Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management

Cover
Maternal-Fetal and Neonatal
Endocrinology:
Physiology, Pathophysiology, and Clinical
Management
Copyright
Contributors
Preface
Acknowledgments and Dedication
	Acknowledgments and Dedication by Cheri L. Deal
When Endocrine Disorders Disrupt Pregnancy: Perspectives of Affected Mothers
When you are Told That Your Fetus or Newborn has an Endocrine Condition: Perspectives of the Parents
Section I - The Mother
Part A: Normal Endocrine Physiology of the Mother During Pregnancy and Lactation
1
Normal Endocrine Physiology of Hypothalamic Hormones During Ovulation, Pregnancy, and Lactation
	Hypothalamic function during ovulation
		GnRH
			Pulsatility of GnRH
			GnRH Pulsatile Pattern Throughout the Ovulatory Cycle
		Kisspeptin
	Adaptive responses of hypothalamic hormones during pregnancy
		GnRH and Kisspeptin
			Maternal GnRH and Kisspeptin
			Placental GnRH
			Placental Kisspeptin
		GHRH and Somatostatin
		Antidiuretic Hormone
		Oxytocin
			Maternal OT
			Peripheral OT
			Insights from OT Deficiency Models
	Adaptive responses of hypothalamic hormones to lactation
		Lactation and Breastfeeding
		Breastfeeding and Amenorrhea
	References
2
The Pineal Gland and its Function in Pregnancy and Lactation
	Introduction
	Anatomy of the pineal gland
		Vascularization
		Innervation
		Cellular Composition
	Role of the pineal gland in human physiology
		Melatonin
			Melatonin Biosynthesis and Regulation
				Biosynthesis
				The Release and Metabolism of Melatonin
				Patterns and Regulation of Melatonin Secretion
					Central control
					Local control
			Melatonin Receptors
				Melatonin Effects on Reproductive Function through MT1 and MT2 Melatonin Receptors
			Melatonin and Biorhythms
				Circadian Rhythm
				Melatonin and Sleep During Pregnancy and Lactation
				Rhythmicity in the Female Reproductive Function
		Other Pineal Hormones
	Specific functions of the pineal gland during pregnancy and lactation
		Role of the Pineal Gland in Fertility and Reproduction
			Antioxidant Properties of Melatonin and Reproductive Function
		Role of Pineal in Pregnancy and Maternal-Fetal Communication
		Role of Pineal During Labor
		Role of Pineal in Lactation
	Conclusions
	References
3
Pituitary Physiology During Pregnancy and Lactation
	Anterior pituitary gland
		Introduction
		Anatomical Changes in Pituitary Gland
		Functional Changes of Pituitary Gland
			Hypothalamic-PRL Axis
			GHRH-Insulin-Like Growth Factor-I Axis
			HPA Axis and Pregnancy
			Hypothalamic-Pituitary-Thyroid (HPT) Axis
			Hypothalamic-Pituitary-Gonadal (HPG) Axis
			Posterior Pituitary Gland
	References
4
Thyroid Physiology During Pregnancy, Postpartum, and Lactation
	Introduction
	Pregnancy
		Early Adaptation of Thyroid Function
		Role of Iodine, Beta-HCG, and TBG
			Iodine
			Human Chorionic Gonadotropin
			Thyroxine-Binding Globulin
		Uteroplacental Transport
		Implications for Fetal Neurodevelopment
		Trimester-Specific TFTs and Interpretation
	Postpartum period and lactation
	References
5
Physiology of Calcium, Phosphorus, and Bone Metabolism During Pregnancy, Lactation, and Postweaning
	Introduction
	Skeletal and mineral physiology during pregnancy
		Changes in Mineral Ions and Calciotropic and Phosphotropic Hormones
			Calcium and Phosphorus
			Parathyroid Hormone
			PTH-Related Protein
			Calcitriol and Calcidiol
			Calcitonin
			Fibroblast Growth Factor-23 (FGF23)
			Sex Steroids and Other Hormones
		Upregulation of Intestinal Absorption of Calcium and Phosphorus
		Altered Renal Mineral Handling
		Altered Skeletal Turnover and Mineral Metabolism
	Skeletal and mineral physiology during lactation and postweaning recovery
		Changes in Mineral Ions and Calciotropic Hormones
			Calcium and Phosphorus
			Parathyroid Hormone
			Parathyroid Hormone-Related Protein
			Calcitriol and Calcidiol
			Calcitonin
			Fibroblast Growth Factor-23
			Sex Steroids and Other Hormones
		Calcium Pumping and Secretion in Mammary Tissue
		Intestinal Mineral Absorption
		Reduced Renal Excretion of Calcium
		Increased Skeletal Resorption and Osteocytic Osteolysis During Lactation
		Breast-Brain-Bone Circuit-Controlling Bone Metabolism During Lactation
		Bone Formation and Skeletal Recovery Postweaning
	Conclusions
	References
6
Gestational Glucose Metabolism: Focus on the Role and Mechanisms of Insulin Resistance
	Introduction
	Gestational glucose metabolism and the role of insulin
		An Overview
		Glucose Homeostasis During the Stages of Pregnancy
		Insulin Sensitivity During the Stages of Pregnancy
	Cellular mechanisms for IR in pregnancy
		Placental Hormones and Adipocytokines in IR During Pregnancy
		Role of Reduced Glucose Transport
		Changes in the Insulin-Signaling Pathway
		Role of Adipose Tissue
	Role of β-cell adaptations in pregnancy
		β-Cell Response to Placental Lactogens
		Other Pathways Mediating β-Cell Expansion in Pregnancy
	Placental hormones and adipocytokines in the control of maternal metabolism
		Early Gestation to Midgestation
		Late Gestation
		Role of Adipocytokines
	Lactation: A postpregnancy challenge
	Future perspectives
	References
7
Gut Hormones in Pregnancy and Lactation
	Introduction to gut hormones
	Individual gut hormones during pregnancy and lactation
		Gastrin
		Ghrelin
		Leptin
		Somatostatin
		Secretin
		Cholecystokinin
		Motilin
		Gastric Inhibitory Peptide
		Glucagonlike Peptide-1
		Glucagonlike Peptide-2
		Oxyntomodulin
		Fibroblast Growth Factor 19
	Conclusion
	References
8
Adrenal Cortex and Medulla Physiology During Pregnancy, Labor, and Puerperium
	Glucocorticoid physiology in pregnancy, labor, and puerperium
		Plasma CRH and CRH-bp: Origin and Roles During Pregnancy
		CRH Receptors
		Urocortin in Pregnancy: Their Origin and Possible Role
		Plasma ACTH: Origin and Roles During Pregnancy
		Cortisol-Binding Globulin: Changes in Levels and Isoforms During Pregnancy and its Possible Role in Pregnancy
		Total and Free Cortisol Levels During Pregnancy
		Diurnal Variation of the HPA Axis and the Feto-Placental Unit During Pregnancy
		Physiologic Hypercortisolism of Pregnancy: Particular Regulation of the HPA Axis During Pregnancy
		Specific Role of Glucocorticoids During Pregnancy and the Impact of Excessive Fetal Glucocorticoid Exposure
		Fetus Protection Against the High Maternal Glucocorticoids Levels During Pregnancy
		Change in the HPA Axis and Cortisol Levels During Parturition and in the Postpartum
	Mineralocorticoid physiology in pregnancy, labor, and puerperium
		RAS Modifications During Pregnancy
		Aldosterone Levels During Pregnancy
		Regulation of RAAS During Pregnancy
		Other Mineralocorticoids
		RAAS in the Postpartum Period
		RAAS in Pregnancy-Associated Hypertension
	Adrenal sex steroids during pregnancy
	Catecholamine physiology during pregnancy
	References
9
Ovarian Function During Pregnancy and Lactation
	Introduction
	Ovarian hormone changes during ovulation, luteinization, implantation, early pregnancy, and luteolysis
		Ovulation
		Formation of the Corpus Luteum
		Corpus luteum Regression
		Rescue of the Corpus Luteum
		Function of the Corpus Luteum
		Progesterone for Development of Lining, Promoting Quiescence, Delaying Transit, and Facilitating Implantation
		Shift from Ovary to Uterus/Placenta
