endometriosis therapi

8/3/2019 endometriosis therapi

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Endometriosis

Dr Cathy Burke

MSc ProgrammeNovember 2009


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Endometriosis


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IntroductionOverview

Outline current treatment modalities

Explore evidence base for treatments

Present recommendations


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DefinitionThe presence of endometrial glands and

stroma outside the uterine cavity

endometrial glands

endometrial stroma

fibrosis

haemorrhage


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PrevalenceWomen with pelvic pain have a higher

incidence of endometriosis (range: 4080%)

than women with infertility without pain (2050%) or control groups (520%)

Koninckx et al, 1991

Prevalence increasing over the yearsGuo et al Gynecol Obstet Invest 2006


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PathologyPeritoneal inflammation and fibrosis

Adhesions

Ovarian cysts

Deep nodules


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SymptomatologyDysmenorrhea

Dyspareunia

Dyschezia / bowel symptoms / rectal bleeding

Non-cyclical pelvic pain

Urinary symptoms / haematuria


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AssociationsMenorrhagia (adenomyosis)

Subfertility

IBS

PID Seaman et al BJOG 2008

Chronic pain syndromesDepression - 86% vs 38%Lorencatto et al Acta Obsstet Gynecol Scand 2006


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PathogenesisRetrograde menstruation / transplantation Sampson

Coelomic metaplasia Meyer

Metastasis (haematogenous / lymphatic) Javert

Genetic basis (Chr 7, 10, 20) Montgomery et al Hum Reprod 08

Immunologic basis


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Susceptibility Genetic predisposition

Increased exposure to menstrual debris

Abnormal eutopic endometrium

Altered peritoneal environment

Reduced immune surveillance

Increased angiogenic capacity

Healy et al 1998; Vinatier et al 2001; Treloar et al 2002; Varma et al 2004


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Natural historyLargely unknown

Average sx duration 7 yrs prior to diagnosis

Remitting / recurring

Hormonally-driven


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Lifetime experience

Symptom duration 16 years

Half tried three / more medical treatments

Half had surgical procedures performed at least3 times

One in five had hysterectomy / oophorectomy -most successful for sxs

Sinaii et al Fertil Steril 2007, 1998 Endometriosis Association Survey


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Symptom-to-diagnosis lag

Confusion with other conditions

Co-existence with other conditions

Lack of awareness of and enquiry intosymptomatology

Un / Mis - diagnosed at laparoscopy


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Mechanisms of pain

Inflammatory cytokines in the peritonealcavity

Focal bleeding from implants

Irritation and direct infiltration of nerves

Hormonal modulation: pain threshold


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Mechanisms of subfertility

Distorted adnexal anatomy

Ovarian cysts

Adverse effects on folliculogenesis

Interference with oocyte/sperm survival,fertilization and embryogenesis


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Endometriosis - diagnosis

Quick

Time and aTIFF (Uncompressed) decompressor

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QuickTime and aTIFF (Uncompressed) decompressor


QuickTime and aTIFF (Uncompressed) decompressor



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VESICULARLESIONS


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PERITONEAL LESIONWITH

NEOVASCULARISATION AND FIBROSIS


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VESICULAR LESIONS


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TUBAL ENDOMETRIOSIS


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KISSING OVARIES


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PERITONEAL SCARRING


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SUBDIAPHRAGMATIC ENDOMETRIOSIS


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SUBDIAPHRAGMATIC SCARRING


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ADHESION-LIKE APPEARANCE


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RECTUM ADHERENTTO POD


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Endometriosis - locationOvaries 60%

Tubes 21%

POD / pelvic sidewall 83%

Ureter 13%

Bowel 51%

Bladder 13%


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Grading of

endometriosis

American Society forReproductive Medicine(ASRM)

Peritoneal disease

Ovarian disease

POD disease Adhesions

Stage I-IV


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Endometriosis -

Grade vs Symptoms

Grade not directly correlated with

symptomatology

Advanced disease more frequently related todysmenorrhea and dyspareunia compared to

early diseaseMilingos et al Gynaeol Obstet Invest 2006


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Endometriosis - what is the

impact?Quality of life(EuroQOL, Health score, EHPQ-30)

Social functioning(SF36/12)

Sexual activity(SAQ)


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Medical treatment


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Medical management

Non-steroidal anti-inflammatory drugs

Inhibition of ovulationOCP

GnRH agonists

Depo-Provera

Atrophy of endometriotic lesions / local effectOral progestogens

Depo-provera

Mirena


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Oral analgaesics

NSAIDS inconclusive evidence for useAllen et al, Cochrane review 2005


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Oral contraceptive pill

OCP effective for dysmenorrhea and reduced

endometrioma size

Harada et al Fertil Steril 2007

OCP equivalent to GnRHCochrane Review 2007

Continuous OCP in women in whom recurrent

dysmenorrhea not controlled by cyclical OCPVercellini et al Fertil Steril 2003


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GnRH agonistsGnRH agonist use for endometriosis-related

pain well-established

Dlugi et at Fertil Steril 1990,W

aller et al Fertil Steil 1993, Henzl et alNEJM 1988

GnRH agonists with or without add-back Ework better than OCP for post-surgicalrelapse. Add-back improves QOL scores

Zupi et al Fertil Steril 2004


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ProgestogensOral progestogens poorly tolerated due to side-

effects

Depo-provera equivalent to GnRH for pain scores.

