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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

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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.

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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

4 CHAPTER 1 Hormones and Hormone Action
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

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This must not, however, lead any one to be careless about
wounds from poisoned arrows: some are always mortal. The stuff
with which they are smeared consists of wax and kuna, or extract of
a common gum, forming a very strong poison which, however,
quickly loses its efficacy. The best thing to do when struck by such
an arrow is to burn the wound immediately, or to inject chloride of
gold all round it under the skin. A simpler treatment still is just to fill
the wound with gunpowder and set fire to it; but this is rather too
Spartan a remedy for everybody.
Our market was the chief excitement of the morning, for in it we
could study typical natives, and note the special peculiarities of each.
The population of Say and the surrounding districts is very mixed,
including Songhays, Fulahs, Haussas, Djermankobes, Macimankes,
Mossi, Gurunsi, Kurteyes, etc., each with cicatrized wounds of a
different kind on their faces, as is the case with so many African
tribes.
The market, too, is the best place for getting reliable news, and
besides, the very attitude of the different traders towards each other
is a revelation of the state of feeling in the country. If a great many
assembled it was a sign that all was going on well for us, that the
report of the French Expedition was spreading, and that Amadu
Saturu was likely to come to his senses about us. If the attendance
at the market fell off, however, it was a sign that hostile columns
were being called together, why we could not tell, but probably to
attack us; or again some new check was to be put upon our buying
or selling. Once indeed Amadu made a feeble effort to reduce us by
famine, and our supply of sheep was stopped for a time. But a threat
made to Osman on purpose that he should repeat it, that we would
go and fetch the sheep from Say for ourselves, was immediately
successful, for the next day the best and cheapest animals we had
yet procured were brought to us. We never ate better mutton before
or since.
TYPICAL NATIVES AT THE FORT ARCHINARD MARKET.
Whilst the market was going on, Taburet used to prescribe for
many natives who came to consult him. But carelessness and
ignorance work terrible havoc among the negroes everywhere.
There would be plenty for a doctor to do who cared to study
diseases now become rare in civilized countries. From amongst the
patients who came to Taburet, a grand or rather terrible list of
miraculous cures might have been drawn up. These patients
included men and women suffering from tubercular and syphilitic
diseases, which had been allowed to run their dread course
unchecked by any remedies whatever; many too were blind or
afflicted with goitre and elephantiasis, whilst there were numerous
lepers. Few, however, were troubled with nervous complaints. It was
indeed difficult to prescribe for such cases as came before the good
doctor; indeed it would often have been quite impossible for his
instructions to be carried out. Many poor cripples came from a long
distance to consult the white doctor, expecting to be made whole
immediately, when they were really incurable. Where, however,
would have been the good of prescribing cleanliness, when one of
their most used remedies is to smear any wound with mud and cow-
dung mixed together, the eyes of ophthalmic patients even being
treated with the horrible stuff? Where would be the good of ordering
them nourishing food such as gravy beef, when they are too poor to
get it? Good wine? Even if we could have supplied them with it, they
would have flung it away with horror, for they are Mussulmans.
Quinine then? Its bitterness would have made them suspect poison.
They all came expecting miracles, and all that could be done for
them was to paint their sore places with iodine, and to give them
various lotions and antiseptic dressings, or a solution of iodide of
potassium, and so on, from the use of which they would, most of
them, obtain no benefit at all.
Taburet was consulted about all sorts of things. For instance, a
pretty Fulah woman from Saga with a pale complexion and engaging
manners had got into trouble. She had overstepped the bounds of
reserve prescribed in her tribe to young girls, and was soon to
become a mother. Well, she came timidly to the doctor to ask for
medicines for her case, and when it was explained to her that that
case was incurable, for the French law forbids the destruction of life,
she went away, only to return the next day with her mother. The latter
explained that if she and her daughter returned to their village as
things were, they would both be stoned to death, or at least, if their
judges were merciful, be put in irons for the rest of their lives. The
young girl was pretty, many men in her village had asked her in
marriage, but she had refused them all. All her people were now
eager to revenge themselves on her, and to apply in all their terrible
rigour, the “just Mussulman laws.” She had neither father, brother,
nor any one to defend her. Her seducer had deserted her, and it is
not customary amongst the Fulahs to make inquiries as to the father
of illegitimate children.
