a LANGE medical book Greenspan’s Basic & Clinical Endocrinology Tenth Edition Edited by David G. Gardner, MD, MS Mount Zion Health Fund Distinguished Professor of Endocrinology and Medicine Chief, Division of Endocrinology and Metabolism Department of Medicine and Diabetes Center University of California, San Francisco Dolores Shoback, MD Professor of Medicine Department of Medicine University of California, San Francisco Staff Physician, Endocrine-Metabolism Section, Department of Medicine San Francisco Veterans Affairs Medical Center New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto 00-Gardner_FM-pi-xxiv.indd 1 09/06/17 4:03 PM Copyright © 2018 by McGraw-Hill Education. All rights reserved. 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THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WAR- RANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. Francis Sorrel Greenspan, M.D. (1920-2016) The tenth edition of Greenspan’s Basic & Clinical Endocrinology is dedicated to the memories of four outstanding endocrinologists—Dr. John Baxter, Dr. Claude Arnaud, Dr. Melvin Grumbach, and, most especially, Dr. Francis Greenspan who was responsible for taking the initial steps to assemble this textbook more than thirty years ago. Each of these individu- als was an outstanding endocrine scientist and/or clinical endocrinologist in the global endocrine community, and each contributed enormously to the success of this textbook. 00-Gardner_FM-pi-xxiv.indd 3 09/06/17 4:03 PM This page intentionally left blank 00-Gardner_FM-pi-xxiv.indd 4 09/06/17 4:03 PM Contents Authors xix Preface xxiii 1. Hormones and Hormone Action 1 Autoimmune Response 39 Animal Models of Autoimmune Thyroid Disease 40 Edward C. Hsiao, MD, PhD and Autoimmune Aspects of Type 1 Diabetes 40 David G. Gardner, MD, MS Genes and Environment 40 Relationship to the Nervous System 2 Autoimmune Response 41 Chemical Nature of Hormones 4 Animal Models of Autoimmune Diabetes Mellitus 42 Endocrine Glands and Target Organs 4 Autoimmune Aspects of Other Endocrinopathies 42 Regulation of Hormone Levels in Plasma 4 Autoimmune Adrenal Failure 42 Hormone Biosynthesis 4 Autoimmune Oophoritis and Orchitis 43 Precursor Processing 4 Autoimmune Hypophysitis 43 Hormone Release 4 Autoimmune Hypoparathyroidism 43 Hormone Binding in Plasma 4 Autoimmune Polyendocrine Syndromes 44 Hormone Metabolism 5 Autoimmune Polyendocrine Syndrome 1 (APS-1) 44 Regulation of Hormone Levels 5 Autoimmune Polyendocrine Syndrome 2 (APS-2) 45 Hormone Action 5 Management of Autoimmune Polyendocrine Receptors 5 Syndromes 46 Neurotransmitter and Peptide Hormone Receptors 6 Immunodeficiency, Polyendocrinopathy, and Enteropathy, G Protein–Coupled Receptors 7 X-Linked (IPEX) Syndrome 46 G Protein Transducers 8 POEMS Syndrome (Osteosclerotic Myeloma) 46 Effectors 9 3. E vidence-Based Endocrinology Disorders of G Proteins and G Protein–Coupled Receptors 11 and Clinical Epidemiology 49 Growth Factor Receptors 13 David C. Aron, MD, MS and Ajay Sood, MD Cytokine Receptors 14 Growth Hormone and Prolactin Receptors 14 Clinical Epidemiology 49 TGF-b Receptors 15 Diagnostic Testing: Test Characteristics 49 TNF-Receptors 16 Sensitivity and Specificity 50 WNT/Beta Catenin 16 ROC Curves 52 Guanylyl Cyclase–Linked Receptors 18 Predictive Values, Likelihood Ratios, and Diagnostic Nuclear Action of Peptide Hormones 19 Accuracy 53 Nuclear Receptors 19 An Approach to Diagnosis in Practice 53 Steroid Receptor Family 20 Clinical Epidemiologic Principles Applied to Treatment Thyroid Receptor Family 22 Decisions 56 Nongenomic Effects