The Role of Inflammatory Pathways in Implantation Failure: Chronic Endometritis and Hydrosalpinges

Abstract

The process of implantation is highly complex and involves a delicate interplay between the embryo and the appropriate maternal environment. The failure to implant is thought to be due to maternal factors or embryonic factors. Inflammation can be a part of the normal physiologic process during implantation; however, there are also pathologic entities that adversely affect uterine receptivity. This review will focus on chronic endometritis and hydrosalpinges as two specific inflammatory processes that contribute to implantation failure. For both chronic endometritis and hydrosalpinges, we will review the diagnosis, pathophysiology, and effect on implantation following treatment. The existing literature conclusively demonstrates that hydrosalpinges should be addressed by either laparoscopic salpingectomy or proximal tubal occlusion prior to in vitro fertilization. The picture for chronic endometritis is less clear since the diagnosis and treatment of chronic endometritis are not standardized, and there are no available randomized controlled trials on this topic. Future studies may target gene expression arrays as a method for further elucidating the role of inflammatory markers in normal and abnormal implantation processes.

Keywords

chronic endometritis - implantation failure - hydrosalpinx

• References

• 1 Morris H, Edwards J, Tiltman A, Emms M. Endometrial lymphoid tissue: an immunohistological study. J Clin Pathol 1985; 38 (6) 644-652
• 2 Disep B, Innes BA, Cochrane HR, Tijani S, Bulmer JN. Immunohistochemical characterization of endometrial leucocytes in endometritis. Histopathology 2004; 45 (6) 625-632
• 3 Salamonsen LA, Zhang J, Brasted M. Leukocyte networks and human endometrial remodelling. J Reprod Immunol 2002; 57 (1-2) 95-108
• 4 Inoue T, Kanzaki H, Iwai M , et al. Tumour necrosis factor alpha inhibits in-vitro decidualization of human endometrial stromal cells. Hum Reprod 1994; 9 (12) 2411-2417
• 5 Kariya M, Kanzaki H, Takakura K , et al. Interleukin-1 inhibits in vitro decidualization of human endometrial stromal cells. J Clin Endocrinol Metab 1991; 73 (6) 1170-1174
• 6 Kojima K, Kanzaki H, Iwai M , et al. Expression of leukemia inhibitory factor in human endometrium and placenta. Biol Reprod 1994; 50 (4) 882-887
• 7 Kitaya K, Yasuo T. Aberrant expression of selectin E, CXCL1, and CXCL13 in chronic endometritis. Mod Pathol 2010; 23 (8) 1136-1146
• 8 van Mourik MS, Macklon NS, Heijnen CJ. Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. J Leukoc Biol 2009; 85 (1) 4-19
• 9 Kämmerer U. Antigen-presenting cells in the decidua. Chem Immunol Allergy 2005; 89: 96-104
• 10 Hanna J, Goldman-Wohl D, Hamani Y , et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12 (9) 1065-1074
• 11 Li R, Hao G. Local injury to the endometrium: its effect on implantation. Curr Opin Obstet Gynecol 2009; 21 (3) 236-239
• 12 Gnainsky Y, Granot I, Aldo PB , et al. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril 2010; 94 (6) 2030-2036
• 13 Raziel A, Schachter M, Strassburger D, Bern O, Ron-El R, Friedler S. Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure. Fertil Steril 2007; 87 (1) 198-201
• 14 Daware MB, Mujumdar AM, Ghaskadbi S. Reproductive toxicity of piperine in Swiss albino mice. Planta Med 2000; 66 (3) 231-236
• 15 Karimzadeh MA, Ayazi Rozbahani M, Tabibnejad N. Endometrial local injury improves the pregnancy rate among recurrent implantation failure patients undergoing in vitro fertilisation/intra cytoplasmic sperm injection: a randomised clinical trial. Aust N Z J Obstet Gynaecol 2009; 49 (6) 677-680
• 16 Narvekar SA, Gupta N, Shetty N, Kottur A, Srinivas M, Rao KA. Does local endometrial injury in the nontransfer cycle improve the IVF-ET outcome in the subsequent cycle in patients with previous unsuccessful IVF? A randomized controlled pilot study. J Hum Reprod Sci 2010; 3 (1) 15-19
• 17 Guven S, Kart C, Unsal MA, Yildirim O, Odaci E, Yulug E. Endometrial injury may increase the clinical pregnancy rate in normoresponders undergoing long agonist protocol ICSI cycles with single embryo transfer. Eur J Obstet Gynecol Reprod Biol 2014; 173: 58-62
• 18 Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril 2008; 89 (5) 1166-1176
• 19 Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online 2012; 25 (6) 561-571
