The Pituitary

Description

The Pituitary, Fourth Edition, continues the tradition of a cogent blend of basic science and clinical medicine which has been the successful hallmark of prior editions. This comprehensive text is devoted to the pathogenesis, diagnosis, and treatment of pituitary disorders. The new edition has been extensively revised to reflect new knowledge derived from advances in molecular and cell biology, biochemistry, diagnostics, and therapeutics as they apply to the pituitary gland. The wide spectrum of clinical disorders emanating from dysfunction of the master gland is described in detail by experts in the field. Fundamental mechanisms underlying disease pathogenesis are presented to provide the reader with an in-depth understanding of mechanisms subserving both normal and disordered pituitary hormone secretion and action. This extensive body of knowledge is useful for students, trainees, physicians, and scientists who need to understand critical pituitary functions and how to care for patients with pituitary disorders. Chapters provide medical students, clinical and basic endocrinology trainees, endocrinologists, internists, pediatricians, gynecologists, and neurosurgeons with a comprehensive, yet integrated, text devoted to the science and art of pituitary medicine. Brings together pituitary experts from all areas of research and practice who take readers all the way from bench research, to genomic and proteomic analysis, clinical analysis, and new therapeutic approaches to pituitary disordersSaves researchers and clinicians time in quickly accessing the very latest details on a broad range of issues related to normal and diseased pituitary functionProvides a common language for endocrinologists, neurosurgeons, OB/GYNs, and endocrine researchers to discuss how the pituitary gland and hormones affect each major organ system Front Cover Title Page Copyright Dedication Contents List of Contributors Preface I: Hypothalamic–Pituitary Function 1 Pituitary Development Introduction The Pituitary Gland Formation of Rathke’s Pouch Glandular or Endocrine Gland Development Signals Controlling Pituitary Development Cell Differentiation Tissue Architecture and Cell Networks Pituitary Cell Cycle Control Progenitors and Stem Cells Corticotrophs Melanotrophs Gonadotrophs Somatotrophs Lactotroph Differentiation Thyrotrophs Perspectives Acknowledgments References 2 Hypothalamic Regulation of Anterior Pituitary Function Introduction Anatomy and Histology of the Hypothalamic–Pituitary Unit The Hypothalamus Pituitary Anatomy Cellular Composition of the Anterior Pituitary Hypothalamic Factors Regulating Pituitary Function Thyrotrophin-Releasing Hormone Corticotrophin-Releasing Hormone Growth Hormone–Releasing Hormone Somatostatin Gonadotrophin-Releasing Hormone Hypothalamic Prolactin Regulators Prolactin-Inhibitory Factors Prolactin-Releasing Factors Summary References 3 Adrenocorticotrophin Introduction Corticotroph Biology Embryology Adult Anatomy Molecular Signals in Development Intrinsic Signals Extrinsic Signals Non-ACTH Peptides Within Corticotrophs ACTH and Related Peptide Expression Outside of Corticotrophs Ectopic ACTH-Secreting Tumors Corticotroph Neoplasms Proopiomelanocortin Gene POMC Gene Structure POMC MRNA Transcription, Splicing, and Polyadenylation POMC Biosynthesis and Processing Glycosylation of POMC C-Terminal Amidation of POMC N-Terminal Acetylation of POMC Proteolytic Processing of POMC Proteolytic Processing Enzymes Tissue Specificity of POMC Processing POMC Mutations Leading to POMC Deficiency Regulation of the HPA Axis POMC Gene Regulation Ontogeny of ACTH Regulation Fetal and Neonatal Regulation of ACTH Secretion Regulation of ACTH Secretion During Adrenarche, Puberty, and Adulthood Hormonal and Pharmacological Regulators of ACTH Corticotrophin-Releasing Hormone CRH Stimulation of ACTH Secretion Modulators of CRH Release CRH Receptors AVP AVP Stimulation of ACTH Secretion Modulators of AVP Release AVP Receptors Synergism Between CRH and AVP Cytokines Oxytocin Glucocorticoids Other Hormones and Pharmacological Regulators of ACTH Secretion Physiological Regulation of ACTH Secretion Secretion Dynamics of ACTH In Vivo Circadian Regulation of ACTH Secretion Physiological Regulators