ENDOMETRIOSISENDOMETRIOSIS

Syeda Komal Siraj08-195

Endometriosis is a disease or better a syndrome Endometriosis is a disease or better a syndrome that starts around the prepubertal age, that starts around the prepubertal age, flourishing after menarche, with symptoms flourishing after menarche, with symptoms progressing in intensity through the years. progressing in intensity through the years.

Predominantly found in women of reproductive Predominantly found in women of reproductive age age

Found in all the ethnic & social groupsFound in all the ethnic & social groups

DEFINITIONDEFINITION EndometriosisEndometriosis (from (from endoendo, "inside", and , "inside", and metrametra, ", "wombwomb""

Presence of endometrial like tissue (glands/stroma) Presence of endometrial like tissue (glands/stroma) outside the uterus which induces chronic inflammatory outside the uterus which induces chronic inflammatory reaction. reaction.

Most frequent sites are pelvic viscera & peritoneum out Most frequent sites are pelvic viscera & peritoneum out of which most common site is ovary (RCOG guideline of which most common site is ovary (RCOG guideline no. 24, 2006)no. 24, 2006)

Adenomyosis is ectopic endometrium inside the Adenomyosis is ectopic endometrium inside the myometrium of uterus, previously known as myometrium of uterus, previously known as endometriosis interna.endometriosis interna.

INCIDENCEINCIDENCE

• Asymptomatic women undergoing tubal sterilization Asymptomatic women undergoing tubal sterilization i.e. women with proven fertility - 7%i.e. women with proven fertility - 7%

• Primary infertility (20-30%)Primary infertility (20-30%)

• Dysmenorrhoea (40-60%)Dysmenorrhoea (40-60%)

• Chronic pelvic pain(71-80%)Chronic pelvic pain(71-80%)

ETIOLOGYETIOLOGY Exact etiology of endometriosis is unknown.Exact etiology of endometriosis is unknown.

Understanding of endometriosis is just a beginning.Understanding of endometriosis is just a beginning.

It is a estrogen dependent disease.It is a estrogen dependent disease.

HYPOTHESISHYPOTHESIS1. 1. Retrograde menstruation/ectopic transplantation/ Retrograde menstruation/ectopic transplantation/

Sampson’s theory –Sampson’s theory –

(Lancet, 2004)

• Most widely recognized & plausible theory on the genesis Most widely recognized & plausible theory on the genesis of endometriosis.of endometriosis.

• Based on the assumption that endometriosis is caused Based on the assumption that endometriosis is caused by the seeding or implantation of endometrial cell by by the seeding or implantation of endometrial cell by trans tubal regurgitation during menstruation.trans tubal regurgitation during menstruation.

• Supported by – Blood can be found in peritoneal cavity Supported by – Blood can be found in peritoneal cavity on laparoscopy during menstruation in 75-90%on laparoscopy during menstruation in 75-90%

- most often found in dependent portions - most often found in dependent portions of the pelvis like ovaries, anterior & posterior cul-de-sac, of the pelvis like ovaries, anterior & posterior cul-de-sac, the uterosacral ligaments, posterior uterus, posterior the uterosacral ligaments, posterior uterus, posterior broad ligaments.broad ligaments.

More in women with stenosis of internal osMore in women with stenosis of internal os

Mullerian abnormalitiesMullerian abnormalities

2. 2. Coelomic Metaplasia/ MetaplasticCoelomic Metaplasia/ Metaplastic

Transformation/ Meyer’s theory Transformation/ Meyer’s theory --

Both peritoneal and endometrial tissues share a Both peritoneal and endometrial tissues share a common embryologic precursor the coelomic cell.common embryologic precursor the coelomic cell.

Metaplastic transformation of coelomic epithelium Metaplastic transformation of coelomic epithelium into endometrial tissue can occur.into endometrial tissue can occur.

