevation of circulating TSH levels. Thus, the diagnosis of
most hormone resistance syndromes can be made by examining the hormone levels at
various points in a given endocrine axis.
In most cases, hormone resistance syndromes are caused by mutations in receptors. In
the case ofp roteins, the mutant receptors are typically membrane receptors. These include
seven transmembrane, G-protein-coupled receptors in the case of resistance to TSH, LH,
FSH, ACTH, GHRH, and vasopressin. However, other classes of membrane receptors
can also be affected. For example, the insulin receptor is a tyrosine kinase receptor, the
GH receptor belongs to a family of cytokine receptors, and the MIS receptor is related to
the TGFp serine kinase group of receptors. G-protein mutations cause Albright's
hereditary osteodystrophy, and, as might be expected, there is resistance to multiple
different hormones that act through G-protein-coupled receptors. A variety of resistance
syndromes involve members ofthe nuclear receptor superfamily, including resistance to
androgens, vitamin D, thyroid hormone, glucocorticoids, and estrogen. Another form of
resistance, sometimes referred to as "post-receptor," is not covered in this book, largely
because its pathophysiology remains elusive. This type of resistance is typified by
acquired forms of insulin resistance that cause type II diabetes mellitus.
A decade ago, studies of hormone resistance syndromes relied almost entirely upon
measurements of circulating hormone levels. Although such measurements are still very
important for diagnostic and therapeutic purposes, the cloning of hormone receptors has
allowed recombinant DNA studies to be used to unequivocally demonstrate the presence
of mutations. These molecular studies allow diagnoses to be made in individual patients,
and also permit genetic counseling within families. In addition, studies of naturally
occurring mutations have provided many insights into the structure and function of
receptors. By definition, the mutations that cause disease identify important functional
domains in the proteins. In some instances, mutations cause large deletions ofthe receptor,
and not much is learned about structure-function. However, in cases such as the thyroid
hormone receptor, the point mutations have identified domains involved in hormone
binding, receptor dimerization, and transactivation.
In virtually every resistance syndrome, it is striking that there is tremendous
heterogeneity in the locations of mutations in different individuals. Though this finding
provides an opportunity to elucidate the structural impact on receptor function, there are
v
VI Preface
also practical implications. First, the heterogeneity suggests that most mutations arise
independently, as opposed to being passed down through a founder effect. Thus, simple
screening tests cannot be used to detect highly prevalent mutations. Second, it raises
the possibility that clinical phenotypes will vary, depending on the location and the type
of mutation that is present in the receptor. The correlation of genotype and phenotype is
an active area of research and requires sophisticated clinical investigation to tease apart
subtle differences in physiology.
In the next decade, we can expect additional resistance syndromes to be described. In
addition, there will be a dramatic increase in the number of different mutations described
as more patients are characterized at a molecular level. Ultimately, it is likely that
databases will exist on the world wide web for each of these syndromes, as is currently
the case for thyroid hormone receptor mutations. Although therapy is straightforward in
some disorders, it is challenging and poorly studied in others. Whether gene therapy will
playa role in some of the resistance syndromes is an interesting topic for speculation, but
will require much further study.
