Practical Guide in Assisted Reproductive Technology Gita Ganguly Mukherjee, Gautam Khastgir, Siddhartha Chatterjee
INDEX
Page numbers followed by, f refer to figure, fc refer to flow chart, and t refer to table.
A
Abdomen 283
Abdominal discomfort 1, 184
Abdominal distension 184
severe 50
Ablation therapy 73
Actinomycin 297
Adenomyoma 158
Adenomyosis 64, 109, 155, 156, 159, 161
coexists 155
degree of 162
diagnosis of 155, 162
features of 158, 158t
impact of 157
management for 159
treatment of 158160
Adenomyotic
lesions, number of 162
region 160
tissue 159
uterus 109f
Adhesion molecules 122
Adult respiratory distress syndrome 185
Adult stem cells 331f, 332
Albumin 48
serum 132
Alfentanil 208
Alpha-2-macroglobulin 132
Amenorrhea, secondary 77
American and European Working Groups 86
American Society for Reproductive Medicine 135, 147, 148, 215, 227, 282, 303
Amino acid 34, 35
Amyotrophic lateral sclerosis 332
Analgesics 205
Androgen 104, 262
insensitivity syndrome 335
role of 177
supplementation group 262
Anesthesia 213
consultation 315
general 60, 206, 208
local 207
regional 206, 207
spinal 207
use of 60
Anesthetic drugs 209
Aneuploidy 280
risk of 179
Angiotensinogen converting enzyme 43
Anovulation 12, 135
Antiemetic agents 209
Antiepileptic medications 315
Antiestrogen clomiphene citrate 4
Anti-müllerian hormone 2, 86, 101, 102, 112, 148, 188, 189t, 191f, 192t, 225, 255, 259, 304
basal 45
importance of 190f
serum 192f
significance 189
Antioxidants 228
Antiphospholipid antibodies 47
Antitubercular drugs 205
Antral follicle
count 45, 86, 108, 112, 112f, 189, 191f, 251, 255, 259, 305t
use of 304
small 188
Anuria 184, 185
Anxiety 24
Anxiolytics 205
Apoptosis 285
premature 236
Arginine 79
Aromatase 311
activity 101
inhibitors 4, 265, 311
Arrhythmia 185
Arterial thrombosis 185
Artificial insemination, introduction of 339
Ascites, ultrasonographic evidence of 184
Asherman's syndrome 77, 217, 230
Assisted hatching, assessment of 178, 227
Assisted reproduction group 277t, 278t
Assisted reproductive technology 1, 21, 42, 62, 81, 83, 91, 100, 108, 135, 136, 138, 141, 142, 150, 155, 157, 164, 165, 173, 179, 183, 188, 190f, 199, 202, 203, 204, 213, 259, 275, 296, 324, 338
anesthesia in 204
complications of 118
cycle
agonist in 33, 36
monitoring 104
future of 338
model 27f
modern 319
past of 338
pregnancies 82
present of 338
risk of 179
Autologous germ cell mitochondrial energy transfer 348
Azoospermia 222
nonobstructive 332
obstructive 17
B
Benzodiazepines 208
Beta-human chorionic gonadotropin 67, 235
Biopsy guide 24
Birth
defect, congenital 179
weight, low 164
Bladder, distended 55
Blastocyst 178
number of 193
transfer 226
Blastomere biopsy 331
Bleeding 82
antepartum 152
intraperitoneal 167
per vaginum 31
Blood
flow, subendometrial 75, 129
grouping 269
investigations 24
pressure, low 184
supply, abnormal 222
Body
mass index 141
tissues 297
Bologna criteria 189, 249
Bone
marrow stem cells 76, 334
morphogenetic protein 333
Bowel perforation 168
Bromocriptine 166, 209
Bupivacaine 208
Buserelin 35, 270, 271
C
Cabergoline 49, 166
group 49
use of 186
Cadaver ovaries, use of 269
Cancers
genital 302
hematological 302
Carbon dioxide 147
Cardiac
defects 180
disease 205
disorders, treatment of 335
Catheter tip 63
Cavity, normal 110f
Cell adhesion molecule 145
Cellular adhesion molecule 128
Centers for Disease Control and Prevention 175
Central venous pressure 184
Cervical
canal 59
corporeal ratio 108
dilatation 56
dilation 65
factor 12
infertility 15
fibroids 57
issue scarring 14
mucus 340
presence of 68
stenosis 55, 56
presence of 56
tenaculum 55
Cervicouterine angle 63
Cesarean section 152, 179
Chemoresistant tumor burden 298
Chemotherapy 299
Chloroprocaine 208
Chromosomal inversions, incidence of 222
Clamping uterine artery 294
Clamydia 73
Clomiphene citrate 4, 15, 103, 244, 263
Clonogenic multipotent stem cell 77
Comprehensive genomic hybridization 345
Corpus
luteal function 1
luteum 81, 82, 85
cyst 111f
Cryobiology, development of 343
Cryocans 24
Cryopreservation 186
options 98
process 282
program 32
stress of 285
techniques 303
unit 32
Crystalloid infusion 200
Cumulus oophorus 115f
Cusco's speculum 67
Cycle cancellation rate 175
Cyclic guanosine monophosphate 75
Cyclophosfamide 297
Cyst
endometriotic 201
hemorrhagic 111f
myometrial 158
Cystectomy, laparoscopic 149
Cytochrome p450 enzyme 311
Cytokines 122, 223, 333
Cytoplasmic mitochondria 348
D
De novo mutations 180
Defective luteal phase 97
Dehydroepiandrosterone 141, 177, 262, 265
role of 177
sulfate 262
Dendritic cells 197
Dermoid cyst 111f
Deslorelin 35
Desynchronization, risk of 93
Dexmedetomidine 208
Diabetes 205, 335
mellitus 199
gestational 179, 185, 202
Diarrhea 184
Diethylstilbestrol, history of 57
Dimethyl sulfoxide 285
Diploid zygote 100
Donor
assisted reproduction 263
egg 259
embryos 164
oocyte 164
cycles 178
indications for 268
pregnancy acts 179
stimulation of 264
Dopamine agonist 49, 166, 209
Duchenne muscular dystrophy 180
Dydrogesterones 83
Dyslipidemia 136
Dysmenorrhea 155
Dyspareunia 155
Dyspnea
mild 184
severe 184
E
Ectocervix 55
Ectopic pregnancy 76, 169, 201
