BOOK
Williams Textbook of Endocrinology E-Book
Shlomo Melmed | Kenneth S. Polonsky | P. Reed Larsen | Henry M. Kronenberg
(2015)
Additional Information
Book Details
Abstract
For more than 65 years, Williams Textbook of Endocrinology has been the gold standard in the field, delivering authoritative guidance on every aspect of adult and pediatric endocrine system disorders. The 13th Edition has been thoroughly updated by Drs. Shlomo Melmed, Kenneth S. Polonsky, P. Reed Larsen, and Henry M. Kronenberg, to bring you state-of-the-art coverage of diabetes, metabolic syndrome, obesity, thyroid disease, testicular disorders, and much more, all designed to help you provide optimal care to every patient. Bridging the gap between basic science and clinical information, it is an essential, relevant resource for endocrinologists, endocrine surgeons, gynecologists, internists, and pediatricians – any clinician who needs the most reliable coverage available on the diverse features across the spectrum of endocrine disease.
- Obtain a better understanding of both scientific insight and clinical data from the classic reference that delivers the current information you need in a highly illustrated, user-friendly format.
- Stay up to date with expanded discussions of autoimmune thyroid diseases, mechanisms, and the appropriate treatment of the ophthalmopathy of Graves’ disease; a new section on the interpretation of fine needle aspiration results in patients with thyroid nodules; and new coverage of when and when not to use radioiodine in the treatment of patients with thyroid cancer.
- Update your knowledge and skills with all-new chapters on Genetics of Endocrine Disease, Endocrinology of Population Health, and Laboratory Techniques for Recognition of Endocrine Disorders.
- Confidently manage any clinical endocrinopathy you may encounter thanks to new information on recent FDA-approved drugs for pituitary disorders, a new focus on pediatrics, and new content on diabetes, obesity, and appetite control.
- Benefit from the expertise of dynamic new contributors who offer fresh perspectives throughout.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | cover | ||
| IFC_Expert Consult ad | IFC2 | ||
| Williams Textbook of Endocrinology | i | ||
| Copyright Page | iv | ||
| Contributors | v | ||
| Preface | xv | ||
| Note from the Editors | xvi | ||
| Table Of Contents | xvii | ||
| I Hormones and Hormone Action | 1 | ||
| 1 Principles of Endocrinology | 2 | ||
| Key Points | 2 | ||
| The Evolutionary Perspective | 2 | ||
| Endocrine Glands | 4 | ||
| Transport of Hormones in Blood | 5 | ||
| Target Cells as Active Participants | 6 | ||
| Control of Hormone Secretion | 7 | ||
| Hormone Measurement | 9 | ||
| Endocrine Diseases | 9 | ||
| Hormone Overproduction | 9 | ||
| Hormone Underproduction | 10 | ||
| Altered Tissue Responses | 10 | ||
| Tumors of Endocrine Glands | 10 | ||
| Excessive Hormone Inactivation or Destruction | 10 | ||
| Diagnostic and Therapeutic Uses of Hormones | 10 | ||
| What We Don’t Know (YET) | 11 | ||
| References | 11 | ||
| 2 Clinical Endocrinology: | 12 | ||
| Key Points | 12 | ||
| The Practice | 12 | ||
| The Rules of Engagement | 12 | ||
| The Covenant | 13 | ||
| The Original Oath | 13 | ||
| The Encounter | 13 | ||
| Physical Examination | 14 | ||
| The Diagnosis | 14 | ||
| Fundamental Lemma | 14 | ||
| Unnecessary Tests | 14 | ||
| A Digression into Test Technology | 15 | ||
| The Therapy | 16 | ||
| Replacement Therapy | 16 | ||
| Surgery | 17 | ||
| Parting Thoughts | 17 | ||
| Criticism | 17 | ||
| References | 17 | ||
| 3 Principles of Hormone Action | 18 | ||
| Key Points | 18 | ||
| Introduction to Hormone Signaling | 18 | ||
| Ligands That Act Through Cell Surface Receptors | 19 | ||
| Classic Peptide Hormones | 19 | ||
| Nonclassic Peptide Hormones | 19 | ||
| Nonpeptide Hormones That Act at Cell Surface Receptors | 20 | ||
| Binding Properties of Cell Surface Receptors | 20 | ||
| Cell Surface Hormone Receptors | 21 | ||
| Ligand-Gated Ion Channels | 21 | ||
| G Protein–Linked Receptors | 22 | ||
| Signaling by Heterotrimeric G Proteins | 22 | ||
| Receptor Tyrosine Protein Kinases as Cell Surface Receptors | 24 | ||
| Signaling by Receptor Tyrosine Protein Kinases | 27 | ||
| Receptor Serine/Threonine Protein Kinases | 28 | ||
| Signaling by Receptors That Associate With Enzymes | 29 | ||
| Coupling of Cell Surface Receptors to Intracellular Signaling | 32 | ||
| Second Messengers | 32 | ||
| Downstream Signaling by Cyclic Adenosine Monophosphate | 33 | ||
| Regulation of Protein Kinases by Second Messengers | 34 | ||
| Regulation of Protein Kinases by PI3K | 34 | ||
| Regulation of Protein Kinases by RAS | 35 | ||
| Disease Caused by Defective Cell Surface Receptors | 35 | ||
| Insulin-Resistance Syndromes | 36 | ||
| Defects in Cell Surface Receptors That Control Growth | 36 | ||
| Diseases Caused by Mutations in GPCRs and G Proteins | 36 | ||
| Ligands That Act Through Nuclear Receptors | 37 | ||
| General Features of Nuclear Receptor Ligands | 37 | ||
| Subclasses of Nuclear Receptor Ligands | 37 | ||
| Classic Hormones | 37 | ||
| Vitamins | 37 | ||
| Metabolic Intermediates and Products | 38 | ||
| Xenobiotics | 38 | ||
| Orphan Receptors | 38 | ||
| Variant Receptors | 38 | ||
| Regulation of Ligand Levels | 38 | ||
| Nuclear Receptor Signaling Mechanisms | 39 | ||
| Domain Structure of Nuclear Receptors | 39 | ||
| Nuclear Localization | 40 | ||
| Hormone Binding | 40 | ||
| Target Gene Recognition by Receptors | 41 | ||
| Receptor Dimerization | 41 | ||
| Receptor Regulation of Gene Transcription | 42 | ||
| Ligand-Dependent Activation | 42 | ||
| Repression of Gene Expression by Unliganded Receptor | 43 | ||
| Ligand-Dependent Negative Regulation of Gene Expression: Transrepression | 43 | ||
| Roles of Other Nuclear Receptor Domains | 44 | ||
| Cross-Talk With Other Signaling Pathways | 44 | ||
| Receptor Antagonists | 44 | ||
| Tissue Selectivity of Ligands Interacting With Nuclear Receptors | 45 | ||
| References | 45 | ||
| 4 Genetics of Endocrinology | 49 | ||
| Key Points | 49 | ||
| The Role of Genetics in Endocrinology | 49 | ||
| Principles of Genetics | 49 | ||
| A Brief Historical Perspective | 49 | ||
| Heritability: An Estimate of the Importance of Genetic Factors to Disease Causation | 50 | ||
| Human DNA Sequence Variation: Molecular Forms and Biologic Effects | 51 | ||
| Factors Influencing the Biologic Impact of Genetic Variants in a Particular Gene | 51 | ||
| Summary | 54 | ||
| Genetics of Endocrine Diseases | 54 | ||
| Mendelian Endocrine Diseases | 55 | ||
| Genetic Architecture | 55 | ||
| Disease Biology | 55 | ||
| Clinical Translation | 56 | ||
| Type 2 Diabetes | 57 | ||
| Genetic Architecture | 57 | ||
| Disease Biology | 57 | ||
| Clinical Translation | 58 | ||
| Short Stature | 58 | ||
| Genetic Architecture | 58 | ||
| Disease Biology | 59 | ||
| Clinical Translation | 59 | ||
| Lipids and Coronary Artery Disease | 60 | ||
| Genetic Architecture | 60 | ||
| Disease Biology | 60 | ||
| Clinical Translation | 61 | ||
| Considerations for Clinical Use of Genetic Information and Sequencing in Endocrinology | 62 | ||
| Genome Screening in the General Population | 62 | ||
| Genetic Information and Sequencing in Individual Patients | 63 | ||
| Asymptomatic Individuals | 63 | ||
| Symptomatic Individuals | 63 | ||
| Selection of Genetic Tests: Targeted Versus Genome-wide Approaches | 63 | ||
| Interpretation of Identified Genetic Variants | 64 | ||
| Using a Genetics Laboratory Report to Make Clinical Decisions | 64 | ||
| Future Perspectives and Summary | 65 | ||
| References | 66 | ||
| 5 Health Care Reform, Population Health, and the Endocrinologist | 69 | ||
| Key Points | 69 | ||
| The Change Imperative That Led to the Affordable Care Act | 69 | ||
| Elements of the Affordable Care Act | 70 | ||
| How Accountable Care Organizations and Other Systems Can Increase Value | 71 | ||
| Role of the Endocrinologist | 72 | ||
| Challenges | 73 | ||
| References | 75 | ||
| 6 Laboratory Techniques for Recognition of Endocrine Disorders | 77 | ||
| Key Points | 77 | ||
| Laboratory Methods | 78 | ||
| Antibody-Based Methods | 79 | ||
| Classic Competitive Binding Immunoassays | 79 | ||
| Antibody. | 80 | ||
| Labeled Antigen. | 80 | ||
| Unlabeled Antigen. | 81 | ||
| Separation of Reactants/Automation. | 81 | ||
| Quantitation. | 81 | ||
| Epitope-Specific Immunometric Assays | 82 | ||
| Molecular Structure–Based Methods | 85 | ||
| Extraction Methods | 85 | ||
| Chromatographic Systems | 85 | ||
| Mass Spectrometry | 86 | ||
| Free Hormone Methods | 89 | ||
| Nucleic Acid–Based Methods | 91 | ||
| Hybridization Assays (Mutation Assays, Genotyping) | 92 | ||
| Restriction Fragmentation | 92 | ||
| Electrophoretic Separation | 92 | ||
| Amplification | 92 | ||
| Sequencing Methods | 92 | ||
| Analytic Validation | 92 | ||
| Intrinsic Performance Parameters | 93 | ||
| Analytic Specificity | 93 | ||
| Cross-Reactivity. | 93 | ||
| Interference. | 95 | ||
| Analytic Sensitivity | 96 | ||
| Precision | 97 | ||
| Accuracy | 97 | ||
| Carryover | 98 | ||
| Utilization Parameters | 99 | ||
| Specimen Stability | 99 | ||
| Reagent Stability | 99 | ||
| Robustness (Assay Stability) | 99 | ||
| Interpretation Parameters | 99 | ||
| Reportable Range | 99 | ||
| Reference Intervals | 99 | ||
| Diagnostic Power | 99 | ||
| Operational Parameters (Preanalytic Considerations) | 100 | ||
| Specimen Types | 100 | ||
| Whole Blood. | 100 | ||
| Serum. | 101 | ||
| Plasma. | 101 | ||
| Urine. | 101 | ||
| Saliva. | 101 | ||
| Fluids and Tissue From Fine-Needle Aspiration. | 102 | ||
| Quality Control | 102 | ||
| Quality Assurance | 102 | ||
| Classes of Assays | 103 | ||
| Conclusion | 104 | ||
| Acknowledgment | 104 | ||
| References | 104 | ||
| II Hypothalamus and Pituitary | 109 | ||
| 7 Neuroendocrinology | 110 | ||
| Key Points | 110 | ||
| Historical Perspective | 110 | ||
| Neural Control of Endocrine Secretion | 111 | ||
| Neurosecretion | 111 | ||
| Contribution of the Autonomic Nervous System to Endocrine Control | 112 | ||
| Hypothalamic-Pituitary Unit | 113 | ||
| Development and Differentiation of Hypothalamic Nuclei | 113 | ||
| Anatomy of the Hypothalamic-Pituitary Unit | 114 | ||
| The Median Eminence and Hypophyseotropic Neuronal System | 114 | ||
| Circumventricular Organs | 116 | ||
| Median Eminence | 118 | ||
| Organum Vasculosum of the Lamina Terminalis and the Subfornical Organ | 118 | ||
| Area Postrema | 119 | ||
| Subcommissural Organ | 119 | ||
| Pineal Gland | 119 | ||
| The Pineal Is the Source of Melatonin | 119 | ||
| Physiologic Roles of Melatonin | 120 | ||
| Melatonin Receptors | 120 | ||
| Melatonin Therapy in Humans | 121 | ||
| Hypophyseotropic Hormones and Neuroendocrine Axes | 121 | ||
| Feedback Concepts in Neuroendocrinology | 121 | ||
| Endocrine Rhythms | 122 | ||
| Thyrotropin-Releasing Hormone | 123 | ||
| Chemistry and Evolution | 123 | ||
| Effects on the Pituitary Gland and Mechanism of Action | 124 | ||
| Extrapituitary Function | 125 | ||
| Clinical Applications | 125 | ||
| Regulation of Thyrotropin Release | 125 | ||
| Feedback Control: Pituitary-Thyroid Axis | 125 | ||
| Neural Control | 125 | ||
| Circadian Rhythm | 126 | ||
| Temperature | 127 | ||
| Stress | 127 | ||
| Starvation | 128 | ||
| Infection and Inflammation | 129 | ||
| Corticotropin-Releasing Hormone | 129 | ||
| Chemistry and Evolution | 129 | ||
| Effects on the Pituitary and Mechanism of Action | 132 | ||
| Extrapituitary Functions | 132 | ||
| Clinical Applications | 133 | ||
| Feedback Control | 133 | ||
| Neural Control | 134 | ||
| Inflammation and Cytokines | 135 | ||
| Other Factors Influencing Secretion of Corticotropin | 136 | ||
| Circadian Rhythms. | 136 | ||
| Growth Hormone–Releasing Hormone | 136 | ||
| Chemistry and Evolution | 136 | ||
| Growth Hormone–Releasing Hormone Receptor | 138 | ||
| Effects on the Pituitary and Mechanism of Action | 138 | ||
| Extrapituitary Functions | 139 | ||
| Growth Hormone–Releasing Peptides | 139 | ||
| Clinical Applications | 140 | ||
| Neuroendocrine Regulation of Growth Hormone Secretion | 140 | ||
| Feedback Control | 140 | ||
| Neural Control | 142 | ||
| Other Factors Influencing Secretion of Growth Hormone | 144 | ||
| Human Growth Hormone Rhythms. | 144 | ||
| External and Metabolic Signals. | 144 | ||
| Somatostatin | 145 | ||
| Chemistry and Evolution | 145 | ||
| Somatostatin Receptors | 146 | ||
| Effects on Target Tissues and Mechanism of Action | 147 | ||
| Clinical Applications of Somatostatin Analogues | 147 | ||
| Prolactin-Regulating Factors | 148 | ||
| Dopamine | 148 | ||
| Prolactin-Releasing Factors | 150 | ||
| Intrapituitary Regulation of Prolactin Secretion | 151 | ||
| Neuroendocrine Regulation of Prolactin Secretion | 151 | ||
| Feedback Control | 151 | ||
| Neural Control | 151 | ||
| Factors Influencing Secretion | 151 | ||
| Circadian Rhythm. | 151 | ||
| External Stimuli. | 151 | ||
| Gonadotropin-Releasing Hormone and Control of the Reproductive Axis | 152 | ||
| Chemistry and Evolution | 152 | ||
| Anatomic Distribution | 153 | ||
| Embryonic Development | 153 | ||
| Action at the Pituitary | 153 | ||
| Receptors. | 153 | ||
| Pulsatile Gonadotropin-Releasing Hormone Stimulation. | 154 | ||
| Regulatory Systems | 155 | ||
| Feedback Regulation | 155 | ||
| Regulation of the Ovarian Cycle | 157 | ||
| Early Development and Puberty | 158 | ||
| Reproductive Function and Stress | 159 | ||
| Neuroendocrine Disease | 159 | ||
| Pituitary Isolation Syndrome | 160 | ||
| Hypophyseotropic Hormone Deficiency | 161 | ||
| Craniopharyngioma | 162 | ||
| Hypophyseotropic Hormone Hypersecretion | 163 | ||
| Neuroendocrine Disorders of Gonadotropin Regulation | 163 | ||
| Precocious Puberty | 163 | ||
| Idiopathic Sexual Precocity. | 163 | ||
| Neurogenic Precocious Puberty. | 163 | ||
| Hypothyroidism. | 163 | ||
| Tumors of the Pineal Gland. | 164 | ||
| Approach to the Patient with Precocious Puberty. | 164 | ||
| Management of Sexual Precocity. | 165 | ||
| Psychogenic Amenorrhea | 165 | ||
| Neurogenic Hypogonadism in Males | 165 | ||
| Neurogenic Disorders of Prolactin Regulation | 165 | ||
| Neurogenic Disorders of Growth Hormone Secretion | 165 | ||
| Hypothalamic Growth Failure | 165 | ||
| Maternal Deprivation Syndrome and Psychosocial Dwarfism | 166 | ||
| Neuroregulatory Growth Hormone Deficiency | 166 | ||
| Neurogenic Hypersecretion of Growth Hormone | 166 | ||
| Diencephalic Syndrome. | 166 | ||
| Growth Hormone Hypersecretion Associated With Metabolic Disturbances. | 166 | ||
| Neurogenic Disorders of Corticotropin Regulation | 166 | ||
| Nonendocrine Manifestations of Hypothalamic Disease | 166 | ||
| Narcolepsy | 167 | ||
| Acknowledgments | 167 | ||
| References | 168 | ||
| 8 Pituitary Physiology and Diagnostic Evaluation | 176 | ||
| Key Points | 176 | ||
| Anatomy, Development, and Overview of Control of Hormone Secretion | 176 | ||
| Anatomy | 176 | ||
| Pituitary Blood Supply | 177 | ||
| Pituitary Development | 178 | ||
| Pituitary Transcription Factors | 179 | ||
| Pituitary Stem Cells | 180 | ||
| Pituitary Control | 181 | ||
| Physiology and Disorders of Pituitary Hormone Axes | 182 | ||
| Prolactin | 182 | ||
| Physiology | 182 | ||
| Lactotroph Cells. | 182 | ||
| Prolactin Structure. | 182 | ||
| Regulation. | 183 | ||
| Prolactin Secretion. | 183 | ||
| Prolactin Action. | 183 | ||
| Prolactin Function. | 183 | ||
| Mammary Gland Development and Lactation | 183 | ||
| Puberty. | 183 | ||
| Lactation. | 184 | ||
| Reproductive Function. | 184 | ||
| Immune Function. | 185 | ||
| Prolactin Assays. | 185 | ||
| Hyperprolactinemia | 185 | ||
| Causes. | 185 | ||
| Physiologic Causes | 185 | ||
| Pregnancy. | 185 | ||
| Suckling. | 185 | ||
| Idiopathic Hyperprolactinemia. | 185 | ||
| Macroprolactinemia. | 185 | ||
| Pathologic Causes. | 185 | ||
| Drug-Induced Hyperprolactinemia. | 187 | ||
| Clinical Features. | 187 | ||
| Galactorrhea. | 187 | ||
| Prolactin Deficiency. | 187 | ||
| Growth Hormone | 187 | ||
| Physiology | 187 | ||
| Somatotroph Cells. | 187 | ||
| Biosynthesis. | 188 | ||
| Regulation. | 188 | ||
| GHRH and SRIF Interaction. | 189 | ||
| Growth Hormone Secretagogues and Ghrelin. | 189 | ||
| Secretion. | 189 | ||
| Interaction With Other Hormone Axes. | 190 | ||
| Growth Hormone–Binding Proteins. | 190 | ||
| Action. | 191 | ||
| Signaling. | 191 | ||
| Metabolic Action. | 191 | ||
| Growth Hormone Deficiency | 192 | ||
| Pathophysiology. | 192 | ||
| Presentation. | 192 | ||
| Evaluation. | 193 | ||
| Provocative Testing. | 193 | ||
| Growth Hormone–Responsive Markers. | 195 | ||
| Spontaneous GH Secretion. | 195 | ||
| Growth Hormone Assays. | 195 | ||
| Growth Hormone Replacement Therapy. | 195 | ||
| Growth Hormone Administration. | 197 | ||
| Transition Age Patients. | 198 | ||
| Precautions and Caveats of Treating With Human Growth Hormone | 198 | ||
| Investigational Uses of Growth Hormone | 198 | ||
| Catabolic States. | 198 | ||
| Osteoporosis. | 199 | ||
| Human Immunodeficiency Virus Infection. | 199 | ||
| Sports. | 199 | ||
| Aging. | 199 | ||
| Adrenocorticotropic Hormone | 199 | ||
| Physiology | 199 | ||
| Corticotroph Cells. | 199 | ||
| Structure. | 199 | ||
| Transcriptional Regulation | 200 | ||
| POMC Processing. | 200 | ||
| Biologic Actions of POMC-Derived Peptides | 201 | ||
| Adrenal Action. | 201 | ||
| Skin Pigmentation. | 201 | ||
| Appetite Regulation. | 201 | ||
| Immune Modulation. | 201 | ||
| Analgesia. | 201 | ||
| Placenta-Derived POMC Peptides. | 201 | ||
| Ectopic ACTH Synthesis | 201 | ||
| ACTH Regulation | 201 | ||
| Stress Response. | 202 | ||
| ACTH Secretion. | 202 | ||
| Action. | 202 | ||
| Disorders of ACTH Secretion | 202 | ||
| ACTH Deficiency | 202 | ||
| Causes. | 202 | ||
| Clinical Features. | 202 | ||
| Evaluation. | 202 | ||
| ACTH Excess | 203 | ||
| Causes. | 203 | ||
| Clinical Features. | 203 | ||
| Measurement of ACTH | 203 | ||
| Dynamic Testing for ACTH Reserve | 203 | ||
| Hypothalamic Testing. | 203 | ||
| Pituitary Stimulation. | 203 | ||
| Adrenal Stimulation. | 203 | ||
| Adrenal Steroid Replacement | 204 | ||
| Gonadotropins | 204 | ||
| Physiology | 204 | ||
| Gonadotroph Cells. | 204 | ||
| Gonadotropin Structure. | 204 | ||
| Regulation | 205 | ||
| Gonadotropin-Releasing Hormone. | 205 | ||
| Inhibins and Activins. | 207 | ||
| Sex Steroids. | 208 | ||
| Secretion | 209 | ||
| Action | 209 | ||
| Female. | 209 | ||
| Male. | 209 | ||
| Gonadotropin Assays | 209 | ||
| α-Subunit Assays. | 209 | ||
| GnRH Stimulation Test. | 209 | ||
| Clomiphene Stimulation Test. | 210 | ||
| Gonadotropin Deficiency | 210 | ||
| Causes. | 210 | ||
| Hypogonadotropic Hypogonadism. | 210 | ||
| Kallmann Syndrome. | 210 | ||
| Prader-Willi Syndrome. | 210 | ||
| Clinical Features. | 210 | ||
| Management. | 211 | ||
| Evaluation. | 211 | ||
| Sex Steroid Replacement Therapy. | 211 | ||
| Fertility. | 212 | ||
| Thyroid-Stimulating Hormone | 212 | ||
| Physiology | 212 | ||
| Thyrotroph Cells. | 212 | ||
| Structure. | 212 | ||
| Secretion | 213 | ||
