Advances in Assisted Reproductive Technology Nayana H Patel, Sandro C Esteves
INDEX
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
A
Abdominal discomfort 67
Abdominal distension 67
Ablation, laparoscopic 190
Aborters, primary 202
Abortion
rate of 162
recurrent 116, 119
ABP See Androgen-binding protein
Absolute uterine factor infertility 235, 243
Acanthosis 207
Accessory gland infection 134
Accurate genetic tests, development of 121
Acquired uterine abnormalities 197
investigations 197
management 197
Acrosome 295
Activated partial thromboplastin time 205
Activated protein C resistance 206
Acupuncture 63, 90
Acute respiratory distress syndrome 71
Adalimumab 211
Adenoma 178
resection 177, 178
techniques of 177, 178f
Adenomyoma
localized 177
resection 177f
Adenomyosis 12, 145, 172, 177
classification of 177
grades of 178f
Adenosine triphosphate 355
Adhesions 110, 172, 175, 263
Adnenomyosis
three-dimensional 145f
two-dimensional 145f
Adnexal pathologies, evaluation of 148
Adnexal soft tissue 151
Advanced maternal age 24, 110, 116, 356
Adverse pregnancy, risks of 206t
AFC See Antral follicle count
African green monkey kidney 268
Agonist protocol 56f, 228f
Agonist trigger
and freeze all 110
use of 69
Air bubbles 149
Alanine 262
Albumin 263
Allelic dropout, phenomenon of 316
Allergies, history of 68
Amenorrhea 115
longer periods of 52
American College of Obstetricians and Gynecologists 176
American Society for Reproductive Medicine 123, 191, 202
American Thyroid Association 209
American Urological Association 125
AMH See Anti-müllerian hormone
Amino acids 262, 263
nonessential 262
Ampullary cell 342
Ampullo-ampullary anastomosis 173
Anasarca 67
Anastomosis, types of 173, 174, 174f
Anastrazole 132
Androgen
binding protein 130
insensitivity syndrome 125
receptor 126
therapy 131
Anemia, aplastic 219
Aneuploidy 122, 319
cells 319
Angiogenesis, mechanisms of 189
Antagonist protocol 57, 58f, 110, 228f
Antiadhesive glycoprotein molecules 161
Antiapoptotic molecules, upregulation of 215
Anti-beta 2 glycoprotein antibodies 205
Antibiotics 262
Anticardiolipin antibodies immunoglobulin G 205
Anti-estrogens, use of 17
Anti-müllerian hormone 2, 16, 21, 24, 29, 30, 34, 41, 51, 108, 184, 329
estimation of 2
levels 67
low levels of 204
Anti-ovarian antibodies 28
Antioxidants 61, 132
newer 133
Antiphospholipid 205, 208
antibody syndrome 205, 206
Antithrombin, deficiency of 203, 206
Antral follicle 151
count 16, 18, 21, 29, 30, 43, 51, 53, 68, 142, 146, 153, 329
estimation of 2
receptors of 52
small 323
stage 323
APL See Antiphospholipid
Apolipoprotein D 162
Apoptosis, mechanisms of 189
AR See Androgen receptor
Arcuate uterus 143f
Argentine 262
Aromatase inhibitors 131, 132, 134, 229
ART See Assisted reproductive technology
Artificial insemination 114
Artificial ovaries 219
Ascites 71
Asherman's fibrosis, treatment of 167f
Asherman's syndrome 250
Asparagine 262
Aspartate 262
Aspirin 70, 90, 95, 109, 199
low dose 31, 62
Assisted hatching 114, 118
procedure 118
Assisted oocyte activation 350, 350t
chemical activation 351
electrical activation 351
mechanical activation 350
Assisted reproductive technology 4, 16, 17, 21, 30, 40, 50, 62, 77, 86, 108, 114, 119, 122, 160, 172, 181, 184, 189, 199, 214, 225, 257t, 261, 290, 307, 314, 334, 334, 342, 355
cryopreservation in 299, 302
evolution of 66
laboratory 257t, 258t
procedures 114, 202
programs 257, 299
recent advances in endometriosis in 188
role of ultrasound in 148
window of implantation in 100
Asthenozoospermia 126, 350
Asynchrony 10
Ataxia-telangiectasia 281
Atelectasis 71
Atraumatic graspers 162
Atraumatic transfers 149
Atretic oocyte 273
cellular 277f
nuclear 277f
Atrophy, endometrial 250
Autoimmune
disorders 205
thyroid disease 204
Autoimmunity 207
Autologous cumulus cell coculture 268, 345
Autologous endometrial cells 268
Autologous endometrial coculture 267, 343
cycle 344
Autologous mesenchymal bone marrow stem cells transplantation 35
Autosomal genetic abnormalities 125
Auxogyn 307
Azoospermia 118, 122, 123, 125, 127, 130, 139, 215, 252
ejaculatory 122
majority of 121
B
Bacterial infections acquired 206
Bacterial protein synthesis 262
Basal estradiol levels 29
Basal follicle-stimulating hormone 29
Batch-to-batch consistency 263
Behçet's disease 219
Bench surgery 238, 238t
Beta-human chorionic gonadotropin 63, 155, 196
embryonic 10
Beta-thalassemia 219
Bicornuate uterus 143f
Biochemical pregnancy 111
lower incidence of 110
rate 102
Biocompatibility testing 263
Biomarkers, analysis of 88
Biopsy, harvesting endometrial 104
Blastocyst 54, 118
biopsy of 316
development rate 257
endometrium dialogue 85
formation 324
formed, number of 324
implantation of 84f
stage 40, 110, 262, 265, 318
biopsy 316
embryo 105
media 266, 267
transfer 105, 185, 198
Blastomere 308, 317
biopsy 316
disadvantages of 316
single 248
transfer 356, 359, 359f
Blood flow velocity wave 87
BMI See Body mass index
Body mass index 153
Bologna criteria 24, 25
Bone morphogenetic protein 27, 331
Borosilicate glass 335
Bovine trophoblastic tissue 343
Braille-driven media 338
Breast cancer 42
Brucella abortus 206
Brucellosis 203
Buffalo rat liver cells 268
Buserelin 79
C
Cabergoline 63
Cadherins 88
downregulation of 88
Calcium 70
detrimental stress-induced 266
Cancer
female survivors of 225
gastrointestinal 218
treatment plan 218
Carbohydrates 262
Cardiac disease 178
Cardinal ligament 238
Carrying cells 305
CBC See Complete blood count
CC See Clomiphene citrate
CCCT See Clomiphene citrate challenge test Cell
cycle checkpoint 285
damage during freezing, mechanisms of 300
mediated function 188
size of 72, 302
survival rate of 300
to-cell interaction scenarios 296
transplantation 252
Cellular
debris 297
metabolism 299
parameters 281
Centers for Disease Control and Prevention 114
Centrifugation, density gradient 292
Cerebral palsy 11
Certolizumab 211
Cervical
biopsy, hysteroscopic 240
factor 114, 115
incompetence 203, 205, 209
stenosis 162
Cervix 145
visual inspection of 240
Cesarean section, lower segment 109
CFTR gene 124, 125
defects 124
CFTR testing 125
Chelators 262
Chemotherapy 27, 216
and radiotherapy, low dose 215
cytotoxic 214
doses of 215
effect of 214, 215
Chloroform 264
Choriodecidual reaction, thin 211
Chorionic gonadotropin follicle 153
Chorionic villus sampling 356
Chromosomal abnormalities 121, 122, 284, 314
Chromosomal aneuploidies, rates of 328
Chromosomal malformations 154
Chromosome 121, 123, 124, 210
alignment 285
malsegregation of 319
number of 273
scattering 359
structural defects in 123
Chronic obstructive pulmonary disease 178
Ciliary dyskinesia, primary 126
Cleavage stage
biopsy 316
embryos 118, 316
media 266, 267
Clinical pregnancy rates 115
Clomiphene 131, 132, 139
citrate 17, 42, 53, 61, 115, 132, 134, 182, 184, 229, 230
challenge test 26, 29, 30
resistance 61
use of 41, 68
flare protocol 33
Clumpy granulosa cells 275
Co-culture
system 267
techniques 342
Coenzyme Q10 133
supplementation 31
COI See Controlled ovarian induction
Colin's knife 163
Colony-stimulating factor 265
Combined oral contraceptive pills 51, 61
Commercial surrogacy arrangement 231
Comparative genomic hybridization 122, 317, 318
Complete blood count 208
Complex cumulus-oocyte appearance 284
Conception
and abortion rates 155t
probability of 142
Congenital uterine anomalies, classification of 143t
Connexion 43 proteins 324
Consecutive minimal stimulation in vitro fertilization 44
Conservative laparoscopic management 189
Control bubble trap 336
Controlled ovarian
hyperstimulation 3, 5, 20, 31, 32, 40, 191, 230, 322
protocols 32
induction 256
stimulation 17, 41, 55, 77, 108
syndrome 19
Conventional controlled ovarian syndrome 19
Conventional insemination 295
Conventional intracytoplasmic sperm injection 296f
Conventional semen parameters 127
Conventional sperm preparation 336
Conventional stimulation protocols 21
Cooling
determines, rate of 299
during vitrification, mechanisms of 301
rate of 302
Corifollitropin 8
alfa 45, 69
single injection of 45
Corpus luteal flow 156
Corpus luteum 77, 156, 264
Corticosteroids 70
COS See Controlled ovarian stimulation
Crescent ooplasm 280f
Cryopreservation 6, 118, 299, 301, 302
principles of 299
risk of 118
Cryopreserved embryo transfers 45
Cryopreserved oocytes, fertilization of 116
Cryoprotectant
concentration of 301
types of 302
Cryotechtm vitrification technology 48
Cryptorchidism 125
Cryptozoospermia 296
Crystallization 299
CSF See Colony-stimulating factor
Culture media 261
Culture systems, quality control of 256
Cumulus cells 116, 342, 346f
monolayer of 346f
transcriptomes of 25
Cumulus co-culture method 345
advantages 345
limitations 345
Cumulus corona complex 274
Cumulus granulosa cell 264, 324
Cumulus oocyte complex, denudation of 345
Cyclic adenosine monophosphate 295, 323
Cyroprotectant 302
Cysteine 262
Cystic fibrosis transmembrane 121
Cysts
functional 147
hemorrhagic 147
multiple 192
Cytoplasm
ability of 273
role of 360
Cytoplasmic maturation 350
Cytoplasmic transfer 356, 357f
Cytosine 27
Cytosolic aspiration and injection 350
Cytosolic sperm factor 349
Cytotoxic agents 214
D
Danazol 189
Daughter chromatids 316
De novo oocytes 252
Decidualization 100
Dehydration, intravascular 117
Dehydroepiandrosterone 31, 60, 61
supplementation 31
Denonvilliers’ fascia 243
Denuded human oocyte 279
Deoxyribonucleic acid 273, 291
methylation patterns 28
sequence 28
Dermoid cysts 148
Device, operation of 336
Dextrocardia 126
D-glucose 266
DHEA See Dehydroepiandrosterone
Diabetes
gestational 117
history of 356
mellitus 204, 251
Dictyotene stage 273
Dimethyl sulfoxide 278
Diminished ovarian reserve 24, 27, 28
Directions macerates testicular tissue 136
Distorted pelvic anatomy 188
DNA See Deoxyribonucleic acid
DNAI1 and DNAH5 gene 126
Dominant follicles, number of 52
Donor
and recipients, counseling of 225
eggs 114
indications of 119
embryos, indications of 119
human fallopian cells 346
insemination 231
oocyte 34
cycles 77
indications of 225
postoperative course of 240
preparation of 227
sperms 114, 118
case of 115
indications of 118, 231
use of 115
surgery 237
uterus 238
laparoscopy assisted dissection of 237f
Dopamine agonist 70, 131
Double-embryo transfer 110
Duphaston 8
Dynamic culture systems 269
Dynamic fluid devices 268
Dyspnea 71
Dyssynchronous follicular growth, phenomenon of 5
E
Early pregnancy transvaginal scan, prognostic factors in 211
Ectopic pregnancy 108, 111, 117
rate, lower 111
EGF See Epithelial growth factor
Egg
banks 226
cryopreservation of 355
cytoplasm 349
donation 35, 225
indications of 225t
donors 226
fertilization of 117
in vitro maturation of 226
nuclear 350
reserve 350
retrieval, techniques of 355
Ejaculation, retrograde 115, 134
Ejaculatory disorder 115
Ejaculatory duct 135
blockage of 118
obstruction 124
Ejaculatory dysfunction 231
Ejaculatory failure 135
sperm retrieval in 138
Electrical stimulation 350
Electrolyte imbalance 71
Elevated serum progesterone 111
levels 109
Ellipsoid 30
Elliptical strip excision technique 177
Embryo 41, 92, 108, 109, 149, 265t, 283, 314, 334
accumulation 111
adoption 225
and oocyte cryopreservation 216, 220
aneuploidy rate, lower 47
assessments, multiple 309
bad 308
biopsy 117
cleavage 310f
co-culture of 266, 346
consequent 360
cryopreservation of 90, 118, 185, 216, 303, 304, 355
culture 336, 337
media 261, 265
system 266, 342
techniques for 34
development 46, 103, 309f, 310f
and function 334
stage 10
donation 225, 230
program, indications for 230
early 262
endometrial dialogue 91
fertilized 316
freezing of 110, 118
good 308
grown 344f
implantation of 91, 251
in vitro 334
metabolism 103
monitoring of 311
normal 339
preimplantation of 263
quality 54, 62, 198, 284, 285, 294
quantity of 340
removal of 336
selection of 100, 309, 311, 355
social freezing of 92
transfer 1, 41, 93, 100, 102f, 104, 116, 148, 149, 198, 229f, 266, 267, 286, 304, 330
adoption of single 1
cycle 109
multiple 283
preparation for 229
procedure 101f
rationale of deferred 41
recipient for 229, 229fc
single 11, 97
stage 103
unscreened 110
without stress 336
Embryogenesis 349
in vitro 342
Embryology 336
laboratory
newer media in 261
quality control in 255
Embryonic development 355
Embryonic feeder cells 267
Embryonic genome 265
Embryonic growth 343
Embryonic morphokinetics 308
Embryonic stem cells 247, 248
Embryoscope 307
Embryotrophic factors 343
Endocrinal disorders, multitude of 204
Endocrine
disruptors 28
monitoring 94
Endocrinological disorders 207
Endocrinopathies
signs of 130
symptoms of 130
Endometrial assessment 148
Endometrial biopsy 63, 63f
molecular analysis of 104
test 104
Endometrial cavity 144
Endometrial cells 342, 344
Endometrial changes, monitoring of 87
Endometrial co-culture 344f
Endometrial cysts, method for 190
Endometrial function 196
Endometrial gene 110, 161
expression, analysis of 286
Endometrial immune markers 89
Endometrial injury 90
local 60
Endometrial morphology, assessment of 87f
Endometrial polyps 110, 146, 197
multiple 146f
Endometrial preparation 229
protocols 92, 92fc
influence of 91
Endometrial proliferation 91
