Female Infertilty: Core Principles and Clinical Management Jayant Mehta, Bryan Woodward
INDEX
Note: Page numbers in bold or italic refer to tables or figures respectively.
A
Abnormal uterine bleeding (AUB) 21
Absolute uterine factor infertility (AUFI) 143, 144 see also Uterine transplantation (UTx)
ACGH see Array comparative genomic hybridization (aCGH)
Acupuncture 34
Adipose tissue 30
distribution of 30, 31
Age
and chromosomal abnormalities risk 108
and fertility 75
Alcohol consumption, and fertility 10, 33
Amenorrhea
causes of 13
history of 12
AMH see Anti-Müllerian hormone (AMH)
Amniocentesis 108, 124, 137
Anaphase lag 113
Androgens 7, 11, 86
Anembryonic pregnancy 106, 107
Anemia, in pregnancy 9, 29
Aneuploidy 113
Angelman's syndrome 115, 115
Anovulation
and female infertility 23
treatment options 2425
WHO I hypogonadotropic-hypogonadism 2324, 24
WHO III hypergonadotropic hypogonadism 24, 24, 25
WHO II normogonadotropic, normogonadism 24, 24
Anticardiolipin antibodies, test for 13
Anticipated gamete exhaustion (AGE) banking 152153
Anti-Müllerian hormone (AMH) 15, 37, 75
automated assays 37
circadian variation in 39
comorbidities and 38
endocrine environment and 38
ethnicitiy and 38
inter-individual variation 37, 37
intra-individual variation 3839
obesity and 38
smoking and 38
Antioxidants 29
food sources of 30
reactive oxygen species and 30
Antiphospholipid syndrome 87
Anti-tuberculous therapy 19
Antral follicle count (AFC) 15,15, 39, 75
age-related decline in 40
inter-individual variation 40, 40
intra-individual variation 40
as measure of ovarian reserve 3940
technical issues in determination of 3940
Apoptotic wave 5
Aromatase inhibitor 4849
Array comparative genomic hybridization (aCGH) 118, 119121, 120
ART see Assisted reproductive technology (ART)
Asherman's syndrome 144
Aspirin 13, 88, 147
Assisted hatching (AH) 89
Assisted reproductive technology (ART) 86, 129
diagnosis of pregnancy 105, 105106, 106
ectopic pregnancy 106
gestational surrogacy and 9192 (see also Surrogacy)
heterotopic pregnancy, risk of 106
and miscarriage 106107
and multiple pregnancies 107108, 108
Azithromycin 19
B
Barker hypothesis 27
Bartholin's glands 5
Basal body temperature (BBT) 14, 14
Benzathine penicillin G 19
Beta-human chorionic gonadotropin (β-hCG) 105, 106
Bicornuate uterus 22, 22
Bioengineered uterine patch 150
Bisphenol A (BPA) 33
Blastocyst biopsy 117118, 118
Blastomere biopsy 117, 117
Body mass index (BMI) 9, 30, 30
Bone marrow stem cells 88
C
Caffeine 3233, 33
Carnitine 34
Carrier screening, for oocyte donors 76
Ceftriaxone 19
Cell culture protocols 130131
Cell cycle 113, 114
Cell-free DNA 108
Cell-free fetal DNA (cffDNA) 124125
Cervical cytology 10
Cervical intraepithelial neoplasia 22
Cervical mucus 2, 15, 22
assessment of 15
Cervical polyps 22, 22
Cervix 2
assessment of 22
tight 22
Chlamydia trachomatis infection 19, 19
Chocolate cysts 23
Chorionicity, determination of 107
Chorionic villus sampling (CVS) 108, 124, 124, 137
Chromosomal abnormalities
analytical methods for detection of 118121
chromosomal structure and origin of 111, 111112
insertions 115
inversions 115
maternal age and risk of 108
numerical 112113
reciprocal translocation 114
Robertsonian translocation 114115
structural 113115, 114
uniparental disomy 115
Chromosome structure 111, 111, 112
Chronic progressive external ophthalmoplegia (CPEO) 138
Cigarette smoking, and pregnancy 1011
Cleavage-stage biopsy 117, 117
Clinical commissioning groups (CCGs) 102
Clomiphene citrate (CC) 48, 61
for polycystic ovary syndrome 24
COC see Cumulus-oocyte complex (COC)
Coenzyme Q10 (CoQ10) 33
Colony-stimulating factors (CSFs) 86
Complementary and alternative medicine (CAM) 34
Controlled ovarian stimulation (COS), in oocyte donors 7879, 151
Corpus luteum 11, 14
Corpus luteum cysts 23
Cortical reaction 66
Counseling services, at fertility clinic 99100
licence conditions for counseling 99
CPAs see Cryoprotective agents (CPAs)
Crown-rump length (CRL) 107
Cryoprotective agents (CPAs) 153
for oocyte vitrification 154
for ovarian tissue freezing 155156
Cumulus-oocyte complex (COC) 67, 70
conventional IVF insemination 7071, 72
CVS see Chorionic villus sampling (CVS)
Cyclosporin A (CsA) 145
Cystadenomas 23
Cystic fibrosis (CF) 77, 116
Cytokines, role of, in implantation 86
D
Dairy products, and fertility 32
Danazol 57, 57, 58
Dehydroepiandrosterone (DHEA) 33
Denudation 7172
Denudation pipettes 72
Dermoid cysts 23
Diet and lifestyle, impact on fertility see Pre-conception nutrition and lifestyle
Differentiation 129
of human pluripotent cells to oocytes 133134
of mouse pluripotent cells to oocytes 131133
Dioxins 31, 32
Dispermy 112
DNA fragmentation index (DFI) 87
Doderlein's bacilli 2, 2, 5
Down syndrome 108, 113, 123
Doxycycline 19
Drug-induced ovulation 61
classical ovulation induction 61
superovulation and IVF 6162, 62
Drugs in fertility treatment and nutrients, interactions between 34
Duchenne muscular dystrophy (DMD) 116
Dysmenorrhea 13, 53
Dyspareunia 53
E
Early pregnancy, management of 105108
chromosomal abnormality, tests for 108
gestational sac 105, 106
pregnancy detection and 105106
ultrasound scan in 105, 105, 106
Ectopic pregnancy 106
Edwards syndrome 113, 123
Elective single-embryo transfer (eSET) 94, 116
Embryonic mosaicism 117118
Embryonic stem cell (ESC) 129, 129
Embryo transfer (ET) 86, 105
Emotional impact, of infertility 99
Endometrial cancer 22
Endometrial hyperplasia 2122
Endometrial polyp 21
Endometrial receptivity array (ERA) 88
Endometrial scratch 89
Endometriosis 31, 53, 53
assisted reproductive techniques 58, 5859
coelomic metaplasia theory 55
deep infiltrating 53
diet and 3132
epidemiology 53
hormonal treatment 57, 58
and infertility 56, 56, 5759
locations of lesions 53, 54
magnetic resonance imaging 54
ovarian 53
pain with 53, 57, 57
retrograde menstruation theory 55
risk factors 56
screening for 54
severity classification 5455, 55
superficial 53
support groups 59
surgical treatment 57, 58
symptoms 53
ultrasonographic diagnosis 54, 54
vascular–lymphatic theory 5556
and vitamin D supplementation 32
Endometriosis fertility index (EFI) 55
Endometrium 2, 86
assessment of 1516
hormonal effects on 11, 12
thin 88
Estradiol 6, 11
Estriol 11
Estrogens 11
Estrone 11
European Union Tissues and Cells Directives (EUTCDs) 81
