FOGSI Focus Use of Adjuvants in Infertility Sunita Tandulwadkar, Madhuri Patil, Nandita Palshetkar
INDEX
Page numbers followed by f refer to figure, and t refer to table
A
Acetylcholinesterase inhibitor 6
Acetylsalicylic acid 7
Acupressure 5, 11
Acupuncture 3, 5, 11, 26, 30, 32, 34
Adhesiolysis 62, 65f
Adjuvants therapy 14
Advanced sperm selection
procedures 6
techniques 2
Adverse pregnancy outcome 64
Alpha-lipoic acid 20
controlled-release 20
Amenorrhea 65
American Society for Reproductive Medicine 59
American Thyroid Association 59
Amino acids 40
Androgens
excess, treatment of 8
pretreatment 6
Androstenedione 23
Anovulation 62
Antibiotics 40
prophylactic 65
Anti-Müllerian hormone 7, 22
Antioxidants 1, 5, 11, 40
scavenging 50, 51
therapy 50
Antithyroglobulin 56
Antithyroid
antibodies 56
peroxidase 56, 59
Antral follicle count 22
Aromatase inhibitors 5, 53
Artificial oocyte activation 2, 41, 46
Asherman's syndrome 28, 63, 65, 65f
Aspirin 2, 3, 5, 7, 10, 26, 29, 32
Assisted hatching 3, 6, 43, 44, 46
Assisted reproductive technology 1, 5, 6, 13, 23, 29, 37, 56, 62
basis of 22
cycle 32
new technologies used in 12
outcome 10
B
Blastocyst
culture 43
transfer 12, 43
trophectoderm cells, biopsy of 45
Bleeding, postoperative 63
Body mass index 8
Bologna criteria 22
Bone marrow-derived stem cells 35
Broad fundus, laparoscopic confirmation of 64f
C
Calcium
ionophores 5
ions 41
Canadian Fertility and Andrology Society Clinical Practice Guidelines 33
Carnitine 51
Catalytic antioxidants 50
Chromium polynicotinate 5, 8, 9
Clinical pregnancy rate 1, 6, 32, 39, 41
Clomiphene citrate 8, 9, 19, 27, 52, 66
Coenzyme Q10 1, 5, 9
Colony-stimulating factor 8
Comet assay 39, 40f
Conception, natural 62
Connective tissue growth factor 29
Controlled ovarian
hyperstimulation 8, 58
stimulation 6
Corticosteroids 2, 3, 32, 34
Cryopreserved oocytes, fertilization of 2
Cumulus-oocyte complexes 6
Cyclic adenosine monophosphate 10
formation 6
Cyclic guanosine monophosphate 27
Cyst, large endometriotic 67f
Cystectomy, laparoscopic 67
Cytokines 2
D
Dehydroepiandrosterone 1, 3, 6, 23
administration 6
sulfate 8
Deoxyribonucleic acid 46
denaturation of 39
Dexamethasone 5, 8
Digital polymerase chain reaction 45
Distal tubal obstruction 62, 63
Dopamine agonist 5
E
Elective single embryo transfer 37
Electroacupuncture 34
Electrosurgical complications 63
Embryo
biopsy 13
glue 3, 46
hydrogen peroxide induced damage prevention of 27
transfer 11, 18
treatment 64
Embryogenesis 59, 60
Endocrine Society 59
Endometrial receptivity
adjuvants for 32
amelioration of 27
Endometrial scratching 6, 13f, 32, 35, 68
Endometrial thickness 32
Endometrioma 66
cystectomy 62
Endometriosis 62, 66, 67
deep 66
minimal-mild 67
moderate 67
moderate-severe 67
severe 67
superficial 66
Endometrium 26, 27, 59, 60
thin 26
Energy substrates 40
Epidermal growth factor 28, 29, 33
Erectile dysfunction, treatment of 27
Estrogen pretreatment 5, 7
European Society of Human Reproduction and Embryology Classification 64
European Thyroid Association 59
F
Fatty liver disease, nonalcoholic 20
Fertility
acupressure points for 12f
acupuncture points for 11f
Fertilization 59, 60
failure 41
rates 57
Fibroblast growth factor 29
Fibroids, multiple 63
Fluid intravasation syndrome 63
Fluorescence in situ hybridization 3, 14, 45
Follicle-stimulating hormone 1, 6, 19, 23, 52, 57
recombinant 50
Follicular-fluid testosterone 23
