Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology

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Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology
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Contributors
Preface
1. Hormones and Perinatal Development
	1. Introduction
	2. Development of Hepatic Metabolic Processes
		2.1 Neonatal Development of Hepatic Gluconeogenesis
		2.2 Neonatal Development of Hepatic Amino Acid Metabolism
		2.3 Applying Neonatal Regulation of Hepatic Enzymes to Generate Functional Hepatocytes for Cell Therapy
	3. Development of the Respiratory System
	4. Postnatal Development of Intestinal Digestion
	5. Conclusions and Future Directions
	Acknowledgments
	References
2. Hormones of Programmed Cell Death
	1. Introduction
	2. Role of Hormones in PCD
	3. Steroids
		3.1 Glucocorticoids
		3.2 Androgens
		3.3 Estrogens
		3.4 Progestogens
	4. Thyroids
	5. Retinoids
	6. Vitamin D3 Derivatives
	7. Tumor Necrosis Factor Superfamily: Death Receptors and Ligands
	8. Conclusions and Future Directions
	References
3. Hypothalamic Releasing Hormones
	1. Corticotropin Releasing Hormone
		1.1 CRH Protein and Gene Structure
		1.2 CRH Receptors
		1.3 CRH–CRH Receptor Interaction and Signaling Pathway
		1.4 Diseases
	2. Thyrotropin-Releasing Hormone
	3. Prolactin-Releasing Factors
	4. Luteinizing Hormone-Releasing Hormone/Gonadotropin-Releasing Hormone
		4.1 Receptors and Signaling
		4.2 Therapeutic Use
	5. Somatostatin (Somatotrophin Release-Inhibiting Factor)
		5.1 Receptors and Signaling
		5.2 Therapeutic Use
	6. Growth Hormone-Releasing Hormone
		6.1 The Gene
		6.2 GH-RH Receptor and GHRH Receptor Gene
		6.3 Signal Transduction
		6.4 Disease and Therapy
	Acknowledgements
	References
4. Neurosteroids: Biosynthesis, Molecular Mechanisms, and Neurophysiological Functions in the Human Brain
	1. Introduction
	2. Biosynthesis of Neurosteroids
	3. Molecular Mechanisms of Neurosteroids
		3.1 Neurosteroid Modulation of GABA-A Receptors
		3.2 Sulfated Neurosteroid Interactions With GABA and Glutamate Receptors
	4. Neurophysiological Functions of Neurosteroids
		4.1 Epilepsy and Neuronal Excitability Disorders
		4.2 Status Epilepticus and Acute Seizures
		4.3 Catamenial Epilepsy and Neuroendocrine Conditions
		4.4 Infantile Spasms and Developmental Conditions
		4.5 Menstrual Mood Disorders
		4.6 Fragile X Syndrome and Genetic Abnormalities
		4.7 Neuronal Injury and Neurotoxicity Conditions
		4.8 Anxiety and Other Psychiatric Conditions
	5. Conclusions and Future Directions
	Acknowledgments
	References
5. Neurotrophins and Neurotrophin Receptors
	1. Introduction
	2. Structures of Neurotrophins and Neurotrophin Receptors
		2.1 Neurotrophins
		2.2 Complex of Neurotrophin With Neurotrophin Receptor
			2.2.1 p75NTR
			2.2.2 TrkA
			2.2.3 p75NTR Interactions With TrkA
	3. Evolution of the Neurotrophin-Signaling System
	4. Biochemical Reactions (Interaction With Receptors, Receptor Activation and Signaling Pathways)
		4.1 p75NTR Signaling
			4.1.1 p75 in Cell Death and Apoptosis: Mature Neurotrophins
			4.1.2 p75 in Cell Death and Apoptosis: Proneurotrophins
			4.1.3 p75 in Cell Survival and Activation of NF-κB
			4.1.4 p75 in Cell Survival and Antioxidative Stress
		4.2 Trk Signaling
			4.2.1 PLC-γ
			4.2.2 PI3K-Akt
			4.2.3 MAPK
	5. Physiologic Functions of the Neurotrophins
		5.1 The Nervous System
			5.1.1 TrkA/NGF Signaling
			5.1.2 TrkB/BDNF/NT4 Signaling
			5.1.3 TrkC-NT3
			5.1.4 Truncated Trks
				5.1.4.1 TrkB-T1
				5.1.4.2 Truncated TrkC
		5.2 Nonnervous System
			5.2.1 Cardiovascular Functions
			5.2.2 Regulation of Energy Balance and Body Weight
	6. Disease and Aging Effects of Neurotrophins
		6.1 Alzheimer Disease
		6.2 Huntington Disease
		6.3 Parkinson Disease
		6.4 Amyotrophic Lateral Sclerosis
		6.5 BDNF Polymorphism and Nervous System Disorders
		6.6 Cancer and Tumor Formation
		6.7 Inflammation, Allergy, and Pain
	7. Conclusions and Future Directions
	Acknowledgments
	References
6. The Pineal as a Gland and Melatonin as a Hormone