of ACTH Secretion Hypoglycemia Exercise Starvation Hypotension and Hypovolemia Surgical Stress Brain Death Critical Illness Cosyntropin Administration High-Dose (HDT=250μg) Versus Low-Dose (LDT=1μg) Cosyntropin Test Psychological and Emotional Stress Effects of Secreted POMC-Derived Peptides in Physiology and Disease ACTH Adrenal Gland Melanocortin 2 Receptor—the ACTH Receptor Familial Glucocorticoid Deficiency Syndrome Type 1 Familial Glucocorticoid Deficiency Syndrome Type 2 Other Causes of Familial Glucocorticoid Deficiency Syndrome ACTH-Independent Activation of ACTH Receptor Pathways Nonadrenal Actions of ACTH α-MSH Skin Melanocortin 1 Receptor Melanocortin 5 Receptor Brain Melanocortin 4 Receptor Melanocortin 3 Receptor β-Endorphin Additional Potential Melanocortin Actions Measurement Assays for ACTH (RIA, IRMA, LC/MS, etc.) References 4 Growth Hormone Introduction Growth Hormone Gene Structure Somatotroph Development and Differentiation GH Synthesis Neuroendocrine Control of GH Hypothalamic Hormones Growth Hormone-Releasing Hormone Somatostatin GHRH and SRIF Interaction in Regulating GH Secretion GH Autoregulation Physiologic Factors Affecting GH Secretion Aging Gender Sleep Exercise Stress Nutritional and Metabolic Regulation GH-Binding Proteins Peripheral GH Action GH Receptor Insulin-Like Growth Factors (IGFs) IGF-Binding Proteins GH Action Role of GH/IGF-1 in Growth and Development Throughout the Lifespan Bone Acquisition Bone Loss GH and Metabolism Lipids Body Composition Carbohydrate Metabolism Protein Metabolism Muscle Strength and Exercise Performance GH and Reproduction GH/IGF-1 and Cardiovascular Function Effects of GH and IGF-1 on Cardiac Structure and Function GH Therapy in Congestive Heart Failure GH as a Biomarker of CVD GH Effects on Renal Function Tests of GH Secretion Integrated 24-Hour GH Concentrations Evaluation of GH Hypersecretion Evaluation of GH Deficiency Single GH and IGF-1 Measurements Provocative Tests Insulin-Induced Hypoglycemia (Insulin Tolerance Test) Clonidine l-Dopa/Propranolol Arginine/GHRH Ghrelin Mimetics Glucagon Approach to Provocative GH Testing Variability of GH Assays Variability of IGF Assays Clinical Use of GH GH Therapy in Childhood Idiopathic Short Stature Turner Syndrome Children Born Small for Gestational Age Chronic Renal Insufficiency SHOX Gene Deficiency GH Therapy in Adults Adult GHD Syndrome Etiology Diagnosis GH Replacement Therapy Effects of GH Replacement Therapy Hypopituitarism Thyroid Hormone Gonadal Steroids Glucocorticoids GH Replacement in Acromegaly GH in the Healthy Elderly GH Abuse by Athletes Testing for GH Doping in Athletes Complications of GH Treatment Decreased IGF-1 Levels Protein–Calorie Malnutrition, Starvation, Anorexia Nervosa Diabetes Mellitus Laron Syndrome References 5 Prolactin Introduction Historical Overview Cell of Origin Lactotroph Ontogeny Prolactin Gene Pit-1 Estrogen Ets Other Transcription Factors Signaling Pathways That Converge Upon the PRL Promoter Hormone Biosynthesis Prolactin Protein Structural Characteristics and Posttranslational Modifications Proteolysis Macroprolactin Placental, Decidual, and Lymphoblastoid Forms Hormone Secretion: Biochemistry Measurement of Prolactin Assays and Bioassays Clinical Testing Artifacts Hook Effect Macroprolactin Physiology Metabolic Clearance and Production Rates of Prolactin Hormone Secretion Patterns Changes in Prolactin With Age Changes in Prolactin Levels during the Menstrual Cycle Changes in Prolactin Levels During Pregnancy Changes in Prolactin Levels With Postpartum Lactation Changes in Prolactin Secretion With Stress Neuroendocrine Regulation Prolactin-Inhibiting Factors Dopamine Gonadotrophin-Associated Peptide γ-Aminobutyric Acid Prolactin-Releasing Factors Thyrotrophin-Releasing Hormone VIP and Peptide Histidine Methionine (PHM)/PHI Serotonin Opioid Peptides Growth Hormone-Releasing Hormone Posterior Pituitary, Oxytocin, and Vasopressin Gonadotrophin-Releasing Hormone Renin–Angiotensin System Other Neuroactive Peptides and Neurotransmitters Histamine Acetylcholine Prolactin Short-Loop Feedback Prolactin Action Prolactin Receptor PRLR Signal Transduction Female Reproductive Tissues PRL Effects on Breast Galactorrhea PRL and Breast Cancer PRL Effects on