	Ovarian hormones in pregnancy
	Ovarian structural changes with pregnancy
		Anatomic Changes to the Ovary During Pregnancy
		Ovarian Cysts of Pregnancy
	Lactation effects on the ovary
		Suppression
		Return of Ovulation
		Other Effects of Lactation on the Ovary
	Conclusion
	References
10
The Physiological Roles of the Renin-Angiotensin Aldosterone System and Vasopressin in Human Pregnancy
	Introduction
	Renin-angiotensin components and pathways for generation of angiotensin peptides
		Renin and Prorenin
		(Pro)renin Receptor
		Soluble (P)RR
		Angiotensinogen
		Angiotensin Converting Enzyme
		ACE2
		ANG Peptides and their Receptors
		Actions of ANG Peptides
	Regulation and actions of the cRAAS and IRAS in pregnancy
		Changes in cRAAS in Human Pregnancy
			Prorenin and Renin
			Prorenin Receptor and s(P)RR
			Angiotensinogen
			ACE and ACE2
			ANG II and ANG-(1-7)
		Regulation and Actions of the cRAAS in Pregnancy
			Ovarian Prorenin
			Relaxin
			Estrogens
		Actions of ANG Peptides in Pregnancy (Fig. 10.9)
			Vasopressin
			The Intrarenal RAS
	Reproductive tract RASs (Fig. 10.10)
		The Ovarian Renin-Angiotensin System
		Intrauterine RASs
	References
11
Central Role of Adipose Tissue in Pregnancy and Lactation
	Introduction
	Overview of maternal metabolism during pregnancy
		Glucose Metabolism
		Lipid Metabolism
		Protein Metabolism
		Changes in the Postpartum Period
	Role of adiposity in pregnancy
	Adipocytokines in pregnancy
		Leptin
		Adiponectin
		Resistin
		Tumor Necrosis Factor-α
		Adipocyte Fatty Acid-Binding Protein
		Vaspin
		Visfatin
		Angiopoietin-Like Protein 8
		Other Adipokines
	Mechanisms of adaptive insulin resistance in pregnancy
	Adipokines and fetal growth
	Changes in maternal adiposity during lactation
	Maternal obesity and pregnancy outcomes
	Adipose tissue transcriptome and metabolomics in pregnancy
	Summary and conclusion
	REFERENCES
12
Hormonal Regulation of the Menstrual Cycle and Ovulation
	Introduction
	Function of the hypothalamus
	Function of the pituitary
	Ovaries
	Endometrium
	Fertilization/implantation
	References
13
Maintenance of Pregnancy and Parturition
	Establishment of pregnancy
	The cervix and its changes in pregnancy
	Maintaining quiescence in the pregnant uterus
		Human Chorionic Gonadotropin
		Progesterone
		Cyclic Adenosine Monophosphate
	Requirements for labor contractions in the uterus
		Corticotropin-Releasing Hormone
		Estrogen
		Oxytocin and the OTR
		Prostaglandins and Prostaglandin Receptors
		Calcium Signaling and Myometrial (Smooth Muscle) Contractility
		Gap Junctions
		Micro-RNA
	Inflammation in pregnancy
		Sterile and Nonsterile (Microbial) Inflammation and the Innate Immune System
		Inflammation in Parturition
	Other mechanisms involved in the activation of parturition
		Oxidative Stress, Aging, and Senescence
		Cell-Free Fetal Dna
	A summary of human parturition
	References
14
The Onset and Maintenance of Human Lactation and its Endocrine Regulation
	Breast development and lactogenesis
		Embryogenesis
		Puberty
		Pregnancy
		Lactogenesis I/Secretory Differentiation
	Endocrine regulation of breast development, LI, and colostrogenesis
		Estrogens and Progestogens
		Prolactin
		Other Endocrine Requirements for LI
	The colostral phase
	Lactogenesis II
		Lactose Biosynthesis
		Tight Junction Closure
		Clinical/Diagnostic Determinants of LII
	Endocrinology of LII
		Progesterone
		Glucocorticoids
		Insulin and Glucose Metabolism
		Oxytocin
		PRL and Growth Hormone
		Induction of Lactation
	Established lactation
		Breast Size and Milk Production
		Milk Synthesis and Composition
		Local Regulation of Milk Synthesis
		Oral Contraceptives
	Adaptations of maternal metabolism
		Food Intake
		Reproductive Function
		Glucose Metabolism
		Lipid Metabolism
		Calcium and Bone Metabolism
	References
15
Postpartum Lactational Amenorrhea and Recovery of Reproductive Function and Normal Ovulatory Menstruation
	Description of postpartum or lactational amenorrhea and relative infertility
		Anthropology and Epidemiology
		Endocrinology of Lactational Amenorrhea and Recovery
		Key Variables Related to Duration of Lactational Amenorrhea and of Ovulatory Disturbances
	Parallels with research on menstrual cycle recovery from amenorrhea of other causes
	Need for further research
	References
Part B: Maternal Endocrine Disorders During Pregnancy and Lactation
16
Hypothalamic Disorders During Ovulation, Pregnancy, and Lactation
	Functional hypothalamic amenorrhea
		Physiopathology and Precipitating Factors
		Clinical Manifestations
		Diagnostic Evaluation and Differential Diagnosis
			Medical History and Physical Exam
			Laboratory Assessment
			Imaging Studies
		Management
		FHA: Pregnancy and Lactation
	Congenital hypogonadotropic hypogonadism
		Genetics
		Clinical Manifestations and Associated Phenotypes
			Hallmarks of CHH in Infancy
			Hallmarks of CHH in Childhood and Adolescence
			Hallmarks of CHH in Adulthood
			CHH Reversal
			CHH-Associated Phenotypes
		Diagnostic Evaluation and Differential Diagnosis
			Clinical Assessment
			Biochemical and Hormonal Testing
			Radiological Examination
			Differential Diagnosis
		Management
			Neonatal CHH in Females
			Induction of Female Secondary Sexual Characteristics
			Treatment of Hypogonadism in Adult Women
			Induction of Fertility in CHH Women
			CHH: Pregnancy and Lactation
	Organic lesions of the hypothalamus
		Tumors and Other Expansive Entities
			CP and Ovulation Disorders
			CP: Pregnancy and Lactation
			Other Hypothalamic Tumors and Links with Ovulation, Pregnancy, and Lactation
		Infiltrative and Inflammatory Disorders
			Hypothalamic Sarcoidosis and its Effect on Ovulation, Pregnancy, and Lactation
			LCH and its Effect on Ovulation, Pregnancy, and Lactation
		Iatrogenic Lesions
			Radiotherapy
			Cranial Irradiation and its Impact on Pregnancy and Lactation
			Postsurgery and Posttraumatic
			Drug-Related
	Ovulation induction in patients with HH of hypothalamic origin
		Pulsatile GnRH Treatment
		Gonadotropin Treatment
		The Role of Kisspeptin in the Ovulation Induction Treatment
		The Place of IVF in the Fertility Treatment of HH Patients
		Summary
	References
17
Pineal Gland Disorders and Circadian Rhythm Alterations in Pregnancy and Lactation
	Pineal gland pathology in pregnancy and lactation
		Pineal Tumors
			Pineal Parenchymal Tumors
			Pineal Glial Tumors
			Therapeutic Approaches
				Surgical Therapeutic Intervention
				Chemotherapy
			Mode of Delivery in Patients with Pineal Tumors
		Pineal Cysts
		Pineal Calcifications
		Pineal Vascular Lesions
	Melatonin deficiency in pregnancy and lactation
		Oxidative Stress
		Chronodisruption
			Chronodisruption During Pregnancy
			Chronodisruption During Lactation
		Impact on Fertility
		Risk of Miscarriage and Preterm Birth
		Preeclampsia/Eclampsia and FGR
	Potential clinical utility of melatonin in disorders of pregnancy and lactation
		Melatonin in Clinical Trials
		Safety and Pharmacokinetic Profile of Exogenous Melatonin
	Conclusions
	References
18
Pituitary Disorders During Pregnancy and Lactation
	Introduction and general approach
		Neuroimaging in Pregnancy
		Pituitary Adenoma Treatment During Pregnancy
		Pharmacological Treatment
		Pituitary Surgery During Pregnancy
		Outcomes of Pregnancies of 20-week Gestation
