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دانلود کتاب Williams Textbook of Endocrinology
دانلود کتاب کتاب غدد درون ریز ویلیامز
مشخصات کتاب
Williams Textbook of Endocrinology
ویرایش: [14 ed.] نویسندگان: Shlomo Melmed MBChB MACP, Ronald Koenig, Clifford Rosen, Richard Auchus, Allison Goldfine سری: ISBN (شابک) : 0323555969, 9780323555968 ناشر: Elsevier سال نشر: 2019 تعداد صفحات: 1792 [2172] زبان: English فرمت فایل : PDF (درصورت درخواست کاربر به PDF، EPUB یا AZW3 تبدیل می شود) حجم فایل: 157 Mb
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توجه داشته باشید کتاب کتاب غدد درون ریز ویلیامز نسخه زبان اصلی می باشد و کتاب ترجمه شده به فارسی نمی باشد. وبسایت اینترنشنال لایبرری ارائه دهنده کتاب های زبان اصلی می باشد و هیچ گونه کتاب ترجمه شده یا نوشته شده به فارسی را ارائه نمی دهد.
توضیحاتی در مورد کتاب کتاب غدد درون ریز ویلیامز
به طور تخصصی پر کردن شکاف بین علوم پایه و اطلاعات بالینی، کتاب درسی غدد درون ریز ویلیامز، ویرایش چهاردهم، مجموعه ای برجسته از نویسندگان مشهور جهان را گرد هم می آورد تا بحث های معتبری را ارائه دهد. از طیف کامل اختلالات سیستم غدد درون ریز بزرگسالان و کودکان. فصل‌های جدید و بازنگری‌های مهم در سرتاسر شما را در جریان پیشرفت‌های اخیر در داروها، درمان‌ها، کارآزمایی‌های بالینی و موارد دیگر قرار می‌دهد. این مرجع ضروری یک منبع ضروری برای متخصصان غدد، جراحان غدد، متخصصین زنان، متخصصین داخلی، متخصصان اطفال و سایر پزشکانی است که نیاز به پوشش فعلی و جامع این حوزه چند وجهی دارند.
-
. li> به روز با پیشرفت های اخیر در داروها، درمان ها و
آزمایشات بالینی.
- پوشش پیشرفته دیابت، سندرم متابولیک، اختلالات متابولیک استخوان، چاقی، بیماری تیروئید، اختلالات بیضه، جدیداً تعریف شده را ارائه می‌کند. اختلالات آدرنال و خیلی چیزهای دیگر - همه برای کمک به ارائه مراقبت مطلوب به هر بیمار طراحی شده اند.
- شامل فصل های جدید در بار جهانی بیماری های غدد درون ریز، پیمایش است. دستورالعمل های غدد درون ریز و غدد درون ریز ترنسجندر.
- شامل به روز رسانی های قابل توجهی در بخش دیابت، از جمله فصل جدیدی در فیزیولوژی ترشح انسولین و پوشش بیشتر دیابت نوع 2.
- اطلاعات فعلی را در یک قالب بسیار مصور و کاربرپسند برای مرجع سریع ارائه می‌کند.
- بهبود یافته li> نسخه کتاب الکترونیکی همراه با خرید. کتاب الکترونیکی پیشرفته شما به شما امکان می دهد به تمام متن، شکل ها و مراجع کتاب در دستگاه های مختلف دسترسی داشته باشید.
توضیحاتی درمورد کتاب به خارجی
Expertly bridging the gap between basic science and clinical information, Williams Textbook of Endocrinology, 14th Edition, brings together an outstanding collection of world-renowned authors to provide authoritative discussions of the full spectrum of adult and pediatric endocrine system disorders. New chapters and significant revisions throughout keep you up to date with recent advances in medications, therapies, clinical trials, and more. This essential reference is a must-have resource for endocrinologists, endocrine surgeons, gynecologists, internists, pediatricians, and other clinicians who need current, comprehensive coverage of this multifaceted field.
- Up to date with recent advances in medications, therapies, and clinical trials.
- Provides state-of-the-art coverage of diabetes, metabolic syndrome, metabolic bones disorders, obesity, thyroid disease, testicular disorders, newly defined adrenal disorders and much more - all designed to help you provide optimal care to every patient.
- Contains new chapters on Global Burden of Endocrine Disease, Navigation of Endocrine Guidelines, and Transgender Endocrinology.
- Includes significant updates to the Diabetes section, including a new chapter on Physiology of Insulin Secretion and greater coverage of Type 2 Diabetes.
- Presents current information in a highly illustrated, user-friendly format for quick reference.
- Enhanced eBook version included with purchase. Your enhanced eBook allows you to access all of the text, figures, and references from the book on a variety of devices.
فهرست مطالب
Williams Textbook of Endocrinology Copyright Contributors Preface 1 - Principles of Endocrinology The Evolutionary Perspective Endocrine Glands Transport of Hormones in Blood Target Cells as Active Participants Control of Hormone Secretion Hormone Measurement Endocrine Diseases Hormone Overproduction Hormone Underproduction Altered Tissue Responses to Hormones Tumors of Endocrine Glands Excessive Hormone Inactivation or Destruction Diagnostic and Therapeutic Uses of Hormones Future Perspectives 2 - Principles of Hormone Action Introduction to Hormone Signaling Ligands That Act Through Cell Surface Receptors Classic Peptide Hormones Nonpeptide Hormones That Act at Cell Surface Receptors Binding Properties of Cell Surface Receptors Cell Surface Hormone Receptors Ligand-Gated Ion Channels G Protein–Coupled Receptors Signaling by Heterotrimeric G Proteins Receptor Tyrosine Protein Kinases as Cell Surface Receptors Signaling by Receptor Tyrosine Protein Kinases Receptor Serine/Threonine Protein Kinases Signaling by Receptors That Associate With Enzymes Coupling of Cell Surface Receptors to Intracellular Signaling Downstream Signaling by Cyclic Adenosine Monophosphate Regulation by the Second Messengers Calcium and PKC Regulation of Protein Kinases by PI3K Regulation of Protein Kinases by Ras Disease Caused by Defective Cell Surface Receptors Insulin Resistance Syndromes Defects in Cell Surface Receptors That Control Growth Diseases Caused by Mutations in GPCRs and G Proteins Ligands That Act Through Nuclear Receptors General Features of Nuclear Receptor Ligands Subclasses of Nuclear Receptor Ligands Classic Hormones Vitamins Metabolic Intermediates and Products Endobiotics and Xenobiotics Orphan Receptors Variant Receptors Regulation of Ligand Levels Nuclear Receptor Signaling Mechanisms Domain Structure of Nuclear Receptors Nuclear Localization Hormone Binding Target Gene Recognition by Receptors Receptor Dimerization Receptor Regulation of Gene Transcription Ligand-Dependent Activation Repression of Gene Expression by Unliganded Receptor Ligand-Dependent Negative Regulation of Gene Expression: Transrepression Roles of Other Nuclear Receptor Domains Cross-Talk With Other Signaling Pathways Receptor Antagonists Tissue Selectivity of Ligands Interacting With Nuclear Receptors Nongenomic Actions of Nuclear Receptor Ligands 3 - Genetics of Endocrinology The Role of Genetics in Endocrinology Principles of Genetics A Brief Historical Perspective Heritability: An Estimate of the Importance of Genetic Factors to Disease Causation Human DNA Sequence Variation: Molecular Forms and Biologic Effects Factors Influencing the Biologic Impact of Genetic Variants in a Particular Gene Summary Genetics of Endocrine Diseases Mendelian Endocrine Diseases Genetic Architecture Disease Biology Clinical Translation Type 2 Diabetes Genetic Architecture Disease Biology Clinical Translation Short Stature Genetic Architecture Disease Biology Clinical Translation Lipids and Coronary Artery Disease Genetic Architecture Disease Biology Clinical Translation Considerations for Clinical Use of Genetic Information and Sequencing in Endocrinology Genome Screening in the General Population Genetic Information and Sequencing in Individual Patients Asymptomatic Individuals Symptomatic Individuals Avoiding Invasive Diagnostics Selection of Genetic Tests: Targeted Versus Genome-wide Approaches Limitations of Genomic Testing Interpretation of Identified Genetic Variants Using a Genetics Laboratory Report to Make Clinical Decisions Future Perspectives and Summary 4 - Laboratory Techniques for Recognition of Endocrine Disorders Laboratory Methods Antibody-Based Methods Classic Competitive Binding Immunoassays Antibody Labeled Antigen Unlabeled Antigen Separation of Reactants/Automation Quantitation Epitope-Specific Immunometric Assays Molecular Structure–Based Methods Extraction Methods Chromatographic Systems Mass Spectrometry Free Hormone Methods Nucleic Acid–Based Methods Hybridization Assays (Mutation Assays, Genotyping) Restriction Fragmentation Electrophoretic Separation Amplification Sequencing Methods Analytic Validation Intrinsic Performance Parameters Analytic Specificity Cross-Reactivity Interference Analytic Sensitivity Precision Accuracy Carryover Utilization Parameters Specimen Stability Reagent Stability Robustness (Assay Stability) Interpretation Parameters Reportable Range Reference Intervals Diagnostic Power Operational Parameters (Preanalytic Considerations) Specimen Types Whole Blood Serum Plasma Urine Saliva Fluids and Tissue From Fine-Needle Aspiration Quality Control Quality Assurance Classes of Assays Conclusion Acknowledgment 5 - The Global Burden of Endocrine Diseases Introduction Obesity and Excess Weight Prevalence and Trends The Burden of Excess Weight The Burden of Diabetes Prevalence, Incidence, and Mortality Trends Burden The Burden of Thyroid Diseases Perspectives for the Next Decade 6 - Navigating Through Clinical Practice Guidelines in Endocrinology Introduction Development of Trustworthy Clinical Practice Guidelines Identification of the Clinical Question Systematic Review of the Literature Evaluation of the Quality of the Evidence From Quality of the Evidence to Strength of Recommendation Clinical Practice Guidelines Recommendations Strong Recommendations Weak Recommendations (Also Called Conditional or Discretionary) Good Practice Statements Clinical Practice Guidelines in Endocrinology Using Clinical Practice Guidelines in Patient Care Case Study: Management of Gestational Diabetes Using Clinical Practice Guidelines in Patient Care Shortcomings of Clinical Practice Guidelines Guidelines as Tools That Support (Not Dictate) Care Disease-Specific and Context-Blind Guidelines Guideline Focus on Surrogate Outcomes (Not Patient-Important Outcomes) Quality and Trustworthiness of Clinical Practice Guidelines Conclusions 7 - Neuroendocrinology Historic Perspective Neural Control of Endocrine Secretion Neurosecretion Contribution of the Autonomic Nervous System to Endocrine Control Hypothalamic-Pituitary Unit Development and Differentiation of Hypothalamic Nuclei Anatomy of the Hypothalamic-Pituitary Unit The Median Eminence and Hypophysiotropic Neuronal System Circumventricular Organs Median Eminence Organum Vasculosum of the Lamina Terminalis and the Subfornical Organ Area Postrema Subcommissural Organ Pineal Gland The Pineal Is the Source of Melatonin Physiologic Roles of Melatonin Melatonin Receptors Melatonin Therapy in Humans Hypophysiotropic Hormones and Neuroendocrine Axes Feedback Concepts in Neuroendocrinology Endocrine Rhythms Thyrotropin-Releasing Hormone Chemistry and Evolution Effects on the Pituitary Gland and Mechanism of Action Extrapituitary Function Clinical Applications Regulation of Thyrotropin Release Feedback Control: Hypothalamic-Pituitary-Thyroid Axis Neural Control Circadian Rhythm Temperature Stress Suckling Starvation Dehydration-Induced Anorexia Infection and Inflammation Corticotropin-Releasing Hormone Chemistry and Evolution Effects on the Pituitary and Mechanism of Action Extrapituitary Functions Clinical Applications Feedback Control Neural Control Inflammation and Cytokines Other Factors Influencing Secretion of Corticotropin Circadian Rhythms Opiates Growth Hormone–Releasing Hormone Chemistry and Evolution Growth Hormone–Releasing Hormone Receptor Effects on the Pituitary and Mechanism of Action Extrapituitary Functions Growth Hormone–Releasing Peptides Clinical Applications Neuroendocrine Regulation of Growth Hormone Secretion Feedback Control Neural Control Other Factors Influencing Secretion of Growth Hormone Human Growth Hormone Rhythms External and Metabolic Signals Somatostatin Chemistry and Evolution Somatostatin Receptors Effects on Target Tissues and Mechanism of Action Clinical Applications of Somatostatin Analogues Prolactin-Regulating Factors Dopamine Prolactin-Releasing Factors Intrapituitary Regulation of Prolactin Secretion Neuroendocrine Regulation of Prolactin Secretion Feedback Control Neural Control Factors Influencing Secretion Circadian Rhythm External Stimuli Gonadotropin-Releasing Hormone and Control of the Reproductive Axis Chemistry and Evolution Anatomic Distribution Embryonic Development Action at the Pituitary Receptors Pulsatile Gonadotropin-Releasing Hormone Stimulation Regulatory Systems Feedback Regulation Regulation of the Ovarian Cycle Early Development and Puberty Reproductive Function and Stress Thermoregulation and Sleep-Wake Cycle Preoptic Area Is the Primary Hypothalamic Thermoregulatory Center Mechanisms for Thermoreception Central Circuitries Mediating Thermoregulation Modulators of Thermoregulatory Responses Thyroid Hormone Estrogen and Progesterone Neurokinin B Orexin-A Prostaglandins Opioids and Endocannabinoids Sleep-Wake Cycle Central Circuitries Mediating the Sleep-Wake Cycle Circadian Regulation of Sleep-Wake Cycle Somnogens Modifying Factors Influencing Sleep Neuroendocrine Disease Pituitary Isolation Syndrome Hypophysiotropic Hormone Deficiency Craniopharyngioma Hypophysiotropic Hormone Hypersecretion Neuroendocrine Disorders of Gonadotropin Regulation Precocious Puberty Idiopathic Sexual Precocity Neurogenic Precocious Puberty Hypothyroidism Tumors of the Pineal Gland Approach to the Patient with Precocious Puberty Management of Sexual Precocity Psychogenic Amenorrhea Neurogenic Hypogonadism in Males Neurogenic Disorders of Prolactin Regulation Neurogenic Disorders of Growth Hormone Secretion Hypothalamic Growth Failure Maternal Deprivation Syndrome and Psychosocial Dwarfism Neuroregulatory Growth Hormone Deficiency Neurogenic Hypersecretion of Growth Hormone Diencephalic Syndrome Growth Hormone Hypersecretion Associated With Metabolic Disturbances X-Linked Gigantism Neurogenic Disorders of Corticotropin Regulation Nonendocrine Manifestations of Hypothalamic Disease Paroxysmal Sympathetic Storms (Diencephalic Epilepsy) Narcolepsy Kleine-Levin Syndrome Hypothalamus and Neuropsychiatric Disorders Acknowledgments 8 - Pituitary Physiology and Diagnostic Evaluation Anatomy, Development, and Overview of Control of Hormone Secretion Anatomy Pituitary Blood Supply Pituitary Development Pituitary Transcription Factors Pituitary Stem Cells Pituitary Control Physiology and Disorders of Pituitary Hormone Axes Prolactin Physiology Lactotroph Cells Prolactin Structure Regulation Prolactin Secretion Prolactin Action Mammary Gland Development Lactation Reproductive Function Other Actions Prolactin Measurements Prolactin Deficiency Causes Manifestations Hyperprolactinemia Causes Physiologic Causes Macroprolactinemia. PRL is a 23-kDa single-chain polypeptide but may also circulate in high-molecular-weight forms. High-molecul... Pathologic Causes. Pathologic hyperprolactinemia may be caused by a prolactinoma, pituitary or sellar tumors that inhibit dopami... Drug-Induced Causes. A variety of medications cause minimal or moderate prolactin elevations. Neuroleptic drugs elevate PRL beca... Clinical Features Growth Hormone Somatotroph Cells Structure Regulation Ghrelin Extrapituitary GH Secretion GHRH and SRIF Interaction Interaction With Other Hormone Axes Action GHR Signaling Growth Hormone–Binding Proteins Metabolic Action Growth Hormone Assays Growth Hormone Deficiency Pathophysiology Presentation Evaluation Provocative Testing. The diagnosis of adult GHD is established by provocative testing of GH secretion (Table 8.7). Other hormone... Growth Hormone–Responsive Markers. These markers include IGF1, IGF binding protein 3 (IGFBP3), and the acid-labile subunit of th... Spontaneous GH Secretion. As pituitary GH secretion occurs episodically, accurate quantification of integrated GH secretion requ... Gene Expression Analysis Growth Hormone Replacement Therapy Growth Hormone Administration. GH secretion is greater in the young and greater in women than in men. It is recommended that the... Transition-Age Patients. GH treatment of the GH-deficient child normally is terminated when final height and epiphysis closure a... Precautions and Caveats of Treating With Human Growth Hormone. The most common side effects of hGH replacement include edema, ar... Investigational Uses of Growth Hormone Catabolic States. The anabolic actions of GH have prompted investigational use of GH in catabolic states, including surgery, tra... Osteoporosis. There is strong evidence that GH administered to otherwise healthy subjects with idiopathic osteoporosis improves ... Human Immunodeficiency Virus Infection. GH is Food and Drug Administration (FDA) approved for administration to adult patients w... Sports. The public policy issues of GH abuse in competitive sports have received much attention. GH has been widely abused by at... Aging. Disease mongering of declining GH status is rampant and spawned by unsubstantiated claims that GH is an antiaging hormone... GH Excess Adrenocorticotropic Hormone