Clinical Neuroendocrinology, a volume in the Handbook of Clinical Neurology Series gives an overview of the current knowledge in the field of clinical neuroendocrinology. It focuses on the pathophysiology, diagnosis, and treatment of diseases of the hypothalamus and the pituitary gland. It integrates a large number of medical disciplines, including clinical endocrinology, pediatrics, neurosurgery, neuroradiology, clinical genetics, and radiotherapy. Psychological consequences of various disorders and therapies, as well as therapeutic controversies, are discussed. It is the first textbook in the field to address all these aspects by a range of international experts. - All contributors are recognized experts in the different fields of clinical neuroendocrinology- The book provides expanded coverage on hypothalamic mechanisms in human pathophysiology- The book includes current perspectives, diagnosis and treatment of pituitary diseases
Front Cover 1
Clinical Neuroendocrinology 4
Copyright 5
Handbook of Clinical Neurology 3rd Series 6
Foreword 8
Preface 10
Contributors 12
Contents 16
Section 1: Clinical aspects of hypothalamic function 20
Chapter 1: Genetic aspects of hypothalamic and pituitary gland development 22
Introduction 22
Development of the hypothalamo-pituitary axis 22
Morphology 22
Timeline of hypothalamo-pituitary Organogenesis 23
Genetic and Molecular Regulation of hypothalamo-pituitary Development 25
Factors Involved in the Early Formation Of the pituitary 26
Bone Morphogenetic Protein 4 and the Sonic Hedgehog Pathway 26
FGF8 26
Lim homeodomain transcription factors 27
Homeobox Embryonic Stem Cell 1 (HESX1) 28
SOX2 and SOX3 28
Orthodentic Homeobox 2 (OTX2) 29
Factors Regulating Cellular Differentiation 29
PROP1 and POU1F1/PIT1 29
GATA2 30
TBX19 30
Factors Involved in Hypothalamic Formation 30
Congenital Hypopituitarism and Associated Defects 32
Overlap Between Congenital Hypopituitarism and Midline Defects With Kallmann Syndrome 32
Conclusion and Future Directions 33
Chapter 2: Neuroendocrinology of Pregnancy and Parturition 36
Introduction 36
The Hypothalamus-pituitary-target Gland Axes During Pregnancy 36
Activity of Hypothalamus-pituitary-adrenal axis 37
Maternal Hypothalamus-pituitary-adrenal axis 37
Early and mid-pregnancy 38
Late Pregnancy 38
Parturition 38
Fetal Hypothalamus-pituitary-adrenal axis 38
Activity of Hypothalamus-pituitary-gonadal axes 39
Activity of the Other Neuroendocrine axes 39
Hypothalamus-prolactin axis 39
Hypothalamus-growth Hormone axis 40
Hypothalamus-pituitary-thyroid axis 40
The Placenta: A Neuroendocrine organ 41
Stress-related Hormones: Implications in Physiologic Pregnancy and Parturition and In obstetric Complications 42
Corticotropin-releasing Hormone Family 42
Corticotropin-releasing Hormone 42
Placental Expression and Regulation 42
Physiologic Pregnancy and Parturition 42
Implications for Maternal/fetal Adverse Programming 45
Urocortins 45
Placental Expression and Regulation 45
Physiologic Pregnancy and Parturition 46
Implications for Maternal/fetal Adverse Programming 47
Oxytocin 47
The Role of Stress in Maternal and Fetal Adverse Programming 48
Conclusions 48
Chapter 3: Disorders of Water Metabolism: Diabetes Insipidus and the Syndrome of Inappropriate Antidiuretic Hormone Secretio... 56
Water Metabolism 56
Thirst 56
Vasopressin Secretion 57
Vasopressin Actions 58
Integration of Thirst and Avp Secretion 58
Sodium Metabolism 58
Salt Appetite 59
Renal Sodium Excretion 59
Hypo-osmolality 59
Differential Diagnosis 59
Decreased Ecf Volume (hypovolemia) 59
Normal ECF Volume (euvolemia) 59
Increased ECF Volume (hypervolemia) 60
Clinical Manifestations 60
Therapy 60
Currently Available Therapies for Treatment Of hyponatremia 61
Isotonic Saline 61
Hypertonic Saline 61
Fluid Restriction 61
Demeclocycline 62
Mineralocorticoids 62
Urea 62
Furosemide And NaCl 62
Arginine Vasopressin Receptor (AVPR) Antagonists 62
Hyponatremia Treatment Guidelines 63
Monitoring the Serum [Na+] in Hyponatremic patients 64
Long-term Treatment of Chronic Hyponatremia 65
Hyperosmolality 65
Etiologies and Diagnosis 65
Diabetes Insipidus 65
Osmoreceptor Dysfunction 66
Differential Diagnosis 66
Clinical Manifestations 67
Therapy 68
