Greenspans Basic and Clinical Endocrinology 10Th Edition David G Gardner Full Chapter

Greenspan’s Basic and Clinical
Endocrinology 10th Edition David G.

Gardner
Visit to download the full and correct content document:
https://ebookmass.com/product/greenspans-basic-and-clinical-endocrinology-10th-edi
tion-david-g-gardner/
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
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. Except as permitted under the United States Copyright Act of 1976,
no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system,
without the prior written permission of the publisher.
ISBN: 978-1-25-958929-4
MHID: 1-25-958929-3.
The material in this eBook also appears in the print version of this title: ISBN: 978-1-25-958928-7,
MHID: 1-25-958928-5.
eBook conversion by codeMantra

Version 1.0
All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked
name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the
trademark. Where such designations appear in this book, they have been printed with initial caps.
McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corpo-
rate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com.
Notice
Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug
therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to
provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view
of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been
involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or com-
plete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in
this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers
are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the
information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications
for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.
TERMS OF USE
This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject
to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may
not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate,
sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your
own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if
you fail to comply with these terms.
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.

This page intentionally left blank

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
Disorders of G Proteins and G Protein–Coupled 3.
Evidence-Based Endocrinology
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
Juan Carlos Jaume, MD Sensitivity Analysis 59
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

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

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
Alan G. Robinson, MD Cerebral Gigantism 167
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
Summary 132
Paul W. Ladenson, MD (Oxon)., MD
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

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 T4 and T3 Measurements 194 Etiology 224
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 T4 Therapy 206 Mechanism of Action of Parathyroid Hormone 244
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

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

x CONTENTS
Clinical Features 320 Cushing Syndrome 356

Secondary Adrenocortical Insufficiency 322 Thyroid Dysfunction 357
Etiology 322 Acromegaly 357
Pathophysiology 322
Clinical Features 322 11. Adrenal Medulla and Paraganglia 359
Diagnosis of Adrenocortical Insufficiency 322 Paul A. Fitzgerald, MD
Diagnostic Tests 322
Rapid ACTH Stimulation Test 322 Anatomy 360
Plasma ACTH Levels 324 Embryology 360
Partial ACTH Deficiency 324 Gross Structure 360
Treatment of Adrenocortical Insufficiency 324 Microscopic Structure 361
Acute Addisonian Crisis 324 Nerve Supply 361
Maintenance Therapy 325 Blood Supply 361
Response to Therapy 325 Hormones of the Adrenal Medulla and Paraganglia 361
Prevention of Adrenal Crisis 326 Catecholamines 361
Steroid Coverage for Surgery 326 Biosynthesis 361
Prognosis of Adrenocortical Insufficiency 326 Storage of Catecholamines 362
Cushing Syndrome 326 Secretion of Catecholamines 363
Classification and Incidence 326 Metabolism and Excretion of Catecholamines 363
Pathology 328 Catecholamine (Adrenergic) Receptors 366
Pathogenesis and Genetics 329 Regulation of Sympathoadrenal Activity 369
Pathophysiology 330 Actions of Circulating Catecholamines 370
Clinical Features 332 Physiologic Effects of Catecholamines 371
Features Suggesting a Specific Cause 333 Disorders of the Adrenal Medulla and Paraganglia 371
Diagnosis 334 Epinephrine and Norepinephrine Deficiency 371
Problems in Diagnosis 334 Autonomic Insufficiency 372
Differential Diagnosis 335 Pheochromocytoma and Paraganglioma 373
Treatment 336 Prevalence 373
Prognosis 337 Screening for Pheochromocytomas and
Hirsutism and Virilism 337 Paragangliomas 375
Incidental Adrenal Mass 338 Genetic Conditions Associated with
Exclusion of Malignancy 338 Pheochromocytomas and Paragangliomas 375
Endocrine Evaluation 338 Somatic Mutations in Pheochromocytoma and
Cortisol-Producing Adenoma 338 Paraganglioma 382
Pheochromocytoma 338 Physiology of Pheochromocytoma and
Aldosterone-Producing Adenoma 339 Paraganglioma 382
Glucocorticoid Therapy for Nonendocrine Disorders 339 Secretion of Other Peptides by Pheochromocytomas
Principles 339 and Paragangliomas 383
Synthetic Glucocorticoids 339 Manifestations of Pheochromocytoma and
Modes of Administration 339 Paraganglioma 384
Side-Effects 339 Biochemical Testing for Pheochromocytoma 388
Factors That May Cause Misleading Biochemical Testing
10. Endocrine Hypertension 343 for Pheochromocytoma 391
Differential Diagnosis of Pheochromocytoma and
William F. Young, Jr, MD, MSc
Paraganglioma 392
Renin-Angiotensin-Aldosterone System 343 Localization Studies for Pheochromocytoma 393
Renin and Angiotensin 343 Incidentally Discovered Adrenal Masses 397
Aldosterone 345 Adrenal Percutaneous Fine-Needle Aspiration (FNA)
Primary Aldosteronism 346 Cytology 397
Prevalence 347 Medical Management of Patients with
Clinical Presentation 347 Pheochromocytoma and Paraganglioma 397
Diagnosis 347 Surgical Management of Pheochromocytoma and
Treatment 353 Paraganglioma 400
Other Forms of Mineralocorticoid Excess or Effect 354 Pregnancy and Pheochromocytoma/
Hyperdeoxycorticosteronism 355 Paraganglioma 402
Apparent Mineralocorticoid Excess Syndrome 355 Pheochromocytoma-Induced Life-Threatening
Liddle Syndrome—Abnormal Renal Tubular Ionic Complications: Cardiomyopathy, ARDS, and
Transport 356 Multisystem Crisis 403
Hypertension Exacerbated by Pregnancy 356 Pathology of Pheochromocytoma and
Other Endocrine Disorders Associated with Paraganglioma 403
Hypertension 356 Metastatic Pheochromocytoma and Paraganglioma 403

CONTENTS xi
Treatment for Patients with Recurrent or Metastatic Complications and Sequelae 428
Pheochromocytoma and Paraganglioma 405 Treatment 428
Prognosis 408 Congenital Bilateral Anorchia (Vanishing Testes
Pheochromocytoma and Paraganglioma: Postoperative Syndrome) 429
Long-Term Surveillance 409 Etiology and Pathophysiology 429
Testicular Pathology 429
12. Testes 413 Clinical Features 429
Bradley D. Anawalt, MD and Differential Diagnosis 429
Treatment 429
Glenn D. Braunstein, MD
Leydig Cell Aplasia 429
Anatomy and Structure-Function Relationships 413 Etiology and Pathophysiology 429
Testes 413 Clinical Features 429
Accessory Structures 415 Differential Diagnosis 430
Physiology of the Male Reproductive System 415 Treatment 430
Gonadal Steroids 415 Noonan Syndrome (Male Turner Syndrome) 430
Control of Testicular Function 417 Clinical Features 430
Hypothalamic-Pituitary-Leydig Cell Axis 417 Differential Diagnosis 430
Hypothalamic-Pituitary-Seminiferous Tubular Treatment 430
Axis 418 Causes of Primary Hypogonadism Presenting in
Evaluation of Male Gonadal Function 418 Adulthood 430
Clinical Evaluation 418 Myotonic Dystrophy 430
Clinical Presentation 418 Clinical Features 430
Genital Examination 419 Treatment 431
Laboratory Tests of Testicular Function 420 Late-Onset Male Hypogonadism 431
Serum Testosterone Measurement 420 Etiology, Pathology, and Pathophysiology 431
Serum Estradiol Measurement 421 Clinical Features 431
Gonadotropin and Prolactin Measurements 421 Differential Diagnosis 431
Special Tests 421 Treatment 431
Semen Analysis 421 Specific Sequelae of Hypogonadism 432
Chorionic Gonadotropin Stimulation Test 422 Male Infertility 432
Testicular Biopsy 422 Etiology and Pathophysiology 432
Evaluation for Male Hypogonadism 422 Clinical Features 433
Drugs Used for Testosterone Replacement Therapy in Male Treatment 433
Hypogonadism 422 Course and Prognosis 434
Androgens 422 Erectile Dysfunction 434
Oral Androgens 422 Etiology and Pathophysiology 434
Injectable Testosterone Esters 423 Clinical Features 434
Implantable Testosterone Pellets 424 Treatment 436
Transdermal Testosterone Therapy 424 Gynecomastia 436
Gonadotropin Therapy 424 Etiology and Pathophysiology 436
Injectable Human Chorionic Gonadotropin 424 Pathology 437
Recombinant Human Luteinizing Hormone 424 Clinical Features 437
Side Effects of Testosterone Replacement Therapy 424 Differential Diagnosis 438
Clinical Male Gonadal Disorders 425 Complications and Sequelae 439
Syndromes Associated with Primary Gonadal Treatment 439
Dysfunction 425 Course and Prognosis 439
Causes of Primary Hypogonadism Presenting in Testicular Tumors 439
Childhood 425 Etiology and Pathophysiology 439
Klinefelter Syndrome (XXY Seminiferous Tubule Pathology 439
Dysgenesis) 425 Clinical Features 440
Etiology and Pathophysiology 426 Differential Diagnosis 440
Testicular Pathology 426 Treatment 441
Clinical Features 426 Course and Prognosis 441
Differential Diagnosis 427
Treatment 427 13. Female Reproductive Endocrinology
Cryptorchidism 427 and Infertility 443
Etiology and Pathophysiology 427
Pathology 427 Mitchell P. Rosen, MD and Marcelle I. Cedars, MD
Clinical Features 428 Embryology and Anatomy 444
Differential Diagnosis 428 Ovarian Steroidogenesis 446

xii CONTENTS
Physiology of Folliculogenesis and the Menstrual Cycle 448 Initial Formation of the Urogenital Ridges 503
The Hypothalamic-Pituitary Axis 448 The Bipotential Gonads 504
Role of the Pituitary 449 The Unipotential Internal Ducts 504
Role of the Ovary 450 Wolffian Ducts 505
Role of the Uterus 456 Müllerian Ducts 505
Menstrual Disturbances 457 The Bipotential Urogenital Sinus and External
Amenorrhea 457 Genitalia 505
Hypothalamic Amenorrhea 457 Gonadal Differentiation 505
Isolated GnRH Deficiency 457 Testicular Differentiation 505
Pituitary Amenorrhea 461 Ovarian Differentiation 506
Ovarian Amenorrhea 463 Genetic Mechanisms 507
Premature Ovarian Failure 464 The Importance of the Y Chromosome
Anovulation 466 and the SRY Gene 507
Hyperandrogenism and Anovulation 466 Other Pathways in Testicular versus Ovarian
Obesity 474 Differentiation 507
Management of Obesity 474 Differences in Testicular and Ovarian Germ Cell
Anovulation Unrelated to Excess Sex Steroid Development 509
Production 474 Hormone-Dependent Differentiation of the
Outflow Tract Disorders 475 Genitalia 509
Menopause 476 One Gonad, Two Cells, Two Hormones 509
Oocyte Depletion 477 AMH and the Fate of Müllerian Ducts 509
Endocrine System Changes with Aging 478 Regulation of AMH Expression 509
Estrogens/Progesterone 479 AMH Action 510
Androgens 479 Müllerian Derivatives in the Female 510
Hypothalamic/Pituitary 479 Androgens and the Fate of the Wolffian Ducts,
Menopausal Consequences 480 Urogenital Sinus, and External Genitalia 510
Vasomotor Symptoms 480 Steroidogenesis 510
Genital Atrophy 480 Androgen Action in Target Tissues 511
Osteoporosis 480 Wolffian Duct Derivatives 512
Atherosclerotic Cardiovascular Disease 482 The Bipotential Urogenital Sinus 512
Treatment—Summary 482 The Bipotential External Genitalia 513
Infertility 483 Testicular Descent 513
Diagnosis of Infertility 483 Disorders of Sex Differentiation (DSD) 513
Ovulatory Defects 483 Definitions and Historical Perspectives 513
Pelvic Disorders 484 Pathogenic Classification 516
Male Factor Causes 484 Malformative DSD: Defects in the Morphogenesis
Unexplained Infertility 485 of the Urogenital Primordia 516
Management of the Infertile Couple 485 Dysgenetic DSD: Abnormal Gonadal
Ovulatory Disorders 485 Differentiation 519
Pelvic Disorders 485 Non-dysgenetic DSD with Testicular
Male Factor Infertility 485 Differentiation 522
Unexplained Infertility 486 Non-dysgenetic DSD with Ovarian
Contraception 486 Differentiation 525
Oral Contraceptives 486 Management of Patients with DSD 532
Combination Pills 486 General Aspects 532
Progestin Only 490 Diagnostic Workup 534
Contraception: Long-Acting Contraceptives 491 Gender Assignment 539
Injectable Contraceptives 492 Long-Term Outcomes 541
Subdermal Implants 494 Fertility Issues 543
Transdermal Patch 495
Vaginal Rings 496 15. Puberty 547
Intrauterine Devices 496
Emergency Contraception 497 Dennis Styne, MD
Physiology of Puberty 547
14. Disorders of Sex Development 501 Physical Changes Associated with Puberty 547
Rodolfo A. Rey, MD, PhD, Endocrine Changes from Fetal Life to Puberty 551
Christopher P. Houk, MD, Ovulation and Menarche 554
Selma Witchel, MD, and Peter A. Lee, MD, PhD Adrenarche 554
Miscellaneous Metabolic Changes 554
Normal Fetal Sex Differentiation 503
Delayed Puberty or Absent Puberty (Sexual
The Undifferentiated Stage 503
Infantilism) 554

CONTENTS xiii
Constitutional Delay in Growth and Adolescence 554 Endocrinology of the Puerperium 588
Hypogonadotropic Hypogonadism 556 Physiologic and Anatomic Changes 588
Hypergonadotropic Hypogonadism 560 Uterine Changes 588
Differential Diagnosis of Delayed Puberty 563 Endocrine Changes 588
Treatment of Delayed Puberty 564 Lactation 589
Precocious Puberty (Sexual Precocity) 566 Endocrine Disorders and Pregnancy 589
Central (Complete or True) Precocious Puberty 566 Hyperthyroidism in Pregnancy 589
Peripheral or Incomplete Isosexual Precocious Puberty in Hypothyroidism in Pregnancy 589
Boys 568 Pituitary Disorders in Pregnancy 589
Peripheral or Incomplete Contrasexual Precocity in Obesity and Pregnancy 590
Boys 568 Parathyroid Disease and Pregnancy 591
Peripheral or Incomplete Isosexual Precocious Puberty Preeclampsia/Eclampsia 591
in Girls 569 Pathophysiology 592
Peripheral or Incomplete Contrasexual Precocity in Clinical Features 592
Girls 569 Treatment/Management of Preeclampsia 592
Variations in Pubertal Development 569
Differential Diagnosis of Precocious 17. Pancreatic Hormones and
Puberty 570 Diabetes Mellitus 595
Treatment of Precocious Puberty 572
Umesh Masharani, MB, BS, MRCP (UK)
16. The Endocrinology of Pregnancy 575 and Michael S. German, MD
Bansari Patel, MD, Joshua F. Nitsche, MD, PhD, The Endocrine Pancreas 596
and Robert N. Taylor, MD, PhD Anatomy and Histology 596
Hormones of the Endocrine Pancreas 597
Conception and Implantation 575 Biosynthesis 597
Fertilization 575 Biochemistry 597
Implantation and hCG Production 576 Secretion 599
Ovarian Hormones of Pregnancy 577 Insulin Receptors and Insulin Action 601
Symptoms and Signs of Pregnancy 577 Metabolic Effects of Insulin 602
Fetal-Placental-Decidual Unit 577 Glucose Transporter Proteins 604
Polypeptide Hormones 577 Islet Amyloid Polypeptide 605
Human Chorionic Gonadotropin 577 Biochemistry 605
Human Placental Lactogen 577 Secretion 605
Other Chorionic Peptide Hormones and Growth Action of Glucagon 605
Factors 580 Glucagon-Related Peptides 606
Steroid Hormones 580 Diabetes Mellitus 609
Progesterone 580 Classification 609
Estrogens 580 Type 1 Diabetes Mellitus 609
Maternal Adaptation to Pregnancy 581 Autoimmunity and Type 1 Diabetes 610
Maternal Pituitary Gland 581 Genetics of Type 1 Diabetes 611
Maternal Thyroid Gland 581 Environmental Factors in Type 1 Diabetes 611
Maternal Parathyroid Gland 581 Type 2 Diabetes 612
Maternal Pancreas 581 Monogenic Diabetes 615
Maternal Adrenal Cortex 583 Autosomal Dominant Genetic Defects of
Fetal Endocrinology 584 Pancreatic b Cells 615
Fetal Pituitary Hormones 584 Other Genetic Defects of Pancreatic b Cells 618
Fetal Thyroid Gland 584 Ketosis-Prone Diabetes 619
Fetal Adrenal Cortex 584 Genetic Defects of Insulin Action 620
Fetal Gonads 584 Neonatal Diabetes 621
Endocrine Control of Parturition 585 Monogenic Autoimmune Syndromes 621
Progesterone and Nuclear Progesterone Other Genetic Syndromes Sometimes Associated
Receptors 585 with Diabetes 621
Estrogens and Nuclear Estrogen Receptors 585 Secondary Diabetes 621
Corticotropin-Releasing Hormone 585 Diabetes due to Diseases of the Exocrine Pancreas 621
Oxytocin 586 Endocrinopathies 622
Prostaglandins 586 Drug- or Chemical-Induced Diabetes 622
Preterm Labor/Birth 586 Infections Causing Diabetes 622
Predictors/Prevention of Preterm Labor 586 Uncommon Forms of Immune-Mediated Diabetes 622
Management of Preterm Labor 587 Clinical Features of Diabetes Mellitus 622
Postterm Pregnancy 587 Type 1 Diabetes 622
Management of Postterm Pregnancy 588

xiv CONTENTS
Type 2 Diabetes 623 Molecular Mechanisms by Which Hyperglycemia Causes

