Cushing's Syndrome (eBook)

Preface 6
Contents 8
Contributors 10
1: Physiology and Pathophysiology of the HPA Axis 14
Neuroendocrine Control of the Hypothalamo-pituitary-adrenal Axis 15
Circadian Rhythm 18
The Stress Response and Immune-endocrine Axis 19
Negative Feedback Control 20
Corticosteroid Hormone Action 21
Hypercortisolism and Pathophysiological Functions 23
References 27
2: Etiologies of Cushing’s Syndrome 34
Definition of Cushing’s Syndrome 34
Exogenous Cushing’s Syndrome 34
Endogenous Cushing’s Syndrome 35
Other Conditions with Hypercortisolemia Without Cushing’s Syndrome 35
Etiology and Pathogenesis 35
ACTH-Dependent Cushing’s Syndrome 36
Cushing’s Disease 36
The Ectopic ACTH Syndrome 37
ACTH-Independent Cushing’s Syndrome 38
Epidemiology 39
Approach to Management 40
References 40
3: Pathogenesis of Corticotropic Tumors 43
Animal Models of Cushing’s Disease 44
Transgenic Oncogene Overexpression in CD Models 44
Transgenic Alterations of Hormonal and Growth Factor Signals in CD Models 45
Genetic Knockout of Cell Cycle Regulators in Pituitary POMC Cell Tumors 46
Pathology of Human Pituitary Corticotroph Adenomas 46
Pathophysiology 47
Molecular Pathogenesis Associated with Human Cushing’s Disease 48
Conclusions 49
References 49
4: Pathogenesis of Adrenocortical Tumors 53
Introduction 54
p53 Tumor Suppressor Gene and Locus 17p13 55
Acth Receptor, GSa Genes, and PKC Activity 58
Multiple Endocrine Neoplasia Type I, MEN1 GENE, and LOCUS 11q13 58
IGF System and Locus 11p15 58
Comparative Genomic Hybridization Analysis 59
Microarray Analysis 60
Steroidogenic Factor 1 60
Wnt-b-Catenin Pathway 60
Conclusions and Perspectives 61
References 62
5: Clinical Features of Cushing’s Syndrome 65
Obesity and Lipid Metabolism 67
Skin Changes 69
Muscle Changes 71
Cardiovascular System 71
Nervous System, Neuropsychological and Psychiatric Changes 71
Electrolyte and Water Balance 71
Glucose Metabolism 72
Bone Metabolism: Osteoporosis 72
Gonadal Changes 72
Growth Retardation 72
Thyroid Gland 73
Immune System 73
In What Clinical Settings Should Cushing’s Syndrome be Suspected? 74
References 75
6: Laboratorial Diagnosis of Cushing’s Syndrome: Differential Diagnosis with Pseudo Cushing’s Conditions as Obesity, Alcoholism and Depression 77
Clinical Assessment 78
Laboratorial Diagnosis of Cushing’s Syndrome 79
Urinary Free Cortisol 79
Midnight Cortisol 79
Low Dose Dexamethasone Suppression Tests 80
Second Tier Tests to Exclude/Confirm Cushing’s Syndrome 80
Depression 81
Alcoholism 82
Obesity 83
Conclusion 84
References 84
7: Laboratorial Diagnosis of Cushing’s Syndrome: Differential Diagnosis Among the Different Causes of ACTH-Dependent and ACTH-Independent Cushing’s Syndrome 91
Introduction 92
ACTH-Independent CS 93
ACTH-Dependent CS 94
Dynamic Tests 95
Non-invasive Tests 95
High-dose Dexamethasone Suppression Test 95
CRH Stimulation Test 96
Desmopressin Stimulation Test 97
Combined Non-invasive Strategies 97
Bilateral Inferior Petrosal Sinus Sampling 98
Final Considerations 99
References 99
8: Imaging for the Differential Diagnosis of Cushing’s Syndrome: MRI, CT, and Isotopic Scanning 102
Radiology in the ACTH-Dependent Cushing’s Syndrome 102
Scintigraphy in the Acth-dependent Cs 104
Somatostatin Receptor Scintigraphy in Cushing’s Disease 104
Adrenal Imaging in Cs 104
Adrenal Radiology in Cs 104
CT 104
MRI 107
Adrenal Scintigraphy in CS 107
Functional Imaging Modalities Specific for Adrenocortical Tumors 107
Non-specific Functional Imaging Modalities for Adrenocortical Tumors 108
Imaging in the Ectopic Acth Syndrome 108
Scintigraphy in the Ectopic Acth Syndrome 108
Somatostatin Receptor Scintigraphy and PET 108
18F-FDG PET 109
18F-L-DOPA PET and /11C-5-HT PET 110
Conclusions 110
References 110
9: Inferior Petrosal Sampling for the Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome 115
Introduction 116
History of Inferior Petrosal Sinus Sampling 116
Anatomy and Technical Details 117
Interpretation of Ipss Data 118
Trial Results: Sensitivity and Specificity 119
Differential Diagnosis 119