Gonadotrophin Secretion PRL Effects on the Ovary and Fertility Clinical Effects of Hyperprolactinemia on Menstrual Function Male Reproductive Tissues Clinical Effects of PRL in Males Carbohydrate Metabolism and Adiposity Adrenal Cortex Calcium and Bone Metabolism Immune System Acknowledgments References 6 Thyroid-Stimulating Hormone Introduction Ontogeny of Thyrotroph Cells TSH Subunit Genes TSH β-Subunit Gene Structure α-Subunit Gene Structure TSH BIOSYNTHESIS TSH transcription TSH translation TSH glycosylation TSH folding, combination, and storage Regulation of TSH Biosynthesis Hypothalamic Regulation of TSH Biosynthesis Peripheral Regulation of TSH Biosynthesis TSH Secretion Ontogeny of TSH Levels Patterns of TSH Secretion Regulation of TSH Secretion Hypothalamic Regulation of TSH Secretion Peripheral Regulation of TSH Secretion Action of TSH TSH Receptor Gene TSH Receptor Structure Determinants of TSH Receptor Binding Signal Transduction at the TSH Receptor TSH actions Effects of TSH on Thyroid Gland Development and Growth Effects of TSH on Thyroid Cell Morphology Effects of TSH on Iodine Metabolism Effects of TSH on the Synthesis of Thyroid Hormone TSH-Induced Receptor Desensitization Extrathyroidal Actions of TSH TSH Measurements Free TSH β- and α-Subunit Measurements Provocative Testing of TSH Drugs and TSH Levels Drugs that Decrease Serum TSH Levels Drugs That Increase Serum TSH Levels Disorders of TSH Production Acquired TSH Deficiency Congenital TSH Deficiency Acquired TSH Excess Congenital TSH Excess References 7 Gonadotrophin Hormones Introduction Development, Embryology, and Histology Gonadotrophic Cells in the Pituitary Molecular Basis of Gonadotroph Development Biochemical Structure and Molecular Biology of LH and FSH Hormone Structure The α-Subunit The LHβ Subunit The FSHβ Subunit Synthesis and Posttranslational Processing of LH and FSH Ontogeny and Physiology of LH and FSH Secretion Fetal Life Postnatal Life and Childhood Years Gonadotrophin Secretion During the Menstrual Cycle Aging and Gonadotrophins Biologic Functions of LH and FSH Roles of LH and FSH in the Male The Roles of LH and FSH in the Female Gonadotrophin Receptors Assay Systems for the Measurement of Gonadotrophins Radioimmunoassays for LH and FSH Improvements in LH and FSH Immunoassays Bioassays for LH and FSH Hypothalamic Regulation of LH and FSH GnRH Neuronal Development GnRH Secretion GnRH Action Influence of Patterns of Pulsatile GnRH Feedback Regulation of LH and FSH Secretion Estrogens Progesterone Androgens Inhibins, Activins, and Follistatins Molecular Biology of LH and FSH Subunit Genes α-Subunit LHβ Subunit FSHβ Subunit Diagnostic Tests GnRH Stimulation Test Clomiphene Test Detection and Characterization of Gonadotrophin Pulse Patterns Clinical Disorders Affecting the Gonadotroph Hypogonadotrophic Disorders Congenital Hypogonadotrophic Disorders Heterogeneity of Pulsatile Gonadotrophin Secretion in Patients with Congenital HH Nonreproductive Phenotypes Associated with Kallmann Syndrome and HH Mutations in the Genes Encoding LHβ and FSHβ Subunits Hypogonadism Associated with Mutations in the FSHβ Gene Hypogonadism Associated with Mutations of the LHβ Gene Inactivating Mutations of LH and FSH Receptor Genes Inactivating Mutations of the LH Receptor Gene Inactivating Mutations of FSH Receptor Gene Other Congenital Hypogonadotrophic Syndromes Prader–Willi Syndrome Laurence–Moon–Biedl Syndrome Miscellaneous Congenital Hypogonadotrophic Syndromes Transcription Factor Mutations Acquired Hypogonadotrophic Disorders Hypothalamic Amenorrhea Chronic Renal Failure and Gonadal Dysfunction Hemochromatosis Hyperprolactinemia and Hypogonadotropism Space-Occupying Lesions Hypothalamic Syndromes Hypergonadotrophic Disorders: Excessive or Nonphysiologic Secretion of Gonadotrophins Ectopic Gonadotrophin Secretion Central or Gonadotrophin-Dependent Precocious Puberty Activating Mutations of the LH Receptor Activating Mutations of the FSH Receptor Polycystic Ovarian Syndrome Treatment of Hypogonadotrophic Disorders Gonadotrophin Treatment of HH Pulsatile GnRH Therapy GnRH Analogues GnRH Agonists GnRH Antagonists Acknowledgments References 8 The Posterior Pituitary Introduction Structure of the Neurohypophysis: Anatomy and Electrophysiology