Chapter 4: The Role of Oxytocin and Vasopressin In emotional and social behaviors 72
Introduction 72
Nonclinical Populations 72
Oxytocin 72
Trust 73
Mind Reading 73
Empathy 75
Positive Communication Between Couples 75
Generosity and Altruism 76
Bonding and Attachment 76
Oxytocin and Mirror Neurons 76
Vasopressin 76
Aggression 77
Psychosocial Stress 77
Empathy 78
Altruism 78
Clinical Populations 79
Oxytocin and Vasopressin in Autism Spectrum disorders 79
Oxytocin and Vasopressin in Eating Pathology 80
Oxytocin and Vasopressin in Depression And anxiety 80
Methodologic Issues in Oxytocin And vasopressin Research 80
CD38 and Abnormal Social and Emotional Behaviors 80
Endophenotypes 81
Future Directions 81
Chapter 5: Corticotropin-releasing Hormone and the Hypothalamic-pituitary-adrenal Axis in Psychiatric Disease 88
Introduction 88
Corticotropin-releasing Hormone and Basal Hypothalamic-pituitary-adrenal axis Activity 88
Hypothalamic-pituitary-adrenal axis Functioning in Major Depression 90
The corticotropin-releasing Hormone System and Dexamethasone/corticotropin-releasing Hormone Studies in Depression... 90
Adrenocorticotropin and Cortisol In depression 92
Dexamethasone Suppression test 93
Adrenocorticotropin Stimulation test 93
Vasopressin in Depression 94
Early Life Stress, Depression, and the Hypothalamic-pituitary-adrenal axis 95
Monoamines, the Hypothalamic-pituitary-adrenal Axis, and the Effects Of antidepressants 95
The Hypothalamic-pituitary-adrenal Axis As a Target for Antidepressant Treatment: CRH1 Receptor Antagonists and C... 96
Corticotropin-releasing Hormone Receptor antagonists 96
Cortisol Synthesis Inhibitors 96
Hypothalamic-pituitary-adrenal axis Functioning in Bipolar Disorder 96
Dexamethasone/corticotropin-releasing Hormone Test in Bipolar Disorder 97
Vasopressin in Bipolar Disorder 97
Monoamines in Bipolar Disorder 97
Hypothalamic-pituitary-adrenal axis Functioning In schizophrenia 97
Basal Cortisol in Schizophrenia 98
The Dexamethasone Suppression Test in schizophrenia 99
Basal Measures of corticotropin-releasing Hormone and Adrenocorticotropin In schizophrenia 99
Corticotropin-releasing Hormone Test in schizophrenia 99
Dexamethasone/corticotropin-releasing Hormone Test in Schizophrenia 99
Effects of Psychological Stress on the Hypothalamic-pituitary-adrenal Axis In schizophrenia 100
Hypothalamic-pituitary-adrenal axis Functioning in Anxiety Disorders 102
Panic Disorder 102
Conclusion 103
Acknowledgments 103
Chapter 6: Genetic Aspects of Human Obesity 112
Introduction 112
Obesity: a Heritable Disorder 112
The Critical Role of the Hypothalamus 112
Integration and Coordination of Peripheral signals 113
Human Monogenic Obesity 114
Congenital Leptin Deficiency 114
Leptin-receptor Deficiency 114
Pro-opiomelanocortin (POMC) Deficiency 114
Prohormone Converatse 1/3 (PC1/3) Deficiency 115
Melanocortin-4-receptor (MC4R) Deficiency 116
Therapies for Melanocortin Pathway disorders 116
Brain-derived Neurotrophic Factor (BDNF) and Obesity 117
Src Homology 2 B adapter Protein 1 (SH2B1) and Obesity 117
Single-minded 1 (SIM1) and Obesity 117
Melanocortin-2-receptor Accessory Protein 2 (MRAP2) and Obesity 118
Human Pleiotropic and ``syndromic´´ Obesity 119
Bardet-Biedl Syndrome 119
Prader-Willi Syndrome 119
New Technologies to Identify Genetic Components of Obesity 120
Genome-wide Association Studies 121
Copy Number Variants 121
Whole Exome Sequencing 121
Conclusions 122
Chapter 7: Sleep Characteristics and Insulin Sensitivity in Humans 126
Introduction 126
Sleep Physiology and Glucose Homeostasis 126
Sleep Deprivation and Insulin Resistance 127
Experimental Studies on the Effects of Sleep Deprivation on Glucose Metabolism 127
Epidemiologic Studies on the Association Between Sleep Duration and Glucose Metabolism 127
Sleep Disorders and Insulin Resistance 128
Population-based Studies on Sleep Disorders and Insulin Resistance 128
Intervention Studies Assessing Sleep Quality and Insulin Sensitivity 129
Diabetes Mellitus, Metabolic Dysregulation, and Sleep Disorders 129
Potential Mechanisms Linking Impaired Sleep and Insulin Resistance 130
Future Research Suggestions 131
Chapter 8: Hypothalamic-pituitary Hormones During Critical Illness: A dynamic Neuroendocrine Response 134