Endometrial receptivity 84, 86, 89, 104, 112, 161, 230
adjuvants for 61
assessment of 87
tests 105
Endometrial scratching 63, 97, 161
Endometrial thickness 11, 87, 251
Endometrial transformation 101
Endometrial vascularity zone 155t
Endometrial volume 88
Endometrioma 149
excision of 190
management of 176, 191
ovarian cystectomy for 26
size of 192
treatment of 191
Endometrio-myometrial junction, irregularity of 154
Endometriosis 26, 54, 86, 109, 114, 116, 172, 188, 219
associated infertility, surgical treatment for 189
chronic 169f
mild 188
severe 19
treatment for 176f, 189
Endometriotic cyst 147
drainage 190
Endometritis, chronic 163
Endometrium 42, 84, 91, 92, 100, 108, 110, 145, 148, 154, 155, 207, 264, 283
assessment of 156
cells 189
morphology of 154
multilayered 154f
regeneration 250
thin 109, 114, 116
with good receptivity, B-mode features of 154
Endopelvic fascia 238
Endoplasmic reticulum 349
Endoscopic surgery, advances in 178
Endoscopy, benefits of 172
Energy substrates 261
Enucleated healthy oocyte 358
Environmental toxins 28
Enzyme inhibition 131
Ephedrine 134
Epidermal growth factor 97, 245, 247
family, members of 324
Epididymal aspiration, simple 136
Epididymal sperm aspiration 122
microsurgical 122, 136
Epididymis 135, 136
complete fibrosis of 135
Epididymo-orchitis, chronic filarial 134
Epigenetic carriers 28
Epithelial cell 342
Epithelial growth factor 264, 265
Equilibrium 266
Equipment
quality control of 258
safety of 308
Erectile dysfunction 130, 248, 251
ESCs See Embryonic stem cells
ESR1 gene 27
Essential amino acids 262
Estradiol 28, 29, 57
high 41, 132
levels 79, 146
progesterone, exogenous 109
role of 79
supraphysiologic levels of 108
Estrogen 61, 101
alpha receptor, polymorphism of 27
and progesterone in generation of endometrium, role of 91
facilitate 85
form of 94
phase, monitoring 94
receptors 92t
replacement 94
therapy, length of 94
ET See Embryo transfer
Etanercept 211
Ethnicity 27
Ethylenediaminetetraacetic acid 262, 344
Euploid
aneuploid mosaic 319
blastocysts 11
embryo 285, 311, 314, 319
normal 11
European Medical Agency 70
European Society of Gastrointestinal Endoscopy 142
European Society of Human Reproduction and Embryology 189, 261
Exfoliating cells 297
Extracellular media 300
Extracellular milieu 300
Extracellular pH 262
F
Fallopian tubal cells 347
Fallopian tube
autologous 346
ciliated epithelium of 340
damage 172
epithelial cells 346, 346f
Garden of ampulla in 334
interstitial portion of 170
Familial genetic disorders 114, 116
Female infertility, regenerative medicine for 249
Fertility
drugs, improvement in 355
enhancing surgeries 172
impairment 350
preservation 118, 214, 216, 216fc, 220, 221, 329, 330
techniques 216, 217fc
protection
and preservation 215
females 215
males 216
treatment, failure of 116
Fertilization 123, 154, 273, 281, 290, 295, 349
failure 350
cause of 351
treatment of 350
low 294
media 267
rate 46, 117, 217, 278, 284, 291
role in 263
Fertilize mouse oocyte 252
Fertoprotective agents 218
FET See Frozen embryo transfer
Fetal bovine uterine fibroblasts 268
Fetal bradycardia 211
Fetal calf serum 251
FGF See Fibroblast growth factor
Fibroblast growth factor 247, 264
Fibroids 143, 172
attenuation of 26
intramural 197
Fibrous adhesions 163
Fimbrioplasty 175
Fine needle aspiration 137
Flagellar movement 290
Fluid
dynamic embryo culture systems 268
fluid interface 335
Fluorescence in situ hybridization 110, 122, 284, 317
FMR1 gene 27
FNPO See Follicle number per ovary
Focal testicular failure 134
Follicle
Frank rupture of 71
growth
abnormal 188, 190
stage of suppressed 50, 51
leads, rupture of 156
number 5, 152
per ovary 153
recruitment, potent stimulus for 3
ruptures 115
with peripheral vascularity 149f
Follicle-stimulating hormone 2, 16, 17, 18, 30, 41, 60, 126, 129, 133, 139, 152, 181, 189, 228, 281, 324, 329, 814
nomogram for calculation of 18f
receptor 25
polymorphism of 27
Follicular angiogenesis-related factor 154
Follicular aspiration 44, 304
Follicular defects 190
Follicular development, earlier stages of 50
Follicular fluid 5, 264, 281, 345
concentrations 154
proteomic analysis of 68
seem 73
Follicular growth 175
Follicular monitoring 53
Follicular phase 19
course of 4
follicular-stimulating hormone, early 51
Follicular progesterone elevation, late 101
Folliculogenesis 20
endocrine regulation of 3
waves of 20
FP See Fertility preservation
Fragile X mental retardation 27, 219
Fragmentation
during embryo development 310f
dynamic pattern of 309
Fragmented polar body 279f
Freeze-all strategy 69, 108
Fresh embryo
implantation 10
transfer 10, 86, 94, 100, 108, 109, 110, 112
Frozen embryo
replacement 77
transfer 4, 42, 80, 91, 92, 95, 95f, 96, 100, 108
cycle 77, 95, 101, 328
donor and recipient cycles 80
hormone replacement therapy 93
indications for 92
modified natural cycle 93
protocols 10
Frozen oocytes 311
FSH See Follicle-stimulating hormone
G
G protein-coupled receptor 3 27
Galactorrhea 207
Galactosemia 219
Gamete 121, 334
cryopreservation of 118
donation and surrogacy 199
freezing of 118
in vivo 350
intrafallopian transfer 114
Gametogenesis 132
G-CSF See Granulocyte colony-stimulating factor
Gender reassignment procedures 219
Gene
abnormalities 124
disease, single 318
disorders, single 121
expression
patterns, divergence of 340
profiling 27
polymorphisms 27
therapy modulating 89
Generate dynamic fluid, platform movement to 268
Genetic analysis, protocols for 316
Genetic cause 204
Genetic condition 214
diagnosis of 314
screening of 314
Genetic diseases, risk of 314
Genetic disorders 314
inheritance of 121
leading to male infertility 125
male 219
Genetic evaluation 130
Genetic factors 121
Genetic material, sources of 315
Genetic techniques 122
Genetic transmittable disorder 225
Genital examination 130
Genital infections 206
Genital tract infections 203
Genital tuberculosis 26
Genitalia, external 125
Genitourinary tuberculosis 206
Genomic dysregulation 286
Genotype, heterozygous 316
Genotyping single cells, protocols for 316
Gentamycin 262
Germ cell
male 252
maturation 3
suspension 220
Germinal epithelium 133
Germinal vesicle 273, 274, 323, 327f
Germline modifications 360
Germline stem cells 253
Gestational age 11
small for 41, 109
Gestational sac 211
Giant oocyte 279, 279f
Gland infections, male accessory 203
Glandular-stromal dyssynchrony 286
Glass wool
fiber
columns 294
effect of 294
filtration 294
Glomerulonephritis 219
Glucocorticoids 62
Glucose metabolism, abnormal 209
Glutamate 262
Glutamine 262
Glycine 262
Glycodelin A 89
Glycodelin actions 161
Glycoprotein 129, 262, 334
Glycosaminoglycans 263
Glycosylated hemoglobin 210
GM-CSF See Granulocyte-macrophage-colony stimulating factor
GnRH See Gonadotropin-releasing hormone
GnRHA See Gonadotropin-releasing hormone agonist
Golan's classification 67t
Gonadal dysgenesis, mixed 125
Gonadal function 218
Gonadotoxicity 214
prevention of 215
Gonadotoxin exposure 130
Gonadotropin 32, 33, 42, 43, 56, 57, 130, 131, 134, 184
consumption 285
dosage, lower 43
dose 33, 286
use of high 40
exogenous 69
long-acting 69
low dose 41, 181
preparations, variety of 68
priming 325
protocols 20
stimulation protocol 152
surge attenuating factor 27
lower 27
types of 33, 68
Gonadotropin releasing hormone 4, 32, 42, 92, 95, 116, 130, 131, 184, 284, 323
agonist 9, 32, 32f, 53, 79, 81, 130, 144, 189, 229
effect of 189
flare protocol 32
protocol 227
role of 79
treatment of 57, 188
trigger 17, 81, 182
analogs 51, 61, 80, 130, 216
dose of 31
antagonist 5, 57, 64, 72, 78, 182, 192, 285
cycles 184
protocol 32f, 228
receptor 182
role of 56
secretion 129
suppression 68
ultrashort protocol of 8
use of 17, 86
Gonadotropin Research for Controlled Ovarian Hyperstimulation 8
Granulocyte colony stimulating factor 60, 63, 96, 211, 218
Granulocyte macrophage-colony stimulating factor 264, 343
Granulomatosis, eosinophilic 219
Granulosa cells 275
surrounding 25
Green monkey kidney 343
Gremlin 1 27
Growth differentiation factor 27
polymorphism of 27
Growth hormone 7, 60, 132
binding protein 41
therapy 132
Growth retardation, early 211
GV See Germinal vesicle
Gynecomastia 122
H
Hair particles 148
HbA1C See Glycosylated haemoglobin
HB-EGF See Heparin-binding epidermal growth factor
hCG See Human chorionic gonadotropin
Heart failure, congestive 178
Hematocele, postoperative 138
Hematocrit 72
Hematomas 178
intratesticular 136
Hematopoietic stem cell transplantation 219
Hematopoietic system 248
Hemochromatosis 131
Hemoconcentration 71
Hemorrhage 178
accidental 108
Heparin 199
binding epidermal growth factor 264, 343
Hepatitis B
core antibody 227
surface antigen 227
Heritable disease, mendelian types of 121
High dose stimulation protocol 43
Hirsutism 207
Histidine 262
HMG See Human menopausal gonadotropin
Homeostasis, hormonal 121
Homogeneous isoechoic endometrium 155
Homologous cell 267
Homologous feeder cell 343
Hormonal disorders 204
Hormonal environment 100
Hormonal replacement therapy 101
Hormonal stimulation before sperm retrieval 139
Hormone
fertility preservation of 331
monitoring, elimination of 111
pattern 85f
replacement therapy 77, 92, 93, 96, 229, 240
cycles 86, 229
stimulation 139
HOXA 10 genes 197
HOXA 11 genes 197
HOXA genes 89
HRT See Hormone replacement therapy
HSG See Hysterosalpingogram
HTF See Human tubal fluid
Human albumin 185
Human ampullary cells 342
Human chorionic gonadotropin 42, 56, 58, 57, 65, 68, 96, 139, 148, 154, 184, 264, 323, 344
injection 86
trigger 81
individualized 69
Human eggs, aging of 25
Human embryo 91, 342
cryopreservation of 303
culture 263, 268
systems for 342
in vitro fertilization 266t
mosaicism of 117
Human embryonic stem cell 252
Human endometrial cell co-culture 342
Human fallopian tubes 263
Human female reproductive tract 263
Human genome 121
Human granulosa cell 342
Human growth hormone 31
Human immunodeficiency virus 206, 218, 303
Human in vitro fertilization 342
Human meiotic spindle 256
Human menopausal gonadotropin 3, 43, 53, 115, 182, 192
use of 34
Human oocyte 324
maturation of 323
Human oviduct cells 268, 342
Human reproduction 91
Human reproductive tissues, cryopreservation of 303
Human semen, evaluation of 290
Human serum albumin 264
Human sperm 161, 350
storing 302
Human tubal fluid 263, 266, 267, 342
Human umbilical cord blood stem cells 251
Hyaluronan 263, 295
Hyaluronic acid 263, 297
binding 296b
Hydrosalpinges 148, 197
removal of 197
Hydrosalpinx 86, 149
Hydroxyethyl starch 70, 185
Hypercoagulable state 71
Hyperechoic stroma 147
Hyperhomocysteinemia 203, 206
Hyperinsulinemia 182
Hyperprolactinemia 131, 207
Hypogonadism 122, 131
idiopathic hypogonadotropic 130
signs of 130
symptoms of 130
Hypogonadotropic hypogonadism 19, 125, 130, 131, 134
Hypogonadotropic state 215
Hypospermia 130
Hypotension 71
Hypothalamic-pituitary
axis deficiency 125
gonadal axis 129
ovary axis, potent stimulants of 182
Hypothesis 6
Hypovolemia 71
Hysterosalpingogram 208
Hysterosalpingography 160
Hysteroscopic endometrial embryo transfer 170
Hysteroscopic examination, role of 161
Hysteroscopic guided
embryo transfer 170
endometrial scratching 162f
myomectomy 165f
Hysteroscopic mechanical
endometrial injury 161
morcellators 162
Hysteroscopic metroplasty 142, 162, 163, 166f
Hysteroscopic polypectomy 162, 164f
Hysteroscopic scissors 167f
Hysteroscopic surgery 161
Hysteroscopic tubal cannulation 172
Hysteroscopy 63, 160, 161
procedure of 161, 162
treatment with 63f
I
Iatrogenic injuries 245
ICOS See Individualized controlled ovarian stimulation
ICSI See Intracytoplasmic sperm injection
Iliac artery, external 239f
Iliac vessels
and anastomoses, Doppler image of 241f
internal 237
Immature eggs, maturation of 322
Immature follicle, aspiration of 326
Immature oocyte 217, 275, 323, 325, 326
cellular 276f
competence of 325
detection of 326
maturation of 325
nuclear 276f
Immature sperm cells 292
Immature testicular tissue, cryopreservation of 220
Immunoglobulin
G 227
intravenous 210
Immunological disease 214
Impaired glucose tolerance test 204
Implantation failure of 10, 104, 110
In vitro development 342
In vitro fertilization 1, 10, 16, 17b, 40, 65, 92, 108, 114, 116, 129, 138, 142, 152, 160, 182, 191, 192, 236, 255, 261, 267, 273, 283, 290, 291, 304, 334, 337, 339f
conventional stimulation for 43
cycles 86, 151, 283, 314
downregulation in 56
failed 35
part of 80
results of 33
embryo transfer 47
failure
multiple 119
risk of 292
inception of 307
intracytoplasmic sperm injection 31, 192
laboratory
environment, quality control of 257
personnel, quality control in 259
process 256t
quality management in 255
minimal stimulation 48
modified natural cycle 42
ovarian stimulation for 46, 100
pregnancy rate 192
procedures 236
programs 226
recurrent 196
repeated failure of 119
role of salpingectomy before 175
standard 322
stimulation 86
treatment 355
In vitro follicular growth 219
In vitro interactions 342
In vitro maturation 70, 183, 216, 217, 322, 329, 330, 336, 337
process of 322f
In vitro oocyte maturation 217
In vitro produced primordial germ cell 220
In vivo fertilization 291
In vivo mature, recognition of 327
Individualized controlled ovarian stimulation 16, 17, 21
