Endometriosis & Fertility Dr. Eeson Sinthamoney MD (Malaysia), MRCOG (London), DFFP (UK) Fellowship in Reproductive Medicine (UK/Singapore) Consultant Obstetrician ,Gynaecologist & Fertility Specialist Pantai Hospital Kuala Lumpur

Preamble Common, difficult disease, 300 years ‘missed disease’ – NEJM June 2010 Incompletely understood pathogenesis Management – complex clinical questions with no simple generic answers Treating symptoms versus fertility issues

Introduction Common – affects 5-12% of women in their reproductive years1,2 The most common cause of pelvic pain in women of reproductive age3 Higher prevalence in infertile women (48%) compared to fertile women (5%)4 Recurrence 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;53:2-11 Human Reprod 1994;9:1158-62 Vercellini. Semin Reprod Endocrinol 1997;15:251-261 Strathy JH et al. Fertil Steril 1982;38:667-72 Guo SW. Human Reprod Update 2009;1:1-21

Types of patients 1. Symptomatic patient without infertility - severe dysmenorrhoea - deep dyspareunia - chronic pelvic pain - dyschezia 2. Infertility (otherwise asymptomatic) Symptomatic with infertility Asymptomatic and fertile: 20-25%

Three main goals of treatment of endometriosis: Reduce pain Increase pregnancy rate To delay recurrence for as long as possible Medical management versus surgical Recurrence (rates, prevention and management) Summary Donnez J et al. Surgical mangement of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004;18:329-348

Using the RCOG guidelines 2006 as a backdrop Is there anything new? Using the RCOG guidelines 2006 as a backdrop

RCOG guidelines ‘Gold standard’ diagnostic test: laparoscopy Screening test: compared to laparoscopy, CA125 no value as a diagnostic tool Medical treatment for pain: suppression of ovarian function for 6 months reduces endometriosis-associated pain, symptom recurrence is common 

RCOG guidelines Surgical 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 

RCOG guidelines 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

Is there anything new?

Laparoscopy – to do or not to do? ‘gold standard’ diagnostic tool When to offer? History and examination may suggest but not diagnostic (dysmen, CPP, adnexal mass, nodularity US thickening/tenderness) Ultrasound findings Peritoneal implants cannot be seen Screening tests? No clear answer

ASRM staging location, extent, and depth of endometriosis implants presence / severity of adhesions and presence and size of ovarian endometriomas Poor co-relation with severity of pain or predict response to treatment

Peripheral biomarkers Useful to diagnose or exclude endometriosis Can be utilized to monitor the effects of treatment Prevents unnecessary diagnostic procedures Identifies treatment failure earlier > 100 biomarkers identified in literature

CA 125 as a peripheral marker Most extensively investigated Of 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 threshold Value 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 markers Hsu 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

For pain associated with endometriosis – all remains true Endometriosis pain RCOG: Medical Mx: Medical therapy effective for relieving pain Surgery: Diagnosis Ablation of endomet. spots reduces pain All stages: sig. symptomatic improvement after excisional surgery and general QOL For pain associated with endometriosis – all remains true

Progestogen-only add-back therapy with GnRH(a) to prevent bone loss RCOG: 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 placebo No  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 2010

Progestogen-only add-back therapy with GnRH(a) to prevent bone loss US 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

Endometriosis and fertility Good evidence: association between endometriosis and infertility However, cause and effect relationship yet to be established Several 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: medical RCOG: Hormonal treatment in endometriosis + infertility: more harm than good due to missed opportunity Post-op hormonal treatment not beneficial All remains true

Endometriosis + 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 coagulation Systematic 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 difference No CRT to answer Non 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 fertility RCOG: 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 fertility

Expectant, SO with TI, SO with IUI or IVF ? Having 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 RCT’s which definitely demonstrate IVF is more effective than expectant management in treatment of stage specific infertility associated with endometriosis

Clinical approach to infertile women with endometriosis With 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) 2006

Clinical approach to infertile women with endometriosis With suspected stage 3/4 disease: surgery recommended despite no RCT’s With stage 3/4 disease with previous surgery: IVF better than another surgery Endometriosis and infertility. The practice committee of the American Society for Reproductive Medicine. Fertility and Sterility. 86(4) 2006

DIE Endometriosis infiltrating posterior vaginal and anterior rectal walls usually causing severe symptoms like deep dyspareunia and dyschezia, in addition to dysmenorrhoea. Surgery is technically demanding Incomplete resection does not achieve benefits Radical interventions  risk of major complications including ureteral and rectal injuries Diagnosis: VE, PR, TVS, Transrectal scan, MRI Pre-op work-up includes US urinary tract + rectosigmoidoscopy No fertility implications *Deep Infiltrating Disease

DIE Rectal 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 retention Rectovaginal fistula (as high as 10%)

Aromatase inhibitors

Sex steroid synthesis

Aromatase inhibitors In normal premenopausal women, primary site for aromatase expression is granulosa cells of the graffian follicle Extraovarian tissues are major source of Oestrogen production in postmenopausal period. These tissues: adipose tissue, skin fibroblasts Oestrogen biosynthesis does not take place in healthy uterine tissue However, aromatase activity shown in uterine leiomyomas, endometrial cancer and endometriosis

