Norman / Henry Hormones

3. Auflage 2014
ISBN: 978-0-08-091906-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 430 Seiten

The 3rd edition of Hormones offers a comprehensive treatment of the hormones of humans all viewed from the context of current theories of their action in the framework of our current understanding their physiological actions as well as their molecular structures, and those of their receptors. This new edition of Hormones is intended to be used by advanced undergraduates and graduate students in the biological sciences. It will also provide useful background information for first year medical students as they engage in studies which are increasingly problem-based rather than discipline-focused. As the field of endocrinology itself has expanded so much in the past two decades, the up to date presentation of the basics presented in this book will be a solid foundation on which more specialized considerations can be based. New to this Edition: Hormones, 3rd Edition is organized with two introductory chapters followed by 15 chapters on selected topics of the molecular biology of the major endocrine systems operative in humans. Coverage, for the first time of the following hormones; ghrelin, oxyntomodulin, kisspeptin, adrenomedullin, FGF23, erythropoietin, VIP and extended coverage of NO. Coverage of the hypothalamus has been integrated with the anterior pituitary because of the intimate functional and relationship between the two. Consideration of the role of hormones in cancer has been integrated into the chapters on the relevant hormones. Each of these areas occupies a unique niche in our understanding of the biological world and is part of the universality of signaling systems and how they govern biological systems. - Organized with two introductory chapters, followed by 15 chapters on selected topics of the molecular biology of the major human endocrine systems - New full color format includes over 300 full color, completely redrawn images - Companion web site will host all images from the book as PPT slides and .jpeg files - All chapters have been completely updated and revitalized. Coverage of the hypothalamus has been integrated into the anterior pituitary chapter and coverage of the thymus has been eliminated and left to immunology textbooks - Provides essential basics for advanced undergraduates and graduate students in the biological sciences, as well as first year medical students as they engage in studies which are increasingly problem-based rather than discipline-focused

Anthony W. Norman received his A.B. from Oberlin College in 1959, and an M.S. and Ph.D. in Biochemistry in 1961 and 1963, respectively, from the University of Wisconsin, Madison. Following postdoctoral work in Paul D. Boyer's group at UCLA, in 1964 he joined the Department of Biochemistry at University of California, Riverside, as an Assistant Professor. From 1976 to 1981 he served as Chair of the department and currently holds a Presidential Chair and is a Distinguished Professor of Biochemistry and Biomedical Sciences. Dr. Norman has also been active for some 25 years in medical education on the UC-Riverside campus and at UCLA through participation in the UR/UCLA Program in Biomedical Sciences, of which he was Dean and Director from 1986 to 1991. Dr. Norman's biomedical research career has focused on the mechanism of action of the vitamin D family of steroids. His chief contributions to these areas of cellular and molecular endocrinology have played a pivotal role in defining the boundaries of this research domain via discoveries that have opened new areas of investigation. The first of these was the discovery in 1968, and chemical characterization in 1971, of the hormonally active form of vitamin D, 1a,25(OH)2-vitamin D3. Subsequent achievements include the discovery and characterization of the nuclear receptor for 1a,25(OH)2D3, the clinical evaluation of 1a,25(OH)2D3 in renal osteodystrophy, articulation of the concept of the vitamin D endocrine system, the importance of 1a,25(OH)2D3 to insulin secretion and the discovery of a new rapid, nongenomic, signal transduction process for 1a,25(OH)2D3. Dr. Norman has been the recipient of awards that include a Fulbright Fellowship, 1970; Public Health Service Career Development Award, 1970; Mead Johnson Award, American Institute of Nutrition, 1977; Ernst Oppenheimer Award, Endocrine Society, 1977; Visiting Lecturer Australian Society of Endocrinology, 1978; Visiting Faculty Member, Mayo Clinic, 1981; Prix Andre.

Autoren/Hrsg.

Norman, Anthony W.

Henry, Helen L.