cause of 68
risk of 169
Edema, pulmonary 313
Egg 332
and embryo selection 344
fertilization of 263
in vitro maturation of 269
multiple 69
Ejaculation, retrograde 13
Ejaculatory dysfunction 13
Elective social oocyte cryopreservation 282
Electrolyte imbalance 313
Embryo 204, 221, 228, 283, 310
atraumatic
delivery of 68
placement of 64
cleavage stage of 85
cryopreservable 6
cryopreservation 60, 230, 280, 281, 304, 307
donation 259, 263, 264, 267, 271, 272
indications for 272
endometrium of 69
expulsion, prevention of 68
factors, evaluation of 225
freezing of 166, 202, 303
implantation 82, 101, 116, 334
mechanism of 5
quality 5, 6
restricting number of 169
screening 342f
synchronization of 92
transfer 28, 29, 54, 58, 60, 62, 65, 65f, 66, 67, 127, 147, 158, 159, 204, 264, 294, 341
advantages of 69
disadvantages of 69
number of 1, 178
procedures 66, 68
single 92, 168
techniques 231
transabdominal ultrasound guided 59
transmyometrial 57
ultrasound image of 64f
vitrification program 22
Embryoid bodies 347
formation of 348f
Embryonic stem cells 331, 346
Embryoscope 27f
Empty follicle syndrome 235
Endocervical canal 58
Endocervix 65
Endocrinal factors 242
Endogenous progesterone secretion 88
Endometrial
adequacy 269
assessment 115
biopsy 196
blood flow 129
carcinoma 295
cavity 68, 108, 109, 269
growth, stimulated 75
injury 197, 230
islands 158
markers 127
parameters 97
pattern 129
perfusion 230
pinopods 130
polyp 64, 110f, 229
preparation 91, 264, 334
methods of 93
receptivity 6, 121, 127, 130, 145
array 73, 121, 123, 131
assessment of 128
morphological assessment of 124
reconstruction 230
scratch 76, 196, 197
striae 158
subendometrial blood flow 130
thickness 72, 129
tissue, disadvantages of 123
vascularity 114, 116f
volume 115f
Endometrioid 299
Endometrioma 24, 111, 215
management for 148, 149fc, 149t
surgical treatment of 150, 150f
Endometriosis 15, 130, 145, 146f, 155, 242, 246
effects of 145
management for 147fc
mild 150
recurrent 151
severe 267
Endometriotic cyst, rupture of 201
Endometrium 63, 72, 77, 96, 113, 131, 132, 197
basalis layer of 77
develops 74
functional assessment of 122
postreceptive 130
synchronization of 92
synchronized maturation of 129
ultrastructural assessment of 122
Endomyometrial junction 108
irregular 158
Epithelial
estrogen receptor alpha 128
ovarian cancers 298
Erectile dysfunction 335
Escherichia coli 73
Estradiol 45, 83, 100, 102
estimation, serum 106
level 48
serum 48, 102, 103
supplementation 85
valerate 271
Estrogen 25, 73, 94
administration 334
dependent condition 146
exogenous 96
receptor 306, 311
sensitive cancers 308, 311, 312, 313
Ethylene glycol 285
Etomidate 208
European Society of Human Reproduction and Embryology Guidelines 140
Extraembryonic tissue 330
Extraovarian spread 299
F
Fallopian tube 111, 204
patency of 111
Female pelvic anatomy, assessment of 108
Fentanyl 208
Fertility
armamentarium of 128
centers 180
following cervical cancer 293
following gynecological cancer 293
loss of 173
preservation 280, 283, 295, 302, 303, 305, 316
methods of 303
sparing procedures 299
sparing surgery 298
treatment 103
Fertilization
rates 308
recurrent 345
Fetal
growth restriction 164
ovarian tissue 269
Fibroids 214, 215, 222
presence of 63
submucous 110f, 222
Flow index 114
Follicle stimulating hormone 2, 33, 45, 100, 101, 112, 136, 137, 139, 188, 192f, 225, 306, 237, 256, 259
Follicular
activity 94
aspiration 168
cells 81
cohort, size of 103
development 15, 308
process of 252
fluid 26, 117, 237
growth 95, 236
  rate 93
monitoring 108
phase 36, 82, 94, 95, 307
culminates 81
late 4
puncture 207
rupture 245
stimulation 42
tracking 113
wall 240
Folliculogenesis 37, 236
Fragile ovary 167
Fresh frozen plasma transfusion 315
Frozen embryo 164
transfer 3, 63, 72, 81, 85, 91, 91f, 92f, 93, 97, 130, 159, 166, 197
cycles 95, 97
natural cycle for 93
over fresh embryo transfer, advantages of 97
G
Gamete
artificial 332
donation 330
functional 332
generation 334f
intrafallopian transfer 58, 204
Genetic
biomarkers 251
connection 322
couple 272
Germ cell 285, 299
generation 346, 347fc
mature 332
primordial 334f
tumors, malignant 299
type 298
Gestational age, large for 164
Gestational trophoblastic
disease 297
neoplasia 298
Gland, pituitary 33
Glycerol 285
Glycine 33, 34
Gonadotoxic
cancer treatment 282
therapy 305
Gonadotrope cell surface 34
Gonadotropin 1, 4, 25, 36, 96, 101, 311
dose during ovarian stimulation 305
exogenous 3
high-dose 177
releasing hormone 2, 24, 33, 35t, 73, 82, 136, 139, 146, 149, 159, 256, 306
agonist 34, 36, 35t, 38t, 74, 83, 9395, 138, 139, 159, 166, 313
analog 4, 85, 270
antagonist 49, 260, 306, 308
molecule 34
physiology 33
structure 33f
requirements 137
stimulation, exogenous 255
therapy 137
total dose of 310
Goserelin 35
Granulocyte colony-stimulating factor 76, 224, 230
Granulosa cells 4, 188, 237, 285
connection of 81
Granulosa lutein cells 43f
Growth hormone 141, 261, 265
use of 177
H
Halosperm test 346f
Hampers endometrial receptivity 223
Hematosalpinx 111
Hemoconcentration 42
Hemoglobin 166
Hemophilia A 180
Hemorrhage
obstetric 162
postpartum 72, 168
Heparin binding growth factor 128
