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Evidence-based management of endometriosis-associated infertility

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.

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Evidence-based management of endometriosis-associated infertility

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  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. 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) Does endometriosis affect infertility?

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

  7. Laparoscopic surgery v/s no surgery(RCT)(Canadian Collaborative Group, Marcoux et al, 1997) 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. Cross-over oocyte donation study (Pellicer et al, 2001) 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 Similar implantation rates Reduced implantation rates

  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

  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) Olive et al, Fertil Steril 44(1):35-41, 1985

  20. Expectant management of stage I and II endometriosis (CCT) 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. CO2 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) Marcoux et al, N Engl J Med 337(4):217-22, 1997

  29. Resection or ablation for minimal or mild endometriosis (RCT) 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)

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

  33. leads torecurrence 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

  36. Drainage + resection/ablation of cyst wall (cont…)

  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) Tulandi and Al-Took, Fertil Steril 69(2):229-31, 1998

  39. Laparoscopy versus laparotomy(Cumulative pregnancy rates – CCT) Adamson et al, Fertil Steril 59(1): 35-44, 1993

  40. Laparoscopy versus laparotomy in severe endometriosis – (CCT) 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)

  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) 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) Donnez et al, Int J Fertil 35(5): 297-301, 1990

  50. Post-operative GnRHa for endometriosis (Cumulative pregnancy rates - CPR)

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