Yen and Jaffe's Reproductive Endocrinology - E-Book Physiology, Pathophysiology, and Clinical Management

Cover IFC Title Page Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 9th edition Copyright Contributors Preface Anchor 20 Contents Video Contents 1. Neuroendocrinology of Reproduction CENTRAL CONTROL OF REPRODUCTION Neuroendocrinology: The Interface Between Neurobiology and Endocrinology Anatomy of the Reproductive Hypothalamic-Pituitary Axis Hypothalamus Median Eminence Hypophyseal Portal Circulation Pituitary Gland (Hypophysis) Gonadotropin-Releasing Hormone: The Final Common Pathway for the Central Control of Reproduction Gonadotropin-Releasing Hormone Structure Anatomy of Gonadotropin-Releasing Hormone-Secreting Neurons Embryologic Development of the Gonadotropin-Releasing Hormone Neuronal Network Gonadotropin-Releasing Hormone Neuronal Firing and Gonadotropin-Releasing Hormone Secretion Gonadotropin-Releasing Hormone Stimulation of Gonadotrope Cells Neuronal Inputs Into Gonadotropin-Releasing Hormone Neurons Kisspeptin Neurokinin B Endogenous Opioid Peptides Kisspeptin, Neurokinin B, Dynorphin (KNDy) Neurons Gonadotropin-Inhibitory Hormone and RFamide-Related Peptides Gonadotropin-Releasing Hormone Pulse Generator Gonadotropin-Releasing Hormone Secretion During Development and in Adulthood Physiologic Development of Reproductive Neuroendocrine Function Patterns of Pulsatile Gonadotropin-Releasing Hormone Secretion in Adults Feedback Regulation of Gonadotropin-Releasing Hormone and Gonadotropin Secretion Negative Feedback Regulation of Gonadotropin-Releasing Hormone and Gonadotropin Secretion in Women Positive Feedback and the Mid-Cycle Gonadotropin Surge Negative Feedback Regulation of Gonadotropin-Releasing Hormone and Gonadotropin Secretion in Men Kisspeptin and KNDy Neurons as Mediators of Sex Steroid Feedback on Gonadotropin-Releasing Hormone Secretion Selective Regulation of Pituitary Follicle-Stimulating Hormone Secretion Reproductive Neuroendocrine Adaptations in Settings of Reduced Energy Availability, Stress, and Lactation Interface Between Reproductive Neuroendocrine Function and Energy Availability Impact of Stress on Reproductive Neuroendocrine Function Lactation and Reproductive Neuroendocrine Function Sleep Pheromones 2. The Gonadotropin Hormones and Their Receptors1 Protein Structural Attributes Glycosylation Folding and Assembly Gonadotropin Structure-Function Studies Site-Directed Mutagenesis Protein Engineering Gonadotropin Genes and Transcripts Gonadotropin Subunit Genes Gonadotropin Subunit Transcripts Naturally Occurring Mutations Polymorphisms Gonadotropin Expression and Secretion Transcriptional Regulation Posttranslational Regulation (Glycosylation) Regulation of Secretion Gonadotropin Clinical Significance Pathophysiological Expression Diagnostic Applications Therapeutic Preparations Gonadotropin Receptors The Extracellular Domain The Extracellular Loops (EL) The Transmembrane Domains The Carboxyl-Terminus (Ctail) Gonadotropin Receptor Gene Expression and Regulation Genes Transcriptional Regulation Transcripts Posttranscriptional Regulation Folding, Maturation, and Intracellular Trafficking Extragonadal Expression Oligomerization Gonadotropin Receptor Signaling Pathways Canonical Pathways, New Pathways, and Adapter Proteins Biased Agonism Gonadotropin Receptor Clinical Significance Naturally Occurring Mutations Polymorphisms of the Gonadotropin Receptor Genes Homologous Receptors Low Molecular Weight Gonadotropin Receptor Agonists and Antagonists 3. Prolactin in Human Reproduction Introduction Lactotroph Development Prolactin Gene Prolactin Synthesis in Pituitary Lactotrophs Prolactin Synthesis in the Decidua and Other Tissues Prolactin Assays Hook