		Outcomes of Pregnancies of 21-39weeks Gestation
		Outcomes of Full-Term Pregnancy
	Prolactinomas
	Acromegaly
		Preconception Counseling and Prenatal Care
		Impact of Pregnancy on Acromegaly
		Impact of Acromegaly During Pregnancy
		GH-IGF-I Axis of Acromegaly During Pregnancy
		Hormonal Evaluation of Acromegaly During Pregnancy
		Treatment of Acromegaly During Pregnancy
		Practical Approach
	Cushing disease and pregnancy
		CS Diagnosis During Pregnancy
		Materno-Fetal Complications
		Treatment of CS During Pregnancy
	Clinically nonfunctioning pituitary adenomas
	TSH-secreting pituitary adenomas
	Pituitary insufficiency
		Hypopituitarism
		ACTH Deficiency
		TSH Deficiency
		GH Deficiency
		PRL Deficiency
	Sheehans syndrome
	Lymphocitic hypophysitis
	Diabetes insipidus during pregnancy
		Gestational Diabetes Insipidus
		Diagnosis of GDI
		Treatment
	Deficiency of oxytocin
	References
19
Thyroid Disorders During Pregnancy, Postpartum, and Lactation
	Introduction
	Biomarkers of thyroid autoimmunity
		Thyroperoxidase Antibody
		Thyroglobulin Antibody
		Thyroid Stimulating Hormone Receptor Antibody
	Primary subclinical hypothyroidism
		Overview
		Definition
		Burden of Disease
		Pathophysiology
		Pregnancy
			Pregnancy Outcomes in SCH and Isolated Hypothyroxinemia
			Thyroid Autoantibody Positivity
			Diagnosis
			Treatment
		Postpartum and Lactation
		Conclusion
	Overt hypothyroidism
		Overview
		Definition
		Pathophysiology
		Causes
		Pregnancy
			Preconception
			Diagnosis
			Treatment
			Monitoring
			Pregnancy Outcomes
		Postpartum and Lactation
		Isolated Hypothyroxinemia
	Secondary hypothyroidism (central hypothyroidism)
	Keywords
	Syndromes of reduced sensitivity to thyroid hormone
		Overview
	Keywords
		Incidence, Prevalence, and Inheritance
		Clinical Features and Maternal and Fetal Outcomes
		Treatment
	Hyperthyroidism
	Keywords
		Overview
		Differential Diagnosis of Hyperthyroidism in Pregnancy
		Graves Disease
			Overview
			Preconception Counseling and Care for Women with a History of GD
			Treatment of GD During Pregnancy
				ATDs
				Other agents
				Treatment targets
				Radioactive iodine
				Surgical management
			Monitoring of the Mother and Fetus
			Complications of Maternal GD in the Mother and Fetus
			Treatment and Monitoring of GD in the Postpartum Period and During Lactation
			Euthyroid Women with a History of Previously Treated GD
		Gestational Transient Thyrotoxicosis
		Toxic Adenomas and Toxic Multinodular Goiters
			Treatment of Nonautoimmune Hyperthyroidism
	Postpartum thyroid dysfunction
	Keywords
		Definition
		Epidemiology
		Screening for PPTD
		Pathophysiology and Clinical Course of PPTD
		Differential Diagnosis and Evaluation of PPTD
		Treatment of PPTD
		Postpartum Depression and its Association with PPTD
			Can PPTD be Prevented in Women with Positive TPO Abs?
	Thyroid emergencies: Thyroid storm and myxedema crisis
		Overview
		Thyroid Storm
	Key clinical findings
		Outline placeholder
			Thyroid Storm: Epidemiology, Precipitating Factors, and Clinical Outcomes
			Pathogenesis and Clinical Presentation
			Maternal Signs and Symptoms Concerning for Impending or Established TS
			Fetal Findings
			Diagnosis
			Treatment
		Myxedema Crisis/Coma
	Key clinical signs of myxedema crisis/coma include
		Outline placeholder
			Epidemiology, Pathogenesis, Precipitating Factors, and Clinical Course
			Diagnosis MC in Pregnancy
			Treatment
	References
20
Thyroid Cancer During Pregnancy and Lactation
	Introduction
	Epidemiology of nodular thyroid disease and thyroid cancer
		Nodular Thyroid Disease
		Thyroid Cancer
		Incidence of Thyroid Cancer in Pregnancy
	Effects of pregnancy on thyroid nodules
		Effects of Pregnancy Hormones on Thyroid Follicular Epithelium
		Physiology of Thyroid Nodules During Pregnancy
	Evaluation of a newly discovered thyroid nodule in pregnancy
	Effect of pregnancy on newly diagnosed thyroid cancer
		Impact on Prognosis
		Timing of Surgery
		Supportive Management in Pregnancy
		Planning for Radioiodine Therapy
	Preconception counseling of women with a prior history of thyroid cancer
		Establishment of Disease Status
		Risk of Recurrence
		Mitigating Pregnancy-Impacts of Prior Thyroid Cancer Treatment
			Levothyroxine Supplementation
			Radioiodine
			Hypoparathyroidism
		Surveillance and Monitoring
			Papillary Thyroid Microcarcinoma
		Germline RET Mutations
	Management of known residual structural disease in pregnancy
	Conclusion
	References
21
Disorders of Mineral and Bone Metabolism During Pregnancy and Lactation
	Introduction
	Disorders of bone and mineral metabolism during pregnancy
		Osteoporosis in Pregnancy
			Vertebral and Appendicular Fractures in Pregnancy
			Transient Osteoporosis of the Hip
			Investigations and Overall Management Considerations
			Nonpharmacological Treatment
			Pharmacological Therapy
			Surgical Therapy
		Primary Hyperparathyroidism
			Incidence and Epidemiology
			Clinical Presentation
			Approach and Management
			Conclusion: Surgical vs Medical Management?
		Familial Hypocalciuric Hypercalcemia
			Clinical Management
		Hypoparathyroidism
			Clinical Management
		Pseudohypoparathyroidism
			Clinical Management
		Pseudohyperparathyroidism
			Clinical Management
		Vitamin D Deficiency, Genetic Vitamin D Resistance, and 24-Hydroxylase Deficiency
			Animal Data: Vitamin D Deficiency and Genetic Vitamin D Resistance
			Animal Data: 24-Hydroxylase Deficiency
			Human Data: Vitamin D Deficiency and Genetic Vitamin D Resistance
			Clinical Management: Vitamin D Deficiency and Genetic Vitamin D Resistance
			Human Data: 24-Hydroxylase Deficiency
			Clinical Management: 24-Hydroxylase Deficiency
		Calcitonin Deficiency
		Low or High Calcium Intake
		Hypercalcemia of Malignancy
		Fibroblast Growth Factor 23 (FGF23)-Related Disorders
		Tocolytic Therapy with Magnesium Sulfate
			Clinical Management
	Disorders of bone and mineral metabolism during lactation
		Osteoporosis of Lactation
			Clinical Management
		Primary Hyperparathyroidism
			Clinical Management
		Familial Hypocalciuric Hypercalcemia
			Clinical Management
		Hypoparathyroidism
			Clinical Management
		Pseudohypoparathyroidism
			Clinical Management
		Pseudohyperparathyroidism
			Clinical Management
		Vitamin D Deficiency, Genetic Vitamin D Resistance, and 24-Hydroxylase Deficiency
			Vitamin D Deficiency and Genetic Vitamin D Resistance
			24-Hydroxylase Deficiency
			Clinical Management: Vitamin D Deficiency and Genetic Vitamin D Resistance
			Clinical Management: 24-Hydroxylase Deficiency
		Calcitonin Deficiency
			Clinical Management
		Low or High Calcium Intake
			Clinical Management
		FGF23-Related Disorders
			Clinical Management
	Conclusions
	References
22
Gestational Diabetes and Type 2 Diabetes During Pregnancy
	Gestational diabetes
		Epidemiology
		Pathophysiology
		Adverse Pregnancy Outcomes Associated with GDM
		Screening for GDM
		Early Screening for GDM/T2DM in Pregnancy
		Diagnosis of GDM: One Step vs Two Step
		Management
			During Pregnancy
				Self-Management
					Frequency of monitoring and targets
					Lifestyle management
				Pharmacological Treatment
					Insulin
					Noninsulin antihyperglycemic agents
						Metformin.
						Glyburide.
						Alpha-glucosidase inhibitors.
						Other oral-antidiabetic agents.