Exercise, effect of 34
Expanded carrier screening (ECS) 76
F
Fallopian tube anatomy and neurovascular supply 34, 3, 5
Fatty acids, effects of, on health and fertility 28, 28
Female menstrual cycle
endometrium, hormonal effects on 11, 12
hormonal changes 11, 11
Female reproductive system anatomy and physiology 14, 24
Fertility counseling process 100
Fertility Europe 100
Fertility Fairness, UK 99, 100, 102
Fertility preservation (FP) 151157 see also Oocyte preservation; Ovarian tissue cryopreservation
Fertilization 3, 7
conventional IVF insemination 7071, 72
intracytoplasmic sperm injection 7173, 73
Fetal alcohol syndrome 10
Fibroids, in uterus 16, 16, 21
Fluorescent in situ hybridization (FISH) 118119, 119
Folate
deficiency 28
supplementation 10, 28, 105
synthesis 28, 29
Follicle stimulating hormone (FSH) 5, 6, 7, 11, 15, 2325, 33, 38, 47
Follicular cysts 23
Follicular fluid (FF) 69
Fragile X syndrome (FXS) 24, 76, 78, 78, 79
Frankenhäuser ganglia 5
Freeze-all strategy 87
FSH see Follicle stimulating hormone (FSH)
G
Galactorrhea 16
Galactose 32
Genetic disorders 115
monogenic autosomal dominant disorders 116
monogenic autosomal recessive disorders 115116
X-linked disorders 116
Gestational diabetes, in oocyte recipients 81
Glycemic control, pre-conception 30
Gonadal dysgenesis 75
Gonadotropin-releasing hormone (GnRH) 6, 7, 11
agonists 61, 79, 86
antagonists 7879
Gonadotropin therapy 4950, 50, 50
Gonorrhea 19, 19
Granulocyte colony-stimulating factor (G-CSF) 88
Gynecological examination 14
H
Hemagglutinating virus of Japan envelope (HVJ-E) 139, 140
Hematinics, deficiency of 9
Hematopoietic stem cells (HSCs) 130
Hemoglobinopathies, screening for 10
Hemorrhagic cyst 23
Herbal medicine 3435
Heteroplasmy 137
Heterotopic pregnancy 106
History taking 1214, 13
Homoplasmy 137
Hormone replacement therapy (HRT) 25
Human chorionic gonadotropin (hCG) 4, 7, 61, 86
Human Fertilisation and Embryology Act 1990, UK 94, 99
Human Fertilization and Embryology Authority (HFEA), UK 91, 93, 99, 102
licence conditions for counseling 99
on mitochondrial donation 141
Multiple Births Report 2015 107
‘One at a Time’ policy 102
Human leukocyte antigen (HLA) system 86, 88
Human menopausal gonadotropin (hMG) 61
Hyaluronan (HA) 72
Hyaluronidase (Hyase) 71, 72
Hydrosalpinx 2021, 21, 88
bilateral 20
unilateral 20
Hyperprolactinemia 16
Hypertensive disorders, in oocyte recipients 81
Hypogonadotrophic hypogonadism 16
Hypothalamic–pituitary–ovarian axis 11, 11
Hysterectomy 143
Hysterosalpingography (HSG) 20, 20
Hysterosalpingo sonography 20
contrast saline-based medium (HyCoSy) 20
hyperechogenic foam (HyFoSy) 20
Hysteroscopy, for uterine cavity evaluation 8788
I
ICSI see Intracytoplasmic sperm injection (ICSI)
Immunomodulatory therapies 88
Implantation 7, 85
adhesion stage 85, 85
apposition phase 85, 85
cumulus cells in, role of 86
definition 85
failure (see Recurrent implantation failure (RIF))
hormonal factors and role of cytokines 86
immune system, role of 86
invasion stage 85, 85
and natural selection 86
window of 86
Imprinting 115
Induced pluripotent stem cells (iPSCs) 129, 129
Infertility
definiton of 9
endocrine investigations 16
examination in 14
female menstrual cycle and 9
history 1214
preconception issues 911
reproductive function assessment 1416
Injectable gonadotropins 61
Inner cell mass (ICM) 129
Insertions, chromosomal 115, 114
Insulin levels, measurement of 16
Insulin sensitizers 49
Interchromosomal effect (ICE) 121
Intercourse frequency, and infertility 12
Interleukin (IL) systems 86
Intraclass correlation coefficient (ICC) 39
Intracytoplasmic sperm injection (ICSI) 19, 65, 7173, 73, 140
considerations for 73
injection procedure 7273
intracytoplasmic morphologically-selected sperm injection (IMSI) 73
micromanipulation equipment 72, 73
motile sperm organelle morphology examination (MSOME) 73
oocytes preparation for 7172
polyvinylpyrrolidone, use of 74
Intraluminal fibrosis 20
Intrauterine insemination (IUI) 91
Intrauterine pregnancy of unknown viability 106
Intrauterine synechaie 21
Inversions 115
paracentric 115
pericentric 115
In vitro fertilization (IVF) 7, 19, 20, 65, 86 see also Recurrent implantation failure (RIF)
funding and financial issues 101102
insemination procedure 7071, 72
for women with polycystic ovaries 5051
Iodine, in pregnancy 29
Iron deficiency anemia 29
Iron supplementation, in pregnancy 29
IVF see In vitro fertilization (IVF)
K
Karyotyping 13, 7778, 88
Kearns–Sayre syndrome (KSS) 138
Klinefelter syndrome 113
L
Laparoscopic oocyte recovery 69 see also Oocyte collection
Laparoscopic ovarian drilling (LOD) 50
L-arginine 88
Leber's hereditary optic neuropathy (LHON) 138
Leigh syndrome 138
Letrozole 25, 4849, 61, 151
Leukemia inhibitory factor (LIF) 86
Lichen simplex chronicus (LSC) 14
Low molecular weight heparin 13
Lupus anticoagulant, test for 13
Luteal phase deficiency (LPD) 23
Luteal phase progesterone 7
Luteinizing hormone (LH) 4, 6, 6, 11, 23
M
Macronutrients
carbohydrates 27
fats 28, 28
female reproduction, influence on 27
protein 28
Macroprolactin 16
Massively parallel shotgun sequencing (MPSS) 125
Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome 14, 91, 143 see also Müllerian agenesis
Meal timing and body weight 31
Mean corpuscular volume (MCV) 78
Mean sac diameter (MSD) 106
Measles, mumps and rubella (MMR) vaccination 910
Mediterranean diet 27, 27
Melatonin 34
Menstruation 11
amount of bleeding during 13
Metabolomics 68
Metformin 30, 49
Methotrexate 106
Microdeletion screening 126
Micronutrients 28
folate 28, 29
iodine 29
iron 29
vitamin D 2829
Miscarriage 106107
recurrent 13
Misoprostol 107
Mitochondria 137, 137
Mitochondrial DNA (mtDNA) disease 137, 138 see also Mitochondrial donation
oocyte donation 138
preimplantation genetic diagnosis 138
prenatal genetic diagnosis 137138
reducing/avoiding of, options for 137138
Mitochondrial donation 137, 138
cytoplast lysis 141
karyoplast lysis 141
procedure 140141
pronuclei (PN) transfer 139, 139140, 140
regulation 141
spindle transfer 138, 139
training for 141
Mitochondrial encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS) 138
Mitotic polyploidy 112, 112
Modified Strassman procedure 143
Monochorionic pregnancies 107
Monogenic autosomal dominant disorders 116
Monogenic autosomal recessive disorders 115116
