Management of Infertility: A Practical Approach

Front Cover
MANAGEMENT OF INFERTILITY
MANAGEMENT OF INFERTILITY
Copyright
Contents
Contributors
Preface
1 - History and epidemiology of human fertility
Fertility in the ancient world
Fertility in the post-Renaissance era
Fertility in modern times
The hypothalamic-pituitary-ovarian axis
The gonadotrophins
Gonadal steroids
Immuno-assays and the female hormonal interplay
Other milestones in the history of fertility
The IVF revolution
Further developments in assisted reproduction
The story of ICSI
Embryo selection, fertility preservation, and the future
Epidemiology of human fertility
Normal fertility patterns and the definition of infertility
Prevalence of infertility
Seeking infertility treatment
Factors affecting the success of infertility treatment
Burden of infertility
Access to infertility services
References
2 - Setting up an ART unit: planning, design, and organization
Planning
Location
Reachability
Communication
Design and building
Required surface
Design
Waiting room
Examination room
Semen pick area
Semen laboratory
IVF laboratory
Storage areas
Controlled accesses
Emergency access
Materials and implants
Materials
Floors
Resilient coatings
Materials for thermal and acoustic insulation
False ceiling
Paints
Plants
Installations
Light
Power and UPS
Gas station
Liquid nitrogen and cryoroom
Air quality
LAN network
PMA and home automation
Ergonomics and flows
Workflows
Ergonomics
Examples about ergonomics in an embryology laboratory
Responsibility and organization
Staff and experience
Stafff requirements
Organization chart
European model [39]
Staff and management
Laboratory director
Laboratory supervisors
Clinical embryologists
American model (ASRM) [40]
Personal
Doctors
Nurses
Laboratory
Auxiliary personnel
Training and specialized experience
Study director
Medical director
Doctor performing egg retrieval and embryo transfers
Nurses
Director of the embryology laboratory
Embryology laboratory technician
References
3 - Building the assisted reproduction laboratory
Introduction
Purposes of the lab
Location
Laboratory
Andrology laboratory
Liquid nitrogen containers storage room
Gas cylinders central and management
General material storage
The building structure
Air flow
Furniture
Equipment
Safety
Personal experience
Concluding remarks
References
4 - Workup of female infertility
Introduction
Classification of infertility interview
Approaching the interview
First interview
Anamnestic interview
Physical examination
Exams required
Ovarian reserve test (ORT)
Serum hormone assessment
Ultrasound assessment
Ovulation and luteal phase support
Coagulation profile assessment
Genetic profile assessment
Serologic assessment
Sonohysterosalpingography
3D transvaginal ultrasound
Hysteroscopy
PAP test or HPV-DNA test
Breast ultrasound or radiography
Timing of exams
Secondary interview
Follow-up interview
Conclusion
References
5 - Work-up of male infertility
Epidemiology
Etiology and risk factors
Diagnostic work-up
Patient's history
Infertility history
Medical history
Lifestyle factors
Surgical history
Family history
Sexual history
Physical examination
Semen analysis
Measurement of sperm DNA fragmentation index
Hormonal evaluation
Genetic testing
Chromosomal abnormalities
Autosomal abnormalities
Cystic fibrosis gene mutations
Y microdeletions
Measurement of oxidative stress
Imaging
Scrotal ultrasound
Transrectal US
Other
Summary
References
6 - Prothrombotic gene polymorphisms and adverse reproductive outcomes in assisted reproductive technology
Physiology of coagulation
Coagulation factors' gene mutations
Activated protein C resistance (factor V Leiden mutation)
Antithrombin deficiency
Protein C and protein S deficiency
Prothrombin G20210A mutation
Hyperhomocysteinemia
Plasminogen activator inhibitor type 1
Elevated factor VIII
Blood coagulation in pregnancy
Prothrombotic hereditary coagulopathies and recurrent pregnancy loss
ART procedures in current practice
Prothrombotic gene polymorphisms and adverse reproductive outcomes in ART
Preconceptional and prenatal diagnostic approach
Possible management options
Conclusions
References
7 - Endocrinological causes of female infertility
Introduction
Anovulation
Ovarian aging
Ovarian reserve
Primary ovarian insufficiency
Polycystic ovary syndrome
Hypothalamic-pituitary axis pathology
Hyperprolactinemia
Hyper- and hypoandrogenism
Therapeutical intervention
Estrogen antagonists
Gonadotropins treatments
Preventing complications
Ovarian hyperstimulation syndrome
Multiple gestations
Final considerations
References
8 - Management of tubal factor
Tubal infertility
Etiology
Tubal lesions
Proximal
Distal
Congenital lesions
What are the subtle tubal lesions?
