DeGroot's Endocrinology-Basic Science and Clinical Practice

Description

Thoroughly updated to reflect today's recent advances in adult and pediatric endocrinology, DeGroot’s Endocrinology, 8th Edition, remains the comprehensive, international reference of choice for today’s endocrinologists and fellows. A full peer review of the previous edition, conducted by a largely new group of renowned editors, was used to update this trusted, two-volume resource. In-depth coverage of both basic and clinical aspects of endocrinology and up-to-date information on the treatment and management of endocrine disorders are provided by a diverse group of expert contributors from six continents. A full-color format and helpful algorithms summarize clinical decision-making and practical approaches to patient management. • Organizes content by all the glands that regulate the endocrine system while integrating basic science and clinical presentations of disease. • Includes new chapters: Anatomy and Physiology of the Hypothalmus and Pituitary, Differentiated Thyroid Cancer, Medullary Thyroid Cancer, Drugs that Affect Thyroid Function, Genetic Disorders of the Adrenal Cortex, Adrenal Pathology, Primary Aldosteronism, Transgender Healthcare, Erectile Dysfunction, Prevalence and Causes of Male Infertility, Sexual Dysfunction in the Female, Glucose Toxicity and Oxidative Stress. • Emphasizes basic science and evidence-based practice throughout. • Features extensive updates to content on thyroid and adrenal disfunction, endocrine-disrupting chemicals and human disease, clinical management of diabetes, and advances in genetics. • Includes algorithms to outline effective treatment protocols. • Contains new emphasis boxes that highlight key points in each chapter. Review The definitive source in endocrinology for more than 40 years About the Author R. Paul Robertson, M.D. is an Emeritus Professor of Medicine at the University of Washington and at the University of Minnesota. Dr. Robertson has published 395 peer-reviewed manuscripts with primary emphasis on pancreatic islet function in humans, animals, and clonal cell lines. His early studies were the first to demonstrate defects involving the adverse effects of glucose toxicity on the critical insulin promoters Pdx-1 and MafA associated with glucose toxicity. More recent research demonstrated adverse metabolic consequences of using the liver as a transplant site for pancreatic islet transplantatio Front Matter DeGroot’s ENDOCRINOLOGY: Basic Science and Clinical Practice Copyright sTOC Vol I Chapter (1) 1 - Principles of Endocrinology Definition and Scope of Endocrinology Historical Perspectives Principles of Hormone Action Hormone Biosynthesis and Secretion Feedback Regulation Paracrine and Autocrine Regulation Hormonal Rhythms and Pulsatility Hormone Transport and Degradation Hormone Action Through Receptors Membrane Receptors Nuclear Receptors Role of the Clinical Endocrinologist Major Unsolved Problems References Chapter (2) 2 - Principles of Endocrine Measurements Principles of Endocrine Measurements Introduction and Brief History of Endocrine Assays Radioimmunoassay Nonisotopic Immunoassays Monoclonal Antibodies Structural Assays Preanalytic Methods and Harmonization of Assays Preanalytic Variables Analytical Parameters Clinical Parameters Reference Intervals General Interferences Summary Principle Modern Example Analytes Advantages Disadvantages Principle Advantages Disadvantages Special Circumstances Methods for Measurement of Free Hormones Additional Techniques Special Circumstances Plasma Renin Activity Assay and its Modifications Advantages Disadvantages Direct Renin Concentration Gas Chromatography—Mass Spectrometry Liquid Chromatography—Tandem Mass Spectrometry Special Circumstances Summary and Future Directions References Chapter (3) 3 - Endocrine Rhythms, the Sleep-­Wake Cycle, and Biological Clocks Endocrine Rhythms, the Sleep-­Wake Cycle, and Biological Clocks Introduction What Are Biological Rhythms The Sleep-­Wake Cycle as a Rhythm Clocks in the Brain and the Periphery Endocrine Rhythms Examples of Endocrine Rhythms in Humans Glucocorticoid Pulsatility Rhythms in Endocrine Disease Limitations of Single Timepoint Assessments Cell Clocks The Sleep-­Wake Cycle Sleep Regulation Sleep Stages Sleep Mistiming and Human Health Jet Lag and Social Jet Lag Summary Conclusions References Chapter (4) 4 - Prolactinomas and Disorders of Prolactin Secretion History Epidemiology Pathogenesis Pathology Nontumoral Lesions Associated With Hyperprolactinemia Pituitary Prolactin-­Secreting Carcinomas Physiologic Hyperprolactinemia Pharmacologic Hyperprolactinemia Pathologic Hyperprolactinemia Diagnosis of Prolactinomas Clinical Features Laboratory Evaluation Imaging Treatment Medical Therapy Surgical Therapy Radiotherapy Therapeutic Advances and Perspectives Prolactinomas and Pregnancy Treatment Planning and Follow-­Up References Chapter (5) 5 - Hypopituitarism Including Growth Hormone Deficiency HISTORY ETIOLOGY OF HYPOPITUITARISM Hypophysitis MORBIDITY AND MORTALITY CLINICAL FEATURES DIAGNOSIS AND ENDOCRINE EVALUATION Adrenocorticotropic Hormone Deficiency: Secondary Adrenal Insufficiency Thyroid-Stimulating Hormone Deficiency: Central Hypothyroidism Luteinizing Hormone/Follicle-Stimulating Hormone Deficiency: Hypogonadotropic Hypogonadism Growth Hormone Deficiency Hypopituitarism Following Pituitary Surgery HORMONE REPLACEMENT THERAPY Adrenocorticotropic Hormone Deficiency: Secondary Adrenal Insufficiency Thyroid-Stimulating Hormone Deficiency Central Hypothyroidism Luteinizing Hormone/Follicle-Stimulating Hormone Deficiency: Hypogonadotropic Hypogonadism Growth Hormone Deficiency Childhood-Onset Growth Hormone Deficiency in Adults Hormone–Hormone Interactions PREGNANCY REFERENCES Chapter (6) 6 - Acromegaly Excess Growth Hormone Secretion Acromegaly 6 Excess Growth Hormone–Releasing Hormone Secretion Role of the Hypothalamus in the Etiology of Acromegaly Intrinsic Pituitary Lesions Candidate Genes in the Etiology of Acromegaly Epidemiology Diagnosis Documenting Growth Hormone Hypersecretion Localizing the Source of Excess Growth Hormone Clinical Manifestations Laboratory Findings Mortality Management Treatment Goals Surgery Pituitary Irradiation Pharmacologic Management (Fig. 6.5) Integrated Treatment Approach to the Management of Acromegaly Patients With Likelihood of Good Surgical Outcome Follow-­Up Additional Management Considerations References Chapter (7) 7 - Cushing Disease Etiology of Cushing Disease Cushing Disease 7 Pathophysiology Clinical Features Clinical Aspects Biochemical Diagnosis of Cushing Syndrome General Considerations First-­Line Biochemical Investigations Second-­Line Biochemical Investigations Other Biochemical Investigations Establishing Adrenocorticotropic Hormone–Dependency of Cushing Syndrome Differential Diagnosis of Adrenocorticotropic Hormone–Dependent Cushing Syndrome Hypercortisolemic States Without Cushing Syndrome Differentiating Cushing disease From Ectopic Adrenocorticotropic Hormone Syndrome and Ectopic Corticotropin-­Releasing Hormone S... Treatment of Cushing Disease General Considerations Somatostatin Analogs Dopamine Agonists Glucocorticoid Receptor–Directed Drugs Combination of Medical Treatments Future Medical Treatments Metabolic Syndrome and Cardiovascular Risk Muscle Bone Disease Mood and Cognitive Function Autoimmunity Quality of Life Mortality in Cushing Disease Implications for Treatment and Long-­Term Care Special Conditions Cushing Disease as an Emergency Condition Cyclic Cushing Syndrome Pediatric Cushing Disease Cushing Disease and Pregnancy Cushing Disease and Chronic Renal Failure Future Directions References Chapter (8) 8 - Clinically Nonfunctioning Sellar Masses Clinically Nonfunctioning Sellar Masses Pituitary Adenomas Etiology of Pituitary Adenomas Other Benign Tumors Malignant Tumors Pituitary Hyperplasia Hypophysitis Other Sellar Masses Clinical Presentations Neurologic Presentations Incidental Finding Endocrinologic Presentations Pituitary Apoplexy Diagnosis Imaging of the Sellar Region Endocrinologic Tests Pathologic Evaluation Treatment Surgery Radiation Pharmacologic Treatment Observation References Chapter (9) 9 - Thyroid-­Stimulating Hormone–Producing Pituitary Tumors Epidemiology Thyroid-­Stimulating Hormone–Producing Pituitary Tumors 9 Etiopathogenesis and Pathology Etiopathogenesis Pathology Clinical Presentation Differential Diagnosis Investigation Step 1 – Clinical Assessment Step 2 – Exclusion of Laboratory Assay Interference Step 3 – Distinguishing a Thyroid-­Stimulating Hormone–Secreting Pituitary Adenoma From TRβ Resistance to Thyroid Hormone Step 4 – Pituitary Imaging Management Conclusions References Chapter (10) 10 - Pituitary Surgery Pituitary Adenoma Pituitary Surgery 10 Rathke’s Cleft Cyst Craniopharyngioma (see also Chapter 11) Other Lesions Preoperative Management Endocrine Status Imaging Evaluation Surgical Technique Endoscopic Endonasal Approach for Pituitary Adenoma, Rathke’s Cleft Cyst, and Craniopharyngioma Diabetes Insipidus Syndrome of Inappropriate Antidiuretic Hormone Early Remission Major Complications Permanent Hypopituitarism Cerebrospinal Fluid Leak and Meningitis Cranial Nerve Injury Postoperative Intrasellar Hematoma Internal Carotid Artery Injury Resection And Remission rates Pituitary Adenoma Rathke’s Cleft Cyst Craniopharyngioma (see also Chapter 11) Pituitary Centers Of Excellence Conclusion References Chapter (11) 11 - Craniopharyngiomas and Parasellar Masses Craniopharyngiomas and Parasellar Masses Types of Parasellar Masses Craniopharyngiomas Epidemiology Pathology Pathogenesis Imaging Features Management Long-­Term Morbidity and Mortality Rathke’s Cleft Cysts Epidemiology Pathology Pathogenesis Imaging Features Management Meningiomas Gliomas Germ Cell Tumors Langerhans Cell Histiocytosis Hamartomas Pituitary Metastasis References Chapter (12) 12 - Disorders of Sodium, Diabetes Insipidus and Hyponatremia Physiology of Sodium and Water Homeostasis Synthesis and Secretion of Vasopressin Disorders of Sodium, Diabetes Insipidus and Hyponatremia 12 Cellular Action of Vasopressin Osmoregulation of Vasopressin Release Baroregulation of Vasopressin Release Other Mechanisms Regulating Vasopressin Release Secretion of Copeptin Diabetes Insipidus Hypothalamic Diabetes Insipidus Nephrogenic Diabetes Insipidus Primary Polydipsia Investigation of Diabetes Insipidus Adipsic Diabetes Insipidus Treatment of Diabetes Insipidus Hyponatremia Morbidity and Mortality Differential Diagnosis of Hyponatremia The Syndrome of Inappropriate Antidiuresis Introduction Causes of Syndrome of Inappropriate Antidiuresis Pathophysiology of Syndrome of Inappropriate Antidiuresis Diagnosis of Syndrome of Inappropriate Antidiuresis Differential Diagnosis of Syndrome of Inappropriate Antidiuresis Treatment of Hyponatremia Factors Affecting Therapy Treatment of Chronic Hyponatremia Owing to Syndrome of Inappropriate Antidiuresis Treatment of Acute Hyponatremia Conclusions References Chapter (13) 13. Anatomy and Physiology of the Hypothalamus and Pituitary Anatomy and Physiology of the Hypothalamus and Pituitary Anatomy of the Hypothalamus Blood Supply of the Hypothalamus The Median Eminence and Tanycytes Anatomy and Histology of the Pituitary The Blood Supply of the Pituitary The Pars Intermedia The Pars Tuberalis The Pars Distalis (Anterior Pituitary) Posterior Pituitary Gland (Neurohypophysis) Conclusions and Future Directions References Chapter (14) 