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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 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.

1. Craig A et al. Gynecol Obstet Invest 2002;53:2-112. Human Reprod 1994;9:1158-623. Vercellini. Semin Reprod Endocrinol 1997;15:251-2614. Strathy JH et al. Fertil Steril 1982;38:667-725. Guo SW. Human Reprod Update 2009;1:1-21

Types of patients

1. Symptomatic patient without infertility - severe dysmenorrhoea - deep dyspareunia - chronic pelvic pain - dyschezia2. Infertility (otherwise asymptomatic)3. Symptomatic with infertility4. Asymptomatic and fertile: 20-25%

Three main goals of treatment of endometriosis:1. Reduce pain2. Increase pregnancy rate3. To 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 backdrop

RCOG guidelines

1. ‘Gold standard’ diagnostic test: laparoscopy2. Screening test: compared to laparoscopy,

CA125 no value as a diagnostic tool3. 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

• 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 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 staginglocation, extent, and depth ofendometriosis implants presence / severity of adhesions and presenceand 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

Endometriosis pain

RCOG:Medical Mx: Medical therapy effective for relieving painSurgery:1. Diagnosis 2. Ablation of endomet. spots reduces pain3. 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

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

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

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:1. Hormonal treatment in endometriosis +

infertility: more harm than good due to missed opportunity

2. 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

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

1. 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.


2. With suspected stage 3/4 disease: surgery recommended despite no RCT’s

3. With stage 3/4 disease with previous surgery: IVF better than another surgery

Clinical approach to infertile women with endometriosis


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


• 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


Endometriotic tissueFibroids

Endometrial cancer cells

PGE2 synthesis

Inflammatory cytokines

Expression of aromatase

Oestrogen local production

Activity of COX-2 activity AI

AI

One aspect of the complex aetiology of

endometriosis

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

1. 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

2. Nawathe A et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG.2008;115(7):818-22

3. Seal SL. Aromatase inhibitors in recurrent ovarian endometriomas: report of five cases with literature review. Fertil Steril 2010. Jun23

4. 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

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

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

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

• SclerotherapyAvoids repeat surgeryEthanol, tetracycline, methotrexateRisks:Missing occult malignancyCausing pelvic abscessSevere 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 removeFisch 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

1. Pain: medical or surgical2. Fertility: surgical3. Fertility treatment: expectant / IUI / IVF4. GnRH(a) – add-back therapy with NE5. Aromatase inhibitors6. Recurrence is common COCP prevents7. Ovarian reserve

Thank you