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The Art & Science of Assisted Reproductive Technology
Sunita R Tandulwadkar
SECTION 1: SETTING-UP AN ART LABORATORY
1:
How to Set-up an ART Laboratory?
INTRODUCTION
LOCATION OF THE ART LABORATORY
CONSTRUCTION MATERIALS
CONSTRUCTION DESIGN
Burning In
CONFIGURATION OF THE AIR-HANDLING VENTILATION AND FILTRATION SYSTEM
USE OF ULTRAVIOLET LAMPS IN IN VITRO FERTILIZATION LABORATORY
LAMINAR AIR FLOW HOODS
INCUBATORS
MICROSCOPES
CENTRIFUGES
LIQUID NITROGEN CANS
CONCLUSION
2:
Quality Control in an ART Laboratory
LABORATORY PERSONNEL
PROCEDURES
Air
Instruments and Equipment
Medium
Electricity
Disposables
CULTURE ROOM
INFECTION/CONTAMINATION CONTROL
INSTRUCTIONS TO PATIENTS
RECORD KEEPING
OTHER ASPECT OF QUALITY CONTROL
3:
Quality Care Management in ART Clinic
INTRODUCTION
OBJECTIVES OF QUALITY CONTROL AND ASSURANCE
MINIMAL PHYSICAL REQUIREMENTS OF AN ART CLINIC
Non-sterile Area
Reception and Waiting Room
Consulting or Doctor’s Room
General Purpose Clinical Laboratory
Store Room
Record Room
Sterilization Area
Vermin Proofing
Semen Collection Room
Room for Intrauterine Insemination
Changing Room
Sterilization Room
Sterile Area
Operation Theater
Operation Theater or Room for Transvaginal Ovum Pickup and Embryo Transfer
Embryology Laboratory Complex
Identification of Patients and their Gametes, Zygotes and Embryos
Protective Measures
Semen Processing Room
DOCUMENTATION
Information Management System8
Composition and Qualifications of the Members of the ART Team
Reproductive Endocrinologist or Gynecologist
Andrologist
Clinical Embryologist
Counselor
Nurse
Genetic Counselor
Program Coordinator or Director
QUALITY CONTROL AND QUALITY ASSURANCE
Elements of Quality Control
Maintenance of the Laboratories
Quality of Consumables Used in the Laboratory
Quality Assurance
DISCUSSION
CONCLUSION
SECTION 2: HOW TO INVESTIGATE AN INFERTILE COUPLE?
4:
Evaluation of the Male Partner
INTRODUCTION
EVALUATION OF MALE PARTNER
Semen Analysis
Color
Odor
Liquefaction
Volume
pH
Sperm Concentration
Motility and Forward Progression
Morphological Evaluation of Spermatozoa
Sperm Viability Tests
Semen Cytology
Semen Biochemistry
Agglutination
Sperm Functional Assessment
Postcoital Test
Sperm Penetration Assays and Sperm Zona Binding Tests
Hypo-osmotic Swelling Test
Trial Wash and Sperm Survival
Postwash Sperm Survival
Acrosome Reaction
Acrosin Activity Test
Computer-assisted Sperm Analysis (CASA)
Sperm DNA Fragmentation Tests
Estimation of Sperm Creatine Kinase and Reactive Oxygen Species (ROS)34
Research Setting
Extended Screening in Male Subfertility
Reproductive and Sexual History
Physical Examination and Ultrasound
Ultrasonography
Scrotal Ultrasonography
Endocrine Evaluation
Postejaculatory Urinalysis
Genetic Screening
Sperm Chromosome Aneuploidy
Testicular Biopsy
Predictor for Sperm Recovery
DISCUSSION
Problems of WHO 2010 Reference Limits
CONCLUSION
5:
Investigation of Infertile Female
INDIVIDUALIZED PRETREATMENT ASSESSMENT
GENERAL ASSESSMENT
HISTORY AND PHYSICAL EXAMINATION
TESTS
Ovarian Factor
Establish Ovulation
Establish cause for Anovulation
Ovarian Reserve Testing
Tubal Factor
Hysterosalpingography
Saline Infusion Salpingosonography
Laparoscopy
Uterine Factor
Body of Uterus
Cervical Factor
6:
Ultrasound and Doppler in Infertility
INTRODUCTION
MONITORING OF TREATMENT CYCLES IN PATIENTS WITH INFERTILITY
EARLY PROLIFERATIVE SCAN
PREOVULATORY SCAN
Follicular Assessment
B-mode Features of a Mature Follicle
Doppler Features of a Mature Pre-hCG Follicle
Implications of Flow Parameters on Ovum Quality
Volume Ultrasound Parameters of Mature Pre-hCG Follicle
Endometrial Evaluation
B-mode Features of Endometrium with Good Receptivity
Doppler Features of Receptive Endometrium
Uterine Artery Doppler
3D and 3D Power Doppler Features of Good Endometrial Receptivity
Uterine Contractions
Secretory Phase Evaluation
LUTEINIZED UNRUPTURED FOLLICLE
Luteal Phase Defect
CONCLUSION
KEY POINTS
7:
Effect of Environment on Fertility
INTRODUCTION
MECHANISM OF DAMAGE TO CELL
COMMON COMPOUNDS DETRIMENTAL TO FERTILITY
Seminal Fluid
Demography
Follicular Environment
Amniotic Sac Microenvironment
CLINICAL CONSIDERATION
CONCLUSION
SECTION 3: ENDOSCOPY IN INFERTILITY
8:
Fertility Enhancing Laparoscopic Surgery
INTRODUCTION
TUBAL SURGERY
Hysteroscopic Transcervical Tubal Cannulation
Tubo-tubal Anastomosis
Brosen’s Classification
Types of Anastomosis
Salpingo-ovariolysis and Fimbrioplasty
Case Type Versus Result