Physiology Corticotroph Cells Structure Regulation POMC Processing Extrapituitary and CNS Expression of POMC Melanocortin Receptors Adrenal Action Stress Response Circadian Periodicity Measurement of ACTH ACTH Deficiency Causes Clinical Features Evaluation Dynamic Testing for ACTH Deficiency Hypothalamic Testing. Insulin hypoglycemia is a potent endogenous stressor that evokes ACTH secretion as well as GH release. Ins... Pituitary Stimulation. Pituitary ACTH secretion is evoked by injecting either CRH or AVP. Ovine or human CRH (100 μg or 1 μg/kg)... Adrenal Stimulation. The acute response of the adrenal gland to a bolus ACTH injection reflects ambient ACTH concentrations to w... Adrenal Steroid Replacement ACTH Excess Causes Clinical Features Gonadotropins Physiology Gonadotroph Cells Gonadotropin Structure Regulation Gonadotropin-Releasing Hormone Inhibins and Activins Sex Steroids Secretion Action Female Male Gonadotropin Measurements α-Subunit Assays GnRH Stimulation Test Clomiphene Stimulation Test Gonadotropin Deficiency Causes Hypogonadotropic Hypogonadism. The genetic basis of HH was recognized over 60 years ago with the description by Kallmann of hypo... Kallmann Syndrome. Kallmann syndrome consists of defective GnRH neuronal development, with olfactory nerve agenesis or hypoplasi... Manifestations Management Evaluation. In evaluating hypogonadal patients in the absence of an obvious pituitary or gonadal disorder, the primary diagnosti... Sex Steroid Replacement Therapy. Estrogen or testosterone replacement is required for inducing and maintaining primary and secon... Fertility. In patients with HH, fertility may be achieved with gonadotropin or GnRH therapy. In males, even relatively low sperm... Thyroid-Stimulating Hormone Physiology Thyrotroph Cells Structure Regulation Secretion Regulatory Factors Action TSH Assays TSH Deficiency Causes Manifestations Treatment TSH Excess Developmental, Genetic, and Acquired Causes of Pituitary Failure Developmental Disorders Heritable Disorders HESX1, SOX2, SOX3, and OTX2 LHX3 and LHX4 PITX1 and PITX2 PROP1 POU1F1 IGSF1 TBX19 NR5A1 and NR0B1 Pituitary Stalk Interruption Syndrome Acquired Disorders Head Trauma Radiation Empty Sella Syndrome Clinical Features of Hypopituitarism Screening for Pituitary Failure 9 - Pituitary Masses and Tumors Pituitary Masses Pituitary Mass Effects Evaluation of Pituitary Masses Approach to the Patient Harboring a Pituitary Mass Imaging Receptor Imaging Neuro-Ophthalmologic Assessment of Pituitary Masses Visual Symptoms Clinical Signs and Approach Management of Pituitary Masses Surgical Management of Pituitary Tumors and Sellar Masses Goals of Surgery Indications for Transsphenoidal Surgery Side Effects Pituitary Radiation Principles Indications Side Effects Medical Management Parasellar Masses Types of Parasellar Masses Rathke Cysts Granular Cell Tumors Chordomas Craniopharyngiomas Meningiomas Gliomas Mucocele Parasellar Aneurysms Pituitary Infections Hematologic Malignancies Pituicytoma Sarcoidosis Langerhans Cell Histiocytosis Hereditary Iron Storage Diseases Idiopathic Retroperitoneal Fibrosis Metastases to the Pituitary Region Evaluation of Parasellar Lesions Primary Hypophysitis Lymphocytic Hypophysitis Clinical Features Laboratory Findings Treatment Granulomatous Hypophysitis Xanthomatous Hypophysitis Necrotizing Infundibulo-Hypophysitis IgG4-Related Hypophysitis Immune Checkpoint Inhibitor-Induced Hypophysitis Hemorrhage and Infarction Postpartum Pituitary Infarction Pituitary Apoplexy Clinical Features Management Pituitary Adenomas Pituitary Trophic Activity Benign Adenomas Hormonal Factors Genetic Factors Pituitary Senescence Familial Syndromes Multiple Endocrine Neoplasia Type 1 Familial Isolated Pituitary Adenomas Carney Complex Pathogenesis Classification of Pituitary Tumors Aggressive Adenomas Malignant Pituitary Tumors Prolactin-Secreting Adenomas Pathology and Pathogenesis Clinical Features Hyperprolactinemia Tumor Mass Effects Evaluation Treatment Medical Treatment Bromocriptine Cabergoline Administration Adverse Effects of Dopamine Agonists Radiation Therapy Surgery Chemotherapy Pregnancy Nonfunctioning Pituitary Tumors Gonadotroph Cell Tumors Presentation Evaluation Treatment Surgery Postoperative Radiotherapy Expectant Observation for Incidentalomas Pregnancy Medications Silent Corticotroph Tumors Silent Subtype 3 Tumors Silent GH-Expressing Tumors Acromegaly Incidence Pathogenesis Pituitary Acromegaly Disordered GHRH Secretion or Action Disordered Somatotroph Cell Function McCune-Albright Syndrome Extrapituitary Acromegaly GHRH Hypersecretion Ectopic Pituitary Adenomas Peripheral Growth Hormone–Secreting Tumors Acromegaloidism Gigantism Clinical Features of Acromegaly Growth Hormone and Tumor Formation Endocrine Complications Morbidity and Mortality Diagnosis Measurement of Growth Hormone and IGF1 Levels Differential Diagnosis Treatment Aims Surgical Management Side Effects Radiation Therapy Side Effects Medical Management Dopamine Agonists SRLs Growth Hormone Receptor Antagonist SRLs and GH Receptor Antagonist Combination Management Approach ACTH-Secreting Tumors (Cushing Disease) Assessment of Surgical Outcome Medical Treatment Thyrotrophic Hormone-Secreting Tumors Pathology Presentation Evaluation Management Surgery Radiation Therapy SRLs Preoperative Management Silent TSH-Secreting Tumors 10 - Posterior Pituitary Anatomy Normal Ectopic Posterior Pituitary Synthesis and Release of Neurohypophyseal Hormones Physiology of Secretion of Vasopressin and Thirst Volume and Pressure Regulation Osmotic Regulation Thirst Clinical Consequences of Osmotic and Volume Regulation Reset Osmostat During Pregnancy Osmotic Regulation in Aging Diabetes Insipidus Causes of Diabetes Insipidus Diabetes Insipidus Due to Excess Fluid Intake (Primary Polydipsia) Hypothalamic/Central Diabetes Insipidus Diabetes Insipidus Due to Accelerated Metabolism of Vasopressin (Diabetes Insipidus of Pregnancy) Nephrogenic Diabetes Insipidus Approach to the Differential Diagnosis of Polyuric States Further Investigations of Diabetes Insipidus Treatment of Polyuric Conditions Central Diabetes Insipidus in Ambulatory Patients Central Diabetes Insipidus in Hospitalized Patients Central Diabetes Insipidus in Neurosurgical Patients Adipsic Diabetes Insipidus Treatment of Diabetes Insipidus in Pregnancy Treatment of Nephrogenic Diabetes Insipidus Treatment of Primary Polydipsia Diabetes Insipidus in Association With Other Therapeutic Decisions Routine Surgical Procedures Panhypopituitarism Hypertonic Encephalopathy The Syndrome of Inappropriate Antidiuresis Hypoosmolality and Hyponatremia Incidence Osmolality, Tonicity, and Serum [Na+] Pathogenesis of Hypoosmolality Solute Depletion Water Retention Adaptation to Hyponatremia: ICF and ECF Volume Regulation Differential Diagnosis of Hyponatremia and Hypoosmolality Decreased Extracellular Fluid Volume Increased Extracellular Fluid Volume Normal Extracellular Fluid Volume Syndrome of Inappropriate Antidiuresis Etiology Tumors Central Nervous System Disorders Drugs Pulmonary Disorders Other Causes Pathophysiology Sources of Vasopressin Secretion Pituitary Vasopressin Secretion—Inappropriate Versus Appropriate Patterns of Vasopressin Secretion Contribution of Natriuresis to the Hyponatremia of SIAD Cerebral Salt Wasting Renal Escape From Antidiuresis Hypoosmolar Symptoms, Morbidity, and Mortality Therapy of SIAD and Other Hypoosmolar Disorders General Principles Therapies for Treatment of Hyponatremia Hypertonic Saline Isotonic Saline Fluid Restriction Arginine Vasopressin Receptor Antagonists Urea Furosemide and NaCl Efficacy of Hyponatremia Treatment Hyponatremia Treatment Guidelines Based on Symptom Severity Monitoring the Serum [Na+] in Hyponatremic Patients Long-Term Treatment of Chronic Hyponatremia Oxytocin Lactation Parturition Behavior 11 - Thyroid Pathophysiology and Diagnostic Evaluation Phylogeny, Embryology, and Ontogeny Phylogeny Structural Embryology Functional Ontogeny Anatomy and Histology Iodine and the Synthesis and Secretion of Thyroid Hormones Dietary Iodine Iodide Metabolism by the Thyroid Cell Iodide Oxidation and Organification Iodothyronine Synthesis Storage and Release of Thyroid Hormone Deiodination of Iodotyrosines Role and Mechanism of Thyrotropin Effects Thyroid Hormones in Peripheral Tissues Plasma Transport Thyroxine-Binding Globulin Transthyretin Competition for T4 and T3 Binding to TBG and TTR by Therapeutic Agents Albumin Other Plasma Thyroid Hormone–Binding Proteins Free Thyroid Hormones T4 and T3 Transport Across Cell Membranes and Intracellular T3 Binding Iodothyronine Deiodination Enzymology and Regulation of the Selenodeiodinases Quantitative and Qualitative Aspects of Thyroid Hormone Metabolism Thyroid Hormone Turnover Sources of Intracellular T3 Pharmacologic Agents Inhibiting Thyroid Hormone Deiodination Mechanism of Thyroid Hormone Action Regulation of Thyroid Function The Hypothalamic-Pituitary-Thyroid Axis Thyrotropin-Releasing Hormone Synthesis and Secretion Thyrotropin Synthesis and Secretion Iodine Deficiency Iodine Excess Effects of Increased Iodine Intake on Thyroid Hormone Synthesis Effects on Thyroid Hormone Release Thyroid Function in Pregnancy and in the Fetus and Newborn Fetal Thyroid Function Maternal-Fetal Interactions Thyroid Function in the Newborn Aging and the Thyroid Thyroid Function During Fasting or Illness The Thyroid Axis and Neuropsychiatric Illness Effects of Hormones on Thyroid Function Glucocorticoids Gonadal Steroids Growth Hormone Physical Evaluation of the Thyroid Gland Physical Examination Laboratory Assessment of Thyroid Status Tests of the Hypothalamic-Pituitary-Thyroid Axis Thyroid-Stimulating Hormone TSH in Patients with Thyroid Dysfunction Quantitation of Serum Thyroid Hormone Concentrations Total T4 and T3 Concentrations of Free T4 and Free T3 The Free T4 Index Causes of Abnormal TSH or Thyroid Hormone Concentrations Causes of a Suppressed TSH Causes of an Elevated TSH Tests That Assess the Metabolic Impact of Thyroid Hormones Basal Metabolic Rate Biochemical Markers of Altered Thyroid Status Serum Thyroglobulin Tests for Thyroid Autoantibodies Autoantibodies to Thyroid Peroxidase and Thyroglobulin Do Thyroglobulin and Thyroid Peroxidase Antibodies Have a Pathogenic Role? Thyroid Autoantibodies in Hashimoto Thyroiditis and Graves Disease Thyroid Autoantibodies in Nonautoimmune Thyroid Disorders Thyroid Autoantibodies in Pregnancy The Normal Population Radioiodine Uptake Physiologic Basis Radioactive Iodine Uptake The Perchlorate Discharge Test States Associated With Increased RAIU Hyperthyroidism Aberrant Hormone Synthesis Iodine Deficiency Response to Thyroid Hormone Depletion Excessive Hormone Losses States Associated With Decreased RAIU Exogenous Thyroid Hormone: Thyrotoxicosis Factitia Disorders of Hormone Storage Exposure to Excessive Iodine 12 - Hyperthyroid Disorders Clinical Manifestations of Thyrotoxicosis Cardiovascular System Protein, Carbohydrate, and Lipid Metabolism Sympathetic Nervous System and Catecholamines Nervous System Muscle Eyes Skin and Hair Respiratory System Alimentary System Skeletal System: Calcium and Phosphorus Metabolism Renal Function: Water and Electrolyte Metabolism Hematopoietic System Pituitary and Adrenocortical Function Reproductive Function Laboratory Diagnosis GRAVES DISEASE Graves Hyperthyroidism Clinical Presentation Pathology Immunopathogenesis TSH Receptor, the Major Autoantigen in Graves Disease Etiology Existential Factors Genetic Variants Environmental Insults Iodine Smoking Alcohol Selenium Stress Infections Drugs Diagnosis and Differential Diagnosis Natural History and Prognosis Treatment Antithyroid Drugs: Thionamides Mechanism of Action Adverse Effects (Table 12.4) Practical Use Other Drugs Used in Hyperthyroidism Radioactive Iodine Choice of Therapy Graves Orbitopathy Clinical Presentation Epidemiology Pathology Immunopathogenesis Genetics and Environment Natural History and Prognosis Diagnosis and Differential Diagnosis Ocular Symptoms and Signs Thyroid Autoimmunity Orbital Imaging Treatment General Measures Thyroid Treatment Eye Treatment Graves Dermopathy Pregnancy and the Thyroid Human Chorionic Gonadotropin Transient Gestational Thyrotoxicosis Abnormal Responses to Human Chorionic Gonadotropin Graves Disease During Pregnancy and the Postpartum Period Influence of Pregnancy on the Immune System Thyroid Antibodies in Pregnant Patients With Graves Disease Differential Diagnosis Diagnosis Treatment During Pregnancy Antithyroid Drugs in Pregnancy Danger of Antithyroid Drugs in Pregnancy Caring for the Pregnant Patient Iodide and Beta Blockers Surgery Consequences of Overtreatment Graves Disease in the Postpartum Period Changes in the Immune Response in the Postpartum Period Transient Postpartum Thyroiditis Presentation of Postpartum Graves Disease Preconception Counseling Nursing and Antithyroid Drugs Inherited Nonimmune Hyperthyroidism Toxic Multinodular Goiter Pathogenesis Clinical Presentation Laboratory Tests and Differential Diagnosis Treatment Radioiodine Therapy Surgery Additional Treatment Options Toxic Adenoma Pathogenesis Clinical Presentation Laboratory Tests Treatment Radioiodine Therapy Surgery Subclinical Hyperthyroidism Definition Diagnosis Treatment Induced Hyperthyroidism Amiodarone-Induced Thyrotoxicosis Epidemiology and Screening Diagnosis Management Prognosis Hyperthyroidism Due to Thyrotropin Secretion Pituitary Tumor Thyroid Hormone Resistance Tumor Chorionic Gonadotropin-Induced Hyperthyroidism Transient Thyrotoxicosis Overview Transient Thyrotoxicosis Due to Autoimmune (Hashimoto) Thyroiditis Transient Thyrotoxicosis From Painless Autoimmune Thyroiditis Transient Thyrotoxicosis from Painful Autoimmune Thyroiditis Clinical Presentation of Transient Autoimmune Thyrotoxicosis Diagnosis Natural History Treatment Subacute Thyroiditis Pathology Pathophysiology Clinical Picture Diagnosis Treatment Drug-Associated Thyroiditis Other Causes of Thyrotoxicosis With a Low Radioiodine Uptake Thyrotoxicosis Factitia Hamburger Thyrotoxicosis Thyrotoxicosis Due to Extrathyroidal Tissue Struma Ovarii Clinical Presentation Treatment Thyrotoxicosis Due to Metastatic Thyroid Carcinoma 13 - Hypothyroidism and Thyroiditis Hypothyroidism Clinical Presentation Skin and Appendages Cardiovascular System Respiratory System Alimentary System Central and Peripheral Nervous Systems Muscular System Skeletal System: Calcium and Phosphorus Metabolism Renal Function: Water and Electrolyte Metabolism Hematopoietic System Pituitary and Adrenocortical Function Reproductive Function Catecholamines Energy Metabolism: Protein, Carbohydrate, and Lipid Metabolism Current Clinical Picture Hypothyroidism in Infants and Children Laboratory Evaluation Primary and Central Hypothyroidism Differential Diagnosis Classification Immune-Mediated Autoimmune Hypothyroidism Risk Factors Iodine Deficiency (Endemic Goiter) Endemic Cretinism Iodide Excess Drugs Blocking Thyroid Hormone Synthesis or Release, Causing Goiter Formation Goitrogens in Foodstuffs or as Endemic Substances or Pollutants Cytokines Congenital Causes of Goiter Thyroid Infiltration Causing Hypothyroidism and Goiter Postablative Hypothyroidism Thyroid Agenesis or Dysplasia Thyroid Aplasia Due to Thyrotropin Receptor Unresponsiveness Transient Hypothyroidism Consumptive Hypothyroidism Defects in Conversion of Thyroxine to Triiodothyronine Hypothyroidism Due to Drug-Induced Thyroid Destruction Central Hypothyroidism Resistance to Thyroid Hormone Treatment Pharmacologic and Physiologic Considerations Institution of Replacement Therapy Infants and Children Monitoring Replacement Therapy Adverse Effects of Levothyroxine Therapy Patients With Hypothyroid Symptoms Despite Restitution of Normal Thyroid Function Special Aspects of Hypothyroidism Subclinical Hypothyroidism Metabolic Insufficiency Thyroid Function Testing in Patients Receiving Replacement Therapy for Unclear Reasons Emergent Surgery in the Hypothyroid Patient Heart Disease and Thyroid Hormone Therapy Coexisting Coronary Artery Disease and Hypothyroidism Thyroid Hormone for Compromised Cardiovascular Function Screening for Primary Hypothyroidism Myxedema Coma Thyroiditis Acute Infectious Thyroiditis Incidence Clinical Manifestations Riedel Thyroiditis Miscellaneous Causes 14 - Nontoxic Diffuse Goiter, Nodular Thyroid Disorders, and Thyroid Malignancies Structural and Functional Imaging of the Thyroid Ultrasonography External Scintiscanning Computed Tomography Magnetic Resonance Imaging Positron Emission Tomography (PET) Nontoxic Goiter and Thyroid Nodular Disease Definitions Epidemiology of Goiter Etiology and Pathophysiology of Diffuse Goiter