Can Endometrial Sractch/Injury Improve Implant

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Can

Endometrial Sractch/Injury

Improve Implant ation ?

Prof.Timur Gürgan MD

Gürgan Women’s Health,Infertility anf IVF Center Ankara,Turkey

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§  a recep've endometrium

§  a normal and func'onal embryo at the blastocyst developmental stage

§  a synchronized dialogue between maternal and embryonic 'ssues

Simon et al 2000

Successful implanta8on requires:

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E8ology of Implanta8on Failure

§  Embryo

Chromosomal abnormality

Low quality

§  Endometrial recep'vity Immune Factors

Endometriosis Hydrosalpinx Leiomyomas, Adenomyosis, PCOS,

Polyps, endometri's ..

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Immune system

&

Implanta8on

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Inflamation and Pregnancy

•  During normal pregnancy ,the human decidua contains high number of immune cels such as macrophages,natural killer (NK)

cells,regulatory T cells. And dentritic cells which infiltrate the decidua and accumulated around the inviding trophoblasts cells

•  The presence of immune cells at the implantation site is not associated with response to the foreign fetus but is attracted to faciliated and protect the pregnancy

•  Implantation,placentation and first and early trimester of pregnancy resemble ’an open wound ‘ that requires a strong inflamatory

response (apposition,attachement and invasion)

•  Epithelial and stromal changes (decidualisation and pinopode formation /window of implantation )

•  Modulation of different gene expressions of different

cytokines,chemokines,growth factors and adhesion molecules

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The role of immune system at the impaltation site

•  High level of the proinflamatory T helper cells (Th-1) and cytokines (IL-6,Il-8,TNF alpha charecterize) early implantation

•  Cytokines secreted by the endometrial cells and by the cells of immune system that are recuited to the site of implantation

•  NK cells : regulates trophoblast invasion, sectretes angiogenic factors to induce vascular growth and decidualisation,

•  Macrophages:

*Pivotal role on cytokine balancing at the maternal-fetal interface.

*Essential for successful decidualisation

*Plays central role in the process of tissue renewal and differentiation

•  Dentritic cells : Initiate and coordinate the innate immune adaptive immune response and also support the effect of macrophages

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Possible regulatory mechanisms for embryo-maternal cross- talk by immune system and endocrine systems

•  Periferally circulating immune cells act on the reproductive organs to facilatate embryo implantation Fujiwara,2006

•  Peripheral immune /peripheral blood mononuclear cells(PBMC) cells in early pregnancy situmulate the corpus luteum function

•  PBMC transmit the information presence of an embryo to various organs throughout the body including the uterus and maternal vessels in order to prepare and maintain the implantation Hashi ,1998

•  PBMC promote endometrial cell receptivity Hosaka 2003

•  hCG alters PBMC function to facilitate embryo invasion Kosaka,2002

•  İmmune cells can induce early endometrial differentiation required for subsequent implantation

•  Succesful allopregnancy is a Th2 phenomenon in local balance in between Th1 and Th2 environment Chaoulat,2002

•  Regulatory T cells and NK cells play impotatnt role in immune tolarence and placentation and angiogenesis Hanna,2006;Saito,2008

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Immune and endocrine system

&

Implanta8on

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Successful Implanta8on & RIF

Embryological and Endometrial Factors for RIF

Cytokines Associated with Reproduc8on

Koot et. al., 2012. Biochem. Biophys. A.

Makrigiannakis et. al., 2011. J. Reprod. Immun.

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Impaired recep8vity and Implanta8onin women with endometriosis,adeneomyosis and PCOS

•  Abnormally expression of endometrial receptivity biomarkers

PCOS Endometriosis ,Adenomyosis

•  Integrins (αVβ3 integrin)

•  Selectin

•  Cadherin

•  Glycodelin

•  Osteopontin

•  MUC1

•  HOXA-10

•  IGFBP-1

•  NK cell activity

•  Appoptosis

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Endometrial Stimuli & Implantation

•  Endometrial receptivity or the ‘window of

implantation’ is dependent on certain stimuli

Mechanical stimuli may activate the implantation :

•  Endometrial biopsy

•  Endometrial sctrach

•  Endometrial injury

•  Hysteroscopic approach

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CONFUSIONS

§  Type of injury (biopsi/injury)

§  Instrumenta8on( cureUe/ pipelle/hysteroscopy)

§  Degree of injury (endometrium/myometrium)

