Fliers / Korbonits / Romijn Clinical Neuroendocrinology

1. Auflage 2014
ISBN: 978-0-444-62612-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 456 Seiten

Reihe: Handbook of Clinical Neurology

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

Autoren/Hrsg.

Fliers, Eric

Korbonits, Marta

Romijn, J. A.

Inhaltsverzeichnis

1;Front Cover;1
2;Clinical Neuroendocrinology;4
3;Copyright;5
4;Handbook of Clinical Neurology 3rd Series;6
5;Foreword;8
6;Preface;10
7;Contributors;12
8;Contents;16
9;Section 1: Clinical aspects of hypothalamic function;20
9.1;Chapter 1: Genetic aspects of hypothalamic and pituitary gland development;22
9.1.1;Introduction;22
9.1.2;Development of the hypothalamo-pituitary axis;22
9.1.2.1;Morphology;22
9.1.2.2;Timeline of hypothalamo-pituitary Organogenesis;23
9.1.2.3;Genetic and Molecular Regulation of hypothalamo-pituitary Development;25
9.1.2.3.1;Factors Involved in the Early Formation Of the pituitary;26
9.1.2.3.1.1;Bone Morphogenetic Protein 4 and the Sonic Hedgehog Pathway;26
9.1.2.3.1.2;FGF8;26
9.1.2.3.1.3;Lim homeodomain transcription factors;27
9.1.2.3.1.4;Homeobox Embryonic Stem Cell 1 (HESX1);28
9.1.2.3.1.5;SOX2 and SOX3;28
9.1.2.3.1.6;Orthodentic Homeobox 2 (OTX2);29
9.1.2.3.2;Factors Regulating Cellular Differentiation;29
9.1.2.3.2.1;PROP1 and POU1F1/PIT1;29
9.1.2.3.2.2;GATA2;30
9.1.2.3.2.3;TBX19;30
9.1.2.3.3;Factors Involved in Hypothalamic Formation;30
9.1.3;Congenital Hypopituitarism and Associated Defects;32
9.1.4;Overlap Between Congenital Hypopituitarism and Midline Defects With Kallmann Syndrome;32
9.1.5;Conclusion and Future Directions;33
9.2;Chapter 2: Neuroendocrinology of Pregnancy and Parturition;36
9.2.1;Introduction;36
9.2.2;The Hypothalamus-pituitary-target Gland Axes During Pregnancy;36
9.2.2.1;Activity of Hypothalamus-pituitary-adrenal axis;37
9.2.2.1.1;Maternal Hypothalamus-pituitary-adrenal axis;37
9.2.2.1.1.1;Early and mid-pregnancy;38
9.2.2.1.1.2;Late Pregnancy;38
9.2.2.1.1.3;Parturition;38
9.2.2.1.2;Fetal Hypothalamus-pituitary-adrenal axis;38
9.2.2.2;Activity of Hypothalamus-pituitary-gonadal axes;39
9.2.2.3;Activity of the Other Neuroendocrine axes;39
9.2.2.3.1;Hypothalamus-prolactin axis;39
9.2.2.3.2;Hypothalamus-growth Hormone axis;40
9.2.2.3.3;Hypothalamus-pituitary-thyroid axis;40
9.2.3;The Placenta: A Neuroendocrine organ;41
9.2.4;Stress-related Hormones: Implications in Physiologic Pregnancy and Parturition and In obstetric Complications;42
9.2.4.1;Corticotropin-releasing Hormone Family;42
9.2.4.1.1;Corticotropin-releasing Hormone;42
9.2.4.1.1.1;Placental Expression and Regulation;42
9.2.4.1.1.2;Physiologic Pregnancy and Parturition;42
9.2.4.1.1.3;Implications for Maternal/fetal Adverse Programming;45
9.2.4.1.2;Urocortins;45
9.2.4.1.2.1;Placental Expression and Regulation;45
9.2.4.1.2.2;Physiologic Pregnancy and Parturition;46
9.2.4.1.2.3;Implications for Maternal/fetal Adverse Programming;47
9.2.4.2;Oxytocin;47
9.2.4.3;The Role of Stress in Maternal and Fetal Adverse Programming;48
9.2.5;Conclusions;48
9.3;Chapter 3: Disorders of Water Metabolism: Diabetes Insipidus and the Syndrome of Inappropriate Antidiuretic Hormone Secretio...;56
9.3.1;Water Metabolism;56
9.3.1.1;Thirst;56
9.3.1.2;Vasopressin Secretion;57
9.3.1.3;Vasopressin Actions;58
9.3.1.4;Integration of Thirst and Avp Secretion;58
9.3.2;Sodium Metabolism;58
9.3.2.1;Salt Appetite;59
9.3.2.2;Renal Sodium Excretion;59
9.3.3;Hypo-osmolality;59
9.3.3.1;Differential Diagnosis;59
9.3.3.1.1;Decreased Ecf Volume (hypovolemia);59
9.3.3.1.2;Normal ECF Volume (euvolemia);59
9.3.3.1.3;Increased ECF Volume (hypervolemia);60
9.3.3.2;Clinical Manifestations;60
9.3.3.3;Therapy;60
9.3.3.4;Currently Available Therapies for Treatment Of hyponatremia;61
9.3.3.4.1;Isotonic Saline;61
9.3.3.4.2;Hypertonic Saline;61
9.3.3.4.3;Fluid Restriction;61
9.3.3.4.4;Demeclocycline;62
9.3.3.4.5;Mineralocorticoids;62
9.3.3.4.6;Urea;62
9.3.3.4.7;Furosemide And NaCl;62
9.3.3.4.8;Arginine Vasopressin Receptor (AVPR) Antagonists;62
