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Aghajanpour, S., Mehraein, F., Amjadi, F., Zandieh, Z., Ghaffari, F., Aflatoonian, K., Hosseini, E., Bakhtiyari, M., & Aflatoonian, R. (2024). Endometrial scratching in unexplained repeated implantation failure causes two competing forces, angiogenesis and anti-angiogenesis: An RCT study. International Journal of Reproductive BioMedicine (IJRM), 22(4), 253–268. https://doi.org/10.18502/ijrm.v22i4.16387
https://doi.org/10.18502/ijrm.v22i4.16387
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authors
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Samaneh Aghajanpour
Samaneh Aghajanpour
Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
-
Fereshteh Mehraein
Fereshteh Mehraein
Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
-
Fatemehsadat Amjadi
Fatemehsadat Amjadi
Reproductive Sciences and Technology Research Center, Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
-
Zahra Zandieh
Zahra Zandieh
Reproductive Sciences and Technology Research Center, Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
-
Firouzeh Ghaffari
Firouzeh Ghaffari
Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
-
Khashayar Aflatoonian
Khashayar Aflatoonian
School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
-
Elham Hosseini
Elham Hosseini
Department of Obstetrics and Gynecology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
-
Mehrdad Bakhtiyari
Mehrdad Bakhtiyari
Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
-
Reza Aflatoonian
Reza Aflatoonian
Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
Published Date
- Jun 8, 2024
Endometrial scratching in unexplained repeated implantation failure causes two competing forces, angiogenesis and anti-angiogenesis: An RCT study
Abstract
Background: A significant association between endometrial vascularity and pregnancy has been shown in previous research, while poor vascularization was attributed to repeated implantation failure (RIF). One possible approach to enhance angiogenesis for successful implantation is endometrial scratching (ES).
Objective: The purpose was to investigate endometrial responses to scratching by profiling angiogenesis-related gene expression in unexplained RIF participants.
Materials and Methods: In this randomized controlled trial study, 20 infertile women with unexplained RIF were assigned to 2 groups by the balanced block randomization method (n = 10/each group): the intervention group (group A) (who received ES in the follicular phase) and the control group (group B). Endometrial biopsy was performed in the secretory phase. Gene expression profiling was performed using a polymerase chain reaction-array kit for humanangiogenic growth factors. The implantation and clinical pregnancy rates were also assessed.
Results: Among the angiogenesis-promoting genes, FGF1, FGF13, FGF2, TGFA, ANG, ANGPT1, and VEGFA were significantly upregulated (p < 0.05). IL12A (an angiogenesis-inhibiting cytokine) was significantly upregulated (p < 0.01). In contrast, 15 genes with angiogenesisrelated functions, including CXCL11, CXCL13, CXCL3, CXCL5, CXCL6, EREG, FIGF, FST, IL10, LEP, PPBP, PROK1, RHOB, TNF, and TYMP, were downregulated after ES. No significant differences were observed between the intervention (group A) and control (group B) groups in terms of implantation (43.75% vs. 28.57%) or clinical pregnancy rates (75% vs. 57.1%).
Conclusion: ES induced significant alterations in the expression of angiogenesis-related genes, with notable up/downregulation of key angiogenic/antiangiogenic factors. These findings enhance our understanding of the molecular responses triggered by ES, underscoring the potential influence of ES on the complex processes of angiogenesis crucial for implantation.
Key words: Endometrium, Angiogenesis, Embryo implantation, Polymerase chain reaction.
References
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[15] Yifu P, Lei Y, Shaoming L, Yujin G, Xingwang Z. Sperm DNA fragmentation index with unexplained recurrent spontaneous abortion: A systematic review and metaanalysis. J Gynecol Obstet Hum Reprod 2020; 49: 101740.
[16] Sellami A, Chakroun N, Ben Zarrouk S, Sellami H, Kebaili S, Rebai T, et al. Assessment of chromatin maturity in human spermatozoa: Useful aniline blue assay for routine diagnosis of male infertility. Adv Urol 2013; 2013: 578631.
[17] Nikmard F, Aflatoonian B, Hosseini E, Aflatoonian A, Bakhtiyari M, Aflatoonian R. A comparative study on the results of agonist and antagonist protocols based on serum AMH levels in patients undergoing intracytoplasmic sperm injection. Int J Reprod BioMed 2016; 14: 769.
[18] Hosseini E, Nikmard F, Aflatoonian B, Vesali S, Alenabi T, Aflatoonian A, et al. Controlled ovarian stimulation in endometriosis patients can be individualized by antimüllerian hormone levels. Acta Endocrinol 2017; 13: 195– 202.
