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    Human Endometrial Receptivity

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    rafifah_nadia
    In IVF / ICSI, pregnancy and birth rates remain low. Out of 3 IVF cycles fail to result in pregnancy. More than 8 out of 10 transferred Embryo fail to implant Requirements for implantation. A receptive endometrium and a functionally normal blastocyst. An adequate cross-communication between 2.

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    Human Endometrial Receptivity

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    rafifah_nadia
    64 views39 pages
    In IVF / ICSI, pregnancy and birth rates remain low. Out of 3 IVF cycles fail to result in pregnancy. More than 8 out of 10 transferred Embryo fail to implant Requirements for implantation. A receptive endometrium and a functionally normal blastocyst. An adequate cross-communication between 2.

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    In IVF / ICSI, pregnancy and birth rates remain low. Out of 3 IVF cycles fail to result in pregnancy. More than 8 out of 10 transferred Embryo fail to implant Requirements for implantation. A receptive endometrium and a functionally normal blastocyst. An adequate cross-communication between 2.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    64 views39 pages

    Human Endometrial Receptivity

    Uploaded by

    rafifah_nadia
    In IVF / ICSI, pregnancy and birth rates remain low. Out of 3 IVF cycles fail to result in pregnancy. More than 8 out of 10 transferred Embryo fail to implant Requirements for implantation. A receptive endometrium and a functionally normal blastocyst. An adequate cross-communication between 2.

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    of 39

    Human endometrial receptivity during

    natural and stimulated cycles

    Samir Hamamah
    Professor of Reproductive Medicine
    Chair, ART/PGD department

    ART/PGD Department
    Arnaud de Villeneuve hospital
    Montpellier, France
    INSERM U 847

    Rational

    . in IVF/ICSI, pregnancy and birth rates remain low


    . out of 3 IVF cycles fail to result in pregnancy
    . more than 8 out of 10 transferred Embryo fail to implant

    Requirements for implantation

    . a receptive endometrium
    . a functionally normal blastocyst
    . an adequate cross-communication between 2

    Conventional approaches used in


    clinical practices for assessing
    endometrial receptivity
    . Morphological examination
    . Ultrasonography
    . Cervicovaginal fluid
    . Single biomarker
    . Omics

    Conventional approaches used in clinical practices


    for assessing endometrial receptivity

    Morphological examination
    . Endometrial dating by histological evaluations : Noyescriteria

    . Pinopode formation

    Remains controversial as marker of endometrial receptivity


    Invasive method (endometrial biopsies) ?

    Conventional approaches used in clinical practices


    for assessing endometrial receptivity

    Ultrasonography
    The 2/3D power Doppler

    .
    .
    .
    .
    .
    .
    .
    .

    Endometrial thickness
    Endometrial pattern
    Pulsatility index of uterine vessels
    Resistance index of uterine vessels
    Endometrial volume
    Vascularization index
    Flow index of endometrial & subendometrial regions
    Vascularization flow index of endometrial & subendometrial regions

    Identification of patients with a poor implantation prognosis, but low


    predictive value in determining endometrial receptivity and IVF outcome

    Conventional approaches used in clinical practices


    for assessing endometrial receptivity

    Cervicovaginal fluid

    Look for cytokine, interleukin and GF secretions

    2 approaches

    Washing

    Higher & variable


    dilution factor

    or

    Direct aspiration

    Contamination by
    cervical mucus
    and/or blood

    To date, supplementary studies should be performed to identify markers


    linked to endometrial receptivity in endometrial secretions

    Fundamental research for assessing endometrial


    receptivity

    Single biomarker
    Numerous endometrial proteins have been suggested based on their sequential
    temporal expression with respect to the implantation window:
    glycodelin A,
    aVb3 integrin,
    osteopontin,
    LIF,
    colony stimulating factor 1 (CSF1),
    mucin 1

    Further studies are needed with large patient cohorts including fertile and
    infertile women in order to determine their predictive value as markers of
    endometrial receptivity

    The implantation window

    . LH day +6 to +10
    . Phases: signaling, apposition, attachment, invasion
    . Key associated findings:
    luminal epithelial pinopodes;
    expression of adhesion molecules, and
    novel cytokines profile

    Do implantation factors explain IVF


    Success/failure ?

    A wide range of potential candidates exists.