			Intrapartum
			Postpartum
				Breastfeeding
				Fetal and Maternal Risks
				Considerations for future pregnancy planning
	Type 2 diabetes
		Epidemiology of T2DM in Pregnancy
		Prepregnancy Counseling
		Prepregnancy Counseling: BMI
		Antenatal Screening of Microvascular and Macrovascular Complications in T2DM
			Nephropathy
			Retinopathy
			Ischemic Heart Disease
		Obstructive Sleep Apnea
		Nonalcoholic Fatty Liver Disease
		Maternal Outcomes with T2DM
			Preeclampsia
		Obstetric Intervention
		Fetal/Perinatal Complications
			Pregnancy Loss
			Congenital Anomalies
				Factors Contributing to Congenital Anomalies in Women with T2DM
					Glycemic control
					Obesity
					Drugs
			Preterm Delivery
			Birth Weight and Peripartum Consequences
		Management
			What is expected at the first diabetes clinic visit in pregnancy for women with T2DM?
			Glucose Control and Glucose Monitoring
			Dietary Advice and Weight Gain
			Drugs/vitamin Supplementation
			Pharmacological Management of Pregnancy in Women with T2DM
				Aspirin
				Oral Hypoglycemic Agents
					Metformin
				Insulin Therapy in T2DM Pregnancy
					Concentrated basal insulin analogs
					Ultralong-acting basal insulin analogs
		Peripartum Monitoring: Maternal and Neonatal
		Postpartum: Insulin Doses and Breastfeeding
		Future Pregnancies
		Risk for Offspring
	REFERENCES
23
Type 1 Diabetes: During Preconception, Pregnancy, Postpartum, and Breastfeeding
	Prepregnancy
		Prepregnancy Care
			Importance of PPC in Women with Type 1 Diabetes
			Elements of PPC
			Optimization of Glycemic Control: Goals and Strategies
				Glucose Monitoring
				Insulin Dosing
				Nutrition and Physical Activity
			Prepregnancy Management of Diabetes Complications and Risk Assessment
				Diabetic Retinopathy
				Hypertension
				Diabetic Nephropathy
				Diabetic Neuropathy
				Cardiovascular Disease
				Smoking Cessation
				Thyroid Function
				Immunization
				Psychological Support
			Neonatal Complications
	Pregnancy
		Glycemic Management Throughout Pregnancy
			The Role of Physiologic Changes in Developing Management Strategies
			The Role of Dietary Strategies and Exercise in Glycemic Control
			Mode of Insulin Delivery
				MDI Injections
				The Insulin Pump
				MDIs vs the Insulin Pump
				Closed-Loop Insulin Delivery
			Types of Insulins and Oral Agents
				Bolus Insulins
				Intermediate and Long-Acting Basal Insulins
				Oral Agents
		Glycemic Measurements and Targets in Pregnancy
			Capillary Blood Glucose Monitoring
			Hemoglobin A1c in Pregnancy
				Limits of HbA1c in Pregnancy
				Targets for Women with Type 1 Diabetes
			Continuous Glucose Monitoring
			Other Measurements of Glycemic Control
		The Prevention and Management of Diabetes Complications
			Retinopathy
			Hypertension and Nephropathy
			Neuropathy
			Hypoglycemia
			Diabetic Ketoacidosis
		Fetal Surveillance and Timing of Delivery
		Management During Labour and Delivery
			Prior to Delivery
			Strategies for Insulin Delivery
			Management of IV Insulin Infusion During Labor and Delivery
				Vaginal Delivery
				Cesarean Section
			Management of the Insulin Pump During Labor and Delivery
				Vaginal Delivery
				Elective Cesarean Section
			Conclusions on Labor and Delivery
	Postpartum
		Physiological Changes and their Impact on Diabetes Management
			For Women on An IV Insulin Infusion for Labor and Delivery
			For Women on an IV Insulin Infusion for Labor and Delivery
			Insulin-Dosing Postpartum Recommendations
		Contraception
		Screening for Diabetes Complications Postpartum
			Thyroid Function
		Breastfeeding
			Challenges in Breastfeeding and Type 1 Diabetes
				Delayed Lactogenesis
				Impact of Dysglycemia on Milk Supply, Milk Content, and Infant
			Strategies to Help Establish and Maintain Breastfeeding
			Impact of Breastfeeding on Glycemic Control and Insulin Requirements
		Risks to Offspring
	References
24
Gut and Pancreatic Neuroendocrine Tumors in Pregnancy and Lactation
	Introduction
	Pregnancy planning and prospective management of gut and pancreatic NETs in women with history of such tumors
		Women with no Current Evidence of NETs
		Women with Active Gut or Pancreatic NETs
	Gut and pancreatic NETs found de novo during pregnancy
	Management of gut and pancreatic NETs during pregnancy and peripartum
		Management of Carcinoid Syndrome in Pregnancy and Peripartum
		Management of Insulinoma During Pregnancy and Peripartum
	Lactation in women with gut and pancreatic NETs
	Conclusions
	References
25
Adrenal Pathologies During Pregnancy and Postpartum
	Introduction
		Adrenal Insufficiency
		Epidemiology
		Etiologies
		Clinical Presentation
			Primary AI
			Secondary and Tertiary AI
		Diagnosis
			Random or Morning Cortisol Levels
			Cosyntropin Stimulation Test
			Differentiation Between Primary and Secondary-Tertiary AI
			Determining the Etiology of Primary or Secondary/Tertiary AI
		Morbidity and Complications Associated with AI in Pregnancy
		Therapy
			Glucocorticoid Replacement
			Mineralocorticoid Replacement
			Adrenal Crisis Management
	Cushings syndrome
		Etiologies of CS
		Clinical Presentation
		Morbidity Associated with CS in Pregnancy
		Diagnosis of CS During Pregnancy
			Biochemical Screening and Diagnosis of CS
			Establishing the Cause of the CS
			Therapy of CS During Pregnancy
			Surgical Therapy of CD
			Surgical Therapy of Adrenal CS
			Medical Treatment of CS
			Medical Treatment During Breastfeeding
			Treatment of Iatrogenic CS During Pregnancy
	Adrenocortical carcinoma
		Clinical Presentation
		Maternal and Fetal Morbidity
		Diagnosis
		Treatment
	Primary aldosteronism
		Etiologies of Hyperaldosteronism
		Clinical Presentation of PA in Pregnancy
		Maternal and Fetal Morbidity Associated with PA During Pregnancy
		Diagnosis of PA During Pregnancy
		Treatment of PA During Pregnancy and Breastfeeding
	Pheochromocytoma and paraganglioma (PPGL)
		Genetic Susceptibility to PPGL
		Clinical Manifestations of PPGL During Pregnancy
		Morbidity and Mortality Associated with PPGL During Pregnancy
		Diagnosis of PPGL During Pregnancy
			Biochemical Diagnosis
			Localization of the Tumor
		Treatment of Pheochromocytoma During Pregnancy
			Preoperative Medical Treatment
			Surgical Resection of the Tumor
			Medical Treatment of Acute Hypertensive crisis
			Special Considerations in Nursing Mothers
	Congenital adrenal hyperplasia
		Treatment of Pregnant Patients with 21-OH Congenital Adrenal Hyperplasia During Pregnancy, Labor, and Postpartum
		Genetics of 21-OH Congenital Adrenal Hyperplasia and Prenatal Genetic Counseling
		Prenatal Treatment to Prevent Virilization in Female Fetuses
	References
26
Hypertension in Pregnancy
	Introduction
		Prevalence and Clinical Significance of Hypertension in Pregnancy
	Physiological changes in normal pregnancy
		Altered Pregnancy Physiology in HDP
	Screening for and prevention of preeclampsia
	Assessment of the hypertensive pregnant woman
		Diagnostic Criteria for Hypertension in Pregnancy and Considerations Specific to the Measurement of Blood Pressur ...
		Diagnostic Criteria for Proteinuria in Pregnancy
		Fetal Assessment
		Differential Diagnosis of Preeclampsia
		Novel Diagnostic Tests-PLGF/sFlt-1
	Classification of hypertensive disorders of pregnancy
		Preexisting Hypertension
		Gestational Hypertension
		Preeclampsia
		Preeclampsia Superimposed on Preexisting Hypertension
		Severe Preeclampsia
		Classification of Severity by Gestation at Onset
		Clinical Features of Severe Preeclampsia
	Complications of preeclampsia
		HELLP Syndrome
		Renal Dysfunction in Preeclampsia
		Pulmonary Edema
		Eclampsia
	Antenatal care of women with hypertensive disorders in pregnancy
		Periconceptual Care
		Antenatal Treatment of Chronic and Gestational Hypertension
		Choice of Antihypertensive Agents in Pregnancy
		Antenatal Monitoring in Gestational and Chronic Hypertension
		Timing of Delivery in Chronic and Gestational Hypertension
	Antenatal management of preeclampsia
		Inpatient or Outpatient Management?