Introduction 134
The Thyroid axis 134
The Thyroid Axis in Acute Critical Illness 134
The Thyroid Axis During Prolonged Critical illness 136
Therapeutic Potential 136
The Somatotropic axis 137
The Somatotropic Axis in Acute Critical Illness 137
The Somatotropic Axis During Prolonged Critical Illness 137
Therapeutic Potential 138
The Gonadal axis 138
The Gonadal Axis in Acute Critical Illness 138
The Gonadal Axis During Prolonged Critical illness 138
Therapeutic Potential 139
The Lactotropic axis 139
The Lactotropic Axis in Acute Critical Illness 139
The Lactotropic Axis During Prolonged Critical illness 139
Therapeutic Potential 139
The Adrenal axis 140
The Adrenal Axis in Acute Critical Illness 140
The Adrenal Axis During Prolonged Critical illness 140
Therapeutic Potential 140
Conclusions 141
Chapter 9: Central Regulation of the Hypothalamo-pituitary-thyroid (Hpt) Axis: Focus on Clinical Aspects 146
Introduction and Outline 146
Hypothalamus and Pituitary 146
The Hypothalamic thyrotropin-releasing Hormone Neuron 146
Pituitary 148
Pulsatility and Diurnal Rhythm 148
Neural Connections of Hypothalamic Nuclei With Adipose Tissue And liver 149
Central Hypothyroidism 151
Central Hypothyroidism in Neonates And children 151
Central Hypothyroidism in Adults 153
Central Hyperthyroidism 154
Conclusion 154
Section 2: Disorders of the Pituitary Gland 158
Chapter 10: Evaluation of Pituitary Function 160
Introduction 160
Reasons for Undertaking Pituitary Investigations 160
Approach to the Patient In pituitary Clinic 161
Principles of Pituitary Assessment 161
Basal Pituitary Blood tests 161
Evaluation of the pituitary-adrenal axis 162
Cortisol Production in Health 162
Measurement of Serum Cortisol 162
Insulin Tolerance test 162
Short Synacthen test 163
Low-dose Short Synacthen test 164
Glucagon Stimulation test 164
Metyrapone test 164
Evaluation of the pituitary-thyroid axis 164
Evaluation of the pituitary-gonadal axis 165
Prolactin 165
Growth Hormone Deficiency In adults 166
Glucagon Stimulation test 166
Arginine Stimulation test 166
Antidiuretic Hormone Deficiency: Diabetes Insipidus 167
Conclusion 167
Chapter 11: Imaging of Pituitary Pathology 170
Introduction 170
Magnetic Resonance Imaging 170
The Normal Pituitary 171
Imaging of Pituitary Adenomas 172
Pituitary Microadenomas 172
Pituitary Macroadenomas 173
Postoperative Magnetic Resonance Imaging and Monitoring of Effects of Other Treatment 174
Intraoperative Magnetic Resonance Imaging 177
Differential Diagnosis 177
Craniopharyngiomas and Rathke's Cleft cyst 178
Suprasellar and Parasellar Meningiomas 179
Chordomas and Chondrosarcomas Of the clivus 179
Hypophysitis 180
Aneurysms 180
Other Intrasellar Lesions 181
Other Suprasellar Lesions 181
Incidentalomas 181
Computed Tomography 181
Spect/Pet 182
Summary 183
Chapter 12: Nonfunctioning Pituitary Tumors 186
Introduction 186
The Asymptomatic, Incidental, Clinically Nonfunctioning Adenoma (pituitary Incidentaloma) 186
Autopsy Findings 186
CT and MRI Scans in Normal Individuals 187
Endocrinologic Evaluation of the Asymptomatic Incidental mass 188
Natural History and follow-up of Incidental Clinically Nonfunctioning Adenomas 190
Management of Incidental Clinically Nonfunctioning Adenomas 191
Symptomatic Clinically Nonfunctioning Adenomas 192
Presenting Symptoms 192
Diagnostic Evaluation 192
Treatment 192
Surgery 195
Radiotherapy 195
Medical Therapy 197
Management of the Symptomatic Patient 198
Chapter 13: Hyperprolactinemia and Prolactinoma 204
Introduction 204
Causes of Hyperprolactinemia 204
Clinical Features Of hyperprolactinemia 205
Laboratory Assessment Of hyperprolactinemia 205
Macroprolactinemia 205
High-dose Hook Effect 206
Dynamic Tests of Prolactin Secretion 206
Radiologic Diagnosis Of prolactinomas 206
Prevalence Rates Of prolactinomas 207
Treatment Of hyperprolactinemia And prolactinoma 207
Normalization of Prolactin Levels 207
Reduction of Prolactinoma size 208
Dopamine agonist-resistant Prolactinomas 208
Symptomatic Patients With Idiopathic Hyperprolactinemia 209
Pregnancy 209
Induction of Pregnancy 209
Effects of Dopamine Agonists on Fetal Development and Pregnancy Outcome 210
Effects of Pregnancy on Prolactinoma size 210
Drug-induced Hyperprolactinemia 210