    Potential markers are in Endometrium, Embryo,
    Immuno system or Vascular system
    Studies must show that a bio-marker is:
    1- measurable without disturbing implantation
    2- sensitive and specific

    Omics

    Transcriptomic approaches have been used to


    identify biomarkers of the human implantation
    window.

    modifications in gene expression profile associated


    with the transition of the human endometrium
    from a pre-receptive to a receptive state

    Carson et al., 2002;


    Riesewijk et al., 2003;
    Mirkin et al., 2005;
    Talbi et al.,2006

    Fundamental research for assessing endometrial receptivity

    Proteomic approach

    Study

    Patient
    First sample:
    Second sample:
    Age
    Fold
    Number of proteins
    population
    day
    of
    cycle
    day
    of
    cycle
    Patients
    change
    (nber of samples) (nber of samples)
    (years, min-max)
    Up Down

    Li et al.
    (2006)

    Candidats

    LH + 2
    (n=?)

    LH + 7
    (n=?)

    Annnexin IV

    LH + 2
    (n=8)

    LH + 7
    (n=8)

    1.3

    12

    23

    Annnexin II (x2.13)
    Stathmin (x-2.13)

    (x2.12)

    Article in Chinese

    Domnguez et al. 23-39


    (2009)

    Oocyte
    donors

    Differential in-gel electrophoresis (DIGE) and mass spectometry


    (MS)

    Further studies are needed to determine their predictive value as markers


    of endometrial receptivity

    Fundamental research for assessing endometrial receptivity


    Transcriptomic approach
    Study

    Age
    Patients
    (years, min-max)

    Carson et al. Not specified


    (2002)
    Mirkin et al.
    (2005)

    24-32

    Riesewijk et al. 23-39


    (2003)

    Patient
    population

    First sample:
    day of cycle

    Second sample: Fold


    Nber of genes
    day of cycle
    change
    (nber of samples) (nber of samples)
    Up Down

    Fertile
    volunteers

    LH + 2/4
    (n=3)

    LH + 7/9
    (n=3)

    Oocyte
    donors

    LH + 3
    (n=3)

    LH + 8
    (n=5)

    Fertile
    volunteers

    LH + 2
    (n=5)

    LH + 7
    (n=5)

    Talbi et al.
    (2006)

    23-50

    Normal responder

    ESP
    (n=3)

    MSP
    (n=8)

    1.5

    Haouzi et al.
    (2009a)

    22-36

    Normal responder

    LH + 2
    (n=31)

    LH + 7
    (n=31)

    323

    370

    (Affymetrix Hu95A
    12 000 genes)

    49

    58

    (Affymetrix Hu95A
    12 000 genes)

    153

    58

    (Affymetrix Hu95A-E
    60 000 uniq Sequ)

    1415 1463

    Affymetrix Hu133P
    (30 000 genes)

    945

    67

    Affymetrix Hu133P
    (30 000 genes)

    This is the first study analyzing by paired samples the endometrial gene
    expression profiles from the same patients during the pre-receptive to the
    receptive transition in a natural cycle.

    we revisited the global gene expression


    profile of human endometrial biopsies of a
    natural and stimulated cycles
    during :

    Natural cycle
    - early secretory phase, 2 days after the LH surge (LH +2)
    - mid-secretory phase (LH +7)

    Stimulated cycle

    - Egg collection day (hCG +2)


    - Transfert dat (hCG +5)

    Experimental design

    Endometrium cells

    AAAAAAA

    AAAAAAA
    AAAAAAA
    AAAAAAA
    AAAAAAA
    AAAAAAA

    RNA extraction

    Amplification & labelling

    Hybridization on chip

    Affymetrix GeneChip
    Operating Software (GCOS)

    Expression
    profile of 30 000
    genes

    Haouzi .Hamamah, HR 2009a

    Haouzi .Hamamah, HR 2009a

    Haouzi .Hamamah, HR 2009a

    Validation of selected genes


    identified by the microarray
    data from natural cycles in the
    pre-receptive (LH + 2) and
    receptive (LH + 7)
    endometrium.