14 - Genetic Disorders of the Pituitary Genetic Disorders of the Pituitary Introduction Familial Isolated Pituitary Adenoma AIP-­Related Familial Isolated Pituitary Adenoma X-­Linked Acrogigantism Syndromic Pituitary Tumors Multiple Endocrine Neoplasia Type 1 Multiple Endocrine Neoplasia Type 4 Carney Complex McCune–Albright Syndrome DICER1 syndrome Lynch Syndrome Neurofibromatosis 1 and Tuberous Sclerosis Complex Somatic Mutations in Pituitary Tumors Conclusion References Chapter (15) 15. Aggressive Pituitary Tumors Aggressive Pituitary Tumors Aggressive Pituitary Tumors Definitions Pituitary Carcinomas Aggressive Pituitary Tumors Epidemiology Natural History of Pituitary Carcinomas Predictive Factors of Aggressiveness Pathological Markers of Aggressiveness Molecular Markers of Aggressiveness Treatment Temozolomide Therapeutic Perspectives Conclusion References Chapter (16) 16. Radiotherapy in Pituitary Tumors Radiotherapy in Pituitary Tumors Introduction Indications for Pituitary Radiotherapy Three-Dimensional Conformal Radiotherapy Stereotactic Radiotherapy Techniques Radiotherapy Fractionation Linear Accelerator–Based Stereotactic Radiosurgery Gamma Knife Stereotactic Radiosurgery CyberKnife Stereotactic Radiosurgery Proton Therapy Development of Radiosurgery Efficacy of Radiotherapy Overall Survival Radiological Tumor Control: Progression-Free Survival Hormone Normalization Visual Function Toxicity of Radiotherapy Hypopituitarism Visual Pathway Damage and other Cranial Nerve Injuries Radionecrosis Cerebrovascular Disease Second Brain Tumors Mortality Proton Therapy Summary Reirradiation Conclusions and Future Directions References Chapter (17) 17. Somatic Growth and Maturation: Growth Hormone and Other Growth Factors Somatic Growth and Maturation: Growth Hormone and Other Growth Factors Introduction Prenatal Considerations Chronological Age Growth Status Growth Rate Maturity Status Skeletal Maturity Status Secondary Sex Characteristics Maturity Timing Tempo of Maturation Evaluation of Children for Disorders of Growth Growth Charts Evaluation of Children With Short Stature History Physical Examination Preliminary Laboratory Evaluation Evaluation for Endocrine Disorders of Growth Growth Hormone/Insulin Growth Factor-1 Axis Growth Hormone Release and Action Diagnostic Approach Growth Hormone Stimulation Tests Limitations of Growth Hormone Stimulation Tests Growth Hormone Treatment (See Also Chapter 18) Dosing and Monitoring of Growth Hormone Therapy Evaluation of Children With Tall Stature Endocrine Causes of Tall Stature Treatment of Children/Adolescents With Tall Stature Growth Evaluation of Children With Obesity Conclusions References Chapter (18) 18 - Growth Hormone Deficiency in Children INTRODUCTION EPIDEMIOLOGY PATHOGENESIS Genetic and Structural Abnormalities Acquired Defects The Hypothalamo-Pituitary-Somatotroph Axis CLINICAL FEATURES Neonatal Presentation Infant And Childhood Years Guidance Derived From Clinical Assessment Principles of Testing Diagnosis of Growth Hormone Deficiency A Practical Approach to Diagnostic Evaluation TREATMENT Growth Hormone Transition to Adult Care CONCLUSIONS REFEERENCES Chapter (19) 19. Basic and Clinical Appetite Regulation and Energy Expenditure Introduction Components of Eating Behavior Appetite Regulation Leptin, Growth Differentiation Factor 15, and Endocannabinoids The Role of Genetics and Epigenetics Components of Energy Expenditure Resting Metabolic Rate Thermic Effect of Food Physical Activity Energy Expenditure Brown Adipose Tissue and Uncoupled Respiration Body Weight Regulation Body Weight Regulation and Eating Behavior: Beyond Homeostasis Contributions of Components of Total Daily Energy Expenditure With Prospective Weight Change Physiological Responses to Weight Loss and Weight Regain The Effects of Exercise on Energy Balance Conclusions References Chapter (20) 20. Obesity: Risk, Risk Factors, and Medical Management Obesity: Risk, Risk Factors, and Medical Management 20 Diseases Associated With Obesity Cardiovascular and Cerebrovascular Disease Type 2 Diabetes Mellitus Nonalcoholic Fatty Liver Disease Gastrointestinal Complications Cancer Reproductive Health Obstructive Sleep Apnea Osteoarthritis Cognitive Dysfunction and Alzheimer Disease Therapy for Obesity Lifestyle Intervention Pharmacotherapy Bariatric Surgery References Chapter (21) 21. Genetic Syndromes Associated With Obesity Genetic Syndromes Associated With Obesity Introduction Monogenic Obesity Syndromes Congenital Leptin and Leptin Receptor Deficiency Proopiomelanocortin and PCSK1 Deficiency MC4R Deficiency SIM1 Deficiency BDNF, TRKB, and sh2b1 Deficiency Pleiotropic Obesity Syndromes Prader–Willi Syndrome Albright’s Hereditary Osteodystrophy Bardet–Biedl Syndrome Alstrom Syndrome Cohen Syndrome Rare Variants Associated with Obesity Conclusions References Chapter (22) 22. Regulation of Intermediary Metabolism During Fasting, Feeding, and Exercise Introduction Regulation of Intermediary Metabolism During Fasting, Feeding, and Exercise 22 Postabsorptive Glucose Utilization Postabsorptive Fatty Acid Utilization Fatty Acid Reesterification as a Component of Flux Postabsorptive Glucose Production Hormonal Governance of Glucose Production Glucose Counterregulation Prandial And Postprandial Intermediary Metabolism Introduction Digestion, Absorption, and Enteroendocrine Cells Insulin and Glucagon Responses Effects on Energy Expenditure and Respiratory Quotient Hepatic Glucose Metabolism Postprandial Adipose Tissue Metabolism Hepatic Metabolism of Fatty Acids and Lipoproteins Protein And Amino Acid Metabolism Exercise Metabolism Exercise Dramatically Increases Demand For Energy Energy Metabolism During Exercise Glucose Metabolism During Exercise Fatty Acid Metabolism During Exercise Effects of Exercise Training on Intermediary Metabolism Summary And Concluding Remarks References Chapter (23) 23. Adipose Tissue Function: Metabolic and Endocrine Different Types of Obesity and Associated Health Risks Adipose Tissue Function: Metabolic and Endocrine 23 Summary Adipogenesis And Its Regulation Adipose Cell Differentiation and Role of Genetic Factors Role of Aging and Cell Senescence Summary Immunometabolism: Its Regulation And Role In Insulin Resistance, Inflammation, And Disease Linking Inflammation to Insulin Resistance Summary Lipid Metabolism In White Adipose Tissue Lipid Turnover Methodology Lipid Uptake and Lipogenesis in Fat Cells Regulation of Lipolysis Glucose Metabolism Summary Brown versus Beige/Brown Adipose Cells Aging Reduces Brown and Beige Adipose Cells Summary Summary Adipose Tissue As A Therapeutic Target Pharmacotherapy in Obesity Summary References Chapter (24) 24. Lipodystrophy Syndromes Lipodystrophy Syndromes 24 Pathophysiology of Lipodystrophy Generalized Lipodystrophies Partial Lipodystrophies Localized Lipodystrophies Fat Redistribution and Fat Metabolism Adipocytokines Inflammation Mitochondrial Stress, Oxidative Stress, and the Endoplasmic Reticulum Other Mechanisms Lifestyle Modification Management of Insulin Resistance Management of Dyslipidemia Management of Human Immunodeficiency Virus–Infected Patients With Highly Active Antiretroviral Therapy–Induced Metabolic Syndrom... Management of Cosmetic Appearance Adipokines in Lipodystrophy Future Perspectives Adiponectin References Chapter (25) 25. Lipoprotein Metabolism and the Treatment of Lipid Disorders LIPOPROTEIN METABOLISM Lipoproteins Metabolism of Lipids and Lipoproteins DISORDERS OF LIPID METABOLISM IN PATIENTS WITH DIABETES Type 1 Diabetes Type 2 Diabetes GENETIC BASIS OF LIPID DISORDERS Monogenic Low-Density Lipoprotein Disorders Monogenic High-Density Lipoprotein Disorders Polygenic Lipid Disorders DIAGNOSIS OF LIPID DISORDERS MANAGEMENT/TREATMENT Dietary and Drug Treatment of Lipid Disorders REFERENCES Chapter (26) 26. Metabolic Syndrome DIAGNOSIS AND PREVALENCE HISTORY Obesity, Type 2 Diabetes, Insulin Resistance, and Cardiovascular Disease The Lipid Theory Inflammation and Oxidative and Endoplasmic Reticulum Stress Specific Tissues AMPK and SIRT1 AMPK and Metabolic Syndrome in Humans DIAGNOSIS CORONARY HEART DISEASE AND TYPE 2 DIABETES Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Polycystic Ovarian Syndrome Certain Cancers Alzheimer Disease Cushing Syndrome and Related Disorders Lipodystrophy Hyperalimentation TREATMENT OF METABOLIC SYNDROME Lifestyle Modification (Weight Loss and Physical Activity) Drug Therapy Special Considerations CHILDREN AND ADOLESCENTS ACKNOWLEDGMENTS REFERENCES Chapter (27) 27. Bariatric Procedures and Operations Bariatric Procedures and Operations Introduction/Overview Commonly Performed Bariatric Operations The Physiology Of Weight Loss After Bariatric Operations And Procedures Physiologic Effects Of Bariatric Surgery On Cardiometabolic Health And Mortality Late and Chronic Complications Weight Regain Dumping Syndrome Summary Chapter (28) 28. Development of the Endocrine Pancreas Pancreas Morphogenesis Early Organ Specification And Bud Formation Tissue Interaction and Signaling Pathways Induction of the Pancreatic Gene Expression Program Cell Type Differentiation Signaling Pathways Transcription Factors Islet Formation References Chapter (29) 29. Regulation of Islet Hormone Synthesis and Secretion Hormonal Synthesis Insulin Regulation of Islet Hormone Synthesis and Secretion 29 Glucagon Hormonal Secretion and Action Insulin Glucagon Glucagon-Like Peptide-1 Secretion and Signaling References Chapter (30) 30. Mechanisms of Insulin Action 30 Introduction Insulin Introduction Regulation of the Insulin Receptor Tyrosine Kinase The Insulin Receptor–Related Receptor The Insulin Signaling Cascade Introduction Insulin Receptor Tyrosine Protein Scaffolds The IRS→PI3K→AKT Cascade Insulin-Regulated Proteostasis Insulin-Regulated Glucose Transport Heterologous Regulation of Insulin Signaling Cascades Proximal Insulin Signals Transcriptional Control of Insulin Receptor Substrate 1 Transcriptional Control of Insulin Receptor Substrate 2 Regulation of Insulin Receptor Substrate Degradation Regulation by Protein and Lipid Phosphatases miRNA-Mediated Posttranscriptional Regulation Mouse Genetics Reveal Tissue-Integrated Insulin Signaling Introduction Systemic Insulin Receptor Signaling Cascade Hepatic InsR─┤FoxO1 Signaling Adipose Insulin Signaling Insulin/IGF Signaling in Neurodegenerative Disease Insulin Resistance and Metabolic Disease Introduction Chronic Hyperinsulinemia Nutrient Excess Proinflammatory Cytokines References Chapter (31) 31. Classification and Diagnosis of Diabetes Mellitus Classification and Diagnosis of Diabetes Mellitus Definition Classification Type 1 Diabetes Type 2 Diabetes Other Specific Types of Diabetes Genetic Defects in β Cell Function Genetic Defects in Insulin Action Diseases of the Exocrine Pancreas Endocrinopathies Drug- or Chemical-Induced Diabetes Infections Uncommon Forms of Immune-Mediated Diabetes Other Genetic Syndromes Sometimes Associated With Diabetes Gestational Diabetes Diagnosis Diagnostic Criteria What Level of Fasting Plasma Glucose Constitutes Diabetes What’s New References Chapter (32) 32. Autoimmune (Type 1) Diabetes Mellitus: Etiology, Pathogenesis, Prediction, and Prevention Epidemiology Prevalence Autoimmune (Type 1) Diabetes Mellitus: Etiology, Pathogenesis, Prediction, and Prevention 32 Incidence Geographical Distribution Variation with Age Variation With Gender Seasonal Variation Inheritance Natural History and Disease Staging Etiology Genetic Etiology Environmental Etiology