Inhaltsverzeichnis

1;Front Cover;1
2;Hormones;4
3;Copyright Page;5
4;Contents;6
5;Preface;14
6;About the Cover;16
6.1;Front Cover Image;16
6.2;Back Cover Image;16
7;1 Hormones: An Introduction;18
7.1;I. Overview of Hormones;18
7.1.1;A. Introduction;18
7.1.2;B. Review of Animal Cell Structure;19
7.1.3;C. Hormones and Their Communication Systems;22
7.1.4;D. Biosynthesis of Peptide and Protein Hormones;23
7.1.5;E. Regulation of Hormone Synthesis, Secretion, and Serum Levels;25
7.2;II. Hormone Receptors;26
7.2.1;A. Introduction;26
7.2.2;B. Membrane Receptors;27
7.2.3;C. The Nuclear Receptor Family;29
7.2.4;D. Measurement of Hormone–Receptor Interactions;31
7.3;III. Mechanisms of Hormone Action;33
7.3.1;A. Cell Signaling by Membrane Receptors;33
7.3.2;B. Regulation of Gene Transcription by Steroid Hormones;37
7.3.3;C. Membrane-Initiated Actions by Steroid Hormones;38
7.4;IV. Clinical Aspects;39
7.5;Further Reading;42
8;2 Steroid Hormones: Chemistry, Biosynthesis, and Metabolism;44
8.1;I. Introduction;44
8.1.1;A. General Comments;44
8.1.2;B. Historical Perspective;44
8.1.3;C. Radioactive Steroids;45
8.1.4;D. Molecular Biology Contributions;45
8.2;II. Chemistry of Steroids;45
8.2.1;A. Basic Ring Structure;45
8.2.2;B. Classes of Steroids;45
8.2.3;C. Structural Modification;47
8.2.4;D. Asymmetric Carbons;47
8.2.5;E. Conformational Flexibility of Steroids;49
8.2.6;F. Other Steroid Structures;52
8.3;III. Biosynthesis of Steroids;53
8.3.1;A. Introduction;53
8.3.2;B. Properties Steroidogenic Enzymes;56
8.3.3;C. Biosynthesis of Pregnenolone and Progestins;66
8.3.4;D. Biosynthesis of Adrenal Cortex Mineralocorticoids, Glucocorticoids, and Some Androgens;67
8.3.5;E. Biosynthesis of Androgens;67
8.3.6;F. Biosynthesis of Progesterone and Estrogens;67
8.3.7;G. Biosynthesis of Vitamin D Metabolites;68
8.3.8;H. Biosynthesis of Bile Acids;68
8.4;IV. Serum Binding Proteins for Steroid Hormones;68
8.4.1;A. Introduction;68
8.4.2;B. Serum Binding Proteins for Steroid Hormones;69
8.5;Further Reading;70
9;3 The Hypothalamus and Anterior Pituitary;72
9.1;I. Introduction;72
9.1.1;A. Overview and CNS Control of the Hypothalamus;72
9.1.2;B. Hypothalamic Control of the Pituitary Gland;72
9.1.3;C. Pituitary Control of Distal Endocrine Glands;74
9.1.4;D. Neuroendocrine Axis Feedback;75
9.2;II. Anatomical Relationships;75
9.2.1;A. Hypothalamic-Pituitary Anatomy;75
9.2.2;B. Hypothalamic Neural Connections;76
9.2.3;C. Hypothalamic-Pituitary Circulatory System;77
9.3;III. Structure, Synthesis, Secretion, and Target Cells of the Hypothalamic Releasing Hormones;77
9.3.1;A. Thyrotropin-Releasing Hormone;78
9.3.2;B. Gonadotropin-Releasing Hormone;80
9.3.3;C. Corticotropin-Releasing Hormone;81
9.3.4;D. Hypothalamic Control of Growth Hormone Secretion;82
9.3.5;E. Hypothalamic Control of Prolactin Secretion;83
9.4;IV. Chemistry of the Anterior Pituitary Hormones;83
9.4.1;A. Glycoprotein Hormones;83
9.4.2;B. Growth Hormone;84
9.4.3;C. Prolactin;84
9.4.4;D. POMC Derivatives: ACTH, a-MSH, ß-Lipotropin, Endorphin;85
9.5;V. Regulation and Biological Actions of Growth Hormone and Prolactin;86
9.5.1;A. Growth Hormone;86
9.5.2;B. Prolactin;91
9.6;VI. The Hypothalamus and Appetite Regulation;93
9.7;VII. Clinical Aspects;94
9.7.1;A. Hypothalamus;94
9.7.2;B. Pituitary;94
9.8;Further Reading;96
10;4 Posterior Pituitary Hormones;98
10.1;I. Introduction;98
10.2;II. Anatomy of the Posterior Pituitary;98
10.3;III. Chemistry, Biosynthesis, and Secretion of the Posterior Pituitary Hormones;98
10.3.1;A. Structures of Oxytocin and Vasopressin;98
10.3.2;B. Synthesis and Secretion of Vasopressin and Oxytocin;100
10.4;IV. Biological Actions of Arginine Vasopressin (AVP);101
10.4.1;A. AVP Receptors;101
10.4.2;B. AVP Regulation of Water Handling;101
10.4.3;C. Cardiovascular Effects of AVP;101