Diagnosis
Therapeutic options
Tubal flushing
Tubal surgery
General principles
Surgery of pelvic adhesions
Proximal pathology
Distal pathology
Subtle tubal lesions
Conclusion
References
9 - Cervical and uterine congenital anomalies
Introduction
Embryology: the origin of anomalies
Pathogenesis
Etiology
Prevalence
Other associated anomalies
Clinical presentation
Classification
Diagnosis
2D ultrasound
Hysterosalpingography
Hysteroscopy
3D ultrasound
Magnetic resonance
Uterine abnormalities
Septate uterus
Diagnosis
Clinical relevance
Surgical treatment
Results after hysteroscopic metroplasty
Complete septa with double cervix
Unicornuate uterus
Diagnosis
Clinical importance
Associated anomalies
Surgical repair
Results after hysteroscopic metroplasty
Dysmorphic uterus
Diagnosis
Clinical importance
Surgical repair
Results after hysteroscopic metroplasty
Bicornate uterus
Clinical importance
Diagnosis
Surgical repair
Results after surgery
Robert's uterus
Diagnosis
Clinical importance
Surgical repair
Control after hysteroscopic surgery
Recommendations and conclusions
References
10 - Uterine fibroids and infertility
Introduction and definition
Uterine fibroids and infertility
Pathophysiology
Uterine myometrial peristalsis
Diagnosis
Management
Recommendation
Conclusion
References
11 - Endometriosis and infertility
Pathophysiology
Potential mechanisms for endometriosis-related infertility
Management of endometriosis-associated infertility
Fertility preservation in women with endometriosis
References
12 - Endocrinological causes of male infertility
Introduction
Hormonal actions on spermatogenesis
Hormonal regulations of spermatogenesis
Endocrine conditions associated with male infertility
Male hypogonadism
Hyperprolactinemia
Thyroid disorders
Obesity
Exogenous administration of testosterone and anabolic steroid
Evaluation of an infertile man from an endocrinological point of view
Therapies
GnRH
Gonadotropin
Antiestrogens
Aromatase inhibitors
The protocol of hormonal treatment of infertile men
References
13 - Sperm DNA fragmentation: impact on ART outcome
Introduction
Measuring SDF within the context of ART
The impact of SDF on IUI
The impact of SDF on IVF and ICSI
Impact of SDF on fertilization
Impact of SDF on clinical pregnancy
Impact of SDF on embryogenesis
Impact of SDF on miscarriage and live birth rate
Approaches to reduce SDF in ART
Varicocele treatment
Treatment of male genital tract infections
Addressing lifestyle and exposure risk factors
Antioxidant therapy
Frequent ejaculation
Sperm selection techniques and use of ART
Future directions
Summary of key points
References
14 - Male accessory gland infection: diagnosis and treatment
Definition and classification
Impact on fertility: explanatory mechanisms
Diagnosis
Microbiological testing
Ultrasound
Therapeutic strategies
Antibiotics
Antiinflammatory drugs
Fibrinolytics
Antioxidants
Conclusion
References
15 - Hormonal and nonhormonal treatment of male infertility
Etiology of male infertility
Pathophysiology of spermatogenesis
Principles of management
Hypothalamo-pituitary disease
Testicular failure
Idiopathic male infertility
Empirical hormonal therapy
GnRH analogs
Gonadotropins
Androgens
Aromatase inhibitors
Selective estrogen receptor modulators
Empirical non-hormonal therapy
Antioxidants
Antibiotics
Lifestyle modification
Obesity and weight loss
Diet and exercise
Alcohol
Smoking
Caffeine
Recreational drugs
Stress
References
16 - Surgical management of male infertility and sperm retrieval
Surgical management of conditions related to male infertility
Varicocele
Introduction
Radiological techniques: retrograde sclerotherapy or embolization
Radiological techniques: anterograde sclerotherapy or embolization
Surgical techniques: retroperitoneal approach
Surgical techniques: laparoscopic approach
Surgical techniques: inguinal and subinguinal approach
Summary about varicocele treatment
Retractile testis in adulthood
Ejaculatory ducts obstruction
Transurethral resection
Vasovasostomy and vasoepididymostomy
Sperm retrieval in azoospermic men
Sperm retrieval in obstructive azoospermia
Sperm retrieval in nonobstructive azoospermia
References
17 - How to choose the appropriate ART technique and counseling about reproductive outcomes
References
Further reading
18 - Preparing the couple for ART: necessary and unnecessary diagnostic tests
Introduction
Tests to be performed by both partners
Blood group with Rh factor
Blood glucose
Kidney and liver function
Viral screening: HIV, HBV, and HCV
Human papillomavirus (HPV) screening
Hemoglobin electrophoresis
Karyotype
Cystic fibrosis mutations
Tests to be performed by the woman
Preconception counseling
Thrombophilia screening
Cervico-vaginal swab
FSH, LH, and estradiol
Clomiphene citrate challenge test
AMH
Progesterone
TSH and TPOAb
Pelvic ultrasound examination
Hysterosalpingography and hysterosonosalpingography
Chlamydia antibody test (CAT)
Hysteroscopy
Laparoscopy
Tests to be performed by the man
Semen analysis
Microbiological assessment
FSH, LH, testosterone, prolactin
Scrotal ultrasonography
Transrectal ultrasonography
Y chromosome microdeletion analysis
Sperm DNA fragmentation tests
Tests for antisperm antibodies
Diagnostic testicular biopsy
References
19 - Ovulation induction protocols
Introduction
Indications
Cervical indications
Sperm etiology
Unexplained etiology
Ejaculation disorders
Immunological etiology
Pre-IUI tests
Performing intrauterine insemination
Ovarian stimulation
Spontaneous cycle
Antiestrogens
Clomiphene citrate
Aromatase inhibitors
Gonadotropins
Semen preparation
IUI procedure
How many IUIs do we need to achieve?
Prognostic factors of IUI
Etiologies and prognostic factors
Rank of the attempt and prognostic factors
Age and duration of infertility
Characteristics of stimulation
Number of motile sperm inseminated (NMSI)
Sperm morphology
Conclusion
Bibliography
20 - Ovarian stimulation protocols
Introduction
Conventional protocols
GnRH agonist protocols
GnRH antagonist protocols
Comparison of GnRH-a and GnRH-ant protocols
Gonadotropins
Novel protocols
References
21 - Oocyte retrieval
Introduction
Setting and equipment
Preparation of the patient for oocyte retrieval
On the day of oocyte retrieval
Technique
Anesthesia during oocyte retrieval
Oocyte recovery
After the oocyte retrieval
Complications
References
22 - Oocyte quality evaluation and cryopreservation
Human oocyte quality evaluation
General aspects
Oocyte quality assessment by morphology under light microscopy
Evaluation of maturity
Morphologic parameters of oocyte quality
Cumulus-oocyte complex morphology
Cytoplasm and polar body morphology
Meiotic spindle evaluation
Oocyte quality assessment by polarized light microscopy
Oocyte quality assessment by follicular fluid dynamics
Follicular fluid hormones
Growth factors of the transforming growth factor-beta (TGF-beta) superfamily in follicular fluid
Insulin-like growth factors in follicular fluid
Reactive oxygen species in follicular fluid
Metabolomics of follicular fluid
Oocyte quality assessment by molecular approaches
Oocyte quality assessment by AI
Metaphase II (MII) oocyte dysmorphisms
Cytoplasmic abnormalities
Extracytoplasmic abnormalities
Factors affecting oocyte quality
Endometriosis
Age
Polycystic ovary syndrome
Oocyte cryopreservation
The current technologies for oocyte cryopreservation
The recommendations for clinical applications of OC as fertility preservation
The clinical outcomes of oocyte cryopreservation
The risks of oocyte cryopreservation
Conclusion
References
23 - Ovarian hyperstimulation syndrome
Introduction
Definition
Epidemiology
Risk factors
Classifications
Timing of presentation
Severity of presentation
Pathophysiology
Clinical presentation
Clinical assessment
History
Physical examination
Laboratory and imaging tests
Prevention
Identification of risk factors
Potential strategies or intervention before ovarian stimulation
Avoid gonadotropin for ovulation induction in non-IVF cycles
Oral contraceptive (OC), progestogen or estrogen
Natural IVF cycles
Gonadotropin starting dose for IVF cycles
Personalization
Mild ovarian stimulation
Choice of the gonadotropin for high-risk patients
Regimens of ovarian stimulation
Drug co-administrations
CC or letrozole
Metformin
FSH dose decrease
Coasting
Strategies for controlling LH surge
GnRH analogs
Use of progestin-primed ovarian stimulation
Ovulation triggering strategies for high-risk patients
hCG
LH
GnRH agonist
Kisspeptin
Elective cryopreservation
Cancellation cycle
Elective single embryo transfer (eSET)
In vitro maturation (IVM) of oocytes
Other treatments or procedures
Intensification of monitoring and surveillance
Dopaminergic agonists (cabergoline, quinagolide)
Aspirin
Corticosteroids (methylprednisolone)
Calcium infusion
Ketoconazole
Diosmin
Luteal GnRH antagonist administration
Volume expanders
Luteal phase support
Treatment
Outpatients
Inpatients
Conclusions
References
24 - Sperm quality evaluation and cryopreservation
Sperm quality evaluation
Sample collection
Reference ranges
Semen analysis
Basic assessments