Laboratory Testing in Diabetes Mellitus 624 Microvascular and Macrovascular Damage 661
Urine Glucose 624 Genetic Factors in Susceptibility to Development of
Microalbuminuria and Proteinuria 624 Chronic Complications of Diabetes 661
Blood Glucose Testing 625 Specific Chronic Complications of Diabetes Mellitus 662
Continuous Glucose Monitoring Systems 626 Diabetic Retinopathy 662
Urine and Serum Ketone Determinations 626 Cataracts 663
Glycated Hemoglobin Assays 627 Glaucoma 663
Serum Fructosamine 628 Diabetic Nephropathy 663
Oral Glucose Tolerance Test 628 Necrotizing Papillitis 664
Insulin Levels 628 Renal Decompensation After Administration of
Intravenous Glucose Tolerance Test 628 Radiographic Dyes 664
Lipoproteins in Diabetes 629 Peripheral Neuropathy 665
Clinical Trials in Diabetes 629 Autonomic Neuropathy 666
Treatment of Diabetes Mellitus 631 Heart Disease 667
Diet 631 Peripheral Vascular Disease 668
Special Considerations in Dietary Control 632 Management of Diabetes in the Hospitalized Patient 670
Agents for the Treatment of Hyperglycemia 632 Targets for Glucose Control in the Hospitalized
Sulfonylureas 634 Patient 671
Meglitinide Analogs 636 Diabetes Mellitus and Pregnancy 673
d-Phenylalanine Derivative 636 Hormone and Fuel Balance During Pregnancy 673
Metformin 636 Pregnancy in Women with Preexisting Diabetes 673
Peroxisome Proliferator–Activated Receptor Management 675
Agonists 637 Gestational Diabetes 677
Alpha-Glucosidase Inhibitors 638
GLP-1 Receptor Agonists 638 18. Hypoglycemic Disorders 683
DPP-4 Inhibitors 639 Umesh Masharani, MB, BS, MRCP (UK),
Drug Combinations 641
Stephen E. Gitelman, MD, and Roger K. Long, MD
Short-Acting Insulin Preparations 642
Long-Acting Insulin Preparations 643 Pathophysiology of the Counterregulatory Response
Insulin Mixtures 644 to Neuroglycopenia 684
Methods of Insulin Administration 644 Counterregulatory Response to Hypoglycemia 685
Steps in the Management of the Diabetic Patient 646 Maintenance of Euglycemia in the Postabsorptive
History and Examination 645 State 686
Laboratory Diagnosis 646 Classification of Hypoglycemic Disorders 687
Patient Education and Self-Management Training 646 Specific Hypoglycemic Disorders 688
Specific Therapy 647 Clinical Findings 690
Immunopathology of Insulin Therapy 651 Diagnostic Testing 691
Acute Complications of Diabetes Mellitus 652 Tumor Localization Studies 692
Hypoglycemia 652 Treatment of Insulinoma 693
Diabetic Ketoacidosis 653 Hypoglycemia Following Gastric Surgery 695
Pathogenesis 653 Noninsulinoma Pancreatogenous Hypoglycemia
Clinical Features 654 Syndrome (NIPHS) 696
Treatment 655 Late Hypoglycemia of Occult Diabetes 696
Transition to Subcutaneous Insulin Regimen 657 Functional Alimentary Hypoglycemia 697
Complications and Prognosis 657 Pediatric Hypoglycemia 697
Disposition 657 Congenital Hyperinsulinism 697
Hyperglycemic, Hyperosmolar State 657 Transient Hyperinsulinism 698
Pathogenesis 658 Persistent Hyperinsulinism 698
Clinical Features 658 Clinical Presentation 700
Treatment 658 Diagnosis 700
Complications and Prognosis 659 Treatment 700
Lactic Acidosis 659 Non-Insulin Dependent Hypoglycemia 701
Pathogenesis 659 Outcome 702
Clinical Features 659
Treatment 659 19. Disorders of Lipoprotein Metabolism 705
Chronic Complications of Diabetes Mellitus 660 Mary J. Malloy, MD and John P. Kane, MD, PhD
Classifications of Diabetic Vascular Disease 660
Prevalence of Chronic Complications by Type of Atherosclerosis 705
Diabetes 660 Reversal of Atherosclerosis 706
Overview of Lipid Transport 706

CONTENTS xv
The Plasma Lipoproteins 706 LP(a) Hyperlipoproteinemia 718

B Apolipoproteins 706 Secondary Hypercholesterolemia 718
Other Apolipoproteins 706 Hypothyroidism 718
Absorption of Dietary Fat; Secretion of Nephrosis 718
Chylomicrons 707 Immunoglobulin Disorders 718
Formation of Very Low Density Lipoproteins 707 Anorexia Nervosa 719
Metabolism of Triglyceride-Rich Lipoproteins in Cholestasis 719
Plasma 707 The Primary Hypolipidemias 719
Catabolism of Low-Density Lipoproteins 709 Primary Hypolipidemia due to Deficiency of High-Density
Metabolism of High-Density Lipoproteins 709 Lipoproteins 719
The Cholesterol Economy 709 Tangier Disease 719
Differentiation of Disorders of Lipoprotein Etiology and Pathogenesis 719
Metabolism 710 Clinical Findings 719
Laboratory Analyses of Lipids and Treatment 719
Lipoproteins 710 Familial Hypoalphalipoproteinemia 719
Clinical Differentiation of Abnormal Patterns of Plasma Etiology and Pathogenesis 719
Lipoproteins 710 Etiologic Factor in Coronary Disease 720
Case 1: Serum Cholesterol Levels Increased; Triglycerides Treatment 720
Normal 711 Primary Hypolipidemia due to Deficiency of
Case 2: Predominant Increase of Triglycerides; Moderate APO B–Containing Lipoproteins 720
Increase in Cholesterol May Be Present 711 Etiology and Pathogenesis 720
Case 3: Cholesterol and Triglyceride Levels Both Clinical Findings 720
Elevated 711 Treatment 721
Clinical Descriptions of Primary and Secondary Disorders Secondary Hypolipidemia 721
of Lipoprotein Metabolism 711 Other Disorders of Lipoprotein Metabolism 721
The Hypertriglyceridemias 711 The Lipodystrophies 721
Atherogenicity 711 Classification 721
Cause of Pancreatitis 711 Associated Disorders 722
Clinical Signs 712 Rare Disorders 722
Effects of Hypertriglyceridemia on Laboratory Werner Syndrome, Progeria, Infantile
Measurements 712 Hypercalcemia, Sphingolipidoses, and
Primary Hypertriglyceridemia 713 Niemann-Pick Disease 722
Deficiency of Liproprotein Lipase Activity 713 Wolman Disease and Cholesteryl Ester Storage
Clinical Findings 713 Disease 722
Treatment 713 Cerebrotendinous Xanthomatosis 722
Endogenous and Mixed Lipemias 713 Phytosterolemia 722
Etiology and Pathogenesis 713 Cholesteryl Ester Transfer Protein (CETP)
Clinical Findings 713 Deficiency 722
Treatment 714 Treatment of Hyperlipidemia 722
Familial Combined Hyperlipidemia 714 Caution Regarding Drug Therapy 723
Etiology 714 Dietary Factors in the Management of Lipoprotein
Clinical Findings 714 Disorders 723
Treatment 714 Restriction of Caloric Intake 723
Familial Dysbetalipoproteinemia (Type III Restriction of Fat Intake 723
Hyperlipoproteinemia) 714 Marine Omega-3 Fatty Acids 723
Etiology and Pathogenesis 714 Reduction of Cholesterol Intake 723
Clinical Findings 714 Role of Carbohydrate in Diet 723
Treatment 714 Alcohol Ingestion 723
Secondary Hypertriglyceridemia 714 Antioxidants 724
Familial Hypercholesterolemia (FH) 717 B Vitamins 724
LDL Receptor Deficiency 717 Other Dietary Substances 724
Etiology and Pathogenesis 717 The Universal Diet 724
Clinical Findings 717 Drugs Used in Treatment of Hyperlipoproteinemia 724
Treatment 717 Bile Acid Sequestrants 724
Familial Combined Hyperlipidemia (FCH) 717 Mechanism of Action and Efficacy 724
Familial Ligand-Defective APO B-100 718 Drug Dosage 724
Cholesterol 7a-Hydroxylase Deficiency 718 Side-Effects 725
Autosomal Recessive Hypercholesterolemia Niacin (Nicotinic Acid) 725
(ARH) 718 Mechanism of Action and Efficacy 725
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Drug Dosage 725
Variants 718 Side-Effects 725

xvi CONTENTS
Fibric Acid Derivatives 725 Screening and Prevention of Complications 738

Mechanism of Action and Efficacy 725 Therapeutic Approaches for Weight Loss 738
Drug Dosage 726
Side-Effects 726 21. Humoral Manifestations of Malignancy 743
HMG-CoA Reductase Inhibitors 726 Dolores M. Shoback, MD and Janet L. Funk, MD
Mechanism of Action and Efficacy 726
Drug Dosage 726 Ectopic Hormone and Receptor Syndromes 743
Side-Effects 726 APUD Concept of Neuroendocrine Cell Tumors 744
Cholesterol Absorption Inhibitors 727 Hypercalcemia of Malignancy 744
Mechanism of Action and Efficacy 727 Pathogenesis 744
Drug Dosage 727 Humoral Mediators 745
Side-Effects 727 Solid Tumors Associated with Hypercalcemia of
PCSK9 Monoclonal Antibody 727 Malignancy 746
Mechanism of Action and Efficacy 727 Hematologic Malignancies Associated with
Drug Dosage 727 Hypercalcemia of Malignancy 746
Side-Effects 727 Diagnosis 747
Inhibition of Microsomal Triglyceride Transfer Treatment 747
Protein 727 Ectopic Cushing Syndrome 747
Mechanism of Action and Efficacy 727 Differential Diagnosis 747
Drug Dosage 727 Clinical Features 749
Side-Effects 727 Treatment 750
APO B Antisense Oligonucleotide 728 Syndrome of Inappropriate Antidiuretic Hormone
Mechanism of Action and Efficacy 728 Secretion 750
Drug Dosage 728 Etiology and Pathogenesis 750
Side-Effects 728 Clinical and Laboratory Features 751
Combined Drug Therapy 728 Non-Islet Cell Tumor-Induced Hypoglycemia 751
Niacin with Other Agents 728 Other Hormones Secreted by Tumors 752
HMG-CoA Reductase Inhibitors with Other Oncogenic Osteomalacia 753
Agents 728 Etiology and Clinical Features 753
Pathology and Pathogenesis 753
20. Obesity 731 Localization 753
Comparison with Other Disorders of FGF23
Alka M. Kanaya, MD and
Overproduction 754
Christian Vaisse, MD, PhD Gut Hormones 754
Definition and Epidemiology 731
Definition 731 22. Multiple Endocrine Neoplasia 757
Prevalence and Projections 732 David G. Gardner, MD, MS
Possible Explanations for the Increased Obesity
Rates 732 Multiple Endocrine Neoplasia Type 1 757
Pathophysiology and Genetics of Obesity 732 Pathogenesis 759
Regulation of Food Intake and Energy Treatment 761
Expenditure 732 Screening 761
Informing the Brain of the Energy Status: Leptin and Multiple Endocrine Neoplasia Type 2 762
Short-Term Gastrointestinal Signals 732 Pathogenesis 764
Central Integration of Energy Homeostasis Signals 733 Treatment 766
Leptin Resistance in Obesity 734 Screening 767
Genetics of Obesity 734 Other Disorders Characterized by Multiple Endocrine
Health Consequences of Obesity 735 Organ Involvement 769
Mechanism Underlying Obesity Complications: Adipose Carney Complex 769
Tissue as an Endocrine Organ 735 McCune-Albright Syndrome 769
Metabolic Complications of Obesity: Insulin Resistance Neurofibromatosis Type 1 769
and Type 2 Diabetes 736 Von Hippel-Lindau Disease 769
Dyslipidemia 737
The Metabolic Syndrome 737 23. Transgender Endocrinology 771
Cardiovascular Complications 737 Stephen M. Rosenthal, MD and
Pulmonary Complications 737 Wylie C. Hembree, MD
Gastrointestinal Complications 738
Reproduction and Gynecologic Complications 738 Part I: Endocrine Management of Transgender Youth 771
Cancer 738 Introduction 771
Management of the Obese Patient 738 Terms and Definitions 771
Prevalence of Transgenderism in Youth 772

CONTENTS xvii
Mental Health Concerns and Impact of Family Clinical Setting 794

Support 772 Diagnosis 794
Biologic Underpinnings of Gender Identity 772 Management 795
Transgender Youth: Natural History 773 Complications 795
Clinical Practice Guidelines for Transgender Hypercalcemic Crisis 796
Youth 774 Clinical Setting 796
Management of Early Pubertal Transgender Diagnosis 796
Youth 774 Management 796
Management of Late Pubertal Transgender Acute Hypocalcemia 798
Youth 775 Clinical Setting 798
Areas of Uncertainty/Barriers to Care/and Priorities for Diagnosis 799
Research 776 Management 799
Endocrine Management of Transgender Youth: Hyponatremia 800
Conclusions 776 Clinical Setting 800
Part II: Endocrine Management of Transgender Diagnosis 800
Adults 777 Management 801
Introduction 777 Complications 802
Adult Presentation of Gender Dysphoria 777 Diabetes Insipidus 803
Endocrine Considerations and Management 778 Clinical Setting 803
Surveillance for Potential Adverse Effects of Hormonal Diagnosis 803
Treatment 779 Management 804
Surgical Considerations 779 Complications 805
Reproductive Options 779
Voice Therapy 780 25. AIDS Endocrinopathies 809
Aging and Transgender Care 780 Carl Grunfeld, MD, PhD
Endocrine Management of Transgender Adults:
Conclusions 780 Thyroid Disorders 809
Alterations in Thyroid Function Tests 810
24. Endocrine Emergencies 783 Opportunistic Infections and Neoplasms 810
Medication Effects 810
David G. Gardner, MD, MS
Adrenal Disorders 811
Myxedema Coma 783 Opportunistic Infections and Neoplasms 811
Clinical Setting 783 Glucocorticoids 811
Diagnosis 783 Adrenal Androgens 812
Management 784 Mineralocorticoids 812
Thyroid Storm 785 Medication Effects 812
Clinical Setting 785 Summary of Adrenal Disorders 812
Diagnosis 785 Bone and Mineral Disorders 813
Management 785 Osteopenia and Osteoporosis 813
Thyrotoxic Periodic Paralysis 786 Osteonecrosis 814
Clinical Setting 786 Calcium and Phosphate Homeostasis 814
Diagnosis 786 Gonadal Disorders 814
Management 787 Testicular Function 814
Amiodarone-Induced Thyrotoxicosis 787 Ovarian Function 815
Clinical Setting 787 Pituitary Disorders 816
Management 788 Opportunistic Infections and Neoplasms 816
Acute Adrenal Insufficiency 788 Anterior Pituitary Function 816
Clinical Setting 788 Posterior Pituitary Function 816
Diagnosis 788 AIDS Wasting Syndrome 816
Management 789 Abnormalities of Fat Distribution Associated with
Pituitary Apoplexy 789 HIV 817
Clinical Setting 789 Disorders of Glucose and Lipid Metabolism 818
Diagnosis 789 Insulin Resistance, Glucose Intolerance, and
Management 789 Diabetes 818
Diabetic Ketoacidosis 790 Lipid Disorders 821
Clinical Setting 790 HIV, Antiretroviral Therapy, and Risk of
Diagnosis 790 Atherosclerosis 823
Management 791 Conclusion 823
Complications 793
Hyperosmolar Nonketotic Coma 794

xviii CONTENTS
26. Endocrine Surgery 825 Hypercortisolism 838

Diagnostic Tests 838
Geeta Lal, MD, MSc, FRCS(C), FACS and Orlo H. Surgical Management 839
Clark, MD Adrenal Cortical Carcinoma 839
Introduction 825 Diagnosis 839
The Thyroid Gland 825 Surgical Treatment 839
Embryology and Anatomy 825 Sex Steroid Excess 839
Indications for Surgery 826 Diagnostic Tests 840
Developmental Thyroid Abnormalities 826 Surgical Management 840
Hyperthyroidism 826 Pheochromocytoma 840
Diagnostic Tests 826 Diagnostic Tests 840
Management of Hyperthyroidism 826 Surgical Treatment 840
Preoperative Preparation 827 Adrenal Incidentaloma 840
Extent of Surgery 827 Diagnosis 841
Thyroiditis 827 Treatment 841
Goiter (Nontoxic) 827 Technique of Adrenalectomy 841
Thyroid Nodules 827 Complications of Laparoscopic Adrenalectomy 842
Diagnostic Tests 828 The Endocrine Pancreas 842
Management 828 Embryology and Anatomy 842
Thyroid Cancer 828 Indications for Surgery 842
Surgical Treatment 828 Insulinoma 842
Postoperative Treatment 830 Diagnostic Tests 842
Conduct of Thyroidectomy 832 Treatment 842
Complications of Thyroidectomy 832 Gastrinoma (Zollinger-Ellison Syndrome) 843
The Parathyroid Gland 832 Diagnostic Tests 843
Embryology and Anatomy 832 Treatment 843
Indications for Surgery 832 VIPoma (Verner-Morrison) Syndrome 844
Primary Hyperparathyroidism 832 Diagnostic Tests 844
Diagnostic Tests 834 Treatment 844
Surgical Management 835 Glucagonoma 844
Normocalcemic Primary Hyperparathyroidism 836 Diagnostic Tests 844
Persistent and Recurrent Primary Treatment 844
Hyperparathyroidism 837 Somatostatinoma 844
Secondary Hyperparathyroidism 837 Nonfunctioning Pancreatic Tumors 844
Special Consideration: Familial Surgical Treatment 844
Hyperparathyroidism 837 Novel Therapies 845
Complications of Parathyroid Surgery 838 Technique of Pancreatic Exploration for Neuroendocrine
The Adrenal (Suprarenal) Gland 838 Tumors 845
Embryology and Anatomy 838 Complications of Pancreatic Surgery 845
Indications for Surgery 838
Primary Hyperaldosteronism 838
Diagnostic Tests 838 Appendix: Normal Hormone Reference Ranges 847
Surgical Management 838 Index 869