Pathogenesis Humoral Immunopathophysiology Cellular Immunopathophysiology Diagnostic Criteria Prediction Prevention Primary Prevention Secondary Prevention Intervention Summary and Future Directions References Chapter (33) 33. Type 2 Diabetes Mellitus: Etiology, Pathogenesis, and Natural History Epidemiology Type 2 Diabetes Mellitus: Etiology, Pathogenesis, and Natural History 33 Origins of the Disease: Etiologic Factors Region, Race, Ethnicity, and Genetic Factors Environment and the Social Determinants of Health Behavior and Culture Biological Factors Natural History of Diabetes as an Evolving Glucoregulatory Defect Diagnosis of Type 2 Diabetes Overview of the Evolving Glucoregulatory Defect Progression of Abnormal Glucose Tolerance Mechanisms Causing Pancreatic β Cell Dysfunction The Pathophysiology of Insulin Resistance Measurement of Insulin Sensitivity in Humans: Defect in Muscle Glucose Uptake Hepatic Insulin Resistance The Molecular Basis of Human Insulin Resistance in Target Tissues General Principles Insulin Resistance at the Level of the Insulin Receptor Insulin Resistance at the Level of Signal Transduction Cell Stress Responses and Insulin Action Nutrient Sensors and Nutrient Stress Syndromes of Severe Insulin Resistance Heterogeneity of Type 2 Diabetes Severe Insulin Resistance The Spectrum of Cardiometabolic Disease Role of Obesity References Chapter (34) 34. Diabetes Mellitus and Pregnancy Metabolic Effects of Pregnancy Diabetes Mellitus and Pregnancy 34 Classification of Diabetes in Pregnancy Diagnostic Criteria for Gestational Diabetes Mellitus Glucokinase Monogenic Diabetes and Pregnancy Bariatric Surgery and Gestational Diabetes Diabetes and Pregnancy and the Offspring Congenital Malformations and Early Fetal Loss Disturbances of Metabolism and Fetal Growth Maternal Obesity and the Offspring Management of Diabetes in Pregnancy Contraception and Preconception Management Management of Type 1 Diabetes Mellitus in Pregnancy Glycemia Monitoring Diet and Physical Activity Insulin Management Management of Diabetes Complications in Pregnancy Management of Gestational Diabetes Mellitus Prevention of Gestational Diabetes Obstetric Management of Diabetes in Pregnancy Obstetric Surveillance Antenatal Steroids for Preterm delivery Hypertensive Disorders of Pregnancy Decrease in Insulin Requirements Peripartum Management and Birth Long-Term Outcomes and Management of Gestational Diabetes Long-Term Risks of Gestational Diabetes to the Mother Benefits of Breastfeeding for the Mother Postpartum Follow-up of Mothers Postpartum Follow-Up of Offspring Risk of Obesity to the Offspring Potential Mechanisms for Long-term Effects of Preexisting Maternal Diabetes and Gestational Diabetes on the Offspring Summary and Future Directions References Chapter (35) 35. Hyperglycemia Secondary to Non-Traditional Diabetic Conditions Hyperglycemia Secondary to Non-Traditional Diabetic Conditions Pancreatectomy Acute Pancreatitis Chronic Pancreatitis Pancreatic Cancer Autoimmune Pancreatitis Hemochromatosis Hemosiderosis Cystic Fibrosis Acromegaly Growth Hormone Treatment Cushing Syndrome Glucagonoma Syndrome Somatostatinoma Pheochromocytoma Hyperglycemia in Critical Care Patients Drugs That can Cause Hyperglycemia Drugs That Directly Adversely Affect β Cell Function Drugs That Inhibit Increases in β Cell Cytosolic Calcium Drugs That Cause Potassium Depletion Antiimmune and Cancer-Treatment Drugs Drugs That Cause Insulin Resistance Oral Contraceptives and Sex Hormones Nicotinic Acid Lipid-Lowering Agents and New-Onset Diabetes Mellitus Statins Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Cholesterol Ester Transfer Protein Inhibitors Acquired Immunodeficiency Syndrome and Antiretroviral Drugs Atypical Antipsychotic Agents Conclusion References Chapter (36) 36. β Cell Glucose Toxicity and Oxidative Stress 36 Introduction Brief Overview of the Contributions of Oxidative Stress to Secondary Complications of Diabetes References Chapter (37) 37. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State Epidemiology Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State 37 Pathogenesis of Diabetic Ketoacidosis Precipitating Factors Diagnosis of Diabetic Ketoacidosis Treatment Complications of Therapy Prevention Hyperglycemic Hyperosmolar State Epidemiology Pathophysiology Precipitating Events Diagnosis Treatment Complications Prevention References Chapter (38) 38. Hypoglycemia and Hypoglycemic Syndromes Accurate Measurement of Blood or Plasma Glucose Physiology of Hypoglycemia Brain Fuel Metabolism Hypoglycemia and Hypoglycemic Syndromes 38 General Approach to the Patient Acute Treatment of Hypoglycemia Evaluation of the Hypoglycemic Patient Hypoglycemia in Diabetes Mortality and Cardiovascular Disease Strategies to Reduce Hypoglycemia Hypoglycemia in the Absence Of Diabetes Hypoglycemia in Medicated or Ill Individuals Hypoglycemia in Apparently Well Individuals Endogenous Hyperinsulinism Neonatal Hypoglycemia Conclusion and Future Directions References Chapter (39) 39. Treatment of Type 1 Diabetes Mellitus in Adults 39 Goals Of Management Glycemic Goals Acute Complications Chronic Complications Quality Of Life Team Approach To Management Monitoring Glycemic Control Ketone Testing Complication Surveillance Insulin Therapy Principles of Insulin Replacement Insulin Preparations Intensive Insulin Therapy Regimens Adjustment of Insulin Therapy in Special Situations Nutrition Other Therapies For Type 1 Diabetes Metformin, DPP-IV Inhibitors, and GLP-1 RAs Future Perspectives References Chapter (40) 40. Clinical Management of Type 2 Diabetes Mellitus Diabetes Education Clinical Management of Type 2 Diabetes Mellitus 40 Individualization of the Diabetes Education Care Plan Nutrition Nutrition Therapy––the Evidence Individualization of the Nutrition Prescription Summary Physical Activity Pharmacotherapy Of Type 2 Diabetes Metformin Thiazolidinediones Insulin Secretagogues Incretin-Based Therapies Glucagon-Like Peptide-1 Receptor Agonists Dipeptidyl Peptidase Inhibitors α-Glucosidase Inhibitors Insulin Therapy In Type 2 Diabetes Short-Acting Insulin Analogs Long-Acting Insulin Analogs (Table 40.5) Initial Therapy (Fig. 40.1) Initial Combination Therapy Diabetes Technology Self-Monitoring of Blood Glucose Digital Health Technology Telemedicine Population Management Conclusion References Chapter (41) 41. Pancreas and Islet Transplantation Pancreas and Islet Transplantation Introduction Historical Perspective Pancreas Transplantation Patient Selection for Pancreas Transplantation Surgical Approaches to Pancreas Transplantation Patient and Graft Survival After Pancreas Transplant Metabolic Outcomes Allogeneic Islet (Alloislet) Transplantation Patient Selection for Alloislet Transplantation Surgical Approaches to Alloislet Transplantation Patient and Graft Survival After Alloislet Transplant Metabolic Outcomes Immunosuppressive Drugs Autologous Islet (Autoislet) Transplantation Patient Selection for Autoislet Transplantation Surgical Approaches to Autoislet Transplantation Patient and Graft Survival After Autoislet Transplant Metabolic Outcomes Effect of Successful Pancreas or Islet Transplantation on Complications of Diabetes Future Directions and Conclusions References Chapter (42) 42. Diabetes and Long-Term Complications Diabetes and Long-Term Complications History Classification Rheumatic, Dermatologic, and Infectious Manifestations Epidemiology Pathophysiology Can We Prevent Macrovascular Disease Effects of Specific Hypoglycemic Agents on Cardiovascular Disease and Renal Outcomes in Patients With Type 2 Diabetes Conclusion References Chapter (43) 43. Diabetic Eye Disease Diabetic Eye Disease 43 Natural History of Diabetic Retinopathy Proliferative Diabetic Retinopathy Diabetic Macular Edema, Ischemia, and Traction Nonproliferative Diabetic Retinopathy Levels Proliferative Diabetic Retinopathy Levels Epidemiology Prevalence and Incidence of Retinopathy Risk Factors for Diabetic Retinopathy Diabetes-Related Risk Factors Other Risk Factors Other Ocular Diseases Associated With Diabetes Glaucoma Visual Impairment Detection Telemedicine Programs for Diabetic Retinopathy Management Ophthalmic Surgical Rehabilitation Protective and Risk Factors for Diabetic Retinopathy Novel Therapies References Chapter (44) 44. Diabetic Neuropathy Diabetic Neuropathy Definition of Diabetic Neuropathies Classification of Diabetic Neuropathies Pathogenesis Distal Symmetrical Polyneuropathy Epidemiology Screening and Diagnosis in Clinical Care Secondary Distal Symmetric Polyneuropathy Complications: Diabetic Foot Ulcers/Charcot Neuroarthropathy Distal Symmetric Polyneuropathy Treatment Diabetic Autonomic Neuropathies Cardiovascular Autonomic Neuropathy Cardiovascular Autonomic Neuropathy Evaluation in Clinical Research Treatment Gastrointestinal Autonomic Neuropathy Urogenital Autonomic Neuropathy Sudomotor Dysfunction Atypical Neuropathies Mononeuropathies Diabetic Radiculoplexus Neuropathy Conclusions References Chapter (45) 45. Diabetic Kidney Disease Diabetic Kidney Disease Epidemiology Risk Factors Diagnosis and Classification Biomarkers Natural History Structural Changes of the Kidney Pathophysiology Increased Glucose Uptake in the Diabetic Kidney Hemodynamic Abnormalities Mechanotransduction Inflammation and Fibrosis Epigenetic Changes Treatment Glycemic Control Glucose-Lowering Agents Blood Pressure Control Cardiovascular Risk Reduction Nutrition Management Additional Interventions and Management Approaches Summary and Future Directions References Chapter (46) 46. Diabetic Foot and Vascular Complications Pathophysiology Diabetic Foot and Vascular Complications 46 Neuropathy Infection Ischemia Bone and Joint Abnormalities Presentation and Diagnosis Diabetic Foot Ulcers Infection/Osteomyelitis Peripheral Arterial Disease Medical Management Prevention and Screening Antibiotics Wound Care Offloading Surgical Management Drainage Procedures Lower Extremity Arterial Reconstruction Endovascular Procedures Amputations Multidisciplinary Approach Future Trends References Chapter (47) 47. Parathyroid Hormone and the Parathyroid Hormone Receptor Type 1 in the Regulation of Calcium and Phosphate Homeostasis and Bone Metabolism Parathyroid Hormone Parathyroid Hormone Chemistry Evolution of Parathyroid Hormone Ligands The Parathyroid Hormone Gene and its mRNA Regulation of Parathyroid Hormone Gene Expression Regulation of Parathyroid Hormone Secretion Mechanism of Extracellular Calcium Ion Sensing by Parathyroid Cells and Other Cells Involved in Mineral Ion Homeostasis Metabolism of Parathyroid Hormone Actions of Parathyroid Hormone on the Kidney Renal Calcium Reabsorption Regulation of 1α- and 24-Hydroxylase Activity Renal Phosphate Transport Actions of Parathyroid Hormone on Bone Molecular Properties Of The Parathyroid Hormone Receptor Type-1 Gene Structure, Protein Topology, and Evolution Disease Mutations in the PTHR-1 and its Ligands Summary References Chapter (48) 48. Parathyroid Hormone-Related Protein Parathyroid Hormone-Related Protein The Skeleton The Mammary Gland The Skin Placenta Endocrine Pancreas Smooth Muscle and the Cardiovascular System Teeth The Nervous System The Immune System Cancer Skeletal Disease Skin Disease Diabetes Conclusion References Chapter (49) 49. Calcitonin 49 Calcitonin Chemistry Calcitonin Gene Calcitonin Gene Alternative Product Calcitonin Receptors Receptor Gene Receptor Isoforms Receptor Polymorphisms Receptor Distribution Calcitonin–Calcitonin Receptor