Premenarchal girl who have never menstruatedPremenarchal girl who have never menstruated

Unusual sites( Extremities, brain, pleura)Unusual sites( Extremities, brain, pleura)

33. Lymphatic or Hematogenous Spread Distant to . Lymphatic or Hematogenous Spread Distant to pelvis/ Hallban’s theory – pelvis/ Hallban’s theory –

Explain the observation of endometriosis in unusual Explain the observation of endometriosis in unusual sites such as brain & pleurasites such as brain & pleura

Extra pelvic endometriosis - vascular or lymphatic Extra pelvic endometriosis - vascular or lymphatic dissemination of endometrial cells dissemination of endometrial cells

Ovarian endometriotic lesion may arise directly from Ovarian endometriotic lesion may arise directly from ovarian surface epithelium through a metaplastic ovarian surface epithelium through a metaplastic differentiation process induced by activation of an differentiation process induced by activation of an oncogenic K-ras allele.oncogenic K-ras allele.

Ovarian endometriosis - retrograde menstruation or Ovarian endometriosis - retrograde menstruation or lymphatic flow from the uterus.lymphatic flow from the uterus.

4.4. Direct Transplantation from Tissue Trauma or Direct Transplantation from Tissue Trauma or SurgerySurgery

Explain the finding of localized endometriosis Explain the finding of localized endometriosis cesarean-section scar or episiotomy sites. cesarean-section scar or episiotomy sites.

• Biologically distinct tissue may directly attach to a Biologically distinct tissue may directly attach to a site accompanied by initiation of localized oncogenic-site accompanied by initiation of localized oncogenic-like cascades leading to implant survival.like cascades leading to implant survival.

• Decreased immunosurveillance which would Decreased immunosurveillance which would normally clear the ectopic tissue--may also be therenormally clear the ectopic tissue--may also be there

5. 5. Induction theory –Induction theory –

An endogenous undefined biochemical factor An endogenous undefined biochemical factor can induce undifferentiated peritoneal cells to can induce undifferentiated peritoneal cells to develop into endometrial tissue.develop into endometrial tissue.

6. 6. Stem cell may be a sourceStem cell may be a source

7. 7. Activation of mullerian cell restActivation of mullerian cell rest

Factor with increase risk of endometriosisFactor with increase risk of endometriosis

In fertility In fertility – when 3 groups of patients were compared i.e.– when 3 groups of patients were compared i.e.

• Asymptomatic patients under going an unrelated procedureAsymptomatic patients under going an unrelated procedure

• Symptomatic patients Symptomatic patients

• In fertile patientsIn fertile patients

• Highest prevalence rate are typically found in infertile patients Highest prevalence rate are typically found in infertile patients ranging from 5-50%.ranging from 5-50%.

Red hair colour Red hair colour – Direct correlation – Direct correlation Early age at menarcheEarly age at menarche Shorter menstrual cycleShorter menstrual cycle Hypermenorrhoea / menorrhagiaHypermenorrhoea / menorrhagia Nulliparity Nulliparity

Mullerian anomalies – obstructive and non obstructive – Mullerian anomalies – obstructive and non obstructive – higher incidence in patients with septate or arcuate uterushigher incidence in patients with septate or arcuate uterus

High social classHigh social class

One of multiple fetal gestation One of multiple fetal gestation – Due to higher estrogen – Due to higher estrogen exposureexposure

DES exposure in utero DES exposure in utero – DES alter estrogen receptor – DES alter estrogen receptor expression and immune system.expression and immune system.

Endometriosis in first degree relative Endometriosis in first degree relative

SITES OF ENDOMETRIOSIS

Sites of EndometriosisSites of Endometriosis

Pelvis – Pelvis – • OvariesOvaries• Pouch of DouglasPouch of Douglas

• Uterosacral ligamentUterosacral ligament

• Broad ligament and round ligamentBroad ligament and round ligament• Recto vaginal septumRecto vaginal septum• Fallopian tubesFallopian tubes• The back of the uterus and posterior cul-de-sacThe back of the uterus and posterior cul-de-sac

• The front of the uterus and the anterior cul-de-sacThe front of the uterus and the anterior cul-de-sac