Authors
Bradley D. Anawalt, MD David S. Cooper, MD
Chief of Medicine Professor of Medicine, Division of Endocrinology and
University of Washington Medical Center Metabolism, Johns Hopkins University School of Medicine;
Professor and Vice Chair Baltimore, Maryland
University of Washington Department of Medicine dscooper@jhmi.edu
Seattle, Washington The Thyroid Gland
Testes
James W. Findling, MD
David C. Aron, MD, MS Professor of Medicine, Director of Community Endocrine
Professor, Department of Medicine and Department of Services, Medical College of Wisconsin, Milwaukee
Epidemiology and Biostatistics, Division of Clinical and jfindling@mcw.edu
Molecular Endocrinology, School of Medicine, Case Hypothalamus and Pituitary Gland
Western Reserve University; Associate Chief of Staff/ Glucocorticoids and Adrenal Androgens
Education, Louis Stokes Cleveland Department of Veterans
Affairs Medical Center, Cleveland, Ohio
Paul A. Fitzgerald, MD
david.aron@med.va.gov
Evidence-Based Endocrinology and Clinical Epidemiology Clinical Professor of Medicine, Division of Endocrinology,
Department of Medicine, University of California,
Hypothalamus and Pituitary Gland
San Francisco
Glucocorticoids and Adrenal Androgens paul.fitzgerald@ucsf.edu
Adrenal Medulla and Paraganglia
Daniel D. Bikle, MD, PhD
Professor of Medicine and Dermatology, Veterans Affairs Janet L. Funk, MD
Medical Center and University of California, San Francisco Associate Professor of Medicine, Division of Endocrinology,
daniel.bikle@ucsf.edu Department of Medicine, University of Arizona, Tucson
Metabolic Bone Disease jfunk@u.arizona.edu
Humoral Manifestations of Malignancy
Glenn D. Braunstein, MD
Professor of Medicine David G. Gardner, MD, MS
Cedars-Sinai Medical Center Mount Zion Health Fund Distinguished Professor of
Emeritus Professor of Medicine Endocrinology and Medicine; Chief, Division of
The David Geffen School of Medicine at UCLA Endocrinology and Metabolism, Department of Medicine
Testes and Diabetes Center, University of California, San Francisco
dgardner@diabetes.ucsf.edu
Ty B. Carroll, MD Hormones and Hormone Action
Assistant Professor, Endocrinology Center, Department of Multiple Endocrine Neoplasia
Medicine, Medical College of Wisconsin, Milwaukee Endocrine Emergencies
tcarroll@mcw.edu
Glucocorticoids and Adrenal Androgens
Michael S. German, MD
Professor and Justine K. Schreyer Endowed Chair in Diabetes
Marcelle I. Cedars, MD Research, Department of Medicine, Division of
Professor and Director, Division of Reproductive Endocrinology and Diabetes Center, University of
Endocrinology, Department of Obstetrics, Gynecology California, San Francisco
and Reproductive Sciences, University of California, mgerman@biochem.ucsf.edu
San Francisco Pancreatic Hormones & Diabetes Mellitus
marcelle.cedars@ucsfmedctr.org
Female Reproductive Endocrinology and Infertility
Stephen E. Gitelman, MD
Professor of Clinical Pediatrics, Chief, Division of Pediatric
Orlo H. Clark, MD Endocrinology, Department of Pediatrics, University of
Professor Emeritus of Surgery, Department of Surgery, California, San Francisco
University of California, San Francisco sgitelma@peds.ucsf.edu
clarko@surgery.ucsf.edu Hypoglycemic Disorders
Endocrine Surgery

xx AUTHORS
Carl Grunfeld, MD, PhD John P. Kane, MD, PhD

Professor of Medicine, University of California, San Francisco; Professor Emeritus of Medicine, Biochemistry, and Biophysics,
Associate Chief of Staff for Research and Development; and and Associate Director, Cardiovascular Research Institute,
Chief, Metabolism and Endocrine Sections, Veterans Affairs University of California, San Francisco
Medical Center, San Francisco john.kane@ucsf.edu
carl.grunfeld@ucsf.edu Disorders of Lipoprotein Metabolism
AIDS Endocrinopathies
Paul W. Ladenson, MD (Oxon)., MD
Wylie C. Hembree, MD
John Eager Howard Professor of Endocrinology and
Associate Attending, New York Presbyterian Hospital; Retired Metabolism; Professor of Medicine, Pathology, Oncology,
Associate Professor of Medicine and of Obstetrics and and Radiology and Radiological Sciences; University
Gynecology; Special Lecturer, Department of Medicine, Distinguished Professor, The Johns Hopkins University
Endocrine Division, College of Physicians and Surgeons, School of Medicine, Baltimore, Maryland
Columbia University Medical Center, New York, New York ladenson@jhmi.edu
wch2@columbia.edu The Thyroid Gland
Transgender Endocrinology
Geeta Lal, MD, MSc, FRCS(C), FACS
Christopher P. Houk, MD
Associate Professor of Surgery; Associate Chief Quality Officer,
Associate Professor of Pediatrics; Chief, Pediatric Adult Inpatient
Endocrinology, Medical College of Georgia, Georgia University of Iowa, Iowa City, Iowa
Regents University, Augusta, Georgia geeta-lal@uiowa.edu
chouk@gru.edu Endocrine Surgery
Disorders of Sex Development
Peter A. Lee, MD, PhD
Edward C. Hsiao, MD, PhD
Professor of Pediatrics, Penn State College of Medicine,
Associate Professor in Residence, Division of Endocrinology
Hershey Medical Center, Hershey, Pennsylvania
and Metabolism and Institute of Human Genetics,
plee@psu.edu
Disorders of Sex Development
edward.hsiao@ucsf.edu
Hormones and Hormone Action
Roger K. Long, MD
Juan Carlos Jaume, MD Associate Clinical Professor of Pediatrics, Division of Pediatric
Professor of Medicine; Chief, Division of Endocrinology, Endocrinology, University of California, San Francisco
Diabetes and Metabolism; and Clinical Director of the Roger.Long@ucsf.edu
Center for Diabetes and Endocrine Research (CeDER), Hypoglycemic Disorders
College of Medicine and Life Sciences, University of Toledo,
Toledo, Ohio Mary J. Malloy, MD
Juan.Jaume@utoledo.edu Professor (Emeritus), Department of Pediatrics and Medicine,
Endocrine Autoimmunity Director, Pediatric Lipid Clinic and Co-Director, Adult
Lipid Clinic, University of California, San Francisco
Bradley R. Javorsky, MD mary.malloy@ucsf.edu
Assistant Professor of Medicine, Endocrinology Center, Disorders of Lipoprotein Metabolism
Medical College of Wisconsin, Menomonee Falls
bjavorsky@mcw.edu Umesh Masharani, MB, BS, MRCP (UK)
Hypothalamus and Pituitary Gland Professor of Clinical Medicine, Division of Endocrinology and
Metabolism, University of California, San Francisco
Alka M. Kanaya, MD umesh.masharani@ucsf.edu
Associate Professor of Medicine, Epidemiology & Biostatistics, Pancreatic Hormones and Diabetes Mellitus
University of California, San Francisco Hypoglycemic Disorders
alka.kanaya@ucsf.edu
Obesity Joshua F. Nitsche, MD, PhD
Assistant Professor, Department of Obstetrics and Gynecology,
Wake Forest School of Medicine, Winston-Salem,
North Carolina
jnitsche@wakehealth.edu
The Endocrinology of Pregnancy

AUTHORS xxi
Bansari Patel, MD Ajay Sood, MD

Assistant Professor, Wake Forest Baptist Medical Center, Chief, Endocrinology Section, and Associate Professor of
Center for Reproductive Medicine, Winston-Salem, Medicine, School of Medicine, Case Western Reserve
North Carolina University and Louis Stokes Cleveland Department of
bgpatel@wakehealth.edu Veterans Affairs Medical Center, Cleveland, Ohio
The Endocrinology of Pregnancy ajay.sood@va.gov
Evidence-Based Endocrinology and Clinical Epidemiology
Rodolfo A. Rey, MD, PhD
Director, Centro de Investigaciones Endocrinologicas Dennis Styne, MD
“Dr. Cesar Bergada”, CONICET - FEI - Division de Professor and Rumsey Chair, Department of Pediatrics,
Endocrinologia, Hospital de Ninos Ricardo Gutierrez, Section of Endocrinology, University of California, Davis,
Buenos Aires, Argentina Sacramento
rodolforey@cedie.org.ar dmstyne@ucdavis.edu
Disorders of Sex Development Growth, Puberty
Alan G. Robinson, MD Robert N. Taylor, MD, PhD

Professor of Medicine, Associate Vice Chancellor, Medical Professor and Vice Chair for Research, Department of
Sciences and Executive Associate Dean, David Geffen Obstetrics and Gynecology; Co-Director, Molecular
School of Medicine at UCLA, University of California, Medicine and Translational Sciences Program, Wake Forest
Los Angeles School of Medicine, Winston-Salem, North Carolina
robinson@ucla.edu rtaylor@wakehealth.edu
The Posterior Pituitary (Neurohypophysis) The Endocrinology of Pregnancy
Mitchell P. Rosen, MD J. Blake Tyrrell, MD

Associate Professor, Director, UCSF Fertility Preservation Clinical Professor Emeritus of Medicine; Chief, Endocrine
Program and Reproductive Laboratories. Division of Clinic, Division of Endocrinology and Metabolism,
Reproductive Endocrinology and Infertility, University of University of California, San Francisco
California, San Francisco blaket@medicine.ucsf.edu
Mitchell.Rosen@ucsf.edu Hypothalamus and Pituitary Gland
Female Reproductive Endocrinology and Infertility Glucocorticoids and Adrenal Androgens
Transgender Endocrinology
Christian Vaisse, MD, PhD
Stephen M. Rosenthal, MD Professor of Medicine, Department of Medicine,
Professor Emeritus of Pediatrics, Division of Pediatric Diabetes Center, University of California, San Francisco
Endocrinology; Medical Director, Child and Adolescent vaisse@medicine.ucsf.edu
Gender Center, University of California, San Francisco Obesity
stephen.rosenthal@ucsf.edu
Transgender Endocrinology Selma Witchel, MD
Director, Pediatric Endocrinology Fellowship Training
Anne L. Schafer, MD Program; and Associate Professor with Tenure, Children’s
Assistant Professor of Medicine, University of California, San Hospital of Pittsburgh and University of Pittsburgh Medical
Francisco; Staff Physician, San Francisco Veterans Affairs Center, Pittsburgh, Pennsylvania
Medical Center, San Francisco, California witchelsf@upmc.edu
anne.schafer@ucsf.edu Disorders of Sex Development
Metabolic Bone Disease
William F. Young, Jr, MD, MSc
Dolores M. Shoback, MD Professor of Medicine, Mayo Clinic College of Medicine,
Professor of Medicine, Department of Medicine, University of Mayo Clinic, Rochester, Minnesota
California, San Francisco; Staff Physician, Endocrine- young.william@mayo.edu
Metabolism Section, Department of Medicine, Endocrine Hypertension
San Francisco Veterans Affairs Medical Center,
San Francisco, California
dolores.shoback@ucsf.edu
Metabolic Bone Disease
Humoral Manifestations of Malignancy


Preface
This represents the tenth edition of Greenspan’s Basic & Clinical Transgender Endocrinology (Chapter 23). We trust that you have
Endocrinology—a bittersweet milestone in that it also marks the found previous versions of this text useful and informative and
recent passing of Dr. Francis Greenspan, the originator and name- that the current version will continue to serve as a valuable tool for
sake of this textbook. Frank’s involvement with this textbook will the education of your trainees and management of your endocrine
be sorely missed in the years to come. As with each of the previous patients.
editions, the individual chapters have been revised and updated to
contain the most current information in the field. Our contributors David G. Gardner, MD, MS
continue to provide comprehensive content in a highly readable Dolores Shoback, MD
format. Chapter 14 (Disorders of Sex Development) has been San Francisco, CA
completely revised and we have added a new chapter dealing with


1
C H A P T E R
Hormones and Hormone

Action
Edward C. Hsiao, MD, PhD and David G. Gardner, MD, MS
ACTH Adrenocorticotropin hormone FAD Flavin adenine dinucleotide

ACVR1 Activin A receptor, type I FGF Fibroblast growth factor
AD1 Activation domain 1 FMN Flavin mononucleotide
AD2 Activation domain 2 FOX A1 Forkhead transcription factor A1
AF-1 Activator function-1 FXR Farnesoid X-activated receptor
AF-2 Activator function-2 GAP GTPase-activating protein
Akt Protein kinase B GAS Interferon gamma activated sequences
AMH Anti-müllerian hormone GDP Guanosine diphosphate
ANP Atrial natriuretic peptide GH Growth hormone
AP-1 Activator protein-1 GHR Growth hormone receptor
APC Adenomatous polyposis coli gene GLUT4 Glucose transporter type 4
AR Androgen receptor GR Glucocorticoid receptor
a-ARK β-Adrenergic receptor kinase GRB2 Growth factor receptor–bound protein-2
a-TrCP Beta-transducin repeats-containing proteins GRE Glucocorticoid response element
BMP Bone morphogenetic protein GRIP Glucocorticoid receptor–interacting protein
BNP B-type natriuretic peptide GSK3 Glycogen synthase kinase-3
BXR Benzoate X receptor GTF General transcription factor
cAMP Cyclic adenosine-3′,5′-monophosphate GTP Guanosine triphosphate
CAR Constitutive androstane receptor HRE Hormone response element
CARM Coactivator-associated arginine HSP Heat shock protein
methyltransferase ID Receptor–repressor interaction domain
CBP CREB-binding protein IGF Insulin-like growth factor
cGMP Cyclic guanosine-3′,5′-monophosphate I-jB Inhibitor of nuclear factor kappa B
CKI Casein kinase I IKK Inhibitor of nuclear factor kappa B kinase
CNP C-type natriuretic peptide IP3 Inositol 1,4,5-trisphosphate
CREB cAMP response element-binding protein IP4 Inositol 1,3,4,5-tetrakis-phosphate
DAG Diacylglycerol ISRE Interferon-stimulated response element
DAN Differential screening-selected gene in JAK Janus kinase
neuroblastoma
KHD Kinase homology domain
DBD DNA-binding domain
LBD Ligand-binding domain
DRIP Vitamin D receptor–interacting protein
LH Luteinizing hormone
DVL Dishevelled
LRP Lipoprotein receptor related protein
EGF Epidermal growth factor
LXR Liver X receptor
ER Estrogen receptor
MAPK Mitogen-activated protein kinase
ERK Extracellular signal–regulated kinase
01-Gardner_ch01-p001-028.indd 1 09/06/17 4:04 PM

2 CHAPTER 1 Hormones and Hormone Action
MEK MAPK kinase RAR Retinoic acid receptor

MR Mineralocorticoid receptor RE Response element
MSH Melanocyte-stimulating hormone RGS Regulators of G protein signaling
N-Cor Nuclear receptor corepressor RSK Ribosomal S6 kinase
NF-κB Nuclear factor kappa B RXR Retinoid X receptor
NO Nitric oxide SH2 src homology domain type 2
NOS Nitric oxide synthase SIE Sis-inducible element
NPR Natriuretic peptide receptor SMRT Silencing mediator for RXR and TR
NR Nuclear receptor SOCS Suppressor of cytokine signaling
NRPTK Non-receptor protein tyrosine kinase SOS Son-of-sevenless
PAK p21-activated kinase SOST Sclerostin
P/CAF p300/CBP-associated factor SR Steroid receptor
P/CIP p300/CBP cointegrator-associated protein SRC Steroid receptor coactivator
PDE Phosphodiesterase
SRE Serum response element
PDGF Platelet-derived growth factor
SRF Serum response factor
PDK Phosphatidylinositol-3,4,5 trisphosphate-
STAT Signal transducer and activator of
dependent kinase
transcription
PHP-1a Pseudohypoparathyroidism type 1a
SWI/SNF ATP-dependent chromatin remodeling
PI-3K Phosphoinositide-3-OH kinase complex
PIP2 Phosphatidylinositol-4,5-bisphosphate TAZ WW domain-containing transcription
PIP3 Phosphatidylinositol-3,4,5-trisphosphate regulator protein 1
PI(3,4)P2 Phosphatidylinositol-3,4-bisphosphate TBP TATA-binding protein
PKA Protein kinase A TCF/LEF T-cell factor/lymphoid enhancer factor
PKB Protein kinase B TGF-β Transforming growth factor beta
PKC Protein kinase C TLE Transducin-like enhancer protein
PKG cGMP-dependent protein kinase TPA 12-O-tetradecanoyl-phorbol 13-acetate
PLCβ Phospholipase C beta TR Thyroid hormone receptor
PLCγ Phospholipase C gamma TRAF Tumor necrosis factor receptor–associated
PLCPC Phosphatidylcholine-selective factor
phospholipase TRAP Thyroid hormone receptor–associated
POL II RNA polymerase II protein
PPAR Peroxisome proliferator–activated receptor TRE TPA response element
PR Progesterone receptor TSH Thyroid-stimulating hormone
PTH Parathyroid hormone VDR Vitamin D receptor
PXR Pregnane X receptor Wnt int/Wingless family
RANK Receptor activator of nuclear factor kappa B YAP Yes-associated protein-1
Hormones are signaling molecules that traffic information from itself (autocrine effect), or without actually being released from
one point to another, typically through a soluble medium like the secretory cell (intracrine effect) (Figure 1–1).
the extracellular fluid or blood. Hormones fall into one of a Identification of a tissue as a target for a particular hormone
number of different hormonal classes (eg, steroids, mono- requires the presence of receptors for the hormone in cells of the target
amines, peptides, proteins, and eicosanoids) and signal through tissue. These receptors, in turn, are linked to effector mechanisms that
a variety of general (eg, nuclear vs cell surface) and specific (eg, lead to the physiological effects associated with the hormone.
tyrosine kinase vs phosphoinositide turnover) mechanisms in
target cells.
Hormones produced in one tissue may promote activity in a RELATIONSHIP TO THE NERVOUS
target tissue at some distance from the point of secretion (endo- SYSTEM
crine effect). In this case the hormone travels through the blood-
stream, often bound to a plasma protein, to access the target Many features of the endocrine system, such as the use of ligands
tissue. In addition, hormones may act locally following secretion; and receptors to communicate between cells, are also found in the
either on a neighboring cell (paracrine effect), on the secretory cell nervous system. In fact, from a functional standpoint, the two

