Ovarian Aging

Preface
Contents
Editors and Contributors
Contributors
Part I: The Basic Issues of Ovarian Aging
	1: Overview of Ovarian Aging: Why Do We Need to Discuss
		1.1	 Aging and Organ Aging
		1.2	 The History of Ovarian Aging Research
		References
	2: The Life Cycle of the Ovary
		2.1	 The Genesis of the Ovary
			2.1.1	 Sexual Undifferentiation: Primitive Gonad Formation
				2.1.1.1	 Genital Crest Formation
					The Gonadal Primordium
					PCG Formation
						The Source
						PGC Specialization
						PGC Migration
			2.1.2	 Sexual Differentiation: Gonad Formation
				2.1.2.1	 Ovary Differentiation
					Determining Factors
						The Forkhead Box L2 (FOXL2) Gene
						WNT4, R-Spondin 1 (RSPO1), and β-Catenin Genes
						GATA Binding Proteins 4 and 6 (GATA4, GATA6) and FOG Family Member 2 (FOG2)
				2.1.2.2	 Oocyte Development
					Primordial Follicular Pool Formation
				2.1.2.3	 Ovarian Development Summary
		2.2	 Growth and Maturation of the Ovarian Function
			2.2.1	 Follicles and Their Surroundings
				2.2.1.1	 The Follicle
					Oocytes
					Granulosa Cells
					Theca Cells
				2.2.1.2	 The Follicle Surroundings
					Steroid-Producing Cells in the Ovary
					Ovarian Stroma
					Ovarian Surface Epithelium
					Ovarian Leukocytes
					Ovarian Innervation, Neurotrophic Factors, and Tachykinin
					Ovarian Stem Cells
			2.2.2	 Follicular Growth
				2.2.2.1	 Oocyte Growth
				2.2.2.2	 Factors Affecting Follicular Growth
			2.2.3	 Ovarian Maturation
				2.2.3.1	 Follicle Maturation
					Antral Follicle Formation
					Dominant Follicle Recruitment and Selection
					Ovulation
					Oocyte Maturation
					Meiosis Restoration
					Cytoplasmic Maturation
				2.2.3.2	 Follicular Atresia
				2.2.3.3	 The Formation, Function, and Dissolution of the Corpus Luteum
					Formation
					Luteolysis
		2.3	 Ovarian Function Prosperity
			2.3.1	 Ovarian Hormone Secretions and Pathway Regulations
				2.3.1.1	 Steroid Hormones
					Cytochrome P450
						Cholesterol Side-Chain Cleavage Enzyme (scc; P450scc, Encoded by CYP1A1)
						17α-Hydroxylase/17,20-Lyase (P450c17, Encoded by CYP17A1)
						Aromatase (p450Aro, Encoded by CYP19A1)
						11β-Hydroxylase and 11β-Hydroxysteroid Dehydrogenase (p450c11β and p450c11AS, Encoded by CYP11B1 and CYP11B2, Respectively)
					Hydroxysteroid Dehydrogenases (HSDs)
						3β-Hydroxysteroid Dehydrogenase/Δ5-4-Isomerase/3β-Hydroxysteroid Dehydrogenase (i.e., 3β-HSD/Δ5-4-Isomerase)
						17β-Hydroxysteroid Dehydrogenases (17β-HSDs)
						17β-HSD1
						17β-HSD2
					Estrogen
						The Reproductive System
						Mammary Glands and Secondary Sexual Characteristics
						The Hypothalamus and Pituitary Gland
						The Metabolic System
						Bones
						The Cardiovascular System
						The Central Nervous System
						Skin
						The Blood System
					Androgen
						The Reproductive System
						Metabolism
						The Vascular System
						Progesterone
						The Reproductive System
						The Hypothalamus and Pituitary Gland
						Mammary Glands
						Metabolism
						The Nervous System
						The Respiratory System
						The Skin
				2.3.1.2	 Protein Hormones
					IHN
					Act
					AMH
					GnRH
					Relaxin and Relaxin-Like Factors
			2.3.2	 Ovarian Hormone Secretion and Regulation
				2.3.2.1	 Ovarian Function Regulation
					Hypothalamus and Pituitary Gland Regulation of Ovarian Function
				2.3.2.2	 Gonadotropin Synthesis and Regulation in the Pituitary Gland
					LH and FSH
					Differential LH and FSH Regulation
					Differential Regulation of GnRH on LH and FSH
					Autocrine and Paracrine Regulation of Gonadotropins
				2.3.2.3	 The Feedback System Between the Ovaries and the Hypothalamus and Pituitary Gland
					Negative Feedback
						Estrogen
						Progesterone
						IHN A and IHN B
						Act and FST
						Gonadotropin Release Inhibitor
					Positive Feedback
						Estrogen
						Progesterone
						IHN A
							Kisspeptin
				2.3.2.4	 The Influence of Other Endocrine Hormones on Ovarian Function
					Adrenal Cortex Hormones
					Thyroid Hormones and Ovarian Function
					Insulin, Opioid Peptides, and Oxytocin
						Insulin
						Opioid Peptides
						Oxytocin
				2.3.2.5	 Conclusions
		2.4	 Ovarian Function Decline
		2.5	 Ovarian Activity Loss
		References
	3: The Systemic Effects of Ovarian Aging
		3.1	 The Reproductive System
			3.1.1	 Reproductive Function
				3.1.1.1	 Fertility Decline
					Pregnancy Rate Decrease
					Miscarriage Rate Increase
					Live Birth Rate Decrease
				3.1.1.2	 Fertility Quality Decline
			3.1.2	 Endocrine Function
				3.1.2.1	 Ovarian Hormone Secretion