§  Number of injury

§  Localiza8on of injury

§  Day /phase of menstruel cycle

§  Time between endometrial injury and embryo transfer cycle

§  Unselected popula8on or previous failures

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Early prolifera8ve phase Demirol and Gurgan 2004 Magrakis et al 2009

Rama Raju et al 2006

Early prolifera8ve and luteal phases Barash et al 2003

Narvekar et al 2010

Luteal phase

Karimzadeh et al 2009 Raziel et al 2007

Once

Zhou et al, 2008

Shohayep & El-‐Khayat 2012 Coughlan et al, 2013

Twice

Raziel et.al, 2007(days 21,26)

Four 8mes

Barash et al,2003

(days 8,12,21,26)

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Endometrial Injury

• Cycle preceeding IVF treatment

• During the treatment cycle

• Follicular phase or luteal phase

• Women with RIF and/or RPL

• Women undergoing IVF treatment

• More indica'on(s)……?

Barash et al., 2003; Raziel et al.,2007; Zhou et al.,2006 Coughlan et al.,2013

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Endometrial Injury

•  Endometrial injury on OPU day is

detrimental to IVF success rate

Karimzade et al., 2010

•  Endometrium requires at least 2 weeks to achieve complete repair after mechanical injury

Li et al.,2011

•  Endometrial changes following injury are sustained,and even increased in the

following cycle

Kalma et al.,2009;Gnainsky et al.,2010

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Endometrial Injury associated with :

•  Local inﬂammatory response,cascading a release of pro-‐inﬂammatory cytokines ang growth factors like IL-‐ 6,IL-‐15,MIP-‐1B,LIF,osteopon'n and TNF alpha which induce decidualisa'on and development of endometrium favourable to

implanta'on

•  Gene expression in the endometrium,with up regula'on of pro-‐implanta'on

proteins such as mucin 1 transmembrane (MUC1),cristallin alpha B,apolipoprotein D (APPOD),phospholipase A2 (PLA2) and uroplakin Ib (UPIb)

•  Increase macrophages and dentri'c cells which play important role in decidualisa'on and implanta'on Kalma et al.,2009 ; Gnainsky et al.,2010

Overall,with local injury there are changes ini'ated within the endometrium the immune system and gene expression,all leading to improve recep'vity and favourable milieu for implanta'on.

It could be that injury in the preceeding cycle is more eﬀec've as all these events require 'me and are governed by the hormones.Interven'on closely to the embryo transfer can poten'ally disturb the endometrium and may have nega've eﬀect

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Endometrial biopsy Endometrial Injury

macrophages/dendritic cells

•  tumor necrosis factor-a (TNF-a),

•  growth-regulated oncogene-a (GROa),

•  interleukin-15 (IL-15),

•  macrophage inflammatory protein 1B (MIP-1B),

•  Osteopontin

A positive correlation was found between the levels of macrophages/

dendritic cells, MIP-1B expression, and TNF-a expression & the pregnancy outcome.

Gnainsky et al. Fertil & Steril 2010;94:2030

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BACKWARD DEVELOPMENT HYPOTHESIS

Endometrial matura8on is abnormally advanced when controlled ovarian

s8mula8on is performed during ART

Lass et al.,1998; Ubaldi et al.,1997

COH cycles depicted structural and func8onal changes when compared with natural cycles, including histological advancement, pinopodes matura8on advancement and steroid receptor downregula8on

Sebas8an et al., 2004

Endometrial injury performed in the previous cycle might retard endometrial matura8on leading to beUer synchronicity between the endometrium and the transferred embryo

Li et al., 2009

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Results: Endometrial sampling of IVF patients using a biopsy catheter substantially increases their chances to conceive at the following IVF-embryo transfer cycle. By transferring a similar number of embryos in the study and control groups, the authors achieved an implantation rate of 28 versus 14%, a clinical pregnancy rate of 67 versus 30% and a live birth rate per embryo transfer of 49 versus 23%.

Conclusion: These results suggest that IVF treatment that is preceded by endometrial biopsy doubles the chance for a take-home baby.

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Significant increase in clinical pregnancy and live birth rate

Fertil & Steril 2003;79:1317

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2012

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Clinical pregnancy rate in the endometrial injury (hysteroscopy and endometrial biopsy) and control groups.

Potdar,2012

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Live birth rate in the endometrial injury (hysteroscopy and endometrial biopsy) and control groups

Potdar,2012

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Live birth rate in the randomized and non-randomized studies for endometrial injury and control groups.