CHAPTER 1 Hormones and Hormone Action 3
Endocrine cell Neurotransmitter cell
H H
H R H R
H H
H
H H H H
H N
Intracrine
H N
R H R H
Axon
Auto-
Endocrine
crine Blood
vessel
Paracrine
R
N
crine
Para N
R H R H H N
N
H N
R R
Hormone target cell
H R
Neurotransmitter and hormone target cell
FIGURE 1–1 Actions of hormones and neurotransmitters. Endocrine and neurotransmitter cells synthesize hormones and release them by
specialized secretory pathways or by diffusion. Hormones can act at the site of production either following release (autocrine) or without
release (intracrine) from the producer cell. They can also act on neighboring target cells, including neurotransmitter-producing cells, without
entering the circulation (paracrine). Finally, they can access target cells through the circulation (endocrine). Neurotransmitters that access the
extracellular compartment, including circulating plasma, can act as paracrine or endocrine regulators of target cell activity (H, hormone;
N, neurotransmitter; R, receptor).
systems are probably related evolutionarily. However, there are neuron. It does this through pulsatile release of secretory granules
some important differences between the two systems. While the into an incredibly small volume (ie, that determined by the vol-
nervous system uses a highly compartmentalized, closed system ume in the synaptic cleft).
of axons and dendrites to connect cells at some distance from one The endocrine system, on the other hand, has a very large
another, the endocrine system relies on circulating plasma to volume of distribution for many of its ligands (eg, circulating
carry newly released hormones to their distant targets. As a result, blood volume). Maintaining ligand concentrations analogous to
the time constants for signal delivery are quite different between those present in the synaptic cleft would require prodigious secre-
the two—virtually instantaneous for the nervous system but tory capacity. The endocrine system circumvents this problem by
delayed, by virtue of circulation times, for the endocrine system. using ligand–receptor interactions with 100-10,000 fold higher
Thus, while neural responses are typically measured in seconds, binding affinity than those used in the nervous system. In effect,
endocrine responses are often measured in minutes to hours— the nervous system is structured to deliver high ligand concentra-
thereby accommodating different needs in the organism. A sections to relatively low-affinity receptors, allowing it to activate and
ond difference relates to the nature of the ligand–receptor inactivate biological effects quickly and in a relatively well-defined
interaction. In the nervous system, the affinity of receptor for topography. Its effects are short lived. In contrast, the endocrine
ligand tends to be relatively low. This allows for rapid dissociation system uses high-affinity receptors to extract and retain ligand
of ligand from receptor and, if that ligand is degraded locally, a from a relatively “dilute” pool in circulating plasma. Its biological
rapid cessation of biological effect. Despite this rapid dissocia- effects are long lasting. It has sacrificed rapid response to accom-
tion, the secretory neuron is able to maintain receptor occupancy modate a wider area of signal distribution and prolongation of the
by keeping concentrations of the ligand high around the target biological effect. Thus, the systems are not only related but

complementary in the respective roles that they play in normal of protein or peptide hormones this usually reflects increased
physiological function. expression of the gene encoding the hormone (ie, increased pro-
duction of the mRNA encoding the hormone) with subsequent
increases in hormone synthesis. In the case of steroid or thyroid
CHEMICAL NATURE OF HORMONES hormones it reflects increased sequestration of precursors for hor-
mone synthesis (eg, cholesterol for steroid hormones or iodide for
Hormones vary widely in terms of their chemical composition. thyroid hormone) as well as increased activity of enzymatic pro-
Specific examples include proteins (eg, adrenocorticotrophin), teins responsible for executing the individual catalytic events
peptides (eg, vasopressin), monoamines (eg, norepinephrine), required for hormone production. The latter may involve a rate-
amino acid derivatives (eg, triiodothyronine), steroids (eg, cortisol), limiting step in the synthetic cascade (eg, 1-alpha hydroxylase
and lipids (eg, prostaglandins). Proteins can be glycosylated (eg, activity in the synthesis of 1,25-dihydroxyvitamin D).
thyroid-stimulating hormone) and/or dimerized (eg, follicle-stim-
ulating hormone) to generate full biological activity. In general,
protein, peptide, monoamine, and lipophilic hormones tend to Precursor Processing
exert their effects primarily through protein receptors at the cell Processing of hormone precursors contributes to varying degrees
membrane, while thyroid hormone and steroids tend to operate in in controlling circulating hormone levels. Most peptide and pro-
the cell nucleus. However, exceptions to these rules are being rec- tein hormones require some processing to generate the mature
ognized (eg, triiodothyronine activates classic thyroid hormone hormonal product (eg, conversion of proinsulin to insulin) and
receptors in the nuclear compartment and the trace amine receptor impairment in the processing activity can alter the ratio of precur-
[TAR1] on the cell surface) and estradiol appears to activate both sor to product in plasma. In other cases, a critical processing event
nuclear and plasma membrane receptors. It is likely that the bio- is part of the secretory process itself (eg, cleavage of thyroxine
logical “effect” of a given hormone reflects a composite of receptor from thyroglobulin) and impaired processing can result in a dra-
activity located in several different cellular compartments. matic reduction in immunoreactivity as well as bioactivity of the
mature hormone. In addition, protein hormones may require
post-translational modification (eg, glycosylation) or assembly (eg,
ENDOCRINE GLANDS AND TARGET heterodimerization) prior to secretion in order to optimize bio-
ORGANS logical activity.
Endocrine glands are traditionally defined as ductless glandular Hormone Release

structures that release their hormonal secretions into the extracellular
space where they can eventually access circulating plasma. Classic Many hormones (eg, peptides, proteins, and monoamines) are
endocrine glands include organs like the pituitary gland, thyroid stored in secretory granules in endocrine cells. Release of these
gland, parathyroid glands, pancreatic islets, adrenal glands, ovaries, granules is promoted by signaling events triggered by exogenous
and testes. It is now clear that hormones can be secreted from non- regulators termed secretagogues. This often requires activation of
traditional endocrine organs and play critical roles in the regulation a second messenger system (see discussion under Receptors) like
of physiological homeostasis. Examples of the latter include the heart cyclic AMP generation or intracellular calcium mobilization in the
(natriuretic peptides), kidney (erythropoietin and renin), adipose endocrine cell. Steroid hormones, on the other hand, are not
tissue (leptin and adiponectin), bone (osteocalcin), and gut (chole- stored to a significant degree in the hormone-producing cells. In
cystokinin and incretins). Once in the circulation, hormones bind to this case synthesis rather than hormone release appears to play the
receptors on target tissues to elicit their biological effects. Target tis- dominant role in controlling hormone levels in circulating plasma.
sues for some hormones (eg, glucocorticoids) are numerous, reflect-
ing the ubiquitous distribution of their receptors, while those for Hormone Binding in Plasma
other tissues have a more limited distribution (eg, androgens). Hormones in plasma can circulate either in a free form, uncom-
plexed with other molecules, or bound to other molecules like
plasma proteins. It is the uncomplexed or free form of the hor-
REGULATION OF HORMONE LEVELS IN mone that represents the biologically active fraction of hormone
PLASMA in the plasma compartment, and it is this fraction which homeo-
static regulatory mechanisms work to preserve.
Hormone levels in plasma determine the effective ligand concen-
However, binding of hormone to plasma proteins plays an
tration at the level of the hormone receptors in peripheral target
important role in endocrine physiology. First, it provides a reser-
cells. Thus, regulation of hormone levels plays an important role
voir of hormone that exchanges with the free hormone fraction
in the control of the biological effects that the hormone exerts.
according to the laws of mass action (see under Receptors). This
makes plasma hormone concentrations less dependent on hor-
Hormone Biosynthesis mone synthesis and release, effectively stabilizing those concentra-
New hormone synthesis is one of the principal mechanisms used tions over extended periods of time. This also helps guarantee a
to raise hormone levels in circulating plasma. In the case uniform distribution of hormone concentration in capillary beds

hormone secretion and synthesis. Many, if not most, hormone

levels are controlled either directly or indirectly by the biological
activity that they serve to control. For example, parathyroid
hormone (PTH) secretion, which responds to low extracellular
calcium levels, mobilizes calcium out of bone which, in turn,
signals back to the parathyroid gland to turn off additional PTH
secretion. This negative feedback loop is a hallmark of endocrine
regulation. The end product or negative regulator can either be
an inorganic ion or metabolite (eg, calcium for PTH) or a hor-
monal product in the endocrine cascade (eg, thyroid hormone
for TSH). Not all feedback is negative in nature. Positive feed-
back loops (eg, mid-cycle estradiol-induced luteinizing hormone
secretion) also play important roles in governing physiological
homeostasis.
HORMONE ACTION
Blood vessel Target tissues Hormones produce their biologic effects through interaction with
high-affinity receptors that are, in turn, linked to one or more
FIGURE 1–2 Role of plasma binding in delivery of hormones to effector systems within the cell. These effectors involve many dif-
peripheral tissues. Example shows a hormone that is bound (small
ferent components of the cell’s metabolic machinery, ranging from
red circles) to a plasma protein (large circles) and a hormone that is
not protein bound (small orange circles). With the bound hormone,
ion transport at the cell surface to stimulation of the nuclear tran-
only the free fraction is available for tissue uptake. As the free frac- scriptional apparatus. Steroids and thyroid hormones exert their
tion is depleted, additional hormone dissociates from the plasma- effects in the cell nucleus, although regulatory activity in the
binding protein, making hormone available to more distal portions extranuclear compartment has also been documented. Peptide
of the tissue. In contrast, all hormones that are not protein bound are hormones and neurotransmitters, on the other hand, trigger a
quickly extracted in the proximal part of the tissue. plethora of signaling activity in the cytoplasmic and membrane
compartments while at the same time exerting parallel effects on
the transcriptional apparatus. The discussion that follows will
perfusing target tissues (Figure 1–2). Second, it slows the metabo- focus on the primary signaling systems employed by selected hor-
lism or turnover of the hormone by sequestering it away from monal agonists and attempt to identify examples where aberrant
degradative enzymes or filtration by the kidney. signaling results in human disease.
Hormone Metabolism RECEPTORS

Metabolism of hormones also plays an important role in regulating
hormone concentrations. In some cases metabolism is responsible The biologic activity of individual hormones is dependent on
for converting precursors with less hormonal activity to products their interactions with specific high-affinity receptors on the sur-
with greater activity (eg, conversion of 25-hydroxyvitamin D to faces or in the cytoplasm or nuclei of target cells. The receptors,
1,25-dihydroxyvitamin D, or conversion of androstenedione to in turn, are linked to signaling effector systems responsible for
testosterone). In other cases, metabolism leads to degradation and generating the observed biologic responses. Receptors, therefore,
inactivation of the hormone with a cessation of hormone activity. convey not only specificity of the response (ie, cells lacking recep-
This type of degradation is often specific to the hormonal class tors lack responsiveness to the hormone) but also the means for
under examination. Steroids, for example, are catalytically con- activating the effector mechanism. In general, receptors for the
verted to inactive metabolites and/or sulfated to promote excretion. peptide hormones and neurotransmitters are aligned on the cell
Thyroid hormones are subjected to deiodination which strips them surface and those for the steroid hormones, thyroid hormone,
of their biological activity. Protein and peptide hormones are inter- and vitamin D are found in the cytoplasmic or nuclear compart-
nalized by target, as well as nontarget, cells and degraded in intra- ments, although, as noted earlier, exceptions have been identified
cellular lysosomes. In general, the more avid the degradative in both cases.
mechanisms, the shorter the plasma half-life of the hormone. Interactions between the hormone ligand and its receptor are
governed by the laws of mass action:
Regulation of Hormone Levels k +1

[ H ] + [ R ]
[HR]
k −1
Hormone levels can be modulated through regulatory factors
affecting any of the steps listed earlier; however, the bulk of the where [H] is the hormone concentration, [R] is the receptor con-
acute “fine-tuning” of hormone levels occurs at the level of centration, [HR] is the concentration of the hormone–receptor

complex, and k+1 and k–1 are the rate constants for [HR] forma- at which one-half of the available receptors are occupied. Thus,
tion and dissociation, respectively. Thus, at equilibrium, knowledge of bound and free ligand concentrations, which can be
determined experimentally, provides information regarding the
k+1[ H ][ R ] = k−1[HR] affinity of the receptor for its ligand and the total concentration of
or receptor in the preparation.
[ H ][ R ] k−1 Agents that bind to receptors with high affinity are classified as
= = KD either agonists or antagonists based on the functional outcome of
[HR] k+1
this receptor–ligand interaction. Agonists are ligands that trigger
where KD is the equilibrium dissociation constant that defines the the effector mechanisms and produce biologic effects. Antagonists
affinity of the hormone–receptor interaction (ie, lower the disso- bind to the receptor but do not activate the effector mechanisms.
ciation constant, higher the affinity). Assuming that total receptor Because they occupy receptor and block association with the ago-
concentration R0 = [HR] + [R], this equation can be rearranged to nist, they antagonize the functional activity of the agonist. Partial
give agonists bind to the receptor but possess limited ability to activate
the effector mechanisms. In different circumstances, partial ago-
[HR]  [HR]  R0
= −  + nists may demonstrate variable biologic activity. For example,
[H]  KD KD when used alone, they may display weak activating activity,
whereas their use together with a full agonist may lead to inhibi-
This is the Scatchard equation and states that when bound ligand
tion of function because the latter is displaced from the receptor
over free ligand (ie, [HR]/[H]) is plotted against bound ligand (ie,
molecule by a ligand with lower intrinsic activity.
[HR]), the slope of the line is defined by -1/KD, the y-intercept by
In some systems, receptors are available in surplus, which may
R0/KD, and the x-intercept by R0 (Figure 1–3). When [HR] = R0/2,
be several-fold higher than that required to elicit a maximal bio-
[H] = KD; therefore, the KD is also the concentration of hormone [H]
logic response. Although such spare receptor systems superficially
appear redundant, they are designed to rectify a mismatch
A R0 between low circulating ligand levels and a relatively low-affinity
ligand–receptor interaction. Thus, by increasing the number of
available receptors, the system is guaranteed a sufficient number of
ligand-bound receptor units to activate downstream effector sys-
tems fully, despite operating at subsaturating levels of ligand.
[HR]
NEUROTRANSMITTER AND PEPTIDE

KD HORMONE RECEPTORS
As mentioned earlier, neurotransmitter and peptide hormones
[H]
interact predominantly with receptors expressed on the plasma
membrane at the cell surface. The KD of a neurotransmitter for its
B
R0 receptor is typically higher than that of a hormone for its receptor,
KD reflecting a higher koff rate constant (see earlier). Neurotransmitter
receptor occupancy is driven by the extraordinarily high concen-
Slope = −
1 trations of ligand that can be achieved in the synaptic cleft, and
KD occupancy of the hormone receptor is driven by its high affinity
[HR]
for ligand. The high koff of the neurotransmitter–receptor interac-
[H ]
tion guarantees that the effect is rapid in onset but of short dura-
tion, whereas the lower koff of the hormone–receptor interaction
guarantees that the effect is slow in onset but difficult to extin-
guish, kinetics that are more appropriate for the hormonal func-
tions of these ligands.
The neurotransmitter and peptide receptors can be divided
R0
into several major groups (Table 1–1 and Figure 1–4). The first
includes the so-called serpentine or “seven-transmembrane-
[HR] domain” receptors. These receptors each contain an amino termi-
FIGURE 1–3 Ligand saturation (A) and Scatchard analysis (B) of nal extracellular domain followed by seven hydrophobic amino
a hypothetical hormone receptor interaction. KD represents the dis- acid segments, each of which is believed to span the membrane
sociation constant; R0 the total receptor concentration; [HR] and [H] bilayer (see Figure 1–4). The seventh of these, in turn, is followed
the bound and free ligand, respectively. Note in (A) that the KD is the by a hydrophilic carboxyl terminal domain that resides within the
concentration [H] at which half of available receptors are occupied. cytoplasmic compartment. As a group, they share a dependence

TABLE 1–1 Major subdivisions (with examples) of Binding domain

Y
Y
the neurotransmitter-peptide hormone NH2
Y
receptor families.a
Seven-
Seven-Transmembrane Domain transmembrane-
β-Adrenergic domain receptor
PTH (eg, β-adrenergic
LH catecholamines)
TSH
GRH
TRH
ACTH
MSH
Glucagon COOH
Dopamine
α2-Adrenergic (–)
Binding domain
Somatostatin (–)
Growth factor
Single-Transmembrane Domain receptor
Growth factor receptors (eg, EGF)
Insulin Tyrosine kinase
IGF domain
EGF
PDGF
Cytokine receptors Binding domain
Growth hormone Cytokine
Prolactin receptor
Erythropoietin (eg, GH)
CSF Accessory protein with
Guanylyl cyclase-linked receptors tyrosine kinase
Natriuretic peptides domain
a
Receptors have been subdivided based on shared structural and functional similari-
ties. Minus (–) sign denotes a negative effect on cyclase activity. Binding domain
TGF-β receptor
(eg, TGF-β)
on the G protein transducers (GPCRs discussed later) to execute
many of their biologic effects. A second group includes the single- Serine/Threonine
Kinase domain
transmembrane-domain receptors that harbor intrinsic tyrosine
kinase activity. This includes the insulin, insulin-like growth factor
(IGF), and epidermal growth factor (EGF) receptors. A third Binding domain
Guanylyl cyclase
group, which is functionally similar to the second group, is char- receptor
acterized by a large, extracellular binding domain followed by a (eg, ANP)
single membrane-spanning segment and a cytoplasmic tail. These Kinase-like domain
receptors do not possess intrinsic tyrosine kinase activity but
appear to function through interactions with soluble transducer Guanylyl cyclase
molecules which do possess such activity. Prolactin and growth
hormone are included in this group. A fourth group is the trans- FIGURE 1–4 Structural schematics of different classes of
forming growth factor beta (TGF-β) family which signals through membrane-associated hormone receptors. Representative ligands
serine/threonine kinase domains in their cytoplasmic tails. A fifth are presented in parentheses (ANP, atrial natriuretic peptide; EGF,
group, which includes the natriuretic peptide receptors, operates epidermal growth factor; GH, growth hormone; TGF-β, transforming
through activation of a particulate guanylyl cyclase and synthesis growth factor beta).
of cGMP. The cyclase is covalently attached at the carboxyl termi-
nal portion of the ligand-binding domain (LBD) and thus repre-
intracellular signaling by activating one (or in some cases multi-
sents an intrinsic part of the receptor molecule.
ple) G proteins resulting in biological responses. These receptors
share overall structural features, most notably seven membrane-
G PROTEIN–COUPLED RECEPTORS spanning regions connected by intracellular and extracellular
loops (see Figure 1–4). The receptors are oriented such that the
G protein–coupled receptors (GPCRs) constitute a large super- amino terminal domain is extracellular, whereas the carboxyl ter-
family of molecules capable of responding to ligands of remark- minal tail is cytoplasmic. The membrane-spanning segments
able structural diversity—ranging from photons to large interact with one another, forming an irregular cylindrical bundle
polypeptide hormones. Because of their diversity, GPCRs are the around a central cavity within the molecule. GPCRs can assume
target of over 40% of modern pharmaceuticals. GPCRs initiate at least two conformations with differing orientations of the