The people of Say had recommended the mother in mockery to
take her girl to the Christians, she was good for nothing else now,
they said. If we could not cure her, there was nothing left for them to
do but to hide themselves in the fetich-worshipping village of Gurma,
where they would lead a miserable life, unnoticed and unknown.
The two poor women with tears in their eyes knelt to the doctor
imploring his help, and crying Safarikoy! Safarikoy! and I asked
myself, what would be the duty of a doctor in this bigoted land if he
had had the necessary instruments for meeting the unfortunate girl’s
wishes. Perhaps it was as well that in this case nothing could be
done.
All the same this domestic drama was very heart-rending. I tried
for a long time to console our visitors. The old woman stuck to her
request for medicine, and promised to reward us with everything she
could think of likely to please us. She even offered us her daughter,
saying that she might remain with us, and could follow us wherever
we went.
I told Digui to get rid of them as gently as possible, and gave them
a good present to enable them to reach some heathen village where
the people would have pity on them. They departed at last, the
mother’s tears soaking her tattered garments, the daughter following
her, her little feet swollen with walking, and her head drooping in her
despair.
À propos of this episode, Suleyman the interpreter held forth in
the following strain—“From the earliest times prophets, marabouts,
and the negro chiefs who founded the religious dynasty of the
country, have been terribly severe on any lapse from morality
amongst their women, but it is all humbug, for most of the marabouts
are the fathers of illegitimate children.
“Amongst Amadu’s people the man and woman who have sinned
are deprived of all their property, but Abdul Bubakar goes still further,
for he sacks the entire village to which a frail woman belongs, a
capital way of getting slaves and everything else. In other districts
the woman is put in irons, but the man goes free; but if the seducer
comes forward and owns his crime, he can obtain remission of the
punishment by payment of a large sum to the chief of the village;
generally, however, the unfortunate girl dies in her chains.
“Such are the manners and customs of the Mussulmans, and God
alone knows what their women are really like.
“Samory used to kill both the guilty parties, but Tieba, his enemy
and neighbour, professed an amiable kind of philosophy on the
subject of the weaker sex and the ways of women. When Samory
was conquered by Tieba, the chief auxiliaries of the latter were the
nomad Diulas who were strangers in the land. These Diulas had
come to the district by way of Sikasso, where they had met with
women of free and easy manners, and had been driven by the force
of circumstances to remain amongst them, adopting their ways. Now
it generally happens amongst the negroes, that those who have
travelled much and seen something of the world are not only brave
but sensible and free from bigotry.
WOMEN OF SAY.
“Samory, who was so fond of cutting off heads in obedience to the

injunctions of the Koran, had a wife named Sarankeni, who is still his
favourite, and she was the one to lay her finger on the cause of his
defeat, when he was still smarting from its effects. She saw that it
was the women of easy morals who prevented the strangers who
had aided Tieba from deserting him in his need. Samory was open to
conviction, and since then”—according to Suleyman, though I think
he exaggerated—“if one of the chief’s people discovers that a
woman or a daughter of his house has gone wrong, he gives a fee to
the seducer, or at least offers him refreshments and speaks him fair,
and this has now become the fashion throughout the districts reigned
over by the great Fama. Sarankeni, the favourite, the giver of the
advice which led to the change, is alone excepted from the new
rule.” Probably, as she is still young, she had a very different motive
for her conduct than that generally accepted.
Whilst the market was going on, we used also to make a tour of
inspection in our kitchen-garden. An officer of the garrison of
Timbuktu had been good enough to give us some packets of the
usual seeds, and under the skilled direction of the doctor we had had
a plot of ground cleared, manured, and planted. To sow seed is one
thing, however, to reap results is another, and in spite of the delicate
attentions of Atchino, our man from Dahomey, our gardener for the
nonce, who religiously watered the seeds every morning, and in
spite of the visits we paid to our plantations at dawn and eventide, no
great results ensued. Probably the sheep and goats, who were
greedy creatures all of them, got the pick of everything, in spite of
the thorn hedge we had put up round our garden.