Mosaicism 113
in trophectoderm biopsies 117118
Multiple cysts, in ovaries 23
Multiple pregnancy 107108
chorionicity in 107
and preterm delivery risk 108
risks associated with 108
Multiplex polymerase chain reaction 118, 119
Mycophenolate mofetil (MMF) 146
Mycoplasma (Ureaplasma urealyticum) 19, 20
Myoclonic epilepsy with ragged-red fibers (MERRF) 138
Myo-inositol 34
Myotonic dystrophy 116
N
Nabothian cysts 2, 5
Neisseria gonorrhoeae 19, 1920
Neural tube defects 105
Neurodermatitis 14
Neuropathy, ataxia and retinitis pigmentosa (NARP) 138
Next-generation sequencing (NGS) 118, 121
NIPT see Noninvasive prenatal testing (NIPT)
Nondisjunction 113, 114
Nongrowing follicles (NGFs) 37
Noninvasive prenatal testing (NIPT) 108, 123, 137138
amniocentesis 108, 124, 137
biology and screening tests 124125
chorionic villus sampling 124, 124
clinical applications 125126
combined test 123, 123
future of 126127
integrated test 123, 123124
massively parallel shotgun sequencing (MPSS) 125
methods 125
quadruple test 123, 123124
qualitative single nucleotide polymorphism (SNP) 125
targeted massively paralleled sequencing (MPS) 125
timing of testing 124
ultrasound scanning and biochemical markers combination 123, 123124
Nucleic acid amplification tests (NAT) 10
Nurses’ Health Study II 28
Nutrition and fertility, link between see Pre-conception nutrition and lifestyle
O
Obesity
insulin resistance in 16
and pregnancy 9
OHSS see Ovarian hyperstimulation syndrome (OHSS)
Oligomenorrhea 23, 24
Oligozoospermia 19
Omega three fatty acids 32
Online support 101
Oocyte 4, 5, 6, 11, 65, 129
biological structure 6567
centrosome 6667
checking for fertilization 73, 73
collection procedure (see Oocyte collection)
conventional IVF insemination 7071, 72
cortical granules (CGs) 66, 67
fertilized 7
grading 68
intracytoplasmic sperm injection 7173, 73
mitochondria 67
oolemma 65
ooplasm 65, 66
perivitelline space (PVS) 65, 66
quality, assessment of 6768, 68
shapes and sizes 68, 68
smooth endoplasmic reticulum (SER) and SER discs 67, 67
transzonal projections (TZPs) 65, 66
in vitro differentiation to oocytes 130131
in vitro maturation (IVM) 151, 154155
in vitro processing of, in IVF laboratory 6970, 71
in vivo oocyte development 130, 131
zona pellucida 6566, 66
Oocyte aneuploidy 67
Oocyte banking
cycles without super-ovulation 151152
cycles with super-ovulation 151
Oocyte collection
day before 6869
double lumen needle use 69
high aspiration pressure during 69, 70
methods for 69
preparation for 68
single lumen needle use 69
Oocyte donation 75
altruism 8182
blood tests 76
carrier screening tests 76
compliance 82
confidentiality 82
controlled ovarian stimulation for 7879
donor candidate, selection of 7576
genetic screening 7677
international legislation and legal framework 81, 81
karyotyping 7778
medical interview 76
number of children born from one donor 82
for older women 75
physical and gynecological examination 76
use of, reasons for 75
Oocyte preservation
for anticipation of gamete exhaustion 152153
for oncofertility 151152
by slow freezing 153
by vitrification 153 (see also Vitrification of oocytes)
Oocyte recipients
artificial endometrial cycle 80
endometrial preparation in 80
medical tests for 79, 7980
natural or modified natural cycle 80
obstetrical risks in 8081
Oocyte vitrification 151, 153 see also Vitrification of oocytes
Oogenesis and oocytes production
follicular growth 5
indifferent gonad stage 5
oogonal multiplication and oocyte formation 5
ovarian differentiation 5
Oral ovulation induction (OI) 25
Ovarian cysts 23, 23
Ovarian drilling 13, 13, 25
Ovarian endometrioma 23
Ovarian follicles 4
Ovarian hyperstimulation syndrome (OHSS) 49, 6263, 63, 78, 151
Ovarian reserve 13, 15, 23, 37
Ovarian response, biomarkers for 37
AMH and AFC performance, comparison of 4143, 42, 42
anti-Mullerian hormone 3739
antral follicle count 3940
tailoring treatment based on 43, 43
Ovarian stimulatory medications 61
Ovarian tissue banking 152
Ovarian tissue cryopreservation
ex-vivo oocyte harvesting and IVM 156157
ovarian cortex preparation 155, 156
ovarian tissue freezing 155156
Ovaries 2223
blood supply to 4
early development of 5
hormone receptor expression 67
innervation of 4
morphology of, checking of 23, 23
structure of 34, 6
Oviducts see fallopian tubes
Ovulation 14
assessment of 1415
induction, medications for 61
Ovulation predictor kits 14, 94
Ovulatory disorders 23 see also Anovulation
P
Parthenogenetic stem cells (PSCs) 129, 129
Patau syndrome 113, 123
PCOS see Polycystic ovary syndrome (PCOS)
Pearson syndrome 138
Pelvic inflammatory disease (PID)
and female infertility 19
sexually transmitted infections 19, 1920
Pelvis, ultrasound assessment of 16, 16, 21
Pentoxifylline 88
PGT see Preimplantation genetic testing (PGT)
Phytoestrogens 32, 33
Polar body biopsy 117
Polarized light microscopy, for oocyte assessment 68
Polycystic ovary syndrome (PCOS) 7, 24, 47, 87
anti-Müllerian hormone level 47
aromatase inhibitor 4849
clomifene citrate 48
definition 47
etiology 47
gonadotropin therapy 4950, 50, 50
hyperinsulinemia in 47
insulin resistance in 166
insulin sensitizers 49
laparoscopic ovarian drilling 50
management of infertility with 4751
pathophysiology 47
treatment for 25
in vitro fertilization 5051
weight loss 48
Polyploidy 112113
Polyspermy 66
Polyvinylpyrrolidone (PVP) 74
Postcoital test (PCT) 15, 22
Potency
concept of 129130
demonstration of 130
nullipotency 129
pluripotent cells 129, 129
reduction of, through differentiation 130
totipotency 129
in vitro differentiation to oocytes 130131
in vivo oocyte development 130, 131
Prader–Willi syndrome 115, 115
Preconception counseling see also Pre-conception nutrition and lifestyle
alcohol 10
anemia 9
caffeine 11
cervical cytology 10
folate 10
hemoglobinopathies 10
obesity 9
rubella infection 910, 10
sexually transmitted infections 10
tobacco 1011
Pre-conception nutrition and lifestyle
alcohol 33
bisphenol A 33
body mass index and body fat 30, 30
caffeine 3233, 33
complementary and alternative medicine 3435
dairy products 32
diet and endometriosis 3132
exercise 34
macronutrients 2728, 28
Mediterranean diet 27, 27
micronutrients 2829, 29
novel supplements and nutraceuticals 3334
overweight 3031, 31
phytoestrogens 32, 33
reactive oxygen species and antioxidants 29, 30