membrane-spanning segments relative to one another. One orien- TABLE 1–2 G protein subunits selectively interact
tation is favored in the absence of an agonist ligand. In this orien- with specific receptor and effector
tation the receptor does not activate a G protein (inactive mechanisms.
conformation). The second orientation is stabilized by the binding
of an appropriate agonist ligand. In this conformation the receptor Representative
G Protein Associated
activates a cognate G protein (active conformation). All GPCRs Subunit Receptors Effector
are thought to undergo a similar conformational switch on agonist
αs β-Adrenergic Adenylyl cyclase
binding, producing a structural change in the cytoplasmic domain
TSH Ca2+ channels
that promotes G protein activation. Some small agonists, such as Glucagon K+ channels
catecholamines, are able to enter the cavity formed by the trans-
αi α2-Adrenergic Adenylyl cyclase
membrane segments, thereby directly stabilizing the active recep- Muscarinic (type II) Ca2+ channels
tor conformation. Other agonists, such as large polypeptide K+ channels
hormones, bind primarily to the extracellular domain of their αq α1-Adrenergic PLCβ
GPCRs. More recently, a number of orphan GPCRs have been β/γ Adenylyl cyclase (+ or –)
found to be activated by hydrophobic ligands including steroids PLC Supports βARK-mediated
(eg, estrogen binding to GPR30) and lipids (eg, LPA binding to receptor phosphorylation and
GPR23). Ligand binding indirectly results in movement of the desensitization
transmembrane region of the receptor and stabilization of the
active receptor conformation.
Until recently, it was thought that GPCRs function exclusively G proteins are noncovalently tethered to the plasma membrane
as monomers. Many GPCRs are now known to dimerize either and are thus proximate to their cognate receptors and to their
with themselves (homodimerization) or with other GPCRs (het- effector targets. The basis for specificity in receptor–G protein
erodimerization). In some cases, dimerization is important for interactions has not been fully defined. It is likely that specific
efficient receptor biosynthesis and membrane localization. In structural determinants presented by the cytoplasmic loops of the
other cases, dimerization is important for optimal ligand affinity, GPCR determine the identity of the G proteins that are activated.
specificity, or receptor signaling. It is the nature of the α subunit of the G protein that is critical for
Heritable mutations in a variety of GPCRs are known to be receptor signaling. There are about a dozen different G protein α
associated with disease. Loss-of-function phenotypes can result subunits and hundreds of distinct GPCRs.
from mutations that eliminate one or both receptor alleles, or Clearly, each specific G protein can be activated by a large
that result in the synthesis of signaling-defective receptors. Gain- number of different receptors. For example, Gs is activated by
of-function phenotypes generally result from point mutations receptors for ligands as diverse as β-adrenergic catecholamines and
that produce constitutively active receptors (ie, stably assume the large polypeptide hormones such as luteinizing hormone (LH).
active receptor conformation even in the absence of an agonist LH is thereby able to stimulate adenylyl cyclase and raise intracel-
ligand). Examples of such GPCR disorders relevant to endocri- lular levels of cAMP in cells that express LH receptors (eg, Leydig
nology are described later and discussed in greater detail else- cells of the testis). In contrast, an individual GPCR can couple to
where in this book. multiple Gα subunits, often in response to different ligands (eg,
PTH receptor can activate Gs, Gi, and Gq).
Figure 1–5 is a schematic representation of the molecular
G PROTEIN TRANSDUCERS events associated with activation of G proteins by GPCRs. In the
basal, inactive state, the G protein is an intact heterotrimer with
G proteins are a family of heterotrimeric proteins that regulate guanosine diphosphate (GDP) bound to the α subunit. Agonist
the activity of effector molecules (eg, enzymes, ion channels) binding to a GPCR promotes the physical interaction between the
(examples in Table 1–2), ultimately resulting in biological receptor and its cognate G protein. This produces a conforma-
responses. The identity of a G protein is defined by the nature tional change in the G protein, resulting in the dissociation of
of its α subunit, which is largely responsible for effector activa- GDP. This in turn allows the binding of GTP (which is present at
tion. The major G proteins involved in hormone action (and a much higher concentration in cells than is GDP) to the α sub-
their actions on effectors) are Gs (stimulation of adenylyl unit. Dissociation of the GTP-bound α subunit from the βγ
cyclase), Gi (inhibition of adenylyl cyclase; regulation of calcium dimer then occurs, allowing these subunits to activate their effec-
and potassium channels), and Gq/11 (stimulation of phospholi- tor targets. Dissociation of the hormone–receptor complex also
pase C [PLC] β). Recently, GPCRs linked to G12/13 were identi- occurs. The duration of activation is determined by the intrinsic
fied as key inputs of the Hippo/YAP/TAZ transcriptional GTPase activity of the G protein α subunit. Hydrolysis of GTP to
regulators, which play a central role in controlling organ size, GDP terminates the activity and promotes reassociation of the
growth, and integrating extracellular cues. In each of these cases, αβγ trimer, returning the system to the basal state. The GTPase
the β and γ subunits of G proteins are tightly associated with one activity of G protein α subunits can be increased by the action of
another and function as a dimer. In some cases, the βγ subunit proteins termed “regulators of G protein signaling” (RGS pro-
dimer can also regulate effector function. teins) which act by increasing the speed of GTP cycling.

R EFFECTORS
H Numerous effectors have been linked to the GPCRs. A number of
R these are presented in Table 1–2. A great many other G pro-
GTP
teins—not dealt with here—are coupled to physical or biochemi-
cal stimuli but have very limited involvement in hormone action.
R α
H H
As discussed, adenylyl cyclase, perhaps the best studied of the
group, is activated by Gs (Figure 1–6). This activation results in a
β/γ transient increase in intracellular cAMP levels. The cAMP binds
α GDP to the inhibitory regulatory subunit of inactive protein kinase A
β/γ GDP (PKA) and promotes its dissociation from the complex, thereby
α permitting enhanced activity of the catalytic subunit. The latter
β/γ GTP phosphorylates a variety of cellular substrates, among them the
E hepatic phosphorylase kinase that initiates the enzymatic cascade
which results in enhanced glycogenolysis. It also phosphorylates
and activates the cAMP response element–binding protein
α α (CREB), which mediates many of the known transcriptional
GDP E GTP responses to cAMP (and to some extent calcium) in the nuclear
compartment. Other transcription factors are also known to be
Pi Biologic effect
phosphorylated by PKA.
FIGURE 1–5 G protein–mediated signal transduction. α and β/γ PLC beta (PLCβ) is a second effector system that has been
subunits of a representative G protein are depicted (see text for studied extensively. The enzyme is activated through Gq-mediated
details) (E, effector; H, hormonal ligand; R, hormone receptor).
Epinephrine Transport to
extracellular space
β-AR Adenylyl
Gs cyclase ATP
cAMP
PKA
regulatory
R cAMP
subunit
R R Phosphodiesterase
PKA 5'-AMP
PKA
catalytic
subunit
Nucleus
Phosphorylate
cytosolic enzymes Core
(eg, phosphorylase transcription
kinase) factors
CREB CREB
TGACGTCA
PO4 PO4
Increased
transcription
CREB CREB
TGACGTCA
FIGURE 1–6 β-Adrenergic receptor/Gs mediated signaling in the cytoplasmic and nuclear compartments. The cAMP response element–
binding protein (CREB) is depicted bound to a consensus CRE in the basal state. Phosphorylation of this protein leads to activation of the juxta-
posed core transcriptional machinery.

transduction of signals generated by a wide array of hormone– However, not all PKC activity derives from the breakdown of
receptor complexes, including those for angiotensin II, α-adrenergic PIP2 substrate. Metabolism of phosphatidylcholine by PLCPC
agonists, and endothelin. Activation of the enzyme leads to cleav- (phosphatidylcholine-selective phospholipase) leads to the genera-
age of phosphoinositol 4,5-bisphosphate in the plasma membrane tion of phosphocholine and DAG. This latter pathway is believed
to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol to be responsible for the more protracted elevations in PKC activ-
(DAG) (Figure 1–7). The former interacts with a specific receptor ity seen following exposure to agonist.
present on the endoplasmic reticulum membrane to promote Other phospholipases may also be important in hormone-
release of Ca2+ into the cytoplasmic compartment. The increased dependent signaling. Phospholipase D employs phosphatidylcho-
calcium, in turn, may activate protein kinases, promote secretion, line as a substrate to generate choline and phosphatidic acid. The
or foster contractile activity. Depletion of intracellular calcium latter may serve as a precursor for subsequent DAG formation. As
pools by IP3 results in enhanced uptake of calcium across the with PLCPC earlier, no IP3 is generated as a consequence of this
plasma membrane (perhaps through generation of IP4 [1,3,4,5- reaction. Phospholipase A2 triggers release of arachidonic acid, a
tetrakisphosphate]), thereby activating a second, albeit indirect, precursor of prostaglandins, leukotrienes, endoperoxides, and
signaling mechanism that serves to increase intracellular calcium thromboxanes, all signaling molecules in their own right. The rela-
levels even further. DAG functions as an activator of several protein tive contribution of these other phospholipases to hormone-
kinase C (PKC) isoforms within cells. Several different isoforms of mediated signal transduction and the role of the specific lipid
PKC (eg, α, β, γ) may exist in a given cell type. A number of these breakdown products (eg, phosphocholine, phosphatidic acid) in
are calcium-dependent, a property which, given the IP3 activity conveying regulatory information remains an area of active research.
mentioned earlier, provides the opportunity for a synergistic inter- Activation of effectors by GPCRs is subject to regulatory
action of the two signaling pathways driven by PLCβ activity. mechanisms that prevent overstimulation of cells by an agonist
Ligand
PLCPC PLCβ2
Phosphatidyl- Receptor PIP2

choline
G? Gq
Choline
DAG DAG IP3
PKC
+ Ca2+
Ca2+
Cytoplasmic and
membrane Ca2+
protein Calmodulin
phosphorylation
Ca2+-calmodulin
CaM kinase
+ Nucleus
+
Increased
transcription
c-jun c-fos CREB CREB
TGACTCA TGACGTCA
Core transcription factors
FIGURE 1–7 PLCβ-coupled receptor/Gq mediated signaling in the cytoplasmic and nuclear compartments (DAG, diacylglycerol;
PC, phosphatidylcholine; PKC, protein kinase C; PLC, phospholipase).

H
H
H H
H
R
ACa
G
ATP cAMP
PKA
β-ARK
Receptor
Adenylyl cyclase
R R
ACi ACi
G P
G protein
Phosphatase
Arrestin
FIGURE 1–8 Kinase-dependent desensitization of the ligand–receptor complex. Schema shown is that for the β-adrenergic receptor, but
similar systems probably exist for other types of G protein–linked receptors (ACa, active adenylyl cyclase; ACi, inactive adenylyl cyclase; β-ARK,
β-adrenergic receptor kinase; PKA, protein kinase A).
ligand. At the level of the receptor, two regulatory events are known lowering steady-state receptor levels. Together, these regulatory
to occur. One is desensitization, wherein initial stimulation of a events ensure that the cell is protected from excessive stimulation
receptor by its agonists leads to a loss of the ability of the receptor in the presence of sustained high levels of an agonist.
to subsequently elicit G protein activation. This is shown schemati- Recently, it has become clear that these events serving to
cally in Figure 1–8 for the β-adrenergic receptor. A similar regula- dampen G protein signaling can also have important roles in pro-
tory mechanism exists for many other GPCRs. Agonist binding to moting cell signaling. For example, arrestin association with
the receptor produces G protein activation and results also in acti- GPCRs can activate specific pathways such as the MAP kinase
vation of a kinase (termed G protein–coupled receptor kinase, pathway independently of G protein signaling. In addition, inter-
GRK) that phosphorylates the cytoplasmic domain of the receptor. nalized GPCRs can, in some cases, retain the ability to signal, and
By virtue of this phosphorylation, the receptor acquires high affin- the effects may differ from those produced when activation occurs
ity for a member of the arrestin family of proteins. The name at the plasma membrane.
“arrestin” derives from the observation that the receptor is no lon-
ger capable of interacting with a G protein when arrestin is bound.
Thus, the phosphorylated receptor becomes uncoupled from its G DISORDERS OF G PROTEINS AND G
protein, preventing signaling to the effector. The receptor remains PROTEIN–COUPLED RECEPTORS
inactive until a phosphatase acts to restore the receptor to its
unphosphorylated state thus releasing the bound arrestin. Recently, Two bacterial toxins are capable of covalently modifying specific G
β arrestin-dependent signaling pathways have been identified protein α subunits, thereby altering their functional activity. Chol-
where the arrestins can link GPCRs to intracellular signaling such era toxin is a protein that binds to receptors present on all cells,
as the MAPK cascades. Beta arrestins also appear to act directly as resulting in the internalization of the enzymatic subunit of the
signal transducers by interacting with regulators of transcription toxin. The toxin enzyme is an ADP-ribosyl transferase that trans-
201
factors. This receptor-independent signaling capacity likely has fers ADP-ribose from NAD to an acceptor site (Arg ) on the α
implications for endocrine diseases including those affecting bone. subunit of Gs. This covalent modification greatly inhibits the
Many GPCRs are also susceptible to agonist-induced down- GTPase activity of αs, enhancing the activation of adenylyl cyclase
regulation, resulting in a reduced level of cell surface receptors by extending the duration of the active GTP-bound form of the G
following exposure of cells to an agonist. This can result from protein. Even in the absence of an active GPCR, GDP dissociates
agonist-induced internalization of receptors, followed by traffick- (albeit very slowly) from the G protein. Thus, cholera toxin will
ing of receptors to lysosomes where degradation occurs. In addi- eventually activate adenylyl cyclase activity even without agonist
tion, chronic exposure of cells to an agonist may result in signaling binding to a GPCR. The result is a large and sustained activation
events that suppress the biosynthesis of new receptors, thereby of adenylyl cyclase. When this occurs in intestinal epithelial cells,

the massive increase in cAMP results in the increased water and salt with haploinsufficiency of αs are resistant to PTH. Interestingly,
secretion into the gut that is characteristic of cholera. essentially all patients with haploinsufficiency of Gαs display
Pertussis toxin is also an ADP-ribosyl transferase. However, in Albright hereditary osteodystrophy, a developmental disorder with
this case, the substrates are α subunits of different G proteins, phenotypic manifestations affecting a variety of tissues. This indi-
most notably Gi and Go. The ADP-ribose moiety is transferred to cates that even a partial loss of adenylyl cyclase signaling is incom-
a cysteine residue near the carboxyl terminus of the α subunit, a patible with normal development.
region required for interaction with activated GPCRs. Once Mutations in the genes encoding GPCRs are being increasingly
ADP-ribosylated by pertussis toxin, these G proteins are no longer recognized as important in the pathogenesis of endocrine disorders.
able to interact with activated receptors and are thus stuck in an Loss-of-function mutations generally need to be homozygous (or
inactive (GDP-bound) conformation. Inhibition of receptor- compound heterozygous) in order to result in a significant disease
mediated activation of Gi and Go accounts for many of the clinical phenotype. This is probably due to the fact that most cells express
manifestations of pertussis infection. higher levels of each receptor, above what is needed for maximal cel-
Genetic mutations in G protein α subunits are seen in a number lular response (spare receptors). Thus, a 50% reduction in the
of human diseases. Acquired activating mutations in Gαs can pro- amount of a cell surface receptor may have little influence on the
duce a variety of phenotypes depending on the site of expression of ability of a target cell to respond. However, in some situations, hap-
the mutant protein. In McCune-Albright syndrome, the mutation loinsufficiency of a GPCR can produce a clinical phenotype. For
occurs in a subset of neural crest cells during embryogenesis. All of instance, heterozygous loss-of-function mutations in the G protein–
the descendants of these cells, including certain osteoblasts, melano- coupled calcium-sensing receptor results in the autosomal dominant
cytes, and ovarian or testicular cells, express the mutant protein. The disorder familial hypocalciuric hypercalcemia type 1 due to usually
result is a form of genetic mosaicism in which the consequence of mild dysregulation of PTH secretion and renal calcium handling.
unregulated production of cAMP in particular tissues is evident (ie, Homozygous loss-of-function of the calcium-sensing receptor results
the progressive bone disorder polyostotic fibrous dysplasia, the in severe neonatal hyperparathyroidism due to the loss of the ability
abnormal skin pigmentation referred to as café au lait spots, and of plasma calcium to suppress PTH secretion and promote renal
gonadotropin-independent precocious puberty). In cells where calcium clearance. Syndromes of hormone resistance have also been
cAMP is linked to cell proliferation (eg, thyrotropes, somatotropes), reported in patients lacking expression of functional GPCRs for
a subset of patients with benign tumors has been shown to have vasopressin, ACTH, and TSH. Loss of functional expression of the
acquired activating mutations in Gαs. Activating mutations in Gαi2, PTH receptor results in Blomstrand chondrodysplasia, a disorder
which is coupled to cell proliferation, have been reported in a subset that is lethal due to the inability of PTH-related protein (a PTH
of adrenal and ovarian tumors. receptor agonist) to promote normal cartilage development.
Loss-of-function mutations in Gαs are associated with the Mutations that render GPCRs constitutively active (in the
hereditary disorder pseudohypoparathyroidism type 1 (PHP-1a). absence of an agonist ligand) are seen in a number of endocrine
This disorder, first described by Fuller Albright, was the first docu- disorders. Generally speaking, such mutations produce a disease
mented example of a human disease attributable to target cell phenotype resembling that seen with excessive levels of the corre-
resistance to a hormone. Affected patients display biochemical sponding hormone agonist. Thus, activating mutations in the TSH
features of hypoparathyroidism (eg, hypocalcemia, hyperphospha- receptor produce neonatal thyrotoxicosis, and activating mutations
temia) but have markedly increased circulating levels of PTH and in the LH receptor result in pseudoprecocious puberty or testotoxi-
display target cell resistance to PTH. Many hormone receptors cosis. Activating mutations in the PTH receptor result in Jansen-
couple to adenylyl cyclase via Gαs, yet patients with PHP-1a gen- type metaphyseal chondrodysplasia; a disorder characterized by
erally display only subtle defects in responsiveness to other hor- hypercalcemia and increased bone resorption (mimicking the effects
mones (eg, TSH, LH). The explanation for this lies in the of excess PTH on bone) and delayed cartilage differentiation (mim-
fascinating genetics of this disorder. In brief, affected patients have icking the effects of excess PTH-related protein on cartilage). An
one normal and one mutated Gαs allele. The mutated allele fails approach to treating disorders resulting from constitutively active
to produce an active form of the protein. Tissues in these patients GPCRs would be administration of “inverse agonists,” agents that
are expected to express about 50% of the normal level of Gαs, a stabilize receptors in their inactive conformation. Although inverse
level sufficient to support signaling to adenylyl cyclase. However, agonists have been identified for a number of GPCRs, they have yet
in certain tissues, the αs gene is subject to genetic imprinting such to be successfully employed as therapeutics. In contrast, molecular
that the paternal allele is expressed poorly or not at all. In indi- mimics of endogenous ligands have found utility as a way to stimu-
viduals harboring inactivating mutations, if the paternal allele has late signaling via allosteric receptor changes. This is the basis for
the mutation, all cells express about 50% of the normal level of cinacalcet’s activity as a calcimimetic on the calcium-sensing recep-
Gαs (derived from the normal maternal allele). However, if the tor in the parathyroid cell and accounts for its utility in treating
maternal allele has the mutation, then the cells in which paternal secondary hyperparathyroidism. Finally, molecular analysis of
imprinting occurs express low levels or no Gαs. One of the major GPCRs has revealed that point mutations, in addition to producing
sites of this paternal imprinting is in the proximal renal tubule, an constitutive activity, can alter the specificity of ligand binding or the
important target tissue for the physiologic actions of PTH. This ability of the receptor to become desensitized. It is almost certain
accounts for the clinical resistance to PTH seen in PHP-1a and that such mutations will be found to provide the basis for some
accounts also for the fact that only a subset of patients more subtle endocrinopathies.