9.3.3.5;Hyponatremia Treatment Guidelines;63
9.3.3.6;Monitoring the Serum [Na+] in Hyponatremic patients;64
9.3.3.7;Long-term Treatment of Chronic Hyponatremia;65
9.3.4;Hyperosmolality;65
9.3.4.1;Etiologies and Diagnosis;65
9.3.4.2;Diabetes Insipidus;65
9.3.4.2.1;Osmoreceptor Dysfunction;66
9.3.4.2.2;Differential Diagnosis;66
9.3.4.3;Clinical Manifestations;67
9.3.4.4;Therapy;68
9.4;Chapter 4: The Role of Oxytocin and Vasopressin In emotional and social behaviors;72
9.4.1;Introduction;72
9.4.2;Nonclinical Populations;72
9.4.2.1;Oxytocin;72
9.4.2.1.1;Trust;73
9.4.2.1.2;Mind Reading;73
9.4.2.1.3;Empathy;75
9.4.2.1.4;Positive Communication Between Couples;75
9.4.2.1.5;Generosity and Altruism;76
9.4.2.1.6;Bonding and Attachment;76
9.4.2.2;Oxytocin and Mirror Neurons;76
9.4.2.3;Vasopressin;76
9.4.2.3.1;Aggression;77
9.4.2.3.2;Psychosocial Stress;77
9.4.2.3.3;Empathy;78
9.4.2.3.4;Altruism;78
9.4.3;Clinical Populations;79
9.4.3.1;Oxytocin and Vasopressin in Autism Spectrum disorders;79
9.4.3.2;Oxytocin and Vasopressin in Eating Pathology;80
9.4.3.3;Oxytocin and Vasopressin in Depression And anxiety;80
9.4.3.4;Methodologic Issues in Oxytocin And vasopressin Research;80
9.4.3.5;CD38 and Abnormal Social and Emotional Behaviors;80
9.4.3.6;Endophenotypes;81
9.4.4;Future Directions;81
9.5;Chapter 5: Corticotropin-releasing Hormone and the Hypothalamic-pituitary-adrenal Axis in Psychiatric Disease;88
9.5.1;Introduction;88
9.5.2;Corticotropin-releasing Hormone and Basal Hypothalamic-pituitary-adrenal axis Activity;88
9.5.3;Hypothalamic-pituitary-adrenal axis Functioning in Major Depression;90
9.5.3.1;The corticotropin-releasing Hormone System and Dexamethasone/corticotropin-releasing Hormone Studies in Depression...;90
9.5.3.2;Adrenocorticotropin and Cortisol In depression;92
9.5.3.3;Dexamethasone Suppression test;93
9.5.3.4;Adrenocorticotropin Stimulation test;93
9.5.3.5;Vasopressin in Depression;94
9.5.3.6;Early Life Stress, Depression, and the Hypothalamic-pituitary-adrenal axis;95
9.5.3.7;Monoamines, the Hypothalamic-pituitary-adrenal Axis, and the Effects Of antidepressants;95
9.5.3.8;The Hypothalamic-pituitary-adrenal Axis As a Target for Antidepressant Treatment: CRH1 Receptor Antagonists and C...;96
9.5.3.8.1;Corticotropin-releasing Hormone Receptor antagonists;96
9.5.3.8.2;Cortisol Synthesis Inhibitors;96
9.5.4;Hypothalamic-pituitary-adrenal axis Functioning in Bipolar Disorder;96
9.5.4.1;Dexamethasone/corticotropin-releasing Hormone Test in Bipolar Disorder;97
9.5.4.2;Vasopressin in Bipolar Disorder;97
9.5.4.3;Monoamines in Bipolar Disorder;97
9.5.5;Hypothalamic-pituitary-adrenal axis Functioning In schizophrenia;97
9.5.5.1;Basal Cortisol in Schizophrenia;98
9.5.5.2;The Dexamethasone Suppression Test in schizophrenia;99
9.5.5.3;Basal Measures of corticotropin-releasing Hormone and Adrenocorticotropin In schizophrenia;99
9.5.5.4;Corticotropin-releasing Hormone Test in schizophrenia;99
9.5.5.5;Dexamethasone/corticotropin-releasing Hormone Test in Schizophrenia;99
9.5.5.6;Effects of Psychological Stress on the Hypothalamic-pituitary-adrenal Axis In schizophrenia;100
9.5.6;Hypothalamic-pituitary-adrenal axis Functioning in Anxiety Disorders;102
9.5.6.1;Panic Disorder;102
9.5.7;Conclusion;103
9.5.8;Acknowledgments;103
9.6;Chapter 6: Genetic Aspects of Human Obesity;112
9.6.1;Introduction;112
9.6.1.1;Obesity: a Heritable Disorder;112
9.6.1.2;The Critical Role of the Hypothalamus;112
9.6.1.3;Integration and Coordination of Peripheral signals;113
9.6.2;Human Monogenic Obesity;114
9.6.2.1;Congenital Leptin Deficiency;114
9.6.2.2;Leptin-receptor Deficiency;114
9.6.2.3;Pro-opiomelanocortin (POMC) Deficiency;114
9.6.2.4;Prohormone Converatse 1/3 (PC1/3) Deficiency;115
9.6.2.5;Melanocortin-4-receptor (MC4R) Deficiency;116
9.6.2.6;Therapies for Melanocortin Pathway disorders;116
9.6.2.7;Brain-derived Neurotrophic Factor (BDNF) and Obesity;117
9.6.2.8;Src Homology 2 B adapter Protein 1 (SH2B1) and Obesity;117