					Estrogen
						A. E2
						E1
					Androgens
						Androstenedione
						Testosterone
						Dehydroepiandrosterone and its Sulfate
					Progesterone
					AMH
					INH
					Activin (Act)
				3.1.2.2	 Local Ovarian Secretion Factors
					Insulin-like Growth Factor
					Interleukin 33
			3.1.3	 Reproductive Organ Morphology
				3.1.3.1	 The Ovaries
					Histology
					Pathology
						Ovarian Interstitial Hyperplasia
						Follicular Hyperplasia
						Leydig Cell Proliferation in the Hilum of the Ovary
				3.1.3.2	 The Uterus
					The Cervix
					The Uterine Body
					The Endometrium
				3.1.3.3	 The Fallopian Tubes
				3.1.3.4	 The Vagina
				3.1.3.5	 The Vulva
			3.1.4	 Menstruation Changes
				3.1.4.1	 The Menstrual Cycle
					A Shortened Menstrual Cycle
					A Prolonged Menstrual Cycle
					An Irregular Menstrual Cycle
			3.1.5	 Sexual Function
			3.1.6	 Conclusions
		3.2	 The Nervous System
			3.2.1	 The Pathophysiological Processes of Ovarian Aging on the Nervous System
				3.2.1.1	 Interactions Between Ovarian Aging and the Nervous System
				3.2.1.2	 The Effects of Estrogen on the Nervous System
					The Expression and Function of Estrogen Receptors (ERs) in the Brain
					Neuron Protective Mechanisms
					The Effects of Estrogen on Classical Neurotransmitters
						Cholinergic System
						Dopaminergic System
						Serotonin System
					The Critical Period Hypothesis: The Effects of Estrogen on Cognition
				3.2.1.3	 The Effects of an Aged Nervous System on GnRH
					Glutamate
					Gaba
					Kisspeptin
					Glial Cell Morphology
		3.3	 The Motor System
			3.3.1	 Bone
				3.3.1.1	 Bone Metabolism
				3.3.1.2	 Estrogen and Bone Metabolism
					The History of Estrogen’s Effect on Bone Metabolism
					Estrogen and Bone Cells
						Osteoclasts
						Osteoblasts
						Indirect Regulation of Estrogen on Bone Metabolism
					FSH and Bone Metabolism
				3.3.1.3	 Muscle
				3.3.1.4	 The Bones and Joints
			3.3.2	 Conclusions
		3.4	 The Cardiovascular System
			3.4.1	 The Cardiovascular System
				3.4.1.1	 Epidemiology
				3.4.1.2	 Ovarian Function and CVD
					E2
						Direct Action on Blood Vessels
						Decrease of the Blood Vessel Tension
						Protection of the Endothelial Cells
						Inhibition of the Vascular Calcification
						Effects on the Myocardium
					Androgens
					Progesterone
				3.4.1.3	 Ovarian Aging and CVD
					Diminished Ovarian Reserve
					Premature Ovarian Insufficiency
					Turner Syndrome
					Menopause
			3.4.2	 Conclusions
		3.5	 The Urinary System
			3.5.1	 Epidemiology
			3.5.2	 Ovarian Aging and the Gynecological Urinary System
				3.5.2.1	 The Pathophysiological Processes and Mechanisms of ER, PR, and AR on the Urogenital System
					Estrogen and Androgens
					ER and UI
					ER and POP
					PR and Urethral Function
					The Effects of Estrogen and Androgens on the Pelvic Floor
				3.5.2.2	 Ovarian-Related Hormones and Chronic Pain Syndrome
			3.5.3	 The Clinical Manifestations of Urinary and Pelvic Floor Function with Ovarian Age
				3.5.3.1	 The Urinary System
				3.5.3.2	 The Pelvic Floor Function
			3.5.4	 Summary and Prospects
		3.6	 The Skin and Microecology
			3.6.1	 Ovarian Aging and the Skin
				3.6.1.1	 Introduction
				3.6.1.2	 Structure and Function Loss
					Structural Changes
					Functional Changes
						Wound Healing
						Thermoregulation
						Other Functional Changes
				3.6.1.3	 The Effects of Estrogen
					Skin Thinning
					Skin Wrinkling
					Skin Dryness
					Wound Healing
						The Inflammatory Phase
						The Proliferative Phase
						The Remodeling Phase
				3.6.1.4	 Conclusions
			3.6.2	 Ovarian Aging and Female Microbiota
				3.6.2.1	 Vaginal Flora
				3.6.2.2	 Intestinal Flora
				3.6.2.3	 Oral Flora
				3.6.2.4	 Conclusions
		References
	4: Ovarian Aging Etiology and Risk Factors
		4.1	 Age-Related Factors
		4.2	 Genetics
			4.2.1	 I. Heritability
			4.2.2	 Nuclear Genome
				4.2.2.1	 Chromosomal Abnormalities
					45,X and 45,X/46,XX Mosaicism
					Trisomy X Syndrome (47,XXX)
					Structurally Abnormal X or X-Autosome Translocations
				4.2.2.2	 Telomere Shortening and Decreased Telomerase Activity
				4.2.2.3	 Submicroscopic Structural Changes: Copy Number Variations (CNV)
				4.2.2.4	 Genes and Mutations
					The Pathogenic Genes Associated with a POF-Inducing Inherited Syndrome
					POF Candidate Genes
				4.2.2.5	 Genetic Polymorphisms
		4.3	 The Hypothalamus and Pituitary Factors
			4.3.1	 Neuroendocrine System-Driven Aging
				4.3.1.1	 Questions
					What Defines the Starting Point of Ovarian and Neuroendocrine Aging?