J. Larry Jameson
CONTENTS
Preface ........................................................................................................ v
Contributors .............................................................................................. ix
1 Dwarfism: GHRH Resistance ........................................................... 1
Gerhard Baumann and Hiralal G. Maheshwari
2 Laron Syndrome: Primary Growth Hormone Resistance .............. 17
Zvi Laron
3 Pseudohypoparathyroidism ............................................................. 39
Ali Al-Zahrani, Michael A. Levine,
and William F. Schwindinger
4 Hereditary Resistance to Vitamin D ............................................... 59
Peter 1. Malloy and David Feldman
5 Decreased Responsiveness to Extracellular Ca2+ Owing
to Abnormalities in the Ca2+o -Sensing Receptor ....................... 87
Edward M. Brown, Olga Kifor, and Mei Bai
6 Resistance to TSH ......................................................................... 111
Peter Kopp
7 Thyroid Hormone Resistance ....................................................... 145
V. Krishna K. Chatterjee, Roderick 1. Clifton-Bligh,
and Mark Gurnell
8 Diabetes Mellitus: Insulin Resistance .......................................... 165
Simeon I. Taylor and ElifA rioglu
9 LH Insensitivity Syndrome ........................................................... 185
Axel P. N. Themmen, John W M. Martens,
and Han G. Brunner
10 FSH Resistance ............................................................................. 197
Kristina Aittomiiki and Ilpo T. Huhtaniemi
11 Genetic Alterations of Androgen Receptor Function .................. 209
Ken Brantley, Tianshu Gao, and Michael 1. McPhaul
12 Retained Mullerian Ducts: AMH Resistance Syndrome .............. 233
Nathalie Josso, Jean-Yves Picard, and Rodolfo Rey
13 Adrenal Insufficiency: ACTH Resistance .................................... 245
Adrian 1. L. Clark
14 Glucocorticoid Resistance and Hypersensitivity ......................... 259
Denis P. Franchimont and George P. Chrousos
Index ....................................................................................................... 273
Vll
CONTRIBUTORS
KRISTINA AITTOMA.KI, MD, PHD, Department ofM edical Genetics, University
ofH elsinki, Finland
ALI AL-ZAHRANI, MD, Division ofE ndocrinology and Metabolism, The Johns Hopkins
University School ofM edicine, Baltimore, MD
ELIF ARIOGLU, MD, National Institute of Diabetes and Digestive and Kidney Disease,
National Institutes ofH ealth, Bethesda, MD
MEl BAI, PHD, Endocrinology-Hypertension Division, Brigham and Women's
Hospital, Boston, MA
GERHARD BAUMANN, MD, Division of Endocrinology, Metabolism and Molecular
Medicine, Department ofM edicine, Northwestern University Medical School,
Chicago,IL
KEN BRANTLEY, MD, PHD, Endocrinology and Metabolism Division, Department of
Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
EDWARD M. BROWN, MD, Endocrinology-Hypertension Division, Brigham and
Women's Hospital, Boston, MA
HAN G. BRUNNER, MD, PHD, Department of Human Genetics, University Hospital,
Nijmegen, The Netherlands
V. KRISHNA K. CHATTERJEE, MD, BMBCH, FRCP, Department of Medicine, University
of Cambridge, UK
GEORGE P. CHROUSOS, MD, National Institute of Child Health and Human
Development, National Institutes ofH ealth, Bethesda, MD
RODERICK 1. CLIFTON-BLIGH, BSC (MED), Department of Medicine, University
of Cambridge, UK
ADRIAN 1. L. CLARK, DSC, FRCP, Molecular Endocrinology Section, Department
ofE ndocrinology, St. Bartholomew's and the Royal London School ofM edicine
and Dentistry, London, UK
DA VID FELDMAN, MD, Department ofM edicine, Stanford University, Stanford, CA
DENIS P. FRANCHIMONT, MD, National Institute of Child Health and Human
Development, National Institutes ofH ealth, Bethesda, MD