| Regulation | 213 | ||
| Other Factors. | 214 | ||
| TSH Action. | 214 | ||
| Disorders of TSH Secretion | 214 | ||
| TSH Deficiency | 214 | ||
| Causes. | 214 | ||
| Clinical Features. | 214 | ||
| TSH Assays. | 214 | ||
| Treatment. | 214 | ||
| Developmental and Genetic Causes of Pituitary Failure | 214 | ||
| Developmental Disorders | 214 | ||
| Heritable Disorders | 215 | ||
| HESX1, SOX2, SOX3, and OTX2 | 215 | ||
| LHX3 and LHX4 | 215 | ||
| PITX1 and PITX2 | 215 | ||
| PROP1 | 215 | ||
| POU1F1 | 216 | ||
| IGSF1 | 216 | ||
| TBX19 | 216 | ||
| NR5A1 and NR0B1 | 217 | ||
| Pituitary Stalk Interruption Syndrome | 217 | ||
| Acquired Disorders | 217 | ||
| Head Trauma | 217 | ||
| Radiation | 218 | ||
| Empty Sella Syndrome | 219 | ||
| Clinical Features of Hypopituitarism | 219 | ||
| Screening for Pituitary Failure | 219 | ||
| References | 221 | ||
| 9 Pituitary Masses and Tumors | 232 | ||
| Key Points | 232 | ||
| Pituitary Masses | 232 | ||
| Pituitary Mass Effects | 232 | ||
| Evaluation of Pituitary Masses | 234 | ||
| Approach to the Patient Harboring a Pituitary Mass | 234 | ||
| Imaging | 235 | ||
| Receptor Imaging. | 236 | ||
| Neuro-ophthalmologic Assessment of Pituitary Masses | 236 | ||
| Visual Symptoms. | 236 | ||
| Clinical Signs | 237 | ||
| Management of Pituitary Masses | 237 | ||
| Surgical Management of Pituitary Tumors and Sellar Masses | 237 | ||
| Goals of Surgery. | 239 | ||
| Indications for Transsphenoidal Surgery. | 240 | ||
| Side Effects. | 242 | ||
| Pituitary Radiation | 242 | ||
| Principles. | 242 | ||
| Indications. | 243 | ||
| Side Effects | 243 | ||
| Hypopituitarism. | 243 | ||
| Second Brain Tumors. | 243 | ||
| Cerebrovascular Disease. | 244 | ||
| Visual Damage. | 244 | ||
| Brain Necrosis. | 244 | ||
| Medical Management | 244 | ||
| Parasellar Masses | 244 | ||
| Types of Parasellar Masses | 244 | ||
| Rathke’s Cyst | 244 | ||
| Granular Cell Tumors | 245 | ||
| Chordomas | 245 | ||
| Craniopharyngiomas | 245 | ||
| Meningiomas | 246 | ||
| Gliomas | 246 | ||
| Mucocele | 246 | ||
| Parasellar Aneurysms | 246 | ||
| Pituitary Infections | 247 | ||
| Hematologic Malignancies | 247 | ||
| Pituicytoma | 247 | ||
| Sarcoidosis | 247 | ||
| Langerhans Cell Histiocytosis | 247 | ||
| Hereditary Iron Storage Diseases | 248 | ||
| Idiopathic Retroperitoneal Fibrosis | 248 | ||
| Metastases to the Pituitary Region | 248 | ||
| Evaluation of Parasellar Lesions | 248 | ||
| Primary Hypophysitis | 248 | ||
| Lymphocytic Hypophysitis | 248 | ||
| Clinical Features. | 248 | ||
| Laboratory Findings. | 249 | ||
| Treatment. | 249 | ||
| Granulomatous Hypophysitis | 249 | ||
| Xanthomatous Hypohysitis | 249 | ||
| Necrotizing Infundibulo-Hypophysitis | 249 | ||
| Ipilimumab-Induced Hypophysitis | 249 | ||
| Hemorrhage and Infarction | 249 | ||
| Postpartum Pituitary Infarction | 250 | ||
| Pituitary Apoplexy | 250 | ||
| Clinical Features. | 251 | ||
| Management. | 251 | ||
| Pituitary Adenomas | 251 | ||
| Pathogenesis | 251 | ||
| Pituitary Trophic Activity | 251 | ||
| Benign Adenomas. | 251 | ||
| Hormonal Factors. | 252 | ||
| Genetic Factors. | 252 | ||
| Pituitary Senescence | 255 | ||
| Familial Syndromes | 256 | ||
| Multiple Endocrine Neoplasia Type 1 | 256 | ||
| Familial Isolated Pituitary Adenomas | 256 | ||
| Carney Complex | 257 | ||
| Classification of Pituitary Tumors | 257 | ||
| Atypical Adenomas | 259 | ||
| Malignant Pituitary Tumors | 260 | ||
| Prolactin-Secreting Adenomas | 260 | ||
| Pathology and Pathogenesis | 260 | ||
| Clinical Features | 260 | ||
| Hyperprolactinemia | 261 | ||
| Tumor Mass Effects | 261 | ||
| Evaluation | 261 | ||
| Treatment | 262 | ||
| Medical Treatment | 262 | ||
| Bromocriptine. | 262 | ||
| Cabergoline. | 262 | ||
| Administration. | 263 | ||
| Adverse Effects of Dopamine Agonists. | 263 | ||
| Radiation Therapy | 263 | ||
| Surgery | 263 | ||
| Chemotherapy | 264 | ||
| Pregnancy | 264 | ||
| Nonfunctioning Pituitary Tumors | 265 | ||
| Gonadotroph Cell Tumors | 265 | ||
| Presentation | 266 | ||
| Evaluation | 266 | ||
| Treatment | 266 | ||
| Surgery. | 266 | ||
| Postoperative Radiotherapy. | 267 | ||
| Expectant Observation. | 267 | ||
| Pregnancy | 267 | ||
| Medications | 268 | ||
| Silent ACTH-Producing Tumors | 268 | ||
| Acromegaly | 268 | ||
| Incidence | 268 | ||
| Pathogenesis | 268 | ||
| Pituitary Acromegaly | 268 | ||
| Pathogenesis of Somatotroph Cell Adenomas. | 268 | ||
| Disordered GHRH Secretion or Action. | 268 | ||
| Disordered Somatotroph Cell Function. | 269 | ||
| Multiple Endocrine Neoplasia. | 269 | ||
| Extrapituitary Acromegaly | 270 | ||
| GHRH Hypersecretion. | 270 | ||
| Ectopic Pituitary Adenomas. | 270 | ||
| Peripheral Growth Hormone–Secreting Tumors. | 271 | ||
| Acromegaloidism. | 271 | ||
| McCune-Albright Syndrome. | 271 | ||
| Clinical Features | 271 | ||
| Gigantism | 271 | ||
| Clinical Features of Acromegaly | 272 | ||
| Growth Hormone and Tumor Formation | 274 | ||
| Endocrine Complications | 275 | ||
| Morbidity and Mortality | 275 | ||
| Diagnosis | 276 | ||
| Measurement of Growth Hormone and IGF-1 Levels | 276 | ||
| Differential Diagnosis of Acromegaly | 276 | ||
| Treatment | 276 | ||
| Aims | 276 | ||
| Surgical Management | 278 | ||
| Side Effects. | 279 | ||
| Radiation Therapy | 279 | ||
| Side Effects. | 280 | ||
| Medical Management | 280 | ||
| Dopamine Agonists. | 280 | ||
| SRIF Receptor Ligands. | 280 | ||
| Effects of SRLs on Pituitary Adenoma. | 280 | ||
| Effects on Clinical Features. | 281 | ||
| Determinants of SRL Responsiveness. | 281 | ||
| III Thyroid | 333 | ||
| 11 Thyroid Physiology and Diagnostic Evaluation of Patients With Thyroid Disorders | 334 | ||
| Key Points | 334 | ||
| Phylogeny, Embryology, and Ontogeny | 334 | ||
| Phylogeny | 334 | ||
| Structural Embryology | 334 | ||
| Functional Ontogeny | 335 | ||
| Anatomy and Histology | 335 | ||
| Iodine and the Synthesis and Secretion of Thyroid Hormones | 336 | ||
| Dietary Iodine | 337 | ||
| Iodide Metabolism by the Thyroid Cell | 337 | ||
| Iodide Oxidation and Organification | 338 | ||
| Iodothyronine Synthesis | 338 | ||
| Storage and Release of Thyroid Hormone | 339 | ||
| Role and Mechanism of Thyrotropin Effects | 339 | ||
| Thyroid Hormones in Peripheral Tissues | 340 | ||
| Plasma Transport | 340 | ||
| Thyroxine-Binding Globulin | 341 | ||
| Transthyretin | 341 | ||
| Competition for T4 and T3 Binding to TBG and TTR by Therapeutic Agents | 341 | ||
| Albumin | 342 | ||
| Other Plasma Thyroid Hormone–Binding Proteins | 342 | ||
| Free Thyroid Hormones | 342 | ||
| T4 and T3 Transport Across Cell Membranes and Intracellular T3 Binding | 342 | ||
| Iodothyronine Deiodination | 344 | ||
| Enzymology and Regulation of the Selenodeiodinases | 344 | ||
| Quantitative and Qualitative Aspects of Thyroid Hormone Metabolism | 345 | ||
| Thyroid Hormone Turnover | 345 | ||
| Sources of Intracellular T3 | 346 | ||
| Pharmacologic Agents Inhibiting Thyroid Hormone Deiodination | 346 | ||
| Mechanism of Thyroid Hormone Action | 347 | ||
| Regulation of Thyroid Function | 348 | ||
| The Hypothalamic-Pituitary-Thyroid Axis | 348 | ||
| Thyrotropin-Releasing Hormone Synthesis and Secretion | 349 | ||
| Thyrotropin Synthesis and Secretion | 349 | ||
| Iodine Deficiency | 350 | ||
| Iodine Excess | 351 | ||
| Effects of Increased Iodine Intake on Thyroid Hormone Synthesis | 351 | ||
| Effects on Thyroid Hormone Release | 352 | ||
| Thyroid Function in Pregnancy and in the Fetus and Newborn | 352 | ||
| Fetal Thyroid Function | 353 | ||
| Maternal-Fetal Interactions | 353 | ||
| Thyroid Function in the Newborn | 353 | ||
| Aging and the Thyroid | 353 | ||
| Thyroid Function During Fasting or Illness | 354 | ||
| The Thyroid Axis and Neuropsychiatric Illness | 355 | ||
| Effects of Hormones on Thyroid Function | 355 | ||
| Glucocorticoids | 355 | ||
| Gonadal Steroids | 355 | ||
| Growth Hormone | 355 | ||
| Physical Evaluation of the Thyroid Gland | 355 | ||
| Physical Examination | 356 | ||
| Laboratory Assessment of Thyroid Status | 356 | ||
| Tests of the Hypothalamic-Pituitary- Thyroid Axis | 356 | ||
| Thyroid-Stimulating Hormone | 356 | ||
| TSH in Patients with Thyroid Dysfunction | 357 | ||
| Quantitation of Serum Thyroid Hormone Concentrations | 357 | ||
| Total T4 and T3 | 357 | ||
| Concentrations of Free T4 and Free T3 | 357 | ||
| The Free T4 Index | 358 | ||
| Causes of Abnormal TSH or Thyroid Hormone Concentrations | 359 | ||
| Causes of a Suppressed TSH | 359 | ||
| Causes of an Elevated TSH | 360 | ||
| Tests That Assess the Metabolic Impact of Thyroid Hormones | 360 | ||
| Basal Metabolic Rate | 360 | ||
| Biochemical Markers of Altered Thyroid Status | 361 | ||
| Serum Thyroglobulin | 361 | ||
| Tests for Thyroid Autoantibodies | 361 | ||
| Autoantibodies to Thyroid Peroxidase and Thyroglobulin | 362 | ||
| Do Thyroglobulin and Thyroid Peroxidase Antibodies Have a Pathogenic Role? | 362 | ||
| Thyroid Autoantibodies in Hashimoto Thyroiditis and Graves Disease | 362 | ||
| Thyroid Autoantibodies in Nonautoimmune Thyroid Disorders | 362 | ||
| Thyroid Autoantibodies in Pregnancy | 362 | ||
| The Normal Population | 362 | ||
| Radioiodine Uptake | 363 | ||
| Physiologic Basis | 363 | ||
| Radioactive Iodine Uptake | 363 | ||
| The Perchlorate Discharge Test | 363 | ||
| States Associated With Increased RAIU | 363 | ||
| Hyperthyroidism. | 363 | ||
| Aberrant Hormone Synthesis. | 364 | ||
| Iodine Deficiency. | 364 | ||
| Response to Thyroid Hormone Depletion. | 364 | ||
| Excessive Hormone Losses. | 364 | ||
| States Associated With Decreased RAIU | 364 | ||
| Exogenous Thyroid Hormone: Thyrotoxicosis Factitia. | 364 | ||
| Disorders of Hormone Storage. | 364 | ||
| Exposure to Excessive Iodine. | 364 | ||
| References | 364 | ||
| 12 Hyperthyroid Disorders | 369 | ||
| Key Points | 369 | ||
| Clinical Manifestations of Thyrotoxicosis | 369 | ||
| Cardiovascular System | 370 | ||
| Protein, Carbohydrate, and Lipid Metabolism | 370 | ||
| Sympathetic Nervous System and Catecholamines | 371 | ||
| Nervous System | 371 | ||
| Muscle | 371 | ||
| Eyes | 371 | ||
| Skin and Hair | 371 | ||
| Respiratory System | 371 | ||
| Alimentary System | 372 | ||
| Skeletal System: Calcium and Phosphorus Metabolism | 372 | ||
| Renal Function: Water and Electrolyte Metabolism | 372 | ||
| Hematopoietic System | 372 | ||
| Pituitary and Adrenocortical Function | 372 | ||
| Reproductive Function | 373 | ||
| Laboratory Diagnosis | 373 | ||
| Graves Disease | 373 | ||
| Discovery | 373 | ||
| Presentation | 373 | ||
| Autoimmune Characteristics | 375 | ||
| Autoimmune Thyroid Pathology | 375 | ||
| Prevalence | 376 | ||
| Pathogenesis | 376 | ||
| The Major Antigen of Graves Disease— the Thyrotropin Receptor | 376 | ||
| Molecular Structure of the Human Thyrotropin Receptor | 376 | ||
| Autoantibodies to the Thyrotropin Receptor | 376 | ||
| First Evidence for Bioactivity of Thyrotropin Receptor Autoantibodies | 377 | ||
| Prevalence of Thyrotropin Receptor Autoantibodies in Graves Disease | 377 | ||
| Intrathyroidal T Cells | 377 | ||
| Regulation of the Immune Response in Autoimmune Thyroid Disease | 377 | ||
| Mechanisms in the Development of Autoimmune Thyroid Disease | 377 | ||
| The Consequences of an Insult | 377 | ||
| IV Adrenal Cortex and Endocrine Hypertension | 489 | ||
| 15 The Adrenal Cortex | 490 | ||
| Key Points | 490 | ||
| THE Adrenal Cortex—Historical Milestones | 490 | ||
| Anatomy and Development | 490 | ||
| Adrenal Steroids and Steroidogenesis | 492 | ||
| Regulation of Adrenal Steroidogenesis: Functional Zonation of the Adrenal Cortex | 495 | ||
| Glucocorticoid Secretion: The Hypothalamic-Pituitary-Adrenal Axis | 495 | ||
| Pro-opiomelanocortin and ACTH | 495 | ||
| Corticotropin-Releasing Hormone and Arginine Vasopressin | 496 | ||
| The Stress Response and Immune-Endocrine Axis. | 497 | ||
| Circadian Rhythm. | 497 | ||
| Negative Feedback. | 497 | ||
| The ACTH Receptor and ACTH Effects on the Adrenal Gland | 498 | ||
| Mineralocorticoid Secretion: The Renin-Angiotensin-Aldosterone Axis | 498 | ||
| Adrenal Androgen Secretion | 499 | ||
| Corticosteroid Hormone Action | 499 | ||
| Receptors and Gene Transcription | 499 | ||
| Cortisol-Binding Globulin and Corticosteroid Hormone Metabolism | 501 | ||
| Effects of Glucocorticoids | 503 | ||
| Carbohydrate, Protein, and Lipid Metabolism | 503 | ||
| Skin, Muscle, and Connective Tissue | 503 | ||
| Bone and Calcium Metabolism | 503 | ||
| Salt and Water Homeostasis and Blood Pressure Control | 504 | ||
| Anti-inflammatory Actions and the Immune System | 505 | ||
| Central Nervous System and Mood | 505 | ||
| Eye | 505 | ||
| Gut | 505 | ||
| Growth and Development | 505 | ||
| Endocrine Effects | 505 | ||
| Therapeutic Corticosteroids | 505 | ||
| Administration | 506 | ||
| Long-Term Therapy | 506 | ||
| Adrenocortical Diseases | 507 | ||
| Glucocorticoid Excess | 507 | ||
| Cushing Syndrome | 507 | ||
| Clinical Features of Cushing Syndrome | 507 | ||
| Obesity. | 507 | ||
| Reproductive Organs. | 508 | ||
| Psychiatric Features. | 508 | ||
| Bone. | 508 | ||
| Skin. | 508 | ||
| Muscle. | 509 | ||
| Cardiovascular Features. | 509 | ||
| Infections. | 510 | ||
| Metabolic and Endocrine Features. | 510 | ||
| Eye. | 510 | ||
| Classification and Pathophysiology of Cushing Syndrome | 510 | ||
| ACTH-Dependent Causes | 510 | ||
| Cushing Disease | 510 | ||
| Ectopic ACTH Syndrome | 511 | ||
| Ectopic Corticotropin-Releasing Hormone Syndrome | 512 | ||
| Macronodular Adrenal Hyperplasia | 512 | ||
| ACTH-Independent Causes | 512 | ||
| Cortisol-Secreting Adrenal Adenoma and Carcinoma | 512 | ||
| Primary Pigmented Nodular Adrenal Hyperplasia and Carney Syndrome | 512 | ||
| McCune-Albright Syndrome | 512 | ||
| Macronodular Hyperplasia | 512 | ||
| Iatrogenic Cushing Syndrome | 513 | ||
| Special Features of Cushing Syndrome | 513 | ||
| Cyclic Cushing Syndrome | 513 | ||
| Cushing Syndrome in Children | 513 | ||
| Pregnancy | 514 | ||
| Other Syndromes of Hypercortisolemia | 514 | ||
| Alcohol | 514 | ||
| Depression | 514 | ||
| Obesity | 514 | ||
| Investigation of Patients With Suspected Cushing Syndrome | 514 | ||
| Question 1: Does This Patient Have Cushing Syndrome? | 514 | ||
| Circadian Rhythm of Plasma Cortisol. | 514 | ||
| Salivary Cortisol. | 515 | ||
| Urinary Free Cortisol Excretion. | 515 | ||
| Low-Dose Overnight Dexamethasone Suppression Tests. | 515 | ||
| Other Causes of Hypercortisolemia: Pseudo-Cushing or True Cushing Syndrome? | 515 | ||
| Diagnostic Guidelines. | 515 | ||
| Question 2: What Is the Cause of Cushing Syndrome in This Patient? | 516 | ||
| Morning Plasma ACTH. | 516 | ||
| Plasma Potassium. | 516 | ||
| High-Dose Dexamethasone Suppression Test. | 516 | ||
| Corticotropin-Releasing Hormone Test. | 517 | ||
| Inferior Petrosal Sinus Sampling and Selective Venous Catheterization. | 517 | ||
| Imaging | 518 | ||
| CT/MRI Scanning of Pituitary and Adrenal Glands. | 518 | ||
| Scintigraphy Studies. | 518 | ||
| Treatment of Cushing Syndrome | 519 | ||
| Adrenal Causes | 519 | ||
| Pituitary-Dependent Cushing Syndrome | 521 | ||
| Ectopic ACTH Syndrome | 523 | ||
| Medical Treatment of Cushing Syndrome | 523 | ||
| Prognosis of Cushing Syndrome | 524 | ||
| Glucocorticoid Resistance | 524 | ||
| Glucocorticoid Deficiency | 524 | ||
| Primary and Central Hypoadrenalism | 524 | ||
| Primary Hypoadrenalism | 524 | ||
| Addison Disease | 524 | ||
| Autoimmune Adrenalitis. | 524 | ||
| Infections. | 525 | ||
| Acquired Primary Adrenal Insufficiency | 525 | ||
| Inherited Primary Adrenal Insufficiency | 526 | ||
| Secondary Hypoadrenalism | 526 | ||
| Inherited Central Hypoadrenalism | 526 | ||
| ACTH Suppression by Exogenous Glucocorticoids | 527 | ||
| Hypoadrenalism During Critical Illness | 527 | ||
| Clinical Features of Adrenal Insufficiency | 528 | ||
| Investigation of Hypoadrenalism | 530 | ||
| Routine Biochemical Profile | 530 | ||
| Mineralocorticoid Status | 530 | ||
| Assessing Adequacy of Function of the HPA Axis | 530 | ||
| Testing the HPA Axis During Critical Illness. | 531 | ||
| Other Tests. | 531 | ||
| Treatment of Acute Adrenal Insufficiency | 531 | ||
| Long-Term Replacement Therapy | 532 | ||
| Congenital Adrenal Hyperplasia | 533 | ||
| 21-Hydroxylase Deficiency | 533 | ||
| Simple Virilizing Form | 533 | ||
| Salt-Wasting Form | 535 | ||
| Nonclassic or Late-Onset 21-Hydroxylase Deficiency | 536 | ||
| Heterozygote 21-Hydroxylase Deficiency | 536 | ||
| Molecular Genetics | 536 | ||
| Diagnostic Criteria | 536 | ||
| Treatment | 536 | ||
| Long-Term Complications and Comorbid Conditions | 539 | ||
| 11β-Hydroxylase Deficiency | 539 | ||
| 17α-Hydroxylase Deficiency | 539 | ||
| P450 Oxidoreductase Deficiency: Apparent Combined 17α-Hydroxylase and 21-Hydroxylase Deficiencies | 541 | ||
| 3β-Hydroxysteroid Dehydrogenase Deficiency | 541 | ||
| StAR Deficiency: Congenital Lipoid Adrenal Hyperplasia | 542 | ||
| P450 Side-Chain Cleavage Deficiency | 542 | ||
| Cortisone Reductase Deficiency | 543 | ||
| Mineralocorticoid Deficiency | 543 | ||
| Primary Defects in Aldosterone Biosynthesis: Aldosterone Synthase Deficiency | 543 | ||
| Postadrenalectomy Hypoaldosteronism | 543 | ||
| Defects in Aldosterone Action: Pseudohypoaldosteronism | 544 | ||
| Hyporeninemic Hypoaldosteronism | 544 | ||
| Adrenal Adenomas, Incidentalomas, and Carcinomas | 544 | ||
| Adenomas | 544 | ||
| Incidentalomas | 545 | ||
| Carcinomas | 546 | ||
| Etiology of Adrenal Tumors | 546 | ||
| Acknowledgments | 546 | ||
| References | 546 | ||
| 16 Endocrine Hypertension | 556 | ||
| Key Points | 556 | ||
| Adrenal Medulla and Catecholamines | 557 | ||
| Catecholamine Synthesis | 558 | ||
| Catecholamine Storage and Secretion | 558 | ||
| Catecholamine Metabolism and Inactivation | 558 | ||
| Pheochromocytoma and Paraganglioma | 559 | ||
| History | 559 | ||
| Clinical Presentation | 560 | ||
| Syndromic Forms of Pheochromocytoma and Paraganglioma | 562 | ||
| Multiple Endocrine Neoplasia Type 2A | 562 | ||
| Multiple Endocrine Neoplasia Type 2B | 562 | ||
| von Hippel-Lindau Disease | 562 | ||
| Neurofibromatosis Type 1 | 563 | ||
| Carney Triad or Syndrome | 563 | ||
| Other Genetic Forms of Pheochromocytoma and Paraganglioma | 563 | ||
| Succinate Dehydrogenase Gene Mutations | 564 | ||
| TMEM127 Mutations | 564 | ||
| MAX Mutations | 564 | ||
| FH Mutations | 564 | ||
| Genetic Testing | 564 | ||
| Evaluation and Monitoring of Carriers of Succinate Dehydrogenase Mutations | 564 | ||
| Diagnostic Investigation | 565 | ||
| Differential Diagnosis | 565 | ||
| Case Detection | 565 | ||
| Measurement of Fractionated Metanephrines and Catecholamines in Urine and Blood. | 565 | ||
| Other Tests That Have Been Used to Assess for Pheochromocytoma. | 567 | ||
| Clonidine Suppression Test. | 567 | ||
| Provocative Testing and Suppression Testing. | 567 | ||
| Renal Failure. | 567 | ||
| Factitious Pheochromocytoma. | 567 | ||
| Localization | 567 | ||
| Imaging Phenotype. | 567 | ||
| 123I-MIBG Scintigraphy. | 568 | ||
| Other Localizing Procedures. | 568 | ||
| Treatment | 569 | ||