Natural History of Goiter and Thyroid Nodules Clinical Presentation of Goiter and Nodules The Approach to Thyroid Nodular Disease The Evaluation of Patients With Nodular Disease Thyroid Nodule Fine-Needle Aspiration Management Options for Patients With Nontoxic Diffuse Goiter and Nodular Thyroid Disease Malignant Thyroid Disorders Classification and Staging of Thyroid Cancer Follicular Adenomas and Borderline Thyroid Lesions With Malignant Potential Papillary Thyroid Carcinoma Molecular Pathogenesis of Papillary Thyroid Carcinoma Presenting Features of Papillary Thyroid Carcinoma Risk of Papillary Thyroid Carcinoma Recurrence and Mortality Prediction of Papillary Thyroid Carcinoma Recurrence Follicular Thyroid Carcinoma Molecular Pathogenesis of Follicular Thyroid Carcinoma Hürthle Cell Carcinoma Presenting Features of Follicular Thyroid Carcinoma Risk of Follicular Thyroid Carcinoma Recurrence and Mortality Outcome Prediction for Follicular Thyroid Carcinoma Poorly Differentiated Carcinoma Undifferentiated (Anaplastic) Carcinoma Medullary Thyroid Carcinoma Histologic Diagnosis of Medullary Thyroid Carcinoma Clinical Presentation of Medullary Thyroid Carcinoma Prognosis for Medullary Thyroid Carcinoma Primary Malignant Lymphoma of the Thyroid The Surgical Treatment of Thyroid Malignancy Active Surveillance as an Alternative to Immediate Surgery in Low-Risk Differentiated Thyroid Cancer Selecting Total Thyroidectomy or Thyroid Lobectomy in Differentiated Thyroid Cancer: A Risk-Adapted Approach Determining the Extent of Initial Cervical Lymph Node Dissection in Differentiated Thyroid Cancer Surgical Approach to Medullary Thyroid Cancer Surgical Approach to Anaplastic Thyroid Cancer Postoperative Management of Thyroid Malignancy 131I Administration External Radiotherapy TSH Suppressive Therapy Long-Term Follow-Up of Patients With Thyroid Cancer Following Initial Therapy Initial Follow-Up Recommendations for Differentiated Thyroid Cancer (First Year After Initial Therapy) Modifying Initial Follow-Up Recommendations for Differentiated Thyroid Cancer Using Response to Therapy Definitions Follow-Up Recommendations Based on Response to Therapy Status Risk-Adapted Follow-Up Recommendations for Medullary Thyroid Cancer Treatment of Thyroid Cancer Recurrence and Distant Disease Locoregional Recurrences of PTC and FTC Management of Distant Metastatic Disease Complications of Treatment With 131I Refractoriness to Radioactive Iodine Molecular Targeted Systemic Therapies Vandetanib Sorafenib Lenvatinib Therapy for Recurrence of Medullary Thyroid Carcinoma Vandetanib and Cabozantinib (XL184) Targeted Molecular Therapy 15 - The Adrenal Cortex The Adrenal Cortex—Historical Milestones Anatomy and Development Adrenal Steroids and Steroidogenesis Regulation of Adrenal Steroidogenesis: Functional Zonation of the Adrenal Cortex Glucocorticoid Secretion: The Hypothalamic-Pituitary-Adrenal Axis Pro-opiomelanocortin and ACTH Corticotropin-Releasing Hormone and Arginine Vasopressin The Stress Response and Immune-Endocrine Axis Circadian Rhythm Negative Feedback The ACTH Receptor and ACTH Effects on the Adrenal Gland Mineralocorticoid Secretion: The Renin-Angiotensin-Aldosterone Axis Adrenal Androgen Secretion Corticosteroid Hormone Action Receptors and Gene Transcription Corticosteroid-Binding Globulin and Corticosteroid Hormone Metabolism Effects of Glucocorticoids Carbohydrate, Protein, and Lipid Metabolism Skin, Muscle, and Connective Tissue Bone and Calcium Metabolism Salt and Water Homeostasis and Blood Pressure Control Anti-inflammatory Actions and the Immune System Central Nervous System and Mood Eye Gut Growth and Development Endocrine Effects Therapeutic Corticosteroids Administration Long-Term Therapy Adrenocortical Diseases Glucocorticoid Excess Cushing Syndrome Clinical Features of Cushing Syndrome Obesity and Weight Gain Reproductive Organs Psychiatric Features Bone Skin Muscle Cardiovascular Features Infections Metabolic and Endocrine Features Eye Classification and Pathophysiology of Cushing Syndrome ACTH-Dependent Causes Cushing Disease Ectopic ACTH Syndrome Ectopic Corticotropin-Releasing Hormone Syndrome Macronodular Adrenal Hyperplasia ACTH-Independent Causes Cortisol-Secreting Adrenal Adenoma and Carcinoma Primary Pigmented Nodular Adrenal Hyperplasia and Carney Syndrome McCune-Albright Syndrome Macronodular Hyperplasia Iatrogenic Cushing Syndrome Special Features of Cushing Syndrome Cyclic Cushing Syndrome Cushing Syndrome in Children Pregnancy Other Syndromes of Hypercortisolemia Alcohol Depression Obesity Investigation of Patients With Suspected Cushing Syndrome Question 1: Does This Patient Have Cushing Syndrome? Circadian Rhythm of Plasma Cortisol Salivary Cortisol Urinary Free Cortisol Excretion Low-Dose Overnight Dexamethasone Suppression Tests Other Causes of Hypercortisolemia: Pseudo-Cushing or True Cushing Syndrome? Diagnostic Guidelines Question 2: What Is the Cause of Cushing Syndrome in This Patient? Morning Plasma ACTH Plasma Potassium High-Dose Dexamethasone Suppression Test Corticotropin-Releasing Hormone Test Inferior Petrosal Sinus Sampling and Selective Venous Catheterization Imaging CT/MRI Scanning of Pituitary and Adrenal Glands Nuclear Medicine and Molecular Imaging Studies Treatment of Cushing Syndrome Adrenal Causes Pituitary-Dependent Cushing Syndrome Ectopic ACTH Syndrome Medical Treatment of Cushing Syndrome Prognosis of Cushing Syndrome Glucocorticoid Resistance Glucocorticoid Deficiency Primary and Central Hypoadrenalism Primary Hypoadrenalism Addison Disease Autoimmune Adrenalitis Infections Acquired Primary Adrenal Insufficiency Inherited Primary Adrenal Insufficiency Secondary Hypoadrenalism Inherited Central Hypoadrenalism ACTH Suppression by Exogenous Glucocorticoids Hypoadrenalism During Critical Illness Clinical Features of Adrenal Insufficiency Investigation of Hypoadrenalism Routine Biochemical Profile Mineralocorticoid Status Assessing Adequacy of Function of the HPA Axis Testing the HPA Axis During Critical Illness Other Tests Treatment of Acute Adrenal Insufficiency Long-Term Replacement Therapy Congenital Adrenal Hyperplasia 21-Hydroxylase Deficiency Simple Virilizing Form Salt-Wasting Form Nonclassic or Late-Onset 21-Hydroxylase Deficiency Heterozygote 21-Hydroxylase Deficiency Molecular Genetics Diagnostic Criteria Treatment Long-Term Complications and Comorbid Conditions 11β-Hydroxylase Deficiency 17α-Hydroxylase Deficiency P450 Oxidoreductase Deficiency: Apparent Combined 17α-Hydroxylase and 21-Hydroxylase Deficiencies 3β-Hydroxysteroid Dehydrogenase Deficiency StAR Deficiency: Congenital Lipoid Adrenal Hyperplasia P450 Side-Chain Cleavage Deficiency Cortisone Reductase Deficiency Mineralocorticoid Deficiency Primary Defects in Aldosterone Biosynthesis: Aldosterone Synthase Deficiency Postadrenalectomy Hypoaldosteronism Defects in Aldosterone Action: Pseudohypoaldosteronism Hyporeninemic Hypoaldosteronism Adrenal Adenomas, Incidentalomas, and Carcinomas Adenomas Incidentalomas Carcinomas Etiology of Adrenal Tumors Acknowledgments 16 - Endocrine Hypertension Adrenal Medulla and Catecholamines Catecholamine Synthesis Catecholamine Storage and Secretion Catecholamine Metabolism and Inactivation Pheochromocytoma and Paraganglioma History Clinical Presentation Syndromic Forms of Pheochromocytoma and Paraganglioma Multiple Endocrine Neoplasia Type 2A Multiple Endocrine Neoplasia Type 2B von Hippel-Lindau Disease Neurofibromatosis Type 1 Congenital Polycythemia Carney Triad Congenital Heart Disease Other Genetic Forms of Pheochromocytoma and Paraganglioma Succinate Dehydrogenase Gene Mutations TMEM127 Mutations MAX Mutations FH Mutations Genetic Testing Evaluation and Monitoring of Carriers of Succinate Dehydrogenase Mutations Diagnostic Investigation Differential Diagnosis Case Detection Measurement of Fractionated Metanephrines and Catecholamines in Urine and Plasma Other Tests That Have Been Used to Assess for Pheochromocytoma Renal Failure Factitious Pheochromocytoma Localization Imaging Phenotype 68Ga-DOTATATE PET/CT and 123I-MIBG Scintigraphy Other Localizing Procedures Treatment Preoperative Management α-Adrenergic Blockade β-Adrenergic Blockade Catecholamine Synthesis Inhibitor Calcium Channel Blockers Acute Hypertensive Crises Anesthesia and Surgery Long-Term Postoperative Follow-Up Metastatic Pheochromocytoma and Paraganglioma Pheochromocytoma in Pregnancy Renin-Angiotensin-Aldosterone System Renin and Angiotensin Aldosterone Primary Aldosteronism History Prevalence Clinical Presentation Diagnosis Case-Detection Tests Confirmatory Tests Oral Sodium Loading Test Intravenous Saline Infusion Test Fludrocortisone Suppression Test Subtype Studies Computed Tomography of the Adrenal Glands Adrenal Venous Sampling Noninvasive Alternatives to Adrenal Vein Sampling Familial Hyperaldosteronism Glucocorticoid-Remediable Aldosteronism: Familial Hyperaldosteronism Type I—CYP11B1/CYP11B2 Germline Chimeric Gene Familial Hyperaldosteronism Type II—CLCN2 Chloride Channel Germline Mutations Familial Hyperaldosteronism Type III—Germline KCNJ5 Mutations Familial Hyperaldosteronism Type IV—Germline CACNA1H Gene Mutations Primary Aldosteronism With Seizures and Neurologic Abnormalities (PASNA)—Germline CACNA1D Mutations Primary Aldosteronism and ARMC5 Mutations Somatic Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 Genes Aldosterone-Producing Cell Clusters Cortisol Cosecretion Principles of Treatment Surgical Treatment of Aldosterone-Producing Adenoma and Unilateral Hyperplasia Pharmacologic Treatment Primary Aldosteronism in the Setting of Pregnancy Other Forms of Mineralocorticoid Excess or Effect Hyperdeoxycorticosteronism Congenital Adrenal Hyperplasia 11β-Hydroxylase Deficiency 17α-Hydroxylase Deficiency Deoxycorticosterone-Producing Tumor Primary Cortisol Resistance Apparent Mineralocorticoid Excess Syndrome Liddle Syndrome: Abnormal Renal Tubular Ionic Transport Other Endocrine Disorders Associated With Hypertension Cushing Syndrome Thyroid Dysfunction Hyperthyroidism Hypothyroidism Renin-Secreting Tumor Acromegaly 17 - Physiology and Pathology of the Female Reproductive Axis Reproductive Physiology Reproductive Functions of the Hypothalamus Gonadotropin-Releasing Hormone Regulation of Gonadotropin-Releasing Hormone Secretion Gonadotropin-Releasing Hormone Analogues Peptide Gonadotropin-Releasing Hormone Agonists Peptide Gonadotropin-Releasing Hormone Antagonists Nonpeptide Gonadotropin-Releasing Hormone Antagonists Reproductive Functions of the Anterior Pituitary Gonadotrophs Gonadotropin-Releasing Hormone Receptor Luteinizing Hormone and Follicle-Stimulating Hormone Regulation of Circulating Levels of Follicle-Stimulating Hormone and Luteinizing Hormone Ovary Genetic Determinants of Ovarian Differentiation and Folliculogenesis Oocytes Granulosa Cell Layer Theca Cell Layer Follicles Ovulation Corpus Luteum Ovarian Follicle-Stimulating Hormone and Luteinizing Hormone Receptors Role of Follicle-Stimulating Hormone in Ovarian Function Role of Luteinizing Hormone in Ovarian Function Ovarian Steroidogenesis Steroidogenic Genes and Their Functions in the Ovary C21 Steroids C19 Steroids C18 Steroids Two-Cell Theory for Ovarian Steroidogenesis Peptide Hormones Produced by the Ovary Overview of the Hormonal Changes During the Ovarian Cycle Extraovarian Steroidogenesis Endometrium Functional Anatomy of the Endometrium Hormone-Induced Morphologic Changes of the Endometrium Effects of Ovarian Steroids on Endometrium Estrogen Action Progesterone Action The Receptive Phase of the Endometrium for Implantation Control of Endometrial Function With the Use of Exogenous Hormones Mechanism of Menstruation Approach to the Woman With Reproductive Dysfunction History Physical Examination Disorders of the Female Reproductive System Chronic Anovulation Hypothalamic Anovulation Functional Hypothalamic Amenorrhea Diagnosis of Functional Hypothalamic Amenorrhea Pathophysiology of Functional Hypothalamic Anovulation Hypothalamic Anovulation and Exercise Hypothalamic Anovulation Associated With Eating Disorders Treatment and Management of Functional Hypothalamic Anovulation Chronic Anovulation Associated With Pituitary Disorders Chronic Anovulation Associated With Androgen Excess Approach to the Patient With Androgen Excess Origins of Androgens Laboratory Evaluation of Androgen Action Causes of Androgen Excess Idiopathic Hirsutism Androgen-Secreting Tumors of the Ovary and Adrenal Nonneoplastic Adrenal Disorders and Androgen Excess Laboratory Testing to Aid the Differential Diagnosis of Androgen Excess Treatment of Hirsutism Oral Contraceptives Spironolactone Cyproterone Acetate Finasteride Flutamide Metformin and Thiazolidinediones Lifestyle Modification A Comprehensive Treatment Strategy for Hirsutism Polycystic Ovary Syndrome Historical Perspective Diagnosis of Polycystic Ovary Syndrome and Laboratory Testing Gonadotropin Production in Polycystic Ovary Syndrome Steroid Production in Polycystic Ovary Syndrome Production of Sex Hormone–Binding Globulin in Polycystic Ovary Syndrome Follicular Fate in Polycystic Ovary Syndrome Ovarian Hyperthecosis Genetics of Polycystic Ovary Syndrome Insulin Resistance and Polycystic Ovary Syndrome Role of Obesity in Insulin Resistance and Anovulation Laboratory Evaluation of Metabolic Syndrome in PCOS Use of Antidiabetic Drugs to Treat Anovulation and Androgen Excess Management of Long-Term Deleterious Effects of Polycystic Ovary Syndrome Ovulation Induction in Polycystic Ovary Syndrome Clomiphene Citrate Aromatase Inhibitors Metformin Low-Dose Gonadotropin Therapy Premature Ovarian Insufficiency Diagnosis and Management of Premature Ovarian Insufficiency Diagnosis and Management of Anovulatory Uterine Bleeding Characteristics of Normal Menses Terminology Describing Abnormal Uterine Bleeding Uterine Bleeding in Response to Steroid Hormones Estrogen Withdrawal Bleeding Estrogen Breakthrough Bleeding Progesterone Withdrawal Bleeding Progestin Breakthrough Bleeding Causes of Irregular Uterine Bleeding Management of Anovulatory Uterine Bleeding Oral Contraceptives Oral Contraceptives and Acute Excessive Uterine Bleeding Associated With Anemia Oral Contraceptives and Chronic Irregular Uterine Bleeding Synthetic Progestins High-Dose Estrogen for Acute Excessive Uterine Bleeding Gonadotropin-Releasing Hormone Analogues for Excessive Anovulatory Uterine Bleeding Hormone-Dependent Benign Gynecologic Disorders Endometriosis Pathology Mechanism of Disease Diagnosis Treatment Uterine Leiomyomas Management of Menopause Consequences of Menopause Perimenopause Stage Menopause Features Biosynthesis of Estrogen and Other Steroids in the Postmenopausal Woman Postmenopausal Uterine Bleeding Hot Flashes Urogenital Atrophy Postmenopausal Osteoporosis Postmenopausal Hormone Therapy The Long-Term Benefits and Side Effects of Hormone Therapy Risks and Contraindications of Hormone Therapy Coronary Heart Disease Stroke Pulmonary Embolism Breast Cancer Dementia Hypertriglyceridemia Gallbladder Disease Urinary Incontinence Indications for Hormone Therapy Hot Flashes Fractures Diabetes Post-WHI Recommendations for Hormone Therapy Target Groups for Hormone Therapy Estrogen Preparations and Beneficial Dose of Estrogen Oral Estrogens: Combined Conjugated Equine Estrogens Transdermal Estrogen Vaginal Estrogen Management of Breakthrough Bleeding During Postmenopausal Hormone Therapy Management of Menopausal Symptoms in Breast Cancer Survivors Selective Estrogen Receptor Modulators and Bisphosphonates for Osteoporosis Prevention Tibolone for Osteoporosis Prevention 18 - Hormonal Contraception Choosing a Contraceptive Method Combined Estrogen and Progestin Contraceptives The Combined Oral Contraceptive Pill Composition and Formulations Mechanism of Action, Efficacy, Administration, and Effect on Pregnancy Noncontraceptive Health Benefits Side Effects Health Risks Thromboembolic Disease Myocardial Infarction and Thrombotic Stroke Breast Cancer Cervical Cancer Use of Concomitant Medications With Combined Oral Contraceptives Pills Contraceptive Vaginal Ring and Transdermal Patch Transdermal Contraceptive Patch Contraceptive Vaginal Ring Progestin-Only Contraceptive Methods Progestin-Only Oral Contraceptive Pill Mechanism of Action Efficacy Starting the Progestin-Only Pill Side Effects of Progestin-Only Oral Contraceptives Other Effects Progestin-Only Oral Contraceptives During Lactation Depot Medroxyprogesterone Acetate for Contraception Formulations and Pharmacology Administration of DMPA Starting Injections Repeat Injections Side Effects of DMPA Risks and Benefits of DMPA Effect on Cancer Risk Effect on Cardiovascular Risk Effect on Skeletal Health Effect on