of Vasopressin-Producing Cells The Vasopressin and Oxytocin Genes Gene Structure Expression of the Vasopressin Gene in Diabetes Insipidus Rats (Brattleboro Rats) Expression of the Vasopressin Gene in Autosomal Dominant and Autosomal Recessive Diabetes Insipidus in Humans Chemistry, Processing, and Metabolism of AVP Control of AVP Secretion Osmotic Stimulation Osmoreceptors in the Brain and the Periphery Osmotic Threshold: Sensitivity or Gain of the Osmoreceptor/AVP-Releasing Unit Baroregulation Hormonal Influences on the Secretion of Vasopressin Vasopressin Receptors and Antagonists Cellular Actions of Vasopressin Quantitating Renal Water Excretion Clinical Characteristics of Diabetes Insipidus Disorders Neurogenic Diabetes Insipidus Common Forms Rare Forms Autosomal Dominant and Recessive Neurogenic Diabetes Insipidus Wolfram Syndrome Syndrome of Hypernatremia and Hypodipsia Nephrogenic Diabetes Insipidus Loss-of-Function Mutations of the AVPR2 Rareness and Diversity of AVPR2 Mutations Most Mutant V2 Receptors are not Transported to the Cell Membrane and are Retained in the Intracellular Compartments Nonpeptide Vasopressin Receptor Antagonists Act as Pharmacological Chaperones to Functionally Rescue Misfolded Mutant V2 Re... Gain-of-Function of the Vasopressin V2 Receptor: Nephrogenic Syndrome of Inappropriate Antidiuresis Loss-of-Function Mutations of AQP2 Complex Polyuropolydipsic Syndrome Acquired NDI (Table 8.3) Primary Polydipsia Diabetes Insipidus and Pregnancy Pregnancy in a Patient Known to Have Diabetes Insipidus Syndromes of Diabetes Insipidus that Begin during Gestation and Remit after Delivery Investigation of a Patient With Polyuria Indirect Tests for Diabetes Insipidus Direct Tests of Diabetes Insipidus Therapeutic Trial of dDAVP Carrier Detection, Perinatal Testing, and Early Treatment Radioimmunoassay of AVP, Copeptin, and Other Laboratory Determinations Radioimmunoassay of AVP AQP2 Measurements Plasma Sodium, Plasma, and Urine Osmolality Magnetic Resonance Imaging in Patients With Diabetes Insipidus Treatment Syndrome of Inappropriate Secretion of the Antidiuretic Hormone (SIADH) Signs, Symptoms, and Treatment of Hyponatremia Acknowledgments References II: Hypothalamic–Pituitary Disorders 9 The Hypothalamus Introduction Anatomy Hypothalamic Physiology Hypothalamic Endocrine and Metabolic Functions Control of Anterior Pituitary Function Appetite Control Water Metabolism Hypothalamic Nonendocrine Functions Temperature Regulation Sleep–Wake Cycle and Circadian Rhythm Control Regulation of Visceral (Autonomic) Functions Emotional and Cognitive Functions Pathophysiology of Hypothalamic syndromes Clinical Features of Hypothalamic Syndromes Endocrine and Metabolic Anterior Pituitary Dysfunction Activating Lesions Central Precocious Puberty Acromegaly Cushing Disease Lesions with Hypothalamic Loss of Function Hyperprolactinemia Hypothalamic Hypogonadism Growth Hormone Deficiency Acquired GH Deficiency Congenital GH Deficiency Hypothalamic Hypoadrenalism Hypothalamic Hypothyroidism Disorders of Water Metabolism Central Diabetes Insipidus Adipsic or Essential Hypernatremia (Cerebral Salt Retention Syndrome) Syndrome of Inappropriate Secretion of Antidiuretic Hormone Disorders of Caloric Balance Hypothalamic Obesity Diencephalic Syndrome of Infancy Anorexia Nervosa Diencephalic Glycosuria Nonendocrine Deranged Control of Body Temperature Hyperthermia Hypothermia Poikilothermia Sleep–Wake Cycle and Circadian Abnormalities Behavioral and Emotional Abnormalities Diencephalic Epilepsy Specific Hypothalamic Disorders Prader–Willi Syndrome Ciliopathies Optic Nerve Hypoplasia Environmental Deprivation Syndrome (Psychosocial Short Stature) Hypothalamic Hamartoma Germ Cell Tumors Optic Chiasm and Hypothalamic Gliomas Craniopharyngioma Suprasellar Meningiomas Suprasellar Arachnoid Cyst Colloid Cyst of the Third Ventricle Hematologic malignancies Leukemia Lymphoma Inflammatory lesions Infiltrative Disorders Hypothalamic–Pituitary Sarcoidosis Langerhans’ Cell Histiocytosis Brain Irradiation Traumatic brain injury Acknowledgments References 10 Anterior Pituitary Failure Introduction Mortality Etiology Structural Causes of Pituitary Failure Mass Lesions Pituitary Tumors Pituitary Surgery Nonpituitary