Effect Macroprolactin Heterophilic Antibodies Exogenous Biotin Prolactin Secretion Changes in Prolactin Levels With Age Prolactin Levels During Physiologic Stress Prolactin Levels During the Menstrual Cycle, Pregnancy, and the Postpartum State Regulation of Systemic Prolactin Levels Prolactin Inhibitory Factors Prolactin-Releasing Factors Thyrotropin-Releasing Hormone Vasoactive Intestinal Peptide and Peptide Histidine Methionine Serotonin Opioids Other Neuropeptides and Neurotransmitters Prolactin Actions Prolactin Receptor Prolactin Effects on the Breast Prolactin Effects on Gonadotropin Secretion Prolactin Effects on the Ovary Prolactin Effects on the Testis Prolactin Effects on the Adrenal Cortex Prolactin and the Skeleton Pathological States of Prolactin Deficiency and Excess Prolactin Deficiency Hyperprolactinemia: Causes Physiological Medications Pituitary Systemic Prolactin Receptor Gene Mutations Idiopathic Hyperprolactinemia: Diagnosis Prolactin-Secreting Pituitary Adenomas (Prolactinomas) Epidemiology and Natural History Pathogenesis Pathology Clinical Manifestations Medical Therapy Surgery Other Treatment Modalities (Radiation Therapy and Chemotherapy) Pregnancy and Prolactinomas Prolactin-Secreting Pituitary Adenomas During Preconception and Pregnancy Effects of Dopamine Agonists During Preconception and Pregnancy Management of Patients With Prolactinomas During Preconception and Pregnancy 4. Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction Steroid Hormones: Structure and Nomenclature Organization of Steroidogenic Organs and Cells Acquisition, Storage, and Trafficking of Cholesterol Regulation of Cellular Cholesterol Balance Overview of Steroidogenesis Cholesterol Side-Chain Cleavage Enzyme (P450scc Encoded by CYP11A1) 17α-Hydroxylase/17,20-Lyase (P450c17; CYP17A1) Aromatase (P450aro, CYP19A1) 11β-Hydroxylases (P450c11β and P450c11AS) 21-Hydroxylase (P450c21,CYP21A2) Hydroxysteroid Dehydrogenases and Reductases 3β-Hydroxysteroid Dehydrogenase/Δ5-4-Isomerases 11β-Hydroxysteroid Dehydrogenases: Key Regulators of the Activity of Glucocorticoids 17β-Hydroxysteroid Dehydrogenases: Multiple Enzymes with Specific Biosynthetic and Catabolic Roles 3α- and 20α-Hydroxysteroid Dehydrogenase Activities Δ4-5-Reductases 5α-Reductases Sulfotransferases Steroid Sulfatase UDP-Glucuronosyl Transferases Other Steroid Hormone Metabolic Pathways An Alternative Pathway for Androgen Synthesis 11-Oxyandrogens Estradiol Metabolites Steroid Fatty Acid Esters Steroid 7α-Hydroxylation B-Ring Unsaturated Steroids Vitamin D Synthesis and Metabolism Regulation of Expression of the Steroidogenic Machinery Examples of Extraglandular Steroidogenesis Synthesis of Neurosteroids Steroid Hormone Metabolism in Skin Secretion, Production, and Metabolic Clearance Rates of Steroid Hormones Plasma Steroid Hormone-Binding Proteins Inhibitors of Enzymes Involved in Synthesis or Metabolism of Sex Steroids Inhibitors of CYP11A1 CYP17A1 Inhibitors CYP11B1 Inhibitors CYP19A1 Inhibitors 5α-reductase Inhibitors 3β−Hydroxysteroid Dehydrogenase/Δ5-4-Isomerase Inhibitors Other Enzyme Targets for Reducing Sex Steroid Production Eicosanoids: Other Bioactive Lipids Playing a Role in Reproduction Eicosanoid Structure and Nomenclature Biosynthesis of Eicosanoids Major Products of the COX Pathway: Prostaglandins, Thromboxanes, and Prostacyclin Major Products of the Lipoxygenase Pathway: The Leukotrienes and HETEs Transport and Metabolism of Eicosanoids Pharmacologic Regulation of Eicosanoid Synthesis Eicosanoid Receptors Eicosanoids and Reproduction Eicosanoids and Ovulation Eicosanoids and Corpus Luteum Function and Luteolysis Eicosanoids and Fertilization, Implantation, and Decidualization Eicosanoids and Menstruation and