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GnRH-agonist triggering of final oocyte maturation: Evidence and practice

GnRH-agonist triggering of final oocyte maturation: Evidence and practice. Georg Griesinger UK-SH, Campus Luebeck Germany. We have a problem …. OHSS. death of a 31-year-old woman …who developed a fatal adult respiratory distress syndrome Fineschi et al., 2006

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GnRH-agonist triggering of final oocyte maturation: Evidence and practice

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  1. GnRH-agonist triggering of final oocyte maturation: Evidence and practice Georg Griesinger UK-SH, Campus Luebeck Germany

  2. We have a problem…

  3. OHSS • death of a 31-year-old woman …who developed a fatal adult respiratory distress syndromeFineschi et al., 2006 • autopsy case of severe OHSS …..28-year-old Japanese female…… who died of rapid respiratory insufficiencySemba et al., 2000 • 21 year old woman ……cerebral infarction….complete persistent hemiplegia Hwang et al., 1998 • ........................

  4. We have another problem… We cannotreliably predictwhichpatients will develop OHSS …

  5. OHSS prediction GnRH-antagonistprotocol 18 follicles >10 mm or E2 > 5,000 pg/l Sens = 83% Spec = 84% 5/53 CASES OF SEVERE OHSS STILL MISSED WITH THESE CRITERIA! OHSS III Papanicolaou et al., Fertil Steril 2006

  6. Solutions to our problems … • Don‘t do ovarian stimulation! IVM: no OHSS efficacy? natural cycle IVF: no OHSS efficacy? • ….or develop ovarian stimulation routines that are associated with a per se decreased risk of OHSS!

  7. Let‘sonlyuseantagonistor ‚mild‘ stimulation! Hospital admission due to OHSS OHSS incidence = 1.5% Kolibianakis et al., Hum Reprod Update 2006

  8. The final solutiontoourproblem… • AbolishhCGas a triggeringagent!?

  9. Bolus dose ofGnRH-agonist Gonen et al., 1990

  10. Competition antagonist agonist

  11. Questions we need to ask GnRH-agonist trigger • Effect on oocyte competence? • Effect on luteal phase? • Efficacy of different protocols? • Does it prevent OHSS? • Protocols for OHSS prevention?

  12. Initial protocols 10.000 IU hCG TRIPTORELIN 0.2 mg antagonist 0.25 mg ≥ 3 follicles ≥ 17 mm 200 IU recombinant FSH cycle days Lutealphasesupport Progesterone 90-600mg vaginally Progynova 2 x 2 mg orally Kolibianakis et al., 2005; Humaidan et al., 2005

  13. No difference between • 0.2 triptorelin/0.5 mg buserelin vs. 10.0000 hCG • Luteal phase: vaginal or i.m. P + oral E2 • number of oocytes • number of MII oocytes • fertilisationrate • embryo Score • BUT: • ongoing PR massively reduced! Hum Reprod Update 2006

  14. Is the oocyte competence impaired? • Good outcome from oocyte donation cycles • Acevedo et al., Fertil Steril 2006 • Shapiro et al., 2007 • Bodri et al., Fertil Steril 2008 • Good live birth rates in frozen-thawed cycles • Eldar-Geva et al., RBMonline 2006 • Griesinger et al., Fertil Steril 2007

  15. How about the luteal phase? • Lutealphasesupplementationwithi.m. P Fauser et al., 2002

  16. Howaboutthelutealphase? • Progesteroneserumvalueswith • NO • lutealphasesupplementation Day ofadministrationofGnRH-a orhCG Beckers et al., 2003

  17. Drasticluteolysis after GnRH-a… • Will itprevent OHSS? Kol S, Fertil Steril 2004

  18. Does GnRH-agonist triggering prevent OHSS? Griesinger et al., RBMonline 2006

  19. OHSS I-II: RR with 95% confidence intervals (heterogeneity p = 0.57) OHSS III Update of : Griesinger et al., Hum Reprod Update 2005

  20. GnRH-agonist triggering in OHSS risk populations

  21. Evidencefromobservational, uncontrolledtrials17 publicationstotal n= 1,123 OHSS riskpatients a singlecasereported: late-onset OHSS in a pregnantwoman Update of : Griesinger et al., RBMonline 2006

  22. Avoiding the luteal phase • Spatially splitting agonist trigger + ET Oocyte donation √ • Acevedo et al., Fertil Steril 2006 • Shapiro et al., Fertil Steril 2007 • Bodri et al., Fertil Steril 2008 • Temporally splitting agonist trigger + ET • Griesinger et al., Hum Reprod 2007

  23. Griesinger et al., Hum Reprod 2007

  24. Update of Griesinger et al., Hum Reprod 2007

  25. Update of Griesinger et al., Hum Reprod 2007

  26. Mean number of ETs: 2.1 Mean number of embryos transferred 2.1 Mean time-to-conception 21 weeks (Jan/08) Cumulative incidence of positive hCG test leading to live birth

  27. German multi-centric study • GnRH-agonist trigger & cryopreservation of 2 PN oocyte for OHSS prevention • Study centres: Lübeck, Bonn, Wiesbaden, Würzburg, Erlangen, Köln, Augsburg, Bad Münder

  28. Modifying the luteal phase • Dual trigger: GnRH-agonist + low dose hCG • Humaidan et al., RBMonline 2006 • Humaidan et al., ESHRE 2007 • Shapiro et al., Fertil Steril 2007 • High dose luteal phase support • Engmann et al., RBMoline 2006 • Engmann et al., Fertil Steril 2008

  29. Low dose hCG + GnRH-a

  30. Prolonged, highdosedLutealphasesupport 50 mg IM P in oil daily + 0.3 transdermal E2 every 2nd day, starting the evening after oocyte retrieval, continuing until a positive heart beat

  31. Avoidingthelutealphase Modifyingthelutealphase Temporally splittingagonist & ET Spatiallysplittingagonist & ET Dual trigger: low dose hCG High dosedi.m. progesterone + transdermal E2 OHSS riskpatients Oocyte donors Feasible, OHSS reduction? Feasible, furtherstudiesneeded √ √

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