Signaling Receptor Regulation Calcitonin Physiology Calcitonin in Growth and Development Calcitonin in Calcium Stress: Pregnancy and Lactation Renal Actions of Calcitonin Calcitonin in the Central Nervous System Peptides Related to Calcitonin Calcitonin and its Receptors in Cancer Medullary Carcinoma of the Thyroid Calcitonin Receptors in Other Cancers Calcitonin As a Therapeutic Hypercalcemia Osteoporosis and Paget Disease of Bone Osteoarthritis Conclusion References Chapter (50) 50. Vitamin D: From Photosynthesis, Metabolism, and Action to Clinical Applications Vitamin D: From Photosynthesis, Metabolism, and Action to Clinical Applications Historic Overview Metabolism of Vitamin D 25-Hydroxylation 1α-Hydroxylation 24-Hydroxylation: Catabolism or Specific Function Vitamin D Transport Action and Mode of Action General Characteristics of the Vitamin D Receptor Classic Target Tissues Clinical Consequences of Vitamin D Status Skeletal Effects of the Vitamin D Endocrine System Extraskeletal Actions of the Vitamin D Endocrine System Clinical Use of Vitamin D Optimal Serum 25OHD Concentration Worldwide Vitamin D Status Vitamin D Requirements Summary References Chapter (51) 51. Bone Development and Remodeling Intramembranous Ossification Bone Development and Remodeling 51 Endochondral Ossification Principles of Bone Remodeling and Skeletal Homeostasis The Bone Remodeling Cycle Cellular and Molecular Control of Skeletal Development and Bone Remodeling Chondrogenesis and Growth Plate Biology Skeletal Vascularization Skeletal Stem and Progenitor Cells Osteoblastogenesis Osteoclastogenesis and Skeletal Tissue Resorption Regulation of Bone Remodeling and Bone Mass Coupling of Bone Resorption and Bone Formation During Remodeling Conclusion References Chapter (52) 52. Regulation of Calcium Homeostasis and Genetic Disorders That Affect Calcium Metabolism Distribution and Metabolic Actions of Calcium Regulation of Calcium Homeostasis and Genetic Disorders That Affect Calcium Metabolism 52 Calcium Absorption Mechanisms and Sites of Calcium Absorption Renal Calcium Excretion Sites and Mechanisms of Renal Calcium Reabsorption Regulation of Renal Calcium Reabsorption PTH Gene Structure and Function Hypercalcemic Diseases Parathyroid Tumors Syndromic Forms of Primary Hyperparathyroidism Nonsyndromic Forms of Primary Hyperparathyroidism Other Hereditary Hypercalcemic Disorders Hypocalcemic Disorders Hypoparathyroidism PTH Gene Abnormalities GCM2 Abnormalities X-Linked Recessive Hypoparathyroidism Pluriglandular Autoimmune Hypoparathyroidism DiGeorge Syndrome Charge Syndrome Calcium-Sensing Receptor Abnormalities Blomstrand Disease Conclusion References Chapter (53) 53. Genetic Disorders of Phosphate Homeostasis Regulation of Phosphate Absorption Phosphate Excretion Genetic Disorders of Phosphate Homeostasis 53 Regulation of Phosphate Reabsorption Fibroblast Growth Factor-23 Fibroblast Growth Factor-23 Activity Regulation of Fibroblast Growth Factor-23 Production Disorders Associated with Increased FGF23 Bioactivity Disorders Associated With Reduced Fibroblast Growth Factor-23 Bioactivity Possible Future Therapeutic Avenues References Chapter (54) 54. Primary Hyperparathyroidism Primary Hyperparathyroidism Introduction Epidemiology, Diagnosis, and Overview of Clinical Features Incidence Diagnosis and Differential Diagnosis Other Biochemical Features Clinical Presentation The Skeleton Bone Turnover Markers Bone Densitometry Bone Histomorphometry New Imaging Technologies Fractures Nephrolithiasis and Renal Function Other Organ Involvement Cardiovascular System Neurological, Psychologic and Cognitive Features Gastrointestinal Manifestations Other Systemic Involvement Unusual Presentations Neonatal Primary Hyperparathyroidism Primary Hyperparathyroidism in Pregnancy Acute Primary Hyperparathyroidism Parathyroid Cancer Evaluation Natural History Natural History With Surgery Natural History Without Surgery Guidelines for Parathyroidectomy Surgery Surgical Approach Immediate Postoperative Course Medical Management General Measures Diet and Supplements Pharmaceuticals Hydrochlorothiazide Treatment of Parathyroid Cancer Summary References Chapter (55) 55. Malignancy-Associated Hypercalcemia Malignancy-Associated Hypercalcemia Introduction and History Normal Physiology of Calcium Metabolism Parathyroid Hormone and the Calcium-Sensing Receptor Vitamin D Parathyroid Hormone–Related Protein Malignancy-Associated Hypercalcemia Humoral Hypercalcemia of Malignancy Local Osteolytic Hypercalcemia Overproduction of 1,25-Dihydroxyvitamin D Ectopic Production of Parathyroid Hormone Treatment Hydration Inhibition of Bone Resorption Glucocorticoids Dialysis Other treatments References Chapter (56) 56. Surgical Management of Hyperparathyroidism Clinical Presentation Indications for Surgery Surgical Management of Hyperparathyroidism 56 Preoperative Preparation Operative Approaches Intraoperative Adjuncts Postoperative Management Outcomes of Parathyroid Surgery Reoperative Parathyroid Surgery Hypercalcemic Crisis Inherited Syndromes Parathyroid Carcinoma Pediatric Parathyroid Surgery Hyperparathyroidism in Pregnancy Secondary Hyperparathyroidism Tertiary Hyperparathyroidism COVID-19 and Parathyroid Surgery Summary References Chapter (57) 57. Pseudohypoparathyroidism, Albright’s Hereditary Osteodystrophy, and Progressive Osseous Heteroplasia: Disorders Caused by GNAS Mutations that Reduce Gsα Activity Pseudohypoparathyroidism, Albright’s Hereditary Osteodystrophy, and Progressive Osseous Heteroplasia: Disorders Caused by GNAS M... Pseudohypoparathyroidism Type-Ia The Complex Gnas Locus The Alpha Subunit of the Stimulatory G Protein (Gsα) Pseudopseudohypoparathyroidism Progressive Osseous Heteroplasia Disorders of Concurrent Gsα Inactivity and Hyperactivity Pseudohypoparathyroidism Type-Ib Autosomal Dominant PHP1B Sporadic Pseudohypoparathyroidism Type-1B Pseudohypoparathyroidism Type-II Acrodysostosis With Hormonal Resistance Treatment Summary References Chapter (58) 58. Genetic Defects in Vitamin D Metabolism and Action Genetic Defects in Vitamin D Metabolism and Action Overview of Vitamin D Metabolism Rickets and Osteomalacia Vitamin D–Deficiency Rickets, Vitamin D Hydroxylation–Deficient Rickets, and Vitamin D–Dependent Rickets CYP2R1 Mutations CYP27B1 Mutations Vitamin D Receptor Mutations Treatment OF Vitamin D-Dependent Rickets, Type 2A Idiopathic Infantile Hypercalcemia CYP24A1 Mutations Future Directions References Chapter (59) 59. Hereditary Disorders of the Skeleton Hereditary Disorders of the Skeleton Dense Bone Disorders Osteopetroses Pycnodysostosis Kenny–Caffey Syndrome Infantile Cortical Hyperostosis (Caffey Disease) Endosteal Hyperostoses Osteopoikilosis Osteopathia Striata Pachydermoperiostosis Paget Disease of Bone Familial Expansile Osteolysis Osteoprotegerin Deficiency References Chapter (60) 60. Osteoporosis Osteoporosis What Is Osteoporosis Origins of Skeletal Fragility Bone Density Bone Quality Falls and Frailty Nutrition Genetics Epidemiology Bone Mineral Density Fractures Assessing Patients at Risk of Fracture Fracture Risk Assessment Bone Turnover Markers Skeletal Imaging Other Investigations Lifestyle Antiresorptive Medications Anabolic Medications Treatment Decisions Whom to Treat Selection of Treatment How Long to Treat Follow-Up Management of Subtypes of Osteoporosis References Chapter (61) 61. CKD-MBD Syndrome: Chronic Kidney Disease Produced Disorders in Skeletal, Vascular, and Cardiac Tissues and Mineral Metabolism Vascular CKD-MBD Syndrome: Chronic Kidney Disease Produced Disorders in Skeletal, Vascular, and Cardiac Tissues and Mineral Metabolism 61 Cardiac Skeletal Plasma Pathogenesis Pathogenic Factors in the Chronic Kidney Disease–Mineral and Bone Disorder FGF23 Klotho Sclerostin Hyperphosphatemia Calcitriol Deficiency Hypocalcemia Hyperparathyroidism Hypogonadism Other Factors Pathology of Renal Osteodystrophy Low-Turnover Bone Disease, Adynamic Bone Disorder Associated Features Osteoporosis and Osteosclerosis Management of Osteoporosis in Chronic Kidney Disease Clinical Manifestations Bone Pain, Fractures, and Skeletal Deformities Conclusion References Chapter (62) 62. Disorders of Mineralization Disorders of Mineralization 62 Radiologic Features Nutritional Osteomalacia and Rickets Gastrointestinal Diseases Disorders of Vitamin D Metabolism Hypophosphatemia FGF23-Mediated Hypophosphatemia Non–FGF23-mediated Hypophosphatemia Miscellaneous Causes of Impaired Mineralization Acidosis Fanconi Syndrome Chronic Kidney Disease Aluminum, Fluoride, and Heavy Metal Intoxication Hypophosphatasia Osteopetrosis Fibrogenesis Imperfecta Ossium Treatment Conclusion References Chapter (63) 63. Paget Disease of Bone Paget Disease of Bone 63 Pathophysiology Clinical Features Regional Manifestations Biochemical Features Indices of Bone Resorption Indices of Bone Formation Calciotropic Hormones Systemic Complications and Associated Diseases Primary Hyperparathyroidism, Nephrolithiasis, Hypercalciuria, Hypercalcemia Hyperuricemia and Gout Cardiovascular Abnormalities Drug Treatment Indications for Treatment Pretreatment Laboratory Evaluation Calcitonin Bisphosphonates Surgery Causes Animal Models of Paget Disease References Vol II Chapter (64) 64. Anatomy and Development of the Thyroid The Anatomy Of The Thyroid Gland Gross Anatomy Blood Supply Lymphatics Innervation Anatomic Variants Other Thyroid Cells C Cells Ultimobranchial Body-Derived Epithelial Cells Thyroid Stem Cells The Development Of The Thyroid Gland Differentiation of C Cells Functional Genomics of Thyroid-Enriched Transcription Factors From Animal Models to Human Diseases Generation of Functional Thyroid Follicles In Vitro Phylogenesis Of The Thyroid Gland References Chapter (65) 65. Thyroid-Stimulating Hormone and TSH Receptor Thyroid-Stimulating Hormone and TSH Receptor 65 Regulation of Thyroid-Stimulating Hormone Secretion Hypothalamic Regulation of Thyroid-Stimulating Hormone Secretion Thyrostimulin Thyroid-Stimulating Hormone Receptor Protein Structure Thyroidal Actions of Thyroid-Stimulating Hormone Regulation of Thyroid-Specific Gene Expression Thyroid-Stimulating Hormone Receptor/Insulin-Like Growth Factor 1 Receptor Crosstalk Regulation of Thyroid Hormone Synthesis Regulation of Thyroid Hormone Secretion References Chapter (66) 66. Thyroid Hormone Transporters and Metabolism Thyroid Hormone Transporters and Metabolism Disorders Of Thyroid Hormone Transport MCT8 Deficiency Disorders Of Thyroid Hormone Metabolism Iodothyronine Deiodinase I Deficiency SBP2 Deficiency Sec-tRNA[Ser]Sec References Chapter (67) 67. Thyroid Hormone Action Thyroid Hormone Action Components Of Thyroid Hormone Action Thyroid Hormone Receptor Coregulatory Proteins Thyroid Hormone Receptor Posttranslational Modifications Nongenomic Thyroid Hormone Action Thyroid Hormone Tissue-Specific Actions Thyroid Hormone Receptor Isoform–Specific Expression Growth Stem Cell Proliferation Thyroid Hormone and Somatic Growth Brain Heart and Blood Vessels Skeletal Muscle Skeletal System Small Intestine Metabolic Regulation and Actions in Liver White and Brown Adipose Tissue Skin Resistance to Thyroid Hormone Beta Resistance to Thyroid Hormone Alpha References Chapter (68) 68. Thyroid Function Testing (Thyrotropin, Triiodothyronine, and Thyroxine) Thyroid Function Testing (Thyrotropin, Triiodothyronine, and Thyroxine) Introduction THYROTROPIN Immunoassay for Thyrotropin Thyrotropin Reference Intervals Standardization of Thyrotropin Immunoassays