All we got ourselves were a few big tomatoes, some cucumbers,
some little pink radishes, and two or three salads. You can just
imagine our delight when on one occasion Taburet triumphantly
brought in three radishes apiece.
For all that, we can’t be too grateful for our garden. If we did not
get many vegetables, we always had the hope of getting some, and
the pleasure of watching the growth of various weeds which we
expected to turn out to be lettuces, beetroots, or cabbages, and we
used to say joyfully, “When that is big enough to eat, or when this is
ready,” and so on. The hope of luxuries, when we are provided with
all that is absolutely necessary, is always cheering.
Whilst we are on the subject of food, I may as well say a little
about what we lived on during our stay at Fort Archinard. In spite of
our long distance from home we must be strictly accurate, and I am
almost ashamed to own that we were never reduced to having to eat
our dogs. Nor was the reason for this the fact that we had no dogs
with us to eat. Far from that; we had three dogs, one after the other,
not to speak of the cats already referred to. Our three dogs were all,
I don’t know why, called Meyer. They were yellow, famished-looking
beasts, who were native to the country, and rather savage. All came
to a sad end and got lost, but I don’t know exactly what became of
them. Once more, however, I swear by Mahomet we did not eat one
of them.
Although we ate no dogs we managed to subsist, for we were
never without sheep or rice. The diet was not much to boast of, and
we had to keep a whole flock in our island always, for there was very
little pasturage on our small domain for some twenty or thirty
animals. After a few days of such nourishment as they got, our
sheep became anæmic, and their flesh turned a greenish colour. Still
we managed to eat it in semi-darkness. On the other hand, our rice
was always good. That grown in the country is small, and of a
slightly reddish colour. It swells less in cooking than the white rice of
Cochin China or Pegu, but it has a nicer and a stronger taste.
Taburet used to swear by all the heathen gods that he would never
eat rice, yet very soon he could not do without it. Fili Kanté, already
mentioned, turned out a first-rate cook, and he really did deserve
praise for what he achieved, for we were none of us able to help him
with advice. True, the Commandant had made everybody’s mouth
water by saying that he would take charge of the pot as soon as the
expedition arrived at Say; but he never troubled his head about the
matter again.
He did, however, sometimes preside at the cooking of mechuis,
that is to say, of sheep roasted whole on the spit in the Arab style,
and the mechuis of Fort Archinard were celebrated—on the island!
Rice and mutton were the staples of our meals. Every morning Fili
Kanté used to come to the chief of the mess and say, as if he were
announcing a new discovery—“I shall give you mutton and rice to-
day, Lieutenant.”—“And what else?” I would ask.—“An
omelette.”—“And after that?”—“A nougat and some cheese.”
You read that word nougat? Well now, would you like to know
what it was made of? Here is the recipe (not quite the same as that
for Montélimar almond cake): Take some honey; make it boil; add to
it some pea-nuts shelled and ground. Turn it all out on to a cold plate
—the bottom of an empty tin will do if you have nothing else—and let
it stand till cold.
It makes a capital dessert, I can tell you, especially when there is
nothing better to be had.
You read, too, that we were to have cheese. We could generally
get as much milk as we liked, and it made a first-rate cheese the
second day; quite delicious, I assure you. We generally had cheese
for all our mid-day meals, and nougat at supper or dinner, whichever
you like to call it.
Sometimes, too, we fished, but there was not very much to be got
out of the Niger near Fort Archinard; now and then, however, we
succeeded in making a good haul, enough for a meal, with the use of
a petard of gun-cotton.