Neoplasms Cystic Lesions Aneurysms Infiltrative Lesions Hypophysitis Sarcoidosis and Other Granulomatous Diseases Hemochromatosis Pituitary Irradiation Infectious Etiologies Pituitary Hemorrhage Apoplexy Sheehan Syndrome Congenital and Inherited Pituitary Insufficiency Developmental Pituitary Dysfunction Genetic Factors Traumatic Brain Injury Empty Sella Syndrome Functional Causes of Pituitary Failure Functional Central Adrenal Insufficiency Functional Central Hypothyroidism Functional Hypogonadotrophic Hypogonadism Functional Growth Hormone Deficiency Clinical Manifestations Manifestations of Secondary Adrenal Insufficiency Adrenal Androgen Insufficiency Manifestations of Thyrotrophin Deficiency Manifestations of Hypogonadotrophic Hypogonadism Adult Males Prepubertal Males Neonatal Males Female Hypogonadotrophic Hypogonadism Adult Females (Secondary Amenorrhea) Primary Amenorrhea/Pubertal Delay Growth Hormone Deficiency Adult-Onset GHD Cardiovascular Risk Childhood-onset GHD Prolactin Deficiency Diagnostic Testing Assay Variability Assessment of Pituitary Function Corticotroph Assessment Basal Testing Dynamic Testing Insulin Tolerance Testing Overnight Metyrapone Test ACTH Stimulation Testing CRH Stimulation Comparison of Tests Testing After Pituitary Surgery Diagnosis of Adrenal Androgen Deficiency in Women Thyrotroph Assessment TRH Testing Gonadotroph Assessment Adult Males Adolescent Males GnRH Stimulation Testing Clomiphene Stimulation Test hCG Stimulation Test Adult Females Primary Amenorrhea Somatotroph Assessment Adults The ITT GHRH–Arginine Stimulation Test Glucagon Stimulation Test Recommendations Somatotroph Assessment in Children GH Stimulation Testing in Children Agents Used for GH Stimulation Testing in Children Lactotroph Assessment Special Considerations Evaluation of Patients After TBI Evaluation of Pituitary Function in Critical Illness Treatment of Hypopituitarism Recovery of Pituitary Function After Neurosurgical Treatment Hormonal Replacement Glucocorticoid Replacement Androgen Replacement in Women Thyroid Hormone Replacement Gonadal Steroid Replacement Female Hypogonadotrophic Hypogonadism Estrogen Replacement in Adult Women Inducing Puberty in Females Inducing Fertility in Females Male Hypogonadotrophic Hypogonadism Testosterone Replacement in Men Inducing Puberty in Males Inducing Fertility in Males Growth Hormone Replacement Adult-Onset GHD Clinical Benefits of GH Replacement Body Composition Bone Density Cardiovascular Markers Quality of Life Monitoring Therapy Children and Adolescents References 11 Pituitary Dysfunction in Systemic Disorders Introduction Systemic Disorders Directly Affecting the Pituitary Gland Pituitary Granulomas Sarcoidosis Granulomatosis With Polyangiitis (Formerly Wegener’s Granulomatosis) Granulomatous Hypophysitis Necrotizing Hypophysitis Langerhans Cell Histiocytosis Erdheim–Chester Disease Autoimmune Lymphocytic Hypophysitis Immunoglobulin G4-related Hypophysitis Polyglandular Autoimmune States Amyloidosis Infectious Diseases Acquired Immune Deficiency Syndrome Other Infectious Diseases Pituitary Abscess Iron Overload Snakebite Metastatic Cancer (see also chapter: Nonpituitary Sellar Masses) Genetic Multiglandular Tumoral Syndromes (see also chapter: Genetics of Pituitary Tumor Syndromes) Multiple Endocrine Neoplasia Carney Complex (see also chapter: Acromegaly) McCune–Albright syndrome (see also chapter: Acromegaly) Other Stalk and Pituitary Lesions (see also chapter: Nonpituitary Sellar Masses) Stalk Hemangioblastoma Chordoid Glioma Hemangiopericytoma Fabry Disease Changes in Pituitary Morphology and Function with Aging General Effects of Systemic Illness on Pituitary Function Pituitary Alterations Associated With Specific Systemic Disorders Obesity Malnutrition Anorexia Nervosa Diabetes Mellitus Chronic Kidney Disease Liver Disease Other Endocrine Disorders Primary Adrenal Insufficiency Primary Hypothyroidism Hyperthyroidism Acknowledgments References 12 Drugs and Pituitary Function Introduction Opiates and Opiate Antagonists Opiates Opiate Antagonists Amphetamines and Methylphenidate Caffeine Benzodiazepines Antidepressants Lithium Antipsychotic Drugs Other Dopamine Antagonists Dopamine Agonists Cholinergic Agonists and Antagonists Antihypertensives