[19] Griesinger G. Beware of the ‘implantation rate’! Why the outcome parameter ‘implantation rate’ should be abandoned from infertility research. Hum Reprod 2016; 31: 249–251.
[20] Tríbulo P, Siqueira L, Oliveira L, Scheffler T, Hansen P. Identification of potential embryokines in the bovine reproductive tract. J Dairy Sci 2018; 101: 690–704.
[21] Sak M, Gul T, Evsen M, Soydinc H, Sak S, Ozler A, et al. Fibroblast growth factor-1 expression in the endometrium of patients with repeated implantation failure after in vitro fertilization. Eur Rev Med Pharmacol Sci 2013; 17: 398– 402.
[22] Yu X, Gao C, Dai C, Yang F, Deng X. Endometrial injury increases expression of hypoxia-inducible factor and angiogenesis in the endometrium of women with recurrent implantation failure. Reprod Biomed Online 2019; 38: 761– 767.
[23] Sebastian-Leon P, Garrido N, Remohí J, Pellicer A, Diaz- Gimeno P. Asynchronous and pathological windows of implantation: Two causes of recurrent implantation failure. Hum Reprod 2018; 33: 626–635.
[24] Tu Y-A, Chou C-H, Yang P-K, Shun C-T, Wen W-F, Tsao P-N, et al. Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-?? and MMP-3 in a mouse model. Mol Hum Reprod 2021; 27: gaab055.
[25] Liang Y, Han J, Jia C, Ma Y, Lan Y, Li Y, et al. Effect of endometrial injury on secretion of endometrial cytokines and IVF outcomes in women with unexplained subfertility. Mediators Inflamm 2015; 2015: 757184.
[26] Das D, Saikia PJ, Gowala U, Sarma HN. Cell specific expression of vascular endothelial growth factor receptor- 2 (Flk-1/KDR) in developing mice embryo and supporting maternal uterine tissue during early gestation (D4-D7). Int J Fertil Steril 2021; 15: 148–157.
[27] Wheeler KC, Jena MK, Pradhan BS, Nayak N, Das S, Hsu CD, et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One 2018; 13: e0191040.
[28] Sun F, Cai H, Tan L, Qin D, Zhang J, Hua J, et al. Placentaspecific miR-125b overexpression leads to increased rates of pregnancy loss in mice. Int J Mol Sci 2022; 23: 943.
[29] Amirchaghmaghi E, Rezaei A, Moini A, Roghaei MA, Hafezi M, Aflatoonian R. Gene expression analysis of VEGF and its receptors and assessment of its serum level in unexplained recurrent spontaneous abortion. Cell J 2015; 16: 538.
[30] Kretschmer M, Rüdiger D, Zahler S. Mechanical aspects of angiogenesis. Cancers 2021; 13: 4987.
[31] Yang Y, Chen X, Saravelos SH, Liu Y, Huang J, Zhang J, et al. HOXA-10 and E-cadherin expression in the endometrium of women with recurrent implantation failure and recurrent miscarriage. Fertil Steril 2017; 107: 136–143.
[32] Nagib RM, Youssef SM, Wageh A. Endometrial biopsy in recurrent implantation failure: A histopathological and immunohistochemical study. Egypt J Pathol 2019; 39: 244–248.
[33] Liu H-Y, Liu Z-K, Chao H, Li Z, Song Z, Yang Y, et al. High-dose interferon-?? promotes abortion in mice by suppressing Treg and Th17 polarization. J Interferon Cytokine Res 2014; 34: 394–403.
[34] Robertson SA, Chin PY, Schjenken JE, Thompson JG. Female tract cytokines and developmental programming in embryos. Adv Exp Med Biol 2015; 843: 173–213.
[35] Sharkey DJ, Glynn DJ, Schjenken JE, Tremellen KP, Robertson SA. Interferon-gamma inhibits seminal plasma induction of colony-stimulating factor 2 in mouse and human reproductive tract epithelial cells. Biol Reprod 2018; 99: 514–526.
[36] Moura GA, Rocha YM, Moura FLD, Freitas JO, Rodrigues JPV, Gonçalves VP, et al. Immune system cells modulation in patients with reproductive issues: A systematic review approach. JBRA Assist Reprod 2023; 28: 78–89.
[37] Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon gamma in successful pregnancies. Biol Reprod 2009; 80: 848–859.
[38] Lee JY, Lee M, Lee SK. Role of endometrial immune cells in implantation. Clin Exp Reprod Med 2011; 38: 119–125.
[39] Critchley HO, Maybin JA, Armstrong GM, Williams AR. Physiology of the endometrium and regulation of menstruation. Physiol Rev 2020; 100: 1149–1179.
