ENDOMETRIOSIS

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Newer Concepts and Management

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ENDOMETRIOSIS: 

ENDOMETRIOSIS Moderator Prof. S. Pandey Speaker Dr. Kusum Lata

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Endometriosis is a disease or better a syndrome that starts around the prepubertal age , flourishing after menarche , with symptoms progressing in intensity through the years . Predominantly found in women of reproductive age Found in all the ethnic & social groups

DEFINITION : 

DEFINITION Endometriosis (from endo , "inside", and metra , " womb " Presence of endometrial like tissue (glands/ stroma ) outside the uterus which induces chronic inflammatory reaction. Most frequent sites are pelvic viscera & peritoneum out of which most common site is ovary (RCOG guideline no. 24, 2006) Adenomyosis is ectopic endometrium inside the myometrium of uterus, previously known as endometriosis interna .

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INCIDENCE Asymptomatic women undergoing tubal sterilization i.e. women with proven fertility - 7% Primary infertility (20-30%) Dysmenorrhoea (40-60%) Chronic pelvic pain(71-80%)

ETIOLOGY: 

ETIOLOGY Exact etiology of endometriosis is unknown. Understanding of endometriosis is just a beginning. It is a estrogen dependent disease.

HYPOTHESIS: 

HYPOTHESIS

HYPOTHESIS: 

HYPOTHESIS 1. Retrograde menstruation/ectopic transplantation/ Sampson’s theory – (Lancet, 2004)

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Most widely recognized & plausible theory on the genesis of endometriosis. Based on the assumption that endometriosis is caused by the seeding or implantation of endometrial cell by trans tubal regurgitation during menstruation. Supported by – Blood can be found in peritoneal cavity on laparoscopy during menstruation in 75-90% - most often found in dependent portions of the pelvis like ovaries, anterior & posterior cul-de-sac, the uterosacral ligaments, posterior uterus, posterior broad ligaments. More in women with stenosis of internal os Mullerian abnormalities

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2. Coelomic Metaplasia / Metaplastic Transformation/ Meyer’s theory - Both peritoneal and endometrial tissues share a common embryologic precursor the coelomic cell. Metaplastic transformation of coelomic epithelium into endometrial tissue can occur. Premenarchal girl who have never menstruated Unusual sites( Extremities, brain, pleura)

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3 . Lymphatic or Hematogenous Spread Distant to pelvis/ Hallban’s theory – Explain the observation of endometriosis in unusual sites such as brain & pleura Extra pelvic endometriosis - vascular or lymphatic dissemination of endometrial cells Ovarian endometriotic lesion may arise directly from ovarian surface epithelium through a metaplastic differentiation process induced by activation of an oncogenic K- ras allele. Ovarian endometriosis - retrograde menstruation or lymphatic flow from the uterus.

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4. Direct Transplantation from Tissue Trauma or Surgery Red wine has described this phenomenon as auto transplantation. Explain the finding of localized endometriosis cesarean-section scar or episiotomy sites. Biologically distinct tissue may directly attach to a site accompanied by initiation of localized oncogenic -like cascades leading to implant survival. Decreased immunosurveillance which would normally clear the ectopic tissue--may also be there

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5. Induction theory – An endogenous undefined biochemical factor can induce undifferentiated peritoneal cells to develop into endometrial tissue. 6. Stem cell may be a source 7. Activation of mullerian cell rest

Pathogenesis of the disease: 

Pathogenesis of the disease Several key steps are required Multiple biologic pathways and certain oncogenic pathways seem to be involved. Steps of pathogenesis 1-Presence of ectopic endometrial glands and stroma 2-Attachment of endometrial cells to the peritoneum – MMPs - involved in the steps of adhesion and invasion Endometriotic tissue and ovarian endometriomas express higher levels of MMPs and also have a higher ratio of MMPs to their tissue inhibitors, known as TIMPs. Inflammation is a key feature of endometriosis Increased level of proinflammatory cytokines- interleukin-1  , interleukin-6, and tumor necrosis factor-  .

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TNF-  increases prostaglandin production and initiates a surge of inflammatory cytokines, which promotes the adherence of ectopic endometrium to the peritoneum. TNF-  also upregulates MMPs, and decrease the effect of TIMPs, thereby increasing the actions of MMPs. Hyaluronic acid and its receptor, CD44 , -initial attachment of ectopic endometrium to peritoneal mesothelial cells (PMCs). Integrins and E- cadherin mediate adhesion of cells to each other and to the extracellular matrix.

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3- Invasion into the mesothelium - MMPs are critical promoters of invasion. PMCs monolayer Colony stimulating factor-1 c- fms (receptor for colony stimulating factor-1) c-Met (the receptor for hepatocyte growth factor) Some unidentified factors 4- Survival and growth of the ectopic tissue – Failed immunosurveillance , which prevent clearance of ectopic tissue. Decreased T cell-mediated cytotoxicity , Decreased T cell-dependent B-cell proliferation, Reduced numbers & activity of natural killer cells --Environmental toxins such as dioxin & poly chlorinated biphenyls Angiogenesis and neovascularization are required for survival and growth of the endometriotic implant.