Hepatitis B 31
Hexaethyl starch 166
Histidine 34
Histrelin 35
Homogeneous echogenic endometrium 57
Hormone
analysis 101
controlled cycle 270
influence of 127
replacement
cycle 94
therapy 72, 93, 160
Human
albumin 166
chorionic gonadotropin 3, 30f, 39, 43, 43f, 72, 74, 8284, 93, 114, 139, 165, 183, 242, 270
dosage 47
low dose 74
supplementation 87
embryo twinning 269
embryonic stem cells 331f, 333, 334f
endometrium 127
regenerates 334
fertilization 175
follicular fluid 43
growth hormone, use of 177
immunodeficiency virus 269
menopausal gonadotropin 75, 263, 340
oocytes, fertilization of 100
ovum 339
Hydrosalpinges 169, 223, 231
presence of 223
Hydrosalpinx 24, 111
surgery for 214
Hydrothorax 184
massive 185
Hydroxyethyl starch
administration 200
solution 49
Hydroxyprogesterone 100
Hyperandrogenemia 136
Hyperinsulinemia 138
Hyperplasia 155
Hyperprolactinemia 242
Hypertension
pregnancy induced 179, 185
uncontrolled 199
Hypertensive disorders 179
Hypoestrogenic side effects, risk of 95
Hypogonadism, hypogonadotropic 101
Hypospadias, anatomical problems like 13
Hypotension 165
Hypothalamopituitary axis 82
Hypothyroidism 103
Hypovolemia 201
Hypovolemic hyponatremic state 185
Hysterosalpingo-contrast-sonography 119
Hysterosalpingography 15
Hysteroscopic
correction 56, 229
examination 230
metroplasty 217
surgeries 213, 215
Hysteroscopy 64, 78, 124
I
Imatinib, use of 315
Immature eggs, retrieval of 6
Immunoglobulin, intravenous 224
In vitro
culture 286
fertilization 1, 12, 13, 62, 100, 117, 121, 139, 141, 147, 149, 149t, 150, 157, 164, 184, 204, 213, 249, 267, 275, 281, 303, 330, 338, 339
batching of 21
complications of 164t
cycle 84
demerits of 21
initiation of 339
merits of 21
oocytes 174
process of 54
technique 319
maturation 281
oocyte maturation 47
In vivo follicular growth 6
Indian Council of Medical Research 298, 319
Indian Society for Promoting Assisted Reproduction 324
Indian Society for Third-Party Assisted Reproduction 327
Infertility 130, 145, 146f, 245
and obstetric complications 216
cause of 15, 204
etiology of 62
female factors of 108
immunological 17
management 18
ovulatory factor 15
risk of 280
treatment 147, 180, 338
Inflammatory bowel diseases 280
Inhibin B 103, 193
Insulin resistance 136
assessment of 138
Intensive luteal phase 87
Interleukins 223
Intra-abdominal pressure 50
Intracytoplasmic sperm injection 21, 81, 150, 151, 164, 164t, 213, 224, 228, 275, 284, 330, 338, 346
physiological 346
Intramural fibroids 214, 222
distorting uterine cavity 124
effects of 215
Intraovarian vascularity 115
Intrauterine
adhesions 229, 230
growth
restriction 217
retardation 277t
insemination 12, 64, 118, 147, 150, 164, 267
indications of 13t
results of 216
pathology 124
pregnancy 169
Intravascular volume depletion 42, 43
J
Japanese intending couple 324
K
Karyotyping 225
Ketamine 208
L
Laminaria tents 56
L-arginine 76
Letrozole 4, 15, 311, 315
plus gonadotropin protocol 312, 316
Leucine 34
Leukemia
chronic myelogenous 315
inhibitory factor 128, 333, 348
Leuprolide 35, 87, 270, 271
Leuprorelin 35
Levonorgestrel-intrauterine device 295
Limb defects 180
Liquid nitrogen 24, 284
Live birth rates 176
Liver dysfunction 165, 313
Local anesthetic agents 208
Loop electrosurgical excision 294
Low dose aspirin 75, 166, 230
Low molecular weight heparin 166, 224
Low ovarian reserve, evidence of 17
Lower embryo implantation 174
Luer lock fitting 57
Luminal epithelial cells 130
Luteal phase
defect 82
insufficiency 141
protocols 86
support 49, 83, 85, 141
postanalog trigger 87
progesterone for 84
Luteinized unruptured follicle 240, 243
cycle 242
syndrome 240, 241, 246
diagnosis of 243
diseases associated with 242
etiopathogenesis of 242
history of 241
management of 244
prevention of 244
signs of 243
symptoms of 243
ultrasound of 241f
Luteinizing hormone 2, 33, 81, 100, 121, 137, 236, 240, 260
baseline 136
role of 252
spontaneous 93
M
Macromolecules, administration of 48
Male fertility 16, 284
Malecot catheter 56
Malignancy, diagnosis of 302
Mammalian reproduction, classical model of 285
Mayer-Rokitansky-Kuster-Hauser syndrome 335
Medical therapy 146
Medroxyprogesterone acetate 295
Megestrol acetate 295
Menopause 146, 173, 268
Menorrhagia 155
Menstrual
blood serves 77
cycle 241, 306
Mesenchymal stem cell 336
Metallic
dilators 56
stylet 55
Metformin 47, 165
Methotrexate 297
single high dose of 297
Methylenetetrahydrofolate reductase 226
Metroplasty 217
Microarray technology, advent of 130
Microdose flare protocol 38
Microfluidics 344
Midazolam 208
Milder stimulation protocols, development of 2
Minimal stimulation 265
protocols 40
Miscarriage 141, 157, 280
rate 176
risk of 179
spontaneous 176
Mitochondria 348
Mock endometrial preparation cycle 269
Molar pregnancies 298
Monolateral disease 149
Mucin 1 128
Müllerian anomalies 109
congenital 73
Müllerian inhibiting substance 102, 188
Multicenter trials, large 335
Multifetal reduction 168
Multifollicular development 13
Muscular disorders, treatment of 335
Myomectomy 64, 229
aggressive 73
Myometrium 57, 108, 155
posterior 57
N
Nafarelin 35
Naphthylamine 34
National Cancer Registry Programme 298