10.4.4;D. Effects of AVP on Glucose Homeostasis;102
10.4.5;E. Effects of AVP on ACTH Secretion;102
10.4.6;F. AVP and the Brain;103
10.5;V. Biological Actions of Oxytocin;103
10.5.1;A. The Oxytocin Receptor;103
10.5.2;B. Oxytocin and Parturition;103
10.5.3;C. Oxytocin and Lactation;104
10.5.4;D. Oxytocin and the Brain;104
10.6;VI. Clinical Aspects;104
10.6.1;A. Oxytocin;104
10.6.2;B. Diabetes Insipidus;105
10.7;Further Reading;105
11;5 Thyroid Hormones;106
11.1;I. Introduction;106
11.1.1;A. The Thyroid Gland and Its Hormones;106
11.1.2;B. Iodine Metabolism;106
11.2;II. Anatomy of the Thyroid Gland;107
11.3;III. Chemistry of the Thyroid Hormones;108
11.4;IV. Synthesis and Secretion of Thyroid Hormones;108
11.4.1;A. The Thyroid Epithelial Cell;108
11.4.2;B. Thyroglobulin;109
11.4.3;C. Iodide Uptake: The Na+/I Symporter;110
11.4.4;D. Thyroid Peroxidase and DUOX: Tyrosine Iodination and Coupling;111
11.4.5;E. Thyroglobulin Storage, Endocytosis, and Breakdown;112
11.4.6;F. Secretion of T4 and T3 and Recycling of I ;113
11.4.7;G. Transport and Metabolism of Thyroid Hormones;113
11.4.8;H. Antithyroid Drugs;115
11.5;V. Regulation of Thyroid Hormone Secretion;116
11.5.1;A. The Hypothalamic-Pituitary-Thyroid Axis;116
11.5.2;B. Autoregulation;117
11.5.3;C. Effects of TSH on the Thyroid Epithelial Cell;117
11.6;VI. Biological Actions of T3;118
11.6.1;A. Thyroid Hormone Receptor;118
11.6.2;B. Membrane Mediated Actions of Thyroid Hormone;120
11.6.3;C. Basal Metabolic Rate and Thermogenesis;120
11.6.4;D. Metabolic Actions;121
11.6.5;E. Neurodevelopment;121
11.7;VII. Clinical Aspects;121
11.7.1;A. Clinical Features of Hyper- and Hypothyroidism;121
11.7.2;B. Hyperthyroidism: Etiology and Treatment;123
11.7.3;C. Hypothyroidism: Etiology and Treatment;123
11.8;Further Reading;124
12;6 Pancreatic Hormones: Insulin and Glucagon;126
12.1;I. Introduction;126
12.1.1;A. Background Information;126
12.1.2;B. Regulation of Blood Glucose;126
12.1.3;C. Nutritional and Metabolic Interrelationships;128
12.2;II. Anatomical, Morphological, and Physiological Relationships;130
12.2.1;A. Anatomy of the Hepatopancreatic Complex;130
12.3;III. Chemistry, Biochemistry, and Biological Activities of the Pancreatic Hormones;133
12.3.1;A. Insulin;133
12.3.2;B. Glucagon and Glucagon-like Peptides;141
12.3.3;C. Insulin and Glucagon Collaborations;145
12.3.4;D. Leptin;149
12.3.5;E. Other Pancreatic Hormones;152
12.4;IV. Clinical Aspects;153
12.4.1;A. Diabetes Mellitus;153
12.5;Further Reading;155
13;7 Gastrointestinal Hormones;158
13.1;I. Introduction;158
13.1.1;A. Background;158
13.1.2;B. Resume of the Gastrointestinal Hormones;158
13.1.3;C. Problems of Food Processing and Digestion;160
13.2;II. Anatomical and Physiological Relationships;160
13.2.1;A. Gastroenteropancreatic System;160
13.2.2;B. Stomach;162
13.2.3;C. Small Intestine and Colon;164
13.2.4;D. Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex;165
13.2.5;E. Pancreatic, Biliary, and Intestinal Secretions;166
13.2.6;F. Coordination of Gastroenteropancreatic Hormone Release;168
13.2.7;G. Motor Functions of the Intestinal Tract;169
13.2.8;H. Brain–Gut Axis;170
13.3;III. Biochemical Properties and Molecular Actions;170
13.3.1;A. General Relationships;170
13.3.2;B. Cholecystokinin/Gastrin Family;171
13.3.3;C. Secretin Family: Secretin, Vasoactive Intestinal Peptide;173
13.3.4;D. Pancreatic Polypeptide Family: Peptide YY and Neuropeptide Y;174
13.3.5;E. Bombesin and Related Peptides: Gastrin Releasing Peptide and Neuromedin C;174
13.3.6;F. Tachykinin Family: Substance P and Neurokinins A and B;175
13.3.7;G. Neurotensin;176
13.3.8;H. Calcitonin Gene-Related Peptide Family: Amylin;177
13.3.9;I. Enteroglucagon and Oxyntomodulin;177
13.3.10;J. Motilin;178
13.3.11;K. Somatostatin;179
13.3.12;L. Gastric Acid Secretion;179