• Pelvic and back wallPelvic and back wall

TUBAL ENDOMETRIOSIS

Extra genital / Extra pelvic – Extra genital / Extra pelvic – • Most common sites of extra pelvic disease is gastro intestinal – Most common sites of extra pelvic disease is gastro intestinal –

rectosigmoid, appendix, small bowel, rectum rectosigmoid, appendix, small bowel, rectum • Urinary tract – ratio of bladder : ureter : kidney is 40:5:1Urinary tract – ratio of bladder : ureter : kidney is 40:5:1• Diaphragmatic or thoracic Diaphragmatic or thoracic • Liver Liver • The only site where extra genital endometriosis has not been The only site where extra genital endometriosis has not been

reported is spleenreported is spleen Other rarer sites – Other rarer sites –

• Described in virtually every location that can be reached by Described in virtually every location that can be reached by hematogenous, lymphatic or direct disseminationhematogenous, lymphatic or direct dissemination

• HepaticHepatic• CutaneousCutaneous• MusculoskeletalMusculoskeletal• Nerve – commonly in sciatic nerveNerve – commonly in sciatic nerve• Surgical scars Surgical scars • Cervical Cervical • BrainBrain• EyesEyes• umblicusumblicus

SUBDIAPHRAGMATIC ENDOMETRIOSIS

LUNG ENDOMETRIOSIS

LUNG ENDOMETRIOSIS

Endometriosis and Infertility Endometriosis and Infertility Numerous mechanisms :Numerous mechanisms :

• Decreased tuboovarian motility Decreased tuboovarian motility • Ovulatory dysfunction Ovulatory dysfunction

Anavulation Anavulation Impaired follicle growthImpaired follicle growth

• Luteal insufficiency Luteal insufficiency Decreased circulatory EDecreased circulatory E22 and progesterone and progesterone

• Luteinized unruptured follicle syndrome Luteinized unruptured follicle syndrome • Intraperitoneal inflammation Intraperitoneal inflammation • Disturbed LH surge Disturbed LH surge • Decreased fertilization Decreased fertilization • Decreased implantation rate Decreased implantation rate • Deleterious effect on sperm motility Deleterious effect on sperm motility • Decreased “Spontaneous Monthly Fecundity Rate” Decreased “Spontaneous Monthly Fecundity Rate”

(MFR)(MFR)

DIAGNOSIS OF ENDOMETRIOSISDIAGNOSIS OF ENDOMETRIOSIS

History Examination BBTor

Benzamine sign

Investigation

Non invasive

Blood investigations

orSerum markers

Imaging |

USGMRI

TVS

TRUS

Invasive

Laparoscopy +

Histology

Laparotomy

SYMPTOMATOLOGY SYMPTOMATOLOGY Pelvic pain Pelvic pain

• Dysmenorrhea – Especially suggestive of endometriosis Dysmenorrhea – Especially suggestive of endometriosis if it occurs after years of pain free menstruation. if it occurs after years of pain free menstruation.

Start before onset of menstruation and continuesStart before onset of menstruation and continues

Usually bilateralUsually bilateral

• Deep dyspareunia Deep dyspareunia

• Chronic pelvic painChronic pelvic pain

• Ovualtion painOvualtion pain

• Other types of pain – SciaticaOther types of pain – Sciatica InfertilityInfertility Symptoms of extra pelvic endometriosis- typically present Symptoms of extra pelvic endometriosis- typically present

cyclicaly, correlated with menstruation so-called cyclicaly, correlated with menstruation so-called catamenial catamenial symptomssymptoms which are considered pathognomonic. Later in which are considered pathognomonic. Later in disease progression, symptoms become more continuous. disease progression, symptoms become more continuous.