Induced pluripotent stem cells 248
Infections 210
acute 207
chronic 207, 290
Infertility 188
age-related 356
cause of 175
color Doppler in 151
duration of 44
endometriosis related 188
etiology of 123
male factor 114, 290
management 144
treatment of 151, 253, 303
ultrasound in 142
unexplained 114, 115, 116
Inflammatory bowel disease 219
Inflammatory cytokines, level of 207
Inflammatory responses, modulation of 90
Infliximab 211
Inhibin B 28, 29
Inositols 183
Insemination 296
intravaginal 114
Insulin
dependent 204
like growth factor 41, 91, 247, 343
binding protein 5
synthesis of 60
resistance 181
and insulin sensitizers 182
Integrins 88
Intensive care unit 240
Interferon beta, ratio of 211
Interleukin 1β 189
International Federation of Gynecology and Obstetrics 160
International Society for Fertility Preservation 218
Intracellular
organelles 299
pH 261
water content 301
Intracytoplasmic morphologically selected sperm injection 295
Intracytoplasmic sperm injection 48, 77, 100, 108, 114, 129, 135, 152, 160, 183, 258, 267, 274, 290, 291, 304, 314, 322, 329, 330, 344, 349, 350, 355
cycles 9, 198
physiological 295
Intrafollicular environment 285
Intralipids 210
Intramuscular progesterone 78
injections 78
Intrauterine adhesions 146, 197
Intrauterine fetal death 205
Intrauterine growth
restriction 11
retardation 205
Intrauterine insemination 77, 79, 80, 114, 115, 129, 148, 162, 192
cycles 77, 151
Intrauterine polyps 162
Intrauterine therapies 90
Ions, balance of 261
IPSCs See Induced pluripotent stem cells
Isoleucine 262
Isopropanol 264
Isthmo-ampullary anastomosis 173
Isthmo-isthmic anastomosis 173
IVF See In vitro fertilization
IVM See In vitro maturation
K
Kallmann syndrome 125, 130
X-linked 125
Kartagener's syndrome 126
Karyotype 122
abnormalities 122
analysis 121, 122, 123
Ketones 264
Kidney retrieval, laparoscopic 241
Kisspeptin trigger 69, 73, 182
Klinefelter syndrome 122, 123, 139, 219
L
LAC See Lupus anticoagulant
Lactate
dehydrogenase 266
lower concentration of 266
Laparoscopic tubal microsurgery 172
contraindications 173
indications 173
intraoperative evaluation 173
Laparoscopic tuboplasty 172
benefits of 173
Laparoscopy
caution for 178
complications 178
in endometriosis, role of 175
in fibroid of uterus, role of 176
L-arginine 61, 96
Laser assisted hatching 355
LEI See Local endometrial injury
Leiomyoma 86
Leptin 154
Letrozole 41-43, 115, 182
coadministration of 42
fail 181
flare protocol 33
induced endometrium 230
use of 217
Leucine 262
Leukemia inhibitory 91
factor 89, 207, 264, 343, 344
Leukocyte 292
concentration 294
Leuprolide acetate 6
Leydig cell 129, 131, 133
function 122
L-glutamine provides nitrogen 262
LH See Luteinizing hormone
LIF See Leukemia inhibitory factor
Live birth
maximizing 11
rate 40, 116, 307
Liver dysfunction 67
L-lactate supporting 266
LMWH See Low-molecular-weight heparin
Low birth weight 10, 41
Low insulin-like growth factor-binding protein 1 86
Low ovarian reserve 191
Low resistance perifollicular flow 153f
Low-molecular-weight heparin 60, 63, 90, 205
Luminal epithelium 84
Lupus anticoagulant 205, 208
Luteal phase 19, 54
defect 188
deficiency 9, 77, 209
diagnosis of 77
endometrium 87
ovarian stimulation 47, 50, 53fc
efficacy of 50
ovulations, phenomenon of 52
progesterone 80
stimulation 50, 55
advantage of 52
protocol 52
support 9, 80
adjuvants in 79
indications for 77b
Luteal progesterone levels, mid 97
Luteal support, types of 78b
Luteinizing hormone 3, 4, 41, 85, 126, 129, 139, 154, 182, 324, 329
endogenous suppression of 77
levels 56
receptors 17
role of 34
Lycopene 132
Lyme disease 203
Lymphocyte immune therapy 210
Lysine 262
M
MacKenrodt's ligament 238
Macromolecules 263
MACS See Magnetic-activated cell sorting
Magnetic cell separation 62
Magnetic-activated cell sorting 294, 297
Male infertility 121, 122
causes of 129
diagnosis of 121
etiology of 129
genetic
investigations of 126fc
testing in 121, 122, 127
idiopathic 122, 131, 132, 134
management 122
medical management of 129
recent advances in genetic evaluation of 126
regenerative medicine for 251
severe 118
treatment of 129
X-linked 125
Male partner
absence of 231
carrying genetic disorder 118
semen analysis for 227
Male reproductive
health 129
system, hormonal regulation of 130f
Malified natural cycle 96
Mammalian embryos, activity of 342
MAR See Mixed agglutination reaction
Maternal illness, severe 206
Maternal killer-cell immunoglobulin-like receptor 212
Mature follicle
B-mode features of 152
features of 148
Maxillofacial surgery 245
Mayer-Rokitansky-Küster-Hauser syndrome 232, 240
Median lethal dose 215
Medical conditions, severe 119
Medical therapy, use of 129
Medroxyprogesterone acetate 8, 20, 44, 52, 189
Meiosis, faultless completion of 6
Meiotic anaphase, second 349
Meiotic arrest 324
Membrane fusion 350
Mendelian inheritance pattern 121
Menopause, reversal of 250
Menstrual cycle 241, 264t
phases of 92t
stage of desynchronized 50, 51
Mesenchymal stem cells 248, 252
Messenger ribonucleic acid 65
Metaphase spindle 154
Metformin 61, 69, 182
evidence of 182
Methionine 262
Methyl tetrahydrofolate 203
Methylprednisolone intravenous 239
Metroplasty, lateral 168f
Microdose flare 18
Microfluidic perfusion system 340f
Microfluidic sperm sorter 337f
Microfluidic technology 334
Microlaminar flow 335
Micropolyps, multiple 163
Microsurgery, principles of 190
Midluteal progesterone 79
Midtubal block 173
Minimally invasive gynecology 235
Miscarriage
risk of 123, 203t, 204
unexplained recurrent 210
Mitochondria 295, 359, 360
energy producing 35
Mitochondrial disease 356
prevent 356
transmission of 358
Mitochondrial DNA disease 355
Mitochondrial transfer techniques 356
Mixed agglutination reaction 291
test 291f
MNC See Malified natural cycle
Modified natural cycle 42, 93, 93f, 230
Modulates endometrial receptivity 90
Molecular cytogenetic methods 122
Molecular signaling pathways 340
Monogenic diseases 316
Monogenic disorders 316
Mononucleated blastomeres 47
Monozygotic twin pregnancy, risk of 118
Morphokinetics, limitations of 311
Mosaic aneuploidies 319
Mosaic turner syndrome 219
Mosaicism challenge 319
Motility 290
Mouse stem cells 252
MRKH See Mayer-Rokitansky-Küster-Hauser syndrome
MSCs See Mesenchymal stem cells
Mucins 88
Mucus, abnormal 115
Müllerian abnormalities 203
Müllerian anomalies 142, 143f
Multidisciplinary care 73
Multiple follicles, development of 108
Multiple pregnancy 1, 48, 115, 117, 118
higher rate of 119
lower incidence of 56
Mural granulosa cell layers 324
Myoinositol 61
Myomas 203
Myomectomy 89
complications of 176
Myometrium 84, 143
N
NAB See Needle aspiration biopsy
NAC See N-acetyl cysteine 60
N-acetyl cysteine 61
National Apex Committee 252
Natural cycle 20, 229
frozen embryo transfer 92
Natural killer cells, number of 207
Nausea 71
Navot's classification 67t
Necklace sign 184
Necrozoospermia 135
sperm retrieval in 138
Needle aspiration biopsy 136
Needle testicular sperm extraction 136
Neonatal intensive care units 11
Neonatal morbidity 101
Neonates 41
Neovagina, impression of 239
Neuronal injury 178
Nitric oxide 61
Nitrogen, liquid 258
Non-Hodgkin's lymphoma 218
Nonhuman feeder cell 343
Noninvasive prenatal testing 314
Nonobstructive azoospermia 121123, 125 127, 134, 135
screening of 122
sperm retrieval in 138
Nononcological diseases 220
Non-spermatic cells 290
NTESE See Needle testicular sperm extraction
Nucleotide polymorphism
analysis, single 318
single 317
Nucleus 295
Numerous growth factors 263
O
Obesity 207
Obstructive azoospermia 124, 127, 130, 135
sperm retrieval in 137
OFNA See Open fine needle aspiration
OHSS See Ovarian hyperstimulation syndrome
Olatile organic compounds 258
Oligoasthenozoospermia 132
Oligospermia 215
idiopathic 129
severe 115, 122
Oligozoospermia 122, 123, 125, 304, 350
severe 122, 123, 127, 231
Omnipotent cells 247
Oncology-related chemoradiotherapy 225
Oocyte 116, 122, 215, 220, 265t, 273, 274, 278f, 279f, 295, 327, 349
activation 349
procedures 349
assessment, method for 273
cryopreservation of 118, 216, 283, 303
cumulus complex 350
degeneration 278
deteriorates 304
development 360
donation 226, 230, 304, 312
programs 118
donor 19
based study 68
complete safety for 19
complications of 230t
screening of 226
selection of 226
dual stimulation for 55
elongated 279, 280f
heterozygous primary 316
in vitro maturation of 322
intermediate 274
mammalian mature 349
maturation of 323, 324
physiology of 323
steps of 324f
trigger 182
mature 274, 337
cellular 275f
nuclear 275f
maturity 281
assessment 281
morphological assessment of 274t
normal 279f
number of 285
oval 279
pick-up 53
postmature 275
proteome 281
purpose for cryopreservation of 304
quality 273, 284
and markers 273
recipient, evaluation of partner of 227
recovered, proportion of 257
retrieval 45, 77, 142, 146, 149, 236, 267, 326
procedure 103f
retrieved, number of 42
secondary 273
stage 322
viability of 281
vitrification of 41, 226
with refractile body 278f
with smooth endoplasmic reticulum 277f
with vacuoles 277f
yield group 40
Oogenesis 350
Oogonial stem cells 215
Oolemma 274, 290
Oophorectomy, cases of bilateral 73
Ooplasm 274
abnormal-shaped 280
cresent 280
plays 357
transfer 357
uneven 280
Ooplasmic transfer 356, 357f
advantage 357
limitations 357
procedure 357
Open fine needle aspiration 136
Operative sperm retrieval
complications of 138
indications for 135
techniques for 136t
Optimum endometrial thickness 148
Optimum endometrium 94
development of 91
OPU See Oocyte pick-up
Oral antagonist 54
Oral antiestrogen 132
Oral clomiphene, effectiveness of 45
Oral contraceptive pill 5, 18, 31, 189
Oral estrogen 94
Oral progesterone tablets 78
Orphan drug designation 248
Osmolality 256, 261
Osmotic effect 299
Ovaprime treatment 35
Ovarian abscess, risk of 193
Ovarian and testicular tissue preservation 304
Ovarian antibodies 28
Ovarian area 147
Ovarian biomarkers 25
Ovarian cancer cell coculture 268
Ovarian cortex
cryopreservation 218
vitrification of 330
Ovarian cysts 172
Ovarian drilling 177
Ovarian dysfunction 225
Ovarian effects 214
Ovarian endometrioma 26, 191
management of 190
recurrent 189
Ovarian endometriosis, presence of 26
Ovarian failure, incidence of 27
Ovarian follicle 266
pool 218
Ovarian follicular development 145
Ovarian function 218
endocrine regulation of 3
impairment 191
normal 225
restoration of 220
Ovarian hyperandrogenism 147
Ovarian hyperstimulation 1
principle of controlled 56
rates 182
role of adjuvants in controlled 60
Ovarian hyperstimulation syndrome 65, 66, 73, 92, 108, 117, 146, 230, 322
classification 66, 184
clinical features 71
etiopathogenesis of 183
incidence of 40
investigations 71
management 71
pathophysiology 65
prevention of 68, 184, 227
primary risk factors 67
risk of 216
severe 61
treatment 72
Ovarian injury 330
Ovarian insufficiency
fourth stage of 51
primary 24
second stage of 51
third stage of 51
Ovarian oophoritis 219
Ovarian pedicles 238
Ovarian protection 215
Ovarian rejuvenation 250
Ovarian reserve 28
determination of 1
normal 40
screening tests of 30t
test 28, 30
abnormal 24
Ovarian resistance syndrome 225
Ovarian response 25, 30, 46
identification of 17
prediction of 16
Ovarian sensitivity index 285
Ovarian stimulation 21, 47, 100, 148, 216, 283, 284
concept of 54
intensity 286
mild 18, 80
monitoring 142
course of 148
regimen 284
Ovarian stromal
blood 152
flow 152f
Ovarian surgery 26
Ovarian tissue
banking 218
cryopreservation of 216, 217
transplantation 218
Ovarian tumors, benign 219
Ovarian volume 30
Ovary 215
enlarged 67, 71
evaluation of 142, 146
functioning 229
hyperstimulated 184f
preservation 218
Overstimulation 48
Oviduct's fluid 345
Oviduct's lumen 268
Ovulation 17
induction 181
gonadotropin dose for 153t
signs of 148
Ovulatory disorders 114, 116
Ovum pick-up 79, 256
Oxidative stress 126
effects of 62f
P
Pain, abdominal 71
Paracentesis 185
Paracetamol 72
Paraovarian cysts 148
Partial thromboplastin time 205
PB See Polar body
PCOS See Polycystic ovarian syndrome
Peak systolic velocity 156
Pelvic
adhesions 26
arteriovenous 330
cavity 218
infection 26
peritoneum and tubes, evaluation of 142
Pemphigus vulgaris 219
Penicillin, antibacterial effect of 262
Pentoxifylline 62, 90, 96
Peptidoglycan, synthesis of 262
Percutaneous epididymal sperm aspiration 122, 136
Percutaneous sperm aspiration 135
Perfusion system, operation in 340
Pericardial effusion 71
Perifollicular vascularity 153f
Perifollicular vessel 153
Peripheral blood
B cells 28
lymphocytes 122
Peripheral granulosa cells 101
Peritonitis 71
Perivitelline
debris 279f
space 278
Permanent azoospermia 215
Peroxide, formation of 263
Persistent postoperative pain 139
PESA See Percutaneous epididymal sperm aspiration
PGD See Preimplantation genetics diagnosis
PGS See Preimplantation genetic screening
Phenol red 262
Phenylalanine 262
Phenylpropanolamine 134
Phosphodiesterases 323
Phospholipids 205
Pituitary
adenoma 131
downregulation 6, 151
insufficiency, treatment of men with 131
Placenta abruption 10
Placenta previa 10, 109, 117
Placental abruption 117
Placental insufficiency 205