TIANSHU GAO, MD, Endocrinology and Metabolism Division, Department ofI nternal
Medicine, University of Texas Southwestern Medical Center, Dallas, TX
MARK GURNELL, BSC, MBBS, MRCP, Department ofM edicine, University ofC ambridge, UK
ILPO T. HUHT ANIEMI, MD, PHD, Department ofP hysiology, University of Turku, Finland
NATHALIE Josso, MD, Unite de Recherches sur l'Endocrinologie du Developpement
(INSERM), Departement de Biologie, Montrouge, France
OLGA KIFOR, MD, Endocrinology-Hypertension Division, Brigham and Women's
Hospital, Boston, MA
PETER Kopp, MD, Division of Endocrinology, Metabolism, and Molecular Medicine,
Northwestern University Medical School, Chicago, IL
ZVI LARON, MD, Endocrine and Diabetes Research Unit, Schneider Children's
Medical Center ofI srael, Petah Tiqva, Israel
MICHAEL A. LEVINE, MD, Division ofE ndocrinology and Metabolism, The Johns
Hopkins University School ofM edicine, Baltimore, MD
i.x
x Contributors
HIRALAL G. MAHESHWARI, MBBS, PHD, Division of Endocrinology, Metabolism
and Molecular Medicine, Department ofM edicine, Northwestern University
Medical School, Chicago, IL
PETER 1. MALLOY, PHD, Department ofM edicine, Stanford University, Stanford, CA
JOHN W. M. MARTENS, PHD, Department ofE ndocrinology and Reproduction, Erasmus
University, Rotterdam, The Netherlands
MICHAEL 1. MCPHAUL, MD, Endocrinology and Metabolism Division, Department
ofI nternal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
JEAN-YVES PICARD, PHD, Unite de Recherches sur l'Endocrinologie du Developpement
(INSERM), Departement de Biologie, Montrouge, France
RODOLFO REY, MD, PHD, Unite de Recherches sur I'Endocrinologie du Developpement
(INSERM), Departement de Biologie, Montrouge, France
WILLIAM F. SCHWINDINGER, MD, PHD, Division ofE ndocrinology and Metabolism,
The Johns Hopkins University School ofM edicine, Baltimore, MD
SIMEON I. T AYLOR, MD, PHD, National Institute ofD iabetes and Digestive and Kidney
Diseases, National Institutes ofH ealth, Bethesda, MD
AXEL P. N. THEMMEN, PHD, Department of Endocrinology and Reproduction, Erasmus
University, Rotterdam, The Netherlands
1
Dwarfism
GHRH Resistance
Gerhard Baumann,
MD
and Hiralal G. Maheshwari, MBBS, PHD
CONTENTS
REGULATION OF GROWTH HORMONE (GH) SECRETION:
THE GROWTH HORMONE-RELEASING HORMONE
(GHRH)/SOMATOSTATIN/GROWTH HORMONE-RELEASING
PEPTIDE (GHRP) SYSTEM
GHRH: STRUCTURE AND ACTIVITY
THE GHRH RECEPTOR: STRUCTURE, EXPRESSION, AND SIGNALING
GHRH AND PITUITARY GROWTH AND DEVELOPMENT
GHRH RESISTANCE
POTENTIAL IMPLICATIONS OF GHRH RESISTANCE SYNDROMES FOR
SHORT STATURE IN THE GENERAL POPULATION
ACKNOWLEDGMENTS
REFERENCES
REGULATION OF GROWTH HORMONE (GH) SECRETION:
THE GROWTH HORMONE-RELEASING HORMONE
(GHRH)/SOMATOSTATIN/GROWTH-HORMONE-RELEASING
PEPTIDE (GHRP) SYSTEM
Growth hormone (GH) synthesis and secretion are governed by at least two, and
probably three, hypothalamic hypophysiotropic factors, delivered to the pituitary gland
via the pituitary portal system (Fig. 1). GHRH is a positive regulator stimulating GH
production (1). It will be described in detail below. Somatostatin is a negative regulator
that inhibits GH secretion. It is widely distributed in the central nervous system and
neuroendocrine tissues, where it acts as an inhibitor of a variety of cellular secretory
functions (2). Recently, a third factor has been postulated, though not yet identified
the endogenous GHRP analog. GHRP, a small peptide existing as several variants,
stimulates GH secretion in conjunction with GHRH (3). Although GHRP is at present
merely a pharmacological agent, the recent cloning of a specific receptor for GHRP from
pituitary (4) lends credence to the view that an endogenous ligand akin to GHRP must
exist and probably participates in the regulation of GH secretion.
From: Contemporary Endocrinology: Hormone Resistance Syndromes
Edited by: J. L. Jameson © Humana Press Inc., Totowa, NJ
1