1. Evidence-based management of endometriosis-associated infertility Hassan N. Sallam, MD, FRCOG, PhD (London) Professor in Obstetrics and Gynaecology The University of Alexandria, and Clinical and Scientific Director, Alexandria Fertility Center, Alexandria, Egypt 3rd Congress of Society of Reproductive Medicine, 5 – 9 October 2011, Antalya / Turkey

2. The old Alexandria medical school

3. The uterus (after Soranos of Ephesus)

4. Karl, baron von Rokitansky (1804-1878)

5. Does endometriosis affect infertility? YES 1. More commonly found in infertility patients (Mahmoud and Templeton, 1991) 2. Pregnancy rates are higher in treated patients (Marcoux et al, 1997) 3. Pregnancy with AID is lower with endometriosis (Jansen, 1986) 4. Pregnancy with IVF is lower with endometriosis (Barnhart et al, 2002)

6. Prevalence of endometriosis (Mahmoud and Templeton, 1991) (OS) Mahmoud and Templeton, Hum Reprod 6(4): 544-9, 1991 6% 21% 15% 25%

7. Laparoscopic surgery v/s no surgery (RCT) (Canadian Collaborative Group, Marcoux et al, 1997) P valueNo surgery (n= 169) Surgery (n=172) 0.00617.7%30.7%CPR <0.052.4%4.7%Fecundity Marcoux et al, N Engl J Med 337(4):217-22, 1997

8. AID in minimal endometriosis (Fecundity rates per month of exposure) Jansen RP, Fertil Steril 46 (1): 141-3, 1986

9. IVF in endometriosis versus tubal infertility (CPR) Barnhart et al, Fertil Steril 77(6): 1148-55, 2002

10. How does endometriosis affect infertility? 1. Tubal adhesions 2. Impaired gamete interaction 3. Impaired implantation

11. i.e. Endometrial receptivity does not play a role in diminished pregnancy rates in endometriosis Oocytes from normal controls to endometriosis patients Oocytes from endometriosis patients to normal controls Reduced implantation ratesSimilar implantation rates Cross-over oocyte donation study (Pellicer et al, 2001)

12. Causes of diminished pregnancy and implantation rates in IVF for endometriosis Poor quality of oocytes (Hull et al, 1998; Norenstedt et al, 2001) Lower quality embryos with a reduced ability to implant (Simon et al, 1994; Arici et al, 1996)

13. The poor quality of the oocytes is probably due to the altered follicular environment: Increased progesterone concentration in FF (Pellicer et al, 1998) Increased concentration of IL-6 in FF (Pellicer et al, 1998) Lower levels of cortisol in FF (Smith et al, 2002) Lower concentrations of IGFBP-1 in FF (Cunha-Filho et al, 2003)

14. The poor quality of the oocytes is probably due to the altered follicular environment (cont…) Increased expression of the TNF-α in the cultured granulosa cells (Carlberg et al, 2000) Increased rate of apoptosis (cell death) in the granulosa cells mediated by elevated concentrations of soluble Fas ligand in serum and peritoneal fluid (Garcia- Velasco et al, 2002)

15. Effect of GnRHa on the endometrium in endometriosis (CCT) Mohamed et al, Eur J Obstet Gynecol Reprod Biol 156(2):177-80, 2011 P valueFresh cycles Frozen cycles <0.0511.9 %16.9 %LBR <0.0512.7 %18.2 %CPR

16. Management of endometriosis- associated infertility 1. Surgical treatment 2. Medical treatment 3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/- IUI 5. Assisted reproductive techniques

17. Evidence-based medicine Level A – The recommendation based on good and consistent scientific evidence (RCT) Level B – The recommendation is based on limited or inconsistent scientific evidence (CT, cohort, case control) Level C – The recommendation is based primarily on consensus and expert opinion

18. Problems in the evaluation of management options 1. Any management option should be compared to expectant management 2. The monthly fecundity rate (MFR) is more meaningful than the pregnancy rate (PR)

19. Expectant management in endometriosis (Prospective cohort study PCS) Monthly fecundity rate (MFR) Cumulative pregnancy rate (CPR) Degree of endometriosis 5.7%52.9%Mild 3.2%25%Moderate 0% Severe 3.1%24.4%All cases Olive et al, Fertil Steril 44(1):35-41, 1985

20. Expectant management of stage I and II endometriosis (CCT) Miscarriage rate Cumulative pregnancy rate 14.3%55%No treatment 6.3%71%MPA 11%46%Danazol NS P value Hull et al, Fertil Steril 47(1):40-4, 1987

21. Management of endometriosis- associated infertility 1. Surgical treatment 2. Medical treatment 3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/- IUI 5. Assisted reproductive techniques