	1. Introduction: History of the Hypothesis that the Mammalian Pineal is a Gland and Secretes the Hormone Melatonin
	2. The Pineal Gland as a Neuroendocrine Transducer: Converting a Neural Input to an Endocrine Output
	3. Melatonin: Distribution, Biosynthesis, Metabolism
	4. Melatonin Rhythms: Circadian and Annual
	5. Melatonin as a “Nutritional Supplement”
	6. Aging, Melatonin and Sleep
	References
	Further Reading
7. Anterior Pituitary: Glycoprotein Hormones From Gonadotrope (FSH and LH) and Thyrotrope (TSH) Cells
	1. Introduction
	2. Gene and Protein Structures
		2.1 Ligand Structures
		2.2 Ligand Glycosylation
		2.3 Receptor Structures
	3. Evolution
	4. Regulation of Synthesis and Secretion
		4.1 Gonadotropins
			4.1.1 Regulation by GnRH
			4.1.2 Regulation by Activins and Inhibins
			4.1.3 Regulation by Sex Steroids
		4.2 Thyrotropin
			4.2.1 Regulation by TRH
			4.2.2 Regulation by Thyroid Hormones
			4.2.3 Regulation by Other Factors
	5. Biochemical Reactions
		5.1 Receptor Activation
		5.2 Receptor Oligomerization
	6. Physiologic Functions
		6.1 Gonadotropins
		6.2 Thyrotropin
	7. Hormone Inactivation
	8. Disease and Aging Effects
		8.1 Gonadotropins
		8.2 Thyrotropin
	9. Conclusions and Future Directions
	Funding
	References
8. Anterior Pituitary and Pars Intermedia Space: Corticotrophs (ACTH) and Melanotrophs (α-MSH)
	1. Introduction
	2. POMC-Derived Peptides and Their Receptors: Structure and Processing
		2.1 POMC—Synthesis and Processing
		2.2 Transcriptional Control of the POMC Gene
		2.3 Posttranslational Control of POMC Production
	3. Pituitary Cells Expressing POMC: Corticotrophs and Melanotrophs
		3.1 Corticotrophs and ACTH
			3.1.1 ACTH Release from Corticotrophs: A Key Mediator of the Neuroendocrine Response to Stress
			3.1.2 Corticotroph Development and Anatomy in the Anterior Pituitary Gland
			3.1.3 CRH and Glucocorticoid Control of POMC Expression in Corticotrophs
			3.1.4 Regulation of ACTH Secretion by CRH, AVP, and Glucocorticoids
			3.1.5 CRH and AVP Activate Distinct G Protein–Coupled Receptor Signaling Pathways in Corticotrophs
			3.1.6 Synergy of CRH- and AVP-Stimulated ACTH Secretion
			3.1.7 Electrical Excitability, Calcium Signaling, and the Control of ACTH Secretion
			3.1.8 Glucocorticoid Feedback Inhibition of ACTH Release
	4. Melanotrophs and α-MSH
		4.1 Anatomic Considerations
		4.2 Control of Melanotroph Activity
	5. The Melanocortin Receptors (MCRs), Accessory Proteins (MRAP), and Their Actions
		5.1 MC2R
		5.2 MC1R
		5.3 MC5R
		5.4 MC3R and MC4R
	6. Hormone Inactivation
	7. Disease and Aging Effects
		7.1 Addison Disease—Adrenal Insufficiency
		7.2 Cushing Disease
		7.3 Familial Glucocorticoid Deficiency
		7.4 Changes with Aging
	8. Conclusions and Future Directions
	References
9. Anterior Pituitary: Somatotrophs (GH) and Lactotrophs (PRL)
	1. Introduction
	2. Structure and Regulation
		2.1 The Structure and Regulation of GH and PRL
		2.2 The Structure and Regulation of GH and PRL Receptors
		2.3 GH- and PRL-Binding Proteins
	3. Evolution
		3.1 Evolution of GH and PRL
		3.2 Evolution of GHR and PRLR
	4. Biochemical Reactions
		4.1 Formation of Receptor Complexes
		4.2 Receptor Signaling
	5. The Pituitary Cells Producing GH and PRL
		5.1 Regulation of GH and PRL Secretion: The Importance of the Hypothalamic–Pituitary Relationship
		5.2 Regulation of GH Secretion
			5.2.1 Hypothalamic Regulation of Pituitary GH Secretion
			5.2.2 Regulation of GH Release by Nutritional Status and Metabolic Factors
			5.2.3 Feedback Regulation of GH Secretion
		5.3 Regulation of PRL Secretion
			5.3.1 Dopamine Is the Primary Inhibitor of PRL Secretion
			5.3.2 Other Factors Regulating PRL Secretion
			5.3.3 Short Loop Feedback Regulation of PRL
		5.4 Regulation of GH and PRL Secretion at the Level of the Pituitary
	6. Physiologic Functions of GH and PRL
		6.1 The Pattern of GH Secretion and Its Physiologic Consequences
		6.2 Changes in GH Secretion Across the Lifespan
		6.3 Physiologic Modifications of GH Secretion