National Institute for Health and Care Excellence 17, 140
National Registry of Assisted Reproductive Technology 327
Natural conception 278, 279
group 277t, 278t
Natural cycle 3, 95, 96, 262, 270
modified 93
stimulation 3
Nausea 185
mild 184
postoperative 209
Neonatal intensive care unit 276
Neural tube defects 180
Neuromuscular electrical stimulation 79
Neutropenia 315
Neutrophil count, absolute 315
Next generation sequencing 342
Nitroglycerin 76
Nitrous oxide 209
Non-adenomyotic group 157
Nonhematopoietic stem cells 77
Nonsteroidal anti-inflammatory drugs 50, 209
Nonsteroidal triphenylethylene compound 310
Nucleotides regulating post-transcriptional gene 132
O
Obesity 136, 137
morbid 205
visceral 136
Office hysteroscopy 217, 269
Oligoasthenozoospermia 222
Oligo-ovulation 135
Oligospermia 218
Oliguria 50, 184
Oncofertility 303
Oocyte 204, 228, 235, 236, 304, 307, 333
aneuploidy, rate of 174
cryopreservation 263, 269, 281283, 313
cumulus complex 26, 238
donation 267
treatment, result of 271
donors
professional 268
source of 268
fertilization, failed 103
immature 281
loss of 173
number of 86
pick-up 3, 86, 201
polscopic evaluation of 345f
poor quality of 174, 221
quality 115, 208, 221, 255, 304
quantity 255
recovery 270, 315
retrieval 108, 116, 117f, 206, 254, 260
complications of 167
unfertilized 344
Opioids 208
Oral contraceptive pills 25, 73
Ovarian
abscesses 168, 201
agenesis 268
biomarkers 255
cancer 298
majority of 298
cyst 201, 213
rupture of 201
failure, premature 268
follicle 114, 117, 235
color Doppler evaluation of 114
function 146fc
tests 225
hormone production 315
hyperstimulation 100, 121, 164, 213
controlled 81, 138, 164, 188, 265
presence of 97
hyperstimulation syndrome 1, 12, 42, 45, 69, 81, 91, 112, 118, 118f, 138, 139, 165, 183, 185, 188, 200, 306, 313
classification of 44, 44t, 184
critical 44fc, 50
development of 49
early 183
management 46, 183, 184
mechanisms of 46f
mild 200
moderate grade 200
pathophysiology 183
physiology of 183
prevention of 200, 313
preventive measures 185
recognition of 200
risk of 237
severe 44fc, 50, 200
treatment of 50
physiology 307
reserve 188, 214, 304
markers 190, 191f
normal 257
test 3, 177, 190, 251
response 255
stem cells 285
maintenance of 286
stimulation 42, 46, 137, 197, 200, 281, 304, 308, 310
beginning of 166
controlled 2, 100, 141, 147, 150, 191, 191f, 281, 308, 314
conventional controlled 306
days of 310
mild 13, 5, 5t
protocols 306
standard 5t
suboptimal 224
tissue cryopreservation 283, 285
torsion 167, 200
transposition 294
tumor 299
borderline 299
vascularity 113
volume 112
Ovary 111
artificial 285
enlargement of 165, 184, 200
hyperstimulated 167
sex cord stromal tumors of 299
Ovulation 82
induction 93
leading 94
trigger agent, modification of 48
triggering 238
Ovum 259
donation 263, 264, 265
pick-up 2, 24, 26, 116, 238
P
Pain, abdominal 67, 184
Paracentesis 50
indications for 50
Paracervical block 207
Paternal leukocyte immunization 231
Patient controlled analgesia 207
Peak systolic velocity 113
Pelvic
adhesions 59, 242, 245
inflammatory disease 223, 242
Pentazocine 208
Pentoxifylline 75
Perinatal mortality 179
Periovarian adhesions 245
Peripheral blood stem cell transplant 335
Peritonitis 168
Personalized embryo transfer 123, 123fc, 131
Peyronie disease 336
Photodynamic therapy 296
Pinopodes-endometrial protrusions 128
Pituitary gonadotropes 34
Placental complications 152
Plasma
androgens, measurement of 104
expanders 166
progesterone 105
Plasmin 237
Platelet-rich plasma
autologous 78
intrauterine infusion of 78
Polscope, use of 345
Polycystic ovarian
disease 2, 7, 242
syndrome 14, 102, 188
Polycystic ovary 31, 113f, 242
syndrome 45, 95, 135, 136, 138, 139, 141, 142
antagonist protocols in 139
severe 36
Polyp 216
Poor ovarian
reserve 250f
response 189, 255, 259
Poseidon classification 249, 250
Poseidon concept 256
Poseidon criteria 255
classification 256
management 256
Poseidon group 256, 257
management for 257
Poseidon subgroups 255
Positron emission tomography 294
Postembryo transfer 67, 88
Postinflammatory disorders 336
Preeclampsia 152, 202
Preembryo transfer procedure 63
Pregnancy 146
clinical 18
complication 168, 169, 179
high rate of 199
heterotopic 169
multifetal 202
multiple 6, 14, 168, 275
outcomes 152
rate 6, 39, 67, 96, 157, 271
clinical 175
higher 15
prediction of 193
spontaneous 183
Pretreatment ovarian reserve assessment, importance of 303
Progesterone 25, 67, 77, 83, 94, 96
dose 95
exogenous 88
free luteal phase 88
intramuscular 84
oral micronized 83
preparations 95
supplementation 142
Progynova 271
Propofol 207, 208
administration of 208
Prostaglandin 43, 122
metabolism 131
role of 242
Protein, alpha-induced 236
Prothrombotic disorder 230
Pulse frequency and amplitude 33
Pvarian hyperstimulation syndrome, pathogenesis of 43f
Q
Quinagolide 166
R
Radiotherapy 298
Randomized controlled trials 177, 181, 214
Random-start controlled ovarian hyperstimulation 307
Recombinant luteinizing hormone supplementation 88
Rectus abdominis myocutaneous flap 315
Recurrent implantation failure 31, 128, 178, 197, 221
etiology of 221, 232
evaluation and management 224
