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Repeated Implantation Failure Mechanisms

Repeated Implantation Failure Mechanisms. Antonis Makrigiannakis MD, PhD Professor of Obstetrics and Gynecology Medical School, University of Crete. What is RIF. How many attempts? How many embryos? Age? Embryo quality? Failure in the presence of potential obstacles?.

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Repeated Implantation Failure Mechanisms

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  1. Repeated Implantation FailureMechanisms Antonis Makrigiannakis MD, PhD Professor of Obstetrics and Gynecology Medical School, University of Crete

  2. What is RIF • How many attempts? • How many embryos? • Age? • Embryo quality? • Failure in the presence of potential obstacles?

  3. RECURRENT IMPLANTATION FAILURE • Failure to achieve a pregnancy after 3 completed fresh IVF-ET cycles (Tan et al 2005) • Failure of ≥4-10 embryos to implant • In the era of SET/DET should the definition of RIF be revised

  4. WHY SHOULD IMPLANTATION FAIL TO TAKE PLACE ?

  5. Difficulties in studying the process of implantation Succesfull implantation requires “two-way interaction” blastocyst - endometrium

  6. Implantation - key event in the establishment of pregnancy Adhesion Apposition Invasion Embryo Uterine epithelium Invading trophoblast Endometrial stroma Continuous process from conception to 22 weeks gestation

  7. Hydrosalpinx/ Uterine alterations Ovarian stimulation Embryos (morphology and genetics) Uterus (morphology) Transfer procedure Factors implicated in RIF

  8. TREATMENT STRATEGIES FOR RECURRENT IMPLANTATION FAILURE • Embryo • Endometrium

  9. EMBRYO • Preimplantation genetic diagnosis • Blastocyst transfer • Assisted hatching • Co-culture of embryos with endometrium • Other methods of embryo selection • Donor oocyte/embryo

  10. TREATMENTS OF PROVEN BENEFIT embryo : assisted hatching

  11. ENDOMETRIUM • Hysteroscopy • Hydrosalpinges • Reproductive immunology • Novel approaches

  12. Histopathology-Immunology of implantation siteT=interstitial EVT, E=intravascular EVT, K=uNK cells, M=macrophage, L=T cells

  13. Cytotoxic T cell Th1 Helper cell Cell mediated immunity -- NK cell M Th0 APC Cell Th2 Helper cell Embryo IL- 4 IL-10 Antibody mediated immunity B cell Th1/Th2 balance in Normal Invasion X X IL-12 IL-18 “Paternal” Antigen IFN IL-4 IL-10

  14. Cytotoxic T cell Th1 Helper cell NK cell M Th0 APC Cell Th2 Helper cell B cell Th1/Th2 balance in failed invasion Cell mediated immunity “Paternal” Antigen IFN IL-12 IL-18 - - IL-4 IL-10 Embryo IL- 4 IL-10 Antibody mediated immunity

  15. ENDOMETRIUM • Hysteroscopy • Hydrosalpinges • Reproductive immunology • Novel approaches

  16. Does endometrial scratching promote implantation and live birth rates in patients with RIF?

  17. The first evidence was reported at the beginning of the 20th century! Mechanical manipulation hasbeen first shown to be associated with decidualformation in guinea pig. scratching the uterus during theprogestational phase of the estrous cycle provoked arapid growth of decidual cells Loeb L. Zentralblatt fur allgemeine Pathologie undpathologische Anatomie 18 563–565. 1907

  18. Systematic local endometrial injury & IVF outcome Local endometrial injury improves clinical pregnancy rate Reproductive BioMedicine Online (2012) 25, 345– 354

  19. Summary of the live birth/ ongoing pregnancy rate for the 5 studies included in the systematic review Improvement of live birth/ongoing pregnancy rate Reproductive BioMedicine Online (2012) 25, 345– 354

  20. Endometrial scratching is beneficial to live birth and ongoing pregnancy rates

  21. Endometrial scratching is beneficial especially to RIF: Clinical pregnancy rate

  22. Endometrial scratching is beneficial especially to RIF: Live birth rate

  23. Issues to be addressed • Which is the best cycle? • Evidence support the performance of endometrial biopsy one cycle prior to IVF • It is advisable not to perform endometrial injury on the day of oocyte retrieval because it appears to significantly reduce clinical and ongoing pregnancy rates. Cochrane Database Syst Rev. 2012 Jul 11;7:CD009517.

