Handbook of Drugs in Infertility Pratik Tambe, Rohan Palshetkar, Nandita Palshetkar, Seema Pandey
INDEX
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
A
Absorption 125, 181
Acetyl-L-carnitine 293
Acetylsalicylic acid 207, 209
Adalimumab 198
Adenomyosis 301
Adenosine
diphosphate 292
triphosphate 202, 291, 292
Adrenocorticotropin 154
Allopregnanolone 125
Alzheimer's disease 115
Amenorrhea 64, 258
treatment of 112
American Society of Reproductive Medicine 312, 313
American Urological Association 152, 153
Amino acid 307
Androgen receptor 113
Anovulatory infertility 14, 30
Anticardiolipin 175
Anti-human immunodeficiency virus 80
Anti-inflammatory dose 209
Anti-müllerian hormone 31, 156, 317, 320
Anti-obesity drugs 265, 266, 267t
Antioxidants 283t
compounds 283
type of 296
Antiphospholipid antibody 210
syndrome 174, 175, 210
Antiplatelet drug 207
Antithyroid drugs, classification of 311, 312fc
Anti-tumor necrosis factor-alpha 198
Antral follicle count 31
Apoptotic mechanisms, role of 319
Aromatase
cellular level action of 47f
inhibitors 4750
generations of 46t
types of 46t
Aseptic meningitis syndrome 196
Asherman's syndrome 167
Asoprisnil 301
Aspirin 207
antiplatelet action of 212
chemical formula of 207f
complications of 212
indication of 210t
mechanism of action of 208, 209fc
pharmacokinetics of 208, 208t
premise of 210
role of 210
therapy 212
Assisted reproductive technology 4, 17, 37, 94, 127, 134, 187, 210, 212, 269, 283fc, 289, 295, 297
cycles 134, 165, 183
Astaxanthin 215
structure of 216f
Asthenozoospermia, idiopathic 293
Asthma 128
Atosiban 269
chemical structure of 269f
mechanism of action of 271fc
Atresia, follicular 232
Autologous peripheral blood-derived mononuclear cell 79
B
Benzoic acid 207
Betamethasone 181
Biotransformation, distribution and 202
Birth prophylaxis, preterm 127
Bleeding, break through 8
Bloating 229
abdominal 8
Blood test 304
Body mass index 265, 318
Brain tumor 16
Breast
carcinoma 56
history of 8
lumps 127
pain 8, 127, 288
tenderness 8, 23, 44, 127
Bromocriptine 260
C
Cabergoline 257, 258, 260, 261
safety profile 261
Calcium 221
influx 221
role of 222f
Carbamazepine 287
Carbohydrate metabolism 115
Carcinogenicity studies 34
Carcinoma in situ, ductal 65
Cardiac valvulopathy 260
Carnitine 293
palmitoyltransferase 294
Cells, endometrial 318
Central nervous system 113, 115
Cerebral thrombosis 106
Cervical ripening 300
Cetrorelix 94
Chloasma 105
Cholesterol synthesis 319
Cirrhosis, severe decompensated 118
Clarithromycin 287
Clinical pregnancy rate 63
Clomiphene 13, 14, 234236
citrate 13, 25, 26, 33, 34, 50, 54, 62, 63, 165, 184, 259
administration 16f
mechanism of action of 14f
pharmacology of 13f
resistant 236
Coenzyme
A 294
Q 292, 293
Q10 291, 292, 293
molecular structure of 291, 291b
Combined oral contraceptive 107
Constipation 44, 127
Contraception 276
impact of 107
Contraceptive
failure 107
pills, part of 119
Controlled ovarian
hyperstimulation 31, 37, 40, 54, 56
stimulation 54, 74, 261
cycle 37
Conventional ovarian stimulation 137f
Copper 220
stimulates 221
Corifollitropin alpha 22
Corpus
luteum 69, 124
luteum cyst 90
Corticosteroids 179, 181, 201
on pregnancy, effect of 182
preparations 180f
use of 183
Corticotropin 154
Cortisol 181
C-reactive protein 199, 211
Creutzfeldt Jakob disease 197
Cryptorchidism 80
C-terminal peptide 22
Cumulus-oocyte complex 303
Cushing's syndrome 299, 300
Cyclic adenosine monophosphate 20, 322
Cyclic guanosine monophosphate 162, 163, 169
Cyclooxygenase 209
inhibitor 207
Cysteamine 279
D
Decapeptyl depot 88
Deep vein thrombosis 174
Dehydroepiandrosterone 47, 154
adverse effects of 158
biochemistry of 154
Dendritic cell 194
Deoxyribonucleic acid 22, 265
Depot medroxyprogesterone acetate 118
Depression 127
Desogestrel 114, 116, 117
Dexamethasone 181
Diabetes mellitus 80
Diarrhea 44, 127, 229, 233
Diclofenac 304, 305
Dienogest 274, 276, 277
actions of 276fc
antiandrogenic effect of 275
clinical use of 275
half-life of 274
mode of action of 275, 275t
properties of 274
structure of 274f
Diiodothyronine 308, 309
Diminished ovarian reserve 90, 156
Diplopia 128
Direct antiglobulin test 196
Dizziness 127, 229, 272
Dominant follicle during luteal phase, effect on 304
Drowsiness 44
Dydrogesterone 129134, 135, 136