Sexually Transmitted Infections Effect on Return of Fertility Progestin-Releasing Intrauterine Devices Contraceptive Uses Expanding the Use of IUDs Abnormal Bleeding, Expulsion, and Uterine Perforation Upper Genital Tract Infection and Infertility Metabolic and Systemic Effects Noncontraceptive Uses of the Levonorgestrel-Releasing Intrauterine System Heavy Menstrual Bleeding Symptomatic Fibroids and Uterine Adenomyosis Endometriosis Endometrial Protection With Estrogen Replacement Therapy Endometrial Protection With Tamoxifen Use Treatment for Endometrial Hyperplasia or Carcinoma Contraceptive Implants Description and Pharmacology Mechanism of Action and Efficacy Safety and Side Effect Profile Patient Selection Insertion and Removal Emergency Contraception Emergency Contraception Regimens Mechanism of Action Efficacy Indications Side Effects Ongoing Contraception Clinical Challenges in Contraceptive Care Hormonal Contraception for Adolescents Combined Hormonal Contraceptives in Adolescents Injectable Contraceptives in Adolescents Hormonal Contraception in Postpartum and Lactating Women Hormonal Contraception in Women Older Than 35 Years Discontinuation of Hormonal Contraception at Menopause Contraception in Women With Underlying Medical Conditions Hormonal Contraception in Obese Women Hormonal Contraception in Women Taking Antiepileptic Drugs Hormonal Contraception in Women Taking Antibiotics Hormonal Contraception in HIV-Positive Women Hormonal Contraception and Chronic Hypertension Hormonal Contraception in Women With Diabetes Hormonal Contraception in Women Awaiting Surgery Hormonal Contraception in Women With a History of Thromboembolism Hormonal Contraception in Women Taking Anticoagulation Therapy Hormonal Contraception for Women With Migraine Headaches Hormonal Contraception in Women With Systemic Lupus Erythematosus Hormonal Contraception in Women With Sickle Cell Disease Hormonal Contraception in Depression 19 - Testicular Disorders Functional Anatomy and Histology The Testis Seminiferous Tubule Spermatogenesis Proliferative Phase Meiotic Phase Spermiogenesis Germ Cell Loss Organization of Spermatogenesis Sperm Transport and Fertilization Spermatozoa Interstitium Testis Development Fetal Development Testis Descent Postnatal Development Pubertal Development Adult Physiology Hypothalamic-Pituitary-Testicular Axis Central Nervous System Regulation of Gonadotropin-Releasing Hormone Secretion GnRH Regulation of Gonadotropin Secretion Gonadotropin Control of Testicular Function LH Regulation of Leydig Cells Leydig Cell Production of Testosterone and INSL3 FSH and Testosterone Regulation of Sertoli Cells Maintenance of Seminiferous Tubule Structure and Compartmentalization Provision of Nutrients and Growth Factors to Developing Germ Cells and Spermatozoa Translocation, Sculpting, and Release of Developing Germ Cells Secretion of Seminiferous Tubule Fluid Production of Reproductive Hormones Paracrine and Autocrine Regulation of Testis Function Hormonal Control of Spermatogenesis Initiation of Spermatogenesis Maintenance of Spermatogenesis Negative Feedback Regulation of Gonadotropin Secretion Testosterone Transport, Metabolism, and Actions Circulating Testosterone Active Metabolism and Catabolism of Testosterone Aromatization of Testosterone to Estradiol 5α-Reduction of Testosterone to DHT Catabolism of Testosterone Mechanisms of Androgen Action Androgen Effects at Various Stages of Sexual Development Male Hypogonadism Clinical Manifestations Fetal Androgen Deficiency Prepubertal Onset of Androgen Deficiency Adult Androgen Deficiency Isolated Impairment of Sperm Production or Function History and Physical Examination Differential Diagnosis Sexual Dysfunction Hypoactive Sexual Desire Disorder and Erectile Dysfunction Ejaculatory Disorders and Orgasmic Dysfunction Gynecomastia Causes of Gynecomastia Evaluation Treatment Infertility Causes of Male Infertility Evaluation Treatment Diagnosis of Male Hypogonadism Clinical Manifestations of Androgen Deficiency Testosterone Measurements Variability in Testosterone Concentrations Total Testosterone Assays Total Testosterone Affected by Alterations in SHBG Transient Suppression of Testosterone Screening and Case Finding for Androgen Deficiency Seminal Fluid Analysis Gonadotropin Measurements Androgen Deficiency and Impaired Sperm Production Isolated Impairment of Sperm Production or Function Further Evaluation Causes of Primary Hypogonadism Androgen Deficiency and Impairment in Sperm Production Congenital or Developmental Disorders Acquired Disorders Systemic Disorders Isolated Impairment of Sperm Production or Function Congenital or Developmental Disorders Varicocele Acquired Disorders Systemic Disorders Causes of Secondary Hypogonadism Androgen Deficiency and Impairment in Sperm Production Congenital or Developmental Disorders Acquired Disorders Systemic Disorders Isolated Impairment of Sperm Production or Function Congenital or Developmental Disorders Acquired Disorders Androgen Resistance Syndromes Congenital Disorders Acquired Disorders Treatment of Androgen Deficiency Functional Versus Organic Causes of Hypogonadism Testosterone Replacement Therapy Therapeutic Goals and Management Testosterone Formulations Testosterone Formulations Available Outside the United States Nontestosterone Therapies for Male Hypogonadism Monitoring Clinical Response and Testosterone Concentrations Risks and Adverse Effects Gonadotropin Therapy 20 - Sexual Dysfunction in Men and Women Human Sexual Response Cycle Physiologic Mechanisms of Human Sexual Response Physiology of Desire and Arousal Functional Brain Imaging of Sexual Arousal in Men and Women Neurotransmitters and Hormones Involved in Sexual Desire and Subjective Arousal Animal Models Genital Sexual Congestion and Arousal Physiologic Mechanisms of Penile Erection Penile Anatomy and Blood Flow Penile Innveration Hemodynamic Changes During Penile Erection Biochemical Regulation of Cavernosal Smooth Muscle Tone Potassium Channels Connexin43 Gap Junctions Nitric Oxide Cyclic Nucleotide Phosphodiesterases Regulation of Sensitivity to Intracellular Calcium by Rho A/Rho Kinase Signaling Mechanisms of Ejaculation Role of Testosterone in Regulating Sexual Function in Men Physiology of Physical Sexual Arousal in Women: Genital Congestion Physiology of Orgasm Revised Definitions of Sexual Dysfunction in Men Male Hypoactive Sexual Desire Disorder Erectile Dysfunction Prevalence and Incidence Risk Factors for Erectile Dysfunction Erectile Dysfunction as a Marker of Cardiovascular Disease Lower Urinary Tract Symptoms and ED Ejaculatory Disorders Delayed Ejaculation Retrograde Ejaculation Current Definitions of Sexual Disorders in Women Sexual Interest/Arousal Disorder Female Orgasmic Disorder Genitopelvic Pain/Penetration Disorder Persistent Genital Arousal Disorder Sexual Dysfunction in the Context of Endocrine Disease Endocrine Disorders and Sexual Dysfunction in Men Androgen Deficiency Syndromes Diabetes and Sexual Dysfunction in Men Sexual Dysfunction Associated With Therapies for Benign Prostatic Hypertrophy Hyperprolactinemia and Sexual Dysfunction Sexual Dysfunction in Patients With Thyroid Disease Sexual Dysfunction in Men With Metabolic Syndrome Endocrine Disorders and Sexual Dysfunction in Women Thyroid Disease in Women Hyperprolactinemia in Women Diabetes in Women Metabolic Syndrome in Women Polycystic Ovary Syndrome Congenital Adrenal Hyperplasia Pituitary Disease in Women Adrenal Insufficiency in Women Natural Menopause Surgical Menopause Aging-Associated Decline in Sex Hormone Precursors in Women Selective Estrogen Receptor Modulators Hormonal Contraceptives Androgen Insensitivity Syndrome Assessment of Sexual Dysfunction Evaluation of Men With Sexual Dysfunction Evaluation of Women With Sexual Dysfunction Physical Examination Laboratory Testing Management of Sexual Dysfunction in Men Treatment of Hypoactive Sexual Desire in Men Treatment of Erectile Dysfunction First-Line Therapies Psychosexual Counseling Selective Phosphodiesterase 5 Inhibitors Second-Line Therapies Vacuum Devices for Inducing Erection Intraurethral Therapies Intracavernosal Injection of Vasoactive Agents Third-Line Therapies Penile Prosthesis Testosterone Replacement in Androgen-Deficient Men Presenting With Erectile Dysfunction Therapies With Either Unproven Efficacy or Limited Efficacy Data Gene Therapy and Erectile Dysfunction Potential of Stem Cell Therapy for Erectile Dysfunction Management of Retrograde Ejaculation Management of Sexual Dysfunction in Women Management of Low Desire and Arousal in Women Psychoeducation Cognitive Behavioral Therapy Mindfulness-Based Cognitive Therapy Sex Therapy Outcome of Psychological Treatments for Women’s Sexual Dysfunctions Management of Women’s Orgasmic Disorder Management of Genitopelvic Pain/Penetration Disorder (Dyspareunia and Vaginismus) Management of Provoked Vestibulodynia Management of Phobic Reflex Pelvic Muscle Contractions Component of Genitopelvic Pain/Penetration Disorder (Vaginismus) Testosterone Therapy for Women With Sexual Dysfunction Testosterone Plus a Phosphodiesterase Inhibitor Limitations of Trials of Testosterone Therapy in Women Risks of Testosterone Therapy Needed Research in the Area of Testosterone Supplementation Oral Dehydroepiandrosterone for Sexual Dysfunction in Healthy Women Local Dehydroepiandrosterone Therapy for Sexual Dysfunction in Healthy Women Estrogen Therapy for Women With Sexual Dysfunction Vaginal Lubricants and Moisturizers Systemic Estrogen Approved But Not Recommended Medication for the Former DSM-IV Hypoactive Sexual Desire Disorder 21 - Transgender Endocrinology Introduction Definitions and Diagnosis of Gender Dysphoria Prevalence of Gender Nonconforming Identity Biological Determinants of Gender Identity Care of Transgender Youth Outcomes of Current Treatment Models for Transgender Youth and Potential Adverse Effects Mental Health Outcomes Potential Adverse Effects of Pubertal Blockers in Transgender Youth Skeletal Health Fertility Brain Body Mass Index and Body Composition Potential Adverse Effects of Gender-Affirming Sex Hormones in Transgender Adolescents Care of Transgender Adults Transfeminine Hormone Therapy Estrogen Testosterone-Lowering Agents 5α-Reductase Inhibitors Progesterone Transmasculine Hormone Therapy Potential Adverse Effects of Gender-Affirming Sex Hormones in Transgender Adults Potential Risks Associated With Transfeminine Hormone Therapy Venous Thrombosis and Pulmonary Embolism Myocardial Infarction and Cerebrovascular Accidents Hypertriglyceridemia Hyperprolactinemia Osteoporosis Breast Cancer Liver Dysfunction Potential Risks Associated With Transmasculine Hormone Therapy Erythrocytosis Hyperlipidemia Uterine and Cervical Cancer Barriers to Care and Priorities for Research for Transgender Youth and Adults References 22 - Endocrine Changes in Pregnancy Placental Development Sex Differences in the Placenta Maternal Adaptations to Pregnancy Physiologic Adaptations Metabolic Adaptations Maternal Endocrine Alterations Pituitary Gland Thyroid Gland Parathyroid Glands Pancreas Adrenal Glands Renin-Angiotensin System Placental Hormone Production Sex Steroid Production From the Maternal-Fetal-Placental Unit Protein Hormones Human Chorionic Gonadotropin Chemistry Biosynthesis Metabolism Physiologic Functions Gestational Trophoblastic Disease Human Placental Lactogen Placental Growth Hormone Human Chorionic Corticotropin Hypothalamic Peptides Gonadotropin-Releasing Hormone Corticotropin-Releasing Hormone Endocrinology of Pregnancy and Parturition Roles of Estrogens and Progesterone Role of Prostaglandins Role of Oxytocin Use of Placental Hormones in Genetic Screening and Pregnancy Outcomes Noninvasive Prenatal Testing and Microchimerism The “Fourth Trimester” and the Parental Brain 23 - Endocrinology of Fetal Development Placental Transfer of Hormones Ectopic Fetal Hormone Production Fetal Endocrine Systems Pituitary Human Hypothalamic-Pituitary Development Anterior Pituitary and Target Organs Intermediate Pituitary Lobe Posterior Pituitary Hypothalamus and Pituitary Stalk Genes Involved in Pituitary Disease Growth Hormone and Prolactin Adrenal Embryology Transcriptional Regulation of Adrenal Development Signaling Pathways in Adrenal Development Fetal Adrenal Steroidogenesis Hormonal Regulation of Adrenal Development The Fetal-Placental Unit Adrenal Insufficiency Thyroid Development Embryology Thyroid Hormone Biosynthesis Thyroid Hormone Action Ontogeny of Thyroid Hormone Secretion Genetic Regulation of Thyroid Development Putative Contributing Mechanisms to Thyroid Morphogenesis Thyroid Function in Preterm Infants Congenital Hypothyroidism Gonadal Development Embryology Fetal Sex Steroid Production Disorders of Sex Development Fetal Autonomic Nervous System Embryology Functional Development of the Sympathoadrenal System Endocrine Pancreas: Insulin and Glucagon Embryology Functional Development of the Endocrine Pancreas Pancreatic Regulation of Blood Glucose Neonatal Diabetes Hyperinsulinemic Hypoglycemia of Infancy Parathyroid/Calcitonin System Embryology Transcription Factors Involved in Development of Parathyroid Glands Fetal and Neonatal Calcium Metabolism Calcium-Sensing Receptor (CaSR) and FGF23 Fetal Growth Insulin-Like Growth Factors Insulin Epidermal Growth Factor/Transforming Growth Factor Other Factors Neutralization of Hormone Actions in the Fetus Limitation of Hormone Secretion Production of Inactive Hormone Metabolites Neutralization of Receptor Response Programming of Fetal Endocrine Systems Transition to Extrauterine Life Cortisol Surge Catecholamine Surge Thermogenesis in Neonatal Brown Adipose Tissue Calcium Homeostasis Glucose Homeostasis Other Hormonal Adaptations Maternal and Fetal Medicine 24 - Disorders of Sex Development Development of the Reproductive Systems Sex Determination and Sex Differentiation Chromosomal Sex The Y Chromosome The X Chromosome Gonadal Sex The Bipotential Gonad Primordial Germ Cell Migration Testis Determination Ovary Development Phenotypic or Anatomic Sex Male Sex Differentiation Female Sex Differentiation Psychosexual Development Development of the Hypothalamic-Pituitary-Gonadal Axis in the Fetus The Hypothalamic-Pituitary-Gonadal Axis in Infancy and Childhood Postnatal Endocrine Changes in Boys Postnatal Endocrine Changes in Girls Disorders (Differences) of Sex Development Nomenclature and Classification of Disorders of Sex Development Sex Chromosome Disorders of Sex Development Klinefelter Syndrome and Its Variants Turner Syndrome and Its Variants 45,X/46,XY Mosaicism and Variants Ovotesticular Disorders of Sex Development: 46,XX/46,XY Chimerism and Variants 46,XY Disorders of Sex Development Disorders of Testis Development Single-Gene Disorders Chromosomal Rearrangements Associated With Gonadal Dysgenesis Syndromic Causes of 46,XY Disorders of Sex Development Genes Involved in Central Hypogonadism Potential Novel Genes and Oligogenic Effects Disorders of Androgen Synthesis Cholesterol Synthesis Defects: Smith-Lemli-Opitz Syndrome Luteinizing Hormone Receptor Mutations Steroidogenic Acute Regulatory Protein Defects P450 Side-Chain Cleavage Enzyme Deficiency 3β-Hydroxysteroid Dehydrogenase/Δ4,5-Isomerase Type 2 Deficiency 17α-Hydroxylase/17,20-Lyase Deficiency Cytochrome b5 Deficiency P450 Oxidoreductase Deficiency 3α-Reductase Type 3 and 3α-Reductase Type 1: AKR1C2 and AKR1C4 17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency Steroid 5α-Reductase Type 2 Deficiency Disorders of Androgen Action Complete Androgen Insensitivity Syndrome Partial Androgen Insensitivity Syndrome Minimal or Mild Androgen Insensitivity Syndrome Hormone Profiles in Androgen Insensitivity Syndromes Molecular Pathogenesis of Androgen Insensitivity Syndromes Androgen Insensitivity Syndromes Without an Androgen Receptor Mutation Management of Androgen Insensitivity Syndromes Other Conditions Affecting 46,XY Sex Development Persistent Müllerian Duct Syndrome Hypospadias Anorchia and Cryptorchidism Anatomic Defects of the Pelvis and Penis Endocrine Disruptors 46,XX Disorders of Sex Development Disorders of Ovarian Development Ovarian Dysgenesis 46,XX Ovotesticular and 46,XX Testicular Disorders of Sex Development Disorders of Androgen Excess 3β-Hydroxysteroid Dehydrogenase Type 2 Deficiency 21-Hydroxylase Deficiency Treatment of 21-Hydroxylase Deficiency P450 Oxidoreductase Deficiency 11β-Hydroxylase Deficiency Familial Glucocorticoid Resistance Aromatase Deficiency Maternal Androgen Excess Other Conditions Affecting 46,XX Sex Development Investigation and Management of Disorders of Sex Development Prenatal Diagnosis The Newborn With Atypical Genitalia History and Examination The Initial