  24. Possible mechanisms Genes up-regulated by endometrial biopsy Up-regulation of receptivity molecules Kalma et al.Fertil Steril 2009;91:1042

  25. Endometrial biopsy • of macrophages/dendritic cells • tumor necrosis factor-a (TNF-a), • growth-regulated oncogene-a (GROa), • interleukin-15 (IL-15), • macrophage inflammatory protein 1B (MIP-1B), • Osteopontin A positive correlation was found between the levels ofmacrophages/dendritic cells, MIP-1B expression, and TNF-aexpression & the pregnancy outcome. Gnainsky et al. Fertil & Steril 2010;94:2030

  26. Suggested mechanism for the role of endometrial injury-dependent inflammation in implantation Reproduction (2012) 144 661–668

  27. Does intrauterine administration of PBMCs promote implantation & pregnancy rates in patients with RIF?

  28. Intrauterine administration of autologous PBMCs promote clinical pregnancy, implantation and live birth rates in patients with repeated failure of IVF-embryo transfer 41.2% vs 11.1% and 23.4% vs 4.1% and 35.3% vs 5.5% Yoshioka et al. Hum Reprod 2006;21:3290

  29. 253 cycles were studied • All women received frozen/thawed embryos. • PBMCs were not treated with HCG Okitsu et al. Journal of Reproductive Immunology 92 (2011) 82– 87

  30. Proposed mechanisms for PBMC actions within the uterine cavity • Activated PBMC that are administered into the uterine cavitycan induce adequate endometrial differentiation forembryo implantation. • PBMC can evoke favorableinflammatory reactions in the uterine cavity, for example,secreting proteases that may effectively change thefunction or structure of surface molecules expressed onthe endometrial luminal epithelial cells. • PBMC may move from the uterinecavity toward the endometrial stromal tissue, creating aleading pathway for subsequent embryo attachment andinvasion J. Mamm. Ova Res. 26, 122–128, 2009 J. Reprod. Immunol. 81, 1–8., 2009

  31. Issues to be addressed • What is the biological impact? • When is the appropriate time to administer the PBMCs? • Should PBMCs be pre-treated with HCG? • Apart from RIF? • Differential(Better) Activation of PBMCs?

  32. DOES INTRAUTERINE ADMINISTRATION OF PBMCs PRETREATED WITH CRH PROMOTE IMPLANTATION RATES IN PATIENTS WITH RIF?

  33. Background • Implantation sites in rat uterus contains increased CRH concentrations. Makrigiannakis et al, JCEM 1995

  34. * *P<0.001

  35. * Results P< 0.05

  36. CRH induces IL 6

  37. The expression of adhesion molecules by endometrial epithelial cells is regulated by blood monocyte-derived DCs. Freshly isolated day-12 epithelial cells were treated with either control culture medium (C) or with conditioned medium collected from cultures of blood monocyte-derived DCs (DC).

  38. CRH decreases IFN

  39. Intrauterine PBMCs administration & IVF outcome in RIF patients CRH added to primary cultures of PBMCs significantly increased IL-6 (Th2-type immunity) release and decreased IFN-γ (Th1-type immunity) levels in a dose dependent manner CRH & cytokine production Makrigiannakis et al,EJCI,2015

  40. YES! DOES INTRAUTERINE ADMINISTRATION OF PBMCs PRETREATED WITH CRH PROMOTE IMPLANTATION RATES IN PATIENTS WITH RIF?

  41. Intrauterine PBMCs administration & IVF outcome in RIF patients CRH & endometrium • CRH induces stromaldecidualization and potentiates the decidualizing effect of progesterone • CRH regulates local modulators of thedecidualization process; it inhibits theenhancer PGE2, induces the inhibitor interleukin (IL) 1and stimulates the inducer IL-6. Makrigiannakis et al,MHR 1999 Zoumakis et al, 2000; Makrigiannakis et al 1999

  42. DOES INTRAUTERINE ADMINISTRATION OF HCG PROMOTE IMPLANTATION RATES IN PATIENTS WITH RIF?

  43. Ye et al 2015: HCG significantly increases biochemical and pregnancy rates Biochemical pregnancy rate Clinical pregnancy rate

  44. However concurrent evidence on blastocyst transfer did not support this finding

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