Lateralization 121
Comparison with Other Tests 121
Cavernous Sinus and Jugular Vein Sampling 122
IPSS with Desmopressin 123
Limitations and Complications 123
IPSS Cannot Diagnose Cushing’s Syndrome 124
Pituitary Venous Drainage Variability 124
Episodic Hypercortisolism 124
Ectopic CRH 124
Complications 124
Role of Ipss in The Evaluation of Cushing’s Syndrome 125
Summary and Conclusions 125
References 126
10: The Surgical Management of Cushing’s Disease 130
Introduction 131
Making the Diagnosis 132
Surgical Principles 133
Technical Aspects of The Surgery for Cushing’s Disease 134
Postoperative Management 134
Complications of Surgery 135
Results of Surgery 135
Postoperative Recurrence of Cushing’s Disease 136
Conclusion 136
References 136
11: Adrenal-Directed Treatment Options for Cushing’s Disease 139
Introduction and Background 139
Advantages of the Laparoscopic Approach 140
Bilateral Laparoscopic Adrenalectomy 140
Surgical Approaches to the Adrenal Gland 142
Laparoscopic Technique 142
Efficacy of Laparoscopic Adrenalectomy 143
Risks of Laparoscopic Adrenalectomy 143
Summary 143
REFERENCES 144
12: Radiation Therapy and Stereotactic Radiosurgery for Cushing’s Disease 146
Summary 146
Introduction and Evolution of Radiation Techniques 146
Established Radiosurgical Modalities for Pituitary Tumors 148
Radiosurgical Planning and Technique 149
Treatment Planning 149
Neuro-Anatomical Considerations: Radiation Effects on the Optic Apparatus, Structures Within the Cavernous Sinus, and the Normal Pituitary Gland 150
Effectiveness of Radiosurgery for Pituitary Adenomas 150
Complications Following Radiosurgery for Cushing’s Disease 152
Prognosis and Follow-up 152
Conclusions 153
References 153
13: Medical Management of Cushing’s Syndrome 157
Summary 157
Introduction 157
Medical Therapy Targets 158
Pituitary Directed Treatment 158
Dopamine Agonists 158
PPAR-g Receptor Agonists 159
Somatostatin Analogues 159
Retinoic Acid 160
Other Agents 160
Drugs Directed At the Adrenal 161
Metyrapone 161
Ketoconazole 161
Mitotane 162
Aminoglutethimide 162
Trilostane 163
Etomidate 163
Agents Blocking Cortisol Action 163
Monitoring of Treatment 163
Summary 164
References 164
14: ACTH-Dependent Cushing Syndrome: Clinical and Diagnostic Aspects, and Treatment Approaches for Ectopic Cushing’s Syndrome 169
Summary 169
Introduction 170
Sources of Eas 171
Diagnosis of Eas 172
Clinical Features, Signs and Symptoms 172
Biochemical Work-up 173
Imaging 175
Treatment of Eas 176
Surgical Approaches 176
Medical Therapy 176
Complementary Therapy 176
Prognosis 177
Other Types of Ecs 177
Pitfalls in Differential Diagnosis 178
Conclusions 178
References 179
15: Revisiting the Nelson’s Syndrome: Corticotroph Tumor Progression After Bilateral Adrenalectomy in Cushing’s Disease 183
A Word of History 184
Nelson’s Syndrome: Is There a Definition? 185
We Should Rather Look At “Corticotroph Tumor Progression” 185
IS Corticotroph Tumor Progression Inevitable? 186
Can We Predict Corticotroph Tumor Progression? 187
Can We Detect Corticotroph Tumor Progression Early? 187
Can We Prevent or Treat Corticotroph Tumor Progression? 187
Is There a Role for Bilateral Adrenalectomy in Cushing’s Disease? 188
Does Pregnancy Accelerate Corticotroph Tumor Progression? 189
What We All Look For In Cushing’s Disease 189
Pathophysiological Hypotheses 189
Back to History 190
References 191
16: ACTH-Independent Cushing’s Syndrome: Adrenocortical Tumors 194
Introduction 195
Epidemiology 195
Clinical Presentation 195
Diagnosis 199
Hormonal Findings 199
Dynamic Tests 200
24-h Urinary Free Cortisol Level 200
Midnight Plasma Cortisol and Late-Night Salivary Cortisol Measurements 200
Dexamethasone Suppression Test 200
Radiological Investigation 200
Histopathological Evaluation 203
Staging 205
Staging of Adrenocortical Tumor 205
Therapy 206
Surgery 206
Radiation Therapy 206
Radiofrequency Thermal Ablation 207
Medical Therapy 207
Mitotane Adjuvant Therapy 207
Treatment of Hormone Excess 208
Future Directions 209
References 210
