Sticky surface: a scientific review of endometrial receptivity Prof. Juan A Garcia-Velasco IVI –...

Sticky surface: a scientific review of

endometrial receptivity

Prof. Juan A Garcia-Velasco IVI – MadridRey Juan Carlos UniversityMadrid – Spain

Limiting factor in achieving pregnancy Multiples embryos transferred:

no implantation? multiple pregnancy?

Poorly understood

Endometrial receptivity

“Restricted time-related period when the uterus is receptive to blastocyst attachment & invasion”

Concept of WOI – window of implantation Temporally frames the period of receptivity 4-5 day interval with peak Progesterone levels Synchrony between embryo and endometrium Opens day 19/20 by loss of epithelial E2 & P receptors


Revel F&S 2012

E 17 18 19 20 21 22 23

P P+4 P+5 P+6 P+7 P+8 P+9 P+10


Embryos attach ONLY underoptimal conditions

When to start progesterone?

TIMING is relevant

IHC Chromatography RT-PCR DNA microarrays microRNAs Proteomics Secretomics ……..

How to assess ER today?

Noyes et al. Fertil Steril 1950

-accuracy?-reproducibility?-clinical utility?

Endometrial dating – fertility status?

Doses for COS (AMH, BMI, age….) Type of protocol IVF vs ICSI Embryo number and quality ………

Personalized Medicine

However:endometrial status at ET is treated equallyneglected customized approachlack of knowledge?

Embryo transfer TIMING can be personalized

Technology helps

Transcriptome Proteome Metabolome

The age of –OMICS

Different subtypes of disease

TRANSCRIPTION TRANSDUCTION

Transcription regulation

Alternative splicing

Transduction regulation

DNA RNA mRNA Protein METABOLITES

JCEM

MHR

MHR

HR

JCEM

Horcajadas JA, Pellicer A, Simón C. Hum Reprod Update 2007.

Endometrial Receptivity Array (ERA)

Customized microarray

Bioinformatic analysis of data obtained by the customized microarray

Classification and prediction from gene expression.

Predictors: Characterization of RECEPTIVITY transcriptome

Endometrial Receptivity Array (ERA)

.

Receptive Profile

..

IF Sample NR1

.

Post-Recep Pre-Receptive

Receptive

Non Receptive samples

Proliferativ

e

Predictor classifies the molecular receptivity status of the endometrium

E :6 mg/day

P :800 mg/day

2

4

NATURAL CYCLE

Endometrial biopsy must be taken on the 7th day after the LH surge (LH+7)

urine or serum preferible

HORMONE REPLACEMENT THERAPY CYCLE

Endometrial biopsy must be taken on day P+5, after proper E2 priming

Endometrial Receptivity Array (ERA) - Timing of the biopsy

Direito A, et al. Fertil Steril 2013

LH surge variantsExtremely variable LH surges in configuration, amplitude and duration

Short Medium

Double Prolonged

Single Plateau

Double Multiple

Direito A, et al. Fertil Steril 2013

LH surge variantsWhen does ovulation happen according to LH surge?

Onset During

End After

Pathologist 1 (P1) Pathologist 2 (P2) P1 vs P2 ERA

Kappa value 0.618 (0.446-0.791) 0.685 (0.545-0.824) 0.622 (0.435-0.839) 0.922 (0.815-1.000)

0.61 - 0.80 - Good Concordance0.81 - 1.00 - Very Good Concordance

In a blinded study ERA classifies better than Noyes criteria

Endometrial Receptivity Array (ERA) – Accuracy

Díaz-Gimeno P, et al. Fertil Steril 2013

ERA TEST ANALYZED IN THE SAME PATIENT in two endometrial biopsies up 2-years apart

Endometrial Receptivity Array (ERA) – Consistency

Code Date First Biopsy

Date Second Biopsy

Months between

First Biopsy Results

Second Biopsy Results

CON1 09/2009 02/2012 29 Receptive Receptive (0.908)