Free Thyroid Hormones Indirect Estimation of Free Thyroid Hormones Free Thyroid Hormones by Equilibrium Dialysis Immunoassay of Free Thyroid Hormones Free Thyroid Hormone Reference Intervals Standardization of Free Thyroid Hormones Total Thyroxine And Triiodothyronine Future Directions References Chapter (69) 69. Thyroid Imaging Indications for Sonographic Assessment Physics of Ultrasonography Thyroid Imaging 69 Diffuse Thyroid Disorders Primary Thyroid Lymphoma Subacute Thyroiditis Sonographic Risk Stratification Systems Korean Thyroid Imaging Reporting and Data System Specialized Sonographic Techniques Scintigraphy Thyroid Nodules Diffuse Thyroid Disorders Congenital Hypothyroidism Perchlorate Discharge Test Incidentalomas Future Directions References Chapter (70) 70. Pathology of the Thyroid Gland Pathology of the Thyroid Gland Thyroid Gland Pathologic Assessment Of Thyroid Lesions Pathology of Thyroid Lesions Diffuse Enlargements of Thyroid Gland Nodular Enlargements and Nodules Benign Neoplasms Malignant Neoplasms Papillary Thyroid Carcinoma Variants of Papillary Cancer Follicular Carcinoma Hürthle Cell (Oncocytic Follicular) Tumors High-Grade Thyroid Carcinoma Poorly Differentiated Carcinoma Anaplastic Carcinoma Familial Follicular-Derived Thyroid Tumors Medullary Carcinoma Rare Tumors of Thyroid Gland Malignant Tumors Arising in Ectopic Thyroid Tissue Secondary Tumors Summary and Future Directions References Chapter (71) Chapter (72) 72. Graves’ Orbitopathy Graves’ Orbitopathy Epidemiology Risk Factors Age Gender Ethnicity Smoking High Thyroid Stimulating Hormone Receptor Antibody Titer Radioactive Iodine Therapy Cholesterol Level and Statin Use Pathogenesis Key Pathological Changes in Graves’ Orbitopathy Thyroid Stimulating Hormone Receptor as the Putative Autoantigen Immune Dysregulation Signaling Pathways Mediating Hyaluronan Production and Adipogenesis (Fig. 72.2) Orbital Infiltration of CD34+ Fibrocytes Thyroid Stimulating Hormone Receptor and Insulin-Like Growth Factor-1 Receptor Crosstalk (Fig. 72.3) Genetic Susceptibility Clinical Manifestations And Diagnosis Clinical Evaluation Thyroid Function Test Thyroid Stimulating Hormone Receptor Antibody Orbital Imaging Quality of Life Assessment Management General Measures Mild Graves’ Orbitopathy Active Moderate-to-Severe Graves’ Orbitopathy Sight-Threatening Graves’ Orbitopathy Inactive Graves’ Orbitopathy and the Role of Rehabilitative Surgery Novel Treatment Approaches for Immunosuppression in Graves’ Orbitopathy Summary And Perspectives References Chapter (73) 73. Thyroiditis Thyroiditis Subtypes of Thyroiditis Hashimoto’s Thyroiditis Definition and Incidence Etiopathogenesis and Physiopathologic Mechanisms in Autoimmune Thyroid Disease Natural History and Clinical Features Relationship With Other Autoimmune Diseases Diagnosis Treatment and Follow-Up Hashimoto’s Encephalopathy Acute/Infectious Thyroiditis Definition and Incidence Clinical and Diagnostic Features Treatment and Follow-Up Subacute Thyroiditis Definition and Incidence Pathology Treatment and Follow-Up Silent Thyroiditis Definition and Incidence Clinical Features Diagnosis: Clinical, Laboratory, and Imaging Findings Treatment Riedel’s Thyroiditis Definition and Incidence Etiology Clinical Features Diagnosis: Laboratory and Imaging Findings Pathology Treatment IgG4 Thyroiditis Definition, Incidence, and Relationships in the Setting of Other Subtypes of Thyroiditis Clinical Aspects Diagnosis Treatment and Follow-Up Summary and Future Directions References Chapter (74) 74. Hypothyroidism Hypothyroidism Brief History Hypothalamic-Pituitary-Thyroid Axis Epidemiology Clinical Manifestations Symptoms Signs Etiology Primary Hypothyroidism Central Hypothyroidism Peripheral Causes of Hypothyroidism Diagnosis Reference Intervals Serum Thyroid-Stimulating Hormone Log-Linear Relationship Free Thyroxine Levels Triiodothyronine Levels Thyroid Antibody Testing Detection of Central Hypothyroidism Subclinical Versus Overt Hypothyroidism Screening Treatment Levothyroxine Therapy Therapy Other Than Levothyroxine Summary and Areas of Future Research References Chapter (75) 75. Thyroid and Pregnancy Epidemiology Physiology Thyroid and Pregnancy 75 Physiology During Assisted Reproduction Technology Clinical Outcomes and Management Maternal and Fetal Physiology in Pregnancy Thyroid Function Tests in Pregnancy Hyperthyroidism in Pregnancy Diagnosis Treatment and Monitoring Lactation Hypothyroidism and Hypothyroxinemia In Pregnancy Overt Hypothyroidism Subclinical Hypothyroidism Isolated Hypothyroxinemia Thyroid Autoimmunity in Pregnancy Associated Obstetric and Fetal Outcomes Potential Mechanisms for Associations Implications for Therapy and Monitoring Screening for Thyroid Dysfunction in Pregnancy Thyroid Nodules and Cancer During Pregnancy Thyroid Disorders in the Postpartum Period Postpartum Thyroiditis Considerations in Lactating Women Summary and Future Directions References Chapter (76) 76. Iodine Nutrition and the Thyroid Iodine Nutrition and the Thyroid Dietary Sources Of Iodine Absorption and Bioavailability of Iodine Thyroidal Iodine Uptake Goitrogens Metabolism Thyroidal Adaptation to Iodine Deficiency Iodine Requirements Methods To Assess Iodine Status Urinary Iodine Concentration Thyroid Size Thyroid-Stimulating Hormone Thyroglobulin Effects of Iodine Deficiency on the Thyroid and Brain Goiter Pregnancy and Infancy Childhood Adulthood Epidemiology of Iodine Deficiency Treatment And Prevention Of Iodine Deficiency Salt Fortification with Iodine Iodine Supplementation Iodine Excess References Chapter (77) 77. Euthyroid and Hyperthyroid Nodules and Goiter Definition and Clinical Manifestation Environment and Heredity Euthyroid and Hyperthyroid Nodules and Goiter 77 Hot Thyroid Nodules Cold Thyroid Nodules Euthyroid Nodules Iodine-Induced Hyperthyroidism Epidemiology, Occurrence, and Natural History of Euthyroid and Hot Thyroid Nodules Thyroid Nodule Diagnostic Pathway to Distinguish Benign and Malignant Thyroid Nodules Clinical Examination Laboratory Investigations Diagnosis of Thyroid Autonomy Malignancy Risk Stratification using Thyroid Ultrasound Fine Needle Aspiration Cytology Treatment of Autonomous Thyroid Nodules Surgery Radioiodine Therapy Follow-Up Treatment of Euthyroid Nodules (see Table 77.3) Iodine Supplementation Thyroid Hormone Treatment Surgery Radioiodine Therapy Nonsurgical Thermal Ablation of Thyroid Nodules References Chapter (78) 78. Differentiated Thyroid Cancer – Streamlining Diagnosis and Optimizing Management Differentiated Thyroid Cancer – Streamlining Diagnosis and Optimizing Management Epidemiology Pathology Papillary Thyroid Carcinoma Variants Follicular Thyroid Carcinoma Hurthle Cell (Oncocytic) Tumors Poorly Differentiated Thyroid Carcinoma Causes Somatic Gene Alterations Germline Genetic Factors Ionizing Radiation Diagnosis, Clinical Features, And Course Response to Therapy Prognostic Factors Age and Gender Histopathological Factors Size of the Primary Tumor and Extrathyroidal Extension Extrathyroidal Extension Lymph Node Metastases Therapy And Monitoring Radioiodine Therapy Levothyroxine Therapy Monitoring for Disease Recurrence Treatment of Metastatic Disease References Chapter (79) 79. Medullary Thyroid Cancer Clinical Presentation And Diagnosis Sporadic Medullary Thyroid Cancer Medullary Thyroid Cancer 79 Hereditary Forms (Multiple Endocrine Neoplasia Type II) Gene Carriers Pathology And Pathogenesis Histology Genetics Initial Therapy Postsurgical Follow-Up Follow-Up of Cured Medullary Thyroid Cancer Patients Follow-Up of Patients with Biochemical Persistent Disease Follow-Up of Patients with Structural Disease Other Therapies Local Treatment of Recurrent or Persistent Neck Disease Conclusions References Chapter (80) 80. Anaplastic (Undifferentiated) Thyroid Carcinoma Epidemiology Clinical Characteristics Diagnosis Biopsy Histopathology Subtypes Anaplastic (Undifferentiated) Thyroid Carcinoma 80 Differential Diagnoses Molecular Genetics Evaluation Clinical and Labs Imaging Staging Establish Goals of Care Multidisciplinary Team Prognosis Predictors of Survival Median and Overall Survival Therapy Treatment Strategies by Stage Surgery Radiation Therapy Multimodal Therapy Future Directions Conclusions Acknowledgments References Chapter (81) 81. Resistance to Thyroid Hormone and Genetic Defects of the Thyroid Resistance to Thyroid Hormone and Genetic Defects of the Thyroid Congenital Primary Hypothyroidism Epidemiology and Screening Genetic Causes of Thyroid Dysgenesis Genetic Causes of Dyshormonogenesis Resistance to Thyroid Hormone β Clinical Features Differential Diagnosis Molecular Genetics Management Resistance to Thyroid Hormone Alpha Background Clinical Features Molecular Genetics Management References Chapter (82) 82. Surgical Management of Thyroid Disease Surgical Management of Thyroid Disease 82 Relevant Surgical Anatomy The Recurrent Laryngeal Nerve The External Branch of the Superior Laryngeal Nerve Parathyroid Glands Lymphatics Imaging For Surgical Planning Ultrasound Axial Imaging Molecular Testing And Its Use For Surgical Planning Indeterminate Nodules Planning the Extent of Surgery Diseases Of The Thyroid And Surgical Procedures To Consider Graves Disease Hashimoto Thyroiditis Thyroglossal Duct Cyst and Surgical Excision Thyroid Hemiagenesis and Agenesis Ectopic Thyroid and Surgical Excision Lingual Thyroid Suprahyoid and Infrahyoid Thyroid Substernal Goiter Papillary Thyroid Cancer Follicular Thyroid Cancer Hurthle Cell Thyroid Cancer Medullary Thyroid Cancer Anaplastic Thyroid Cancer Radioactive Iodine Therapy Indications For Surgery Of The Thyroid Gland Indications for Lobectomy versus Total Thyroidectomy Indications for Active Surveillance Indications for Remote Access Surgery Indications for Prophylactic Central Neck Dissection Indications for Therapeutic Central Neck Dissection Indications for Lateral Neck Dissection Transoral Approach To Thyroidectomy Open Surgical Techniques Lobectomy and Total Thyroidectomy Retrograde Medial Approach to the Thyroid Dissection Central Neck Dissection Lateral Neck Dissection Minimally Invasive Techniques Radiofrequency Ablation Technique Surgical Complications Recurrent Laryngeal Nerve Injury Hypoparathyroidism Spinal Accessory Nerve Injury Greater Auricular Nerve Injury and Sensory Cervical Rootlets Other Cranial Neuropathies Chyle Leak Cosmesis Complications Associated with Transoral Surgery Complications Associated with Radiofrequency Ablation References Chapter (83) 83. Nonthyroidal Illness Syndrome Nonthyroidal Illness Syndrome Low Triiodothyronine States Serum Hormone Levels Serum Total and Free Triiodothyronine Serum Reverse Triiodothyronine Serum Total and Free Thyroxine Serum Thyroid-Stimulating Hormone Thyroid Hormone Transport Thyroid Hormone Metabolism and Action Hypothalamus Pituitary Liver Muscle Adipose Tissue Neutrophils and Macrophages Mechanism of Altered Thyroid Hormone Metabolism in Nonthyroidal Illness Syndrome Cyrokines Nuclear Factor κB Alternative Mechanisms Energy Status Conclusion References Chapter (84) 84. Drugs and Thyroid Drugs and Thyroid 84 Drugs That Enhance Thyroid Autoimmunity Drugs Causing Direct Thyroid Damage Drugs Affecting Protein Binding Of Thyroid Hormone Changes in Binding Proteins Displacement of Thyroid Hormone From Binding Proteins Drugs Affecting Thyroid Hormone Activation, Metabolism, And Excretion Thyroxine-to-Triiodothyronine Conversion Thyroid Hormone Metabolism Disposal of Thyroid Hormone