GROWTH FACTOR RECEPTORS receptor dimerization. The duration of signaling can be regulated
by clathrin, a protein that is required for cellular endocytosis.
The growth factor receptors differ from those described earlier Internalization of the ligand/receptor complex results in phos-
both structurally and functionally. Unlike the GPCRs, the growth phorylation of tyrosines both on the receptor itself as well as on
factor receptors span the membrane only once and acquire their nonreceptor substrates. It is assumed that phosphorylation of
signaling ability, at least in part, through activation of tyrosine these substrates results in a cascade of activation events, similar to
kinase activity, which is intrinsic to the individual receptor mole- those described for the G protein–coupled systems, which con-
cules. The insulin and IGF receptors fall within this group, as do tribute to perturbations in intracellular pathways. The autophos-
those for the autocrine or paracrine regulators platelet-derived phorylation of the receptor molecules themselves has been studied
growth factor (PDGF), fibroblast growth factor (FGF), and EGF. extensively and provide some intriguing insights into the mecha-
Signaling is initiated by the association of ligand (eg, insulin) with nisms that underlie signal transduction by this group of proteins.
the receptor’s extracellular domain (Figure 1–9) and subsequent Tyrosine phosphorylation takes place at specific locations in
the receptor molecule. Once phosphorylated, these sites associ-
ate, in highly specific fashion, with a variety of accessory proteins
that possess independent signaling capability. These include
PLCγ, phosphoinositol (PI) 3′ kinase, GTPase-activating protein
Ligand (GAP), growth factor receptor–bound protein-2 (GRB2), and
the Src family nonreceptor tyrosine kinases. These interactions
Receptor are fostered by the presence of highly conserved type 2 src
homology (based on sequence homology to the src proto-onco-
gene) domains (SH2) in each of the accessory molecules. Each
individual SH2 domain displays specificity for the contextual
amino acids surrounding the phosphotyrosine residues in the
Y Y P receptor molecule. In the PDGF receptor, for example, the SH2
domain of PLCγ associates selectively with Tyr977 and Tyr989,
whereas that of PI 3′ kinase associates with Tyr708 and Tyr719.
Thus, diversity of response is controlled by contextual sequences
around individual phosphotyrosine residues that determine the
types of accessory proteins brought into the signaling complex.
These protein–protein interactions may provide a means of
directly controlling the signaling molecule in question, perhaps
P P through a change in steric conformation. Alternatively, they may
Y Y
SH3
SH3
facilitate the sequestration of these accessory proteins in or near

SH2 SH2
the plasma membrane compartment, in close proximity to key
substrates (eg, membrane lipids in the case of PLCγ) or other
Y
Y
P important regulatory proteins.

Some of these associations trigger immediate signaling
events, but others (eg, GRB2) may act largely to provide the
scaffolding needed to construct a more complex signaling
Further apparatus (Figure 1–10). In the case of GRB2, another acces-
Biologic
complex sory protein (son-of-sevenless; SOS) associates with the recep-
assembly tor–GRB2 complex through a type 3 src homology (SH3)
effect
domain present in the latter. This domain recognizes a sequence
P
of proline-rich amino acids present in the SOS protein. SOS, in
Y
SH3
turn, facilitates assembly of the Ras–Raf complex, which permits

SH2
Biologic activation of downstream effectors such as mitogen-activated
effect protein kinase (MAPK) kinase (MEK). This latter kinase, which
Y
P possesses both serine-threonine and tyrosine kinase activity, acti-

vates the p42 and p44 MAPKs (also called extracellular signal–
FIGURE 1–9 Signaling by a tyrosine kinase–containing growth regulated kinases; ERKs). ERK acts on a variety of substrates
factor receptor. Receptors depicted here as monomers for simplicity;
typically dimerization of receptors follows association with ligand.
within the cell, including the RSK kinases, which, in turn,
Autophosphorylation of one or more critically positioned tyrosine phosphorylate the ribosomal S6 protein and thereby stimulate
residues in the receptor leads to association with accessory proteins protein synthesis. These phosphorylation reactions (and their
or effectors through SH2 domains present on the latter. In some amplification in those instances where the MAPK substrate is a
cases, an SH3 domain present on the same protein leads to recruit- kinase itself ) often lead to protean changes in the phenotype of
ment of yet other proteins leading to further complex assembly. the target cells.

Ligand
PIP3
PI(3,4)P2
P Raf-1
p110 GRB2 SOS Ras
PKB p85 P MEK-1
P
PI3K
P ERK
PDK1
PDK2
ERK
6-PFK SRF AP-1

GSK3
GLUT4
S6 kinase
FIGURE 1–10 Growth factor–dependent pathway. Assembly of the components involved in the Ras/Raf/MEK/MAPK and PI-3K/PKB–
signaling mechanisms.
The ligand bound growth factor receptors, including the insulin through a nonreceptor protein tyrosine kinase (NRPTK such as
receptor, may also signal through the phosphoinositide 3-OH kinase Src and Fyn) rather than the traditional growth factor receptor–
(PI-3K). SH2 domains of the p85 regulatory subunit of PI-3K asso- linked tyrosine kinases. The details of the mechanism are incom-
ciate with the growth factor receptor through specific phosphotyro- pletely understood, but it appears to require the participation of
sine residues (Tyr740 and Tyr751 in the PDGF receptor) in a manner β-arrestin (discussed earlier) as an adaptor molecule linking the G
similar to that described earlier for GRB2 (see Figure 1–10). This protein receptor to the NRPTK. Interestingly, this implies that
leads to activation of the p110 catalytic subunit of PI-3K and β-arrestin, which normally terminates coupling between the
increased production of phosphatidylinositol-3,4,5-trisphosphate receptor and G protein, can actually promote coupling between
(PIP3) and phosphatidylinositol-3,4-bisphosphate (PI[3,4]P2). These the desensitized receptor and downstream effectors traditionally
latter molecules sequester protein kinase B (also known as Akt) at the associated with growth factor–dependent activation.
cell membrane through association with the plekstrin homology
domains in the amino terminal of the kinase molecule. This in turn
leads to phosphorylation of PKB at two separate sites (Thr308 in the CYTOKINE RECEPTORS
active kinase domain and Ser473 in the carboxyl terminal tail) by
These include the receptors for a variety of cytokines, such as
PIP3-dependent kinases (PDK1 and PDK2). These phosphoryla-
erythropoietin, colony-stimulating factor, GH, and prolactin.
tions result in activation of PKB. In the case of insulin-sensitive tar-
These cell membrane receptors have a single internal hydrophobic
get cells, downstream targets of activated PKB (eg, following insulin
stretch of amino acids, suggesting that they span the membrane
stimulation) include 6-phosphofructo-2-kinase (increased activity),
once (see Figure 1–4). They can be composed of monomers or
glycogen synthase kinase-3 (GSK3) (decreased activity), the insulin-
heterodimers of different molecules.
responsive glucose transporter GLUT 4 (translocation and increased
activity), and p70 S6 kinase (increased activity). This leads to
increased glycolysis, increased glycogen synthesis, increased glucose Growth Hormone and Prolactin Receptors
transport, and increased protein synthesis, respectively. There is also Receptors for GH and prolactin are prototypical cytokine recep-
a growing body of evidence suggesting that PKB may protect cells tors (Figure 1–11). Interestingly, alternative splicing of the GH
from programmed cell death through phosphorylation of key pro- receptor gene primary transcript results in a foreshortened “recep-
teins in the apoptotic pathway. tor” that lacks the membrane anchor and carboxyl terminal
It has been reported that GPCRs may also activate the Raf- domain of the protein. This “receptor” is secreted and serves to
MEK-ERK cascade, although in this case the signal traffics bind GH in the extracellular space (eg, circulating plasma). Unlike

GH
GH
GHR GHR GHR GHR
Y Y P JAK2 Y Y JAK2 P
Y Y
JAK2 JAK2
Y Y
P P
STAT STAT
GH
STAT STAT
GHR GHR P P
Transcription
JAK2 JAK2 DNA
P Y Y Y Y P SIE GAS ISRE
P P
STAT STAT
P P
FIGURE 1–11 Signaling by the growth hormone receptor (GHR). Different portions of a single growth hormone molecule associate with
homologous regions of two independent GHR molecules. This is believed to lead to the recruitment of JAK2, which phosphorylates the GHR,
providing a docking site for STAT. The latter is phosphorylated, dissociates from the liganded receptor complex, and migrates to the nucleus,
where it associates with binding elements of target genes and regulates transcription.
the growth factor receptors described earlier, GH receptors lack a bone morphogenetic protein (BMP) family. Diseases associated
tyrosine kinase domain. Different domains of a single GH mole- with mutations in the TGF-β receptor pathways can be very
cule associate with homologous regions of two independent GH dramatic. For example, activating mutations in the type 1
receptors, promoting dimerization of the receptors and subse- activin A receptor ACVR1 result in severe heterotopic ossifica-
quent association with and activation of Janus kinase (JAK) 2. tion in a disorder known as fibrodysplasia ossificans progressiva
Janus kinase 2 (JAK2) undergoes autophosphorylation and con- (FOP). The ligands for these receptors are typically homo- or
currently tyrosine phosphorylates the GH receptors. The latter heterodimers of subunits that have a highly conserved, cyste-
provides a docking site for the signal transducer and activator of ine-dependent structure. TGF-β family receptors bind to
transcription (STAT) factors; STAT 5a and 5b appear to be par- ligands through a heterodimeric receptor consisting of two
ticularly relevant to GH and prolactin action. The STATs are transmembrane subunits known as type I and type II receptors
phosphorylated, dissociate from the GH receptor, migrate to the (Figure 1–12). There are a number of different type I and type
nucleus, and bind to specific STAT-binding DNA regulatory ele- II receptor subunits in this family and type I/type II pairs can
ments (SIE/ISRE/GAS) responsible for transcriptional control of form between several different family members. Both type I
GH target genes such as IGF-1. There are a number of different and type II receptors have an intracellular serine/threonine
STAT family members, and there is specificity of certain cytokine kinase domain. The type II receptor is constitutively phos-
receptors for certain STAT family members. This helps direct the phorylated and active, while the type I receptor is not. The
specificity of signaling by each type of receptor. STAT signaling is ligands in this family initially bind the type II receptor. The
also regulated by a family of inhibitors referred to as suppressor of type I receptor is then recruited to the complex where the type
cytokine signaling (SOCS) proteins. SOCS proteins bind to JAK II receptor kinase phosphorylates and activates the type I
and STAT proteins and target them for degradation. SOCS pro- receptor, which then further propagates the signal. Down-
teins are induced after cytokine/hormone binding and help to stream in the signaling pathway are a group of phosphorylation
autoregulate signaling in this pathway. targets called the Smad proteins. These proteins, upon phos-
phorylation, can migrate to the nucleus to activate and/or
repress transcription of target genes.
TGF-a Receptors Modulators of TGF-β signaling also play critical roles in
These receptors bind a variety of ligands that include the cyto- human disease. Members of the differential screening-selected
kine transforming growth factor beta (TGF-β), the hormones gene in neuroblastoma (DAN) family were originally identified
inhibin, activin, anti-müllerian hormone (AMH), and the as BMP inhibitors and comprise a diverse group of antagonists.

Type II receptor Type I receptor Type II receptor Type I receptor

P P
P P
TGF-β
TGF-β
Type II receptor Type I receptor

P P
P P P
P
Smad Smad P
FIGURE 1–12 Signaling by the TGF-β receptors. TGF-β ligand first docks with the type II receptor which has an intracellular serine/
threonine kinase domain that is constitutively active. After ligand binding, the type I receptor is then recruited to the complex and the type II
receptor can phosphorylate the intracellular serine/threonine kinase domain of the type I receptor. This then propagates the signal downstream
leading to the phosphorylation and activation of Smad proteins which can migrate to the nucleus and activate or repress gene transcription.
One DAN protein, sclerostin (SOST), is of particular interest proteasome pathway. NF-κB then translocates to the nucleus
because of its key role in regulating osteoblast anabolic function where it regulates gene transcription.
through the LRP5/6 and Frizzled receptors that bind Wnt.
Patients with loss of function mutations in SOST show dramati-
cally increased bone mass and sclerosteosis or van Buchem dis- WNT/Beta Catenin
ease. Antibodies that inhibit sclerostin activity show great Signaling through the Wnt/β-catenin complex is critical for
promise as bone anabolic agents for treating conditions associ- embryonic development and cellular homeostasis. The β-catenin
ated with bone loss.
Ligand
TNF-Receptors
The tumor necrosis factor (TNF) family of receptors is a large TNF-receptor
group of cytokine receptors that bind to both soluble and cell-
membrane-associated ligands. One important member of this Cytoplasm
family is the receptor activator of nuclear factor kappa B
(RANK) which plays a critical function in the regulation of Degradation
IKK IKK P
bone physiology (see Chapter 8). These receptors consist of a Iκ−B
P
trimeric complex of three single transmembrane receptors that
bind to ligand. The cytoplasmic tail of many TNF-receptors Iκ−B
(including RANK) interacts with a family of adapter molecules Nucleus
NFκ−B NFκ−B
called TNF receptor–associated factors (TRAFs) that further
Activation and/or
activate a number of downstream pathways, the most of repression of
important of which is the activation of nuclear factor kappa B gene
transcription
(NF-κB) (Figure 1–13). Activation of NF-κB is a central event
in many if not all inflammatory responses and leads to the
induction of many molecules including those involved in apop-
totic, cytokine, and chemokine pathways. TNF-receptor signal-
FIGURE 1–13 TNF receptor signaling. TNF binds to a trimolecu-
ing leads to the activation of NF-κB through phosphorylation
lar cell surface receptor which transmits a downstream signal that
of the heterotrimeric I-κB kinase (IKK) complex, which then leads to the phosphorylation and activation of the I-κB kinase (IKK).
phosphorylates the inhibitor of NF-κB (I-κB). I-κB complexes IKK phosphorylates the inhibitor of NF-κB (I-κB) which is then tagged
with NF-κB in the cytosol and keeps it inactive; however, when for degradation through a ubiquitin-dependent proteosomal path-
I-κB is phosphorylated it dissociates from the complex and way. This allows NF-κB to migrate to the nucleus where it can carry
undergoes degradation through the ubiquitin-dependent out activation or repression of gene transcription.

proteins are found in two main complexes: as a cadherin cel- through phosphorylation by glycogen synthase kinase 3 alpha and
lular adhesion protein-bound form in adherens junctions beta (GSK3α and β) and casein kinase I (CKI). This process is
(Figure 1–14A), and in a complex with APC, Axin, and GSK3 as amplified by the scaffolding proteins Disheveled and Axin. These
part of the Wnt signaling pathway (Figure 1–14B). components assemble to create a large complex that marks β-catenin
At the cell membrane, β-catenins serve to promote cell-cell adhe- molecules for subsequent destruction by proteasomes.
sions by linking cadherins to actin filaments (see Figure 1–14A). Recently, the activation of the Wnt/β-catenin pathway in
Mutations in β-catenins appear to play a critical role in the pro- osteocytes has been identified as a critical regulator of anabolic
gression towards cancer by regulating the degradation of the bone activity, while activation of the same pathway in osteoblasts
Wnt/β-catenin complex or by changing cellular adhesion proper- may be responsible for decreased bone resorption. As described
ties. These mutations are found in colorectal, breast, ovarian, and previously, mutations in the Wnt receptor LRP5/6 can also
endometrial cancers. change osteoblast anabolic function, contributing to high bone
Beta-catenin can also be regulated by secreted Wnt proteins, mass (activating mutations in LRP5) and diseases such as osteopo-
providing a key link between extracellular Wnt signaling and activa- rosis-pseudoglioma syndrome (loss of function mutations in
tion of genetic developmental programs (see Figure 1–14B). In the LRP5). These features make the Wnt/β-catenin pathway particu-
Wnt signaling pathway, levels of β-catenins are primarily controlled larly intriguing as a therapeutic target for a wide spectrum of
by ubiquitination and proteosomal degradation. This is triggered disorders.
Cadherin
β-Catenin β-Catenin
α-Catenin α-Catenin
F actin F actin
B Off On
LRP5/6 Wnt LRP5/6
Wnt
Wnt
Frizzled Frizzled
P
CKI P GSK3 l
Dvl Dv
Axin
AP Ub
C β-Catenin
GSK3 PPPP β-Catenin
Axin
β-Catenin β-Trcp
PPPP β-Catenin
CKI
Proteosome
degradation
TLE β-Catenin
TCF TCF
Wnt responsive gene Wnt responsive gene
FIGURE 1–14 Beta-catenin signaling. β-catenin proteins are found in two main signaling complexes: as a cadherin cellular adhesion pro-
tein-bound form in adherens junctions (A) that promotes cell-cell adhesion and as part of the Wnt signaling pathway in a complex associated
with APC, Axin, and GSK3 (B). When the pathway is inactive, the β-catenin complex forms and CKI adds the 4th phosphate, thus activating ubiq-
uitination and subsequent proteasome degradation of β-catenin. Activation of the Wnt signaling receptors Frizzled and LRP5/6 allows unphos-
phorylated β-catenin to enter the nucleus and activate Wnt responsive genes.

GUANYLYL CYCLASE–LINKED The inducible (i) form of NO synthase (NOS-2) is found pre-
dominantly in inflammatory cells of the immune system, although
RECEPTORS it has also been reported to be present in smooth muscle cells of
Activation of guanylyl cyclase–dependent signaling cascades can the vascular wall. Unlike the endothelial form of NO synthase,
occur through two independent mechanisms. The first involves expression of iNO synthase is low in the basal state. Treatment of
activation of the soluble guanylyl cyclase, a heme-containing cells with a variety of cytokines triggers an increase in new iNO
enzyme that is activated by the gas nitric oxide (NO) generated in synthase synthesis (hence, the inducible component of iNO syn-
the same or neighboring cells. NO is produced by the heme-con- thase activity), probably through activation of specific cis elements
taining enzyme nitric oxide synthase. NO synthase exists as three in the iNO synthase promoter. Thus, hormones, cytokines, or
different isozymes in selected body tissues. Constitutive forms of growth factors with the capacity for induction of iNO synthase
NO synthase (NOS) are produced in endothelial (NOS-3) and activity may direct at least a portion of their signaling activity
neuronal (NOS-1) cells. The endothelial enzyme possesses bind- through a cGMP-dependent pathway.
ing sites for FAD and FMN as well as calcium and appears to A third mechanism for increasing cGMP levels within target
require calcium for optimal activity. Endothelial NOS activity is cells involves the activation of particulate guanylyl cyclases
regulated by myristoylation and palmitoylation, which anchor the (Figure 1–16). From an endocrine standpoint, this involves
enzyme in the membrane compartment, and by phosphorylation. predominantly the natriuretic peptide receptors (NPR). NPR-A is
Agents such as bradykinin and acetylcholine, which interact with a single-transmembrane-domain receptor (about 130 kDa) with a
receptors on the surface of endothelial cells and increase intracel- large extracellular domain that provides ligand recognition and
lular calcium levels, trigger an increase in constitutive NO syn- binding. This is followed by a hydrophobic transmembrane
thase activity with consequent generation of NO and activation of domain and a large intracellular domain that harbors the signaling
soluble guanylyl cyclase activity in neighboring vascular smooth function. The amino terminal portion of this intracellular region
muscle cells (Figure 1–15). Thus, in this instance, the cGMP- contains an ATP-binding kinase homology domain (KHD) that is
dependent vasodilatory activity of acetylcholine requires sequen- involved in regulating cyclase activity, whereas the carboxyl termi-
tial waves of signaling activity in two different cell types to realize nal domain contains the catalytic core of the particulate guanylyl
the ultimate physiologic effect. cyclase. It is believed that association of ligand with the
Acetylcholine
Bradykinin
O2 Arginine
Ca2+ eNOS Endothelium
NO Citrulline
+
Smooth
NO Soluble GC muscle
Soluble GC
iNOS GTP cGMP
GTP cGMP PKG PKG
−
Vasorelaxation
Steroids
Cytokines
FIGURE 1–15 Signaling through the endothelial (e) and inducible (i) nitric oxide synthases (NOS) in the vascular wall. Activation of eNOS
in the endothelial cell or iNOS in the vascular smooth muscle cell leads to an increase in NO and stimulation of soluble guanylyl cyclase (GC)
activity. Subsequent elevations in cGMP activate cGMP-dependent protein kinase (PKG) and promote vasorelaxation.