13.3.13;M. Ghrelin, Leptin, and Energy Use;181
13.4;IV. Clinical Aspects;185
13.4.1;A. Peptic Ulcer Disease;185
13.4.2;B. Carcinoid Syndrome;185
13.4.3;C. Zollinger-Ellison Syndrome;186
13.5;Further Reading;186
14;8 Eicosanoids;188
14.1;I. Introduction;188
14.2;II. Structure and Nomenclature of Eicosanoids;189
14.3;III. Synthesis and Inactivation of Eicosanoids;189
14.3.1;A. Overview of Eicosanoid Synthesis;189
14.3.2;B. Phospholipase A2;191
14.3.3;C. Prostaglandin H Synthase/Cyclooxygenase;194
14.3.4;D. Cyclooxygenase Inhibitors;195
14.3.5;E. Lipoxygenase;195
14.3.6;F. Transport and Inactivation of Prostanoids;197
14.4;IV. Eicosanoid Receptors and Signaling;198
14.5;V. Examples of Biological Actions of Prostaglandins;198
14.5.1;A. Prostacyclin and Thromboxane in the Vasculature;199
14.5.2;B. Prostaglandins in the Kidney;199
14.5.3;C. Prostaglandins and Pain Perception;200
14.5.4;D. Prostaglandins in Reproduction;201
14.6;VI. Clinical Aspects;202
14.6.1;A. Prostaglandins and Cancer;202
14.6.2;B. Leukotrienes in Human Disease;203
14.7;Further Reading;204
15;9 Calcium-Regulating Hormones: Vitamin D, Parathyroid Hormone, Calcitonin, and Fibroblast Growth Factor 23;206
15.1;I. Introduction;206
15.1.1;A. Background Information;206
15.1.2;B. Calcium and Phosphorus Homeostasis;207
15.2;II. Anatomical and Physiological Relationships;209
15.2.1;A. Intestine;209
15.2.2;B. Bone;209
15.2.3;C. Kidney;212
15.2.4;D. Parathyroid Gland;212
15.2.5;E. Calcitonin-Secreting Cells;212
15.3;III. Chemistry and Biochemistry;213
15.3.1;A. Vitamin D and 1a,25(OH)2D3;213
15.3.2;B. Parathyroid Hormone;215
15.3.3;C. Parathyroid Hormone-Related Protein;217
15.3.4;D. Calcitonin;218
15.3.5;E. Fibroblast Growth Factor 23;219
15.4;IV. Biology and Molecular Actions;219
15.4.1;A. Parathyroid Hormone Receptor and Biological Actions;219
15.4.2;B. Parathyroid Hormone-Related Protein Receptor and Biological Actions;220
15.4.3;C. Calcitonin Receptor and Biological Actions;222
15.4.4;D. Vitamin D Receptor and Biological Actions;223
15.4.5;E. Fibroblast Growth Factor-23;230
15.4.6;F. Integrated Actions of 1a,25(OH)2D3, PTH, Calcitonin, and FGF23 on Bone Remodeling and Calcium Homeostasis;232
15.5;V. Clinical Aspects;234
15.5.1;A. Vitamin D Nutrition;234
15.5.2;B. Osteoporosis;235
15.5.3;C. Tuberculosis;236
15.5.4;D. Parathyroid Hormone;236
15.5.5;E. Parathyroid Hormone-Related Protein;237
15.5.6;F. Calcitonin;237
15.5.7;G. FGF23;237
15.6;Further Reading;238
16;10 Adrenal Corticoids;240
16.1;I. Introduction;240
16.1.1;A. Background;240
16.1.2;B. Glucocorticoids;240
16.1.3;C. Mineralocorticoids;240
16.2;II. Anatomy;241
16.2.1;A. Adrenal Cortex;241
16.2.2;B. Liver;242
16.3;III. Biochemistry and Biosynthesis of Adrenal Steroids and Testosterone Steroids;242
16.4;IV. Biological and Molecular Actions of Glucocorticoids;244
16.4.1;A. Hypothalamic-Pituitary-Adrenal Axis;244
16.4.2;B. Corticotropin-Releasing Hormone;244
16.4.3;C. Transport of Glucocorticoids in the Blood (CBG);244
16.4.4;D. ACTH Modes of Action;247
16.4.5;E. Glucocorticoids and Stress;248
16.4.6;F. Immunosuppression and Apoptosis Induced by Glucocorticoids;250
16.4.7;G. Feedback Effects of Glucocorticoids;250
16.4.8;H. Glucocorticoid Receptor;251
16.4.9;I. Dehydroepiandrosterone and Zona Reticularis;251
16.5;V. Clinical Aspects;251
16.5.1;A. Cushing’s Disease;251
16.5.2;B. Addison’s Disease;252
16.5.3;C. Congenital Adrenal Hyperplasia and Others;253
16.5.4;D. Mifepristone (RU-486);253
16.6;Further Reading;255
17;11 Hormones of the Adrenal Medulla;256
17.1;I. Introduction;256
17.2;II. Anatomical and Physiological Relationships;256
17.2.1;A. The Adrenal Gland;256
17.2.2;B. The Adrenal Medulla and the Sympathetic Nervous System;257
17.2.3;C. Chromaffin Cells of the Adrenal;259
17.3;III. Chemistry and Biochemistry of the Catecholamines;259