Placental protein 89
Plasma 129
leukocytes 292
rich protein 35
Plasminogen activator inhibitor 203
Platelet
activating factor 343
derived growth factor 245, 247
rich plasma 97, 162, 245, 247t
constitution of 246f
Pluripotent stem cells 220, 247, 248
POC See Products of conception
Polar body 274, 278, 325
biopsy 314, 316
extrusion 327
Poly spermia, prevent 337
Polycystic ovarian syndrome 2, 16, 19, 48, 58, 86, 95, 101, 108, 147, 181, 183, 204, 285, 312, 322, 329t, 330
and infertility, laparoscopy for 177
management of 181
symptoms of 17
Polycystic ovary 108, 147, 172
morphology 181
Polydimethylsiloxane 335, 336, 338, 339f
Polyethylene glycol methacrylate 336
Polymerase chain reaction 163, 358
Polyploidy 121
Polysomy 121
Poor antral follicle count 204
Poor ovarian
capacity 116
reserve 43, 50, 52
responders 31
etiopathology of 25
management of 31
Postacrosoma lamina 295
Postmature oocyte
cellular 276f
nuclear 276f
Postpartum hemorrhage 232
Potassium, concentration of 263
Pouch of Douglas 175, 237
PPH See Postpartum hemorrhage
Preantral follicles, grafting of 219
Pre-conceptional folic acid supplementation 61
Precycle oral contraceptive pills 31
Pre-eclampsia 117
incidence of 73
severe 205
Pregnancy
and live birth rates 1
delaying 304
induced hypertension 108, 205
loss 111, 205
early 108
unexplained recurrent 80
rate 54, 173, 217
improved 110
ongoing 312
with egg donation program 230
Preimplantation development 265
Preimplantation embryo development 264
Preimplantation genetic
diagnosis 117, 123, 208, 233, 277, 314, 316, 355
history of 315
technology 315
screening 11, 34, 46, 110, 114, 117, 208, 210, 248, 314, 355
use of 226
testing 314, 315
indications for 315
Premature luteinization 11
Premature luteinizing hormone 32, 188
avoidance of 61
Premature ovarian
failure 27, 214
types of 250
insufficiency 28, 219
Premature ovulation 6
Premature progesterone rise 109
Preprepared pellet 292
Preterm birth, lower risk of 10
Preterm delivery 162
Preterm labor 111
Pretrigger 68
Primordial germ cells 1
Products of conception 208
Progesterone 4, 77, 91, 94, 100, 101
addition of 94
administration 102
amount of 156
duration 97
effect on 4
facilitate 85
level drops 52
production
adequate 157
continues 52
receptor 92t
isoform 86
supplementation 78, 102, 103
supraphysiologic levels of 108
with endometrial protein 89
Progestin, use of 44
Progynova 327
Prolactin receptors 131
Proline 262
Pronuclear transfer 356, 357, 358f
advantages 358
limitations 358
procedure 357
Pronuclei formation, female 349
Prophylactic anti-coagulation 72
Prostaglandins 89
Protein 281
analysis of 73
C, deficiency of 206
metabolism 265
S, deficiency of 206
Prothrombin gene mutation 203
Proximal tubal occlusion, causes of 172t
Pseudoephedrine 134
Pseudoperitoneal cysts 148
PSV See Peak systolic velocity
Pulmonary embolism 71
Pulmonary problem, severe 178
Pulsatility index 88
Pyruvate concentration 265
Q
Quality management 255
level of 255
system 255, 259
R
Rabau's classification 66t
Radical hysterectomy, laparoscopic 243
Radiotherapy 27
doses of 215
effect of 215
Randomized control trial 92, 111, 312
Reactive oxygen species 292, 294b, 296, 297
Reanastomosis 238
Recipient, evaluation of 226
Recipient's cervicovesical fascia 243
Reciprocal translocations 123
Recombinant follicle-stimulating hormone 34, 323
Recurrent miscarriage 202
causes of 203b
etiology of 204f
initial evaluation of 208fc
Recurrent pregnancy loss 77, 202, 208, 208fc, 225
abnormal tests in 210t
causes of 61
etiology 202
hormonal causes 209
incidence 202
prognosis of 212f
treatment 209
Red blood cell 246, 251, 297
Regenerative medicine 245, 252
application of 250t
in infertility 245
application of 249
Remote embryo transfer 48
Renal agenesis, unilateral 124
Renal anomalies, unilateral 124
Renal disease, chronic 203
Reproductive cells 303
Reproductive physiology, female 356
Reproductive system 121
disorders, severe 245
Reproductive technique, marvel of 231
Reproductive tourism 233
Reproductive tract, female 265
Resectoscope 162
Reserve ovary, normal 146
Resveratrol 31
Retrieve testicular sperm 138
Retrieved oocytes 285
increases 285
number of 285
Retrieving immature oocytes 330
Retroperitoneal dissection 239
Rhesus sensitization 231
severe 203
Rheumatoid arthritis 219
Rizk and Aboulghar's classification 67t
Robertsonian translocation 123, 318
ROS See Reactive oxygen species
S
Saline infusion hysterography 160
Salpingitis isthmica nodosa 173
Salpingo-ovariolysis, laparoscopic 175
Salpingoscopy grade 173, 173f, 174f
Sarcoidosis 131
Scanty body hair 122
Scrotal fungal dermatitis, chronic 134
Secretory phase assessment 156
Selectins 88, 91
Selective estrogen receptor modulators 132
Semen 304
analysis 122, 290, 291
cryopreservation 221
culture 290
donors 303
factors 203
processing techniques, number of 297
purpose for cryopreservation of 303
quality, improvement of 251
sample 294
by masturbation 115
Seminal plasma 133
Seminiferous tubule 134, 137
dysgenesis 122
single 137
Septal metroplasty abortions 162
Sequential media 265
Serine 262
Sertoli cell 129, 131
only syndrome 123, 215
Serum
anti-Müllerian hormone 325
electrolyte concentrations 72
protein 263
proteomic analysis of 68
testosterone 131
levels 131
thyroid-stimulating hormone 209
Sex autosomal abnormalities 123
Sex cells 121
Sex chromosomal abnormalities 123
Sex chromosome 121
Sex couples 225
Sexual development, disorder of 123
Sexual dysfunction 115
Sexual problems 121
Shorter follicular phase 51
Sickle cell anemia 219
Sildenafil citrate 90
Silica particles, colloidal suspension of 294
Silicone 335
Simple wash method 292
Skeletonization 237
Slice technique 177
Slow freezing 103, 304, 305
Social freezing 110
Somatic cells 121
Sonographic monitoring 93
SOP See Standard operating procedure
Sperm 139, 295, 304, 349
aneuploidies 203
anomalies 129
banks 118
cases of high 295
chemotaxis 345
concentration 130
containing tubules 137
donation 225, 231
donors, selection of 231
dysfunction 133
function, integrity of 290
injection, selected 129
morphology 295
nucleus 349
parameters 133
plasma 294
production, difficulty in 118
recovered, pregnancy with 135
stays, normal 115
wash 292
Sperm cell 290, 294, 295
concentration 290
nonviable 292
Sperm count
absent 116
low 116
Sperm DNA fragmentation 198, 291
assisted laser hatching 198
embryo transfer 198
empirical therapies 199
preimplantation genetic diagnosis 198
thin endometrium 199
Sperm motility 126, 295, 297
defects and testing, genetic basis of 126
postpreparation 257
Sperm preparation 266, 267, 297t
techniques 293f
Sperm retrieval 127, 138, 139
method 137
predictors of 139
techniques 135
advances in 135
Sperm selection 296, 296f
methods 292
optimizing 290
Sperm separation
device 338f
techniques 292
Spermatogenesis 121, 123, 133
impairment 125
Spermatogenic cell injection 350
Spermatozoa 198, 220, 292, 295, 357
purpose for cryopreservation of 303
Spherical oocytes 280
Sphingosine-1-phosphate 215
Spindle transfer 356, 358, 358f
limitations 359
procedure 359
Spontaneous conception 54
Spontaneous miscarriage 202
recurrent 202
Spontaneous pregnancies 220
Sporadic miscarriage 202
Standard operating procedure 256
Stem cell 247, 248, 252
artificial gametes from 220
characteristics of 247
current status of 252
derived oocytes 252
for male gametes 252
potential
advantages of 248t
disadvantages of 248t
replacement 248
strategies for transplantation of 249
therapy 35, 97
Sterile inflammatory response 209
Steroid
hormones 129
resistant 219
Stimulate sperm motility 295
Stimulated cycles 41, 95, 100
Stimulated frozen embryo transfer 95f
Stimulates calcium ions 349
Stimulation protocol
mild 44, 90
minimal 33
Stimulation
mild 44, 45
number of 44
treatment with minimum-dose 43
Stromal blood flows 152
Stromal hypertrophy 147
Structural chromosomal abnormalities 123
Subchorionic hemorrhage 211
Subcutaneous progesterone injection 78
Subendometrial blood flow 93f, 155
Subendometrial embryo delivery 170
Submucous fibroid 165f
classification of 145
Submucous myoma 145f
indenting cavity 145f
Suboptimal spermatogenesis 130
Subsequent fertilization 118
Substantial mutations 356
Superovulation strategies 182
Supraphysiological estradiol levels 217
Surgical sperm extraction, optimizing 134
Surrogacy 225, 231
arrangement 231
current status of 231
gestational 231
indications of 119, 232, 232t
steps in 232
Surrogate
counseling for 232
screening for 232
Syphilis, serologic test for 227
Systematic diseases 131
Systemic disorders 126
Systemic infections like syphilis 203, 206
Systemic lupus erythematosus 205, 219
Systemic sclerosis 205
T
Tacrolimus 240
levels, measuring of 240
Tamoxifen 131, 132
TEFNA See Testicular fine needle aspiration
Termination of pregnancy 314
Testes, restore functions of 251
Testicular biopsy sample 118
Testicular damage 219
Testicular failure 118
primary 130, 139
Testicular fine needle aspiration 136
Testicular infection 138
Testicular sperm
aspiration 136
extraction 136
use of 138, 297
Testicular tissue 221
cryopreservation 221
Testis 135
fibrotic 138
Testosterone 61, 126, 131
intratesticular 130
monotherapy 131
peripheral metabolism of 132
synthesis of 129
therapy 131
Theca cells 324
Theophylline's action 295
Theoretical oocyte retrieval 103
Therapeutic donor insemination 231
Third-party reproduction 118, 225
Threonine 262
Thrombophilia 196, 206
inherited 203
Thrombophilic conditions 197
Thromboprophylaxis 73
Thyroid
dysfunction 207, 209
enlargement 207
stimulating hormone 210
Time-lapse technology 307
Tissue
extraembryonic 316
in humans 303
in situ generation of 248
T-lymphocyte 28
Toluene 264
TOR See Theoretical oocyte retrieval
Totipotent cells 247
Toxoplasmosis 203
Transdermal estrogen group 94
Transdermal ring 94
Transferred embryos, number of 44
Transforming growth factor 97, 245, 247, 267
Transmitting genetic disorders 314
Transvaginal aspiration 117
Transvaginal ring 94
Transvaginal sonography 94, 154
with color Doppler, three-dimensional 160
Transvaginal ultrasonography 30
guided oocyte 53
Transvaginal ultrasound 116, 142, 207
Tricarboxylic acid, metabolism of 356
Trophectoderm cells 316
Tryptophan 262
TSH See Thyroid-stimulating hormone
Tubal cells 343
Tubal infertility 172
Tubal pathology 114
Tubal sterilization reversal 173
Tubal surgery, types of 172
Tuberculosis endometritis 163
Tubo-cornual anastomosis 173
Tyrode's solution 315
Tyrosine kinase receptors 66
U
Ubiquinol 133
Ultrasonography, aspiration with 190
Ultrasound 142
guided procedures 149
role of 87
Undescended testes 125
Uneven ooplasm 280f
Ureter, left 237
Urinary
follicle stimulating hormone 57
meatus 130
menotropins 57
retention 178
tract infection 178
Uterine anomalies 205
classification of 144f
Uterine artery 87, 239f
Doppler 88f
embolization 26, 27
flow, color Doppler for 240
high resistance 156f
impedance 87
resistive index 87
Uterine cavity 160
small tubular 205
Uterine cells 343
Uterine contractions 149
Uterine effect 215
Uterine embryo asynchrony 11
Uterine growth starts 215
Uterine morphology 143
Uterine pathologies, acquired 197
Uterine sarcoma 161
Uterine secretions 89
Uterine septum 208
Uterine transplant 239f
surgery 237
Uterocervical length 148
Uterosacral cuff 238
Uterosacral ligaments 240
Uterus 266
congenital absence of 119
didelphys 143f
evaluation of 142
harvested 238
heterogeneous 145
retrieval 241
septate 143f, 203
T-shaped 143f, 203
unicornuate 143f
Utrogestan 8
V
Vacuoles 277
Vaginal administration 8
Vaginal and intramuscular routes 94
Vaginal gel 78
Vaginal pessary 78
Vaginal progesterone 94
preparations 78
Vaginal sildenafil 62, 96, 109
Vaginal suture 240
Vaginal ultrasound 250
Vaginosis, bacterial 203
Valine 262
Varicocele 126
Varicocelectomy 126
Vas aplasia 135
Vas deferens, congenital absence of 231
Vasa deferentia 131
Vascular clamps 238
Vascular endothelial growth factor 5, 91, 189, 245, 247
expression of 65
Vascular injury 178
Vascularization flow index 152
Vasectomy 231
Venereal disease research laboratory 232
Venous thromboembolism 40
Vero cell 268, 343
Very low serum progesterone levels 109
Vessels, reanastomosis of 239f
Vitamin 61, 263
D
deficiency 210
levels, correction of low 210
E 90
Vitrification 305
efficacy of 302
Vitrolife 307
VOC See Volatile organic compound
Volatile organic compound 256
Volume expanders 70
Vomiting 71
Vulsellum 243
W
Weeping peritoneum 178
White cells 292
Window of implantation 10, 85, 91
WOI See Window of implantation
Woman's own egg precursor cells 35
World Health Organization 181
Wound infection 178
X
X-sperm 295
Xylene 264
Y
Y chromosomal abnormalities 203
Y chromosome 130, 139
microdeletions 123, 127
testing 122
Yolk sac 211
large 211
Z
Zinc 133
Zona pellucida 118, 161, 274, 278, 315, 350
Zygote 122, 247, 358
development of 262
freezing
advantages of 304
disadvantages of 304
intrafallopian transfer 114, 199
purpose for cryopreservation of 304
to blastocyst, assessment from 311
Zygotic transition, maternal to 267, 343
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Controlled Ovarian Hyperstimulation for IVF Embryo Transfer and its Influence on OutcomesChapter 1