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Various angiogenic factors are :- Peroxisome proliferator -activated receptors (a group of nuclear receptors). VEGF – Angiogenesis & peritoneal adhesion formation Induce expression of COX-2, a key enzyme in prostaglandin production. Estrogen – -Enhance survival -2 sources *De novo conversion from cholesterol * Aromatase enzyme converts androgenic (C19) steroids to estrogen in skin and adipose tissue. IL-6 IL-8

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IMMUNOLBIOLOGY Subclinical inflammation Increase number of immune cells in peritoneal fluid Action as a scavenger  Dysregulated secretion of cytokines and growth factors  Impaired immune response resulting in ineffective removal of reflux menstrual debris

IMMUNOLBIOLOGY: 

IMMUNOLBIOLOGY Sub clinical peritoneal inflammation, evidenced by – Increased peritoneal fluid volume & PF- WBCs Increased macrophage number and activity Activity as a scavenger Secretary activity NKcells - Antibody dependent cellular cytotoxicity No Over expression of killer inhibitory receptors

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Increased inflammatory cytokines – TNF  , IL-6, IL-8, MCP-  , expressed in dysregulated manner in endometriotic implant. Regulate chemostasis , mitosis, angiogenesis & differentiation Increased growth factors and angiogenesis promoting substances – EFG, MDGF, Fibronectine , Adhesion molecule such as integrin . IL-6- Stimulate the release of angiogenic factors -Induce the release of soluble form of ICAM-1 ICAM-I competes for immune recognition sites on NK cells and other immune cells  Bind to these cells  Immune cells are not available to clear the endometrial tissue

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IL-6- Potent angiogenic Promote adhesion, implantation & growth Mcp-1 & RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted) Chemoattractant Recruit macrophages Increased MMPs Increased expression of cyto chrome 450 protein and m-RNA only in a ectopic implants – increased estrogen

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Progesterone resistance 17 HSD-Type I Estrone Estradiol 17 HSD-Type II Progesterone + In normal conditions 17 HSD-Type I is expressed 17 HSD-Type II is less expressed Progesterone induces 17 HSD-Type II in normal epithelium In endometriotic implant progesterone receptor expression is abnormal so no induction of 17 HSD-Type II

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Immunobiology of endometriosis (Lancet, 2004, modified)

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Auto reactivity i.e. development of anti endometrial or non tissue specific auto antibodies. Specific antigen targeted by anti endometrial antibodies include  -2 Herman Schmidt Glycoprotein, Transferin , Laminin-1 – also found in embryonic tissue suggesting to contribute to miscarriage in patients with endometriosis. Coexistence with auto immune disease

Studying of endometriosis: 

Studying of endometriosis Multiple in vitro and in vivo models have been developed Initial in vitro models- 2 dimensional later on 3-D and animal models were developed. Various models are – Chicken chorioallantoic membrane (CAM) model – Multiple adhesion molecules have been shown to be expressed by CAMs, including fibronectin , laminin , collagen type I and several matrix metalloproteinases (MMPs) Human amniotic membranes – used to model basement membranes, but stripping of the epithelial lining is required.

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In vitro 3-D models – better suited to study invasion Matrigel – A commercially available basic membrane matrix Fibrin matrices Animal model – Rodent models – Rats, mice and hamsters. Rabbits Nonhuman primates – rhesus money, baboons Both immunocompetent and immunocompromised animals have been studied.

Genetics and Genomics : 

Genetics and Genomics Familial in nature Inheritance occur in a polygenic multi factorial fashion. Familial clustering -5-7 times more in 1st degree relative Similar age of onset in affected non twin sisters Higher concordance in monozygotic verses dizygotic twin Loss of heterozygocity at 5q, 6q, 9p, 11q, 22q, Monosomy 17 Activation of K- ras allele gene HLA Linkage Relationship between SLE, dysplastic neavi , history of melanoma

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The underlying principle is that affected relatives inherit identical copies of any given causative allele VARIOUS GENES- (Quantitative genetic analysis (QTL) by sib-pair analysis method) Galactose-1-phosphate uridyl transferase polymorphism - first candidate gene studied Phase I detoxification genes (Ah receptor, CYP1A1, NAT2) Phase II detoxification genes (GSTs, NAT2) detoxification of the products of oxidative stress, Steroid-related genes (Estrogen receptor 1 (PVU ІІ ), Progesterone receptor (PROGINS) , aromatase gene)-polymorphism Intercellular adhesion genes (ICAM-1), matrix metalloproteinase, and angiogenic factors Cytokines DNA mismatch repair genes - LoH for several DNA mismatch repair genes MSH2, MSH6, MLH1, and PMS1 p16, (INK41), Tumor suppressor genes (TP53, PTEN)- LoH

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Endometrial reflux and lysis (phagocytosis) First hit / Initial mutation (somatic or heritable in germ line) Cell scavenger gene e.g. macrophage receptor Cell adhesions gene e.g. Integrine, MMPs Attachment of first hit cells Second hit (always somatic) ER DMEs AhR Survival of first hit cells More hit (somatic) P53 HER-neu bcl ras C-myc Uncontrolled growth and aggressive behaviour