management of 224fc, 226
treatment of 224
Remifentanil 208
Renal disease, severe 205
Renal dysfunction 165
Reproductive
health 280
medicine 330
surgery 204
Retrieved oocytes, number of 255
Rokitansky-Kuster-Hauser syndrome 273
Royal College of Obstetricians and Gynaecologists 44
S
Saline infusion sonography 110f, 111
Salpingitis, subclinical 294
Secretomics 123
Selective estrogen receptor modulator 75
Selective serotonin reuptake inhibitors 205
Semen
cryopreservation of 284, 303
parameters 16
samples 28f
well-arranged 29f
Sepsis 185
Septoplasty 73
Sexual dysfunction 335
Sham embryo transfer 63
Sildenafil 79
positive effect of 75
Sleep disorders 295
Small for gestational age 179
Smooth muscle myometrial cells 155
Somatic cell 332
nuclear transfer 331, 346, 347f
Sonohysterography 225
Sperm 164, 332
biology, development in 345
capacitation of 100
cryopreservation 284
deoxyribonucleic acid
fragmentation 346f
integrity tests 225
discovery of 339
donation 263, 264, 267
parameters, subnormal 13
retrieval, surgical 204
surgical retrieval of 229
survival 16
Spermatogonial stem cells
in vitro generation of 286
preservation of 284
Staphylococcus 73
Stem cell 230, 334f, 335
application of 330
culture 346, 347fc
application of 331f
muscle-derived 335
ovarian 263
pluripotent 330, 331
research 330
role of 334, 335
source of 330
spermatogonial 284, 332
therapy 77, 78, 330
role of 335
types of 330
Steroidogenesis 131
Steroids 100
Stimulation protocol 1
mild 6
protocol, refinements of 343
Strassman surgery 73
Streptococcus 73
Stromal fibroblast, source of 77
Subfertility 156, 245
Supraphysiological steroid hormone levels, secretion of 82
Surrogacy 263, 267, 272, 318, 320, 326
altruistic 321, 326
arrangement 321
background of 318
bisexual 322
child born of 326
commercial 321
contemporary modern forms of 322
counseling in 274
developments on 324
emphasizes 322
favorable over adoption 323
for medical reasons 323
full 322
gestational 273, 322
host 322
in ancient India 318
in early human civilizations 318
in India and foreign nations 320
in India medicolegal arrangement 320
in mesopotamia civilization 318
international 322
legal regulations on 326
natural 273
on monetary payment 321
overseas 322
partial 322
process 321
(regulations) Bill 2016 326
same sex 322
significance of 322
single parent 322
social 322
straight 322
traditional 273, 322
transgender 322
transnational 322
types of 321
Surrogate, screening of 273
Swiss cheese appearance 109
Syncope 184
Synechiae 217
T
Tachycardia 50, 165
Tachyphylaxis, phenomenon of 35
Tailored gonadotropin regimen 165
Tamoxifen 75, 310, 311
selective antagonist action of 311
Tenaculum 55, 58, 60
Tension ascites 200
Testicular
failure 222
sperm aspiration 25
stem cells 286
tissue 284, 303
cryopreservation 284
grafting 285
integrity 285
proliferative capacity of 285
relies 285
Testosterone 100, 261
gel 261
transdermal 261, 265
Theca cells migrate 81
Thin endometrium 229
causes of 73
treatment of 73
Thromboembolism 166, 185
Thrombophilia 47
evaluation of 226
management for 230
Thrombophlebitis, risk of 295
Thromboprophylaxis 50, 314
Thyroid
disorders 204
dysfunction, assessment of 103
function tests 100
medications 205
profile 269
Tissue
function 130
integrity 285
Titrate letrozole dose 312
Tocopherol 75, 79
Totipotent cell 330
Touching uterine fundus 67
Trachelectomy
radical 294
abdominal 294
vaginal 294
Transcervical
placement 56
uterine instillation 77
Transcriptomic signature 130
Transvaginal
ovum retrieval 204
scan 164
sonography 25, 108, 109, 109f, 111, 112, 116, 118, 156, 295
role of 108
ultrasonography 104, 108, 116, 124, 156, 223
Trapped egg syndrome 241
Trauma, myometrial 57
Trazodone 205
Trial embryo transfer 59, 63
Triptorelin 35, 48
T-shaped cavity 216
Tubal
embryo transfer 58
endometriosis 111
Tuberculosis 73
genital 242
Tubo-adnexal mass 201
Tubo-ovarian masses, laparoscopic management of 24
Tumors, borderline 299
Tyrosine-glycine-leucine-arginine 33
U
Ureaplasma urealyticum 73
Urological disorders, treatment of 335
Uterine 276
anomalies, congenital 222
artery pulsatility index 129
biophysical profile 124
bleeding, abnormal 64
cavity 59, 64, 65
functional 222
contraction 54, 59
dimensions 108
dysmorphism 216
factor 222, 229
evaluation of 225
fibroids 64, 273
hemorrhage, massive 298
junctional zone contractions 55
malformations cervical stenosis 64
polyp 124
receptivity 118
relaxing substances 68
secretome 132
wall, anterior 57
Uterocervical
axis 55
acute anteflexion of 55
canal 55
Uterus 108, 197
anteverted 55
hypoplastic 217
normal 109f
retroverted 55, 57
V
Vaginal
estrogen 74
fornices 116
functions 335
micronized progesterone 84, 87
progesterone 84
reconstruction 335
sildenafil 75, 76, 230, 334
Varicocelectomy 218
Vascular endothelial growth factor 43, 43f, 165, 183, 223
Vascularity flow index 114
Vasopressin injection technique 149
Vincristine 297
Vitamin E 334
Vomiting 184
postoperative 209
Vulsellum 55, 58
W
Wallace malleable stylet 58
Water-soluble progesterone, subcutaneous 84
Wilms tumor 180
World Health Organization 330
Z
Zona hardening 222
Zygote 295
×
Chapter Notes