GI symptom :-GI symptom :-• DiarrhoeaDiarrhoea• ConstipationConstipation• TenesmusTenesmus• Abdominal distensionAbdominal distension• Bowel obstruction – Bowel obstruction –

In more advance In more advance disease & perforationdisease & perforation

• Urinary Symptom:– Hematuria– Dysuria

– Backache

Diaphragmatic and thoracic symptoms

Other symptoms – Cyclical Sciatica

– Catamenial seizure

– Chronic fatigue

– Mood swing– Intermittent pyrexia

(Benjamin sign)

EXAMINATIONEXAMINATIONINSPECTION: INSPECTION: Scar endometriosisScar endometriosis

PER SPECULUM EXAMINATION: PER SPECULUM EXAMINATION: Cervical endometriosisCervical endometriosis

BIMANUAL EXAMINATION:BIMANUAL EXAMINATION: Focal tendernessFocal tenderness Lateral cervical displacement Lateral cervical displacement Fixed retroverted uterus Fixed retroverted uterus Uterosacral / cul-de-sac nodularity Uterosacral / cul-de-sac nodularity Painful swelling of rectovaginal septum Painful swelling of rectovaginal septum Unilateral cystic ovarian enlargement Unilateral cystic ovarian enlargement ↓↓ mobility of fallopian tubes / ovaries mobility of fallopian tubes / ovaries

““Deeply infiltrating nodules are most reliably detected when Deeply infiltrating nodules are most reliably detected when clinical examination is performed during menstruation” clinical examination is performed during menstruation” (Evidence level III, RCOG Guideline No. 24, 2006).(Evidence level III, RCOG Guideline No. 24, 2006).

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

37,5

37,4

37,3 37,2 37,1 37 36.9 36,8 36,7

36,6

36,5

Menstruación

Atypical Benjamin sign

Invasive procedures should not be used in adolescents with Invasive procedures should not be used in adolescents with severe dysmenorrhea if their basal body temperature, the severe dysmenorrhea if their basal body temperature, the

so called “so called “Benjamin signBenjamin sign”, has not been investigated.”, has not been investigated.

BBT is charted from BBT is charted from 22 day of the cycle 22 day of the cycle to end of flow for at to end of flow for at least 2cycle. There least 2cycle. There is a late decline of is a late decline of BBT after the onset BBT after the onset of menstruation in of menstruation in 34.5% of cases.34.5% of cases.

Markers for endometriosisMarkers for endometriosis No blood test is reliable for the diagnosis of No blood test is reliable for the diagnosis of

endometriosisendometriosis

Tumour markers and polypeptidesTumour markers and polypeptides CA-125, CA-19-9CA-125, CA-19-9

Immunological markersImmunological markers Cytokines: IL-6, TNFCytokines: IL-6, TNF AutoantibodiesAutoantibodies

(1) Antiendometrial: Serum & Peritoneal fluid(1) Antiendometrial: Serum & Peritoneal fluid

(2) Autoantibodies to markers of oxidative stress(2) Autoantibodies to markers of oxidative stress

ULTRASONOGRAPHYULTRASONOGRAPHY

Limited utilityLimited utility

Lacks adequate resolution to identify superficial Lacks adequate resolution to identify superficial

peritoneal implants, peritoneal implants, small (<2 cm) ovarian small (<2 cm) ovarian

endometriomata and adhesionsendometriomata and adhesions

TVSTVS

Help in the diagnosis of endometriomas, bladder lesions, Help in the diagnosis of endometriomas, bladder lesions,

deep nodules e.g. on rectovaginal septumdeep nodules e.g. on rectovaginal septum

TRUSTRUS

Demonstrate rectovaginal Demonstrate rectovaginal septum involvement & septum involvement & posterior bladder better posterior bladder better than MRIthan MRI

Sensitivity- 97%Sensitivity- 97%

Specificity- 96%Specificity- 96%

(ESHRE guideline)(ESHRE guideline)

CT - ScanCT - Scan• Endometriomas may Endometriomas may

appear solid, cystic or appear solid, cystic or mixedmixed

• Because of poor Because of poor specificity & high specificity & high radiation, CT has been radiation, CT has been replaced by MRIreplaced by MRI

MRIMRI Use full in deep pelvic endometriosisUse full in deep pelvic endometriosis

Magnetic resonance imaging using fat saturation can Magnetic resonance imaging using fat saturation can detect up to 50% of small, haemorrhagic lesions detect up to 50% of small, haemorrhagic lesions measuring not more than 5 mm and allows then measuring not more than 5 mm and allows then diagnose of mild disease in 75% of cases.diagnose of mild disease in 75% of cases.