| Preoperative Management | 569 | ||
| α-Adrenergic Blockade. | 570 | ||
| β-Adrenergic Blockade. | 570 | ||
| Catecholamine Synthesis Inhibitor. | 570 | ||
| Calcium Channel Blockers. | 570 | ||
| Acute Hypertensive Crises | 571 | ||
| Anesthesia and Surgery | 571 | ||
| Long-Term Postoperative Follow-Up | 572 | ||
| Malignant Pheochromocytoma and Paraganglioma | 572 | ||
| Pheochromocytoma in Pregnancy | 572 | ||
| Renin-Angiotensin- Aldosterone System | 573 | ||
| Renin and Angiotensin | 573 | ||
| Aldosterone | 573 | ||
| Primary Aldosteronism | 574 | ||
| History | 575 | ||
| Prevalence | 575 | ||
| Clinical Presentation | 575 | ||
| Diagnosis | 576 | ||
| Case-Detection Tests | 576 | ||
| Confirmatory Tests | 577 | ||
| Oral Sodium Loading Test. | 577 | ||
| Intravenous Saline Infusion Test. | 577 | ||
| Fludrocortisone Suppression Test. | 578 | ||
| Subtype Studies | 578 | ||
| Computed Tomography of the Adrenal Glands. | 578 | ||
| Adrenal Venous Sampling. | 578 | ||
| Familial Hyperaldosteronism | 579 | ||
| Glucocorticoid-Remediable Aldosteronism: Familial Hyperaldosteronism Type I. | 579 | ||
| Familial Hyperaldosteronism Type II. | 580 | ||
| Familial Hyperaldosteronism Type III. | 580 | ||
| Somatic Mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D Genes. | 580 | ||
| Principles of Treatment | 580 | ||
| Surgical Treatment of Aldosterone-Producing Adenoma and Unilateral Hyperplasia | 580 | ||
| Pharmacologic Treatment | 581 | ||
| Other Forms of Mineralocorticoid Excess or Effect | 581 | ||
| Hyperdeoxycorticosteronism | 581 | ||
| Congenital Adrenal Hyperplasia | 581 | ||
| 11β-Hydroxylase Deficiency. | 582 | ||
| 17α-Hydroxylase Deficiency. | 582 | ||
| Deoxycorticosterone-Producing Tumor | 582 | ||
| Primary Cortisol Resistance | 582 | ||
| Apparent Mineralocorticoid Excess Syndrome | 582 | ||
| Liddle Syndrome: Abnormal Renal Tubular Ionic Transport | 582 | ||
| Other Endocrine Disorders Associated with Hypertension | 583 | ||
| Cushing Syndrome | 583 | ||
| Thyroid Dysfunction | 583 | ||
| Hyperthyroidism | 583 | ||
| Hypothyroidism | 583 | ||
| Hypercalcemia and Primary Hyperparathyroidism | 583 | ||
| Acromegaly | 583 | ||
| References | 583 | ||
| V Reproduction | 589 | ||
| 17 Physiology and Pathology of the Female Reproductive Axis | 590 | ||
| Key Points | 590 | ||
| Reproductive Physiology | 590 | ||
| Reproductive Functions of the Hypothalamus | 592 | ||
| Gonadotropin-Releasing Hormone | 592 | ||
| Regulation of Gonadotropin-Releasing Hormone Secretion | 593 | ||
| Gonadotropin-Releasing Hormone Analogues | 594 | ||
| Peptide Gonadotropin-Releasing Hormone Agonists | 594 | ||
| Peptide Gonadotropin-Releasing Hormone Antagonists | 595 | ||
| Nonpeptide Gonadotropin-Releasing Hormone Antagonists | 595 | ||
| Reproductive Functions of the Anterior Pituitary | 595 | ||
| Gonadotrophs | 595 | ||
| Gonadotropin-Releasing Hormone Receptor | 595 | ||
| Luteinizing Hormone and Follicle-Stimulating Hormone | 595 | ||
| Regulation of Circulating Levels of Follicle-Stimulating Hormone and Luteinizing Hormone | 596 | ||
| Ovary | 596 | ||
| Genetic Determinants of Ovarian Differentiation and Folliculogenesis | 597 | ||
| Oocytes | 598 | ||
| Granulosa Cell Layer | 599 | ||
| Theca Cell Layer | 601 | ||
| Follicles | 602 | ||
| Ovulation | 603 | ||
| Corpus Luteum | 603 | ||
| Ovarian Follicle-Stimulating Hormone and Luteinizing Hormone Receptors | 604 | ||
| Role of Follicle-Stimulating Hormone in Ovarian Function. | 605 | ||
| Role of Luteinizing Hormone in Ovarian Function. | 605 | ||
| Ovarian Steroidogenesis | 605 | ||
| Steroidogenic Genes and Their Functions in the Ovary | 606 | ||
| C21 Steroids. | 607 | ||
| C19 Steroids. | 607 | ||
| C18 Steroids. | 607 | ||
| Two-Cell Theory for Ovarian Steroidogenesis | 607 | ||
| Peptide Hormones Produced by the Ovary | 609 | ||
| Overview of the Hormonal Changes During the Ovarian Cycle | 610 | ||
| Extraovarian Steroidogenesis | 610 | ||
| Endometrium | 611 | ||
| Functional Anatomy of the Endometrium | 611 | ||
| Hormone-Induced Morphologic Changes of the Endometrium | 612 | ||
| Effects of Ovarian Steroids on Endometrium | 612 | ||
| Estrogen Action | 613 | ||
| Progesterone Action | 613 | ||
| The Receptive Phase of the Endometrium for Implantation | 614 | ||
| Control of Endometrial Function With the Use of Exogenous Hormones | 614 | ||
| Mechanism of Menstruation | 615 | ||
| Approach to the Woman with Reproductive Dysfunction | 615 | ||
| History | 615 | ||
| Physical Examination | 616 | ||
| Disorders of the Female Reproductive System | 616 | ||
| Chronic Anovulation | 616 | ||
| Hypothalamic Anovulation | 617 | ||
| Functional Hypothalamic Amenorrhea | 617 | ||
| Diagnosis of Functional Hypothalamic Amenorrhea. | 617 | ||
| Pathophysiology of Functional Hypothalamic Anovulation. | 618 | ||
| Hypothalamic Anovulation and Exercise. | 619 | ||
| Hypothalamic Anovulation Associated with Eating Disorders. | 619 | ||
| Treatment and Management of Functional Hypothalamic Anovulation. | 620 | ||
| Chronic Anovulation Associated With Pituitary Disorders | 620 | ||
| Chronic Anovulation Associated With Androgen Excess | 620 | ||
| Approach to the Patient With Androgen Excess | 620 | ||
| Origins of Androgens | 621 | ||
| Laboratory Evaluation of Androgen Action | 622 | ||
| Causes of Androgen Excess | 623 | ||
| Idiopathic Hirsutism | 623 | ||
| Androgen-Secreting Tumors of the Ovary and Adrenal | 624 | ||
| Non-neoplastic Adrenal Disorders and Androgen Excess | 625 | ||
| Laboratory Testing to Aid the Differential Diagnosis of Androgen Excess | 625 | ||
| Treatment of Hirsutism | 626 | ||
| Oral Contraceptives. | 626 | ||
| Spironolactone. | 626 | ||
| Cyproterone Acetate. | 627 | ||
| Finasteride. | 627 | ||
| Flutamide. | 627 | ||
| Metformin and Thiazolidinediones. | 627 | ||
| Lifestyle Modification. | 627 | ||
| A Comprehensive Treatment Strategy for Hirsutism. | 627 | ||
| Polycystic Ovary Syndrome | 627 | ||
| Historical Perspective | 628 | ||
| Diagnosis of Polycystic Ovary Syndrome and Laboratory Testing | 628 | ||
| Gonadotropin Production in Polycystic Ovary Syndrome | 631 | ||
| Steroid Production in Polycystic Ovary Syndrome | 631 | ||
| Production of Sex Hormone–Binding Globulin in Polycystic Ovary Syndrome | 632 | ||
| Follicular Fate in Polycystic Ovary Syndrome | 632 | ||
| Ovarian Hyperthecosis | 633 | ||
| Genetics of Polycystic Ovary Syndrome | 633 | ||
| Insulin Resistance and Polycystic Ovary Syndrome | 633 | ||
| Role of Obesity in Insulin Resistance and Anovulation. | 634 | ||
| Laboratory Evaluation of Metabolic Syndrome in PCOS. | 634 | ||
| Use of Antidiabetic Drugs to Treat Anovulation and Androgen Excess. | 634 | ||
| Management of Long-Term Deleterious Effects of Polycystic Ovary Syndrome | 635 | ||
| Ovulation Induction in Polycystic Ovary Syndrome | 635 | ||
| Clomiphene Citrate. | 636 | ||
| Aromatase Inhibitors. | 636 | ||
| Metformin. | 636 | ||
| Low-Dose Gonadotropin Therapy. | 637 | ||
| Premature Ovarian Insufficiency | 637 | ||
| Diagnosis and Management of Premature Ovarian Insufficiency | 637 | ||
| Diagnosis and Management of Anovulatory Uterine Bleeding | 638 | ||
| Characteristics of Normal Menses | 639 | ||
| Terminology Describing Abnormal Uterine Bleeding | 639 | ||
| Uterine Bleeding in Response to Steroid Hormones | 639 | ||
| Estrogen Withdrawal Bleeding | 639 | ||
| Estrogen Breakthrough Bleeding | 639 | ||
| Progesterone Withdrawal Bleeding | 640 | ||
| Progestin Breakthrough Bleeding | 640 | ||
| Causes of Irregular Uterine Bleeding | 640 | ||
| Management of Anovulatory Uterine Bleeding | 641 | ||
| Oral Contraceptives | 641 | ||
| Oral Contraceptives and Acute Excessive Uterine Bleeding Associated With Anemia. | 641 | ||
| Oral Contraceptives and Chronic Irregular Uterine Bleeding. | 642 | ||
| Synthetic Progestins | 642 | ||
| High-Dose Estrogen for Acute Excessive Uterine Bleeding | 642 | ||
| Gonadotropin-Releasing Hormone Analogues for Excessive Anovulatory Uterine Bleeding | 643 | ||
| Hormone-Dependent Benign Gynecologic Disorders | 643 | ||
| Endometriosis | 643 | ||
| Pathology | 643 | ||
| Mechanism of Disease | 643 | ||
| Diagnosis | 645 | ||
| Treatment | 645 | ||
| Uterine Leiomyomas | 645 | ||
| Management of Menopause | 646 | ||
| Consequences of Menopause | 646 | ||
| Perimenopause Stage | 646 | ||
| Menopause Features | 646 | ||
| Biosynthesis of Estrogen and Other Steroids in the Postmenopausal Woman | 647 | ||
| Postmenopausal Uterine Bleeding | 647 | ||
| Hot Flashes | 648 | ||
| Urogenital Atrophy | 648 | ||
| Postmenopausal Osteoporosis | 649 | ||
| Postmenopausal Hormone Therapy | 649 | ||
| The Fundamental Findings of the WHI Trials | 650 | ||
| Risks and Contraindications of Hormone Therapy | 651 | ||
| Coronary Heart Disease | 651 | ||
| Stroke | 651 | ||
| Pulmonary Embolism | 651 | ||
| Breast Cancer | 651 | ||
| Ovarian Cancer | 651 | ||
| Dementia | 651 | ||
| Hyperlipidemia | 651 | ||
| Gallbladder Disease | 651 | ||
| Indications for Hormone Therapy | 652 | ||
| Hot Flashes | 652 | ||
| Fractures | 652 | ||
| Colon Cancer | 652 | ||
| Post-WHI Recommendations for Hormone Therapy | 652 | ||
| Target Groups for Hormone Therapy | 652 | ||
| Estrogen Preparations and Beneficial Dose of Estrogen | 652 | ||
| Oral Estrogens: Combined Conjugated Equine Estrogens | 652 | ||
| Transdermal Estrogen | 653 | ||
| Vaginal Estrogen | 653 | ||
| Management of Breakthrough Bleeding During Postmenopausal Hormone Therapy | 654 | ||
| Management of Menopausal Symptoms in Breast Cancer Survivors | 654 | ||
| Selective Estrogen Receptor Modulators and Bisphosphonates for Osteoporosis Prevention | 654 | ||
| Tibolone for Osteoporosis Prevention | 655 | ||
| References | 656 | ||
| 18 Hormonal Contraception | 664 | ||
| Key Points | 664 | ||
| Combined Estrogen and Progestin Contraceptives | 665 | ||
| The Combined Oral Contraceptive Pill | 665 | ||
| Composition and Formulations | 665 | ||
| Mechanism of Action, Efficacy, Administration, and Effect on Pregnancy | 666 | ||
| Noncontraceptive Health Benefits | 667 | ||
| Side Effects | 667 | ||
| Health Risks | 668 | ||
| Thromboembolic Disease. | 668 | ||
| Myocardial Infarction and Thrombotic and Hemorrhagic Stroke. | 669 | ||
| Breast Cancer. | 670 | ||
| Cervical Cancer. | 670 | ||
| Use of Combined Oral Contraceptive Pills After Pregnancy | 670 | ||
| Use of Concomitant Medications With Combined Oral Contraceptive Pills | 670 | ||
| Contraceptive Vaginal Ring and Contraceptive Patch | 670 | ||
| Transdermal Contraceptive Patch | 670 | ||
| Contraceptive Vaginal Ring | 671 | ||
| Progestin-Only Contraceptive Methods | 671 | ||
| Oral Progestin-Only Contraception | 671 | ||
| Mechanism of Action | 671 | ||
| Efficacy | 672 | ||
| Starting the Progestin-Only Pill | 672 | ||
| Side Effects of the Progestin-Only Oral Contraceptives | 672 | ||
| Other Effects | 672 | ||
| Progestin-Only Oral Contraceptives During Lactation | 672 | ||
| Depot Medroxyprogesterone Acetate for Contraception | 672 | ||
| Formulations and Pharmacology | 672 | ||
| Administration of Depot Medroxyprogesterone Acetate | 673 | ||
| Starting Injections. | 673 | ||
| Repeat Injections. | 673 | ||
| Side Effects of Depot Medroxyprogesterone Acetate | 673 | ||
| Risks and Benefits of Depot Medroxyprogesterone Acetate | 674 | ||
| Effect on Cancer Risk. | 674 | ||
| Effect on Cardiovascular Risk. | 674 | ||
| Effect on Skeletal Health. | 674 | ||
| Effect on Sexually Transmitted Infections. | 674 | ||
| Effect on Return of Fertility. | 675 | ||
| Intrauterine Progestins | 675 | ||
| Contraceptive Uses | 675 | ||
| Expanding the Use of Intrauterine Devices | 675 | ||
| Abnormal Bleeding, Expulsion, and Uterine Perforation | 675 | ||
| Upper Genital Tract Infection and Infertility | 676 | ||
| Metabolic and Systemic Effects | 676 | ||
| Noncontraceptive Uses of the Levonorgestrel-Releasing Intrauterine System | 676 | ||
| Heavy Menstrual Bleeding. | 676 | ||
| Symptomatic Fibroids and Uterine Adenomyosis. | 676 | ||
| Endometriosis. | 676 | ||
| Endometrial Protection With Estrogen Replacement Therapy. | 676 | ||
| Endometrial Protection With Tamoxifen Use. | 676 | ||
| Treatment for Endometrial Hyperplasia or Carcinoma. | 677 | ||
| Contraceptive Implants | 677 | ||
| Description and Pharmacology | 677 | ||
| Mechanism of Action and Efficacy | 677 | ||
| Safety and Side Effect Profile | 678 | ||
| Patient Selection | 678 | ||
| Insertion and Removal | 678 | ||
| Emergency Contraception | 678 | ||
| Emergency Contraception Regimens | 679 | ||
| Mechanism of Action | 679 | ||
| Efficacy | 679 | ||
| Indications | 679 | ||
| Side Effects | 680 | ||
| Clinical Challenges in Contraceptive Care | 680 | ||
| Hormonal Contraception for Adolescents | 680 | ||
| Combined Hormonal Contraceptives in Adolescents | 680 | ||
| Injectable Contraceptives in Adolescents | 681 | ||
| Hormonal Contraception in Postpartum and Lactating Women | 681 | ||
| Hormonal Contraception in Women Older Than 35 Years | 681 | ||
| Discontinuation of Hormonal Contraception at Menopause | 681 | ||
| Contraception in Women With Underlying Medical Conditions | 682 | ||
| Hormonal Contraception in Obese Women | 682 | ||
| Hormonal Contraception in Women Taking Antiepileptic Drugs | 683 | ||
| Hormonal Contraception in Women Taking Antibiotics | 683 | ||
| Hormonal Contraception in HIV-Positive Women | 683 | ||
| Hormonal Contraception and Chronic Hypertension | 684 | ||
| Hormonal Contraception in Women with Lipid Disorders | 684 | ||
| Hormonal Contraception in Women with Diabetes | 684 | ||
| Hormonal Contraception in Women With Hypercoagulable States | 685 | ||
| Hormonal Contraception in Women Awaiting Surgery | 685 | ||
| Hormonal Contraception in Women With a History of Thromboembolism | 685 | ||
| Hormonal Contraception in Women Taking Anticoagulation Therapy | 685 | ||
| Hormonal Contraception for Women With Migraine Headaches | 685 | ||
| Hormonal Contraception in Women With Systemic Lupus Erythematosus | 686 | ||
| Hormonal Contraception in Women With Sickle Cell Disease | 686 | ||
| Hormonal Contraception in Depression | 686 | ||
| Choosing a Contraceptive Method | 687 | ||
| References | 688 | ||
| 19 Testicular Disorders | 694 | ||
| Key Points | 694 | ||
| Functional Anatomy and Histology | 695 | ||
| The Testis | 695 | ||
| Seminiferous Tubule | 695 | ||
| Spermatogenesis | 696 | ||
| Proliferative Phase | 697 | ||
| Meiotic Phase | 697 | ||
| Spermiogenesis | 698 | ||
| Germ Cell Loss | 698 | ||
| Organization of Spermatogenesis | 698 | ||
| Sperm Transport and Fertilization | 698 | ||
| Spermatozoa | 698 | ||
| Interstitium | 699 | ||
| Testis Development | 699 | ||
| Fetal Development | 699 | ||
| Testis Descent | 699 | ||
| Postnatal Development | 700 | ||
| Pubertal Development | 700 | ||
| Adult Physiology | 700 | ||
| Hypothalamic-Pituitary-Testicular Axis | 700 | ||
| Central Nervous System Regulation of Gonadotropin-Releasing Hormone Secretion | 700 | ||
| Gonadotropin-Releasing Hormone Regulation of Gonadotropin Secretion | 702 | ||
| Gonadotropin Control of Testicular Function | 704 | ||
| Luteinizing Hormone Regulation of Leydig Cells | 704 | ||
| Leydig Cell Production of Testosterone and Insulin-like Factor 3 | 704 | ||
| Follicle-Stimulating Hormone and Testosterone Regulation of Sertoli Cells | 705 | ||
| Maintenance of Seminiferous Tubule Structure and Compartmentalization. | 705 | ||
| Provision of Nutrients and Growth Factors to Developing Germ Cells and Spermatozoa. | 706 | ||
| Translocation, Sculpting, and Release of Developing Germ Cells. | 706 | ||
| Secretion of Seminiferous Tubule Fluid. | 706 | ||
| Production of Reproductive Hormones. | 706 | ||
| Paracrine and Autocrine Regulation of Testis Function | 706 | ||
| Hormonal Control of Spermatogenesis | 706 | ||
| Initiation of Spermatogenesis. | 707 | ||
| Maintenance of Spermatogenesis. | 707 | ||
| Negative Feedback Regulation of Gonadotropin Secretion | 708 | ||
| Testosterone Transport, Metabolism, and Actions | 709 | ||
| Circulating Testosterone | 709 | ||
| Active Metabolism and Catabolism of Testosterone | 710 | ||
| Aromatization of Testosterone to Estradiol. | 710 | ||
| 5α-Reduction of Testosterone to Dihydrotestosterone. | 711 | ||
| Catabolism of Testosterone. | 711 | ||
| Mechanisms of Androgen Action | 712 | ||
| Androgen Effects at Various Stages of Sexual Development | 713 | ||
| Male Hypogonadism | 714 | ||
| Clinical Manifestations | 714 | ||
| Androgen Deficiency and Impairment in Sperm Production | 714 | ||
| Fetal Androgen Deficiency. | 715 | ||
| Prepubertal Androgen Deficiency. | 715 | ||
| Adult Androgen Deficiency. | 716 | ||
| Isolated Impairment of Sperm Production or Function | 717 | ||
| History and Physical Examination | 717 | ||
| Differential Diagnosis | 719 | ||
| Sexual Dysfunction | 719 | ||
| Hypoactive Sexual Desire Disorder and Erectile Dysfunction. | 720 | ||
| Hypoactive Sexual Desire Disorder and Erectile Dysfunction Due to Brain Disorders. | 720 | ||
| Erectile Dysfunction Due to Spinal Cord or Peripheral Disorders. | 721 | ||
| Evaluation of Erectile Dysfunction. | 722 | ||
| Ejaculatory Disorders and Orgasmic Dysfunction. | 723 | ||
| Disorders of Detumescence. | 723 | ||
| Gynecomastia | 723 | ||
| Causes of Gynecomastia. | 724 | ||
| Evaluation. | 725 | ||
| Treatment. | 726 | ||
| Infertility | 726 | ||
| Causes of Male Infertility. | 726 | ||
| Evaluation. | 727 | ||
| Treatment. | 728 | ||
| Diagnosis of Male Hypogonadism | 729 | ||
| Clinical Manifestations of Androgen Deficiency | 729 | ||
| Testosterone Measurements | 730 | ||
| Variability in Testosterone Levels. | 730 | ||
| Total Testosterone Assays. | 731 | ||
| Total Testosterone Affected by Alterations in Sex Hormone–Binding Globulin. | 731 | ||
| Transient Suppression of Testosterone. | 732 | ||
| Case-Finding in Androgen Deficiency | 732 | ||
| Seminal Fluid Analysis | 732 | ||
| Gonadotropin Measurements | 732 | ||
| Androgen Deficiency and Impaired Sperm Production. | 732 | ||
| Isolated Impairment of Sperm Production or Function. | 733 | ||
| Further Evaluation | 736 | ||
| Causes of Primary Hypogonadism | 737 | ||
| Androgen Deficiency and Impairment in Sperm Production | 737 | ||
| Congenital or Developmental Disorders | 737 | ||
| Klinefelter Syndrome. | 737 | ||
| Myotonic Dystrophy. | 739 | ||
| Cryptorchidism. | 740 | ||
| Noonan Syndrome. | 741 | ||
| Bilateral Congenital Anorchia. | 741 | ||
| Autoimmune Polyglandular Syndrome. | 741 | ||
| Defects in Testosterone Biosynthetic Enzymes. | 742 | ||
| Congenital Adrenal Hyperplasia. | 742 | ||
| Complex Genetic Syndromes. | 742 | ||
| Down Syndrome. | 743 | ||
| Luteinizing Hormone Receptor Mutations. | 743 | ||
| Acquired Disorders | 743 | ||
| Bilateral Surgical Castration and Trauma. | 743 | ||
| Drugs and Ionizing Radiation. | 743 | ||
| Orchitis. | 743 | ||
| Systemic Disorders. | 744 | ||
| Chronic Liver Disease. | 744 | ||
| Chronic Kidney Disease. | 744 | ||
| Aging. | 744 | ||
| Other Systemic Disorders. | 745 | ||
| Isolated Impairment of Sperm Production or Function | 745 | ||
| Congenital or Developmental Disorders. | 745 | ||