smoking 33
underweight 31
vegetarian and vegan diets 32
Prednisolone 146
Pre-eclampsia, in oocyte recipients 81
Preimplantation genetic diagnosis (PGD) 75, 138
Preimplantation genetic testing (PGT) 112, 116
for aneuploidy 116
blastocyst biopsy 117118, 118
cleavage-stage biopsy 117, 117
polar body biopsy 117
for structural rearrangements/monogenic disorders 116
Premature ovarian failure 75
Premature ovarian insufficiency (POI) 24, 25
Primordial germ cells (PGCs) 129, 130
PGC-like cells (PGCLCs) 133
Progesterone 6, 7, 11, 14
ovulation and level of 1415
Progesterone receptor (PR) expression 7
Progesterone test 15, 16
Progesterone withdrawal bleed 16
Prolactin 16
and infertility 16
Progestogens 16, 61
P
Qualitative single nucleotide polymorphism (SNP) 125
R
Rare autosomal trisomies (RATs) 126
Reactive oxygen species (ROS) 29
Reciprocal translocation 114
Recurrent implantation failure (RIF) 86
altered sex steroids and 87
and assisted hatching 89
embryonic genetic aneuploidy and 8687
endometrial receptivity assessment 88
endometrial scratch, use of 89
gynecological diseases and 87
hydrosalpinx and 88
immunological factors 87, 88
investigations and possible treatments 8789
and karyotyping 88
oocyte quality and 87
sperm quality and 87
thin endometrium and 88
thrombophilias and 87, 88
uterine cavity evaluation 8788
Reference nutrient intake (RNI) 29
for iodine 29
Reproductive function, assessment of
anti-Müllerian hormone 15
antral follicle count 15, 15
cervical mucus 15
endometrium 1516
ovarian reserve testing 15
ovulation 14, 1415
pelvic scan 16, 16
woman's age and serum follicle stimulating hormone 15
Reprogramming 129
Resistant ovary syndrome 24
Resveratrol 32
Rete ovarii 4
RIF see Recurrent implantation failure (RIF)
Robertsonian translocation 114115
Rubella infection, in pregnancy 910, 10
S
Salpingectomy 2021, 88, 106
Salpingitis isthmica nodosa (SIN) 20
Salpingotomy 106
Secondary infertility care, investigations in 19
aim of 19
anovulation 2225, 23
cervix 22, 22
fallopian tubes 19, 1921, 20
ovaries 2223, 23
uterine cavity 2122
Selective salpingography, for proximal tubal disease 20, 21
Self-renewal 129
Serum insulin 16
Serum prolactin 16
Sex steroid hormones, ovarian-derived 6
Sexually transmitted infections (STIs)
pelvic inflammatory disease and tubal blockage by 19, 1920
screening for 10
Sickle-cell anemia (SCA) 77
Sickle-cell disease (SCD) 77, 78
Sildenafil 88
Skene's gland 5
Smoking, effect of 1011, 33
Somatic cell nuclear transfer (SCNT) pluripotent cells 129, 129
Soya phytoestrogens 32
Speculum examination 14
Sperm DNA testing 87
Spina bifida 10
Spinal muscular atrophy (SMA) 77, 77
Submucosal fibroid, on hysterosonogram 21, 22
Superovulation 61, 62
cycle monitoring 62
long protocols 6162
luteal support after 63
and ovarian hyperstimulation syndrome 6263
short protocols 62
Support groups 100101
aim of 100
in Europe 103
male partners, support for 101
online support 101
specialist 101
support after unsuccessful treatment 102103
support in clinic 101
Surrogacy 91 see also Surrogate
altruistic 92
commercial 92
contract 95
counseling for 95
cross-border 95
embryo creation 95
ethical considerations 9596
gestational 9192, 92, 94
incidence of 93
legal parenthood 9293
legal perspectives 92, 93
as option for parenthood, reasons for 91, 91
Parental Orders 93
procedures 94
screening for 94
sperm provider 94
success rates 95
traditional 91, 92, 94
types of 9192, 92
Surrogacy Arrangements Act 1985, UK 94
Surrogate 91
anonymous 93
criteria 9394
Syphilis (Treponema pallidum) 19, 20
T
Tacrolimus 145, 146
Tamoxifen 61
Targeted massively paralleled sequencing (MPS) 125
Testosterone 6
Tetraploidy 112, 112
Textured vegetable protein (TVP) 32
Thalassemias 77, 115
alpha thalassemia 77
beta thalassemia 77
Thrombophilias
and implantation failure 87
and recurrent pregnancy losses 87, 88
Thymoglobulin 146
Timed intercourse 12
Transforming growth factor beta 1 (TGF-b1) 86
Transvaginal ultrasonography (TVS)
antral follicle count 39
cervical polyps 22, 22
in early pregnancy 105, 106
endometriosis 54, 54
ovarian morphology 23
Triploidy 112
Trisomies 113, 113
Trisomy 21 see Down syndrome
Tubal infertility 1920
distal tubal blockage 20
pelvic inflammatory disease and 19, 1920
pelvic surgery and 20
previous pelvic pathology and 20
proximal tubal blockage 20
Tubal patency, investigations for 20
hysterosalpingography 20, 20
hysterosalpingo sonography 20
and management 2021
Tuberculosis (Mycobacterium tuberculosis) 19, 20
Turner syndrome 113
U
Ultrasound-guided follicle aspiration 69 see also Oocyte collection
Under-nutrition and fertility, relationship between 31
Unicornuate uterus 22, 22
Uniparental disomy 115
Uterine fibroids 14, 16, 21, 22
Uterine malformations 22, 22
and miscarriage 22
Uterine natural killer (uNK) cells 86, 87
Uterine transplantation (UTx) 91, 143
animal models, lessons from 144145
Asherman's syndrome and 144
bioengineered uterine patch 150
donor inclusion and exclusion criteria 148
donor surgery incisions 148
future prospects 147148
history 144
human cases, lessons from 145147
hysterectomy and 143
intrafamilial donation 149
living donors, use of 148149
MRKH syndrome and 143
radical hysterectomy 149150
recipient anatomy following uterine transplantation 149
recipient inclusion and exclusion criteria 148
recipient preoperative counseling and investigations 147
transgender donors 149
uterine transplant graft following retrieval 149
Uterus
anatomy of 2, 23, 4
assessment of 2122
menstrual cycle and 3
V
Vagina anatomy and neurovascular supply 14, 2
Vaginal progesterone 63
Vegetarian and vegan diets 32
Visceral adipose tissue 30, 31
Vitamin D
and endometriosis 32
infertility and 2930
Vitrification of oocytes 153
cryoprotectants 154
devices 154, 154
procedures 153
vitrification and warming protocol 155
Vulva 1, 1
Vulvar intraepithelial neoplasia (VIN) 14
W
Weight loss 24
and fertility 24
polycystic ovary syndrome and 48
Weight loss surgery, and conception 9
Wheat/gluten-free diets 32
Whole genome amplification (WGA) and analysis 127
Window of implantation (WOI) 86
disturbance in 87
World Health Organization (WHO), anovulation classification by 2324, 24
X
X-linked disorders 116
Z
Zona pellucida (ZP) 6566, 66
Zygote 7
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Chapter Notes

