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Endometriosis: Current Management and Future Trends
Juan A García-Velasco, Botros RMB Rizk
SECTION 1: EPIDEMIOLOGY
CHAPTER 1:
Endometriosis—How Big is the Problem?
Introduction
Problem of Endometriosis
Endometriosis: A Disease of Many Illnesses
Diagnostic Delay
Taboos
Hit and Miss Treatments
Semi-solutions: Specialist Care, Communication, and Setting Expectations
Specialist Care/Centers of Excellence
Communicating and Setting Realistic Expectations
Semi-solutions: Coping and Living with a Chronic Disease, and Tackling its Taboos
Recognizing What We Don't Talk About
Pain
Infertility
Endometriosis—The Way Forward
Conclusion
CHAPTER 2:
Epidemiology of Endometriosis
Introduction
Endometriosis in Animal Models
Prevalence of Endometriosis
Prevalence Based on Population Data
Prevalence of Endometriosis in Selected Populations
Prevalence in Women Undergoing Laparoscopy because of Infertility (Table 2-1)
Prevalence in Women Undergoing Laparoscopy because of Pelvic Pain (Table 2-2)
Prevalence in Women Undergoing Laparoscopy because of Tubal Sterilization (Table 2-3)
Endometriosis and Autoimmune Diseases
Endometriosis after the Menopause
Prevalence in Unselected Populations (Table 2-4)
Is Endometriosis always a Disease?
Risk Factors (Table 2-6)
Environmental Factors
Increasing Frequency of Endometriosis
SECTION 2: PATHOGENESIS OF THE DISEASE
CHAPTER 3:
Implantation or Metaplasia: What Type of Disease?
Introduction
Implantation Theory
“Metaplasia Theory” and the Different Entities of the Disease
Animal Studies
“Anatomical Distribution” Studies
“Association” Studies
Basic Research
CHAPTER 4:
Role of Inflammation in the Pathogenesis of Endometriosis
Introduction
Cellular Constituents
Cytokines
Endometriosis and Defective Immunity
Conclusions
CHAPTER 5:
Oxidative Stress and the Pathogenesis of Endometriosis
Introduction
Endometriosis: Theories of Etiology
Investigating Role of Oxidative Stress in Endometriosis
ROS and Antioxidants
Role of Iron
Role of TNF-α in Pathogenesis of Endometriosis
Interleukin 6
Role of Leptin in Endometriosis
Conclusion
CHAPTER 6:
Relevance of Genetics to Endometriosis
Summary
Introduction
Appeals of Identification of Endometriosis Susceptibility Genes
A Reality Check: Much Ado about too Little?
Familial Aggregation, Heritability, and Genetics of Endometriosis: A Case Study
Causal Relationship between Genes and Endometriosis: Does it Exist?
Complex Diseases: Emergent Properties of Molecular Networks
Endometriosis: An Ultimate Epigenetic Disease?
Genetic Association Hang-up
Will Genetics Revolutionize the Diagnosis and Treatment of Endometriosis?
Historical Lessons
Conclusions
Acknowledgment
CHAPTER 7:
Tuning of Endometriosis: Review of Environmental Effects on a Disease of Unknown Origin
Introduction
Environmental Estrogens
Environmental Dioxins and Endometriosis
Food and Endometriosis
Epigenetic Modulation of Local Production and Metabolism of E2 and Progesterone
Environmental Perspectives for Endometriosis Treatment: The Medicinal Plants
Conclusion
CHAPTER 8:
Role of Endogenous Hormones in Endometriosis
Introduction
Roles of Various Endogenous Hormones
Conclusion
CHAPTER 9:
Immunology and Endometriosis: Is there a Link?
Introduction
Immune System and its Function
Innate and Adaptive Specific Immune Responses
Humoral and Cell-mediated Immunity
Elimination of Senescent, Misplaced or Ectopic Cells
Recognition of Self, Non-self, and Altered-self
Is Altered Immune Response a Cause or a Consequence of Endometriosis?
How Might Disturbances in Cellular Immunity Contribute to Endometriosis?
Mechanisms for Disruption of Cellular Immunity in Endometriosis
How Might NK Cells Participate in Endometriosis Causation or Pathogenesis?
How Might T Cells Play a Role in Endometriosis Causation or Pathogenesis?
How Might Macrophages Play a Role in Endometriosis Causation or Pathogenesis?