17.3.1;A. Biosynthesis and Secretion of Catecholamines;259
17.3.2;B. Regulation of Catecholamine Synthesis and Secretion;260
17.3.3;C. Catabolism of Catecholamines;263
17.3.4;D. Pharmacology of Catecholamines;264
17.4;IV. Biological Actions of Catecholamines;265
17.4.1;A. Adrenergic Receptors;265
17.4.2;B. Biological Responses to Epinephrine;265
17.5;V. Clinical Aspects;268
17.5.1;A. Pheochromocytoma;268
17.5.2;B. Chronic Stress;270
17.6;Further Reading;270
18;12 Androgens;272
18.1;I. Introduction;272
18.2;II. Anatomy of the Male Reproductive System;272
18.2.1;A. Testes, Ducts, and Accessory Structures;272
18.2.2;B. Seminiferous Tubules;274
18.2.3;C. Leydig/Interstitial Cells;274
18.3;III. Chemistry and Metabolism of Androgens;274
18.3.1;A. Androgens and Related Molecules;274
18.3.2;B. Androgen Biosynthesis;277
18.3.3;C. Modification of Testosterone in Target Tissues;277
18.3.4;D. Sex Hormone-binding Globulin;279
18.3.5;E. Catabolism of Androgens;279
18.4;IV. Regulation of Androgen Production;279
18.4.1;A. Hypothalamic-Pituitary-Testes Axis: Hormonal Control of the Testis;279
18.4.2;B. Hypothalamic-Pituitary-Testis Axis: Feedback Control;281
18.4.3;C. Prolactin;282
18.5;V. Biological Responses to Androgens;282
18.5.1;A. The Androgen Receptor;282
18.5.2;B. Sexual Differentiation;283
18.5.3;C. Puberty;285
18.5.4;D. Spermatogenesis;287
18.5.5;E. Estrogens in Males;288
18.5.6;F. Androgens in Females;288
18.6;VI. Clinical Aspects;289
18.6.1;A. 5a-Reductase Deficiency;289
18.6.2;B. Androgen Insensitivity Syndrome;289
18.6.3;C. Androgen Abuse;289
18.6.4;D. Prostate Cancer;289
18.7;Further Reading;290
19;13 Estrogens and Progestins;292
19.1;I. Introduction;292
19.2;II. Anatomy of the Female Reproductive System;292
19.2.1;A. Components of the Female Reproductive System;292
19.2.2;B. The Ovarian Follicle and Corpus Luteum;294
19.3;III. Chemistry and Metabolism of Female Steroid Hormones;298
19.3.1;A. Female Steroid Hormones;298
19.3.2;B. Synthesis of Progesterone and Estrogens;298
19.3.3;C. Catabolism of Progesterone and Estrogens;299
19.4;IV. Hypothalamic-Pituitary-Ovary Axis;300
19.4.1;A. Introduction;300
19.4.2;B. Control of the Ovary by the Hypothalamus and Pituitary;301
19.4.3;C. Feedback Effects on the Hypothalamus and Pituitary;303
19.4.4;D. The Human Menstrual Cycle;303
19.4.5;E. Menopause;306
19.5;V. Biological Responses to Female Sex Steroids;306
19.5.1;A. Estrogen and Progesterone Receptors;306
19.5.2;B. Uterine Effects of Estrogen and Progesterone;308
19.5.3;C. Effects of Estrogen on Bone;309
19.5.4;D. Estrogen and the Cardiovascular System;310
19.6;VI. Clinical Aspects;310
19.6.1;A. Hormonal Contraception;310
19.6.2;B. Postmenopausal Hormone Replacement Therapy;312
19.6.3;C. Polycystic Ovary Syndrome (PCOS);312
19.7;Further Reading;313
20;14 Hormones of Pregnancy, Parturition and Lactation;314
20.1;I. Introduction;314
20.2;II. Anatomical Relationships and the Beginning of Pregnancy;315
20.2.1;A. Fertilization;315
20.2.2;B. Implantation;316
20.2.3;C. Placental Development;317
20.2.4;D. Mammary Glands;319
20.3;III. Chemistry, Biochemistry, and Activity of the Hormones of Pregnancy;319
20.3.1;A. Human Chorionic Gonadotrophin;320
20.3.2;B. Placental Lactogen and Placental Growth Hormone;321
20.3.3;C. Other Peptide Hormones;322
20.3.4;D. Steroid Hormones;323
20.3.5;E. Maternal Adaptations to Pregnancy;324
20.4;IV. Parturition;325
20.4.1;A. Introduction;325
20.4.2;B. Progesterone and Estrogen;326
20.4.3;C. The Fetal Adrenal, Placenta, and Posterior Pituitary;327
20.5;V. Lactation;328
20.5.1;A. Mammogenesis;328
20.5.2;B. Lactogenesis;329
20.5.3;C. Suckling;330
20.6;VI. Clinical Aspects;331
20.6.1;A. Assisted Reproductive Technology;331
20.6.2;B. Breast Cancer;334
20.7;Further Reading;336
21;15 Hormones Related to the Kidney and Cardiovascular System;338