Approach to the Baby With Atypical Genitalia Support for the Parents Sex Designation Investigations for DSDs Chromosomal DSD 46,XX DSD 46,XY DSD Genetic Testing and DSDs Presentation During Childhood Presentation During Adolescence Presentation During Adulthood Information Sharing, Transitioning, and Adult Services Support Groups and Information Tumor Risk and DSDs Surgery and DSDs Fertility/Family Building DSD in Resource-Limited Countries Outcome Studies Acknowledgments 25 - Normal and Aberrant Growth in Children Normal Growth Overview Measurement Growth Charts Body Proportions Parental Target Height Skeletal Maturation Phases of Normal Growth Crossing Linear Percentiles of Infancy Constitutional Delay of Growth and Development Secular Changes in Height Endocrine Regulation of Growth The Hypothalamic-Pituitary Axis: Embryogenesis and Anatomy Growth Hormone–Releasing Hormone Somatostatin (SST) Growth Hormone Growth Hormone Pulsatility Ghrelin Pituitary Adenylate Cyclase–Activating Polypeptide Growth Hormone Secretion in Humans Peripheral Modulators of Growth Hormone Glucocorticoids Thyroid Hormones Insulin and IGF1 Free Fatty Acids Adipokines Estrogens The Growth Hormone Receptor and Growth Hormone–Binding Protein Insulin-Like Growth Factors Historic Background. The IGFs (somatomedins) are a family of peptides that are, in part, GH dependent and mediate many of the an... IGF Genes and Protein Structure. There are two IGFs circulating in humans, IGF1 and IGF2. IGF1 is a basic peptide of 70 amino ac... Insulin-Like Growth Factor 1 Gene Regulation. The human IGF1 gene (IGF1) is located on the long arm of chromosome 12 and contains at least six exons (Fig. 25... Serum Levels. In human fetal serum, IGF1 levels are relatively low and positively correlated with gestational age.237 There is a... Insulin-Like Growth Factor 2 Gene Regulation. The gene for IGF2 (IGF2) is located on the short arm of chromosome 11, adjacent to the insulin gene, and contai... Serum Levels. Human newborn levels of IGF2 are typically 50% of adult levels. By 1 year of age, adult levels are attained, and t... Insulin-Like Growth Factor Receptors Function-Targeted Disruption of IGF and IGF Receptor Genes Insulin-Like Growth Factor–Binding Proteins Structure of IGFBPs Role of IGFBPs in IGF Physiology IGFBPs as Carrier Proteins IGFBPs as Modulators of IGF Action IGF-Independent Actions of IGFBPs Characteristics of IGFBPs 1 Through 6 Gonadal Steroids Thyroid Hormone Glucocorticoids Pathologic Basis of Growth Retardation Disorders of the GH-IGF1 Axis Growth Hormone Deficiency The Hypothalamus Congenital Disorders Holoprosencephaly. Holoprosencephaly, which is caused by abnormal midline development of the embryonic forebrain, usually result... Septo-Optic Dysplasia. In its complete form, the rare syndrome of septo-optic dysplasia (SOD) combines hypoplasia or absence of ... HESX1. The first homozygous missense mutation (N53C) has been detected within the homeobox domain of HESX1 in two siblings born ... OTX2. Mutations in other genes have been associated with CNS anatomic abnormalities and hypopituitarism. OTX2 is a homeobox gene... SOX3. A syndrome of X-linked hypopituitarism and mental retardation involving duplications of Xq26-27 encompassing SOX3 (OMIM 31... SOX2. Heterozygous mutations within SOX2 in males have been associated with anophthalmia or microphthalmia and anterior pituitar... GLI2. Heterozygous frameshift or nonsense GLI2 mutations have been reported in patients with holoprosencephaly. In addition, non... PROKR2. Patients with septo-optic dysplasia with CPHD have been found to have mutations in PROKR2, a known cause of isolated idi... Acquired Disorders Inflammation of the Brain or Hypothalamus. Bacterial, viral, or fungal infections may result in hypothalamic/pituitary insuffici... Tumors of the Brain or Hypothalamus. Brain tumors are a major cause of hypothalamic insufficiency,408 especially midline brain t... Trauma of the Brain or Hypothalamus. Head trauma, resulting from boxing and various injuries, can cause IGHD or multiple anterio... Psychosocial Dwarfism. An extreme form of failure to thrive is termed psychosocial dwarfism or emotional deprivation dwarfism.41... The Anterior Pituitary Congenital Disorders. As many as 3% to 30% of patients with GHD have an affected parent, sibling, or child.418 Inborn errors of ... Combined Pituitary Hormone Deficiency. During pituitary development, a series of transcription factors are expressed in a specif... PITX2. PITX2 (also known as RIEG) is a member of the bicoid-like homeobox transcription factor family that is closely related to... SOX2. Heterozygous mutations in SOX2 (sex-determining region Y box 2) have been associated with eye abnormalities (i.e., anophth... LHX3. LHX3 is a member of the LIM-type homeodomain protein family of transcription factors that feature two LIM domains in their... LHX4. LHX4 is another LIM homeodomain protein with homology to LHX3, and it is also expressed in the developing brain, including... SIX6. SIX6 is a member of the SIX/sine oculis family of homeobox genes that is expressed in retina, optic nerve, hypothalamus, a... ISL1. ISL1 is a member of the LIM homeodomain family of transcription factors, which are characterized by two tandemly repeated ... PROP1. Mutations in PROP1, a paired-like homeodomain transcription factor with expression restricted to the anterior pituitary d... POU1F1. The POU1F1 gene (chromosome 3p11, OMIM 173110) encodes Pit1, a member of a large family of transcription factors referre... ARNT2 GRP161 Isolated Growth Hormone Deficiency. The incidence of IGHD is estimated to be 1 in every 3480 to 10,000 live births.86,547–549 In... IGHD Type I. IGHD type IA results primarily from large deletions, with rare frameshift and nonsense mutations of the GH1 gene th... IGHD Type II. IGHD type II is inherited as an autosomal dominant trait. The most common cause appears to be mutations that inact... IGHD Type III. IGHD type III, transmitted as an X-linked trait with associated hypogammaglobulinemia (XLA),593 has not yet been ... SOX3. Mutations in SOX3, a member of the SOX (SRY-related high mobility group box) family of transcription factors on Xq27.1, ha... Bioinactive GH. Serum GH exists in multiple molecular forms, reflecting the consequences of alternative post-transcriptional or ... Acquired Disorders Craniopharyngiomas and Other Tumors. Many tumors that impair hypothalamic function also affect pituitary secretion of GH. In add... Histiocytosis X. The localized or generalized proliferation of mononuclear macrophages (histiocytes) characterizes Langerhans ce... Growth Hormone Insensitivity Mutations in GHR Signaling Proteins and ALS. GH insensitivity, also known as primary IGF1 deficiency, encompasses a variety of g... Abnormalities of IGF1 and IGF1 Receptor Signaling. Woods and colleagues656 described a 15-year-old boy with deletion of exons 4 ... Inactivating Mutation of the IGF1 Gene. An adult with the same phenotype as the boy with the IGF1 deletion but with markedly ele... Primary Defects of IGF Transport and Clearance. Siblings from two families with high IGF1 and IGF2 levels, normal to high IGFBP3... Primary Defects of IGF1 Receptor Production or Responsiveness. Patients with IUGR and postnatal growth failure, microcephaly, an... Disorders Outside the Growth Hormone–IGF Axis Malnutrition Chronic or Systemic Diseases Malabsorption and Gastrointestinal Diseases Chronic Liver Disease Cardiovascular Disease Renal Disease Hematologic Disorders Inborn Errors of Metabolism Pulmonary Disease Chronic Inflammation and Infection Endocrine Disorders Hypothyroidism Diabetes Mellitus Cushing Syndrome: Glucocorticoid Excess Pseudohypoparathyroidism: Albright Hereditary Osteodystrophy Rickets Hypophosphatemic Rickets Osteochondrodysplasias Chromosomal Abnormalities Down Syndrome Turner Syndrome Noonan Syndrome Prader-Willi Syndrome Other Syndromes Small for Gestational Age Maternal and Placental Factors Pathologic Basis of Excess Growth Statural Overgrowth in the Fetus Sotos Syndrome Beckwith-Wiedemann Syndrome Postnatal Statural Overgrowth Tall Stature Obesity Tumors Evaluation and Treatment of Growth Abnormalities Clinical Evaluation of Growth Retardation History and Physical Examination Laboratory Testing Screening Tests Bone Age Prediction of Adult Height Tests of the GH-IGF1 Axis Insulin-Like Growth Factor 1 Insulin-Like Growth Factor–Binding Protein 3 Insulin-Like Growth Factor 2 Growth Hormone Assay Limitations. One of the biggest confounders in the evaluation of GH secretion is the variability of measured GH levels acr... Provocative Tests. Because random GH levels cannot be used to diagnose GHD, evaluation of GH secretion requires that samples be ... Determination of the “Subnormal” Response to Provocative Tests. GH secretion has a continuous distribution; there is not a bimod... Specificity of Provocative Tests for Growth Hormone Deficiency. The data that are available suggest a low specificity for the pr... Sex Hormone Priming. Serum GH levels rise during puberty, with GH secretion stimulated by the rise in estrogen produced from the... Tests of Spontaneous Growth Hormone Secretion. Another diagnostic approach to evaluate GH secretion involves measurement of spon... Summary. Despite the many problems associated with GH measurement methods, there continues to be value in determining GH secreto... Growth Hormone–Binding Protein IGF1 and IGFBP Generation Tests Interpretation of Tests Neonate Growth Hormone Deficiency Growth Hormone Insensitivity Constitutional Delay of Growth and Development Genetic (Familial) Short Stature Idiopathic Short Stature Treatment of Growth Failure Treatment of Constitutional Delay Androgen (Oxandrolone and Testosterone) Growth Hormone Aromatase Inhibitor Treatment of Growth Hormone Deficiency Nomenclature and Potency Estimation Historical Perspective Treatment Regimens Adult Height Outcomes Benefits of GH Treatment Other Than Improved Growth Combined Pituitary Hormone Deficiencies Monitoring Growth Hormone Therapy Treatment During the Transition to Adulthood and in Adulthood Growth Hormone Treatment of Other Forms of Short Stature Prader-Willi Syndrome Chronic Renal Disease Juvenile Idiopathic Arthritis Turner Syndrome Small for Gestational Age Osteochondrodysplasias SHOX Haploinsufficiency and Léri-Weill Syndrome. Patients with mutations or deletions of the SHOX gene have variable degrees of ... Turner Syndrome and Langer Mesomelic Dysplasia. Homozygous mutation of the SHOX gene results in the Langer type of mesomelic dwa... Noonan Syndrome Idiopathic Short Stature (Subtle Errors Throughout the Growth Axis) Miscellaneous Causes of Growth Failure Down Syndrome. The encouraging results of GH trials in TS led to studies of GH therapy in children with Down syndrome. In severa... Normal Aging and Other Catabolic States. Detailed consideration of the potential use of GH in normal aging is beyond the scope o... Adverse Effects of Growth Hormone Development of Leukemia and Other Malignancies Recurrence of Central Nervous System Tumors Development of Subsequent Neoplasms Pseudotumor Cerebri Slipped Capital Femoral Epiphysis Scoliosis Diabetes Mellitus Miscellaneous Side Effects1307,1442,1516 The Question of Long-Term Cancer Risk Long-Term Mortality with GH Treatment IGF1 Treatment Other Treatments to Promote Growth Aromatase Inhibitors Oxandrolone Diagnosis and Treatment of Excess Growth and Tall Stature Diagnosis Treatment 26 - Physiology and Disorders of Puberty Puberty and Evolution Fetal Origins of Adult Disease Determinants of the Age of Puberty and Menarche The Secular Trend in Puberty and Menarche The Developed World The Developing World Factors Affecting the Age of Puberty and Menarche Stress and Puberty Genetic Effects on Puberty and Menarche Cancer and Age of Puberty Other Factors The Comorbid Conditions of Early Puberty National Trends in Pubertal Development Limits of Normal Pubertal Development Secondary Sexual Characteristics and Physical Changes of Puberty Female Development Ovarian Development Menarche and Teenage Pregnancy Male Development Male Testicular Development in Puberty Spermatogenesis Other Physical and Biochemical Changes of Puberty Adolescent Growth Pubertal Growth Spurt Bone Age Skeletal Density Body Composition Obesity, Puberty, and the Metabolic Syndrome Serum Lipids in Normal Puberty and in Obesity and the Metabolic Syndrome Insulin and Insulin Resistance Blood Pressure Central Nervous System Anatomy, Function, Psychology, and Electroencephalographic Rhythm in Puberty Sleep Patterns in Puberty Characteristics of Adolescence Behavior and Normal Puberty Mood and Self-Image in Puberty Behavior in Variations of the Normal Age at Onset of Puberty Risk-Taking Behavior Sexuality During Puberty Hormonal and Metabolic Changes in Puberty Gonadotropins Gonadal Steroids Testosterone Estrogens Protein Products of the Gonads Inhibin, Activin, and Follistatin Antimüllerian Hormone Adrenal Androgens Testosterone-Binding Globulin Prolactin Insulin-Like 3 Protein Prostate-Specific Antigen Hormonal Control of the Pubertal Growth Spurt Gonadal Steroids159,160 Growth Hormone and Growth Factors Growth Hormone–Binding Protein Insulin-Like Growth Factor Type 1 Other Hormones Central Nervous System and Puberty Pattern of Gonadotropin Secretion Tonic Secretion Pulsatile Secretion The GnRH Pulse Generator GnRH. Generation of the GnRH pulse is an intrinsic property of the GnRH neurosecretory neuronal network, and other factors modul... Gonadotropin-Inhibitory Hormone. Gonadotropin-inhibitory hormone (GnIH), a peptide first described in quail but now homologues o... Kisspeptins and KISS1R. Kisspeptins and their receptors (KISS1R or GRP54) in the CNS hypothalamic-pituitary-gonadal axis play a ... Ontogeny Human Fetus Sheep Fetus Human Neonate and Infant291,326 Neural Control Timing and Onset of Puberty Genetic Neural Control Nutrition and Metabolic Control Mechanisms of Control Gonadal Steroid–Dependent Negative Feedback Mechanism Gonadal Steroid–Independent (Intrinsic) Central Nervous System Inhibitory Mechanism Interaction of the Negative Feedback Mechanism and the Intrinsic Central Nervous System Inhibitory Mechanism Potential Components of the Intrinsic Central Nervous System Inhibitory Mechanism Sleep-Associated Luteinizing Hormone Release and Onset of Puberty Pituitary and Gonadal Sensitivity to Tropic Stimuli Maturation of Positive Feedback Mechanism Overview of Current Concept Adrenal Androgens and Adrenarche Nature and Regulation of Adrenal Androgens Adrenal Androgens and Puberty Disorders of Puberty Delayed Puberty and Sexual Infantilism Idiopathic or Constitutional Delay in Growth and Puberty Hypogonadotropic Hypogonadism: Sexual Infantilism Related to Gonadotropin Deficiency Isolated Hypogonadal Hypogonadism Kallmann Syndrome. Anosmia or hyposmia resulting from agenesis or hypoplasia of the olfactory lobes or sulci is associated with ... KAL1. In classic, X-linked KAL1, fetal GnRH neurosecretory neurons do not migrate from the olfactory placode to the medial basal... KAL2. The autosomal dominant form is known as Kallmann syndrome type 2 (KAL2), and the associated gene is fibroblast growth fact... KAL3. Apparent autosomal recessive inheritance characterizes other kindreds with Kallmann syndrome type 3 (KAL3), for which the ... Other Forms of Kallmann Syndrome. The human equivalent of the mouse nasal embryonic GnRH factor gene (Nelf) is NELF; a mutation ... Other Forms of Isolated Hypogonadotropic Hypogonadism. Only about 15% of normosmic hypogonadotropic patients have a definable ge... Gonadotropin-Releasing Hormone Gene Mutations. The GnRH gene (GNRH1) would seem a likely candidate for the cause of hypogonadotr... Gonadotropin-Releasing Hormone Receptor Mutations. Mutations of the gene encoding the type 1 GnRH receptor (GNRHR, gene map locu... KISS1/KISS1R Axis Mutations. The KISS1/KISS1R axis plays a role in the increased amplitude of GnRH signaling in puberty. KISS1/K... X-Linked Congenital Adrenal Hypoplasia and Hypogonadotropic Hypogonadism. A rare deletion or mutation in the dosage-sensitive se... Isolated Luteinizing Hormone Deficiency. Isolated LH deficiency (fertile eunuch syndrome) is associated with deficient testoster... Isolated Follicle-Stimulating Hormone Deficiency. Homozy-gous or compound heterozygous mutations in the FSH β-subunit have been ... Follicle-Stimulating Hormone Receptor Mutations. Hypergonadotropic hypogonadism is noted with rare mutations in FSH receptors.54... Developmental Defect of the Midline Idiopathic Hypopituitary Dwarfism Miscellaneous Conditions Prader-Willi Syndrome. Prader-Willi syndrome is an autosomal dominant disorder