Folliculogenesis 57
Food and Drug Administration 34
Frozen embryo transfer 26
Frozen-thawed embryo transfer 33, 40
G
Genomic hybridization 45
Germ cells 53
Glucocorticoids 5, 8
Glyceryl trinitrate 27
Gonadotropin-releasing hormone 1, 8, 18, 23, 53, 63
agonist 32, 33
Granulocyte colony stimulating factor 6, 29, 32, 34
intrauterine perfusion of 26
Granulocyte-macrophage colony-stimulating factor 40
Granulosa cells 6
Growth hormone 1, 3, 5, 6, 23, 32, 35, 50, 52
releasing
factor 6
hormones 23
H
Heparin 2, 3, 5, 10, 28, 32, 33
mechanism of action of 28f
Homeostatic model assessment 19
Human chorionic gonadotropin 5, 23, 29, 32, 33, 50, 52, 56
low-dose 26, 29
Human fertilization and embryology authority 40, 46
Human menopausal gonadotropin 8
Human oocytes activation 41
Human serum albumin 40
Hyaluronan-enriched transfer medium 40
Hyaluronic acid 39
Hyaluronic binding assay score 39
Hydrosalpinx 68
bilateral 68f
disconnection of 6
removal of 6
Hydroxyvitamin D 19
Hyperinsulinemia 8
Hyperthyroid 53
Hypnosis 5, 11
Hypomenorrhea 65
Hypothesis 45
Hypothyroid 53
Hypothyroidism, subclinical 56, 59
Hysterosalpingography, abnormal 11
Hysteroscopic myomectomy 62, 63
complications of 63
Hysteroscopic surgeries, postoperative management in 65
I
Immune therapy 2, 5
Immunoglobulin 10
A 10
G 10
Implantation 59, 60
failure, recurrent 10, 63
rate 32
In vitro fertilization 3, 5, 32
additional therapy in 1
outcome 6, 11
program 5
treatment 1, 5, 18, 23, 28, 37, 59, 62, 64, 67
Infertility 62, 65
globally, prevalence of 37
history of 64
severe male factor 38
Injury, endometrial 3
Inositol 8, 9, 18
Insulin
growth factor 1 18, 23, 28, 29, 41
resistance 8
sensitizing agents 18
International Committee for Monitoring Assisted Reproductive Technology 37
International Federation of Gynecology and Obstetrics Classification 63
International Societies, guidelines of 59t
Intracytoplasmic morphologically selected sperm injection 12, 13, 37, 38f, 46
Intracytoplasmic sperm injection 1, 2, 7, 23, 29, 32, 37, 58
Intralipid 10
Intramural fibroids 63
Intrauterine granulocyte-colony stimulating factor instillation 29
Intrauterine insemination 67
cycles 27
Ions 40
K
Ketoconazole 8
L
L-arginine 5, 7, 26, 28, 32, 33
Laser-assisted zona hatching technology 44
Letrozole 8, 53
Leukemia inhibiting factor 59
Levothyroxine 58, 59
Leydig cells 52, 53
Lipids 40
Lipoic acid 20
Live birth rate 6, 32, 37
L-methylfolate 8, 9
Low molecular weight heparin 26, 28
inhibits 2
Luteal phase
adjuvants for 32
estradiol in 24
Luteinizing hormone 6, 18, 23, 27, 57, 66
recombinant 23
therapy 52
Lycopene 52
M
Magnesium 19
Massage therapy 11
Matrix metalloproteinase 59
Meiotic spindle 42f
Melatonin 3, 5, 8, 9
Methylprednisolone 5, 8
Methylxanthine 33
Metroplasty, hysteroscopic lateral 64
Micronutrients 5, 11
Mid-tubal block 62
Miscarriage
idiopathic recurrent 2
recurrent 45
Mitochondrial deoxyribonucleic acid 41
load measurement 41
Mitochondrial function 41
Morcellator, hysteroscopic 63
Müllerian anomalies 64
Myoinositol 5
Myomas 63
Myomectomy, laparoscopic 62, 63
Myometrium 27
N
N-acetylcysteine 5, 8, 9, 19, 50
Natural killer cell 2, 10, 27, 34
Neuromuscular electric stimulation 34
Nimodipine 27
Nitric oxide donor 33
Nonpharmacological adjuvants 5, 11
O
Obesity 53
Omega-3 fatty acids 20
Oocyte 42f, 59, 60
matured in vitro, fertilization of 2
meiotic stage, assessment of 42f
Ovarian