homozygous mutation of the NPR-B genes results in acromeso-

Natriuretic peptide ligand melic dysplasia Maroteaux type (AMDM), a rare form of autoso-
mal recessive, short-limbed dwarfism.
NUCLEAR ACTION OF PEPTIDE

HORMONES
Extracellular ligand-binding
domain
Although the initial targets of peptide hormone receptor signaling
appear to be confined to the cytoplasm, it is clear that these recep-
Plasma
membrane
tors can also have profound effects on nuclear transcriptional
Kinase homology activity. They accomplish this through the same mechanisms they
domain
use to regulate enzymatic activity in the cytoplasmic compartment
(eg, through activation of kinases and phosphatases) via second-
Rac/PAK-1
Particulate guanylyl messengers that transmit information into the nucleus. In this
cyclase case, however, the ultimate targets are transcription factors that
govern the expression of target genes. Examples include hormonal
activation of c-Jun and c-Fos nuclear transcription factors that
GTP cGMP make up the heterodimeric AP-1 complex. This complex has been
shown to alter the expression of a wide variety of eukaryotic genes
PDE PKG Direct effects through association with a specific recognition element, termed
ion channels
the phorbol ester (TPA) response element (TRE), present within
FIGURE 1–16 Signaling by particulate guanylyl cyclase. Ligand the DNA sequence of their respective promoters. Other growth
(ANP or BNP for the type A natriuretic peptide receptor or CNP for factor receptors that use the MAPK-dependent signaling mecha-
the type B receptor) associates with the extracellular domain of the nism appear to target the serum response factor (SRF) and its
receptor. This effects a change in the receptor that reduces affinity associated ternary complex proteins. Post-translational modifica-
for ligand and alters conformation of the KHD which, in turn, reverses tion of these transcription factors is believed to amplify the signal
tonic inhibition of particulate guanylyl cyclase activity at the carboxy that traffics from this complex, when associated with the cognate
terminal portion of the receptor. Rac and PAK-1 are thought to acti- serum response element (SRE), to the core transcriptional apparatus.
vate the receptor through a more direct interaction with the guanylyl
The cAMP-dependent activation of protein kinase A results in
cyclase domain. Increased cyclase activity increases cellular cGMP
levels which increase protein kinase G (PKG) activity through a mech-
the phosphorylation of a nuclear protein CREB (cAMP response
anism similar to that described for cAMP (see Figure 1–6), regulates element–binding protein) at Ser119, an event that results in
phosphodiesterase (PDE) activity, and alters the ion transport proper- enhanced transcriptional activity of closely positioned promoters.
ties of the target cell. The latter requires the participation of an intermediate CREB-
binding protein (CBP). CBP is a co-activator molecule that func-
tionally tethers CREB to proteins of the core transcriptional
extracellular domain leads to a conformational change in the machinery. Interestingly, CBP may also play a similar role in
receptor that arrests the tonic inhibitory control of the kinase-like nuclear receptor (NR) signaling (see Nuclear Receptors). Several
domain and permits activation of guanylyl cyclase activity. Recent recent studies have provided evidence suggesting that a number of
studies suggest that the small GTPase Rac can directly activate the peptide hormones and growth factors may bind to high-affinity
catalytic domain through its effector kinase PAK (p21-activated receptors in the cell nucleus. The role these receptors play—if
kinase). NPR-B, the product of a separate gene, has a similar any—in contributing to the signaling profile of these peptides
topology and a relatively high level of sequence homology to the remains undefined.
NPR-A gene product; however, while NPR-A responds predomi-
nantly to the cardiac atrial natriuretic peptide (ANP) and brain
natriuretic peptide (BNP), NPR-B is activated by the C-type NP NUCLEAR RECEPTORS
(CNP), a peptide found in the central nervous system, endothe-
lium, and reproductive tissues but not in the heart. Thus, segre- The NRs, which include those for the glucocorticoids, mineralo-
gated expression of the ligand and its cognate receptor convey a corticoids, androgens, progesterone, estrogens, thyroid hormone,
high level of response specificity to these two systems despite the and vitamin D, differ from the receptors of the surface membrane
fact that they share a common final effector mechanism. Notewor- described earlier in that they are soluble receptors with a proclivity
thy, both NPR-A and NPR-B require a high degree of phosphory- for using transcriptional regulation as a means of promoting their
lation in the KHD to retain sensitivity to agonist. biologic effects. Thus, although some receptors are compartmen-
Dephosphorylation, perhaps through agonist-triggered exposure talized in the cytoplasm (eg, glucocorticoid receptor), whereas
of the phosphoserine residues to regulatory phosphatase activity in others are confined to the nucleus (eg, thyroid hormone receptor),
the target cell, results in receptor desensitization. In humans, they all operate within the nuclear chromatin to initiate the

signaling cascade. These receptors can be grouped into two major STEROID RECEPTOR FAMILY
subtypes based on shared structural and functional properties. The
first, the steroid receptor family, includes the prototypical glucocor- Steroid receptors (ie, GR, MR, AR, and PR), under basal con-
ticoid receptor (GR) and the receptors for mineralocorticoids (MR), ditions, exist as cytoplasmic, multimeric complexes that
androgens (AR), and progesterone (PR). The second, the thyroid include the heat shock proteins (HSPs) 90, 70, and 56 and
receptor family, includes the thyroid hormone receptor (TR) and immunophilins of the FK506 family (FKBP51 and FKBP52).
the receptors for estrogen (ER), retinoic acid (RAR and RXR), and ER, although demonstrating similar association with HSP, is
vitamin D (VDR) as well as the peroxisome proliferator–activated largely confined to the nuclear compartment. Association of
receptor (PPAR). There are also so-called orphan receptors that bear the steroid ligand with the receptor results in dissociation of
structural homology to members of the extended NR family. For the HSP. This in turn exposes a nuclear translocation signal
many of these, the “ligand” is unknown, and their functional roles previously buried in the receptor structure (near DNA binding
in the regulation of gene expression have yet to be determined. Oth- and hinge regions, see later) and initiates transport of the
ers have been linked to specific ligands. For example, PPARs bind receptor to the nucleus, where it associates with the hormone
to fatty acids, FXR with isoprenoids and bile acids, LXR with oxy- response element (Figure 1–17).
sterols, PXR with steroid metabolites, CAR with xenobiotics, and Each of the family members has been cloned and sequenced,
BXR with folic acid derivatives. In total, there are more than 70 and crystallographic structures have been obtained for many of
nuclear receptors and orphan receptors in humans. them. Consequently, we know a great deal about their structure
H
Plasma membrane
HSP
HSP
R
R
HSP
Protein
H H
R R
mRNA
meG AAAA
Nuclear membrane
pre-mRNA
Core
H H transcription
factors
R R
HRE TATA
Alteration nucleosome phasing/

chromatin structure
FIGURE 1–17 Signaling through the steroid receptor complex. Similar mechanisms are employed by members of the TR gene family,
though most of the latter are concentrated in the nuclear compartment and are not associated with the HSP complex prior to binding ligand
(meG, methyl guanosine).

Another random document with
no related content on Scribd:
“I suppose we do enjoy things better when we have to work for
them,” said old Mrs. Granby. “We rush round helter skelter, get our
puddings shaken up and our nice crisp pie-crust jammed and
broken, and eat biscuits that have been spread for three hours, and
a bite of cold meat, and after we have gone home to think it over it
seems ever so much better than a great dinner.”
“The good-fellowship adds. I never go on a picnic but I think of the
Apostles having all things in common;” returned Miss Oldways.
“Yes,” said papa, “they gave of their time and interest, and love, as
well. It was not merely a little money. They brought in the whole
family and bestowed with the open-handed tenderness that blesses
the giver as well.”
I heard snatches of their talk as I ran onward, and snatches of
other talk. Here were sandwiches dripping with jelly, that had
somehow been upturned in the basket.
“Jelly is fashionable with meats,” suggested some one.
“There! I haven’t put in a single spoon. And I took the trouble to tie
red threads around each handle, then left them on the dresser. That
was smart!”
“We will reverse the order of things and have two creams with one
spoon, the second to wait until the first is served.”
“Is every plate used? Let’s count. All the elders must come first—
thirty, thirty-one, and the young girls wait on the table—thirty-eight—
it is but fair that their mothers should have the best once in a while.
Sixty-one! Now ring the bell.”
They filled up the first table, putting a little child in here and there.
The tea and coffee steamed out their appetizing fragrance, and as
we had no vases, we placed mounds of fern, grasses and wild
flowers on the table. Every body ate and drank and had a good time.
The dishes were washed, wiped, and put on again, the children
summoned, and after a while all had been feasted. Then there was a
general clearing away, except at one end of the long table where the
fragments were collected for those who might get hungry by and by.
“ Sweets to the Sweet.” Page 181.
CHAPTER X.
FTER the eating and drinking, the elders gathered for a

sociable chat. It was as good as old-fashioned country
visiting. Modern calls seem to have carried away the
charm of social intercourse. After you have staid five
minutes you begin to think you must go. You cannot stop
to tell this or that bit of pleasantness, or get near to each other. But
there was no hurry here. Phases of religious experiences were
compared in a homely way, mixed up with the turning of a gown, or
buying of a new carpet. With others grace and gardening went hand
in hand. Such magnificent clove pinks, great double luscious
blossoms!—blue salvias that were quite a rarity—ivies, geraniums—
sick neighbors who enjoyed them—odd enough snatches where one
couldn’t understand.
Well, is it not the true living after all? Is religion the sacred Sunday
thing that must be laid by and not profaned by common every-day
uses? Did anyone ever hear of it wearing out? When these people
had exchanged thoughts on trials and mercies, faith that could see,
and weak faith that stumbled, compared and comforted each other,
who shall say it was not as good as a sermon? Why should we not
help to lift each other up in our common needs?—Great things come
to very few, only.
I lingered for quite a while, resting myself and answering questions
about mamma, baby and Mr. Duncan. It was so dreamily pleasant.
The sun high over head had found our little nook and was making it
all alight with quivering golden rays. Hill seemed to lapse into hill,
tree interlaced with tree, nook, corner and ravine added their
suggestive tender gloom. People came and went, groups of children
rushed in and devoured plates of fragments. They played various
games, and at last settled to a tremendous circle of Copenhagen.
“Where is your sister?” asked Winthrop, “I have been hunting
everywhere for her. Will you not take a walk with me?”
We had not gone very far before the bell rang.
“The children are to sing their carols now.”
“I suppose you have heard them fifty times?”
“Fifty-one will not surfeit me. Besides, I must look after my class.”
“O, bother! Look after me a little while. I am going back to the city
on Saturday, and I shall not see you for ever so long. I actually envy
that dolt of a Duncan who is sick at your house. I never met two girls
that I liked so well. I don’t see how there is any goodness left for the
parish.”
He uttered all this in a rather cross, aggrieved tone which made it
sound so comically I could not forbear laughing.
“O, you don’t know—I wonder if I might trust you with—a—
secret?”
He flushed to the roots of his hair. An uncomfortable chill went
over me.
“There are your Aunts!” I said, glad to be relieved from the sudden
embarrassment.
The carriage came up through the opening. Miss Lucy dressed in
white and looking very sweet. Papa went to speak to them.
The children were gathering from “near and from far.” We teachers
“counted noses,” begged the groups not to disperse, ran hither and
thither, and at last settled to the business before us. I was so glad
that Miss Churchill and Miss Lucy had reached us in time for the
singing. What if dresses were a little limp and stained and soiled,
hats awry and curls blown in tangles, there were hosts of happy
faces and lightsome, ringing voices.
Papa generally wrote a childish hymn for special occasions and
mamma arranged the music. They sang that, then several Easter
Carols.
Miss Lucy beckoned me toward her.
“How delightful it is!” she exclaimed. “And you’ve had a good time
all day long. I wish I was a little girl! Oh, they are not going to stop?
Please ask them to sing again. Would Christmas carols be out of
place?”
I mentioned it to papa who smiled in his sweet fashion and
acquiesced. We had the “Kings of Orient,” “Wonderful Night,” and
“Ring out merry bells for Christmas.” How sweet those young voices
sounded on the summer air! I was really proud of the children.
“Now,” began papa after the last echoes had dropped from the
tree-tops, “we must form a line for our homeward march. We have
had a pleasant day and enjoyed ourselves to the uttermost. Let us
thank God for this great blessing.”
They stood reverently until he dismissed them with the
benediction.
The wagons and carriages began to come in and were filled.
Some chose to walk home and let others ride. Mr. Trafford started to
form the ranks again. Fan came up and we paused to say a few
words to the Churchills, then to Mrs. Ryder who declared that
everything had been just delightful, and that she felt ten years
younger. Dick was very grave, I remarked, and scarcely spoke.
The very last of the line was Fan and Mr. Ogden. I gave them a
quick glance but was hurried on by the throng behind me, and
occupied with answering the childrens’ questions. Yet I wondered a
little what she had been about since dinner.
We heard it all afterward, but it is fresher just as it happened to
her. She and Jennie Ryder, and Annie and Chris Fellows went first to
gather ferns and mosses. Of course some of the young men
followed in their wake. When their basket had been filled they
strolled off two and two, presently losing sight of each other. The day
gave its touch of grace and romance to their lives. We all guessed
that Mr. Hunter cared for Annie Fellows, and were not much
surprised when we heard a little later, that they had “made up their
minds” during the ramble.
Fan and Dick strolled onward as well. Dick was unusually silent.
“Shall we go back?” Fan asked softly by and by.
“Go back!” and Dick looked surprised. “Not unless you are tired of
me.”
He seemed so down-hearted that Fan had not the courage to
confess even in her laughing way.
“I am afraid you have not enjoyed yourself very well. But you have
given a great pleasure to Mrs. Ryder—and Jennie could not have
come without her. She has to stay at home so much.”
“She is a splendid girl,” said Dick.
“Indeed she is. Dick, I have a bright idea! Why couldn’t we when
the evenings are a little cooler, get up a surprise party for her? It
would be jolly.”
“Yes.”
“But you do not seem very much interested.”
“I am interested in anything you like. Only I was thinking;” and he
paused to study her face.
“How queer you are!” with an embarrassed laugh.
“Am I? And you don’t like queerness—you don’t like me?”
Fan began to pull a fern leaf to pieces. It was an odd personal
question, but it could not mean anything. Still her heart beat
strangely, and her breath seemed to tangle as it came up.
“You know I like you of course,” in a sharp, saucy way, flinging out
her curls. “And you are good and pleasant and clever. Don’t I ask
favors first of you?”
“You never ask—for yourself.”
“Why, yes, it is because it pleases me.”
“I wish I could do something for you, alone.”
He snapped off a dry twig and began to break it into bits. Then he
kicked a stone out of the path, keeping his face away from her.
She experienced a peculiar embarrassment. Where was the
happy medium between warmth and coolness? She liked the
brotherly friendship they had fallen into. Was it friendship really?
“If I did want anything,—I should not hesitate—to come to you.”
Then they walked on in uncomfortable silence. It was very
awkward. In the new light coming to Fan, she felt there was
something unsaid. Was it best to get over it as rapidly as possible,
leave it behind?
“I think we must return. Papa may want me.”
He turned reluctantly. She quickened her pace at first.
“Don’t hurry. The day will come to an end soon enough. I should
like it to last a week, at least.”
“What an odd idea. We only want pleasant days to last.”
“Isn’t this pleasant to you?”
“Why—yes. All my days are pleasant for that matter. But I thought
it was beginning to bore you.”
He did not answer for quite a while, then he seemed to go far
away from the subject.
“It’s been nice for you at the Churchills.”
“Well—yes. Though I don’t want you to think I was pleased with
the notice because they are rich.”
“I know that does not make any difference with you.”
“But then for that matter your father is rich, too. And there are only
two children.”
“Yet I wish the home—was like yours.”
“With seven girls? You would have no comfort of your life if you
were the only boy among them,” and Fan laughed merrily.
“I would not mind trying it. Or at least—”
“Be warned in time,” and Fan shook her fore-finger threateningly.
“I can’t,” he exclaimed, with a sudden vehemence in his tone.
“Only—I’d be contented with one. Fanny, couldn’t you?—I mean—I
love you!”
It was all out then! Fan stood still and white while he was scarlet
and trembling. Both were surprised with a deep solemn awe, as if
amazed to have reached such a point.
“I didn’t mean to tell you so soon. I had hardly put it into shape
myself. But when I saw that Winthrop Ogden hanging round after
you, I knew it all then just like a flash. And why shouldn’t it be? They
have enough at home without you. And it would be so sweet! I
should think of nothing but your happiness. I dreamed it all out on
the porch last night, sitting alone with father.”
His eyes and voice were alike imploring, and he had spoken so
rapidly that it carried her right along. Now she put up her hand with a
gesture of pain.
“Oh, Dick, dear Dick, I am so sorry! I never thought of this!”
“Well!” with a kind of manly assurance, “think of it now. I will be
patient. We can ask your mother and see what she says.”
“Dick, I had better tell you just the truth. I am sorry there is any
need to say it. I like you very much in the pleasant, sisterly fashion
that has grown up between us. I do not believe it can ever be any
different. So it is best not to hope, not to plan—”
“Oh, Fanny, I cannot help it. How could I stop all at once?”
She was touched to the heart. What should she do? The tears
came into her eyes.
“I must have acted very wrongly to make you care so much for me
in this way. I can never, never forgive myself.”
He could not bear to hear the woman he loved blamed, and the
tears conquered him.
“It is nothing you have done, don’t think that,” he said earnestly.
“You can’t help being sweet and pretty, any more than that bird up
there can help singing. And you can’t help being just what I want.
You have treated me the same as you have others, that is, I mean
you never tried in any way to make me love you. It just came. And if
you will only try—”
“If I did try, Dick, I should be ashamed to confess that I could not
love so good, and tender, and true a man as you are. Then, perhaps
I might marry you, not loving you the best, which would be very, very
wicked, and ruin your happiness. Oh, Dick, forgive me and let me be
your sister or your friend, or else let me go quite away. I am so
sorry.”
They walked on until the sound of voices reached them. “Please
leave me here,” she entreated falteringly.
“I’m a great blundering chap, I know. I might have said it all better
—”
“It isn’t the saying, it is the thing itself.—O, Dick, don’t you see that
if I had loved you, one word would have been enough. I should be
too honest to tease or make excuses.”
“Yes, I suppose it is so,” in a slow, pathetic way that made Fan
think she was a miserable wretch. “And you can’t help it, I know. I’ll
try to—leave matters as they were, to be a—brother.”
He swallowed over a great lump in his throat, and turned away
without another word. When she found herself quite alone she threw
her trembling figure on the mossy tree-roots and sobbed bitterly. The
glad unconsciousness of girlhood was over.
“If he were not so good,” she thought, “or so rich, or so kind! If I
could find some fault. And that makes it appear all the worse in me.
Oh, papa, dear, what have I done? Why does every one want to—?”
And then she knew it was the old, old story, that had began way
back in Eden-days. People always did, and always would, and
sometimes there was a hitch and a snarl, and the thread broke.
She heard the bell calling the children together, so she rose, and
went to the tiny brook to bathe her face. But she felt so shame-faced
and cowardly that she did not dare join them until the singing was
done. Then Dick would be putting Mrs. Ryder in his wagon, and all
the others bustling about. No one would take much notice of her.
“O, here you are, run-away!” said a bright, rather imperious voice.
“Your sister has been worried to death about you. I thought I should
have to begin and search the mountains. Come along. I shall not
give you another chance to go astray.”
With that Winthrop Ogden took possession of her. The carriages
began to move on. The line was forming, and Mr. Endicott walked
down its length.
“I have Miss Fannie here, safe;” Mr. Ogden said, with a confident
nod.
Fan was so glad to escape observation that she uttered not a
word.
“My Uncle and Aunts are here waiting to speak to you.”
She suffered herself to be led thither, listened to the chat and
answered again without understanding a word.
They fell in the rear of the procession. Indeed she hardly noticed
how they lagged behind, until the tramp of the feet had quite a
distant sound.
“Where were you all the afternoon?” Mr. Ogden asked. “Your sister
and I started once to find you.”
“Did you?” absently.
“Yes. We did not know but the bears might have come out and
eaten you up.”
“Hardly.”
“You were not alone?”
“No. We went for ferns. Jennie Ryder and the rest.”
“Miss Ryder has been back this hour. She and her mother went
away with the very first—with Mr. Fairlie.”
“Oh,” indifferently.
“Well, what were you doing?”
“I won’t be questioned, there!”
“You are sure you were not in mischief?”
No answer to this, and a long silence.
“Well, Miss Obstinacy,” he began at length, “I really am afraid
something has occurred to ruffle your temper.”
“I do not know as you are compelled to suffer from it!” she
returned, positively provoked.
“Ah, but I couldn’t leave you here in a howling wilderness, with the
others miles ahead.”
“You exaggerate. Suppose we walk on and overtake them?”
“We are walking on.”
She was in no mood for badinage. Indeed, her heart smote her
bitterly for the pain she had unwittingly caused. She was upbraiding
herself and trying to think where the first false step had begun.
“Are you tired?” he asked presently in a gentler tone.
“Not much. But a day like this always finds one rather stupid at its
close.”
“Were your mental exertions in the woods very severe? Did you
stop to analyze and classify the ferns?”
“No.”
“You must have found some delightful employment.”
No answer again.
“Do you know that I am going back to the city on Saturday?”
“Are you?—indeed!”
“I dare say you will not miss me.”
“I do not know why I should, specially.”
“That is unfriendly.”
“Is it? Well,” rousing herself a trifle, “I suppose we do miss any one
with whom we have had a bright, pleasant time. And your Aunt Lucy
will be very sorry to have you go.”
“And yet, she will have you.”
“I am only one of the incidentals, Mr. Ogden. People who don’t
belong truly, step into each others’ lives and when the time comes,
step out again. But one born in the household is different.”
“They all like you—so much. I am almost jealous of uncle
Churchill’s regard.”
“O, you need not be.”
“He is old-fashioned and strict in some of his notions, but he has a
splendid heart.”
“I believe that.”
“O, Miss Endicott, please look back at this sunset! It is still more
glorious than the one we saw the evening of our ride! Do you know, I
hate to return. Everything is so lovely here.”
Some of the wide fields lay in the shade, some in the bronze light
of the dying sun. All the tree-tops were burnished, and now it was so
still that not a leaf stirred. A distant Whip-poor-will began his
melancholy lay.
“Oh, we must hurry on;” said Fanny recollecting herself. “The
others have passed the curve of the road and are out of sight.”
They quickened their pace a trifle. Presently he inquired—
“What is to be done to-morrow?”
“Why—nothing.”
“No tea parties nor croquet?”
“I believe not. We shall all be tired. I have had two or three weeks
of dissipation and think it high time to rest up a little.”
“Suppose you take a drive with me? That will not be tiresome.
About four in the afternoon, say.”
Fan started again.
“I think I would rather not;” she replied, curtly.
“Why?”
“For various reasons that I cannot enumerate.”
“I am glad you have more than one, for that might be rather hard
upon me. Well, can I come over to tea then? that is if you are not to
have other company.”
“I dare say they will all be glad to entertain you.”
“I don’t wish any one but just you. I shall have to take the others
part of the time. But on my last day I deserve some indulgence.”
“I may not feel indulgent;” she answered carelessly.
“Miss Fanny—and I have so many things to ask!”
“Don’t ask them;” she said recklessly. Was she walking into
another fire?
“I must ask one.”
She expressed no curiosity or anxiety, but her heart beat so loudly
it seemed as if he must hear it. Dick Fairlie’s love-making had been
honest and true, but this young man?—So she walked on more
rapidly.
“Yes; one question. How else should I know? And it is too great a
risk to leave you here with no word—”
“Mr. Ogden, I think you have lost your senses;” she interrupted
sharply.
“I thought so myself to-day. When you went off with that Fairlie! I
know he was with you this afternoon, and I resolved then to have my
say. I do not mean to lose through being a laggard. My darling, can
you—do you—?”
Fan turned and faced him. She was cool and angry.
“Mr. Ogden,” she said decisively, “that is enough! It may be your
habit to make love to city girls on a fortnight’s acquaintance, but it is
not mine to receive it. I have been friendly because I thought you a
gentleman!”
“Fanny! Miss Endicott,” and he confronted her in so authoritative a
fashion, that she felt his strength at once. “You mistake me
altogether. I am not in the habit of trifling. If I speak soon it is
because I must leave you, and I know another loves you. You have
only to say that you prefer him, and I will be silent.”
He waited several minutes for her to answer, but how could she? It
was a cruel strait. Her cheeks were crimson with shame.
“Then I think I have a right to be heard.”
She summoned all her reckless bravery.
“Mr. Ogden,” she began in an ironical tone; “how long do you
suppose you could remember? It would be the wildest of folly to
listen to you.”
“You doubt me altogether! What shall I do to convince you? Let me
have that withered rose at your throat. I gave it to you this morning
and it will be precious to me. How long a probation will you set me—
a year? Well, when you receive this rose back some day you will
know that I am of the same mind.”
He took it and dropped it into his pocket memorandum. Then they
walked on in silence.
On the way the children were dispersed nearest their homes. By
the Church, Fanny and Mr. Ogden came up with the last. She did not
dare leave him or she would have joined her father. A kind of
fascination kept her under his influence.
They paused at the gate. The others had entered.
“Do you want me to come to-morrow?” His tone was almost
peremptory.
“I—no—” Hers sounded as if tears were not far off, and the long
lashes shaded her eyes, but still he read the face, and read in it,
furthermore, something she did not know was there.
“Very well. If you love me, as I hope you will some day, I can wait.
You will learn how truly every word was meant. I think then you will
be noble enough to admit it. Good by, little darling.”
He gave her one kiss and was gone. She flew up the path and into
the wide hall, pale as a ghost.
We were all there, mamma with baby in her arms, tiny Tim
hanging to her skirt, Lily and Daisy talking like two chatter-boxes.
There was a promiscuous heap of hats and baskets on the floor.
“Children!” exclaimed papa, “don’t set your mother crazy! Take
some of these articles to the kitchen. There, I nearly stepped into
some one’s hat. Rose my dear—”
Fan entered at this moment. Papa stood first, so she put her arm
around his neck and gave a little sob.
“My dear girl, you are tired to death! How pale you look. Mamma
would a cup of tea do her any good? And isn’t our supper ready?”
I hung up the hats, and sent Daisy off with a cargo of baskets.
“No, I don’t want a mouthful,” Fan said. “It was a splendid day, but
I am tired to the uttermost and would like to drop into bed without a
word. Or if I was Edith and mamma could cuddle me in her arms. Oh
dear!”
I think that mamma guessed something was amiss. She gave
baby to me and went straight to Fan.
“Oh, mamma, darling, what would the world be without you? I feel
as if I had been lost somewhere and just come to light. Do I really
belong to you?”
With that she gave a little hysterical laugh which ended with
passionate crying.
“I am a baby, there! I am ashamed of myself. Let me run and put
away my toggery, and maybe I shall come to my senses.”
The children were washed and brushed. Stuart had just come in,
and we sat down to the table. Fanny entered presently, but she
neither ate nor drank, and seemed to be quite unlike herself.
Indeed, I do not think she came to her senses until she and
mamma had a good long talk, she lying in her fresh, cool bed. The
friendly dusk hid her scarlet cheeks, but it could not keep her voice
steady. All the naughtiness was confessed except the little that could
not be told until long afterward, when events justified it.
“My dear girl, I am extremely sorry, and yet I do not know how you
could have avoided the trouble. You did quite right if you could not
love Mr. Fairlie, and Mr. Ogden’s haste was ungenerous and
inexcusable. I am glad you had the good sense to see this. And now
go to sleep my darling. If we have any better thoughts to-morrow we
will comfort one another with them.”
So she kissed her and left her alone.
CHAPTER XI.
E were all pretty tired the next morning. The children