Summary And Future Directions References Chapter (85) 85. Adrenal Development and Homeostasis Introduction and Historical Background Anatomy Adrenal Cortex Embryonic Adrenal Development Overview Adrenal Fate Determination Fetal Adrenal Development Postnatal Adrenal Development Fetal Zone Involution Establishment of Adrenal Cortex Zonation Homeostatic Renewal Role of Renin-Angiotensin-Aldosterone System and Adrenocorticotropic Hormone/PKA Signaling in Regulation of Renewal Sexual Dimorphism in Renewal Adrenal Cortex Regeneration Tissue Stress Progenitors and Adrenal Aging Conclusion and Future Directions References Chapter (86) 86. Genetic Disorders of the Adrenal Cortex Genetic Disorders of the Adrenal Cortex Genetic Disorders of the Adrenal Cortex Steroidogenesis Hypoplasia Familial Glucocorticoid Deficiency-Like (FGD-Like) Other Causes Of Syndromic Adrenal Insufficiency Conclusion References Chapter (87) 87. Enzymes and Pathways of Human Steroidogenesis 87 Cytochrome P450 Enzymes Hydroxysteroid Dehydrogenases and Reductases Acute Regulation of Steroidogenesis Chronic Maintenance of the Steroidogenic Machinery Human Steroidogenic Cytochrome P450 Enzymes P450scc (Encoded by CYP11A1) P450c17 (Encoded by CYP17A1) P450c21 (Encoded by CYP21A2) P450aro (Aromatase) Redox Partner Proteins Ferredoxin Ferredoxin Reductase P450 Oxidoreductase Cytochrome b5 Steroidogenic Dehydrogenases and Reductases 3β-Hydroxysteroid Dehydrogenase/Δ5→Δ4-Isomerases 17β-Hydroxysteroid Dehydrogenases Steroid 5α-Reductases 3α-Hydroxysteroid Dehydrogenases 11β-Hydroxysteroid Dehydrogenases Steroid Sulfonation Pathways Adrenal Steroidogenic Pathways Gonadal Steroidogenic Pathways The Backdoor Pathway to Dihydrotestosterone Pathways to 11-Oxygenated Androgens Androgen Synthesis in Prostate Cancer References Chapter (88) 88. Mineralocorticoids: Physiology, Metabolism, Receptors, and Resistance 88 Sodium Homeostasis Potassium Homeostasis Specificity-Conferring Enzymes 11β-Hydroxysteroid Dehydrogenase Type 2 Mineralocorticoid Receptors Evolution Structure Genomic Versus Nongenomic Aldosterone Actions Sodium Transport Epithelial Sodium Channels Na+/K+-ATPase Potassium Transport Hydrogen Ion Transport Nonepithelial Tissues Cardiovascular System Central Nervous System Summary and Future Directions References Chapter (89) 89. Glucocorticoid Receptors: Mechanisms of Action in Health and Disease Glucocorticoid Receptors: Mechanisms of Action in Health and Disease Introduction Glucocorticoid Receptor Polymorphisms Glucocorticoid Receptor Physiology Immune System Cardiovascular System Central Nervous System Hepatic Carbohydrate and Lipid Metabolism Glucocorticoid Receptor Resistance Summary and Future Directions References Chapter (90) 90. Adrenal Androgens, Adrenarche, and Adrenopause Adrenal Androgens, Adrenarche, and Adrenopause Adrenarche The Adrenal Glands The Fetal Adrenal Gland Clinical Facets of Adrenarche Adrenal Steroidogenesis Adrenopause Epidemiology/Associations with Dehydroepiandrosterone Sulfate Concentrations, Aging, and Cardiovascular Risks Conclusion References Chapter (91) 91. Adrenal Pathology Accessory or Heterotopic Adrenal Tissue Adrenal Pathology 91 Adrenal Myelolipoma Ectopic Thyroid Tissue Ovarian Thecal Metaplasia Adrenal Amyloidosis Adrenal Calcification Adrenal Cysts Adrenal Infection and Abscess Congenital Adrenal Hyperplasia Adrenal Cytomegaly Inflammatory Adrenalitis Functional Approach In Adrenal Pathology Pathological Correlates of Primary Aldosteronism Pathological Correlates of Adrenal Cushing Syndrome Pathological Correlates of Virilism/Feminization Pathological Correlates of Catecholamine Excess Confirmation of Adrenocortical and Medullary Origin Confirmation of Functional Sites in Primary Aldosteronism Diagnostic and Predictive Biomarkers of Adrenocortical Carcinoma Molecular Immunohistochemistry in Pheochromocytoma References Chapter (92) 92. Adrenal Gland Imaging Adrenal Gland Imaging Adrenal Gland Imaging Introduction Adrenal Gland Anatomy Adrenal Gland Imaging Adrenal Gland Imaging Arteriography and Adrenal Vein Sampling Clinical Utility Adenoma or Metastases Benign Adrenal Lesions Neoplastic Adrenal Lesions Functional Imaging in Primary Hyperaldosteronism Summary References Chapter (93) 93. Adrenal Insufficiency Adrenal Insufficiency 93 Epidemiology of Adrenal Insufficiency Pathogenesis of Adrenal Insufficiency Clinical Features of Adrenal Insufficiency Etiology Primary Adrenal Insufficiency Diagnosis of Adrenal Insufficiency Adrenocorticotropic Hormone Stimulation Testing Overnight Metyrapone Test Insulin Tolerance Test Adrenal Autoantibody Tests Serum 17-Hydroxyprogesterone Very Long Chain Fatty Acids Adrenal Imaging Treatment of Adrenal Insufficiency Replacement of Dehydroepiandrosterone Quality of Life in Adrenal Insufficiency Adrenal Suppression Adrenal Crisis Treatment of Adrenal Crisis Prevention of Adrenal Crises The Need for Novel Treatments for Adrenal Insufficiency References Chapter (94) 94. Defects of Adrenal Steroidogenesis 94 Virilizing Forms of Congenital Adrenal Hyperplasia 21-Hydroxylase Deficiency 11β-Hydroxylase Deficiency P450 Oxidoreductase Deficiency 3β-Hydroxysteroid Dehydrogenase Type 2 Deficiency Nonvirilizing Forms of Congenital Adrenal Hyperplasia 17α-Hydroxylase/17,20 Lyase Deficiency Diagnosis of 17α-Hydroxylase/17,20 Lyase Deficiency Other Conditions Affecting Adrenal Steroid Synthesis Aldosterone Synthase Deficiency Glucocorticoid-Remediable Aldosteronism Smith–Lemli–Opitz Syndrome Differential Diagnosis Medical Therapy of Congenital Adrenal Hyperplasia Glucocorticoid Therapy Mineralocorticoid Therapy Sex Steroid Replacement Antihypertensive Therapy Management of Atypical Genitalia Future Directions and Novel Therapies Conclusion References Chapter (95) 95. Adrenal Genomics II: Familial and Sporadic Neoplasia Adrenal Genomics II: Familial and Sporadic Neoplasia Genetic Causes Of Adrenal Neoplasia Adrenocortical Tumors Pheochromocytoma Summary And Future Directions References Chapter (96) 96. Primary Aldosteronism Pathogenesis And Genetics Primary Aldosteronism 96 Familial Forms of Primary Aldosteronism Somatic Mutations in Unilateral Primary Aldosteronism Somatic Mutations in Bilateral Adrenal Hyperplasia Prevalence Clinical Diagnosis Symptoms and Signs of Primary Aldosteronism Diagnostic Workup for Primary Aldosteronism Treatment Anchor 472 References Chapter (97) 97. Adrenocorticotropic Hormone–Independent Cushing Syndrome Adrenocorticotropic Hormone–Independent Cushing Syndrome Pathophysiology––Molecular Genetics and Animal Models Molecular and Genetic Causes of Cortisol-Producing Adrenocortical Lesions Animal Models Clinical Manifestations Hormonal Evaluation Unilateral Tumors Adrenocortical Adenoma Adrenocortical Cancer Bilateral Adrenocortical Tumors Micronodular Adrenal Hyperplasia and Primary Pigmented Nodular Adrenal Disease Primary Macronodular Adrenal Hyperplasia Medical Treatment with Steroidogenesis Inhibitors (Table 97.5) Surgery Perspectives References Chapter (98) 98. Adrenocortical Carcinoma Adrenocortical Carcinoma Diagnosis Hormonal Evaluation Imaging Histopathology Staging Therapy (Fig. 98.3) Surgery Radiation Therapy Medical Therapy Mitotane Cytotoxic Chemotherapy Targeted Therapies Immunotherapy Follow-Up References Chapter (99) 99. Pheochromocytoma Pheochromocytoma Catecholamine Production, Secretion, And Metabolism Who to Test According to Presentation Signs and Symptoms Differential Diagnosis Multiple Endocrine Neoplasia Syndromes Von Hippel–Lindau Syndrome Neurofibromatosis Type 1 Succinate Dehydrogenase Gene Family Less Common Hereditary or Other Causes Biochemical Diagnosis Of Pheochromocytoma Preanalytics and Analytics Interpretative Considerations Follow-Up Biochemical Testing Anatomic Imaging Differential Diagnosis Functional Imaging Metaiodobenzylguanidine Scintigraphy Positron Emission Tomography Medical Therapy and Preparation for Surgery Postoperative Management Special Presentations And Therapeutic Problems Multifocal and Metastatic Pheochromocytoma/Paraganglioma Pheochromocytoma in Pregnancy Future Directions References Chapter (100) 100. Adrenal Surgery Adrenal Surgery 100 Preoperative Evaluation Clinical Familial History and Genetic Testing Biochemical Evaluation Imaging Fine-Needle Aspiration Disease-Specific Decision-Making For Surgery Benign Nonfunctional Adrenal Tumors Myelolipomas Adrenal Cysts Biochemically Functional Adrenal Disorders Hypercortisolism Congenital Adrenal Hyperplasia Bilateral Macronodular Adrenal Hyperplasia Primary Aldosteronism Androgen- and Estrogen-Secreting Tumors Pheochromocytoma Adrenocortical Carcinoma Metastatic Disease to the Adrenal Gland Surgical Approaches To The Adrenal Gland Open Anterior Transabdominal Right Left Open Posterior (Lumbotomy) Laparoscopic Anterior Transabdominal Right Left Laparoscopic Lateral Transabdominal Adrenalectomy Right Left Robot-Assisted Adrenalectomy Bilateral Adrenalectomy Partial Adrenalectomy Surgical Complications Intraoperative Complications Postoperative Complications Complications and Operative Approach Bilateral Adrenalectomy Nelson Syndrome Additional Considerations Conclusion References Chapter (101) 101. Differences of Sex Development Introduction To Sexual Development Embryology Gonadal Development (Sex Determination) Development of Internal and External Genitalia (Sex Differentiation) Genetic Pathways Of Sex Development And Their Variations Genetic Pathways Differences Of Sex Development 46,XX Differences of Sex Development 46,XY Differences of Sex Development Sex Chromosome Differences of Sex Development Syndromic Differences of Sex Development Tools in Differences of Sex Development Evaluation Initial Gender Assignment Management of Differences of Sex Development Acknowledgements REFERENCES Chapter (102) 102. Endocrinology of Sexual Maturation and Puberty Gonadarche Endocrinology of Sexual Maturation and Puberty 102 Adrenarche Control Of The Onset Of Puberty Genetics of Pubertal Onset Timing of Puberty Physical Changes Of Puberty Boys Girls Additional Changes During Sexual Maturation Changes in Body Composition and Bone Mineral Density Changes in Sleep and Brain Development Other Changes at Puberty Laboratory Testing During Puberty Summary References Chapter (103) 103. Endocrinology of Pubertal Disorders Precocious Puberty Variants of Precocious Puberty Endocrinology of Pubertal Disorders 103 Premature Thelarche Premature Pubarche Pathologic Precocious Puberty Central Precocious Puberty Peripheral Precocious Puberty Abnormalities of G Proteins Abnormalities of Gonadotropin Receptors Tumors Gonadal Tumors Adrenal Tumors Germ Cell Tumors Exogenous Sex Steroids Hypothyroidism Delayed Puberty Definition Benign Variants of Delayed Puberty Constitutional Delay of Growth and Puberty Pathologic Delayed Puberty Hypothalamic-Pituitary Hypogonadism Primary Hypogonadism Treatment of Delayed Puberty Girls Boys Conclusion References Chapter (104) 104. Transgender Healthcare Transgender Healthcare Overview Goal-Driven Approach to Hormone Therapy Physical––Feminizing Physical––Masculinizing Sexuality Changes Sexuality Changes––Feminizing Sexuality Changes––Masculinizing Sexuality and Gender-Affirming Hormone Therapy Reproductive System Changes––Feminizing Reproductive System Changes––Masculinizing Risks Laboratory Monitoring Considerations Summary References Chapter (105) 105. Gonadotropin Regulation and Androgen and Estrogen Physiology Regulation Of Gonadotropin The Gonadotropins Gonadotropin-Releasing Hormone