Cover

Title page

Copyright page

Dedication

Contents

List of Contributors

Preface

List of Abbreviations

Introductiona

Chapter 1 - The Pituitary Gland: Anatomy, Physiology, and its Function as the Master Gland

1 - Introduction

2 - History

3 - Embryology

4 - Anatomy

4.1 - Histology

4.2 - Hypothalamus

4.3 - Vascular Anatomy

4.4 - Surgical Anatomy

4.4.1 - Nasal Cavity Anatomy

4.4.2 - Sphenoid Sinus Anatomy

4.5 - Radiographic Anatomy

5 - Physiology

5.1 - Hypothalamic Physiology

5.1.1 - Hypothalamus-Pituitary-Adrenal Axis

5.1.2 - Hypothalamus-Pituitary-Thyroid Axis

5.1.3 - Hypothalamus-Pituitary-Growth Hormone Axis

5.1.4 - Hypothalamus-Pituitary-Gonadal Axis

5.1.4.1 - Effects on Men

5.1.4.2 - Effects on Women

5.1.5 - Lactotroph Axis

5.2 - Posterior Pituitary Function

5.3 - Intermediate Gland Function

6 - Homeostasis

7 - Hypopituitarism

8 - Conclusions

References

Chapter 2 - Epidemiology and Etiology of Cushing’s Disease

1 - Introduction

2 - Epidemiology of Cushing’s Disease

2.1 - Incidence and Prevalence

2.1.1 - Population-Based Data

2.1.2 - Hypercortisolism in Patients with Incidentally Found Pituitary Masses

2.1.3 - “Occult” Cushing’s Disease in Patients with Diabetes Mellitus, Hypertension, Polycystic Ovary Syndrome, Obesity, an...

2.2 - Mortality

2.3 - Long-Term Morbidity and Quality of Life

3 - Etiology of Cushing’s Disease

3.1 - Mutations in the Deubiquitinase Gene (USP8)

3.2 - Multiple Endocrine Neoplasia 1 Syndrome

3.3 - Mutations in the Aryl-hydrocarbon Receptor Interacting Protein (AIP) Gene

3.4 - Other Gene Mutations

3.4.1 - Mutations in the DICER1 (Ribonuclease Type III) Gene

3.4.2 - Mutations in Cyclin-Dependent Kinase Inhibitor Subtype 1B Gene

3.4.3 - Mutations in the GR Gene

3.4.4 - Mutations in the p53 Gene

3.5 - Gene and Protein Expression Abnormalities in Corticotropinomas

4 - Conclusions

Disclosures

References

Chapter 3 - Physical Presentation of Cushing’s Syndrome: Typical and Atypical Presentations

1 - Introduction

2 - Symptoms of Cushing’s disease

2.1 - Subjective Symptoms

2.2 - Objective Symptoms

2.3 - Atypical Symptoms

3 - Signs of Cushing’s disease

4 - Comorbidities associated with Cushing’s syndrome

4.1 - Diabetes Mellitus

4.2 - Hypertension

4.3 - Sleep Disturbances

4.4 - Osteoporosis and Bone Fractures

4.5 - Depression and Psychosis

4.6 - Memory and Cognitive Function

5 - Cyclical Cushing’s syndrome

6 - Cushing’s syndrome in athletes

7 - Pseudo-Cushing’s disease

8 - Cushing’s syndrome in children and adolescents

9 - Conclusions

Chapter 4 - The Cognitive, Psychological, and Emotional Presentation of Cushing’s Disease

1 - Introduction

2 - Cognitive and emotional aspects of Cushing’s disease

2.1 - Clinical Presentations

2.1.1 - Effects on Psychological Health

2.1.2 - Effects on Sleep

2.1.3 - Effects on Cognitive Function

3 - Effects of glucocorticoid excess on brain structures

3.1 - Hippocampal Size and Atrophy

3.1.1 - Animal Models

3.1.2 - Clinical Studies

3.2 - Neurons: Mechanism of Changes in Hippocampal and Cortical Size

3.3 - Impact of Duration of Excess Glucocorticoid Exposure on Brain Atrophy

4 - Effects of glucocorticoid excess on brain metabolism

5 - Reversibility of cognitive and psychological effects with treatment of Cushing’s disease