			6.3.1 Gonadal Steroids
			6.3.2 Sleep
			6.3.3 Stress
			6.3.4 Pregnancy and Lactation
		6.4 Changes in PRL Secretion Across the Lifespan
		6.5 Physiologic Modifications of PRL Secretion
			6.5.1 PRL secretion in Pregnant and Lactating Rodents
			6.5.2 PRL Secretion in Pregnant and Lactating Women
		6.6 GH and PRL in Circulation
		6.7 The Physiologic Functions of GH
			6.7.1 Skeletal Growth and Bone Metabolism
			6.7.2 Metabolism
			6.7.3 Protein Metabolism
			6.7.4 Fat Metabolism
			6.7.5 Carbohydrate Metabolism
			6.7.6 Interaction With Insulin and Secretion
			6.7.7 Electrolyte/Fluid Homeostasis
		6.8 The Physiologic Functions of PRL
			6.8.1 Mammary Gland Regulation
			6.8.2 Pregnancy
			6.8.3 Reproductive Behavior
			6.8.4 Regulation of Hypothalamic Neurones
			6.8.5 Effects on Metabolism
	7. Disorders of the GH and PRL Axes
		7.1 Hormone Deficiency
		7.2 Congenital Causes of GH and PRL Deficiency
		7.3 Acquired GH and PRL Deficiency
		7.4 Consequences of GH and PRL Deficiency
		7.5 Hormone Excess
		7.6 Consequences of GH Excess
		7.7 Consequences of PRL Excess
	8. Conclusions
	References
10. Posterior Pituitary Hormones
	1. Introduction
	2. Evolution of Neurohypophyseal Hormones
	3. The Structure and Synthesis of Neurohypophyseal Hormones
		3.1 Peptide Structure
		3.2 Gene Structure
		3.3 Synthesis of Vasopressin
		3.4 Synthesis of Oxytocin
		3.5 Distribution of Oxytocin- and Vasopressin-Synthesizing Neurons in the Brain
	4. The Oxytocin/Vasopressin Receptor Family
		4.1 Oxytocin Receptor
		4.2 Vasopressin Receptors
	5. Physiologic Functions and Behavior
		5.1 Oxytocin
			5.1.1 Oxytocin in Reproduction
			5.1.2 Oxytocin in Cardiac Function
			5.1.3 Oxytocin in Fluid Balance
			5.1.4 Oxytocin Neurocircuitry and Behavior
				5.1.4.1 Reproductive Behavior
				5.1.4.2 Parental Care
				5.1.4.3 Social Behavior
				5.1.4.4 Stress Responsivity and Anxiety-Like Behavior
				5.1.4.5 Osmoregulatory Behavior
				5.1.4.6 Feeding Behavior
		5.2 Vasopressin
			5.2.1 Vasopressin in Water Balance
			5.2.2 Vasopressin in Vasoregulation
			5.2.3 Vasopressin Neurocircuitry and Behavior
				5.2.3.1 Reproductive Behavior
				5.2.3.2 Parental Care
				5.2.3.3 Social Behavior
				5.2.3.4 Stress Reactivity
	6. Disease and Aging
		6.1 Neurohypophyseal Hormones and Disease
		6.2 Metabolic Disorders
		6.3 Cardiovascular Disease
		6.4 Neurodevelopmental Disorders
		6.5 Neuropsychiatric Disorders
		6.6 Neurodegenerative Disorders
		6.7 Neurohypophyseal Hormones and Aging
	7. Conclusions and Future Directions
	Acknowledgments
	References
11. Hormones and the Regulation of Neuronal Voltage-Sensing Ion Channels
	1. Introduction
	2. Ion Channels
	3. Hormones and Neuronal Ion Channel Regulation
		3.1 Peripheral Hormones
			3.1.1 Leptin
			3.1.2 Insulin
			3.1.3 Ghrelin
			3.1.4 Prolactin
		3.2 Neurohormones
			3.2.1 TRH
			3.2.2 Oxytocin and Vasopressin
	4. Concluding Remarks
	References
12. Hormonal Regulation of Epithelial Sodium Channel (ENaC) and Other Nonneuronal Epithelial Ion Channels
	1. The Epithelium
	2. Structure of ENaC Channel
		2.1 Amiloride Inhibitor and ENaC Current
		2.2 Regulation of ENaC Mainly by Aldosterone and Other Hormones
		2.3 Bradykinin
		2.4 Endothelin
	3. Renal Outer Medullary K+ (ROMK or Kir1) Channel
	4. Potassium Channels Activated by Calcium, BK Channel (Maxi-K Channel)
		4.1 Magnesium Channels (TRPM6 and TRPM7)
	5. Epithelial Basolateral Na+/K+ ATPase Pump
	6. Apical Brush Border Renal Phosphate Channels (SLC34 Transporters, NPT2 and NPT3)
		6.1 Parathyroid Hormone
		6.2 Fibroblast Growth Factor 23
	7. Aquaporins
	8. TRPV Epithelial Calcium Transport Channels (TRPV5 and TRPV6)
	9. Chloride Transport, Cystic Fibrosis Transmembrane Conductance Regulator
	10. Pendrin, Apical Iodide Transporting Channel in Thyroid Follicular Cell (Thyrocyte)
		10.1 Aldosterone
	11. Sodium/Iodide Transporter
	12. MDR, Multidrug Resistance Channel, P-glycoprotein
	References
	Further Reading
13. Thymosins
	1. Structures of Thymosin Proteins