Adverse Effects of Dopamine Agonists 211
Withdrawal of Dopamine Agonist Treatment 211
Conclusion 212
Chapter 14: Acromegaly 216
Introduction 216
Epidemiology 216
Pathophysiology 216
Acromegaly Related to a Pituitary tumor 216
Somatotroph Pituitary Adenomas 216
Growth hormone-secreting Carcinomas 217
Genetic Syndromes Associated With Acromegaly 217
Extrapituitary Acromegaly 217
Signs and Symptoms 218
The Dysmorphic Syndrome 218
Symptoms 219
Skin Changes 219
Bone Changes 219
Craniofacial 219
Extremities 219
Trunk 219
Limbs 219
Bone Mineral Density 219
Rheumatologic Complications 219
Peripheral Arthropathy 219
Spinal Involvement 220
Neuropathies 220
Cardiovascular Manifestations 221
Arterial Hypertension 221
Specific Cardiomyopathy 221
Valve Disease 222
Metabolic Complications 222
Respiratory Complications 222
Neoplasia and Acromegaly 223
Gastrointestinal Tumors 223
Thyroid Nodules 223
Diagnosis of Acromegaly 223
Growth Hormone Assays 223
Which Growth Hormone Cutoff to Use For diagnosis? 224
IGF-1 Assays 224
Stimulation tests 224
Difficult and Borderline Clinical Situations 224
Differential Diagnosis 225
Tumoral and Functional Pituitary Assessment 225
Prognosis and Outcome 225
Management and Treatment 226
Treatment aims 226
Surgery is Generally the first-line Treatment 226
Radiotherapy 226
Medical Treatment 227
Dopamine Agonists 227
Somatostatin Analogs 228
Gh-receptor Antagonists 229
Current Therapeutic Strategy 230
Conclusion 230
Chapter 15: Cushing´s Disease 240
Introduction 240
Clinical Features and Diagnosis 240
Clinical Features 240
Diagnosis 241
Management 244
Pituitary Surgery 244
Management of Recurrent Cushing's Disease 246
Medical Therapy 247
Conclusion 249
Notes Added in Proof 249
Chapter 16: Craniopharyngioma 254
Introduction 254
Epidemiology and Pathology 254
Clinical Manifestations At the time of Diagnosis 254
Imaging Studies 255
Treatment Strategies 255
Neurosurgery: Strategies and Effects 255
Irradiation 257
Proton Beam Therapy 258
Radiosurgery 258
Hypofractionated Stereotactic Radiotherapy: CyberKnife 258
Intracavitary ß Irradiation 258
Instillation of Sclerosing Substances For cystic recurrent Tumors 258
Sequelae 259
Pituitary Deficiencies 259
Neurologic and Visual Outcomes 259
Hypothalamic Dysfunction 259
Obesity and Eating Disorders 260
Physical Activity and Energy Expenditure 261
Autonomous Nervous System 261
Appetite Regulation 261
Pharmacologic Treatment of Hypothalamic Obesity 262
Bariatric Treatment of Hypothalamic Obesity 262
Quality of Life, Neurocognitive Outcome, And psychosocial Functioning 262
Survival and Late Mortality 263
Cerebrovascular Morbidity 263
Second Malignant Neoplasms 264
Adult-onset Craniopharyngioma 264
Questions and Treatment Perspectives 264
Surgical Treatment Strategies: Degree Of resection 264
Controversy Over Time Point of Irradiation 264
Expertise 265
Risk-adapted Strategies/treatment Algorithms for Craniopharyngioma 265
Conclusions 268
Note 268
Acknowledgments 268
Chapter 17: Rathke´s Cleft cyst 274
Introduction 274
Epidemiology 274
Pathology 275
Pathogenesis 276
Formation of Rathke's Pouch and Pituitary Organogenesis 276
Pathogenesis of Rathke's Cleft Cyst and Other Cystic Sellar Lesions 276
Presenting Manifestations 279
Headaches 279
Visual Field Disturbance 279
Endocrine Dysfunction 280
Diabetes Insipidus 280
Apoplexy 280
Other Presenting Manifestations 280
Location and Imaging Features 280
Computed Tomography 281
Magnetic Resonance Imaging 281
Natural History 281
Treatment 283
Treatment Strategies 283
Complications 283
Outcomes 283
Recurrence 283
Relapse rates 283
Risk Factors for Relapse 284
Acknowledgments 285
Chapter 18: Alternative Causes of Hypopituitarism: Traumatic Brain Injury, Cranial Irradiation, and Infections 290
Introduction 290
Traumatic Brain Injury 290
Historical Background of Hypopituitarism After Traumatic Brain Injury 290
Neuroendocrine Dysfunction After Traumatic brain Injury 291
Predictors of Neuroendocrine Dysfunction After Traumatic Brain Injury 293
Sport 293
Modern Military Operations: blast-related Traumatic Brain Injury 293
Traumatic Brain Injury in Children And adolescents 293
Pathophysiologic Mechanisms Of neuroendocrine Dysfunction Due to traumatic Brain Injury 294