Feedback on Gonadotropin Secretion by Sex Steroids Metabolic Regulation of Gonadotropins Regulation of Gonadotropins by Stress Seasonal Regulation of Gonadotropin Secretion Androgen Physiology Biosynthesis of Testosterone and Other Androgens Structure Activity Relationship in Steroidal Androgens The Regulation of Testosterone Production by LH Transport and Bioavailability Testosterone Metabolism Mechanisms of Testosterone’s Action Estrogen Physiology Endogenous Estrogens Regulation of Estradiol Production Estrogen Transport and Bioavailability Estrogen Metabolism Mechanisms of Estrogen Action References Chapter (106) 106. Hypogonadism: Pathogenesis, Diagnosis, and Treatment Introduction 106 Pathogenesis Primary Hypogonadism Klinefelter Syndrome Other Sex Chromosome Disorders Cryptorchidism and Spermatogenic Failure Congenital Anorchia Acquired Anorchia Orchitis Gonadotoxic Cancer Treatment Noonan Syndrome Myotonic Dystrophy Autoimmune Polyglandular Syndrome Sickle Cell Disease Secondary Hypogonadism Congenital Isolated Hypogonadotropic Hypogonadism Congenital Hypogonadotropic Hypogonadism in Complex Genetic Syndromes Congenital Combined Pituitary Hormone Deficiency Pituitary and Nonpituitary Tumors Nontumorous Hypothalamic-Pituitary Diseases/Injuries Drug-induced Diagnosis Of Hypogonadism Clinical Diagnosis History Examination Laboratory Diagnosis Testosterone Treatment Of Hypogonadism Testosterone Replacement Therapy Indications Testosterone Preparations Parenteral Testosterone Preparations Transdermal Testosterone Preparations Efficacy Contraindications and Adverse Events Monitoring of Treatment Indications Gonadotropin Treatment . LH-like preparations can stimulate Leydig cells (Table 106.6). Recombinant LH is expensive, has a very short half-life, and ha... Gonadotropin-Releasing Hormone Treatment Future Directions References Chapter (107) 107. Testosterone Deficiency: Aging and Chronic Disease Testosterone Deficiency: Aging and Chronic Disease References Chapter (108) 108. Gynecomastia Physiologic Forms of Gynecomastia Newborn Gynecomastia Pubertal Gynecomastia 108 Adult and Senescent Gynecomastia Pathologic Forms of Gynecomastia Related to Elevated Estrogen Related to Testosterone Deficiency Related to Estradiol/Testosterone Imbalance Related to Modulatory Hormones Other Causes Uncertain Causes Treatment and Prevention References Chapter (109) 109. Erectile Dysfunction Introduction Guidelines 109 Epidemiology Psychogenic Erectile Dysfunction Organic Erectile Dysfunction Penile Physiology Anatomy of the Penis Hemodynamics of Penile Erection Innervation of the Penis Neurotransmitters and Pharmacology of Erection Testosterone and Male Sexual Function Discussing Sexual Health with Patients History Physical Examination Laboratory Testing Specialized Testing for Erectile Dysfunction (Table 109.6) Treatment Of Erectile Dysfunction Adaptive Sexuality Lifestyle Modification Mental Health Vacuum Erection Device Medical Therapy For Erectile Dysfunction Herbal Supplements and Complementary Medicine Phosphodiesterase Type 5 Inhibitors Intracavernosal Injection Therapy Urethral Prostaglandin Suppositories Malleable Penile Prostheses Inflatable Penile Prostheses Penile Vascular Surgery Additional Conditions Contributing To Male Sexual Dysfunction Disorders of Ejaculation, Emission, and Orgasm Peyronie Disease Priapism New Pharmacotherapeutics Stem Cell Therapy Low-Intensity Extracorporeal Shock Wave Therapy Platelet-Rich Plasma Conclusions References Chapter (110) 110. Misuse and Abuse of Anabolic Hormones Misuse and Abuse of Anabolic Hormones AAS: Use, Misuse, and Abuse Use Misuse Abuse History and Epidemiology of Anabolic Steroid Abuse History of Anabolic Steroid Abuse Epidemiology of Anabolic Steroid Abuse Ergogenic Potential of Anabolic Steroids Types and Patterns of Androgen Doping Direct Doping Indirect Doping Detection of Androgen Doping Detection of Compounds Used in Direct Androgen Doping Evaluation Process of AAS Abuse in Elite Athletes Assessment of Men Abusing AAS in the Clinics Administration of Epitestosterone Masking Agents Cardiovascular Reproductive Gynecomastia Hepatic Musculoskeletal Renal Dermatologic Neuropsychiatric and Behavioral Dependence Elite Athletes General Public Conclusion References Chapter (111) 111. Regulation of Spermatogenesis The Seminiferous Tubules The Intertubular Tissue 111 Postnatal Growth Cellular Development and Organization for Functional Control The Spermatogenic Epithelium Sertoli Cells Spermatogonia and Spermatogonial Stem Cells The Spermatogonial Stem Cell Niche Spermatogonial Differentiation and Its Control Meiosis Spermiogenesis: Emergence of Spermatozoa Germ Cell Associations and the Spermatogenic Cycle Spermatogenic Efficiency and Germ Cell Loss Genetic Defects and Spermatogenesis Epigenetics in the Male Germline The Intertubular Compartment Leydig Cells Other Interstitial Cells The Immunologic Environment of the Testis Endocrine and Local Control of Spermatogenesis Interactions Between the Testis, Hypothalamus, and Pituitary Gland Control of Sertoli Cell Function Sertoli Cells During Fetal and Postnatal Development Control of Spermatogenesis: Challenges Ahead References Chapter (112) 112. Prevalence and Causes of Male Infertility Prevalence and Causes of Male Infertility Common Causes Of Male Infertility Hypothalamic-Pituitary Disorders Testicular Disorders With Spermatogenesis Defects Sperm Motility, Morphology, Function, or Genetic Incompetence—Spermatogenesis Qualitative Defects Ductal Obstruction or Dysfunction Idiopathic Azoospermia, Oligozoospermia, Asthenozoospermia, and Teratozoospermia Other Possible Contributing Factors To Male Infertiliy Obesity Environmental Factors: Endocrine Disruptors Cigarette Smoking Cell Phone Scrotal Hyperthermia Epigenetics And Male Infertility Summary And Future Directions References Chapter (113) 113. Clinical Management of Male Infertility Clinical Management of Male Infertility Introduction Health Considerations For Infertile Men Evaluation of Male Infertility History and Physical Examination Semen Analysis Further Investigations and Complete Evaluation Endocrine Evaluation Low Semen Volume Postejaculatory Urinalysis Transrectal Ultrasound Oligospermia/Asthenospermia/Teratospermia Semen Leukocytes and Screening for Genital Infection Antisperm Antibodies (ASA) Genetic Testing (see Chapter 112) Sperm DNA Fragmentation Other Genetic Anomalies Azoospermia Management of Male Infertility Lifestyle Modifications Hormone Optimization Ejaculatory Dysfunction Ejaculatory Duct Obstruction Pyospermia Immunological Infertility Varicocele Repair Vasal Reconstruction Assisted Reproductive Techniques (ART) Sperm Retrieval Conclusion References Chapter (114) 114. Male Contraception The Need for Male Contraception Current Methods Withdrawal Male Condom 114 Vas Occlusion Male-Directed Contraceptive Methods in Development Hormonal Male Contraception Other New Hormonal Agents for Male Contraception Nonhormonal Targets for Male Contraception Men’s Attitude and Acceptability of Male Contraception Summary and Future Directions References Chapter (115) 115. Testicular Dysgenesis Syndrome and Testicular Tumors Testicular Dysgenesis Syndrome and Testicular Tumors Testicular Dysgenesis Syndrome Epidemiology Biological Evidence Cryptorchidism Classification Embryology Etiology Prevalence Treatment Long-Term Effects Hypospadias Embryology Etiology Prevalence Treatment Long-term Effects Minipuberty Minipuberty in Healthy Infants Minipuberty in Various DSD and TDS Conditions Testicular Tumors Classification Testicular Germ Cell Tumors Fertility Preservation and Long-Term Effects of Testicular Cancer Sex Cord-Stromal Tumors of the Testis Other Testicular Tumors Conclusion References Chapter (116) 116. Benign Prostatic Hyperplasia and Prostate Cancer Introduction Benign Prostatic Hyperplasia Diagnosis 116 Management and Treatment of BPH Summary and Future Research Prostate Cancer Diagnosis and Detection of Localized Prostate Cancer Management and Treatment of Localized Prostate Cancer Diagnosis and Detection of Advanced Prostate Cancer Management and Treatment of Advanced Prostate Cancer Summary and Future Challenges References Chapter (117) 117 - The Menstrual Cycle and Disorders of Ovulation THE MENSTRUAL CYCLE: AN INTRODUCTION Overview of the Hypothalamic-­Pituitary-­Ovarian Axis The GnRH Pulse Generator Anterior Pituitary Gonadotropes and Regulation of Gonadotropin Secretion Ovarian Folliculogenesis and Steroidogenesis Mechanisms of Ovarian Feedback Control of GnRH and Gonadotropin Secretion Uterine Events During the Menstrual Cycle Integrated Physiology of the Menstrual Cycle Luteal-­Follicular Transition Follicular Phase Midcycle Gonadotropin Surge and Ovulation Luteal Phase Neuroendocrine Mechanisms of Anovulation Physiological Anovulation Selected Causes of Pathological Anovulation Conclusion References The Menstrual Cycle: An Introduction Overview of the Hypothalamic-­Pituitary-­Ovarian Axis The GnRH Pulse Generator Anterior Pituitary Gonadotropes and Regulation of Gonadotropin Secretion Ovarian Folliculogenesis and Steroidogenesis Mechanisms of Ovarian Feedback Control of GnRH and Gonadotropin Secretion Uterine Events During the Menstrual Cycle Integrated Physiology of the Menstrual Cycle Luteal-­Follicular Transition Follicular Phase Midcycle Gonadotropin Surge and Ovulation Luteal Phase Neuroendocrine Mechanisms of Anovulation Physiological Anovulation Selected Causes of Pathological Anovulation Conclusion Chapter (118) 118 - Folliculogenesis, Ovulation, and Luteogenesis Folliculogenesis Folliculogenesis, Ovulation, and Luteogenesis 118 Preantral Follicles Antral or Graafian Follicles Oocyte Maturation Following the LH Surge Luteinization Luteolysis Conclusion References Chapter (119) 119 - Ovarian Hormone Synthesis Ovarian Hormone Synthesis 119 Acquisition of Cholesterol The Cholesterol Side-­Chain Cleavage Reaction Synthesis of Androgens Synthesis of Estrogens Steroid Hormone Metabolites MicroRNA Regulation of Steroidogenic Enzymes Peptide Hormones and Growth Factors Produced by the Ovary Transforming Growth Factor-­β Superfamily Relaxin Gonadotropin Control of Ovarian Steroid Production Follicle-­Stimulating Hormone and Luteinizing Hormone Mechanisms of Gonadotropin Action Other Hormones with Possible Actions in the Ovary Intraovarian Regulators Cholesterol Precursors Role of Estrogens Role of Androgens Role of Progesterone Transforming Growth Factor-­β Superfamily Eicosanoids Insulin-­Like Growth Factors and Their Binding Proteins Other Intraovarian Regulators Hormone Production During the Ovarian Life Cycle The Fetal and Prepubertal Ovary The Ovary During Reproductive Life Endocrine Activity of the Postmenopausal Ovary Conclusion References Chapter (120) 120. Estrogen and Progesterone Action 120 Nuclear Receptor Structure Coactivators and Corepressors Coactivators Corepressors Mechanisms of Estrogen Action Estrogen Receptor Ligands Estrogen Receptor Structure Estrogen Receptor-Coactivator Interactions Molecular Mechanisms of Estrogen Receptor Action Mechanisms of Progesterone Action Progesterone Receptor Isoforms Molecular Mechanisms of Progesterone Action in the Endometrium and on Blastocyst Implantation Conclusions References Chapter (121) 121. Contraception Contraception 121 Drug Interactions Medical Eligibility Criteria High-Effectiveness Methods Intrauterine Devices Progestogen-Only Implant Medium Effectiveness Methods Progestogen-Only Injectable Combined Hormonal