Chronic Inflammation as a Mediator and Modulator of Endometriosis
Endometriosis and Immune Suppression: Is there a Relationship?
Changes in Endometrial Cell Proliferation/Apoptosis; Implications for Immunologic Resistance and Promotion of Endometriosis
Does Genetic/Epigenetic Immune Modulation Play a Role in Endometriosis?
Are Changes in the Immune Response a Result of Ectopic Endometrial Growth?
Humoral Immunity in Endometriosis: What can this tell us about Endometrial Cell Antigenicity?
Conclusions
CHAPTER 10:
Sampson Revisited: A Critical Review of the Development of Sampson's Theory of Origin of Endometriosis
Introduction
Development of Sampson's Theory of Origin of Endometriosis
Conclusion
CHAPTER 11:
Endometrial Changes in Women with Endometriosis
Introduction
Endometrial Histology, Ultrastructure and Glycosylation in Endometriosis
Cell Cycling Abnormalities in Eutopic Endometriotic Endometrium
Altered Glycosylation in Eutopic Endometriotic Endometrium
Genomic Alterations in Endometriosis
Peritoneal Fluid Abnormalities
Effects of Medical Treatment of Endometriosis on the Endometrium
SECTION 3: DIAGNOSTIC DILEMMAS
CHAPTER 12:
Diagnosis of Endometriosis: Pitfalls of Current Methods
Introduction
Symptoms
Serum Markers
Ultrasound
Computed Tomography (CT) Scans
Magnetic Resonance Imaging (MRI)
Other Imaging Modalities
Transvaginal Hydrolaparoscopy
Laparoscopic Visualization of the Pelvis
Novel Diagnostic Tests
Conclusion
CHAPTER 13:
Novel Non-invasive Diagnosis of Endometriosis
Introduction
Imaging Techniques
Superficial Endometriosis and Endometriotic Adhesions
Ovarian Endometrioma
Deep Retroperitoneal Endometriosis
Bladder Endometriosis
Endometriosis Serum Markers
Transcriptomics and Proteomic Analysis in Endometriosis
Conclusion
SECTION 4: CLINICAL RELEVANCE AND TREATMENT OPTIONS
CHAPTER 14:
Endometriosis in Adolescents
Introduction
Pathogenesis of Endometriosis
Diagnosis of Endometriosis
Evaluation of Pelvic Pain
History
Normalization of Symptoms and Delay in Diagnosis
Physical Examination
Radiologic Examination
Laboratory Evaluation
Treatment
Initiating Empiric Treatment
Laparoscopy
Treatment of Laparoscopically-Proven Endometriosis
Medical Management
Oral Contraceptive Pills
GnRH Agonist Therapy
Progestins
Danazol
Key Points
CHAPTER 15:
Asymptomatic Endometriosis in Infertile Patients
Introduction
Prevalence of Asymptomatic Endometriosis
Evolution of Endometriosis in Asymptomatic Patients
Diagnostic of Nonsymptomatic Endometriosis
Clinical Diagnosis
Ultrasound Diagnosis
Endoscopic Diagnosis
What to do in Cases of Asymptomatic Endometriosis?
Discussion
Conclusion
CHAPTER 16:
Endometriosis and Infertility: Much Ado about Nothing?
Introduction
Is there an Association Between Endometriosis and Clinical Infertility?
Yes, There is an Association
No, There is no Association
Pathophysiology of Infertility in Patients with Endometriosis
Peritoneal Fluid Abnormalities
Cellular Components of Peritoneal Fluid; Macrophages and Lymphocytes
Embryo Growth
Sperm Motility and Binding
Vascular Endothelial Growth Factor (VEGF) and Interleukins
Prostaglandin Levels
Increase in Fluid Volume
Eutopic Endometrium Abnormalities
Myometrial Architecture and Peristalsis Abnormalities
Follicular Environment and Embryo Quality
Ovulation Disorders
Anovulation
Hyperprolactinemia
Abnormal Follicular Dynamics
Luteinized Unruptured Follicle Syndrome
Luteal Phase Defect
Immunological Abnormalities
Cell Mediated Immunological Factors
Humoral Immunological Factors
Spontaneous Abortion
Implantation
Pelvic Pain
Assisted Reproductive Technology in Patients with Endometriosis
Conclusion
CHAPTER 17:
Endometriosis and Miscarriage: Is there any Association?
Definitions
Abortion
Clinical Abortion
Preclinical Abortion (Biochemical Pregnancy)
Recurrent Abortion
Implantation Rate per Embryo
Association between Endometriosis and Spontaneous/Recurrent Abortion
Endometriosis and Implantation Failure after Assisted Reproduction
Possible Mechanisms involved in the Reduction of Implantation Rates after ART in Women with Endometriosis
Anti-endometrial Autoantibodies
Anti-laminin-1 Autoantibodies
Other Autoantibodies
Cell-mediated Immunological Changes in Endometriosis
Cytokines
Effects on Early Embryonic Development
Abortion and Aberrantly Expressed Genes and Gene Products in Endometrium
Prevention of (Recurrent) Abortion in Women with Endometriosis
Specific Interventions
Non-specific Interventions
Summary
CHAPTER 18:
Assisted Reproductive Technology and Endometriosis
What is the Real Chance of Conceiving? Is it Really Worth the Effort?
Where Exactly is the Endometriosis Problem Located?
Proper Selection of Patients and Appropriate Treatment
Intrauterine Insemination (IUI) and Controlled ovarian hyperstimulation (COH)
In Vitro Fertilization
Oocyte Donation
Oocyte Cryopreservation
How can Endometriosis Surgery Affect IVF Outcome?
Conclusions
SECTION 5: SURGICAL TREATMENT
CHAPTER 19:
What is Good Surgery for Endometriosis Patients?
Introduction
Deeply Infiltrating Endometriosis: Two Major Specificities
DIE is a Multifocal Pathology
DIE is Very Often Associated with Other Endometriotic Lesions
Deeply Infiltrating Endometriosis: How to make a Correct DIE Diagnosis
Questioning
Clinical Examination
Radiological Work-up
Deeply Infiltrating Endometriosis: What are the Therapeutic Options?
Context of Pelvic Pain
Context of Infertility
Conclusion
CHAPTER 20:
Risk of Recurrence after Surgery
Introduction
Definition
Rate of Recurrence and Risk Factors
Place of Medical Therapy
Preoperative Medical Therapy
Postoperative Medical Therapy
Comparison between Preoperative or Postoperative Medical Therapy
Place of Surgery
Ovarian Endometrioma
Deep Infiltrating Endometriosis
Conclusion
SECTION 6: CLASSICAL MEDICAL TREATMENTS
CHAPTER 21:
Oral Contraceptive Pills (OCPs) for Treatment of Endometriosis
Introduction
Biological Rationale for the Use of OCP in the Treatment of Endometriosis
OCP for Treatment of Endometriosis Itself
OCP for Treatment of Infertility Associated with Endometriosis
OCP for Treatment of Pain Associated with Endometriosis
OCP in the Empirical Treatment of Chronic Pelvic Pain and Endometriosis
Summary and Concluding Remarks
CHAPTER 22:
Nonsteroidal Anti-inflammatory Drugs
Introduction
Endometriosis as an Inflammatory Process
Prostanoid Biosynthetic and Cyclooxygenase (COX) Signaling Pathways
Prostaglandins
Prostaglandin Receptors
Cyclooxygenase Enzymes
Nonsteroidal Anti-inflammatory Drugs
First-generation COX-2 Inhibitors54
Second-generation COX-2 Inhibitors
NSAIDs and Endometriosis
Management of Pain Related to Endometriosis
NSAIDs Inhibition of Endometriosis
NSAIDs and Recurrent Lesions of Endometriosis
Conclusion
Web Resources
CHAPTER 23:
Progestins in Endometriosis Treatment
Introduction
Oral Route
Norethisterone Acetate
Cyproterone Acetate
Dienogest
Oral Progestins and Rectovaginal Endometriosis
Intramuscular and Subcutaneous Routes: The Depot Medroxyprogesterone (DMPA) Option