of the Steroid Hormones 26 Decision Analysis 57 Steroid and Thyroid Hormone Receptor Resistance Determine the Probability of Each Chance Event 59 Syndromes 26 Deciding on a Strategy: Averaging Out and Folding Back the Tree 59 2. Endocrine Autoimmunity 29 Discounting Future Events 59 Sensitivity Analysis 59 Juan Carlos Jaume, MD Cost-Effectiveness Analysis Using Decision Analysis 59 Basic Immune Components and Mechanisms 30 Other Aspects of Clinical Epidemiology 60 Immune Recognition and Response 30 Evidence-Based Endocrinology 60 Tolerance 33 Step One: Translation of the Clinical Problem into T-Cell Tolerance 33 Answerable Questions 60 B-Cell Tolerance 35 Step Two: Finding the Best Evidence 60 Autoimmunity Is Multifactorial 37 Step Three: Appraising the Evidence for Its Validity and Genetic Factors in Autoimmunity 37 Usefulness 63 Environmental Factors in Autoimmunity 38 Steps Four and Five: Applying the Results in Practice and Single-Gland Autoimmune Syndromes 38 Evaluating Performance 65 Autoimmune Aspects of Thyroid Disease 38 Developments That May Affect the EBM Approach 65 Genes and Environment 39 00-Gardner_FM-pi-xxiv.indd 5 09/06/17 4:03 PM vi CONTENTS 4. Hypothalamus and Pituitary Gland 69 Evaluation of LH and FSH 92 Testosterone and Estrogen Levels 92 Bradley R. Javorsky, MD, David C. Aron, MD, MS, LH and FSH Levels 92 James W. Findling, MD, and J. Blake Tyrrell, MD GnRH Test 92 Anatomy and Embryology 70 Problems in Evaluation of the Hypothalamic- Blood Supply 72 Pituitary Axis 92 Pituitary Development and Histology 72 Obesity 93 Hypothalamic Hormones 75 Diabetes Mellitus 93 Hypophysiotropic Hormones 75 Uremia 93 Neuroendocrinology: The Hypothalamus as Part of a Starvation and Anorexia Nervosa 93 Larger System 78 Depression 93 The Hypothalamus and the Control of Appetite 79 Pharmacologic Agents and Alcohol 93 The Pineal Gland and the Circumventricular Endocrine Tests of Hypothalamic-Pituitary Organs 79 Function 93 Anterior Pituitary Hormones 80 Neuroradiologic Evaluation 93 Adrenocorticotropic Hormone and Related Magnetic Resonance Imaging (MRI) 94 Peptides 80 Pituitary and Hypothalamic Disorders 95 Biosynthesis 80 Etiology and Early Manifestations 95 Function 81 Common and Later Manifestations 95 Measurement 81 Empty Sella Syndrome 96 Secretion 81 Etiology and Incidence 96 Growth Hormone 82 Clinical Features 96 Biosynthesis 82 Diagnosis 96 Function 82 Hypothalamic Dysfunction 97 Measurement 82 Clinical Features 97 Secretion 83 Diagnosis 97 Prolactin 84 Treatment 97 Biosynthesis 84 Hypopituitarism 98 Function 84 Etiology 98 Measurement 85 Clinical Features 100 Secretion 85 Diagnosis 102 Thyrotropin 86 Treatment 103 Biosynthesis 86 Pituitary Adenomas 104 Function 86 Treatment 105 Measurement 86 Posttreatment Follow-Up 105 Secretion 86 Prolactinomas 106 Gonadotropins: Luteinizing Hormone (LH) and Pathology 106 Follicle-Stimulating Hormone (FSH) 87 Clinical Features 106 Biosynthesis 87 Differential Diagnosis 107 Function 88 Diagnosis 107 Measurement 88 Treatment 108 Secretion 88 Selection of Therapy for Prolactinomas 109 Endocrinologic Evaluation of the Hypothalamic- Acromegaly and Gigantism 109 Pituitary Axis 89 Pathology 110 Evaluation of Adrenocorticotropic Hormone 89 Etiology and Pathogenesis 110 Plasma ACTH Levels 89 Pathophysiology 110 Evaluation of ACTH Deficiency 89 Clinical Features 110 Adrenal Stimulation 89 Diagnosis 112 Pituitary Stimulation 89 Differential Diagnosis 113 ACTH Hypersecretion 91 Treatment 113 Evaluation of Growth Hormone 91 Response to Treatment 114 Insulin-Induced Hypoglycemia 92 Posttreatment Follow-Up 