advantages of 133
analogs of 130
chemical structure of 130f
pharmacokinetics of 131t
properties of 131t, 132
role of 133
side effects of 132, 132b
Dysmenorrhea, primary 320
E
Embolic disorders 128
Embryo 273
cryopreserved 271
quality 265
transfer 26, 54, 75, 270273
cycle, frozen-thaw 210
Enclomiphene 13
mixture of 13
Endogenous corpora lutea, absence of 135
Endometrial cancer, history of 8
Endometrial growth 190
Endometrial receptivity 56, 78, 191
Endometrial thickness 162, 165
Endometriosis 50, 92, 109, 136, 275, 320
treatment of 300
Endometriotic stromal cell 320
Endometrium 115, 124, 189, 286
Endoplasmic reticulum 211, 294
Enoxaparin 173
Enzymatic antioxidants 278t
Enzyme 131
inducers 107, 287
linked immunosorbent assay 175
Epilepsy 128
Equine estrogen, conjugated 8
Erectile dysfunction 162
Erythrocyte sedimentation rate 197
Erythromycin 287
Estradiol 3, 7, 31, 48, 54, 293
hemihydrate 8
Estriol 3
Estrogen 3, 113
administration, routes of 3
isoforms, structure of 3f
preparations 8t
uses of 5
receptor 48, 50
modulator, selective 13, 60
therapy
contraindications for 8
side effects of 8
uses of 7
Estrone 3
sulfate 4
European Society of Human Reproduction and Embryology 174
Eutropin 145
Excretion 126, 310
Exogenous progesterone supplementation 123
Extracellular
fluid 270
matrix 286
Eyelids 127
F
Face, swelling of 127
Facial skin, Freckles or Darkening of 8
Fatigue 44
Fatty acid
deficiency 201
omega-3 225
polyunsaturated 225
role of omega-3 226
structure 226, 226f
Feet 127
Female fertility, antioxidants in 295
Fertility
after ulipristal treatment 289
contraception 276
preservation stimulation protocols 56
reduced 265
subsequent 107
Fertilization
failure of 207
rates 265
Fever 127, 203f
Fibroid, medical management of 289, 301
Fluid
follicular 188
retention 64
Flushes 272
Folate supplementation 223t
Folic acid 222, 223
Follicle syndrome, empty 75
Follicle-stimulating hormone 14, 16, 1821, 24, 26, 27, 29, 31, 37, 38, 38f, 4850, 54, 56, 69, 72, 94, 98, 104, 149, 223, 286, 294
long-acting recombinant 22
molecular structure of 19f
receptor 18
Follicular genesis, abnormal 233
Food and Drug Administration 231, 266, 268
Fragmentation index 265
Free fatty acid 294
Free radicals 278, 282fc
Frozen embryo transfer 50, 54, 78
cycle 78, 135, 167
Frozen thawed
cycles, artificial 135
embryo transfer cycle 92
G
Galactorrhea 258
Gametes, imperfect 207
Genes 303
Gestational sac 82t
Glucocorticoid 16, 179, 181, 185
effects of 181, 182
half life 181t
receptor 113, 194
Glucose-6-phosphate isomerase 175
Glutathione 279
Glycoprotein 29
hormones 19
Gonadotropic cells 94
Gonadotropin 24, 25, 27, 29, 236
dose of 31t
fixed dose of 32
only regimens 24
release, inhibition of 103
releasing hormone 14, 21, 26, 37, 48, 54, 87, 88, 94, 97, 104, 109, 134, 137f, 258, 285, 293, 294, 305
agonist 25, 27, 74, 87, 97
analogs 39
antagonist 94, 109
secretion, altered 232
usage of 31t
G-protein-coupled receptors 19
Graafian follicle 221
Granulocyte colony stimulating 188
factor 187189, 191193
follicular fluid level of 188t
mechanism of action of 189f
molecule 187, 187f
presentation of 190f
Granulosa cell 89, 233
proliferation, promotor of 18
Growth hormone 143
Guanosine triphosphate 20, 163
Guanylate cyclase 163
H
Hair
loss 127
thinning of 127
Headache 23, 44, 127, 203f, 229, 272, 288, 301
Hemolysis 196
Hemorrhage subchorionic 212
Heparin 173
therapeutic usage of 178t
unfractionated 173
Hepatitis 200
Homocysteine, damaging effects of 216
Hormone 103, 124
adrenocorticotropic 72, 113
estrogen 103f
pharmacokinetics of 310t
replacement therapy 276
Hot flash 65, 127
Human chorionic gonadotropin 25, 26, 29, 38f, 54, 65, 69, 70, 72, 76f, 80, 82, 97, 129, 145, 165, 305
administration 98
diagnostic uses of 81, 81b
therapeutics of 73
Human growth hormone 143
Human immunodeficiency virus 80
Human leukocyte antigen 124
Human luteinizing hormone 69
Human menopausal gonadotropin 21, 22, 2931, 39, 54, 76, 98, 136, 166
types of 30
Humira 193
Hydroxychloroquine 193, 204
Hydroxylation 319
Hyperglycemia 272
Hyperinsulinemia 232, 233, 318
Hyperlipidemia 203
Hyperplasia, endometrial 286
Hyperprolactinemia 257, 258
management of 260
Hyperproteinemia 196
Hypersensitivity 81, 127, 196, 209
reaction 95