		1.1 Structures of Uncomplexed Thymosin Proteins
			1.1.1 Prothymosin-α (ProTα), Parathymosin, and α-Thymosin-1 (Tα1)
			1.1.2 Beta Thymosin Proteins
				1.1.2.1 Thymosin Beta 4
				1.1.2.2 Thymosin Beta 9 and Beta 10
		1.2 Structures of Thymosin Proteins in Complexes and Chimeras
			1.2.1 Structures of Alpha Thymosins in Complexes
			1.2.2 Structures of Beta Thymosins in Complexes and Chimeras
	2. Evolution of Thymosin Proteins
	3. Biochemical Reactions
		3.1 Alpha Thymosins
		3.2 Beta Thymosins
	4. Thymosins and Disease
		4.1 Thymosins and Fibrosis
		4.2 Thymosin and Viruses
			4.2.1 HIV
			4.2.2 Chronic Hepatitis
		4.3 Thymosins and Vaccines
		4.4 Thymosins and Stroke
		4.5 Thymosins and Cancer
		4.6 Thymosin and Liver
		4.7 Cardiology
		4.8 Sepsis
	5. Conclusions and Future
	References
	Further Reading
14. Heart Hormones
	1. Introduction
	2. Natriuretic Peptides
		2.1 Cardiac NPs
		2.2 Evolution of NPs
		2.3 NP Receptors
		2.4 Structure of NPs
	3. Physiologic Functions of NPs
		3.1 Secretion of ANP
		3.2 Clearance and Degradation of NPs
		3.3 NPs Inhibit Cardiac Hypertrophy
		3.4 NPs Regulate Cardiomyocyte Proliferation
		3.5 NPs Inhibit Cardiac Fibrosis
		3.6 NPs Decrease Blood Pressure
		3.7 NPs Regulate Metabolism
		3.8 NPs Control Satiety
	4. Pathologic Functions of NPs
		4.1 NP Secretion in Pathologic Conditions
		4.2 NPs Suppress Inflammation
		4.3 NPs Suppress Cardiovascular Diseases
		4.4 NPs Affect Metabolic Diseases
		4.5 NPs as Biomarkers
		4.6 NPs as Therapeutic Targets
	5. Other Cardiomyokines
		5.1 Follistatin-Like 1
		5.2 Secreted Phospholipase A2
		5.3 Fibroblast Growth Factors
		5.4 Others
	6. Conclusions and Future Directions
	References
15. Stomach Hormones
	1. Gastric Cells Producing Signal Substances
	2. Methods for Identifying Cells Producing Signal Substances
	3. Types of “Endocrine” Cells in the Gastric Mucosa, Their Localization and Distribution
	4. The EC Cell and 5-Hydroxytrypatamine (5-HT) (Serotonin)
	5. The D Cell and Somatostatin
	6. The G Cell and Its Regulation
	7. The ECL Cell
	8. Gastrin
		8.1 History
		8.2 Structure
		8.3 Physiology
		8.4 Role in Disease
	9. A-Like Cells and Ghrelin/Obestatin
		9.1 History
		9.2 Structure
		9.3 Physiology
		9.4 Obestatin
	10. Neural Influence on Gastric Secretory and Signal-Producing Cells
	11. Conclusion
	References
16. Intestinal Hormones
	1. Overview of the Intestinal Hormones
	2. The Intestinal Enteroendocrine Cells and the Enteroendocrine System
	3. The Main Intestinal Hormones
		3.1 Secretin
		3.2 Cholecystokinin
		3.3 Neurotensin
		3.4 Peptide YY3−36
		3.5 Incretins
			3.5.1 Glucose-Dependent Insulinotropic Peptide
			3.5.2 Glucagon-Like Peptide 1
		3.6 Glucagon-Like Peptide 2
		3.7 Oxyntomodulin
	4. The Paradigm of Coevolution of Glucagon-Like Receptors and Their Ligands
	5. The Glucagon-Like Peptide-1 Receptor
	6. The Glucagon-Like Peptide-1 Receptor Ligands
	7. Intestinal Hormones in the Pathogenesis of T2D
	8. Intestinal Hormones in the Treatment of T2D
	9. Intestinal Hormones in the Pathogenesis of Obesity
	10. Intestinal Hormones in the Treatment of Obesity
	11. Conclusions and Future Directions
	References
	Further Reading
17. Pancreatic Hormones
	1. The Endocrine Pancreas
		1.1 History
		1.2 Evolution of the Endocrine Pancreas
		1.3 Developmental Aspects
		1.4 Cellular Architecture of the Islets of Langerhans
	2. Insulin
		2.1 History
		2.2 Structure of Insulin
		2.3 Biosynthesis, Processing, and Secretion
		2.4 Insulin Clearance and Inactivation
		2.5 The Insulin Receptor and Its Apo Structure
		2.6 Mechanism of Insulin Receptor Binding
		2.7 Structure of the Site 1 Insulin Receptor Complex
		2.8 Structure of the Insulin Receptor Kinase and Mechanism of Activation
		2.9 Insulin Intracellular Signaling Pathways
		2.10 Pathophysiologic and Clinical Implications of Insulin Signaling
	3. Glucagon
		3.1 History
		3.2 Amino Acid Sequence, Evolution, and Structure
		3.3 Biosynthesis and Processing
		3.4 The Glucagon Receptor
		3.5 Glucagon Receptor Inactivation and Mutations