9.6.2.9;Single-minded 1 (SIM1) and Obesity;117
9.6.2.10;Melanocortin-2-receptor Accessory Protein 2 (MRAP2) and Obesity;118
9.6.3;Human Pleiotropic and ``syndromic´´ Obesity;119
9.6.3.1;Bardet-Biedl Syndrome;119
9.6.3.2;Prader-Willi Syndrome;119
9.6.4;New Technologies to Identify Genetic Components of Obesity;120
9.6.4.1;Genome-wide Association Studies;121
9.6.4.2;Copy Number Variants;121
9.6.4.3;Whole Exome Sequencing;121
9.6.5;Conclusions;122
9.7;Chapter 7: Sleep Characteristics and Insulin Sensitivity in Humans;126
9.7.1;Introduction;126
9.7.2;Sleep Physiology and Glucose Homeostasis;126
9.7.3;Sleep Deprivation and Insulin Resistance;127
9.7.3.1;Experimental Studies on the Effects of Sleep Deprivation on Glucose Metabolism;127
9.7.3.2;Epidemiologic Studies on the Association Between Sleep Duration and Glucose Metabolism;127
9.7.4;Sleep Disorders and Insulin Resistance;128
9.7.4.1;Population-based Studies on Sleep Disorders and Insulin Resistance;128
9.7.4.2;Intervention Studies Assessing Sleep Quality and Insulin Sensitivity;129
9.7.5;Diabetes Mellitus, Metabolic Dysregulation, and Sleep Disorders;129
9.7.6;Potential Mechanisms Linking Impaired Sleep and Insulin Resistance;130
9.7.7;Future Research Suggestions;131
9.8;Chapter 8: Hypothalamic-pituitary Hormones During Critical Illness: A dynamic Neuroendocrine Response;134
9.8.1;Introduction;134
9.8.2;The Thyroid axis;134
9.8.2.1;The Thyroid Axis in Acute Critical Illness;134
9.8.2.2;The Thyroid Axis During Prolonged Critical illness;136
9.8.2.3;Therapeutic Potential;136
9.8.3;The Somatotropic axis;137
9.8.3.1;The Somatotropic Axis in Acute Critical Illness;137
9.8.3.2;The Somatotropic Axis During Prolonged Critical Illness;137
9.8.3.3;Therapeutic Potential;138
9.8.4;The Gonadal axis;138
9.8.4.1;The Gonadal Axis in Acute Critical Illness;138
9.8.4.2;The Gonadal Axis During Prolonged Critical illness;138
9.8.4.3;Therapeutic Potential;139
9.8.5;The Lactotropic axis;139
9.8.5.1;The Lactotropic Axis in Acute Critical Illness;139
9.8.5.2;The Lactotropic Axis During Prolonged Critical illness;139
9.8.5.3;Therapeutic Potential;139
9.8.6;The Adrenal axis;140
9.8.6.1;The Adrenal Axis in Acute Critical Illness;140
9.8.6.2;The Adrenal Axis During Prolonged Critical illness;140
9.8.6.3;Therapeutic Potential;140
9.8.7;Conclusions;141
9.9;Chapter 9: Central Regulation of the Hypothalamo-pituitary-thyroid (Hpt) Axis: Focus on Clinical Aspects;146
9.9.1;Introduction and Outline;146
9.9.2;Hypothalamus and Pituitary;146
9.9.2.1;The Hypothalamic thyrotropin-releasing Hormone Neuron;146
9.9.2.2;Pituitary;148
9.9.2.3;Pulsatility and Diurnal Rhythm;148
9.9.2.4;Neural Connections of Hypothalamic Nuclei With Adipose Tissue And liver;149
9.9.3;Central Hypothyroidism;151
9.9.3.1;Central Hypothyroidism in Neonates And children;151
9.9.3.2;Central Hypothyroidism in Adults;153
9.9.4;Central Hyperthyroidism;154
9.9.5;Conclusion;154
10;Section 2: Disorders of the Pituitary Gland;158
10.1;Chapter 10: Evaluation of Pituitary Function;160
10.1.1;Introduction;160
10.1.2;Reasons for Undertaking Pituitary Investigations;160
10.1.3;Approach to the Patient In pituitary Clinic;161
10.1.4;Principles of Pituitary Assessment;161
10.1.5;Basal Pituitary Blood tests;161
10.1.6;Evaluation of the pituitary-adrenal axis;162
10.1.6.1;Cortisol Production in Health;162
10.1.6.2;Measurement of Serum Cortisol;162
10.1.6.3;Insulin Tolerance test;162
10.1.6.4;Short Synacthen test;163
10.1.6.5;Low-dose Short Synacthen test;164
10.1.6.6;Glucagon Stimulation test;164
10.1.6.7;Metyrapone test;164
10.1.7;Evaluation of the pituitary-thyroid axis;164
10.1.8;Evaluation of the pituitary-gonadal axis;165
10.1.9;Prolactin;165
10.1.10;Growth Hormone Deficiency In adults;166
10.1.10.1;Glucagon Stimulation test;166
10.1.10.2;Arginine Stimulation test;166
10.1.11;Antidiuretic Hormone Deficiency: Diabetes Insipidus;167
10.1.12;Conclusion;167
10.2;Chapter 11: Imaging of Pituitary Pathology;170
10.2.1;Introduction;170
10.2.2;Magnetic Resonance Imaging;170