Differential Gene Expression Between Eutopic and Ectopic Endometrium : Confirmed in  Human DNA Microarray Studies. : 

Differential Gene Expression Between Eutopic and Ectopic Endometrium : Confirmed in  Human DNA Microarray Studies. Acession No. Gene Name Gene Ontology NM_033139 Caldesmon 1 (CALDI) Cytoskeleton NM_000591 CD 14 antigen (CD14) Defense NM_000740 Cholinergic receptor, muscarinic 3 (CHRM3) Signal transduction NM_001733 Complement component Ir (CIR) Defense NM_002474 Myosin, heavy polypeptide 11 (MYH11) Cytoskeleton NM_021127 Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIPI) Signal transduction NM_206963 Retinoic acid receptor responder 1 (RARRESI) Cell cycle NM_198235 Ribonuclease, RNase A family, 1 (RNASEI) Nucleic and regulation NM_003246 Thrombospondin 1 (THBS1) Extracellular matrix NM_000362 Tissue inhibitor of metalloproteinase 3 (TIMP3) Proteinase regulation

Epidemiology of Endometriosis and Risk Factors: 

Epidemiology of Endometriosis and Risk Factors 3rd leading cause of gynecologic hospitalization in united state. Pandemic disease process Precise timing of onset of disease is not known. There is a frequent delay from the onset of symptoms to a conformed diagnosis which may average 6 year or more. Estrogen is one of the principle endocrine risk factor Progesterone is some what protective

Factor with increase risk of endometriosis: 

Factor with increase risk of endometriosis In fertility – when 3 groups of patients were compared i.e. Asymptomatic patients under going an unrelated procedure Symptomatic patients In fertile patients Highest prevalence rate are typically found in infertile patients ranging from 5-50%. Red hair colour – Direct correlation Early age at menarche Shorter menstrual cycle Hypermenorrhoea / menorrhagia Nulliparity

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Mullerian anomalies – obstructive and non obstructive – higher incidence in patients with septate or arcuate uterus Birth weight (<7 pounds) – Due to multiple unknown factor including environmental and genetic One of multiple fetal gestation – Due to higher estrogen exposure DES exposure in utero – DES alter estrogen receptor expression and immune system. Endometriosis in first degree relative

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Dioxin/PCB exposure (poly chlorinated biphenyl) Alcohol/ caffeine exposure – Both increase the estrogen levels and may disrupt the immune system. Diet high in fat and red meat Immune disorder – prevalence of rheumatoid, hypo/hyperthyroidism, multiple sclerosis was higher High rAFS score Prior surgeries or medical therapy Tall-taller women have higher follicular phage estrdiol level Family history of carcinoma – breast and ovarian

Factor with decreased risk of endometriosis: 

Factor with decreased risk of endometriosis Pregnancy Greater parity Lactation Increased BMI and waist to hip ratio – due to the fact that women with these traits have more irregular menstrual cycle and more anovulatory cycles which decrease the life time number of months exposed to menses For every unit increased in BMI there was in approximate 12 to 14% decrease in endometriosis Exercise Diet higher in vegetable and fruits Tobacco exposure in utero

Factor with conflicting risk : 

Factor with conflicting risk Race – some study say that rate of endometriosis is 40% lower in African American Hispanics as compare to white women. Where as other say that there is no substantial difference in term of race OCP – OCPs may decreased the risk via ovulation cessation. They may also simultaneously increase the risk by exposure to exogenous harmone . Cigarette smoking – smoke contain both nicotine and cotinine which decreased estrogen production. Dioxin is by product of combustion of smoke which increase the incidence of endometriosis.

Factor with no change in risk: 

Factor with no change in risk Age Tampoon use Irregular mens IUCD use Dysmenorrhoea is consider both a symptom as well as a risk factor. It causes stronger uterine contraction and increase retrograde menstruation

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SITES OF ENDOMETRIOSIS

Sites of Endometriosis : 

Sites of Endometriosis Pelvis – Ovaries Pouch of Douglas Uterosacral ligament Broad ligament and round ligament Recto vaginal septum Fallopian tubes The back of the uterus and posterior cul-de-sac The front of the uterus and the anterior cul-de-sac Pelvic and back wall

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TUBAL ENDOMETRIOSIS COLON ENDOMETRIOSIS ANTERIOR ABDOMINAL WALL

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Extra genital / Extra pelvic – Most common sites of extra pelvic disease is gastro intestinal – rectosigmoid , appendix, small bowel, rectum Urinary tract – ratio of bladder : ureter : kidney is 40:5:1 Diaphragmatic or thoracic Liver The only site where extra genital endometriosis has not been reported is spleen Other rarer sites – Described in virtually every location that can be reached by hematogenous , lymphatic or direct dissemination Hepatic Cutaneous Musculoskeletal Nerve – commonly in sciatic nerve Surgical scars Cervical Brain Eyes umblicus

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SUBDIAPHRAGMATIC ENDOMETRIOSIS LUNG ENDOMETRIOSIS

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LUNG ENDOMETRIOSIS

Types of lesion : 

Types of lesion Three primary types of endometriosis are Superficial peritoneal lesion, Ovarian endometrioma Deep infiltrating endometriosis

ADOLESCENT ENDOMETRIOSIS: 

ADOLESCENT ENDOMETRIOSIS Evaluation and management of chronic pelvic pain in adolescents is a challenge In majority it is primary or functional in nature associated with normal ovulatory cycles making the diagnosis more difficult. Majority report both cylic and acylic pain in contrast to the traditional cylic pain.