ENDOMETRIOSIS SURGERY
Surgical Management of Ovarian Endometriosis
Surgical Management of Fallopian Tube in Endometriosis
Surgical Management of Uterus in Endometriosis
Classification of Endometriosis at Our Institute
LAPAROSCOPIC MYOMECTOMY
LAPAROSCOPIC ADENOMYOMECTOMY
9:
Fertility Enhancing Hysteroscopic Surgery
INTRODUCTION
ENDOMETRIAL POLYPS
Hysteroscopic Polypectomy
Office Technique
MYOMAS
Hysteroscopic Myomectomy
Office Technique
Myomas and Assisted Reproductive Techniques
SEPTATE UTERUS
Hysteroscopic Metroplasty (Figs 3A to C)
Office Technique
INTRAUTERINE ADHESIONS
Hysteroscopic Synechiolysis (Fig. 4)
Office Technique
KEY POINTS
10:
Pilot Hysteroscopy before ART
INTRODUCTION
GENERAL CONSIDERATIONS
Indications
Absolute Contraindications
Relative Contraindications
The Procedure
Distension Media
Instruments
DIAGNOSTIC HYSTEROSCOPY PRIORTO ART
Hysteroscopy Assesses
“Fertility Effect” of Diagnostic Hysteroscopy
Advantages of Pre-ART Office Hysteroscopy14
HYSTEROSCOPY IN CASES OF REPEATED IVF FAILURES15,16
OPERATIVE HYSTEROSCOPY
Endometrial Biopsy and Polypectomy
Uterine Myomas
Asherman’s Syndrome
Congenital Uterine Abnormalities
Septate Uterus
Proximal Tubal Occlusion
OTHER INDICATIONS
CONCLUSION
SECTION 4: ENDOCRINOLOGY AND STIMULATION PROTOCOLS
11:
Genetic Markers of Ovarian Response
OVARIAN RESPONSE
GENETIC ASPECTS
GENOMIC STRUCTURES
GENETIC POLYMORPHISMS AND OVARIAN RESPONSE TO GONADOTROPINS
Ovulation Induction and Controlled Ovarian Stimulation
Ovarian Hyperstimulation Syndrome
CONCLUSION AND FUTURE PERSPECTIVES
12:
Physiology of Follicular Phase
INTRODUCTION
THE SAGA OF PRIMORDIAL GERM CELLS
Hormonal Regulation of Folliculogenesis During the Menstrual Cycle
Primordial Follicle
The TGF-β Protein Family
Primary Follicle
Secondary Follicle
Graafian Follicle
Ovulation
Corpus Luteum
Corpus Albicans
CONCLUSION
FUTURE PERSPECTIVES
13:
Progesterone in Follicular Phase during Controlled Ovarian Stimulation
INTRODUCTION
IMPACT OF PROGESTERONE ON PREGNANCY
IMPACT OF PROGESTERONE ON OOCYTES AND ENDOMETRIUM
PATHOGENESIS
Elevation of Follicular LH Levels
Accumulation of hCG from hMG
Increased LH Receptor Sensitivity of the Granulosa Cells to FSH
Poor Ovarian Response with Increased LH Sensitivity
“Cross Talk” between Ovaries and Adrenals
Multivariate Approach
FOLLICULAR-PHASE PROFILE IN THE NORMAL CYCLE “TWO-CELL, TWO-GONADOTROPIN”
PROFILES DURING OVARIAN STIMULATION
CLINICAL IMPLICATIONS OF ELEVATED PROGESTERONE IN FOLLICULAR PHASE
CONCLUSION
14:
Therapeutic Window for Luteinizing Hormone in Controlled Ovarian Stimulation
INTRODUCTION
PHYSIOLOGICAL ROLE OF LUTEINIZING HORMONE
Therapeutic LH Window
Two-cell–Two-gonadotropin Concept
LUTEINIZING HORMONE: DIFFERENT FORMS
Role of Human Menopausal Gonadotropins
Role of Recombinant Human LH
Role of hCG in the Mid to Late Follicular Phase
hCG/hMG may Induce LH Receptor Internalization
ROLE OF LH IN ASSISTED REPRODUCTIVE TECHNOLOGY
Exogenous LH and ART Outcome in Unselected Population
Exogenous LH and ART Outcome in Selected Population
Severe Endogenous LH Deficiency
Severe LH Deficiency due to Suppression by GnRH Analogs in ART
Poor Responders
Patients at Risk of Hyporesponse during Ovarian Stimulation
Advanced Reproductive Age
FSH/LH Ratio
Polycystic Ovary Syndrome
Exogenous LH Supplementation in Asian Population
Dose and Timing of Initiation of r-hLH
CONCLUSION
MESSAGE BOX
15:
Stimulation Protocols for ART
INTRODUCTION
OVARIAN STIMULATION
Gonadotropin-releasing Hormone Analogs
Gonadotropin-releasing Hormone Agonist Long Protocol
Short Agonist (Flare-up) Protocol
Antagonist Protocols
Mild or Minimal Stimulation IVF
CONCLUSION
16:
Stimulation Protocols for Polycystic ovarian Syndrome in ART
INTRODUCTION
OVARIAN STIMULATION IN IVF
PREVENTION OF PREMATURE LUTEINIZATION
PRETREATMENT
METFORMIN AS AN ADJUVANT WITH GONADOTROPINS IN IVF
OVULATION TRIGGER
COASTING
IN VITRO MATURATION OF OOCYTES
CONCLUSION
17:
GnRH Agonists and Antagonists in Assisted Reproduction
INTRODUCTION
EXOGENOUS GONADOTROPIN STIMULATION AFTER DOWNREGULATION WITH A LONG-ACTING GnRH AGONIST: LONG PROTOCOLS
Disadvantages
Monitoring the Cycle
High Responders
Poor Responders
Sequential Stimulation with a GnRH Agonist and Exogenous Gonadotropins the “Short”or “Flare” Protocols
STIMULATION WITH EXOGENOUS GONADOTROPINS WITH ADDITION OF A GnRH ANTAGONIST
Advantages
Disadvantages
Review of Literature
CONCLUSION
18:
Monitoring Ovarian Stimulation
INTRODUCTION
WHY MONITOR OVULATION INDUCTION CYCLES?
HOW DO WE MONITOR THE OVULATION INDUCTION CYCLE?
ASSESSMENT OF OVARIAN RESERVE
OVARIAN RESERVE TEST
Age
Biochemical Test
Basal FSH
Estradiol
Inhibin B
Anti-Müllerian Hormone
Dynamic Test
Clomiphene Citrate Challenge Test
Exogenous FSH Ovarian Reserve Test
Biophysical Tests
Antral Follicle Count
Ovarian Biopsy
Monitoring Ovulation Induction Cycle
Ultrasound Monitoring
Monitoring Ovarian Response to Ovulation Induction Agents
Color Doppler Studies of Ovarian Circulation
Luteal Phase Doppler (Fig. 10)
Effect of Ovarian Stimulation Drugs on PFBF
Perifollicular Blood Flow and ART Results
Ultrasound Assessment of the Endometrium
Endometrial Receptivity Markers
Endometrial Volume
Endometrial and Subendometrial Vascularity
Endometrial Blood Flow Quantification
Endometrial Vascularization Using 3D Power Doppler
Endometrial Vascularity in Special Situations
Correlation of Endometrial and Subendometrial Blood Flow to Pregnancy Rate in ART
Maintenance of Records during Monitoring of an Ovulation Induction Cycle
Uterine Artery Blood Flow
Monitoring Abnormal Response
Premature Luteinization (Fig. 18)
Luteinized Unruptured Follicle (Fig. 19)
Endogenous LH Surge
Poor Response (Fig. 20)
Ovarian Hyperstimulation Syndrome (Fig. 21)
Functional Cyst (Fig. 22)
Persistent/Retention Cyst (Fig. 23)
Hormonal Monitoring
Hormonal Monitoring in an Ovulation Induction Cycle
Serum LH
Serum Estradiol Levels
Progesterone
Cancelation of Ovarian Stimulation Cycles
Monitoring a Frozen Embryo Transfer Cycle
Natural Cycle Frozen Embryo Transfer
Detection of Ovulation
Hormone Replacement Therapy Cycle FET
Monitoring Luteal Phase
Luteal Phase
Luteal-follicular Transition
Monitoring Early Pregnancy after Ovulation Induction
Monitoring FET Cycle
DISCUSSION
SUMMARY
19:
Ovulation Trigger
INTRODUCTION
HUMAN CHORIONIC GONADOTROPIN
When hCG should be Administered?
Time Interval between hCG and Follicular Rupture
Time Interval between hCG and Oocyte Retrieval
Minimal Effective Dose of hCG
Route of hCG Administration
Recombinant hCG
GnRH Agonist Triggering of Final Oocyte Maturation
Recombinant LH
MESSAGE
SECTION 5: GAMETE COLLECTION AND PREPARATION
20:
Oocyte Retrieval
INTRODUCTION
PRIMARY ASSESSMENT
TECHNIQUES
Ultrasound-guided Method
Laparoscopic Method
TIMING
EQUIPMENT
PROCEDURE (FIGS 1 TO 18)
COMPLICATIONS
CONCLUSION
21:
Oocyte Evaluation and Preparation
INTRODUCTION
THE OOCYTE
Oocyte Grading
Grade I
Grade II
Grade III
Grade IV
Grade V
OOCYTE ABNORMALITIES
CONCLUSION
22:
Semen Analysis and Evaluation of Sperm
SEMEN ANALYSIS
The Wet Preparation
Azoospermia and Severe Oligozoospermia
Sperm Concentration
Sperm Motility
Sperm Vitality
Sperm Morphology
EVALUATION OF SPERM AND SPERM FUNCTION
Sperm Zona Pellucida Binding
Acrosome Reaction
DNA Integrity
Perspectives
23:
Semen Collection and Preparation
INTRODUCTION
SEMEN COLLECTION
Instructions to the Patient for Sperm Collection: Cleveland Clinic Protocol
COMMONLY USED MOVEMENT-BASED TECHNIQUES
Swim-up
Handling of Patient Sample
Analysis and Processing of Patient Sample
Advantages
Disadvantages
Swim-down Technique
Density Gradient Centrifugation
Density Gradient Centrifugation: Cleveland Clinic Protocol (Fig. 2)
Conventional Sperm Preparation Techniques
Simple Wash and Resuspend
Glass Wool Filtration
Migration-Sedimentation
Advanced Sperm Preparation Techniques
Magnetic Activated Cell Sorting
Electrophoresis
Special Cases of Sperm Retrieval
Testicular Sperm Recovery
Retrograde Ejaculation
SALIENT POINTS
SECTION 6: MICROMANIPULATION
24:
Micromanipulation: Instrument, Technique and ICSI Procedure
INTRODUCTION
INDICATIONS OF INTRACYTOPLASMIC SPERM INJECTION
EJACULATED SPERMATOZOA
Epididymal Spermatozoa
Testicular Spermatozoa
EQUIPMENT AND MATERIALS
Manipulators
Optics
Stereomicroscope
Heated Stages
Microsyringes, Tubing, and Tool Chucks
Glass Micro Tools
Benchtop Incubators
INTRACYTOPLASMIC SPERM INJECTION PROCEDURE
Sperm Collection and Processing Priorto Microinjection
Sperm Selection for ICSI
Pentoxifylline
Hypo-osmotic Swell Test
Morphologically Selected Sperm Injection
Hyaluronic Acid-mediated Sperm Selections
COLLECTION AND PREPARATION OF THE OOCYTES
PolScope
Manipulation Plate Setup
SETTING FOR THE MICROINJECTION
SPERM IMMOBILIZATION
PENETRATION INTO THE OOPLASM
EVALUATION OF FERTILIZATION, EMBRYO DEVELOPMENT, CULTURE CONDITIONS, AND EMBRYO REPLACEMENT
CONCLUSION
SECTION 7: ENHANCING SPERM, OOCYTE, EMBRYO QUALITY
25:
Polarized Light Microscopy
INTRODUCTION
POLARIZED LIGHT MICROSCOPY
Principle
Use of Polarized Light Microscopy
Presence of the Meiotic Spindle
Spindle Quality and Retardance
ICSI after Spindle Assessment by PLM
Imaging of the Zona Pellucida
Spindle Assessment Related to PositivePregnancy Rate
Sperm Birefringence
CONCLUSION
26:
IMSI in Daily Laboratory Practice: Lights and Shadows
INTRODUCTION
MATERIAL AND METHODS
Intracytoplasmic Morphologically Selected Sperm Injection Procedure
Pre-Intracytoplasmic Morphologically Selected Sperm Injection Tests
Patient Selection
End Points
Statistical Analysis
RESULTS
Pre-Intracytoplasmic Morphologically Selected Sperm Injection Tests
Intracytoplasmic Morphologically Selected Sperm Injection Results
Intracytoplasmic Morphologically Selected Sperm Injection Outcome in Young and Older Patients
Intracytoplasmic Morphologically Selected Sperm Injection Outcome According to the Attempt Number in Less than or Equal to38-Year-Old Patients
DISCUSSION
27:
Role of Preimplantation Genetic Diagnosis in ART
INTRODUCTION
METHODS OF BREACHING THE ZONA
Partial Zona Dissection
Zona Drilling
Laser
POLAR BODY BIOPSY
CLEAVAGE-STAGE EMBRYO BIOPSY
BLASTOCYST BIOPSY
Technique
Advantages
Disadvantages
CHROMOSOMAL ANEUPLOIDIES
CHROMOSOMAL TRANSLOCATIONS
BLASTOCYST TRANSFER FOLLOWING BIOPSY
IMPACT OF PGD ON IVF OUTCOME
CONCLUSION
28:
Assisted Hatching of Human Embryos
INTRODUCTION
STRUCTURE AND FUNCTION OF ZONA PELLUCIDA
INDICATIONS FOR ASSISTED HATCHING
MECHANISM OF ASSISTED HATCHING
TECHNIQUES OF ASSISTED HATCHING
Mechanical Techniques
Mechanically Expanding the ZP
Chemical Techniques
Piezo Micromanipulation
LASER-ASSISTED HATCHING
REVIEW OF LITERATURE
RISKS ASSOCIATED WITH ASSISTED HATCHING
CONCLUSION
SECTION 8: CULTURE OF EMBRYOS AND TRANSFER
29:
Culture and Evaluation of Embryos: From Fertilization to Transfer
INTRODUCTION
CULTURE MEDIA FOR ART
BASIC COMPOSITION OF CULTURE MEDIA FOR ART
Carbohydrates
Proteins and Amino Acids
Antibiotics
Buffers
pH Indicators
SEQUENTIAL VERSUS SINGLE STEP CULTURE MEDIUM
Sequential Media
Single Step Media
IN VITRO CULTURE CONDITIONS
Temperature
pH
Relationship between pH and Embryonic Development
Maintenance of pH
Epigenetic Effects of pH Fluctuation
Osmolality
Factors That Influence the Osmolality
Oil
EVALUATION OF ZYGOTES AND EMBRYOS
Criteria for Grading Embryos
The Number of Cells
Size and Uniformity of Blastomeres
Fragmentation
Multinucleation
Grading of Embryos
Grading of Blastocysts
Time Lapse Imaging
CONCLUSION
30:
Proteomics and Metabolomics in ART
INTRODUCTION
WHAT ARE GENOMICS, PROTEOMICS AND METABOLOMICS?
PROTEOMICS IN ART
PROTEOMIC STUDIES ON THE MALE REPRODUCTIVE SYSTEM
Proteomics Studies on the Female Reproductive System
Proteomics of Embryos
METABOLOMICS IN ART
Selecting the Best Embryo
Selecting the Best Oocyte
Metabolomic Assessment of Follicular Fluid
CONCLUSION
31:
Time-lapse Microscopy
INTRODUCTION
STAGES OF EMBRYO DEVELOPMENT
TIME-LAPSE MICROSCOPY
Advantages of Time-lapse Microscopy
Morphological Assessment of Embryos in a Continuous Time Period
Maintenance of External Environment Homeostasis
Molecular Level Assessment of Embryos
Eliminating the Need for PGD
Noninvasive TLM Markers
Critical Evaluation of TLM
Computer-assisted Analysis: Alternative to TLM
FUTURE PROSPECTS
CONCLUSION
32:
Embryo Transfer: Catheters and Techniques
INTRODUCTION
HISTORICAL ASPECTS
PREPARATORY TECHNIQUES
Role of Hysteroscopy Prior to Embryo Transfer
Medication Prior to Embryo Transfer
Uterine Relaxants
Prophylactic Antibiotic Administration
Choice of Catheter
Soft vs Rigid
Newer Catheters
Timing of Embryo Transfer
Sequential Embryo Transfer
Role of Ultrasound in Embryo Transfer
Procedure of ET
Post-transfer Instructions
Number of Embryos Transferred
Single Embryo Transfer
Difficult Embryo Transfer
Rest After Embryo Transfer
OTHER TECHNIQUES
Frozen Thaw Embryo Transfer
Role of Granulocyte Colony-stimulating Factor
CONCLUSION
SECTION 9: IMPLANTATION
33:
Endometrial Receptivity
INTRODUCTION
THE PROCESS OF IMPLANTATION
ENDOMETRIAL RECEPTIVITY
THE ROLE OF STEROID HORMONES
MORPHOLOGIC AND MOLECULAR MARKERS OF RECEPTIVITY IN HUMAN ENDOMETRIUM
Histological Evidence
Pinopodes
Genetic Factors: Role of Homeobox Genes
Cellular Adhesion Molecules Family
Integrins
Selectins
Cytokines
Interleukins
Leukemia Inhibiting Factor
Tumor Growth Factor β (TGFβ)
NON-INVASIVE ASSESSMENT OF ENDOMETRIAL RECEPTIVITY
CONCLUSION
MESSAGE BOX
34:
Embryo Endometrial Dialogue
SYNOPSIS
Implantation
Successful Implantation
Embryo: Uterine Interaction During Implantation
INTRODUCTION
PREIMPLANTATION EMBRYO DEVELOPMENT
UTERINE RECEPTIVITY AND IMPLANTATION
IMPLANTATION WINDOW
SUSCEPTIBILITY TO IMMUNITY
RELEVANCE OF THE LEPTIN SYSTEM IN THE EMBRYO: ENDOMETRIAL DIALOGUE
POTENTIAL MOLECULAR SIGNALING DURING IMPLANTATION
Autocrine Secretion
Paracrine Secretion
Juxtacrine Signals
IMMUNOMODULATION
Hormonal and Immunological Factors: Progesterone as an Immunomodulatory Molecule (Flow chart 1)
CYTOKINES
Carbohydrate Chains of Glycoproteins Expression
CONCLUSION
35:
Physiology of Implantation in Natural Cycle Versus Stimulated Cycle
INTRODUCTION
CHANGES IN ENDOMETRIUM DURING MENSTRUAL CYCLE
EARLY EMBRYO DEVELOPMENT AND IMPLANTATION
STIMULATED CYCLE
CONCLUSION
36:
Recurrent Implantation Failure: Strategies and Intervention
INTRODUCTION
EMBRYO AS A POSSIBLE CAUSE OF RIF: STRATEGIES AND INTERVENTION
Ovarian Stimulation Regimen
Blastocyst Transfer
Sequential Embryo Transfer
Assisted Hatching
Cocultures
Preimplantation Genetic Diagnosis for Aneuploidy Screening
Evaluating Embryonic Potential
ENDOMETRIUM AS POSSIBLE CAUSE OF RIF: STRATEGIES AND INTERVENTION
Embryo Transfer Technique
Screening Hysteroscopy
Endometrial Injury
Thin Endometrium
IMMUNOLOGICAL FACTORS
Allogeneic Lymphocyte Therapy
Thrombophilia
Transfer in Hormone Replacement Therapy Cycles
Concept of Personalized Embryo Transfer and Endometrial Receptivity Assay
ADJUVANT PHARMACEUTICAL THERAPIES
Aspirin
Nitric Oxide Donors
Aromatase Inhibitors
Ascorbic Acid
Prolonged Progesterone
Estradiol Supplementation
Glucocorticoids Use
Insulin Sensitizing Agents
ALTERNATIVE MEDICINES TO IMPROVE IMPLANTATION
SURROGACY AND GAMETE DONATION
CONCLUSION
37:
Implantation and the Endometrium in Uterine Fibroid
INTRODUCTION
FIBROIDS AND FERTILITY
FIBROIDS AND IN VITRO FERTILIZATION TREATMENT OUTCOME
FERTILITY AFTER MYOMECTOMY
IN VITRO FERTILIZATION OUTCOME AFTER MYOMECTOMY
ALTERNATIVE TREATMENTS FOR FIBROIDS
38:
Implantation in Endometriosis
INTRODUCTION
PHYSIOLOGY OF IMPLANTATION
Cytokines
Adhesion Molecules
Immune Cells, Complement Factors and Major Histocompatibility Complex
PATHOGENESIS OF DEFECTIVE IMPLANTATION
TREATMENT OF ENDOMETRIOSIS
FUTURE RESEARCH AREAS
SECTION 10: CRYOPRESERVATION
39:
Oocyte Cryopreservation
INTRODUCTION
EFFICIENCY OF OOCYTE CRYOPRESERVATION
Clinical Outcome
Neonatal Outcome
CLINICAL APPLICATIONS
Infertile Patients
Oocyte Donation
Fertility Preservation
Banking for AGE (Anticipated Gamete Exhaustion)
CONCLUSION
40:
Embryo Cryopreservation
INTRODUCTION
CRYOPRESERVATION OF TWO PRONUCLEAR STAGE ZYGOTES
Slow Freezing Technique
Preparation of Oocytes
Freezing and Thawing Procedures
Ultra-Rapid Freezing Technique
Vitrification
COMPARISON OF THE DIFFERENT CRYOPRESERVATION TECHNIQUES
Cryopreservation of Cleavage Embryos
Is Vitrification More Favorable than Slow Freezing of Cleaved Stage Embryos?
Cryopreservation of Blastocyst Stage Embryos
Key Points of Blastocysts Vitrification Improvement
Blastocyst Selection for Vitrification
Influence of Early Embryonic Quality
Day 5 Versus Day 6 Vitrification
Post-thawing Selection
Interventions
Previtrification Interventions
Post-warming Intervention
Improvements in Vitrification Methods
Improving Media Protocols
Minimal Volume Vitrification
Increasing Cooling and Warming Rates
Operator Training
FUTURE PERSPECTIVES
KEY POINTS
41:
Cryopreservation of Ovarian Tissue
INTRODUCTION
History
Indications
Procedure
OVARIAN CORTICAL TISSUE
WHOLE OVARY CRYOPRESERVATION
METHODS OF FREEZING
Slow Freezing
Vitrification
PREGNANCY AFTER OVARIAN TISSUE CRYOPRESERVATION
TRANSPLANTATION
Orthotropic Transplantation of Ovarian Cortex
Heterotropic Transplantation of Ovarian Cortical Tissue
RISK OF CANCER RECURRENCE
ALTERNATIVES TO OVARIAN TISSUE CRYOPRESERVATION
In Vitro Maturation
CONCLUSION
42:
In Vitro Maturation of Oocytes
INTRODUCTION
HISTORY OF IN VITRO MATURATION OF OOCYTES
IN VITRO MATURATION OF OOCYTES
APPLICATIONS OF IN VITRO MATURATION
DISADVANTAGES OF IN VITRO MATURATION
ANIMAL MODELS FOR IN VITRO MATURATION
DISCUSSION
CONCLUSION
43:
Semen Banking
GENERAL ASPECTS OF SEMEN BANKING
THE PRINCIPAL VARIABLES OF CRYOPRESERVATION: SOLUTIONS, TEMPERATURES AND RATE CHANGES
SPERM CRYOPRESERVATION
APOPTOSIS IN EJACULATED HUMAN SPERMATOZOA
MECHANISMS AND MANIFESTATIONS OF CRYOINJURY IN SPERMATOZOA
Implication of Apoptosis in Sperm Cryoinjury/Increased Apoptosis in Cryopreserved Spermatozoa
APOPTOSIS IN CRYOPRESERVED SUBFERTILE SEMEN SAMPLES
METHODS TO DECREASE APOPTOSIS DURING SPERM CRYOPRESERVATION
PROCESSING OF SEMEN CAN RESULT IN INCREASED SPERM DEOXYRIBONUCLEIC ACID FRAGMENTATION
EFFECTS OF CRYOPRESERVATION ON HUMAN SPERM DEOXYRIBONUCLEIC ACID INTEGRITY
CANCER AND FERTILITY: STRATEGIES TO PRESERVE FERTILITY
EFFECTS OF CANCER AND ITS TREATMENT ON FERTILITY
Male Reproductive System
PRESERVATION OF FERTILITY FOR YOUNG ADULTS WITH CANCER
CRYOPRESERVATION TECHNIQUES
MALE FERTILITY PRESERVATION
Cryopreservation of Sperm
SPERM VACUOLES ARE NOT MODIFIED BY FREEZING–THAWING PROCEDURES
SIMPLE VITRIFICATION FOR SMALL NUMBERS OF HUMAN SPERMATOZOA
PROTOCOLS FOR LABORATORY PROCEDURES
Equipment and Reagents
PROCEDURES (ASPIRATION FROM SURGERY)
Technical Note
PROCEDURE (SEMEN FROM EJACULATE)
Technical Note
SUMMARY
44:
Fertility Preservation in Cancer (Male and Female)
INTRODUCTION
EFFECTS OF CANCER AND ITS TREATMENT ON FERTILITY
Male Reproductive System
Female Reproductive System
PATIENTS’ DILEMMA: COPING WITH CANCER AND DECISION ON FERTILITY PRESERVATION
MALIGNANT CONDITIONS NECESSITATING FERTILITY PRESERVATION
Childhood Cancers
Breast Cancer
Cancer of the Cervix
Patients Receiving Pelvic Radiation
Endometrial Cancer
Cancers in Males
METHODS OF FERTILITY PRESERVATION IN MALES
Fertility Preservation Options for the Adult Male
Semen Cryopreservation
Cryopreservation of Testicular Tissue
Fertility Preservation Options in Prepubertal Males
METHODS OF FERTILITY PRESERVATION IN FEMALES
Embryo Cryopreservation
Mature Oocyte Cryopreservation
Ovarian Tissue Cryopreservation
Development of Human Ovarian Transplantation Techniques
Orthotopic Ovarian Transplantation
Heterotopic Ovarian Transplantation
Risk of Metastatic Disease
Shielding of Ovaries
GnRH Analog Co-treatment
In Vitro Maturation of Oocytes
In Vitro Grown Human Ovarian Follicles
Donor Oocytes and Surrogacy
SPECIAL CONSIDERATIONS FOR OVARIAN STIMULATION IN CANCER PATIENTS
OBSTACLES TO FERTILITY PRESERVATION
ETHICAL DILEMMA
CURRENT GUIDELINES FOR FERTILITY PRESERVATION
ASCO Guidelines for Fertility Preservation
Adult Males
Adult Females
Children
Role of Oncologists
CONCLUSION
SECTION 11: LUTEAL PHASE IN ART
45:
Luteal Phase Support in ART
INTRODUCTION
LUTEAL PHASE IN NATURAL CYCLES
Role of Progesterone in Luteal Phase
LUTEAL PHASE DEFECT
Diagnosis of LPD
LUTEAL PHASE IN STIMULATED CYCLES
RATIONALE BEHIND LUTEAL SUPPORT IN AGONIST/ANTAGONIST CYCLES
PRACTICAL OPTIONS FOR LUTEAL SUPPORT
Progesterone for LPS
Oral Route
Vaginal Route
Parenteral Route
EFFICACY OF VARIOUS PROGESTERONE PREPARATIONS
DURATION OF LUTEAL SUPPORT
Optimum Timing of the LPS Initiation
Discontinuation of Luteal Phase Support
ADJUNCT THERAPY FOR LUTEAL PHASE SUPPORT
Esradiol
GnRH Agonist
Human Chorionic Gonadotropin
LUTEAL PHASE IN SPECIAL CASES
CONCLUSION
SECTION 12: ART IN SPECIAL CONDITIONS
46:
Endometriosis and ART
INTRODUCTION
MEDICAL TREATMENT PRIOR TOIN VITRO FERTILIZATION
MANAGEMENT OF OVARIAN ENDOMETRIOMAS
Expectant Approach: Impact on Reproduction
Surgical Approach: Impact on Reproduction
RISKS OF EXPECTANT MANAGEMENT AND SURGERY
Expectant Management
Missing an Occult Early Stage Malignancy
Development of a Pelvic Abscess
Impairment of Endometriosis
Other Complications
Surgery
CONCLUSION
MESSAGE BOX
47:
Myomas in Infertility
INTRODUCTION
RECENT EVIDENCE
EFFECT OF LOCATION OF MYOMA ON IVF OUTCOME
EFFECT OF SIZE OF MYOMA ON IVF OUTCOME
EFFECT OF MYOMECTOMY ON IVF OUTCOMES
CONCLUSION
Location of Myoma
Size of Myoma
Role of Myomectomy
48:
Genital Tuberculosis and ART
INTRODUCTION
EPIDEMIOLOGY OF GENITAL TUBERCULOSIS
ETIOPATHOGENESIS OF INFERTILITY IN GENITAL TUBERCULOSIS
DIAGNOSIS OF GENITAL TUBERCULOSIS
ENDOSCOPY PRIOR TO IN VITRO FERTILIZATION
INDICATIONS OF ASSISTED REPRODUCTION TECHNIQUES
PRE-IN VITRO FERTILIZATION EVALUATION
MEDICAL TREATMENT PRIOR TO IN VITRO FERTILIZATION
SURGICAL TREATMENT PRIOR TO IN VITRO FERTILIZATION
PROBLEMS DURING IN VITRO FERTILIZATION
OUTCOME OF ASSISTED REPRODUCTION TECHNIQUES
CONCLUSION
KEY POINTS
49:
Poor Ovarian Response
INTRODUCTION
DEFINITION
INCIDENCE
ETIOLOGY
PREDICTORS OF POOR OVARIAN RESPONSE
Static Tests40
Biochemical Tests
Sonographic Tests40
Dynamic Tests
TREATMENT
Precycle Adjuvants
Dehydroepiandrosterone
Simple Cyst Drainage Prior to Stimulation Protocols
The Benefits and Risk of Precycle Oral Contraceptive Pill or Antagonist Suppression Combined with Estrogen Priming
Adjuvants at the Initiation of a Cycle
GnRH Agonists
GnRH Antagonists
Gonadotropins and their Stimulation Doses
Dose
NATURAL CYCLE IVF AND MODIFIED NATURAL CYCLE IVF
OTHER ADJUVANTS
hGH
Low Dose Aspirin
LABORATORY OPTIONS IN POOR RESPONSE CYCLES
Intracytoplasmic Sperm Injection for Low Oocyte Yield
Preimplantation Genetic Screening for Poor Responders
Assisted Hatching
Ideal Day of Transfer
Number of Embryos for Transfer
Donor Oocytes
CONCLUSION
50:
ART in Polycystic Ovary Syndrome
INTRODUCTION
CHALLENGES IN PCOS
PATHOPHYSIOLOGY AND OOCYTE ABNORMALITIES IN PCOS
Extraovarian Factors
Hyperinsulinemia and Premature Follicle Luteinization
FSH Deficiency
Luteinizing Hormone Hypersecretion
Hyperandrogenism
Intraovarian Factors
Transforming Growth Factor—Beta-related Proteins
OVARIAN STIMULATION PROTOCOLS FOR ART CYCLES IN PCOS
Choice of Gonadotropin
Which Protocol to be Used—GnRH Agonist vs GnRH Antagonist?
Which Trigger for Final Oocyte Maturation?
Luteal Phase Rescue after GnRH Agonist Triggering—Modified Luteal Phase Support
Supplementation with hCG27
Supplementation with Recombinant LH
INSULIN SENSITIZERS IN PCOS
Metformin
Role of Metformin for COH Cycles for IVF-ICSI
Effect of Metformin on Pregnancy Outcomes
Metformin and Gestational Diabetes Mellitus
Metformin and Pre-eclampsia
Side Effects of Metformin
Myo-inositol
COMPLICATIONS OF OVARIAN STIMULATION IN PCOS
Classification of Ovarian Hyperstimulation Syndrome
Strategies for Prevention of OHSS
IN VITRO MATURATION
CONCLUSION
SECTION 13: THIRD PARTY ART
51:
Gamete Donation
INTRODUCTION
SPERM DONATION
Requirements of Recipient Female
Preparation of Sperm Recipient
Requirements for a Sperm Donor (ICMR Guidelines)2
Semen Banks
Collection of Semen
Contract
Consent and Counseling of Donor
Cryopreservation
Types of Frozen Preserved Semen Sample
Drawbacks and Benefit of Various Freezing Methods
Screening of Semen Donor
Information to be Given by Semen Donor in “ICMR Form M”
Differences in Guidelines from Various Countries Regarding Gamete Donation
ICMR Criteria for Running of a Semen Bank2
OOCYTE DONATION
Indications of Oocyte Donation
Requirements for an Oocyte Donor (ICMR Guidelines)
Requirements of Oocyte Recipient
Preparation of Oocyte Recipient
Methods of Endometrial Preparation
Requirements for Partner of Oocyte Recipient
Rights and Duties of Donor14
Duties of ART Clinic in Reference Oocyte Donation
Problem of Donor Shortage
CHANGING PRACTICE OF ANONYMITY
LEVELS OF INFORMATION SHARING
CONCLUSION
MESSAGE BOX
Endorsement by the ART Clinic
Basic Information
History
Investigations
Features
Detailed Physical Examination
Endorsement by the ART Clinic
Endorsement by the ART Clinic
Consent of Husband/Partner (As and if Applicable)
52:
Embryo Donation
DEFINITION
HISTORY
TYPES
SOURCE
INDICATIONS FOR EMBRYO DONATION
GUIDELINES
RECORD KEEPING
Protection of Confidentiality
Screening: Donors or Recipients
PROTOCOL
SUCCESS
LEGAL ISSUES
ETHICAL ISSUES
DONOR ISSUES, OBSTACLES AND DILEMMAS
CONCLUSION
53:
Surrogacy
INTRODUCTION
INDIAN MYTHOLOGY
BIBLE MYTHOLOGY
DEFINITIONS
INDICATIONS FOR GESTATIONAL SURROGACY (FIG. 1)
STEPS IN SURROGACY
Patient Selection
Counseling for the Intended Parents
Selection of the Surrogate
Counseling of the Surrogate
Screening of the Surrogate
Overview of Surrogacy Process
Preparing the Surrogate for Embryo Transfer
Luteal Phase Support
Detection of Pregnancy
What are the Success Rates for Gestational Surrogacy?