	Treatment of severe preeclampsia
		Severe Hypertension
		Magnesium Sulfate for Women with Severe Preeclampsia
		Plasma Volume Expansion and Fluid Restriction
		HELLP Syndrome
		Acute Management of Eclampsia
	Timing and mode of delivery in preeclampsia
	Intrapartum care of hypertensive women
		Normal Intrapartum Hemodynamics and Physiological Changes
		Intrapartum Maternal and Fetal Monitoring
		Intrapartum Analgesia and Anesthetic Considerations
	Postnatal care and follow-up of women affected by hypertension in pregnancy
		Immediate Postpartum Management of Women Affected by HDP
		Choice of Antihypertensive in the Puerperium and Lactation
		Complications of Hypertensive Disease in the Puerperium
	Long-term implications of hypertension in pregnancy
		Future Pregnancies
		Longer-Term Maternal Health Implications
	Conclusion
	References
27
Preconception and Pregnancy in Women with Obesity, Postbariatric Surgery, and Polycystic Ovarian Syndrome
	OVERALL PERSPECTIVE
	Epidemiology of overweight and obesity among women during pregnancy
	Epidemiology of excessive gestational weight gain
	Overview of maternal complications related to overweight/obesity
	Care of the obese woman before and during pregnancy
		Preconception
		Early Pregnancy and Antepartum Care
		Antepartum Care
		Gestational Diabetes
		Intrapartum Care
		Prevention of Cesarean Delivery
		Prevention of Complications During Cesarean Delivery
	Visualization and preventing wound complications
		Postpartum Hemorrhage
		Anesthesia
		Thromboembolism
		Postpartum Care
		Long-Term Outcomes for Offspring
	Special considerations
		Women with History of Bariatric Surgery
		Polycystic Ovarian Syndrome
		Infertility and Conception
		Complications During Pregnancy
		Postpartum
	Conclusion
	References
Part C: Transgendered Issues
28
Fertility, Pregnancy, and Chest Feeding in Transgendered Individuals
	Introduction
		Terminology and Transgender Identity
		Transgender Statistics
		Heath-Care Discrimination and Barriers to Care
	Reproductive desires
	Gender-affirming care and fertility
		Transgender Men and Fertility
		Transgender Females and Fertility
	Fertility options
		Fertility Preservation and Transgender Men
		Assisted Reproduction and Transgender Men
		Fertility Preservation and Transgender Women
		Assisted Reproduction and Transgender Women
		Fertility Preservation and Adolescents
	Transgender pregnancy
		Preconception Counseling
		Obstetrical Care for Transgender Patients
		Transgender Men and the Labor and Delivery Experience
	Postpartum considerations
		Postpartum Contraception
		Postpartum Depression
	Chest feeding
	Conclusion
	References
Section 2 - The Child
Part D: Normal Endocrine Development and Physiology of the Fetus and Neonate
29
Endocrinology of Implantation
	REFERENCES
30
Normal Hypothalamic and Pituitary Development and Physiology in the Fetus and Neonate
	Introduction: The hypothalamo-pituitary neuroendocrine axis
	Normal development of the hypothalamus and pituitary (adenohypophysis and neurohypophysis)
		Genes Involved in Pituitary Development
			Morphogenetic Signals (BMPs, FGFs, SHH, Wnt/β-Catenin Pathway)
			Early Transcription Factors
			Terminal Cell Differentiation
		Hypothalamus and Pituitary Stalk Development
		Human Hypothalamo-Pituitary Development
	Physiology of the fetal and neonatal hypothalamo-pituitary hormone axes
		GHRH/Somatostatin-GH/PRL
		TRH-TSH
		GnRH-LH/FSH
		CRH-ACTH
		POMC and POMC-Derivates
		AVP and OT
	Hypothalamo-pituitary regulation of transition to extrauterine life
	Conclusions
	References
31
The Pineal Gland Development and its Physiology in Fetus and Neonate
	Introduction
	Pineal development and circadian rhythm ontogenesis
	Melatonin synthesis
		Melatonin Sources for the Fetus
	Melatonin and oogenesis
	Pineal during development
		Melatonin Levels in the Neonatal Period
	Dynamics of melatonin secretion during normal and pathological pregnancies
	Melatonin antioxidative properties during fetal development
	Melatonin and neurodevelopment
	Melatonin and perinatal neuroprotection
	Melatonin and behavior
		Serotonin
		Norepinephrine
		Dopamine
	Melatonin role in immunomodulation in the fetus and neonate
	Normal relationship between mother and fetal circadian rhythms
	Conclusion
	REFERENCES
32
Normal Thyroid Development and Function in the Fetus and Neonate
	Introduction
	Embryology of the hypothalamic-pituitary-thyroid axis
		The Pituitary
		The Thyroid
		Possible Role of Embryonic Vasculogenesis on Thyroid Development
	Maternal and placental influences on fetal thyroid hormone levels
	Maturation of thyroid hormone synthesis and secretion
	Maturation of thyroid hormone metabolism and transport
	Extrauterine thyroid adaptation
	Thyroid hormone actions
	References
33
Physiology of Calcium, Phosphorus, and Bone Metabolism During Fetal and Neonatal Development
	Introduction
	Overview of fetal mineral metabolism
		Serum Mineral Concentrations
		Calciotropic and Phosphotropic Hormone Concentrations
			Parathyroid Hormone
			Calcitriol
			Parathyroid Hormone-Related Protein
			FGF23
			Calcitonin
			Sex Steroids
		Fetal Parathyroids
		Renal Mineral Reabsorption and Excretion, and the Amniotic Fluid
		Intestinal Mineral Absorption
		Placental Mineral Transport
		Endochondral Bone Formation, Mineralization, and Remodeling
	Overview of neonatal mineral homeostasis
		Serum Mineral Concentrations
		Calciotropic and Phosphotropic Hormone Concentrations
		Neonatal Parathyroid Function
		Renal Mineral Reabsorption and Excretion
		Intestinal Mineral Absorption
		Skeletal Metabolism
	Conclusions
	References
34
Developmental Physiology of Carbohydrate Metabolism and the Pancreas
	Introduction
	Prenatal
		Placental Function and Glucose Transport
		Maternal Effects
		Fetal Role
			Fetal Metabolism
			Fetal Glycogen Metabolism
			Fetal Glucose Production
			Fetal Pancreatic Development
			The Insulin/IGF-I Axis
	Transition
	Newborn
		Postprandial State: Glycogen Storage and Fat Metabolism
		Intestinal Transport
			Glucose Uptake
			Glucose Utilization
			Insulin Secretion
		Preprandial State and Gluconeogenesis
			Enzyme Induction
			Substrate Availability
	Clinical implications
	References
35
Developmental Origins and Roles of Intestinal Enteroendocrine Hormones
	Developmental origins of enteroendocrine cells
		Gastrulation and Endoderm Specification
		Gut Tube Formation and Patterning
		Early Intestinal Development
		Development of Enteroendocrine Cells
	Role of enteroendocrine hormones in fetal and neonatal homeostasis
		Cholecystokinin
		Glucose-Dependent Insulinotropic Peptide
		Glicentin
		Glucagon-Like Peptide-1
		Glucagon-Like Peptide-2
		Motilin
		Neurotensin
		Oxyntomodulin
		Peptide YY
		Secretin
		Serotonin
		Somatostatin
		Xenin
	Conclusion
	References
36
Development and Function of the Adrenal Cortex and Medulla in the Fetus and Neonate
	Introduction
	Adrenal development
		Prenatal Period
		Postnatal Period
	Adrenal cortex
		Structure and Function
			Prenatal Adrenal Cortex
			Neonatal Adrenal Cortex
			Adult Adrenal Cortex
		Physiology
			Prenatal Period
				Fetal Hypothalamic-Pituitary-Adrenal Axis
				Placental Factors
				Prenatal Exposure to Glucocorticoids
			Neonatal Period
			Adulthood
		Adrenal Steroidogenesis
			Prenatal Period
			Neonatal Period
		Circadian Rhythm
		Molecular Aspects
			SF1 (NR5A1)
			DAX1 (NR0B1)
			IGF2
			WNT/β-Catenin-Signaling Pathway
			Sonic Hedgehog-Signaling Pathway
	Adrenal medulla
		Structure and Function
			Prenatal Adrenal Medulla
			Neonatal Adrenal Medulla
			Adult Adrenal Medulla
		Physiology
		Catecholamine Synthesis
	Conclusion
	References
37
Development and Function of the Ovaries and Testes in the Fetus and Neonate
	Sex differentiation of the reproductive system
	The hypothalamic-pituitary-gonadal axis
	Early organogenesis of the reproductive organs
	The bipotential gonad