17: ACTH-Independent Cushing’s Syndrome: Bilateral Macronodular Hyperplasia 214
Introduction 215
Epidemiology 215
Genetic Causes of Aimah 215
Clinical and Laboratory Features 215
Imaging in Aimah 216
Pathology 217
Pathophysiology of Aimah 217
Aberrant Hormone Adrenal Receptors in Adrenal CS 217
GIP-Dependent AIMAH 218
Vasopressin-Responsive CS 219
Catecholamine-Responsive AIMAH 219
LH/hCG-Responsive AIMAH 219
Serotonin-Responsive AIMAH 220
Angiotensin-Responsive AIMAH 220
Other Abnormal Responses in AIMAH 220
Aberrant Hormone Receptors in Familial Forms of AIMAH 220
Molecular Mechanisms of Aberrant Hormone Receptors 221
Paracrine Mechanisms in AIMAH 221
Investigation Protocol for Aberrant Receptors 222
Treatment of Aimah 223
Conclusion 224
References 225
18: ACTH-Independent Cushing’s Syndrome: Primary Pigmented Nodular Adrenal Disease in the Context of Carney’s Complex 230
Introduction 231
Adrenocortical Hyperplasias: Nomenclature and Features 231
Genetics of Micronodular Adrenocortical Disease 233
Primary Pigmented Nodular Adrenocortical Disease Associated with Carney Complex 233
Isolated Primary Pigmented Nodular Adrenocortical Disease 235
Isolated Micronodular Adrenocortical Disease 235
Adrenocortical Hyperplasia Associated with McCune–Albright Syndrome 236
Expressed Genes and Pathways in Primary Pigmented Nodular Adrenocortical Disease 236
Conclusion 237
References 237
19: Glucocorticoid Resistance 240
Introduction 241
Clinical Features of the Glucocorticoid Resistance Syndrome 242
Physiology of the Glucocorticoid Receptor 242
Glucocorticoid Receptor Gene Mutations 242
Unexplained Glucocorticoid Resistance 245
Other Forms of Gc Resistance 246
Mild Glucocorticoid Resistance Due to Polymorphisms in the Glucocorticoid Receptor Gene 247
Diagnosis of Glucocorticoid Resistance 248
Treatment of Glucocorticoid Resistance 249
References 250
20: Post-operative Replacement and Assessment of HPA Axis Recovery in Cushing’s Syndrome 254
Introduction 254
Post-operative Pituitary Hormone Replacement 255
ACTH Axis 255
Cushing’s disease 255
Cushing’s syndrome of adrenal origin 256
Ectopic Cushing’s syndrome 257
Other Pituitary Hormones (FSH/LH, TSH, GH, ADH) 257
Assessment of Recovery of the Hpa Axis and Follow-up for Relapse 258
Cushing’s Disease 258
Cushing’s Syndrome of Adrenal Origin 260
Ectopic Cushing’s Syndrome 261
Conclusion 261
References 262
21: Special Aspects of Cushing’s Syndrome: Pregnancy 264
Introduction 265
Clinical Features 265
Biochemical and Imaging Diagnosis 265
Hypothalamus-Pituitary-Adrenal Axis in Pregnancy 265
Establishing the Diagnosis of Cushing’s Syndrome in Pregnancy 266
Determining the Etiology of Cushing’s Syndrome in Pregnancy 268
Outcomes of Cushing’s Syndrome in Pregnancy 270
Maternal Morbidity 270
Fetal Outcomes 270
Management of Cushing’s Syndrome During Pregnancy 271
Surgical Treatment 271
Medical Treatment 272
Conclusion 273
References 274
22: Special Aspects of Cushing’s Syndrome: Childhood 277
McCune–Albright Syndrome 278
Adrenocortical Tumors 278
Ectopic ACTH Syndrome 279
Primary Nodular Adrenal Hyperplasia 279
Cushing’s Disease 279
Clinical Assessment of the Child with Suspected Cushing’s Syndrome 279
Linear Growth 279
Puberty Development 280
Investigation of Cushing’s Syndrome 280
Confirmation or Exclusion of Cushing’s Syndrome 280
Definition of the Etiology of Cushing’s Syndrome 281
Biochemical Features in Nodular Adrenal Hyperplasia 281
Genetics of Nodular Adrenal Hyperplasia 281
Adrenal Imaging 282
Pituitary Imaging 282
Bilateral Inferior Petrosal Sinus Sampling for ACTH 282
Treatment of Cushing’s Syndrome 283
Primary Adrenal Lesions 283
Cushing’s Disease 283
Transsphenoidal Surgery 283
Pituitary Radiotherapy 284
Post-cure Growth and Development 284
Conclusions 284
References 285
23: Special Aspects of Cushing’s Syndrome: Cyclic Cushing’s Syndrome 287
Introduction 288
Causes And Potential Mechanisms Implicated In The Physiopathology Of Cyclic Cushing’s Syndrome 289
Clinical Presentation 290
Diagnosis 291
Therapy 293
Conclusion 294
References 294
Index 298