FOGSI FOCUS Endometriosis: Current Trends Kuldeep Jain, Sudha Prasad, Nandita Palshetkar, T Ramani Devi, Fessy Louis T
INDEX
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
A
Abscess 63
Adenomyoma
large 27f
removal of 27
Adenomyomectomy, laparoscopic 27f
Adenomyosis 17, 24, 26, 27, 37, 74
effect of 25
focal 25f, 27
large focal 25f
Adhesiolysis 44
Adhesion prevention 45
Alcohol consumption 63
American College of Obstetricians and Gynecologists 9fc
American Reproductive Society 13
American Society for Reproductive Medicine 13, 30
classification of Müllerian anomalies 30
Anastrozole 68
Androgens 63
Angiogenesis inhibitors 68
Antiangiogenesis factors 21
Anti-inflammatory agents 68
Anti-Müllerian hormone 58
serum 38
Antioxidants 68
Antiretroviral therapy 17
Antral follicle count 38
Anxiety 6
Aromatase 3
inhibitors 20, 68
Assisted reproductive technology 15, 24, 37, 53, 70, 73
Autoimmune theory 49
B
Biochemical tests 13
Biomolecular theory 2
Bladder 46, 50, 51
endometriosis of 46f, 49, 52, 53
Blood, collection of 25f
Bone mineral density 9
Bowel
disease 7
endometriosis 42, 46
preparations 51
wall infiltration, depth of 51
C
Cabergoline quinagolide 68
Cancer antigen 7
Carbon dioxide 75
Carcinoma 63
Cells
contractile nonmuscle 49
endometrial 49
Cervical
agenesis 30
anomaly 29
aplasia 29
unilateral 29
dysgenesis 30
Cervix
distension of 31
double normal 29
normal 29
Cesarean section 62, 63
Cetrorelix acetate 68
Coelomic metaplasia 1
Meyer and Ivanoff theory of 2
theory 48, 62
Coital function 66
Conservative uterine, role of 27
Constipation 7
Contraceptives pill
combined
hormonal 18
oral 8, 18, 63, 69
oral 6, 19, 26, 39
Controlled ovarian hyperstimulation 75
Corpus
luteal cyst 14
luteum 67
Cyclooxygenase 68
Cyst 63
complex 14, 14f
enucleation 44f
hemorrhagic 14, 67
management, endometrial 10
myometrial 25f
ovarian 15
Cystadenoma 67
Cystectomy 75
endometriotic 44, 45fc
ovarian 38, 75
Cystitis, recurrent 51
Cytochrome P450 3
D
D-amino acid 69
Danazol 20, 26, 68
Deep infiltrating endometriosis 42f, 43, 43f, 48, 50, 53, 54, 69
classification of 53, 54
intestinal 49, 53
retroperitoneal 50f
Depomedroxyprogesterone acetate 9, 68
Depression 6
Dermoid 67
cyst 67
Diarrhea 7, 49
Dienogest 9, 67, 68t
Diethylstilbestrol 30
Direct implantation theory 2
Dopamine receptor 2 agonists 21
Doppler ultrasound 67
Dr David experience 35fc
Drosophila, Ortholog of 4
Dyschezia 49-51
Dysfunction, endometrial 66
Dysmenorrhea 26, 42, 49-51
severe 43, 51
Dyspareunia 6, 42, 49-51, 66
deep 43, 51
E
Elagolix 68
Embryo freezing 59, 60
Embryonic cell rest 1
Endogenous anti-angiogenic activity 21
Endometrioma 9, 11, 14f, 15f, 32, 33, 44, 48, 58, 60, 67, 70, 76
ablation 75
aspiration 75
atypical features of 67, 67t
bilateral 44, 58, 70
externa 62
left-sided 1f, 10
multiple 14f
right ovarian 33f
typical USG features of 67, 67t
Endometriosis 1, 2f, 6, 7, 8f, 13, 17, 18, 21, 29-32, 35, 37-40, 42, 46, 48, 49, 52, 58-60, 62, 66, 67, 70, 73, 74, 77
abdominal wall 62
adolescent 6, 9fc
associated infertility 14, 15
bilateral ovarian 49
challenges in 37
clinical features of 66b
course of 7
cutaneous 62
deep 40, 48, 51
invasive 48
development of 48
diagnosis of 1, 11, 66
endopelvic 62
etiopathogenesis of 1
excise deep 44
extraovarian 67
histological diagnosis of 63
ideal protocol for 38
impact of 58
in vitro fertilization outcomes in 59
infiltrative 14