[40] Maged AM, Al-Inany H, Salama KM, Souidan II, Abo Ragab HM, Elnassery N. Endometrial scratch injury induces higher pregnancy rate for women with unexplained infertility undergoing IUI with ovarian stimulation: A randomized controlled trial. Reprod Sci 2016; 23: 239– 243.
[2] Muter J, Lynch VJ, McCoy RC, Brosens JJ. Human embryo implantation. Development 2023; 150: dev201507.
[3] Chen X, Man GCW, Liu Y, Wu F, Huang J, Li TC, et al. Physiological and pathological angiogenesis in endometrium at the time of embryo implantation. Am J Reprod Immunol 2017; 78: e12693.
[4] Peyvandi Karizbodagh M, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H. Implantation window and angiogenesis. J Cell Biochem 2017; 118: 4141–4151.
[5] Boldeanu L, Dijmarescu AL, Radu M, Silosi CA, Popescu- Driga MV, Poenariu IS, et al. The role of mediating factors involved in angiogenesis during implantation. Rom J Morphol Embryol 2020; 61: 665.
[6] Guo X, Yi H, Li TC, Wang Y, Wang H, Chen X. Role of vascular endothelial growth factor (VEGF) in human embryo implantation: Clinical implications. Biomolecules 2021; 11: 253.
[7] Ma J, Gao W, Li D. Recurrent implantation failure: A comprehensive summary from etiology to treatment. Front Endocrinol 2023; 13: 1061766.
[8] Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril 2003; 79: 1317– 1322.
[9] Elsawi NM, Abo Kresha SAT, Mohamed MAA, Khorshed A, Aldajani WA, Rajeh NA, et al. Curcumin ameliorates acrylamide induced ovarian toxicity in albino female rats: A biochemical and histological study. Egypt J Chem 2023; 66: 157–168.
[10] Aghajanpour S, Hosseini E, Amirchaghmaghi E, Zandieh Z, Amjadi F, Yahyaei A, et al. Differential expression of innate/adaptive immunity genes induced by endometrial scratching as a hopeful approach for implantation boosting in unexplained, repeated implantation failure: An RCT. J Reprod Immunol 2021; 148: 103426.
[11] Scheliga I, Baston-Buest DM, Poschmann G, Stuehler K, Kruessel J-S, Bielfeld AP. Closer to the reality- proteome changes evoked by endometrial scratching in fertile females. Int J Mol Sci 2023; 24: 13577.
[12] Rahmati M, Lédée N. Targeted endometrial scratching: An example of endometrial diagnosis usage in reproductive medicine. Front Immunol 2020; 11: 589677.
[13] Günther V, von Otte S, Maass N, Alkatout I. Endometrial “scratching” an update and overview of current research. J Turk German Gynecol Assoc 2020; 21: 124–129.
[14] Bar G, Harlev A, Alfayumi-Zeadna S, Zeadna A, Bord I, Har- Vardi I, et al. Recurrent implantation failure: Which patients benefit from endometrial scratching prior to IVF? Arch Gynecol Obstet 2020; 301: 817–822.
[15] Yifu P, Lei Y, Shaoming L, Yujin G, Xingwang Z. Sperm DNA fragmentation index with unexplained recurrent spontaneous abortion: A systematic review and metaanalysis. J Gynecol Obstet Hum Reprod 2020; 49: 101740.
[16] Sellami A, Chakroun N, Ben Zarrouk S, Sellami H, Kebaili S, Rebai T, et al. Assessment of chromatin maturity in human spermatozoa: Useful aniline blue assay for routine diagnosis of male infertility. Adv Urol 2013; 2013: 578631.
[17] Nikmard F, Aflatoonian B, Hosseini E, Aflatoonian A, Bakhtiyari M, Aflatoonian R. A comparative study on the results of agonist and antagonist protocols based on serum AMH levels in patients undergoing intracytoplasmic sperm injection. Int J Reprod BioMed 2016; 14: 769.
[18] Hosseini E, Nikmard F, Aflatoonian B, Vesali S, Alenabi T, Aflatoonian A, et al. Controlled ovarian stimulation in endometriosis patients can be individualized by antimüllerian hormone levels. Acta Endocrinol 2017; 13: 195– 202.
[19] Griesinger G. Beware of the ‘implantation rate’! Why the outcome parameter ‘implantation rate’ should be abandoned from infertility research. Hum Reprod 2016; 31: 249–251.
[20] Tríbulo P, Siqueira L, Oliveira L, Scheffler T, Hansen P. Identification of potential embryokines in the bovine reproductive tract. J Dairy Sci 2018; 101: 690–704.