		The Gonadal Ridge
		The Germ Cells
	The testes
		Fetal Sex Determination and Differentiation
			Seminiferous Cord Formation. Differentiation of Sertoli and Leydig Cells
			Molecular Pathways
			Spermatogenic Development
			Hormone Synthesis and Secretion
		Postnatal Changes
			Anatomical Aspects and Histological Changes
			The Physiology of the Postnatal Activation
			Childhood and Puberty: Brief Description
	The ovaries
		Fetal Differentiation
			Oogenesis and Folliculogenesis
			Molecular Pathways
		Postnatal Changes
			Anatomical Aspects and Histological Changes
			The Physiology of the Postnatal Activation
			Childhood and Puberty: Brief Description
	The reproductive tract and external genitalia
		The Sexually Undifferentiated Embryo
			Morphogenesis of the Anlagen
			Molecular Pathways
		Male Differentiation
			Anatomic Aspects and Hormonal Regulation
			Testicular Descent
			Postnatal Changes
		Female Differentiation
			Anatomic Aspects and Hormonal Regulation
			Postnatal Changes
	The role of epigenetics
	References
38
Development of Renin-Angiotensin-Aldosterone and Nitric Oxide System in the Fetus and Neonate
	Introduction of renin-angiotensin-aldosterone system and nitric oxide
		Renin-Angiotensin-Aldosterone System
		Nitric Oxide
	Endocrine physiology of RAAS in placenta, fetus, and neonate
		Placental RAAS
			Components of RAAS in the Placenta
				Renin
				ACE and ACE2
				Angiotensinogen
				Angiotensin Receptors
				Aldosterone
			Functions of RAAS in the Placenta
				Placentation
				Placental Hormone Secretion
				Placental Vascular Function
		Fetal and Neonate RAAS
			Components of RAAS in Fetus and Neonate
				Systemic RAAS in Fetus and Neonate
				Local RAAS in the Fetus and Neonate
					Kidney
					Adrenal glands
					Heart
					Vasculature
					Brain
			Functions of RAAS in Fetus and Neonate
				The RAAS in the Kidney
				The RAAS in the Cardiovascular System
				The RAAS in the Central Nervous System
	Physiological functions of NO in pregnancy and fetuses
		Signaling Pathway in Regulation of NO Generation
			Synthesis of NO
			Regulation of NO Synthesis
		Nitric Oxide and Pregnancy
			Circulating NO Concentration During Pregnancy
			NO and Maternal Cardiovascular Systems
			NO and Uterine Arteries
			NO and Ovulation, Implantation, Uterine Contractility, and Cervical Ripening
				Follicular Development and Ovulation
				Implantation
				Uterine Contractility
				Cervical Ripening
		Nitric Oxide and Placenta
			Nitric Oxide and Fetoplacental Circulation and Placenta
			Nitric Oxide and Vasoreactivity of Fetoplacental Vessels
			Nitric Oxide and Placental Vascular Development
				Vasculogenesis
				Angiogenesis
			Nitric Oxide and Trophoblast Invasion
			Nitric Oxide and Placental Glucocorticoid Metabolism
		Nitric Oxide and the Fetus
			Brain
			Pulmonary System
			Ductus Arteriosus
			Heart
			Adrenal Glands
	References
39
Origins of Adipose Tissue and Adipose Regulating Hormones
	Adipose tissue
		Evolutionary Origins of Adipose Tissue Storage and Regulation
		White and Brown Adipose Tissue: Physiological Role and Developmental Origins
		Adipose Tissue Cell Lineage
	Brown adipose tissue
		Structure and Physiology
	White adipose tissue
		Structure and Physiology
	Neonatal and fetal adipose tissue development
		The Endocrine System and Adipose Tissue Regulating Hormones
		Adipose Tissue Regulating Hormones
	Cytokines
		Insulin
		Ghrelin
		Glucocorticoids
		Leptin
		Others
		Adiponectin
		Resistin
	Perspectives
	References
40
Fetal and Placental Growth Physiology and Pathophysiology
	Normal physiological growth of the fetus and placenta
		Normal Growth-Cell-Based
			Cell Replication in Development
		Totipotency, Pluripotency, and Differentiation
		Regulation of Cell Replication and Differentiation
		Cell Type-Specific Adaptation During Development
		Regulation of Growth
			Mechanistic Target of Rapamycin
	Developmental origins of health and disease
	Placental growth and development
		Evidence from Gene Targeting Studies
	Fetal growth and development
		Optimal Fetal Growth
		Normal Growth-Population-Based
		Parturition
		Antenatal Corticosteroid Therapy
	Neonatal, infantile, and early childhood growth and development
		Normal Neonatal, Infantile, and Early Childhood Growth
	Regulation of normal neonatal, infantile, and early childhood growth
	Summary and clinical implications
	References
41
Placental Production of Peptide, Steroid, and Lipid Hormones
	Introduction: The placenta-maternal endocrine interface
	Hypothalamic-pituitary hormone analogues
		Gonadotropin-Releasing Hormone/Gonadotropin
		Corticotrophin-Releasing Hormone/Pro-Opiomelanocortin Derivatives
		Somatotropins
	Growth factors
		Insulin-Like Growth Factors
		Vascular Endothelial Growth Factor Family
		Fibroblast Growth Factor Family
		Transforming Growth Factor β Family
		Activins and Inhibins
		Epidermal Growth Factor Family
	Adipokines
	Steroid hormones
		Progesterone
		Estrogens
		Glucocorticoid Metabolism
	Lipid mediators
		Prostanoids
		Prostanoids and Parturition
		Prostanoids and Pregnancy-Induced Hypertension/Preeclampsia
		Other Lipid Mediators
	Extravillous trophoblasts, syncytial fragments, microvesicles, exosomes, and cell free nucleic acids
		Exosomes
		Cell-Free Fetal Nucleic Acids
	References
Part E: Endocrine Disorders Affecting the Fetus or Neonate
42
Hypothalamic and Pituitary Disorders Affecting the Fetus and Neonate
	Introduction: Congenital disorders of hypothalamo-pituitary (H-P) development
	Combined pituitary hormone deficiencies (Table 42.1)
		Nonsyndromic CPHD
			PROP1 Mutations
			POU1F1 Mutations
		Syndromic CPHD
			Septo-Optic Dysplasia (SOD) and its Variants
			Hypopituitarism with Associated Learning Difficulties
			Holoprosencephaly
			Congenital Hypopituitarism with Neck or Cerebellar Abnormalities
			Other Syndromic Forms
	Isolated pituitary hormone deficiencies (Table 42.1)
		Isolated GH Deficiency
			IGHD Caused by GH1 Mutations
			IGHD Caused by GHRHR Mutations
			Other Genetic Factors and IGHD
		Isolated TSH Deficiency
		Isolated ACTH Deficiency
		Isolated Hypogonadotrophic Hypogonadism
		Isolated Central Diabetes Insipidus (ICDI)
	Acquired forms of neonatal hypopituitarism
	Approach to the neonate with suspected congenital hypopituitarism
	Management of congenital hypopituitarism presenting in the neonatal period
		GH Treatment
		Treatment of Micropenis and Cryptorchidism
		Levo-Thyroxine (L-T4) Treatment
		Hydrocortisone Treatment
		Desmopressin (DDAVP) Treatment
	Conclusions
	REFERENCES
43
Fetal and Postnatal Disorders of Thyroid Function
	Congenital hypothyroidism
		Newborn Screening
		Thyroid Dysgenesis
			General Features
			Thyroid Ectopy
			Athyreosis, Hypoplasia, and Hemiagenesis
			Genetics and Inheritance
			TSH Receptor Mutations
			Thyroid Transcription Factor Mutations
			NKX2-1
			FOXE1
			PAX8
			GLIS3
			HHEX
			NKX2.5
		Thyroid Dyshormonogenesis
			General Features
			Sodium-Iodine Symporter Defects
			Pendred Syndrome
			Thyroperoxidase Defects
			DUOX2 Defects
			Thyroglobulin (TG) Defects
			Iodotyrosine Deiodinase (IYD) Mutations
		Transient Neonatal Hyperthyrotropinemia and Hypothyroidism
			Iodine Deficiency
			Iodine Excess
			Maternal Factors
			Other Causes of Persistent Neonatal hyperthyrotropinemia
			Diagnosis and Management of TCH
		Thyroid Function and Prematurity
		Consumptive Hypothyroidism
		Central Congenital Hypothyroidism
	Evaluation of infants with a positive newborn screening test
		History and Physical Examination
		Laboratory Investigations
		Imaging
	Treatment of affected infants with congenital hypothyroidism
		Initial Therapy
		Follow-Up
	Neonatal hyperthyroidism
	Impaired sensitivity to thyroid hormone
		Thyroid Hormone Metabolism Defects
		Thyroid Hormone Cell Membrane Transport Defects
		Thyroid Hormone Action Defects
