Endometriosis & Fertility
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Endometriosis - is anything new?
Endometriosis & Fertility
Dr. Eeson SinthamoneyMD (Malaysia), MRCOG (London), DFFP (UK)Fellowship in Reproductive Medicine (UK/Singapore)Consultant Obstetrician ,Gynaecologist & Fertility SpecialistPantai Hospital Kuala Lumpur
Preamble Common, difficult disease, 300 yearsmissed disease NEJM June 2010Incompletely understood pathogenesisManagement complex clinical questions with no simple generic answersTreating symptoms versus fertility issues
Introduction Common affects 5-12% of women in their reproductive years1,2The most common cause of pelvic pain in women of reproductive age3Higher prevalence in infertile women (48%) compared to fertile women (5%)4Recurrence is common: 10-15% at 1 year and up to 40-50% at 5 years follow-up.Craig A et al. Gynecol Obstet Invest 2002;53:2-11Human Reprod 1994;9:1158-62Vercellini. Semin Reprod Endocrinol 1997;15:251-261Strathy JH et al. Fertil Steril 1982;38:667-72Guo SW. Human Reprod Update 2009;1:1-21
Types of patients1. Symptomatic patient without infertility - severe dysmenorrhoea - deep dyspareunia - chronic pelvic pain - dyschezia2. Infertility (otherwise asymptomatic)Symptomatic with infertilityAsymptomatic and fertile: 20-25%
Three main goals of treatment of endometriosis:Reduce painIncrease pregnancy rateTo delay recurrence for as long as possible
Medical management versus surgicalRecurrence (rates, prevention and management)Summary
Donnez J et al. Surgical mangement of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004;18:329-348 Is there anything new?Using the RCOG guidelines 2006 as a backdropRCOG guidelines Gold standard diagnostic test: laparoscopy Screening test: compared to laparoscopy, CA125 no value as a diagnostic toolMedical treatment for pain: suppression of ovarian function for 6 months reduces endometriosis-associated pain, symptom recurrence is common
RCOG guidelinesSurgical treatment for pain: -Ablation of endo. lesions reduces pain compared with diagnostic laparoscopy -Hormonal therapy pre/post surgery: Insufficient evidence to justify does not reduce pain recurrence or disease recurrence
Endometriosis infertility: -Hormonal treatment in minimal-mild endomet. not effective -Ablation of endo. lesions + adhesiolysis improves fertility compared to diag. laparoscopy alone -Role of surgery in improving preg. rates in moderate-severe disease uncertain -Post-op hormonal treatment no benefit on pregnancy rates
RCOG guidelines Is there anything new?Laparoscopy to do or not to do?gold standard diagnostic toolWhen to offer?History and examination may suggest but not diagnostic (dysmen, CPP, adnexal mass, nodularity US thickening/tenderness)Ultrasound findingsPeritoneal implants cannot be seenScreening tests?
No clear answerASRM staging
location, extent, and depth ofendometriosis implants presence / severity of adhesions and presenceand size of ovarian endometriomasPoor co-relation with severity of pain or predict response to treatmentPeripheral biomarkersUseful to diagnose or exclude endometriosisCan be utilized to monitor the effects of treatmentPrevents unnecessary diagnostic proceduresIdentifies treatment failure earlier> 100 biomarkers identified in literatureCA 125 as a peripheral markerMost extensively investigatedOf more benefit in diagnosing stage 3/4 Accuracy of diagnosis better in women with endometrioma (sensitivity 79%) compared to women without (sensitivity 44%) with 30iu/ml thresholdValue of measurements during treatment?May KE et al. Peripheral biomarkers of endometriosis: a systematic review. Human Reproduction Update (Advanced Access May 2010)CA 125 Currently investigating use of panels of markersHsu AL et al. Invasive and non-invasive methods for the diagnosis of endometriosis. Clinical Obstetrics and Gynecology 2010.53(2):413-419
Of the >100 possible biomarkers investigated and reported in the past 25 years, NONE of them have been clearly shown to be of clinical use Endometriosis painRCOG:Medical Mx: Medical therapy effective for relieving painSurgery:Diagnosis Ablation of endomet. spots reduces painAll stages: sig. symptomatic improvement after excisional surgery and general QOLFor pain associated with endometriosis all remains true Progestogen-only add-back therapy with GnRH(a) to prevent bone lossRCOG: Progestogen add-back is not protective
Multicentre, placebo-controlled, double blind CRT investigating 12 months leuprolide acetate depot together with either Norethindrone acetate 5mg alone / NE+CEE 0.625mg / NE+CEE 1.25mg daily (Hornstein et al) Pelvic pain improved in all groups, vasomotors symptoms suppressed equally but frequent and persistent in placeboNo in BMD in add-back groups but decline noted in placebo group.Lost BMD in placebo group not completely reversed for up to 18 months after cessation of treatment