| Varicocele. | 745 | ||
| Y Chromosome Microdeletion. | 746 | ||
| Sertoli Cell–Only Syndrome (Germ Cell Aplasia). | 746 | ||
| Primary Ciliary Dyskinesia (Immotile Cilia Syndrome). | 747 | ||
| Follicle-Stimulating Hormone Receptor Mutations. | 747 | ||
| Acquired Disorders. | 747 | ||
| Systemic Disorders. | 747 | ||
| Causes of Secondary Hypogonadism | 747 | ||
| Androgen Deficiency and Impairment in Sperm Production | 747 | ||
| Congenital or Developmental Disorders | 747 | ||
| Constitutional Delay of Growth and Puberty. | 747 | ||
| Hereditary Hemochromatosis. | 748 | ||
| Idiopathic Hypogonadotropic Hypogonadism. | 749 | ||
| Complex Genetic Syndromes. | 750 | ||
| Acquired Disorders | 750 | ||
| Hyperprolactinemia. | 750 | ||
| Opioids. | 751 | ||
| Sex Steroids. | 752 | ||
| Gonadotropin-Releasing Hormone Analogues. | 752 | ||
| Hypopituitarism. | 753 | ||
| Systemic Disorders | 754 | ||
| Glucocorticoid Excess (Cushing Syndrome). | 754 | ||
| Chronic Organ Failure. | 754 | ||
| Chronic Systemic Illness. | 755 | ||
| Nutritional Disorders or Endurance Exercise. | 756 | ||
| Acute and Critical Illness. | 757 | ||
| Aging. | 757 | ||
| Isolated Impairment of Sperm Production or Function | 758 | ||
| Congenital or Developmental Disorders | 758 | ||
| Congenital Adrenal Hyperplasia. | 758 | ||
| Isolated Follicle-Stimulating Hormone Deficiency and FSHB Mutations. | 758 | ||
| Acquired Disorders | 758 | ||
| Androgen Administration or Excess. | 758 | ||
| Malignancy. | 758 | ||
| Hyperprolactinemia. | 758 | ||
| Androgen Resistance Syndromes | 759 | ||
| Congenital Disorders | 759 | ||
| Acquired Disorders | 760 | ||
| Treatment of Androgen Deficiency | 760 | ||
| Functional Versus Organic Causes of Hypogonadism | 760 | ||
| Testosterone Replacement Therapy | 760 | ||
| Therapeutic Goals and Management. | 760 | ||
| Testosterone Formulations. | 761 | ||
| Parenteral Testosterone Esters. | 764 | ||
| Transdermal Testosterone. | 766 | ||
| Transbuccal Testosterone. | 768 | ||
| Testosterone Nasal Gel. | 768 | ||
| Testosterone Pellets. | 768 | ||
| Testosterone Formulations Available Outside the United States | 768 | ||
| Oral Testosterone Undecanoate. | 768 | ||
| Transdermal Testosterone Formulations. | 769 | ||
| Selective Androgen Receptor Modulators. | 769 | ||
| Monitoring Clinical Response and Testosterone Levels. | 769 | ||
| Risks and Adverse Effects | 769 | ||
| Contraindications and Precautions. | 769 | ||
| Potential Adverse Effects and Monitoring. | 771 | ||
| Hematocrit. | 771 | ||
| Prostate. | 771 | ||
| Sleep Apnea. | 772 | ||
| Reduced Sperm Production and Fertility. | 772 | ||
| Acne and Oily Skin. | 772 | ||
| Gynecomastia. | 772 | ||
| Lipids. | 772 | ||
| Other Potential Adverse Effects. | 772 | ||
| Formulation-Specific Adverse Effects. | 773 | ||
| Gonadotropin Therapy | 773 | ||
| References | 774 | ||
| 20 Sexual Dysfunction in Men and Women | 785 | ||
| Key Points | 785 | ||
| Human Sexual Response Cycle | 787 | ||
| Physiologic Mechanisms of Human Sexual Response | 788 | ||
| Physiology of Desire and Arousal | 788 | ||
| Functional Brain Imaging of Sexual Arousal in Men and Women | 788 | ||
| Neurotransmitters and Hormones Involved in Sexual Desire and Subjective Arousal | 789 | ||
| Animal Models. | 789 | ||
| Genital Sexual Congestion and Arousal | 790 | ||
| Physiologic Mechanisms of Penile Erection | 790 | ||
| Penile Anatomy and Blood Flow | 790 | ||
| Penile Innveration | 791 | ||
| Hemodynamic Changes During Penile Erection | 791 | ||
| Biochemical Regulation of Cavernosal Smooth Muscle Tone | 791 | ||
| Potassium Channels. | 791 | ||
| Connexin43 Gap Junctions. | 791 | ||
| Nitric Oxide. | 792 | ||
| Cyclic Nucleotide Phosphodiesterases. | 792 | ||
| Regulation of Sensitivity to Intracellular Calcium by Rho A/Rho Kinase Signaling. | 792 | ||
| Mechanisms of Ejaculation | 794 | ||
| The Role of Testosterone in Regulating Sexual Function in Men | 794 | ||
| Physiology of Physical Sexual Arousal in Women: Genital Congestion | 795 | ||
| Physiology of Orgasm | 796 | ||
| The Revised Definitions of Sexual Dysfunction in Men | 797 | ||
| Male Hypoactive Sexual Desire Disorder | 797 | ||
| Erectile Disorder | 797 | ||
| Prevalence and Incidence | 797 | ||
| Risk Factors for Erectile Disorder | 798 | ||
| Erectile Disorder as a Marker of Cardiovascular Disease | 798 | ||
| Lower Urinary Tract Symptoms and Erectile Disorder | 798 | ||
| Ejaculatory Disorders | 798 | ||
| Current Definitions of Sexual Disorders in Women | 799 | ||
| Sexual Interest/Arousal Disorder | 799 | ||
| Female Orgasmic Disorder | 799 | ||
| Genitopelvic Pain/Penetration Disorder | 799 | ||
| Persistent Genital Arousal Disorder | 799 | ||
| Sexual Dysfunction in the Context of Endocrine Disease | 800 | ||
| Endocrine Disorders and Sexual Dysfunction in Men | 800 | ||
| Androgen Deficiency Syndromes | 800 | ||
| Diabetes and Sexual Dysfunction in Men | 800 | ||
| Sexual Dysfunction Associated With Therapies for Benign Prostatic Hypertrophy | 801 | ||
| Hyperprolactinemia and Sexual Dysfunction | 801 | ||
| Sexual Dysfunction in Patients With Thyroid Disease | 801 | ||
| Sexual Dysfunction in Men With Metabolic Syndrome | 801 | ||
| Endocrine Disorders and Sexual Dysfunction in Women | 801 | ||
| Thyroid Disease in Women | 801 | ||
| Hyperprolactinemia in Women | 801 | ||
| Diabetes in Women | 801 | ||
| Pathogenesis of Sexual Dysfunction in Diabetes. | 802 | ||
| Metabolic Syndrome in Women | 802 | ||
| Polycystic Ovary Syndrome | 802 | ||
| Congenital Adrenal Hyperplasia | 802 | ||
| Pituitary Disease in Women | 802 | ||
| Adrenal Insufficiency in Women | 802 | ||
| Natural Menopause | 802 | ||
| Surgical Menopause | 803 | ||
| Aging-Associated Decline in Sex Hormone Precursors in Women | 803 | ||
| Selective Estrogen Receptor Modulators | 803 | ||
| Hormonal Contraceptives | 803 | ||
| Androgen Insensitivity Syndrome | 803 | ||
| Assessment of Sexual Dysfunction | 804 | ||
| Evaluation of Men With Sexual Dysfunction | 804 | ||
| Evaluation of Women With Sexual Dysfunction | 806 | ||
| Physical Examination | 807 | ||
| Laboratory Testing | 807 | ||
| Management of Sexual Dysfunction in Men | 807 | ||
| Treatment of Hypoactive Sexual Desire in Men | 807 | ||
| Treatment of Erectile Disorder | 807 | ||
| First-Line Therapies | 808 | ||
| Psychosexual Counseling. | 808 | ||
| Selective Phosphodiesterase 5 Inhibitors (Tables 20-8 and 20-9). | 809 | ||
| Mechanisms of Action. | 809 | ||
| Clinical Pharmacology (see Table 20-8). | 809 | ||
| Pharmacokinetics (see Table 20-8). | 810 | ||
| Efficacy. | 810 | ||
| Adverse Effects (see Table 20-9). | 810 | ||
| Cardiovascular and Hemodynamic Effects. | 810 | ||
| Drug-Drug Interactions. | 811 | ||
| Therapeutic Regimens. | 811 | ||
| The Use of Phosphodiesterase 5 Inhibitors in Men With Coronary Artery Disease (see Table 20-10). | 812 | ||
| Treatment of Patients Who Do Not Respond to Phosphodiesterase 5 Inhibitors. | 812 | ||
| Cost-Effectiveness of Phosphodiesterase 5 Inhibitor Use for Erectile Disorder. | 812 | ||
| Second-Line Therapies | 812 | ||
| Vacuum Devices for Inducing Erection. | 812 | ||
| Intraurethral Therapies. | 813 | ||
| Intracavernosal Injection of Vasoactive Agents (Table 20-11). | 813 | ||
| Third-Line Therapies | 813 | ||
| Penile Prosthesis. | 813 | ||
| Testosterone Replacement in Androgen-Deficient Men Presenting With Erectile Disorder. | 814 | ||
| Therapies With Either Unproven Efficacy or Limited Efficacy Data. | 814 | ||
| Gene Therapy and Erectile Disorder. | 814 | ||
| The Potential of Stem Cell Therapy for Erectile Disorder. | 815 | ||
| Management of Retrograde Ejaculation | 815 | ||
| Management of Sexual Dysfunction in Women | 816 | ||
| Management of Low Desire and Arousal in Women | 816 | ||
| Psychoeducation | 816 | ||
| Cognitive Behavioral Therapy | 817 | ||
| Mindfulness-Based Cognitive Therapy | 817 | ||
| Sex Therapy | 817 | ||
| Outcome of Psychological Treatments for Women’s Sexual Dysfunctions | 817 | ||
| Management of Women’s Orgasmic Disorder | 817 | ||
| Management of Genitopelvic Pain/Penetration Disorder (Dyspareunia and Vaginismus) | 817 | ||
| Management of Provoked Vestibulodynia | 817 | ||
| Management of Phobic Reflex Pelvic Muscle Contractions (Vaginismus) | 818 | ||
| Testosterone Therapy for Women With Sexual Dysfunction | 818 | ||
| Negative Trials of Testosterone Therapy | 819 | ||
| Testosterone Plus a Phosphodiesterase Inhibitor | 819 | ||
| Limitations of Trials of Testosterone Therapy in Women | 819 | ||
| Risks of Testosterone Therapy | 819 | ||
| Needed Research in the Area of Testosterone Supplementation | 820 | ||
| Oral Dehydroepiandrosterone for Sexual Dysfunction in Healthy Women | 820 | ||
| Local DHEA Therapy for Sexual Dysfunction in Healthy Women | 820 | ||
| Estrogen Therapy for Women With Sexual Dysfunction | 820 | ||
| References | 820 | ||
| VI Endocrinology and the Life Span | 831 | ||
| VI A Maternal-Fetal | 832 | ||
| 21 Endocrine Changes in Pregnancy | 832 | ||
| Key Points | 832 | ||
| Placental Development | 832 | ||
| Maternal Adaptations to Pregnancy | 833 | ||
| Physiologic Adaptations | 833 | ||
| Metabolic Adaptations | 835 | ||
| Maternal Endocrine Alterations | 835 | ||
| Pituitary Gland | 835 | ||
| Thyroid Gland | 837 | ||
| Parathyroid Glands | 837 | ||
| Pancreas | 837 | ||
| Adrenal Glands | 838 | ||
| Renin-Angiotensin System | 838 | ||
| Placental Hormone Production | 838 | ||
| Sex-Steroid Production From the Maternal-Fetal-Placental Unit | 838 | ||
| Protein Hormones | 839 | ||
| Human Chorionic Gonadotropin | 839 | ||
| Chemistry. | 839 | ||
| Biosynthesis. | 840 | ||
| Metabolism. | 840 | ||
| Physiologic Functions. | 841 | ||
| Gestational Trophoblastic Disease. | 842 | ||
| Human Placental Lactogen | 842 | ||
| Placental Growth Hormone | 843 | ||
| Human Chorionic Corticotropin | 843 | ||
| Hypothalamic Peptides | 844 | ||
| Gonadotropin-Releasing Hormone. | 844 | ||
| Corticotropin-Releasing Hormone. | 844 | ||
| The Endocrinology of Pregnancy and Parturition | 844 | ||
| The Role of Estrogen and Progesterone | 844 | ||
| The Role of Prostaglandins | 845 | ||
| The Role of Oxytocin | 845 | ||
| The Use of Placental Hormones in Genetic Screening | 845 | ||
| References | 846 | ||
| 22 Endocrinology of Fetal Development | 849 | ||
| Key Points | 849 | ||
| Placental Hormone Transfer | 849 | ||
| Ectopic Fetal Hormone Production | 850 | ||
| Fetal Endocrine Systems | 851 | ||
| Anterior Pituitary and Target Organs | 851 | ||
| Hypothalamus and Pituitary Stalk Development | 852 | ||
| Human Hypothalamic-Pituitary Development | 852 | ||
| Genes Involved in Pituitary Development and Disease | 852 | ||
| Growth Hormone and Prolactin | 856 | ||
| Adrenal System | 857 | ||
| Embryology | 857 | ||
| Genetic Regulation of Adrenal Development | 857 | ||
| Adrenal Steroidogenesis | 858 | ||
| Defects of Adrenal Steroidogenesis | 860 | ||
| Thyroid System | 861 | ||
| Embryology | 861 | ||
| Thyroid Hormonogenesis | 863 | ||
| Thyroid Hormone Action | 864 | ||
| Ontogeny of Thyroid Hormone Secretion | 865 | ||
| Congenital Hypothyroidism | 866 | ||
| Pituitary-Gonadal Axis | 866 | ||
| Intermediate Lobe of the Pituitary | 869 | ||
| Posterior Pituitary | 869 | ||
| Fetal Autonomic Nervous System | 870 | ||
| Parathyroid Hormone/Calcitonin System | 871 | ||
| Calcium-Sensing Receptor and Fibroblast Growth Factor 23 | 873 | ||
| Endocrine Pancreas: Insulin and Glucagon | 873 | ||
| Neonatal Diabetes | 875 | ||
| Hyperinsulinemic Hypoglycemia of Infancy | 875 | ||
| Neutralization of Hormone Actions in the Fetus | 876 | ||
| Limitation of Hormone Secretion | 876 | ||
| Production of Inactive Hormone Metabolites | 876 | ||
| Neutralization of Receptor Response | 877 | ||
| Fetal Growth | 877 | ||
| Insulin-like Growth Factors | 877 | ||
| Insulin | 878 | ||
| Epidermal Growth Factor/Transforming Growth Factor System | 878 | ||
| Nerve Growth Factor | 879 | ||
| Other Factors | 879 | ||
| Transition to Extrauterine Life | 880 | ||
| Cortisol Surge | 880 | ||
| Catecholamine Surge | 880 | ||
| Thermogenesis in Neonatal Brown Adipose Tissue | 881 | ||
| Calcium Homeostasis | 882 | ||
| Glucose Homeostasis | 882 | ||
| Other Hormonal Adaptations | 882 | ||
| Programming of Developing Endocrine Systems | 883 | ||
| Maternal and Fetal Medicine | 883 | ||
| References | 884 | ||
| VI B Childhood | 893 | ||
| 23 Pediatric Disorders of Sex Development | 893 | ||
| Key Points | 893 | ||
| Development of Reproductive Systems | 893 | ||
| Sex Determination and Sex Differentiation | 894 | ||
| Chromosomal Sex | 895 | ||
| The Y Chromosome. | 896 | ||
| The X Chromosome. | 897 | ||
| Gonadal Sex | 898 | ||
| The Bipotential Gonad. | 898 | ||
| Primordial Germ Cell Migration. | 899 | ||
| Testis Determination. | 900 | ||
| Ovary Development. | 902 | ||
| Phenotypic or Anatomic Sex | 903 | ||
| Male Sexual Differentiation | 903 | ||
| Sertoli Cells and Müllerian Regression. | 903 | ||
| Fetal Leydig Cells and Steroidogenesis. | 903 | ||
| Testis Descent. | 905 | ||
| Subsequent Testicular Development. | 905 | ||
| Female Sexual Differentiation. | 905 | ||
| Psychosexual Development | 905 | ||
| Development of the Hypothalamic-Pituitary-Gonadal Axis in the Fetus | 907 | ||
| The Hypothalamic-Pituitary-Gonadal Axis in Infancy and Childhood | 908 | ||
| Postnatal Endocrine Changes in Boys | 908 | ||
| Postnatal Endocrine Changes in Girls | 908 | ||
| Disorders (Differences) of Sex Development | 908 | ||
| Nomenclature and Classification of Disorders of Sex Development | 909 | ||
| Sex Chromosome Disorders of Sex Development | 909 | ||
| Klinefelter Syndrome and Its Variants | 909 | ||
| Turner Syndrome and Its Variants | 911 | ||
| 45,X/46,XY Mosaicism and Variants | 912 | ||
| Ovotesticular Disorders of Sex Development: 46,XX/46,XY Chimerism and Variants | 913 | ||
| 46,XY Disorders of Sex Development | 914 | ||
| Disorders of Testis Development | 914 | ||
| Single-Gene Disorders | 914 | ||
| Steroidogenic Factor 1: NR5A1. | 914 | ||
| Wilms Tumor 1 Gene: WT1. | 918 | ||
| Gata-Binding Protein 4: GATA4. | 919 | ||
| Friend of GATA2 (FOG2): ZFPM2. | 919 | ||
| Chromobox Homolog 2: CBX2. | 919 | ||
| Sex-Determining Region of the Y Chromosome: SRY. | 919 | ||
| SRY Box 9: SOX9. | 919 | ||
| Mitogen-Activated Protein Kinase Kinase Kinase-1: MAP3K1. | 920 | ||
| Desert Hedgehog: DHH. | 920 | ||
| Aristaless-Related Homeobox, X-Linked Gene: ARX. | 921 | ||
| Testis-Specific Protein, Y-Linked–like 1 Gene: TSPYL1. | 921 | ||
| Mastermind-like Domain-Containing 1: MAMLD1. | 921 | ||
| Chromosomal Rearrangements Associated with Gonadal Dysgenesis. | 921 | ||
| Syndromic Causes of 46,XY Disorders of Sex Development. | 921 | ||
| Disorders of Androgen Synthesis | 921 | ||
| Cholesterol Synthesis Defects: Smith-Lemli-Opitz Syndrome. | 921 | ||
| Luteinizing Hormone Receptor Mutations. | 921 | ||
| Steroidogenic Acute Regulatory Protein Defects. | 923 | ||
| P450 Side-Chain Cleavage Enzyme Deficiency. | 923 | ||
| 3β-Hydroxysteroid Dehydrogenase/Δ4,5-Isomerase Type 2 Deficiency. | 925 | ||
| 17α-Hydroxylase/17,20-Lyase Deficiency. | 925 | ||
| Cytochrome b5 Deficiency. | 928 | ||
| P450 Oxidoreductase Deficiency. | 928 | ||
| 3α-Reductase Type 3 and 3α-Reductase Type 1: AKR1C2 and AKR1C4. | 929 | ||
| 17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency. | 929 | ||
| Steroid 5α-Reductase Type 2 Deficiency. | 930 | ||
| Disorders of Androgen Action | 932 | ||
| Complete Androgen Insensitivity Syndrome. | 933 | ||
| Partial Androgen Insensitivity Syndrome. | 933 | ||
| Minimal or Mild Androgen Insensitivity Syndrome. | 934 | ||
| Hormone Profiles in Androgen Insensitivity Syndromes. | 934 | ||
| Molecular Pathogenesis of Androgen Insensitivity Syndromes. | 934 | ||
| Androgen Insensitivity Syndromes Without an Androgen Receptor Mutation. | 935 | ||
| Management of Androgen Insensitivity Syndromes. | 936 | ||
| Other Conditions Affecting 46,XY Sex Development | 936 | ||
| Persistent Müllerian Duct Syndrome. | 936 | ||
| Hypospadias. | 937 | ||
| Anorchia and Cryptorchidism. | 938 | ||
| Endocrine Disruptors. | 938 | ||
| 46,XX Disorders of Sex Development | 939 | ||
| Disorders of Ovary Development | 939 | ||
| Ovarian Dysgenesis. | 939 | ||
| 46,XX Ovotesticular and 46,XX Testicular Disorders of Sex Development. | 940 | ||
| Disorders of Androgen Excess | 940 | ||
| 3β-Hydroxysteroid Dehydrogenase Type 2 Deficiency. | 940 | ||
| 21-Hydroxylase Deficiency. | 940 | ||
| P450 Oxidoreductase Deficiency. | 942 | ||
| 11β-Hydroxylase Deficiency. | 942 | ||
| Familial Glucocorticoid Resistance. | 942 | ||
| Aromatase Deficiency. | 942 | ||
| Maternal Androgen Excess. | 944 | ||
| Other Conditions Affecting 46,XX Sex Development | 944 | ||
| Investigation and Management of Disorders of Sex Development | 944 | ||
| Prenatal Diagnosis | 945 | ||
| The Newborn with Atypical Genitalia | 945 | ||
| Examination and History | 946 | ||
| The Initial Approach to the Baby With Atypical Genitalia | 946 | ||
| Support for the Parents | 947 | ||
| The Multidisciplinary Team | 947 | ||
| Assigning Sex | 947 | ||
| Investigations for DSDs | 947 | ||
| Presentation During Childhood | 951 | ||
| Presentation During Adolescence | 951 | ||
| Presentation During Adulthood | 951 | ||
| Information Sharing, Transitioning, and Adult Services | 951 | ||
| Support Groups and Information | 952 | ||
| Genetic Testing and DSDs | 952 | ||
| Tumor Risk and DSDs | 952 | ||
| Surgery and DSDs | 952 | ||
| DSD in Resource-Limited Countries | 953 | ||
| Outcome Studies | 953 | ||
| Acknowledgments | 954 | ||
| References | 954 | ||
| 24 Normal and Aberrant Growth in Children | 964 | ||
| Key Points | 964 | ||
| Normal Growth | 964 | ||
| Overview | 964 | ||
| Measurement | 964 | ||
| Growth Charts | 965 | ||
| Body Proportions | 966 | ||
| Parental Target Height | 967 | ||
| Skeletal Maturation | 967 | ||
| Phases of Normal Growth | 968 | ||
| Crossing Linear Percentiles of Infancy | 970 | ||
| Constitutional Delay of Growth and Development | 970 | ||
| Secular Changes in Height | 970 | ||
| Endocrine Regulation of Growth | 971 | ||
| The Hypothalamic-Pituitary Axis: Embryogenesis and Anatomy | 971 | ||
| Growth Hormone | 972 | ||
| Growth Hormone Secretion in Humans | 974 | ||
| The Growth Hormone Receptor and Growth Hormone Binding Protein | 976 | ||
| Insulin-like Growth Factors | 977 | ||
| Historical Background | 977 | ||
| IGF Genes and Protein Structure | 977 | ||
| Insulin-like Growth Factor 1 | 977 | ||
| Gene Regulation. | 977 | ||
| Serum Levels. | 978 | ||
| Insulin-like Growth Factor 2 | 978 | ||
| Gene Regulation. | 978 | ||
| Serum Levels. | 980 | ||
| Insulin-like Growth Factor Receptors | 980 | ||
| Function-Targeted Disruption of IGF and IGF Receptor Genes | 982 | ||
| Insulin-like Growth Factor–Binding Proteins | 983 | ||
| Structure of IGFBPs. | 983 | ||
| Role of IGFBPs in IGF Physiology | 984 | ||
| IGFBPs as Carrier Proteins. | 984 | ||
| IGFBPs as Modulators of IGF Action. | 985 | ||
| IGF-Independent Actions of IGFBPs. | 985 | ||
| Characteristics of IGFBPs 1 through 6. | 986 | ||