Endometrial cancer cells Endometriotic tissue Fibroids Endometrial cancer cells AI   Expression of aromatase  Oestrogen local production Aromatase inhibitors  Activity of COX-2 activity AI  PGE2 synthesis One aspect of the complex aetiology of endometriosis  Inflammatory cytokines

Aromatase inhibitors Large quantities of oestrogen can be produced locally within endometriotic cells Local oestrogen biosynthesis is not blocked by any of the currently used treatments (eg: GnRH(a)) Peripheral tissue production of oestrogen may be significant. GnRH(a) does not inhibit this peripheral oestrogen formation These 2 extra-ovarian sources may explain high treatment failure with GnRH(a) Bulun SE et al. Molecular basis for treating endometriosis with aromatase inhibitors. Human Reproduction Update 2000.6(5);413-418

Aromatase inhibitors Beneficial in premenopausal women with CPP secondary to refractory endometriosis. Minimal side effects1 Systematic review: AI appear to have a promising effect on pain associated with endometriosis, but the strength of this inference is limited due to the dearth of evidence available2 Given together with COCP achieved in complete regression of recurrent endometriotic cysts and pain relief in all cases3 Combination with NE compared to NE alone was more effective in reducing pain and deep dyspareunia but higher incidence of side effects, costs more and did not improve patients satisfaction4 Verma A et al. Successful treatment of refractory endometriosis-related chronic pelvic pain with aromatase inhibitors in premenopausal patients. Eur J Obstet Gynecol Reprod Biol. 2009;143(2):112-5 Nawathe A et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG.2008;115(7):818-22 Seal SL. Aromatase inhibitors in recurrent ovarian endometriomas: report of five cases with literature review. Fertil Steril 2010. Jun23 Ferrero S et al. Letrozole combined with norethisterone acetate compared with norethisterone alone in the treatment of pain symptoms caused by endometriosis. Human Reproduction 2009.24(12);3033-3041

Recurrence Surgical management is treatment of choice, but: - 40-45% of patients have relapse of the disease 5 years after the primary surgery - likelihood of readmission for additional surgical procedure 27% over next 4 years - Risk of requiring reoperation- up to 50% - 27% require 3 or more surgeries - Likelihood of subsequent hysterectomy- 12%

Preventing recurrences How do we effectively prevent recurrence in women post laparoscopy, either to maintain long term symptom relief or maintain ‘improved’ fertility for as long as possible?

Preventing recurrences RCOG guidelines: symptom recurrence common following medical mx for pain Adverse effects, cost, effectiveness and compliance LNG-IUS reduced pain, maintained over 3 years Long term: GnRH(a) with add-back therapy up to 2 years appeared to be safe Post-op hormonal tx does not sig reduce pain recurrence and does not reduce disease recurrence

Preventing recurrences 311 patients post laparoscopic excision of symptomatic endometrioma. Not attempting to conceive for 2 years. No previous surgery or hormonal treatment. No C/I to COCP. Randomly divided into 3 groups. Ethinyl E2 0.02mg + Gestodene 0.075mg. Started on discharge for 24 months. Recurrence rates of dysmenorrhoea, dyspareunia and CPP Seracchioli. R et al. Long term contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled trial. Fertility and Sterility 2010.94(2) July

Dysmenorrhoea recurrence in continuous COCP users sig Dysmenorrhoea recurrence in continuous COCP users sig. lower than cyclic and non-users in entire period (P<0.0005). Cyclic users showed sig reduction compared to non-users at 18-24 months. No difference among three groups for entire period wrt dyspareunia and CPP Kaplan- Meier survival analysis: sig. difference among 3 groups wrt first re-occurence of mod-severe dysmenorrhoea. Cumulative Pain free survival sig. higher in cont versus cyclic and in cyclic versus non users

Remove recurrent endometriomas? Endometrioma with diameter > 4cm should be removed. -Creates difficulties during oocyte retrieval -Cyst may rupture or get infected -Follicular fluid contamination

Dealing with recurrence Sclerotherapy Avoids repeat surgery Ethanol, tetracycline, methotrexate Risks: Missing occult malignancy Causing pelvic abscess Severe pelvic adhesions

sclerotherapy Conscious sedation TVS guided 18g single-lumen needle Sequential aspiration and flushing with sterile n/s Once aspirated fluid clear, TCN 5%, volume slightly less than approx volume of endometrioma, instilled into cyst Avoid over-distension 100-300ml sterile n/s instilled into cul-de-sac, keep for 2-3 minutes, then remove Fisch JD et al. Sclerotherapy with 5% tetracycline is a simpke alternative to potentially complex surgical treatment of ovarian endometriomas before in-vitro fertilization. Fertility Serility 2004.82(2);437-41

Ovarian reserve There is growing and consistent evidence showing that ovarian reserve is affected following surgical excision of ovarian endometriomas. Of concern: risk of severe damage leading to unresponsiveness to ovarian hyperstimulation Benaglia L et al. Rate of severe ovarian damage following surgery for endometriomas. Human Reproduction 2010.25(3);678-682

Summary Pain: medical or surgical Fertility: surgical Fertility treatment: expectant / IUI / IVF GnRH(a) – add-back therapy with NE Aromatase inhibitors Recurrence is common  COCP prevents Ovarian reserve

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