    Haouzi .Hamamah, HR 2009a

    Number of genes significantly modulated in 6 microarray analyses


    between natural and stimulated cycles
    Study

    Mirkin et al.
    (2004)

    Number
    of
    samples

    Natural cycle
    (nber of samples)

    13

    LH+8

    hCG+9 Atg

    LH +8

    hCG+9 Ag

    LH +7

    hCG +7

    LH +7

    hCG +7 Atg standard dose

    (n=14)

    (n=4)

    LH +7

    19

    49

    1.2

    No

    281

    277

    No

    22

    69

    hCG +7 Atg high dose

    88

    24

    LH +7

    hCG +7 Ag

    (n=14)

    (n=5)

    22

    100

    LH+2

    hCG+2

    (n=5)

    (n=5)

    LH+7

    hCG+7

    69

    73

    LH+7

    hCG+7 high serum E2 levels

    244

    159

    LH+7

    hCG+7 low serum E2 levels

    (n=5)

    Liu et al.
    (2008)

    13

    (n=5)
    (n=5)

    Haouzi et al.
    (2009b)

    84

    Number of genes

    1.19

    (n=5)

    (n=14)

    Horcajadas et al.
    (2008)

    Fold
    change

    Down

    (n=14)

    28

    Paired
    analysis

    Up

    (n=5)

    Horcajadas et al.
    (2005)
    Simon et al.
    (2005)

    Stimulated cycle
    (nber of samples)

    (n=5)
    (n=3)

    (n=5)

    (n=5)

    (n=4)

    No

    (n=4)

    hCG+2

    LH+7

    hCG+5

    (n=21)

    No

    (n=5)

    LH+2
    (n=21)

    No

    (n=21)

    Yes

    321

    657

    (n=21)

    This is the first study analyzing by paired samples the endometrial gene
    expression profiles from the same patients during the pre-receptive to the
    receptive transition both in a natural and in a subsequent stimulated cycle.

    Comparison of gene expression profiling across the


    WI in natural Vs stimulated cycles

    Elucidate the genomic impact of COS on endometrial


    development and
    Search for novel gene targets to improve endometrial
    receptivity in IVF

    LH+2 versus hCG+2


    LH+7 versus hCG+5

    Haouzi .Hamamah, HR 2009b

    Haouzi .Hamamah, HR 2009b

    Haouzi .Hamamah, HR 2009b

    15% Atypical profiles

    Molecular signature
    of COS cycles
    during the WI
    differs from natural
    cycles

    EFR
    ER after freezigthawing on NC

    PP 27
    27

    PP 22
    22

    P 25

    P 42

    Haouzi .Hamamah, HR 2009b

    Haouzi .Hamamah, HR 2009b

    Haouzi .Hamamah, HR 2009b

    GnRH agonist long protocol affects more the


    local microenvironment of the human
    endometrial receptivity than antagonist
    protocol

    % of genes in
    common between
    stimulated and
    natural cycles
    during the
    receptive
    endometrium.

    Major differences of chemokines, and growth factors involved during


    endometrial receptivity between natural, GnRH antagonist and agonist
    long protocols.
    Chemokines (A), and growth factors (B) up-regulated during the
    endometrial receptivity under natural, GnRH agonist long and
    antagonist protocols.
    Red, not present in natural cycles

    Unsupervised classification with PCA of the hCG+2 and


    hCG+5 samples under GnRH agonist long and antagonist
    protocols with the predictor list.

    CONCLUSIONS

    The transcriptomic pattern of endometrial cells in N and S


    cycles in the same patients reveals either moderate or strong
    alterations of endometrial receptivity under COS protocols.
    This information open new perspectives, particularly in patients
    with multiple implantation failures.
    In this case, analysis of the endometrial profile could reveal a
    strongly altered profile during COS protocols, prompting the
    clinician to either adapt the IVF stimulation protocol or to
    perform embryo transfer later during a N cycle.

    CONCLUSIONS

    Both protocols affect endometrial receptivity in comparison


    with their N cycle.
    Major differences in endometrial chemokines and growth
    factors in S cycles in comparison with N cycles were observed,
    associated with gene expression alterations of endometrial
    receptivity genes.
    The endometrial receptivity under GnRH antagonist was closer
    to the N cycle receptivity than under GnRH agonist protocols.

    CONCLUSIONS

    GnRH antagonist mimics more closely the natural


    endometrial receptivity than GnRH agonist long
    protocols.
    The use as a first choice of GnRH agonist long
    protocol for normal responder patients should be
    reconsidered.

    Aknowledgements
    ART/PGD Department

    INSERM U 847

    Prof. Samir Hamamah


    Pr. Herv Dechaud
    Pr. Bernard Hedon
    Dr. Lionel Reyftman
    Dr. Tal Anahory
    Dr. Alice Ferriere
    Dr. Vanessa Loup

    Dr. Meryline Dijon


    Dr. John De Vos
    Dr. Franck Pellestor
    Dr. Dephine Haouzi
    Dr. Said Assou
    Mis. Cecile Donzo

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