The fish we caught in the Niger were much the same as those
found in the Senegal. The kind the natives call “captains” and ntébés
are very delicate in flavour, and often of considerable size. We once
caught a “captain” at Gurao on the Debo, weighing nearly 80 lbs. It
took two men to carry it, and when it was hung from a pole it trailed
on the ground. But we rarely had such luck as this at Fort Archinard.
Another kind of fish, called the machoiran, with very flat jaws, was
to be found in the mud and ooze of the Niger, but beware of eating
its flesh. If, it is said, you cut the fat off its tail (Heaven only knows if
it has any), by mistake, at full moon, and then drink some fresh milk,
and sleep out of doors for the rest of the night on a white coverlet,
and then in the morning drink a basin of water, you will surely catch
leprosy. I don’t suppose the lepers of Say had really taken all these
precautions to ensure having the disease.
I must add that there is one thing which all travellers in Africa will
find very useful. I allude to the Prevet tablets of condensed food. We
can justly testify to their efficacy, whether they are Julienne, carrots,
Brussels sprouts, pears, or apples. They are light, easily carried, and
easily divided. To have used them once is recommendation enough,
but it is necessary to know how to prepare them, and not to follow
Baudry’s example, who one day served us some Prevet spinach,
which tasted for all the world like boiled hay. If ever you travel with
him, don’t make him chief of the commissariat.
In the morning we also worked at making our map, for we should
certainly never have been able to finish it in Paris in the limited time
we should be allowed for it. We made a duplicate copy of the map,
grosso modo, from Timbuktu to Say, to guard against the possible
loss of one of the barges. Then came the time for taking our daily
dose of twenty centigrammes of quinine dissolved in two centilitres
of alcohol, which, truth to tell, was anything but pleasant to the taste.
Even Abdulaye himself, who could swallow anything, made a wry
face at this terrible mixture; but to help us to digest the everlasting
mutton and rice boiled in water, and to keep down the symptoms of
fever which threatened us all, nothing could be better.
FORT ARCHINARD.
I cannot too often insist on the fact that it was, thanks to the daily
dose of quinine regularly administered by order to every member of
the expedition, that we owe our safe return in good health, and with
appetites unimpaired.
We owe to it, too, the fact that in spite of many fevers in past
days, we actually had gained, on our return to Paris, not only in
weight, but in our power of enjoying a joke.
Last January, after my return to France, I had been giving an
account at a public meeting of the results of my expedition, and my
companions and I were going down the staircase of the Sorbonne,
attended by a considerable crowd, when two gentlemen, radiant with
health, evidently from the French colonies, and geographers, else
why were they there? exchanged their impressions as they passed
us. “Pooh,” said one of them, shrugging his shoulders, “they have
not even got dirty heads!”
After lunch we all went to take a little siesta, or at least to rest
during the great heat of the day. The siesta, though so much in use
in the tropics, is really a very bad habit, and many ailments of the
stomach are caused by it. It is really better only to indulge in a
noonday nap after exceptional fatigue; but of course it is a very
different matter just to avoid active exercise immediately after a
meal, and to read quietly without going to sleep. To wind up all this
advice to future travellers in the Sudan, let me just add this one more
word, “Do as I say rather than as I did.”
Many of the coolies did not go to sleep in the resting hour, but
chatted together about the news of the day, or gave each other a
little elementary instruction, for negroes, even when grown up, are
very fond of teaching and of being taught. Their ambition, however,
is generally limited to learning to write a letter to their friends or
family. They take great delight in corresponding with the absent, and
I have known young fellows in the Sudan who spend nearly all their
salaries in sending telegraphic despatches to their friends. I knew
others, amongst whom was Baudry’s servant, who gave up most of
their free time at Say to writing letters which never reached their
destination, for a very good reason. They were all much in the style
of the one quoted below—
“Dear Mr. Fili Kanté,—I write to inform you that the Niger
Hydrographical Expedition has arrived at Fort Archinard, and that,
thanks to God, all are well. When you write to me, send me news of
my father and mother, and my friends at Diamu (the writer’s native
village). I shall be very pleased, too, if you will send the twelve
samba (sembé) (coverlets), four horses, ten sheep, etc.