LAPAROSCOPY

LAPAROSCOPYLAPAROSCOPY For definitive diagnosis of endometriosis visual For definitive diagnosis of endometriosis visual

inspection of the pelvis at laparoscopy is gold inspection of the pelvis at laparoscopy is gold standard, unless disease is visible in vagina or standard, unless disease is visible in vagina or elsewhere elsewhere

Should not be performed during or within 3 Should not be performed during or within 3 months of hormonal treatment to avoid under months of hormonal treatment to avoid under diagnosis diagnosis

Types of lesionTypes of lesion

Three primary types of endometriosis are Three primary types of endometriosis are

• Superficial peritoneal lesion,Superficial peritoneal lesion,

• Ovarian endometriomaOvarian endometrioma

• Deep infiltrating endometriosis Deep infiltrating endometriosis

Superficial peritoneal lesionSuperficial peritoneal lesion Typically located on pelvic organ or pelvic Typically located on pelvic organ or pelvic

peritoneum peritoneum Classical lesion are ‘Classical lesion are ‘powder burn or gun shot powder burn or gun shot

lesionlesion.’ These are black, dark brown or bluish .’ These are black, dark brown or bluish nodules or small cyst containing old hemorrhage.nodules or small cyst containing old hemorrhage.

May be associated with hemosiderin deposit May be associated with hemosiderin deposit Non classical lesion are subtle lesions – Red Non classical lesion are subtle lesions – Red

implants implants (Petechial/vasicular/polypoidal/hemorrhage/ red (Petechial/vasicular/polypoidal/hemorrhage/ red flame like.flame like.

Serous or clear vesicles Serous or clear vesicles White plaquesScaring White plaquesScaring Yellow-brown discoloration of the peritoneum Yellow-brown discoloration of the peritoneum Sub ovarian adhesionSub ovarian adhesion

Variety of endometriotic lesions seen at laparoscopy

Endometrioma (Chocolate cyst)Endometrioma (Chocolate cyst) Usually located on Usually located on

anterior surface of the anterior surface of the ovary ovary

Diameter <Diameter < 12cm12cm Associated with retraction Associated with retraction

pigmentation and pigmentation and adhesion to posterior adhesion to posterior peritoneumperitoneum

Endometrioma(Chocolate cyst)Endometrioma(Chocolate cyst)

Contain tarry,thick Contain tarry,thick chocolate coloured fluid chocolate coloured fluid composed of hemosiderin composed of hemosiderin derived from previous derived from previous intraovarian hemorrhage intraovarian hemorrhage

Marker of more extensive Marker of more extensive pelvic and intestinal pelvic and intestinal diseasedisease

Histological conformation Histological conformation is necessaryis necessary

CLASSIFICATION CLASSIFICATION Current classification is by “American society of Current classification is by “American society of

Reproductive Medicine”Reproductive Medicine”, former “American , former “American Fertility Society”(AFS) systemFertility Society”(AFS) system

Based on morphology, size and depth of Based on morphology, size and depth of peritoneal implant peritoneal implant

Morphology-Morphology-

Red ( Red, Red-pink & clear lesions)Red ( Red, Red-pink & clear lesions)

White (White, yellow-brown & peritoneal defects)White (White, yellow-brown & peritoneal defects)

Black (Black & blue lesions)Black (Black & blue lesions)

Presence extent and type of peritoneal Presence extent and type of peritoneal adhesionsadhesions

Degree of cul-de-sac obliterationDegree of cul-de-sac obliteration

Staging – American society of Reproductive Medicine, 1996

Stage I – Minimal Isolated superficial implants,No adhesions

Stage II – MildMore superficial implants (<5cm), No significant adhesions

Stage III – ModerateMultiple superficial & invasive implants,Peritubal & Periovarian adhesions may be present