21.1;I. Introduction;338
21.1.1;A. Background;338
21.2;II. Anatomical, Morphological, and Physiological Relationships;339
21.2.1;A. The Kidney;339
21.2.2;B. Cardiovascular System;343
21.3;III. Homeostasis of Fluid, Electrolytes, and Blood Pressure;343
21.3.1;A. Introduction;343
21.3.2;B. Renin–Angiotensin II;345
21.3.3;C. Angiotensins I and II;345
21.3.4;D. Aldosterone Biosynthesis and Actions in Renal Tubular Reabsorption;348
21.3.5;E. Atrial Natriuretic Protein System;348
21.3.6;F. Endothelins;353
21.3.7;G. Nitric Oxide System;356
21.3.8;H. Kallikreins and Kinins;358
21.3.9;I. Adrenomedullin;358
21.3.10;J. Summary;360
21.4;IV. Hormones and Blood Cell Production;360
21.4.1;A. Introduction;360
21.4.2;B. Process of Erythropoiesis;361
21.4.3;C. Erythropoietin (the Protein);361
21.4.4;D. Hemoglobin;363
21.5;V. Clinical Aspects;363
21.5.1;A. Anemia;363
21.5.2;B. Cardiovascular Events in Hypertension;365
21.6;Further Reading;365
22;16 The Pineal Gland;368
22.1;I. Introduction;368
22.2;II. Anatomical Features of the Pineal Gland;369
22.2.1;A. Anatomical Location and Cellular Composition;369
22.2.2;B. Connection with the Visual System;369
22.3;III. Synthesis and Secretion of Melatonin;369
22.3.1;A. Melatonin Biosynthetic Pathway: Catabolism;369
22.3.2;B. Patterns and Regulation of Melatonin Secretion;371
22.4;IV. Biological Actions of melatonin;374
22.4.1;A. The Melatonin Receptors;374
22.4.2;B. Sleep and Jet Lag;375
22.4.3;C. Adrenal Cortex;376
22.4.4;D. Reproduction;376
22.4.5;E. Cancer;377
22.4.6;F. Melatonin as an Antioxidant;377
22.5;V. Clinical Aspects;377
22.6;Further Reading;378
23;17 Growth Factors;380
23.1;I. Introduction;380
23.2;II. Epidermal Growth Factor;380
23.2.1;A. Structure and Synthesis;380
23.2.2;B. EGF Receptors and Signaling;381
23.3;III. Fibroblast Growth Factor Family;382
23.3.1;A. Members of the FGF Family;382
23.3.2;B. The FGF Receptors and Signaling;386
23.4;IV. Platelet Derived Growth Factors;387
23.4.1;A. Structure of PDGFs;387
23.4.2;B. PDGF Receptors and Signaling;388
23.5;V. Insulin-Like Growth Factors;390
23.5.1;A. Structure of IGF1 and IGF2;390
23.5.2;B. Insulin and IGF Receptors and Signaling;390
23.5.3;C. IGF Binding Proteins;392
23.6;VI. Transforming Growth Factor ß;393
23.6.1;A. Structure and Secretion of TGFß;393
23.6.2;B. TGFß Receptors and Signaling;393
23.7;VII. Clinical Aspects;395
23.8;Further Reading;396
24;Appendix A;398
25;Appendix B;404
26;Appendix C;408
27;Appendix D;410
28;Appendix E;412
29;Appendix F;414
30;Index;416

Leseproben

Chapter 2 Steroid Hormones
Chemistry, Biosynthesis, and Metabolism
This chapter deals with the structural chemistry and biosynthetic pathways of the major classes of steroid hormones. All have a complicated structure of fused rings which can be modified by functional group substitution at many points. Furthermore, the presence of asymmetric carbon atoms introduces steric modifications and isomeric possibilities. The reader will find it prudent to first grasp the essential features of the steroid structures and relationships before attempting to delve into a consideration of their specific hormonal activities in later chapters. Then, when so doing, it may be helpful to turn back to the appropriate portion of this chapter to further heighten understanding of the structures of the hormones under review. Keywords
Anterior pituitary; hypothalamic-pituitary system; hypothalamic releasing hormone; hypothalamus; steroid structure I Introduction
A General Comments