| Gonadal Steroids | 987 | ||
| Thyroid Hormone | 987 | ||
| Glucocorticoids | 987 | ||
| Pathologic Basis of Growth Retardation | 988 | ||
| Disorders of the GH/IGF-1 Axis | 988 | ||
| Growth Hormone Deficiency | 988 | ||
| The Hypothalamus | 988 | ||
| Congenital Disorders. | 988 | ||
| Holoprosencephaly. | 990 | ||
| Septo-optic Dysplasia. | 990 | ||
| HESX1. | 991 | ||
| OTX2. | 992 | ||
| SOX3. | 992 | ||
| SOX2. | 992 | ||
| Acquired Disorders | 992 | ||
| Inflammation of the Brain or Hypothalamus. | 992 | ||
| Tumors of the Brain or Hypothalamus. | 992 | ||
| Trauma of the Brain or Hypothalamus. | 992 | ||
| Psychosocial Dwarfism. | 992 | ||
| The Anterior Pituitary | 993 | ||
| Congenital Disorders. | 993 | ||
| Combined Pituitary Hormone Deficiency. | 993 | ||
| PITX2. | 993 | ||
| SOX2. | 993 | ||
| LHX3. | 993 | ||
| LHX4. | 993 | ||
| SIX6. | 993 | ||
| ISL1. | 994 | ||
| PROP1. | 994 | ||
| POU1F1. | 994 | ||
| Isolated Growth Hormone Deficiency. | 995 | ||
| IGHD Type I. | 995 | ||
| IGHD Type II. | 995 | ||
| IGHD Type III. | 996 | ||
| Bioinactive GH. | 996 | ||
| Acquired Disorders | 996 | ||
| Craniopharyngiomas and Other Tumors. | 996 | ||
| Histiocytosis X. | 997 | ||
| Growth Hormone Insensitivity | 997 | ||
| Mutations in GHR Signaling Proteins and ALS. | 997 | ||
| Abnormalities of IGF-1 and IGF-1 Receptor Signaling. | 998 | ||
| Inactivating Mutation of the IGF1 Gene. | 999 | ||
| Primary Defects of IGF Transport and Clearance. | 999 | ||
| Primary Defects of IGF-1 Receptor Production or Responsiveness. | 999 | ||
| Disorders Outside the Growth Hormone/IGF Axis | 999 | ||
| Malnutrition | 999 | ||
| Chronic or Systemic Diseases | 1000 | ||
| Malabsorption and Gastrointestinal Diseases. | 1000 | ||
| Chronic Liver Disease. | 1001 | ||
| Cardiovascular Disease. | 1001 | ||
| Renal Disease. | 1002 | ||
| Hematologic Disorders. | 1002 | ||
| Inborn Errors of Metabolism. | 1003 | ||
| Pulmonary Disease. | 1003 | ||
| Chronic Inflammation and Infection. | 1003 | ||
| Endocrine Disorders | 1004 | ||
| Hypothyroidism. | 1004 | ||
| Diabetes Mellitus. | 1004 | ||
| Cushing Syndrome: Glucocorticoid Excess. | 1004 | ||
| Pseudohypoparathyroidism: Albright Hereditary Osteodystrophy. | 1005 | ||
| Rickets. | 1005 | ||
| Hypophosphatemic Rickets. | 1005 | ||
| Osteochondrodysplasias | 1006 | ||
| Chromosomal Abnormalities | 1007 | ||
| Down Syndrome. | 1007 | ||
| Turner Syndrome. | 1007 | ||
| Noonan Syndrome. | 1007 | ||
| Prader-Willi Syndrome. | 1008 | ||
| Other Syndromes. | 1008 | ||
| Small for Gestational Age | 1008 | ||
| Maternal and Placental Factors | 1010 | ||
| Pathologic Basis of Excess Growth | 1010 | ||
| Statural Overgrowth in the Fetus | 1010 | ||
| Sotos Syndrome | 1010 | ||
| Beckwith-Weidemann Syndrome | 1011 | ||
| Postnatal Statural Overgrowth | 1011 | ||
| Tall Stature | 1011 | ||
| Obesity | 1011 | ||
| Tumors | 1012 | ||
| Evaluation and Treatment of Growth Abnormalities | 1012 | ||
| Clinical Evaluation of Growth Retardation | 1012 | ||
| History and Physical Examination | 1013 | ||
| Laboratory Testing | 1013 | ||
| Screening Tests | 1013 | ||
| Bone Age. | 1014 | ||
| Prediction of Adult Height. | 1014 | ||
| Tests of the GH/IGF-1 Axis | 1014 | ||
| Insulin-like Growth Factor 1. | 1015 | ||
| Insulin-like Growth Factor–Binding Protein 3. | 1017 | ||
| Insulin-like Growth Factor 2. | 1017 | ||
| Growth Hormone. | 1018 | ||
| Assay Limitations. | 1018 | ||
| Provocative Tests. | 1018 | ||
| Determination of the “Subnormal” Response to Provocative Tests. | 1018 | ||
| Specificity of Provocative Tests for Growth Hormone Deficiency. | 1019 | ||
| Sex Hormone Priming. | 1019 | ||
| Tests of Spontaneous Growth Hormone Secretion. | 1020 | ||
| Summary. | 1020 | ||
| Growth Hormone–Binding Protein. | 1020 | ||
| IGF-1 and IGFBP Generation Tests. | 1020 | ||
| Interpretation of Tests | 1020 | ||
| Neonate. | 1020 | ||
| Growth Hormone Deficiency. | 1021 | ||
| Growth Hormone Insensitivity. | 1021 | ||
| Constitutional Delay of Growth and Development. | 1022 | ||
| Genetic (Familial) Short Stature. | 1023 | ||
| Idiopathic Short Stature. | 1023 | ||
| Treatment of Growth Failure | 1023 | ||
| Treatment of Constitutional Delay | 1024 | ||
| Androgen (Oxandrolone and Testosterone). | 1024 | ||
| Growth Hormone. | 1024 | ||
| Aromatase Inhibitor. | 1025 | ||
| Treatment of Growth Hormone Deficiency | 1025 | ||
| Nomenclature and Potency Estimation. | 1025 | ||
| Historical Perspective. | 1025 | ||
| Treatment Regimens. | 1025 | ||
| Adult Height Outcomes. | 1026 | ||
| Combined Pituitary Hormone Deficiencies. | 1028 | ||
| Monitoring Growth Hormone Therapy. | 1028 | ||
| Treatment During the Transition to Adulthood and in Adulthood. | 1029 | ||
| Growth Hormone Treatment of Other Forms of Short Stature | 1031 | ||
| Prader-Willi Syndrome. | 1031 | ||
| Chronic Renal Disease. | 1032 | ||
| Juvenile Idiopathic Arthritis. | 1033 | ||
| Turner Syndrome. | 1033 | ||
| Small for Gestational Age. | 1035 | ||
| Osteochondrodysplasias. | 1036 | ||
| SHOX Haploinsufficiency and Léri-Weill Syndrome. | 1036 | ||
| Turner Syndrome and Langer Mesomelic Dysplasia. | 1037 | ||
| Noonan Syndrome. | 1037 | ||
| Idiopathic Short Stature (Subtle Errors Throughout the Growth Axis). | 1037 | ||
| Miscellaneous Causes of Growth Failure. | 1039 | ||
| Down Syndrome. | 1039 | ||
| Normal Aging and Other Catabolic States. | 1039 | ||
| Adverse Effects of Growth Hormone | 1039 | ||
| Development of Leukemia and Other Malignancies. | 1040 | ||
| Recurrence of Central Nervous System Tumors. | 1040 | ||
| Development of Subsequent Neoplasms. | 1040 | ||
| Pseudotumor Cerebri. | 1040 | ||
| Slipped Capital Femoral Epiphysis. | 1041 | ||
| Scoliosis. | 1041 | ||
| Diabetes Mellitus. | 1041 | ||
| Miscellaneous Side Effects. | 1041 | ||
| The Question of Long-Term Cancer Risk. | 1041 | ||
| Long-Term Mortality with GH Treatment. | 1042 | ||
| IGF-1 Treatment | 1042 | ||
| Other Treatments to Promote Growth | 1043 | ||
| GnRH Agonists | 1043 | ||
| Increasing Adult Height of Children with Idiopathic Short Stature. | 1043 | ||
| Increasing Adult Height of Children Born Small for Gestational Age. | 1043 | ||
| Increasing Adult Height of Children with Growth Hormone Deficiency. | 1043 | ||
| Aromatase Inhibitors. | 1043 | ||
| Oxandrolone. | 1044 | ||
| Clinical Trials of Efficacy. | 1044 | ||
| Side Effects. | 1044 | ||
| Diagnosis and Treatment of Excess Growth and Tall Stature | 1044 | ||
| Diagnosis | 1044 | ||
| Treatment | 1044 | ||
| References | 1045 | ||
| 25 Physiology and Disorders of Puberty | 1074 | ||
| Key Points | 1074 | ||
| Fetal Origins of Adult Disease | 1075 | ||
| Determinants of the Age of Puberty and Menarche | 1076 | ||
| The Secular Trend in Puberty and Menarche | 1077 | ||
| The Developed World | 1077 | ||
| The Developing World | 1078 | ||
| Factors Affecting the Age of Puberty and Menarche | 1078 | ||
| Stress and Puberty. | 1078 | ||
| Genetic Effects on Puberty and Menarche. | 1079 | ||
| Other Factors. | 1079 | ||
| The Comorbid Conditions of Early Puberty | 1079 | ||
| National Trends in Pubertal Development | 1080 | ||
| Limits of Normal Pubertal Development | 1080 | ||
| Secondary Sexual Characteristics and Physical Changes of Puberty | 1081 | ||
| Female Development | 1081 | ||
| Ovarian Development | 1083 | ||
| Menarche and Teenage Pregnancy | 1083 | ||
| Male Development | 1084 | ||
| Male Testicular Development in Puberty | 1085 | ||
| Spermatogenesis | 1085 | ||
| Other Physical and Biochemical Changes of Puberty | 1086 | ||
| Adolescent Growth | 1089 | ||
| Pubertal Growth Spurt | 1089 | ||
| Bone Age | 1089 | ||
| Skeletal Density | 1091 | ||
| Body Composition | 1093 | ||
| Obesity, Puberty, and the Metabolic Syndrome | 1094 | ||
| Serum Lipids in Normal Puberty and in Obesity and the Metabolic Syndrome. | 1094 | ||
| Insulin and Insulin Resistance. | 1094 | ||
| Blood Pressure. | 1095 | ||
| Central Nervous System Anatomy, Function, Psychology, and Electroencephalographic Rhythm in Puberty | 1095 | ||
| Sleep Patterns in Puberty | 1097 | ||
| Characteristics of Adolescence | 1097 | ||
| Behavior and Normal Puberty | 1097 | ||
| Mood and Self-Image in Puberty | 1098 | ||
| Behavior in Variations of the Normal Age at Onset of Puberty | 1098 | ||
| Risk-Taking Behavior | 1099 | ||
| Sexuality During Puberty | 1099 | ||
| Hormonal and Metabolic Changes in Puberty | 1099 | ||
| Gonadotropins | 1099 | ||
| Gonadal Steroids | 1100 | ||
| Testosterone | 1100 | ||
| Estrogens | 1101 | ||
| Protein Products of the Gonads | 1101 | ||
| Inhibin, Activin, and Follistatin | 1101 | ||
| Antimüllerian Hormone | 1103 | ||
| Adrenal Androgens | 1104 | ||
| Testosterone-Binding Globulin | 1104 | ||
| Prolactin | 1104 | ||
| Insulin-like 3 Protein | 1104 | ||
| Prostate-Specific Antigen | 1104 | ||
| Hormonal Control of the Pubertal Growth Spurt | 1104 | ||
| Gonadal Steroids | 1105 | ||
| Growth Hormone and Growth Factors | 1105 | ||
| Growth Hormone–Binding Protein | 1106 | ||
| Insulin-like Growth Factor Type 1 | 1106 | ||
| Other Hormones | 1107 | ||
| Central Nervous System and Puberty | 1107 | ||
| Pattern of Gonadotropin Secretion | 1109 | ||
| Tonic Secretion | 1109 | ||
| Pulsatile Secretion | 1109 | ||
| The GnRH Pulse Generator | 1109 | ||
| GnRH. | 1109 | ||
| Gonadotropin-Inhibitory Hormone. | 1110 | ||
| Kisspeptins and KISS1R. | 1110 | ||
| Ontogeny | 1113 | ||
| Human Fetus | 1113 | ||
| Sheep Fetus | 1115 | ||
| Human Neonate and Infant | 1115 | ||
| Neural Control | 1115 | ||
| Timing and Onset of Puberty | 1116 | ||
| Genetic Neural Control | 1116 | ||
| Nutrition and Metabolic Control | 1116 | ||
| Mechanisms of Control | 1118 | ||
| Gonadal Steroid–Dependent Negative Feedback Mechanism. | 1118 | ||
| Gonadal Steroid–Independent (Intrinsic) Central Nervous System Inhibitory Mechanism. | 1119 | ||
| Interaction of the Negative Feedback Mechanism and the Intrinsic Central Nervous System Inhibitory Mechanism. | 1119 | ||
| Potential Components of the Intrinsic Central Nervous System Inhibitory Mechanism. | 1120 | ||
| Sleep-Associated Luteinizing Hormone Release and Onset of Puberty | 1123 | ||
| Pituitary and Gonadal Sensitivity to Tropic Stimuli | 1123 | ||
| Maturation of Positive Feedback Mechanism | 1124 | ||
| Overview of Current Concept | 1125 | ||
| Adrenal Androgens and Adrenarche | 1125 | ||
| Nature and Regulation of Adrenal Androgens | 1125 | ||
| Adrenal Androgens and Puberty | 1127 | ||
| Disorders of Puberty | 1127 | ||
| Delayed Puberty and Sexual Infantilism | 1127 | ||
| Idiopathic or Constitutional Delay in Growth and Puberty | 1127 | ||
| Hypogonadotropic Hypogonadism: Sexual Infantilism Related to Gonadotropin Deficiency | 1130 | ||
| Central Nervous System Tumors | 1131 | ||
| Craniopharyngioma. | 1131 | ||
| Other Extrasellar Tumors | 1132 | ||
| Germinomas. | 1132 | ||
| Pituitary Adenomas. | 1133 | ||
| Other Central Nervous System Disorders Leading to Delayed Puberty | 1133 | ||
| Langerhans Cell Histiocytosis. | 1133 | ||
| Postinfectious Inflammatory Lesions of the Central Nervous System, Vascular Abnormalities, and Head Trauma. | 1133 | ||
| Irradiation of the Central Nervous System. | 1134 | ||
| Fröhlich Syndrome. | 1134 | ||
| Isolated Hypogonadal Hypogonadism | 1134 | ||
| Kallmann Syndrome | 1134 | ||
| Other Forms of Isolated Hypogonadotropic Hypogonadism | 1138 | ||
| Gonadotropin-Releasing Hormone Gene Mutations. | 1138 | ||
| Gonadotropin-Releasing Hormone Receptor Mutations. | 1139 | ||
| KISS1/KISS1R Axis Mutations. | 1139 | ||
| X-Linked Congenital Adrenal Hypoplasia and Hypogonadotropic Hypogonadism. | 1139 | ||
| Other Presentations of Hypogonadotropic Hypogonadism | 1140 | ||
| Isolated Luteinizing Hormone Deficiency. | 1140 | ||
| Isolated Follicle-Stimulating Hormone Deficiency. | 1140 | ||
| Follicle-Stimulating Hormone Receptor Mutations. | 1141 | ||
| Developmental Defect of the Midline | 1141 | ||
| Idiopathic Hypopituitary Dwarfism | 1142 | ||
| Miscellaneous Conditions | 1143 | ||
| Prader-Willi Syndrome | 1143 | ||
| Laurence-Moon and Bardet-Biedl Syndromes | 1143 | ||
| Functional Gonadotropin Deficiencies | 1143 | ||
| Anorexia Nervosa and Variants | 1145 | ||
| Anorexia Nervosa. | 1145 | ||
| Bulimia Nervosa. | 1145 | ||
| Exercise, Hypo-ovarianism, and Amenorrhea: The Female Athlete Triad. | 1146 | ||
| Other Causes of Delayed Puberty | 1146 | ||
| Hypergonadotropic Hypogonadism: Sexual Infantilism Caused by Primary Gonadal Disorders | 1147 | ||
| Boys | 1147 | ||
| Klinefelter Syndrome and Its Variants (see Chapter 23). | 1147 | ||
| Behavior and Development in Klinefelter Syndrome. | 1148 | ||
| Other Aspects of Klinefelter Syndrome. | 1148 | ||
| Other Forms of Primary Testicular Failure | 1148 | ||
| Cancer Survivors | 1148 | ||
| Chemotherapy. | 1148 | ||
| Radiation Therapy. | 1149 | ||
| Testicular Biosynthetic Defects. | 1149 | ||
| Luteinizing Hormone Resistance. | 1149 | ||
| Anorchia and Cryptorchidism. | 1149 | ||
| Small for Gestational Age. | 1151 | ||
| Girls | 1151 | ||
| Syndrome of Gonadal Dysgenesis and Its Variants. | 1151 | ||
| 45,X Turner Syndrome. | 1151 | ||
| Behavior and Development of Turner Syndrome. | 1153 | ||
| Sex Chromatin–Positive Variants of the Syndrome of Gonadal Dysgenesis. | 1154 | ||
| Sex Chromatin–Negative Variants of Gonadal Dysgenesis. | 1154 | ||
| 46,XX and 46,XY Gonadal Dysgenesis. | 1154 | ||
| Familial and Sporadic 46,XX Gonadal Dysgenesis and Its Variants. | 1154 | ||
| Familial and Sporadic 46,XY Gonadal Dysgenesis and Its Variants. | 1154 | ||
| Other Causes of Primary Ovarian Failure. | 1154 | ||
| Radiation Therapy. | 1154 | ||
| Chemotherapy. | 1154 | ||
| Autoimmune Oophoritis. | 1154 | ||
| Homozygous Galactosemia. | 1155 | ||
| Haploinsufficiency of the FOXL2 Gene. | 1155 | ||
| Congential Disorders of Glycosylation-1: Carbohydrate-Deficient Glycoprotein Syndrome Type Ia. | 1155 | ||
| Follicle-Stimulating Hormone Receptor Resistance: Gene Mutations and Hypergonadotropic Hypogonadism. | 1155 | ||
| Luteinizing Hormone and Human Chorionic Gonadotropin Resistance. | 1155 | ||
| Polycystic Ovary Syndrome. | 1155 | ||
| Noonan Syndrome. | 1155 | ||
| Frasier Syndrome. | 1156 | ||
| Diagnosis of Delayed Puberty and Sexual Infantilism | 1156 | ||
| Treatment of Delayed Puberty and Sexual Infantilism | 1160 | ||
| Sexual Precocity | 1162 | ||
| True or Central Precocious Puberty: Complete Isosexual Precocity | 1164 | ||
| Idiopathic True or Central Precocious Puberty. | 1164 | ||
| Gain-of-Function Mutations as Cause of Central Precocious Puberty | 1167 | ||
| KISSIR/GRP54. | 1167 | ||
| KISS Mutations. | 1167 | ||
| Loss-of-Function Mutations as Cause of Central Precocious Puberty | 1167 | ||
| MKRN3. | 1167 | ||
| Central Nervous System Tumors Causing True Precocious Puberty. | 1168 | ||
| Hamartomas of the Tuber Cinereum. | 1168 | ||
| Neurofibromatosis Type 1. | 1170 | ||
| Other Central Nervous System Conditions. | 1171 | ||
| Arachnoid Cysts. | 1172 | ||
| Other Central Nervous System Abnormalities. | 1172 | ||
| Miscellaneous Causes | 1172 | ||
| Central Precocious Puberty in Children Adopted From Developing Countries. | 1172 | ||
| True Precocious Puberty After Virilizing Disorders. | 1172 | ||
| Marfan Syndrome. | 1172 | ||
| Management of Central Precocious Puberty. | 1172 | ||
| Medroxyprogesterone Acetate and Cyproterone Acetate. | 1172 | ||
| Superactive Gonadotropin-Releasing Hormone Agonists. | 1173 | ||
| Adverse Effects. | 1177 | ||
| Other Treatment for Precocious Puberty. | 1178 | ||
| Psychosocial Aspects. | 1178 | ||
| Incomplete Isosexual Precocity: Gonadotropin-Releasing Hormone–Independent Sexual Precocity | 1178 | ||
| Boys | 1178 | ||
| Chorionic Gonadotropin–Secreting Tumors. | 1178 | ||
| Precocious Androgen Secretion Caused by the Adrenal Gland | 1180 | ||
| Virilizing Congenital Adrenal Hyperplasia. | 1180 | ||
| Virilizing Adrenal Tumor. | 1180 | ||
| NR0B1 (DAX1) Gene Mutations. | 1180 | ||
| Leydig Cell Tumor. | 1180 | ||
| Pituitary Gonadotropin–Independent Familial Premature Leydig Cell and Germ Cell Maturation: Familial or Sporadic Testotoxicosis. | 1180 | ||
| Gonadotropin-Independent Sexual Precocity and Pseudohypoparathyroidism Type Ia. | 1183 | ||
| Girls. | 1183 | ||
| Autonomous Ovarian Follicular Cysts. | 1183 | ||
| Ovarian Tumors. | 1184 | ||
| Peutz-Jeghers Syndrome. | 1184 | ||
| Adrenal Adenomas. | 1185 | ||
| Boys and Girls | 1185 | ||
| McCune-Albright Syndrome. | 1185 | ||
| Juvenile Hypothyroidism. | 1190 | ||
| Iatrogenic Sexual Precocity and Endocrine Disruptors. | 1192 | ||
| Diagnosis of Sexual Precocity | 1193 | ||
| Contrasexual Precocity: Feminization in Boys and Virilization in Girls | 1198 | ||
| Boys. | 1198 | ||
| Aromatase Excess Syndrome. | 1198 | ||
| Feminizing Testicular Tumors. | 1198 | ||
| Girls | 1198 | ||
| Adrenal Causes of Virilization. | 1198 | ||
| Syndrome of Glucocorticoid Resistance. | 1198 | ||
| Virilizing Ovarian Tumors. | 1198 | ||
| Variations of Pubertal Development | 1199 | ||
| Premature Thelarche. | 1199 | ||
| Premature Isolated Menarche. | 1199 | ||
| Premature Adrenarche. | 1199 | ||
| Polycystic Ovary Disease. | 1201 | ||
| Adolescent Gynecomastia. | 1201 | ||
| Macroorchidism. | 1202 | ||
| References | 1202 | ||
| VI C Adult | 1219 | ||
| 26 Hormones and Athletic Performance | 1219 | ||
| Key Points | 1219 | ||
| Effect of Athletic Performance on Hormonal Systems | 1219 | ||
| Catecholamines | 1219 | ||
| Fluid Homeostasis: Vasopressin and the Renin-Angiotensin-Aldosterone System | 1220 | ||
| Hypothalamic-Pituitary-Adrenal Axis | 1220 | ||
| Glucocorticoids | 1220 | ||
| Mineralocorticoids | 1221 | ||
| Endorphins | 1221 | ||
| Hypothalamic-Pituitary-Gonadal Axis | 1221 | ||
| Male Gonadal Axis | 1221 | ||
| Female Gonadal Axis | 1222 | ||
| Prolactin | 1223 | ||
| Growth Hormone and the Insulin-like Growth Factor 1 Axis | 1223 | ||
| Hypothalamic-Pituitary-Thyroid Axis | 1224 | ||
| Insulin and Glucose Metabolism | 1224 | ||
| Performance-Enhancing (Ab)use of Hormones | 1224 | ||
| Anabolic Androgenic Steroids | 1224 | ||
| Adverse Effects | 1225 | ||
| Detection | 1226 | ||
| Growth Hormone | 1227 | ||
| Adverse Effects | 1227 | ||
| Detection | 1227 | ||
| Growth Hormone Secretagogues | 1227 | ||
| Insulin-like Growth Factor-1 | 1227 | ||
| Adverse Effects | 1228 | ||
| Detection | 1228 | ||
| Insulin | 1228 | ||
| VII Mineral Metabolism | 1253 | ||
| 28 Hormones and Disorders of Mineral Metabolism | 1254 | ||
| Key Points | 1254 | ||
| Basic Biology of Mineral Metabolism: Roles of the Mineral Ions | 1254 | ||
| Parathyroid Hormone | 1255 | ||
| Parathyroid Gland Biology | 1256 | ||
| Parathyroid Hormone Biosynthesis | 1256 | ||
| Parathyroid Hormone Secretion | 1257 | ||
| Regulation of the Parathyroid Hormone Gene | 1258 | ||
| Regulation of Parathyroid Cell Number | 1259 | ||
| Parathyroid Gland Development | 1259 | ||
| Metabolism of Parathyroid Hormone | 1260 | ||
| Actions of Parathyroid Hormone | 1260 | ||
| Actions of Parathyroid Hormone on the Kidney | 1260 | ||
| Stimulation of Calcium Reabsorption. | 1260 | ||