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Mild Ovarian Stimulation: Recent Status in Assisted Reproductive TechnologyCHAPTER 1

Gita Ganguly Mukherjee,
Siddhartha Chatterjee
 
INTRODUCTION
In vitro fertilization (IVF) has generally been used for years with idea for retrieving many eggs, created by ovarian stimulation, to enable production of many embryos, such that multiple embryos can be transferred, cryopreserved for future cycles, to find best embryos by allowing natural selection through blastocyst culture. Ovarian stimulation is utilized to increase the number of oocytes which might compensate the drawbacks of IVF procedure, enabling the selection of one or more embryos for transfer.1 In recent past, long protocol (agonist suppression) along with gonadotropin (Gn) stimulation was the most frequently used stimulation protocol.2,3 Such high dose of Gn (up to 450 IU per day) failed to demonstrate improvement in the outcome.4,5 Even in recent days, the antagonist protocol where Gn use is less than Long protocol, has proved to be of comparable success as the previous protocol, but with less complications. Long protocol always associates with the risk of complication like ovarian hyperstimulation syndrome (OHSS),6,7 and so also can lead to high dropout, emotional stress, as well as abdominal discomfort.1 Whether such a long stimulation cycle raises the long-term health risk like ovarian cancer, is still uncertain. Some authorities opine that there is increased incidence of low birth rate and birth defect following IVF treatment.8,9 Edwards et al. as far back in 1996 called for the use of milder stimulation protocols which they thought to be safer, more patient friendly, and with minimized risk of treatment, as compared to standard stimulation protocols.10
The problem of use of milder stimulation protocol in practice is availability of diminished number of eggs which may lead to diminished pregnancy rate. However, improved culture condition and instrumentation in many IVF laboratories and recent trend of diminishing the number of embryo transfer (ET) together reduce the need of large quantities of oocytes. The supportive evidence regarding potential negative effect of supra-physiological estradiol (E2) level on endometrial receptivity,11,12 corpus luteal function,13,14 oocyte and embryo qualities,15,16 impress that mild ovarian stimulation might lead to beneficial effect on implantation potential as well as corpus luteal function.2
 
CLINICAL INDICATION OF MILD OVARIAN STIMULATION
  1. Normogonadotrophic women with—(a) repeated failure of conventional stimulation, (b) repeated implantation failure with standard protocol
  2. Poor responders and hypergonadotrophic women
  3. Hyper-responders—polycystic ovarian (PCO) disease and high anti-Mullerian hormone (AMH).
Normogonadotrophic women may face recurrent IVF failure. Embryos those develop from high stimulation may present with high degree of chromosomal anomalies. There may be mitochondrial defects in eggs which may be inherent or age related leading to recurrent failure, after high stimulation (conventional stimulation). This may also lead to defect in endometrial receptivity.
Poor responders may be normogonadotrophic or hypergonadotrophic, with or without diminished ovarian reserve. Normo-Gn poor responders may face downregulation of follicle-stimulating hormone (FSH) receptors due to higher FSH dose received in conventional stimulation, leading to poor number of follicular growth. Women with diminished ovarian reserve (DOR) may have poor number of antral follicles available to be stimulated for ovulation.
Women with PCOD as well as high AMH level in serum are hyper-responders. With conventional stimulation, there is every possibility of development of OHSS. Moreover, such a large number of follicles often contain eggs of lower quality; even they may be empty follicles.
 