Manchi Bharucha,
Faram E Irani
 
INTRODUCTION
Several million oocytes are residing in each ovary at mid-gestation. Let us look at the journey of primordial follicles from conception to birth and until menopause and thereafter. The resting primordial follicles are initiated in the fetus and some 100–2,000 primordial germ cells enter the massive proliferation process that results in about 70 million potential oocytes at mid-gestation and about 85% of these oocytes are lost before birth. The decline in number of follicles continues throughout the woman's reproductive life and reaching negligible level at menopause, resulting in impaired quality of life, thereafter. The life expectancy of 48.3 years in 1900 has now increased to 80 years or beyond in 2000 due to various advancements in improved healthcare, both in diagnosis and treatment areas. In this chapter, we shall deal with some of these developments in the area of reproduction. In our view, the two major areas are: (1) Young women suffering from cancer being able to produce their own genetic children after treatment and (2) Women being able to postpone menopause by 5–10 years and lead better quality of life through ovarian tissue freezing and reimplantation at convenience.
 
RECENT ADVANCEMENTS
During the last decade or so, highly significant advances aimed at optimizing results, both on clinical and laboratory sides, with the approach of individualizing diagnosis and treatment rather than adopting “one size fits all” approach, have taken place. This patient-centric approach, aided by advancements in imaging techniques, has satisfied increasing patient requirements and challenging scenario to the clinician and embryologist alike resulting in enhanced patient satisfaction, perhaps with reduced cost in some. Notable advancements have been made in the areas of determining ovarian reserve prior to treatment cycle, reducing length of treatment cycle with enhanced safety and neither under nor over response, greater dependence on laparoscopic intervention for treatment of common ailments associated with infertility like uterine leiomyomas, pelvic and ovarian endometriosis, increasing demand for preimplantation genetic screening, especially beneficial to women of advanced age, women with history of recurrent implantation failure with in vitro fertilization (IVF), women experiencing repeated early pregnancy loss and last but not the least, cryofreezing techniques resulting in higher pregnancy and live birth rates (LBRs) and found beneficial to young women suffering from pelvic cancer desiring future pregnancies with their own genetic children.
In this chapter, we shall deal with selected few developments, viz. determination of ovarian reserve prior to treatment cycle for IVF, refinements in stimulation for optimal mature oocyte recovery, adoption of single embryo transfer (SET) to avoid multiple pregnancy and consequent perinatal morbidity, adoption of freeze all strategy and policy for attaining higher pregnancy rates without complications like ovarian hyperstimulation syndrome (OHSS).
 
Determination of Ovarian Reserve
The ovarian reserve is typically referred to as population of primordial follicles. The model devised by Wallace and Kelsey in 2010 allows estimation of primordial follicles at any age of a woman. In practice, we find three types of 2response in women undergoing treatment for IVF-ET. They are normal response, poor response, and hyper response. Anticipation of the right response helps devising the most appropriate strategy in terms of the gonadotropin selection and its dosage for maximizing mature oocyte recovery (MII oocytes) with safety from complications and avoidance of suboptimal or poor response. It should be noted that maximum mature oocyte recovery has direct relationship with prospect of pregnancy. Earlier, determination of ovarian reserve used to be on determination of basal follicle stimulating hormone (FSH). However, it was soon realized after multiple studies that the sensitivity and positive predictive value of FSH was far from satisfactory and least reliable for prediction of right type of response. A potential, highly sensitive, and far more reliable is the anti-Müllerian hormone (AMH) or Müllerian inhibitory substance (MIS) test.
 
Estimation of AMH
Anti-Müllerian hormone is a dimeric glycoprotein belonging to the family of transforming growth factor-beta (TGF-β). AMH is involved in regression of Müllerian ducts during male fetal development and is expressed in Sertoli cells from testicular differentiation up to puberty. In females, it is exclusively produced in granulosa cells from birth to menopause. AMH production starts once the primordial follicles have differentiated to primary stage and it continues until the follicles have reached the antral stage corresponding to diameter of 2–6 mm. The number of small antral follicles is related to the size of the primordial follicle pool and with decrease in number of antral follicles with age, AMH production appears to get diminished and it invariably becomes undetectable at and after menopause. There is increasing accumulated evidence demonstrating usefulness of AMH as a cycle-independent biomarker of ovarian reserve which is in contrast to FSH, serum estradiol (E2), and inhibin B. In women, serum AMH expression can first be observed in granulosa cells of primary follicles and the expression is strongest in preantral and small antral follicles. Expression of AMH disappears in follicles of increasing size and is almost lost in follicles of >8 mm. Another advantage is AMH can be measured at any stage of the menstrual cycle, though recent evidence suggests that AMH attains its peak on Day 7 corresponding to 4–5 days before ovulation of idealized cycle of 28 days. Another observation made is the predictive power of AMH for poor response to controlled ovarian hyperstimulation (COH) and is comparable to that of AFC, another useful biomarker to be dealt with later. AFC is cycle specific and it can concomitantly predict high and low or poor responders. In one study, a strong association was found between mid-luteal, early follicular, and pre-ovulatory AMH levels and number of oocytes retrieved. It was concluded by the authors that mid-luteal and early follicular AMH levels could offer good prognostic value for prediction of clinical pregnancy. The cutoff value observed for prediction of pregnancy in this study was 2.7 ng/mL.
A number of other studies have advocated the level of AMH at below 1 ng/mL for prediction of poor response and even lower chances of pregnancy. Further, as per one study, AMH levels have been shown to be independently associated with occurrence of miscarriage. Higher AMH levels (5.61–35.00 ng/mL) have also been shown to be associated with lowest miscarriage rates and lowest AMH levels (0.08–1.60 ng/mL) with lowest response to COH and negligible chance of pregnancy, regardless of age of women. Overall, it appears from this study and other studies that AMH is not only a useful biomarker quantitatively but also qualitatively, including oocyte/embryo competence. In fact, diminished ovarian reserve has been found to be a cause of recurrent miscarriage defined as 3–4 failed clinical pregnancies of <20 weeks of gestational or fetal weight of <500 g.
Polycystic ovarian syndrome (PCOS) is known to be associated with raised levels of AMH at >4 ng/mL and high AFC.
 
Estimation of Antral Follicle Count
Ovarian reserve can also be estimated by transvaginal ultrasound by counting number of antral follicles in both the ovaries. AFC consists of counting antral follicles of 2–8 mm. Both AMH and AFC reflect the age-dependent decline in ovarian function. The difference between the two is, whereas AMH indicates ovarian reserve in general, AFC is more cycle specific as it could differ in each cycle. To elaborate further, AMH can be the same in the age range of 10 years in different women, but AFC can be different amongst them and that too different in each cycle in each woman. Hence AFC is more dependable for response in a particular treatment cycle. It should be noted that AFC must be measured in the treatment cycle only on any day from Day 2 to Day 4 and not in the cycle of evaluation or downregulated cycle. AMH has been shown to be a weak marker of pregnancy, but AMH and AFC combined together may indicate higher chance of pregnancy. AMH of <1 ng/mL and/or AFC of <8 has been shown to indicate low response to stimulation suggesting aggressive approach to stimulation in terms of higher doses of gonadotropins and perhaps longer duration of stimulation in some. There is consistent biological evidence suggesting detrimental effect 3of endometrioma and even stripping during surgery, on ovarian reserve resulting from reduced AFC. In cases where the endometriotic or any other functional cyst, unilateral or bilateral, AMH reading becomes debatable, in which case AFC would be the only dependable marker of ovarian reserve. There is high evidence in the literature validating the use of AFC as a surrogate marker of ovarian reserve. However, based on currently accepted recommendations, AFC assessment in women with ovarian endometriosis or in women having undergone previously ovarian surgery has been questioned. Hence, ovarian responsiveness to COH is actually considered the best noninvasive surrogate marker of ovarian reserve in these women.
Conclusively, it can be said and believed that the predictive power of AMH for live birth is higher than that of AFC with the predictive error of 1% to <5% with AMH, both being regarded independent of age. Further, it has been suggested that antral follicles of 5–8 mm size make greatest contribution to AMH levels compared to follicles of 2–6 mm size, providing the most accurate estimate of ovarian response.
 
Controlled Ovarian Hyperstimulation
Since the birth of Louise Brown 39 years before, IVF centers worldwide have been utilizing COH to enhance oocyte recovery to maximize development of good quality viable embryos for transfer to optimize chances of pregnancy. Care is taken in devising the protocol that no woman is excessively stimulated to avoid OHSS and at the same time she is not understimulated to avoid low or poor response. This dual objective calls for individualized patient tailored strategy in devising stimulation. The physician, today, is required to consider a number of parameters, partly based on findings of determination of ovarian reserve, and others like age, BMI, cause and duration of infertility, other existing comorbid illnesses, menstrual irregularity, etc. Care should be taken to see that duration of stimulation is not too long as too long a stimulation could compromise the result. Equal care needs to be taken for choosing single or combination of gonadotropins considering age, BMI, and ovarian reserve. Dyssynchronous growth of follicles is a known phenomenon and this is avoidable by the use of FSH and luteinizing hormone (LH) together right from the start and so also chance of poor response. Minimum possible dosage is used, avoiding chance of over response. Before starting stimulation, uterine status must be evaluated by transvaginal ultrasonography, 3D or 4D, and if necessary, by hysteroscopy. History and findings of sonography should be carefully weighed to rule out need for surgical intervention prior to IVF in case of common illness like uterine leiomyoma, pelvic endometriosis, etc.
Controlled ovarian hyperstimulation is considered to be a key factor for success of IVF, enabling recruitment of multiple dominant follicles to realize maximum mature oocyte recovery. The current standard of care is to use combination of FSH and LH as either human menopausal gonadotropin (hMG) or combination of rFSH and rLH in suitable dosages and to avoid single gonadotropin like FSH alone for reasons to be cited later.
 