					How Are the Relationships at the Molecular, Cellular, and Organ Levels Coordinated?
					Would the Ovaries and Other Organs Be an Ideal Experimental Model If They Could Be Independently Studied?
					How Do the Thymus and Skin Initiate Ovarian Aging Outside the HPO Axis?
					What Other Elements Are Critical Regulators of the Body?
			4.3.2	 An Introduction to the Neuroendocrine System
				4.3.2.1	 The Hypothalamus
				4.3.2.2	 The Pituitary Gland
				4.3.2.3	 Adenohypophyseal Hormone Regulation
			4.3.3	 Neuroendocrine System Aging
				4.3.3.1	 GnRH Regulates Ovarian Aging
				4.3.3.2	 The Circadian Clock Regulates the Hypothalamic-Pituitary System
					The Biological Clock (i.e., Circadian Rhythm)
					Influences on the HPO Axis
				4.3.3.3	 The Extragonadal Effects of FSH
					The FSH Mechanism in Osteoporosis
					The FSH Mechanism in Cardiovascular Disease
			4.3.4	 Conclusions
		4.4	 Social and Psychological Factors
			4.4.1	 Stress
				4.4.1.1	 Stress and Ovarian Function
					Ovarian Function Decline
					Stress Mechanisms
						The Hypothalamic Level
						The Pituitary Level
						The Ovarian Level
				4.4.1.2	 Glucocorticoids and Ovarian Function
					Stress Mechanisms
						The Hypothalamic Level
						The Pituitary Level
						The Ovarian Level
				4.4.1.3	 Conclusions
			4.4.2	 Adverse Psychological Factors
			4.4.3	 Educational Level and Social Status
			4.4.4	 Conclusions
		4.5	 Environmental Factors
			4.5.1	 Air Pollution
			4.5.2	 EDCs
				4.5.2.1	 Heavy Metals
					Lead
					Mercury
					Cadmium
				4.5.2.2	 PAHs
				4.5.2.3	 PCBs
				4.5.2.4	 Pesticides
				4.5.2.5	 BPA
				4.5.2.6	 PAEs
				4.5.2.7	 PBs
				4.5.2.8	 Others
					Perfluorinated Compounds (PFCs)
					4-Vinylcyclohexene (VCH) and 4-Vinylcyclohexene Double-Loop Oxide (VCD)
					Triclosan
				4.5.2.9	 Conclusions
			4.5.3	 Occupational Exposure
				4.5.3.1	 Anesthetic Gas
				4.5.3.2	 Electromagnetic Radiation
				4.5.3.3	 Noise
			4.5.4	 Conclusions
		4.6	 Behavioral Factors
			4.6.1	 Smoking
				4.6.1.1	 Smoking and Menopausal Age
				4.6.1.2	 Smoking and Ovarian Reserve
					Smoking and the Follicle Number
					Smoking and AMH
					Smoking and Hormone Secretion
				4.6.1.3	 Conclusions
			4.6.2	 Alcohol Consumption
				4.6.2.1	 Alcohol Consumption and Menopausal Age
				4.6.2.2	 Alcohol Consumption and Ovarian Reserve
					Alcohol Consumption and Follicle Number
					Alcohol Consumption and AMH
					Alcohol Consumption and Hormone Secretion
				4.6.2.3	 Conclusions
			4.6.3	 High-Fat Diets and Obesity
				4.6.3.1	 Obesity and Ovarian Reserve
					Decreased Ovarian Reserve
					Mechanisms of Diet-Induced Ovarian Reserve Decline
					HFD, Obesity, and Ovarian Endocrine Function
			4.6.4	 Oral Contraceptives
				4.6.4.1	 Oral Contraceptives and the Biological Menopausal Age
				4.6.4.2	 Oral Contraceptives and the Ovarian Reserve
			4.6.5	 Sleep
			4.6.6	 Conclusions
		4.7	 Iatrogenic Factors
			4.7.1	 Chemotherapy
				4.7.1.1	 High-Risk Chemotherapy Drugs
				4.7.1.2	 Medium-Risk Chemotherapy Drugs
					Platinum Drugs
					Anthracyclines
				4.7.1.3	 Low-Risk Chemotherapy Drugs
					Antimetabolites
					Vinblastine
				4.7.1.4	 Other Chemotherapy Drugs
					Irinotecan and Etoposide (Topoisomerase Inhibitor)
					Arsenic Trioxide (ATO)
			4.7.2	 Radiotherapy
			4.7.3	 Surgical Interventions
				4.7.3.1	 Ovariectomy
					Ovarian Mass Removal Surgery
					Ovarian Puncture
					Hysterectomy
					Internal Iliac Artery or Uterine Artery Embolization
					Salpingectomy (Fallopian Tube Resection)
			4.7.4	 Other Iatrogenic Factors
				4.7.4.1	 The Human Papillomavirus (HPV) Vaccine
				4.7.4.2	 ART
				4.7.4.3	 Other Drugs
			4.7.5	 Conclusions
		4.8	 Immunological Factors
			4.8.1	 Abnormal Humoral Immunity
				4.8.1.1	 AOAs
				4.8.1.2	 Other Antibodies
			4.8.2	 Abnormal Cellular Immunity
				4.8.2.1	 CD4 Cells
				4.8.2.2	 CD8 Cells
				4.8.2.3	 The Ratio of CD4 to CD8 Cells
				4.8.2.4	 Natural Killer (NK) Cells
				4.8.2.5	 B Cells
			4.8.3	 Cytokines
				4.8.3.1	 IFN
				4.8.3.2	 IL-1
				4.8.3.3	 IL-6
				4.8.3.4	 Others
			4.8.4	 MHC Antigens