Antihistamines H1-Antihistamines H2-Antihistamines Cancer Therapies Antineoplastic Chemotherapy Immunotherapies Estrogens Androgens Antiandrogens Glucocorticoids Endocrine-Disrupting Chemicals Miscellaneous Drugs Alcohol Smoking Cigarettes and Nicotine Marijuana Cocaine Acknowledgments References 13 The Pituitary Gland in Pregnancy Introduction Normal Pituitary during Pregnancy Prolactin Gonadotrophins Growth Hormone Thyrotrophin Corticotrophin Posterior Pituitary Pituitary Tumors and Pregnancy Prolactinomas Acromegaly Cushing Disease Thyrotrophinomas Clinically Nonfunctioning Pituitary Adenomas Nontumoral Pituitary Disturbances Related to Pregnancy Lymphocytic Hypophysitis Hypopituitarism Conclusions References 14 Psychiatric Disease in Hypothalamic–Pituitary Disorders Introduction Historical Perspective Psychiatric Diseases in Hypothalamic–Pituitary Disorders Hypopituitarism Corticotroph Insufficiency Thyrotrophin Insufficiency Gonadotrophin Insufficiency Somatotrophin Insufficiency Hormone Excess Syndrome and Psychiatric Disorders Acromegaly Cushing’s Syndrome Prolactinoma Rare Diseases of the Hypothalamus/Pituitary Gland and Psychiatric Disorders Diagnosing Psychiatric Disorders in Hypothalamlic–Pituitary Diseases Therapy of Psychiatric Disorders in Hypothalamic–Pituitary Disease Acknowledgments References III: Pituitary Tumors 15 Acromegaly Introduction Epidemiology Animal Models of Hypersomatotrophism Pathogenesis Pituitary Acromegaly Pathogenesis of Somatotroph Cell Adenomas Extrapituitary Acromegaly Criteria for Diagnosis of Ectopic Acromegaly GHRH Hypersecretion GH Hypersecretion Acromegaloidism Genetic Syndromes McCune–Albright Syndrome Multiple Endocrine Neoplasia Carney Complex Familial Acromegaly Gigantism Clinical Features of Acromegaly GH Action in Acromegaly Effects of Excessive GH Secretion Skeletal Changes Skin Changes Cardiovascular Complications Respiratory Complications Neuromuscular Changes Psychologic Changes Development of Neoplasms Endocrine Complications Effects on Morbidity and Mortality Diagnosis Differential Diagnosis Treatment of Acromegaly Aims Goals of Therapy Surgical Management Side Effects of Surgery Radiation Treatment Stereotactic Radiosurgery Side Effects of Radiotherapy Medical Treatment Dopamine Agonists Somatostatin Receptor Ligands Oral Octreotide Capsules GH Receptor Antagonist Selective Estrogen Receptor Modulators Choice of Therapy References 16 Prolactinoma Introduction Classification Epidemiology and Natural History of Prolactinomas Pathogenesis Familial Prolactinomas Altered Chromatin Remodeling Cell Cycle Dysregulation Growth Factor and Hormone Signaling Aberrant Expression of Developmental Factors Other Mechanisms Clinical Manifestations Endocrine Symptoms Women Men Children and Adolescents Local Mass Effects Diagnosis Hyperprolactinemia Prevalence of Hyperprolactinemia Causes of Hyperprolactinemia Other Than Prolactinomas Pregnancy Medications (Table 16.2) Antipsychotics Antidepressants Opiates Antihypertensive Drugs Other Medications Stress Renal Disease Cirrhosis Hypothyroidism Adrenal Insufficiency Neurogenic Ectopic Prolactin Secretion Hypothalamic/Pituitary Stalk Disease “Idiopathic” Hyperprolactinemia Hyperprolactinemia Due to Genetic Resistance to PRL Imaging Treatment Observation Medical Therapy Efficacy of Dopamine Agonists Bromocriptine Cabergoline Pergolide Quinagolide Side Effects of Dopamine Agonists Cabergoline: Possible Association with Cardiac Valve Disease Discontinuation of Medical Therapy Dopamine Agonist Resistance Definition of Dopamine Agonist Resistance Mechanisms of Dopamine Agonist Resistance Resistance to Prolactin-Lowering and Antitumoral Effects of Dopamine Agonists Medical Treatment of Prolactinomas in Children and Adolescents Medical Therapy: Conclusions Surgery Surgical Indications and Approaches Surgical Success Rates Recurrence and Long-Term Cure Predictors of Remission and Cure Complications of Surgery Radiotherapy Pitfalls in Analysis of Radiotherapy Studies Efficacy of Fractionated Radiotherapy Efficacy of Stereotactic Radiosurgery Selecting the Mode of Radiotherapy Complications of Fractionated Radiotherapy Complications of Stereotactic Radiosurgery Which Therapeutic Strategy? Microadenomas Macroadenomas Special