Characteristics of Endometriosis in Adolescents: 

Characteristics of Endometriosis in Adolescents Characteristic Frequency Incidence* 19%-73% Prevalence* 47% Incidence in premenarcheal girls who have initiated puberty 25%-38% Symptom onset before age 20 in adults with endometriosis 66% Average time from onset of symptoms to diagnosis 9.28 y Varied presentation in adolescents : Classic dymenorrhea 64%-94% Other acyclic pain 36%-91% * In population presenting with chronic or cyclic pelvic pain.

Invasive procedures should not be used in adolescents with severe dysmenorrhea if their basal body temperature, the so called “Benjamin sign”, has not been investigated.: 

Invasive procedures should not be used in adolescents with severe dysmenorrhea if their basal body temperature , the so called “ Benjamin sign ”, has not been investigated . BBT is charted from 22 day of the cycle to end of flow for at least 2cycle. There is a late decline of BBT after the onset of menstruation in 34.5% of cases.

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THE BENJAMIN SIGN : When Basal Body Temperature (BBT) of an adolescent girl , with an endometriotic syndrome , stays high during the menstrual flow or has up and downs during the same and falls only at the end of it , we should strongly suspect endometriosis and go for a laparoscopy . Atypical Benjamin sign

Endometriosis in menopausal women: 

Endometriosis in menopausal women Endometriosis usually regresses after the menopause. Occasionally it persists postmenopausally Patients who take hormone therapy (HT); especially estrogen only therapy (ET). Infers a risk of recurrence and malignant transformation Treatment primarily surgery ( hysterectomy and bilateral salpingoophorectomy) Little experience with medical treatment (aromatase inhibitors) (Oxholm Dorthe et al, 2007).

Endometriosis and Infertility : 

Endometriosis and Infertility Numerous mechanisms : Decreased tuboovarian motility Ovulatory dysfunction Anavulation Impaired follicle growth Luteal insufficiency Decreased circulatory E 2 and progesterone Luteinized unruptured follicle syndrome Intraperitoneal inflammation Disturbed LH surge Decreased fertilization Decreased implantation rate Increased ROS Deleterious effect on sperm motility Galactorrhoea , hyperprolactinemia Decreased “Spontaneous Monthly Fecundity Rate” (MFR)

DIAGNOSIS OF ENDOMETRIOSIS: 

DIAGNOSIS OF ENDOMETRIOSIS History Examination BBT or Benzamine sign Investigation Non invasive Blood investigations or Serum markers Imaging | USG MRI TVS TRUS Invasive Laparoscopy + Histology Laparotomy

SYMPTOMATOLOGY : 

SYMPTOMATOLOGY Pelvic pain Dysmenorrhea – Especially suggestive of endometriosis if it occurs after years of pain free menstruation. Start before onset of mens and continues Usually bilateral Deep dyspareunia Chronic pelvic pain Ovualtion pain Other types of pain – Sciatica Infertility Symptoms of extra pelvic endometriosis- typically present cyclicaly , correlated with menstruation so-called catamenial symptoms which are considered pathognomonic . Later in disease progression, symptoms become more continuous.

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70% 40% 35% 33% 15% 1-2% Dysmenorrhoea Pelvic pain Infertility Dyspareunia Menstrual irregularities Other cyclic bleeding

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GI symptom :- Diarrhoea Constipation Premenstrual changes in bowel habbits Rectal bleeding Pain with defecation Tenesmus Abdominal distension Small caliber stool Colicily abdominal pain Bowel obstruction – In more advance disease & perforation Urinary Symptom:- Urgency Frequency Supra pubic pain Flank pain Urge incontinence Dyspareunia Hematuria Dysuria Backache Hydronephrosis

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Diaphragmatic and thoracic Chest pain Catamenial Pneumo thorax – most frequent presentation Catamenial hemothorax Catamenial hemoptysis Lung nodules Other symptoms Cyclical Sciatica Catamenial seizure Chronic fatigue Mood swing Intermittent pyrexia (Benjamin sign) Endometriosis in men- Reported in men undergoing treatment of prostatic cancer with orchidectomy & high dose estrogen therapy

EXAMINATION: 

EXAMINATION INSPECTION: Scar endometriosis PER SPECULUM EXAMINATION: Cervical endometriosis BIMANUAL EXAMINATION: Focal tenderness Lateral cervical displacement Fixed retroverted uterus Uterosacral / cul-de-sac nodularity Painful swelling of rectovaginal septum Unilateral cystic ovarian enlargement  mobility of fallopian tubes / ovaries “Deeply infiltrating nodules are most reliably detected when clinical examination is performed during menstruation” (Evidence level III, RCOG Guideline No. 24, 2006).

