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Farifteh, F., Fazeli, E., Hosseini, S. Z., Aref, S. S., Moini, A., Taheripanah, R., Rouhollah, F., Salehi, M., Hosseini, A., & Benkhalifa, M. (2023). Intrauterine administration of autologous peripheral blood mononuclear cells regulates the endometrium estrogen and progesterone receptor expression: An RCT. International Journal of Reproductive BioMedicine (IJRM), 21(4), 343–354. https://doi.org/10.18502/ijrm.v21i4.13273
https://doi.org/10.18502/ijrm.v21i4.13273
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authors
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Fattaneh Farifteh
Fattaneh Farifteh
Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
-
Elham Fazeli
Elham Fazeli
Mehr Fertility Research Center, Guilan University of Medical Sciences, Rasht, Iran.
-
Seyedeh Zeinab Hosseini
Seyedeh Zeinab Hosseini
Department of Cellular and Molecular Sciences, Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Seyedeh Soheila Aref
Seyedeh Soheila Aref
Genetics and In Vitro Assisted Reproductive (GIVAR) Center, Erfan Hospital, Tehran, Iran.
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Ashraf Moini
Ashraf Moini
Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Robabeh Taheripanah
Robabeh Taheripanah
Infertility and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
-
Fatemeh Rouhollah
Fatemeh Rouhollah
Department of Cellular and Molecular Sciences, Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
-
Mohammad Salehi
Mohammad Salehi
Genetics and In Vitro Assisted Reproductive (GIVAR) Center, Erfan Hospital, Tehran, Iran.
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Ahmad Hosseini
Ahmad Hosseini
Genetics and In Vitro Assisted Reproductive (GIVAR) Center, Erfan Hospital, Tehran, Iran.
-
Moncef Benkhalifa
Moncef Benkhalifa
ART and Reproductive Genetics Department and PERITOX Laboratory, CURS, University Hospital and School of Medicine, Picardie University Jules Verne, Amiens Sud, France
Published Date
- May 6, 2023
Intrauterine administration of autologous peripheral blood mononuclear cells regulates the endometrium estrogen and progesterone receptor expression: An RCT
Abstract
Background: Repeated implantation failure (RIF) affects 15% of women of reproductive age. There is a high endometrial expression of both estrogen receptors and progesterone receptors (PRs) during the window of implantation in women with RIF.
Objective: To evaluate the effects of intrauterine administration of human peripheral blood mononuclear cells (PBMC) on estrogen receptor α (ERα) and PRs expression in the endometrium of women with RIF during the implantation window.
Materials and Methods: This randomized clinical trial study was conducted on 22 women with RIF history from January 2018 to August 2019 in Erfan hospital, Tehran, Iran. Participants were divided into 2 groups (PBMC-treated group [n = 11] and control group [n = 11]). Endometrial tissue samples were collected at the implantation window time, during the mid-secretory phase (luteinizing hormone surge +7 days) of each menstrual cycle. The quantitative real-time polymerase chain reaction technique was used to measure the mRNA levels of ERα and PRs isoforms (PR-A and PR-B) in endometrial tissues. Furthermore, the protein expression of ERα and PRs was investigated using immunohistochemical staining.
Results: PBMC treatment significantly decreased the mRNA expression of endometrial ERα and PRs isoforms at the time of the implantation window (p < 0.001). Moreover, the endometrial ERα and PRs protein localization were significantly lower in PBMC-treated women compared with controls (p = 0.01, and p < 0.001 respectively).
Conclusion: The intrauterine administration of PBMC decreased the endometrial ERα and PRs expression during the window of implantation in women with RIF. This local response to PBMC therapy could promote endometrial receptivity and embryo implantation.
Key words: Peripheral blood mononuclear cell, Estrogen receptors, Progesterone receptors.
References
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[4] Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril 2019; 111: 611–617.
[5] Azeez JM, Susmi TR, Remadevi V, Ravindran V, Sujatha AS, Ayswarya RNS, et al. New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling. Am J Cancer Res 2021; 11: 5214–5232.
[6] Hamilton KJ, Hewitt SC, Arao Y, Korach KS. Estrogen hormone biology. Curr Top Dev Biol 2017; 125: 109–146.