ENDOCRINE REGULATION OF OVARIAN FUNCTION AND FOLLICULOGENESIS
Folliculogenesis is the result of complex and closely integrated series of events which start soon after conception and end about five decades later with menopause. The ovulatory menstrual cycle is the final result of these processes and it relies upon a complex series of physiological mechanisms that link the hypothalamus, the pituitary gland, and the ovary. Although gonadotropins are the key drivers of the menstrual cycle, other compounds such as ovarian steroids and inhibins critically affect and modulate hypothalamic and pituitary hormone selection as well as local gonadal function. Further, folliculogenesis and oocyte maturation depend upon an integration of cellular and endocrine mechanisms which are only in part under gonadotropin control. Much of the germ cell maturation occurs during intrauterine life (Adashi, 1996). These germ cells undergo mitosis and achieve their peak number (6–7 million) by mid-gestation; thereafter, due to initiation of meiosis and follicular atresia, the number of female germ cells drastically declines, so that about 300,000 oocytes are present at puberty.
Gonadotropin levels are low in the prepubertal period, but during fetal life, gonadotropin stimulation may be relevant even in these early stages of development (Gulyas et al., 1977). After attaining antral stage, FSH plays only permissive role in follicular development and ovarian follicles grow slowly. At the recruitable stage which begins in the luteal phase of the cycle, preceding ovulation, follicles can be stimulated by FSH to grow rapidly and enlarge beyond 2 mm diameter. The selective rise of FSH that occurs during luteal-follicular transition is a potent stimulus for follicle recruitment and several early antral follicles respond by beginning to enlarge. Endogenous and exogenous gonadotropins can now exert their full traditional stimulating effects and follicular growth becomes rapid.4
Luteinizing hormone is also critically involved in the physiological events that lead to development of reproductively competent preovulatory follicle. LH is capable of stimulating androgen substrate from theca cells in fetal life, as attested by the elevated steroid levels found in female neonates (Winter et al., 1995). This modular action of gonadotropins has been named “two-cell two-gonadotropin model” (Dorrington and Armstrong, 1979). Estrogens in turn play fundamental role through improving follicle and oocyte maturity, in priming the hypothalamus-pituitary unit in preparation for the preovulatory gonadotropin surge as well as inducing the morphological uterine and endometrial changes needed for embryo implantation. Finally, LH-follicle intersections disrupt theca cell contacts in the cumulus and induce oocyte meiotic maturation to cause follicular rupture (Espey, 1974; Lawrence et al., 1980) and induce granulosa cell luteinization (Brailly et al., 1981).
In the course of follicular phase, FSH stimulates granulosa cells to express LH receptors and this action is facilitated by estrogens (Rani et al., 1981). Thus, in the late stages of follicular development, once antral follicle diameter increases beyond 10 mm, LH receptors are expressed by granulosa cells which become receptive to LH stimulation. LH then is capable of exerting its actions on both granulosa and theca cells (Hillier, 1994). At this stage, LH can exert virtually all physiological actions of FSH on granulosa cells, including stimulation of aromatase system (Zeleznik and Hillier, 1984). Serum FSH levels are reduced during most of the luteal phase, beginning to increase only a few days before menses, and are elevated throughout luteal–follicular transition. FSH thus progressively declines across the follicular phase until the mid-cycle surge is triggered by rising estrogen and progesterone concentrations.
Thus, it is evident that physiological follicular growth and maturation is dependent upon the dynamic interplay between FSH and LH, key physiological events such as follicular recruitment and dominant follicle selection rely upon both the prevalence of FSH and LH activity.
 
Selective LH activity in Controlled Ovarian Hyperstimulation
Selective LH activity administration in the mid and late stages of ovulation induction, both in COH and anovulatory patients has been demonstrated. Low dose of 75 IU/day of rLH administration, after at least one 14 mm follicle development, has impact on oocyte yield and pregnancy rates in assisted reproductive technology (ART) (Ben-AMOL, 2000). Available data suggests that LH activity can be used to improve and optimize FSH stimulation for COH. LH activity during ovulation induction also causes noticeable and significant modifications in ovarian response. The addition of LH to the FSH therapy during COH consistently and significantly shortens the duration of treatment and reduces the amount of FSH required for final oocyte maturation [Filicori et al., (1999b, 2001)], especially toward the end. Gonadotropin releasing hormone (GnRH) analog type, formulation, and route of administration can undoubtedly contribute to results, when both FSH and LH preparations, individually or in combined form as hMG, are used. GnRH antagonist when started from Day 6 of stimulation or when lead follicle attains 12–14 mm size is known to synergize with exogenous FSH and provide adequate follicle stimulation. In the short flare-up protocol of GnRH agonists (GnRHa), supported by hMG, endogenous FSH and LH are elevated for the first 3 days of administration and thereafter endogenous LH secretion is maintained till the day of trigger. Intranasal administration of GnRHa is associated with low absorption (about 3%) rate and less profound suppression of FSH and LH (Filicori, 1994). In the long mid-luteal suppression protocol, where GnRHa is administered from mid-luteal phase of the previous cycle, downregulation is achieved in about 10–20 days of administration and then switched over to stimulation by hMG or rFSH + rLH till the day of trigger. It is also recognized that during highly purified hMG (HP hMG) administration, estradiol level rise is brisk as compared to slow rise in case of HP FSH.
 
Effect on Progesterone
Serum levels of progesterone usually remain low during natural cycle or during COH. GnRHa or GnRH antagonist prevents untimely LH surge leading to premature ovulation (Filicori, 1996). Moderate rise of P, around 1.3 ng/mL, is occasionally observed during COH and is equated with premature follicle luteinization (Silverberg et al., 1991; Fanchin et al., 1993). This phenomenon, however, does not affect oocyte or embryo quality (Hofmann et al., 1993a; Legro et al., 1993) but may reduce IVF success through secretory endometrial transformation and impair chance of embryo implantation. Progesterone rise can take place with any preparation like hMG or FSH or rFSH + rLH and in spite of using GnRHa or GnRH antagonist. However, in practice, P rise is observed more often with increased dosage of FSH at the end of stimulation. Hence, it is considered prudent to reduce the dose of FSH and proportionately increase the dose of LH. It is further observed from some studies that if P level on the day of trigger is above 2.5 ng/mL, it is better to avoid fresh transfer and consider frozen embryo transfer (FET) in subsequent natural or modified natural cycle.5
The phenomenon of dyssynchronous follicular growth between both ovaries is well known during the beginning of COH. This is largely due to use of FSH alone, which stimulates unselectively or due to differential uptake of FSH by multitude of follicles. Hence, it is better to start with FSH + LH or hMG, which could provide a means to selectively achieve both large follicles and curtailment of small follicular development (Marco Filicori et al., 2002). In addition to supporting the growth of larger follicles, LH activity appears to exert other important actions on the dynamics of folliculogenesis. In 2001, (Filicori et al., 2001) it was shown that hMG administration leads to progressive decline in number of small follicles (<10 mm) and this was significantly more marked than with HP FSH. This finding was confirmed by significant inverse relationship between the amount of LH administered and the number of small follicles in a study on 120 patients (Filicori et al., 2002a).
Conclusively, therefore administration of rFSH + rLH or hMG promotes synchronized growth of follicles which in turn could help realizing greater yield of mature oocytes. In case of hyper responders, care has to be taken especially in case of younger women. In case of women of advanced age (≥ 35 years) and/or women with high BMI (>29 kg/m2), this procedure may be found equally useful. In women with PCOS, both GnRHa long protocol and fixed protocol of GnRH antagonist can be used. In the case of young lean women with PCOS (BMI < 28 kg/m2 and basal LH >5 mIU/mL), GnRH antagonist in the dose of 0.25 mg/day and FSH 150 or 225 IU from Day 1 of cycle may be preferred, the antagonist continued till the day of trigger. In these patients in whom antagonist is started on Day 1 of cycle, more rapid follicular development and earlier rise in E2 levels can be expected; another advantage being, LH can be suppressed within a matter of hours of starting the antagonist, whereas in case of GnRHa long protocol, suppression takes nearly 2 weeks, not to speak of higher gonadotropin requirement.
Oral contraceptive pill (OCP) pretreatment is used by some physicians for suppression in women with normal basal levels of FSH and LH for not more than 15 days. Women with OCP intake of >15 days are known to consume more gonadotropins and have longer duration of treatment. The antagonist usage is known for much lesser or negligible prevalence of OHSS compared to usage of long GnRHa protocol, both in normal and hyper responders.
 
UNEXPECTED LOW OR POOR RESPONSE IN WOMEN WITH NORMAL BASELINE HORMONAL LEVELS
Adequate follicular development in response to gonadotropic treatment is a prerequisite to successful IVF program. However, many women respond poorly or not at all to the standard COH protocols. Such patients account for 10–25% of IVF population. Some of these patients have age-related decline in their reproductive performance. Also, a low response is one of the most problematic issues in reproductive medicine.
It has been reported that the follicular fluid (FF) secretes multiple autocrine and paracrine factors that affect follicular development (Weng et al., 2006; Choi YS et al., 2006). There is evidence suggesting that ovarian insulin-like growth factor (IGF-II), insulin-like growth factor binding protein 4 (IGFBP4), and pregnancy-associated plasma protein-A (PAPP-A) system plays a major role in follicular development (Keay SD et al., 2003; Choi YS et al., 2006). Thus, FF levels are significantly lower in poor responders. A correlation is also reported between AMH levels in FF and the responsiveness to stimulation (Fallet ME et al., 1997). In addition, other follicular markers like soluble Fas and vascular endothelial growth factors (VEGFs) could be altered in ovarian response to stimulation (Hasyakor D, 2004; Neulan J et al., 2001). Soluble Fas is anti-apoptotic molecule reported to be positively correlated with oocyte maturation (Malamutsi-Puckner A et al., 2004). A negative correlation has also been suggested between VEGF in FF and the number of follicles (Tokuyama O et al., 2002). In one study (Young AG; Koo et al., 2009), multiple follicular development was found associated with higher levels of VEGF expression in FF and the same was observed in unexpected low responders and normal responder patients. Several other studies have also reported that regulation of follicular angiogenesis is important for normal development of follicles (Fauser BCJM, 1997; Schimizu T et al., 2003; Taylor PD et al., 2004).
 