isolated deep 48
lesions 49
main sites for 42
majority of 14
mechanical cause of 31
medical management of 17
medications used in 18b
mild 2f, 44
mild-to-moderate 73
minimal 44
moderate 44
natural course of 7
pathogenesis of 1, 2
pathophysiology of 18b
prevalence of 6, 48
rectosigmoid 48
rectovaginal 42, 67
recurrence 40
retrocervical 42, 46
retroperitoneal 48
severe 44
stage of 38
suppression of 38
symptoms of 6, 63
theories of 2
treatment of 12, 19
types of 48
ureteric 49, 53
Endometriotic
cells, lymphovascular dissemination of 3f
cyst 73
differential diagnosis of 67, 67t
drainage of 10f
implants 17
ablation of 43
lesions 21, 50
Endometrium, germinal epithelia of 48
Enigmatic disease 42
Environment theory 3
Episiotomy 62
Equine estrogens, conjugated 11
Estradiol 69
Estrogen 18
dependent disease, benign 48
formation, inhibition of 68
Estrogenic receptor isoforms 4
Etanercept 68
Etonogestrel implant 20
European Society of Gastrointestinal Endoscopy 29
European Society of Human Reproduction and Embryology 29, 70
F
Fallopian tubes 62
Fertility
preservation 59
cost-benefit analysis of 60
options of 59
technology 58
preserving surgery 27, 59
prevention 58
sparing
surgery 27
treatment 24
Fertilization 3
Fine-needle aspiration cytology 63
Follicle-stimulating hormone 19, 58, 69
Food and Drug Administration 68t, 69
G
Galactose-1-phosphate uridyltransferase 30
Gastrointestinal symptoms 6, 51
Genes
angiogenic 21
anti-inflammatory 21
Genetic theory 2
Genital tract anomalies, female 29
Gestrinone 68
Glands 48
endometrial 1, 49, 63
Gonadotropin-releasing hormone 9, 18, 26, 67, 68
agonist 8, 19, 38, 39, 67, 69t, 73
therapy 26
analogs 63
antagonists 19, 68
Goserelin 68
acetate 69
Granule 63
Granulosa cells, ovarian 68
Ground glass homogeneous echoes 14f
H
Halban's theory 2
Heavy menstrual flow 63
Hematocolpometra 31
Hematocolpos 31
Hematoma 63
Hematometra 33, 33f
laparoscopic view of 33f
ultrasonography of 33f
Hemiuterus 29
Hemorrhage 14, 15
Hemosiderin-Laden macrophages 1
Herlyn-Werner-Wunderlich syndrome 32, 32f
magnetic resonance imaging of 33f
Hilus sign 67
Hormone
luteinizing 19, 69
therapy 69
combination 9
Hydronephrosis 51, 52
Hydrosalpinx 74
development of 74
Hyperechogenic wall 67
Hypoplasia 29
Hypothalamic-pituitary-ovarian axis 67
Hysterectomy 62
early 63
Hysterolaparoscopy, combined 32
I
Iliac spine, anterior superior 42
Imperforate hymen 29
Implantation
failure 4
impaired 38
In vitro fertilization 37, 67, 73, 76
cycle 59
outcome 59, 74
Incision hernia 63
Infertility 25, 37, 50, 66, 77
Infliximab 68
International Ovarian Tumor Analysis 14
Intestine 50
Intracytoplasmic sperm injection 39, 67, 74
Intrauterine insemination 15, 40, 67
Ipsilateral renal agenesis 32
syndrome 30
Isoflavones 68
K
Kissing ovaries, bilateral 42f
L
Labor, spontaneous onset of 63
L-amino acid, substitution of 69
Laparoscopy 1f, 31, 37, 42, 73
advantages of 9
diagnostic 7
Laparotomy 62
Lesions, hourglass-shaped 50
Letrozole 39, 68
Leuprolide 68
acetate 69
Levonorgestrel intrauterine
device 68
system 8, 19
Lipoma 63
Low ovarian reserve 38
Lower urinary tract symptoms 51
Lymphatic spread, Halban's theory of 2
Lymphoma 63
M
Macrophages 66
Magnetic resonance imaging 31, 37, 50, 52, 67
Malignancy, risk of 64
Mass
abdominal 31
oval 67
Mayer-Rokitansky-Küster-Hauser syndrome 32, 34
Medroxyprogesterone 19
Melatonin 68
Menses, irregular 6
