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.
2. Dr. Priya Chittawar
Associate Professor and Head of Unit
Mohak Laparoscopy and Infertility Center
Sri Aurobindo Institute of Medical Sciences
Indore
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. 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. 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. 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. 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.
11. Average pregnancy rate of 50% cannot be further
increased by the improvement of embryo transfer and
culture conditions or by optimal selection of
blastocysts
The endometrial function and endometrial receptivity
have been accepted to be major limiting factors in the
establishment of pregnancy.
12. Implantation
The process by which the embryo attaches to the
uterine wall and first penetrates the epithelium and
then the circulatory system of the mother to form the
placenta.
Most vital and the least understood part of
reproduction
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 endometrium
1. Glandular epithelium
2. Luminal epithelium
3. Stroma
4. Resident immune cells ( NK cells)
14. Successful implantation
Embryo at the blastocyst stage
Endometrium in the short spanned ‘implantation
window’
Successful cross talk between the two
16. Apposition
Progressively increasing contact between trophoblast
and uterine epithelium by
1.Decrease in uterine fluid volume
2.Edema of the endometrium
3.Enlargement of the embryo
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. 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. Because of the need for invasive biopsy, pinopod
determination cannot be done in treatment cycles
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
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. 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. Invasion
1. Trobhoblastic cells invade between the uterine
epithelial cells on their path to basment membrane
2. Epithelial cells lift off the basement membranes,
allowing the trophoblast to insinuate underneath
the epithelium
3. Fusion of trophoblast with uterine epithelial cells.
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
30. Select the best ‘seed’
Prepare the soil
Plant at the appropriate time
31. Improving implantation…
Improving embryo quality
Better ovarian stimulation, good lab performance,
extended culture
Better way to choose the embryos for transfer
Be wary of multiple pregnancies
32.
33. BESST IVF OUTCOME
BESST: Birth of a successful singleton at term
Avoid multiple births in IVF
Improving implantation is vital to achieving this
goal.
36. 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
37. 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
38. 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