			4.8.5	 The Complement System
			4.8.6	 Other Autoimmune Diseases
			4.8.7	 Conclusions
		4.9	 Infectious Factors
			4.9.1	 I. MuV
			4.9.2	 Human Immunodeficiency Virus (HIV)
			4.9.3	 M. tuberculosis
			4.9.4	 Pelvic Inflammatory Disease (PID)
			4.9.5	 Other Risk Factors
			4.9.6	 Conclusions
		4.10	 Endocrine Factors
			4.10.1	 Thyroid Disease
				4.10.1.1	 Thyroid Hormone and Follicular Development
				4.10.1.2	 Hyperthyroidism and Ovarian Function
				4.10.1.3	 Hypothyroidism and Ovarian Function
			4.10.2	 Metabolic Diseases and Ovarian Aging
				4.10.2.1	 Diabetes and Ovarian Aging
					The Effects of Diabetes on the HPO Axis
					Diabetes, Ovarian Cells, and Follicular Development Disorder
						Abnormal Insulin Levels and Follicular Development
						The Effect of Hyperglycemia on Granulosa Cell Apoptosis
						The Effect of Hyperglycemia on the Mitochondrial Function of Oocytes
						The Effects of AGEs on Follicular Development
						The Effects of Hyperglycemia on the Adenosine Monophosphate (AMP)-Activated Protein Kinase (AMPK) Pathway
				4.10.2.2	 The Effects of the IGF and Insulin-Like Growth Factor Binding Protein (IGFBP) Systems on Ovarian Aging
					The Effects of IGFs on Ovarian Aging
					The Role of IGFBP in Ovarian Follicular Dominance, Follicular Atresia, and Granulosa Cell Apoptosis11
				4.10.2.3	 Metabolic Syndrome (MS)
			4.10.3	 Abnormal Enzymes and Ovarian Aging
			4.10.4	 Nutrition and Ovarian Aging
			4.10.5	 Conclusions
		References
	5: The Cellular and Molecular Mechanisms of Ovarian Aging
		5.1	 Primordial Follicle Activation and Follicular Atresia
			5.1.1	 I. PFA Molecular Mechanisms
				5.1.1.1	 Inhibitory Factors
					Anti-Müllerian Hormone (AMH)
					Phosphatase and Tensin Homolog (PTEN)
					Forkhead Box O3 (FOXO3a)
					Forkhead Box Protein L2 (FOXL2)
					Tuberous Sclerosis Proteins (TSC)
					Yes-Associated Protein (YAP)
				5.1.1.2	 Irritating Factors
					Kit
					PI3K
					mTORC1
					Insulin
				5.1.1.3	 Conclusions
			5.1.2	 Follicular Atresia
				5.1.2.1	 Apoptosis
					Apoptotic Stages
						Stage One: Signal Transduction
						Stage Two: Gene Activation
						Stage Three: Execution
						Stage Four: Clearance
				5.1.2.2	 Apoptosis in Follicular Atresia
					The Primordial Follicle Stage
					The Preantral Follicle Stage
					The Early Antral Follicle Stage
					The Pre-ovulation Follicle Stage
					The Periovulatory Follicle Stage
				5.1.2.3	 Autophagy and Follicular Atresia
			5.1.3	 Conclusions
		5.2	 Gene Mutations, DNA Damage, and Ovarian Aging
			5.2.1	 DNA Damage and Ovarian Aging
				5.2.1.1	 DNA Damage and Oocyte Function
					DNA Damage and Oocyte Apoptosis
					DNA Damage and the Cell Cycle in Germinal Vesicle (GV) Oocytes
					DNA Damage and Primordial Follicle Development
				5.2.1.2	 DNA Damage and Granulosa Cell Function
				5.2.1.3	 Factors Influencing DNA Damage
					Environmental Factors
						Heavy Metals
						Environmental Endocrine Disruptors
					Medical Factors
						A. Chemotherapy Drugs
						Radiotherapy
					Behavioral Factors
			5.2.2	 Conclusions
		5.3	 Epigenetic Modification and Ovarian Aging
			5.3.1	 DNA Methylation
				5.3.1.1	 DNA Methylation
				5.3.1.2	 DNA Methylation and Aging
				5.3.1.3	 DNA Methylation and Ovarian Aging
			5.3.2	 Histone Modification and Ovarian Aging
				5.3.2.1	 An Introduction to Histone Modifications
					Histone Modifications
					Histone Methylation
					Other Histone Modifications
				5.3.2.2	 Histone Modification and Aging
					Histone Acetylation
					Histone Methylation
					Histone Modifications and Ovarian Aging
					Histone Modifications and Genes Related to Ovarian Hormone Synthesis
						StAR
						LHR
				5.3.2.3	 ncRNA and Ovarian Aging
					miRNA
						Follicle Development
						Primordial Follicle Activation and Maintenance
						Growing Follicle Development and Maturation
						Follicular Quality
						Granulosa Cell Function
				5.3.2.4	 LncRNA and Ovarian Aging
				5.3.2.5	 circRNA and Ovarian Aging
			5.3.3	 Conclusions
		5.4	 Telomerases
			5.4.1	 Introduction
			5.4.2	 Follicular Development
			5.4.3	 Ovarian Aging
