Annexin-2, pentraxin-3, and osteopontin expressions in the endometrium of women with idiopathic recurrent pregnancy loss during the implantation window



Pregnancy loss, Annexin-2, Endometrium, Osteopontin, Pentraxin-3


Aim: Failed expression of endometrial receptivity molecules and genes during the implantation window may lead to idiopathic recurrent pregnancy loss (IRPL). The aim of this study was to investigate annexin-2 (ANXA-2), pentraxin-3 (PTX-3) and osteopontin (OPN) expressions in the endometrium of women with IRPL. Methods: A total of 34 women with IRPL and 34 age-matched healthy women were recruited in this case control study. Serum samples were collected in the mid-luteal phase of the menstrual cycle and endometrial biopsies were harvested in the window of implantation days. The expressions of ANXA-2, PTX-3, and OPN in the endometrial biopsies according to localizations were examined by immunohistochemistry. The H-score method was used to evaluate the intensity of endometrial ANXA-2, PTX-3, and OPN immune-reactivity. Results: The mean PTX-3 score was significantly higher in the epithelial endometrium of women with IRPL compared with control cases (2.47 (0.56) vs 1.44 (0.50), P<0.001). Both luminal and glandular epithelial and stromal components of the endometrium showed increased staining for PTX-3 in women with IRPL. The increase of PTX-3 expression in the epithelial endometrium correlated with the decrease of serum progesterone level (P=0.016). When ANXA-2 and OPN expressions in the epithelial endometrium of IRPL samples were compared with the age-matched control subjects, although there was lower expression, no statistically significant difference was observed (1.97 (0.71) vs 2.21 (0.59), P=0.145 and 1.97 (0.79) vs 2.12 (0.68), P=0.418). Conclusion: PTX-3 expression increases in the epithelial and stromal endometrium of women with IRPL during the implantation window. As the serum progesterone level decreases, endometrial PTX-3 expression increases in glandular and luminal epithelium in women with IRPL. Endometrial PTX-3 may be a potential molecular target for IRPL.


Download data is not yet available.


Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion, Fertil Steril. 2020;113(3):533-5. doi: 10.1016/j.fertnstert.2019.11.025

Hong Li Y, Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust J Gen Pract. 2018;47(7):432-6.

Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion, Fertil Steril, 2012;98(5):1103-11. doi: 10.1016/j.fertnstert.2012.06.048

Dominguez F, Yáñez-Mó M, Sanchez-Madrid F, Simón C. Embryonic implantation and leukocyte transendothelial migration: different processes with similar players? FASEB J. 2005;19(9):1056‐60.

Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril. 2019;111(4):611‐7.

Wu F, Chen X, Liu Y, Liang B, Xu H, Li TC, et al. Decreased MUC1 in endometrium is an independent receptivity marker in recurrent implantation failure during implantation window. Reprod Biol Endocrinol. 2018;16(1):60.

Huang J, Qin H, Yang Y, Chen X, Zhang J, Laird S, et al. A comparison of transcriptomic profiles in endometrium during window of implantation between women with unexplained recurrent implantation failure and recurrent miscarriage. Reproduction. 2017;153:749-58.

Dhaenens L, Lierman S, De Clerck L, Govaert E, Deforce D, Tilleman K, et al. Endometrial stromal cell proteome mapping in repeated implantation failure and recurrent pregnancy loss cases and fertile women. Reprod Biomed Online. 2019;38(3):442-54.

Gerke V, Moss S E. Annexins and membrane dynamics. Biochim Biophys Acta. 1997;1357:129-54.

Filipenko NR, Waisman DM. The C terminus of annexin II mediates binding to F-actin. J Biol Chem. 2001;276:5310-5.

Dominguez F, Garrido-Gomez T, Lopez JA, Camafeita E, Quinonero A, Pellicer A, et al. Proteomic analysis of the human receptive versus non-receptive endometrium using differential in-gel electrophoresis and MALDI-MS unveils stathmin 1 and annexin A2 as differentially regulated. Human Reprod. 2009;24:2607-17.

Garrido-Gómez T, Dominguez F, Quiñonero A, Estella C, Vilella F, Pellicer A, et al. Annexin A2 is critical for embryo adhesiveness to the human endometrium by RhoA activation through F-actin regulation. FASEB J. 2012;26(9):3715-27.

Bottazzi B, Garlanda C, Cotena A, Moalli F, Jaillon S, Deban L, et al. The long pentraxin PTX3 as a prototypic humoral pattern recognition receptor: interplay with cellular innate immunity. Immunological Reviews. 2009;227: 9-18.

Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol. 2005;23:337-66.

Garlanda C, Maina V, Martinez de la Torre Y, Nebuloni M, Locati M. Inflammatory reaction and implantation: the new entries PTX3 and D6. Placenta. 2008;29:129-34.