Surrogacy and Law
Indian Scenario and Legal Issues
National Guidelines
Highlights of Indian Council of Medical Research Guidelines
Ethical Issues
Ethical Consideration
OUR EXPERIENCE
Justification for Surrogate
Suggestions
Cost for Surrogacy
Socioeconomic Upliftment of the Surrogates (Akanksha IVF Clinic)
Surrogate House
CONCLUSION
MESSAGE BOX
SECTION 14: PREGNANCY AND ART
54:
First Trimester Screening in Pregnancies Conceived with ART
INTRODUCTION
FIRST TRIMESTER SCREENING
How is FTS different in ART Pregnancies than Spontaneous Conceptions?
EFFECT OF ART ON FIRST TRIMESTER SCREENING
Cause of Infertility
Stimulation Protocol
Type of ART
Number of Oocytes Retrieved
EFFECT OF FTS ON ART PREGNANCY
Maternal Serum Biochemistry (PAPP-A, β-hCG)
Nuchal Translucency
False-positive Rates and Invasive Testing
OTHER IMPLICATIONS OF FTS RESULTS FOR ART
POSSIBLE EXPLANATIONS FOR DIFFERENCES IN FTS IN ART PREGNANCIES
KEY POINTS
55:
Obstetric Outcome Following ART
INTRODUCTION
COMPARISON OF PREGNANCY OUTCOME IN FERTILE VERSUS SUBFERTILE WOMEN
COMPARISON OF THE PREGNANCY OUTCOMES OF SUBFERTILE WOMEN AFTER INFERTILITY TREATMENT AND IN NATURALLY CONCEIVED PREGNANCIES
COMPARISON OF PREGNANCY OUTCOME IN FERTILE WOMEN VERSUS ART PREGNANCIES IN SUBFERTILE WOMEN
COMPARISON OF PREGNANCY OUTCOME IN NATURAL CONCEPTION IN SUBFERTILE WOMEN OR USE OF OVULATION INDUCTION (WITH OR WITHOUT INTRAUTERINE INSEMINATION) AND USE OF IN VITRO FERTILIZATION
CONCLUSION
56:
ART to Antenatal Care
INTRODUCTION
FIRST TRIMESTER
First Trimester Bleeding
Abortions
Ectopic Gestation
Congenital Malformations
Multiple Gestations
SECOND AND THIRD TRIMESTER
Preterm Labor and PPROM
Pre-eclampsia and IUGR
Diabetes Mellitus
Antepartum Hemorrhage
Cesarean Sections
CONCLUSION
SECTION 15: COMPLICATIONS IN ART
57:
Ovarian Hyperstimulation Syndrome
PATHOPHYSIOLOGY
CLINICAL PRESENTATION AND CLASSIFICATION OF OVARIAN HYPERSTIMULATION SYNDROME
Golan Classification
Rizk and Aboulghar Classification
Categorization for Treatment
Identifying the Patient at Risk
Primary Risk Factors
Secondary Risk Factors
OVARIAN HYPERSTIMULATION SYNDROME PREVENTION
Primary Prevention
Reducing Dose of Gonadotropin
Use of Gonadotropin-releasing Hormone Antagonist Protocols
Avoid Human Chorionic Gonadotropin for Luteal Phase Support
In Vitro Maturation
Insulin-sensitizing Agents
Secondary Prevention Strategies
Coasting
Reduced Dose of Human Chorionic Gonadotropin Trigger
Gonadotropin-releasing Hormone Agonist Trigger
Triggering with Recombinant Luteinizing Hormone
Cryopreservation of All Embryos
Dopamine Agonists
Plasma Expanders: Intravenous Albumin and Hydroxyethyl Starch
Cycle Cancelation
Other Strategies
MANAGEMENT OF OVARIAN HYPERSTIMULATION SYNDROME
Outpatient Management
Recommendations for the Outpatient Management of Persistent and Worsening OHSS Include
Hospitalization
Laboratory findings in severe OHSS
Fluid Management
Guidelines for Fluid Management of Hospitalized Patients
Paracentesis
CONCLUSION
TAKE HOME MESSAGE
58:
Ovarian Cancer and ART
INTRODUCTION
INFERTILITY AND OVARIAN CANCER RISK
DRAWBACKS OF THE STUDIES EVALUATING IVF AND OVARIAN CANCER RISK
CONCLUSION
59:
Ethical and Stress Issues in ART
ETHICAL ISSUES
General
Current Ethical Issues
Definition of When Life (or “Personhood”) Begins
Stem Cells
Donor Gametes
Nonmedical Sex Selection
Surrogacy
Postmortem use of Gametes
Access and Cost in Low Resource Environments
Local Ethics Committees
Conclusion
STRESS ISSUES
Principal Elements
Patient Screening
Patient Centered Care
Interventions
COUNSELING
CONCLUSION
MESSAGE BOX
INDEX
TOC
Index
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