that combines a tendency for intrauterine growth ... Laurence-Moon and Bardet-Biedl Syndromes. The Laurence-Moon syndrome and the Bardet-Biedl syndrome were previously separated as ... Functional Gonadotropin Deficiencies and Other Chronic Conditions. The effects of malnutrition, which can lead to functional hyp... Other Endocrine Conditions and Puberty. Hypothyroidism may delay the onset of puberty or menarche (except in extreme cases in wh... Anorexia Nervosa and Variants.580,581,990 Anorexia Nervosa. Anorexia nervosa,582 a common cause of gonadotropin deficiency in adolescence, is a functional disorder. Preva... Bulimia Nervosa. Bulimia nervosa is now separated from the diagnosis of anorexia nervosa582; DSM-IV diagnostic criteria are as f... Exercise, Hypo-ovarianism, and Amenorrhea: The Female Athlete Triad. In 1992, the American College of Sports Medicine defined th... Other Causes of Delayed Puberty Central Nervous System Tumors Craniopharyngioma. Craniopharyngioma is a rare embryonic malformation of nonglial origin in childhood (0.5–2 new cases per 1 mil... Other Extrasellar Tumors Germinomas. Germinomas (i.e., pinealomas, ectopic pinealomas, atypical teratomas, or dysgerminomas) and other germ cell tumors o... Pituitary Adenomas. Only 2% to 6% of all surgically treated pituitary tumors occur in childhood and adolescence, with about 1 in... Other Central Nervous System Disorders Leading to Delayed Puberty Langerhans Cell Histiocytosis. Langerhans cell histiocytosis (i.e., Hand-Schüller-Christian disease or histiocytosis X) is a clo... Postinfectious Inflammatory Lesions of the Central Nervous System, Vascular Abnormalities, and Head Trauma. Tuberculous or sarco... Irradiation of the Central Nervous System. Irradiation of the CNS for treatment of tumors, leukemia, or neoplasms of the head an... Fröhlich Syndrome. Fröhlich syndrome or adiposodysgenesis is a constellation of endocrine abnormalities, combining findings of o... Hypergonadotropic Hypogonadism: Sexual Infantilism Caused by Primary Gonadal Disorders Boys Klinefelter Syndrome and Its Variants (see Chapter 24). Klinefelter syndrome (i.e., syndrome of seminiferous tubular dysgenesis)... Behavior and Development in Klinefelter Syndrome. Neurobehavioral abnormalities, primarily in language, speech, learning, and fr... Other Aspects of Klinefelter Syndrome. Conditions associated with Klinefelter syndrome include aortic valvular disease and ruptu... Other Forms of Primary Testicular Failure Cancer Survivors. Chemotherapy Chemotherapy and direct radiotherapy affect testicular function, and as more children survive wit... Radiation Therapy. Radiation to the gonads can cause primary testicular failure, usually resulting in azoospermia, although norm... Testicular Biosynthetic Defects. The 46,XY disorder of sex development is caused by 17α-hydroxylase/17,20-lyase deficiency resul... Luteinizing Hormone Resistance. Presumptive evidence of LH resistance caused by an LH receptor abnormality on the Leydig cell wa... Anorchia and Cryptorchidism. Cryptorchidism is the condition in which one or both testes have not reached the bottom of the scro... Small for Gestational Age. SGA predisposes males to reproductive problems and is also associated with the TDS. Males born SGA te... Girls Syndrome of Gonadal Dysgenesis and Its Variants.622. The most common form of hypergonadotropic hypogonadism in the female is the... 45,X Turner Syndrome.993 Short stature and sexual infantilism are typical features of sex chromatin–negative 45,X gonadal dysgen... Behavior and Development of Turner Syndrome. Counseling and a peer support group are exceedingly important components of long-te... Sex Chromatin–Positive Variants of the Syndrome of Gonadal Dysgenesis. Mosaicism of 45,X/46,XX; 45,X/47,XXX; or 45,X/46,XX/47,XX... Sex Chromatin–Negative Variants of Gonadal Dysgenesis. These variants include 45,X/46,XY mosaicism and structural abnormalities ... 46,XX and 46,XY Gonadal Dysgenesis. The term pure gonadal dysgenesis refers to phenotypic females with sexual infantilism and a ... Familial and Sporadic 46,XX Gonadal Dysgenesis and Its Variants. The usual phenotype of 46,XX gonadal dysgenesis includes normal... Familial and Sporadic 46,XY Gonadal Dysgenesis and Its Variants. A phenotype that includes female genitalia with or without clit... Other Causes of Primary Ovarian Failure. The prevalence of primary ovarian failure is increasing as a consequence of the long-te... Chemotherapy. Successful treatment of childhood acute lymphoblastic leukemia has become commonplace. Chemotherapy and radiation ... Radiation Therapy. Ovarian transposition, moving the ovaries out of the radiation field if they are not the target of therapy, b... Autoimmune Oophoritis. Premature menopause may occur at any age before the normal climacteric and has been reported in adolescen... Homozygous Galactosemia. Homozygous galactosemia due to mutation in the galactose-1-phosphate uridylyltransferase (GALT) gene is... Haploinsufficiency of the FOXL2 Gene. A rare autosomal dominant disorder involving eyelid dysplasia and premature ovarian failur... Congenital Disorders of Glycosylation-1: Carbohydrate-Deficient Glycoprotein Syndrome Type Ia. The congenital disorders of glyco... Follicle-Stimulating Hormone Receptor Resistance: Gene Mutations and Hypergonadotropic Hypogonadism. The FSH receptor is a membe... Luteinizing Hormone and Human Chorionic Gonadotropin Resistance. LH/hCG resistance due to mutations in the gene encoding the sev... Polycystic Ovary Syndrome. PCOS, or functional ovarian hyperandrogenism, does not delay the onset of puberty but often delays me... Noonan Syndrome. Individuals with Noonan syndrome (i.e., pseudo-Turner syndrome, Ullrich syndrome) have webbed neck, ptosis, dow... Frasier Syndrome. Germline mutations in exon 8 or 9, coding for zinc fingers 2 or 3 of the Wilms tumor suppressor gene, WT1, lea... Williams-Beuren Syndrome. Williams-Beuren syndrome is a microdeletion disorder, or contiguous-gene-deletion disorder caused by d... Diagnosis of Delayed Puberty and Sexual Infantilism Treatment of Delayed Puberty and Sexual Infantilism Sexual Precocity994 Central Precocious Puberty: Complete Isosexual Precocity Idiopathic True or Central Precocious Puberty159,160,316,423,726,727 Gain-of-Function Mutations as Cause of Central Precocious Puberty KISS and KISSIR/GRP54 Mutations KISS Mutations. Whereas inactivating mutations in the KISS1R receptor cause hypogonadotropic hypogonadism, recently the first de... Loss-of-Function Mutations as Cause of Central Precocious Puberty MKRN3. Ten different loss-of-function mutations of MKRN3, an imprinted gene located on the long arm of chromosome 15q11.2 in the... DLK1. Delta-like 1 homolog (DLK1) is another paternally imprinted gene recently reported to be associated with precocious pubert... Central Nervous System Tumors Causing True Precocious Puberty Hamartomas of the Tuber Cinereum. Hamartomas are congenital malformations composed of a heterotopic mass of nervous tissue conta... Neurofibromatosis Type 1. Neurofibromatosis type 1 (NF1 or von Recklinghausen disease) is associated with a propensity to develo... Other Central Nervous System Conditions Arachnoid Cysts. Arachnoid cysts arising de novo, after infection or after surgery, can cause premature sexual development, poss... Other Central Nervous System Abnormalities. Other CNS abnormalities associated with CPP but without demonstrable lesions on imag... Miscellaneous Causes Central Precocious Puberty in Children Adopted From Developing Countries. There was a 15-fold to 20-fold increased prevalence of... True Precocious Puberty After Virilizing Disorders. Correction of long-standing virilization may be followed by development of C... Marfan Syndrome. Marfan syndrome may be associated with tall stature and early PHV and menarche compared with North American ave... Management of Central Precocious Puberty Medroxyprogesterone Acetate and Cyproterone Acetate. Medroxyprogesterone and cyproterone reversed or arrested the progression of... Superactive Gonadotropin-Releasing Hormone Agonists. The GnRH agonists, synthetic analogues of the amino acid sequence of the na... Adverse Effects. Rare reactions to GnRH agonists include local and systemic allergic reactions, including asthmatic episodes whe... Other Treatment for Precocious Puberty. The GnRH agonists are useful in conjunction with GH in the management of organic or neur... Psychosocial Aspects. Psychologic management is a critical aspect of the care of children with CPP. With the advanced physical m... Peripheral Precocious Puberty or Incomplete Isosexual Precocity: Gonadotropin-Releasing Hormone–Independent Sexual Precocity995 Boys Chorionic Gonadotropin–Secreting Tumors. Several types of germ cell tumors secrete hCG, which may cross-react in some polyclonal... Precocious Androgen Secretion Caused by the Adrenal Gland Virilizing Congenital Adrenal Hyperplasia. Virilizing CAH caused by a defect in 21-hydroxylation (CYP21 deficiency) leads to ele... Virilizing Adrenal Tumor. Virilizing adrenal carcinomas or adenomas secrete large amounts of DHEA and DHEAS and, on occasion, te... NR0B1 (DAX1) Gene Mutations. Two cases of NR0B1 frameshift mutations demonstrated adrenal failure and GISP that were suppressibl... Leydig Cell Tumor. Testicular tumors are rare in childhood, representing 1% to 2% of all pediatric solid tumors, and Leydig cell... Pituitary Gonadotropin–Independent Familial Premature Leydig Cell and Germ Cell Maturation: Familial or Sporadic Testotoxicosis.... Gonadotropin-Independent Sexual Precocity and Pseudohypoparathyroidism Type Ia. A mutation in Gsα can constitutively activate or... Girls Autonomous Ovarian Follicular Cysts. The most common childhood estrogen-secreting ovarian mass and ovarian cause of sexual preco... Ovarian Tumors. Ovarian tumors are the most common genitourinary tumors of girls,847,848 accounting for about 1% of all tumors i... Peutz-Jeghers Syndrome. Peutz-Jeghers syndrome, an autosomal dominant syndrome, is usually caused by mutations in the gene locat... Adrenal Tumors. Adrenocortical tumors are rare in childhood (0.6% of all childhood tumors and 0.3% of all malignant childhood tu... Boys and Girls McCune-Albright Syndrome. McCune-Albright syndrome846,1003 occurs about twice as often in girls than in boys; it is sporadic an... Juvenile Hypothyroidism. Long-standing untreated primary hypothyroidism, usually a consequence of Hashimoto thyroiditis, is an u... Iatrogenic Sexual Precocity and Endocrine Disruptors. Prepubertal children are remarkably sensitive to exogenous gonadal steroid... Diagnosis of Sexual Precocity Contrasexual Precocity: Feminization in Boys and Virilization in Girls Boys Aromatase Excess Syndrome. Gynecomastia in prepubertal boys can be caused by increased extraglandular aromatization of C19 stero... Feminizing Testicular Tumors. Feminizing testicular tumors may cause gynecomastia in boys younger than 6 years of age who have t... Girls Adrenal Causes of Virilization. CAH resulting from 21-hydroxylase or 11β-hydroxylase deficiency or from androgen-producing tumor... Syndrome of Glucocorticoid Resistance. The syndrome of glucocorticoid resistance has variable manifestations. Some patients demo... Virilizing Ovarian Tumors. Arrhenoblastoma, also called Sertoli tumor of the ovary, is the most common virilizing ovarian tumor,... Variations of Pubertal Development Premature Thelarche Premature Isolated Menarche Premature Adrenarche Polycystic Ovary Disease958,959 Adolescent Gynecomastia970 Macroorchidism 27 - Hormones and Athletic Performance Effect of Athletic Performance onHormonal Systems Catecholamines Fluid Homeostasis–Vasopressin–Renin-Angiotensin-Aldosterone System Hypothalamus-Pituitary-Adrenal Axis Glucocorticoids Response to Endurance Exercise Response to Resistance Exercise Mineralocorticoids Endorphins Hypothalamic-Pituitary-Gonadal Axis Male Gonadal Axis Female Gonadal Axis Prolactin GH/IGF1 Axis Hypothalamus-Pituitary-Thyroid Axis Insulin and Glucose Metabolism Erythropoietin Anabolic Androgenic Steroids Adverse Effects Detection Growth Hormone Adverse Effects Detection GH Secretagogues Insulin-like Growth Factor 1 Adverse Effects Detection Insulin Adverse Effects Detection Erythropoietin and the Erythropoietin System Adverse Effects Detection Glucocorticosteroids Adverse Effects Detection 28 - Endocrinology and Aging Aging and Physical Frailty The Endocrinology of Aging Menopause Perimenopausal Use of Hormone Therapy Long-Term Hormone Replacement Therapy Selective Estrogen Receptor Modulators Androgen Replacement HT, SERMs, or No Treatment? Andropause Versus Late-Onset Hypogonadism Role of Testosterone During Aging Testosterone Replacement Therapy Which Elderly Men Should Be Treated? Adrenopause Role of DHEA During Aging DHEA Replacement Therapy Conclusions Somatopause Role of GH and IGF1 During Aging GH Therapy Conclusions The Concept of Successful Aging 29 - Hormones and Disorders of Mineral Metabolism Basic Biology of Mineral Metabolism: Roles of the Mineral Ions Parathyroid Hormone Parathyroid Gland Biology Parathyroid Hormone Biosynthesis Parathyroid Hormone Secretion Regulation of the Parathyroid Hormone Gene Regulation of Parathyroid Cell Number Parathyroid Gland Development Metabolism of Parathyroid Hormone Actions of Parathyroid Hormone Actions of Parathyroid Hormone on the Kidney Stimulation of Calcium Reabsorption Inhibition of Phosphate Transport Other Renal Effects of Parathyroid Hormone Actions of Parathyroid Hormone on Bone PTH Increases Bone Formation PTH Increases Bone Resorption Molecular Basis of Parathyroid Hormone Action Parathyroid Hormone and Parathyroid Hormone–Related Protein Receptors Functional Implications of Parathyroid Hormone Structure Activation of Second Messengers Second Messengers and Distal Effects of Parathyroid Hormone Target Cell Responsiveness to Parathyroid Hormone Parathyroid Hormone–Related Protein Gene and Protein Structure Functions of Parathyroid Hormone–Related Protein Calcitonin Synthesis and Secretion Calcitonin Family: Calcitonin Gene-Related Peptide, Amylin, Adrenomedullin, Calcitonin Receptor–Stimulating Peptides, and Interm... Calcitonin in Human Disease Therapeutic Uses Vitamin D Metabolism of Vitamin D Actions of Vitamin D Vitamin D Receptors Intestinal Calcium Absorption Entry Into the Enterocyte Transcellular Transport Exit From the Enterocyte Actions on the Parathyroid Gland Actions on Bone Other Actions of Vitamin D Vitamin D Analogs Fibroblast Growth Factor-23 FGF23 in Human Disease Actions of FGF23 Regulation of FGF23 Calcium and Phosphate Homeostasis Laboratory Assessment of Mineral Metabolism Parathyroid Hormone Parathyroid Hormone–Related Protein Calcitonin Vitamin D Metabolites Fibroblast Growth Factor-23 Hypercalcemic Disorders Parathyroid-Dependent Hypercalcemia Primary Hyperparathyroidism Classic Primary Hyperparathyroidism Contemporary Primary Hyperparathyroidism Etiology and Pathogenesis Inherited Primary Hyperparathyroidism Management of Primary Hyperparathyroidism Familial Hypocalciuric Hypercalcemia Lithium Toxicity Parathyroid-Independent Hypercalcemia Hypercalcemia of Malignancy Local Osteolytic Hypercalcemia Humoral Hypercalcemia of Malignancy Vitamin D Intoxication Sarcoidosis and Other Granulomatous Diseases CYP24A1 Loss of Function Hyperthyroidism Vitamin A Intoxication Adrenal Insufficiency Thiazide Diuretics Milk-Alkali Syndrome Immobilization Renal Failure Williams Syndrome Jansen Metaphyseal Chondrodysplasia Approach to the Hypercalcemic Patient Causes of Severe Hypercalcemia Clinical Features of Severe Hypercalcemia Management of Severe Hypercalcemia Volume Repletion Bisphosphonates Denosumab Calcitonin Other Approaches to Treatment of Severe Hypercalcemia Hypocalcemic Disorders Clinical Presentation Parathyroid-Related Disorders Congenital or Inherited Parathyroid Disorders Abnormalities in the PTH Gene Destruction of the Parathyroid Glands Impaired PTH Secretion Pseudohypoparathyroidism Vitamin D–Related Disorders Vitamin D Deficiency Accelerated Loss or Inactivation of Vitamin D Impaired 25-Hydroxylation of Vitamin D Impaired 1α-Hydroxylation of 25-Hydroxyvitamin D Target Organ Resistance to 1,25(OH)2D3 Other Causes of Hypocalcemia Excessive Deposition Into the Skeleton Impaired Resorption Chelation Neonatal Hypocalcemia HIV Critical Illness Treatment of Hypocalcemia Disorders of Phosphate Metabolism Hyperphosphatemia Hypophosphatemia Etiology Continued Clinical Features Treatment Disorders of Magnesium Metabolism Hypermagnesemia Hypomagnesemia Etiology Intestinal Causes of Hypomagnesemia Renal Causes of Hypomagnesemia Other Causes of Hypomagnesemia Consequences