Freis A, Von Horn K, Göggl T, Hecht S, Roesner S, Strowitzki T, et al. Serum levels of Pentraxin 3 differ significantly at the time of blastocyst transfer depending on implantation success: a pilot study. Arch Gynecol Obstet. 2018;297(6):1565-70.

Larsson A, Palm M, Helmersson J, Axelsson O. Pentraxin 3 values during normal pregnancy. Inflammation. 2011;34:448-51.

Zhou P, Luo X, Qi HB, Zong WJ, Zhang H, Liu DD, et al. The expression of pentraxin 3 and tumor necrosis factor-alpha is increased in preeclamptic placental tissue and maternal serum. Inflamm Res. 2012;61(9):1005-12.

Johnson GA, Burghardt RC, Bazer FW, Spencer TE. Osteopontin: roles in implantation and placentation. Biol Reprod. 2003;69:1458-71.

Casals G, Ordi J, Creus M, Fábregues F, Carmona F, Casamitjana R, et al. Osteopontin and alphavbeta3 integrin as markers of endometrial receptivity: the effect of different hormone therapies. Reprod Biomed Online. 2010;21(3):349-59.

Qu X, Yang M, Zhang W, Liang L, Yang Y, Zhang Y, et al. Osteopontin expression in human decidua is associated with decidual natural killer cells recruitment and regulated by progesterone. In Vivo. 2008;22(1):55-61.

Noyes RW, Hertig AT, Rock J. Reprint of: Dating the Endometrial Biopsy. Fertil Steril. 2019;112:93-115.

Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, et al. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986,46(10):5419-25.

Creus M, Ordi J, Fábregues F, Casamitjana R, Ferrer B, Coll E, et al. alphavbeta3 integrin expression and pinopod formation in normal and out-of-phase endometria of fertile and infertile women. Hum Reprod. 2002;17(9):2279-86.

Hemberger M. Immune balance at the foeto-maternal interface as the fulcrum of reproductive success. J Reprod Immunol. 2012;97:36-42.

Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010;63:425-33.

Apparao KB, Murray MJ, Fritz MA, Meye, WR, Chambers AF, Truong PR, et al. Osteopontin and its receptor alphav beta (3) integrin are coexpressed in the human endometrium during the menstrual cycle but regulated differentially. J Clin Endocrinol Metab. 2001;86:4991-5000.

Aplin JD, Kimber SJ. Trophoblast-uterine interactions at implantation. Reprod Biol Endocrinol. 2004;2: 48.

Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, et al. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod. 2007;76:102-17.

Popovici RM, Betzler NK, Krause MS, Luo M, Jauckus J, Germeyer A, et al. Gene expression profiling of human endometrial–trophoblast interaction in a coculture model. Endocrinology. 2006;147:5662-75.

Doni A, Michela M, Bottazzi B, Peri G, Valentino S, Polentarutti N, et al. Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-gamma. J Leukoc Biol. 2006;79:797-802.

Cetin I, Cozzi V, Pasqualini F, Nebuloni M, Garlanda C, Vago L, et al. Elevated maternal levels of the long pentraxin 3 (PTX3) in preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol. 2006;194:1347-53.

Fowler PA, Tattum J, Bhattacharya S, Klonisch T, Hombach-Klonisch S, Gazvani R, et al. An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: a heterogeneous tissue with a complex disease. Proteomics. 2007;7:130-42.

Brachvogel B, Moch H, Pausch F. Perivascular cells expressing annexin A5 define a novel mesenchymal stem cell-like population with the capacity to differentiate into multiple mesenchymal lineages. Development. 2005;132:2657-68.

Udry S, Aranda F, Latino O. Annexins and recurrent pregnancy loss. Medicina (B Aires). 2013;73(5):495-500.

Gris JC, Perneger TV, Quere I. Antiphospholipid/antiprotein antibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for a first early pregnancy loss: a matched case-control study. Blood. 2003;102:3504-13.

Ueki H, Mizushina T, Laoharatchatathanin T, Terashima R, Nishimura Y, Rieanrakwong D, et al. Loss of maternal annexin A5 increases the likelihood placental thrombosis and foetal loss. Sci Rep. 2012;2:827.

Makker A, Singh MM. Endometrial receptivity: clinical assessment in relation to fertility, infertility, and antifertility. Med Res Rev. 2006;26:699-746.

Peyghambari F, Salehnia M, Forouzandeh Moghadam M, Rezazadeh Valujerdi M, Hajizadeh E. The correlation between the endometrial integrins and osteopontin expression with pinopodes development in ovariectomized mice in response to exogenous steroids hormone. Iran Biomed J. 2010;14(3):109-19.






Research Article

How to Cite

Şahin B, Alataş E, Özkan S. Annexin-2, pentraxin-3, and osteopontin expressions in the endometrium of women with idiopathic recurrent pregnancy loss during the implantation window. J Surg Med [Internet]. 2020 Sep. 1 [cited 2024 Feb. 28];4(9):817-21. Available from: