1. The Management of Recurrent Endometriosis Prof. Cihat ÜNLÜ, M.D. Acibadem University Hospital, Department of Obstetrics & Gynecology, Istanbul/TURKEY President of the Turkish-German Gynecology Association (TAJEV) Editor of the Journal of the Turkish-German Gynecology Association (JTGGA)

2. Disclosure No financial relationships to disclose.

3. Recurrence: Definitions Reoperation because of reappearanceof symptoms Ultrasonography Second laparoscopy at the end of thesecond year Ultrasonographic evidence and theneed for reoperation due to pains Presence of clinical and/orbiopsy-proven endometriosis atlaparoscopy or as the presence of anendometriotic cyst on ultrasound withcytological confirmation Recurrence of 1 symptom (urgency,frequency and pain at micturition) ofmoderate-to-severe intensity Clinical examinationUltrasonographic exam during theproliferative phase of the menstrualCycle Evaluation of symptoms, pelvicexamination, transvaginalultrasonography and renal ultrasound Detection of cysts 2 cm byUltrasonography Presence of endometrioma 2 cm asdetected by ultrasonography Exacerbated symptoms 3 monthsafter surgery plus at least one of: (i)reappearance of disappeared positivepelvic characteristics followingsurgery; (ii) ultrasonography and (iii)arise of serum CA125 following fall The presence of ovarian cysts morethan 3 cm in diameter with a typicalaspect detected by ultrasonography For two consecutive menstrual cycles Not clearly defined Either pain or ultrasonographicEvidence Pain: evaluated by visual analog scale(VAS) Symptom recurrence Clinical exam, ultrasound, CA-125,second look laparoscopy based onclinical finding The sum of pain score (total pelvicsymptom score) 7 Four-point grading of dysmenorrhea, Non-menstrual pain and deep Dyspareunia, and the total score 5

4. 36 month cumulative recurrence rates according to disease stage From Vercellini et al. Human Reprod 2006

5. From Vercellini et al. RBM Online 2010

6. More Radical Many I ntervention More Radical Many I ntervention Impaired ovarian reserve Less Radical Recurrence Endometrioma Surgery

7. Endometrioma recurrence More common when the endometrioma is removed piecemeal and the tissue planes are scarred More common when the ovarian reserve is better From Somigliana et al. AJOG 2011

8. The reported recurrence rate was high, estimated as 21.5% at 2 years and 40-50% at 5 years. (23 years follow up)

9. Risk factors for Recurrence

10. Predictive factors for recurrence of endometriotic lesions and pain

11. Recurrence & Problems 1.Impaired QoL (Pain) 2.Infertility 3.Asymptomatic Endometrioma

12. Impaired QoL Pain 1.Second Surgery 2.Medical Supression 3.Expectant Management

13. Impaired QoL Second Surgery Re-Excision Pelvic Denervations – Presacral Neurectomy – LUNA Hysterectomy

14. Re-Excision Pain symptoms (42 women ) – StageIV in 14 – Stage III in 25 – Stage I in 3 Follow-up of 42 months Dysmenorrhea and deep dyspareunia reappeared in 8 women Non-cyclical pelvic pain in 7 women A third operation was necessary in 6 women (14%) The symptoms recurrence rate when repeat laparotomy was performed specifically for pain is 25% Candiani GB, Fedele L, Vercellini P, Bianchi S, Di Nola G. Repetitive conservativesurgery for recurrence of endometriosis. Obstet Gynecol 1991;77:421–4.

15. Repetetive Surgery for Pelvic Pain Berlando N, Curr Opin Obstet Gynecol 2010, 2nd Surgery 3rd Surgery

16. Re-Excision 81 women re-operated, 60 months Laparotomy (n = 41) Laparoscopy(n = 40) Stage IV………………..14………………………………….. 11 Stage III ………………..25………………………………….. 21 Stage II…………………..0……………………………………...2 Stage I…………………… 2……………………………………...6 Dysmenorrhea……..22%(7/32)………………………29%(10/35) Deep dyspareunia.. 30%(7/23)…………………….25%(4/16) Pelvic pain............... 35%(9/26)..................... 32%(7/22) Busacca M, Fedele L, Bianchi S, et al. Surgical treatment of recurrent endometriosis:laparotomy versus laparoscopy. Hum Reprod 1998;13:2271–4.

17. Re-Excision Recurrence rate (5-year cumulative pain) After the first surgical procedure 20% After the second procedure 17% Fedele L, Bianchi S, Zanconato G, et al. Laparoscopic excision of recurrent endometriomas: long-term outcome and comparison with primary surgery. Fertil Steril 2006;85:694–9.

18. The effect of repetitive laparoscopic surgery on pain is similar to that observed after first-line surgery. Re-Excision

19. Ovarian surgery for bilateral endometriomas influences age at menopause Patients who had been operated on for bilateral endometriomas have an increased risk of POF.