CON4 05/2009 05/2012 36 Proliferative Non Receptive (0.864)

CON5 01/2009 05/2012 40 Proliferative Non Receptive (0.864)


Díaz-Gimeno P, et al. Fertil Steril 2013

Ruiz-Alonso M, et al. Fertil Steril 2013

0

10

20

30

40

50

60

70

80

IR

PR

Rate

(%

)

Months after ERA test 1 2 3 4 5 6Number of patients 91 87 47 30 15 40Implantation Rate (%) 37.9 43.1 44.6 45.8 58.3 48.6Pregnancy Rate (%) 54.9 59.8 55.3 53.3 73.3 70.0

First pET outcome after RECEPTIVE ERAin RIF patients (n=310)

No relationship with endometrial biopsy

Ruiz-Alonso M, et al. Fertil Steril 2013

Progesterone

EpithelialPR

Window of Endometrial Receptivity (WOI)

P P+1 P+2 P+3 P+4 P+5 P+6 P+7 P+8 P+9

ERA clinical applicabilityA case report and pilot study comparing routine embryo transfer versus pET

(Ruiz-Alonso et al. 2014 Hum Reprod 2014).

8. OD with pET using day-5 blastocysts in HRT cycle after 7 days of progesterone (P+7) Succesful twin pregnancy

Ruiz-Alonso, et al. 2014

DIAGNOSTIC INTERVENTION ERApre-receptive at P+5, being receptive at P+7

CASE REPORT

ART treatments in our center

3. IVF with fresh day-5 ET 4. IVF with differed day -5 ET in natural cycle 5. OD with day-3 ET in HRT cycle (P+3) 6. OD with day-3 ET in natural cycle 7. OD with day-5 ET in HRT cycle (P+5)

Routine work-up negative 1. IVF with fresh day-3 ET 2. IVF with fresh day-3 ETPrevious ART treatments

CLINICAL OUTCOMEET

Number of patients 17Source of oocytes Ovum donationAge 40.7 ± 4.7 (32-49)Number of embryos transferred 1.8 ± 0.4Implantation rate 12.9% (4/31)Pregnancy rate 23.5% (4/17)Ongoing pregnancy rate 0% (0/4)Clinical abortion 100% (4/4)Biochemical pregnancy 0.0% (0/4)Total attempts 2.1 ± 1.3Number of embryos transferred 1.8 ± 0.4Implantation rate 10.8% (7/65)Pregnancy rate 19.4% (7/36)Ongoing pregnancy rate 0% (0/7)Clinical abortion 71.4% (5/7)Biochemical pregnancy 28.6% (2/7)

Firs

t att

empt

Cum

ulati

ve

Ruiz-Alonso, et al. 2014

CLINICAL OUTCOMEET

Number of patients 17Source of oocytes Ovum donationAge 40.7 ± 4.7 (32-49)Number of embryos transferred 1.8 ± 0.4Implantation rate 12.9% (4/31)Pregnancy rate 23.5% (4/17)Ongoing pregnancy rate 0% (0/4)Clinical abortion 100% (4/4)Biochemical pregnancy 0.0% (0/4)Total attempts 2.1 ± 1.3Number of embryos transferred 1.8 ± 0.4Implantation rate 10.8% (7/65)Pregnancy rate 19.4% (7/36)Ongoing pregnancy rate 0% (0/7)Clinical abortion 71.4% (5/7)Biochemical pregnancy 28.6% (2/7)

ENDOMETRIAL RECEPTIVITY DIAGNOSIS USING ERAET

Receptive 0% (0/17)Pre-receptive 94% (16/17) WOI delayed 1 day 19% (3/16) WOI delayed 2 days 81% (13/16)Post-receptive 6% (1/17) WOI advanced 1 day 100% (1/1)

