endometrial receptivity still one of the mysterious areas in reproduction. Many have tried to solve it but failed. What to do?

1. Updates in Endometrial
Receptivity
Hesham Al-Inany, PhD, M.D

2. - dynamic tissue
- changes during the menstrual cycle
- Decidualization is the most imazing
- E.R : balance between adhesion, invasion, growth differentiation, immuno-
modulation.
Endometrium

3. Endometrial receptivity & Age
70%

4. Conception needs a receptive endometrium and a competent blastocyst. (Kim
SM et al.,2017)
It usually occurs between day 20-24 of the menstrual cycle or day 6-10 post
ovulation. (Bruce Lessey ., 2011)
Window of Implantation (WOI) : Max receptivity

5. 1
5
2 4
3
6
1. Pre-receptive endometrium
2. Initial embryo attachment
3. Continuing embryo attachment
4. Signaling between embryo, epithelium and stroma
5. Stromal invasion
6. Desidualization
8
7
Implantation
5
Fatemi et al., 2008, Human Reproduction Update

6. How to Diagnose E.R
1st Part

7. - Endometrial biopsy at time of OPU
- Ultrasound markers
- Biochemical markers
- OMICS
Markers of Endometrial Receptivity

8. • Noyes et al 1950 established morphological criteria to evaluate endometrial
development and receptivity. The use of Noyes criteria to predict the WOI
accurately has been questioned and randomized studies have invalidated
their use.(Coutifaris C .,2004)
• It needs biopsy !!
Histological Markers

9. Endometrial pinopods 2010
Normal endometrial secretory
epithelial cells. Most secretory cells
bears a fully developed pinopodes
which may protrude beyond the length
of ciliated cells
(Marina Aunapuu et al .,2018)
Again require biopsy

10. IVF & Endometrial receptivity
High
Estradiol
Up-regulates
PR-rec
Progesterone
rise
Advanced
endometriu
m
Implantation
failure

11. OPU If advancement > 3days No pregnancy!!!
(Ubaldi,1997; Kolibianakis, 2002)
HCG
B B
High estradiol
up-regulates
PR
Day-3
Day-5
14

12. Other Factors
CD
56
Il-1
• Stimulates Il-6, Il-8, LIF, TNFa,
PGE2, COX-2, MMP, Integrins
• Knockouts not infertile
Gp 130 cytokines
• Il-6, increases MMP-9
• Il-11, decidualization of stroma
• LIF, decidualization,
cytotrophoblast anchoring
Il-15
• Cell-cell interaction decidua-Nkcell
CRH
• Decidualization
• Inhibit immune response with Fas-
ligand
MUC-1
Natural Killer
Leucocytes

13. • endometrial thickness and pattern
• Endometrial volume
• sub-endometrial vascularization index
• Not reliable as a diagnostic marker for endometrial receptivity
Ultrasound markers

14. Biochemical Markers
Biochemical
markers
Endometrial
adhesion
molecules
Endometrial
anti-adhesion
molecules
Endometrial
cytokines
Endometrial
growth factors
• Integrins
• Cadherins
• Selectins
• immunoglobulin
superfamily
• mucin 1(MUC-1) • Leukaemia inhibitory factor
• interleukin-1
• interleukin-11
• colony-stimulating factor
• Heparin binding-
epidermal growth
factor (HBEGF)
• Insulin like growth
factor binding
protein1(IGFBP-1)
Cavagna M et al.,2003

15. Biochemical markers
E-tegrity test
E-tegrity Plus test
Endometrial
function test (EFT)
based on Beta-3 integrin expression
Which is a glue-like protein, necessary for implantation to take
place
combines Beta-3 integrin, with a newly discovered biomarker,
BCL6 which is a gene repressor and accurate predictor for the
presence of inflammation caused by endometriosis,
adenomyosis, or tubal disease
is based on alterations in cyclin E and on p27 expression
(Kliman HJ et al.,2006) (Germeyer A et al., 2014) (Chelsea Fox et al .,2016)

16. - lack accuracy and a predictive value.
- All fades away
Unfortunately

17. biological samples
- genomics (study of genes),
- transcriptomics (study of gene expression),
- proteomics (quantification of proteins),
- metabolomics
Currently, transcriptomics are considered the most established technology
available for evaluation of E.R (Messaoudi S et al.,2019)
OMICS

18. The age of (OMICS)
Bissonnette et al., 2016

19. How it works
Amplification & labelling
Hybridization on chip
Endometrium cells
RNA extraction
Affymetrix GeneChip®
Operating Software
(GCOS)

20. - Require frozen embryo transfer (FET)
Commercially available
the ERA test (Endometrial
Receptivity Array) :
a customized array based on the
expression of 238 genes coupled
to a computational predictor
capable of diagnosing a
functionally receptive
endometrium.(Diaz-Gimeno P et
al.,2011)

21. - Recurrent implantation failure
- Single embryo transfer (sET). (Barzilay Eran et al.,2018)
- endometrial biopsy must be performed at P+5 (hormone replacement
therapy cycle) or at LH+7 (natural cycle)
Invasive

22. But
• No RCT have been conducted
• Commercially propagated without clear evidence

23. EMMA
ALICE
EndomeTRIO
Coming soon

24. • Recent research has identified the existence of an endometrial microbiome,
• pathogenic variations of endometrial Lactobacilli levels could play a role in
RIF. (Moreno et al., 2016).
• EMMA can determine if the uterine microbial environment is optimal for
embryo implantation.
• Percentage of Lactobacilli in the endometrial sample
Endometrial microbiome metagenomic Analysis
(EMMA)

25. the aim of improving the clinical management of patients with this silent
disease. (Moreno et al.,2018)
Analysis of chronic infectious endometritis
(ALICE)

26. A combination of ERA,EMMA and ALICE tests
EndomeTRIO

27. Conclusion I : E.R can not be accurately predicted

28. How to Improve ?
2nd Part

29. what to do ?
• Increase vascularity
• Reducing Gn dose
• Immunomodulaion
• Endometrial scratch
• PRP

30. Increase Endometrial Vascularity
• Aspirin
• Viagra
• Nitric oxide donor
• All no beneficial effects

31. Gn effect on endometrium ( September 2020)
• Reducing dose of Gn in COH
• Max dose is 300 Iu
• Preferable starting dose is 150 IU for those with AMH 1-4

33. Immune system
• NK cells assay
• Intralipid infusion
• No evidence of effectiveness

34. Many papers in favor

35. Evidence is clear : 2020

36. PRP : Feb,2020
• Intrauterine infusion of autologous PRP in women undergoing IVF: A
meta-analysis
• 625 women
• clinical pregnancy (RR: 1.79, 95 % CI: 1.37, 2.32; P < 0.001)
• endometrial thickness increased (SMD: 1.79 mm, 95 % CI: 1.13, 2.44;
P < 0.001

37. Endometrial compaction (May, 2020)
• (Decreased Thickness) in Response to Progesterone : Results in
Optimal Pregnancy Outcome in Frozen-Thawed Embryo Transfers.

38. Fresh cycles ?
• No answer yet
• Needs RCT
• Sample size : 1400 participants

39. Requires only
• U/S on day of hCG
• U/S before ET
• Calculate the difference
• If more than 15% reduction : good prognosis

40. Advantages
• Non invasive
• Cheap
• Available
• Respect the concept : Dynamic

41. Conclusion II
• Three factors could be of help to improve endometrial receptivity
• Reducing Gn dose
• PRP
• Check for endometrial compaction

42. Thank you