Markers for endometriosis: 

Markers for endometriosis No blood test is reliable for the diagnosis of endometriosis Tumour markers and polypeptides CA-125, CA-19-9 SICAM-1 (soluble forms of the intercellular-adhesion molecule-1) Glycodelin -A (PP 14) Immunological markers Cytokines: IL-6, TNF Autoantibodies (1) Antiendometrial : Serum & Peritoneal fluid (2) Autoantibodies to markers of oxidative stress

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Genetic markers Early growth response (EGR)-1 gene P450 aromatase Placental Protein 14 (PP14) Tissue markers (A) Aromatase P 450 (B) Cytokeratins (C) Hormone receptors There are two isoforms for estrogen (ER) and progesterone (PR) receptors—ER-a and ER-h, PRA and PR-B Beta-3 In healthy women, beta-3 appears on endometrial epithelial cells on the 19th or 20th day of the menstrual cycle in women with endometriosis, beta-3 is absent on day 19 and 20

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CA-125: No value as a diagnostic tool as compared to laparoscopy Useful to predict the recurrence Sensitivity 20-50% Specificity >80% Elevated in women of advanced endometriosis

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ULTRASONOGRAPHY Limited utility Lacks adequate resolution to identify superficial peritoneal implants, small (<2 cm) ovarian endometriomata and adhesions TVS Help in the diagnosis of endometriomas, bladder lesions, deep nodules e.g. on rectovaginal septum

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ENDOMETRIOMA Homogenously, hypoechoic , cystic mass with diffuse low level internal echoes & posterior acoustic enhancement, termed as “ GROUND GLASS APPEARANCE” Multiloculated Hyperechoic , thickened cyst wall

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Presence of punctate, peripheral echogenic foci wihin the cyst wall is very specific “ BRIGHT SPOT” Diagnostic accuracy is increased by Doppler flow indices Blood flow in endometrioma is usually pericystic with resistive index above 0.45 Sonovaginography/ Saline infusion sonography - identification of the rectovaginal lesion might be improved by the instillation of saline in the vagina,

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TRUS Demonstrate rectovaginal septum involvement & posterior bladder better than MRI Sensitivity- 97% Specificity- 96% (ESHRE guideline)

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Rectal endoscopic sonography showing the normal anatomy of the rectal wall. P = probe; MP = muscularis propria; SM = submucosa; M = mucosa. Rectal endoscopic sonography showing an endometriotic nodule (E) involving the rectal wall (R).

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CT - Scan Endometriomas may appear solid, cystic or mixed Because of poor specificity & high radiation, CT has been replaced by MRI

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MRI Use full in deep pelvic endometriosis Magnetic resonance imaging using fat saturation can detect up to 50% of small, haemorrhagic lesions measuring not more than 5 mm and allows then diagnose of mild disease in 75% of cases. Lesions appear T1WSE- Hyperintense T2WSTE- Hypointense (shading)

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Uterosacral ligament endometriosis : axial T2-weighted magnetic resonance imaging (MRI) passing through the cervix and the posterior vaginal fornix and showing irregular thickening of the left uterosacral ligament (arrow).

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Vaginal endometriosis: sagittal T1-weighted MRI showing hyperintense spots within the posterior vaginal fornix (arrow). Note the presence of the endometrioma in the pouch of Douglas.

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Bladder endometriosis: sagittal T2-weighted MRI showing a fibrotic mass in the dome of the bladder, in front of the vesico -uterine pouch (arrow). Note the associated anterior adenomyosis (arrowhead).

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Rectosigmoid colon endometriosis : sagittal T2-weighted MRI showing complete obliteration of the cul-de-sac due to intestinal endometriosis (white arrow) associated with endometrioma (arrowhead). Note the retroperitoneal collection behind the rectosigmoid colon (star).

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LAPAROSCOPY

LAPAROSCOPY: 

LAPAROSCOPY For definitive diagnosis of endometriosis visual inspection of the pelvis at laparoscopy is gold standard, unless disease is visible in vagina or elsewhere Should not be performed during or within 3 months of hormonal treatment to avoid under diagnosis

Superficial peritoneal lesion : 

Superficial peritoneal lesion Typically located on pelvic organ or pelvic peritoneum Classical lesion are ‘ powder burn or gun shot lesion .’ These are black, dark brown or bluish nodules or small cyst containing old hemorrhage. May be associated with hemosiderin deposit Non classical lesion are subtle lesions – Red implants ( Petechial / vasicular / polypoidal /hemorrhage/ red flame like. Serous or clear vesicles White plaques Scaring Yellow-brown discoloration of the peritoneum Sub ovarian adhesion Can also be found in the base of peritoneal defect called an “ Allen Masters ” window.

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Variety of endometriotic lesions seen at laparoscopy

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Black puckered lesion

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VESICULAR LESIONS VESICULAR LESIONS Non classical lesion are subtle lesions – Red implants (Petechial/ vasicular/ polypoidal/ hemorrhage/ red flame like. Serous or clear vesicles

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“Allen Masters” window.