				5.4.3.1	 Natural Ovarian Aging
				5.4.3.2	 POF
				5.4.3.3	 Telomerase and Sex Hormone Regulation
			5.4.4	 Influencing Factors
			5.4.5	 Conclusions
			5.4.6	 Attachments
				5.4.6.1	 Milestone Events Related to Telomere and Telomerase [192]
					Telomeres
					Telomeres and Chromosome Integrity
					Immortalization of Cultured Cells
					Challenging the Concept of Immortal Cells
					The End Replication Problem
					Cellular Senescence Hypothesis
					Protozoa Telomeres Are Composed of Tandem Repeats
					Telomerase
					Human Telomeres Shorten with Age
					Telomere Binding Protein
					Telomere Shortening
					Human Telomerase
					Telomeres and HeLa Cells
					Cancer
					hTERT
		5.5	 Mitochondrial Dysfunction and Ovarian Aging
			5.5.1	 Mitochondrial Structure and Function
				5.5.1.1	 Mitochondrial Structure
				5.5.1.2	 Mitochondrial Function
					Energy Transformation: Mitochondrial OXPHOS
					Calcium Ion Storage and Maintaining Calcium Homeostasis
					OS
					Regulating Cell Apoptosis
			5.5.2	 Mitochondrial Dysfunction and Aging
				5.5.2.1	 Mitochondrial Function and Aging
				5.5.2.2	 Mitochondrial Function and Stem Cell Senescence
			5.5.3	 Mitochondrial Dysfunction and Ovarian Aging
				5.5.3.1	 Mitochondrial Numbers
				5.5.3.2	 Mitochondrial Morphology
				5.5.3.3	 Mitochondrial DNA Copy Number
				5.5.3.4	 Mitochondrial DNA Deletions and Mutations
				5.5.3.5	 Cell-Free DNA (cfDNA)
				5.5.3.6	 Key Mitochondrial Function Genes
			5.5.4	 Conclusions
		5.6	 Free Radicals and Ovarian Aging
			5.6.1	 Free Radicals and the Antioxidant System
				5.6.1.1	 Free Radicals
				5.6.1.2	 The Antioxidant System
			5.6.2	 Free Radicals and Aging
				5.6.2.1	 Free Radicals and Lifespan
				5.6.2.2	 Free Radicals Aging Theories
			5.6.3	 Free Radicals and Ovarian Aging
				5.6.3.1	 The Physiological Functions of ROS in the Ovaries
					ROS Participates in Follicular Development and Oocyte Maturation
					ROS Participates in Hormone Synthesis Regulation
					ROS Participates in Ovulation
					ROS Regulates Luteal Degeneration
				5.6.3.2	 Free Radical Damage Advances Ovarian Aging
			5.6.4	 Conclusions
		5.7	 The Ovarian Microenvironment and Aging
			5.7.1	 The Ovarian Microenvironment
				5.7.1.1	 The Ovarian Immune Microenvironment
				5.7.1.2	 The Ovarian ECM
				5.7.1.3	 The Ovarian Vascular System
			5.7.2	 The Ovarian Microenvironment and Ovarian Aging
				5.7.2.1	 The Immune Microenvironment
					Macrophages
					Lymphocytes
					Immune Cytokines
					Age-related secretory phenotypes
				5.7.2.2	 Ovarian ECM and Ovarian Aging
				5.7.2.3	 The Ovarian Vascular System and Ovarian Aging
					Ovarian Blood Vessels
					Ovarian Lymphatic Vessels
			5.7.3	 Conclusions
		5.8	 Other Mechanisms of Ovarian Aging
			5.8.1	 FGSCs and Ovarian Aging
				5.8.1.1	 FGSCs
				5.8.1.2	 FGSC Differentiation and Self-Renewal
				5.8.1.3	 FGSCs and Ovarian Aging
			5.8.2	 Cellular Senescence and Ovarian Aging
				5.8.2.1	 Senescent Cells
				5.8.2.2	 Cellular Senescence and Ovarian Aging
					Chemotherapy-Induced Ovarian Injury Protection
					Improving the Ovarian Function of Patients with Diminished Ovarian Reserve (DOR)
		References
Part II: The Clinical Management of Ovarian Aging
	6: Evaluation and Early Warning Systems of Ovarian Aging
		6.1	 Markers of Ovarian Aging
			6.1.1	 Age
			6.1.2	 Menstrual Patterns
			6.1.3	 Endocrine Markers
				6.1.3.1	 Static Markers
					FSH, FSH/LH Ratio, and E2
						FSH
						The FSH/LH Ratio
						E2
					AMH
					Inhibin B
					Activin
				6.1.3.2	 Dynamic Markers
					CCCT
					GAST
					EFORT
			6.1.4	 Imaging Examination
				6.1.4.1	 Ultrasonic Markers
					AFC
					OV
					Ovarian Stromal Blood Flow
						Spectral Doppler Blood Flow Parameters
						3D Power Doppler Blood Flow Parameters
				6.1.4.2	 Other Image Examinations
					CT
					MRI
			6.1.5	 Histological Examination
			6.1.6	 Other Potential Markers
				6.1.6.1	 Metabolic Markers
				6.1.6.2	 Dehydroepiandrosterone (DHEA)
				6.1.6.3	 Insulin-Like Growth Factor-1 (IGF-1)
			6.1.7	 Summary
		6.2	 Evaluation of Ovarian Aging