Potdar,2012

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Peer review is the basis for the crea'on of solid and trustable knowledge that we can

implement in the treatment of our pa'ents. Now, this concept is being tainted and diluted by a vicious circle created by the use of inadequate or insuﬃcient data to compute incorrect or incomplete conclusions that are touted as evidence-‐based medicine, crea'ng confusion instead of clariﬁca'on.

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Endometrial straching prior star8ng ART treatment may improve the chance of implanta8on ?

•  First publica'on made by Barash et al., in 2003 decade later this interven'on being

used widely by some colleaques widely advier'sed on their the web sites and pa'ents are paying to undergo ‘straching cycle ‘ before their ART treatment cycle !

•  Following a ‘trustworthy’ evidence-‐based medical approach,these colleaques believe that there giving the pa'ents the best treatment

possible because new treatment op'on based on more thn 300 referances (case series,case reports,case controlled studies,expert opinions etc. ), 4 randomised RCT and 3 meta –analyses

•  RCT published in journals very low impact factors

•  Meta-‐analyses some very important methodological problems( different pa'ent groups,different defini'on of RIF, some pa'ents have no

implanta'on failure,diﬀerent interven'on procedures and techniques etc. )

•  There is no enough data and it is not suﬃciently conclusive to merrit such conﬁdance in this interven'on !

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Endometrial straching prior starting ART treatment may improve the chance of implantation ?

•  In the second systamatic review Potdar (2012),include the which have been already analysed,and hysteroscopy was included as another way of injuring endometrium. It should be kept in mind that hysteroscopic

intervention may give additional benefit to the effect of the endometrial stracthing alone !

•  Combined effects of various procedures (using OC,GnRHa,GnRHant

•  Incorrect choosing of the studies to be included

•  If you put trush in, you get the trash out ????

Simon C and Bellver J, HR,2014

•  Is there evidence to demonstrate that ‘straching ‘ in the previous cycle modulates molecular/cellular phenotype induced by COS ?

WHAT DO YOU THINK ?

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Conclusion

There is an urgent need for large,mul8centre randomised studies inves8ga8ng local endometrial injury and pregnancy outcomes in the unexplained RIF,in pa8ents unexplained subfer8lity undergoing ﬁrst IVF cycle and some pathologies with dimineshed endometrial recep8vity such as PCOS and endometriosis

The evidence must be strengthened by simultenous molecular and gene expression studies on endometrium

Un8l the results of such studies available,or an expert consor8um

quideline proposed,it should be a blanket policy to induce local

endometrial injury for women undergoing ﬁrst cycle of IVF and

perhaps there is a role for this in women with unexplained RIF

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Systema8c and standardized hysteroscopic endometrial injury for treatment of recurrent implanta8on failure (RIF):

Preliminary results of prospec8ve and randomized trial.

Timur Gürgan¹, Ziya Kalem¹, Işın Kocabaş¹, Müberra Namlı Kalem², Halil Ruso¹, Antonis Makrigiannakis³

1: Gürgan Clinic Women’s Health and IVF Centre, Ankara, Turkey.

2:Turgut Özal University Hospital, Department Obstetrics and Gynecology, Ankara, Turkey.

3: University of Crete, Department of Obstetrics and Gynecology, Crete, Greece

Purpose: To inves'gate the eﬀect of hysteroscopic symmetrical endometrial injury for RIF pa'ents.

Method: This is a prospec've and randomized controlled trial for RIF pa'ents inves'ga'ng the eﬀect of systemic and symmetric endometrial injury using oﬃce hysteroscopy. Endometrial injury was performed on the follicular phase of the

menstrual cycle under general anesthesia. The main variant analyzed was the clinical pregnancy rates. Sta's'cal calcula'ons were performed on GraphPad Prism version 6.0 and p<0.05 were considered sta's'cally signiﬁcant.

Findings: Following randomized controlled trial we propose that the systemic

endometrial injury model can be standardized to increase the odds of implanta'on in RIF pa'ents to achieve clinical pregnancy.

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Our Technique :

§  Symmetric,systema8c Injury on the fundus a. One transverse incision

b. Symmetric ver8cal incisions (6-‐8) around line

§  Hysteroscopy

§  Follicular phase

§  Previous cycle before ET

§  RIF

RIF(Recurrent Implantation Failure):

Failure to achieve a clinical pregnancy aher transfer of at least 4 good-‐quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years.

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VIDEO

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