Successful embryo implantation is a complex process that involves multiple biological mechanisms and reciprocal interactions between the embryo and the proliferated endometrium. In this review, we provide an informative contribution on the pathways underlying the beneficial nature of endometrial injury toward improving implantation rates of embryos conceived and through in vitro fertilization. The evidence published to date are in favor of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained and recurrent implantation failure. Endometrial injury triggers a series of biological responses but the findings suggest that no particular pathway is solely adequate to explain the association between trauma and improved pregnancy rates rather than a cluster of events in response to trauma which benefits embryo implantation in ways both known and unknown to the scientific community.
National Collaborating Centre for Women's and Children's Health/National Institute for Clinical Excellence (NICE). Fertility: Assessment and Treatment for People With Fertility Problems. London: RCOG Press; 2004.
2.
DunnCLKellyRWCritchleyHO. Decidualization of the human endometrial stromal cell: an enigmatic transformation. Reprod Biomed Online. 2003;7(2):151–161.
3.
PariaBCDasSKDeySK. Deciphering the cross-talk of implantation: advances and challenges. Science. 2002;296(5576):2185–2188.
4.
DekelNGnainskyYGranotIMorG. Inflammation and Implantation. Am J Reprod Immunol. 2010;63(1):17–21.
5.
KalmaYGranotIGnainskyY. Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium. Fertil Steril. 2009;91(4):1042–1049.
6.
DettiLSaedGMFletcherNMKrugerMLBrossoitMDiamondMP. Endometrial morphology and modulation of hormone receptors during ovarian stimulation for assisted reproductive technology cycles. Fertil Steril. 2011;95(3):1037–1041.
7.
BourgainC.Apport de la biopsie d’endomètre dans l’évaluation de la réceptivité uterine. Endometrial biopsy: relevance for endometrial receptivity. J Gynecol Obstet Biol Reprod (Paris). 2004;33(1 pt 2):S13–S17.
8.
ChenQJSunXXLiLGaoXHGemzell-DanielssonKChengLN. Effects of ovarian stimulation on endometrial integrin beta3 and leukemia inhibitory factor expression in the peri-implantation phase. Fertil Steril. 2008;89(5 suppl):1357–1363.
9.
AbateVDe CoratoRCaliAStinchiA. Endometrial biopsy at the time of embryo transfer: correlation of histological diagnosis with therapy and pregnancy rate. J In Vitro Fert Embryo Transf. 1987;4(3):173–176.
10.
KarimzadeMAOskouianHAhmadiSOskouianL. Local injury to the endometrium on the day of oocyte retrieval has a negative impact on implantation in assisted reproductive cycles: a randomized controlled trial. Arch Gynecol Obstet. 2010;281(3):499–503.
11.
BarashADekelNFieldustSSegalISchechtmanEGranotI. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003;79(6):1317–1322.
12.
RazielASchachterMStrassburgerDBernORon-ElRFriedlerS. Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure. Fertil Steril. 2007;87:198–201.
13.
ZhouLLiRWangRHuangHXZhongK. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril. 2008;89(5):1166–1176.
14.
LiRHaoG. Local injury to the endometrium: its effect on implantation. Curr Opin Obstet Gynecol. 2009;21(3):236–239.
15.
SegevYCarpHAuslenderRDirnfeldM. Is there a place for adjuvant therapy in IVF?Obstet Gynecol Surv. 2010;65(4):260–272.
16.
CiapponiAGlujovskyDBardachAGarcía MartíSComandeD. EROS: a new software for early stage of systematic reviews. Paper presented at: HTAi 2011 Conference in 2011; Rio de Janeiro, Brazil. Insituto de Efectivdad Clinica y Sanitaria (IECS). EROS (Early Review Organizing Software); 2011. http://www.eros-systematic-review.org. Accessed July 29, 2013.
17.
AlmogBShalom-PazEDufortDTulandiT. Promoting implantation by local injury to the endometrium. Fertil Steril. 2010;94(6):2026–2029.
18.
LoebL. Uber die experimentelle Erzeugung von Knoten von Deciduagewebe in dem Uterus des Meerschweinchens nach stattgefundener Copulation [The experimental proof changes in the uterine deciduas of guinea pig after mating]. Zentralbl Allg Pathol. 1907;18(14):563–565.
19.
FinnCMartinL. Endocrine control of the timing of endometrial sensitivity to a decidual stimulus. Biol Reprod. 1972;7(1):82–86.
20.