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Anatomy and physiologyChapter 1

Fidelis T Akagbosu
 
ANATOMY OF THE FEMALE REPRODUCTIVE SYSTEM
The human female reproductive system is composed of anatomical structures that must interact with hormones within a defined time-frame in order for conception, pregnancy, and birth to occur. The primary sex organs are the ovaries which produce oocytes and hormones, mainly estrogen and progesterone. The secondary sex organs are the external genitalia, vagina, uterus and fallopian tubes. Their function is to receive sperm, and to provide sites for fertilization, implantation and development of the embryo to term and parturition. The mammary glands provide nourishment for the young and may be considered accessory reproductive organs.
 
External genitalia
The vulva (or pudendum) is the collective term for all the visible external genital organs in the female. It consists of the mons pubis, labia majora, labia minora, hymen, clitoris, vestibule, urethra and Skene's and Bartholin's glands (see Figure 1.1).
The mons pubis is the subcutaneous fat pad overlying the symphysis pubis. The labia majora are two folds of fat pad and skin that have hair and sweat glands. The labia majora are homologous to the scrotum in the male. They act together with the labia minora as the gatekeeper into the vagina. The vulva is covered by keratinized stratified squamous epithelium. The labia minora are two folds of hairless skin with sweat glands that merge anteriorly to form the prepuce (covering of the clitoris) and serve to protect the vaginal and urethral openings. The labia minora are homologous to the penile urethra and part of the skin of the penis in males. The clitoris is a small cylindrical erectile body, situated in the most anterior part of the vulva. It is homologous to the penis in the male but it differs in being entirely separate from the urethra. It is attached to the under surface of the symphysis pubis by the suspensory ligament.
The vestibule is the triangular space bounded anteriorly by the clitoris, posteriorly by the fourchette and on either side by labia minora. The four openings into the vestibule are the urethral opening, the vaginal orifice and hymen, the opening of Bartholin's ducts, and the Skene's ducts openings in the vestibule on either side of the external urethral meatus. The vestibular bulbs are bilateral elongated masses of erectile tissues situated beneath the mucus membrane of the vestibule. Each bulb lies on either side of the vaginal orifice in front of the Bartholin's gland and is incorporated with the bulbocavernosus muscle. They are homologous to the bulb of the penis and corpus spongiosum in the male.
The external genitalia develop in the region of the cranial aspect of ectodermal cloacal fossa and form by the end of the 12th week of fetal development. The clitoris develops from the genital tubercle, the labia minora from the genital folds, the labia majora from the labioscrotal swelling and the vestibule from the urogenital sinus.
 
Internal genitalia
The internal genital organs are located in the lower abdominal/pelvic cavity and include the vagina, uterus, fallopian tubes and ovaries (Figure 1.2).
 
Vagina
The vagina is a flattened but distensible musculomembranous canal that links the uterine cavity with the exterior at the vulva. It is the excretory channel for uterine secretions and menstrual blood, the organ of copulation and forms the birth canal of parturition.
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Figure 1.1: The external structure of the female reproductive system. The vulva is the collective term for all the visible external genital organs in the female. This includes of the mons pubis, labia majora, labia minora, hymen, clitoris, vestibule, urethra and Skene's and Bartholin's glands and mons pubis. The labia minora and majora protect the clitoris, urethral meatus and vaginal entrance.
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Figure 1.2: The internal structures of the female reproductive system. The female internal genital organs are located in the lower abdominal/pelvic cavity and include the vagina, cervix uterus, fallopian tubes and ovaries. The uterine wall has three layers: the perimetrium is the outer serosal layer; the myometrium is the middle muscular layer; and the endometrium is the inner mucosal lining. The endometrium consists of a functional layer, which contains secretory glands and is shed during menses, and a basal layer, which is highly vascularized and regenerates the functional layer.
The canal is directed upwards and backwards forming an angle of about 45° with the horizontal in erect posture. The length of the anterior wall is about 7 cm and that of the posterior wall is about 9 cm (Dutta 2015). The vaginal walls are separated where the uterine cervix projects into the vaginal cavity. The space which exists between the intravaginal part of the cervix and the vaginal wall is divided into anterior, lateral and posterior fornices.
The vagina has three layers: an inner mucosal layer that is comprised of non-keratinized stratified squamous epithelium; a muscularis layer made of smooth muscle; and a fibrous layer that covers the vagina and attaches it to the surrounding pelvic organs. The vaginal pH, from puberty to menopause, is acidic because of the presence of Doderlein's bacilli which are large gram-positive bacteria that produce lactic acid from the glycogen present in the exfoliated cells (Figure 1.3).
The mucus membrane of the upper four-fifth of the vagina, above the hymen, is derived from endoderm of the canalized sinovaginal bulbs, while the musculature is developed from the mesoderm of two fused paramesonephric (Müllerian) ducts. The lower one-fifth, below the hymen, is developed from the endoderm of the urogenital sinus. The external vaginal orifice is formed from the genital fold ectoderm after rupture of the urogenital membrane (Dutta 2015).
 