Hyperstimulation, risk of 110
Hypertension 196
Hyperthyroid 311, 311fc
Hyperthyroidism 313
signs of 313t
symptoms of 313t
Hypoandrogenism 232
Hypogonadism, hypogonadotropic 30, 34
Hyponatremia 196
Hypotension 272
Hypothalamic gonadotropin-releasing hormone 18
Hypothalamic-pituitary-adrenal axis 47
Hypothalamus 14
Hypothyroid 313
Hypothyroidism 312, 312fc, 313
signs of 313t
subclinical 313
symptoms of 313t
I
Ibuprofen 304, 305
Immune cellular mechanisms 201
Immunoglobulin 175, 198
Implantation failure 207
recurrent 211
Implantation rate 188
In vitro fertilization 19, 31, 43, 54, 55, 76, 91, 94, 127, 162, 193, 199, 210, 223, 265, 271, 317, 318
cycles 15
failures, recurrent 190, 191
mild 303
pregnancies 211
program 154
treatment 108
natural cycle 305f
Indirect thrombin inhibitors 173
pros and cons of 173t
Indomethacin 304, 305
Infection 200
Infertile population 296t
Infertility 51t, 258, 311, 311fc, 313
adenomyosis-induced 136
female factor 164
free radical scavengers in 278
human 303
management 183
mechanism of 312, 312fc
practice 5, 8t
unexplained 14, 212
Inner mitochondrial membrane 294
Inositol triphosphate 271
Insomnia 272
Insulin resistance 232
role of 318
International Consultation for Sexual Medicine 152
International Society for Sexual Medicine 152
International Society for Study of Aging Male 152
International Society on Thrombosis and Hemostasis 175
Intestinal microflora, suppression of 107
Intracytoplasmic sperm injection 24, 31, 43, 54
Intralipids 193, 201
molecule 201
Intramuscular injection 113
Intranasal route 89
Intrauterine device 126
Intrauterine growth retardation 279
Intrauterine insemination 14, 31, 54, 164
cycle 133
Intrauterine instillation before embryo transfer 78
Intravenous immunoglobulin 193, 199
molecule 194f
Iodine 307
Iron 223
dynamics of 224t
hemostasis 224
pharmacokinetics of 224t
recycling 224
requirement of 225t
role of 225, 224f
Itching 44
J
Joint pain 127
K
Ketocarotenoids 215
Ketoconazole 287
L
Labor, induction of 300
L-carnitine 292, 293
mechanism of action of 294f
Leg vein thrombosis 105
Leiomyomas 285
Letrozole 33, 34, 46, 47, 4951, 51t, 5558, 235
advantages of 50b
coadministration of 56
discovery of 46
efficacy of 48
mechanism of action of 48fc
optimal dose of 49
pharmacokinetics of 48t
plus human menopausal gonadotropin 54
regimen, extended 54
resistance 57
Leuprolide 88
Levonorgestrel 114, 116, 117
releasing intrauterine device 117
Levothyroxine 310t
Lipoprotein, high-density 118
Lips 127
Liraglutide 268
Live birth rate 63, 176, 235
Liver
disease 16
active 118
severe active 8
function
analysis 138
tests 287
tumors
benign 118
malignant 118
Living organisms, development of 215
Lorcaserin 267
Low molecular weight heparin 172174, 174t, 176, 193, 201
infertility of 177t
structure of 172f
types of 173
Low testosterone values, laboratory diagnosis of 151
Lung embolism 8
Lupus anticoagulant 175
Luteal phase
defect 126
deficiency 134
dosage regimen for 136
insufficiency 126, 133
preceding menstrual cycle 145
support
concept of 133
drugs for 121
Luteal support 75, 92, 99, 127
Luteinized unruptured follicle syndrome 190, 191
Luteinizing hormone 14, 16, 18, 21, 29, 37, 38, 47, 64, 69, 70, 72, 87, 94, 97, 98, 104, 112, 113, 134, 149, 232, 286, 293, 305
control of 303
mid-cycle 132
structure of 38f
therapeutic window, concept of 40t
M
Magnesium 227
deficiency 227fc
dietary sources of 227
Male infertility 34, 92, 164, 168, 322fc
role in 78, 228
Mammary gland 124
Maternal gastrointestinal adverse effects 212
Maternal inflammation 211
Matrix metalloproteinase 173, 187
Medroxyprogesterone acetate 112114, 116118, 132
Melasma 8
Melatonin 280, 280f
structure of 280f
Meloxicam 304
Menotropin 21, 29
structure of 29f
Menstrual cycle 103f, 125f
regulation of 112
Menstrual pattern change 8
Menstruation 115
Messenger ribonucleic acid 20, 91, 309
Metabolism 310, 316
Metabolite, active 129
Metalloproteinase 173
tissue inhibitors of 320
Metformin 231, 233236
addition 17
comparing 236
decrease 234
efficacy of 237
evidence of 236
prepregnancy use of 236
side effect of 233
treatment with 236
uses of 234
Methyl prednisolone 181
Methyltetrahydrofolate, role of 223
Microflare 90
Micronutrients 215
Mifepristone 299, 300, 301
chemical structure of 299f
indications of 300t
