Textbook of Minimal Stimulation IVF: Milder Mildest or Back to Nature

This textbook discusses Assisted Reproductive Technology (ART) and alternative solutions that mimic natural phenomena.
With contributions from leading international experts, the book describes risks and complications, such as ovarian
hyperstimulation and multiple pregnancies, as well as the financial, psychological, ethical and legal issues involved.
Separate chapters are dedicated to IVF in developing countries, the mini-IVF experience at the New Hope Fertility
Center, and the Kato Ladies Clinic Experience.


Author information

Alejandro Chavez-Badiola MD; Medical Director, New Hope Fertility Center, Guadalajara, Mexico



Gautam N Allahbadia MD DNB FNAMS; Medical Director, Rotunda ?The Center for Human Reproduction, Rotunda Blue Fertility
Clinic and Keyhole Surgery Center, Mumbai, India


Contents
1. Time to Rethink ---------------- 1
Gautam N Allahbadia
The Concerns --- 1
Multiple gestations, perinatal morbidity and mortality -- 1
The availability of ART ---- 2
The developments ----------- 3
The results -- 4
Result analysis --------------- 4
2. Terminology in Ovarian Stimulation for IVF -------------- 6
Alejandro Ch?ez-Badiola, John J Zhang
Clinical Discussion -------------- 6
Natural cycles --------------- 6
Stimulated cycles ------------ 7
3. Mild Approaches: A Whole Different Philosophy in IVF Approaches뾃n Overview ------- 8
Alejandro Ch?ez-Badiola
Clinical Discussion -------------- 8
Clomiphene citrate ---------- 8
Letrozole ---- 9
Gonadotropins --------------- 9
Results ----------- 9
Pregnancy rates -------------- 9
Complication rates ---------- 9
Dropout rate ---------------- 10
Cost-effective treatment --- 10
Drawbacks - 10
Case Studies ---- 10
Patients with poor ovarian reserve ------------------------ 10
Polycystic ovary syndrome and patients at risk of OHSS --------------- 10
Recent Advances --------------- 11
Vitrification 11
Genetics ---- 11
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Textbook of Minimal Stimulation IVF ?Milder, Mildest or Back to Nature
4. Neuroendocrine Regulation of the Menstrual Cycle and the Effect of Controlled Ovarian
Hyperstimulation on Follicle and Endometrial Development ---------- 13
Peter Kovacs
Clinical Discussion ------------- 13
Ovarian organogenesis ---- 13
Folliculogenesis ------------ 13
Endometrial cycle ---------- 16
Controlled ovarian hyperstimulation (COH) ------------- 17
Effect of GnRH agonist and antagonist ------------------- 17
LH levels during stimulation ------ 17
Endometrial changes during COH 19
5. Natural and Modified Natural IVF in Patients with Diminished Ovarian Reserve 22
Eran Horowitz, David Lavran, Ariel Weissman
Clinical Discussion ------------- 23
Natural cycle IVF (NC-IVF) ------ 23
Modified natural cycle (MNC-IVF) ----------------------- 24
6. Protocols for Mild Ovarian Stimulation ------------------- 28
Markus Eckart Nitzschke
Clinical Discussion ------------- 28
Protocols for patients with regular menstrual cycles and normal ovarian reserves --- 28
Protocols for patients with long cycles (> 35 Days) and PCO patients ---------------- 29
Protocols for patients with a compromised ovarian reserve ------------ 30
Case Studies ---- 30
Case 1: Natural cycle IVF following failed IUI -------- 30
Case 2: Programmed mild gonadotropin stimulation cycle with a GnRH agonist trigger and IVF ----------------- 31
Case 3: Programmed Letrozole stimulation cycle with a GnRH agonist trigger in
a patient with PCOS-like symptoms ------------ 31
Case 4: Natural cycle IVF in an elderly patient with previously failed multiple
gonadotropin-stimulated IUI and IVF attempts ---------------- 31
Case 5: ---- 32
7. Cycle Preparation: Use of Oral Contraceptives before Ovarian Stimulation in
In Vitro Fertilization Cycles 33
Ronit Machtinger, Daniel S Seidman
Clinical Discussion ------------- 33
Oral contraceptive pretreatment and GnRH agonists --- 33
Oral contraceptive pretreatment and GnRH antagonists ---------------- 34
Oral contraceptive pills and poor responders ------------ 34
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Contents
8. Clomiphene Citrate for IVF 37
Shokichi Teramoto
Clinical Discussion ------------- 38
Hormonal measurement --- 38
Hormone kinetics of the natural cycle -------------------- 38
Logic of avoiding the LH surge --- 39
Clomiphene citrate regimen ------- 39