10.2.2.1;The Normal Pituitary;171
10.2.3;Imaging of Pituitary Adenomas;172
10.2.3.1;Pituitary Microadenomas;172
10.2.3.2;Pituitary Macroadenomas;173
10.2.3.3;Postoperative Magnetic Resonance Imaging and Monitoring of Effects of Other Treatment;174
10.2.3.4;Intraoperative Magnetic Resonance Imaging;177
10.2.4;Differential Diagnosis;177
10.2.4.1;Craniopharyngiomas and Rathke's Cleft cyst;178
10.2.4.2;Suprasellar and Parasellar Meningiomas;179
10.2.4.3;Chordomas and Chondrosarcomas Of the clivus;179
10.2.4.4;Hypophysitis;180
10.2.4.5;Aneurysms;180
10.2.4.6;Other Intrasellar Lesions;181
10.2.4.7;Other Suprasellar Lesions;181
10.2.4.8;Incidentalomas;181
10.2.5;Computed Tomography;181
10.2.6;Spect/Pet;182
10.2.7;Summary;183
10.3;Chapter 12: Nonfunctioning Pituitary Tumors;186
10.3.1;Introduction;186
10.3.2;The Asymptomatic, Incidental, Clinically Nonfunctioning Adenoma (pituitary Incidentaloma);186
10.3.2.1;Autopsy Findings;186
10.3.2.2;CT and MRI Scans in Normal Individuals;187
10.3.2.3;Endocrinologic Evaluation of the Asymptomatic Incidental mass;188
10.3.2.4;Natural History and follow-up of Incidental Clinically Nonfunctioning Adenomas;190
10.3.2.5;Management of Incidental Clinically Nonfunctioning Adenomas;191
10.3.3;Symptomatic Clinically Nonfunctioning Adenomas;192
10.3.3.1;Presenting Symptoms;192
10.3.3.2;Diagnostic Evaluation;192
10.3.3.3;Treatment;192
10.3.3.3.1;Surgery;195
10.3.3.3.2;Radiotherapy;195
10.3.3.3.3;Medical Therapy;197
10.3.3.3.4;Management of the Symptomatic Patient;198
10.4;Chapter 13: Hyperprolactinemia and Prolactinoma;204
10.4.1;Introduction;204
10.4.2;Causes of Hyperprolactinemia;204
10.4.3;Clinical Features Of hyperprolactinemia;205
10.4.4;Laboratory Assessment Of hyperprolactinemia;205
10.4.4.1;Macroprolactinemia;205
10.4.4.2;High-dose Hook Effect;206
10.4.4.3;Dynamic Tests of Prolactin Secretion;206
10.4.5;Radiologic Diagnosis Of prolactinomas;206
10.4.6;Prevalence Rates Of prolactinomas;207
10.4.7;Treatment Of hyperprolactinemia And prolactinoma;207
10.4.7.1;Normalization of Prolactin Levels;207
10.4.7.2;Reduction of Prolactinoma size;208
10.4.7.3;Dopamine agonist-resistant Prolactinomas;208
10.4.7.4;Symptomatic Patients With Idiopathic Hyperprolactinemia;209
10.4.7.5;Pregnancy;209
10.4.7.5.1;Induction of Pregnancy;209
10.4.7.5.2;Effects of Dopamine Agonists on Fetal Development and Pregnancy Outcome;210
10.4.7.5.3;Effects of Pregnancy on Prolactinoma size;210
10.4.7.6;Drug-induced Hyperprolactinemia;210
10.4.8;Adverse Effects of Dopamine Agonists;211
10.4.9;Withdrawal of Dopamine Agonist Treatment;211
10.4.10;Conclusion;212
10.5;Chapter 14: Acromegaly;216
10.5.1;Introduction;216
10.5.2;Epidemiology;216
10.5.3;Pathophysiology;216
10.5.3.1;Acromegaly Related to a Pituitary tumor;216
10.5.3.1.1;Somatotroph Pituitary Adenomas;216
10.5.3.1.2;Growth hormone-secreting Carcinomas;217
10.5.3.1.3;Genetic Syndromes Associated With Acromegaly;217
10.5.3.2;Extrapituitary Acromegaly;217
10.5.4;Signs and Symptoms;218
10.5.4.1;The Dysmorphic Syndrome;218
10.5.4.2;Symptoms;219
10.5.4.3;Skin Changes;219
10.5.4.4;Bone Changes;219
10.5.4.4.1;Craniofacial;219
10.5.4.4.2;Extremities;219
10.5.4.4.3;Trunk;219
10.5.4.4.4;Limbs;219
10.5.4.4.5;Bone Mineral Density;219
10.5.4.5;Rheumatologic Complications;219
10.5.4.5.1;Peripheral Arthropathy;219
10.5.4.5.2;Spinal Involvement;220
10.5.4.6;Neuropathies;220
10.5.4.7;Cardiovascular Manifestations;221
10.5.4.7.1;Arterial Hypertension;221
10.5.4.7.2;Specific Cardiomyopathy;221
10.5.4.7.3;Valve Disease;222
10.5.4.8;Metabolic Complications;222
10.5.4.9;Respiratory Complications;222
10.5.4.10;Neoplasia and Acromegaly;223
10.5.4.10.1;Gastrointestinal Tumors;223
10.5.4.10.2;Thyroid Nodules;223
10.5.5;Diagnosis of Acromegaly;223
10.5.5.1;Growth Hormone Assays;223
10.5.5.2;Which Growth Hormone Cutoff to Use For diagnosis?;224
10.5.5.3;IGF-1 Assays;224
10.5.5.4;Stimulation tests;224
10.5.5.5;Difficult and Borderline Clinical Situations;224
10.5.5.6;Differential Diagnosis;225