| Inhibition of Phosphate Transport. | 1260 | ||
| Other Renal Effects of Parathyroid Hormone. | 1261 | ||
| Actions of Parathyroid Hormone on Bone | 1261 | ||
| PTH Increases Bone Formation. | 1261 | ||
| PTH Increases Bone Resorption. | 1262 | ||
| Molecular Basis of Parathyroid Hormone Action | 1263 | ||
| Parathyroid Hormone and Parathyroid Hormone–Related Protein Receptors. | 1263 | ||
| Functional Implications of Parathyroid Hormone Structure. | 1264 | ||
| Activation of Second Messengers. | 1264 | ||
| Second Messengers and Distal Effects of Parathyroid Hormone. | 1265 | ||
| Target Cell Responsiveness to Parathyroid Hormone. | 1265 | ||
| Parathyroid Hormone–Related Protein | 1265 | ||
| Gene and Protein Structure | 1265 | ||
| Functions of Parathyroid Hormone–Related Protein | 1266 | ||
| Calcitonin | 1267 | ||
| Synthesis and Secretion | 1267 | ||
| Calcitonin Family: Calcitonin Gene-Related Peptide, Amylin, Adrenomedullin, Calcitonin Receptor-Stimulating Peptides, and Intermedin | 1268 | ||
| Calcitonin in Human Disease | 1268 | ||
| Therapeutic Uses | 1269 | ||
| Vitamin D | 1269 | ||
| Metabolism of Vitamin D | 1269 | ||
| Actions of Vitamin D | 1270 | ||
| Vitamin D Receptors | 1270 | ||
| Intestinal Calcium Absorption | 1271 | ||
| Entry into the Enterocyte. | 1271 | ||
| Transcellular Transport. | 1272 | ||
| Exit from the Enterocyte. | 1272 | ||
| Actions on the Parathyroid Gland | 1272 | ||
| Actions on Bone | 1272 | ||
| Other Actions of Vitamin D | 1272 | ||
| Vitamin D Analogues | 1272 | ||
| Fibroblast Growth Factor 23 | 1273 | ||
| FGF23 in Human Disease | 1273 | ||
| Actions of FGF23 | 1273 | ||
| Regulation of FGF23 | 1273 | ||
| Calcium and Phosphate Homeostasis | 1274 | ||
| Laboratory Assessment of Mineral Metabolism | 1275 | ||
| Parathyroid Hormone | 1275 | ||
| Parathyroid Hormone–Related Protein | 1276 | ||
| Calcitonin | 1276 | ||
| Vitamin D Metabolites | 1276 | ||
| Fibroblast Growth Factor 23 | 1277 | ||
| Hypercalcemic Disorders | 1277 | ||
| Parathyroid-Dependent Hypercalcemia | 1277 | ||
| Primary Hyperparathyroidism | 1277 | ||
| Classical Primary Hyperparathyroidism. | 1277 | ||
| Contemporary Primary Hyperparathyroidism. | 1278 | ||
| Etiology and Pathogenesis. | 1280 | ||
| Inherited Primary Hyperparathyroidism. | 1281 | ||
| Multiple Endocrine Neoplasia Type 1 (see also Chapter 39). | 1281 | ||
| Multiple Endocrine Neoplasia Type 2a (see also Chapter 39). | 1282 | ||
| Hyperparathyroidism–Jaw Tumor Syndrome. | 1282 | ||
| Management of Primary Hyperparathyroidism. | 1282 | ||
| Medical Monitoring of Primary Hyperparathyroidism. | 1283 | ||
| Surgical Treatment of Primary Hyperparathyroidism. | 1283 | ||
| Familial Hypocalciuric Hypercalcemia | 1285 | ||
| Lithium Toxicity | 1286 | ||
| Parathyroid-Independent Hypercalcemia | 1287 | ||
| Hypercalcemia of Malignancy | 1287 | ||
| Local Osteolytic Hypercalcemia. | 1287 | ||
| Humoral Hypercalcemia of Malignancy. | 1287 | ||
| Vitamin D Intoxication | 1288 | ||
| Sarcoidosis and Other Granulomatous Diseases | 1288 | ||
| Hyperthyroidism | 1289 | ||
| Vitamin A Intoxication | 1289 | ||
| Adrenal Insufficiency | 1289 | ||
| Thiazide Diuretics | 1289 | ||
| Milk-Alkali Syndrome | 1289 | ||
| Immobilization | 1289 | ||
| Renal Failure | 1289 | ||
| Williams Syndrome | 1290 | ||
| Jansen Metaphyseal Chondrodysplasia | 1290 | ||
| Approach to the Hypercalcemic Patient | 1290 | ||
| Causes of Severe Hypercalcemia | 1293 | ||
| Clinical Features of Severe Hypercalcemia | 1293 | ||
| Management of Severe Hypercalcemia | 1293 | ||
| Volume Repletion | 1294 | ||
| Bisphosphonates | 1294 | ||
| Denosumab | 1294 | ||
| Calcitonin | 1294 | ||
| Other Approaches to Treatment of Severe Hypercalcemia | 1294 | ||
| Hypocalcemic Disorders | 1294 | ||
| Clinical Presentation | 1294 | ||
| Parathyroid-Related Disorders | 1296 | ||
| Congenital or Inherited Parathyroid Disorders | 1296 | ||
| Abnormalities in the Parathyroid Hormone Gene | 1296 | ||
| Destruction of the Parathyroid Glands | 1296 | ||
| Impaired Parathyroid Hormone Secretion | 1296 | ||
| Pseudohypoparathyroidism | 1297 | ||
| Vitamin D–Related Disorders | 1299 | ||
| Vitamin D Deficiency | 1300 | ||
| Accelerated Loss of Vitamin D | 1300 | ||
| Impaired 25-Hydroxylation of Vitamin D | 1300 | ||
| Impaired 1α-Hydroxylation of 25-Hydroxyvitamin D | 1300 | ||
| Target Organ Resistance to 1,25-Dihydroxyvitamin D3 | 1301 | ||
| Other Causes of Hypocalcemia | 1301 | ||
| Excessive Deposition into the Skeleton | 1301 | ||
| Chelation | 1301 | ||
| Neonatal Hypocalcemia | 1301 | ||
| Human Immunodeficiency Virus Infection | 1302 | ||
| Critical Illness | 1302 | ||
| Treatment of Hypocalcemia | 1302 | ||
| Disorders of Phosphate Metabolism | 1304 | ||
| Hyperphosphatemia | 1304 | ||
| Hypophosphatemia | 1305 | ||
| Etiology | 1305 | ||
| Clinical Features | 1306 | ||
| Treatment | 1306 | ||
| Disorders of Magnesium Metabolism | 1307 | ||
| Hypermagnesemia | 1307 | ||
| Hypomagnesemia | 1308 | ||
| Etiology | 1308 | ||
| Intestinal Causes of Hypomagnesemia. | 1308 | ||
| Renal Causes of Hypomagnesemia. | 1309 | ||
| Other Causes of Hypomagnesemia. | 1309 | ||
| Consequences of Hypomagnesemia | 1310 | ||
| Therapy of Hypomagnesemia | 1310 | ||
| References | 1310 | ||
| 29 Osteoporosis and Bone Biology | 1323 | ||
| Key Points | 1323 | ||
| Historical Context | 1323 | ||
| Skeletal Biology | 1323 | ||
| Structure and Function of the Skeleton | 1323 | ||
| Embryology and Anatomy | 1324 | ||
| Bone Matrix and Mineral | 1324 | ||
| Collagen Synthesis | 1325 | ||
| Mineralization | 1326 | ||
| Collagen Degradation by Osteoblasts and Osteocytes | 1326 | ||
| Bone Lining Cells, Osteoblasts, and Osteocytes | 1327 | ||
| Osteoclast Differentiation and Function | 1332 | ||
| Bone Remodeling and Its Regulation | 1335 | ||
| Overview of Remodeling | 1335 | ||
| Local Regulators of Remodeling | 1337 | ||
| Cytokines | 1337 | ||
| Transforming Growth Factor-α and Epidermal Growth Factor | 1337 | ||
| Prostaglandins | 1337 | ||
| Peptide Growth Factors | 1337 | ||
| Fibroblast Growth Factors. | 1337 | ||
| Platelet-Derived Growth Factors, Vascular Endothelial Growth Factors, Hypoxia-Inducible Factors, and Reactive Oxygen Species. | 1338 | ||
| Insulin-like Growth Factors. | 1338 | ||
| Transforming Growth Factor-β. | 1338 | ||
| Bone Morphogenetic Proteins and Wnt Proteins. | 1338 | ||
| Systemic Hormones and Bone Remodeling | 1339 | ||
| Calcium-Regulating Hormones | 1339 | ||
| Parathyroid Hormone. | 1339 | ||
| Vitamin D. | 1339 | ||
| Calcitonin. | 1340 | ||
| Other Systemic Hormones That Influence Remodeling | 1340 | ||
| Growth Hormone. | 1340 | ||
| Glucocorticoids. | 1340 | ||
| Thyroid Hormones. | 1340 | ||
| Insulin. | 1341 | ||
| Gonadal Hormones. | 1341 | ||
| Epidemiology of Osteoporosis and Fractures | 1341 | ||
| Fractures | 1341 | ||
| Hip Fractures | 1341 | ||
| Vertebral Fractures | 1341 | ||
| Wrist Fractures | 1342 | ||
| Other Types of Fractures | 1342 | ||
| Clinical Assessments of Osteoporosis | 1342 | ||
| Dual-Energy X-Ray Absorptiometry | 1342 | ||
| Quantitative Computed Tomography | 1343 | ||
| Bone Turnover Markers | 1343 | ||
| Bone Biopsy | 1345 | ||
| Fracture Epidemiology | 1345 | ||
| Clinical Risk Factors and Their Combination With Bone Mineral Density | 1345 | ||
| Prevalence of Osteoporosis and Incidence of Fractures in the Population | 1347 | ||
| Pathogenesis of Osteoporosis | 1348 | ||
| Gonadal Deficiency | 1348 | ||
| Estrogen | 1348 | ||
| Androgens | 1349 | ||
| Age-Related Bone Loss | 1349 | ||
| Secondary Osteoporosis | 1350 | ||
| Glucocorticoid-Induced Bone Loss | 1350 | ||
| Factors That Impair Peak Bone Acquisition | 1351 | ||
| Genetic Factors That Determine Peak Bone Mass | 1352 | ||
| Approach to Management of Osteoporosis | 1353 | ||
| General Measures | 1354 | ||
| Diet | 1354 | ||
| Calcium. | 1354 | ||
| Vitamin D. | 1354 | ||
| Physical Activity | 1354 | ||
| Lifestyle | 1355 | ||
| Pharmacologic Approaches to the Treatment of Osteoporosis | 1355 | ||
| Antiresorptive Agents | 1355 | ||
| Estrogen. | 1355 | ||
| Selective Estrogen Receptor Modulators. | 1355 | ||
| Bisphosphonates. | 1355 | ||
| Calcitonin. | 1356 | ||
| Strontium Ranelate. | 1356 | ||
| Denosumab. | 1357 | ||
| Cathepsin K Inhibitors. | 1357 | ||
| Anabolic Agents | 1357 | ||
| Parathyroid Hormone. | 1357 | ||
| Future Anabolic Agents. | 1358 | ||
| Monoclonal Antibodies to Sclerostin. | 1358 | ||
| References | 1358 | ||
| 30 Kidney Stones | 1365 | ||
| Key Points | 1365 | ||
| Epidemiology of Stone Formation | 1365 | ||
| Pathogenesis of Stone Formation | 1366 | ||
| Physiology | 1366 | ||
| Diet | 1366 | ||
| Pathogenesis of Idiopathic Hypercalciuria | 1367 | ||
| Calcium Homeostasis (Also See Chapter 28) | 1367 | ||
| Potential Mechanisms for the Development of Idiopathic Hypercalciuria | 1367 | ||
| Human Data | 1368 | ||
| Genetic Hypercalciuric Stone-Forming Rats | 1368 | ||
| Genetics of Idiopathic Hypercalciuria in Humans | 1369 | ||
| Other Genetic Causes of Stones and Nephrocalcinosis | 1369 | ||
| X-Linked Hypercalciuric Nephrolithiasis (Dent Disease and Others) | 1369 | ||
| Bartter Syndrome | 1369 | ||
| Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis | 1370 | ||
| Distal Renal Tubular Acidosis | 1370 | ||
| Hereditary Hypophosphatemic Rickets With Hypercalciuria | 1370 | ||
| Primary Hyperoxaluria and Cystinuria | 1370 | ||
| Clinical Presentation and Evaluation | 1370 | ||
| Metabolic Evaluation of Stone Formers | 1371 | ||
| The Basic Evaluation | 1371 | ||
| History | 1371 | ||
| Stone History. | 1371 | ||
| Medical History. | 1371 | ||
| Family History. | 1372 | ||
| Medications | 1372 | ||
| Lifestyle and Diet | 1372 | ||
| Physical Examination | 1372 | ||
| Laboratory Tests | 1373 | ||
| Stone Analysis | 1373 | ||
| Radiologic Evaluation | 1374 | ||
| The Complete Evaluation | 1375 | ||
| Therapy | 1375 | ||
| Surgical Treatment | 1375 | ||
| Medical Expulsive Therapy | 1376 | ||
| Medical Preventive Therapy | 1376 | ||
| Nonspecific Preventive Therapy | 1376 | ||
| Specific Therapy Matched to Specific Pathogenesis | 1376 | ||
| Calcium Stones. | 1376 | ||
| Hypercalciuria. | 1376 | ||
| Hyperoxaluria. | 1377 | ||
| Dietary Oxaluria. | 1377 | ||
| Enteric Oxaluria. | 1377 | ||
| Primary Hyperoxaluria. | 1378 | ||
| Hyperuricosuria. | 1378 | ||
| Hypocitraturia. | 1378 | ||
| Renal Tubular Acidosis. | 1379 | ||
| Nephrocalcinosis. | 1379 | ||
| Uric Acid Stones. | 1379 | ||
| Struvite Stones. | 1380 | ||
| Urease-Producing Bacteria. | 1380 | ||
| Therapy for Struvite Stones. | 1380 | ||
| Cystine Stones. | 1381 | ||
| Therapy for Cystine Stones. | 1381 | ||
| References | 1381 | ||
| VIII Disorders of Carbohydrate and Fat Metabolism | 1385 | ||
| 31 Type 2 Diabetes Mellitus | 1386 | ||
| Key Points | 1386 | ||
| Epidemiology and Diagnosis | 1386 | ||
| Epidemiology | 1386 | ||
| Diagnostic Criteria | 1387 | ||
| Screening | 1387 | ||
| Pathogenesis | 1388 | ||
| Genetic Factors in the Development of Type 2 Diabetes Mellitus | 1389 | ||
| Monogenic Forms of Diabetes | 1389 | ||
| Monogenic Forms of Diabetes Associated With Insulin Resistance | 1389 | ||
| Mutations in the Insulin Receptor. | 1389 | ||
| Lipoatrophic Diabetes. | 1389 | ||
| Mutations in Peroxisome Proliferator-Activated Receptor-γ. | 1389 | ||
| Neonatal Diabetes. | 1390 | ||
| Etiology. | 1390 | ||
| Therapy. | 1390 | ||
| Monogenic Forms of Diabetes Associated With Defects in Insulin Secretion | 1390 | ||
| Mutant Insulin Syndromes. | 1390 | ||
| Mitochondrial Diabetes. | 1390 | ||
| Maturity-Onset Diabetes of the Young. | 1391 | ||
| Etiology and Clinical Presentation. | 1391 | ||
| Functional Effects of MODY Genes. | 1391 | ||
| Glucokinase. | 1391 | ||
| Liver-Enriched Transcription Factors. | 1391 | ||
| Insulin Promoter Factor 1. | 1392 | ||
| Neurogenic Differentiation-1 Transcription Factor. | 1392 | ||
| Genetics of the Polygenic Forms of Type 2 Diabetes Mellitus | 1392 | ||
| Calpain-10 Gene | 1392 | ||
| Kir6.2 Gene | 1393 | ||
| Peroxisome Proliferator-Activated Receptor-γ Gene | 1393 | ||
| Hepatocyte Nuclear Factor-4α Gene | 1393 | ||
| Transcription Factor 7–like 2 Gene | 1393 | ||
| Diabetes Genes Identified by Genome-Wide Association Studies | 1394 | ||
| Insulin Signaling | 1394 | ||
| Downstream Events After Insulin Receptor Phosphorylation | 1394 | ||
| Central Control of Glucose Metabolism | 1396 | ||
| Insulin Resistance and the Risk of Type 2 Diabetes Mellitus | 1396 | ||
| Insulin Resistance | 1396 | ||
| Obesity and Type 2 Diabetes Mellitus | 1397 | ||
| Hyperinsulinemia and Insulin Resistance | 1398 | ||
| Nutrient Overload and Insulin Resistance. | 1398 | ||
| Adipose Tissue and Insulin Resistance. | 1398 | ||
| Mammalian Target of Rapamycin. | 1398 | ||
| Unfolded Protein Response. | 1398 | ||
| Innate Immunity. | 1399 | ||
| Circadian Rhythms, Obesity, and Insulin Resistance. | 1399 | ||
| Skeletal Muscle Insulin Resistance | 1399 | ||
| Intramuscular Triglycerides. | 1400 | ||
| Fatty Acid Metabolism in Skeletal Muscle. | 1400 | ||
| Mitochondrial Abnormalities and Insulin Resistance | 1402 | ||
| Glucose Influence on Skeletal Muscle Fatty Acid Metabolism | 1402 | ||
| Increased Hepatic Glucose Production in Diabetes Mellitus | 1403 | ||
| Glucocorticoid-Induced Insulin Resistance | 1403 | ||
| Tumor Necrosis Factor-α | 1403 | ||
| Glucotoxicity, Glucosamine | 1404 | ||
| Insulin Resistance and Lipodystrophy Associated With Human Immunodeficiency Virus Infection | 1404 | ||
| Measures to Improve Insulin Sensitivity | 1404 | ||
| Mechanisms of Reducing Insulin Resistance | 1404 | ||
| Mechanisms for Improved Insulin Sensitivity With Weight Loss | 1405 | ||
| Mechanisms for Improved Insulin Sensitivity With Exercise | 1405 | ||
| Acute Exercise | 1405 | ||
| Exercise Training | 1405 | ||
| Mechanisms that Link Cardiovascular Disease and Insulin Resistance | 1406 | ||
| The Metabolic Syndrome | 1406 | ||
| Insulin Secretion | 1407 | ||
| Quantitation of Beta-Cell Function | 1407 | ||
| Signaling Pathways in the Beta Cell and Insulin Secretion | 1408 | ||
| Physiologic Factors Regulating Insulin Secretion | 1409 | ||
| Carbohydrate Nutrients | 1409 | ||
| Noncarbohydrate Nutrients | 1409 | ||
| Hormonal Factors | 1409 | ||
| Neural Factors | 1410 | ||
| Temporal Pattern of Insulin Secretion | 1410 | ||
| Rapid Oscillations | 1411 | ||
| Ultradian Oscillations | 1411 | ||
| Circadian Oscillations | 1412 | ||
| Insulin Secretion in Obesity and Insulin Resistance | 1412 | ||
| Insulin Secretion in Subjects With Impaired Glucose Tolerance | 1413 | ||
| Insulin Secretion in Type 2 Diabetes Mellitus | 1414 | ||
| Effects of Genetic Variants on Insulin Secretion | 1416 | ||
| Rodent Models | 1416 | ||
| Mouse Models of Type 2 Diabetes Mellitus | 1416 | ||
| Leptin (Lepob) and Leptin Receptor (db) Mutations | 1416 | ||
| Agouti Mouse | 1416 | ||
| KK Mouse | 1417 | ||
| New Zealand Obese Mouse | 1417 | ||
| Gold Thioglucose–Induced Diabetes | 1417 | ||
| Diabetes Induced by Fat Ablation | 1417 | ||
| C57BL/6J Mouse Fed a High-Fat Diet. | 1417 | ||
| Rat Models of Type 2 Diabetes Mellitus | 1417 | ||
| Zucker Diabetic Fatty Rat | 1417 | ||
| Goto-Kakizaki Rat | 1418 | ||
| BHE/Cdb Rat | 1418 | ||
| Psammomys obesus (Sand Rat) | 1418 | ||
| Otsuka Long-Evans Tokushima Fatty Rat | 1418 | ||
| Neonatal Streptozotocin | 1418 | ||
| Management | 1418 | ||
| Scope of the Problem | 1419 | ||
| Glucose Treatment Guidelines | 1419 | ||
| Study Results and Recommendations | 1419 | ||
| Blood Glucose Treatment Targets | 1420 | ||
| Lifestyle Intervention | 1420 | ||
| Patient Education | 1421 | ||
| Nutrition | 1422 | ||
| Exercise | 1424 | ||
| Self-Monitoring of Blood Glucose | 1424 | ||
| Pharmacotherapy for Type 2 Diabetes Mellitus | 1425 | ||
| Insulin Sensitizers With Predominant Action in the Liver | 1425 | ||
| Insulin Sensitizers With Predominant Action in Peripheral Insulin-Sensitive Tissues | 1427 | ||
| Insulin Secretagogues | 1428 | ||
| Sulfonylureas. | 1428 | ||
| Glinides. | 1429 | ||
| Carbohydrate Absorption Inhibitors: α-Glucosidase Inhibitors | 1429 | ||
| Incretin-Related Therapies | 1430 | ||
| GLP-1 Receptor Agonists. | 1430 | ||
| DPP4 Inhibitors. | 1430 | ||
| Sodium-Glucose Transporter-2 Inhibitors. | 1431 | ||
| Insulins | 1431 | ||
| Amylinomimetics. | 1432 | ||
| Colesevelam. | 1432 | ||
| Bromocriptine. | 1432 | ||
| Practical Aspects of Initiating and Progressively Managing Type 2 Diabetes Mellitus | 1433 | ||
| General Approach | 1433 | ||
| Strategies | 1433 | ||
| Minimal Cost Strategy. | 1433 | ||
| Minimal Weight Gain Strategy. | 1434 | ||
| Minimal Progressive Beta-Cell Loss Strategy. | 1435 | ||
| Minimal Injection Strategy. | 1435 | ||
| Minimal Insulin Resistance Strategy. | 1435 | ||
| Minimal Effort Strategy. | 1435 | ||
| Hypoglycemia Avoidance Strategy. | 1435 | ||
| Postprandial Targeting Strategy. | 1435 | ||
| Preventing Type 2 Diabetes Mellitus | 1435 | ||
| Future Directions | 1436 | ||
| References | 1436 | ||
| 32 Type 1 Diabetes Mellitus | 1451 | ||
| Key Points | 1451 | ||
| Diagnosis | 1452 | ||
| Animal Models | 1452 | ||
| Nonobese Diabetic Mice | 1453 | ||
| BioBreeding Rat | 1454 | ||
| Induced Models of Type 1 Diabetes Mellitus | 1454 | ||
| Histopathology | 1454 | ||
| Genetics | 1455 | ||
| Overview of Prevalence and Genetics | 1455 | ||
| Twin Studies | 1457 | ||
| The Major Histocompatibility Complex | 1457 | ||
| Insulin Locus | 1458 | ||
| PTPN22 Gene | 1458 | ||
| Other Loci | 1458 | ||
| Monogenic Forms | 1458 | ||
| Neonatal Diabetes | 1461 | ||
| Maturity-Onset Diabetes of the Young | 1461 | ||
| Autoimmune Polyendocrine Syndrome Type I (AIRE Gene Mutations) | 1461 | ||
| X-Linked Polyendocrinopathy, Immune Dysfunction, and Diarrhea (Scurfy Gene) | 1461 | ||
| Environmental Factors | 1461 | ||
| Models to Explain the Influence of Environment | 1461 | ||
| Candidate Environmental Factors | 1462 | ||
| Natural History | 1462 | ||
| Genetic and Immunologic Heterogeneity by Age of Onset | 1463 | ||
| Beta-Cell Mass Is Not Equal in All Individuals | 1463 | ||
| Metabolic Progression Before Hyperglycemia | 1464 | ||
| C-Peptide Loss After Hyperglycemia | 1464 | ||
| Transient Hyperglycemia | 1464 | ||
| Immunotherapy for the Prevention and Reversal of Type 1 Diabetes Mellitus | 1464 | ||
| Immunosuppression | 1464 | ||
| Immunologic Vaccination | 1465 | ||
| Targeting Mechanisms of Beta-Cell Death | 1465 | ||
| Pancreas and Islet Cell Transplantation | 1465 | ||
| Disorders Associated with Immunity to Insulin/Insulin Receptor | 1466 | ||
| Insulin Autoimmune Syndrome | 1466 | ||
| Insulin Allergy | 1466 | ||
| Anti-insulin Receptor Autoantibodies | 1466 | ||
| Clinical Presentation | 1466 | ||
| Laboratory Findings | 1467 | ||
| Treatment | 1467 | ||
| Importance of Tight Glucose Control | 1467 | ||
| Goals of Treatment | 1468 | ||
| Team Approach to Treatment | 1468 | ||
| Pharmacokinetics of Available Insulin Preparations | 1468 | ||
| Rapid-Acting Insulins | 1469 | ||
| Regular Insulin. | 1469 | ||
| Insulin Analogues | 1469 | ||
| Insulin Lispro. | 1469 | ||
| Insulin Aspart. | 1469 | ||