Menstrual bleeding 51
Mesothelial cells 2
Metalloproteinase 3
Meyer and Ivanoff theory 2
Mifepristone 68
Migraine 6
Müllerian agenesis 32
Müllerian anomalies 6, 7, 29-31, 33, 35
classification of 29t
higher incidence of 30
incidence of 34
nonobstructive 31
obstructive 30
prevalence of 30
range of 29
Müllerian defects 30
Müllerian duct 29
anomalies 29
Müllerian malformations 31
Müllerian remnant 2
theory 3
Müllerian structures, abnormal 31
Musculoskeletal disorders 7
Myofibroblasts 49
Myometrium, adjacent 24
N
Nafarelin 68
acetate 69
Nausea 7
Nerves
retroperitoneal 53
sparing surgery, nerve dissection for 45f
Neuroma 63
Nodules
endometriotic 44
excised rectovaginal 43f
Nonsteroidal anti-inflammatory drugs 7-9, 18, 67, 68
Norethindrone acetate 9, 11, 68, 69
O
Obstructed hemivagina, ipsilateral renal agenesis syndrome 30, 32
Oocyte
freezing 59, 60, 67
retrieval 59, 74
risk of 60
Oral lichen planus 68
Ovarian
cortex 70
freezing 60
endometrioma 10, 10f, 70, 74, 77
asymptomatic 74
differential diagnosis of 67, 67t
management of 73
hyperstimulation syndrome 39
inflammation, mechanism of 74
reserve 38, 58
stimulation 40, 59
Ovary 62
endometrioma of 10, 42, 44, 44f
germinal epithelia of 48
Ovulation suppressing agents 68
Ovulatory dysfunction 66
Ovum pick up 66
P
Pain 45
abdominal 7
killers 6
rectal 49
severe
chronic 51
hypogastric 51
Papillae, absence of 67
Papillary projections 67
Parenchyma, ovarian 67
Peculiar atypical red vascular lesions 8f
Pelvic
adhesions 44
endometriosis 62
mass 6
organs 13
pain 18, 32, 37, 42
chronic 6, 42, 43, 50
Pelvis
final appearance of 44f
MRI of 51
Pentoxifylline 21, 68
Peptidoglycan 68
Peripheral estrogen levels 40
Peritoneal endometriosis 42, 48
fulguration of 44f
Peritoneal windows 8f
Peritoneum 62
germinal epithelia of 48
Peritubal adhesions 66
Periureteral vessels 53
Phagocytosis 66
Phytoestrogens 68
Polycystic ovaries 30
Poor oocyte quality 38
Posterior wall fornix lesions 50, 50f
Pouch of Douglas 2, 13, 44, 49-52, 62
Pregnancy loss, recurrent 30
Progesterone 18, 69
containing contraceptives 19
receptor antagonists 68
Progestins 9, 68
Progestogens 63
Progressive estrogen-dependent disease 48
Prostaglandins 7
Protein kinase, mitogen-activated 4
R
Radical surgery 53
Raloxifene 68
Ramakrishna experience 35fc
Randomized controlled trial 39, 75
Rectal
aqueous contrast 51
evaluation 52
excision 45
mobilization 43f
mucosa 52
submucosa 52
Rectovaginal nodule, excision of 43f
Rectovaginal septum
endometriosis of 44, 45f
lesions 50
Rectovaginal space 51
Rectum 45
Renal agenesis 30
Retrograde menstruation 48
Sampson's theory of 2
Retroperitoneal lesions, subclassification of 50
Robert's uterus 33
hysteroscopic
resection of 34f
view of 34f
laparoscopic view of 34f
magnetic resonance imaging of 34f
relook hysterscopic view of 34f
ultrasonography of 33f
S
Saline, normal 42
Sampson's theory 2, 48, 62
Scar endometriosis 62, 64
therapy of 63
Selective estrogen receptor modulator 11, 68
Selective progesterone receptor modulators 20, 68
Septa 67
fibrin 14
Septate
cervix 29
uterus 29, 30, 34
Septostomy 32
Simvastatin 68
Soft tissue sarcoma 63
Sonography
high-frequency 52
transvaginal 1f, 14, 67
Sperm inactivation 66
Statins 21
Stroma 1, 48
leads 49
Subfertility 6
Surface endometriosis 48
electrocoagulation 9f
Surgery 70
conservative 26, 53
endometriotic 42
laparoscopic 62