	Disorders of thyroid hormone transport
	References
44
Disorders of Calcium, Phosphorus, and Bone Metabolism During Fetal and Neonatal Development
	Introduction
	Absence of PTH (hypoparathyroidism, aparathyroidism, PTH receptor)
		Fetal Animal Data
		Neonatal Animal Data
		Human Data
		Clinical Management
	Pseudohypoparathyroidism
		Animal Data
		Human Data
		Clinical Management
	Primary hyperparathyroidism
	Absence of PTHrP
		Fetal Animal Data
		Neonatal Animal Data
		Human Data
		Clinical Management
	Absence of the PTH1R or both PTH and PTHrP
		Fetal Animal Data
		Fetal Neonatal Data
		Human Data
		Clinical Management
	Disorders of the CaSR
		Fetal Animal Data
		Neonatal Animal Data
		Human Data
		Clinical Management
	Vitamin D deficiency, genetic vitamin D resistance, and 24-hydroxylase deficiency
		Preamble About Rickets And Osteomalacia
		Fetal Animal Data: Vitamin D Deficiency and Genetic Vitamin D Resistance
		Fetal Animal Data: 24-Hydroxylase Deficiency
		Neonatal Animal Data: Vitamin D Deficiency and Genetic Vitamin D Resistance
		Neonatal Animal Data: 24-Hydroxylase Deficiency
		Human Data: Vitamin D Deficiency and Genetic Vitamin D Resistance
			Observational Studies and Case Reports
			Randomized Interventional Studies
			Associational Studies
			Overall Conclusions From Observational, Clinical Trial, and Associational Studies
		Human Data: 24-Hydroxylase Deficiency
		Clinical Management
			Vitamin D Deficiency
			VDDR-I and II
			24-Hydroxylase Deficiency
	Calcitonin deficiency
		Fetal Animal Data
		Neonatal Animal Data
		Human Data
	FGF23: Deficiency or excess
		Fetal Animal Data
		Neonatal Animal Data
		Human Data
		Clinical Management
	Sex steroid deficiency
		Animal Data
		Human Data
	Fetal and neonatal responses to maternal mineral disturbances
		Primary Hyperparathyroidism in the Mother
			Animal data
			Human Data
			Clinical Management
		Familial Hypocalciuric Hypercalcemia in the Mother
			Animal Data
			Human Data
			Clinical Management
		Hypoparathyroidism and Activating Mutations of the Calcium-Sensing Receptor in the Mother
			Animal Data
			Human Data
			Clinical Management
		Pseudohypoparathyroidism in the Mother
			Animal Data
			Human Data
			Clinical Management
		Vitamin D-Related Disorders in the Mother
			Animal Data
			Human Data
			Clinical Management
		Maternal Magnesium Infusions (Tocolytic Therapy)
		Hypercalcemia of Malignancy in the Mother
		Pseudohyperparathyroidism in the Mother
		Maternal Diabetes Causing Fetal and Neonatal Hypoparathyroidism
	Conclusions
	References
45
Pathophysiology and Management of Disorders of Carbohydrate Metabolism and Neonatal Diabetes
	Introduction
	In utero pathophysiological effects on fetal glucose
		Placental Dysfunction and Intrauterine Growth Restriction
		Maternal Diabetes
		Maternal Obesity
		Fetal Genotype
		Drugs
	Postnatal glucose metabolism
		Measurement of Glucose in the Newborn
		Defining Euglycemia in the Newborn
		Timing and Transition
	Hypoglycemia in the newborn
		Clinical Approach to Hypoglycemia
		Clinical Intervention and Investigation
	Transient hypoglycemia in infants at risk
		Preterm
		Small for Gestational Age and Growth Restriction
		Hypoxic-Ischemic Encephalopathy
		Infants of Diabetic Mothers
		Large for Gestational Age Babies
		Other Risk Factors
	Persistent or severe hypoglycemia
		Congenital Hyperinsulinism
		Disorders of Carbohydrate Metabolism/Inborn Errors of Metabolism
			Galactosemia
			Fructose-1,6-Diphosphatase (or Biphosphatase) Deficiency
			Glycogen Storage Diseases
			Maple Syrup Urine Disease
		Deficiencies of Counterregulatory Hormones
	Hyperglycemia in the newborn
		Prematurity
			Pathology
				Central Insulin Resistance: Hepatic Glucose Production
				Peripheral Insulin Resistance
				Relative Insulin Deficiency
					Feeding and Incretins
					Growth Restriction
					Pancreatic Glucose Sensitivity
			Clinical Consequences
				Primary Role of Hyperglycemia
				Relative Insulin Deficiency
				Association with Impaired IGF-I Generation
		Neonatal Diabetes Mellitus
			Transient Neonatal Diabetes Mellitus
			Permanent Neonatal Diabetes Mellitus
			Treatment and Prognosis
	Long-term consequences: Programming of glucose metabolism
		Small for Gestational Age
		Prematurity
		Infants of Diabetic Mothers
	Summary
	References
46
Intestinal Enteroendocrine Disorders in the Fetus and Neonate
	Part 1. Disorders resulting from defects in enteroendocrine cells
		NEUROG3
		PCSK1
		RFX6
		NEUROD1
		FOXP3
		ARX
		AIRE
		Gene Mutations that Could Affect Enteroendocrine Cell Populations
	Part 2. Disorders resulting from excess enteroendocrine hormone secretion
		Dumping Syndrome
	References
47
Disorders of the Adrenal Cortex in the Fetus and Neonate
	Ancient history of adrenal steroid disorders
	Adrenal development and function
	Signs and symptoms of adrenal disease in the newborn period
	Congenital adrenal hyperplasia
		21-Hydroxylase Deficiency
		Clinical Features of 21-Hydroxylase Deficiency
		11β-Hydroxylase Deficiency
		3β-Hydroxysteroid Dehydrogenase Deficiency
		StAR Protein Deficiency
		17-Hydroxylase/17, 20-Lyase Deficiency
	P450 oxidoreductase deficiency
	Prenatal diagnosis and treatment-Noninvasive prenatal diagnosis of CAH
	X-linked primary adrenal insufficiency
		Adrenal Hypoplasia Congenita
		Adrenoleukodystrophy
	Familial glucocorticoid deficiency
		Pathophysiology of ACTH Resistance
			Melanocortin 2 Receptor (MC2R) and Melanocortin 2 Receptor Accessory Protein (MRAP) Defects
			Lipoid CAH and CYP11A1 Defects
			Minichromosome Maintenance Complex Component 4 (MCM4) and Nicotinamide Nucleotide Transhydrogenase (NNT)
			Triple-A Syndrome
	Mineralocorticoid pathway defects
		Hyperaldosteronism
		Glucocorticoid-Remediable Hyperaldosteronism
		Pseudohypoaldosteronism
		Hypoaldosteronism
	Other causes of primary adrenal insufficiency (see Table 47.4)
		Steroidogenic Factor 1 Deficiency
		Zellweger Syndrome
		Wolman Syndrome
		Smith-Lemli-Opitz Syndrome
		IMAGe Syndrome
		MIRAGE Syndrome
		SGPL1 Mutations
		Secondary Adrenal Insufficiency
	References
48
Disorders of Sex Development
	Definitions
	Classification of DSD based on the karyotype
		46,XY DSD
		46,XX DSD
		Sex Chromosome DSD
	Pathogenesis of DSD
		Malformative DSD
			Defective Morphogenesis of the Müllerian Ducts
			Defective Morphogenesis of the Wolffian Ducts
			Defective Morphogenesis of the Cloaca and the Urogenital Sinus
			Defective Morphogenesis of the Primordia of the External Genitalia
		Dysgenetic DSD
			Dysgenetic DSD in 46,XY Patients
			Dysgenetic DSD in Patients with Mosaicisms/Chimerism Carrying a Y Chromosome
			Dysgenetic DSD in 46,XX Patients
			Gonadal Dysgenesis in Sex Chromosome Aneuploidies
		Nondysgenetic Sex Hormone-Dependent DSD
			46,XY Nondysgenetic DSD With Testicular Differentiation
				Disorders of Androgen Synthesis
				Disorders of Androgen Action
				Disorders of AMH Synthesis or Action
			46,XX Nondysgenetic DSD With Ovarian Differentiation
				Disorders of Adrenal Steroidogenesis
				Generalized Glucocorticoid Resistance
				Aromatase deficiency
				Maternal Sources: Androgens and Progestogens
	Diagnosis
		Assessment During Gestation
		Newborns with Ambiguous Genitalia
			Initial Assessment
				Physical Examination
				Laboratory
				Imaging
			Following Steps
				46,XY DSD
				46,XX DSD
				Chromosomal DSD
		Newborns with Normal External Genitalia and Discordant Karyotype
			46,XY DSD
			46,XX DSD
		Genetic Testing
	Management of the newborn with DSD
		Sex Assignment
			46,XY DSD with Female Genitalia
			46,XY DSD with Ambiguous Genitalia
			46,XX DSD with Male Genitalia
			46,XX DSD with Ambiguous Genitalia
			Chromosomal DSD
		Medical Treatment and Surgical Options
	Long-term outcomes
	References
49
Pathophysiological Roles and Disorders of Renin-Angiotensin-Aldosterone System and Nitric Oxide During Perina ...