Intrauterine Route
Symptomatic Peritoneal and Superficial Ovarian Lesions
Rectovaginal Endometriosis
Recurrent Endometriosis
Postoperative Adjuvant Treatment
Advantages and Drawbacks of the Lng-IUD for Endometriosis
Conclusions
CHAPTER 24:
Danazol in the Medical Treatment of Endometriosis
Introduction to Danazole
Chemical Structure and Activity
Importance of Measuring Estradiol Levels during Danazol Treatment
Relationship of E2 Levels at the End of Danazol Treatment, Initial Stage of Endometriosis, and Extent of Improvement
Relation of E2 Suppression to Weight
Relationship of E2 Levels to Side Effects
Effect of Increasing the Frequency of Danazol Administration
Effect of Concurrent Administration of Dexamethasone or Spironolactone to Decrease Androgenic Side Effects
Clinical Management of Endometriosis with Danazol
Indication
Initiating and Monitoring Danazol
CHAPTER 25:
Agonists and Antagonists of Luteinizing Hormone-releasing Hormone (LHRH) in the Treatment of Endometriosis
Summary
Introduction
LHRH-analogs: Agonists and Antagonists
LHRH Agonists in the Treatment of Endometriosis
Dosage and Timing of Administration
Treatment of Endometriosis-related Symptoms
Surgical Adjunctive Therapy
Add-back Therapy
Endometriomas
Infertility
Direct Effects on Endometriotic Tissue
Antagonists of LHRH in the Treatment of Endometriosis
Antagonists of Growth Hormone-releasing Hormone (GHRH) in the Treatment of Endometriosis
Conclusion
CHAPTER 26:
Controlled Ovarian Hyperstimulation in Endometriosis Patients
Introduction
COH: Clomiphene and Aromatase Inhibitors
COH: Gonadotropins
COH: Assisted Reproductive Technologies (ART)
Does Adjuvant Therapy Improve COH Outcomes?
Summary
SECTION 7: NEW MEDICAL TREATMENTS
CHAPTER 27:
Progesterone Receptor Modulators in Endometriosis: A New Therapeutic Option
Introduction
Rationale for the use of Progesterone Receptor Modulators
PR Receptor
Estrogen and Progesterone Dependency
Matrix Metalloprotease Inhibitors (MMPs)
Apoptosis
Angiogenesis
Case Studies
Studies in Animals
Studies in Women
CDB-4124 in the Treatment of Endometriosis
Study Design
Women Studied
Results
Demographic Characteristics
Discussion
Acknowledgments
CHAPTER 28:
Statins as Potential Novel Medical Treatment of Endometriosis
Introduction
Scope of Problem
Hypothesis
Endometriosis: Relevant Pathophysiology
Growth of Endometrial Stroma and Invasiveness
Endometriosis and Angiogenesis
Endometriosis: Inflammation and Oxidative Stress
Statins: Pleiotropic Activities
Overview
Effects on Growth of Mesenchymal Tissues
Statins and Endometrium: Inhibition of Endometrial Stromal Growth
Effects on MMPs
Statins and Endometrium: Inhibition of MMPs
Effects on Angiogenesis
Statins and Endometrium: Inhibition of Angiogenesis
Effects on Inflammation and Oxidative Stress
Statins: Effects in vivo (Rodent Models of Endometriosis)
Overview
Summary
Future Directions
CHAPTER 29:
Aromatase Inhibitors for Endometriosis
Introduction
Scientific Hypothesis Behind using Aromatase Inhibitors for Endometriosis
Estrogen Synthesis and Production
Aromatase Inhibitors
Development of Aromatase Inhibitors
Third Generation Aromatase Inhibitors
Is there a Difference in Response to Individual Aromatase Inhibitors?