• 20 Greenwood SM, Moran JJ. Chronic endometritis: morphologic and clinical observations. Obstet Gynecol 1981; 58 (2) 176-184
• 21 Kasius JC, Fatemi HM, Bourgain C , et al. The impact of chronic endometritis on reproductive outcome. Fertil Steril 2011; 96 (6) 1451-1456
• 22 Romero R, Espinoza J, Mazor M. Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization?. Fertil Steril 2004; 82 (4) 799-804
• 23 Rinehart J. Recurrent implantation failure: definition. J Assist Reprod Genet 2007; 24 (7) 284-287
• 24 Thornhill AR, deDie-Smulders CE, Geraedts JP , et al; ESHRE PGD Consortium. ESHRE PGD Consortium ‘Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)’. Hum Reprod 2005; 20 (1) 35-48
• 25 Cicinelli E, Matteo M, Tinelli R , et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 2015; 30 (2) 323-330
• 26 Coughlan C, Ledger W, Wang Q , et al. Recurrent implantation failure: definition and management. Reprod Biomed Online 2014; 28 (1) 14-38
• 27 Yang R, Du X, Wang Y, Song X, Yang Y, Qiao J. The hysteroscopy and histological diagnosis and treatment value of chronic endometritis in recurrent implantation failure patients. Arch Gynecol Obstet 2014; 289 (6) 1363-1369
• 28 Cicinelli E, De Ziegler D, Nicoletti R , et al. Chronic endometritis: correlation among hysteroscopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril 2008; 89 (3) 677-684
• 29 Polisseni F, Bambirra EA, Camargos AF. Detection of chronic endometritis by diagnostic hysteroscopy in asymptomatic infertile patients. Gynecol Obstet Invest 2003; 55 (4) 205-210
• 30 Matteo M, Cicinelli E, Greco P , et al. Abnormal pattern of lymphocyte subpopulations in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol 2009; 61 (5) 322-329
• 31 Xu Z, Zan H, Pone EJ, Mai T, Casali P. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat Rev Immunol 2012; 12 (7) 517-531
• 32 Kitaya K, Tada Y, Hayashi T, Taguchi S, Funabiki M, Nakamura Y. Comprehensive endometrial immunoglobulin subclass analysis in infertile women suffering from repeated implantation failure with or without chronic endometritis. Am J Reprod Immunol 2014; 72 (4) 386-391
• 33 Pitsos M, Kanakas N. The role of matrix metalloproteinases in the pathogenesis of endometriosis. Reprod Sci 2009; 16 (8) 717-726
• 34 Inagaki N, Stern C, McBain J, Lopata A, Kornman L, Wilkinson D. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum Reprod 2003; 18 (3) 608-615
• 35 Liu G, Zhang X, Lin H , et al. Effects of E-cadherin on mouse embryo implantation and expression of matrix metalloproteinase-2 and -9. Biochem Biophys Res Commun 2006; 343 (3) 832-838
• 36 Yoshii N, Hamatani T, Inagaki N , et al. Successful implantation after reducing matrix metalloproteinase activity in the uterine cavity. Reprod Biol Endocrinol 2013; 11: 37
• 37 Di Pietro C, Cicinelli E, Guglielmino MR , et al. Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol 2013; 69 (5) 509-517
• 38 Johnston-MacAnanny EB, Hartnett J, Engmann LL, Nulsen JC, Sanders MM, Benadiva CA. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril 2010; 93 (2) 437-441
• 39 Savaris RF, Giudice LC. The influence of hydrosalpinx on markers of endometrial receptivity. Semin Reprod Med 2007; 25 (6) 476-482
• 40 Bloechle M. What is a hydrosalpinx? A plea for the use of a proper terminology in scientific discussion. Hum Reprod 1999; 14 (3) 578
• 41 de Wit W, Gowrising CJ, Kuik DJ, Lens JW, Schats R. Only hydrosalpinges visible on ultrasound are associated with reduced implantation and pregnancy rates after in-vitro fertilization. Hum Reprod 1998; 13 (6) 1696-1701
• 42 Renbaum L, Ufberg D, Sammel M, Zhou L, Jabara S, Barnhart K. Reliability of clinicians versus radiologists for detecting abnormalities on hysterosalpingogram films. Fertil Steril 2002; 78 (3) 614-618
• 43 Omurtag K, Grindler NM, Roehl KA , et al. How members of the Society for Reproductive Endocrinology and Infertility and Society of Reproductive Surgeons evaluate, define, and manage hydrosalpinges. Fertil Steril 2012; 97 (5) 1095-100.e1 , 2
• 44 Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization-embryo transfer. Fertil Steril 1998; 70 (3) 492-499
• 45 Camus E, Poncelet C, Goffinet F , et al. Pregnancy rates after in-vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies. Hum Reprod 1999; 14 (5) 1243-1249
• 46 Mukherjee T, Copperman AB, McCaffrey C, Cook CA, Bustillo M, Obasaju MF. Hydrosalpinx fluid has embryotoxic effects on murine embryogenesis: a case for prophylactic salpingectomy. Fertil Steril 1996; 66 (5) 851-853
• 47 Ng EH, Chan CC, Tang OS, Ho PC. Comparison of endometrial and subendometrial blood flows among patients with and without hydrosalpinx shown on scanning during in vitro fertilization treatment. Fertil Steril 2006; 85 (2) 333-338
• 48 Meyer WR, Castelbaum AJ, Somkuti S , et al. Hydrosalpinges adversely affect markers of endometrial receptivity. Hum Reprod 1997; 12 (7) 1393-1398
• 49 Lessey BA. Endometrial integrins and the establishment of uterine receptivity. Hum Reprod 1998; 13 (Suppl. 03) 247-258 , discussion 259–261
• 50 Mansour RT, Aboulghar MA, Serour GI, Riad R. Fluid accumulation of the uterine cavity before embryo transfer: a possible hindrance for implantation. J In Vitro Fert Embryo Transf 1991; 8 (3) 157-159
• 51 Bloechle M, Schreiner T, Lisse K. Recurrence of hydrosalpinges after transvaginal aspiration of tubal fluid in an IVF cycle with development of a serometra. Hum Reprod 1997; 12 (4) 703-705
• 52 Copperman AB, Wells V, Luna M, Kalir T, Sandler B, Mukherjee T. Presence of hydrosalpinx correlated to endometrial inflammatory response in vivo. Fertil Steril 2006; 86 (4) 972-976
• 53 Hill JA, Polgar K, Anderson DJ. T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion. JAMA 1995; 273 (24) 1933-1936
• 54 Song Y, Wang Q, Huang W, Xiao L, Shen L, Xu W. NF κB expression increases and CFTR and MUC1 expression decreases in the endometrium of infertile patients with hydrosalpinx: a comparative study. Reprod Biol Endocrinol 2012; 10: 86
• 55 Charnock-Jones DS, Sharkey AM, Fenwick P, Smith SK. Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. J Reprod Fertil 1994; 101 (2) 421-426
• 56 Seli E, Kayisli UA, Cakmak H , et al. Removal of hydrosalpinges increases endometrial leukaemia inhibitory factor (LIF) expression at the time of the implantation window. Hum Reprod 2005; 20 (11) 3012-3017
• 57 Bildirici I, Bukulmez O, Ensari A, Yarali H, Gurgan T. A prospective evaluation of the effect of salpingectomy on endometrial receptivity in cases of women with communicating hydrosalpinges. Hum Reprod 2001; 16 (11) 2422-2426
• 58 Lessey BA, Damjanovich L, Coutifaris C, Castelbaum A, Albelda SM, Buck CA. Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest 1992; 90 (1) 188-195
• 59 Déchaud H, Daurès JP, Arnal F, Humeau C, Hédon B. Does previous salpingectomy improve implantation and pregnancy rates in patients with severe tubal factor infertility who are undergoing in vitro fertilization? A pilot prospective randomized study. Fertil Steril 1998; 69 (6) 1020-1025
• 60 Strandell A, Lindhard A, Waldenström U, Thorburn J, Janson PO, Hamberger L. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999; 14 (11) 2762-2769
• 61 Kontoravdis A, Makrakis E, Pantos K, Botsis D, Deligeoroglou E, Creatsas G. Proximal tubal occlusion and salpingectomy result in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx. Fertil Steril 2006; 86 (6) 1642-1649
• 62 Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Salpingectomy for hydrosalpinx prior to in vitro fertilization. Fertil Steril 2008; 90 (5, Suppl): S66-S68
• 63 Zhang Y, Sun Y, Guo Y, Li TC, Duan H. Salpingectomy and proximal tubal occlusion for hydrosalpinx prior to in vitro fertilization: a meta-analysis of randomized controlled trials. Obstet Gynecol Surv 2015; 70 (1) 33-38
• 64 Rosenfield RB, Stones RE, Coates A, Matteri RK, Hesla JS. Proximal occlusion of hydrosalpinx by hysteroscopic placement of microinsert before in vitro fertilization-embryo transfer. Fertil Steril 2005; 83 (5) 1547-1550
• 65 Matorras R, Rabanal A, Prieto B , et al. Hysteroscopic hydrosalpinx occlusion with Essure device in IVF patients when salpingectomy or laparoscopy is contraindicated. Eur J Obstet Gynecol Reprod Biol 2013; 169 (1) 54-59
• 66 Hitkari JA, Singh SS, Shapiro HM, Leyland N. Essure treatment of hydrosalpinges. Fertil Steril 2007; 88 (6) 1663-1666
• 67 Sowter MC, Akande VA, Williams JA, Hull MG. Is the outcome of in-vitro fertilization and embryo transfer treatment improved by spontaneous or surgical drainage of a hydrosalpinx?. Hum Reprod 1997; 12 (10) 2147-2150
• 68 Hammadieh N, Coomarasamy A, Ola B, Papaioannou S, Afnan M, Sharif K. Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum Reprod 2008; 23 (5) 1113-1117
• 69 Fatemi HM, Popovic-Todorovic B, Ameryckx L, Bourgain C, Fauser B, Devroey P. In vitro fertilization pregnancy in a patient with proven chronic endometritis. Fertil Steril 2009; 91 (4) 1293.e9-1293.e11