mechanism of action of 301fc
structure of 299
Migraine 128, 197
headache 8
Minimal stimulation protocol 33
advantages of 32
Miscarriage 135, 138
rate 63
recurrent 167, 184, 192, 193, 199
risk of 236
Mitochondrial energizers
dosage of 295, 295t
effects of 296t
mechanism of action of 292f
Mitochondrial energy boosters 291
Mitochondrial membrane, outer 294
Mitochondrial permeability transition pore 294
Mitochondrial respiratory chain 291
Molecular formula 94
Molecular weight 94
Molecule, basic introduction of 172, 172f
Monoiodothyronine 308, 309
Multiphasic lotus trial 134
Multiple drugs 201
Multiple pregnancy 35
rate 63
Muscle 127
Myocardial infarction 106, 174
Myomatous uterus, symptomatic 259
Myometrium 115
N
Naltrexone-bupropion 268
Natural defense mechanism 215
Natural micronized progesterone 123, 123f, 126
adverse effects of 127t
Natural progesterone, nonhormonal actions of 124f
Nausea 23, 44, 65, 127, 233, 272, 301
Nonenzymatic antioxidants 278t
Nonsteroidal anti-inflammatory drugs 303, 304
doses of 305t
indications of 303
mechanism of action of 304f
Nonsteroidal triphenylethylene derivative 13
Norethindrone 114, 116, 117
Norprogesterone 285
O
Obesity 266
role of 318
Oligoasthenoteratozospermia 297
Oocyte 265
membrane 294
number of 109
quality 291
improves 295
retrieval 26
Oral antioxidant energizer, effects of 296t
Oral contraception, role of 109
Oral contraceptive pill 35, 89, 97, 98, 103, 103f, 105, 108, 109
mechanism of action of 104f
types of 103
Oral dydrogesterone 131, 132, 134136
compared 134, 135
Oral estradiol valerate 8
Oral estrogen preparations 7
Oral formulations 5
Oral micronized progesterone 132
Oral natural micronized progesterone
administering of 127
sustained release 124
Oral ovulogen 33
Organic cation transporter 2 294
Ovarian cyst 16, 115
formation 108
Ovarian dysfunction 232
Ovarian function 232
Ovarian hyperstimulation
pathogenesis of 233
risk of 109
syndrome 18, 25, 31, 35, 42, 49, 50, 57, 63, 72, 74, 81, 90, 97, 134, 305
prevention of 259
Ovarian response, normal 110
Ovarian stimulation 76, 109
protocol 137f
Ovulation induction 30, 31t, 48fc, 49, 50, 54, 60, 62, 259
role in 234
standard protocol for 51
Ovulation
impact on 235
physiology of 303
Ovulatory dysfunction 183
cause of 303
Ovum pick-up 90
Oxidant antioxidant balance 279f
Oxidative stress 215, 227fc, 278
Oxytocin 269
antagonists 269
P
Pain 23, 44
abdominal 301
chest 127
mild abdominal 23
Peripheral insulin resistance 231
Phentermine-topiramate 267
Phenytoin 287
Phosphatase 221
Phosphodiesterase 163, 221
Physicochemical characteristics 201
Pituitary apoplexy 260
Pituitary gonadotropin release 14
Pituitary injury 151
Pituitary suppression 109
Placental syncytiotrophoblasts: 318
Plasma
concentration 270
proteins 285
triglyceride concentrations 202
Platelets
maternal 212
role of 212
Polycystic ovarian syndrome 14, 31, 33, 42, 47, 50, 54, 93, 143, 156, 184, 231, 259, 266, 279, 294, 317, 318
Polymerase chain reaction 321
Poor ovarian responders 154
Poor responder 190, 191
Porphyria 8
Postcoital emergency contraceptive 300
Precocious puberty 81
Prednisolone 16
Prednisone 181
Preeclampsia, prevention of 212
Pregnancy 16, 34, 199
failures, early 207
loss
recurrent 34, 174, 175, 190, 192, 211
unexplained recurrent 175
rate 54
termination of 300
test, false positive 81
Pregnanolone 125
Premature ovarian failure 136
Progesterone 103f, 112, 113, 124, 126, 126t, 129, 293, 294
absence of 299
action 124
functions of 133b
hormone 123
induced blocking factor 124
levels 124, 125f
mechanism of action of 113f
micronized 125, 133, 136
presence of 299
primed ovarian stimulation 136
receptor 113, 130, 285, 299
modulator 286, 299
selective 129
Progestins 113
micronized 119
molecular structure of 116t
pharmacokinetics of 114t
Prolactin 257, 294
Prolactinoma 258
Propylthiouracil 311
Prostaglandin 54, 306
E 271
F 271
production of 270
synthesis inhibition 208
Prostate cancer 93
Protein
C deficiency 8
kinase 221
A 20, 322
Proteomic gene expression 79
Pruritis 272
Puberty, central precocious 93
Pulmonary embolism 105, 174
Pulmonary infarction 35
Pyrexia 272
R
Radiation 151
Randomized comparative trial 127
Randomized controlled trial 6, 33, 54, 157, 210, 318
Rash 272
Reactive oxygen species 291, 294