Firs

t att

empt

Cum

ulati

ve

CLINICAL OUTCOMEET pET

Number of patients 17Source of oocytes Ovum donationAge 40.7 ± 4.7 (32-49)Number of embryos transferred 1.8 ± 0.4 1.7 ± 0.5Implantation rate 12.9% (4/31) 34.5% (10/29)Pregnancy rate 23.5% (4/17) 52.9% (9/17)Ongoing pregnancy rate 0% (0/4) 32.3% (6/17)Clinical abortion 100% (4/4) 0% (0/9)Biochemical pregnancy 0.0% (0/4) 17.6% (3/17)Total attempts 2.1 ± 1.3 1.2 ± 0.4Number of embryos transferred 1.8 ± 0.4 1.8 ± 0.4Implantation rate 10.8% (7/65) 40.0% (14/35)Pregnancy rate 19.4% (7/36) 60.0% (12/20)Ongoing pregnancy rate 0% (0/7) 45.0% (9/20)Clinical abortion 71.4% (5/7) 0% (0/12)Biochemical pregnancy 28.6% (2/7) 15.0% (3/20)

ENDOMETRIAL RECEPTIVITY DIAGNOSIS USING ERAET

Receptive 0% (0/17)Pre-receptive 94% (16/17) WOI delayed 1 day 19% (3/16) WOI delayed 2 days 81% (13/16)Post-receptive 6% (1/17) WOI advanced 1 day 100% (1/1)

Firs

t att

empt

Cum

ulati

ve

IVF Patients

ReproductiveFollow-up


pET vs. ET

Group C Biopsy & ERA

N= 814

Report

Group AET in COS

N= 814

Group BET in HRT

N= 814


ReFollow-upproductive

Randomization

ET in COS vs.

ET in HRT

ReceptiveN= 732

Non-receptiveN= 82

Randomization

Randomized, multicenter, international clinical trial

Group C (NR1) pET in HRT

N= 41

Group C (R) pET in HRT

N= 732

Group C (NR2)ET in HRT

N= 41


Stanford UniversityCalifornia, USA

IVI MEXICOIECH Monterrey IVI PANAMA

FertilityHuntingtonUSP Sao PaoloBRASIL

IVI SPAIN

Fertility center, Brussels, BELGIUMVersys clinics,Budapest,

HUNGARYSbalagrm Sofia,BULGARY

Bahceci health group Istambul,TURKEY

ERA RCT EN EL MUNDO: 21 CENTROS

KKH,SINGAPORE

Hannam IVF TorontoCANADA

Seoul Maria HospitalSOUTH KOREA

Genesis IVF, SERBIA

Non-invasive diagnostic methods for the endometrial factor based on secretomics of the EFg

Cytokines

Signaling Factors

Proteins

ChemokinesProstaglandins

miRNAs

Glycoproteins

Salamonsen 2012

Simon 2010Matorras 2011

Greenblatt 2011

Simon 2013Hamamah 2013

Vilella, et al. 2013

*(p<0.05)**(p<0.01)

*

**

PGs LEVELS IN EF OBTAINED 24H BEFORE DAY 3 ET

PGE2

PGF2a

Con

cent

ratio

n (n

mol

/g)


PGs LEVELS IN EF OBTAINED 24H BEFORE DAY 5 ET C

once

ntra

tion

(nm

ol/g

)

PGE2

PGF2a


The transcriptomic signature of endometrial receptivity (ERA

test) revealed that the endometrial factor is responsible for

25% of cases of patients with RIF.

Personalized Embryo Transfer (pET) normalized clinical

results.

We will be able to investigate ER through novel non-invasive

biomarkers, such as lipidomics (PG´s) in endometrial

secretions

Conclusions

[email protected]

Thank you!

Sticky surface: a scientific review of endometrial receptivity Prof. Juan A Garcia-Velasco IVI –...

Documents

Transcript of Sticky surface: a scientific review of endometrial receptivity Prof. Juan A Garcia-Velasco IVI –...