“With my best greetings, dear Mr. Fili Kanté.
“(Signed) Mussa Diakhite
(in the service of Mr. Baudry.)”
Might you not fancy this letter, with all its decorative strokes, to be
one from the soldier Dumanet to his parents? Nothing is wanted to
complete the resemblance, not even the attempt to fleece his
correspondent.
Besides these lovers of correspondence, there were others who
were mad about arithmetic. Samba Demba, Suzanne’s groom,
already often mentioned, wanted to know enough arithmetic to
matriculate. All through the hour of the siesta, and often also when
he was at work, he was muttering the most absurd numbers over to
himself; absurd for him, at least, for the negroes who do not live
where the cowry serves as currency, cannot conceive the idea of any
number beyond a thousand. Samba Demba would read what he
called his “matricula” of nine figures and more, to Father Hacquart,
with the greatest complacency, whilst Ahmady-Mody, who had
patched up the Aube, strove in vain to learn b-a ba, b-e be, or twice
two are four, twice three are six, with his head bent over a big card.
The marabout Tierno Abdulaye actually composed and sung Arabic
verses. In the midst of it all the voice of Dr. Taburet would be heard
from his tent hard by complaining that he could not sleep.
All these good fellows, with their eagerness to learn, had a child-
like side to their characters. There is no doubt that they would very
quickly learn to read, write, and cipher, as the advertisements of
elementary schools express it—read without understanding too
much, write without knowing what, and calculate without ever being
able to apply their arithmetic. Anyhow, however, even this little
knowledge will wean them from the pernicious influence of the
marabouts.
After sunset the heat
became more bearable,
and the time for our
evening bath arrived. At
the northern extremity of
our island were a number
of pools amongst the
rocks, varying in depth
according to the tide. Here
and there were regular
cascades, and we could
stand on the sand bottom
and get a natural shower-
OUR COOLIES AT THEIR TOILETTE. bath. Some of us became
perfectly enamoured of
this style of bathing. Opinions differ in Africa as to the healthiness of
it, however. For my part, I know that bathing in the tepid water,
warmed as it was by the heat of the sun, was very refreshing, and of
course the cleaner we kept ourselves the better the pores of our skin
acted. It may be that stopping long in the water every day was
weakening, and some fevers may have been caused by it when it
happened to be colder than usual. There are two opinions on this as
on every subject, but where is the good of discussing them?—the
best plan is to do what you like yourself.
In the river near Fort Archinard there were lots of common fish,
which used to shoot down the cascades of an evening for the sake
of the greater freshness and coolness of the water below. These fish
would actually strike us now and then on the shoulders, making us
start by the suddenness of the unexpected blows. It was still more
unpleasant to know that other denizens of the river, the terrible
crocodiles, though further off, were still there.
Oh, what numbers of the horrible great grey creatures we used to
see floating down with the stream or lying about the banks! Some of
them had taken up their abode quite near to us, along the side of our
island, just where we used to do our fishing with the gun-cotton, but
their being close to us did not prevent either the coolies, or for the
matter of that the whites, from going into the river.
With sunset came the hour of supper or dinner, and what grand
sky effects we used to see whilst we were at that meal in these
winter quarters of ours! Our walls were flecked with every colour of
the rainbow, whilst in the east, above the sombre wooded banks,
would often rise red masses of curious-looking clouds, precursors of
the approaching tornado. Sometimes the sun had not quite set
before the lightning would begin to flash, and the thunder to roll
incessantly, sounding like the roar of artillery in battle. As we sat at
table we would discuss the situation: what would the tornado do this
time? Would our huts be able to bear up against it? Would much
water come in? “Make haste, Fili, bring us that nougat before it
rains!” said Bluzet. And were the barges securely moored? Had the
sentry got his cloak? and so on.
A WOMAN OF SAY.
Father Hacquart became as time went on, quite an expert

meteorologist, and only once or twice made a mistake in his
predictions about the weather.