Recombinant follicle-stimulating hormone 22, 54
Recombinant granulocyte colony-stimulating factor 191
Recombinant human chorionic gonadotropin 70, 80
Recurrent implantation failure 79, 162, 175, 191, 195, 199, 271
Renal dysfunction 128, 198
Renal failure, acute 196
Renin-angiotensin-aldosterone system 227
Reproduction 34, 199
Reproductive dysfunction 207
Reproductive failure 193
Reproductive immunology 193
Reproductive medicine 76t
Resistance index 166
Respiratory distress syndrome, acute 35
Retroprogesterone 129
Revised Sapporo criteria 175t
Ribonucleic acid 223
Rifampicin 287
S
Salicylate poisoning, acute 209
Salicylism syndrome 209
Selenium 220, 281
lack of 220
Seminal plasma calcium 221
Semisynthetic ergot alkaloids 257
Serum estradiol 32
Sex hormone-binding globulin 113, 151, 232
Signal transductional pathways, model of 20f
Sildenafil 162, 163, 167
beneficial effect of 167
citrate 162, 169t
molecular structure of 163f
on sperms, effect of 168
review of literature on 165
role of 165, 166, 167
Skin changes 65
Small intestine 221, 222
upper 223
Smooth muscle cells 212
Sole agonist 91
Sperm
function 322
parameters 322
Spermatogenesis, stages of 219
Spermatozoa 221
mature 223
Spermatozoal oxidative stress 292
Steroid 179, 201
administration, physiological effects of 180f
Stimulation protocols 89
mild 55
Stomach 221
Stroke 8, 35, 106
Superoxide anion 291
Suprachiasmatic nuclei 280
Synchronize cycles 115
Synthetic progestational hormone 129
Synthetic progestins 112
classification of 112
indications of 117t
T
Tachycardia 272
Tacrolimus 193
Tacrolimus 203
Tamoxifen 60, 6264
molecular characteristics of 61t
molecule 60
chemical structure of 61f
three-dimensional representation of 61f
side effects 64
Telapristone 301
Tenderness 288
Testes, undescended 80
Testicular function 321
Testicular sperm extraction 168
Testosterone 149, 150
deficiency
laboratory diagnosis of 152t
treatment for 153
hormone synthesis 150fc
indications of 150, 151
levels, regulation of 150f
replacement therapy 152
supplementation
forms of 151
therapy 152
Thermosensitive bioadhesive vaginal gel 164
Thioredoxin system 280
Thrombocytopenia, heparin-induced 173
Thromboembolic disorder 8
Thrombophilia, inherited 175
Thrombophlebitis 127
Thrombosis 196
Thyroid
disorders 307, 314fc
hormone
pharmacodynamics of 311, 311t
synthesis of 308, 309fc
peroxidase antibodies 314
releasing hormone 308, 309
status 313t
stimulating hormone 19, 69, 72, 308, 309, 314
receptor 309
Thyroxine 307
chemical structure of 307f
different forms of 308f
hormone 308, 310
excretion of 310fc
Tongue 127
Total testosterone 151, 152
Transdermal estradiol patches 8
Transfusion-related acute lung injury 197
Transient hot flushes 15
Transvaginal ultrasound 31
Trauma 151
Triamcinolone 181
Triglycerides 268
Trigonella foenum-graecum Linn 228
Triiodothyronine 307, 310t
Trophoblastic invasion 77
Trophoblastic tissue 189, 190f
Tuberculosis 200
Tuberoinfundibular neurons 257
Tumor necrosis factor 198
alpha 198, 320
Tyrosine 307
U
Ubiquinol 292
Ulipristal acetate 285, 287, 299
structure of 285f
Ultraviolet B 316
Urinary follicle-stimulating hormone 22
Urinary gonadotropins 23, 36
Urinary human chorionic gonadotropin 70
Urofollitropin 22
Uterine artery blood flow 166
Uterine bleeding
abnormal 117
treatment of 112
dysfunctional 93, 123
Uterine contractions 270, 273
reduction of 271
Uterine fibroids 92
management of 285
Uterine leiomyoma 106
Uterine volumetric flow 166
V
Vaginal bleeding 8, 16, 127
Vaginal discharge 65
Vaginal progesterone 135, 137
groups 135
Vaginal sildenafil, role of 166
Vaginal suppositories 164
Vascular endothelial growth factor 57, 91, 167, 184, 189, 190, 233, 259
Vasopressin 269
Venous thromboembolism 174, 175
enoxaparin, prophylaxis of 176t
Viagra 168
Viral hepatitis, acute 118
Viral infections 127
Visual disturbances 16
Vitamin
A 228
B, water-soluble group 222
B12 217, 228
structure of 217f
B2 228
B6 216, 228
structure of 216f
binding protein 316
chemical structure of 315f
deficiency 318, 321
in testicular function, role of 322t
insufficient 321
levels 322
mechanism of action of 317fc
metabolism 316fc
receptor 316, 322
receptor polymorphism, role of 319
role of 316
status 321
sufficient 321
supplementation 321t