[7] Polikarpova AV, Levina IS, Sigai NV, Zavarzin IV, Morozov IA, Rubtsov PM, et al. Immunomodulatory effects of progesterone and selective ligands of membrane progesterone receptors. Steroids 2019; 145: 5–18.
[8] Piccinni M-P, Raghupathy R, Saito S, Szekeres-Bartho J. Cytokines, hormones and cellular regulatory mechanisms favoring successful reproduction. Front Immunol 2021; 12: 717808.
[9] Zhao Y, Zhu Y, Chen X, Lin H, Qin N, Zhou Z, et al. Circulating innate lymphoid cells exhibit distinctive distribution during normal pregnancy. Reprod Sci 2022; 29: 1124–1135.
[10] Wang L, Lv Q, Wu P, Luo S, Liu S, Chen X, et al. RNA-seq and ATAC-seq analysis of CD163+ macrophage-induced progestin-insensitive endometrial cancer cells. Cancer Med 2023; 12: 5964–5978.
[11] Verma P, Verma R, Nair RR, Budhwar S, Khanna A, Agrawal NR, et al. Altered crosstalk of estradiol and progesterone with Myeloid-derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal-fetal tolerance. Am J Reprod Immunol 2019; 81: e13081.
[12] Yang L, Yao X, Li S, Chen K, Wang Y, Chen L, et al. Expression of genes associated with luteolysis in peripheral blood mononuclear cells during early pregnancy in cattle. Mol Reprod Dev 2016; 83: 509–515.
[13] Brundin PM, Landgren B-M, Fjällström P, Shamekh MM, Gustafsson J-Å, Johansson AF, et al. Expression of sex hormone receptor and immune response genes in peripheral blood mononuclear cells during the menstrual cycle. Front Endocrinol 2021; 12: 721813.
[14] Li S, Wang J, Cheng Y, Zhou D, Yin T, Xu W, et al. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol 2017; 119: 15–22.
[15] Fan L, Sha M, Li W, Kang Q, Wu J, Chen S, et al. Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance. J Reprod Dev 2021; 67: 359–368.
[16] Madkour A, Bouamoud N, Louanjli N, Kaarouch I, Copin H, Benkhalifa M, et al. Intrauterine insemination of cultured peripheral blood mononuclear cells prior to embryo transfer improves clinical outcome for patients with repeated implantation failures. Zygote 2016; 24: 58– 69.
[17] Farifteh Nobijari F, Arefi SS, Moini A, Taheripanah R, Fazeli E, Kharazi H, et al. Endometrium immunomodulation by intrauterine insemination administration of treated peripheral blood mononuclear cell prior frozen/thawed embryos in patients with repeated implantation failure. Zygote 2019; 27: 214–218.
[18] Yakin K, Oktem O, Urman B. Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: A systematic review and meta-analysis. Sci Rep 2019; 9: 3897.
[19] Pourmoghadam Z, Soltani-Zangbar MS, Sheikhansari G, Azizi R, Eghbal-Fard S, Mohammadi H, et al. Intrauterine administration of autologous hCG-activated peripheral blood mononuclear cells improves pregnancy outcomes in patients with recurrent implantation failure; A double-blind, randomized control trial study. J Reprod Immunol 2020; 142: 103182.
[20] Mei J, Yan Y, Jiang R, Zhu YC, Ding L, Sun H. Clinical outcome of intrauterine administration of peripheral mononuclear cells or human chorionic gonadotropin in unexplained implantation failure. Am J Reprod Immunol 2022; 87: e13529.
[21] Makrigiannakis A, Vrekoussis T, Makrygiannakis F, Ruso H, Kalantaridou SN, Gurgan T. Intrauterine CRH-treated PBMC in repeated implantation failure. Eur J Clin Invest 2019; 49: e13084.
[22] Rezaee D, Bandehpour M, Kazemi B, Hosseini S, Dehghan Z, Bastaminejad S, et al. Effects of human chorionic gonadotropin-producing peripheral blood mononuclear cells on the endometrial receptivity and implantation sites of the mouse uterus. Clin Exp Reprod Med 2022; 49: 248– 258.