Uterus
The uterus is a pear-shaped muscular organ that is intermediate in position between the bladder, rectum and broad ligaments. After puberty, the normal length is about 7.6 cm and width is 4.5 cm. The normal uterus weighs about 60 g but can weigh up to 200 g when associated with various pathologies. The uterus is developed from the fused vertical part of the two Müllerian ducts.
The uterus is composed of three regions: the bulging upper section called the fundus; the body which is the usual site of implantation; and the narrow lower section called the cervix. The cervix is about 2.5 cm long and is divided into supravaginal and intravaginal portions. The inner walls of the cervix contain nabothian follicles, small sacs that, in response to rising estradiol levels, secrete an alkaline mucus which protects sperm from the acidity of the vaginal secretions. These follicles are also known as nabothian cysts, which may appear as harmless bumps on the surface on the cervix.
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Figure 1.3: Doderlein's bacilli are large rod-shaped gram-positive bacteria that produce lactic acid from the substrate glycogen present in exfoliated cells. Vaginal pH is acidic because of the presence of these bacteria, and this environment prevents the growth of other pathogens. They are detectable in the vagina 3–4 days after birth, and then at puberty; however, they are no longer detectable postmenopause. They most likely originate from the intestine and their presence is dependent on estrogen.
The uterus is supported by four paired ligaments. The broad ligament attaches the pelvis walls and floor to the uterus; the uterosacral ligament attaches the lateral pelvic wall to the uterus; the cardinal 3ligament runs laterally from the cervix and vagina to the walls of the pelvis; and the round ligament extends from the lateral border of the uterus below the uterine tube to the lateral pelvic wall.
The uterine wall has three layers:
  1. The perimetrium is the outer serosal layer
  2. The middle muscular layer is called the myometrium
  3. The endometrium is the inner mucosal lining. The endometrium consists of a functional layer, which contains secretory glands and is shed during menses, and a basal layer, which is highly vascularized and regenerates the functional layer (see Figure 1.2).
The uterus is capable of undergoing major changes during a woman's reproductive life. From puberty to menopause, the inner lining of the uterus (the endometrium) provides a suitable environment for embryo implantation and development during pregnancy. The endometrial lining in response to hormones released from the ovaries, thickens during the proliferative phase of the menstrual cycle, and then forms secretory glands in the second half of the menstrual cycle. If implantation does not occur, the endometrium is shed and excreted from the body via the vagina during menstruation (see Figure 1.4).
 
Fallopian tubes
The fallopian tubes, or oviducts, are paired structures approximately 10 cm long that lead from the uterus and end in finger-like projections called fimbriae. The fimbriae are suspended over the ovaries, and during ovulation receive the mature oocyte that is released from an ovarian follicle.
The fallopian tube has four subdivisions; the interstitial part is the short portion that begins at the upper angle of the uterine cavity with which it connects by a minute ostium; the isthmus is the medial 2.5 cm; the ampulla is the widest and longest subdivision of the tube; and the infundibulum is funnel-shaped leading from the ampulla, which contains the fimbriae.
After release from the follicle, the oocyte remains in the fallopian tube for about 3 days, with fertilization normally taking place at the distal end. The resulting embryo is propelled through the fallopian tube by a combination of rhythmic contractions of the muscular layer and the action of tiny hair-like projections, called cilia, toward the uterus. Pregnancy may be established via implantation of the embryo into the uterine lining 5 or 6 days following fertilization.
The fallopian tube has three layers (see Figure 1.5):
  1. A serous layer (serosa) has peritoneum on all sides except along the line of attachment of mesosalpinx
  2. A muscular layer (smooth muscle) has an outer longitudinal and inner circular layer
  3. A mucus membrane layer (mucosa). Columnar ciliated epithelial cells line the mucus membrane layer and are predominant near the ovarian end of the tube, whilst secretory columnar cells are present at the isthmic segment, with peg cells found in between
The fallopian tube is developed from the upper vertical part of the corresponding Müllerian duct at about 6–10th week of pregnancy.
 
Ovaries
The ovaries are paired sex glands in the female, located on either side of the uterus. Each ovary is a pinkish/white ovoid structure which resembles a large almond in size and shape. A normal adult healthy ovary measures about 3 cm long × 1.5 cm wide × 1 cm thick.
The ovary lies near the lateral wall of the pelvic cavity in a slight depression between the ureter posterior medially, the external iliac artery being lateral and the uterine tube in the free margin of the broad ligament anteriorly. The extremity of the uterine tube curves around the lateral end of the ovary and is attached to it by one of its fimbriae. The ovary is attached to the superior surface of the broad ligament by a short peritoneal fold (mesovarium), through which the ovarian vessels enter its hilus. The medial extremity of the ovary is attached to the uterus by the ligament of the ovary.
The ovary consists of four layers. The germinal epithelium is the outermost layer and is made up of simple cuboidal epithelium. Next is the tunica albuginea, a collagenous layer, then the outer cortex and inner medulla layers. Throughout the cortex and medulla is a connective tissue matrix known as stroma.
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Figure 1.4: The menstrual cycle. The uterus undergoes major changes during the menstrual cycle. The inner lining of the uterus (the endometrium) provides a suitable environment for embryo implantation. The endometrial lining responds to hormonal signals from the ovaries, thickening during the proliferative phase and then forming secretory glands in the second half of the cycle. If implantation does not occur, the endometrium is shed and excreted from the body via the vagina during menstruation.
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Figure 1.5: A cross-section of a fallopian tube, showing the three layers: the serosa layer has peritoneum on all sides except along the line of attachment of mesosalpinx; the smooth muscle layer has outer longitudinal and inner circular layers; and the mucosa layer is lined with columnar ciliated epithelial cells, predominantly near the ovarian end of the tube, whilst secretory columnar cells are present at the isthmic segment, with peg cells found in between.
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The stromal tissue has the ability to respond to luteinizing hormone (LH) or human chorionic gonadotropin (hCG) with androgen production (Speroff & Fritz 2005). Embedded in the stroma are blood vessels and thousands of microscopic structures called ovarian follicles. Each follicle contains an oocyte. The rete ovarii (the hilum) is the point of attachment of the ovary to the mesovarium. It contains nerves, blood vessels, and hilus cells, which have the potential to become active in steroidogenesis or to form tumors. The ovary is developed from the cortex of the undifferentiated genital ridges by about 9th week of gestation.
 
BLOOD SUPPLY AND INNERVATION OF THE FEMALE SEX ORGANS
 
External genitalia
The arterial blood supply to the external genitalia is via:
  • Branches of internal pudendal artery – the labial, transverse perineal, artery to the vestibular bulb and deep and dorsal arteries to the clitoris
  • Branches of femoral artery – superficial and deep external pudendal. Venous drainage of the external genitalia is via venous plexuses that drain into the internal pudendal vein, the vesical or vaginal venous plexus and the long saphenous vein
Innervation of the external genitalia is through bilateral spinal somatic nerves. The anterosuperior part is supplied by the cutaneous branches from the ilio-inguinal and genital branch of genitofemoral nerve (L1 and L2) and the posterior-inferior part by the pudendal branches from the posterior cutaneous nerve of thigh (S1.2.3). The vulva is also supplied by the labial and perineal branches of the pudendal nerve (S2.3.4).
 
Internal genitalia
 
Vagina
Arterial blood supply to the vagina is via:
  • The cervicovaginal branch of the uterine artery
  • The vaginal artery – branch of anterior division of internal iliac
  • The middle rectal artery
  • The internal pudendal artery
These anastomose with one another and form two azygos arteries – anterior and posterior. The veins drain into internal iliac veins and internal pudendal veins.
Nerve supply of the vagina is via sympathetic and parasympathetic fibers from the pelvic plexus. The lower part of the vagina is supplied by the pudendal nerve.
 