| Insulin Glulisine. | 1469 | ||
| Advantages of Analogues. | 1469 | ||
| Intermediate- and Long-Acting Insulins | 1469 | ||
| Neutral Protamine Hagedorn Insulin. | 1469 | ||
| Insulin Glargine. | 1469 | ||
| Insulin Detemir. | 1470 | ||
| Novel Basal Insulins | 1470 | ||
| Alternative Routes of Insulin Administration | 1470 | ||
| Approaches to the Treatment of Type 1 Diabetes Mellitus | 1470 | ||
| Combination of Rapid-Acting and Intermediate-Acting Insulin with Breakfast and Dinner and Intermediate-Acting Insulin at Bedtime | 1470 | ||
| Combination of Rapid-Acting Insulin Given with Meals and Long-Acting Insulin at Bedtime | 1470 | ||
| Insulin Administration by an External Insulin Pump | 1470 | ||
| Sensor-Augmented Pump Therapy and Low-Glucose Suspend | 1471 | ||
| Algorithms of Insulin Administration | 1471 | ||
| Pramlintide | 1471 | ||
| Use of Type 2 Diabetes Drugs in Type 1 Diabetes | 1472 | ||
| Complications of Intensive Management | 1472 | ||
| Hypoglycemia | 1472 | ||
| Weight Gain | 1472 | ||
| Worsening of Retinopathy | 1473 | ||
| Insulin Allergy | 1473 | ||
| Acute Diabetic Emergencies: Diabetic Ketoacidosis | 1473 | ||
| Clinical Presentation | 1473 | ||
| Laboratory Test Results and Differential Diagnosis | 1473 | ||
| Laboratory Tests | 1473 | ||
| Differential Diagnosis | 1474 | ||
| Osmolarity | 1474 | ||
| Therapy | 1475 | ||
| Fluids | 1475 | ||
| Insulin | 1475 | ||
| Potassium | 1476 | ||
| Phosphate | 1476 | ||
| Bicarbonate | 1476 | ||
| Monitoring | 1476 | ||
| Search for Underlying Causes | 1476 | ||
| Complications and Prognosis | 1477 | ||
| References | 1477 | ||
| 33 Complications of Diabetes Mellitus | 1484 | ||
| Key Points | 1484 | ||
| Biochemistry and Molecular Cell Biology | 1484 | ||
| Shared Pathophysiologic Features of Microvascular Complications | 1485 | ||
| Requirement for Intracellular Hyperglycemia | 1485 | ||
| Abnormal Cell Function | 1485 | ||
| Increased Vessel Wall Protein Accumulation | 1486 | ||
| Microvascular Cell Loss and Vessel Occlusion | 1486 | ||
| Development of Microvascular Complications During Posthyperglycemic Euglycemia | 1486 | ||
| Genetic Determinants of Susceptibility to Microvascular Complications | 1487 | ||
| MicroRNAs and Diabetic Complications | 1488 | ||
| Progenitor Cells and Microvascular Complications | 1489 | ||
| Pathophysiologic Features of Macrovascular Complications | 1489 | ||
| Impaired Collateral Blood Vessel Formation From Bone Marrow Progenitor Cells | 1491 | ||
| Mechanisms of Hyperglycemia-Induced Damage | 1491 | ||
| Increased Polyol Pathway Flux | 1492 | ||
| Increased Intracellular Formation of Advanced Glycation End Products | 1493 | ||
| Advanced Glycation End Products Are Formed From Intracellular Dicarbonyl Precursors. | 1493 | ||
| Advanced Glycation End Products Alter Intracellular Protein Function. | 1494 | ||
| Advanced Glycation End Products Interfere with Normal Matrix-Matrix and Matrix-Cell Interactions. | 1494 | ||
| Advanced Glycation End Product Receptors Mediate Pathologic Changes in Gene Expression. | 1495 | ||
| Activation of Protein Kinase C | 1495 | ||
| Mechanism of Hyperglycemia-Induced Protein Kinase C Activation. | 1495 | ||
| Consequences of Hyperglycemia-Induced Protein Kinase C Activation. | 1496 | ||
| Increased Hexosamine Pathway Flux | 1496 | ||
| Different Hyperglycemia-Induced Pathogenic Mechanisms Reflect a Single Upstream Process | 1498 | ||
| Free Fatty Acid–Induced Proatherogenic Changes Are Also Caused by Mitochondrial Production of Reactive Oxygen Species | 1502 | ||
| Possible Molecular Basis for Hyperglycemic Memory | 1502 | ||
| Retinopathy, Macular Edema, and Other Ocular Complications* | 1503 | ||
| Epidemiology and Impact | 1504 | ||
| Pathophysiology | 1504 | ||
| Clinical Features | 1505 | ||
| Risk Factors | 1505 | ||
| Clinical Findings | 1507 | ||
| Classification Systems | 1507 | ||
| Classification of Diabetic Retinopathy. | 1507 | ||
| Classification of Diabetic Macular Edema. | 1507 | ||
| International Classification of Diabetic Retinopathy. | 1507 | ||
| Other Ocular Manifestations of Diabetes | 1509 | ||
| Monitoring and Treatment of Diabetic Retinopathy | 1509 | ||
| Comprehensive Eye Examination | 1510 | ||
| Initial Ophthalmic Evaluation | 1511 | ||
| Follow-Up Ophthalmic Examination | 1513 | ||
| Proliferative Diabetic Retinopathy. | 1513 | ||
| Macular Edema. | 1514 | ||
| Antiangiogenic Therapy | 1515 | ||
| Control of Systemic Disorders and Effect of Systemic Medications | 1515 | ||
| Diabetic Nephropathy | 1516 | ||
| Natural History of Nephropathy in Type 1 Diabetes | 1516 | ||
| Stage 1: Hyperfiltration | 1517 | ||
| Stage 2: The Silent Stage | 1517 | ||
| Stage 3: Microalbuminuria | 1517 | ||
| Stage 4: Macroalbuminuria | 1518 | ||
| Stage 5: Uremia | 1518 | ||
| Natural History of Nephropathy in Type 2 Diabetes | 1518 | ||
| Pathogenesis | 1519 | ||
| Pathology | 1519 | ||
| Renal Artery Stenosis | 1520 | ||
| Renal Papillary Necrosis | 1520 | ||
| Renal Tubular Acidosis | 1520 | ||
| Other Renal Manifestations | 1521 | ||
| Management | 1521 | ||
| Glycemic Control | 1521 | ||
| Blood Pressure Control | 1522 | ||
| Other Approaches | 1523 | ||
| Treatment of the Diabetic Uremic Patient | 1524 | ||
| The Burden of Nephropathy | 1525 | ||
| Diabetic Neuropathies | 1525 | ||
| Classification | 1526 | ||
| Natural History | 1526 | ||
| Clinical Presentation | 1527 | ||
| Focal Neuropathies | 1528 | ||
| Diffuse Neuropathies | 1528 | ||
| Proximal Motor Neuropathies. | 1528 | ||
| Distal Symmetric Polyneuropathy. | 1529 | ||
| Pain in Diabetic Neuropathies | 1530 | ||
| Acute Painful Neuropathy | 1530 | ||
| Chronic Painful Neuropathy | 1531 | ||
| Small-Fiber Neuropathies | 1531 | ||
| Large-Fiber Neuropathies | 1531 | ||
| Clinical Presentation | 1532 | ||
| Diagnosis and Differential Diagnosis of Peripheral Neuropathy | 1532 | ||
| Peripheral Testing Devices | 1533 | ||
| CardiovascularTesting Devices | 1534 | ||
| Biopsy | 1534 | ||
| Differential Diagnosis | 1534 | ||
| Nerve Conduction Studies | 1534 | ||
| Management | 1536 | ||
| Control of Hypergylcemia | 1536 | ||
| Pharmacologic Therapy | 1537 | ||
| Aldose Reductase Inhibitors. | 1537 | ||
| α-Lipoic Acid. | 1537 | ||
| γ-Linolenic Acid. | 1537 | ||
| Protein Kinase C-β Inhibition. | 1537 | ||
| Benfotiamine. | 1538 | ||
| Metanx. | 1538 | ||
| Human Intravenous Immunoglobulin. | 1538 | ||
| Neurotrophic Therapy | 1538 | ||
| Islet Neogenesis-Associated Protein. | 1538 | ||
| Human Hepatocyte Growth Factor. | 1538 | ||
| Pain Control | 1538 | ||
| Calcitonin. | 1538 | ||
| C-Fiber Pain. | 1538 | ||
| Capsaicin. | 1539 | ||
| Clonidine. | 1539 | ||
| Aδ-Fiber Pain. | 1539 | ||
| Nerve Blocking. | 1539 | ||
| Tramadol and Dextromethorphan. | 1539 | ||
| Antidepressants. | 1540 | ||
| Antiepileptic Drugs. | 1541 | ||
| Adjunct Management and Treatment of Complications | 1542 | ||
| Prevention. | 1542 | ||
| Stimulation. | 1542 | ||
| Management of Small-Fiber Neuropathies | 1542 | ||
| Management of Large-Fiber Neuropathies | 1542 | ||
| Autonomic Neuropathies | 1542 | ||
| Prevention and Reversibility | 1543 | ||
| Management | 1543 | ||
| Postural Hypotension. | 1543 | ||
| Supportive Garments. | 1544 | ||
| Drug Therapy. | 1544 | ||
| Gastropathy. | 1546 | ||
| Enteropathy. | 1546 | ||
| Antibiotics. | 1546 | ||
| Cholestyramine. | 1546 | ||
| Octreotide. | 1546 | ||
| Diet. | 1546 | ||
| Sexual Dysfunction | 1546 | ||
| Male Sexual Dysfunction. | 1546 | ||
| Diagnosis. | 1547 | ||
| Treatment. | 1547 | ||
| Female Sexual Dysfunction. | 1547 | ||
| Cystopathy. | 1547 | ||
| Sweating Disturbances | 1547 | ||
| Metabolic Dysfunction | 1547 | ||
| Diabetic Heart Disease | 1548 | ||
| Coronary Heart Disease | 1548 | ||
| Effect of Diabetes on Risk of Coronary Heart Disease | 1548 | ||
| Aggregation of Traditional Coronary Heart Disease Risk Factors in Diabetes | 1549 | ||
| Plasma Glucose and Insulin Resistance as Independent Risk Factors for Atherosclerosis | 1550 | ||
| The Metabolic Syndrome | 1551 | ||
| Definitions and Diagnosis | 1551 | ||
| Epidemiology | 1551 | ||
| The Metabolic Syndrome and Cardiovascular Disease | 1551 | ||
| The Role of Glycemic Control | 1551 | ||
| Dyslipidemia and Its Treatment in Patients with Diabetes Mellitus | 1553 | ||
| Signature Features and Treatment of Hypertension in Diabetic Patients | 1555 | ||
| Acute Coronary Syndromes in Diabetes Mellitus | 1556 | ||
| Cardiomyopathy in Patients with Diabetes Mellitus | 1557 | ||
| The Diabetic Foot | 1558 | ||
| Epidemiology and Pathogenesis of Diabetic Foot Ulceration | 1558 | ||
| Pathway to Ulceration | 1558 | ||
| Diabetic Neuropathy | 1558 | ||
| Peripheral Vascular Disease | 1558 | ||
| Past Foot Ulceration or Foot Surgery | 1558 | ||
| Other Diabetic Complications | 1558 | ||
| Callus, Deformity, and High Foot Pressures | 1559 | ||
| Prevention of Foot Ulceration and Amputation | 1559 | ||
| The Diabetic Foot Care Team | 1560 | ||
| Classification of Foot Ulcers | 1560 | ||
| Management of Diabetic Foot Ulcers | 1560 | ||
| Neuropathic Foot Ulcer Without Osteomyelitis (Wagner Grades 1, 2; University of Texas Grades 1a, 1b, 2a, 2b) | 1561 | ||
| Neuroischemic Ulcers (Wagner Grades 1, 2; University of Texas Grades 1c, 1d) | 1561 | ||
| Osteomyelitis (Wagner Grade 3; University of Texas Grades 3b, 3d) | 1561 | ||
| Gangrene (Wagner Grades 4, 5) | 1562 | ||
| Adjunct Treatments for Foot Ulcers | 1562 | ||
| Platelet-Derived Growth Factors and Tissue-Engineered Skin | 1562 | ||
| Negative-Pressure Wound Therapy | 1562 | ||
| Charcot Neuroarthropathy | 1562 | ||
| Acknowledgments | 1562 | ||
| References | 1563 | ||
| 34 Hypoglycemia | 1582 | ||
| Key Points | 1582 | ||
| Physiology of Defense Against Hypoglycemia | 1582 | ||
| Glucose Metabolism | 1582 | ||
| Systemic Glucose Balance | 1583 | ||
| Responses to Hypoglycemia | 1584 | ||
| Clinical Manifestations of Hypoglycemia | 1584 | ||
| Maintenance of Systemic Glucose Balance | 1585 | ||
| Clinical Hypoglycemia | 1586 | ||
| Definition and Diagnosis | 1586 | ||
| General Mechanisms of Hypoglycemia | 1587 | ||
| Clinical Classification of Hypoglycemia | 1587 | ||
| Hypoglycemia in Persons with Diabetes | 1587 | ||
| The Clinical Problem of Hypoglycemia in Diabetes | 1587 | ||
| Frequency of Hypoglycemia in Diabetes | 1588 | ||
| Impact of Hypoglycemia in Diabetes | 1588 | ||
| Clinical Definition and Classification of Hypoglycemia in Diabetes | 1589 | ||
| Pathophysiology of Glucose Counterregulation in Diabetes | 1589 | ||
| Insulin Excess | 1589 | ||
| Defective Glucose Counterregulation and Hypoglycemia Unawareness | 1589 | ||
| Hypoglycemia-Associated Autonomic Failure in Diabetes | 1591 | ||
| Risk Factors for Hypoglycemia in Diabetes | 1593 | ||
| Absolute or Relative Insulin Excess | 1593 | ||
| Risk Factors for HAAF | 1594 | ||
| Prevention of Hypoglycemia in Diabetes | 1594 | ||
| Acknowledge the Problem | 1594 | ||
| Apply the Principles of Aggressive Glycemic Therapy | 1594 | ||
| Consider the Conventional Risk Factors | 1595 | ||
| Consider the Risk Factors for HAAF | 1595 | ||
| Treatment of Hypoglycemia in Diabetes | 1595 | ||
| Hypoglycemia in Persons without Diabetes | 1596 | ||
| The Decision to Evaluate for Hypoglycemia | 1596 | ||
| Clinical Classification of Hypoglycemic Disorders | 1596 | ||
| Ill or Medicated Individual | 1596 | ||
| Seemingly Well Individual | 1597 | ||
| Diagnostic Approach | 1598 | ||
| Treatment of Hypoglycemia Disorders | 1600 | ||
| Hypoglycemia in Infancy and Childhood | 1600 | ||
| Intolerance of Fasting | 1600 | ||
| Hyperinsulinism | 1600 | ||
| Enzyme Defects | 1601 | ||
| Acknowledgments | 1602 | ||
| Disclosures | 1602 | ||
| References | 1602 | ||
| 35 Neuroendocrine Control of Energy Stores | 1608 | ||
| Key Points | 1608 | ||
| Historical Perspective | 1608 | ||
| Circuits Regulating Energy Balance | 1609 | ||
| Ventromedial Hypothalamic Neuron Control of Glucose and Energy Homeostasis | 1610 | ||
| The Arcuate Nucleus Is a Key Node of Hypothalamic Control of Energy Balance | 1611 | ||
| Melanocortin-4 Receptors Regulate Energy and Glucose Homeostasis | 1612 | ||
| The Lateral Hypothalamus Links Coordinated Food Intake Control and Arousal | 1615 | ||
| Central Nervous System Control of Thermogenesis | 1615 | ||
| Hormonal and Nutritional Regulators of Energy Balance Circuits | 1616 | ||
| Adipostatic Factors | 1616 | ||
| Leptin Is the Prototypical Regulator of Energy Homeostasis | 1616 | ||
| Distribution of Leptin Receptors | 1616 | ||
| The Role of Insulin and Glucose in the Regulation of Energy Homeostasis | 1617 | ||
| Insulin Action in the Brain | 1617 | ||
| Glucose Levels Are Sensed by Neurons in the Brain | 1617 | ||
| Pro-opiomelanocortin Neurons Sense Changes in Glucose Concentration | 1617 | ||
| Satiety and Hunger Factors | 1618 | ||
| Role of the Brainstem in Satiety and Hunger | 1618 | ||
| Gut Peptides Involved in Satiety and Hunger | 1618 | ||
| Cholecystokinin. | 1618 | ||
| Peptide YY. | 1619 | ||
| Ghrelin. | 1619 | ||
| Preproglucagon-Derived Peptides. | 1620 | ||
| GLP-1 and GLP-1R Neurons in the Central Nervous System. | 1621 | ||
| Amylin. | 1621 | ||
| Bariatric Surgery and the Role of the Gastrointestinal System in the Control of Energy Homeostasis | 1621 | ||
| Steroid Hormones | 1622 | ||
| Hypothalamic Inflammation | 1622 | ||
| Intersection of Energy Balance and Reward Circuits | 1623 | ||
| Monogenic Disorders of Energy Homeostasis | 1623 | ||
| Leptin and Leptin Receptor Deficiency in Humans | 1623 | ||
| Obesity Resulting From Defective Melanocortin Signaling | 1624 | ||
| References | 1624 | ||
| 36 Obesity | 1633 | ||
| Key Points | 1633 | ||
| Definition of Obesity | 1633 | ||
| Body Mass Index | 1633 | ||
| Factors Affecting Body Mass Index–Related Risk | 1634 | ||
| Body Fat Distribution | 1634 | ||
| Age | 1634 | ||
| Concomitant Medical Illness | 1634 | ||
| Weight Gain | 1634 | ||
| Aerobic Fitness | 1635 | ||
| Ethnicity | 1635 | ||
| Physiology of Energy Homeostasis | 1635 | ||
| Pathogenesis | 1635 | ||
| Energy Balance | 1635 | ||
| Genes and Environment | 1635 | ||
| Environmental Effects in High-Risk Populations | 1635 | ||
| Influences of Childhood and Parental Obesity | 1636 | ||
| Genetics and Obesity | 1636 | ||
| Monogenic Causes of Obesity | 1636 | ||
| Leptin Gene Mutation. | 1636 | ||
| Leptin Receptor Mutation. | 1636 | ||
| Prohormone Convertase 1 Gene Mutation. | 1636 | ||
| Pro-opiomelanocortin Gene Mutation. | 1636 | ||
| Melanocortin 4 Receptor Mutation. | 1636 | ||
| Mutation of the Neurotrophin Receptor TrkB. | 1637 | ||
| Obesity in Pleiotropic Syndromes. | 1637 | ||
| Obesity Syndromes Due to Chromosomal Rearrangements | 1637 | ||
| Prader-Willi Syndrome. | 1637 | ||
| SIM1 Gene Mutation. | 1637 | ||
| Polygenic Causes of Obesity | 1637 | ||
| Energy Metabolism | 1637 | ||
| Adipose Tissue and Triglyceride Metabolism | 1638 | ||
| Triglyceride Storage | 1638 | ||
| Lipolysis | 1639 | ||
| Adipose Tissue as an Endocrine and Immune Organ | 1639 | ||
| Leptin | 1639 | ||
| Resistin | 1640 | ||
| Adiponectin | 1640 | ||
| Estrogens | 1640 | ||
| Selected Cytokines | 1640 | ||
| Tumor Necrosis Factor-α | 1640 | ||
| Interleukin 6 | 1640 | ||
| Adipocyte Biology | 1640 | ||
| White Adipose Tissue | 1640 | ||
| Brown Adipose Tissue | 1640 | ||
| Prevalence of Obesity | 1641 | ||
| Metabolically Normal Obesity | 1641 | ||
| Clinical Features and Complications of Obesity | 1641 | ||
| Endocrine and Metabolic Diseases | 1641 | ||
| The Dysmetabolic Syndrome | 1641 | ||
| Type 2 Diabetes Mellitus | 1642 | ||
| Dyslipidemia | 1642 | ||
| Cardiovascular Disease | 1642 | ||
| Hypertension | 1642 | ||
| Coronary Heart Disease | 1642 | ||
| Cerebrovascular and Thromboembolic Disease | 1642 | ||
| Pulmonary Disease | 1642 | ||
| Restrictive Lung Disease | 1642 | ||
| Obesity-Hypoventilation Syndrome | 1642 | ||
| Obstructive Sleep Apnea | 1643 | ||
| Musculoskeletal Disease | 1643 | ||
| Gout | 1643 | ||
| Osteoarthritis | 1643 | ||
| Cancer | 1643 | ||
| Genitourinary Disease in Women | 1643 | ||
| Neurologic Disease | 1643 | ||
| Cataracts | 1643 | ||
| Gastrointestinal Disease | 1643 | ||
| Gastroesophageal Reflux Disease | 1643 | ||
| Gallstones | 1643 | ||
| Pancreatitis | 1644 | ||
| Liver Disease | 1644 | ||
| Benefits of Intentional Weight Loss | 1644 | ||
| Effect on Morbidity | 1644 | ||
| Type 2 Diabetes Mellitus | 1644 | ||
| Nonalcoholic Fatty Liver Disease | 1644 | ||
| Dyslipidemia | 1644 | ||
| Hypertension | 1645 | ||
| Cardiovascular Disease | 1645 | ||
| Pulmonary Disease | 1645 | ||
| Reproductive and Urinary Tract Function in Women | 1645 | ||
| Effect on Mortality | 1645 | ||
| Obesity Therapy | 1645 | ||
| Dietary Intervention | 1645 | ||
| Energy Content | 1646 | ||
| Macronutrient Composition | 1646 | ||
| Physical Activity | 1647 | ||
| Metabolic Rate | 1647 | ||
| Body Composition | 1647 | ||
| Diabetes and Coronary Heart Disease | 1647 | ||
| Weight Loss | 1647 | ||
| Behavior Modification | 1647 | ||
| Principles | 1647 | ||
| Effectiveness | 1647 | ||
| Pharmacotherapy | 1648 | ||
| Phentermine | 1648 | ||
| Orlistat | 1648 | ||
| Lorcaserin | 1649 | ||
| Phentermine and Topiramate Extended Release | 1649 | ||
| Diabetes Medications That Cause Weight Loss | 1649 | ||
| Surgical Therapy | 1650 | ||
| Indications | 1650 | ||
| Types of Procedures | 1650 | ||
| Weight Loss | 1651 | ||
| Effect of Bariatric Surgery on Type 2 Diabetes | 1651 | ||
| Selected Complications | 1651 | ||
| Perioperative Mortality and Morbidity. | 1651 | ||
| Postprandial Hypoglycemia. | 1651 | ||
| Treatment Guidelines | 1651 | ||
| References | 1652 | ||
| 37 Disorders of Lipid Metabolism | 1660 | ||
| Key Points | 1660 | ||
| Lipid Biochemistry and Metabolism | 1660 | ||
| Simple and Complex Lipids | 1660 | ||
| Fatty Acids | 1660 | ||
| Triglycerides | 1661 | ||
| Phospholipids | 1661 | ||
| Cholesterol | 1662 | ||
| Fatty Acid Metabolism | 1662 | ||
| Fatty Acid Biosynthesis | 1662 | ||
| Fatty Acid Oxidation | 1662 | ||
| Triglyceride and Phospholipid Metabolism | 1663 | ||
| Lipolysis of Triglyceride Stores in Adipose Tissue | 1663 | ||
| Triglyceride and Phospholipid Synthesis and Tissue Delivery of Lipids | 1663 | ||
| Triglyceride Synthesis. | 1663 | ||
| Phospholipid Synthesis. | 1664 | ||
| Lipoprotein Lipase. | 1664 | ||
| Cholesterol Metabolism | 1664 | ||
| Cholesterol Absorption, Synthesis, and Excretion | 1664 | ||
| Nuclear Receptors and Lipid Metabolism | 1665 | ||
| Plasma Lipoproteins, Apolipoproteins, Receptors, and Other Proteins | 1666 | ||
| Major Lipoproteins | 1666 | ||
| Major Apolipoproteins | 1667 | ||
| Apolipoproteins AI, AII, AIV, and AV | 1667 | ||
| Apolipoprotein B | 1668 | ||
| Apolipoproteins CI, CII, and CIII | 1669 | ||
| Apolipoprotein E | 1669 | ||
| Major Receptors Involved in Lipid Metabolism | 1670 | ||
| Low-Density Lipoprotein Receptor Gene Family | 1670 | ||
| Low-Density Lipoprotein Receptor. | 1671 | ||
| LDL Receptor–Related Protein 1. | 1672 | ||
| Pattern Recognition Receptors | 1672 | ||
| Scavenger Receptors. | 1672 | ||
| Toll-like Receptors. | 1673 | ||