22. Problems in evaluating surgical management of endometriosis 1. Few studies are controlled 2. Few studies report the fecundity rate 3. Techniques/skills differ 4. Recognition of “atypical” lesions 5. Use of adhesion prevention agents

23. White endometriosis, clear endometriosis, red endometriosis and powder burn lesions.

24. Powder burns on the right uterosacral ligament causing painful intercourse

25. Surgical treatment of endometriosis 1. Ablation and/or resection of laparoscopic lesions 2. Drainage +/- excision/ablation of endometriomas

26. Surgical treatment of endometriosis 1. Ablation and/or resection of laparoscopic lesions 2. Drainage +/- excision/ablation of endometriomas

27. Power sources in endoscopic surgery (Sutton, 1995) 1. Electrocautery (mono or bipolar) 2. CO 2 Laser 3. Fibre lasers (KTP, argon, contact Nd:YAG, tunable dye or diode laser) 4. Harmonic scalpel 5. Helica thermal coagulator

28. Resection or ablation for minimal or mild endometriosis - Canadian Collaborative Group (RCT) P value Diagnostic laparoscopy (n = 169) Resection or ablation (n = 172) <0.0117.7%30.7%Clinical pregnancy rate <0.052.4%4.7%Fecundity rate 0.9121.6%20.6%Miscarriage rate Marcoux et al, N Engl J Med 337(4):217-22, 1997

29. Resection or ablation for minimal or mild endometriosis (RCT) P value Diagnostic laparoscopy (n = 47) Resection or ablation (n = 54) NS29%24%Clinical pregnancy rate NS22.2%19.6%Birth rate NS23.1%16.7%Miscarriage rate Parazzini et al, Hum Reprod 14:1332-4, 1999

30. Resection or ablation versus no surgery for minimal or mild endometriosis (MA) Clinical pregnancy rate OR = 1.613 (95% CI = 1.04 – 2.50)* P = 0.042 Sallam et al, submitted for publication

31. Resection or ablation for moderate and severe endometriosis (stages III and IV) Fecundity rate Cumulative pregnancy rate 6.7%70%Luciano et al, 1992 (OS) 2.4%57.5%Busacca et al, 1999 (OS)

32. Surgical treatment of endometriosis 1. Ablation and/or resection of laparoscopic lesions 2. Drainage +/- excision/ablation of endometriomas.

33. leads to recurrence in 50-100% of cases (Nezhat et al, 1988; Vercillini et al, 1992; Olive, 1989) Simple drainage of endometriomas

34. Excision of endometriomas

35. Drainage + resection/ablation of cyst wall CPRTechniquenStudy 38%Laser + stripping32Daniell et al, 1991 30.4%KTP laser ablation23Marrs et al, 1991 50%Cyst stripping52Wood et al, 1992 42.8%Cyst stripping21Bateman et al, 1994 45%Stripping + GnRHa11Montanino et al, 1996 51%CO 2 Laser + GnRHa814Donnez et al, 1996

36. Drainage + resection/ablation of cyst wall (cont…) CPRTechniquenStudy 45%CO 2 Laser + KTP66Sutton et al, 1997 50%Cyst stripping84Hemings et al, 1998 66.7%Cyst stripping64Beretta et al, 1998 57.5%Cyst stripping57Busacca et al, 1999 53%Cyst stripping32Milingos et al, 1999 39.5%KTP laser/diathermy39Jones & Sutton, 2002

37. Surgical versus non-surgical therapy Adamson and Pasta, Am J Obstet Gynecol 171:1488-504, 1994

38. Laparoscopic excision versus electro- coagulation in mild endometriosis (CCT) P value Excision (n = 53) Electro- coagulation (n = 48) NS53.5%57.1%Pregnacy rate NS17.4%12.5%Miscarriage rate 13.3 months 10.7 monthsDuration to pregnancy Tulandi and Al-Took, Fertil Steril 69(2):229-31, 1998

39. Laparoscopy versus laparotomy (Cumulative pregnancy rates – CCT) P valueLaparotomyLaparoscopy NS74.3%67.4%Stage I & II <0.0544.4%62.2%Stage III & IV Adamson et al, Fertil Steril 59(1): 35-44, 1993

40. Laparoscopy versus laparotomy in severe endometriosis – (CCT) P value Laparotomy (n = 149) Laparoscopy (n = 67) NS62.7%44.9%CPR NS20.3%16.4%Recurrence of dysmenorrhoa NS15.433.3%Recurrence of dyspareunia Crosignani et al, Fertil Steril 66(5): 706-11, 1996

41. Management of endometriosis- associated infertility 1. Surgical treatment 2. Medical treatment 3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/- IUI 5. Assisted reproductive techniques