HumphreyKW. Interaction between estrogen-17 and progesterone on the induction of deciduomata in ovariectomized mice. Aust J Biol Sci. 1969;22(3):689–699.
21.
BasakSDubanchetSZourbasSChaouatGDasC. Expression of pro-inflammatory cytokines in mouse blastocysts during implantation: modulation by steroid hormones. Am J Reprod Immunol. 2002;47(1):2–11.
22.
HyodoSMatsubaraKKamedaKMatsubaraY. Endometrial injury increases side population cells in the uterine endometrium: a decisive role of estrogen. Tohoku J Exp Med. 2011;224(1):47–55.
23.
NastriCOGibreelARaine-FenningN. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2012;7:CD009517.
24.
PotdarNGelbayaTNardoLG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25(6):561–571.
25.
El-ToukhyTSunkaraSKhalafY. Local endometrial injury and IVF outcome: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25(4):345–354.
26.
DominguezFYanez-MoMSanchez-MadridFSimonC. Embryonic implantation and leukocyte transendothelial migration: different processes with similar players?FASEB J. 2005;19(9):1056–1060.
27.
LassAPeatDAverySBrinsdenP. Histological evaluation of endometrium on the day of oocyte retrieval after gonadotrophin-releasing hormone agonist-follicle stimulating hormone ovulation induction for in-vitro fertilization. Hum Reprod. 1998;13(11):3203–3205.
28.
UbaldiFBourgainCTournayeHSmitzJVan SteirteghemADevroeyP. Endometrial evaluation by aspiration biopsy on the day of oocyte retrieval in the embryo transfer cycles in patients with serum progesterone rise during the follicular phase. Fertil Steril. 1997;67(3):521–526.
29.
MirkinSNikasGHsiuJGDiazJOehningerS. Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. J Clin Endocrinol Metab. 2004;89(11):5742–5752.
30.
El-ToukhyTSunkaraSKCoomarasamyAGraceJKhalafY. Outpatient hysteroscopy and subsequent IVF outcome: a systematic review and meta-analysis. Reprod Biomed Online. 2008;16(5):712–719.
31.
BosteelsJWeyersSPuttemansP. The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review. Hum Reprod Update. 2010;16(1):1–11.
32.
HuangSWangCSoongY. Site-specific endometrial injury improves implantation and pregnancy in patients with repeated implantation failures. Reprod Biol Endocrinol. 2011;9:140.
33.
ChallisJRLockwoodCJMyattLNormanJEStraussJFIIIPetragliaF. Inflammation and pregnancy. Reprod Sci. 2009;16(2):206–215.
34.
MorGCardenasIAbrahamsVGullerS. Inflammation an pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221:80–87.
35.
KellyRWKingAECritchleyHO. Cytokine control in human endometrium. Reproduction. 2001;121(1):3–19.
36.
David DongZMAplinACNicosiaRF. Regulation of angiogenesis by macrophages, dendritic cells, and circulating myelomonocytic cells. Curr Pharm Des. 2009;15(4):365–379.
37.
GnainskyYGranotIAldoPB. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril. 2010;94(6):2030–2036.
38.
HannanNJJonesRLWhiteCASalamonsenLA. The chemokines, CX3CL1, CCL14, and CCL4, promote human trophoblast migration at the feto-maternal interface. Biol Reprod. 2006;74(5):896–904.
GranotIGnainskyYDekelN. Endometrial inflammation and effect on implantation improvement and pregnancy outcome. Reproduction. 2012;144(6):661–668.
41.
LusterADAlonRvon AndrianUH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol. 2005;6(12):1182–1190.
42.
McIntireRHGanaciasKGHuntJS. Programming of human monocytes by the uteroplacental environment. Reprod Sci. 2008;15(5):437–447.
43.
ZhengWLiRPanH. Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1beta through the NF-kappaB and MAPK pathways in rheumatoid arthritis. Arthritis Rheum. 2009;60(7):1957–1965.
44.
QuenbySBatesMDoigT. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod. 1999;14(9):2386–2391.
45.
BoomsmaCMKavelaarsAEijkemansMJ. Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF. Hum Reprod. 2009;24(6):1427–1435.
46.
SalamonsenLA. Tissue injury and repair in the female human reproductive tract. Reproduction. 2003;125(3 suppl):301–311.
47.
GargettCE. Uterine stem cells: what is the evidence?Hum Reprod Update2007;13(1 suppl):87–101.
48.