Contraception CHC Pill CHC Patch and Vaginal Ring Progestogen-Only Pill Low Effectiveness Methods Condoms Diaphragm and Cap Fertility Awareness-Based Methods Lactational Amenorrhea Sterilization Emergency Contraception Non-Contraceptive Benefits of Contraception Summary and Future Directions References Chapter (122) 122. Menopause and Perimenopause Menopause and Perimenopause Staging Reproductive Aging Late Reproductive Stage (Stage –3) Menopausal Transition Menopause Postmenopause Epidemiology (TABLE 122.1) Age of Menopause Population-Level Determinants of Menopause Determinants of Early Menopause and Primary Ovarian Insufficiency Pathophysiology Of Menopause Ovarian Follicle Depletion—Current State of Knowledge Follicular Growth Activation and Atresia Ovarian and Pituitary Hormones Clinical Presentation The “Core Four” Symptoms: Hot Flashes, Vaginal Dryness, Adverse Mood, and Poor Sleep Vasomotor Symptoms (Hot Flashes and Night Sweats) Vaginal Dryness Adverse Mood Sleep Disturbances Other Symptoms Reproductive And Somatic Aging Hypothalamic-Pituitary-Ovarian Axis Somatotropic Axis Thyroid Adrenal Bone Cognition Cardiovascular Estrogen-Dependent Disorders Diagnosis Treatment Hormone Therapy Overview Vasomotor Symptoms Urogenital Symptoms (GSM) Sleep Disturbances Adverse Mood Other Common Issues Complementary and Alternative Medicine in the Treatment of Menopausal Symptoms Long-Term Use for Prevention of Chronic Conditions Cancer Risks and Mitigation of Risk With Hormone Therapy Summary References Chapter (123) 123. Female Infertility: Evaluation and Management Female Infertility: Evaluation and Management Introduction History Epidemiology Pathogenesis And Clinical Features Ovulatory Dysfunction Anatomic Dysfunction Ovarian Aging Unexplained Infertility Assessment of the Normal Menstrual Cycle Assessment of Anatomic Dysfunction Assessment of Cervical Mucus–Sperm Interaction Assessment of Ovarian Aging From Diagnosis to Prognosis Ovarian Stimulation Intrauterine Insemination In Vitro Fertilization Summary And Future Developments References Chapter (124) 124. Androgen Excess Disorders in Women Androgen Excess Disorders in Women Androgen Physiology and Pathophysiology Androgen Biosynthesis Regulation of Androgen Secretion Blood Levels and Transport of Androgens Mechanisms of Androgen Action Clinical Manifestation of Androgen Excess Cutaneous Manifestations Polycystic Ovary and Polycystic Ovary Morphology Metabolic Dysfunction Common Androgen Excess Disorders Polycystic Ovary Syndrome Ovarian Neoplasms Other Ovarian Hyperandrogenic Disorders Congenital Adrenal Hyperplasia Other Adrenal Hyperandrogenic Disorders Idiopathic Hyperandrogenism Diagnosis of Hyperandrogenism Clinical Hyperandrogenism Biochemical Hyperandrogenism Treatment of Polycystic Ovary Syndrome and other Androgen Excess Disorders Androgen Suppression Ovulation Induction and Assisted Reproduction Prevention of Long-Term Complications Summary and Future Directions References Chapter (125) 125. Endometriosis Pathogenesis Endometriosis 125 Genetic Basis Environment Somatic Mutations Pathophysiology Cell Survival and Adhesion Matrix Degradation And Invasion Cell Growth and Neoangiogenesis Altered Endocrine Activity Immunity and Inflammation Mechanisms Underlying Pain and Infertility Diagnosis Therapies Medical Surgical Integrated Approach to the Patient With Endometriosis Endometriosis-Associated Cancer Risk Summary References Chapter (126) 126. Uterine Fibroids and Adenomyosis Introduction Epidemiology and Classification Uterine Fibroids and Adenomyosis 126 Pathogenesis Diagnosis Therapies Adenomyosis Overview Epidemiology and Classification Pathogenesis Diagnosis Treatment Summary References Chapter (127) 127. Hormonal Control of the Breast* Hormonal Control of the Breast* Adolescence Anchor 466 The Mature Breast Nulliparous Women Parous Women The Menopausal Breast References Chapter (128) 128. Sexual Dysfunction in the Female Sexual Dysfunction in the Female Normal Female Sexual Response Neurotransmitters of Desire and Arousal Endocrinology of Desire and Subjective Arousal Endocrinology of Objective Arousal Normal Vulvar and Vaginal Anatomy and Role of Hormones Pathophysiology of Female Sexual Dysfunction Hypoactive Sexual Desire Disorder Sexual Arousal Disorders Orgasmic Disorder Sexual Pain Disorders Treatments For Sexual Dysfunction Hypoactive Sexual Desire Disorder Nonhormonal Treatments Hormonal Management of Hypoactive Sexual Desire Disorder Genital Arousal and Sexual Pain Persistent Genital Arousal Disorder Conclusion References Chapter (129) 129. Hormonal Control of Human Pregnancy and Parturition Preparation of the Endometrium Embryo Competency Hormonal Control of Human Pregnancy and Parturition 129 Decidualization of the Endometrium Implantation and Placentation Immune Tolerance of the Conceptus Pregnancy Maintenance Chorionic Gonadotropin Gonadotropin-Releasing Hormone Proopiomelanocortin-Derived Hormones Corticotropin-Releasing Hormone Placental Lactogen and Placental Growth Hormone Modulation of Maternal Energy Homeostasis Growth Factors and Cytokines Steroid Hormones Parturition and Birth Timing Evolutionary Perspective Fetal Maturation Progesterone Withdrawal Stress and Tissue-Level Inflammation Progestin Therapy to Prevent Preterm Birth Estrogens Conclusion/Future Directions References Chapter (130) 130. Fetal and Neonatal Endocrinology Fetal and Neonatal Endocrinology Overview Ectopic Fetal Hormone Production The Hypothalamic-Pituitary Systems Fetal Adrenal Fetal Thyroid The Fetal Autonomic Nervous System Fetal Pancreas and Glucose Homeostasis Fetal Parathryoid and Bone Metabolism Parathyroid Development Fetal Calcium and Phosphate Metabolism Regulation of Calcium Homeostasis by PTH/PTHrP Fetal Growth Insulin-Like Growth Factors Insulin Fibroblast Growth Factor Other Growth Factors and Signaling Pathways Cortisol-Mediated Adaptations Catecholamine-Mediated Adaptations BAT Thermogenesis Glucose Homeostasis Calcium Homeostasis Other Hormonal Adaptations Future Directions References Chapter (131) 131. Hormonal Changes and Pregnancy Testing Hormonal Changes and Pregnancy Testing Introduction Pituitary Gland Hypopituitarism Prolactin Changes in Prolactin Physiology Prolactinomas in Pregnancy The Effect of Pregnancy on a Preexisting Prolactinoma The Effect of Dopamine Agonists on a Developing Fetus Prolactin and Antipsychotic Medication Breastfeeding and Prolactin Growth Hormone Changes in GH Physiology During Pregnancy GH Deficiency GH Excess Vasopressin Thyroid Gland Thyroid Hormones and Thyroid Regulation Hyperthyroidism Hypothyroidism Adrenal Gland Regulation of Glucocorticosteroid Synthesis Parathyroid Glands Regulation of Calcium During Pregnancy Parathyroid Hormone–Related Protein Vitamin D Deficiency Hypercalcemia Conclusion References Chapter (132) 132. Autoimmune Polyglandular Syndromes Background The Basis of Autoimmune Disease The Normal Immune Response Self-Tolerance Central Tolerance Peripheral Tolerance Pathogenesis of Autoimmune Disease Autoimmune Polyglandular Syndrome Type 1 Definition Pathogenesis Clinical Features Chronic Mucocutaneous Candidiasis Hypoparathyroidism Adrenal Insufficiency Gonadal Insufficiency Other Endocrinopathies Gastrointestinal Manifestations Ectodermal Manifestations Other Manifestations Natural Course and Mortality Diagnosis and Management Autoimmune Polyglandular Syndrome Type 2 Definition Pathogenesis Clinical Features and Diagnosis Management References Chapter (133) 133 - Multiple Endocrine Neoplasia Type 1 CLINICAL FINDINGS AND TREATMENT Parathyroid Tumors Pancreatic Tumors Pituitary Tumors Associated Tumors Carcinoid Tumors Other Clinical Considerations MOLECULAR GENETICS The MEN1 Gene MEN1 Germline Mutations MEN1 Germline Coding Variants MEN1 Somatic Mutations MEN1 Phenocopies and Mutations in Other Genes MEN1 Mutational Analysis in Clinical Practice SURVEILLANCE OF INDIVIDUALS AT RISK OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 TUMORS FUNCTION OF THE MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 PROTEIN, MENIN, AND FUTURE TARGETED TREATMENTS CONCLUSION REFERENCES Chapter (134) 134. Multiple Endocrine Neoplasia Types 2 and 3, and Medullary Thyroid Carcinoma Multiple Endocrine Neoplasia Types 2 and 3, and Medullary Thyroid Carcinoma Prevalence and Epidemiology RET Structure and Function RET Ligands Functional Effects of RET Variants Histology C-Cells C-Cell Hyperplasia Clinical Relevance of Germline Ret Variants in Multiple Endocrine Neoplasia Type 2 and Multiple Endocrine Neoplasia Type 3 Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma Multiple Endocrine Neoplasia Type 3 Specific Genotype-Phenotype Correlations Clinical Presentation Medullary Thyroid Carcinoma Pheochromocytoma Hyperparathyroidism Screening in Multiple Endocrine Neoplasia Type 2 and Multiple Endocrine Neoplasia Type 3 Biochemical Screening Genetic Screening Management Implications of Genetic Results Timing and Benefits of Prophylactic Thyroidectomy Strategy and Extent of Thyroidectomy The Role of Somatic Mutations Sporadic Medullary Thyroid Carcinoma Low-Penetrance Phenotypes Hereditary Medullary Thyroid Carcinoma Germline Screening Sporadic Medullary Thyroid Carcinoma Staging of Medullary Thyroid Carcinoma Pheochromocytoma Hyperparathyroidism Management Of Medullary Thyroid Carcinoma Localized Medullary Thyroid Carcinoma Recurrent Medullary Thyroid Carcinoma Persistent and Metastatic Medullary Thyroid Carcinoma Management of Pheochromocytoma Management of Hyperparathyroidism Conclusion References Chapter (135) 135. Neuroendocrine Tumor Syndromes Neuroendocrine Tumor Syndromes Introduction Epidemiology Etiology Pathologic Classification and Prognosis Laboratory Tests and Biomarkers Imaging Biopsy Clinical Features of Functional net and Their Syndromes Insulinoma Gastrinoma VIPoma Glucagonoma Somatostatinoma PPoma Serotoninoma Carcinoid Syndrome Surgical Resection Ablation of Primary Pancreas Neuroendocrine Tumors Hepatic Arterial Embolization Selective Internal Radiation Therapy Systemic Therapies Palliative Symptom Management Conclusion References Chapter (136) 136. Ectopic Hormone Syndromes History Theoretical Considerations 136 Theories of the Origin of Ectopic Hormones Hormones in Small-Cell Lung Carcinoma Ectopic Adrenocorticotropic Hormone Syndrome The POMC Gene Regulation of POMC Gene Expression Ectopic Adrenocorticotropic Hormone Syndrome Pro-Opiomelanocortin Processing Diagnosis Treatment Diagnosis Management Humoral Hypercalcemia of Malignancy Parathyroid Hormone–Related Protein Hypercalcemia in Hematologic Malignancy Diagnosis Treatment Oncogenic Osteomalacia Non–Islet Cell Tumor Hypoglycemia Diagnosis Management Other Pituitary Ectopic Hormones Gonadotropins Ectopic Gut Hormone Syndromes Ectopic Renin Secretion Acknowledgments References Chapter (137) 137. Endocrine-Disrupting Chemicals and Human Health Endocrine-Disrupting Chemicals and Human Health 137 Health Effects of Environmental Chemicals The Lessons of Lead The Lessons of PCBs The Lessons of Diethylstilbestrol (DES) Windows of Susceptibility Mechanisms of EDC Actions Dose-Response Characteristics of EDCS Chemical Exposures in the Human Population Disease Trends and Effects of EDCs Cancer Thyroid Disruption Neurobehavior Emerging Issues Endocrine Disruptors, the Epigenome, and Transgenerational Effects Increasing Exposures Worldwide Expanded List of Diseases Related to EDCs Mixtures E-Waste Green Chemistry Conclusion and Guidance for Clinicians References