Situations Giant Prolactinomas Malignant Prolactinomas Prolactinomas in Multiple Endocrine Neoplasia Acknowledgment References 17 Cushing Disease Introduction Pathophysiology Epidemiology Chronic ACTH and Proopiomelanocortin (POMC) Peptide Oversecretion by the Pituitary ACTH Synthesis and Secretion Mechanisms of ACTH Biosynthesis Regulation of ACTH Secretion Oversecretion of ACTH in Cushing Disease Cushing’s Hypothesis Demonstrating ACTH Oversecretion ACTH Secretion is Dysregulated, Not Autonomous The Source and Mechanism of ACTH Oversecretion in Cushing Disease Anterior Pituitary Corticotroph Adenoma POMC Gene Expression is Qualitatively Unaltered POMC Gene Expression is Relatively Resistant to Glucocorticoid Feedback Variants of the Anterior Pituitary Corticotroph Adenoma Familial Pituitary Adenomas and Cushing Disease Intermediate Lobe Pituitary Adenoma Hypothalamus-Dependent Cushing Disease Corticotroph Cell Hyperplasia and Adenoma Formation Effects of Chronic ACTH and POMC Peptide Oversecretion Effects of ACTH on Corticosteroid Secretion and the Adrenal Gland Extra-Adrenal Effects of ACTH and POMC Peptides Pathology of the Adrenal in Cushing Disease Simple Diffuse Hyperplasia Multinodular Hyperplasia Adrenal Rests Other Causes of Cushing’s Syndrome ACTH-Dependent Spontaneous Cushing’s Syndromes CRH-Secreting Tumors Ectopic ACTH Syndrome ACTH-Independent Spontaneous Cushing’s Syndrome Primary Adrenocortical Tumors Other Adrenocortical Disorders Gonadal Tumors Iatrogenic Cushing’s Syndromes Exogenous Glucocorticoids Exogenous Cosyntropin Clinical Features Diagnosis of Cushing Disease Routine Laboratory Tests Clues to Clinical Diagnosis of Chronic Hypercortisolism Challenges in Diagnosis Cushing Disease in Children Cushing Disease in Pregnant Women Long-Term Outcome of Cushing Disease Diagnostic Approach Question 1: “Does This Patient Have Cushing’s Syndrome?” Baseline Measurements Suppression Tests Question 2: “What is the Cause of Cushing’s Syndrome in this Patient?” Plasma ACTH Plasma Non-ACTH POMC Peptides Plasma Adrenocortical Androgens Establishing the Pituitary Origin of the ACTH-Driven Hypercortisolemic State Noninvasive Baseline Tests Dynamic Noninvasive Testing Invasive Testing: Bilateral Inferior Petrosal Sinus Sampling Imaging Techniques Pituitary MRI CT Scanning Skull X-rays Adrenal Glands Pitfalls in Diagnosis Drug Interactions Inducers of High CBG Plasma Levels Liver Enzyme Inducers Antiglucocorticoids (Mifepristone) Glucocorticoids Glycyrrhetinic Acid Intercurrent Illness Hypercortisolemic States Without Cushing’s Syndrome Depression Anorexia Nervosa Alcohol Stress Strenuous Exercise Pregnancy Familial Resistance to Glucocorticoids Tests to Distinguish Between “Pseudo-Cushing” and Cushing’s Syndrome Pitfalls in Differential Diagnosis Cushing Disease Mimicking an Autonomous Adrenocortical Tumor Severe Cushing Disease Mimicking Classic Ectopic ACTH Syndrome Mild Ectopic ACTH Syndrome Mimicking Classic Cushing Disease Strategy for Diagnosis and Differential Diagnosis Whom to Screen for Cushing’s Syndrome When to Screen for Cushing’s Syndrome A Stepwise Strategy The Hypercortisolemic State Causes of the Hypercortisolemic State Treatment Pituitary Surgery and Radiation Surgery Radiation Conventional Radiotherapy Stereotactic Radiosurgery with the Gamma Knife Heavy-Particle Radiotherapy Medical Treatments Reversible Adrenal Steroidogenesis Inhibitors (Table 17.5) Metyrapone Imidazole Derivatives Irreversible Adrenal Steroidogenesis Inhibitors Therapy to Lower ACTH from the Corticotroph Tumor Blockade of the Glucocorticoid Receptor Adrenal Surgery Total Bilateral Adrenalectomy Nelson Syndrome Overall Approach for Treatment Pituitary Surgery as the First-Line Treatment Failure of Pituitary Surgery Pituitary Surgery for Failed Remission or Relapse When Other Options May be Better as First-Line Treatment Other Options for Persistent/Recurrent Disease Future Directions Acknowledgments References 18 Thyrotrophin-Secreting Pituitary Tumors Introduction Pathogenesis Hormone-Regulatory Pathways Pituitary Hyperplasia in Long-Standing Hypothyroidism Impaired Thyroid Hormone Negative Feedback Altered Hypothalamic Signaling Thyrotrophin-Releasing Hormone (TRH) Dopamine Somatostatin Alterations in