20. Surgery plus PSN vs Surgery Alone Berlando N, Curr Opin Obstet Gynecol 2010,

21. Presacral Neurectomy Conservative surgery Conservative plus PSN surgery (n:63) (n:63) Dysmenorrhea cure rate – 6-month follow-up …………………………87% ……………………………….57% – 12-month follow-up ………………………60%....................................86% – 24-month follow-up ……………………….83%...................................53% At the end of the study period, the frequency and severity of deep dyspareunia and non-menstrual pain were also significantly lower in women from the PSN those in conservative. 11 women who underwent PSN referred long-term complaints such as de-novo constipation (n = 9,15%) and urinary urgency (n = 3, 5%). Zullo F, Palomba S, Zupi E, et al. Am J Obstet Gynecol 2003;189:5–10. Zullo F, Palomba S, Zupi E, et al. J AmAssoc Gynecol Laparosc 2004;11:23–8.

22. Presacral neurectomy From Berlanda et al. Curr Opin Obstet Gynecol 2010

23. Addition of pelvic denervation PSN has been reported as an effective procedure in reducing pain recurrences in women undergoing first-line surgical treatment of endometriosis Although no data are available in women with recurrent endometriosis, it might be argued that women with recurrent pain are those in whom the greatest surgical effort should be made in order to cure the disease, including therefore PSN

24. Limitations of PSN Effective in reducing midline pain only, whereas lateral, adnexal pain is not influenced Denervation of bowel and bladder might cause constipation and urinary dysfunction It must be performed by an experienced surgeon because it is carried out in a complex anatomic area and great care must be taken to avoid damaging the right ureter as well as major and midsacral vessels

25. LUNA Conservative surgery Conservative plus LUNA surgery (n:78) (n:78) Dysmenorrhea recurrence rate – 12-month follow-up ………………………29% ………………………………..27% – 24-month follow-up ………………………36%....................................32% 68 of 90 (75%) patients in the LUNA group and 67 of 90 (75%) patients in the conservative surgery only group were satisfied at 1 year. Vercellini P et al Fertil Steril 2003;80:310–9.

26. Hysterectomy Young patients????????????????? Ovaries??????????????????????? Symptomatic endometriosis in 29 women Ovarian tissue was preserved Both ovaries removed n: 29 n:109 Recurrent pain…………… 18 (62%)……………………........11 (10%) Required reoperation……. 9 (31%)…………………………...4 (3.7%) Patients who underwent hysterectomy with ovarian conservation had 6.1 times greater risk of developing recurrent pain and 8.1 times greater risk of re-operation. Namnoum AB et al. Fertil Steril1995;64:898–902.

27. Removal of the ovaries at definitive surgery

28. Reoperation rates-definitive vs conservative surgery SurgeryReoperation rate Definitive with removal of the ovaries Definitive with ovarian conservation2.89 Conservative surgery6.16

29. Impaired QoL Medical Suppression

33. Recurrent Endometriosis Aromatase Inhibitors Good case reports No randomized controlled studies Lall Seal S, Kamilya G, Mukherji J, De A, Ghosh D, Majhi AK. Aromatase inhibitors in recurrent ovarian endometriomas: report of five cases with literature review. Fertil Steril. 2011 Jan;95(1):291.e15-8.

34. Recurrent Endometriosis GnRH Analogues Sesti F, Capozzolo T, Pietropolli A, Marziali M, Bollea MR, Piccione E. Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo. Eur J Obstet Gynecol Reprod Biol. 2009 Nov;147(1):72-7.

35. A 6-month course of hormonal suppression treatment or dietary therapy after laparoscopic cystectomy had no significant effect on the recurrence rate of ovarian endometriosis when compared with surgery plus placebo. So, treatment of endometrioma can be carried out exclusively by laparoscopic cystectomy without post- operative therapy, if a complete excision of ovarian endometriosis has been assured. Sesti F, Capozzolo T, Pietropolli A, Marziali M, Bollea MR, Piccione E. Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo. Eur J Obstet Gynecol Reprod Biol. 2009 Nov;147(1):72-7. Recurrent Endometriosis GnRH Analogues

36. Recurrence & Problems Impaired QoL-Pain Infertility Asymptomatic Endometrioma

37. Recurrent Endometriosis Infertility 2 nd Surgery Medical Therapy Medical Therapy + ART ART – KOH – KOH +IUI – ICSI-ET

38. Pregnancy rates after second-line surgical treatment for infertility in women with recurrent endometriosis The mean conception rate among women undergoing repetitive surgery for recurrent endometriosis associated with infertility was 26%, whereas the overall crude pregnancy rate after a primary procedure was 41%. Berlando N, Current Opinion in Obstetrics and Gynecology 2010, 22:320–325 Recurrent Endometriosis Infertility/2 nd Surgery

39. LAPAROTOMYLAPAROSCOPY Acta Obstet Gynecol Scand 2009

40. (41%) Spontaneous Pregnancy After 1  surgery 236/577 (41%) (23%) Spontaneous Pregnancy After 2  surgery 28/124 (23%) Recurrent Endometriosis Infertility/2 nd Surgery Vercellini P, Somigliana E, Viganò P, De Matteis S, Barbara G, Fedele L. The effect of second-line surgery on reproductive performance of women with recurrent endometriosis: a systematic review. Acta Obstet Gynecol Scand. 2009;88(10):1074-82.