Surgical therapy
advantages of 70t
disadvantages of 70t
T
Tanner system 7
Tenesmus 49
Thromboembolism, risk of 18
Tissue
adenomyomatous 27
adenomyotic 27
endometrial 48, 67
endometriotic 32
ovarian 58
Torus uterinus 49
Transverse vaginal septum 29, 30
Triptorelin 69
Tubal motility 66
Tubes, anatomical distortion of 66
Tumor necrosis factor 3
alpha blockers 21
U
Ultra-long protocol 38
Ultrasonography 63, 67
three-dimensional 31, 67
transrectal 50-52
Ureter, endometriosis of 42, 46, 53
Ureteral involvement 49, 52
Ureteric dissection 43f
Urinary bladder, endometriosis of 42, 46
Urinary tract
disease 51
endometriosis 48
Uterine
agenesis 30
anomaly 29
nonobstructive 31
cavity 27, 48
didelphys 33f
fibroid 74
incision 27
Uterosacral ligament 1, 2f, 45, 49-53, 62
Uterovaginal agenesis 29
Uterus
arcuate 29, 30
asymmetric
dissection of 27
enlarged 25
bicornuate 29, 34
bicorporeal 29
carina of 49
didelphys 29, 30, 32, 34
distension of 31
dysmorphic 29
normal 29
right horn of 33f
unicornuate 29, 30, 34
V
Vagina 50, 51
distension of 31
normal 29
Vaginal
agenesis 30
anomaly 29
aplasia 29
excision 43
fornix, posterior 49
injection 51
septa 31
septum, longitudinal
nonobstructing 29
obstructing 29
Valproic acid 68
Vascular
dissemination theory 48
endothelial growth factor 3
theory 2
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Chapter Notes

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Newer Insights in Etiopathogenesis of EndometriosisCHAPTER 1

Saumya Prasad,
Sudha Prasad
 
INTRODUCTION
Endometriosis is a chronic, estrogen-dependent inflammatory, heritable disorder which is characterized by growth of endometrial tissue in sites other than the uterine cavity, most commonly in the pelvic cavity, including the ovaries, the uterosacral ligaments, and the pouch of Douglas.1 The disease affects approximately 10% of the women in reproductive age group.2 Despite not being at their normal anatomical positions these heterotopic endometrial tissues remain responsive to the circulating estrogen levels. Just like their normal anatomical counterparts these grow and shed with each cycle of ovulation. The shed endometrial glands and stroma incite strong chronic inflammatory response via cytokines leading to production of prostaglandins and ultimately fibrosis.3
Clinical diagnosis of endometriosis is often difficult due to the wide spectrum of symptoms which are mostly nonspecific. There are no pathognomonic features necessary and sufficient to define endometriosis. Endometriosis is typically defined by its histology: extra uterine lesions consisting of endometrial glands, stroma, and hemosiderin-laden macrophages.4 Based on location and depth, lesions are further described as superficial, ovarian endometrioma or deep endometriosis. Visual observation through transvaginal sonography (Fig. 1), laparoscopy (Fig. 2), and histopathological sampling are the gold standards.5 The most common complaints in endometriosis patients are dysmenorrhea (79%) and chronic pelvic pain (69%).6
The pathogenesis of endometriosis is still not definitive, though many theories have been proposed including retrograde menstruation, coelomic metaplasia, embryonic cell rest, lymphovascular metastasis, and stem cell.
zoom view
Fig. 1:: Left-sided endometrioma on transvaginal sonography.
zoom view
Fig. 2:: Left-sided endometrioma on laparoscopy.