Ejaculate volume
Macroscopic assessment
Microscopic assessment
Extended assessments
Sperm DNA fragmentation
Genetic and genomic tests
Testing for antibody coating of spermatozoa
Assessment of accessory gland function (biochemical assays)
Advanced assessments
Quantification of reactive oxygen species
Computer-aided sperm analysis
Sperm preparation and selection
Routine techniques
Advanced techniques
Cryopreservation of spermatozoa
Sample collection
Cryopreservation techniques
Indications
Fertility preservation
Cancer treatment
Gender reassignment
With assisted reproductive techniques
Autologous use
Heterologous use
Risks
Challenges
Future
References
25 - In vitro fertilization and embryo culture in time-lapse imaging
Introducing time-lapse devices
Embryo selection using time lapse
Patient perspectives and feedback
Anticipating the future
Summary
References
26 - Intracytoplasmic sperm injection
Background
Indications
Male factor
Non-male factor
Popularity
Results
Ejaculated spermatozoa
Surgically retrieved spermatozoa
ICSI for difficult cases
Extreme male factor
Elevated DNA fragmentation
Persistent fertilization failure
Considerations and future perspective
References
27 - Embryo transfer
Introduction
Learning curves
Biofluidic dynamics of embryo transfer
The role of the catheter and loading embryos
Preparation of the uterus for transfer
Mock transfer and transvaginal ultrasound for the measurement of the endometrial cavity length and position
Is the ultrasound support effective?
Placement of embryos in the uterine cavity
Conclusions
References
Further reading
28 - Luteal phase support
Introduction
Physiology of the luteal phase
Pharmacodynamics and types of presentation of progesterone
Routes of administration
Oral progesterone
Intramuscular progesterone
Vaginal progesterone
Subcutaneous progesterone
Transdermal progesterone
LPS in assisted reproductive treatments
Intrauterine insemination
In vitro fertilization
Progesterone's dosages and routes
Personalized luteal phase
The onset of progesterone supplementation
Ending of LPS
LPS and egg donation/frozen-thawed embryo transfer (FET) cycles
Use of estradiol in LPS
Use of hCG in LPS
Use of LH in LPS
Use of GnRH agonists in LPS
Disorders of endometrial receptivity and Personalized Embryo Transfer
Conclusions
References
29 - Preimplantation genetic testing
Principle and history of preimplantation genetic testing
Principle
The first steps of clinical preimplantation genetic testing
Worldwide applications of PGT and the first questions on its efficacy
Protocol of PGT
ICSI and embryo culture
Embryo biopsy
Molecular analysis
Embryo vitrification/warming and embryo transfer
Genetic counseling
Quality and risk assessment
Results and efficacy of PGT
Efficacy of embryo culture, embryo biopsy, and consequences on clinical outcomes
Database results
Results and efficacy of PGT-M
Results and efficacy of PGT-SR
Results and efficacy of PGT-A to indications
Whole chromosome mosaicisms and segmental chromosomal abnormalities
Chromosomal concordance between inner cell mass and trophectoderm cells
Noninvasive PGT
Conclusions and the future of PGT
Acknowledgments
References
30 - Embryo quality evaluation and cryopreservation
Embryo quality evaluation
Cryopreservation
References
31 - Frozen embryo transfer
Introduction
Background
How to prepare the endometrium for FET
Natural cycle and modified natural cycle
Hormone replacement treatment
Maternal and obstetric outcomes of FET
Conclusions
References
32 - Egg and sperm donation
Introduction
Indications for egg donation
Indications for sperm donation
Legal aspects
Organizing a gamete donation program
Phenotype matching
Genetic matching
Donors
Selection of donors
Donor age
Treatment protocol for the donor
Synchronous donation
Synchronization with the recipient
Ovarian stimulation for the donor and trigger
Donor pick-up
Asynchronous donation
Complications
Recipients
Recipient selection
Recipient's age
Synchronization with the donor
Endometrial preparation and growth
Endometrial preparation for embryo reception
Type and route of progesterone to be used
Start day
Post-transfer treatment
Exclusive or shared donor and number of eggs per recipient
Treatment complications in the recipient
Complications for the mother
Complications in the newborn
Results
Egg bank
References
33 - Recurrent miscarriage
Introduction
Definition
Epidemiology
Etiologies
Genetic causes
Parental chromosomal anomalies
Embryonic aneuploidy
Parental karyotyping and products of conception cytogenetic analysis
