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Background: Mothers experiencing recurrent spontaneous abortion (RSA) along with repeated implantation failures (RIF) could potentially have abnormalities in their immune systems. Vitamin D is known as a crucial immunomodulatory agent. This study aimed to assess the ratio of Natural Killer T-cells (NKTs) and the correlation between this ratio with serum vitamin D levels among women with RSA and RIF. Methods: In this research, blood samples were collected from both patients and a group of healthy individuals. The flow cytometry technique was used to determine the proportion of NKT and activated NKT cells. Additionally, Vitamin D and IFN-γ levels were measured using the ELISA technique. Results: The mean ratio of NKT cells and IFN-γ levels increased significantly in those women with RSA relative to our healthy control group [(P < 0.018) and (p < 0.031), respectively]. Nevertheless, women in the RIF and control groups did not show any significant differences. Serum vitamin D levels significantly decreased in RIF (p < 0.04) and RSA (p < 0.01) groups relative to the control group. Conclusions: It was found that increasing ratio as well as inflammatory activity of NKT cells correlated with repeated miscarriage. Reduced vitamin D levels could cause immune system disorder along with pregnancy complications. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) is a complex clinical issue affecting the fertility health of many women. The treatment of RSA through the integration of traditional Chinese medicine (TCM) and western medicine had attracted attention due to the complementary advantages of both approaches. This article aimed to introduce professor Wang Wen-jun’s unique diagnostic and therapeutic philosophy and methods in the prevention and treatment of RSA using an integrated approach of TCM and western medicine. Professor Wang Wen-jun excelled at combining disease identification with syndrome differentiation and treatment, and the precise application of both Chinese and western pharmaceuticals, and she emphasized pre-pregnancy conditioning and post-pregnancy fetal security, providing an efficient and safe therapeutic approach for the prevention and treatment of RSA, which had significantly improved the pregnancy outcomes for RSA patients. [ABSTRACT FROM AUTHOR]

Aims: We aimed to elucidate the mechanism leading to polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA). Background: PCOS is an endocrine disorder. Patients with RSA also have a high incidence rate of PCOS, implying that PCOS and RSA may share the same pathological mechanism. Objective: The single-cell RNA-seq datasets of PCOS (GSE168404 and GSE193123) and RSA GSE113790 and GSE178535) were downloaded from the Gene Expression Omnibus (GEO) database. Methods: Datasets of PSCO and RSA patients were retrieved from the Gene Expression Omnibus (GEO) database. The "WGCNA" package was used to determine the module eigengenes associated with the PCOS and RSA phenotypes and the gene functions were analyzed using the "DAVID" database. The GSEA analysis was performed in "clusterProfiler" package, and key genes in the activated pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Real-time quantitative PCR (RT-qPCR) was conducted to determine the mRNA level. Cell viability and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry, respectively. Results: The modules related to PCOS and RSA were sectioned by weighted gene co-expression network analysis (WGCNA) and positive correlation modules of PCOS and RSA were all enriched in angiogenesis and Wnt pathways. The GSEA further revealed that these biological processes of angiogenesis, Wnt and regulation of cell cycle were significantly positively correlated with the PCOS and RSA phenotypes. The intersection of the positive correlation modules of PCOS and RSA contained 80 key genes, which were mainly enriched in kinase-related signal pathways and were significant high-expressed in the disease samples. Subsequently, visualization of these genes including PDGFC, GHR, PRLR and ITGA3 showed that these genes were associated with the PI3K-AKT signal pathway. Moreover, the experimental results showed that PRLR had a higher expression in KGN cells, and that knocking PRLR down suppressed cell viability and promoted apoptosis of KGN cells. Conclusion: This study revealed the common pathological mechanisms between PCOS and RSA and explored the role of the PI3K-AKT signaling pathway in the two diseases, providing a new direction for the clinical treatment of PCOS and RSA. [ABSTRACT FROM AUTHOR]