Supplementing exogenous FSH --- 40
9. Letrozole Protocols for Ovarian Stimulation -------------- 44
Mohamed F Mitwally, Robert F Casper
Aromatase enzyme and aromatase inhibitors ------------ 44
Clinical Discussion ------------- 45
Letrozole use for ART: hypothetical role ----------------- 45
Hypotheses of Letrozole mechanism of ovarian stimulation ----------- 45
Hypotheses for detrimental effects of supraphysiological estrogen levels on the outcome of fertility treatment -- 46
Reducing the risk of ovarian hyperstimulation syndrome (OHSS) ---- 46
In vitro maturation --------- 46
Patient subgroups benefitting from low estrogen levels 47
Available evidence for Letrozole use during ART treatment ----------- 48
Improving response to gonadotropins in poor responders -------------- 48
Safety of Letrozole for ovarian stimulation -------------- 49
Adverse effects of Letrozole ------ 49
Pregnancy outcome following Letrozole treatment ----- 49
10. Ovarian Stimulation and Embryo Quality ----------------- 52
Alpesh Doshi, Wael Saab
Clinical Discussion ------------- 52
Basic follicular physiology -------- 52
Natural cycle IVF and minimal stimulation IVF -------- 53
Optimizing embryo culture in an IVF laboratory ------- 54
Insemination and intracytoplasmic sperm injection (ICSI) ------------- 56
11. Ovarian Stimulation and Endometrial Receptivity ------ 62
Isabel Santill? Palencia, Victoria Verd? Jose Manuel Bajo Arenas
Gene expression profiling - 62
Clinical Discussion ------------- 63
Secretory endometrial ultrastructure ---------------------- 63
Trophoblast invasion and placentation -------------------- 63
Effects of ovarian stimulation on endometrial receptivity -------------- 64
Luteinizing hormone (LH) deficiency --------------------- 65
Follicular phase importance ------- 65
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Textbook of Minimal Stimulation IVF ?Milder, Mildest or Back to Nature
Luteal phase support and supplementation --------------- 66
Human chorionic gonadotropin (hCG) -------------------- 66
Progesterone ---------------- 66
Cryotransfer versus fresh embryo transfer ---------------- 67
12. Significance of the Retrieval of a Low Number of Oocytes following Mild Ovarian Stimulation for IVF ------ 69
Marieke FG Verberg, Bart CJM Fauser
Clinical Discussion ------------- 69
Basic physiology of follicle development ---------------- 69
Concept of mild disruption of single dominant follicle selection in IVF treatment -- 70
Implications of mild ovarian stimulation on oocyte and embryo quality -------------- 71
Recent Advances --------------- 73
13. Use of GnRH Antagonists --- 76
Andrea Borini, Luca Dal Prato
Clinical Discussion ------------- 76
Use of GnRH antagonists in ovarian stimulation for IVF --------------- 76
Case Studies ---- 78
Antagonist protocols versus long luteal agonist protocols ----------- 78
Fixed versus flexible antagonist administration --------- 79
LH supplementation ------- 79
Luteal phase supplementation ----- 79
Patients with poor response ------- 80
Patients with PCOS and risk of OHSS ------------------- 80
Minimal stimulation ------- 80
Recent Advances --------------- 80
14. Premature Ovulation and Cycle Cancellation ------------ 84
Anna Livshits, Daniel S Seidman
Clinical Discussion ------------- 85
Case Studies ---- 85
Human chorionic gonadotropin (hCG) -------------------- 85
Indomethacin --------------- 85
GnRH antagonists ---------- 86
Recent Advances --------------- 87
15. Ovulation Triggering and Prevention of the Premature LH Surge ------ 89
Kaushal Kadam
Ovulation trigger ----------- 89
Clinical Discussion ------------- 90
Spontaneous LH/FSH surge ------- 90
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Contents
GnRHa-induced LH/FSH surge --- 90
Prevention of premature LH surge ------------------------ 90
GnRH agonist stimulation protocol ----------------------- 91
Role of the GnRH antagonist in mild stimulation protocols -------------- 93
Recent Advances --------------- 94
16. Optimizing Technique in Follicular Aspiration and Flushing ------------- 98
Hans-Peter Steiner
Introduction ---- 98
History ------ 98
Simple basics of physics for aspiration and flushing of fluids in pipes ----------- 98
Clinical Discussion ------------- 99
Innovative devices for oocyte retrieval and follicular flushing ------------ 99
Gauge finding study ----- 101
17. Single Embryo Transfer --- 103