transport 319
D1 315
D2 315
D3 315
E 215, 217, 281
pharmacokinetics of 219t
role of 282
structure of 218f
role of 218
Vomiting 23, 44, 127, 233, 272, 301
W
Weight loss 65
World Health Organization 112, 265
Z
Zinc 219, 282
role of 219, 220t
Zomacton 145
Zuclomiphene 13, 14
×
Chapter Notes

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1Drugs Used in Endometrial Preparation
SECTION OUTLINE
  1. Estrogen2

EstrogenCHAPTER 1

Fessy Louis T,
Parvathy T
 
INTRODUCTION
Estrogen is one of the female sex hormone. There are three major endogenous estrogens namely estrone (E1), estradiol (E2), and estriol (Fig. 1). Among them E2 is the most potent and the most prevalent one. There are a large number of synthetic estrogen preparations which might be steroidal or nonsteroidal. Various preparations of synthetic estrogens that are clinically used include E2 valerate, E2 cypionate, E2 benzoate, E2 undecylate, and polyestradiol phosphate. Ethinyl E2 is the most widely used synthetic analog of E2.
 
ROUTES OF ADMINISTRATION
There are various routes of estrogen administration namely oral, vaginal, intramuscular, and patches or gel. Among these, oral route is the simplest and well-tolerated mode of administration. E2 form after oral administration undergo extensive metabolism in the intestinal mucosa and in liver and is converted to E1 and estrone sulfate (E1S). The E1 level gradually increases after oral administration and become higher than E2. While in transdermal preparations significantly less amount of E2 is converted to E1.
zoom view
Fig. 1: Structure of estrogen isoforms.
4
 
PHARMACOKINETICS
After oral or parenteral administration, E2 valerate, the synthesis compound contained in various commercially available preparations, is completely converted into the natural substances 17p-E2 and valeric acid. The 17 beta-E2 produced on cleavage of the ester behaves in the organism like the endogenous steroid hormone. E2 valerate and 17 beta-E2 are virtually dose equivalent. No differences in the spectrum of action of the estrogen and its ester have been found either in animal experiments or man. The pharmacokinetic behavior and the biotransformation of the 17p-E2 originating from E2 valerate are no different from those of natural 17 beta-E2. Differences of practical significance exist in respect of the quantitative effect of E2 valerate following oral and intramuscular administration. 4 mg E2 valerate administered intramuscularly is therapeutically sufficient for a period of 2–4 weeks producing a depot effect. While 2 mg daily oral preparation need to give for 3 weeks to produce the same effect.
 
Pharmacodynamics
Following parenteral administration of E2 valerate, 17% E2 becomes completely bioavailable in man. Because of the delayed release of the steroid ester from the intramuscular depot referred to earlier the blood level does not reach its maximum for 3–5 days, after which it falls slowly, with a half-life of 4–5 days. A distinct increase in the 17p-E2 level can be achieved over a period of about 14 days, with an intramuscular injection of 4 mg E2 valerate.
When compared with the parenteral route of administration, the bioavailability of the estrogen after oral administration is greatly limited due to the metabolic process in the gastrointestinal tract, the intestinal wall, and the liver (during the first passage). As the metabolites are much less estrogenic than unchanged 17 beta-E2, higher dose E2 valerate must be used for oral medication than for parenteral administration.
 
METABOLISM AND ELIMINATION
The 17 beta-E2 arising in vivo from E2 valerate behaves in the organism behaves like endogenous 17 beta-E2 and is subject to intermediate metabolism. Regardless of the route of administration, not only 17 beta-E2 but also E1 and estriol occur in human plasma following administration of E2 valerate. However, the plasma concentration of the free steroids, with their differing potency, is low in comparison with the concentration of their 5conjugates. In man the metabolites of 17 beta-E2 are primarily eliminated by the kidneys regardless of the route of administration, the vast majority of the metabolites arising from E2 valerate (80%) were found in the urine.