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PERITONEAL SCARRING SUBDIAPHRAGMATIC SCARRING Peritoneal endometrioma Reddened lesion of the peritoneum

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PERITONEAL LESION WITH NEOVASCULARISATION AND FIBROSIS RECTUM ADHERENT TO POD CUL-DE-SAC COLLECTION White opacifications of the peritoneum

Endometrioma (Chocolate cyst): 

Endometrioma (Chocolate cyst) Usually located on anterior surfaced of the ovary Diameter < 12cm Associated with retraction pigmentation and adhesion to posterior peritoneam Adhesion to pelvic side wall and broad ligament. Associated superficial endometriosis with adjacent puckering on surface of ovary.

Endometrioma(Chocolate cyst): 

Endometrioma(Chocolate cyst) Contain tarry,thick chocolate coloured fluid composed of hemosiderin derived from previous intraovarian hemorrhage Marker of more extensive pelvic and intestinal disease Histological conformation is necessary

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“ KISSING OVARIES”

HISTOLOGY: 

HISTOLOGY Whether should be obtained or not – controversial In cases of ovarian endometrioma >3 cm in diameter and in deeply infiltrating diseases, histology should be obtained Diagnosis requires 2 or more of these features Endometrial epithelium Endometrial glands Endometrial stroma Endometrial hemosiderin laden macrophages

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Microphotograph showing monolayered sheets of endometrial glandular cells and spindled stromal cells with capillary meshwork (Pap, ×100). Inset: (a) Epithelial cells (Pap, ×400) (b) hemosiderin laden macrophages (Leishman’s, ×400)

Large endometrial fragment in peritoneal wash fluid showing epithelial lining on the outside, seen on the sides and as honeycombed cells as well as compact stromal cells within (PAP, ×400) : 

Large endometrial fragment in peritoneal wash fluid showing epithelial lining on the outside, seen on the sides and as honeycombed cells as well as compact stromal cells within (PAP, ×400)

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ENDOMETRIAL GLANDS AND STROMA

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Recent studies have shown an increased number of nerve fibres in endometriosis These are primarily small unmyelinated sensory C fibres in the functional layer of endometrium Identified by their staining with protein gene product 9.5, vasoactive intestinal peptide and substance P, but not with neurofilament (COG, June 2010, vol. 53, No. 2 )

CLASSIFICATION : 

CLASSIFICATION Current classification is by “American society of Reproductive Medicine” , former “American Fertility Society”(AFS) system Based on morphology, size and depth of peritoneal implant Morphology- Red ( Red, Red-pink & clear lesions) White (White, yellow-brown & peritoneal defects) Black (Black & blue lesions) Presence extent and type of peritoneal adhesions Degree of cul-de-sac obliteration

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Staging – American society of Reproductive Medicine, 1996 Stage I – Minimal Isolated superficial implants, No adhesions Stage II – Mild More superficial implants (<5cm), No significant adhesions

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Stage III – Moderate Multiple superficial & invasive implants, Peritubal & Periovarian adhesions may be present Stage IV – Severe Multiple implants, Ovarian endometriomas, Many dense adhesions

CLASSIFICATION OF EXTRGENITAL ENDOMETRIOSIS: 

CLASSIFICATION OF EXTRGENITAL ENDOMETRIOSIS Currently no accepted classification Markham et all in 1989 proposed asystem Class -I: Intestinal tract Class –U: Urinary system Class –L: Lung and thorasic cavity Class –O: all other sites (COG, June 2010, vol. 53, No. 2 )

TREATMENT: 

TREATMENT Must be individualized Highly dependent on the wishes of the patient - fertility or contraception Symptom and severity of the disease Location of the disease

MEDICAL TREATMENT: 

MEDICAL TREATMENT Four chief medical approaches- 1- Analgesia 2- Suppresion of ovulatory function 3- Direct action of endometrial implant 4- Modulation of immune system

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Non Hormonal Medications NSAIDs : Naproxen Mechanism: Local anti- nocioceptive effect  central sensitization Anti-inflammatory effects Side effects: Gastric ulcerations Inhibition of ovulation “Inconclusive evidence regarding their effectiveness (especially Naproxen)” ( ESHRE, 2007 update )

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Immuno/ Inflammatory modulators Recombinant human TNF-  binding protein Recombinant IFN-  2b Loxoribine Levamisole Peroxisome proliferator activated receptor gamma ligands(Thiazolidinediones): Rosiglitazone, pioglitazone Leukotriene receptor antagonist: Pentoxifyline: Oral, 800 mg/day, 12 month

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Antiangiogenic- Statins Thalidomide Inhibition of MMPs : Progesterone Anti VEGF antibodies Angiostatic agents (TNP470, endostatin, rapamycin)

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HORMONAL MEDICATIONS Suppress estrogen synthesis Suppression of ovarian function for 6 months reduces pain associated with endometriosis

Progestins : 