		3.6 Glucagon Receptor Signaling Pathways and Endpoint Metabolic Effects
		3.7 Control of Secretion
		3.8 Physiologic Functions
		3.9 Pathophysiologic and Therapeutic Implications for Diabetes Mellitus and Obesity
	4. Other Pancreatic Hormones
		4.1 Somatostatin
			4.1.1 History
			4.1.2 Amino Acid Sequence, Evolution, and Structure (Ando, 2016)
			4.1.3 Biosynthesis and Processing (Ando, 2016)
			4.1.4 Somatostatin Receptors and Signaling Pathways
			4.1.5 Physiologic Actions (Huang, 1997; Ando, 2016)
			4.1.6 Pathophysiologic and Therapeutic Implications (Ando, 2016)
		4.2 Pancreatic Polypeptide (Williams, 2014)
			4.2.1 History
			4.2.2 Amino Acid Sequence, Evolution, and Structure
			4.2.3 Biosynthesis, Processing, and Secretion
			4.2.4 PP Receptors and Signaling Pathways
			4.2.5 PP Receptors Inactivation
			4.2.6 Physiologic Actions
			4.2.7 Pathophysiologic and Therapeutic Implications
		4.3 Amylin
			4.3.1 History
			4.3.2 Amino Acid Sequence and Structure
			4.3.3 Biosynthesis, Processing, and Secretion (Ogoshi, 2016)
			4.3.4 The Amylin Receptor and Signaling Pathways (Ogoshi, 2016)
			4.3.5 Physiologic Functions
		4.4 Ghrelin
		4.5 Urocortin III
		4.6 Stanniocalcin 2
		4.7 Serotonin-Producing Enterochromaffin Cells and Gastrin-Producing G Cells
		4.8 Gamma-Aminobutyric Acid (GABA) Production by β cells (Braun et al., 2010)
	5. Conclusions and Perspectives
	Acknowledgments
	References
18. Liver Hormones
	1. Angiotensinogen
		1.1 Structure
		1.2 Evolution
		1.3 Biochemical Reactions
		1.4 Physiological Functions
		1.5 Mouse Models with Altered AGT Expression
		1.6 AGT in Human Disease
		1.7 Conclusions and Clinical Applications
	2. Hepcidin
		2.1 Structure
		2.2 Evolution
		2.3 Biochemical Reactions
		2.4 Physiological Functions
		2.5 Hormone Inactivation
			2.5.1 Hereditary Hemochromatosis
			2.5.2 Iron-Loading Anemias
			2.5.3 Chronic Liver Diseases
		2.6 Hormone Hyperactivation
			2.6.1 Anemias with Iron-Restricted Erythropoiesis
			2.6.2 Chronic Liver Diseases
		2.7 Conclusions and Clinical Applications
	3. Insulin-Like Growth Factors
		3.1 Structure
		3.2 Evolution
		3.3 Biochemical Reactions
		3.4 Physiological Functions
		3.5 Hormone Inactivation
			3.5.1 Growth Disorders
			3.5.2 Metabolic Disorders
		3.6 Hormone Hyperactivation
			3.6.1 Acromegaly
			3.6.2 Cancer
		3.7 Conclusions and Clinical Applications
	4. Thrombopoietin
		4.1 Structure
		4.2 Evolution
		4.3 Biochemical Reactions
		4.4 Physiological Functions
		4.5 Hormone Inactivation
			4.5.1 Congenital Amegakaryocytic Thrombocytopenia
			4.5.2 Thrombocytopenia in Liver Disease
			4.5.3 Exogenous TPO-Induced Immune Thrombocytopenia
		4.6 Hormone Hyperactivation
			4.6.1 Congenital Thrombocythemia
			4.6.2 Myeloproliferative Neoplasms
		4.7 Conclusions and Clinical Applications
	References
19. The Endocrine Kidney: Local and Systemic Actions of Renal Hormones
	1. Introduction
	2. Renin-Angiotensin System
		2.1 Angiotensin II-Activated Cellular Signaling
		2.2 Adverse Effects of AngII in Chronic Kidney Disease
	3. Vasoconstrictors: Endothelin-1 and Urotensin II
		3.1 Endothelin-1
			3.1.1 Endothelin Receptors and Signaling Mechanisms
			3.1.2 Modulators of ET-1
			3.1.3 Actions of ET-1
			3.1.4 Endothelin-Enhanced H+ excretion
			3.1.5 Endothelin-I in Chronic Kidney Diseases
		3.2 Urotensin II
			3.2.1 Ca2+-Mediated UII Signaling
			3.2.2 Urotensin II in Chronic Diseases
	4. The Natriuretic Peptides: ANP, BNP, and Urodilatin
		4.1 Natriuretic Peptide Signaling
		4.2 Renal Actions of Natriuretic Peptides
		4.3 Natriuretic Peptides: Potential Interventions for Heart Failure Management
	5. Calcitonin Gene-Related Peptides: Adrenomedullin and Intermedin
		5.1 Adrenomedullin
			5.1.1 Adrenomedullin Signaling Mechanisms
			5.1.2 Physiologic Actions of Adrenomedullin
			5.1.3 Renoprotective Mechanisms of Adrenomedullin
			5.1.4 Antihypertensive Actions of Adrenomedullin
		5.2 Intermedin
			5.2.1 Physiologic Effects of Intermedin
			5.2.2 Intermedin's Actions Against Renal and Cardiovascular Disease