Dysmenorrhea Eicosanoids and Parturition and Preterm Labor Eicosanoids and Ductus Arteriosus Remodeling Eicosanoids and Preeclampsia Eicosanoids in Male Reproduction Other Lipid Mediators: Lysophosphatidic Acid and Sphingosine-1-Phosphate LPA and S1P in Reproductive Function 5. Steroid Hormone Action Steroid Hormone Receptor Structure and the Evolution of Specificity Steroid Hormone Receptor Function Estrogen Receptor Progesterone Receptor Androgen Receptor Glucocorticoid Receptor Mineralocorticoid Receptor General Factors That Influence Steroid Hormone Action Hormone Bioavailability Receptor Expression Ligand-Bound Changes to Receptor Conformation Posttranslational Modifications of the Steroid Hormone Receptors Interaction With DNA Interaction With Coactivators and Corepressors Interaction With Other Transcription Factors Nongenomic Actions of Steroids Signaling via Second Messenger Cascades Summary 6. Growth Factors and Reproduction Ovary Development Growth Factors in Primordial Germ Cell Formation and Migration Ovary Specification Formation of the Ovarian Reserve Ovarian Folliculogenesis Ovarian Follicle Development Cumulus Expansion and Ovulation Formation of the Reproductive Tracts Regression of the Müllerian Ducts Müllerian Duct Development Growth Factors in Uterine Biology Regulation of Uterine Receptivity Embryo Implantation Regulation of Trophoblast Proliferation, Invasion, and Migration Growth Factor Pathways in Male Reproduction Conclusion 7. Neuroendocrine Control of the Menstrual Cycle The Reproductive Axis Neuroendocrine Components of the Reproductive Axis Gonadotropin-Releasing Hormones Pulsatile Secretion of GnRH Neuromodulators of GnRH Secretion Kisspeptin Neurokinin B Endogenous Opioids/Dynorphin KNDy Neurons RFamide-Related Peptides Sleep and Circadian Effects on GnRH Secretion in Women Gonadotropin-Producing Cells of the Pituitary Gonadotropn Isoforms Effect of Obesity Differential Control of LH and FSH Secretion Gonadotropin-Releasing Hormone Autocrine/Paracrine Regulation of Gonadotropins: Activin, Inhibin, and Follistatin Negative Feedback Progesterone Inhibin A and Inhibin B Regulation of Inhibin A and Inhibin B by Gonadotropins.A significant body of data has demonstrated an increase in inhibin B secr... Evidence for an Endocrine Negative Feedback Role for Inhibin A or Inhibin B. Inhibin was initially discovered based on its abili... Activin/Follistatin Gonadotropin Surge Attenuating Factor Pituitary effect of high levels of estrogen.There is ample evidence that high levels of estrogen augment the pituitary response ... Pituitary effect of progesterone.In GnRH-deficient women receiving pulsatile GnRH with or without progesterone indicate that low... Inhibin A augments the effect of high estrogen levels at the pituitary.Inhibin A is elevated in women before ovulation,130,163 a... Pituitary effects of kisspeptin.An emerging body of data suggests that there may be a pituitary role for kisspeptin in addition ... Species Differences in Hypothalamic Input to the Preovulatory Surge The Normal Menstrual Cycle Clinical Characteristics Ovarian Feedback and the Dynamics of GnRH Secretion and Pituitary Responsiveness Follicular Phase Midcycle Surge Luteal Phase Luteal-Follicular Transition Racial Differences in Menstrual Cycle Dynamics and Fertility 8. The Ovarian Life Cycle Introduction Primordial Germ Cells Ovarian Morphogenesis Epigenetic Programming and Germ Cell Development The Follicle and Its Surroundings Critical Genes Expressed During Oocyte Growth Oocyte-Derived Factors and the Control of Follicular Growth and Maturation Growth Differentiation Factor-9 Bone Morphogenetic Protein-15 Granulosa Cells Intercellular Communication Between Granulosa Cells and the Oocyte Granulosa