Richard Thomas Russell, Andrew John Drakeley
Clinical Discussion ----------- 103
Why choose single embryo transfer? -------------------- 103
Single embryo transfer뾡efinitions --------------------- 105
Introducing a single embryo transfer policy in practice ---------- 105
Optimizing the day of transfer -- 109
Cryopreservation --------- 110
18. Natural Cycle and Endometrial Preparation Protocols for Frozen Embryo Transfer -- 114
Julio Martin Voget, Daniel Gustavo Fa?des Hardy, Carlos Alberto Petta
Clinical Discussion ----------- 114
Frozen-thawed embryo transfer (FET)?endometrial preparation protocols ------- 114
Natural Cycle (NC) ------ 117
Endometrial thickness --- 118
Endometrial pattern ------ 118
Doppler ultrasound ------ 119
Case Studies -- 119
Natural cycle in patients with oligomenorrhea --------- 119
Poorly developing endometrium 119
Recent Advances ------------- 119
Genomics - 119
Pinopode formation assessment - 119
Vitrification --------------- 119
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Textbook of Minimal Stimulation IVF ?Milder, Mildest or Back to Nature
19. Luteal Phase Support in Mildly Stimulated IVF Cycles ------------ 122
Luciano G Nardo, Tarek A Gelbaya
Clinical Discussion ----------- 122
Normal luteal phase ----- 122
Luteal phase defect ------ 123
Luteal phase and controlled ovarian hyperstimulation 123
Luteal phase in mildly stimulated cycles --------------- 123
Luteal phase support ----- 124
20. Reliable Cryopreserving Techniques ---------------------- 131
Alejandro Ch?ez-Badiola, Lizeth Barrientos-Avalos, John J Zhang
Clinical Discussion ----------- 131
Oocyte cryopreservation 131
Embryo cryopreservation -------- 132
21. Embryo and Oocyte Vitrification Banking through Natural or Minimal Ovarian Stimulation ------------------ 134
Alejandro Ch?ez-Badiola, John J Zhang
Clinical Discussion ----------- 134
Oocyte banking for donation programs ----------------- 134
Embryo vs oocyte banking ------ 135
Case Studies -- 135
Embryo banking through minimal stimulation and natural cycle IVF in women with a low ovarian reserve ---- 135
Live birth in a premature ovarian failure patient through ovarian tissue transplantation and embryo banking -- 136
22. In Vitro Maturation of Oocytes --- 138
Benny Almog, Einat Shalom-Paz, Fady Shehata, Weon-Young Son, Hananel EG Holzer
Clinical Discussion ----------- 138
Oocyte maturation in vivo and in vitro ----------------- 138
Outline of an IVM treatment cycle ---------------------- 144
23. Patient with a Previous Poor Ovarian Response ------- 151
Gautam N Allahbadia
Markers of ovarian reserve ------ 151
Clinical Discussion ----------- 152
Treatment options in patients with a previous poor ovarian response ------------- 152
Recent Advances ------------- 154
24. PCOS and Patients at Risk for OHSS -------------------- 157
Richard S Legro
Clinical Presentation --------- 157
Clinical Discussion ----------- 157
Polycystic ovaries and other risk factors --------------- 157
Etiology of OHSS -------- 158
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Contents
Prevention of OHSS ----- 158
Treatment of OHSS ------ 160
25. Results in ART: How should these be Measured? ----- 162
Padma Rekha Jirge
Clinical Discussion ----------- 162
Patient characteristics --- 162
Treatment characteristics 162
ART pregnancies --------- 163
National registries -------- 163
26. Low Cost IVF for Developing Countries ----------------- 165
Ian D Cooke
Clinical Discussion ----------- 166
Ethics ----- 166
Cost ------- 166
Infrastructure -------------- 166
Protocols - 167
Procedures leading to ART ------ 168
Supplementary techniques ------- 168
Patient referral systems -- 168
Training --- 168
Cost-effectiveness -------- 169
Case studies --------------- 169
Recent Advances ------------- 169
27. Mini-IVF Experience at the New Hope Fertility Center ----------------- 171
John J Zhang, Lyndon Chang, Yoshie Sone, Sherman J Silber
Clinical Discussion ----------- 171
Study subjects and protocol ----- 171
Results -------- 172
Case Study ---- 177
28. The Kato Ladies Clinic Experience ----------------------- 179
Yuji Takehara, Osamu Kato
Circumstances that led to the switch from stimulation cycle egg recovery to natural cycle egg recovery -------- 179
What is wrong with stimulation cycles? ---------------- 180
Drug-free IVF stimulation vs Clomiphene cycle IVF 181
What is nasal hMG spray? ------- 184
Index -------------------- 191