	6. Calcitriol and Ca2+ Metabolism
		6.1 Regulation of Calcitriol Activity
		6.2 FGF23-Klotho
		6.3 Calcitriol in Renal Disease
		6.4 Estrogen Replacement and Calcitriol
	7. Erythropoietin
		7.1 O2 regulation of Renal Erythropoietin Production
		7.2 Erythropoietin: Renoprotective Hormone?
	8. Summary
	Acknowledgments
	References
20. Adipocyte-Derived Hormones
	1. Introduction
	2. Leptin
		2.1 Leptin Structure
		2.2 Leptin Signaling and Metabolic Function
		2.3 Other Functions of Leptin
		2.4 Leptin and Cancer
		2.5 Future of Leptin
	3. Adiponectin
		3.1 Adiponectin Structure
		3.2 Adiponectin Signaling
		3.3 Adiponectin Functions
	4. Resistin
		4.1 Background on Resistin/FIZZ3/ADSF
		4.2 Resistin Structure
		4.3 Complexities of Resistin Expression
		4.4 Resistin Signaling
		4.5 Physiological and Pathologic Roles of Resistin
		4.6 Conclusions and Future Directions of Resistin Research
	5. Future Outlook for Adipokines and Adipose Tissue Secreted Factors
	Acknowledgments
	References
21. Thyroid Hormones
	1. Introduction
		1.1 Structure and Synthesis of Thyroid Hormone
		1.2 Evolution of Thyroid Hormone
		1.3 Thyroid Hormone Transport
		1.4 Thyroid Hormone Receptors
		1.5 TH/THR Signaling Pathways and Mechanisms
		1.6 Physiological Actions Development and Tissue-Specific Expression of THR
		1.7 Regulation of Thyroid Hormone Metabolism
		1.8 Functional Thyroid Diseases, Clinical Manifestations, and Pathophysiology
		1.9 Changes in the Thyroid and Thyroid Function with Age
		1.10 Conclusions and Future Directions
	Acknowledgments
	References
22. Parathyroid Hormones
	1. Introduction
	2. Structures
		2.1 Parathyroid Hormone
			2.1.1 PTH Synthesis and Secretion from Parathyroid Glands
			2.1.2 PTH Regulation by Serum Calcium and Phosphate Homeostasis
			2.1.3 PTH Regulation by Magnesium Homeostasis
			2.1.4 PTH Regulation by Fluoride
			2.1.5 PTH Regulation by Vitamin D
			2.1.6 PTH Regulation by FGF23
			2.1.7 Other PTH Fragments
			2.1.8 PTH Mutations
				2.1.8.1 Hyperparathyroidism
				2.1.8.2 Hypoparathyroidism
		2.2 PTH Receptors
			2.2.1 PTH/PTHrP Receptor 1
				2.2.1.1 PTH/PTHrP Receptor 1 Expression
				2.2.1.2 PTH/PTHrP Receptor 1 Mutations
					2.2.1.2.1 Loss of Function Mutations
					2.2.1.2.2 Gain of Function Mutations
			2.2.2 PTH Receptor 2
	3. Biochemical Reactions
		3.1 Interaction of the Hormones/Receptor
		3.2 Signaling Pathways Activated by PTHR1
			3.2.1 Canonical G Protein–Dependent Pathways
			3.2.2 PTHR1 and Epigenetic Regulation
			3.2.3 Β-Arrestin Pathway
			3.3.1 Wnt Pathway
	4. Physiologic Function of PTH
		4.1 PTH in Calcium/Phosphate/Vitamin D Homeostasis
		4.2 PTH and FGF23
		4.3 PTH and Bone Remodeling
			4.3.1 Anabolic Action of PTH
			4.3.2 Catabolic Action of PTH
				4.3.2.1 OPG/RANKL Balance
				4.3.2.2 Monocyte Chemoattractant Protein-1 (MCP1)
	5. Conclusions and Future Directions
	References
23. Hormones and Hormone Precursors of the Skin
	1. Introduction
	2. Skin Function and Anatomy
	3. Hormones Produced in the Skin
		3.1 Vitamin D
			3.1.1 Evolution and Vitamin D
			3.1.2 Structure and Synthesis of Vitamin D
			3.1.3 Structure of VDR
			3.1.4 Biochemical Reactions (VDR Activation and Signaling)
				3.1.4.1 Genomic Actions of VDR
				3.1.4.2 Nongenomic Actions of VDR
			3.1.5 Vitamin D Signaling in Physiology and Pathophysiology
				3.1.5.1 VDR Signaling in Skin
				3.1.5.2 Skeletal Effects of Vitamin D
				3.1.5.3 Nonskeletal Effects of Vitamin D
			3.1.6 Hormone Inactivation
			3.1.7 Vitamin D and Aging
		3.2 HPA Axis Equivalent of the Skin
			3.2.1 Expression of HPA Axis Hormones in the Skin
			3.2.2 Skin HPA Axis and UV
		3.3 Steroid Regulation of the Skin
			3.3.1 Sex Steroids
				3.3.1.1 Androgens in the Skin
				3.3.1.2 Estrogens in the Skin
			3.3.2 Corticosteroids in the Skin
	4. Skin Hormones in Dermatology
		4.1 Acne
		4.2 Rosacea
		4.3 Atopic Dermatitis
		4.4 Alopecia
		4.5 Psoriasis
		4.6 Skin Cancer
	5. Future Directions
	References
24. Hormones of the Testes
	1. Steroid Hormones