Cells and the Convergence of Multiple Signaling Pathways Granulosa Cell Endocrine Activity Granulosa Cell Phenotypic Heterogeneity Theca Cells Other Steroidogenic Cells in the Ovary Ovarian Stroma Ovarian Surface Epithelium Ovarian Leukocytes and Macrophages Ovarian Innervation, Neurotrophins, and Tachykinins Ovarian Stem Cells Follicular Life Cycle Follicular Growth Oocyte Growth Factors and Pathways Initiating Follicular Growth Formation of Antral Follicles Follicular Recruitment, Selection, and Dominance Endocrine Characteristics of Follicles on the Way to Dominance Ovulation Requirements for Progesterone Requirements for Prostaglandins Requirement for Epidermal Growth Factor-Like Factors Mechanisms of Follicular Rupture Oocyte Maturation Empty Follicle Syndrome Atresia Spontaneous Twinning Spontaneous Ovarian Hyperstimulation Syndrome Role of Luteinizing Hormone in the Corpus Luteum Progesterone as a Luteotropin Luteolysis Rescue of the Corpus Luteum in the Cycle of Conception Luteoma of Pregnancy and Hyperreactio Luteinalis Ovarian Aging and Insufficiency Mechanisms of Natural Ovarian Aging Genetic Loci Influencing the Age at Natural Menopause Defects in Genes on the X Chromosome and Ovarian Function Assessment of Ovarian Reserve and Prediction of Reproductive Age Endocrine Activity of the Postmenopausal Ovary 9. Meiosis, Fertilization, and Preimplantation Embryo Development Introduction Meiosis Overview Meiotic Initiation Prophase I Oocyte Growth Phase Oocyte Meiotic Maturation Prophase I Arrest and Meiotic Resumption Completion of Meiosis I Meiosis II Oocyte Maturation-Associated Changes Sperm Transport Female Reproductive Tract Contributions to Sperm Transport Sperm Interactions With the Female Reproductive Tract Cues That Direct Sperm Migration Sperm Capacitation Sperm Membrane Changes Sperm Ionic Changes Competence for Acrosomal Exocytosis Fertilization Sperm Penetration of Egg Vestments Sperm-Egg Adhesion and Fusion Sperm Incorporation Egg Activation Induction and Regulation of Calcium Oscillations Calcium-Induced Signaling Blocks to Polyspermy Pronucleus Development and Migration Cleavage Stage Development Reprogramming the Embryo Cytoplasm Chromatin Reprogramming and Embryonic Genome Activation Compaction and Blastocyst Development Compaction Morula to Blastocyst Transition Monozygotic Twinning Formation of Distinct Cell Lineages Blastocyst Expansion and Hatching 10. Structure, Function, and Evaluation of the Female Reproductive Tract Structure and Function Ontogeny of the Uterus Role of the WNT Family and Homeobox Genes Steroid Action in the Endometrium Estrogen Receptor Signaling Progesterone Receptor Signaling Paracrine Actions of Steroid Hormones in the Endometrium Steroid Hormone Metabolism in the Endometrium Menstrual Cycle Late Proliferative Phase Early Secretory Phase Midsecretory Phase Premenstrual and Menstrual Phase Menstruation Stem Cells and Telomerase in Endometrial Renewal. Menstruation and cyclic repair of the endometrial lining require both stem cel... Vascular Remodeling and Angiogenesis. Angiogenesis, the formation of new blood vessels from preexisting vessels, rarely occurs w... Extracellular Matrix Remodeling. The biochemical basis for the dramatic structural changes in the endometrium in the perimenstru... Vasoactive Substances. The endothelins are a family of potent vasoconstrictors produced by endothelial cells that act on two typ... Hemostatic and Fibrinolytic Mechanisms. The relative activities of the hemostatic and fibrinolytic systems in the endometrium ar... Secreted Proteins of the Endometrium Glycogen Insulin-Like Growth Factor Binding-Protein One Osteopontin Prolactin Endometrial Preparation for Implantation Early Implantation Events Growth