The terrible arch of clouds peculiar to a tornado, meanwhile, goes
up and up till it nearly reaches the zenith. Behind it in the east is a
great glow of light, resembling the reflection of a conflagration in the
big plate-glass windows of some shop on the Paris boulevards seen
through the rain.
We all disperse now, going to our huts to light our candles, whilst
the rain pours down in torrents, and the leaves are torn from the
trees and whirled round and round. The branches are creaking, the
roofs are bending beneath the fury of the storm, the rain turns to hail,
and through the great sabbat of the elements, the voices of the
sentries are heard calling out from beneath the deluge pouring down
upon them, “Is all well?” and the reply comes soon, “All is well.”
Then when the worst seems to be over, we go to examine how
much damage is done, and Father Hacquart comes out to have one
more look at the weather. Presently we hear some one growling out
that the rain has come through his roof like a thief in the night, or that
it is pouring over his threshold. We all laugh together, for we are all
in the same boat.
Fortunately the damage done is seldom greater than this, for the
huts stand the strain well. We only once had to deplore a real
misfortune, and that not a very serious one, only it made us fear that
a worse might happen.
A pair of white and black storks had nested in the big tamarind
tree which formed the eastern corner of the tata looking down-
stream, and we considered this a good omen for us, a talisman
ensuring to us the protection of Allah during our stay in the island.
Storks, as is well known, are very peculiar birds, and acts of
extraordinary intelligence are attributed to them, which would appear
to prove that their lives are regulated by certain social laws. It was an
amusement to us to watch them of an evening, and to note all the
details of their family life; the first finding of a home, for instance,
their courtship, their talks in the gloaming; when perched together on
one branch they would seem to be looking at us, balancing
themselves with their heavy heads on one side, with the air of old
men considering some new invention, or savants discussing abstract
verities.
Our pair of storks, in spite of their calm and sedate appearance,
must really have been only just beginning their joint ménage, and
can have had no real experience of life. They evidently knew how to
fish by instinct; but a sad catastrophe befell their home, which they
had built on a big dead branch, for in a specially violent tornado the
bough was torn off, nest and all, and flung upon the quick-firing gun
pointing up-stream, knocking over Ibrahim Bubakar, who was on
sentry duty, but who fortunately escaped with a fright and a few
bruises on the legs. Alas! however, three young storks, the children
of the pair, were flung to the ground and killed. We picked them up
dead the day after the tornado, and stuffed them.
A NATIVE WOMAN WITH

GOITRE.
Our men were in great despair. The charm which would have
brought luck to our camp was broken; but the parent birds, in spite of
the loss of their little ones, evidently determined to act as our
talisman to the end of our stay, for they continued to fly round and
round our tamarind, and to talk together of an evening, though sadly.
It was not until a few days before we left that they flew away towards
the north. Thanks to them, perhaps, we had a run of good luck to the
last.
The tornado freshened the atmosphere very considerably, and the
sudden change could only be fully realized by consulting the
thermometer. In five minutes the glass would sometimes fall from
forty-five to thirty degrees. A corresponding and sympathetic change
would take place in the state of our nerves; we could sleep a little if
only the mosquitoes would let us, but, alas! their droning never
ceased. Oh, that horrible music, which went on for ever without
mercy, causing us more anguish even than the bites, and against
which no curtain could protect.
The frogs, too, added to the droning of the mosquitoes what we
may call their peculiar Plain Songs or Gregorian chants. They were
very tame, showing no fear of us, but took up their abode here,
there, and everywhere: out in the open air, or in the huts, in our
books, under our tins, and in our water-vessels, and their ceaseless
singing in full solemn tones, echoed that of the distant choirs of their
wilder brethren chattering together amongst the grass by the river-
side. Although not composed on the spot, I cannot refrain from
quoting the following sonnet, produced by a member of our
expedition, and which forms a kind of sequel to the others I have
transcribed above—
LOVE-SONG.