42. Medical treatment of endometriosis (A) Ovarian suppression - Medroxyprogesterone (MPA) - Gestrinone - GnRH agonists - Danazol (B) Aromatase inhibitors - Letrozole (C) Novel approaches

43. Ovarian suppression for endometriosis (CPR) P value Ovarian suppression No therapy NS25%24%Thomas et al, 1987 (RCT) (Gestrinone) NS37.2%57.4%Bayer et al, 1988 (RCT) (Danazol) NS33%46%Telimaa et al, 1988 (RCT) (Danazol) NS42%46%Telimaa et al, 1988 (RCT) (MPA) NS37%61%Fedele et al, 1992 (RCT) (Buserelin)

44. Ovarian suppression for endometriosis (Hughes et al, 2007) (Odds ratio for pregnancy) Ovarian suppression v/s no treatment or placebo OR = 0.79 (95% CI = 0.54 – 1.14) Ovarian suppression v/s danazol OR = 1.37 (95% CI = 0.94 – 1.99) Hughes et al, Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000155

45. Effect of letrozole on the ASRM score (OS) Ailawadi et al, Fertil Steril 81(2): 290-6, 2004

46. Letrozole for the treatment of endometriosis (RCT) P value Controls (n = 57) Triptorelin (n = 40) Letrozole (n = 47) NS28.1%27.5%23.4%CPR after 12 months NS5.3%5%6.4%Recur- rence Alborzi et al, Arch Gynecol Obstet 284: 105-10, 2011

47. Novel medical therapies 1. Antiangiogenic agents (Dabrosin et al, 2002) 2. SPRMs (e.g. J867) (Chwalisz et al, 2002) 3. GnRH antagonists (e.g. ganirelix and cetrorelix) (Kupker et al, 2002) 4. Mifepristone (Murphy et al, 2002) 5. Local therapy (e.g. methotrexate) (Mesogitsis et al, 2000)

48. Management of endometriosis- associated infertility 1. Surgical treatment 2. Medical treatment 3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/- IUI 5. Assisted reproductive techniques

49. Pre-operative medical treatment for endometriosis (CCT) BuserelinGestrinoneDanazol 73% *34%30%Regression of endometriosis 58% *47%45%Cumulative pregnancy rate Donnez et al, Int J Fertil 35(5): 297-301, 1990

50. Post-operative GnRHa for endometriosis (Cumulative pregnancy rates - CPR) P value Surgery without GnRHa Surgery with GnRHa NS18%19%Parazzini et al, 1994 (RCT) NS18.4%11.6%Vercellini et al, 1999 (RCT)

51. Pre and post operative medical therapy for endometriosis surgery (Cochrane review) Pre-surgical medical therapy showed a significant improvement in AFS scores Post-surgical hormonal suppression showed no benefit for the outcomes of pain or pregnancy rates but a significant improvement in disease recurrence Yap et al, Cochrane Database Syst 2004;(3):CD003678

52. Management of endometriosis- associated infertility 1. Surgical treatment 2. Medical treatment 3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/- IUI 5. Assisted reproductive techniques

53. COH in stages I & II endometriosis P valueCOHNo therapy Intervention <0.0522%9%Clomiphene citrate Simpson et al, 1992 (CCT) NS37.4%24%HMGFedele et al, 1992 (RCT)

54. COH + IUI in stages I & II endometriosis P value COH + IUINo therapy <0.059.5%3.3%Deaton et al, 1990 (RCT) <0.00511%2%Tummon et al, 1997 (RCT) NS32% Serta et al, 1992 (CCT) <0.00515%1.4%Peterson et al, 1994 (CCT)

55. COH + IUI in endometriosis (Meta-analysis) Mean cycle fecundity (SD) Number of cycles Number of studies 0.14 *7835Stage I & II 0.081793Stage III & IV Peterson et al, Fertil Steril 62(3):535-44, 1994

56. Management of endometriosis- associated infertility 1. Surgical treatment 2. Medical treatment 3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/- IUI 5. Assisted reproductive techniques

57. Intracytoplasmic sperm injection (ICSI)

58. IVF in endometriosis versus tubal infertility (CPR) Barnhart et al, Fertil Steril 77(6): 1148-55, 2002

59. Surgical approaches to treat endometriosis before IVF and ICSI 1. Surgical removal of endometriomas appears to diminish the success rate of IVF/ICSI (Aboulghar et al, 2003) 2. Laparoscopic cystectomy has no effect (Canis et al, 2001; Marconi 2002)

60. Surgical approaches to treat endometriosis before IVF and ICSI (cont…) 3. LASER vaporization of the internal wall of endometriomas did not affect the outcome (Donnez et al, 2001; Wyns et al, 2003) 4. Ultrasound-directed cyst aspiration is associated with mixed results (Dicker et al, 1991; Suganuma et al, 2002) and an increased incidence of infection (Nargund and Parsons, 1995)