41. Sp. Pregnancy following L/T(27%) Sp. Pregnancy following L/T 12 – 47% (27%) Sp. Pregnancy following L/S(25%) Sp. Pregnancy following L/S22 – 42% (25%) Recurrent Endometriosis Infertility/2 nd Surgery Vercellini P, Somigliana E, Viganò P, De Matteis S, Barbara G, Fedele L. The effect of second-line surgery on reproductive performance of women with recurrent endometriosis: a systematic review. Acta Obstet Gynecol Scand. 2009;88(10):1074-82.

42. TVUSG Guided Aspiration Agostini A et al, Eur J Obstet Gynecol Rep Biol, 2007

43. Repeat surgery for infertility Repeat surgery for infertility is associated with low pregnancy rates This is mainly due to affected ovarian reserve When there is no risk of malignancy and no pain IVF should be preferred over surgery in these patients

44. Is it possible to avoid repeat surgery for endometriosis? Refrain from operating early in the asymptomatic patient Operation should be done by surgeons with expertise and training in endometriosis surgery-to preserve the ovarian reserve; to remove DIE Complete excision or destruction of all endometriosis lesions should be carried out although there is no randomized study showing the effectiveness of this approach Postoperative suppressive treatment with OCPs or insertion of LNG IUD Removal of the ovaries in women who have completed their family

45. Alternatives to surgery in recurrent endometriosis Long term BCPs Long term GnRHa with add back LNG IUD Aromatase inhibitors

46. There is no evidence to support the use of ovarian suppression agents in the treatment of endometriosis-associated infertility. More harm than good can be done by treatment, because of side-effects and the lost opportunity to conceive The RCOG Guidelines N.24, 2000 ESHRE Guidelines 2005 Recurrent Endometriosis Infertility/Medical Supressive Therapy

47. P. Vercellini, 2009 Recurrent Endometriosis Infertility/2 nd Surgery NO DIFFERENCES

48. In patients with endometriosis-associated infertility, surgery followed by IVF–ET is more effective than surgery alone. When patients fail to conceive spontaneously, after a maximum of 1 year from laparoscopic surgery, IVF should be suggested.

49. When reoperation is being considered with the specific aim of achieving conception, and not because severe symptoms or large cysts are present, the caring gynecologist should warn the patient that – the chances of pregnancy may be substantially lower than after the primary procedure and the role of IVF should be considered adequately as an alternative to repetitive surgery Recurrent Endometriosis Infertility/2 nd Surgery or ART

50. Meta-analysis of Surgery vs No Surgery for endometriomas before IVF Tsoumpou et al, FS 2009

52. Who have previously had one or more infertility operations IVF-ET is often a better therapeutic option than another surgical intervention, though this is another question that has not been addressed in any randomized trial. If initial surgery fails to restore fertility in patients with moderate to severe endometriosis, IVF-ET is an effective alternative. Current data are insufficient to estimate the effect of surgical treatment in addition to IVF-ET on the outcome of pregnancy in endometriosis associated infertility. DECISIONS AMONG INFERTILE WOMEN WITH ENDOMETRIOSIS

53. Recurrence & Problems Impaired QoL-Pain Infertility Asymptomatic Endometrioma

54. Endometriosis and ovarian cancer There may be a link between endometriosis and ovarian cancer – x2 risk in women with endometriosis – x4 risk in women with endometriosis and infertility The etiology of both diseases appears to be multifactorial with hormonal, genetic, and immunologic factors potentially playing a role

55. From the Ovarian Cancer Association Consortium Lancet Oncology 2012

56. Recommendation: – Surgery+ Long term suppression Only supression is not effective Definitive surgery—based on patients requirements LUNA—Not effective for pain PSN – Effective but creates new long term problems Conclusion-1 Recurrent Endometrioma and Pain

57. Recommendation: – Long term suppression OCP can be used AI or GnRH Analogs can be used, need RCT If there is DIE, first surgery then long term suppression Conclusion-2 No Endometrioma and Pain

58. Recommendation: – ART ART has the same effect in comparison with re-surgery But Every surgery increase the complications Every surgery impaired the ovarian reserve It seems that ART can be first recommendation Conclusion-3 Recurrent Endometrioma and Infertility

59. Recommendation: – Expectant Management If there are strong evidence for malignancy then surgery can be recommended Conclusion-4 Asymptomatic Endometrioma