	2. Testicular Steroidogenesis
	3. Secretion and Transport of Testicular Steroids
		3.1 Associating Proteins
	4. Testosterone is a Direct Precursor for Other Bioactive Steroids: DHT and Estrogen
	5. Metabolism of Testicular Steroids
	6. Function: Testosterone and DHT Receptors: Crosstalk of Genomic and Nongenomic Mechanisms
	7. Testicular Protein and Peptide Hormones: Inhibin, Activin, and Follistatin
	References
25. Ovarian Hormones
	1. Introduction
		1.1 Age-Related Changes in Ovarian Hormones
	2. Estradiol
		2.1 Structure
		2.2 Synthesis
			2.2.1 Aromatase
			2.2.2 Estradiol Is Produced in Incomplete Synthesis Pathways
			2.2.3 Regulation of Estradiol Synthesis
		2.3 Estradiol Receptor and Signaling
			2.3.1 Membrane Estrogen Receptors
		2.4 Physiological Effects of Ovarian Estrogens
			2.4.1 Ovarian Effects
			2.4.2 Estradiol Guards the Embryo in the Oviduct
			2.4.3 Estradiol Effects on the Uterus
			2.4.4 Estradiol Regulation of the Mammary Gland
			2.4.5 Effects of Estradiol on LH Secretion
			2.4.6 Nonreproductive Effects of Estradiol
	3. Progesterone
		3.1 Structure and Synthesis
			3.1.1 Hormonal Regulation
		3.2 Progesterone Receptor and Signaling
			3.2.1 Membrane Progesterone Receptors
		3.3 Physiological Effects of Progesterone
			3.3.1 Autoregulation of Ovarian Function by Progesterone
			3.3.2 The Fallopian Tube
			3.3.3 Progesterone Effects in the Uterus
			3.3.4 Progesterone Regulation of the Mammary Gland
			3.3.5 Effects of Progesterone on LH Secretion
			3.3.6 Nonreproductive Effects of Progesterone in the Brain
	4. Conclusions
	Acknowledgments
	References
26. Muscle Hormones
	1. Introduction
	2. Interleukin-6
		2.1 Structure of IL-6 and Its Receptor Complex
		2.2 Biochemical Reactions of IL-6: Signaling and Secretion
			2.2.1 Mechanisms of Signal Transduction Induced by IL-6
			2.2.2 IL-6 Signaling in Skeletal Muscle
			2.2.3 IL-6 Production and Secretion by Muscle Cells
		2.3 Physiological Functions of IL-6: Muscle IL-6 in Health and Disease
			2.3.1 Muscle IL6 Physiology and Effects in Skeletal Muscle
			2.3.2 Effects of Muscle IL-6 in Adipose Tissue
			2.3.3 Effects of Muscle IL-6 in Brain
			2.3.4 Effects of Muscle IL-6 on Liver Glucose Homeostasis
			2.3.5 Effects of Muscle IL-6 in Pancreas: More About Glucose Homeostasis
			2.3.6 IL-6 as an Antiinflammatory Myokine
			2.3.7 Muscle IL-6 in Health and Disease, Cancer, and Beyond
	3. Irisin
		3.1 Structure of Irisin
		3.2 Biochemical Reactions of Irisin: Signaling and Secretion
		3.3 Physiological Functions of Irisin and Their Relation With Health and Disease
			3.3.1 Effects of Irisin in Skeletal Muscle
			3.3.2 Effects of Irisin in Adipose Tissues
			3.3.3 Effects of Irisin in Bone
			3.3.4 Effects of Irisin in Brain and Cognitive Function
			3.3.5 Effects of Irisin in Liver
			3.3.6 Effects of Irisin in Pancreas
			3.3.7 Antiinflammatory Effects of Irisin
			3.3.8 Irisin Effects on Disease and Aging
	4. Other Myokines
	5. Conclusions and Future Directions
	References
27. Hormones From Bone
	1. Confirmed Bone-Derived Endocrine Hormones
		1.1 Fibroblast Growth Factor-23
			1.1.1 Structures
			1.1.2 Evolution
			1.1.3 Biochemical Reactions
			1.1.4 Physiologic Functions
			1.1.5 Hormone Inactivation
			1.1.6 Disease and Aging Effects
				1.1.6.1 Inherited Loss-of-Function Disorders
				1.1.6.2 Inherited Gain-of-Function Disorders
				1.1.6.3 Tumor-Induced Osteomalacia
				1.1.6.4 Renal Failure
				1.1.6.5 Cardiovascular Disease
				1.1.6.6 Aging
		1.2 Osteocalcin
			1.2.1 Structures
			1.2.2 Evolution
			1.2.3 Biochemical Reactions
			1.2.4 Physiologic Functions
			1.2.5 Hormone Inactivation
			1.2.6 Disease and Aging Effects
	2. Bone-Derived Paracrine Factors That Reach the Circulation
		2.1 Sclerostin
		2.2 RANK-L
	3. Bone-Derived Paracrine Factors That Are Hormones When Produced Elsewhere
		3.1 IGF-I and II
		3.2 Parathyroid Hormone-Related Protein
		3.3 Prostaglandins
		3.4 Calcitriol
	4. Conclusions and Future Directions
	References
28. Adrenal Cortex Hormones