| Other Enzymes and Transfer Proteins Mediating Lipid Metabolism | 1673 | ||
| Hepatic Lipase | 1673 | ||
| Endothelial Lipase | 1673 | ||
| Proprotein Convertase Subtilisin/Kexin Type 9 | 1673 | ||
| Lipoprotein-Associated Phospholipase A2 | 1673 | ||
| Cholesteryl Ester Transfer Protein | 1673 | ||
| Lecithin:Cholesterol Acyltransferase | 1673 | ||
| Integrative Physiology of Lipid Metabolism | 1674 | ||
| Exogenous Lipid Transport | 1674 | ||
| Endogenous Lipid Transport | 1674 | ||
| Reverse Cholesterol Transport and Dysfunctional HDL | 1675 | ||
| Overview of Hyperlipidemia and Dyslipidemia | 1675 | ||
| Hypertriglyceridemia | 1676 | ||
| Fasting Hyperchylomicronemia | 1676 | ||
| Lipoprotein Lipase Deficiency | 1677 | ||
| Postprandial Hyperlipidemia | 1677 | ||
| Diagnostic Evaluation of Severe Hypertriglyceridemia | 1677 | ||
| Moderate Fasting Hypertriglyceridemia Due to Elevated Very Low Density Lipoprotein | 1679 | ||
| Secondary Causes of Hypertriglyceridemia | 1679 | ||
| Diabetes Mellitus. | 1679 | ||
| Renal Failure. | 1679 | ||
| Drugs. | 1680 | ||
| Diet and Alcohol. | 1680 | ||
| Diagnostic Evaluation of Moderate Hypertriglyceridemia | 1680 | ||
| Hypercholesterolemia Without Hypertriglyceridemia | 1680 | ||
| Genetic Familial Hypercholesterolemia | 1680 | ||
| Familial Defective Apolipoprotein B100 | 1681 | ||
| Rare Mutations Associated With Elevated LDL Levels | 1681 | ||
| Elevated Plasma Lipoprotein(a) | 1681 | ||
| Polygenic Hypercholesterolemia | 1681 | ||
| Lipoprotein(X) | 1681 | ||
| Sitosterolemia | 1681 | ||
| Cerebrotendinous Xanthomatosis | 1682 | ||
| Hypothyroidism and Elevated Cholesterol | 1682 | ||
| Diagnostic Evaluation of Isolated Hypercholesterolemia | 1682 | ||
| Increased High-Density Lipoprotein | 1682 | ||
| Genetic Disorders Causing Increased High-Density Lipoprotein | 1682 | ||
| Elevated Triglycerides and Cholesterol | 1682 | ||
| Combined Hyperlipidemia | 1682 | ||
| Familial Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) | 1683 | ||
| Hepatic Lipase Deficiency | 1683 | ||
| Nephrotic Syndrome | 1683 | ||
| Protease Inhibitor Use in Human Immunodeficiency Virus Infection | 1683 | ||
| Immunosuppressive Regimens | 1683 | ||
| Diagnostic Evaluation of Elevated Triglycerides and Cholesterol | 1683 | ||
| Hypocholesterolemia | 1684 | ||
| Familial Hypobetalipoproteinemia | 1684 | ||
| Abetalipoproteinemia | 1684 | ||
| Chylomicron Retention Syndrome | 1684 | ||
| Familial Hypoalphalipoproteinemia | 1684 | ||
| Apolipoprotein AI Mutations | 1684 | ||
| Lecithin:Cholesterol Acyltransferase Deficiency | 1684 | ||
| Adenosine Triphosphate–Binding Cassette Transporter A1 Deficiency | 1684 | ||
| Overview of Atherogenesis | 1685 | ||
| Cholesterol-Induced Atherosclerosis | 1685 | ||
| Unstable Plaque and Regression | 1685 | ||
| Evidence Supporting Treatment of Lipid Disorders | 1685 | ||
| Cholesterol and Cardiovascular Disease | 1685 | ||
| Epidemiologic Evidence | 1686 | ||
| Clinical Trials | 1686 | ||
| Treatment of Lipid Disorders | 1687 | ||
| Rationale for Treating Hyperlipidemia | 1687 | ||
| Approach to the Hyperlipidemic Patient | 1687 | ||
| Physical Examination | 1687 | ||
| Screening for Secondary Disorders | 1688 | ||
| Measurement of Plasma Lipids | 1688 | ||
| Patient Selection and Treatment Goals | 1688 | ||
| Specific Therapies | 1690 | ||
| Lifestyle Treatment | 1690 | ||
| Drug Treatment | 1690 | ||
| HMG-CoA Reductase Inhibitors (Statins). | 1691 | ||
| Bile Acid Sequestrants. | 1693 | ||
| Niacin. | 1693 | ||
| Fibrates. | 1694 | ||
| Ezetimibe. | 1694 | ||
| Omega-3 Fatty Acids. | 1694 | ||
| Combination Therapies | 1694 | ||
| Combination Therapy for Reduction of Low-Density Lipoprotein Cholesterol | 1694 | ||
| Statin Plus Bile Acid Sequestrants. | 1694 | ||
| Statin Plus Ezetimibe. | 1695 | ||
| Statin Plus Niacin. | 1695 | ||
| Bile Acid Sequestrants Plus Niacin. | 1695 | ||
| Ezetimibe Plus Bile Acid Sequestrants. | 1695 | ||
| Three-Drug Combinations. | 1695 | ||
| Four-Drug Combinations. | 1695 | ||
| Combination Therapy for Other Hyperlipidemias | 1695 | ||
| Statin Plus Fibrate. | 1695 | ||
| Other Combinations. | 1695 | ||
| Surgical Treatment and Other Modalities | 1695 | ||
| Specific Disorders and Therapy | 1695 | ||
| Treatment for Chylomicronemia Syndrome. | 1695 | ||
| Treatment for Familial Hypercholesterolemia. | 1695 | ||
| Treatment for Familial Combined Hyperlipidemia. | 1696 | ||
| Treatment for Metabolic Syndrome. | 1696 | ||
| Treatment for Dysbetalipoproteinemia. | 1696 | ||
| Treatment for Elevated Plasma Lipoprotein(a). | 1696 | ||
| Treatment for Low Levels of High-Density Lipoproteins. | 1696 | ||
| Drugs in Development | 1696 | ||
| References | 1696 | ||
| 38 Gastrointestinal Hormones and Gut Endocrine Tumors | 1701 | ||
| Key Points | 1701 | ||
| Endocrine Cell Development in the Pancreas | 1701 | ||
| Endocrine Cell Development in the Intestine | 1703 | ||
| Pancreatic and Gut Hormones | 1703 | ||
| Amylin | 1703 | ||
| Apelin | 1704 | ||
| Calcitonin Gene–Related Peptide | 1704 | ||
| Cholecystokinin | 1704 | ||
| Galanin | 1705 | ||
| Gastric Inhibitory Polypeptide | 1705 | ||
| Gastrin | 1706 | ||
| Gastrin-Releasing Peptide and Related Peptides | 1706 | ||
| Ghrelin | 1706 | ||
| Glucagon, Glucagon-like Peptide 1, and Glucagon-like Peptide 2 | 1707 | ||
| Motilin | 1708 | ||
| Neuropeptide Y | 1708 | ||
| Neurotensin | 1709 | ||
| Pituitary Adenylate Cyclase–Activating Peptide | 1709 | ||
| Peptide YY | 1709 | ||
| Pancreatic Polypeptide | 1710 | ||
| Secretin | 1710 | ||
| Somatostatin | 1710 | ||
| Tachykinins | 1710 | ||
| Thyrotropin-Releasing Hormone | 1711 | ||
| Vasoactive Intestinal Peptide | 1711 | ||
| Miscellaneous Gut Endocrine Peptides | 1711 | ||
| Pancreatic and Gut Endocrine Tumors | 1715 | ||
| Insulinomas | 1716 | ||
| Gastrinoma | 1717 | ||
| Glucagonomas | 1718 | ||
| Somatostatinomas | 1718 | ||
| Vasoactive Intestinal Peptide– Secreting Tumors | 1719 | ||
| Miscellaneous Gut Hormone– Producing Tumors | 1719 | ||
| References | 1719 | ||
| IX Polyendocrine and Neoplastic Disorders | 1723 | ||
| 39 Multiple Endocrine Neoplasia | 1724 | ||
| Key Points | 1724 | ||
| Introduction to Multiple Endocrine Neoplasia Syndromes | 1724 | ||
| Multiple Endocrine Neoplasia Type 1 Syndrome | 1725 | ||
| Tumor Expression and Management | 1725 | ||
| Parathyroid Tumors in Multiple Endocrine Neoplasia Type 1 | 1725 | ||
| Expressions of Parathyroid Tumors. | 1725 | ||
| Management of Parathyroid Tumors | 1726 | ||
| Decision for Surgery. | 1726 | ||
| Preoperative and Intraoperative Assessment of Parathyroid Tumors. | 1727 | ||
| Removal of Parathyroid Tumors. | 1727 | ||
| Pancreaticoduodenal Neuroendocrine Tumors | 1728 | ||
| Gastrinoma | 1728 | ||
| Expressions of Gastrinoma. | 1728 | ||
| Therapy for Gastrinoma. | 1729 | ||
| Insulinoma. | 1729 | ||
| Tumors Secreting Glucagon, Vasoactive Intestinal Peptide, or Other Hormones | 1730 | ||
| Glucagonoma. | 1730 | ||
| VIPoma. | 1730 | ||
| Growth Hormone–Releasing Hormone Oversecretion. | 1730 | ||
| Other Ectopic Hormones. | 1730 | ||
| NonfunctionalTumors. | 1730 | ||
| Staging of Pancreaticoduodenal Neuroendocrine Tumors. | 1730 | ||
| Treatment of Pancreaticoduodenal Neuroendocrine Tumors. | 1731 | ||
| Is Tumor Size Important? | 1731 | ||
| Should All Pancreaticoduodenal Neuroendocrine Tumors in MEN1 Be Removed? | 1731 | ||
| Should Metastatic Pancreaticoduodenal Cancer Be Debulked? | 1731 | ||
| Should Medications Be Used to Control Tumor Progression? | 1731 | ||
| Somatostatin Analogue Linked to a Radioisotope. | 1731 | ||
| Pituitary Tumor or Adrenal Cortical Tumor | 1731 | ||
| Prolactinoma. | 1731 | ||
| Tumors That Produce Growth Hormone or Growth Hormone–Releasing Hormone. | 1731 | ||
| Corticotropin Hypersecretion. | 1731 | ||
| Primary Adrenocortical Hyperfunction. | 1732 | ||
| Foregut Carcinoid Tumors | 1732 | ||
| Miscellaneous Tumors of MEN1 | 1732 | ||
| Miscellaneous Endocrine Tumors in MEN1 | 1732 | ||
| Pheochromocytoma. | 1732 | ||
| Thyroid Follicular Neoplasm. | 1732 | ||
| Miscellaneous Nonendocrine Tumors. | 1732 | ||
| Lipoma. | 1732 | ||
| Angiofibromas. | 1732 | ||
| Collagenoma. | 1732 | ||
| Spinal Cerebellar Ependymoma. | 1733 | ||
| Malignant Melanoma. | 1733 | ||
| Leiomyoma (of Esophagus, Lung, Rectum, or Uterus). | 1733 | ||
| Meningioma (Cranial). | 1733 | ||
| Barrett Esophagus. | 1733 | ||
| MEN1-like Phenotypes | 1733 | ||
| Phenocopies and Differential Diagnosis of Multiple Endocrine Neoplasia Type 1 | 1733 | ||
| Varying Penetrance of Tumors by Tissue or by Age | 1733 | ||
| Familial Variation in Phenotype | 1733 | ||
| Prolactinoma Variant of MEN1 | 1733 | ||
| Isolated Hyperparathyroidism Variant of MEN1 | 1733 | ||
| Sporadic Tumor or Tumors | 1733 | ||
| Familial Isolated Endocrine Tumors Not From the MEN1 Gene | 1734 | ||
| Familial Isolated Hyperparathyroidism. | 1734 | ||
| Familial Isolated Pituitary Tumor. | 1734 | ||
| Other Familial Endocrine Tumors | 1734 | ||
| Isolated Chromaffin Tumor. | 1734 | ||
| Isolated Carcinoid Tumor. | 1734 | ||
| The Normal MEN1 Gene and Normal Menin Protein | 1734 | ||
| Abnormal MEN1 Gene: Tumorigenesis Roles of the MEN1 Gene | 1735 | ||
| Two-Step Inactivation of the MEN1 Gene | 1735 | ||
| Somatic Point Mutations (First Hits) of the MEN1 Gene in Sporadic Tumors. | 1735 | ||
| The First Step (First Hit) Can Be in the Germline or in Somatic Tissue. | 1735 | ||
| The Second Hit in MEN1 Tumorigenesis. | 1735 | ||
| Loss of Heterozygosity About the Locus of the MEN1 Gene. | 1735 | ||
| Hyperplasia and DNA Repair. | 1737 | ||
| MEN1 Mutations and Tumor Phenotypes | 1737 | ||
| Germline Mutation of a Cyclin-Dependent Kinase Inhibitor Gene or Other Gene as a Rare Cause of MEN1 | 1737 | ||
| Testing for Carrier State or for Tumor Emergence in MEN1 | 1737 | ||
| The Carrier of the MEN1 Syndrome | 1737 | ||
| Screening and Counseling for Multiple Endocrine Neoplasia Type 1 | 1737 | ||
| Benefits and Limitations of Carrier Ascertainment | 1738 | ||
| Germline DNA: Mutation or Haplotype Ascertainment | 1738 | ||
| Carrier Ascertainment for Multiple Endocrine Neoplasia Type 1 by Streamlined Surveillance for Tumors: An Alternative to DNA Testing | 1739 | ||
| Periodic Surveillance for Tumors After Proving the MEN1 Carrier State | 1739 | ||
| Multiple Endocrine Neoplasia Type 2 Syndrome | 1739 | ||
| The Molecular Basis for Medullary Thyroid Carcinoma | 1740 | ||
| Structure and Function of the Normal RET Proto-oncogene | 1740 | ||
| Cloning of the RET Proto-oncogene and Its Role in Sporadic and Hereditary Medullary Thyroid Carcinoma | 1740 | ||
| Histopathology of Medullary Thyroid Carcinoma | 1742 | ||
| Clinical Expression and Genotype-Phenotype Correlation of Patients With Sporadic and Hereditary Medullary Thyroid Carcinoma | 1742 | ||
| Sporadic Medullary Thyroid Carcinoma | 1742 | ||
| Hereditary Medullary Thyroid Carcinoma | 1742 | ||
| Classical MEN2A. | 1742 | ||
| MEN2A and Cutaneous Lichen Amyloidosis. | 1743 | ||
| MEN2A and Hirschsprung Disease. | 1743 | ||
| Familial Medullary Thyroid Carcinoma. | 1744 | ||
| MEN2B. | 1744 | ||
| Secretory Products of Medullary Thyroid Carcinoma | 1744 | ||
| Calcitonin | 1744 | ||
| Measurement of Serum Calcitonin. | 1745 | ||
| Carcinoembryonic Antigen | 1745 | ||
| The Clinical Diagnosis of Medullary Thyroid Carcinoma | 1745 | ||
| Fine-Needle Aspiration Biopsy | 1745 | ||
| Measurement of Basal Serum Calcitonin Levels | 1746 | ||
| Direct DNA Analysis to Detect Mutations in the RET Proto-oncogene | 1746 | ||
| Genetic Counseling | 1746 | ||
| The Management of the Tumors Associated With MEN2A and MEN2B | 1747 | ||
| Medullary Thyroid Carcinoma | 1747 | ||
| Prophylactic Thyroidectomy in Children With Hereditary Medullary Thyroid Carcinoma | 1747 | ||
| Prophylactic Thyroidectomy in Children With MEN2A. | 1747 | ||
| Prophylactic Thyroidectomy for Children With MEN2B. | 1748 | ||
| Pheochromocytomas | 1748 | ||
| Hyperparathyroidism | 1749 | ||
| Evaluation of Patients Following Thyroidectomy for Medullary Thyroid Carcinoma | 1750 | ||
| Treatment of Patients With Local or Regional Metastases | 1750 | ||
| Management of Patients With Distant Metastases | 1750 | ||
| Hormonally Active Metastases | 1751 | ||
| Systemic Therapy | 1751 | ||
| References | 1752 | ||
| References | 1761.e1 | ||
| 40 The Immunoendocrinopathy Syndromes | 1762 | ||
| Key Points | 1762 | ||
| Autoimmunity Primer | 1763 | ||
| Natural History of Autoimmune Disorders | 1764 | ||
| Genetic Associations | 1764 | ||
| Environmental Triggers | 1765 | ||
| Development of Organ-Specific Autoimmunity | 1766 | ||
| Failure of Gland | 1766 | ||
| Autoimmune Polyendocrine Syndrome Type I | 1766 | ||
| Clinical Features | 1766 | ||
| Genetics | 1768 | ||
| Diagnosis | 1768 | ||
| Therapy and Follow-up | 1769 | ||
| Autoimmune Polyendocrine Syndrome Type II | 1769 | ||
| Clinical Features | 1769 | ||
| Diagnosis | 1770 | ||
| Therapy | 1770 | ||
| Other Polyendocrine Deficiency Autoimmune Syndromes | 1771 | ||
| Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome | 1771 | ||
| Anti–Insulin Receptor Autoantibodies | 1772 | ||
| POEMS Syndrome | 1772 | ||
| Kearns-Sayre Syndrome | 1772 | ||
| Thymic Tumors | 1772 | ||
| Wolfram Syndrome | 1773 | ||
| Omenn Syndrome | 1773 | ||
| Chromosomal Disorders | 1773 | ||
| Conclusion | 1773 | ||
| References | 1773 | ||
| 41 Endocrinology of HIV/AIDS | 1776 | ||
| Key Points | 1776 | ||
| Adrenal Function | 1776 | ||
| Adrenal Insufficiency | 1777 | ||
| Glucocorticoid Excess: Adrenal Shunting and Cortisol Resistance | 1777 | ||
| Medication Effects | 1777 | ||
| Clinical Assessment | 1777 | ||
| Gonadal Function | 1777 | ||
| Male Gonadal Dysfunction | 1777 | ||
| Female Gonadal Dysfunction | 1779 | ||
| Thyroid Function | 1779 | ||
| Fluid Balance and Electrolytes | 1780 | ||
| Sodium | 1780 | ||
| Potassium | 1780 | ||
| Calcium Homeostasis and Bone Changes | 1780 | ||
| Calcium Homeostasis | 1780 | ||
| Bone Loss: Prevalence, Etiologic Factors, and Treatment Strategies | 1781 | ||
| Bone Metabolism in HIV-Infected Children | 1783 | ||
| Avascular Necrosis of Bone | 1784 | ||
| The Growth Hormone/Insulin-Like Growth Factor 1 Axis | 1784 | ||
| Glucose Homeostasis and Pancreatic Function | 1784 | ||
| Metabolic and Body Composition Changes in HIV-Infected Patients | 1784 | ||
| The AIDS Wasting Syndrome and Loss of Lean Body Mass | 1785 | ||
| Changes in Fat Mass and Distribution | 1785 | ||
| Lipid Abnormalities | 1786 | ||
| Hyperglycemia and Insulin Resistance | 1787 | ||
| Treatment of Metabolic and Body Composition Changes in HIV-Infected Patients | 1788 | ||
| Treatment of AIDS Wasting and Loss of Lean Body Mass | 1788 | ||
| Strategies for Treating Lipoatrophy and Subcutaneous Fat Loss | 1789 | ||
| Treatments for Visceral Fat Accumulation | 1789 | ||
| Insulin-Sensitizing Strategies | 1790 | ||
| Leptin Treatment for Metabolic Dysregulation Among HIV-Infected Patients With Lipoatrophy | 1790 | ||
| Lipid Management | 1790 | ||
| Cardiovascular Disease in HIV-Infected Patients | 1790 | ||
| Strategies for Hyperlipidemia Among HIV-Infected Patients | 1793 | ||
| Anti-inflammatory Strategies for Cardiovascular Disease in HIV | 1793 | ||
| Acknowledgment | 1794 | ||
| References | 1794 | ||
| 42 The Long-Term Endocrine Sequelae of Multimodality Cancer Therapy | 1799 | ||
| Key Points | 1799 | ||
| Growth | 1800 | ||
| The Hypothalamic-Pituitary Axis | 1801 | ||
| Growth Hormone Deficiency | 1802 | ||
| Childhood Growth Hormone Deficiency | 1802 | ||
| Adult Growth Hormone Deficiency | 1803 | ||
| Adult Survivors of Childhood Cancer. | 1803 | ||
| Survivors of Cancer Treated in Adult Life. | 1804 | ||
| The Diagnosis of Radiation-Induced Growth Hormone Deficiency | 1804 | ||
| Growth Hormone Replacement in Adult Cancer Survivors | 1805 | ||
| Cranial Irradiation and Additional Anterior Pituitary Hormone Deficits | 1805 | ||
| Gonadotropins | 1806 | ||
| Adrenocorticotropic Hormone | 1807 | ||
| Thyroid-Stimulating Hormone | 1807 | ||
| Hyperprolactinemia | 1808 | ||
| Gonadal Function | 1808 | ||
| Male Gonadal Function and Cancer Therapy | 1808 | ||
| Radiation and the Testis | 1808 | ||
| Chemotherapy and the Testis | 1809 | ||
| Preservation of Male Fertility and Sex Hormone Replacement | 1810 | ||
| Female Gonadal Function and Cancer Therapy | 1811 | ||
| Radiation and the Female Reproductive Tract | 1811 | ||
| Chemotherapy and the Ovary | 1812 | ||
| Assessment and Preservation of Female Fertility | 1812 | ||
| Radioiodine Therapy and the Gonadal Axis | 1813 | ||
| Primary Thyroid Disease | 1813 | ||
| Thyroid Dysfunction | 1813 | ||
| Hypothyroidism | 1813 | ||
| Hyperthyroidism | 1814 | ||
| Effects of Chemotherapy | 1814 | ||
| Thyroid Nodules | 1814 | ||
| Hyperparathyroidism | 1815 | ||
| Bone Health | 1816 | ||
| Childhood Cancer Survivors | 1816 | ||
| Adult Cancer Survivors | 1817 | ||
| Androgen Deprivation Therapy | 1817 | ||
| Aromatase Inhibitors | 1818 | ||
| The Metabolic Syndrome and Vascular Risk | 1819 | ||
| Bone Marrow Transplantation | 1819 | ||
| Growth and Growth Hormone | 1819 | ||
| Hypopituitarism | 1820 | ||
| Primary Thyroid Disorders | 1820 | ||
| Gonadal Failure | 1821 | ||
| Effects of Chemotherapy-Only Preparatory Regimens | 1821 | ||
| Targeted Therapies | 1822 | ||
| Immune-Modulating Therapies | 1822 | ||
| Monoclonal Antibodies to CTLA4 | 1822 | ||
| Monoclonal Antibodies to PD1 | 1823 | ||
| Tyrosine Kinase Inhibitors | 1823 | ||
| References | 1824 | ||
| 43 Neuroendocrine Gastrointestinal and Lung Tumors (Carcinoid Tumors), the Carcinoid Syndrome, and Related Disorders | 1833 | ||
| Key Points | 1833 | ||
| Phylogenesis and Embryology | 1833 | ||
| Molecular Genetics | 1834 | ||
| Classification | 1834 | ||
| Biochemistry | 1835 | ||
| Clinical Presentation | 1838 | ||
| The Carcinoid Syndrome | 1838 | ||
| Flushing | 1838 | ||
| Diarrhea | 1839 | ||
| Carcinoid Heart Disease | 1840 | ||
| Bronchial Constriction | 1840 | ||
| Other Manifestations of the Carcinoid Syndrome | 1841 | ||
| Carcinoid Crisis | 1841 | ||
| Other Clinical Manifestations of Carcinoid Tumors | 1841 | ||
| Diagnosis | 1841 | ||
| Histopathologic Diagnosis | 1841 | ||
| Biochemical Diagnosis | 1841 | ||
| Localization Procedures | 1843 | ||
| Treatment | 1844 | ||
| Somatostatin Analogues | 1845 | ||
| Interferons | 1846 | ||
| Chemotherapy | 1846 | ||
| Other Agents | 1846 | ||
| Surgery | 1847 | ||
| Irradiation | 1847 | ||
| Prognosis | 1848 | ||
| Other Flushing Disorders | 1848 | ||
| Medullary Thyroid Carcinoma and VIPoma | 1848 | ||
| Mastocytosis and Related Disorders | 1848 | ||
| References | 1849 | ||
| Index | 1855 | ||
| A | 1855 | ||
| B | 1859 | ||
| C | 1861 | ||
| D | 1866 | ||
| E | 1869 | ||
| F | 1872 | ||
| G | 1874 | ||
| H | 1880 | ||
| I | 1885 | ||
| J | 1888 | ||
| K | 1888 | ||
| L | 1888 | ||
| M | 1890 | ||
| N | 1894 | ||
| O | 1895 | ||
| P | 1897 | ||
| Q | 1904 | ||
| R | 1904 | ||
| S | 1905 | ||
| T | 1909 | ||
| U | 1913 | ||
| V | 1914 | ||
| W | 1915 | ||
| X | 1915 | ||
| Y | 1916 | ||
| Z | 1916 | ||
| IBC_Clinical Key | IBC1 |