When evening falls upon the land asleep,

When mute the singers of the tropic plain,
When winds die down, and every bird’s refrain
Or insect’s cry is hush’d in silence deep;
Then from the lotus beds triumphant leap
Frantic crescendoes of a rhythmic strain,
Wild cadences mount up, to sink again
Lamenting, as when mourners wail and weep;—
Comes to the traveller upon the stream,
A Plain-Song Litany of high despair;
The notes Gregorian fit into his dream
Of home and fatherland, remotely fair;—
Whilst from the gleaming mud in Niger’s course
Rises an amorous croak, now sweet, now hoarse.
In every country in the world fine weather comes after rain, and
the tornado was succeeded on the Niger by a star-light night of a
clearness and limpidity such as is never seen anywhere out of the
tropics. The soft murmur of the Niger was borne to us upon the
gentle night breeze, reminding us of the Fulah proverb—
“Ulululu ko tiaygueul, so mayo héwi, déguiet,” which may be
translated—
“Ulululu cries the brook, the big river is silent.”
A true description indeed of what really often seemed to happen
during our long imprisonment on our island, for we could hear the
gurgling of the rapid further down-stream, but the voice of the river
was hushed.
Our nights passed quietly enough, watch being always kept by
one white man, one black subordinate officer, and two coolies. From
Timbuktu to Lokodja, that is to say, from January 21 to October 21,
we five Europeans had taken the night-watch in turn. It must be
admitted that at Fort Archinard it was sometimes rather difficult to
remain awake, and to keep ourselves from yielding to our exhausting
fatigue. We had to resort to various manœuvres, such as pinching
ourselves, bathing our feet, wrists, or head, and walking rapidly up
and down. Sometimes, as one or another of us sat in Father
Hacquart’s folding-chair, looking out upon the moon-lit scene, there
was something very charming about the silence and repose, and as
we have already given several quotations of poetical effusions, I
think I must add just one more on the night-watch, also composed by
one of our party.
NIGHT-WATCH.
I loll and smoke, with mind a-blank;—we sail

Together, all ye stars of motion slow!
Moon! a poor trophy you may hang me now
Upon one horn—Moon! like a fairy’s nail
Curved, tilted, thin and delicately pale!
You, old Orion, may not lift your brow
To where on high the mystic symbols glow
Of Cross and Angel’s Car that next I hail;
Then Venus—Beauty bathed in lambent stream
Of astral milk, outpour’d long ages past
From time-worn breasts!—to these, in the first gleam
Of morning freshness, from the dreary waste,
Whilst as our bark adown the dim stream floats,
With rower’s boat-song blends the frog’s last notes.
Thus the days went on monotonously, so monotonously that we

were often quite feverish with ennui! At the beginning, the building of
the fort and settling down gave us a little variety, but of course that
did not last.
Winter in the Sudan would really not be much worse than
anywhere else if plenty of occupation and movement could be
secured, with occasional change of air; but it becomes simply deadly
dull when one is limited to a small space, compelled to inhale the
same miasmic exhalations, and absorb the same kind of microbes
every day and every night.
Yet this was exactly our position. We were a small party in the
midst of a hostile population. Even if we had ventured to leave our
camp we should have had to divide, one-half of us remaining on
guard; but neither division would have been strong enough in any
emergency, for those who went could not spare any coolies as
scouts, whilst those who remained would have no sentries. When we
went to fetch wood, we did not go out of sight of our fort, which was
left to the care of the halt and lame, so to speak: the interpreters and
the scullions, and I was quite uneasy about them when I saw the
men leave of a morning.
A TOWER OF FORT ARCHINARD.
Our one safe road, the river, was blocked above and below the
camp, for we had a rapid up-stream and a rapid down-stream, so
that even quite small canoes could not pass.
There has been much talk of winter in the Arctic regions, and of
course such a winter is always very severe, but the one we passed
at Say was simply miserable. I really do think that the fact of all five
of us Europeans having survived it, is a proof that we were endowed
with a great amount of energy and vitality.
The temperature had much to do with our sufferings. It increased
steadily until June, and then remained pretty stationary. The

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Greenspan’s Basic and Clinical

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A NATIVE WOMAN WITH