5.1 - Clinical Presentation

5.2 - Brain Structures and Function

5.2.1 - Brain Atrophy

5.2.2 - Cerebral Metabolism

6 - Conclusions

References

Chapter 5 - Making the Diagnosis: Laboratory Testing and Imaging Studies

1 - Making the diagnosis of Cushing’s syndrome

1.1 - History and Physical Examination

1.2 - Screening Biochemical Tests for the Diagnosis of Cushing’s Syndrome

1.2.1 - Urinary Free Cortisol

1.2.2 - Late-Night Salivary Cortisol

1.2.3 - Dexamethasone Suppression Tests

1.2.4 - Other Useful Tests

1.3 - Other Conditions with Physiologic Increases in Cortisol

1.3.1 - Depression, Stress, and Other Psychiatric Conditions

1.3.2 - Polycystic Ovary Syndrome

1.3.3 - Diabetes Mellitus

2 - The differential diagnosis of Cushing’s syndrome

2.1 - ACTH-Dependent and ACTH-Independent Causes of Cushing’s Syndrome

2.1.1 - ACTH-Dependent Forms

2.1.1.1 - Pituitary tumor production of ACTH: Cushing’s disease

2.1.1.2 - Ectopic tumor production of ACTH

2.1.2 - ACTH-Independent Forms

2.1.2.1 - Adrenal adenoma

2.1.2.2 - Adrenal carcinoma

2.1.2.3 - Bilateral macronodular adrenal disease

2.1.2.4 - Micronodular adrenal disease

3 - Prerequisites for differential diagnostic testing

3.1 - Consistent Hypercortisolism

3.2 - Testing Strategies for the Differential Diagnosis

3.2.1 - ACTH Level

3.2.2 - CRH Stimulation Test

3.2.3 - High-Dose (8-mg) DST

3.2.4 - Inferior Petrosal Sinus Sampling

3.3 - Imaging

3.3.1 - Pituitary Magnetic Resonance Imaging

3.3.2 - Localization Studies for Ectopic ACTH-Producing Tumors

References

Chapter 6 - Surgical Treatment of Cushing’s Disease

1 - Indications for surgery

1.1 - Signs and Symptoms

1.2 - Diagnostic Laboratory Studies and Imaging

1.3 - Ideal and Less Than Ideal Surgical Candidates

2 - Preoperative considerations

3 - Operative considerations

3.1 - Transsphenoidal Surgery

3.2 - Bilateral Adrenalectomy

4 - Potential complications of surgery

5 - Surgical techniques

6 - Postoperative routines

7 - Discharge and postdischarge care

8 - Outcomes of surgery for Cushing’s disease

References

Chapter 7 - Medical Treatment of Cushing’s Disease

1 - Overview of medical therapy and its role in the management of Cushing’s Disease

2 - Classification of medical therapies used in the treatment of Cushing’s disease

2.1 - Pituitary-directed Neuromodulators of ACTH Release

2.1.1 - Pasireotide

2.1.2 - Cabergoline

2.2 - Adrenal Steroidogenesis Inhibitors

2.2.1 - Ketoconazole

2.2.2 - Levoketoconazole

2.2.3 - Metyrapone

2.2.4 - Mitotane

2.2.5 - Etomidate

2.2.6 - Osilodrostat

2.2.7 - Levoketoconazole

2.3 - Glucocorticoid Receptor Blockers

2.3.1 - Mifepristone

2.4 - Combination Therapies

2.4.1 - Cabergoline and Ketoconazole

2.4.2 - Pasireotide, Cabergoline, and Ketoconazole

3 - Special populations

3.1 - Life-threatening Hypercortisolism

3.2 - Medical Treatment of Patients with Cushing’s Disease in Pregnancy

4 - Conclusions

References

Chapter 8 - Multidisciplinary Management of Cushing’s Disease: Centers of Excellence Approach