[23] Zare Z, Masteri Farahani R, Salehi M, Piryaei A, Ghaffari Novin M, Fadaei Fathabadi F, et al. Effect of L-carnitine supplementation on maturation and early embryo development of immature mouse oocytes selected by brilliant cresyle blue staining. J Assist Reprod Genet 2015; 32: 635–643.
[24] Hu M, Li J, Zhang Y, Li X, Brännström M, Shao LR, et al. Endometrial progesterone receptor isoforms in women with polycystic ovary syndrome. Am J Transl Res 2018; 10: 2696–2705.
[25] Achilli C, Duran-Retamal M, Saab W, Serhal P, Seshadri S. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: A systematic review and metaanalysis. Fertil Steril 2018; 110: 1089–1100.
[26] Rutigliano HM, Thomas AJ, Umbaugh JJ, Wilhelm A, Sessions BR, Kaundal R, et al. Increased expression of proinflammatory cytokines at the fetal–maternal interface in bovine pregnancies produced by cloning. Am J Reprod Immunol 2022; 87: e13520.
[27] Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, et al. Inflammation influences steroid hormones receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol 2016; 117: 30–38.
[28] Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: Origins, consequences and interventions. Acta Obstet Gynecol Scand 2017; 96: 623– 632.
[29] McKinnon B, Mueller M, Montgomery G. Progesterone resistance in endometriosis: An acquired property? Trends Endocrinol Metab 2018; 29: 535–548.
[30] Lessey BA, Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: It is affected, and let me show you why. Fertil Steril 2017; 108: 19–27.
[31] Huang P, Zheng N, Zhou H-B, Huang J. Curcumin inhibits BACE1 expression through the interaction between ERβ and NFκB signaling pathway in SH-SY5Y cells. Mol Cell Biochem 2020; 463: 161–173.
[32] Situmorang H, Hestiantoro A, Purbadi S, Flamandita D, Sahlan M. IN-SILICO dynamic analysis of Sulawesi propolis as anti-endometriosis drug: Interaction study with TNF alpha receptor, NF-kB, estrogen receptor, progesterone receptor and prostaglandin receptor. Ann Med Surg 2021; 67: 102459.
[33] Hua H, Zhang H, Kong Q, Jiang Y. Mechanisms for estrogen receptor expression in human cancer. Exp Hematol Oncol 2018; 7: 24.
[34] Liu L, Ahn KS, Shanmugam MK, Wang H, Shen H, Arfuso F, et al. Oleuropein induces apoptosis via abrogating NF-κB activation cascade in estrogen receptor–negative breast cancer cells. J Cell Biochem 2019; 120: 4504–4513.
[35] Aspros KGM, Carter JM, Hoskin TL, Suman VJ, Subramaniam M, Emch MJ, et al. Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer. NPJ Breast Cancer 2022; 8: 20.
[36] Zdrojkowski Ł, Jasiński T, Ferreira-Dias G, Pawliński B, Domino M. The role of NF-κB in endometrial diseases in humans and animals: A review. Int J Mol Sci 2023; 24: 2901.
[37] Pourmoghadam Z, Abdolmohammadi-Vahid S, Pashazadeh F, Aghebati-Maleki L, Ansari F, Yousefi M. Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells on the pregnancy outcomes in patients with recurrent implantation failure: A systematic review and meta-analysis. J Reprod Immunol 2020; 137: 103077.
[38] Wu Y, Li L, Liu L, Yang X, Yan P, Yang K, et al. Autologous peripheral blood mononuclear cells intrauterine instillation to improve pregnancy outcomes after recurrent implantation failure: A systematic review and metaanalysis. Arch Gynecol Obstet 2019; 300: 1445–1459
[2] Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: It is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 2017; 108: 15–18.
[3] Yu N, Zhang B, Xu M, Wang S, Liu R, Wu J, et al. Intrauterine administration of autologous peripheral blood mononuclear cells (PBMC s) activated by HCG improves the implantation and pregnancy rates in patients with repeated implantation failure: A prospective randomized study. Am J Reprod Immunol 2016; 76: 212–216.