 
2PATHOGENESIS OF ENDOMETRIOSIS
 
Theories of Endometriosis7
  • Sampson theory of retrograde menstruation: This is the most popular theory. This theory explains retrograde flow of menstrual blood from uterus through fallopian tubes into the peritoneal cavity. Endometrial fragments get implanted onto peritoneal surface at dependent sites like ovaries, uterosacral ligaments and pouch of Douglas (Figs. 3 and 4). Although this theory can explain pelvic endometriosis, it fails to explain distant endometriosis. Moreover, implantation of endometrial tissue has been shown to be dependent more on genetic predisposition and hormonal environment and not merely on retrograde menstruation.
    This theory is supported by laparoscopic findings of menstrual blood components during perimenstrual period.
  • Halban's theory of lymphatic spread: This theory can explain endometriosis inflicting pelvic lymph nodes. This theory proposes that endometrial tissue can metastasize through the draining lymph channels of uterus to the lymph nodes.
  • Meyer and Ivanoff theory of coelomic metaplasia: Mesothelial cells from peritoneal and ovarian surfaces may undergo metaplasia to endometrial tissue. This can occur due to chronic irritation by the menstrual blood. Alternatively, Müllerian remnants in form of primordial cells might get trapped into the peritoneum of posterior pelvic wall during embryogenesis and later undergo metaplasia under high serum estrogen levels. Stem cells can also transform into endometrial tissue under hyperestrogenic state.
  • Direct implantation theory: This theory postulates that endometrial cells can directly get implanted at new sites and grow. These sites can be abdominal scar after hysterotomy, cesarean section or myomectomy and episiotomy scars. However, this theory does not explain endometriosis at other sites.
  • Vascular theory: This is the least explained theory but it can explain endometriosis at distant sites like lungs and brain (Fig. 5).
  • Genetic theory: A multifactorial or polygenic inheritance is seen in patients of endometriosis. There is 6−7 times increased risk in first degree relatives. However, such inheritance is observed in merely 10% of patients. Also concordance for endometriosis is frequently observed in monozygotic twin-pairs. Predisposed women are more prone to grow endometrium at ectopic sites. Genes responsible for increased susceptibility have been found to be EMX2—a transcriptional factor encoding proteins for reproductive tract development and PTEN—a tumor suppressor gene responsible for malignant transformation to endometroid adenocarcinoma in ovarian endometriosis. Both these genes are located within or near 20p13 locus. Other genes implicated in pathogenesis of endometriosis are those encoding for interleukin (IL)-15, glycodelin, Dickkopf-1, semaphoring E, aromatase, progesterone receptor (PR), and multiple angiogenic factors.
    zoom view
    Fig. 3:: Endometriosis involving uterosacral ligament (red arrow).
    zoom view
    Fig. 4:: Burnt out areas of mild endometriosis.
  • Biomolecular theory: Patients of endometriosis have an impaired immune system response, increased production of cytokines and proinflammatory mediators, increased overall angiogenic activity, excessive estrogen production, and progesterone resistance. Peritoneal 3macrophages phagocytize menstrual debris in normal women. Ectopic endometriotic implants do not undergo phagocytosis and apoptosis due to decreased expression of metalloproteinase, CD36, and increased production of dissolved intercellular adhesion molecule-1. In patients of endometriosis due to subclinical peritoneal inflammatory response, activated macrophages secrete increasing amounts of proinflammatory cytokines like IL-1, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T-cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, TNF-β, integrins, and angiogenic factors. These cytokines promote growth of endometrium at ectopic sites and makes them more resistant to apoptosis by further triggering release of more prostaglandins and proangiogenic vascular endothelial growth factor (VEGF). In addition, these cytokines have detrimental impact on sperm motility. They promote phagocytosis of sperms and can interfere with fertilization process. Prostaglandins also increase activity of aromatase (p450arom) and the production of tissue estrogen promoting an overall hyper estrogenic milieu.
