The Enigma of implantation

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Successful implantation of the embryos in the uterus after IVF cycle is about 20%. It represents the bottleneck in the procedure of in vitro fertilization and embryo transfer. In this presentation we look at factors affecting implantation and how to improve it.

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  • Up- and down-regulated factors of the proliferative and secretory phase.
  • The Enigma of implantation

    1. 1. The Enigma ofImplantation
    2. 2. Dr. Priya ChittawarAssociate Professor and Head of UnitMohak Laparoscopy and Infertility CenterSri Aurobindo Institute of Medical SciencesIndore
    3. 3. Natural Cycle
    4. 4. IVF
    5. 5. The Patients Perspective Egg+ Sperm= Baby Surprised to learn that 60% of the ivf cycles don’t end in a pregnancy What went wrong?
    6. 6. What Went Wrong? The follicles did not develop as expected? The oocyte|sperm quality was not so good? The fertilization rate was suboptimal? The embryo quality on morphology was not good? The embryo transfer was difficult? The endometrial development was suboptimal?
    7. 7.  Even after an ivf cycle in which everything apparently goes well, after transfer of apparently good quality 3 embryos the pregnancy rates are around 30 to 40 % Pregnancies are known after transfer of poor quality single embryo.
    8. 8.  Is the fertility and implantation in human beings naturally low ? Monthly fecundity rate in a normal couple is 20 to 25% Is the low implantation rates in ART cycles due to an altered physiological state?
    9. 9.  Almost 30 to 70% of conceptus are lost before or at the time of implantation. We have improved almost all aspects of ivf: ovarian stimulation, embryo culture and transfer but pregnancy rates hover around 30 to 40% The bottleneck is the process of implantation.
    10. 10. The Bottleneck!
    11. 11. Average pregnancy rate of 50% cannot be furtherincreased by the improvement of embryo transfer andculture conditions or by optimal selection ofblastocysts The endometrial function and endometrial receptivityhave been accepted to be major limiting factors in theestablishment of pregnancy.
    12. 12. ImplantationThe process by which the embryo attaches to theuterine wall and first penetrates the epithelium andthen the circulatory system of the mother to form theplacenta.Most vital and the least understood part ofreproduction
    13. 13.  Implantation begins 2-3days after the fertilized egg enters the uterus on day 18-19 of the cycle, 5 to 7 days after fertilization. Hormone dependent changes in the four compartments of the endometrium1. Glandular epithelium2. Luminal epithelium3. Stroma4. Resident immune cells ( NK cells)
    14. 14. Successful implantation Embryo at the blastocyst stage Endometrium in the short spanned ‘implantation window’ Successful cross talk between the two
    15. 15. Implantation Apposition Adhesion Invasion
    16. 16. AppositionProgressively increasing contact between trophoblastand uterine epithelium by1.Decrease in uterine fluid volume2.Edema of the endometrium3.Enlargement of the embryo
    17. 17. The Implantation Window
    18. 18. Pinopodes
    19. 19.  Pinopodes are surface epithelial microvilli that exhibit cystic changes They appear in normal cycles from day 20-22 and in stimulated cycle from 18-22 They live for 48 hours Presumably reduce the uterine fluid volume and facilitate intimate contact between blastocyst and uterine epithelium
    20. 20.  Pinopods are visible on conventional histology as bulbous protrusions of the cell apices Histology is performed on tissue sections where only a small area of the surface can be examined Scanning Electron Microscopy is most appropriate to study pinopod formation Mirrors serum progesterone concentration.
    21. 21.  Because of the need for invasive biopsy, pinopod determination cannot be done in treatment cycles
    22. 22.  The interactions between fertilized egg and the endometrium is determined by the interplay of hormones estrogen and progesterone There bind to intracellular receptors and the resulting proteins upregulate or downregulate genes which influence implantation
    23. 23. Up- and down-regulated factors of the proliferative and secretory phase. Strowitzki T et al. Hum. Reprod. Update 2006;12:617-630© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
    24. 24.  There is loosening of epithelial cell to cell contacts during pinopod formation which may facilitate invasion In endometrial epithelial cells growing on stromal cells in vitro, human blastocysts adhered only to areas bearing the pinopods
    25. 25. Adhesion Expression of extracellular matrix components occurs in the endometrium which helps adhesion of the blastocyst to the endometrium Alpha five beta four integrin , leukemia inhibiting factor and insulin like growth factor.
    26. 26. Invasion1. Trobhoblastic cells invade between the uterine epithelial cells on their path to basment membrane2. Epithelial cells lift off the basement membranes, allowing the trophoblast to insinuate underneath the epithelium3. Fusion of trophoblast with uterine epithelial cells.
    27. 27. Implantation in IVF cycles Embryos transferred on day 2/day 3/day5 The embryos are transferred transcervically with some amount of culture media Endometrial development is accelerated due to high concentrations of steroids Culture conditions may speed up or retard embryonic development
    28. 28. Estrogen Levels in IVF
    29. 29. Seed or Soil?
    30. 30.  Select the best ‘seed’ Prepare the soil Plant at the appropriate time
    31. 31. Improving implantation… Improving embryo qualityBetter ovarian stimulation, good lab performance, extended culture Better way to choose the embryos for transfer Be wary of multiple pregnancies
    32. 32. BESST IVF OUTCOME BESST: Birth of a successful singleton at term Avoid multiple births in IVF Improving implantation is vital to achieving this goal.
    33. 33. Improving Implantation
    34. 34. Problems in assessing Endometrium Complex interaction of biomarkers In vivo studies are done in non conception cycles as invasive sampling is needed Gene suppression experiments provide only indirect evidence about the role of the the resulting biomarker
    35. 35. What Tomorrow Holds Better assessment of endometrial receptivity using integrin and pinopode assessment Study of endometrial secretions by microdialysis for glycodelin and other biomarkers Assessment of endometrial gene expression and Therapeutic applications of HOX 10 gene by gene therapy to improve implantation
    36. 36. What Tomorrow Holds Optimizing implantation will increase pregnancy rates Evaluation of implantation biomarkers will help predict pregnancy outcome and detect occult implantation defects Gene therapy targeted at genes responsible for implantation will give a new therapeutic option Manipulating the expression of key implantaton genes by surgical medical or future gene therapy will help improve implantation rates
    37. 37. Thank You!

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