114 GHRH-Arginine Test 92 ACTH-Secreting Pituitary Adenomas: Glucagon Stimulation Test 92 Cushing Disease 114 Tests with Levodopa, Arginine, and Other Stimuli 92 Pathology 114 GH Hypersecretion 92 Pathogenesis 114 Evaluation of Prolactin 92 Clinical Features 115 Evaluation of Thyroid-Stimulating Hormone 92 Diagnosis 115 Basal Measurements 92 Treatment 115 TRH Test 92 Nelson Syndrome 116 00-Gardner_FM-pi-xxiv.indd 6 09/06/17 4:03 PM CONTENTS vii Pathogenesis 116 Autosomal Chromosome Disorders and Incidence 116 Syndromes 152 Clinical Features 117 Skeletal Dysplasias 152 Diagnosis 117 Short Stature due to Endocrine Disorders 154 Treatment 117 Congenital Growth Hormone Deficiency 154 Thyrotropin-Secreting Adenomas 117 Acquired Growth Hormone Deficiency 155 Gonadotropin-Secreting Pituitary Adenomas 117 Other Types of GH Dysfunction 156 Alpha Subunit-Secreting Pituitary Adenomas 117 Diagnosis of GH Deficiency 156 Nonfunctional Pituitary Adenomas 117 Treatment of GH Deficiency 157 Pituitary Carcinoma 118 Diagnosis of Short Stature 165 Evaluation of Short Stature 165 5. The Posterior Pituitary (Neurohypophysis) 121 Tall Stature due to Nonendocrine Causes 167 Cerebral Gigantism 167 Alan G. Robinson, MD Marfan Syndrome 167 Physiology of Hormone Function 121 Homocystinuria 167 Anatomy of Hormone Synthesis and Release 123 Beckwith-Wiedemann Syndrome 167 Pathophysiology 123 XYY Syndrome 167 Deficient Vasopressin: Diabetes Insipidus 124 Klinefelter Syndrome 167 Diagnostic Tests of Diabetes Insipidus 127 Tall Stature due to Endocrine Disorders 167 Treatment of Diabetes Insipidus 128 Excess Vasopressin: Syndrome of Inappropriate Antidiuretic 7. The Thyroid Gland 171 Hormone 128 David S. Cooper, MD and Treatment of Hyponatremia in SIADH 131 Paul W. Ladenson, MD (Oxon)., MD Summary 132 Oxytocin 132 Embryology, Anatomy, and Histology 171 Physiology 172 6. Growth 137 Structure and Synthesis of Thyroid Hormones 172 Dennis Styne, MD Iodine Metabolism 172 Thyroid Hormone Synthesis and Secretion 174 Normal Growth 137 Thyroglobulin 174 Intrauterine Growth 137 Iodide Transport 175 The Placenta 138 Thyroid Peroxidase 176 Classic Hormones of Growth and Fetal Growth 138 Iodination of Thyroglobulin 176 Growth Factors and Oncogenes in Fetal Growth 138 Coupling of Iodotyrosyl Residues in Thyroglobulin 176 Insulin-Like Growth Factors, Receptors, and Binding Proteolysis of Thyroglobulin and Thyroid Hormone Proteins 138 Secretion 176 Insulin 139 Intrathyroidal Deiodination 177 Epidermal Growth Factor 139 Abnormalities in Thyroid Hormone Synthesis and Fibroblast Growth Factor 139 Release 177 Genetic, Maternal, and Uterine Factors 139 Dietary Iodine Deficiency and Inherited Defects 177 Chromosomal Abnormalities and Malformation Effects of Iodine Excess on Hormone Biosynthesis 178 Syndromes 140 Thyroid Hormone Transport 178 Fetal Origins of Adult Disease 140 Thyroxine-Binding Globulin 178 Postnatal Growth 140 Transthyretin (Thyroxine-Binding Prealbumin) 179 Endocrine Factors 141 Albumin 179 Other Factors 144 Metabolism of Thyroid Hormones 180 Catch-up Growth 146 Control of Thyroid Function and Hormone Action 181 Measurement of Growth 146 Thyrotropin-Releasing Hormone 182 Height 147 Thyrotropin (Thyroid-Stimulating Hormone) 182 Relation to Midparental Height: The Target Height 147 Effects of TSH on the Thyroid Cell 183 Technique of Measurement 148 Serum TSH 184 Height and Growth Rate Summary 148 Control of Pituitary TSH Secretion 185 Weight and BMI 148 Other Thyroid Stimulators and Inhibitors 185 Skeletal (Bone) Age 150 The Actions of Thyroid Hormones 185 Disorders of