DIFFERENT PROCEDURES OF MILD OVARIAN STIMULATION
  1. Natural cycle
  2. Natural cycle with FSH boost/add-back
  3. Minimal Gn stimulation (low dose), alone or with adjuvants like oral ovulation-inducing (OI) agents.
 
Development of Milder Stimulation Protocols
The introduction of gonadotropin-releasing hormone (GnRH) antagonist for downregulation of pituitary, brought into clinical practice of controlled ovarian stimulation (COS), has made planning of milder stimulation protocol possible.17 Unlike GnRH agonist, GnRH antagonist does not cause initial flare of endogenous Gn release, instead cause reversible suppression of Gn secretion. The administration of GnRH antagonist in mid and late stimulation/follicular phase prevents any premature luteinizing hormone (LH) surge. This has made planned ovum pick-up (OPU) possible even in a natural menstrual cycle. This approach utilizes the endogenous intercycle FSH rise rather than suppressing it, resulting in reduction in the medication needed. The use of GnRH antagonist had made the stimulation period shorter (number of day of Gn stimulation) 3and diminished number of Gn ampoules required for stimulation and does not cause cyst formation. Though the initial studies suggested a detrimental effect on pregnancy rate following antagonist use, as compared to agonist,18,19 a recent meta-analysis comprising of 22 randomized controlled trials (RCTs) showed no significant difference in probability of live birth.20
 
Natural Cycle Stimulation for IVF
The first IVF baby was born out is a natural cycle oocyte recovery.21 Thereafter, ovarian stimulation was used instead of natural cycle to improve success rate per cycle.3,22 Natural cycle IVF requires simple monitoring of spontaneous cycle and retrieval of single oocyte prior to spontaneous LH surge or following attenuated LH surge by antagonist along with human chorionic gonadotropin (hCG) trigger. This excludes the possibilities of OHSS and multiple pregnancies. The cost per cycle becomes almost one-fourth as compared to a stimulated cycle.23,24 Ongoing pregnancy rate was found to be quite low, for which it has not become popular. Repeated collection of oocytes in multiple natural cycles followed by multiple frozen embryo transfer (FET) might increase the success rate, particularly in elderly poor responders. The most drawback of natural cycle, IVF is premature LH surge leading to premature ovulation, and reduced chance of successful oocyte pick-up (OPU).25 It is safe and less stressful method of stimulation and in selected cases, the cumulative pregnancy rate and live birth rate may be 45% and 32% respectively.24 The use of antagonist in a natural cycle can be called to be a modified natural cycle. Modified natural cycle is quite useful in patients having previous poor ovarian response to conventional ovarian stimulation.
 
Natural Cycle with FSH Add-back/Boost
The ongoing growth of dominant follicle is supported by addition of exogenous Gn (FSH add back) and use of antagonist to prevent premature LH surge. In most of the centers, GnRH antagonist and Gn (75–300 IU per day) initiated a follicular diameter of 12–14 mm. This protocol is also popular in patients with poor response with conventional stimulation or poor responders with poor ovarian reserve test (ORT). This protocol yields best success rate in young couple with severe male infertility, as an only fertility compromising factor. Modified natural cycle IVF in consecutive cycles in selected population may result in improved effectiveness.
 
EXOGENOUS GONADOTROPIN FOR MILD OVARIAN STIMULATION
Mild ovarian stimulation in which low-dose gonadotropin (FSH/hMG–human menopausal gonadotropin) administration is delayed until the mid-follicular phase is based on the FSH window concept.26 Exogenous FSH administration is 4limited to the mid to late follicular phase with the aim of preventing a decrease of FSH levels and thus inducing multifollicular development.27 The use of GnRH antagonists for suppression of premature LH rise enabled this concept to be introduced into IVF.28 A pilot study showed that multiple dominant follicles could even be induced when the initiation of FSH was postponed until CD 7.29 However, there was a tendency toward a lower percentage of women presenting with multiple dominant follicle development compared with patients started on CD 3 or 5.30 A fixed daily dose of 150 IU rFSH compared with 100 IU/day was found to be more effective in consistently inducing multiple follicular growths when ovarian stimulation was initiated on CD 5.29
A large randomized study to compare the efficacy of mild strategy (mild ovarian stimulation with antagonist) as compared to conventional stimulation protocol with agonist showed comparable live birth rate at the end of 1 year along with reduction in Gn requirement multiple pregnancy and overall cost involved.31
 
Gonadotropin with Clomiphene Citrate or Aromatase Inhibitors
The antiestrogen clomiphene citrate (CC) was the first preparation used for ovarian stimulation in IVF.22,32 Important advantages of CC compared with gonadotropins remain including its oral administration, low price and widespread availability. CC acts to increase pituitary FSH secretion by reducing negative estrogen feedback. An ovarian stimulation protocol combining CC with gonadotropins could lead to a reduction in the amount of gonadotropins required due to the combined synergistic effects. Additionally, because gonadotropins may counterbalance the undesired antiestrogenic effects of CC on the endometrium, it may be counterbalanced with Gn addition.33,34 This combination might lead to improved pregnancy rates compared with CC alone. CC has now been largely replaced by more effective hMG/FSH protocols in combination with GnRH analog (GnRH-a) cotreatment.3,35
The available clinical data available for aromatase inhibitors (AI) in IVF treatment is limited. One uncontrolled study with 22 good responders with limited financial means, where Letrozole was used for first 5 days of cycle (CD 3–7), followed by hMG from CD-7 yielded 27% pregnancy rate. In other RCTs, AI did not show any significant benefit when used in IVF program.36,37 A third RCT38 showed more number of available oocytes following AI used.
 