1 - Introduction

2 - Brief history of COEs in medicine

3 - Rationale for COE models in pituitary tumor management

4 - Essential components of a team approach to Cushing’s disease

5 - Team management of the Cushing’s disease patient over time

6 - The role of pituitary COEs in advancing education and research in cushing’s disease

7 - The future of pituitary Centers of Excellence and working with available expertise

References

Chapter 9 - Posttreatment Management of Cushing’s Disease

1 - Introduction

2 - Definitions: cured, persistent, and recurrent Cushing’s disease

2.1 - Nonprovocative Tests

2.2 - Provocative Tests

3 - Management of persistent and recurrent Cushing’s disease

3.1 - Wait-and-see

3.2 - Surgical Reintervention

3.3 - Radiotherapy and Radiosurgery

3.4 - Medical Therapy

3.5 - Adrenal Surgery

4 - Posttreatment management of Cushing’s disease

4.1 - After Pituitary Surgery

4.1.1 - Central Adrenal Insufficiency

4.1.2 - Central Diabetes Insipidus

4.1.3 - Follow-Up

4.2 - After Radiotherapy and Radiosurgery

4.2.1 - Pituitary Insufficiency

4.2.2 - Follow-Up

4.3 - After Bilateral Adrenalectomy

4.3.1 - Primary Adrenal Insufficiency

4.3.2 - Follow-Up

4.3.3 - Corticotroph Tumor Progression

5 - Long-term effects of hypercortisolism in cured patients

5.1 - Cardiovascular Risk

5.2 - Thromboembolic Events

5.3 - Osteoporosis

5.4 - Neurocognitive Impairment

References

Chapter 10 - Coping with Cushing’s Disease: the Patients’ Perspectives

1 - Introduction

2 - Coping with a rare disease

3 - Health complaints in the active phase

3.1 - Quality of Life

3.2 - Physical Appearance

3.3 - Psychological and Cognitive Aspects

3.4 - Dealing with Comorbidities

3.5 - Family and Social Support

4 - Diagnosis

5 - Treatment

5.1 - Medications

5.2 - Surgery

5.3 - Radiotherapy

6 - Recovery and long-term comorbidities

6.1 - Quality of Life

6.2 - Physical Aspects

6.3 - Psychological and Cognitive Aspects

6.4 - Dealing with Long-term Consequences: The Aftermath of Cushing’s Syndrome

6.5 - Family, Background, and Social Support

6.6 - Relapses

7 - Conclusions

References

Chapter 11 - Cushing’s Disease in Children and Adolescents: Diagnosis and Management

1 - Introduction

2 - Epidemiology

3 - Etiology and pathogenesis

4 - Clinical presentation

4.1 - Age and Gender Distribution

4.2 - Growth and Puberty in Pediatric Cushing’s Disease

4.3 - Signs and Symptoms

4.4 - Body Composition

5 - Diagnostic guidelines and confirmation of the diagnosis of cushing’s disease

5.1 - When to Screen

5.2 - How to Screen

5.2.1 - Urinary Free Cortisol

5.2.2 - Late-night Salivary Cortisol

5.2.3 - Sleeping Midnight Serum Cortisol

5.2.4 - The 1-mg Overnight DST

5.2.5 - The 48-h (2-mg/day) Low-dose DST

5.3 - Confirmation of Causes of Cushing’s Syndrome

5.4 - Imaging

6 - Therapy

6.1 - Goals

6.2 - Primary Therapy

6.3 - Secondary Therapy

6.3.1 - Repeat Transsphenoidal Surgery and Radiation Therapy

6.3.2 - Medical Therapy and Bilateral Adrenalectomy

6.4 - Follow-up

7 - Conclusions

References

Chapter 12 - Challenges and Future Developments for Improvement in the Diagnosis and Management of Cushing’s Disease

1 - Imaging

2 - Intraoperative techniques

3 - Genetic factors and potential therapies

References

Appendix - Patients’ Perspectives

Classic features of Cushing’s syndrome

Diagnosis

Recovery

Support Networks

Acknowledgments

Support Groups

Index

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