drilling, laparoscopic 6, 62, 66
endometrioma, management of 6
follicle 57
hyperstimulation
function 58
syndrome 7, 10, 66
response 22
stimulation 14, 59
Ovulation 59, 60
Ovum pick-up 29
Oxidative stress 11
P
Pelvic floor neuromuscular electrical stimulation 30, 34
Pentoxifylline 26, 28, 32, 33, 51
Phosphodiesterase type 5 27
Physiological intracytoplasmic sperm injection 12, 13, 37, 39, 46
Pituitary downregulation 14
Placentation 59, 60
Platelet
derived growth factor 29
rich plasma 26, 29, 32, 35
Polar body 42f
Polycystic ovary
disease 66
laparoscopic drilling of 66, 66f
syndrome 6, 8, 18, 66
treatment of 5
Polyps
endometrial 65
hysteroscopic removal of 6
treatment of 66
Poor ovarian
reserve 7, 22
response 22
Poor responders
in vitro fertilization outcome in 6
treatment of 5
Poseidon classification 22, 22t
Prednisone 5, 8
Pregnancy
multiple 66
rate 27, 32
Preimplantation genetic
diagnosis 2
screening 3, 6, 13, 44, 46
cycles 2
testing 13, 44
Prolactin 53
Proximal tubal occlusion 62
Pyridostigmine 5, 6
addition of 6
R
Randomized controlled trial 1, 7, 24, 27, 32, 39, 50, 66
Reactive oxygen species 9, 32, 50
Recombinant human growth hormone, low dose of 35
Reproductive surgery 12f
Resectoscope 63
Resistance index 27, 32
Routine hysteroscopy 6, 11
laparoscopy 13f
S
Salpingitis isthmica nodosa 62
Selective estrogen receptor modulator 52
Selenium 51
Semen parameters, abnormal 2
Septal resection, methods for 64
Septate uterus 64
Septoplasty, hysteroscopic 64
Septum 6
Sertoli cells 53
Sex hormone binding globulin 53
Sildenafil 2, 5, 27, 32, 34
additional actions of 27
citrate 10, 26, 27, 34
mechanism of action of 27f
Single-nucleotide polymorphism 45
Smooth muscle relaxation 27
Somatostatin analogs 18
Sperm 59, 60
chromatin
dispersion test 40, 40f
structure assay 39, 40f
deoxyribonucleic acid fragmentation 37, 39
fertility 37
Spermatogenesis 57
Spermatozoa 39f
classification of 38, 39f
heads 38f
normal 38f
vacuolated 38f
Spindle imaging 42
Stem cell 26, 32
therapy 30, 35
Steroidogenesis, gonadotropin-induced 6
Steroids 10, 24
Subfertility, male 50
Submucous myoma 6, 63
hysteroscopic resection of 63f
Surgeries, fertility-enhancing 62, 68
T
Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-nick-end labeling assay 39, 40f
Testis, Sertoli cells of 53
Testosterone 3, 5, 23
Thyroid
autoimmunity 56, 58, 60
effect of 60
impact of 56
on fertilization, effect of 57
on implantation, effect of 58
on ovarian reserve, effect of 57
function 58
hormone 53, 59, 59t
receptor alpha 59
receptor beta 59
peroxidase autoantibodies 60t
stimulating hormone 59, 60
Thyroxine 59
Time-lapse embryo monitoring 2, 6
Tocopherol 33
Total failed fertilization with standard insemination 2
Transcutaneous electrical acupuncture point stimulation 34
Transdermal testosterone 6
Transforming growth factor 29
Triiodothyronine 59
T-shaped
uterine cavity 64
uterus 64
Tubal
cannulation 62
factor 62
reconstruction 62
sterilization reversal 62
Tumor necrosis factor alpha 2, 28
U
Ultrasonography 66
Uterine
artery
pulsatility index 32
vasodilators 2
blood flow 26
cavity 63
factors 64
myomas 62
polyp 62, 65, 65f
radial artery 30
septum 64, 64f
volumetric flow 27
V
Varicocelectomy 53
Vascular endothelial growth factor 10, 27
Vasodilators 5, 10, 26
functions of 27
Vitamin 40
C 51
D 5, 8, 9
deficiency 19
E 26-28, 32, 33, 50
Z
Zinc 51
deficiency 51
Zona pellucida 43
×
Chapter Notes