	1. Adrenal Glands: Anatomy and Histology
	2. Biosynthesis of Adrenal Cortex Hormones
	3. Evolution of Adrenal Cortex Hormone Receptors
	4. Glucocorticoids
		4.1 Regulation of Glucocorticoid Secretion
		4.2 Glucocorticoid Receptor
		4.3 Glucocorticoid Signaling
	5. Mineralocorticoids
		5.1 Regulation of Mineralocorticoid Secretion
		5.2 Mineralocorticoid Receptor
		5.3 Mineralocorticoid Signaling
	6. Adrenal Androgens
	7. Clinical Implications
		7.1 Adrenal Insufficiency
		7.2 Congenital Adrenal Hyperplasia
		7.3 Primary Generalized Glucocorticoid Resistance (Chrousos Syndrome)
		7.4 Mineralocorticoid Resistance
	8. Conclusions and Future Directions
	References
	Further Reading
29. Adrenal Medulla Hormones
	1. Anatomy and Functional Organization of the Adrenal Medulla
		1.1 General Organization of the Adrenal Medulla
		1.2 Blood Supply to the Adrenal Medulla
		1.3 Innervation of the Adrenal Medulla
	2. Biosynthesis and Metabolism of Adrenal Catecholamines
		2.1 Biosynthetic Pathway for Norepinephrine and Epinephrine
		2.2 Catabolism of Norepinephrine and Epinephrine
	3. Epinephrine and Norepinephrine Act Through G Protein–Coupled Adrenoceptors
		3.1 GPCR Signaling Through β-Arrestin
	4. Release of Catecholamines From Adrenal Chromaffin Cells (Stimulus-Secretion Coupling)
		4.1 Autocrine/Paracrine Control of Adrenal Catecholamine Secretion
	5. Physiologic Effects of Adrenal Catecholamines
		5.1 The Sympathoadrenal Stress Response
		5.2 Cardiovascular System Effects of Adrenal Catecholamines
		5.3 Metabolic Effects of Adrenal Catecholamines
		5.4 Effects of Adrenal Catecholamines on Pulmonary and Gastrointestinal Smooth Muscle
		5.5 Other Effects of Adrenal Catecholamines
	6. Adrenal Catecholamines and Pathophysiology
		6.1 Pheochromocytoma
		6.2 Cardiovascular Pathologies Associated With Adrenal Catecholamines
		6.3 Metabolic Pathologies Associated With Adrenal Catecholamines
		6.4 Other Pathologies Associated With Adrenal Catecholamines
	7. Summary
	References
30. Overproduction of Hormones by Pituitary Tumors
	1. Introduction
	2. Pituitary Adenomas
	3. Classification of Pituitary Adenomas
	4. Overproduction of Growth Hormone
	5. Overproduction of Adrenocorticotropic Hormone
	6. Overproduction of Prolactin
	7. Overproduction of Thyroid-Stimulating Hormone
	8. Overproduction of Follicle-Stimulating Hormone and Luteinizing Hormone
	9. Conclusion
	References
31. Hormone Effects on Tumors
	1. Introduction
	2. Corticosteroids
		2.1 Tumors Affected by Corticosteroids
		2.2 Mechanisms of Tumor Promotion
		2.3 Agents, Approaches, and Mechanisms of Tumor Inhibition and Interference
		2.4 Corticosteroid Resistance
	3. Future Directions in Corticosteroid Therapeutic Approaches
		3.1 Synergistic Actions of Corticosteroid Hormones With Novel Therapeutic Agents
		3.2 Corticosteroid Regulation of Micro-RNAs
		3.3 Antiinflammatory Action of Corticosteroids
	4. Androgens
		4.1 Perspective on Androgen Metabolism in Prostate Cancer
		4.2 Androgen Deprivation Therapy
		4.3 Targeting Androgen Synthesis and Androgen Receptor Blockade
	5. Estrogens and Progestogens
		5.1 Tumors Affected by Estrogens and Progestogens
		5.2 Mechanisms of Tumor Promotion
		5.3 Agents, Approaches, and Mechanisms of Tumor Inhibition and Interference
		5.4 Breast Cancer Resistance to Endocrine Therapy
		5.5 Future Directions
	6. Insulin and Insulin-Like Peptides
		6.1 Insulin, IGFs, and Insulin Receptors
		6.2 Insulin-Promoted Tumors
		6.3 Insulin Resistance and Hyperinsulinemia
		6.4 Insulin Signaling as a Therapeutic Target
		6.5 Oral Antidiabetic Agents in Cancer Therapy
	7. Insulin-Like Growth Factors
		7.1 IGFs and Cancer-Related Syndromes
		7.2 IGFs and IGF Receptors
	8. Growth Hormone
	9. Adipocytokines
		9.1 Leptin Effects on Tumors
		9.2 Adiponectin Effects on Tumors
		9.3 Visfatin Effects on Tumors
		9.4 Retinol Binding Protein 4
	Acknowledgments
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	R
	S
	T
	U
	V
	W
	X
	Y
	Z
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