[4] Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril 2019; 111: 611–617.
[5] Azeez JM, Susmi TR, Remadevi V, Ravindran V, Sujatha AS, Ayswarya RNS, et al. New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling. Am J Cancer Res 2021; 11: 5214–5232.
[6] Hamilton KJ, Hewitt SC, Arao Y, Korach KS. Estrogen hormone biology. Curr Top Dev Biol 2017; 125: 109–146.
[7] Polikarpova AV, Levina IS, Sigai NV, Zavarzin IV, Morozov IA, Rubtsov PM, et al. Immunomodulatory effects of progesterone and selective ligands of membrane progesterone receptors. Steroids 2019; 145: 5–18.
[8] Piccinni M-P, Raghupathy R, Saito S, Szekeres-Bartho J. Cytokines, hormones and cellular regulatory mechanisms favoring successful reproduction. Front Immunol 2021; 12: 717808.
[9] Zhao Y, Zhu Y, Chen X, Lin H, Qin N, Zhou Z, et al. Circulating innate lymphoid cells exhibit distinctive distribution during normal pregnancy. Reprod Sci 2022; 29: 1124–1135.
[10] Wang L, Lv Q, Wu P, Luo S, Liu S, Chen X, et al. RNA-seq and ATAC-seq analysis of CD163+ macrophage-induced progestin-insensitive endometrial cancer cells. Cancer Med 2023; 12: 5964–5978.
[11] Verma P, Verma R, Nair RR, Budhwar S, Khanna A, Agrawal NR, et al. Altered crosstalk of estradiol and progesterone with Myeloid-derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal-fetal tolerance. Am J Reprod Immunol 2019; 81: e13081.
[12] Yang L, Yao X, Li S, Chen K, Wang Y, Chen L, et al. Expression of genes associated with luteolysis in peripheral blood mononuclear cells during early pregnancy in cattle. Mol Reprod Dev 2016; 83: 509–515.
[13] Brundin PM, Landgren B-M, Fjällström P, Shamekh MM, Gustafsson J-Å, Johansson AF, et al. Expression of sex hormone receptor and immune response genes in peripheral blood mononuclear cells during the menstrual cycle. Front Endocrinol 2021; 12: 721813.
[14] Li S, Wang J, Cheng Y, Zhou D, Yin T, Xu W, et al. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol 2017; 119: 15–22.
[15] Fan L, Sha M, Li W, Kang Q, Wu J, Chen S, et al. Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance. J Reprod Dev 2021; 67: 359–368.
[16] Madkour A, Bouamoud N, Louanjli N, Kaarouch I, Copin H, Benkhalifa M, et al. Intrauterine insemination of cultured peripheral blood mononuclear cells prior to embryo transfer improves clinical outcome for patients with repeated implantation failures. Zygote 2016; 24: 58– 69.
[17] Farifteh Nobijari F, Arefi SS, Moini A, Taheripanah R, Fazeli E, Kharazi H, et al. Endometrium immunomodulation by intrauterine insemination administration of treated peripheral blood mononuclear cell prior frozen/thawed embryos in patients with repeated implantation failure. Zygote 2019; 27: 214–218.
[18] Yakin K, Oktem O, Urman B. Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: A systematic review and meta-analysis. Sci Rep 2019; 9: 3897.
[19] Pourmoghadam Z, Soltani-Zangbar MS, Sheikhansari G, Azizi R, Eghbal-Fard S, Mohammadi H, et al. Intrauterine administration of autologous hCG-activated peripheral blood mononuclear cells improves pregnancy outcomes in patients with recurrent implantation failure; A double-blind, randomized control trial study. J Reprod Immunol 2020; 142: 103182.
[20] Mei J, Yan Y, Jiang R, Zhu YC, Ding L, Sun H. Clinical outcome of intrauterine administration of peripheral mononuclear cells or human chorionic gonadotropin in unexplained implantation failure. Am J Reprod Immunol 2022; 87: e13529.
[21] Makrigiannakis A, Vrekoussis T, Makrygiannakis F, Ruso H, Kalantaridou SN, Gurgan T. Intrauterine CRH-treated PBMC in repeated implantation failure. Eur J Clin Invest 2019; 49: e13084.