10.5.6;Tumoral and Functional Pituitary Assessment;225
10.5.7;Prognosis and Outcome;225
10.5.8;Management and Treatment;226
10.5.8.1;Treatment aims;226
10.5.8.2;Surgery is Generally the first-line Treatment;226
10.5.8.3;Radiotherapy;226
10.5.8.4;Medical Treatment;227
10.5.8.4.1;Dopamine Agonists;227
10.5.8.4.2;Somatostatin Analogs;228
10.5.8.4.3;Gh-receptor Antagonists;229
10.5.8.5;Current Therapeutic Strategy;230
10.5.9;Conclusion;230
10.6;Chapter 15: Cushing´s Disease;240
10.6.1;Introduction;240
10.6.2;Clinical Features and Diagnosis;240
10.6.2.1;Clinical Features;240
10.6.2.2;Diagnosis;241
10.6.3;Management;244
10.6.3.1;Pituitary Surgery;244
10.6.3.2;Management of Recurrent Cushing's Disease;246
10.6.3.3;Medical Therapy;247
10.6.4;Conclusion;249
10.6.5;Notes Added in Proof;249
10.7;Chapter 16: Craniopharyngioma;254
10.7.1;Introduction;254
10.7.2;Epidemiology and Pathology;254
10.7.3;Clinical Manifestations At the time of Diagnosis;254
10.7.4;Imaging Studies;255
10.7.5;Treatment Strategies;255
10.7.5.1;Neurosurgery: Strategies and Effects;255
10.7.5.2;Irradiation;257
10.7.5.2.1;Proton Beam Therapy;258
10.7.5.2.2;Radiosurgery;258
10.7.5.2.3;Hypofractionated Stereotactic Radiotherapy: CyberKnife;258
10.7.5.2.4;Intracavitary ß Irradiation;258
10.7.5.3;Instillation of Sclerosing Substances For cystic recurrent Tumors;258
10.7.6;Sequelae;259
10.7.6.1;Pituitary Deficiencies;259
10.7.6.2;Neurologic and Visual Outcomes;259
10.7.6.3;Hypothalamic Dysfunction;259
10.7.6.4;Obesity and Eating Disorders;260
10.7.6.5;Physical Activity and Energy Expenditure;261
10.7.6.6;Autonomous Nervous System;261
10.7.6.7;Appetite Regulation;261
10.7.6.7.1;Pharmacologic Treatment of Hypothalamic Obesity;262
10.7.6.7.2;Bariatric Treatment of Hypothalamic Obesity;262
10.7.6.8;Quality of Life, Neurocognitive Outcome, And psychosocial Functioning;262
10.7.6.9;Survival and Late Mortality;263
10.7.6.9.1;Cerebrovascular Morbidity;263
10.7.6.9.2;Second Malignant Neoplasms;264
10.7.7;Adult-onset Craniopharyngioma;264
10.7.8;Questions and Treatment Perspectives;264
10.7.8.1;Surgical Treatment Strategies: Degree Of resection;264
10.7.8.2;Controversy Over Time Point of Irradiation;264
10.7.8.3;Expertise;265
10.7.8.4;Risk-adapted Strategies/treatment Algorithms for Craniopharyngioma;265
10.7.9;Conclusions;268
10.7.10;Note;268
10.7.11;Acknowledgments;268
10.8;Chapter 17: Rathke´s Cleft cyst;274
10.8.1;Introduction;274
10.8.2;Epidemiology;274
10.8.3;Pathology;275
10.8.4;Pathogenesis;276
10.8.4.1;Formation of Rathke's Pouch and Pituitary Organogenesis;276
10.8.4.2;Pathogenesis of Rathke's Cleft Cyst and Other Cystic Sellar Lesions;276
10.8.5;Presenting Manifestations;279
10.8.5.1;Headaches;279
10.8.5.2;Visual Field Disturbance;279
10.8.5.3;Endocrine Dysfunction;280
10.8.5.4;Diabetes Insipidus;280
10.8.5.5;Apoplexy;280
10.8.5.6;Other Presenting Manifestations;280
10.8.6;Location and Imaging Features;280
10.8.6.1;Computed Tomography;281
10.8.6.2;Magnetic Resonance Imaging;281
10.8.7;Natural History;281
10.8.8;Treatment;283
10.8.8.1;Treatment Strategies;283
10.8.8.2;Complications;283
10.8.8.3;Outcomes;283
10.8.9;Recurrence;283
10.8.9.1;Relapse rates;283
10.8.9.2;Risk Factors for Relapse;284
10.8.10;Acknowledgments;285
10.9;Chapter 18: Alternative Causes of Hypopituitarism: Traumatic Brain Injury, Cranial Irradiation, and Infections;290
10.9.1;Introduction;290
10.9.2;Traumatic Brain Injury;290
10.9.2.1;Historical Background of Hypopituitarism After Traumatic Brain Injury;290
10.9.2.2;Neuroendocrine Dysfunction After Traumatic brain Injury;291
10.9.2.3;Predictors of Neuroendocrine Dysfunction After Traumatic Brain Injury;293
10.9.2.4;Sport;293
10.9.2.5;Modern Military Operations: blast-related Traumatic Brain Injury;293
10.9.2.6;Traumatic Brain Injury in Children And adolescents;293
10.9.2.7;Pathophysiologic Mechanisms Of neuroendocrine Dysfunction Due to traumatic Brain Injury;294
10.9.2.8;Diagnosis of Neuroendocrine Dysfunction After Brain Injury;294