slept late, and Fanny was unusually languid for her.—
Stuart was the only one who did not appear to feel the
effects of dissipation, for he was off bright and early on
another excursion with the boys.
It seemed so strange to think of Fan having had two offers of
marriage; at least, one we knew was made in good faith. The other
mamma was not decided about.
“Poor little girl;” said papa kissing her. “Your troubles are beginning
early in life.”
“You think like the old lady in the couplet—
‘Wires and briars, needles and pins,

When you are married your trouble begins.’”
and Fan laughed with a trifle of the old archness.

“Not exactly. Your mamma and I have been very happy.” Still there
was a perplexed expression on papa’s face as if he could not quite
explain the puzzle.
“But then no one ever could be as good or as splendid or as lovely
as you!”
“Any more adjectives, Fanny!” and he smiled.
“Yes, a host of them, but I am generous and spare your blushes.
Mamma—” in a sort of absent, thoughtful way, “there is one man
who, I think, would make a royal husband.”
“Are you quite sure you understand the requisite qualities?”
Fanny blushed.
“It is Stephen Duncan. I don’t know what put it in my mind. But he
seems so tender and thoughtful and patient.”
“He must have taken all the family virtues,” I made answer.
“He was different in his boyhood from the others;” said papa. “He
is a fine and noble man.”
“But what troubles me most now,” began Fanny with a certain
funny lugubriousness, “is how I am to meet all these people again.
What will the Churchills think? And oh, if Dick had not—”
“Such matters have to settle themselves,” returned mamma. “In all
probability the Churchills will know nothing about it. Try and be a little
careful in the future. You are no longer a child.”
“Must I wear a veil or enter a convent? Papa, suppose you lock
me up in the study? Then they will all flock to Rose, and it will be the
same trouble over again. What are we to do?”
“Just now you had better find some employment. I cut out half a
dozen aprons for Daisy yesterday;” said mamma.
“Then I will open my beloved machine, so good-bye to romance.
Work and you are adversaries.”
I wondered how she could take events so coolly. She sang with
her sewing as if her heart was as light as thistle-down.
Nelly in the meanwhile was made ready and sent off to visit an old
parishioner, living on a farm thirty miles away. One of the children
went for awhile every summer.
Louis improved rapidly. He had fretted somewhat about accepting
the Churchills’ carriage, and begged papa to hire one for him, which
had been done. He went out nearly every morning now, or if it was
too warm, late in the afternoon. I think he was getting a little
humanized, too. Occasionally he joined our circle and would often
play with baby Edith, who laughed and talked her fashion if you
looked at her. She was just as good and sweet as she could be.
Mr. Ogden did not come over, and went away on Saturday. That
somehow stamped the episode as pastime. With all her gayety Fan
did feel badly over it—a trifle mortified, I think, that he should have
ventured upon such a freedom.
It was to make no change with the Churchills however. Indeed, we
received quite a handsome compliment from them the next week.
Mr. Churchill invited papa to go up in the mountains with him. He had
some business with a tract of woodland that the railroad company
wanted to purchase, and thought it would be a nice trip. They were
to start Tuesday night and return Saturday noon.
The house always appeared so strange without him. Not but what
mamma was quite capable of carrying it on, yet we missed him
sadly. Ann lamented Nelly’s absence, and declared “there wasn’t a
childer too many”. Fan and I sewed and had peculiar talks with
Louis. I never could tell what he thought or what he believed, or
whether he advanced these opinions for arguments’ sake. He had a
great deal of morbid pride, and a way of putting all the briary parts
outside. Everybody was selfish, he averred.
And he did have a fearful temper. Beside the quickness, it had in it
a brooding vindictiveness. He couldn’t seem to forgive injuries or
slights, and he was very jealous of Stuart, though he affected a lofty
indifference to those bright engaging qualities.
Stuart on the other hand did get into a good deal of mischief. He
headed raids on the farmers’ trees and melon-patches, and one
night the water was let out of the dam, which caused a great
commotion. Of course he was an immense favorite with the boys.
When papa came home there was a letter from Stephen,
answering the one announcing the illness. He had been very much
perplexed in the business and found it necessary to go to Paris. He
would not be able to return until late in the Fall. As school began the
tenth of September it would be best to send Stuart immediately.
Would Mrs. Endicott see that his clothes were in order? If Louis
preferred, when he was well enough to resume his studies, to board
in some quiet family and take the lessons he needed, Stephen
considered it a better plan.
“Not that I mean this to be construed into a desire for you to keep
him, my dear friend,” he wrote. “You have too much on your hands
already, and I feel as if I had added a great burthen. But if he
decides upon this course will you make some inquiries for him, and
help him to find a suitable person? I do not think him strong enough
to be regularly in school.”
Louis made no comment for several days, then declared that he
did not mean to be buried alive in a country village through a dreary
winter. He would go back to Wilburton, but not enter the school.
There were plenty of families who would take him to board, and he
liked it there.
Just at this juncture one of his cousins, a year or two older than
himself, invited him to go to Canada to recruit his health. He was to
start early in September and would call for him.
He accepted the invitation at once, without even consulting papa.
“I suppose it is as well, though,” papa said thoughtfully. “He does
need bracing up, and the change will be just the thing for him. We
can hear meanwhile from Stephen about this Wilburton
arrangement.”
The boys both went to Westburg with papa to get some new
clothes. Mamma packed Stuart’s trunk, and then he was frantic to
return to the boys. Monday would be the tenth but he insisted upon
starting on Friday. He wanted to get a good room, to see old friends
and feel settled before school began. He had enjoyed himself
splendidly, to be sure, and there were lots of jolly fellows in
Wachusett, to say nothing of the girls. He meant to come back some
time and have it all over. But since he couldn’t go to Canada, which
he thought rather rough, he might as well march off at once. The
sooner a thing was well over, the better.
He spent a day and evening saying good-bye to his friends in the
village. The stage was to come at eight Friday morn. He had his
trunk strapped and out on the porch; ate his breakfast in a hurry,
kissed the children and bade Ann a laughing farewell accompanied
with a new calico gown, which she thought an immense favor.

Greenspans Basic and Clinical Endocrinology 10Th Edition David G Gardner Full Chapter

Uploaded by

Copyright:

Available Formats

You might also like

Greenspans Basic and Clinical Endocrinology 10Th Edition David G Gardner Full Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Greenspans Basic and Clinical Endocrinology 10Th Edition David G Gardner Full Chapter

Uploaded by

Copyright:

Available Formats

Greenspan’s Basic and Clinical

Endocrinology 10th Edition David G.

00-Gardner_FM-pi-xxiv.indd 1 09/06/17 4:03 PM

eBook conversion by codeMantra

00-Gardner_FM-pi-xxiv.indd 3 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 4 09/06/17 4:03 PM

1. Hormones and Hormone Action 1 Autoimmune Response 39

00-Gardner_FM-pi-xxiv.indd 5 09/06/17 4:03 PM

4. Hypothalamus and Pituitary Gland 69 Evaluation of LH and FSH 92

00-Gardner_FM-pi-xxiv.indd 6 09/06/17 4:03 PM

Pathogenesis 116 Autosomal Chromosome Disorders and

00-Gardner_FM-pi-xxiv.indd 7 09/06/17 4:03 PM

Gastrointestinal Effects 188 Treatment 219

00-Gardner_FM-pi-xxiv.indd 8 09/06/17 4:03 PM

Treatment of Hypercalcemia 266 Hypophosphatasia 290

00-Gardner_FM-pi-xxiv.indd 9 09/06/17 4:03 PM

Clinical Features 320 Cushing Syndrome 356

00-Gardner_FM-pi-xxiv.indd 10 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 11 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 12 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 13 09/06/17 4:03 PM

Type 2 Diabetes 623 Molecular Mechanisms by Which Hyperglycemia Causes

00-Gardner_FM-pi-xxiv.indd 14 09/06/17 4:03 PM

The Plasma Lipoproteins 706 LP(a) Hyperlipoproteinemia 718

00-Gardner_FM-pi-xxiv.indd 15 09/06/17 4:03 PM

Fibric Acid Derivatives 725 Screening and Prevention of Complications 738

00-Gardner_FM-pi-xxiv.indd 16 09/06/17 4:03 PM

Mental Health Concerns and Impact of Family Clinical Setting 794

00-Gardner_FM-pi-xxiv.indd 17 09/06/17 4:03 PM

26. Endocrine Surgery 825 Hypercortisolism 838

00-Gardner_FM-pi-xxiv.indd 18 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 19 09/06/17 4:03 PM

Carl Grunfeld, MD, PhD John P. Kane, MD, PhD

00-Gardner_FM-pi-xxiv.indd 20 09/06/17 4:03 PM

Bansari Patel, MD Ajay Sood, MD

Alan G. Robinson, MD Robert N. Taylor, MD, PhD

Mitchell P. Rosen, MD J. Blake Tyrrell, MD

00-Gardner_FM-pi-xxiv.indd 21 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 22 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 23 09/06/17 4:03 PM

00-Gardner_FM-pi-xxiv.indd 24 09/06/17 4:03 PM

Hormones and Hormone

ACTH Adrenocorticotropin hormone FAD Flavin adenine dinucleotide

01-Gardner_ch01-p001-028.indd 1 09/06/17 4:04 PM

MEK MAPK kinase RAR Retinoic acid receptor

01-Gardner_ch01-p001-028.indd 2 09/06/17 4:04 PM

Endocrine cell Neurotransmitter cell

Hormone target cell

Neurotransmitter and hormone target cell

01-Gardner_ch01-p001-028.indd 3 09/06/17 4:04 PM

Endocrine glands are traditionally defined as ductless glandular Hormone Release

01-Gardner_ch01-p001-028.indd 4 09/06/17 4:04 PM

hormone secretion and synthesis. Many, if not most, hormone

Hormone Metabolism RECEPTORS

01-Gardner_ch01-p001-028.indd 5 09/06/17 4:04 PM

NEUROTRANSMITTER AND PEPTIDE

01-Gardner_ch01-p001-028.indd 6 09/06/17 4:04 PM

TABLE 1–1 Major subdivisions (with examples) of Binding domain

TABLE 1–1 Major subdivisions (with examples) of Binding domain