	Renin-angiotensin-aldosterone system
		Dysfunction of RAAS in Fetus and Neonate
			Abnormal RAAS in the Placenta
				Placental Abnormal Secretion
				Placental Vascular Dysfunction
			Abnormal RAAS in Fetus and Neonate
				Abnormal RAAS in the Kidney
					Maternal Malnutrition
					Maternal High-Salt Diets
					Maternal Glucocorticoid Exposure
					Other Factors
				Altered RAAS in the Cardiovascular System
				Abnormal RAAS in the Central Nervous System
		Diseases Related to RAAS Dysfunction
			Preterm Birth
			Kidney Disorders
				Developmental Programming of Kidney Diseases
					Prenatal Glucocorticoids Exposure
					High Salt Intake
					Intrauterine Growth Restriction
					Sex differences in Programmed Renal Hypertension
				Genetic Renal Disorders
					Renal Tubular Dysgenesis (MIM 267430)
					Hyperuricemic Nephropathy, Familial Juvenile 2 (MIM 613092)
			Aldosteronism-Related Diseases
				Primary Aldosteronism
				Primary Hypoaldosteronism
	Pathophysiological roles of nitric oxide in maternal, fetal, and neonatal diseases
		Pregnant Mother
			Nitric Oxide (NO) and Preeclampsia
			Nitric Oxide and Gestational Diabetes
		Fetus and Neonate
			Nitric Oxide and Intrauterine Growth Restriction (IUGR)
			Nitric Oxide and Early Embryo Loss
			NO and Neonatal Pulmonary Hypertension
	References
50
Obesity/Perinatal Origins of Obesity
	Background
	What is obesity?
		Fetal Macrosomia
			Clinical Findings
			Ultrasonography
			Magnetic Resonance Imaging
		Neonatal Obesity
			Body Mass Index
			Body Composition
	Developmental origins of health and disease
		From Epidemiological Studies to DOHAD
		``U´´-Shaped Relationship
	Hypothalamus-adipose axis
		Hypothalamus
			Appetite Regulatory Pathway
			The Action of Neuropeptides Expressed by Neurons in the Arcuate Nucleus
		Adipose Tissue
			Role of Adipose Tissue
			Types of Adipose Tissue
	The mechanism leading to perinatal origins of obesity
		Circulating Factors
		Epigenetics
			Epigenetic Mechanism
			Examples of Epigenetic Modification
			Transgenerational Epigenetic Modification
			Gender-Specific Effect of Perinatal Programming of Obesity
	Environmental insults resulting in the perinatal programming of obesity
		Maternal Nutrition
			Maternal Undernutrition
			Maternal Overnutrition
		Maternal Glucose Control
		Multiple Births
		Placental Insufficiency
		Birthweight
		Gestational Age
		Weight Gain in Early Infancy
		Nutrition in Early Infancy
	Complication of obesity
		Fetal Macrosomia
			Maternal Risks
			Neonatal Risks
		Early Childhood Obesity
			Obesity in Adulthood
			Metabolic Syndrome
			Insulin Resistance
			Cardiovascular
			Nonalcoholic Fatty Liver Disease
			Respiratory Disorders
			Orthopedic Disorder
			Psychological Impact
	Conclusion
	References
51
Abnormal Fetal Growth
	Introduction
	Definitions and terminology issues for the abnormally small or large fetus and neonate
		Small for Gestational Age Fetus and Newborn
		Large for Gestational Age Fetus and Newborn
	Accurate determination of newborn anthropometry
	Understanding the etiology of growth disorders in the fetus
	Causes and consequences of fetal growth restriction
		Twin or Multiple Gestation Pregnancies
		Constitutionally Small Fetus
		Trisomy 13, 18, and 21
		Turner Syndrome and Abnormal Fetal Growth in Sex Chromosome Deletions
		Unexplained Postnatal Growth and the Importance of a Second Look at BL and BW
		Uniparental Disomy for Chromosomes 6, 7, 11, 14, 15, 16, or 20
	Specific syndromes associated with birth of an SGA infant with relative macrocephaly
		Silver-Russell Syndrome
		Temple Syndrome
		3-M Syndrome
		Mulibrey Nanism
		Short Syndrome
		Floating-Harbor Syndrome
		IMAGe Syndrome
		MIRAGE Syndrome
		Primordial Microcephalic Dwarfism
		Meier-Gorlin Syndrome
		Seckel Syndrome
		Microcephalic Osteodysplasitic Primordial Dwarfism, Type I/III (MOPDI/III) or Tabi-Linder Syndrome
		Microcephalic Osteodysplastic Primordial Dwarfism, Type II (MOPDII)
	Specific genetic defects in the insulin-like growth factor axis and insulin axis associated with FGR and postnatal  ...
		IGF-I Deficiency
		IGF-I Resistance/Insensitivity
		IGF-II Deficiency
		Insulin Receptor Gene Defects
		ZFP57 Mutations and Related Molecular Changes Causing TNDM
		Defective Genes Involving Pancreatic Development
	Causes and consequences of being born large for gestational age
		Chromosomal Abnormalities Associated with Generalized Prenatal Overgrowth
		Syndromes Associated with Excess Fetal Growth/LGA
			Beckwith-Wiedemann Syndrome
			Sotos Syndrome
			Perlman Syndrome
			Simpson-Golabi-Behmel Syndrome
			Weaver Syndrome
			Costello Syndrome
	Conclusion and future directions
	References
Part F: New Diagnostic Technologies
52
New Technologies in Pre- and Postnatal Diagnosis
	Benefits and caveats for the clinician using genomics technologies
	DNA sequencing
		Next-Generation Sequencing Technology Overview
		What is Used for the ``Reference´´ or ``Normal´´ Genome?
		Whole-Genome, Whole-Exome, and Targeted-Gene Panels
			Whole-Genome Sequencing
			Exome Sequencing
			Candidate-Gene Panels
		Reporting of Genomic-Sequence Data
		Copy Number Variants and Other Large-Scale Chromosomal Rearrangements
		Mosaicism
		Mitochondrial Genomics
		RNA-Sequencing and Transcriptomics
		The Microbiome
		Helpful Reference Databases
		Next-Generation Sequencing in Endocrinology
		An Example
	Proteomics and metabolomics
		Introduction to Analytical Approaches
		Key Techniques
			Sample Workup
			Separation
			Detection
		Proteomics
		Metabolomics
		Bioinformatics
			Clinical Example-Newborn Screening
	Cell-free fetal DNA testing
		Methodology of CELL-FREE Fetal DNA Testing
		Current Recommendations about the use of Cell-Free Fetal DNA in Practice
		Ethical and Social Issues Raised by the use of Cell-Free Fetal DNA Testing
		Ethical Issues of Genetic and Genomic Tests in General
	REFERENCES
Index
Back Cover