Surrey ES. Gonadotrophin-releasing hormone agonist and add-back therapy: what do the data show? Current Opinion in Obstetrics and Gynecology 2010US Food and Drug Administration: approved labeling for depot GnRH(a) should not be used without add-back if repeat treatment or > 6months. Recommended add-back therapy: Norethindrone acetate 5mg/daily Progestogen-only add-back therapy with GnRH(a) to prevent bone lossEndometriosis and fertilityGood evidence: association between endometriosis and infertilityHowever, cause and effect relationship yet to be establishedSeveral mechanisms: - distorted pelvic anatomy - altered peritoneal function: increased macrophages and PG, IL-1, TNF in fluid - IgA and IgG ab and lymphocytes in endometrium + other evidence ( endometrial expression of certain cell adhesion molecules at time of implantation) endometrial receptivity and implantation
Endometriosis and fertility: medicalRCOG:Hormonal treatment in endometriosis + infertility: more harm than good due to missed opportunityPost-op hormonal treatment not beneficialAll remains trueEndometriosis + infertility: Surgical RCOG: - ablation of endometriotic lesions + adhesiolysis is effective in improving birth rates - for moderate/severe disease role of surgery is uncertain Surgery: excision of cyst pseudo-capsule or drainage and electro-coagulation of pseudo-cyst wall?RCOG: Laparoscopic cystectomy is better than drainage and coagulationSystematic review (Hart et al. Cochrane Database Syst Rev 2005;5:CD004992) recurrence rate requirement for further surgery recurrence of dysmenorrhoea recurrence of dyspareunia recurrence of pelvic pain spontaneous pregnancy rates
Moderate-severe Endometriosis does surgery make any differenceNo CRT to answerNon randomized and other observational studies (that may be bias) suggest that women with stage 3/4 disease, without other identifiable infertility factors, surgery may increase fertility* CRT tend to be bias.Endometriosis and infertility. The practice committee of the American Society for Reproductive Medicine. Fertility and Sterility. 86(4) 2006
Combined medical & surgery: Endometriosis and fertilityRCOG: no role for post surgery hormonal treatment to improve pregnancy rates Remains true.Pre-surgery hormonal treatment? To reduce vascularity and size of implants? Neither pre nor post surgery hormonal treatment has been proven to enhance fertilityHaving made a diagnosis of endometriosis in a woman with infertility, provided appropriate initial management, what then?Expectant, SO with TI, SO with IUI or IVF ?
No large RCTs which definitely demonstrate IVF is more effective than expectant management in treatment of stage specific infertility associated with endometriosisClinical approach to infertile women with endometriosisWith suspected stage 1/2: laparoscopy before treatment? - Depends on age, duration, pain - See and treat (ablation and excision) - Expectant versus SOIUI versus IVF - The decrease in fertility due to 2 variables (age + endometriosis) may be additive -Older patient more aggressive fert. Mx.
Endometriosis and infertility. The practice committee of the American Society for Reproductive Medicine. Fertility and Sterility. 86(4) 2006With suspected stage 3/4 disease: surgery recommended despite no RCTsWith stage 3/4 disease with previous surgery: IVF better than another surgery
Clinical approach to infertile women with endometriosisEndometriosis and infertility. The practice committee of the American Society for Reproductive Medicine. Fertility and Sterility. 86(4) 2006
Endometriosis infiltrating posterior vaginal and anterior rectal walls usually causing severe symptoms like deep dyspareunia and dyschezia, in addition to dysmenorrhoea.Surgery is technically demandingIncomplete resection does not achieve benefitsRadical interventions risk of major complications including ureteral and rectal injuriesDiagnosis: VE, PR, TVS, Transrectal scan, MRIPre-op work-up includes US urinary tract + rectosigmoidoscopyNo fertility implications
*Deep Infiltrating DiseaseDIERectal endometriosis: superficial thickness excision (shaving), full thickness discoid resection/ anterior rectal wall excision (lesions < 2cm in size or less than 1/3 rectal circumference) and segmental colorectal resection Severe complications: urinary retentionRectovaginal fistula (as high as 10%)
Aromatase inhibitorsSex steroid synthesis
Aromatase inhibitorsIn normal premenopausal women, primary site for aromatase expression is granulosa cells of the graffian follicleExtraovarian tissues are major source of Oestrogen production in postmenopausal period. These tissues: adipose tissue, skin fibroblastsOestrogen biosynthesis does not t