Diagnosis of Neuroendocrine Dysfunction After Brain Injury 294
Cognitive Impairments After Traumatic Brain injury 296
Cranial Irradiation 296
Introduction 296
Neuroendocrine Dysfunction After Cranial Irradiation 296
Diagnosis of Impaired Growth Hormone Secretion After Cranial Irradiation 298
Abnormalities in Other Pituitary Hormones 298
Infections in the Hypothalamic-pituitary Region 299
Sources of Infections Spreading to the Hypothalamic-pituitary Region 299
Predisposing Factors for Pituitary Infections 299
Clinical Features of Pituitary Infections 299
Neurologic Symptoms 299
Endocrine Dysfunction 299
Pituitary Abscess 299
Nonspecific Inflammation of the Cavernous Sinus: the Tolosa-Hunt Syndrome 300
Hypothalamic-pituitary Tuberculosis 300
Fungal Infections 301
Viral Infections Affecting the Hypothalmus And/or Pituitary 302
Parasites in the Pituitary: Toxoplasma Gondii 304
Summary 304
Acknowledgment 304
Chapter 19: Surgical Approach to Pituitary Tumors 310
Introduction 310
Historical Background 310
Surgery 311
Transsphenoidal Approaches 312
Microsurgical Transsphenoidal Approaches 313
Microsurgical Transnasal Transseptal Transsphenoidal Approach 313
Microsurgical Sublabial Transseptal Transsphenoidal Approach 313
Microsurgical Endonasal Transsphenoidal Approach 313
Endoscopic Endonasal Transsphenoidal Approach 313
Transcranial Approaches 315
Complications 315
Final Remarks 317
Chapter 20: Medical Approach to Pituitary Tumors 322
Introduction 322
Nonfunctional Adenoma 322
Medical Treatment 322
Side-effects of Medical Treatment 322
Prolactinoma 322
Medical Treatment 323
Efficacy 323
Withdrawal of Dopamine Agonists 323
Adverse Effects 323
Valvular Heart Disease 324
Acromegaly 324
Medical Treatment 324
Somatostatin Analogs 325
Efficacy 325
Pegvisomant 325
Efficacy 326
Combination Therapy With Pegvisomant and Somatostatin Analogs 326
Quality of Life Aspects of Combination Therapy 327
New Developments 327
Adverse Effects 329
Cushing's Disease 330
Medical Treatment 330
Side-effects of Medical Treatment 331
Thyrotropin-secrecting Adenoma 331
Medical Treatment 331
Dopamine Agonists 331
Somatostatin Analogs 331
Antithyroid Treatment 332
Side-effects 332
Chapter 21: Radiation Therapy in the Management of Pituitary Adenomas 336
Introduction 336
Background on Fractionated Radiation Therapy and single-fraction Radiosurgery 336
Deciding Between Fractionated Radiotherapy and single-fraction Radiosurgery 337
Radiation Treatment Planning 337
Normal Tissue Tolerances 337
Proton Therapy 338
Clinical Outcomes of Radiation Therapy in Pituitary Adenomas 338
Nonfunctioning Adenomas 338
Functioning Adenomas 339
Prolactinomas 339
Adrenocorticotropic hormone-secreting Adenomas 339
Growth hormone-secreting Adenomas 340
Thyroid-stimulating hormone-secreting Adenomas 340
Pituitary Carcinomas 341
Sequelae After Radiation Therapy 341
Conclusion 342
Section 3: Controversial Issues and Hot Topics 344
Chapter 22: Nelson Syndrome: Definition and Management 346
Introduction 346
Effective Diagnosis of Nelson Syndrome 347
Clinical, Biochemical, and Radiologic Features 347
Diagnostic Criteria 348
Predictive Factors for the Onset and Progression of Nelson Syndrome 348
Residual Pituitary Tumor Shown on Imaging Prior to Total Bilateral Adrenalectomy 349
Adrenocorticotropic Hormone Levels In the first Postoperative year 349
Administration of Neoadjuvant Radiotherapy post-total Bilateral Adrenalectomy Surgery 349
Duration of Cushing's Disease Prior to Total Bilateral Adrenalectomy 349
Residual Adrenal Remnant After Total Bilateral Adrenalectomy 350
Age 350
High Urinary Cortisol 350
Insufficient Exogenous Steroid Replacement Therapy post-total Bilateral Adrenalectomy Surgery 350
Lack of Cortisol Suppression on high-dose Dexamethasone Pre-total Bilateral Adrenalectomy 350
Pathophysiology of Nelson Syndrome 350
Pathologic Features of Corticotropinomas in Nelson Syndrome 351
Effective Management of Nelson syndrome 351
Pituitary Surgery 351
Adjuvant Radiotherapy 352
Stereotactic Radiosurgery 352
Selective Somatostatin Analogs 352
Peroxisome proliferator-activated Receptor . agonists 352
Sodium Valproate 353
Dopamine Agonists 353
Temozolomide 353
Conclusions 353
Acknowledgments 353
Chapter 23: Familial Pituitary Tumors 358
Introduction 358