Uterus
Blood supply to the uterus is from the uterine artery, one on each side. The artery arises directly from the anterior division of the internal iliac. Other sources are ovarian and vaginal arteries with which the uterine arteries anastomose. The venous channels correspond to the arterial course and drain into the internal iliac veins (see Figure 1.6).
The nerve supply of the uterus is derived principally from the sympathetic system and partly from the parasympathetic system. Sympathetic components are from T5 and T6 (motor) and T10 to L1 spinal segments (sensory). The somatic distribution of uterine pain is that area of the abdomen supplied by T10 to L8. The parasympathetic system is represented on either side by the pelvic nerve which consists of both motor and sensory fibers from S2, S3, S4 and ends in the ganglia of Frankenhauser.
 
Fallopian tubes
Arterial supply to the fallopian tubes is from the uterine and ovarian arteries. Venous drainage is through the pampiniform plexus into the ovarian veins. The nerve supply is derived from the uterine and ovarian nerves.
 
Ovaries
Arterial supply to the ovary is from the ovarian artery, a branch of the abdominal aorta. The ovarian artery sends branches through the mesovarium to the ovary, continues medially in the broad ligament, gives branches to the uterus and anastomoses with the uterine artery. Venous drainage is through the pampiniform plexus, to form the ovarian veins, which drain into the inferior vena cava on the right side and the left renal vein on the left side. Sympathetic innervation of the ovary is from T10 segment (Dutta 2015).
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Figure 1.6: The blood supply to the uterus is from the uterine artery. This artery arises directly from the anterior division of the internal iliac. The venous channels correspond to the arterial course and drain into the internal iliac veins.
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OOGENESIS AND PRODUCTION OF OOCYTES
 
Early development of the ovary
During fetal life, the development of the ovary can be traced through three stages:
  1. Indifferent gonad stage
  2. Ovarian differentiation, oogonal multiplication and oocyte formation
  3. Follicle formation
 
Indifferent gonad stage
At approximately 5 weeks of gestation, the paired gonads are structurally consolidated coelomic prominences overlying the mesonephros forming the genital ridge. This indifferent gonad stage lasts approximately 7 days. The primordial germ cells originate within the primitive ectoderm and are first identified at the end of the 3rd week after fertilization. They ‘migrate’ from the yolk sac around the hindgut to their gonadal sites between 4–6 weeks of gestation. The germ cells are the direct precursors of sperm and oocytes and, by the 6th week of gestation, on completion of the indifferent stage, have multiplied by mitosis to an estimated 10,000 (Speroff & Fritz 2005).
 
Ovarian differentiation, oogonal multiplication and oocyte formation
Oogenesis refers to the sequence of events by which oogonia (primordial oocytes) are transformed into primary oocytes. The process begins during the fetal period but is not completed until after puberty. At 6–8 weeks of development, the first signs of ovarian differentiation are reflected in the rapid mitotic multiplication of germ cells, reaching 6–7 million oogonia by 16–20 weeks of development (Baker 1963, Gordon et al. 1971). This is the maximal oogonal content of the gonad. At 11–12 weeks of development, the oogonia are transformed into primary oocytes as they enter the first meiotic division and arrest in the diplotene stage of prophase I. It is estimated that two-thirds of all primordial oocytes undergo programmed cell death. This ‘quality control’ mechanism occurs via an intrinsic apoptosis pathway and has been named the ‘apoptotic wave’ (De Felici et al. 2005).
At 18–20 weeks, the newly formed oogonia begin to be surrounded by the pregranulosa cells to become primordial follicles. As soon as the oocyte is surrounded by the rosette of pregranulosa cells, the entire follicle has the potential to undergo variable degrees of maturation.
At birth, the ovaries contain about 2 million primordial follicles with germinal vesicles and stay at this stage of development until puberty. Atresia of the primordial follicles persists and at puberty there are approximately 3–400,000 primordial follicles left. During reproductive life, 400–500 are selected to ovulate if there are regular menstrual cycles. The primary follicles will eventually be depleted to a point at menopause, when only a few hundred remain (Richardson et al. 1987).
 
Follicular growth
The time that elapses in progressing from a primary follicle to ovulation is approximately 85 days (Gougeon 1996). The number of follicles that mature is dependent on the amount of follicle stimulating hormone (FSH) available to the gonad and the sensitivity of the follicles to the gonadotropins. FSH receptor expression is greatest in granulosa cells, but significant expression can be detected in ovarian surface epithelium and fallopian tube epithelium. FSH acts on the growing cohort of follicles and causes an increase in size of the primary oocyte and the follicle.
On the first day of the menstrual cycle, about 5–10 growing follicles in the ovaries are available for recruitment. The increasing concentration of FSH causes selection of usually one follicle to grow, with proliferating granulosa cells. The follicle forms an antrum and the granulosa cells now make estrogen. The tertiary follicle is the last stage of the folliculogenesis before ovulation, growing to 16–19 mm in diameter (as assessed by ultrasonography). Granulosa cells give rise to all the cells of the follicle – the theca (interna and externa), the coronal radiata directly adjacent to zona pellucida (ZP) and the cumulus oophorus (Figure 1.7).
The rising estradiol level just before ovulation triggers a surge of LH, and informs the oocyte to resume its division via gap junction communication. The primary oocyte completes the first meiotic division (meiosis I) just before ovulation. At ovulation, the secondary oocyte begins meiosis II, but progresses only to the metaphase II stage, where the cell cycle is temporarily arrested. If the secondary oocyte is fertilized by a sperm, meiosis II is completed and a second polar body is formed. At this stage, the secondary oocyte is large, being just visible to the unaided eye (see Chapter 9 for a detailed description of the oocyte).
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Figure 1.7: (a) Structure of the ovary and (b) oocyte. The ovary consists of the cortex which contains developing follicles and a vascular central core, the medulla. On the first day of the menstrual cycle, about 5–10 growing follicles are available for recruitment. As follicle-stimulating hormone (FSH) levels rise, usually one follicle is selected to grow. The follicle forms an antrum and makes estrogen via granulosa cells. The tertiary follicle is the last stage of the follicle before ovulation, growing to 16–19 mm in diameter. After ovulation, the empty follicle forms the corpus luteum.
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Figure 1.8: Levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) during gestation, childhood and adulthood. There is a postnatal rise in FSH and LH. Between the ages of 2 and 11 there is very low amplitude and episodic release of both FSH and LH. By the ages of 11-13 secretion and episodic release of FSH and LH both rise - FSH to a higher level than LH - and then level out between the ages of 14 and 17 with amplitude and frequency of release dependent on the phase of cycle.
 