    The most important factor in the pathogenesis of endometriosis is estrogen dysregulation and progesterone resistance. In normal females, there is dominance of alpha subtypes of estrogen receptors (ER-α). In endometriosis beta subtypes of estrogen receptors (ER-β) overwhelm alpha receptors. It is postulated that epigenetic mutation by hypomethylation of the CpG cluster of estrogen receptor genes is responsible for this change from alpha to beta dominance. The increased levels of ER-β suppress production of ER-α. This in turn reduces the formation of PRs, resulting in progesterone resistance in endometriosis. ER-β also regulates cell cycle progression and leads to increased proliferation of endometriotic cells.
  • Environment theory: The most important toxin are dioxins (e.g. TCDD-2,3,7,8-tetracholorodibenzo-p-dioxin). These are by-products of industrial processing and often enter our body through food chain. These promote somatic mutation of endometrium by acting as transcription factors promoting increased ILs synthesis, activation of cytochrome P450, and alteration of tissue remodeling.
zoom view
Fig. 5:: Lymphovascular dissemination of endometriotic cells.
Among these existing theories on endometriosis pathogenesis, Sampson's retrograde menstruation theory is scientifically proven, easy to understand and widely acceptable.8 The theory is also supported by laparoscopic findings where menstrual blood components were found in peritoneal cavity. Consistently, Müllerian remnant theory also describes that spreading of primordial cells across the posterior pelvic wall may transform into endometrial tissue when exposed to high-level estrogenic stimulus.9
Technological progress in molecular biology has increased the interest in genetic polymorphism identification and 4its involvement in endometriosis development. A polygenic inheritance is seen in patients of endometriosis.10 The endometriotic tissue is sensitive to estrogen and progesterone. The two estrogenic receptor isoforms (ER-α, ER-β) are codified by two different genes (ESR1 and ESR2) with different tissue-specific distributions; they can join to different ligands and activate different genes for transcription. The influence of ESR1 has been correlated with severe endometriosis in various studies.11 There is 6−7 times increased risk in first degree relatives. Endometriotic genes responsible for increased susceptibility have been found to be EMX2—a transcriptional factor encoding proteins for reproductive tract development.12
Implantation failure in patients with endometriosis is directly associated with low endometrial HOXA10 levels. EMX2, a mammalian ortholog of Drosophila empty spiracles gene, is a transcription factor which is necessary for Müllerian duct and renal development.13 High endometrial HOXA10 expression occurs in mid-late secretory phase of the menstrual cycle. Conversely, it is observed that high levels of EMX2 mRNA were reported in the proliferative in association with the low levels of HOXA10.13
Long noncoding RNAs (lncRNAs) are a class of noncoding RNAs with at least 200 nucleotides.14 The major pathway involved in up regulating mRNAs in eutopic vs. normal endometrium included cytokine−cytokine receptor interaction, hypoxia-inducible factor-1 signaling, mitogen-activated protein kinase (MAPK) signaling, apoptosis, NF-κB signaling, and focal adhesions. Enrichment of mRNAs in innate immune response indicated correlation between immune factors and endometriosis.15
Endometriosis patients have an impaired immune system response, increased production of cytokines and proinflammatory mediators, increased overall angiogenic activity, excessive estrogen production, and progesterone resistance. Endometriotic cells have the ability to avoid immune surveillance, granting them easier implantation and growth in ectopic places. Cytokines like TNF-α, TNF-β, and integrins promote growth of endometrium at ectopic sites and makes them resistant to apoptosis.16 Whereas estrogen dysregulation and progesterone resistance are important factor in the pathogenesis of endometriosis. In healthy females, alpha subtype of estrogen receptors is dominant while beta subtype of estrogen receptor is seen in endometriosis. It is postulated that epigenetic mutation by hypomethylation of the CpG cluster of estrogen receptor genes is responsible for this change from alpha to beta dominance.17 The increased level of ER-β suppresses production of ER-α.
While treating these women, one should always keep in mind that genetic variability in humans can cause numerous mutations which alter at cellular and molecular level and maintain the development of illness. Understanding the role of genetics, epithelial progenitor cells will allow a more targeted and effective therapeutic approach to this poorly understood disorder.
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