Growth 150 Effects on Fetal Development 187 Short Stature due to Nonendocrine Causes 150 Effects on Oxygen Consumption, Heat Production, Turner Syndrome and Its Variants 152 and Free Radical Formation 187 Noonan Syndrome (Pseudo-Turner Syndrome) 152 Cardiovascular Effects 187 Prader-Willi Syndrome 152 Sympathetic Effects 187 Bardet-Biedl Syndrome 152 Pulmonary Effects 188 Hematopoietic Effects 188 00-Gardner_FM-pi-xxiv.indd 7 09/06/17 4:03 PM viii CONTENTS Gastrointestinal Effects 188 Treatment 219 Skeletal Effects 189 Course and Prognosis 220 Neuromuscular Effects 189 Thyroiditis 220 Effects on Lipid and Carbohydrate Metabolism 189 Clinical Features 220 Endocrine Effects 189 Differential Diagnosis 220 Physiologic Changes in Thyroid Function 189 Treatment 221 Thyroid Function in the Fetus 189 Course and Prognosis 221 Thyroid Function in Pregnancy 189 Etiology and Pathogenesis 221 Changes in Thyroid Function with Aging 190 Clinical Features 221 Effects of Acute and Chronic Illness on Thyroid Function Differential Diagnosis 222 (Euthyroid Sick Syndrome) 190 Complications and Sequelae 222 Thyroid Autoimmunity 191 Treatment 222 Tests of Thyroid Function 191 Course and Prognosis 222 Tests of Thyroid Hormones in Blood 192 Effects of Ionizing Radiation on the Thyroid Gland 223 Serum TSH Measurement 192 Thyroid Nodules and Thyroid Cancer 223 Serum T and T Measurements 194 Etiology 224 4 3 Assessment of Thyroid Iodine Metabolism and Biosynthetic Differentiation of Benign and Malignant Lesions 224 Activity 195 Management of Thyroid Nodules 227 Thyroid Imaging 195 Pathology 229 Thyroid Ultrasonography and Other Imaging Management of Thyroid Cancer 231 Techniques 196 Thyroid Biopsy 197 8. Metabolic Bone Disease 239 Test of Peripheral Thyroid Hormone Actions 198 Dolores M. Shoback, MD, Anne L. Schafer, MD, Measurement of Thyroid Autoantibodies 198 and Daniel D. Bikle, MD, PhD Disorders of the Thyroid 199 History 199 Cellular and Extracellular Calcium Metabolism 239 Physical Examination 199 Parathyroid Hormone 240 Hypothyroidism 200 Anatomy and Embryology of the Parathyroid Etiology and Incidence 200 Glands 240 Pathogenesis 201 Secretion of Parathyroid Hormone 241 Clinical Presentations and Findings 201 Synthesis and Processing of Parathyroid Hormone 242 Diagnosis 203 Clearance and Metabolism of PTH 243 Complications 204 Assays of PTH 243 Treatment 205 Biologic Effects of PTH 244 Adverse Effects of T Therapy 206 Mechanism of Action of Parathyroid Hormone 244 4 Course and Prognosis 206 PTHrP 245 Hyperthyroidism and Thyrotoxicosis 206 Calcitonin 245 Etiology 207 Vitamin D 246 Pathogenesis 207 Nomenclature 246 Clinical Features 208 Cutaneous Synthesis of Vitamin D 248 Other Presentations 210 Dietary Sources and Intestinal Absorption 248 Complications 211 Binding Proteins for Vitamin D Metabolites 248 Treatment of Graves Disease 211 Metabolism 249 Choice of Therapy 213 Mechanisms of Action 251 Treatment of Complications 213 How Vitamin D and PTH Control Mineral Homeostasis 253 Course and Prognosis 214 Medullary Carcinoma of the Thyroid 254 Toxic Adenoma 215 Hypercalcemia 256 Toxic Multinodular Goiter Clinical Features 256 (Plummer Disease) 215 Mechanisms 256 Amiodarone-Induced Thyrotoxicosis 215 Differential Diagnosis 257 Subacute and Silent Thyroiditis 216 Disorders Causing Hypercalcemia 258 Thyrotoxicosis Factitia 216 Etiology and Pathogenesis 258 Rare Forms of Thyrotoxicosis 216 Clinical Features 259 Resistance to Thyroid Hormone Treatment 260 Syndromes 217 Variants of Primary Hyperparathyroidism 263 TSH Receptor Gene Mutations 217 Thyrotoxicosis 