of Hypomagnesemia Therapy of Hypomagnesemia 30 - Osteoporosis: Basic and Clinical Aspects Historical Context Skeletal Biology Structure and Function of the Skeleton Embryology and Anatomy Bone Matrix and Mineral Collagen Synthesis Mineralization Collagen Degradation by Osteoblasts and Osteocytes Bone Lining Cells, Osteoblasts, and Osteocytes Osteoclast Differentiation and Function Bone Remodeling and Its Regulation Overview of Remodeling Local Regulators of Remodeling Cytokines TGFα and Epidermal Growth Factor Prostaglandins Peptide Growth Factors Fibroblast Growth Factors Platelet-Derived Growth Factors, Vascular Endothelial Growth Factors, Hypoxia-Inducible Factors, and Reactive Oxygen Species Insulin-Like Growth Factors Transforming Growth Factor β BMPs and Wnt Proteins Systemic Hormones and Bone Remodeling Calcium-Regulating Hormones Parathyroid Hormone Vitamin D Calcitonin Other Systemic Hormones That Influence Remodeling Growth Hormone Glucocorticoids Thyroid Hormones Insulin Gonadal Hormones Epidemiology of Osteoporosis and Fractures Fractures Hip Fractures Vertebral Fractures Wrist Fractures Other Types of Fractures Clinical Assessments of Osteoporosis Dual-Energy X-Ray Absorptiometry Trabecular Bone Score Quantitative Computed Tomography Bone Turnover Markers Bone Biopsy Fracture Epidemiology Continued Clinical Risk Factors and Their Combination With BMD Prevalence of Osteoporosis and Incidence of Fractures in the Population Pathogenesis of Osteoporosis Gonadal Deficiency Estrogen Androgens Age-Related Bone Loss Secondary Osteoporosis Glucocorticoid-Induced Bone Loss Osteoporosis Associated With Diabetes Mellitus Factors That Impair Peak Bone Acquisition Genetic Factors That Determine Peak Bone Mass Approach to Management of Osteoporosis General Measures Diet Calcium Vitamin D Physical Activity Lifestyle Pharmacologic Approaches to the Treatment of Osteoporosis Antiresorptive Agents Estrogen Selective Estrogen Receptor Modulators Bisphosphonates Calcitonin Strontium Ranelate Denosumab Cathepsin K Inhibitors Anabolic Agents Parathyroid Hormone PTH-Related Protein Future Anabolic Agents Monoclonal Antibodies to Sclerostin 31 - Rickets and Osteomalacia Introduction Historical Perspective Rickets Osteomalacia Epidemiology and Demographics Bone Remodeling and Mineralization Definition and Histologic Evolution of Osteomalacia Pathogenesis of Rickets and Osteomalacia Calcium-Deficiency Rickets Phosphate-Deficiency/Depletion Rickets and Osteomalacia Clinical Manifestations of Classical Rickets and Osteomalacia Bone Pain Muscle Weakness Skeletal Deformities and Fractures Biochemical Changes Radiologic Imaging Features Bone Mineral Density Treatment of Nutritional Rickets and Osteomalacia Rickets Due to Genetic Disorders of Vitamin D Metabolism Vitamin D–Dependent Rickets Types 1A, 1B, and 2 Hereditary Hypophosphatemic Rickets and Osteomalacia Autosomal Dominant and Recessive Rickets X-Linked Recessive Hypophosphatemic Rickets X-Linked Hypophosphatemic Rickets and Osteomalacia Radiologic and Biochemical Findings Treatment of Hereditary Hypophosphatemic Rickets and Osteomalacia Standard Treatments Novel Treatments Long-Term Management Tumor-Induced Osteomalacia Drug-Induced Osteomalacia Conditions That Resemble Rickets and Osteomalacia Concluding Remarks Acknowledgments 32 - Kidney Stones Epidemiology of Stone Formation Pathogenesis of Stone Formation Physiology Diet Pathogenesis of Idiopathic Hypercalciuria Calcium Homeostasis Potential Mechanisms for the Development of IH Human Data Genetic Hypercalciuric Stone-Forming Rats Genetics of IH in Humans Other Genetic Causes of Stones and Nephrocalcinosis X-Linked Hypercalciuric Nephrolithiasis (Dent Disease and Others) Bartter Syndrome Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis Distal Renal Tubular Acidosis Hereditary Hypophosphatemic Rickets With Hypercalciuria Primary Hyperoxaluria and Cystinuria Clinical Presentation and Evaluation Metabolic Evaluation of Stone Formers The Basic Evaluation History Stone History Medical History Family History Medications Lifestyle and Diet Physical Examination Laboratory Tests Stone Analysis Radiologic Evaluation The Complete Evaluation Therapy Surgical Treatment Medical Expulsive Therapy Medical Preventative Therapy Nonspecific Therapy Specific Therapy Matched to Specific Pathogenesis Calcium Stones Hypercalciuria. Patients with persistent hypercalciuria often benefit from a thiazide diuretic. This class of drugs is inexpensi... Hyperoxaluria. Oxalate is produced predominantly by endogenous metabolism of glyoxylate and, to a lesser extent, by ascorbic aci... Dietary Oxaluria. Dietary oxaluria results in urinary oxalate levels that are mildly elevated (40–60 mg/day). Many high-oxalate ... Enteric Oxaluria. Enteric oxaluria results in higher urinary oxalate levels (60–100 mg/day) than dietary hyperoxaluria. GI malab... Primary Hyperoxaluria. Primary hyperoxaluria (PHO) leads to nephrolithiasis because of hepatic enzyme deficiencies that lead to ... Hyperuricosuria. Up to 15% of patients with hyperuricosuria have calcium stones. In contrast to patients with pure calcium oxala... Hypocitraturia. Citrate, by combining with calcium to form a soluble complex, reduces calcium oxalate and calcium phosphate prec... Renal Tubular Acidosis. dRTA (type 1) is a disorder in which distal tubular hydrogen ion excretion is impaired, resulting in a n... Nephrocalcinosis. Nephrocalcinosis is a process in which calcium is deposited in the renal parenchyma.6 There are two forms: dys... Uric Acid Stones Struvite Stones Urease-Producing Bacteria. The formation of struvite stones depends on the presence of both ammonium ions and an alkaline urinar... Therapy for Struvite Stones. To eradicate struvite stones, early and aggressive medical and urologic management is required.237 ... Cystine Stones Therapy for Cystine Stones. The aim of treatment is to lower the urinary cystine concentration below the limits of solubility (∼... 33 - Physiology of Insulin Secretion Introduction Neural Regulation of Beta-Cell Function Beta-Cell Mass Beta-Cell Insulin Content Insulin Secretion Versus Plasma Insulin Characteristics of Insulin Secretion In Vivo Modes of Beta-Cell Response Insulin Secretion in the Fasting State Insulin Secretory Response to Intravenous Glucose Various formats of intravenous glucose administration have been used to gauge beta-cell response independently of gastrointestin... Hyperglycemic Clamp and Biphasic Insulin Secretion Intravenous Glucose Tolerance Test Graded Glucose Infusion Test and Beta-Cell Dose Response Slow Beta-Cell Response Modes and Adaptation Mechanisms Insulin Secretory Response to Oral Stimuli Insulin Secretion and Insulin Sensitivity Genetic Influences on Insulin Secretion Insulin Secretion, Insulin Action, and Glucose Homeostasis 34 - Pathophysiology of Type 2 Diabetes Mellitus Epidemiology Pathogenesis Genetic Factors in the Development of Type 2 Diabetes Mellitus Monogenic Forms of Diabetes Associated With Insulin Resistance Mutations in the Insulin Receptor Lipodystrophic Diabetes Genetics of the Polygenic Forms of Type 2 Diabetes Mellitus Insulin Receptor Substrate 1 Gene Transcription Factor 7–Like 2 Gene KATP Channel Genes: KCNJ11 and ABCC8 Peroxisome Proliferator-Activated Receptor γ Gene Hepatocyte Nuclear Factor 4α Gene Kruppel-like Factor 14 (KLF14) Diabetes Genes Identified by Genome-Wide Association Studies Epigenetic Risk of Diabetes Insulin Signaling Downstream Events After Insulin Receptor Phosphorylation Tissue-Specific Actions of Insulin Mechanisms of Insulin-Mediated Glucose Uptake in Muscle and Fat Insulin Regulation of Lipolysis and Lipogenesis Insulin Regulation of Hepatic Carbohydrate Metabolism Expanding Collection of Insulin-Sensitive Tissues Insulin Signaling in the Central Nervous System Insulin Resistance and the Risk of Type 2 Diabetes Mellitus Insulin Resistance Obesity and Type 2 Diabetes Mellitus Hyperinsulinemia and Insulin Resistance Nutrient Overload and Insulin Resistance Adipose Tissue and Insulin Resistance Ectopic Lipid Accumulation Endoplasmic Reticulum Stress/Unfolded Protein Response Innate Immunity Mitochondrial Abnormalities Skeletal Muscle Insulin Resistance Fatty Acid Metabolism in Skeletal Muscle Glucose Influence on Skeletal Muscle Fatty Acid Metabolism Circadian Rhythms, Obesity, and Insulin Resistance Role of the Gut Microbiome and Metabolome in Diabetes and Insulin Resistance Special Conditions That Induce Insulin Resistance Gestational Diabetes Drugs and Stress-Induced Insulin Resistance Glucocorticoid-Induced Insulin Resistance Post-Transplant Diabetes Mellitus Inflammation and Inflammatory Cytokines Human Immunodeficiency Virus Infection Statins Glucotoxicity, Glucosamine Postoperative Hyperglycemia 35 - Therapeutics of Type 2 Diabetes Mellitus Epidemiology Diagnostic Criteria General Approaches to Management Public Health Measures Primary Care Management Complex Diabetes Care Screening Interventional Study Results Glycemic Treatment Targets Monitoring of Glucose During Treatment Hemoglobin A1c Self-Monitoring of Blood Glucose Continuous Glucose Monitoring Hypoglycemia Lifestyle Interventions Diabetes Self-Management Education and Support Medical Nutrition Therapy Physical Activity and Exercise Addressing Psychosocial Needs Glucose-Lowering Pharmacotherapy Oral Agents Biguanides Insulin Secretagogues Sulfonylureas Glinides Thiazolidinediones DPP4 Inhibitors α-Glucosidase Inhibitors Sodium-Glucose Transporter Inhibitors Colesevelam Bromocriptine Glucose-Lowering Agents Requiring Injection Insulins Long-Acting Insulins Short-Acting Insulins Premixed Insulins Human Versus Analogue Insulins Insulin Delivery Devices GLP1 Receptor Agonists Short-Acting GLP1 Agonists Long-Acting GLP1 Agonists Amylin Receptor Agonists Practical Aspects of Treatment A Team Approach Identifying Pathophysiologic Subgroups Latent Autoimmune Diabetes of Adulthood Pancreatic Diabetes Monogenic Diabetes Standardized Versus Personalized Tactics A Standardized Initial Therapeutic Approach Metformin Stepwise Combination Therapy Considerations in Personalizing Therapy Oral Agents and Injected Therapies Other than Insulin Basal Insulin Treating Postprandial Hyperglycemia Examples of Personalized Choices of Therapy Minimizing Cardiovascular Risks Minimizing Hypoglycemia Minimizing Weight Gain Minimizing Costs Special Situations in Clinical Management Severe Hyperglycemia at Diagnosis Youth-Onset T2DM Pregnancy Preventing Type 2 Diabetes Mellitus Future Directions 36 - Type 1 Diabetes Mellitus Diagnosis Animal Models Nonobese Diabetic Mouse Model Induced Models of T1DM Histopathology Mechanisms of Beta-Cell Death in T1DM Natural History of T1DM—Historical Concepts Natural History of T1DM From Long-Term Family and Population Studies Genetics Overview of Disease Prevalence Twin Studies The Major Histocompatibility Complex Other Loci Genetic and Immunologic Heterogeneity by Age of Onset Monogenic Forms of Diabetes Neonatal Diabetes Maturity-Onset Diabetes of the Young Autoimmune Polyendocrine Syndrome Type I (AIRE Gene Mutations) X-Linked Polyendocrinopathy, Immune Dysfunction, and Diarrhea (Scurfy Gene) The Genetic Risk Score Environmental Factors Models to Explain the Influence of Environment Candidate Environmental Factors Infection Vaccines Dietary Factors Natural History of T1DM—Emerging Concepts Beta-Cell Mass Is Not Equal in All Individuals Pancreatic Exocrine Abnormalities in T1DM Metabolic Progression Before Hyperglycemia C-Peptide Loss After Hyperglycemia Transient Hyperglycemia Emerging Biomarkers of T1DM Natural History and Diagnosis Stages in the Natural History of T1DM Immunotherapy for the Prevention and Reversal of T1DM Immunosuppression Immunologic Vaccination Therapeutic Targeting for Mechanisms of Beta-Cell Death Pancreas and Islet Cell Transplantation Stem Cell or Xenogeneic Islet Cell Transplantation Disorders Associated With Immunity to Insulin/Insulin Receptor Insulin Autoimmune Syndrome Insulin Allergy Anti-Insulin Receptor Autoantibodies Clinical Presentation Laboratory Findings at Presentation Treatment Principles of T1DM Management Glycemic Targets Lifestyle Management: Nutrition and Exercise Nutrition Therapy Physical Activity and Exercise Insulin Therapy Background Insulin Preparations Initial Management of Newly Diagnosed T1DM Initiation of Insulin Therapy Insulin Dose Determination Other Insulin Regimen Options Blood Glucose Monitoring Continuous Glucose Monitoring Continuous Subcutaneous Insulin Infusion AID: “The Artificial Pancreas” Proportional Integral Derivative AID Fuzzy Logic AID Model Predictive Control AID Decision Support Systems Use of Adjunctive Drugs in T1DM Pramlintide Metformin Incretin-Based Therapies SGTL1 and SGLT2 Inhibitors Outcomes Beyond HbA1c Transition in Care From Pediatric to Adult Health Care Settings and Beyond Acute Diabetic Emergencies Diabetic Ketoacidosis Pathophysiology of DKA Epidemiology and Risk Factors for DKA Prevention of DKA /Sick Day Management Insulin Dosing During Sick Days Prevention/Treatment of Dehydration During Sick Days Mini-Dose Glucagon Education Treatment of DKA Other Complications Comorbidities Thyroid Disease Celiac Disease 37 - Complications of Diabetes Mellitus Biochemistry and Molecular Cell Biology Clinical Overview Physiologic Reactive Oxygen Species Production Is Essential for Normal Intracellular Signaling and Cellular Homeostasis Mechanisms of Hyperglycemia-Induced Damage Increased Aldose Reductase Substrate Conversion Increased Intracellular Formation of the Major Advanced Glycation End Products—Precursor Methylglyoxal Activation of Protein Kinase C β, δ, and θ Increased Protein Modification by O-GlcNAc Increased Soluble Epoxide Hydrolase Reduced Pyruvate Kinase M2 Activity Different Hyperglycemia-Induced Pathogenic Mechanisms Reflect a Single Upstream Process: Mitochondrial Overproduction of ROS Insulin Resistance Increases Fatty Acid Oxidation, Causing Mitochondrial Overproduction of ROS Diabetes Reduces Activity of Nuclear Erythroid-Related Factor 2, the Master Regulator of Antioxidant Gene Expression Diabetes Activates the NLR Family Pyrin Domain Containing 3 Inflammasome Diabetes Activates the Transcription Factor NFAT Diabetes Increases Neutrophil Extracellular Traps Nonresolving Inflammation in Metabolic Syndrome, Diabetes, and Atherosclerosis Diabetes Alters Mitochondrial Dynamics Genetic Determinants of Susceptibility to Microvascular Complications Noncoding RNAs and Diabetic Complications Molecular Basis for Metabolic Memory Epidemiology and Impact of Proliferative Diabetic Retinopathy and Diabetic Macular Edema Pathophysiology of Diabetic Retinopathy Clinical Features of Diabetic Retinopathy Risk Factors Clinical Findings Classification Systems Classification of Diabetic Retinopathy Classification of Diabetic Macular Edema International Classification of Diabetic Retinopathy and Diabetic Macular Edema Other Ocular Manifestations of Diabetes Monitoring and Treatment of Diabetic Retinopathy Comprehensive Eye Examination Initial Ophthalmic Evaluation Follow-Up Ophthalmic Examination Evaluation and Treatment of Proliferative Diabetic Retinopathy Treatment of Nonproliferative Diabetic Retinopathy Treatment of Diabetic Macular Edema The pathogenesis of DME is highly complex, and a variable response to treatment modalities has been observed in many patients. I... Control of Systemic Disorders and Effect of Systemic Medications Diabetic Nephropathy Natural History of Nephropathy in Type 1 Diabetes Stage 1: Hyperfiltration Stage 2: The Silent Stage Stage 3: Microalbuminuria Stage 4: Macroalbuminuria Stage 5: Uremia Natural History of Nephropathy in Type 2 Diabetes Pathogenesis of Diabetic Nephropathy Pathology of Diabetic Renal Disease Other Renal Manifestations of Diabetes Renal Artery Stenosis Renal Papillary Necrosis Renal Tubular Acidosis Contrast-Induced Nephropathy Management of Diabetic Kidney Disease Glycemic Control in Diabetic Kidney Disease Blood Pressure Control in Diabetic Kidney Disease Evaluation of Additional Approaches to the Management of Diabetic Kidney Disease Treatment of the Diabetic Uremic Patient The Burden of Nephropathy Diabetic Neuropathies Epidemiology and Impact of Diabetic Neuropathies Pathophysiology of Diabetic Neuropathies Clinical Features of Diabetic Distal Symmetrical Polyneuropathy Clinical Symptoms Clinical Signs of Diabetic Neuropathy Differential Diagnosis of Diabetic Neuropathy Classification of Diabetic DSPN Graded Scores for the Classification of DSPN Treatment of DSPN Disease-Modifying Therapy in DSPN Treatment of Painful Neuropathy Other Diabetic Somatic Neuropathies: Clinical Features and Treatment Paradigms Clinical