Sperm DNA fragmentation
Uterine factors
Uterine structural anomalies
Congenital uterine anomalies
Acquired uterine abnormalities
Chronic endometritis
Immunologic factors
Autoimmune disorders: antiphospholipid syndrome
Uterine immune system and immunotherapy
Endocrine disorders
Thyroid disorders
Diabetes
Hyperprolactinemia
Polycystic ovary syndrome
Vitamin D deficiency
Luteal phase deficiency
Inherited thrombophilia
Evaluation for recurrent miscarriage
Conclusion
References
34 - Repeated implantation failure
Introduction
Definitions
Causes
Diagnostic work-up
General
Hysteroscopy
Immune profile biomarkers
Investigation of chromosomal abnormalities
Molecular assays
Metabolomics
Reaching a robust conclusion
Interventions
Endometrial injury
Antibiotics
Human chorionic gonadotropin
Immunotherapy
Intravenous immunoglobulin
Granulocyte colony-stimulating factor
Tacrolimus and sirolimus
Other immunomodulatory agents
Conclusion on immunotherapy
Atosiban
Low molecular weight heparin
Freeze-all policy
Growth hormone
Gonadotropin-releasing hormone
Assisted hatching
Combined strategies
Other treatment options
Conclusion
References
35 - Gestational carrier
Introduction
Indications for surrogacy
Selection process and criteria of gestational carrier
Counseling and legal requirements
Synchronization of cycle
Obstetric care of surrogate
Risks associated with surrogacy
Ethical, religious, and financial concerns about the surrogacy procedure
Psychological impact with surrogacy
Conclusion
References
36 - Female and male fertility preservation in oncology
Introduction
Multidisciplinary fertility sparing team
Counseling and psychological support
Eligibility for fertility sparing
Cancer treatments that affect female fertility
Treatment for breast cancer
Treatment for Hodgkin lymphoma
Ovarian and uterine exposure to radiotherapy
Cancer treatments that affect male fertility
Chemotherapy side effects
Radiation therapy side effects
Surgery effects
Techniques for fertility preservation of female patients
Oocyte and embryo cryopreservation
Cryopreservation of ovarian tissue
GnRH agonists
Fertility-sparing surgery in gynecological cancers
Conservative treatment for cervical cancer
Conservative treatment for ovarian neoplasms
Ovarian borderline tumors
Invasive epithelial ovarian cancer
Conservative treatment for endometrial hyperplasia and cancer
Techniques for fertility preservation in males
Semen cryopreservation
Gonadic suppression
Cryopreservation of testicular tissue
Techniques for fertility preservation in pediatric patients
Pregnancy after fertility preservation in cancer survivors
References
37 - Psychological impact of infertility and ART procedures
Introduction
The psychosocial impact of infertility
Coping and adjustment and the couple unit
Psychosocial impact during treatment
Ending fertility treatment
Recommendations for clinicians
Research limitations
Conclusion
References
38 - Risk, safety, and outcome monitoring in the IVF clinic
Introduction
Monitoring of risk, safety, and outcome in ovarian stimulation
Monitoring of risk, safety, and outcome in oocyte retrieval
Monitoring of risk, safety, and outcome for semen collection and preparation
Monitoring of risk, safety, and outcome in laboratory
In vitro fertilization
Intracytoplasmatic sperm injection
Embryo culture
Preimplantation genetic/diagnostic test
Cryopreservation
Embryo transfer
Other outcomes
Monitoring of risk, safety, and outcome for the entire IVF process
Efficacy outcomes
Safety outcomes
Long-term outcomes for progeny and women
Progeny
Oncological risk
References
39 - Regulation, data management, informed consent, and legal issues for ART
Introduction
ART regulation
ART regulation in European countries
The role of religion
Cross-border reproductive care
Quality and data management
Informed consent
References
40 - Impact of COVID-19 on ART (Assisted Reproductive Technologies)
Introduction
SARS-CoV-2 and reproductive system
Some questions in the practice of ART
The impact of COVID-19 on ART care in Europe and the United States
The impact of vaccine for couples who want a pregnancy or for responsible parenting
The COVID-19 Pfizer and Moderna vaccine
The COVID-19 AstraZeneca and Johnson vaccine
References
Index
A
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D
E
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J
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M
N
O
P
Q
R
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T
U
V
W
Y
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