			6.2.1	 Evaluation of Ovarian Aging
				6.2.1.1	 DOR
				6.2.1.2	 POR
				6.2.1.3	 POI
				6.2.1.4	 Early Menopause
			6.2.2	 Individualized Functional Assessment and Ovarian Age
			6.2.3	 Summary
		6.3	 Early Warning Systems of Ovarian Aging and Related Diseases
			6.3.1	 Prediction of Age at Menopause
				6.3.1.1	 Endocrine Markers
					FSH
					AMH
				6.3.1.2	 Ultrasound Markers
				6.3.1.3	 Other Markers: Genetic Markers
			6.3.2	 Prediction of Reproductive Potential
				6.3.2.1	 Age
				6.3.2.2	 Menstrual Changes
				6.3.2.3	 Endocrine Markers
					FSH
					AMH
					Inhibin B
					E2
					The FSH/LH Ratio
				6.3.2.4	 Ultrasound Markers
				6.3.2.5	 Other Predictive Indicators
					CCCT
					GAST
			6.3.3	 Risk Prediction of Diseases Related to Ovarian Aging
				6.3.3.1	 Prediction of the Risk of CVD Associated with Ovarian Aging
					Age at Menarche
					Age at Menopause
					Duration of Reproductive Life Span
					AMH
					E2
					Vasomotor Symptoms
			6.3.4	 Susceptibility of Ovarian Aging (SOA) Test
		References
	7: Prevention and Management of Ovarian Aging
		7.1	 Prevention and Treatment Strategies
			7.1.1	 Popular Science Education
			7.1.2	 Sociopsychological Support
			7.1.3	 Lifestyle Interventions
			7.1.4	 Genetic Counseling
			7.1.5	 Ovarian Protection against Medical Injuries
			7.1.6	 Management of Fertility-Related Issues
			7.1.7	 Hormone Replacement Therapy
			7.1.8	 The Frontier of Exploration
		7.2	 Hospital Education and Management of Ovarian Aging
			7.2.1	 Health Education for Patients
			7.2.2	 Continuing Medical Education
			7.2.3	 Ovarian Aging Characteristic Professional Subjects
		7.3	 Menopause Hormone Therapy
			7.3.1	 Historical Overview of MHT Applications
			7.3.2	 Clinical Applications of MHT
				7.3.2.1	 General Principles for Using MHT
				7.3.2.2	 MHT Risk-Benefit Assessment
				7.3.2.3	 Therapeutic Options
				7.3.2.4	 Implications for Practice and Patient Education
			7.3.3	 Problems and Future Directions of MHT
		7.4	 Clinical Management of POI and DOR
			7.4.1	 Clinical Management of POI
				7.4.1.1	 General Management of POI
					POI and Life Expectancy
					POI and Bone Health
					POI and Cardiovascular Health
					POI and Quality of Life
					POI, Sexual Desire, and Genitourinary System Function
						Transvaginal Estrogen
						Drugs to Improve Libido
							Tiburon
							Testosterone
						Vaginal Lubricants
					POI and Nervous System Function
					POI and Endocrine System Health
						Thyroid Function
						Adrenal Function
						Diabetes
					Management of the Relatives of Patients with POI
			7.4.2	 Clinical Management of Special Problems with POI
				7.4.2.1	 Clinical Management of Fertility-Related Problems and POI
					POI and Fertility
						Oocyte Donation
						Fertility Preservation
					Pregnancy Management of Patients with POI
				7.4.2.2	 Particular Problems of Hormone Therapy in Women with POI and Puberty Induction
					Particular Problems of Hormone Therapy in Women with POI
					Puberty Induction in Patients with POI
						Commonly Used Drugs and Programs for Puberty Induction
						Dose
						Monitoring during Treatment
			7.4.3	 Clinical Management of DOR
				7.4.3.1	 General Management of DOR
					Management of the Environment, Social Psychology, and Lifestyle
					Ovarian Destructive Factors and Management
						Ovarian Destructive Factors
							Ovarian Surgery
							Chemotherapy
							Radiotherapy
						Management of Destructive Ovarian Factors
							Treatment of Related Chronic Diseases
							Infectious Factors
					Drug Treatment for DOR
						Western Medicine
							Dehydroepiandrosterone (DHEA)
							Growth Hormone (GH)
							Aspirin
							Heparin
							Melatonin
							Coenzyme Q10 (CoQ10)
						Traditional Chinese Medicine (TCM) Treatment
						Physical Therapy
						Hormone Therapy
				7.4.3.2	 Clinical Management of Special Problems with DOR
					Clinical Management of DOR Patients with Fertility Requirements
					Clinical Management of the Fertility-Related Problems of DOR
						Pregnancy Success Rates in Patients with DOR
							Natural Pregnancy Success Rate