 
USES OF ESTROGEN PREPARATIONS
The clinical uses of E2 include for synchronization and preparation of endometrium in frozen embryo transfer (FET) cycle, treatment of thin endometrium and as a luteal phase manipulator in poor responders prior to stimulation to increase the number of oocytes.
Now FET is one of the most common components of assisted reproductive technology (ART). The FET cycle is having success rate in par with the fresh embryo transfer cycles. Implantation is one of the most important components of successful ART which depend on three factors including embryo quality, endometrial receptivity, and synchrony between embryo and endometrium. The endometrial receptivity during the implantation depend on both progesterone and estrogen level. The role of progesterone in luteal phase support has been well documented, while the exact role of estrogen in luteal phase is not clear. Some investigators have advocated supplementing E2 during the luteal phase of ART cycles. Subsequently, meta-analyses argued against this practice as being not justified based on results. The debate persists; however, some groups prefer estrogen for luteal phase support after ET while others do not.
Estradiol pretreatment is mandatory; however, for priming endometrial receptivity for FET. Decades of ART and donor egg activity have revealed that E2 administration is relatively simple, effective, and extremely forgiving. Various regimens are proposed for endometrial preparation in FET. E2 supplementation causes the proliferation of endometrial cells and causes endometrial thickness. The E2 supplementation not only causes endometrial thickening but also induction of appropriate progesterone receptors to improve the endometrial receptivity. The daily oral administration of 4–8 mg of E2 reproduces the serum levels and peripheral effects of E2 as seen in the menstrual cycle. The excess liver exposure due to the first liver pass effect inherent to oral administration may cause problem in certain individuals, notably in women at higher risk of venothromboembolism accidents. In these individuals, E2 should not be administered orally if at all possible and/or preventive medication (e.g. low molecular weight heparin) should be provided simultaneously.
 
ORAL FORMULATIONS USED IN INFERTILITY PRACTICE
Oral preparation, E2 valerate is subjected to extensive first pass metabolism and gets converted to E1, estriol, and 17 beta-E2. There are various regimens used for estrogen supplementation. Usually used regimen is variable low-dose step-up regimen starting with E2 valerate 2 mg once daily for 2–4 days 6followed by twice daily for 4 days and then stepped up to thrice daily for 4 days. Progesterone is added once the endometrial thickness reaches 7 mm or more. Some prefer using transdermal patches for endometrial preparation.
The intense liver metabolism of orally administered E2 renders this route of administration vulnerable to the effect of enzymatic inductors, such as psychotropic medications. Women exposed to enzymatic inductors are notably resistant to the effect of oral E2. In these cases, it is preferable to revert to nonoral administration.
Estradiol valerate, a prodrug of E2 is an E2 ester. It can be considered as an agonist of estrogen receptors. The affinity of E2 valerate for estrogen receptors is approximately 50 times lower than that of E2. Micronized E2 is rapidly and completely absorbed on oral administration.
Estradiol hemihydrate is the micronized form of 17 beta-E2, the most potent naturally produced estrogen. E2 hemihydrate diffuses through the cell membrane and binds to and subsequently activates nuclear estrogen receptor.
 
OTHER ROUTES OF ADMINISTRATION
Apart from the oral mode of administration, other routes of administration include intramuscular, transdermal, and vaginal. All these routes help to avoid first pass liver metabolism which is one of the main limitation of oral mode of administration. But on comparing the pregnancy rates with different modes of administration all the preparations achieved almost similar rates. Among these, commonly used regimen is the transdermal mode. Transdermal administration of E2 can be done using skin systems or gels. In ART, skin systems have been generally preferred because they allow us to more precisely adjust the administered dose. Basically, it suffices to choose the doses of E2 normally produced by the ovary (mean production rate of 0.2 mg/24 hours) for reproducing similar blood levels and peripheral effects of E2. During nonoral administration of E2, E1 levels remain in the physiological range: E2/E1 >1. By contrast, E1 levels are nearly 10 times higher than E2 following oral administration. To this day; however, no detrimental effects have been recognized regarding the pharmacological levels of E1 induced by oral E2 administration. The transdermal systems have been found to be possibly weakly effective in overweight and/or obese women, in whom oral administration will be preferred. Finally, transdermal systems may become poorly effective in case of hot and humid weather. One practical element for enhancing the adhesion of transdermal skin systems consists of wiping off skin grease with a tissue. The advantage over oral form is that it attains good serum concentration. Its disadvantage is that it might prove to be slightly inconvenient because several patches have to be simultaneously used to achieve and maintain serum concentration. One of the randomized controlled trial (RCT) comparing the use of E2 patches with the oral E2 in FET cycles found no difference in FET cycles.7
Estradiol can also be administered vaginally. While especially designed creams exist in the USA, numerous investigators have simply given oral tablets vaginally. This, however, results in extremely high serum levels, but without further hepatic impact than is encountered with oral tablets. Vaginal E2 can be a valuable alternative, particularly for women whose endometrial response to E2 appears impaired. With transvaginal estrogen it can attain high serum and endometrial concentration and is considered as a good alternative to oral preparation. Usually used preparation includes hemihydrate. Many studies have shown that when hemihydrates is combined with clomiphene, the endometrial thickness improves but with no effect on pregnancy rates. Similarly, data from egg donation programs, in which oral and vaginal micronized estrogen administration were compared, proved a valid alternative in safety terms. But this is not the only alternative, as possible interactions between estrogens and progesterone may occur at the vaginal mucosa, as well as a drop in serum E2 concentrations in the luteal phase, or even a more marked difficulty of progesterone compensating higher uterine contractility due to increased E2 concentrations. These phenomena might have a negative impact on embryo implantation. The vaginal route may improve patient tolerance and symptoms, but one RCT have not shown any improvement in endometrial thickness, not even with other cointerventions, although the study sample was limited.