Factors and Cytokines Leukemia Inhibitor Factor (LIF) and IL-11 Epidermal Growth Factor Family of Growth Factors Transforming Growth Factor Beta Family Other Growth Factors Human Chorionic Gonadotropin Prostanoids and Other Lipids Immunology of the Endometrium Leukocytes and Lymphocytes T-Regulatory and TH-17 Cells Regulate Endometrial Receptivity Uterine Natural Killer Cells Innate Lymphoid Cells Regulation of Endometrial Immune Cells Complement System Antimicrobial Peptides Endometrial Microbiome Clinical Evaluation of the Endometrium Endometrial Biopsy Endometrial Receptivity Biomarkers and Clinical Evaluation Global Gene Expression Patterns During the Window of Implantation Inflammatory Conditions and the Endometrium and Reproductive Tract Adenomyosis Inflammation and MicroRNAs Ultrasonography Sonohysterography Hysteroscopy Endometrial Bleeding Endometrium in Advancing Age 11. Endocrinology of Human Pregnancy and Fetal-Placental Neuroendocrine Development Introduction Establishment of Pregnancy Endometrial Receptivity Decidualization of the Endometrial Stroma Implantation Placentation Immune Tolerance of the Conceptus The Placenta as an Endocrine Organ Chorionic Gonadotropin Gonadotropin-Releasing Hormone Activins and Inhibins Corticotrophin-Releasing Hormone POMC Derivatives Thyrotropin-Releasing Hormone Placental Somatotropins Placental lactogen Placental Growth Hormone. Two forms of PGH have been identified in the human placenta, both of which are expressed by the syncyt... Function of PL and PGH. Studies of PL and PGH deficiency have revealed their potential synergistic roles in human pregnancy.158 ... Growth Factors Insulin-like growth factors. The human placenta produces IGF-I, expressed by the syncytiotrophoblast, and IGF-II, expressed by c... Epidermal growth factor family. The epidermal growth factor (EGF) family includes EGF, heparin-binding EGF-like growth factor (H... Vascular endothelial growth factor family. The vascular endothelial growth factor (VEGF) family of peptides comprises VEGF-A (re... Fibroblast growth factor family. Like VEGF, the fibroblast growth factor (FGF) family (comprises 23 members: FGF-1 to -23) of po... Adipokines. Adipokines are factors produced by adipose tissue that affect metabolic homeostasis, satiety, and reproduction. Curr... Steroid Hormones and the Fetal-Placental Unit Progesterone. The human placenta produces large amounts of progesterone throughout pregnancy. It does this mainly by converting ... Estrogens. The principal roles of estrogens in human pregnancy are to stimulate uterine growth and increase uterine blood flow. ... Placental Extracellular Vesicles Cell-Free Fetal DNA Fetal Neuroendocrine Systems Hypothalamic Hormones Gonadotropin-Releasing Hormone Thyrotropin-Releasing Hormone Growth Hormone-Releasing Factor and Somatostatin Corticotropin-Releasing Hormone and Arginine Vasopressin Catecholamine-Dopamine Pituitary Hormones Fetal Pituitary-Adrenal Axis Fetal Pituitary-Gonadal Axis Fetal Pituitary-Thyroid Axis Fetal Pituitary-Growth Hormone Axis Fetal Pituitary-Prolactin Axis Fetal Maturation and the Timing of Parturition Fetal Organ Maturation and Preparation for Extrauterine Life Process of Human Parturition Hormonal Control of Human Parturition Progesterone withdrawal Inflammation and progesterone withdrawal Progestin therapy for Preterm Birth Prevention Estrogen activation Placental CRH Prostaglandins Oxytocin Fetal Lung Maturation Uterine Stretch Evolutionary Perspective 12. The Breast Introduction Structural and Histological Features of the Breast Development of the Breast Estradiol and Testosterone: Dueling Steroids Gynecomastia Lactation and Breastfeeding Prolactin Stimulation of β-Casein Transcription Breastfeeding And