This chapter deals with the structural chemistry and biosynthetic pathways of the major classes of steroid hormones. All have a complicated structure of fused rings which can be modified by functional group substitution at many points. Furthermore, the presence of asymmetric carbon atoms introduces steric modifications and isomeric possibilities. The reader will find it prudent to first grasp the essential features of the steroid structures and relationships before attempting to delve into a consideration of their specific hormonal activities in later chapters. Then, when so doing, it may be helpful to turn back to the appropriate portion of this chapter to further heighten understanding of the structures of the hormones under review. B Historical Perspective
The first steroid hormone, estrone, was isolated in 1929 at a time before the characteristic ring structure of the steroid nucleus had been elucidated. Today well over 230 naturally occurring steroids have been isolated and chemically characterized. In addition, an uncountable number of steroids and steroid analogs have been chemically synthesized and evaluated for their drug properties. The development of our modern understanding of hormones and the science of endocrinology has closely paralleled studies on the isolation, chemical characterization, and synthesis of steroids and the subsequent elucidation of their pathways of biosynthesis and catabolism. The foundation of many of these developments with steroid hormones is to be found in a lengthy series of papers authored by Professor Adolf O. R. Windaus’ chemistry laboratory in Gottingen, Germany (1925–19351) that led to the structural determination of cholesterol. This was an extraordinarily challenging problem given the limitation that the techniques of nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, and ultraviolet (UV) and infrared (IR) spectroscopy were not available at that time. Instead, the structure was determined through elaborate classical organic chemistry manipulations, which involved the conversion of the compound under study to known reference compounds. At the present time, application of the powerful separation techniques of high-performance liquid chromatography (HPLC) or gas chromatography, combined with the use of continuous on-line monitoring by mass spectrometry with computer-assisted data storage and analysis, frequently permit unequivocal structural determinations on impure samples that contain less than 1 ng of the steroid of interest. C Radioactive Steroids
An equally important contribution to our present understanding of the biochemical properties and structure of steroids was the introduction and general availability of radioactively labeled compounds in the 1960s. Radioactive steroids offer two major advantages: firstly, the presence of the radioactive label provides a significant increase in the sensitivity of detection of the steroid under study in living animals or cells. Prior to the advent of radioactive steroids, investigators relied upon colorimetric or bioassay procedures to quantitate the steroid of interest. Secondly, the availability of radioactive compounds permitted the investigator to detect, from either in vivo whole animals or in vitro experiments with perfused organs, tissue slices, cell suspensions, cell homogenates, or purified enzyme preparations, the presence of new compounds that in the absence of a radioactive label would otherwise not have been discovered. Thus, it was through the application of radioisotope techniques, modern procedures of chromatography, and structure determination that whole categories of new steroid hormones were discovered. For example, research on vitamin D metabolites (Chapter 9) and catechol estrogens (Chapter 13) benefited from preparations of radioactive vitamin D3 and catechol estrogens. D Molecular Biology Contributions