[22] Rezaee D, Bandehpour M, Kazemi B, Hosseini S, Dehghan Z, Bastaminejad S, et al. Effects of human chorionic gonadotropin-producing peripheral blood mononuclear cells on the endometrial receptivity and implantation sites of the mouse uterus. Clin Exp Reprod Med 2022; 49: 248– 258.
[23] Zare Z, Masteri Farahani R, Salehi M, Piryaei A, Ghaffari Novin M, Fadaei Fathabadi F, et al. Effect of L-carnitine supplementation on maturation and early embryo development of immature mouse oocytes selected by brilliant cresyle blue staining. J Assist Reprod Genet 2015; 32: 635–643.
[24] Hu M, Li J, Zhang Y, Li X, Brännström M, Shao LR, et al. Endometrial progesterone receptor isoforms in women with polycystic ovary syndrome. Am J Transl Res 2018; 10: 2696–2705.
[25] Achilli C, Duran-Retamal M, Saab W, Serhal P, Seshadri S. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: A systematic review and metaanalysis. Fertil Steril 2018; 110: 1089–1100.
[26] Rutigliano HM, Thomas AJ, Umbaugh JJ, Wilhelm A, Sessions BR, Kaundal R, et al. Increased expression of proinflammatory cytokines at the fetal–maternal interface in bovine pregnancies produced by cloning. Am J Reprod Immunol 2022; 87: e13520.
[27] Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, et al. Inflammation influences steroid hormones receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol 2016; 117: 30–38.
[28] Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: Origins, consequences and interventions. Acta Obstet Gynecol Scand 2017; 96: 623– 632.
[29] McKinnon B, Mueller M, Montgomery G. Progesterone resistance in endometriosis: An acquired property? Trends Endocrinol Metab 2018; 29: 535–548.
[30] Lessey BA, Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: It is affected, and let me show you why. Fertil Steril 2017; 108: 19–27.
[31] Huang P, Zheng N, Zhou H-B, Huang J. Curcumin inhibits BACE1 expression through the interaction between ERβ and NFκB signaling pathway in SH-SY5Y cells. Mol Cell Biochem 2020; 463: 161–173.
[32] Situmorang H, Hestiantoro A, Purbadi S, Flamandita D, Sahlan M. IN-SILICO dynamic analysis of Sulawesi propolis as anti-endometriosis drug: Interaction study with TNF alpha receptor, NF-kB, estrogen receptor, progesterone receptor and prostaglandin receptor. Ann Med Surg 2021; 67: 102459.
[33] Hua H, Zhang H, Kong Q, Jiang Y. Mechanisms for estrogen receptor expression in human cancer. Exp Hematol Oncol 2018; 7: 24.
[34] Liu L, Ahn KS, Shanmugam MK, Wang H, Shen H, Arfuso F, et al. Oleuropein induces apoptosis via abrogating NF-κB activation cascade in estrogen receptor–negative breast cancer cells. J Cell Biochem 2019; 120: 4504–4513.
[35] Aspros KGM, Carter JM, Hoskin TL, Suman VJ, Subramaniam M, Emch MJ, et al. Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer. NPJ Breast Cancer 2022; 8: 20.
[36] Zdrojkowski Ł, Jasiński T, Ferreira-Dias G, Pawliński B, Domino M. The role of NF-κB in endometrial diseases in humans and animals: A review. Int J Mol Sci 2023; 24: 2901.
[37] Pourmoghadam Z, Abdolmohammadi-Vahid S, Pashazadeh F, Aghebati-Maleki L, Ansari F, Yousefi M. Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells on the pregnancy outcomes in patients with recurrent implantation failure: A systematic review and meta-analysis. J Reprod Immunol 2020; 137: 103077.
[38] Wu Y, Li L, Liu L, Yang X, Yan P, Yang K, et al. Autologous peripheral blood mononuclear cells intrauterine instillation to improve pregnancy outcomes after recurrent implantation failure: A systematic review and metaanalysis. Arch Gynecol Obstet 2019; 300: 1445–1459