 
OTHER USES OF ESTROGEN
Another application of estrogen supplementation is as part of treatment of thin endometrium. One of the treatments proposed is progressive step up increase in the dose that stimulates a natural cycle. So patients can start with high dose (6–8 mg or up to 16 mg) continuously from cycle day 1, unless the tolerance is poor. In general, 2 mg suffice to block the hypothalamus–pituitary–ovary axis so there is no need to add gonadotropin-releasing hormone analogs in the luteal phase as this may compromise endometrial vascular flow and proliferation. Another treatment suggested for thin endometrium is the use of extended use of estrogen. However, most studies come from the FET cycles. Chen et al. have evaluated the effect of extended administration of E2 valerate during controlled ovarian hyperstimulation cycles and found that mean endometrial thickness in the study group increased significantly from 6.7 mm to 8.6 mm following an extended estrogen therapy for 14–82 days. The pregnancy rate in the study group was significantly higher than that in the control group (38.5% vs. 4.3%). Embryo implantation is undoubtedly one of the most critical steps in the ART process. Implantation success depends on the cross talk between embryo and endometrium. A critical level of estrogen is essential in regulating the window of uterine receptivity for implantation. Oral estrogen preparations are preferred due to their efficacy and ease of use (Table 1).8
Table 1   Pharmacologically available estrogen preparations in infertility practice.
Drug
Dose
Oral estradiol valerate
2 mg step up protocol
Conjugated equine estrogen
0.625 mg
Transdermal estradiol patches/gels
0.1–0.2 mg step up protocol
Estradiol hemihydrate
2 mg step up protocol
 
CONTRAINDICATIONS FOR ESTROGEN THERAPY
  • History of breast cancer
  • History of endometrial cancer
  • Porphyria
  • Severe active liver disease
  • Thromboembolic disorder
  • Undiagnosed vaginal bleeding
  • Migraine headache
  • Stroke
  • Lung embolism
  • Increased risk of cardiovascular event
  • Protein C deficiency
 
SIDE EFFECTS OF ESTROGEN THERAPY
  • Abdominal bloating
  • Bloating
  • Break through bleeding
  • Breast tenderness/pain
  • Freckles or darkening of facial skin (melasma)
  • Menstrual pattern change
SUGGESTED READING
  1. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731–46.
  1. Cetinkaya K, Kandanali S. The effect of administering vaginal estrogen to clomiphene citrate stimulated cycles on endometrial thickness and pregnancy in unexplained infertility. J Turk Ger Gynecol Assoc. 2012;13:157–61.
  1. Chen MJ, Yang JH, Peng FH, et al. Extended estrogen administration for women with thin endometrium in frozen-thawed in-vitro fertilization programs. J Assist Reprod Genet. 2006;23:337–42.
  1. Davar R, Janati S, Mohseni F, et al. A comparison of the effects of transdermal estradiol and estradiol valerate on endometrial receptivity in frozen-thawed embryo transfer cycles: a randomized controlled trial. J Reprod Infertil. 2016;17(2):97–103.9
  1. Fanchin R, Righini C, Schönauer LM, et al. Vaginal versus oral E(2) administration: effects on endometrial thickness, uterine perfusion, and contractility. Fertil Steril. 2001;76:994–8.
  1. Kuhl H. Pharmacokinetics of estrogen and progesterone. Matuuritas. 1990;12(3):171–97.
  1. Serna J, Cholquevilque JL, Cela V, et al. Estradiol supplementation during the luteal phase of IVF–ICSI patients: a randomized, controlled trial. Fertil Steril. 2008;90:2190–5.
  1. Shen MS, Wang CW, Chen CH, et al. New horizon on successful management for a woman with repeated implantation failure due to unresponsive thin endometrium: use of extended estrogen supplementation. J Obstet Gynaecol Res. 2013;39:1092–4.
  1. Tourgeman DE, Gentzchein E, Stanczyk FZ, et al. Serum and tissue hormone levels of vaginally and orally administered estradiol. Am J Obstet Gynecol. 1999;180:1480–3.10