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Rational for Additional Therapy in In Vitro FertilizationCHAPTER 1

Bhavana Mittal
 
INTRODUCTION
The problem of infertility is at a rise. The treatments for infertility are, however, bound by a limited success rate. Since “necessity is the mother of invention”, assisted reproductive technology (ART) is a rapidly evolving field of medicine. Newer drugs and technologies are being tried to improve the result of the procedure. But only a few of them are actually beneficial, safe, and cost effective.
 
PHARMACOLOGICAL ADJUVANTS
 
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA) is a food supplement in many countries. Its mechanism of action in women with decreased ovarian reserve is:
  • To increase the production of insulin-like growth factor 1 and estradiol in granulose cells
  • To act as a precursor of androstenedione and testosterone in theca cells.
Thereby it improves the follicular function.
In women with normal ovarian reserve, DHEA has not demonstrated any benefit.1
In women with diminished ovarian reserve, one meta-analysis has shown improvement in clinical pregnancy rate.2 A Cochrane review on the same subject, showed a higher pregnancy rate and live birth rate but the benefit was not obvious when studies with high risk of performance bias were excluded.3
Side-effects noted with use of long-term DHEA are minor androgenic effects but no long-term risks are seen.
At present, routine DHEA supplementation cannot be recommended in absence of good quality evidence.
 
Antioxidants Including CoenzymeQ10
Coenzyme Q10 (CoQ10) has been proposed to rejuvenate mitochondrial energy stores in granulosa cells.4 CoQ10 supplementation has been proposed to defer ovarian aging.5
There are only few clinical trials on the application of CoQ10 in assisted reproduction. One randomized controlled trial (RCT) found no improvement in clinical pregnancy rate on use of CoQ10 in a dose of 600 mg daily in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients between the age of 35 years and 43 years.6
Serious side effects are noted with the use of CoQ10.
CoQ10 cannot be recommended for all poor responders without further evidence.
 
Growth Hormone
Growth hormone (GH) increases the insulin-like growth factor 1 (IGF-1) level in follicles which potentiates follicle-stimulating hormone (FSH) action on granulosa cells, increases estradiol production and oocyte maturation.
Growth hormone used in a dose of 8–24 IU/day and given daily or alternate day has found to improve live birth rate in poor responders.7 Low dose (0.5 IU/day) of GH is also sufficient to improve live birth rate in poor responders.8 A Cochrane review of 10 RCTs showed higher clinical pregnancy rate (CPR) and live birth rate (LBR) when GH was added in women suspected of having low ovarian reserve.9
No benefit has been found in the use of GH in normal responders. Also, use of GH is seen in gonadotropin-releasing hormone (GnRH) agonist and not antagonist cycle.10,11
Overall, the use of GH as an adjuvant remains inconclusive.2
 
Immune Therapy
The rationale behind immune therapy is maternal immunomodulation around implantation window. Natural killer cells, cytokines, tumor necrosis factor alpha (TNFα), growth factors, and balance between Th1 and Th2 cells are important factors at this time.
However, there are no RCTs on the subject. Also, this treatment can result in some serious side effects and is expensive. At present, immune therapy cannot be offered due to lack of proper evidence, cost, and potential side effects.
 
Artificial Oocyte Activation
Calcium ionophore releases calcium ions around ooplasm after sperm–oocyte fusion. This can enhance fertilization rate and has been proposed to be beneficial in women with previous ICSI cycle with total failed fertilization.
RCTs in women with reduced ovarian reserve12 and male infertility13 did not find any advantage of this intervention. Another systemic review 14 also could not prove any benefit of this treatment.
There is insufficient safety data. At present, this intervention cannot be recommended.
 
Corticosteroids
Drugs like prednisolone and dexamethasone have been used for immunomodulation at the time of implantation by suppressing natural killer (NK) cells and maintaining cytokines and growth factors.
Use of prednisolone in women with increased NK cells has shown to improve IVF outcome.15 A significant benefit of prednisolone and heparin has been found in women with unexplained recurrent implantation failure (RIF).16,17
Dan et al.18 found benefit of prednisolone in idiopathic recurrent miscarriage (RM) in terms of increased LBR and reduced miscarriage rate. Short-term use of corticosteroids is not associated with many risks. Currently, prednisolone can be offered in selected patients.
 
Heparin
Low molecular weight heparin inhibits clotting factor Xa and has been used to prevent microthrombi at implantation site. This promotes trophoblast invasion. Significant improvement in LBR has been shown in women with more than 3 recurrent implantation failure19 and first IVF cycle.20 A third RCT, however, failed to show such benefit.21 Risks associated with heparin are bleeding and thrombocytopenia. Heparin treatment is acceptable in women with thrombophilia. In women without thrombophilia, it should be prescribed in selected cases with proper counseling.
 
