Endometrial Expression of Insulin Signaling Pathway Genes in Pregnancy Leading to Abortion under 20 Weeks in Infertile Women: A Case-Control Study

Document Type : Original Article


Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran


Background: Impaired expression of genes which act on hormone signaling pathways is one of the factors affecting miscarriage. In this study, the expression levels of insulin receptor (INSR) and insulin receptor substrates-1 (IRS-1) genes in endometrial tissue of infertile women and fertile women with miscarriage in less than twenty weeks gestation for unknown reasons were evaluated.
Materials and Methods: In this case-control study, forty-two fertile women with children and 42 infertile women, who underwent in vitro fertilization (IVF), were selected. Both groups had abortions under twenty weeks gestation for unknown reasons. The endometrial tissue of all patients was prepared to evaluate the expression of INSR and IRS-1 genes by quantitative real-time polymerase chain reaction (PCR) method after RNA extraction.
Results: There was a statistically significant relationship between the expressions of INSR and IRS-1 genes in the endometrial tissue of the infertile women compared with the fertile women (P=0.002 and P=0.008, respectively). The expression level of genes was decreased in both groups by age and increasing body mass index (BMI). Comparison of genes expression levels in healthy and diabetic participants in each group showed a significant difference (P<0.0001), but no meaningful difference was indicated between diabetic infertile and fertile groups in terms of gene expression. INSR gene expression levels showed an increase in the fertile group in the second 10 weeks and a decrease in IRS-1 gene expression. But in the infertile group, both genes showed a slight increase in expression.
Conclusion: It seems a decreased expression of insulin signaling pathway genes in the endometrial tissue of infertile women can be one of reasons for unspecified abortion. These genes may be strong molecular markers for infertility


1. Ochoa-Bernal MA, Fazleabas AT. Physiologic events of embryo implantation and decidualization in human and non-human primates. Int J Mol Sci. 2020; 21(6): 1973.
2 . Wang HY, Qiao J, Sun XX, Wang ShY, Liang XY, Sun Y, et al. Epidemiological survey and risk factor analysis of recurrent spontaneous miscarriages in infertile women at large infertility centers. Chin Med J (Engl). 2017; 130(17): 2056-2062.
3 . Laskowska D, Sjunnesson Y, Humblot P, Andersson G, Gustafsson H, Bage R. The functional role of insulin in fertility and embryonic development—What can we learn from the bovine model? Theriogenology. 2016; 86(1): 457-464.
4 . Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A. Proinsulin binds with high affinity the insulin receptor isoform a and predominantly activates the mitogenic pathway. Endocrinology. 2012; 153(5): 2152-2163.
5 . Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85α. Diabetes. 2006; 55(8): 2392-2397.
6 . Wang Y, Hua Sh, Tian W, Zhang L, Zhao J, Zhang H, et al. Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent. Gynecol Oncol. 2012; 125(3): 734-741.
7 . Tian W, Teng F, Gao J, Gao Ch, Liu G, Zhang Y, et al. Estrogen and insulin synergistically promote endometrial cancer progression via crosstalk between their receptor signaling pathways. Cancer Biol Med. 2019; 16(1): 555-570.
8 . Codner E, Merino PM, Tena-Sempere M. Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Hum Reprod. 2012; 18(5): 568-585.
9 . Yang WM, Min KH, Lee W. Induction of miR-96 by dietary saturated fatty acids exacerbates hepatic insulin resistance through the suppression of INSR and IRS-1. PLoS One. 2016; 11(12): e0169039.
10 . Neykova K, Tosto V, Giardina I, Tsibizova V, Vakrilov G. Endometrial receptivity and pregnancy outcome. J Matern Fetal Neonatal Med. 2020; 2: 1-15.
11 . Cozzolino M, Diaz-Gimeno P, Pellicer A, Garrido N. Evaluation of the endometrial receptivity assay and the preimplantation genetic test for aneuploidy in overcoming recurrent implantation failure. J Assist Reprod Genet. 2020; 37: 2989-2997.
12 . Barra F, Laganà AS , Scala C, Garzon S, Ghezzi F, Ferrero S. Pretreatment with dienogest in women with endometriosis undergoing IVF after a previous failed cycle. Reprod Biomed Online. 2020; 41(5): 859-868.
13 . Dunson DB, Donna DB, Bernardo C. Increased infertility with age in men and women. Obstet Gynecol. 2004; 103(1): 51-56.
14 . Borges BC, Garcia-Galiano D, Cruz-Machado SS, Han X, Gavrilina GB, Saunders TL, et al. Obesity-induced infertility in male mice is associated with disruption of Crisp4 expression and sperm fertilization capacity. Endocrinology. 2017; 158(9): 2930-2943.
15 . Maresch CC, Stute DC, Alves MG, Oliveira PF, Kretser DM, Linn T. Diabetes-induced hyperglycemia impairs male reproductive function: a systematic review. Hum Reprod. 2018; 24(1): 86-105.
16 . Mansour R, El-Faissal Y, Kamel A, Kamal O, Aboulserour G, Aboulghar M, et al. Increased insulin resistance in men with unexplained infertility. Reprod Biomed Online. 2017; 35(5): 571-575.