Endometrioseassosiert infertilitet

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1 Hva er endometriose? Endometrioseassosiert infertilitet Hans Kristian Opøien, Seksjon for reproduksjonsmedisin og Nasjonal kompetansesenter for kvinnehelse, Gynekologisk avdeling, Kvinne og barnklinikken, OUS Rikshospitalet. Endometrium like tissue outside the uterus which induces a chronic inflammatory reaction. ESHRE Hum Reprod Prevalens Kumulativ graviditetsrate for normale kvinner vs kvinner med ubehandlet endometriose Prevalence of endometriosis amongst previously fertile women undergoing sterilization was just 4%....among women undergoing laparoscopic surgery to investigate the cause of their infertility the rates was as high as 33%. D'Hooghe T et al., 2003 Hull MG, Hum Reprod 1992

2 Utvikling av endometriose 2) The invagination theory 1) Sampson s theory on retrograde menstruation Endometriom / endometriosecyste: Inklusjonscyste med kledning av ektopisk endometrium. Figur Hypothesis of histogenesis of ovarian endometriomas. Nisolle M, Donnez J. Fertil Steril 1997 Mulige mekanismer for endometrioseassosiert infertilitet Disponerende faktorer Forstyrret ovarie og / eller tube funksjon 1. Anatomical disturbances and tubal obstruction 2. Failure of ovulation a. Disturbed follicular development b. LUF (luteinized unruptured follicle) c. LPD (luteal phase defect) Skade av eggcellen / oocyten 1. Økt frekvens av aneuploidi 2. Skade på cytoskellettet og den meiotike spindelen Forandringer i peritonealvæsken 1. Aktiverte macrophager 2. Prostaglandiner 3. Cytokiner Immunologiske defekter 1. Autoimmunitet 2. Anti endometrielle antistoffer Nedsatt spermiemotilitet Age < 11 years at menarche Menstrual intervals < 27 days No pregnancies Dysmenorrhea Endometriosis in mother and / or sister Alcohol and coffein Environmental exposures (PCB, dioxine)

3 Beskyttende faktorer Høy alder ved menarche Uregelmessige perioder Multi para P piller Trening Røyking Diagnostikk Sykehistorie GU, palpasjon CA125 Radiologi LAPAROSKOPI LAPAROSKOPI LAPAROSKOPI Predilleksjonssteder Peritoneal endometriose ts img/2008/l08 13 Med jpg

4 Hormoner Behandling Endometriose klassifikasjon (ASRM) 1) Utbredelse 2) Dybde 3) Lokalisasjon 4) Adheranser Kirurgi Assisted reproduction technology; ART Inseminering; IUI med eller uten COH Prøverørsbehandling; IVF/ICSI 3 praktiske grupper etter ASRM: ASRM Stage I og II Minimal / mild Peritoneal endometriose ASRM Stage III og IV Moderat / alvorlig Peritoneal endometriose m/ uttalte adherenser Endometriomer (>1cm = Stage III) Strength of evidence A ESHRE Guidelines Hormonell behandling. Suppression ovarian function to improve fertility in minimal mild endometriosis is not effective and should not be offered for this indication alone (Huges et al., 2004). There is no evidence of its effectiveness in more severe disease. Evidence level 1a

5 KIRURGSK BEHANDLING peritoneal endometriose Spontane graviditeter Diatermi Laservaporiesering Eksisjon Grad I & II endometriose: ablation. Grad I & II endometriose; INGEN behandling. KONTROLL. Marcoux et al., NEJM, 1997 Cochrane Review ESHRE guidelines.. Strenght of evidence A Ablation of endometriotic lesions plus adhesiolysis to improve fertility in minimal mild endometriosis is effective compared to diagnostic laparoscopy alone. (Jacobson et al., 2004b). Evidence level 1a Jacobson et al., Cochrane Review 2002