Less loss of bone mineral density with DMPASchlaff et al Fertil Steril 2006


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Mirena70% symptomatic relief after 12 months

Vercellini et al 1999

Radiographic evidence of regression of rectovaginallesions

Fedele et al 2001

Improvement in severity and frequency of pain andmenstrual sxs, and staging of diseaseLockhat et al Hum Reprod 2004

Mirena equivalent to GnRH for pain

Petta et al Hum Reprod 2005


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Surgical treatment


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Surgery for endometriosis

Ablation / excision of superficial peritonealdeposits

Excision of deep peritoneal deposits

Stripping / drainage and ablation of

endometriomata

Hysterectomy / Oophorectomy


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Evidence for surgical treatment


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Ablation of endometriosis

Laser ablation superior to expectant mgt 62% vs25% clinical response at 6/12

Sutton et al Fertil Steril 1994

Helica thermal coagulation - 87% response at 6/12

Nardo et al Fertil Steril 2005

LUNA has no effect on endometriosis-relateddysmenorrhea

Vercellini et al Fertil Steril 2003


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Excision of deep endometriosis

Lap excision superior to placebo for pain and QOLAbbott et al Fertil Steril 2004

Symptoms, QOL and sexual function improved after

excisional surgeryGarry et al, Anaf et al, Redwine et al, Ford et al, Lyons et al, Dubernard et al,

Wykes et al


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Treatment of endometriomas

Stripping vs drainage and ablation of

endometriomas reduces pain symptoms

and recurrenceHart et al Fertil Steril 2005, Cochrane Review


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Hysterectomy / Oophorectomy

Hysterectomy associated with high rate ofsymptom resolution and low re-operation

rateShakiba et al Obstet Gynecol 2008

Ovarian conservation associated with

increased risk of recurrent pain (x 6) and re-operation rate (x 8)

Namnoun et al Fertil Steril 1995


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omplications of surgery

Complications of laparoscopy

Organ injury

ureter

bowel

bladder

Bleeding


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Adhesion prevention in

endometriosis surgerySuturing of ovary decreases adhesion formationPellicano et al Fertil Steril 2008

Adhesion prevention agents

Barrier Interceed reduces adhesionsCochrane 2008

Fluid Limited evidenceCochrane 2006

Icodextrin 4% (Adept) reduces adhesions

Brown et al Fertil Steril 2007


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Surgery - outcomesMean pre-op

VAS scores

Mean post-op

VAS scores

(Med FU 6/12)

Improvement

in mean

scores

p-value

Period pain 8 4.5 2.5


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Evidence for surgery

Pain and QOLImprovement in pain, SAQ and QOL scores up

to 5 years Placebo response rate 30%

Non-responsiveness to surgery 20%

Ford et al 2004; Abbott et al 2003 & 2005

LUNA is not effective in this groupJohnson et al 2005


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Evidence for surgery - FertilityLaparoscopic ablation of minimal/mild endo

improves fertilityMarcoux et al NEJM 1997, Cochrane Review 2002

Endometrioma excision

Ovulation rate in natural cycles reducedcompared with pre-opHorikawa et al, J Assist Reprod Genet 2008

Ovarian response in IVF-ET cycles reducedYazbeck et al, Gynecol Obstet Fertil 2006


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Post-operative treatment

Post-op continuous OCP and POP usefulRazzi et al Eur J Obstet Gynaecol Rep Biol 2007

Postoperative GnRH improved pain when usedfor 3/12 and 6/12

Parazzini et al Am J Obstet Gynecol 1994, Vercellini et al BJOG 1999

Post-op Mirena usefulAbbou Setta et al Cochrane Review 2006


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Post-operative treatment

Post-operative hormonal suppression (COCP or

GnRH) reduces dysmenorrhea vs placebo

Dietary supplementation improves non-

menstrual pain post-operatively as much as

OCP

Quality of life scores better with hormonal

suppressionSesti et al Fertil Steril 2007


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Endometriosis recurrence

30% recurrence of endometriomata 2 years

after surgical excisionKoga et al Hum Reprod 2006

Re-operation rate 35% after 3 yearsAbbott et al 2005


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Multidisciplinary management

of endometriosisAssociated with decrease in pain, anxiety,

depression in CPP groupKames et al Pain 1990

Integrated approach improved painsignificantly more than standard

approach with CPPPeters et al Obstet Gynecol 1991


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Complementary therapies

and endometriosisAcupuncture;

Japanese-style acupuncture vs sham acupunctureWayne et at J Paed Adolesc Gynecol

Shu Mu vs standard vs danazol on clinical sxs andCA125

Sun et al, Zhongguo Zhen Jiu 2006

Traditional Chinese medicine;

Neiyi pill / enema vs danazol x 3/12 on CA125levels

Lu et al Zhongguo Zhen Jiu, 2007


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ESHRE guideline

Laparoscopy desirable for women presenting

with sxs of endometriosis

Therapeutic trial of hormonal agents may be

used first line

Laparoscopically-diagnosed endometriosis

treated for 6/12 with ovarian suppression

drug


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ESHRE guideline

Inconclusive evidence that NSAIDS (Naproxen)efffective

Suppression of ovarian function for 6/12 reducesendometriosis-related pain. All hormonal drugsequally effective but side-effect and cost profilesdiffer

LNG-IUS reduces pain

GnRH treatment for up to 2 years with E/P addback

acceptable


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ESHRE guideline

Ideal practice is to diagnose and removeendometriosis at the same time provided consent hasbeen obtained

Ablation of endometriosis reduces pain, less so withmild disease

No evidence that LUNA is effective

Excision of deeply-infiltrating lesions reduces pain

Severe / deeply infiltrating endometriosis should bereferred to a centre with ex ertise


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ESHRE guideline

Suppression of ovarian function not effective

to enhance fertility

Insufficient evidence that excision ofmoderate-severe endometriosis enhances

pregnancy rates


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Future treatments for

endometriosisPresacral neurectomy

Mifepristone (anti-progesterone)

Aromatase inhibitors (anastrozole,

letrozole)

TNF alpha inhibitors

Thalidomide


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THANK YOU

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