Stage IV – SevereMultiple implants,Ovarian endometriomas,Many dense adhesions

TREATMENTTREATMENT

Must be individualizedMust be individualized

Highly dependent on the wishes of the patient - Highly dependent on the wishes of the patient - fertility or contraceptionfertility or contraception

Symptom and severity of the disease Symptom and severity of the disease

Location of the disease Location of the disease

MEDICAL TREATMENTMEDICAL TREATMENT

Four chief medical approaches-Four chief medical approaches-

1- Analgesia1- Analgesia

2- Suppresion of ovulatory function2- Suppresion of ovulatory function

3- Direct action of endometrial implant3- Direct action of endometrial implant

4- Modulation of immune system4- Modulation of immune system

Non Hormonal MedicationsNon Hormonal Medications NSAIDs :NSAIDs : Naproxen Naproxen

• Mechanism:Mechanism: Local anti-nocioceptive effect Local anti-nocioceptive effect

↓↓ central sensitization central sensitization

Anti-inflammatory effects Anti-inflammatory effects

• Side effects:Side effects: Gastric ulcerations Gastric ulcerations

Inhibition of ovulationInhibition of ovulation

““Inconclusive evidence regarding their effectiveness Inconclusive evidence regarding their effectiveness (especially Naproxen)” (especially Naproxen)” ((ESHRE, 2007 updateESHRE, 2007 update))

Antiangiogenic-Antiangiogenic-

StatinsStatins

ThalidomideThalidomide

Inhibition of MMPs : ProgesteroneInhibition of MMPs : Progesterone

Anti VEGF antibodiesAnti VEGF antibodies

Angiostatic agents (TNP470, endostatin, Angiostatic agents (TNP470, endostatin, rapamycin)rapamycin)

Table 1. Medical treatment options in women with symptomatic endometriosis who are not seeking pregnancy.First-line treatmentsPeritoneal 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 osSpecific conditionsParous women with dysmenorrhoea as main symptom Levonorgestrel-releasing intra-uterine deviceHysterectomized 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

GoalGoal

To excise all visible lesions and associated adhesions To excise all visible lesions and associated adhesions

To restore normal anatomyTo restore normal anatomy

Laparoscopy is better Laparoscopy is better

Laparotomy – reserve for Laparotomy – reserve for

• Advanced stage disease Advanced stage disease

• Who cannot go laparoscopy Who cannot go laparoscopy

• Fertility is not desired Fertility is not desired

Laparoscopic Management Laparoscopic Management

LAPAROTOMYLAPAROTOMY

LAPAROTOMY LAPAROTOMY

Total abdominal hysterectomy + bilateral salpingo-Total abdominal hysterectomy + bilateral salpingo-oophrectomy oophrectomy

Hysterectomy alone is not effectiveHysterectomy alone is not effective

• Reserve for severe situation Reserve for severe situation

• HRT is recommended in young women after HRT is recommended in young women after bilateral oophorectomy (bilateral oophorectomy (ROCG guideline 24, 2006).ROCG guideline 24, 2006).

• Estrogen should be withheld until 3 month after Estrogen should be withheld until 3 month after surgery surgery

Empirical treatment of pain symptoms Empirical treatment of pain symptoms without a definitive Diagnosiswithout a definitive Diagnosis

CounsellingCounselling

Adequate analgesiaAdequate analgesia

Nutritional therapyNutritional therapy

ProgestagensProgestagens

Combined oral contraceptive (COC)Combined oral contraceptive (COC)

Treatment of endometriosis-associated Treatment of endometriosis-associated pain in confirmed diseasepain in confirmed disease

Non-steroidal anti-inflammatory drugsNon-steroidal anti-inflammatory drugs

Hormonal treatmentHormonal treatment

Surgical treatmentSurgical treatment

Infertility &Suspected endometriosis

Operative Laparoscopy

Watchful waitingSuccessPregnancy FailureAssistedAssisted

ReproductionReproduction

TREATMENT PROTOCOL FOR ENDOMETRIOSIS ASSOCIATED INFERTILITY