6 ovarium KIRURGISK BEHANDLING moderat til alvorlig endometriose tube adheranser uterus RCOG The role of surgery in improving pregnancy rates for moderatesevere disease is uncertain. ESHRE No RCT or meta analyses are available to answer the question whether surgical excision of moderate severe endometriosis enhances pregnancy rates Har kirurgi en tilleggseffekt ved inseminering og IVF / ICSI? Inseminering ubehandlet minimal/mild endometriose Inseminering kirurgisk behandlet minimal / mild endometriose Author No. cycles endometriosis No.pregn. endometriosis No. cycles unexpl. inf. No. pregn. unexpl. inf. Yovich Kahn Karlstrom Omland Nuojua Huttunen Singh Total (7.9%) P < (13.4%) Surgical treatment of minimal and mild endometriosis, normalizes the outcome of COH and IUI to the level of unexplained infertility. Werbrouck E et al.,2006

7 IVF Unadjusted meta analysis of odds of pregnancy in patients vs. tubal factor controls. ESHRE guidelines: A IVF pregnancy rates are lower in patients with endometriosis than with tubal infertility (Barnard et al., 2002) 1a Barnhart. IVF in endometriosisassociated infertility. Fertil Steril IVF / ICSI Komplett diatermi Partiell diatermi Diagnostisk lapraroskopi Antall initierte sykluser Antall oocytter v/ OPU Implantasjonsrate 30.9 % ¹ 27.4 % 23.9 % Graviditetsrate / OPU 40.3 % ² 34.1 % 29.4 % Prolonged treatment with a GnRH agonist before IVF in moderate severe endometriosis have been reported to give improved pregnancy rates (Rickes, Nickel et al., 2002;Surrey, Silverberg et al., 2002). LBR / OPU 27.7 % ³ 24.4 % 20.6 % ¹ p<0.01; ²p<0.005; ³ p<0.05 Opøien et al, RBMOnline In press.

8 ENDOMETRIOMER Ubehandlede endometriomers innvirkning på graviditetsraten v/ IVF Gupta et al Kirurgi vs IVF ESHRE Kun en RCT Kirurgi gir lengre stimulering (14.0 v10.8 dager; p=0.001) høyere FSH forbruk (4575 IU vs 3675 IU ; p = 0.001) fertilisering (p=ns) implantasjonsrate (p=ns) GPP Laparoscopic ovarian cystectomi is recommended if an ovarian endometrioma is 4 cm in diameter is present to confirm the diagnosis histologically; reduce the risk of infection; improve access to follicles and possibly improve ovarian response. The decision should be reconsidered if she has had a previous ovarian surgery. færre modne oocytter (7.8 vs 8.6; p = 0.032) graviditetsrate (p=ns) Demirol et al, 2006

9 Cochrane Database of Systematic Reviews Excisional surgery vs ablative surgery for ovarian endometriomata Authors' conclusions: There is good evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation with regard to the recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile, subsequent spontaneous pregnancy. Consequently this approach should be the favoured surgical approach. However in women who may subsequently may undergo fertility treatment insufficient evidence exists to determine the favoured surgical approach. Hart RJ et al. Cochrane Database of Systematic Reviews 2008, Issue 2. Postoperative hormonal treatment Postoperative hormonal treatment has no beneficial effect on pregnancy rates after surgery. RCOG, online 2010 Treatment with...gnrh agonist after surgery does not improve fertility compared with expected management. (Vercellini et al 1999b, Busacca et al 2001) ESHRE guidelines. Take home messages Kirurgisk eliminering av minimal/mild eller peritoneal endometriose gir økt spontan graviditetsrate (Marcoux et al., 1997; Jacobson et al., 2002), sammenlignbare rater ved IUI (Werbrouck et al, 2006) økt fødselsrate ved IVF/ICSI (Opøien et al, 2011) Kirurgisk behandl av moderat/alvorlig endometriose ingen dokumentert effekt Kirurgisk behandling endometriomer / endometriosecyster redusert ovariell respons og antall modne oocytter ved OPU og ikke høyere graviditetsrate preoperativt IVF prøveforsøk uansett størrelse av endometriomet?