Another chapter of steroid biochemical discovery related to the isolation and purification of key steroid enzymes. Initially the premise was one step in steroid metabolism was handled by one enzyme. However, the advent of cloning of the cDNAs of each enzymatic step resulted in the discovery that there were fewer steroid proteins than the number of separate enzyme steps. That is to say, one steroid enzyme could carry out two to three quite different catalytic steps. Also it was learned that certain enzymatic steps that occurred in several different tissues were, in fact, carried out by the same enzyme. II Chemistry of Steroids
A Basic Ring Structure
Steroids are derived from a phenanthrene ring structure to which a pentano ring has been attached; this yields in the completely hydrogenated form, cyclopentano-perhydrophenanthrene, or the sterane ring structure (see Figure 2-1).
Figure 2-1 Parent ring structures of steroids.
The creation of the 5-carbon (pentano) ring on phenanthrene followed by reduction of all the aromatic double bonds creates the foundational, completely hydrogenated, cyclopentanoperhydrophenathrene, also known as sterane (the middle structure). The bottom structure is a different presentation of sterane that illustrates the numbering system or zip code for each of its 17 carbons and the convention for the A, B, C, and D labels for the 4 rings. Steroid structures are not normally written with all the carbon and hydrogen atoms as illustrated in the middle panel of Figure 2-1; instead, the shorthand notation as presented in the bottom panel for sterane of Figure 2-1 is usually employed. In this representation the hydrogen atoms are not indicated, and unless specified otherwise it is assumed that the cyclohexane A, B, and C rings and the cyclopentane D ring are fully reduced; that is, each carbon has its full complement of carbon and/or hydrogen bonds. Also, indicated for the bottom sterane structure (Figure 2-1) is the standard numbering system for each of the 17 carbon atoms in the four rings. The three six-carbon cyclohexane rings are designated A, B, and C rings and the five-carbon cyclopentane ring is denoted as the D ring. B Classes of Steroids
In mammalian systems, there are six families of steroid hormones that can be classified on both a structural and a biological (hormonal) basis (see Figure 2-2). They are the estrogens and progestins (female sex steroids), androgens (male sex steroids), mineralocorticoids (aldosterone), glucocorticoids (cortisol), and vitamin D [1a,25(OH)2D3]. Also, the bile acids are structurally related to cholesterol and thus constitute a seventh member of the steroid family. All of these steroids are biologically derived from cholesterol. Table 2-1 summarizes some fundamental relationships of these principal mammalian classes of steroids.
Figure 2-2 Family tree of the seven principal classes of steroids (bottom row) that are structurally derived from the parent cholestane (top row).
Cholestane has 10 additional carbons added to sterane (see Figure 2-1); these include two methyl groups, C-18 and C-19, added respectively to C-13 and C-10 and an eight-carbon side chain (C-20 to C-27) attached to C-17 of the D-ring. Table 2-1 Classes of Steroids Estrogens Estradiol 18 Estrane Androgens Testosterone 19 Androstane Progestins Progesterone 21 Pregnane Glucocorticoids Cortisol 21 Pregnane Mineralocorticoids Aldosterone 21 Pregnane Vitamin D steroids 1,25-Dihydroxyvitamin D3 27 Cholestane Bile acids Cholic acid 24 Cholane aThe parent ring steroid structures and active steroid hormone are given in Figure 2-2. The parent ring structure for cholesterol is the fully saturated ring structure cholestane (see top row of Figure 2-3). Cholestane, which has 27 carbons, differs from sterane (Figure 2-2) by the addition of an eight-carbon side chain on carbon-17 of ring D and the presence of two angular methyl groups at the junctures of the A:B (carbon-10) and C:D rings (carbon-13). The cholestane ring structure also gives rise to the parent ring...