10.9.2.9;Cognitive Impairments After Traumatic Brain injury;296
10.9.3;Cranial Irradiation;296
10.9.3.1;Introduction;296
10.9.3.2;Neuroendocrine Dysfunction After Cranial Irradiation;296
10.9.3.3;Diagnosis of Impaired Growth Hormone Secretion After Cranial Irradiation;298
10.9.3.4;Abnormalities in Other Pituitary Hormones;298
10.9.4;Infections in the Hypothalamic-pituitary Region;299
10.9.4.1;Sources of Infections Spreading to the Hypothalamic-pituitary Region;299
10.9.4.2;Predisposing Factors for Pituitary Infections;299
10.9.4.3;Clinical Features of Pituitary Infections;299
10.9.4.3.1;Neurologic Symptoms;299
10.9.4.3.2;Endocrine Dysfunction;299
10.9.4.4;Pituitary Abscess;299
10.9.4.5;Nonspecific Inflammation of the Cavernous Sinus: the Tolosa-Hunt Syndrome;300
10.9.4.6;Hypothalamic-pituitary Tuberculosis;300
10.9.4.7;Fungal Infections;301
10.9.4.8;Viral Infections Affecting the Hypothalmus And/or Pituitary;302
10.9.5;Parasites in the Pituitary: Toxoplasma Gondii;304
10.9.6;Summary;304
10.9.7;Acknowledgment;304
10.10;Chapter 19: Surgical Approach to Pituitary Tumors;310
10.10.1;Introduction;310
10.10.2;Historical Background;310
10.10.3;Surgery;311
10.10.4;Transsphenoidal Approaches;312
10.10.4.1;Microsurgical Transsphenoidal Approaches;313
10.10.4.1.1;Microsurgical Transnasal Transseptal Transsphenoidal Approach;313
10.10.4.1.2;Microsurgical Sublabial Transseptal Transsphenoidal Approach;313
10.10.4.1.3;Microsurgical Endonasal Transsphenoidal Approach;313
10.10.4.2;Endoscopic Endonasal Transsphenoidal Approach;313
10.10.5;Transcranial Approaches;315
10.10.6;Complications;315
10.10.7;Final Remarks;317
10.11;Chapter 20: Medical Approach to Pituitary Tumors;322
10.11.1;Introduction;322
10.11.2;Nonfunctional Adenoma;322
10.11.2.1;Medical Treatment;322
10.11.2.2;Side-effects of Medical Treatment;322
10.11.3;Prolactinoma;322
10.11.3.1;Medical Treatment;323
10.11.3.1.1;Efficacy;323
10.11.3.1.2;Withdrawal of Dopamine Agonists;323
10.11.3.2;Adverse Effects;323
10.11.3.3;Valvular Heart Disease;324
10.11.4;Acromegaly;324
10.11.4.1;Medical Treatment;324
10.11.4.2;Somatostatin Analogs;325
10.11.4.2.1;Efficacy;325
10.11.4.3;Pegvisomant;325
10.11.4.3.1;Efficacy;326
10.11.4.4;Combination Therapy With Pegvisomant and Somatostatin Analogs;326
10.11.4.5;Quality of Life Aspects of Combination Therapy;327
10.11.4.6;New Developments;327
10.11.4.7;Adverse Effects;329
10.11.5;Cushing's Disease;330
10.11.5.1;Medical Treatment;330
10.11.5.2;Side-effects of Medical Treatment;331
10.11.6;Thyrotropin-secrecting Adenoma;331
10.11.6.1;Medical Treatment;331
10.11.6.1.1;Dopamine Agonists;331
10.11.6.1.2;Somatostatin Analogs;331
10.11.6.1.3;Antithyroid Treatment;332
10.11.6.1.4;Side-effects;332
10.12;Chapter 21: Radiation Therapy in the Management of Pituitary Adenomas;336
10.12.1;Introduction;336
10.12.2;Background on Fractionated Radiation Therapy and single-fraction Radiosurgery;336
10.12.2.1;Deciding Between Fractionated Radiotherapy and single-fraction Radiosurgery;337
10.12.2.2;Radiation Treatment Planning;337
10.12.2.3;Normal Tissue Tolerances;337
10.12.2.4;Proton Therapy;338
10.12.3;Clinical Outcomes of Radiation Therapy in Pituitary Adenomas;338
10.12.3.1;Nonfunctioning Adenomas;338
10.12.3.2;Functioning Adenomas;339
10.12.3.2.1;Prolactinomas;339
10.12.3.2.2;Adrenocorticotropic hormone-secreting Adenomas;339
10.12.3.2.3;Growth hormone-secreting Adenomas;340
10.12.3.2.4;Thyroid-stimulating hormone-secreting Adenomas;340
10.12.3.2.5;Pituitary Carcinomas;341
10.12.4;Sequelae After Radiation Therapy;341
10.12.5;Conclusion;342
11;Section 3: Controversial Issues and Hot Topics;344
11.1;Chapter 22: Nelson Syndrome: Definition and Management;346
11.1.1;Introduction;346
11.1.2;Effective Diagnosis of Nelson Syndrome;347
11.1.2.1;Clinical, Biochemical, and Radiologic Features;347
11.1.2.2;Diagnostic Criteria;348
11.1.3;Predictive Factors for the Onset and Progression of Nelson Syndrome;348
11.1.3.1;Residual Pituitary Tumor Shown on Imaging Prior to Total Bilateral Adrenalectomy;349