61. Medical approaches to treat endometriosis before IVF and ICSI 1. Corticosteroids (Kim et al, 1997) (RCT but small and not repeated) 2. Danazol (Tei et al, 1998) (RCT but small and not repeated) 3. GnRH agonists (Oehninger et al, 1989; Dicker et al, 1990; Dale et al, 1990; Nakamura et al, 1992; Curtis et al, 1993; Marcus et al, 1994; Chedid et al, 1995; Ruiz-Velasco and Allende, 1998)

62. Corticosteroids before IVF in endometriosis (RCT) P valueControls (n = 57) Corticosteroids (n = 54) <0.0522.8%42.6%CPR NS15.4%21.7%Miscarriage rate NS15.4%17.4%Multiple pregnancy rate Kim et al, J Obstet Gynaecol Res 23(5): 463-70, 1997

63. Danazol before IVF in repeated IVF failures (RCT) P valueControlsDanazol (400 mg/d for 12 wks) 41 Number <0.0519.5%40%CPR Tei et al, J Reprod Med 43(6): 541-6, 1998

64. Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006

65. GnRH agonist v/s no agonist before IVF (Clinical pregnancy rate per woman) Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006

66. GnRH agonist v/s no agonist before IVF (Ongoing pregnancy rate per woman) Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006

67. GnRH agonist v/s no agonist before IVF (Number of oocytes retrieved) Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006

68. GnRH agonist v/s no agonist before IVF (Dose of HMG or FSH required) Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006

69. Effect of GnRHa on adenomyosis (CCT) Mijatovic et al, Eur J Obstet Gynecol Reprod Biol 151(1):62-5, 2010 P value Control cycles (n=54) Adenomyosis cycles (n=20) NS42.0 %48.0 %Fertilization NS28.2 %31.0 %Implantation NS26.1 %19.0 %Miscarriage NS30.0 %35.0 %Preg >12 wks

70. Conclusions 1. In endometriosis-associated infertility, expectant management is associated with ~ 50% CPR in stages I and II, while patients with stages III and IV rarely become pregnant (B) 2. In general, surgical management is associated with a significantly higher pregnancy rate compared to medical or no treatment (B) 3. Simple cyst aspiration results in recurrence in ~ 50% of instances (B)

71. Conclusions (cont…) 4. Drainage of endometriomas + ablation or resection of their walls results in a higher pregnancy rate compared to no therapy (B) 5. Laparoscopic ablation and/or resection in stages I & II is associated with a significantly higher pregnancy rate compared to diagnostic laparoscopy (A) 6. Danazol, gestrinone, MPA, letrozole and GnRH agonists do not improve pregnancy rates over placebo or no therapy (A)

72. Conclusions (cont…) 7. Combining laparoscopic surgery and medical therapy does not improve pregnancy rates over surgery alone (A) 8. COH+IUI improves the pregnancy rates significantly compared to no therapy in stages I and II endometriosis (A) 9. Women with endometriosis treated with IVF have significantly lower pregnancy rates compared to tubal infertility (B) 10. Long-term GnRHa before IVF improves the pregnancy rates significantly (A)

73. Bibliotheca Alexandrina

74. Evidence-based management of endometriosis-associated infertility Hassan N. Sallam, MD, FRCOG, PhD (London) Professor in Obstetrics and Gynaecology The University of Alexandria, and Clinical and Scientific Director, Alexandria Fertility Center, Alexandria, Egypt 3rd Congress of Society of Reproductive Medicine, 5 – 9 October 2011, Antalya / Turkey

76. GIFT versus COH+IUI in endometriosis (CCT) (Delivery rate per cycle) P valueCOH+IUIGIFT <0.0514.7%28.1%Stages I & II NS12.5%40.9%Stages III & IV Lodhi et al, Gynecol Endocrinol 19(3):152-9, 2004

77. Effect of GnRHa on stage III and IV endometriosis Ma et al, Int J Gynaecol Obstet 100(2):167-70, 2008 P valueControl cycles Long term GnRH agonist

78. -Mohamed et al, Eur J Obstet Gynecol Reprod Biol. 2011 Jun;156(2):177-80 - Mijatovic et al, Eur J Obstet Gynecol Reprod Biol. 2010 Jul;151(1):62-5 - Tavmergen et al, Curr Opin Obstet Gynecol. 2007 Jun;19(3):284-8 - Gong et al, Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009 Mar;34(3):185-9 - Ma et al, Int J Gynaecol Obstet. 2008 Feb;100(2):167-70 - Tokushige et al. Discovery of a novel biomarker in the urine in women with endometriosis Fertility and Sterility 95(1): 46-49, 2011