Pituitary Tumorigenesis 358
Pituitary Adenomas of Genetic Origin 359
Multiple Endocrine Neoplasia Type 1 (MEN1) OMIM #131100 359
Clinical Features Of MEN1 359
Parathyroid Tumors 359
Pancreatic Tumors 361
Pituitary Tumors 361
Genetics of MEN1 Syndrome 362
Management of Pituitary Disease In MEN1 363
Familial Isolated Pituitary Adenoma (FIPA): Related OMIM Entries: Pituitary Adenoma, Growth hormone-secreting #102200 and ... 364
Clinical Features Of FIPA 364
Genetics Of FIPA 364
Management of Pituitary Disease In FIPA 366
Carney Complex Syndrome (CNC): Related OMIM Entries: CNC1 #160980, PRKAR1A 188830 366
Clinical Features Of CNC 367
Genetics Of CNC 368
Management of Pituitary Disease In CNC 369
McCune-Albright Syndrome: OMIM 174800 369
Clinical Features of McCune-Albright Syndrome 369
Genetics of McCune-Albright Syndrome 372
Management of Pituitary Disease In McCune-Albright Syndrome 372
Familial Hyperprolactinemia 374
Conclusion 374
Abbreviations 374
Chapter 24: Long-term Effects of Treatment of Pituitary Adenomas 380
Treatment of Pituitary Adenomas: the Historical Perspective 380
Mortality 380
Hypopituitarism and Mortality 381
Cardiovascular Morbidity And pituitary Disease 381
Failure to Mimic Physiologic Hormone Secretion With Substitution 383
Hypothalamic Dysfunction 383
Quality Of life 384
Cognitive Function And psychopathology 385
Acromegalic Arthropathy As a model for disease-specific Persistent Morbidity 386
Implications for Treatment And follow-up 387
Chapter 25: Neuroendocrine Mechanisms in Athletes 392
Introduction 392
Neuroendocrine Alterations In athletes 392
Hypothalamic-pituitary-gonadal axis 392
Spectrum of Menstrual Function in the Female Athlete 392
Luteinizing Hormone and follicle-stimulating Hormone Secretion in Female Athletes 393
Pulsatility Patterns of Luteinizing Hormone and follicle-stimulating Hormone in Athletes 393
Determinants of Altered Luteinizing Hormone Pulsatility in Athletes 393
Kisspeptin in Athletes and Nonathletes 394
Prolactin and Oxytocin in Athletes And nonathletes 394
Appetite Regulating and Gut Peptides That May regulate Energy Homeostasis and Impact The hypothalamic-pituitary-go... 394
Leptin 394
Ghrelin 395
Peptide YY 395
Insulin 395
Adiponectin 395
Reproductive Function in Male Athletes 395
Hypothalamic-pituitary-adrenal axis 396
Growth Hormone-insulin-like Growth Factor 1 (IGF-1) axis 396
Hypothalamic-pituitary-thyroid axis 397
Impact on Bone Metabolism of Athletic Activity and Associated Neuroendocrine Changes 397
Areal Bone Density in Athletes 397
Impact of Physical Activity and the Nature Of the sport 398
Impact of Energy Deficiency And/or Hypogonadism 398
Modifying Effect of the Nature of Impact 398
Bone Turnover in Athletes 398
Determinants of Bone Density in Athletes 398
Limitations of Areal Bone Density Assessment 399
Bone Microarchitecture, Volumetric Bone Density, and Estimates of Bone Strength In athletes 399
Bone Structural Changes 399
Cortical and Trabecular Microarchitectural Changes 399
Volumetric Bone Density 399
Estimated Bone Strength and Fractures 400
Determinants of Bone Structure, Microarchitecture, Volumetric Bone Density, And estimated Strength 400
Strategies to Optimize Bone Health in Athletes 400
Impact on Neurocognitive Function 400
Impact on Fertility 401
Conclusion 401
Acknowledgments 402
Chapter 26: Uncertainties in Endocrine Substitution Therapy For central hypocortisolism 406
Introduction 406
Clinical Assessment For hypocortisolism 406
Dynamic Tests of Hypocortisolism 407
Standard Treatments for Hypocortisolism 408
What is the Optimal agent? 408
Total Daily Glucocorticoid Dosing 408
Multiple Daily Dosing and Monitoring Of glucocorticoid Replacement 410
Modified-release Hydrocortisone 411
Future Glucocorticoid Treatments 412
Other Adrenal Androgens 412
Adrenal Suppression 412
Patient Education 413
Conclusions 413
Chapter 27: Uncertainties in Endocrine Substitution Therapy for Central Endocrine Insufficiencies: Hypothyroidism 416
Introduction 416
Facts and Uncertainties in Central Hypothyroidism Diagnosis 416
Inheritable Central Hypothyroidism 416
Acquired Forms of Central Hypothyroidism 417
Facts and Uncertainties in Central Hypothyroidism Replacement Therapy 419