EXPLORING UNCHARTED TERRITORIES IN CONTROLLED OVARIAN HYPERSTIMULATION
There are several situations we come across in practice during COH, considered uncommon, but of practical importance and without knowledge of which, they could become hazardous and/or not cost-effective to implement, though they are evidence-based. Let us deal with them individually.
  • Pretreatment with OCP: OCP is being used by some in antagonist cycle for the dual purpose of suppression and planning the cycle, both for convenience of patient and the physician. A systematic review and meta-analysis conducted revealed no difference in pregnancy rates between patients who used OCP and those who did not. But gonadotropin consumption and duration of treatment cycle were increased significantly after OCP pretreatment (Georg Griesinger et al., 2008).6
  • Importance of LH supplementation: Utilizing beneficial effect of LH activity routinely helps realizing greater yield of mature oocytes and preventing P rise on the day of trigger, thus protecting favorable implantation prospect in fresh ET cycle, as P rise is known to impair implantation by disturbing the window of implantation.
During mid and late follicular phase of natural menstrual cycle, preovulatory follicular development proceeds despite progressive fall in serum FSH level. Studies conducted in women of reproductive age, using rFSH and rLH after downregulation of pituitary in the long protocol with leuprolide acetate (LA) demonstrated that LH sustains follicular E2 production in presence of falling FSH and E2 levels, which were used as index of follicular development (Michael Sullivan et al., 1999). The E2 levels of women receiving LH toward the final stage of stimulation increase throughout despite declining FSH level. It was also observed that thecal androgen production was exquisitely sensitive to LH.
The hypothesis is LH protects the maturing follicles from declining FSH levels. In this study, the FSH treatment was arbitrarily discontinued, when lead follicles reached 14 mm or more in diameter and LH treatment introduced till the end of the cycle. In practical terms it can be stated that when lead follicles reached 14 mm size or so, rFSH dose could be reduced by 75 IU or more depending on size of follicles lagging behind and rLH in the proportionate dose of 75 IU or more introduced and continued till the end of the cycle.
  • Inadequate response to FSH in the beginning of COH is a frequent occurrence: After 5 days of stimulation with FSH alone. This phenomenon is observed in about 12–14% of young normogonadotropic women treated with long mid-luteal GnRHa protocol. In such an event, rLH can be introduced from Day 6 of stimulation in the dose of 75 IU or more, depending upon size of growing follicles on Day 6, which are usually <11 mm in diameter. With this strategy, good response can be expected on Day 8 or Day 9 in terms of increased size of follicles coupled with rising level of E2 and this combination continued till the day of trigger. In one study with this strategy, it was found that LH supplementation was more effective than increasing the dose of FSH in terms of mature oocyte outcome (G De Placido et al., 2005).
There are a number of situations where gonadotropin-deficient women do not respond to FSH alone adequately in the initial stage, and the E2 level on Day 6 of stimulation is lower than expected (<250 pg/mL), the follicles stimulated with FSH alone do not consistently rupture after hCG administration and they luteinize poorly and their oocytes may have lower fertilization rates. In this population of women, addition of rLH from Day 6 of stimulation in the dose of 75 IU/day or 150 IU/day has been shown to be effective to achieve adequate follicular development and steroidogenesis (European rLH study group, 1998).
  • After pituitary downregulation with GnRHa in the long protocol, suppression of endogenous LH is more profound than of FSH. These are young normogonadotropic women in whom, if FSH is used alone, the oocyte yield is not seen to be adequate and their developmental competence is compromised. They develop poorly as zygotes and their embryos show lower implantation rates compared to those in whom rLH was administered along with rFSH during COH. A number of studies have shown higher implantation and pregnancy rates with combined administration of rFSH and rLH for COH (Jan Tesarik and Carman Mendoza, 2002; Westrgard LG et al., 1996).
  • The phenomenon of premature LH surge is known to occur in many women, regardless of age, during COH, it is known to occur even in natural cycle resulting in premature ovulation. This is more commonly encountered in women of advanced age (>35 years). In such women, when GnRHa or GnRH antagonist is used, suppression of LH is seen to be more profound and if FSH is used alone for stimulation, the cycle outcome in terms of oocyte yield becomes suboptimal and consequently number of viable embryos may be less for transfer. Several studies performed to investigate whether the cycle outcome improves if rLH is added to rFSH during initial stage of stimulation. One such study has demonstrated that addition of rLH is essential for oocyte maturation (Mochtiar, 2011). Even in natural cycle, LH is shown to be essential for oocyte maturation (Hillier, 2001). Low LH levels in IVF cycles have been found to be associated with availability of fewer embryos for cryopreservation and transfer (Fleming et al., 1998; Marrs et al., 2004). Bosch et al., 2011, in their study in GnRH antagonist cycles further confirmed this finding and found higher clinical and ongoing pregnancy rates in women of 36–39 years.
  • Faultless completion of meiosis I and II is crucial to chromosomal integrity of oocyte and hence oocyte diploidy (Verlinsky and Kuliev, 1996). If meiosis, a process extremely sensitive to disruption, was to be influenced by the presence or lack of appropriate LH level, LH supplementation in the course of fertility treatment could indeed influence diploidy rates in cleavage stage embryos. It has also been observed that diploid embryos are more likely to implant (Santiago Munne et al., 2005) and hence higher percentage 7of diploid embryos would ultimately lead to higher pregnancy chances. These data have also been confirmed by studies by Lisi et al., 2005, and Anderson et al., 2006, who reported higher pregnancy rates in women receiving LH supplemented stimulation rather than stimulation with FSH alone.
Younger women, especially those with normal ovarian reserve or function, are more likely to have low basal LH level and are therefore at higher risk of profound LH suppression during pituitary downregulation (Flamming et al., 1998). The data on beneficial influence LH supplemented embryo diploidy are particularly evident in women who lack adequate endogenous LH level. This interpretation has been supported by Van Waly et al., 2003a, who reported in younger women, significantly higher clinical pregnancy rates after long agonist protocol for COH, using hMG in comparison to using FSH alone. The likely beneficial effect of hMG stimulation in poor responders has also been supported by Cochrane working group (Van Waly et al., 2003b).
In conclusion, the data presented provides overwhelming evidence that in selected patient population, LH supplemented ovarian stimulation protocols could beneficially affect diploidy rates in preimplantation embryos.
  • Beneficial effect of androgens in COH: In some cases of poor response to FSH alone or rFSH + rLH or hMG, androgenic agents like hCG and testosterone (T) do impart beneficial effect to folliculogenesis in patients who fail to show adequate response to conventional therapy. Even these agents can be straight away incorporated in stimulation protocol in patients with documented or clinical poor response. This alternative can be deployed in all types of cases except in women with PCOS. In this alternative, downregulation is carried out with long mid-luteal GnRHa protocol. Once downregulation is confirmed by clinical and laboratory criteria, testosterone in the form of intradermal patch in the dose of 1.2 mg/day for 5 days is administered followed by hMG or rFSH + rLH in the appropriate doses is given till lead follicles of minimum 17 mm are seen (Lossi et al., 2006). If T patch is not available, hCG in a small dose of 1,250 IU/day could be used at least for 8 days in the same manner.
  • Does growth hormone (GH) has a place in poor responders?: The incidence of poor ovarian response to COH varies from 9% to 24% (Surrey ES et al., 2000).
How do we define poor response?
A consensus study organized by European Society of Human Reproduction and Embryology (ESHRE) 2011 defined poor ovarian response (POR) to include any two of the following three features. They are also referred to as Bologna criteria.
  1. Maternal age (≥ 40 years) or any other risk factor for POR.
  2. Clinical evidence of POR [Three or fewer oocytes with ovulation induction in earlier cycle(s)].
  3. Documented POR by ovarian reserve testing. AMH <0.5–1.1 ng/mL and/or AFC of <8 between both ovaries.
Deficiency of GH causes delay in onset of puberty in addition to growth retardation during childhood. Treatment of these patients with human GH induces sexual maturation (Zachman et al., 2003). These findings suggest that GH influences gonadal function. GH is reported to enhance responsiveness of follicles to gonadotropins leading to stimulation of folliculogenesis in infertile women who fail to respond to exogenous gonadotropins (Burger HG et al., 1991). The action of GH is partly mediated by IGF-1 production from the liver (Homburg R et al., 1996). Both GH and IGF-1 are detected in FF and their receptors are also expressed in the ovary (Givdice LC, 1992; Johnson MC et al., 1996). The role of GH and IGF-1 in follicular development has been examined in humans (Givdice LC, 1992; AdashI EY, 1985).
Growth hormone is also known to influence luteal function, directly or indirectly, to affect P production by luteal cells in vitro (Bergh C et al., 1991).
One of the options to improve the situation of poor response is addition of GH as an adjuvant to other ovulation inducing agents like FSH, LH, etc. (Kucvk T et al., 2008). The efficacy of GH in improving cycle outcome has been controversial till today. A recent, parallel, open-label, randomized study conducted from 2014 to 2016 (Yasmin Ahmed Bassionny, 2016) incorporated GH in antagonist cycles of proven poor responders. The protocol in the study group consisted of hMG 300–450 IU/day from Day 1 or Day 2 of the cycle depending on age and ovarian reserve markers like FSH, AMH, and AFC. GnRH antagonist added when lead follicles were 12–14 mm and GH added from Day 6 of stimulation in the dose of 2.5 mg/day SC, until the day of trigger. Norditropin (Novo Nordisk) 2.5 mg is equivalent to 7.5–8.0 IU/day or 0.1 IU/kg/day. The control group consisted of hMG + antagonist given in the same manner as in the study group patients. The total number of patients was 140 and the results were as below:
  • Duration of treatment in both groups, study group and control group, was 10.77 days and 12.02 days, respectively.
  • Total dose of GT was 3,900 IU and 4,906 IU.
  • E2 on day of trigger was 1,862 and 1,854.
  • Number of MII oocytes was 4.53 and 2.53.8
Reproductive outcomes were as below:
  • Implantation rates were 11.98% and 9.88%.
  • Clinical pregnancy rate/cycle was 22.1% and 15%.
  • Live birth rate was 17.5% and 13.6%.
Several studies to improve results in poor responders have reported increase in number of retrieved and MII oocytes (Kucuk T et al., 2008; Effthekar M et al., 2013; Bergh C et al., 1994). One meta-analysis suggested that GH administration is associated with increased proportion of patients who reach ET stage and are thus exposed to chance of pregnancy (Kolibianaskis EM et al., 2009). This finding, in our view, appears illusory. In another systematic review and meta-analysis, different interventions to improve outcome in poor responders were investigated and two interventions with a favorable impact and increased pregnancy rates were the use of GH and Day 2 transfer (Kyton D et al., 2009). The data provided above shows that GH cotreatment with antagonist results in improved parameters assessed, including LBR, and the differences between study group patients and control group patients did not reach statistical significance. Although these data are encouraging, the use of GH as an adjunct treatment in poor responders should be implemented cautiously till further larger and conclusive systematic studies, reviews, and meta-analysis are available.
Additional useful information on poor responders: In view of increasing prevalence of poor or low response to COH, more and more studies are forthcoming leading to availability of beneficial information on the subject, which are as below:
  • Poor ovarian response is observed more in younger women of <35 years than in women of advance age.
  • Poor ovarian response can be anticipated through determination of ovarian reserve; AMH of <1 ng/mL and/or AFC of <8 is indicative.
  • Ultrashort protocol of GnRHa for first 3 days with added hMG from Day 1 till the day of trigger works well in some women.
  • GnRH antagonist is known not to act in many of these cases in whom AMH is <1 ng/mL and AFC <8. Hence, use of progestogens like medroxyprogesterone acetate (MPA), Utrogestan, and Duphaston have been tried and found successful. In this protocol, Utrogestan 100 mg/day or MPA 10 mg/day or Duphaston 10 mg/day along with hMG 375–450 IU/day are started from Day 1 or Day 2 or Day 3 till the day of trigger.
  • The protocol of double stimulation can be attempted in some. In this protocol, start stimulation with any of aforesaid formulations from Day 1 or Day 2 till follicles of 17–18 mm are seen and proceed with oocyte pickup (OPU) after the trigger. Freeze the embryos and after 3–5 days, assess E2 and P levels and E2, if found at 35 pg/mL or less, and P of up to 2.5 ng/mL, resume stimulation again as earlier, at once and proceed with 2nd OPU, and freeze the additional embryos for transfer of good quality selected embryos in natural or modified natural cycle.
 
NEWER DEVELOPMENTS IN GONADOTROPIN RESEARCH FOR CONTROLLED OVARIAN HYPERSTIMULATION
There are two new drugs in the category of rFSH under clinical trials for stimulation during COH for IVF patients. They are follitropin delta and corifollitropin. Both appear to be promising. Corifollitropin is long acting rFSH with single dose administration from Day 1 having duration of 7 days, after which current rFSH with one dose/day in the aqueous form is to be administered till the day of trigger. Follitropin delta is rFSH, uniquely expressed in fetal retinal cell line, which owing to differences in glycosylation profile, has a lower clearance and induces higher ovarian response than the existing rFSH preparations, when administered in equal doses of biological activity (IU).
Additional useful information on prevention of premature LH surge: The phenomenon of premature LH surge has been known for a number of years, not only in COH but even in natural cycle. It can take place anywhere from early follicular phase to the point where the follicles of 12–14 mm, inducing ovulation before trigger, thus impairing oocyte recovery and culminating into empty follicle syndrome in some cases. It is also known that P inhibits E2-induced positive feedback by reduced GnRH pulse frequency. It has also been seen that GnRH antagonist does not work in some cases where AMH is <1 ng/mL in which case, as per early preliminary studies, both MPA and Utrogestan can be used as they have been validated as effective oral alternatives to GnRH antagonist for prevention of this phenomenon. Didrogestral (Duphaston), a synthetic P, differing from Utrogestan in its molecular structure and pharmacological effects, has also been found useful for this purpose but not to have androgenic effects, even at high doses. Utrogestan, a natural micronized P, is fit for both oral and vaginal administration. Duphaston 20 mg has been found to be equivalent to Utrogestan 200 mg. Both have been found to be effective in preventing premature LH surge in a randomized controlled trial (RCT). In the same study, it was also observed that high doses of progestins could swiftly decrease circulating LH levels and low doses could achieve the same effect by prolonged duration. Such a “dose–time” effect has been 9elucidated in large scale investigations for endometrial transformation or ovulatory inhibition. In another similar study, Utrogestan 100 mg/day was found to be as effective as Utrogestan 200 mg/day in preventing premature LH surge.
Further, it is suggested that for optimal effect of preventing premature LH surge, both Utrogestan and Duphaston must be given simultaneously with hMG or rFSH + rLH from Day 1 of stimulation till the day of trigger. MPA in 10 mg/day dosage is also effective in preventing premature LH surge.
Conclusively, it can be said that for poor responder women in whom GnRH antagonist may not work for the purpose of preventing premature LH surge, we have a choice of three progestins. Besides, oral progestins may be more cost-effective than the antagonist.
 
Application of GnRHa as a Trigger during Controlled Ovarian Hyperstimulation
In the history of IVF over nearly four decades, extraordinary advances have been made by physicians and scientists alike to increase its efficiency and safety. Equally important are the techniques introduced. One such technique is the use of GnRHa as a trigger instead of hCG in the antagonist based protocol to reduce or to avoid the likelihood of OHSS. Initial concerns over altered luteal phase E2 levels in the antagonist cycles with GnRHa as trigger were largely alleviated by administering aggressive luteal support. However, despite its demonstrated efficacy and safety, some clinicians hesitate to use it widely because a small subset of women do not respond with adequate LH rise, which is the obligatory finding or signal for final oocyte maturation. The following information would adequately explain what is the optimal LH rise level desirable for attaining oocyte maturity and what are the factors or reasons why some patients do not adequately respond to GnRHa trigger for oocyte maturity. The contribution made on this subject by Weill Cornell Medical Center, New York and George Washington University, Washington DC has been more than significant. Their study involving 500 fresh IVF cycles over a period of 6 years has suggested the optimal LH level, post-trigger with GnRHa on the day of trigger, required for adequate response and the risk factors present in women not responding adequately to post-GnRHa trigger for oocyte maturity. A number of outcome variables were assessed in this study, viz. suboptimal response to GnRHa trigger in the morning after the trigger, optimal response in the morning after the trigger, age, BMI, trigger type, i.e. single versus double trigger, history of irregular menses or amenorrhea, insignificant basal FSH and LH levels, and OCP pretreatment. The cycle evaluated showed that those patients who had single GnRHa trigger and who exhibited LH level of ≥15–30 mIU/mL had at least eight mature oocytes retrieved with an oocyte maturity rate of 68–100% and had a LBR of 57%. But those who had post-trigger LH of <15 mIU/mL in the morning after trigger, had either three or fewer mature oocytes or had OPU cancelled. Statistical analysis further revealed that suboptimal responders had post-trigger LH of <15 mIU/mL and normal responders, some of them having been given dual GnRHa trigger, had ≥15 mIU. The GnRHa used was LA 2 mg or 4 mg or triptorelin 0.2 mg (decapeptyl). The dual trigger consisted of GnRHa + hCG 1,500 IU immediately after post-trigger LH level was available.
The authors suggested that certain demographic parameters like irregular menses, BMI of < 29 kg/m2, FSH level of <0.1 IU/mL, LH level of <4 mIU/mL on the day of trigger, and OCP intake of >2 weeks, should be regarded as risk factors for optimal response. The authors contend that suboptimal group of patients almost always occurs and advance identification of this group should be guided by the risk factors present, so that precautionary measure like use of double trigger can be taken to avoid cancellation of the cycle. The GnRHa trigger has an added advantage of inducing mid-cycle FSH surge which also contributes to oocyte maturity. It is noteworthy to consider that though LH surge induced by GnRHa trigger effectively secures oocyte maturity, low circulating level of endogenous LH level during early luteal phase could result in corpus luteum demise and poor reproductive outcome, unless the standard luteal phase support is modified and made more aggressive.
 