Aspirin
Low dose aspirin is an antiplatelet agent, it improves trophoblast invasion and has been used for implantation failure. A Cochrane review did not find benefit of use of aspirin in RMs.22 In a review on women with congenital thrombophilia, no benefit of addition of aspirin was seen in terms of LBR or miscarriage rate.23 Therefore, aspirin should be used in selected cases at present.
 
Uterine Artery Vasodilators
Sildenafil has been used as a nitric oxide donor. This cause vasodilation and improves endometrial blood flow and thickness. Currently, there is not enough evidence to justify the use of vasodilators to improve implantation.
 
TECHNOLOGICAL ADJUVANTS
 
Intracytoplasmic Sperm Injection
Intracytoplasmic sperm injection has been accepted in cases of:
  • Abnormal semen parameters
  • Total failed fertilization with standard insemination
  • Fertilization of cryopreserved oocytes
  • Fertilization of oocytes matured in vitro
  • Preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) cycles
There is not much evidence in support of the same.
 
Advanced Sperm Selection Techniques
Embryos with good morphology may not be genetically competent.24
Morphology has limited value in predicting implantation potential.25 It is affected by timing and is observer dependent.26 There is an effort to select the most competent embryos to increase the success of IVF.
 
Time Lapse Monitoring
Time lapse monitoring (TLM) has the advantage of continuous monitoring, avoids exposure of embryos, reproducibility, and flexibility of laboratory work. Currently, there is not enough evidence in favor of TLM over conventional morphological assessment.27 Also, there are concerns over UV rays exposure while taking images and cost of procedure. It can be offered in situations like repeated implantation failure.3
TABLE 1   Potential role of various adjuvant therapies in IVF practice.
Therapy or medication
Proposed use in IVF
Safety and possible side effects
Efficacy
Evidence
Acupuncture
Increases pregnancy rates
Safe
Limited evidence
Meta-analysis shows possible benefit with pregnancy in IVF patients
Low dose aspirin
To improve implantation and decrease miscarriage rate
No/low risk/mild side-effects
Limited evidence
Insufficient evidence of the benefit in pregnancy rates in IVF patients
Heparin
To improve implantation and decrease miscarriage rate
No/low risk/mild side-effects
Limited evidence
Studies show inconsistent results
Overall, no benefit shown in the pregnancy rate of IVF patients
Melatonin
To improve egg and embryo quality
No/low risk/mild side-effects
No evidence
Antioxidant effect on egg and embryo quality being evaluated
Testosterone
To increase egg numbers and quality in poor responders
Moderate risk/moderate side effects
No/limited evidence
Currently being trialed
DHEA
To increase egg numbers and quality in poor responder
Moderate risk/moderate side-effects
No/limited evidence
Limited small trials with variable results
Growth hormone
To increase egg numbers and quality in poor responders
Moderate risk/moderate side- effects
No evidence
Limited small trials with variable results
Corticosteroids
To improve the implantation rate in patients experiencing repeated IVF failure due to immune dysfunction
High risk/serious side-effects
No evidence
Currently no evidence Still under research
Endometrial injury
To improve embryo implantation
No/low risk Mild side-effects
Limited evidence
To date, studies have been too small to draw any conclusion
(IVF: in vitro fertilization; DHEA: dehydroepiandrosterone)
 
Preimplantation Genetic Screening
Use of PGS by fluorescence in situ hybridization (FISH) technique has shown lower success rates in RCTs.28 No effect was seen in good prognosis women.29 Next generation sequencing (NGS) in PGS is very accurate, reliable and shows 63.8 % CPR per embryo transfer following NGS.30,31
 
Endometrial Injury
Moderate quality of evidence in favor of endometrial scratching has been found in different RCTs.32-34 However, these studies have been found to be very heterogeneous in methodology.35 Endometrial scratching can only be recommended in RIF at present.
 
Embryo Glue
A Cochrane review on the subject demonstrated increased LBR but increased multiple pregnancy rate also.36 Embryo glue can be used at present only after proper counseling.
 
Assisted Hatching
Assisted hatching (AH) has not been found beneficial in good prognosis patients.37 Another Cochrane review found significant improvement in CPR but no difference in LBR with AH.38 In women with decreased ovarian reserve, AH showed decreased LBR (Butts, 2014).39 In absence of corroborative evidence, AH cannot be routinely offered.
 
CONCLUSION
Improvement in the result of ART is the need of the hour. However, any new treatment or “adjuvant” should be judged in terms of theoretical basis of benefit, evidence and favor of its use, potential side-effects, and use (Table 1). There should be proper counseling of the patient before the use of such treatment.
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