Non-aromatase Inhibition Actions of Third Generation Aromatase Inhibitors
Differences among Aromatase Inhibitors
Adverse Effects Associated with Third Generation Aromatase Inhibitors
Aromatase Enzyme in Endometriotic Tissues
Aromatase Inhibitors in Premenopausal Women
Evidence for Success of Aromatase Inhibitors for the Treatment of Endometriosis
Aromatase Inhibitors for Postmenopausal Women with Endometriosis
Aromatase Inhibitors for Premenopausal Women with Endometriosis
Endometriosis-associated Pain
Endometriosis-associated Infertility
Aromatase Inhibitors to Prevent Flare Associated with GnRH Agonist
Aromatase Inhibitors for Adenomyosis
Conclusion
CHAPTER 30:
Botanical Therapies
Introduction
Nuclear Factor-KappaB (NF-κB) Pathway – A Target for Treatment of Endometriosis
Treatment Strategies
Herbal Therapies
Clinical Trials of Herbal Therapies for Endometriosis
In vitro and In vivo Studies of Herbal Therapies for Endometriosis
Clinical Application of Plant-derived Pharmaceuticals
Curcuma (Curcumin)
Dahurian Angelica (Coumarins)
Chinese Angelica (Ferulic Acid)
Corydalis (Tetrahydropalamatine)
Salvia Root (Tanshinone)
Frankincense (Boswellic Acids)
Cinnamon (Cinnamonaldehyde)
Drawbacks and Pitfalls of Herbal Therapies
Conclusions
CHAPTER 31:
Antiangiogenic Agents in Endometriosis
Introduction
Angiogenesis
Endometriosis and Angiogenic Factors
Antiangiogenic Therapy in Endometriosis
Dopamine Agonist in the Treatment of Endometriosis
CHAPTER 32:
New Delivery for Classical Drugs: Intrauterine or Intravaginal
Introduction: New Routes of Administration for Hormones
Intrauterine Device Releasing Levonorgestrel
Intrauterine Device Releasing Danazol
Vaginal Administration of Danazol
Conclusion
SECTION 8: FUTURE TRENDS
CHAPTER 33:
New Drugs in the Pipeline
Introduction
Current Pipeline Therapy
Drug Development
GnRH Analogues
Survival and Growth Factor Targets
Tumor Necrosis Factor-Alpha (TNF-ɑ)
Tumor Necrosis Factor Alpha Converting Enzyme (TACE)
Telomerase
Cyclooxygenase-2 (COX-2)
Relaxin
Serotonergic Modulators
Peroxisome Proliferators-activated Receptors (PPARs)
Hepatocyte Growth Factor (HGF)
Protease Targets
Matrix Metalloproteinases (MMPs)
Tryptase
Hepsin and Matriptase
Conclusion
CHAPTER 34:
Fertility Preservation in Women with Endometriosis
Introduction
Laparoscopic Management of Endometriomas Using a Combined Technique of Excisional and Ablative Surgery
Autotransplantation of Human Ovarian Tissue in Endometriosis Patients
Orthotopic Transplantation of Fresh Ovarian Cortex in Endometriosis Patients
Orthotopic Transplantation of Cryopreserved Ovarian Tissue
Ovarian Biopsy Samples
Freezing and Thawing Procedures
Orthotopic Transplantation Techniques
Isolation of Primordial Follicles from Cryopreserved Ovarian Tissue
Conclusion
CHAPTER 35:
The Link Between Endometriosis and Cancer
Introduction
Epidemiological Evidence
Histological Evidence
Molecular/Genetic Evidence
Conclusion
CHAPTER 36:
Stem Cells and Clonality in Endometriosis
Introduction
Endometrial Stem/Progenitor Cells
Endometrial Epithelial Stem/Progenitor Cells
Cell Cloning Studies
Clonality of Human Endometrium
Label Retaining Cells
Endometrial Gland Methylation Patterns
Endometrial Stromal/Mesenchymal Stem-like Cells
Cell Cloning Studies
Multilineage Differentiation
Label Retaining Cells
Human Endometrial Side Population Cells
Endometrial Stem/Progenitor Cell Reconstitution of Endometrial Tissue in vivo
Markers of Endometrial Stem / Progenitor Cells
Source of Endometrial Stem/Progenitor Cells
Endometrial Stem/Progenitor Cells and Endometriosis
Clonality of Ectopic Endometrium
Reconstruction of Cellular Genealogy in Endometrial Cells
Menstrual Blood Stem/Progenitor Cells
Transdifferentiation, Metaplasia and Endometrial Stem/Progenitor Cells
Summary
Acknowledgments
CHAPTER 37:
Quality of Life Questionnaires
Summary
Introduction
Quality of Life Questionnaires
Generic Questionnaires of Quality of Life
Quality of Life Questionnaires Evaluating Specific Dimensions
Quality of Life Questionnaires Specific for Women with Endometriosis
Limits of Quality of Life Questionnaires
Impact of Medical and Surgical Therapies on Quality of Life as Evaluated by Questionnaires
Quality of Life after Medical Treatment of Endometriosis
Quality of Life after Surgery for Endometriosis
Use of Quality of Life Questionnaires as a Predictor of Outcome after Surgery
Conclusion
Epilogue
The Future: Our Field Could Be World Leaders – Will We Meet the Challenge?
Developing Nations' Perspective on Endometriosis Will Help the Whole World
Noninvasive Diagnostic Test Will Open Surprising New Doors
Are Taboos Keeping Us from Taking Endometriosis Seriously?
INDEX
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