HORMONE RECEPTOR EXPRESSION (ABILITY OF THE OVARY TO RESPOND TO ENDOCRINE SIGNALS)
The anterior pituitary gland begins development between 4 and 5 weeks of gestation and the hypothalamic-pituitary portal circulation is functional by the 12th week. Pituitary levels of FSH peak at 20–23 weeks, and circulating levels peak at 28 weeks. Ovaries in anencephalic fetuses, which lack gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, lack antral follicles and are smaller at term; progression through meiosis and development of primordial follicles occur, indicating that this process is independent on gonadotropins (Rabinovici 1990). The ovary develops gonadotropin receptors only in the second trimester. There is a postnatal rise in FSH with levels greater than the levels reached during a normal adult menstrual cycle, decreasing to low levels usually by 1 year of age, but sometimes later (Burger et al. 1991). LH levels are in the range of lower adult levels (Figure 1.8).
Ovarian-derived sex steroid hormones dictate the menstrual cycle in humans and are essential for the establishment and maintenance of pregnancy. The steroid receptors are part of the family of nuclear receptors and consist of estrogen, progesterone, androgen and glucocorticoid receptors. The functions of the sex steroids and their cognate receptors in ovarian function are multifaceted. Progesterone, testosterone and estradiol are all synthesized in the ovary during folliculogenesis and act via both extraovarian (i.e. endocrine) and intraovarian (i.e. paracrine/autocrine) pathways to influence all aspects of ovarian function. The endocrine actions of the sex steroids in the hypothalamic-pituitary axis are critical to the regulation of gonadotropin secretion and the ovarian cycle (Binder et al. 2015).
High-affinity estradiol binding sites in normal human ovaries have been described. Estrogen receptor beta (ER beta) is the predominant estrogen receptor form and is most often exclusively localized to granulosa cells of follicles from the primary to pre-ovulatory stage. Although FSH is the primary stimulus for both granulosa cell proliferation and differentiation, both FSH and estrogen are required for full antrum formation in pre-ovulatory follicles (Binder et al. 2015). Acquisition of aromatase activity and estradiol synthesis is a hallmark of healthy pre-ovulatory follicles and 90% of the circulating estrogen is estimated to originate from the dominant follicle in the ovary. Unlike thecal cells, granulosa cells express LH only in follicles in the late pre-ovulatory stage. This limited expression of LH receptors in the granulosa cells of healthy pre-ovulatory follicles provides for an intraovarian mechanism that ensures only those follicles that are suitable for ovulation acquire the capacity to respond to the LH surge (Binder et al. 2015).
Like granulosa cells, follicular thecal cells also undergo a process of differentiation during progression from a pre-antral to pre-ovulatory follicle. The two-cell, two gonadotropin paradigm of steroidogenesis in maturing follicles is that thecal cells exclusively possess the 17-β hydroxylase: C17-20-lyase activity necessary for synthesizing androgens, forcing the granulosa cell layer to be dependent on the theca as a source of aromatizable precursors (see Figure 1.9).7
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Figure 1.9: The two-cell, two-gonadotropin theory of steroidogenesis in maturing follicles. Thecal cells possess the 17-β hydroxylase: C17-20-lyase activity necessary for synthesizing androgens, forcing the granulosa cell layer to be dependent on the theca as a source of aromatizable precursors.
Androgens are necessary and serve as both a stimulus of and substrate for aromatase activity in granulosa cells. An intraovarian mechanism exists to negatively modulate thecal cell androgen synthesis so that levels do not surpass the aromatase capacity of the granulosa cell layer. Defects in this intraovarian mechanism are postulated to be an underlying cause of the excess thecal cell androgen synthesis that is a hallmark of polycystic ovarian syndrome in women (Binder et al. 2015).
Progesterone receptor (PR) expression has been primarily localized to the theca of large pre-ovulatory follicles, the surface epithelium, and ovarian stroma. The dramatic increase in PR expression in the granulosa cells of ovulatory follicles is absolutely essential to follicle rupture (Conneely et al. 2002).
 
The hypothalamic feedback mechanism and ovulation
The hormonal interactions that regulate the female reproductive cycle are initiated and maintained by a feedback mechanism that originates in the hypothalamus. The hypothalamus influences the anterior pituitary gland's secretion of FSH and LH by transmitting gonadotropin releasing hormone (GnRH) in a pulsatile fashion. In normal menstrual cycles, the hypothalamus releases GnRH at 60–120 minute intervals in the follicular phase. The FSH and LH stimulate follicular development in the ovary, resulting in the production of estradiol. Rising levels of estradiol in the bloodstream provide the ‘feedback’ to the hypothalamus for further regulation of FSH and LH. Shortly following ovulation, the high levels of progesterone and estradiol promote a negative feedback mechanism causing the pituitary gland to taper off the release of FSH and LH. As a result, concentrations of estrogen and progesterone decrease until levels are low enough to trigger menstruation and start the next menstrual cycle (Figure 1.4). In anovulatory cycles, the endometrium remains in the proliferative phase until menstruation begins.
 
Fertilization, implantation and initiation of pregnancy
Fertilization occurs when the mature oocyte is penetrated by one of the few sperm that survives the journey to enter the fallopian tube. If the oocyte is fertilized, a cortical reaction within the ooplasm changes the oolemma and causes structural changes in the protective ZP. This prevents other sperm from entering. Unfertilized oocytes are expelled during menstruation.
The fertilized oocyte, now termed a zygote, migrates down the fallopian tube, propelled by the action of cilia lining the tubal lumen. The early preimplantation embryo divides several times during this period to form a morula on day 4 and then a blastocyst on day 5. Approximately 5–6 days following fertilization, the blastocyst reaches the uterus where it implants itself in the endometrium. Implantation is dependent on several factors, such as adequate formation of the corpus luteum and an adequately developed endometrial lining. If implantation is not successful, the blastocyst is expelled from the uterus with menstruation. Pregnancy can only ensue following successful implantation.
Implantation signals the pituitary gland to release additional LH. This hormone supports the granulosa cells in their critical role of maintaining early pregnancy, by continuing to release an increasing amount of progesterone. Progesterone is vital to maintaining the endometrium during this phase. The corpus luteum continues to produce progesterone until the placenta is able to produce a sufficient supply of its own progesterone, typically at about the 9th or 10th week of pregnancy.
During the assisted conception cycle, additional supplies of progesterone are usually provided to the female once oocytes have been released, either via ovulation induction or egg collection for in-vitro fertilization (IVF) treatment. This is known as ‘luteal phase progesterone’ and the hormone is usually supplemented in the form of vaginal pessaries or gel, which needs to be continued on a daily basis.
Just before implantation, the developing blastocyst starts to produce hCG from the outer cell's layer, known at the trophectoderm. The rise in secretion of hCG is exponential, as the blastocyst implants and the trophectoderm cells continue to divide and grow.
The hCG is the hormone tested to determine pregnancy; hCG can be detected in urine or via a blood test. At the end of a successful pregnancy, the uterus undergoes powerful, rhythmic contractions during labor, resulting in the delivery of the fetus at birth.8
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  1. Burger HG, Famada Y, Bangah MI, et al. Serum gonadotropin, sex steroid, and immunoreactive inhibin levels in the first two years of life. J Clin Endocrinol Metab 1991;72:682.
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