Amenorrhea The Effect of Steroid Contraceptives on Lactation and Breastfeeding Suppression of Lactation Induction of Lactation Breastfeeding Reduces the Risk of Endometriosis Breastfeeding Reduces the Risk of Breast Cancer and Ovarian Cancer Breastfeeding Reduces the risk of Developing Diabetes or Cardiovascular Disease Galactorrhea Hormonal Control of Breast Density Breast Cancer Cyclical Mastalgia 13. The Hypothalamo-Pituitary Unit, Testis, and Male Accessory Organs Physiology of the Male Gonadal Axis Overview: Ensemble Nature of Reproductive System Essential Roles of GnRH and Upstream KiSS1 Neurons Differential Control of LH and FSH Secretion GnRH and GnRH Receptors Gonadotropins and Cognate Receptors Testicular Steroidogenesis Aromatization, 5α-Reduction, and Inactivation of Te Progesterone Sex-Steroid Receptors and Sex Hormone-Binding Globulin Androgen Receptor in Testes Estrogen Receptors Progesterone Receptor Sex Hormone-Binding Globulin: Steroid Transporter and Putative Ligand Physiology of Hypothalamo-Pituitary-Testicular Network The Testis Accessory Organs Vas Deferens Epididymis Seminal Vesicles Prostate Gland Spermatogenesis Sertoli Cells Regulation of Male Fertility Decremental Changes in GnRH-LH-Te Axis in Aging 14. Menopause and Aging Epidemiology Premature Ovarian Insufficiency Management of Primary Ovarian Insufficiency Menopausal Transition (Perimenopause) Types of Ovarian Changes Hormonal Changes With Established Menopause Effects on Various Organ Systems Central Nervous System Collagen The Genitourinary Syndrome of Menopause Bone Loss Degenerative Arthritis Cardiovascular Effects Stroke Breast Cancer Decision to Use Estrogen Risk-Benefit Assessment What Are the Real Risks of Hormonal Treatment in Young Healthy Women Endometrial Disease Risk and Other Cancers Hormone Regimens Androgen Therapy Phytoestrogens Use of a Progestogen Tissue Selective Estrogen Complex Aging Telomeres Cellular Senescence Epigenetic Clocks Transcriptomic Aging Functional Genomics of Menopause Deregulated Signaling and Metabolic Changes Somatotrophic Axis Metabolic Changes Adrenal Steroids 15. Male Reproductive Aging Changes in Male Reproductive Function with Age Spermatogenesis and Semen Parameters Serum Estradiol Concentration Serum Gonadotropin Concentration Consequences of Decreased Serum Testosterone Concentrations Bone Body Composition Muscle Strength Physical Function Cardiovascular and Metabolic Risk Energy Cognition Sexual Function Attempts to Reverse the Consequences of Aging by Testosterone Treatment Testosterone Preparations Available for Treatment of Male Hypogonadism Parameters of Improvement Sexual Function Body Composition and Muscle Strength Physical Function Bone Anemia Energy and Mood Cognition Potential Deleterious Consequences of Testosterone Treatment of Elderly Men Prostate Events Erythrocytosis Cardiovascular Risk Sleep Apnea Conclusion 16. Immunology and Reproduction Introduction Basic Immune Principles Innate and Acquired/Adaptive Immune Defense Systems Innate Immunity Acquired/Adaptive Immunity T (Thymus Derived) Cells. In humans, T cells circulate through the thymus, where they gain specific CD markers, antigen specific... B (Bone Marrow Derived) Cells. B cells appear to be educated in the bone marrow prior to exit into the peripheral immune system.... ILC (Innate Lymphoid) Cells. ILCs are the third general class of lymphocytes, sharing transcriptional and cytokine effector prof... Monocytes, Macrophage, and Dendritic Cells. Like other leukocytes, monocytes are derived from bone marrow stem cells. Monocytes ... Other Effector Cells. Neutrophils, eosinophils, and basophils are effector cells with specific importance in innate defense agai... Primary and Secondary Immune