Late Follicular Phase hCG or LH
Human chorionic gonadotropin or LH administration in low doses may replace FSH administration in late follicular phase, as mild stimulation approach. This is based on acquired LH responsiveness of granulosa cells in dominant follicles in late follicular phase.39 The administration of recombinant LH was found to be sufficient to maintain follicular growth in late follicular phase after initial 5stimulation with FSH.40 Though this approach has been postulated to reduce OHSS,41 this has not been substantiated till date.
 
CONVENTIONAL STIMULATION VERSUS MILD OVARIAN STIMULATION
The pros and cons of standard and mild ovarian stimulations are given in Table 1.
Table 1   Pros and cons of standard and mild ovarian stimulations.
Parameters
Standard Ovarian Stimulation
Mild Ovarian Stimulation
Stimulation
Complex
Less complex
Number of oocyte retrieved
Maximum
Less
Time counseled for stimulation
More
Less
Cost
High
Low
Patient discomfort
More
Less
Dropout
More
Less
Short-term complications (OHSS)
More
Less
Long-term health consequences, e.g. ovarian cancer
Uncertain, may be more
Probably less
Embryo quality and endometrial receptivity
Impaired due to supraphysiological E2
Not affected
Available embryo for freezing
Yes
Mostly no
 
Embryo Quality
Some observations indicated relation between degree of ovarian stimulation and embryo quality, either morphologically or by chromosomal constitution,16,42 by disrupting natural selection of good quality oocytes.
In mouse oocytes, high dose of Gn stimulation during in vitro maturation increased incidence of chromosomal abnormality had been observed.43,44 High E2 level following conventional ovarian stimulation has negative impact on implantation potential,45,46 as well as chromosomal constitution of human embryos.47 One study indicated that high stimulation may disrupt the chromosomal segregation mechanism of embryo.48,49
The retrieval of modest number of oocytes following mild stimulation leads to distinctly higher implantation rate compared to conventional stimulation.50 This may be due to retrieval of more homogenous group of good quality oocytes instead of pathological reduction of ovarian response. The fear of getting low number of oocytes following mild stimulation thus may be compensated in getting increased oocyte number, but lower pregnancy rate with high dose stimulation.51,526
It is true that with mild stimulation, cryopreservable embryos are less, leading to unavailability of subsequent FET. However, lesser number of good quality embryos leads to similar results as compared to conventional stimulation protocol, so far as the number of pregnancy is concerned.16
 
Luteal Function and Endometrial Receptivity
Supraphysiological steroid levels are widely held responsible53 for poor endometrial receptivity with high dose of Gn in COS. This results in impaired embryo implantation when compared with natural cycle with oocyte donation.54 E2 level of more than 3,000 pg/mL on hCG day has been shown to reduce implantation rate, independent of embryo quality.55 In contrary, improved implantation rate has been observed with mild stimulation approached12 due to more physiological response. Increased pregnancy rate has been observed following FSH step down in high responders due to decrease in E2 in preimplantation period.56
 
Economic Consideration
It is obvious that the cost involved in mild stimulation is much less as compared to conventional group. Moreover, mild stimulation carries negligible chance of OHSS which otherwise can impart more cost in treatment. Less chances of multiple pregnancies and preterm birth in mild strategy57 leads to reduced cost involvement.
 
Psychological Aspects
Mild stimulation which is a more shorter and patient-friendly protocol with little complication might decrease the treatment-related stress. In natural cycle, excess chance of cycle cancellation is not also that stressful, if patient is counseled properly. Furthermore, mild stimulation has been found to reduce significant dropout rate per cycle. A mild IVF treatment strategy was found to be associated with fewer symptoms of depression after overall treatment failure, than a standard IVF treatment.31,58 As there is less psychological burden in mild stimulation, even a failure as accepted by the patient positively with a hope of having success in the following cycles, which compensates the low pregnancy rate per cycle.59
 
FUTURE DEVELOPMENT
It will be not far when ovarian stimulation will be replaced by in vitro maturation of the oocytes, after retrieval of immature eggs from unstimulated or minimally stimulated cycles, avoiding requirement of Gn stimulation for invivo follicular growth and oocyte maturation.60,61 Till date, this procedure has not produced increased pregnancy rates due to poor implantation. Moreover, safety of this technique for the offsprings has not been identified.62,637
 
CONCLUSION
Since the mid-90s, the long agonist stimulation protocol has been widely used worldwide. This was lengthy, expensive protocol, with advantages of more programmed IVF, less cycle cancellation and more number of oocytes of available with better pregnancy rate.64 When compared against complications and disadvantages, long protocol showed more OHSS, more short- and long-term risks, more physical and emotional burden along with increased dropouts. It involved long continued repeated injections, multiple blood sample tests, and repeated ovarian ultrasound scan, requiring more attendance to the clinic.
The mild stimulation on the other hand, was devoid of more disadvantages of the long protocol, requiring shortened stimulation period. Though the retrieved oocytes were less in number, the pregnancy rate per ET seems to be comparable between two approaches (P-679–outlook–Hohmann). The embryo quality of mild regime was much better.16,65
Another aspect is very important as in many countries like Italy, there are IVF legislations which do not allow embryo banking. Hence, availability of excess number of oocytes is of no use.
Mild ovarian stimulation for IVF is gaining ground gradually, as evidenced in recent literature. It is very useful for selected group of patients like good responders of young age, some having polycystic ovarian disease (PCOD), but the drawback being reduction in pregnancy rate per cycle. The best part is less chance of complication, increased patient compliance and economic benefit, which is making it more popular day by day. It is difficult to draw a conclusion about the best agents for mild stimulation till date. A better understanding of physiology of follicular dynamics may lead to individual approaches.66 It should be the aim to develop at least 3 follicles in mild stimulation to produce competitive IVF treatment outcomes. Reduction in dose of medication becomes highly beneficial so far embryo quality and implantation rate is concerned.
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