Features of Diabetic Autonomic Neuropathy Diabetic Heart Disease Coronary Artery Disease Effect of Diabetes on Risk of Coronary Heart Disease (CHD) Aggregation of Traditional CHD Risk Factors in Diabetes Insulin Resistance, Plasma Glucose, and Excess CHD Risk in Diabetes Cardiovascular Disease in Patients With Metabolic Syndrome Definitions and Diagnosis Cardiovascular Consequences of Metabolic Syndrome The Role of Glycemic Control in Improving Cardiovascular Outcomes Studies Using Insulin-Sensitizer Medications Studies Using Newer Antidiabetic Medications: A New Era? Dipeptidyl Peptidase 4 Inhibitors and Cardiovascular Disease GLP1RAs and Cardiovascular Disease SGLT2 Inhibitors and Cardiovascular Disease Characteristic Features and Treatment of Dyslipidemia in Diabetic Patients Characteristic Features and Treatment of Hypertension in Diabetic Patients Acute Coronary Syndromes in Diabetes Mellitus Cardiomyopathy in Patients With Diabetes Mellitus The Diabetic Foot Epidemiology of Diabetic Foot Ulceration Pathogenesis of Foot Ulceration Diabetic Neuropathy and the Foot Ulcer Callus, Deformity, and High Foot Pressures Peripheral Vascular Disease, Diabetic Foot Ulcers, and Amputation Risk Prevention of Foot Ulceration and Amputation The Diabetic Foot Care Team Classification of Foot Ulcers Management of Diabetic Foot Ulcers Neuropathic Foot Ulcer Without Osteomyelitis (Wagner Grades 1, 2; University of Texas Grades 1a, 1b, 2a, 2b) Neuroischemic Ulcers (Wagner Grades 1, 2; University of Texas Grades 1c, 1d) Osteomyelitis (Wagner Grade 3; University of Texas Grades 3b, 3d) Gangrene (Wagner Grades 4, 5) Charcot Neuroarthropathy Adjunct Treatments for Foot Ulcers Tissue-Engineered Skin and Platelet-Derived Growth Factors Negative-Pressure Wound Therapy (NPWT) Achilles Tendon Lengthening Procedures SGLT2 Inhibitors and Diabetic Foot Disease 38 - Hypoglycemia Physiology of Defense Against Hypoglycemia Glucose Metabolism Systemic Glucose Balance Responses to Hypoglycemia Clinical Manifestations of Hypoglycemia Maintenance of Systemic Glucose Balance Clinical Hypoglycemia Definition and Diagnosis Clinical Classification of Hypoglycemia Hypoglycemia in Persons With Diabetes The Clinical Problem of Hypoglycemia in Diabetes Frequency of Hypoglycemia in Diabetes Impact of Hypoglycemia in Diabetes Clinical Definition and Classification of Hypoglycemia in Diabetes Pathophysiology of Glucose Counterregulation in Diabetes Insulin Excess Defective Glucose Counterregulation and Hypoglycemia Unawareness HAAF in Diabetes Risk Factors for Hypoglycemia in Diabetes Absolute or Relative Insulin Excess Risk Factors for HAAF Prevention of Hypoglycemia in Diabetes Acknowledge the Problem Apply the Principles of Aggressive Glycemic Therapy Consider the Conventional Risk Factors Consider the Risk Factors for HAAF Treatment of Hypoglycemia in Diabetes Hypoglycemia in Persons Without Diabetes The Decision to Evaluate for Hypoglycemia Clinical Classification of Hypoglycemic Disorders Ill or Medicated Individual Seemingly Well Individual Diagnostic Approach Treatment of Hypoglycemia Disorders Hypoglycemia in Infancy and Childhood Intolerance of Fasting Hyperinsulinism Inborn Errors of Metabolism (Enzyme Deficiencies) Acknowledgments Disclosures 39 - Neuroendocrine Control of Energy Stores The Biologic Control of Energy Balance Leptin Signals the Repletion of Adipose Stores The Hypothalamic Melanocortin System Hypothalamic Systems and Signals That Regulate Energy Balance Leptin-Regulated Hypothalamic Circuits Roles for NPY/AGRP Neurons in Energy Balance Ghrelin Roles for the Paraventricular Nucleus in Energy Balance Specific Roles of Paraventricular Nucleus Neuronal Subsets in Metabolic Homeostasis Role for the Ventromedial Nucleus in Energy Balance Serotonergic Control of Energy Balance The Role of Insulin and Glucose in the Regulation of Energy Homeostasis Estrogen Central Nervous System Control of Thermogenesis Control of Glucose Homeostasis by the Brain Ventromedial Nucleus Control of Glucose and Energy Homeostasis POMC Neurons Sense Changes in Glucose Concentration Glucose-Inhibited Neurons of the Arcuate Nucleus and Lateral Hypothalamic Area Intersection of Energy Balance and Reward Circuits The Lateral Hypothalamic Area Links Food Intake Control and Arousal Brainstem Circuits That Regulate Energy Balance Gut Peptides Involved in Satiety and Hunger GLP1 Action in the Central Nervous System Peptide YY (PYY) Cholecystokinin (CKK) Amylin GDF15 Bariatric Surgery 40 - Obesity Definition of Obesity Body Mass Index Body Fat Distribution Physiology of Energy Balance Central Nervous System Regulation of Appetite Signals From the Periphery Regulating Appetite Energy Expenditure Body Weight Set-Point Pathogenesis of Obesity: Genes and Environment Environmental Effects in High-Risk Populations Influences of Childhood and Parental Obesity Genetics and Obesity Monogenic Causes of Obesity Prohormone Convertase 1 Gene Mutation Mutation of the Neurotrophin Receptor TrkB Single-Minded Homolog 1 (SIM1) Gene Mutation Src Homology 2B 1 (SH2B1) Deficiency Obesity Syndromes Prader-Willi Syndrome Bardet-Biedl Syndrome Polygenic Causes of Obesity Adipose Tissue as an Endocrine and Immune Organ Leptin Resistin Adiponectin Estrogens Selected Cytokines Tumor Necrosis Factor α Interleukin 6 Brown Adipose Tissue Metabolically Normal Obesity Adverse Consequences of Obesity Obesity as a Disease Risk Factor Metabolic Syndrome Type 2 Diabetes Dyslipidemia Hypertension Cardiovascular Disease Liver Disease Obstructive Sleep Apnea Musculoskeletal Disease Cancer Diagnostic and Therapeutic Approach Benefits of Intentional Weight Loss Dietary Intervention Caloric Restriction Macronutrient Composition Physical Activity Behavior Modification Pharmacotherapy Endoscopic Gastric Therapies Bariatric Surgery 41 - Disorders of Lipid Metabolism Lipid Biochemistry and Metabolism Simple and Complex Lipid Structure Fatty Acids Triglycerides Phospholipids Cholesterol Fatty Acid Metabolism Fatty Acid Biosynthesis Fatty Acid Oxidation Triglyceride and Phospholipid Metabolism Triglyceride Synthesis Phospholipid Synthesis Lipolysis of Triglyceride Stores in Adipose Tissue Lipoprotein Lipase Cholesterol Metabolism Cholesterol Absorption, Synthesis, and Excretion Nuclear Receptors and Lipid Metabolism Plasma Lipoproteins, Apolipoproteins, Receptors, and Other Proteins Major Lipoproteins Major Apolipoproteins Apolipoproteins AI, AII, AIV, and AV Apolipoprotein B Apolipoproteins CI, CII, and CIII Apolipoprotein E Major Receptors Involved in Lipid Metabolism LDL Receptor Gene Family LDL Receptor LDL Receptor–Related Protein 1 Pattern Recognition Receptors Scavenger Receptors Toll-Like Receptors Other Enzymes and Transfer Proteins Mediating Lipid Metabolism Hepatic Lipase Endothelial Lipase Proprotein Convertase Subtilisin/Kexin Type 9 Lipoprotein-Associated Phospholipase A2 Cholesteryl Ester Transfer Protein Lecithin:Cholesterol Acyltransferase Integrative Physiology of Lipid Metabolism Exogenous Lipid Transport Endogenous Lipid Transport Reverse Cholesterol Transport and Dysfunctional HDL Overview of Hyperlipidemia, Dyslipidemia, and Atherogenesis Hypertriglyceridemia Fasting Hyperchylomicronemia LPL Deficiency Postprandial Hyperlipidemia Diagnostic Evaluation of Severe Hypertriglyceridemia Moderate Fasting Hypertriglyceridemia Due to Elevated VLDL Secondary Causes of Hypertriglyceridemia Diabetes Mellitus Renal Failure Drugs Diet and Alcohol Diagnostic Evaluation of Moderate Hypertriglyceridemia Hypercholesterolemia Without Hypertriglyceridemia Polygenic Hypercholesterolemia Genetic FH Familial Defective Apolipoprotein B100 Rare Mutations Associated With Elevated LDL Levels Elevated Plasma Lp(a) Lipoprotein(X) Sitosterolemia Cerebrotendinous Xanthomatosis Hypothyroidism and Elevated Cholesterol Diagnostic Evaluation of Isolated Hypercholesterolemia Increased HDL Genetic Disorders Causing Increased HDL Elevated Triglycerides and Cholesterol Combined Hyperlipidemia Familial Dysbetalipoproteinemia Hepatic Lipase Deficiency Nephrotic Syndrome Protease Inhibitor Use in Human Immunodeficiency Virus Infection Immunosuppressive Regimens Diagnostic Evaluation of Elevated Triglycerides and Cholesterol Hypocholesterolemia Familial Hypobetalipoproteinemia Abetalipoproteinemia Chylomicron Retention Syndrome Familial Hypoalphalipoproteinemia Apolipoprotein AI Mutations Lecithin: Cholesterol Acyltransferase Deficiency ABCA1 Deficiency Treatment of Lipid Disorders Evidence Supporting Treatment of Lipid Disorders: Cholesterol and Cardiovascular Disease Measurement of Plasma Lipids Treatment of High LDL Hyperchylomicronemia-Induced Pancreatitis Screening for Secondary Disorders Patient Selection and Treatment Goals Specific Therapies Lifestyle Treatment Drug Treatment HMG-CoA Reductase Inhibitors (Statins) Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Ezetimibe Bile Acid Sequestrants Fibrates Omega-3 Fatty Acids Niacin Combination Therapies Combination Therapy for Other Hyperlipidemias Statin Plus Fibrate Other Combinations Treatment for Chylomicronemia Syndrome Treatment of FH Treatment of Familial Combined Hyperlipidemia Treatment of Metabolic Syndrome Treatment of Dysbetalipoproteinemia Treatment for Elevated Plasma Lp(a) Treatment for Low Levels of HDL Summary of Treatment of Lipid Disorders 42 - Multiple Endocrine Neoplasia Introduction to Multiple Endocrine Neoplasia Syndromes MEN Type 1 Clinical Features and Management Parathyroid Tumors Clinical Features Treatment Pancreatic NETs Gastrinoma Clinical Features Treatment Insulinoma Clinical Features Treatment Glucagonoma Clinical Features Treatment VIPoma Clinical Features Treatment NF Pancreatic NETs Clinical Features Treatment Somatostatinoma GHRHoma Pituitary Tumors Clinical Features Treatment Adrenal Tumors Clinical Features Treatment Carcinoid Tumors Thymic Carcinoids Bronchial Carcinoids Gastric Carcinoids Other Tumors Central Nervous System Tumors Lipomas Facial Angiofibromas and Collagenomas Thyroid Tumors Breast Cancer Molecular Genetics MEN1 Gene Germline MEN1 Mutations MEN1 Polymorphisms MEN1 Phenocopies and Mutations in Other Genes Somatic MEN1 Mutations Functions of the Menin Protein and Insights Into Mechanisms of Tumorigenesis Animal Models Conventional Men1 Mouse Knockout Models Conditional Men1 Mouse Knockout Models Nonendocrine Phenotypes in Men1 Mouse Knockout Models Preclinical Evaluation of Drug Therapies in Men1 Mouse Models Genetic Testing, Tumor Surveillance, and Organization of Care Clinical Utility of MEN1 Mutational Analysis Surveillance of “At-Risk” Individuals MEN Types 2 and 3 Clinical Features and Management Medullary Thyroid Carcinoma Clinical Features Treatment Prophylactic Thyroidectomy in MEN2 Postoperative Evaluation and Management of Patients With MTC Management of Advanced Disease Targeted Therapies for MEN2-Associated MTC Pheochromocytoma Clinical Features Treatment Primary Hyperparathyroidism Clinical Features Treatment Additional Clinical Features Associated With MEN2A Variant Disorders Familial MTC-Only MEN2 With CLA MEN2 With HSCR Additional Clinical Manifestations Associated With MEN3 Molecular Genetics The RET Proto-Oncogene Germline RET Mutations Somatic RET Mutations and Rearrangements RET Polymorphisms RET Structure and Function RET Mutations and Receptor Function Animal Models Genetic Testing, Tumor Surveillance, and Organization of Care Clinical Utility of Genetic Testing for MEN2 and MEN3 Screening and Intervention in RET Mutation Carriers MEN Type 4 Clinical Features and Management Molecular Genetics and Animal Models Genetic Testing, Tumor Surveillance, and Organization of Care Future Directions and Concluding Remarks Acknowledgments 43 - The Immunoendocrinopathy Syndromes Autoimmunity Primer Natural History of Autoimmune Disorders Genetic Associations Environmental Triggers Development of Organ-Specific Autoimmunity Failure of Gland Autoimmune Polyendocrine Syndrome Type I Clinical Features Genetics Diagnosis Therapy and Follow-Up Autoimmune Polyendocrine Syndrome Type II Clinical Features Diagnosis Therapy Other Polyendocrine Deficiency Autoimmune Syndromes Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome CTLA4, STAT3, and LRBA Mutations Anti–Insulin Receptor Autoantibodies POEMS Syndrome Kearns-Sayre Syndrome Thymic Tumors Wolfram Syndrome Omenn Syndrome Chromosomal Disorders Conclusion 44 - Endocrinology of HIV/AIDS Adrenal Function Adrenal Insufficiency Glucocorticoid Excess: Adrenal Shunting and Cortisol Resistance Medication Effects Clinical Assessment Gonadal Function Male Gonadal Dysfunction Female Gonadal Dysfunction Thyroid Function Fluid Balance and Electrolytes Sodium Potassium Calcium Homeostasis and Bone Changes Calcium Homeostasis Bone Loss: Prevalence, Etiologic Factors, and Treatment Strategies Bone Metabolism in HIV-Infected Children Avascular Necrosis of Bone The GH/IGF1 Axis Glucose Homeostasis and Pancreatic Function Metabolic and Body Composition Changes in HIV-Infected Patients The AIDS Wasting Syndrome and Loss of Lean Body Mass Changes in Fat Mass and Distribution Lipid Abnormalities Hyperglycemia and Insulin Resistance Treatment of Metabolic and Body Composition Changes in HIV-Infected Patients Treatment of AIDS Wasting and Loss of Lean Body Mass Strategies for Treating Lipoatrophy and Subcutaneous Fat Loss Treatments for Visceral Fat Accumulation Insulin-Sensitizing Strategies Leptin Treatment for Metabolic Dysregulation Among HIV-Infected Patients With Lipoatrophy Lipid Management CVD in HIV-Infected Patients Strategies for Hyperlipidemia Among HIV-Infected Patients Anti-Inflammatory Strategies for CVD in HIV 45 - Neuroendocrine Tumors and Related Disorders Phylogenesis and Embryology Molecular Genetics Classification Biochemistry Clinical Presentation The Carcinoid Syndrome Flushing Diarrhea Carcinoid Heart Disease Bronchial Constriction Other Manifestations of the Carcinoid Syndrome Carcinoid Crisis Other Clinical Manifestations of Carcinoid Tumors Diagnosis Histopathologic Diagnosis Biochemical Diagnosis Localization Procedures Treatment Somatostatin Analogues Interferons Chemotherapy Other Agents Surgery Irradiation Prognosis Other Flushing Disorders Medullary Thyroid Carcinoma and VIPoma Mastocytosis and Related Disorders 46 - Managing Reproductive Disorders in Cancer What Is Oncofertility, and Why Is It Important? Scope of the Problem Reproductive Health Concerns During Cancer Treatment Fertility Contraception During Cancer Therapy Gonadal Dysfunction Women With Cancer Men With Cancer Physical Changes Related to Cancer Therapy Logistics of Fertility Preservation Importance of Fertility Preservation and Restoration Fertility Loss, Preservation, and Restoration in Female Cancer Patients Epidemiology of Cancer in Young Female Patients Risks of Gonadotoxicity and Fertility Loss in Young Female Patients Fertility Preservation and Restoration Options for Young Female Patients Established Options for Fertility Preservation in Women and Girls Embryo Freezing Egg Freezing Debatable Options for Fertility Preservation in Women and Girls GnRH Analogues and Hormonal Suppression Oophoropexy Gonadal Shielding Fractionated Chemotherapy and Radiotherapy Experimental Options for Fertility Preservation in Women and Girls Ovarian Tissue Freezing and Autotransplantation IVM of Oocytes Artificial Ovary Stem Cells Neoadjuvant Cytoprotective Pharmacotherapy Fertility Loss, Preservation, and Restoration in Male Patients With Cancer Epidemiology of Cancer in Young Male Patients Risks of Gonadotoxicity and Fertility Loss in Young Male Patients Fertility Preservation and Restoration Options in Young Male Patients Established Options for Fertility Preservation in Men and Boys Sperm Freezing Debatable Options for Fertility Preservation in Men and Boys GnRH Analogues and Hormonal Suppression Gonadal Shielding Fractionated Chemotherapy and Radiotherapy Experimental Options for Fertility Preservation in Men and Boys Testicular Tissue Freezing Stem Cells Neoadjuvant Cytoprotective Pharmacotherapy Other Experimental Options Decision-Making Strategies for Young Female and Male Patients With Cancer Challenges of Fertility Preservation Factors That Prohibit Oncofertility Support Special Patient Populations Financial and Ethical Considerations Methods for Addressing Challenges Providing Personalized Risk Assessment Practice Management, Knowledge, and Access Barriers to Clinical Care Inclusion of Psychological Support Is Critical to Oncofertility Clinical Care Models Access and Affordability Public Awareness Distinguishing Between Oncofertility, Infertility, and Social Egg Freezing Summary and Next Steps
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