Responses. Collaboration between helper T cells and B cells is essential during the generation of p... Complement. The complement cascade is a vital part of innate immunity. It may be useful to compare the complement cascade to a m... Cytokines. The rapidly enlarging and pleiomorphic family of cytokines joins the immunoglobulins and the components of the comple... Basis of Immune Specificity and Immune Cell Education Antigen Presentation The Major Histocompatibility Complex (MHC) Lymphocyte Education The Mucosal Immune System of the Female Reproductive Tract Immunoglobulins in Genital Tract Secretions. Immunoglobulin (Ig) concentrations in the genital tract are dependent on hormonal a... Cytokines in Genital Tract Secretions. Unlike other mucosal tissues, the reproductive tract is characterized by progressive tiss... Cells of the Female Reproductive Tract. Estradiol and progesterone secreted during the menstrual cycle act both directly and ind... Independence of the Secretory and Systemic Immune Systems Alloimmunity and Reproduction The Fetal Allograft Antigen Presentation in the Placenta Immunomodulation and Pregnancy Maintenance Male Contributions to Alloimmunity Alloimmunity and Recurrent Pregnancy Loss (please also see Chapter 28, “Recurrent Pregnancy Loss,” subsection III, “Immunologic ... Autoimmunity and Reproduction Antiphospholipid Antibodies (aPL) Recurrent Pregnancy Loss (RPL) and aPL Infertility and aPL Antithyroid Antibodies (ATA) Pregnancy Loss and ATA Infertility and ATA Autoimmune Ovarian Insufficiency (AOI) Polyglandular Autoimmune Syndrome Type I (Blizzard Syndrome) Polyglandular Autoimmune Syndrome Type II (Schmidt Syndrome) Immune Etiology of Ovarian Insufficiency Antigliadin Antibodies (AGA) (See Chapter 28: Recurrent Pregnancy Loss) Antinuclear Antibodies (ANA) Endometriosis-Associated Immune Responses (see Chapter 27: Endometriosis) Conclusions 17. Differences of Sex Development Introduction Mechanisms of Human Sex Development Sex Determination: Testes or Ovary Sex Differentiation Differences of Sex Development Sex Chromosome DSD Turner Syndrome Presentation and Diagnosis of Turner Syndrome Management of Turner Syndrome Klinefelter Syndrome Presentation and Diagnosis of Klinefelter Syndrome Management of Klinefelter Syndrome 46,XY Differences of Sex Development Etiology and Pathophysiology of Partial or Mixed Gonadal Dysgenesis Presentation and Diagnosis of Gonadal Dysgenesis Management of XY Gonadal Dysgenesis Differential Diagnosis: Testicular Regression Syndrome 46,XY Disorders of Androgen Biosynthesis Congenital Lipoid Adrenal Hyperplasia Presentation and Diagnosis of Congenital Lipoid Adrenal Hyperplasia.Congenital lipoid adrenal hyperplasia (lipoid CAH) usually p... Management of Congenital Lipoid Adrenal Hyperplasia 3β-Hydroxysteroid Dehydrogenase Deficiency 17α-Hydroxylase/17,20-Lyase Deficiency Presentation and Diagnosis of 17α-Hydroxylase/17,20-Lyase Deficiency.Most patients present at puberty with primary amenorrhea, l... Management of 17α-Hydroxylase/17,20-Lyase Deficiency P450 Oxidoreductase Deficiency Presentation and Diagnosis of Oxidoreductase Deficiency 17β-Hydroxysteroid Dehydrogenase Deficiency Presentation and Diagnosis of HSD17B3 Deficiency.In XY individuals with female external genitalia, HSD17B3 deficiency may be dif... Management of HSD17B3 Deficiency.XY patients can be raised as females or males. However, in one study, up to 40% of affected XY ... 