11.1.3.2;Adrenocorticotropic Hormone Levels In the first Postoperative year;349
11.1.3.3;Administration of Neoadjuvant Radiotherapy post-total Bilateral Adrenalectomy Surgery;349
11.1.3.4;Duration of Cushing's Disease Prior to Total Bilateral Adrenalectomy;349
11.1.3.5;Residual Adrenal Remnant After Total Bilateral Adrenalectomy;350
11.1.3.6;Age;350
11.1.3.7;High Urinary Cortisol;350
11.1.3.8;Insufficient Exogenous Steroid Replacement Therapy post-total Bilateral Adrenalectomy Surgery;350
11.1.3.9;Lack of Cortisol Suppression on high-dose Dexamethasone Pre-total Bilateral Adrenalectomy;350
11.1.4;Pathophysiology of Nelson Syndrome;350
11.1.5;Pathologic Features of Corticotropinomas in Nelson Syndrome;351
11.1.6;Effective Management of Nelson syndrome;351
11.1.6.1;Pituitary Surgery;351
11.1.6.2;Adjuvant Radiotherapy;352
11.1.6.3;Stereotactic Radiosurgery;352
11.1.6.4;Selective Somatostatin Analogs;352
11.1.6.5;Peroxisome proliferator-activated Receptor . agonists;352
11.1.6.6;Sodium Valproate;353
11.1.6.7;Dopamine Agonists;353
11.1.6.8;Temozolomide;353
11.1.7;Conclusions;353
11.1.8;Acknowledgments;353
11.2;Chapter 23: Familial Pituitary Tumors;358
11.2.1;Introduction;358
11.2.2;Pituitary Tumorigenesis;358
11.2.3;Pituitary Adenomas of Genetic Origin;359
11.2.4;Multiple Endocrine Neoplasia Type 1 (MEN1) OMIM #131100;359
11.2.4.1;Clinical Features Of MEN1;359
11.2.4.1.1;Parathyroid Tumors;359
11.2.4.1.2;Pancreatic Tumors;361
11.2.4.1.3;Pituitary Tumors;361
11.2.4.2;Genetics of MEN1 Syndrome;362
11.2.4.3;Management of Pituitary Disease In MEN1;363
11.2.5;Familial Isolated Pituitary Adenoma (FIPA): Related OMIM Entries: Pituitary Adenoma, Growth hormone-secreting #102200 and ...;364
11.2.5.1;Clinical Features Of FIPA;364
11.2.5.2;Genetics Of FIPA;364
11.2.5.3;Management of Pituitary Disease In FIPA;366
11.2.6;Carney Complex Syndrome (CNC): Related OMIM Entries: CNC1 #160980, PRKAR1A 188830;366
11.2.6.1;Clinical Features Of CNC;367
11.2.6.2;Genetics Of CNC;368
11.2.6.3;Management of Pituitary Disease In CNC;369
11.2.7;McCune-Albright Syndrome: OMIM 174800;369
11.2.7.1;Clinical Features of McCune-Albright Syndrome;369
11.2.7.2;Genetics of McCune-Albright Syndrome;372
11.2.7.3;Management of Pituitary Disease In McCune-Albright Syndrome;372
11.2.7.4;Familial Hyperprolactinemia;374
11.2.8;Conclusion;374
11.2.9;Abbreviations;374
11.3;Chapter 24: Long-term Effects of Treatment of Pituitary Adenomas;380
11.3.1;Treatment of Pituitary Adenomas: the Historical Perspective;380
11.3.2;Mortality;380
11.3.3;Hypopituitarism and Mortality;381
11.3.4;Cardiovascular Morbidity And pituitary Disease;381
11.3.5;Failure to Mimic Physiologic Hormone Secretion With Substitution;383
11.3.6;Hypothalamic Dysfunction;383
11.3.7;Quality Of life;384
11.3.8;Cognitive Function And psychopathology;385
11.3.9;Acromegalic Arthropathy As a model for disease-specific Persistent Morbidity;386
11.3.10;Implications for Treatment And follow-up;387
11.4;Chapter 25: Neuroendocrine Mechanisms in Athletes;392
11.4.1;Introduction;392
11.4.2;Neuroendocrine Alterations In athletes;392
11.4.2.1;Hypothalamic-pituitary-gonadal axis;392
11.4.2.1.1;Spectrum of Menstrual Function in the Female Athlete;392
11.4.2.1.2;Luteinizing Hormone and follicle-stimulating Hormone Secretion in Female Athletes;393
11.4.2.1.2.1;Pulsatility Patterns of Luteinizing Hormone and follicle-stimulating Hormone in Athletes;393
11.4.2.1.2.2;Determinants of Altered Luteinizing Hormone Pulsatility in Athletes;393
11.4.2.1.3;Kisspeptin in Athletes and Nonathletes;394
11.4.2.1.4;Prolactin and Oxytocin in Athletes And nonathletes;394
11.4.2.1.5;Appetite Regulating and Gut Peptides That May regulate Energy Homeostasis and Impact The hypothalamic-pituitary-go...;394
11.4.2.1.5.1;Leptin;394
11.4.2.1.5.2;Ghrelin;395
11.4.2.1.5.3;Peptide YY;395
11.4.2.1.5.4;Insulin;395
11.4.2.1.5.5;Adiponectin;395
11.4.2.1.6;Reproductive Function in Male Athletes;395