Progestins First choice treatment Initial decidualization of endometrial tissue followed by atrophy (Pseudo- decidual endometrial response ) Hypogonadotropic-hypogonadal state ORAL - Medroxy progesterone acetate (30 mg/day x 3-6 mts ) - Megestrol acetate : 40 mg/day - Lynestrenol : 10 mg/day - Dydrogesterone : 20-30 mg/day I NTRAMUSCULAR - MPA (150 mg) every 3 months Intrauterine : LNG-IUS for 12 months

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Progesterone Antagonists Mifepristone (RU-486) 25-100 mg/day Onapristone (ZK98299) and ZK136799, ZK 230211 Direct inhibitory effect on human endometrial cells

OCPs: 

OCPs Continuous Low dose monophasic combinations ( ethinyl estradiol-30 to 35  gm), 1 pill/day x 6-12 months Pseudopregnancy state Causes amenorrhoea Decidualization of endometrium Cyclical 21 day OCP (EE 20  gm + Desogestrel 0.15 mg) Useful in prolonged, frequent bleeding

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VAGINAL RING 15  gm ethinyl estradiol and 120  gm of etonorgestrel TRANSDERMAL PATCH 20  gm ethinyl estradiol and 150  gm norelgestromin

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Gestrinone 19-Nor testosterone derivative Androgenic / anti estrogenic / antigonadotrophic / antiprogestagenic Acts centrally & peripheraly 2.5 mg twice a week x 24 weeks Side effects: Nausea, muscle cramps, androgenic effect As effective as GnRH in pain Advantage- fewer side effects -twice weekly administration Pregnancy – CI

Danazol or Danocrine: 

Danazol or Danocrine Isoxazole derivative of 12 α -ethinyl estradiol Complex mechanism of action High androgen low estrogen enviornment -Start with 200 mg BD orally Side effects: androgenic and hypoestrogenic properties CI: liver disease, HT, CHF, impaired renal function, pregnancy

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Vaginal Danazol Ring (1,500 mg) Effective for pain relief in deeply infiltrating endometriosis Allows ovulation and conception to occur Does not cause classic danazol SE or detectable serum danazol levels

GnRH Agonist: 

GnRH Agonist Creates a reversible state of pseudomenopause Pitutary downregulation of GnRH receptors Cause initial flare  activity of plasminogen activators and MMPs

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GnRH Agonist Agents – leuprolide , buserelin , nafarelin , hitrelin , goserelin , deslorelin , triptorelin ( Decapeptyl ) Routes – I/M, S/C, intranasal , inactive orally Dose- Leuprolide ( IM- 3.75 mg, monthly or SC- 500 mg daily) Side effect: hypoestrogenism features Add back therapy with estrogen or progestins , tibolone

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GnRH Antagonist No initial flare, More rapid onset of action, immediate suppression Quick recovery Less OHSS Less expensive Ganirelix , Cetrorelix

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Aromatase Inhibitor Anastrazole 1 mg/day + calcium 1.5 g/d x 9 months Selective estrogen receptor modulator (SERM) Raloxifene Can be considered in postmenopausal endometriosis (Vegnali et al, 2002) Selective progesterone receptor modulator (SPRM) Asoprisinil Antiproliferative effect on endometrium and breast Favourable pharmacological profile Estrogen receptor (ER) ligand/Selective estrogen receptor beta agonist – selective binding on ER-beta

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Table 1. Medical treatment options in women with symptomatic endometriosis who are not seeking pregnancy. First-line treatments Peritoneal disease and endometriotic cysts 3 cm Oestrogeneprogestin combinations used cyclically or continuously* (oral, intravaginal or transdermic use) Rectovaginal lesions- Noretistherone acetate, 2.5 mg/day per os used continuously* Second-line treatments Depot GnRH analogues plus add-back therapy (e.g. tibolone 2.5 mg/day per os) Alternative progestins (e.g. medroxyprogesterone acetate, desogestrel, cyproterone acetate) Third-line treatments Low-dose danazol (e.g. 200 mg/day, oral or intravaginal use) Gestrinone, 2.5 mg twice weekly per os Specific conditions Parous women with dysmenorrhoea as main symptom Levonorgestrel-releasing intra-uterine device Hysterectomized women with residual disease Depot medroxyprogesterone acetate (150 mg intramuscularly every 3e6 months) GnRH, gonadotrophin-releasing hormone. * A 7-day interruption is suggested in case of breakthrough bleeding during continuous use

SURGICAL TREATMENT : 

SURGICAL TREATMENT Goal To excise all visible lesions and associated adhesions To restore normal anatomy Laparoscopy is better Laparotomy – reserve for Advanced stage disease Who cannot go laparoscopy Fertility is not desired

Laparoscopic Management : 

Laparoscopic Management

Laparoscopic Management : 

Laparoscopic Management Pelvic adhesions – lysis by various methods Blunt dissection or acqua dissection with a grasping forcep KTP laser Endoloop sutures or clips Superficial peritoneal endometriosis For <5 mm lesion- sharp dissection with tissue margin 2-4 mm under a constant stream of irrigation Excision Normal cold scissor 3 mm monopolar scissors used at a high power of 90 W Laser Excision – CO 2 laser, potassium titanium phosphate(KTP) laser