[21] Sak M, Gul T, Evsen M, Soydinc H, Sak S, Ozler A, et al. Fibroblast growth factor-1 expression in the endometrium of patients with repeated implantation failure after in vitro fertilization. Eur Rev Med Pharmacol Sci 2013; 17: 398– 402.
[22] Yu X, Gao C, Dai C, Yang F, Deng X. Endometrial injury increases expression of hypoxia-inducible factor and angiogenesis in the endometrium of women with recurrent implantation failure. Reprod Biomed Online 2019; 38: 761– 767.
[23] Sebastian-Leon P, Garrido N, Remohí J, Pellicer A, Diaz- Gimeno P. Asynchronous and pathological windows of implantation: Two causes of recurrent implantation failure. Hum Reprod 2018; 33: 626–635.
[24] Tu Y-A, Chou C-H, Yang P-K, Shun C-T, Wen W-F, Tsao P-N, et al. Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-?? and MMP-3 in a mouse model. Mol Hum Reprod 2021; 27: gaab055.
[25] Liang Y, Han J, Jia C, Ma Y, Lan Y, Li Y, et al. Effect of endometrial injury on secretion of endometrial cytokines and IVF outcomes in women with unexplained subfertility. Mediators Inflamm 2015; 2015: 757184.
[26] Das D, Saikia PJ, Gowala U, Sarma HN. Cell specific expression of vascular endothelial growth factor receptor- 2 (Flk-1/KDR) in developing mice embryo and supporting maternal uterine tissue during early gestation (D4-D7). Int J Fertil Steril 2021; 15: 148–157.
[27] Wheeler KC, Jena MK, Pradhan BS, Nayak N, Das S, Hsu CD, et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One 2018; 13: e0191040.
[28] Sun F, Cai H, Tan L, Qin D, Zhang J, Hua J, et al. Placentaspecific miR-125b overexpression leads to increased rates of pregnancy loss in mice. Int J Mol Sci 2022; 23: 943.
[29] Amirchaghmaghi E, Rezaei A, Moini A, Roghaei MA, Hafezi M, Aflatoonian R. Gene expression analysis of VEGF and its receptors and assessment of its serum level in unexplained recurrent spontaneous abortion. Cell J 2015; 16: 538.
[30] Kretschmer M, Rüdiger D, Zahler S. Mechanical aspects of angiogenesis. Cancers 2021; 13: 4987.
[31] Yang Y, Chen X, Saravelos SH, Liu Y, Huang J, Zhang J, et al. HOXA-10 and E-cadherin expression in the endometrium of women with recurrent implantation failure and recurrent miscarriage. Fertil Steril 2017; 107: 136–143.
[32] Nagib RM, Youssef SM, Wageh A. Endometrial biopsy in recurrent implantation failure: A histopathological and immunohistochemical study. Egypt J Pathol 2019; 39: 244–248.
[33] Liu H-Y, Liu Z-K, Chao H, Li Z, Song Z, Yang Y, et al. High-dose interferon-?? promotes abortion in mice by suppressing Treg and Th17 polarization. J Interferon Cytokine Res 2014; 34: 394–403.
[34] Robertson SA, Chin PY, Schjenken JE, Thompson JG. Female tract cytokines and developmental programming in embryos. Adv Exp Med Biol 2015; 843: 173–213.
[35] Sharkey DJ, Glynn DJ, Schjenken JE, Tremellen KP, Robertson SA. Interferon-gamma inhibits seminal plasma induction of colony-stimulating factor 2 in mouse and human reproductive tract epithelial cells. Biol Reprod 2018; 99: 514–526.
[36] Moura GA, Rocha YM, Moura FLD, Freitas JO, Rodrigues JPV, Gonçalves VP, et al. Immune system cells modulation in patients with reproductive issues: A systematic review approach. JBRA Assist Reprod 2023; 28: 78–89.
[37] Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon gamma in successful pregnancies. Biol Reprod 2009; 80: 848–859.
[38] Lee JY, Lee M, Lee SK. Role of endometrial immune cells in implantation. Clin Exp Reprod Med 2011; 38: 119–125.
[39] Critchley HO, Maybin JA, Armstrong GM, Williams AR. Physiology of the endometrium and regulation of menstruation. Physiol Rev 2020; 100: 1149–1179.
[40] Maged AM, Al-Inany H, Salama KM, Souidan II, Abo Ragab HM, Elnassery N. Endometrial scratch injury induces higher pregnancy rate for women with unexplained infertility undergoing IUI with ovarian stimulation: A randomized controlled trial. Reprod Sci 2016; 23: 239– 243.