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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 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
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?
Prevalence of endometriosis (Mahmoud and Templeton, 1991) (OS) 25% 21% 15% 6% Mahmoud and Templeton, Hum Reprod 6(4): 544-9, 1991
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
AID in minimal endometriosis(Fecundity rates per month of exposure) Jansen RP, Fertil Steril 46 (1): 141-3, 1986
IVF in endometriosis versus tubal infertility (CPR) Barnhart et al, Fertil Steril 77(6): 1148-55, 2002
How does endometriosis affect infertility? 1. Tubal adhesions 2. Impaired gamete interaction 3. Impaired implantation
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
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)
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)
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)
Effect of GnRHa on the endometrium in endometriosis (CCT) Mohamed et al, Eur J Obstet Gynecol Reprod Biol 156(2):177-80 , 2011
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
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
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)
Expectant management in endometriosis (Prospective cohort study PCS) Olive et al, Fertil Steril 44(1):35-41, 1985
Expectant management of stage I and II endometriosis (CCT) Hull et al, Fertil Steril 47(1):40-4, 1987
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
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
White endometriosis, clear endometriosis, red endometriosis and powder burn lesions.
Powder burns on the right uterosacral ligament causing painful intercourse
Surgical treatment of endometriosis 1. Ablation and/or resection of laparoscopic lesions 2. Drainage +/- excision/ablation of endometriomas
Surgical treatment of endometriosis 1.Ablation and/or resection of laparoscopic lesions 2. Drainage +/- excision/ablation of endometriomas
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
Resection or ablation for minimal or mild endometriosis - Canadian Collaborative Group (RCT) Marcoux et al, N Engl J Med 337(4):217-22, 1997
Resection or ablation for minimal or mild endometriosis (RCT) Parazzini et al, Hum Reprod 14:1332-4, 1999
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
Resection or ablation for moderate and severe endometriosis (stages III and IV)
Surgical treatment of endometriosis 1. Ablation and/or resection of laparoscopic lesions 2.Drainage +/- excision/ablation of endometriomas.
leads torecurrence in 50-100% of cases(Nezhat et al, 1988; Vercillini et al, 1992; Olive, 1989) Simple drainage of endometriomas
Surgical versus non-surgical therapy Adamson and Pasta, Am J Obstet Gynecol 171:1488-504, 1994
Laparoscopic excision versus electro-coagulation in mild endometriosis (CCT) Tulandi and Al-Took, Fertil Steril 69(2):229-31, 1998
Laparoscopy versus laparotomy(Cumulative pregnancy rates – CCT) Adamson et al, Fertil Steril 59(1): 35-44, 1993
Laparoscopy versus laparotomy in severe endometriosis – (CCT) Crosignani et al, Fertil Steril 66(5): 706-11, 1996
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
Medical treatment of endometriosis (A) Ovarian suppression - Medroxyprogesterone (MPA) - Gestrinone - GnRH agonists - Danazol (B) Aromatase inhibitors - Letrozole (C) Novel approaches
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
Effect of letrozole on the ASRM score (OS) Ailawadi et al, Fertil Steril 81(2): 290-6, 2004
Letrozole for the treatment of endometriosis (RCT) Alborzi et al, Arch Gynecol Obstet 284: 105-10, 2011
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)
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
Pre-operative medical treatment for endometriosis (CCT) Donnez et al, Int J Fertil 35(5): 297-301, 1990
Post-operative GnRHa for endometriosis (Cumulative pregnancy rates - CPR)