Novel Perspectives for Therapy of Central Hypothyroidism 421
Chapter 28: Uncertainties in Endocrine Substitution Therapy for Central Endocrine Insufficiencies: Growth Hormone Deficiency... 426
Introduction 426
Patients With Isolated Growth Hormone Deficiency (e.g., Caused By Treatment With Prophylactic Cranial Radiotherapy for Lympho.. 427
Cardiovascular Risk After Acute Lymphoblastic Leukemia 427
Bone Health After Acute Lymphoblastic Leukemia 428
Patients With Growth Hormone Deficiency and Multiple Hormone Deficiencies Caused By Nonsecreting Pituitary Macroadenomas Treat. 428
Cardiovascular Risk in Hypopituitary Patients With Nonsecreting Pituitary Macroadenomas 428
Bone Health in Patients With Growth Hormone Deficiency Due to Pituitary Macroadenomas 429
Patients With Growth Hormone Deficiency and Multiple Hormone Deficiencies and With Hypothalamic Involvement Caused By a Cranio. 429
Cardiovascular Risk in Patients With A craniopharyngioma 429
Hypothalamic Damage and Obesity In craniopharyngioma Patients 431
Bone Health in Craniopharyngioma Patients 431
General Uncertainties of Growth Hormone Therapy 432
Conclusion 432
Chapter 29: Autoimmune Hypophysitis: New Developments 436
Introduction 436
Pituitary Autoantibodies 437
IGG4-Related Hypophysitis 437
Anti-PIT-1 Antibody Syndrome 438
Autoimmunity and Metabolic Disease 439
Conclusion 440
Abbreviations 440
Index 442
Genetic aspects of hypothalamic and pituitary gland development
Mark J. McCabe; Mehul T. Dattani* Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London–Institute of Child Health, London, UK
* Correspondence to: Professor Mehul T. Dattani, UCL-Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. Tel: + 44-207-905-2657, Fax: + 44-207-404-619 email address: m.dattani@ucl.ac.uk
Abstract
Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and septo-optic dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.
Key words
Hypopituitarism
septo-optic dysplasia
holoprosencephaly
Kallmann syndrome
craniofacial
midline
pituitary
hypothalamus
Introduction
The primordial central nervous system develops during the third week of human gestation during neurulation, a process which gives rise to the neural plate with subsequent derivations into the spinal cord and brain. Fate map studies, which aim to follow the development of cells or tissues from early stages of embryogenesis, have shown that the pituitary, hypothalamus, optic nerves, and forebrain each develop from the anterior neural plate (Schlosser, 2006). Complex interactions of spatiotemporally regulated signaling molecules and transcription factors are critically important for their successful development.
The pituitary gland is a midline structure located in the sella turcica recess of the sphenoid bone at the base of the brain. It is composed of three lobes which have dual embryonic ectodermal origins, the oral ectoderm giving rise to the hormone-secreting anterior and intermediate lobes and the overlying neural ectoderm giving rise to the posterior lobe (Cohen, 2012). The posterior lobe is the only neural component of the pituitary gland and provides a direct link to the hypothalamus, which is also derived from the neural ectoderm. Maintained apposition and interactions between these two ectodermal layers is crucial for normal pituitary development. Insults to this developmental process can result in the loss or reduction of pituitary hormone-secreting cells resulting in congenital hypopituitarism, with phenotypes ranging from multiple pituitary hormone deficiencies (combined/multiple pituitary hormone deficiency (CPHD/MPHD)) to deficiencies in single hormones only, the most common isolated hormone deficiency being attributed to growth hormone (Alatzoglou and Dattani, 2009). Given its midline location, and that the pituitary gland is derived from the same region of the neural plate as the hypothalamus, optic nerves, and forebrain as described above, hypopituitarism is often associated with craniofacial/midline disorders affecting these structures also. Such disorders are characteristically heterogeneous but range from incompatibility with life, to holoprosencephaly (HPE) and cleft palate and septo-optic dysplasia (SOD), which will be described later (McCabe et al., 2011a).