264 Nontoxic Goiter 217 Adrenal Insufficiency 264 Etiology 217 Hypervitaminosis D 265 Pathogenesis 218 Hypervitaminosis A 265 Clinical Features 218 Immobilization 265 Differential Diagnosis 218 Acute Renal Failure 265 00-Gardner_FM-pi-xxiv.indd 8 09/06/17 4:03 PM CONTENTS ix Treatment of Hypercalcemia 266 Hypophosphatasia 290 Hypocalcemia 266 Fibrogenesis Imperfecta Ossium 290 Classification 266 Inhibitors of Mineralization 291 Clinical Features 266 Aluminum 291 Causes of Hypocalcemia 267 Fluoride 291 Surgical Hypoparathyroidism 267 Paget Disease of Bone (Osteitis Deformans) 291 Idiopathic Hypoparathyroidism 268 Etiology 291 Familial Hypoparathyroidism 268 Pathology 291 Other Causes of Hypoparathyroidism 268 Pathogenesis 291 Clinical Features 269 Genetic Forms 291 Pathophysiology 269 Clinical Features 292 Genetics 270 Complications 292 Diagnosis 270 Treatment 293 Pathogenesis 270 Bone Disease in Chronic Kidney Disease 294 Clinical Features 271 Pathogenesis 294 Treatment 271 Clinical Features 295 Treatment of Hypocalcemia 272 Treatment 295 Acute Hypocalcemia 272 Hereditary Forms of Hyperphosphatemia 295 Chronic Hypocalcemia 272 Tumoral Calcinosis 295 Bone Anatomy and Remodeling 272 Functions of Bone 272 9. Glucocorticoids and Adrenal Androgens 299 Structure of Bone 273 Ty B. Carroll, MD, David C. Aron, MD, MS, Bone Mineral 274 James W. Findling, MD, and J. Blake Tyrrell, MD Bone Cells 274 Bone Modeling and Remodeling 275 Embryology and Anatomy 300 Osteoporosis 276 Embryology 300 Gain, Maintenance, and Loss of Bone 277 Anatomy 300 Bone Loss Associated with Estrogen Deficiency 278 Microscopic Anatomy 300 Bone Loss in Later Life 279 Biosynthesis of Cortisol and Adrenal Androgens 301 Diagnosis of Osteoporosis 279 Steroidogenesis 301 Management of Osteoporosis 280 Regulation of Secretion 304 Nonpharmacologic Aspects of Osteoporosis Circulation of Cortisol and Adrenal Androgens 306 Management 280 Plasma-Binding Proteins 306 Pharmacologic Approaches to Osteoporosis Free and Bound Cortisol 306 Management 281 Metabolism of Cortisol and Adrenal Androgens 306 Antiresorptive Agents 282 Conversion and Excretion of Cortisol 306 Bone-Forming Agents 283 Conversion and Excretion of Adrenal Glucocorticoid-Induced Osteoporosis 283 Androgens 308 Pathophysiology 284 Biologic Effects of Adrenal Steroids 308 Prevention and Treatment of Glucocorticoid-Related Glucocorticoids 308 Osteoporosis 284 Molecular Mechanisms 308 Pharmacologic Therapy of Glucocorticoid-Related Glucocorticoid Agonists and Antagonists 308 Osteoporosis 285 Intermediary Metabolism 311 Osteomalacia and Rickets 285 Effects on Other Tissues and Functions 311 Pathogenesis 285 Adrenal Androgens 313 Diagnosis 285 Effects in Males 313 Clinical Features 285 Effects in Females 313 Treatment 287 Laboratory Evaluation 313 Nephrotic Syndrome 287 Plasma ACTH 314 Hepatic Osteodystrophy 288 Plasma Cortisol 314 Drug-Induced Osteomalacia 288 Salivary Cortisol 314 Hypophosphatemic Disorders 288 Plasma Free Cortisol 315 X-Linked and Autosomal Dominant Urinary Corticosteroids 315 Hypophosphatemia 288 Dexamethasone Suppression Tests 315 Tumor-Induced Osteomalacia 289 Pituitary-Adrenal Reserve 316 Fibrous Dysplasia 289 Androgens 317 De Toni-Debré-Fanconi Syndrome and Hereditary Disorders of Adrenocortical Insufficiency 317 Hypophosphatemic Rickets with Hypercalciuria 289 Primary Adrenocortical Insufficiency Calcium Deficiency 290 (Addison Disease) 317 Primary Disorders of the Bone Matrix 290 Etiology and Pathology 317 Osteogenesis Imperfecta 290 Pathophysiology 320 00-Gardner_FM-pi-xxiv.indd 9 09/06/17 4:03 PM