5α-Reductase Type 2 Deficiency Presentation and Diagnosis of 5α-Reductase Type 2 Deficiency.In 46,XY infants with mutations in SRD5A2, the degree of ambiguity ... Management of 5α-Reductase Type 2 Deficiency.This autosomal recessive disorder has been described in a number of consanguineous ... “Backdoor” Pathway to Fetal Testicular Androgen Production.An alternative pathway toward androgen synthesis, via the conversion ... Presentation and Diagnosis of Androgen Insensitivity Syndrome.The phenotype of patients with PAIS is extremely heterogeneous. Pa... Presentation and Diagnosis of Leydig Cell Hypoplasia 46,XX Disorders of Sex Development Presentation of 46,XX Testicular Disorders/Differences of Sex Development.In the classic medical literature, individuals with 46... 46,XX Ovotesticular Disorders/Differences of Sex Development Presentation of 46,XX Ovotesticular Disorders/Differences of Sex Development.The majority of patients with ovotesticular DSDs pr... Diagnosis of 46,XX Testicular and 46,XX Ovotesticular Disorders/Differences of Sex Development.In males without genital ambiguit... Management of 46,XX Testicular and Ovotesticular Disorders/Differences in Sex Development.Of primary concern in patients with te... 46,XX Gonadal (Ovarian) Dysgenesis 46,XX Disorders of Sex Differentiation: Androgen Excess Congenital Adrenal Hyperplasia Presentation and Diagnosis of Congenital Adrenal Hyperplasia.XX fetuses typically present at birth with ambiguous genitalia. How... Management of Congenital Adrenal Hyperplasia.Newborns diagnosed with a 21-hydroxylase deficiency should be monitored carefully f... P450 Aromatase Deficiency Presentation and Diagnosis.The initial manifestation of aromatase deficiency is placental, with maternal virilization.237–239 Th... P450 Oxidoreductase Deficiency Maternal Etiologies of Androgen Excess General Management for Patients With Differences of Sex Development Multidisciplinary Approach Diagnosis Gender Assignment Genital Surgery Hormonal Therapy Glucocorticoid Replacement Therapy Mineralocorticoid Replacement Therapy Testosterone Replacement Therapy Estrogen Therapy Disclosure Mental Health Fertility Cancer Patient-Centered Care 18 - Puberty: Gonadarche and Adrenarche Introduction Stages of Pubertal Development, Secular Trends, and Racial and Ethnic Differences in the Onset and Tempo of Puberty Pubertal Staging Secular Trends and Racial and Ethnic Differences in the Onset and Tempo of Puberty Physiology of Puberty Steroidogenesis Activation of Gonadarche Hypothalamic Gonadotropin-­Releasing Hormone Pulse Generator Neurobiology of Gonadarche Fetal Development of the Gonadotropin-­Releasing Hormone Pulse Generator Postnatal Development of Gonadotropin-­Releasing Hormone Pulsatility Nature of the Neurobiological Brake Putative Physiological Control Systems Governing the Timing of Gonadarche Activation and Timing of Adrenarche Genetics and Puberty Genes Factors Modulating the Timing of Puberty Nutrition and Diet Environmental Disruptors Prenatal Influences Adoption or Migration From Developing to Developed Countries Disorders of Puberty Disorders of Early Puberty Treatment of Central Precocious Puberty Nonprogressive Precocious Gonadarche Gonadotropin-­Releasing Hormone-­Independent Precocious Pubertal Development McCune-­Albright Syndrome Estrogen Secretion Unrelated to Tumors Isolated Premature Menarche Premature Thelarche Hypothyroidism Exogenous Hormone Exposures Virilizing Disorders Premature Adrenarche Rett Syndrome 21-­Hydroxylase Deficiency 3β-­Hydroxysteroid Dehydrogenase Deficiency 11β-­Hydroxylase Deficiency Apparent Cortisone Reductase Deficiency Apparent Dehydroepiandrosterone Sulfotransferase Deficiency (PAPSS2). In the adrenal cortex, DHEA can be converted to DHEAS by t... Diagnosis and Treatment of Congenital Adrenal Hyperplasia and Other Disorders of Steroidogenesis Inherited Glucocorticoid Resistance Familial Male-­Limited Precocious Puberty Androgen-­Secreting Tumors Human Chorionic Gonadotropin-­Secreting Tumors Cushing Syndrome Approach to the