This chapter will review the molecular basis underlying the development of the hypothalamo-pituitary axis and will detail how known defects in many of the required genes can lead to HPE and SOD as well as isolated CPHD/MPHD. Furthermore, this chapter will discuss the increasing evidence of overlapping genotypes between congenital hypopituitarism and Kallmann syndrome (KS), defined as the combination of hypogonadotropic hypogonadism (HH) and anosmia.
Development of the hypothalamo-pituitary axis
Morphology
As mentioned briefly in the introduction, the three lobes of the pituitary are derived from two adjacent ectodermal layers. The primordium of the anterior lobe is termed Rathke's pouch (RP), and this structure develops through the dorsal invagination of the oral ectoderm toward the overlying neuroectoderm containing the primordium of the hypothalamus, the ventral diencephalon (VD). The invagination of RP involves tight regulation of cellular proliferation and subsequent differentiation events to give rise to five highly differentiated cell types secreting a total of six different hormones: (1) corticotrophs produce adrenocorticotropic hormone (ACTH), (2) thyrotrophs produce thyrotropin or thyroid-stimulating hormone (TSH), (3) somatotrophs produce growth hormone, (4) lactotrophs (which are derived from the same precursor cells as the somatotrophs; termed somatomammotrophs) produce prolactin, and (5) gonadotrophs produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Cohen, 2012). This invagination event also leads to the formation of the intermediate lobe, and this contains the melanotrophs which secrete pro-opiomelanocortin (POMC). POMC is a major precursor protein to endorphins, melanocyte-stimulating hormone (MSH), and ACTH (Alatzoglou and Dattani, 2009). Humans contain only a vestigial intermediate lobe and as such do not secrete large amounts of POMC-derived hormones. Once secreted, each of the hormones targets distant tissues and organs throughout the body.
As RP invaginates, part of the VD evaginates ventrally to form the infundibulum and later the posterior pituitary lobe and pituitary stalk. Throughout development there is a close association between the infundibulum and RP and the interactions and apposition between these structures must be maintained for successful organogenesis. The pituitary stalk acts as a physical connection between the pituitary gland and brain and contains the hypophyseal (hypothalamo-pituitary) portal system, as well as the neuronal connections traversing across the hypothalamic median eminence. These neurons originate from the supraoptic, suprachiasmatic, and paraventricular nuclei which are large hypothalamic magnocellular bodies located within the periventricular region of the hypothalamus (Szarek et al., 2010). The supraoptic and suprachiasmatic nuclei release arginine vasopressin while the paraventricular nuclei release oxytocin (Kelberman et al., 2009). Within the median eminence itself at the base of the hypothalamus is the capillary bed, into which the widely dispersed hypothalamic parvocellular neurons secrete hypophysiotropic hormones. These stimulate the release of the seven anterior/intermediate pituitary lobe hormones described above via the hypophyseal portal system. Interestingly, the parvocellular neurons also secrete oxytocin and arginine vasopressin, although at much lower concentrations than the magnocellular neurons, with the parvocellular-derived arginine vasopressin being implicated in acting synergistically with corticotropin-releasing hormone in regulating ACTH release. It is therefore evident that it is the hypothalamus that is the central mediator of growth, reproduction, and homeostasis, acting through the pituitary gland (Kelberman et al., 2009).
The anatomy of the developed hypothalamus is well understood. It extends from the anteriorly located optic chiasm to the posteriorly located mammillary body and is organized into distinct rostral to caudal regions: preoptic, anterior, tuberal, and mammillary (Szarek et al., 2010). The organ is also subdivided into three medial to lateral regions: periventricular, medial, and lateral (Szarek et al., 2010). The periventricular region was described above, but contained within the medial region is the medial preoptic nucleus, the anterior hypothalamus, the dorsomedial nucleus, the ventromedial nucleus, and the mammillary nuclei (Szarek et al., 2010). The lateral zone consists of the preoptic area and hypothalamic area.
Interestingly, however, deciphering hypothalamic development during embryogenesis has proved problematic, perhaps due to its anatomic complexity and highly diverse collection of cell groups and neuronal subtypes for which there is a dearth of literature defining the genetics and signaling and marker molecules involved in their delineation and identification (Blackshaw et al., 2010). Furthermore, genetic expression studies within the hypothalamus have knock-on effects on multiple neuronal subtypes and downstream physiologic processes. However, studies are slowly elucidating hypothalamic development. Structural organization of the developing human hypothalamus was nicely assessed by immunohistochemistry in more than 30 brains over the entire course of gestation, and provided evidence for architectural homologies between species, particularly that of the better characterized rat (Koutcherov et al.,...
| Erscheint lt. Verlag | 28.8.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Humanbiologie | |
| Naturwissenschaften ► Biologie ► Zoologie | |
| ISBN-10 | 0-444-62612-3 / 0444626123 |
| ISBN-13 | 978-0-444-62612-7 / 9780444626127 |
| Haben Sie eine Frage zum Produkt? |
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