HartmanCG. Regeneration of the monkey uterus after surgical removal of the endometrium and accidental endometriosis. W J Surg Obstet Gynecol. 1944;52:87–102.
49.
ContiCJGimenez-ContiIBConnerEALehmanJMGerschensonLE. Estrogen and progesterone regulation of proliferation, migration, and loss in different target cells of rabbit uterine epithelium. Endocrinology. 1984;114(2 suppl):345–351.
50.
WyssPSteinerRLiawLH. Regeneration processes in rabbit endometrium: a photodynamic therapy model. Hum Reprod. 1996;11(9 suppl):1992–1997.
51.
DuHTaylorHS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8 suppl):2082–2086.
52.
ShererDMAbulafiaO. Angiogenesis during implantation, and placental and early embryonic development. Placenta. 2001;22(1):1–13.
53.
AkitaSIshiharaHMohammad AbdurRFujiiT. Leukemia inhibitory factor gene improves skin allograft survival in the mouse model. Transplantation. 2000;70(7):1026–1031.
54.
RuszczakZSchwartzRA. Modern aspects of wound healing: an update. Dermatol Surg. 2000;26(3):219–229.
55.
EngertSRiegerLKappMBeckerJCDietlJKämmererU. Profiling chemokines, cytokines and growth factors in human early pregnancy decidua by protein array. Am J Reprod Immunol. 2007;58(2):129–137.
56.
van MourikMSHeijnenCJMacklonNS. Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. J Leukoc Biol. 2009;85(1):4–19.
JunovichGMayerYAzpirozA. Ovarian stimulation affects the levels of regulatory endometrial NK cells and angiogenic cytokine VEGF. Am J Reprod Immunol. 2011;65(2):146–153.
59.
ZhangJChenZSmithGNCroyBA. Natural killer cell-triggered vascular transformation: maternal care before birth?Cell Mol Immunol. 2011;8(1):1–11.
60.
SunJCBeilkeJNLanierLL. Adaptive immune features of natural killer cells. Nature. 2009;457(7729):557–561.
61.
BloisSMKlappBFBarrientosG. Decidualization and angiogenesis in early pregnancy: unravelling the functions of DC and NK cells. J Reprod Immunol. 2011;88(2):86–92.
62.
LédéeNMunautCAubertJ. Specific and extensive endometrial deregulation is present before conception in IVF/ICSI repeated implantation failures (IF) or recurrent miscarriages. J Pathol. 2011;225(4):554–564.
63.
MirkinSNikasGHsiuJGDíazJOehningerS. Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotrophin-stimulated cycles. J Clin Endocrinol Metab. 2004;89(11):5742–5752.
64.
DeyS. Reproductive biology fatty link to fertility. Nature. 2005;435(7038):34–35.
65.
MirkinSArslanMChurikovD. In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum Reprod. 2005;20(8):2104–2217.
66.
SpitzerTLRojasAZelenkoZ. Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype. Biol Reprod. 2012;86(2):58.
67.
KaoLTulacSLoboS. Global gene profiling in human endometrium during the window of implantation. Endocrine Soc. 2002;143(6):2119–2138.
68.
CrisanMYapSCasteillaL. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301–313.
69.
AzpirozAJunovichGFerrerCPasqualiniAPasqualiniSGutierrezG. Is ovarian stimulation affecting endometrial NK cell response during implantation window?J Reprod Immunol. 2011;90(2):165–166.
70.
QuenbySNikHInnesB. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod. 2009;24(1):45–54.
71.
SeppäläMKoistinenHKoistinenRHautalaLChiuPCYeungWS. Glycodelin in reproductive endocrinology and hormone-related cancer. Eur J Endocrinol. 2009;160(2):121–133.
72.
LairdSMTuckermanEMDaltonCFDunphyBCLiTCZhangX. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum Reprod. 1997;12(3):569–574.
73.
Vicetti MiguelRDHarveySALaFramboiseWAReighardSDMatthewsDBCherpesTL. Human female genital tract infection by the obligate intracellular bacterium Chlamydia trachomatis elicits robust type 2 immunity. PLoS One. 2013;8(3):e58565.
74.
SalkerMSChristianMSteelJH. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med. 2011;17(11):1509–1513.
75.
PonsuksiliSMuraniESchwerinMSchellanderKTesfayeDWimmersK. Gene expression and DNA-methylation of bovine pretransfer endometrium depending on its receptivity after in vitro-produced embryo transfer. PLoS One. 2012;7(8):e42402.