Luteal Phase Support by GnRH Agonist as a Sole Support in Antagonist Cycles
Luteal phase deficiency is being observed as an unfavorable sequela to OPU in all IVF–intracytoplasmic sperm injection (ICSI) cycles. Therefore luteal support is being offered routinely in all IVF cycles in the form of P or P + E. Administration of a single or multiple boluses of luteal GnRHa has been gaining popularity in recent years as it has been observed to improve pregnancy rates and LBR. The beginning was made in 2004–2005 by Pirard et al., who investigated use of GnRHa as a substitute to P for luteal support. The same authors conducted a feasibility study followed by pilot study in 2006 and in 2015. All the above studies demonstrated efficiency of GnRHa as a sole luteal support in non-downregulated cycles. Subsequently, a large randomized control study on 2,529 antagonist cycles on 1,479 women, aged 25–41 years by Itai Bar Hava et al., conducted over a period of 6 years from 2009–2015, showed a higher LBR in the entire GnRHa group as compared with 10the P group. GnRHa administration was by intranasal route and P by vaginal route. In the GnRHa group, significantly higher levels of mid-luteal E2 and P were observed. Clinical pregnancy rates were also higher in GnRHa group (27.9% vs. 19.8%). In our opinion, luteal support with intranasal GnRHa spray has several advantages over P by vaginal or P by IM or SC route. It is much more convenient without any irritation and not at all painful unlike P by IM or SC.
The above large study also illustrates that GnRHa as luteal support not only rescues corpus luteum function but is also sufficient to support embryo implantation and further development without any other luteal phase support. The luteal support needs to be given only implantation and on embryonic β-human chorionic for 2 weeks after ET. The observed effects of GnRHa on implantation and on embryonic β-human chorionic gonadotropin (β-hCG) secretion are attributed to direct effect on embryo and on endometrium mediated by LH, in accordance with the previous observations on the effects of LH activity on endometrial receptivity, independent of ovarian function. Further studies have also shown similar beneficial effects of GnRHa administration on implantation. At present, many centers worldwide have been using GnRHa as an effective luteal support. As per our knowledge, GnRHa for luteal support is likely to replace currently used P administration, given higher pregnancy rates and LBRs.
 
FROZEN VERSUS FRESH EMBRYO TRANSFER
In vitro fertilization with FET has become increasingly common with IVF centers the world over. The number of FETs increased by 80% in the US from 2006–2012, which far outpaced the rate of increase of fresh ETs over the same period. Advances in cryopreservation of embryos have contributed immensely to this trend, as newer vitrification techniques have improved embryo survival rates as compared with slow freezing. In addition, there is increasing evidence of FET leading to more favorable perinatal and live birth outcomes including a lower risk of preterm birth (PTB), low birth weight (LBW), placenta previa, and placenta abruption. One large multicenter matched cohort study on over 2,900 cycles found significantly higher implantation rates and ongoing pregnancy rates with FET cycles compared with fresh transfers. The ongoing PRs with FET cycles were 52% and with fresh cycles it was 45.3%. This effect was most pronounced with P >1 ng/mL on the day of trigger and also in women of advanced age. There are a number of RCTs reporting higher PRs in normal and high responders.
Frozen embryo transfer protocols are thought to have several potential advantages over fresh transfer protocols. Multiple mechanisms have been suggested for the negative impact of COH on implantation and on pregnancy. Hormone regulation plays a large role in endometrial receptivity and high E2 and P levels from COH may affect hundreds of genes involved in implantation. High E2 levels during COH have also been hypothesized to interfere with endometrial perfusion. On the other hand, endometrium in an unstimulated cycle is more receptive to early placentation and embryogenesis than endometrium during COH.
It is believed by most centers that FET is most likely to yield higher implantation and clinical pregnancy rates than fresh transfers, regardless of age, infertility cause, duration of infertility, etc. In fact, many have adopted FET as policy in their centers. In our center, we have adopted FET as a policy for all patients since a year and we have observed more than double the PRs with FET than what it was with fresh transfers.
There are two major considerations for FET as a policy: (1) Premature rise in P is known to occur in most cases, making difficult the determination of opening and closing of the window of implantation (WOI), affecting adversely the chance of fresh embryo implantation. (2) It is much easier for the clinician to determine WOI in natural or modified natural cycle to facilitate FET and to maximize the pregnancy rates.
 
CORRELATION BETWEEN EMBRYO DEVELOPMENTAL STAGE AND ENDOMETRIAL STATUS
Asynchrony between embryo developmental stage and endometrium can result from COH leading to advanced histology and downregulation of P receptors. Prior to this event, COH may lead to premature rise in P, which is more due to FSH than to LH. Hence higher dependence on LH than on FSH toward the end of stimulation may prevent rise in P on the day of trigger, which can induce premature decidualization disrupting or advancing WOI, which is known to last for about 48 hours. It has also been hypothesized that the freeze-thaw process in freeze-only cycles serves as filter for embryos of poor quality, which may not survive the thaw process, FET procedure can also reduce the risk of OHSS.
Failure of implantation is the biggest challenge to IVF today. Uterine contribution to implantation success should never be underestimated. Uterine receptivity, 11which facilitates implantation besides embryo quality, is controlled by hormonal milieu during COH and the appropriate timing of embryo transfer, which in turn depends upon whether the WOI is open. The WOI opens with the appearance of P (including endogenous P) in serum, which is difficult to determine in stimulated cycles but not in unstimulated ones.
Another important factor for effective implantation is the endometrial thickness (EnT) on the day of ET influenced by rising E2 level. However, contribution of EnT to implantation is considered controversial. EnT of 6–7 mm or >10–14 mm has been reported to affect implantation adversely. Other studies have shown no association between EnT and implantation process. In view of this controversy, some studies have advocated using endometrial pattern on the day of ET for implantation. The reduced implantation rate in patients with a particular type of endo pattern suggests that premature luteinization leading to uterine-embryo asynchrony is a significant contributor to implantation failure.
 
MAXIMIZING LIVE BIRTH WITH SINGLE EMBRYO TRANSFER
Today, every couple desires birth of one healthy child at a time. However, in India, a woman willingly and gracefully accepts twins or triplets under compelling circumstances. So is the gentle nature of an Indian woman. The increase in multiple births observed in the last 25 years or so is largely attributed to ART. Many consider multiple births as an adverse outcome because of the associated maternal and neonatal morbidity as well as adverse economic impact. The risks with multiple pregnancies include prematurity, intrauterine growth restriction, LBW, cerebral palsy, learning disabilities, and developmental delays. Strategies to curb multiple births, to improve implantation by transfer of single blastocyst transfer, preferably FET, are being increasingly adopted all over the world, including India, today. In the US, the practice of SET increased from 2% in 2002 to 12% in 2011. However, it appears underutilized compared to European countries, particularly Sweden, which was 73.3%. The number of SETs performed in the US increased by 82.5% from 2006 to 2012. It is well established and acknowledged now that SET reduces multiple births and improves neonatal end points, while providing acceptable LBRs.
In Japan, in early 2000s, conflict developed between ART specialists and obstetricians. The neonatal intensive care units (NICUs) throughout the country were occupied by babies born after infertility treatment. ART specialists were accused of producing multiple pregnancies by their ignorance. Since then, the need for SET has been seriously contemplated. The study by Takeshima et al. highlights the success of SET policy for improvement of perinatal outcome and mortality rate. SET policy was adopted by the entire country. It is noteworthy that Japanese medical practices for ART are self-regulated by the rules of the society and not by legislation. The policy, thereafter, produced SET rate of 82.6% in 2012.
The important pre-requisite for the success of SET policy is the “normal euploid embryo”. There are several methods to ensure euploid embryo morphology, the latest being preimplantation genetic screening (PGS). The study by Kazumi Takeshima et al., reviewed retrospectively the total of 140,718 live births and 510 stillbirths (after 22 weeks of gestation) conceived by ART between 2007 and 2012. The following were the findings, based on analysis of Japanese registry data:
  • The practice of SET increased from 52.2% in 2007 to 82.6% in 2012.
  • The multiple pregnancy prevalence decreased from 10.7% to 4.1% during the same period.
  • The prevalence of PTB, LBW, and small for gestational age (SGA) decreased significantly while that of large for gestational age (LGA) increased.
  • Perinatal morbidity decreased from 0.7% to 0.4% in fresh cycles, while that of FET cycles did not change.
The scenario in South Asian countries, as indicated by one British study, showed higher cancellation rates and lower LBRs. Another collaborative study by two centers based in the US demonstrated lower implantation rates in south Asian women versus Caucasian women (28% vs 39%) and lower LBRs among South Asian women versus Caucasians (24% vs 41%).
Summarily, there is enough data to support transfer of single frozen blastocyst, providing excellent LBRs, greatly reduced multiple and preterm births. In our view all patients should be encouraged to opt for frozen thawed blastocyst transfer with autologous oocytes and sperm.
Why euploid blastocysts do not always implant?
Early on, higher number of oocytes harvested could produce higher number of embryos to enable transfer of multiple embryos because of enhanced efficacy of ovarian stimulation to establish implantation and possibly pregnancy.
Today, this practice has changed. Improvements in IVF technology have rendered multiple embryo transfer unacceptable to both, clinicians and patients. The obligation to foster SET for reducing multiple pregnancy 12has underscored the need for ideal endometrial receptivity conditions prior to transfer. To achieve the ideal eutopic endometrial status, the clinician may be required to look at number of abnormalities, both in the woman's pelvis and the uterus itself. There could be several abnormal conditions, such as inflammation of the endometrium arising from primary infection, other conditions distorting the pelvic anatomy such as endometriosis, and/or adenomyosis, asymptomatic endometriosis producing P resistance or P block, leiomyomatosis requiring surgical intervention prior to IVF treatment, numerous endometrial gene expressions known to occur after COH rendering endometrium simply abnormal, etc. In fact, when office hysteroscopy is performed in women undergoing first IVF attempt and in women with history of repeat implantation failures or early pregnancy failures, uterine abnormalities are detected in as much as 11–22% and 26–45%, respectively. Myometrial pathologies like leiomyoma or fibroids, submucosal or intramural myomas are known to encroach uterine cavity with associated reduced implantation and increased miscarriage rates. Adenomyosis, which is steroid dependent and which is identified in 27–79% of infertile women and up to 90% of women with endometriosis, has been shown to significantly reduce pregnancy rates as per recent meta-analysis.
In view of the above conditions, impairing endometrial receptivity, euploid blastocyst, certified by PGS, cannot be expected to implant or to produce pregnancy.
 
CONCLUSION
Quite often, question is raised, especially in non-medical society, are we moving forward with assisted reproductive technology? Some say Yes and some No.
We shall attempt to answer. Let us look at the journey that began about 30 years back. The process was termed inefficient, full of failures like multiple births, intolerable prevalence of implantation failures and early pregnancy loss, no cost-effectiveness, to name the few. The positive side of the scenario has been contributed by advancements like extended culture of cleavage stage embryos, cryopreservation techniques, especially, the vitrification process, time lapse morphokinetics, preimplantation genetic screening, oocyte and embryo freezing techniques, ovarian tissue freezing and reimplantation, uterine transposition and transplant, preservation of fertility in young women suffering from pelvic and uterine cancers, etc. The future, in our view, appears full of promise. Already, young cancer survivors are having better quality of life and expecting their own genetic children. Shortly, women will be able to postpone menopause by at least 5–10 years, possibly because of depleted ovarian reserve, to have better quality of living, with no possibility of early menopause, reduction in the incidence of aneuploidy in embryos of women of advance age, and so on.
Taking stock of all these and other positive developments and future possibilities, we can confidently say that we have progressed well through the journey and the future is highly promising.
Lastly, we wish all readers a happy reading and hope that they would add to their skills and efficiency. Thank you all.
 
EDITORS' COMMENTS
  1. Demographic characteristics, genetic predisposition, and diverse pathologies should also be considered and extensively studied while performing COS and while assessing its response.
  2. Individualized COS (iCOS) optimizes outcomes and safety issues by adapting patient specific characteristics. With endocrine, paracrine, and genetic biomarkers iCOS can be refined further.
  3. Natural and modified natural cycle protocols may be discussed to complete knowledge on COS.
  4. Assisted reproductive technology is such an ever expanding field, that to summarize it in a few words is next to impossible. From discovering the importance of sex hormones, studying impact of age, hormones on eggs, understanding ovum and embryo genetics, to newer advances in ART technology like Embryoscope, Poloscope, etc., the infertility specialist is exposed to wide option to maximise the success.
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