							In Vitro Fertilization Pregnancy Success Rate
					Pregnancy Outcomes in Patients with DOR
						Abortion Rate
						Ectopic Pregnancy
		7.5	 Other Treatment Strategies
			7.5.1	 Mitochondrial Transplantation and Ovarian Aging
				7.5.1.1	 Introduction
				7.5.1.2	 Development of Mitochondrial Transplantation
				7.5.1.3	 Classification of Mitochondrial Transplantation
					Heterologous Transplantation
						Cytoplasmic/Isolated Mitochondrial Transfer
						Nuclear Transfer
							GVT
							ST
							PNT
							PBT
					Autologous Mitochondrial Transplantation
				7.5.1.4	 Conclusion
			7.5.2	 In Vitro Activation of Ovaries
				7.5.2.1	 Background of IVA Development
				7.5.2.2	 Clinical Application of IVA
				7.5.2.3	 Potential Application Range of IVA
			7.5.3	 Ovarian Tissue Transplantation
				7.5.3.1	 The History of Ovarian Transplantation
				7.5.3.2	 Ovarian Allogeneic and Autologous Transplantation
					Allotransplantation and Autotransplantation
					Ovarian Autotransplantation
				7.5.3.3	 Ovarian Cortical Strips and Whole Ovarian Transplantation
					Transplantation of Ovarian Cortical Strips
					Whole Ovarian Transplantation
				7.5.3.4	 Orthotopic and Heterotopic Ovarian Transplantation
					Orthotopic Ovarian Transplantation
					Heterotopic Ovarian Transplantation
				7.5.3.5	 Frozen OTT and Fresh OTT
					Frozen OTT
						Screening Criteria for OTC
						Indications for OTC
						OTC Process
					Fresh Ovarian Transplantation
				7.5.3.6	 OTT and Follow-Up
					Follow-Up after Transplantation
					Patient Management before and after Cryopreserved OTT
						Safety Concerns
						Follicle Loss
						Limited and Inaccurate Reports
						Heterogeneity Between Reproduction Centers
							Summary and Outlook
			7.5.4	 Stem Cell Therapy
				7.5.4.1	 Overview
				7.5.4.2	 History of Research with Stem Cells for the Prevention and Treatment of Aging
				7.5.4.3	 Status of Research on Various Stem Cells Treating Ovarian Aging/Injury
					Mesenchymal Stem Cells
					Adult Germ Stem Cells
					Embryonic Stem Cells and Induced Pluripotent Stem Cells
					Other Types of Stem Cells
				7.5.4.4	 Opportunities and Challenges of Stem Cell Therapy
					Heterogeneity of Stem Cells
					Detection Method of the Biological Efficacy of Stem Cells
					Safety of Stem Cells
					Ethical Issues in Stem Cell Transplantation Therapy
					Standardized Management of Stem Cell Therapy
					Other Issues
				7.5.4.5	 Summary and Prospects
		References
	8: Therapy-Associated Ovarian Damage and its Management Strategies
		8.1	 Chemotherapy-Associated Ovarian Damage
			8.1.1	 Cryopreservation and Transplantation of Embryos, Eggs, and the Ovarian Cortex before Chemotherapy
			8.1.2	 Formulation of Chemotherapy Regimens
			8.1.3	 Protective Drugs for Ovarian Function Damage Caused by Chemotherapy
				8.1.3.1	 Gonadotropin-Releasing Hormone Agonist (GNRH-A)
					Mechanism of Ovarian Function Protection during Chemotherapy
					Clinical Studies on GNRH-A Protection of Ovarian Function during Chemotherapy
					GNRH-A Protects Ovarian Function from Chemotherapy
				8.1.3.2	 Oral Contraceptives
				8.1.3.3	 Other Small-Molecule Drugs and Plant Extracts
			8.1.4	 Summary
		8.2	 Surgery-Associated Ovarian Damage
			8.2.1	 Preoperative Evaluation of Ovarian Function and Selection of Surgical Methods
				8.2.1.1	 Preoperative Evaluation of Ovarian Function
				8.2.1.2	 Selection of Surgical Methods
				8.2.1.3	 Selection of Fertility Protection Measures
			8.2.2	 Intraoperative Protection of Ovarian Function
				8.2.2.1	 Reducing the Loss of Normal Ovarian Tissue
				8.2.2.2	 Ensuring a Good Ovarian Blood Supply
				8.2.2.3	 Selecting Reasonable Homeostasis Methods
			8.2.3	 Postoperative Monitoring, Evaluation, and Measures of Ovarian Function
				8.2.3.1	 Monitoring Ovarian Reserve/Function
				8.2.3.2	 Assessment of Fertility
				8.2.3.3	 Hormone Replacement Therapy
			8.2.4	 Psychological Support
		8.3	 Radiotherapy-Associated Ovarian Damage
			8.3.1	 Ovarian Protection from Pelvic Radiotherapy
				8.3.1.1	 Ovarian Transposition
					Transposition Site
