The Pituitary

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