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Coagulation and vaporasation Argon beam coagulator Helica thermal coagulator. Very low electrical power is used to produced a plasma beam developed in 1995 (NICE Interventional Procedure, Guideline No. 42) Ethicon Endo-Surgery LCS-C5,5 mm Harmonic Scalpel- Use Ultrasound generated energy Cuts and causes haemostasis, by coaptation more than coagulation,

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Ovarian endometriosis Superficial ovarian lesions – vaporization Endometrioma <3 cm – aspiration, irrigation, inspection with ovarian cystoscope for intraovarian lesions, anterior wall vaporization Endometrioma >3 mm – aspiration, incision and removal of cyst wall (ovarian cystectomy ) Laparoscopic uterosacral nerve ablation (LUNA) Disruption of mid portion of uterosacral ligament Presacral neurectomy (PSN ) Interrupting the sympathetic innervation of uterus at the level of superior hypogastric plexuses Deep rectovaginal or rectosigmoid endometriosis Surgical excision Segmental rectosigmoid resection

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Genitourinary Ureter Superficial implant – hydrodisection Ureteral obstruction – laparoscopic uretro-uretrostomy Bladder Superficial – vaporization and hydro dissection Deep – excision + bladder reconstruction + cystoscopy Diaphragmatic Laparoscopic hydrodissection and vaporization

Severe/ Deeply infiltrating disease: 

Severe/ Deeply infiltrating disease Management is complex Advanced lapraroscopic surgery and laparotomy is strongly recommended (RCOG Guide line No24, oct-2006)

LAPAROTOMY: 

LAPAROTOMY

LAPAROTOMY : 

LAPAROTOMY Total abdominal hysterectomy + bilateral salpingo-oophrectomy Hysterectomy alone is not effective Reserve for severe situation HRT is recommended in young women after bilateral oophorectomy ( ROCG guideline 24, 2006). Estrogen should be withheld until 3 month after surgery

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COMPLEMENTARY THERAPY Role unclear High frequency TENS, acupuncture, Vit . B, magnesium, Vit . E. may relieve dysmenorroea Homeopathy, reflexology, traditional Chinese medicine or herbal treatment Patient self-help groups can provide invaluable counselling , support and advice (ROCG guideline 24, 2006)

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Insufficient evidence to justify the use of pre and postoperative Hormonal treatment (ROCG guideline 24, 2006). PREOPERATIVE HORMONAL THERAPY- Although it improves r AFS scores but insufficient evidence for pain relief (Level Ia , ESHRE, 2007). POSTOPERATIVE HORMONAL THERAPY- Does not produce significant reduction in pain recurrence at 12-24 months and has no effect on disease recurrence (Level Ia , ESHRE, 2007).

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Empirical treatment of pain symptoms without a definitive Diagnosis Counselling Adequate analgesia Nutritional therapy Progestagens Combined oral contraceptive (COC)

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Treatment of endometriosis-associated pain in confirmed disease Non-steroidal anti-inflammatory drugs Hormonal treatment Surgical treatment

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Protocol for Evaluation and Treatment of adolescent Pelvic Pain and endometriosis

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TREATMENT OF ENDOMETRIOSIS ASSOCIATED INFERTILITY Treatment Depends on: Age of women Duration of infertility Stage of endometriosis Involvement of ovary / tubes Previous therapy Association of pain Cost of treatment Financial means Expected results

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Infertility & Suspected endometriosis Operative Laparoscopy Watchful waiting Success Pregnancy Failure Assisted Reproduction TREATMENT PROTOCOL FOR ENDOMETRIOSIS ASSOCIATED INFERTILITY

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Minimal -mild endometriosis : Suppression of ovarian function to improve infertility is not effective Ablation of endometriotic lesion + adhesiolysis is more effective compared with diagnostic laproscopy alone Moderate – severe endometriosis – role of surgery in improving pregnancy rates is uncertain Laparoscopic cystectomy of endometrioma improves pregnancy rate better than drainage & coagulation Tubal flushing improves fertility rate Postoperative harmonal treatment has no beneficial effect on pregnancy after surgery (RCOG Guideline 24, 2006).

ASSISTED REPRODUCTION: 

ASSISTED REPRODUCTION METHODS: Controlled ovarian hyperstimulation + IUI improves fertility in minimal to mild endometriosis IVF - Method of choice when Distortion of tubo ovarian anatomy Male factor infertility Other treatment have failed Gamete intra fallopian transfer (RCOG Guideline 24, 2006) Intracytoplasmic Sperm injection- Reduced no of oocyts recoverd but normal fertilization, Implantation & pregnancy rate IUI

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Treatment with GnRH agonist for 3-6 months before IVF/ICSI in women with endometriosis  the rate of clinical pregnancy (level Ia) (RCOG, 2006). Risk of recurrence is no reason to withhold IVF therapy after surgery for endometriosis stage III/IV since cumulative endometriosis recurrence rates are not increased after ovarian hyperstimulation of IVF

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Thank You