11.4.2.2;Hypothalamic-pituitary-adrenal axis;396
11.4.2.3;Growth Hormone-insulin-like Growth Factor 1 (IGF-1) axis;396
11.4.2.4;Hypothalamic-pituitary-thyroid axis;397
11.4.3;Impact on Bone Metabolism of Athletic Activity and Associated Neuroendocrine Changes;397
11.4.3.1;Areal Bone Density in Athletes;397
11.4.3.2;Impact of Physical Activity and the Nature Of the sport;398
11.4.3.3;Impact of Energy Deficiency And/or Hypogonadism;398
11.4.3.4;Modifying Effect of the Nature of Impact;398
11.4.3.5;Bone Turnover in Athletes;398
11.4.3.6;Determinants of Bone Density in Athletes;398
11.4.3.7;Limitations of Areal Bone Density Assessment;399
11.4.3.8;Bone Microarchitecture, Volumetric Bone Density, and Estimates of Bone Strength In athletes;399
11.4.3.8.1;Bone Structural Changes;399
11.4.3.8.2;Cortical and Trabecular Microarchitectural Changes;399
11.4.3.8.3;Volumetric Bone Density;399
11.4.3.8.4;Estimated Bone Strength and Fractures;400
11.4.3.8.5;Determinants of Bone Structure, Microarchitecture, Volumetric Bone Density, And estimated Strength;400
11.4.3.9;Strategies to Optimize Bone Health in Athletes;400
11.4.4;Impact on Neurocognitive Function;400
11.4.5;Impact on Fertility;401
11.4.6;Conclusion;401
11.4.7;Acknowledgments;402
11.5;Chapter 26: Uncertainties in Endocrine Substitution Therapy For central hypocortisolism;406
11.5.1;Introduction;406
11.5.2;Clinical Assessment For hypocortisolism;406
11.5.3;Dynamic Tests of Hypocortisolism;407
11.5.4;Standard Treatments for Hypocortisolism;408
11.5.4.1;What is the Optimal agent?;408
11.5.4.2;Total Daily Glucocorticoid Dosing;408
11.5.4.3;Multiple Daily Dosing and Monitoring Of glucocorticoid Replacement;410
11.5.4.4;Modified-release Hydrocortisone;411
11.5.4.5;Future Glucocorticoid Treatments;412
11.5.4.6;Other Adrenal Androgens;412
11.5.4.7;Adrenal Suppression;412
11.5.4.8;Patient Education;413
11.5.5;Conclusions;413
11.6;Chapter 27: Uncertainties in Endocrine Substitution Therapy for Central Endocrine Insufficiencies: Hypothyroidism;416
11.6.1;Introduction;416
11.6.2;Facts and Uncertainties in Central Hypothyroidism Diagnosis;416
11.6.2.1;Inheritable Central Hypothyroidism;416
11.6.2.2;Acquired Forms of Central Hypothyroidism;417
11.6.3;Facts and Uncertainties in Central Hypothyroidism Replacement Therapy;419
11.6.4;Novel Perspectives for Therapy of Central Hypothyroidism;421
11.7;Chapter 28: Uncertainties in Endocrine Substitution Therapy for Central Endocrine Insufficiencies: Growth Hormone Deficiency...;426
11.7.1;Introduction;426
11.7.2;Patients With Isolated Growth Hormone Deficiency (e.g., Caused By Treatment With Prophylactic Cranial Radiotherapy for Lympho..;427
11.7.2.1;Cardiovascular Risk After Acute Lymphoblastic Leukemia;427
11.7.2.2;Bone Health After Acute Lymphoblastic Leukemia;428
11.7.3;Patients With Growth Hormone Deficiency and Multiple Hormone Deficiencies Caused By Nonsecreting Pituitary Macroadenomas Treat.;428
11.7.3.1;Cardiovascular Risk in Hypopituitary Patients With Nonsecreting Pituitary Macroadenomas;428
11.7.3.2;Bone Health in Patients With Growth Hormone Deficiency Due to Pituitary Macroadenomas;429
11.7.4;Patients With Growth Hormone Deficiency and Multiple Hormone Deficiencies and With Hypothalamic Involvement Caused By a Cranio.;429
11.7.4.1;Cardiovascular Risk in Patients With A craniopharyngioma;429
11.7.4.2;Hypothalamic Damage and Obesity In craniopharyngioma Patients;431
11.7.4.3;Bone Health in Craniopharyngioma Patients;431
11.7.5;General Uncertainties of Growth Hormone Therapy;432
11.7.6;Conclusion;432
11.8;Chapter 29: Autoimmune Hypophysitis: New Developments;436
11.8.1;Introduction;436
11.8.2;Pituitary Autoantibodies;437
11.8.3;IGG4-Related Hypophysitis;437
11.8.4;Anti-PIT-1 Antibody Syndrome;438
11.8.5;Autoimmunity and Metabolic Disease;439
11.8.6;Conclusion;440
11.8.7;Abbreviations;440
11.9;Index;442

Leseproben

Chapter 1

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: [e-mail]

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.,...