					Ovarian Function after Transposition and its Influencing Factors
					Complications after Ovarian Transposition
					Risk for Tumor Recurrence, Metastasis, and Transplanted Ovarian Cancer after Ovarian Transposition
				8.3.1.2	 Cryopreservation and Transplantation of Ovarian Tissue
				8.3.1.3	 Protective Treatment with Drugs
					GNRH-A
					Gonadotropin-Releasing Hormone Antagonist (GNRH-ANT)
				8.3.1.4	 Improvement of Radiotherapy Technology
			8.3.2	 Monitoring Ovarian Function after Radiotherapy and Corresponding Treatment Methods
				8.3.2.1	 Evaluation of Ovarian Function
				8.3.2.2	 Clinical Management of Ovarian Function Decline
		References
	9: Strategies to Maintain Ovarian Function
		9.1	 Maintaining a Healthy Lifestyle
			9.1.1	 Sufficient Sleep and Ovarian Aging
				9.1.1.1	 Sleep Rhythm and Quality Assessment
				9.1.1.2	 The Influence of Sleep on Health and Ovarian Function
				9.1.1.3	 Sleep Improvement Methods
			9.1.2	 Maintaining Moderate Exercise
				9.1.2.1	 Moderate Exercise and Health
				9.1.2.2	 Moderate Exercise and Ovarian Function
			9.1.3	 Drinking Tea
				9.1.3.1	 Introduction of Tea
				9.1.3.2	 The Health Benefits of Tea
				9.1.3.3	 Protection of Female Fertility by Tea
			9.1.4	 Alcohol Restriction
				9.1.4.1	 Drinking and Health
				9.1.4.2	 Moderate Drinking May Delay Menopausal Age
				9.1.4.3	 Alcohol Consumption and Ovarian Aging
					Alcohol Consumption and Follicle Number
					Alcohol Consumption and AMH Level
					Recommended Alcohol Intake
		9.2	 Calorie Restriction and a Balanced Diet
			9.2.1	 Calorie Restriction and Aging
				9.2.1.1	 Caloric Restriction Models
				9.2.1.2	 Calorie Restriction and Body Aging
			9.2.2	 Calorie Restriction and Ovarian Aging
				9.2.2.1	 CR and Ovarian Reserve
				9.2.2.2	 CR and Oocyte Quality and Quantity
				9.2.2.3	 CR
			9.2.3	 Balanced Diet
				9.2.3.1	 Carbohydrates
				9.2.3.2	 Fat
				9.2.3.3	 Protein
				9.2.3.4	 Vitamins
					Vitamin D and 25-Hydroxyvitamin D [25-(OH)D]
					Vitamin A
						Vitamin A
						β-Cryptoxanthin
					Antioxidant Vitamins
				9.2.3.5	 Microelements
					Zinc
					Copper
				9.2.3.6	 Vegetables and Fruits
		9.3	 Potential Drug Therapies
			9.3.1	 Antioxidants
				9.3.1.1	 Vitamins C and E
				9.3.1.2	 Melatonin
				9.3.1.3	 N-Acetyl-L-Cysteine
				9.3.1.4	 Coenzyme Q10
				9.3.1.5	 Other Small-Molecule Compounds and Plant Extracts
			9.3.2	 Small-Molecule Compounds and Plant Extracts
				9.3.2.1	 Small-Molecule Compounds
					AS101
					Sphingosine-1-Phosphate
					The SIRT1 Agonist, SRT1720
					Erythropoietin
					Selenium Compounds
				9.3.2.2	 Plant Extracts
					Ginsenoside
					Lycium Barbarum Polysaccharide
					Tanshinone
					Puerarin
					Allicin
					Proanthocyanidin
					Quercetin and Other Plant Polyphenols
					Curcumin
			9.3.3	 Hormone Drugs
				9.3.3.1	 Androgens for the Prevention and Treatment of Ovarian Aging
				9.3.3.2	 Use of Other Hormone Drugs in Ovarian Aging
					Leptin
					Growth Hormone
			9.3.4	 Immunomodulatory Drugs
				9.3.4.1	 The Role of Immunomodulators in Organ Aging
				9.3.4.2	 Immunomodulators and Ovarian Aging
			9.3.5	 Caloric Restriction Mimetic
				9.3.5.1	 Metformin
				9.3.5.2	 ω-3 Fatty Acids
				9.3.5.3	 Resveratrol
		9.4	 Other Explorations
			9.4.1	 Artificial Ovaries
				9.4.1.1	 Development of the Artificial Ovary
					Follicles
					Ovarian Stromal Cells
					Biological Materials
						Natural Polymers
						Synthetic Polymers
					Alternative Sources of Follicles and Oocytes
				9.4.1.2	 Clinical Applications of Artificial Ovaries
					Restoration of Reproductive Function
					Restoration of Endocrine Function
			9.4.2	 Probiotics
				9.4.2.1	 Probiotics Improve Osteoporosis in Postmenopausal Women
				9.4.2.2	 Probiotics Improve Metabolic Syndrome in Postmenopausal Women
				9.4.2.3	 Probiotics Improve Cardiovascular Function in Postmenopausal Women
			9.4.3	 Telomere Protection
				9.4.3.1	 Telomere System and Aging
				9.4.3.2	 Telomere Protection and Ovarian Reserve and Function
				9.4.3.3	 Summary and Prospects
			9.4.4	 Gene Therapy
		References