Pituitary Transcription Factors Oncogenes, Tumor Suppressor Genes, and Growth Factors Familial/Genetic Syndromes Pathology Clinical Features Hyperthyroidism Goiter Pituitary Tumor Mass Effect Hormone Cosecretion Diagnosis Laboratory Studies Dynamic Tests TRH Test T3 Suppression Test Octreotide Test Circadian Secretion of TSH Pituitary Imaging Differential Diagnosis Impaired Sensitivity to Thyroid Hormones Resistance to Thyroid Hormone β (RTHβ) Resistance to Thyroid Hormone α (TRHα) Monocarboxylate Transporter 8 (MCT8) Defect Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Defect Euthyroid Hyperthyroxinemia Treatment Surgery Medical Treatment Somatostatin Analogues Dopamine Agonists Radiotherapy Criteria of Cure and Follow-Up Conclusions References 19 Nonfunctioning and Gonadotrophin-Secreting Adenomas Introduction Epidemiology Pathology Gonadotroph Adenoma Hormone Secretion Gonadotrophin Subunits: α, FSHβ, and LHβ Other Secretory Products Stimulated Secretion (Figs. 19.1 and 19.2) Gross Pathology Etiology Clinical Features Visual Field Defects Headaches Hypopituitarism Assessment Imaging Neuro-Ophthalmological Evaluation Hormonal Evaluation Differential Diagnosis Treatment Surgery Radiotherapy Medical Therapy Predictors of Regrowth Follow-Up Gonadotrophinomas Clinical Features Hormonal Evaluation Men Women Distinguishing a Gonadotroph Adenoma From Primary Hypogonadism References 20 Atypical Pituitary Adenomas Introduction Current WHO Definition of Atypical Pituitary Adenomas Controversies Regarding the Nature and Diagnosis of Atypical Pituitary Adenomas Genetics and Molecular Basis of Atypical Pituitary Adenomas Genetic and Chromosomal Factors Clinical Characteristics and the Functional Status of Atypical Pituitary Adenomas Prognostic Factors in Atypical Pituitary Adenomas Surgical Management of Atypical Pituitary Adenomas Medical Management of Atypical Pituitary Adenomas Temozolamide and Other Systemic Chemotherapies Direct Chemotherapy Radiation Therapy/Stereotactic Radiosurgery Future Avenues MicroRNA Chemokines Galectin-3 Novel Peptide Receptor Radionuclide Therapies Conclusions References 21 Genetics of Pituitary Tumor Syndromes Introduction Syndromic Conditions Associated With Pituitary Adenomas Multiple Endocrine Neoplasia Type 1 (MEN1) Multiple Endocrine Neoplasia Type 4 (MEN4) Carney Complex McCune–Albright Syndrome Genetic Forms of Isolated Pituitary Adenomas Familial Isolated Pituitary Adenomas Aryl Hydrocarbon-Receptor Interacting Protein (AIP) Mutations X-Linked Acrogigantism (X-LAG) Syndrome Genetic Testing Overview References 22 Nonpituitary Sellar Masses Introduction Clinical Diagnosis Imaging Diagnosis Morphological Diagnosis Specific Lesions Craniopharyngioma Meningioma TTF-1-Expressing Sellar Region Tumors Metastatic Tumors [37,70–73] Germinomas Cysts Inflammatory Lesions Vascular Lesions Conclusion References IV: Pituitary Procedures 23 Pituitary Imaging Introduction History of Pituitary Imaging Plain Films and Tomograms Size and Shape of Sella Angiography Computed Tomography CT: Technical Factors CT: Normal Anatomy MR: Technique and Anatomy Pituitary Size and Shape Microadenomas Gadolinium Enhancement Macroadenomas Posterior Pituitary Other Intrasellar/Suprasellar Masses Rathke’s Cleft Cysts Craniopharyngiomas Hamartomas Aneurysms Meningiomas Hypothalamic–Chiasmatic Gliomas Lymphocytic Hypophysitis Other Empty Sella Imaging of the Empty Sella References 24 Pituitary Surgery Historical Overview Diagnostic Evaluation Surgical and FunctionalAnatomy Surgical Techniques Transsphenoidal Approach Transcranial Pterional Approach Complications Further Treatment Radiotherapy Recurrences Medical Treatment Pituitary Tumors Pituitary Adenomas Nonfunctioning Pituitary Adenomas Prolactinomas Growth-Hormone-Producing Pituitary Adenomas Cushing Disease Nelson Syndrome TSH-Producing Adenomas Gonadotrophin-Producing Adenomas Craniopharyngiomas Supra- and Parasellar Meningiomas Miscellaneous Cystic Lesions Rathke’s Cleft Cysts Intra- and Suprasellar Colloid Cysts Arachnoid Cysts Rare Pituitary Tumors Optico–Hypothalamic Gliomas Metastatic Tumors Chordomas Inflammatory Lesions Hypophysitis Pituitary Abscess Hypothalamic Hamartomas Germ Cell Tumors Epidermoid Cysts Evolving Technologies References Index