Aims We aimed to elucidate the mechanism leading to polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA). Background PCOS is an endocrine disorder. Patients with RSA also have a high incidence rate of PCOS, implying that PCOS and RSA may share the same pathological mechanism. Objective The single-cell RNA-seq datasets of PCOS (GSE168404 and GSE193123) and RSA GSE113790 and GSE178535) were downloaded from the Gene Expression Omnibus (GEO) database. Methods Datasets of PSCO and RSA patients were retrieved from the Gene Expression Omnibus (GEO) database. The “WGCNA” package was used to determine the module eigengenes associated with the PCOS and RSA phenotypes and the gene functions were analyzed using the “DAVID” database. The GSEA analysis was performed in “clusterProfiler” package, and key genes in the activated pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Real-time quantitative PCR (RT-qPCR) was conducted to determine the mRNA level. Cell viability and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry, respectively. Results The modules related to PCOS and RSA were sectioned by weighted gene co-expression network analysis (WGCNA) and positive correlation modules of PCOS and RSA were all enriched in angiogenesis and Wnt pathways. The GSEA further revealed that these biological processes of angiogenesis, Wnt and regulation of cell cycle were significantly positively correlated with the PCOS and RSA phenotypes. The intersection of the positive correlation modules of PCOS and RSA contained 80 key genes, which were mainly enriched in kinase-related signal pathways and were significant high-expressed in the disease samples. Subsequently, visualization of these genes including PDGFC, GHR, PRLR and ITGA3 showed that these genes were associated with the PI3K-AKT signal pathway. Moreover, the experimental results showed that PRLR had a higher expression in KGN cells, and that knocking PRLR down suppressed cell viability and promoted apoptosis of KGN cells. Conclusion This study revealed the common pathological mechanisms between PCOS and RSA and explored the role of the PI3K-AKT signaling pathway in the two diseases, providing a new direction for the clinical treatment of PCOS and RSA.

Background: The polymorphisms of the FOXP3 gene may mediate abnormalities in Tregs, leading to an imbalance in maternal‐fetal immune tolerance and ultimately resulting in recurrent spontaneous abortion (RSA). This meta‐analysis aims to assess the potential association between FOXP3 polymorphisms and susceptibility to RSA using five specific single nucleotide polymorphisms (SNPs). Materials and methods: By conducting a comprehensive search across databases such as EMBASE, PubMed, Web of Science, Cochrane Library, CNKI, Wanfang, and CBM, we identified suitable studies for inclusion in the meta‐analysis. The data extracted from these studies were subjected to analysis using Stata SE 15. To assess the degree of association, we utilized the odds ratio (OR) along with its corresponding 95% confidence intervals (CI). Five specific single nucleotide polymorphisms (SNPs) were employed in assessing the connection between FOXP3 gene polymorphisms and RSA. Results: The meta‐analysis demonstrated a significant association between several polymorphisms (rs3761548, rs2232365, rs2232368, rs2280883, and rs2294021) and susceptibility to RSA. Conversely, the FOXP3 rs5902434 polymorphism was not associated with susceptibility to RSA. Conclusion: Our meta‐analysis suggests that these genetic variations within the FOXP3 gene might play a role in the progression of RSA disease. Meanwhile, large‐scale studies that consider multiple factors are needed to validate this finding. [ABSTRACT FROM AUTHOR]

Problem: We aimed to explore the risk factors in patients with unexplained recurrent spontaneous abortion (URSA) and to provide a basis for clinically targeted therapy. Method of study: This case‐control study comprised 202 patients with URSA treated at our hospital and 115 women in early pregnancy with a normal birth history during the same period. After procuring the data we conducted a multivariate logistic regression analysis of risk factors related to URSA. Results: Logistic regression analysis showed (i) that the number of spontaneous abortions (SAs; odds ratio [OR] = 492.123), the levels of autoantibodies (OR = 19.322) and tumor necrosis factor alpha (TNF‐α; OR = 9.615), and the CT and TT genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T (OR = 6.217 and 15.009, respectively) were risk factors for URSA and (ii) that 25‐hydroxyvitamin D (25‐(OH)D; OR = 0.919) was a protective factor. The most important risk factor was a history of one or more SAs, with the risk of pregnancy loss increasing 491.123‐fold. Every unit increase in serum 25‐(OH)D reduced the risk of SA by 8.1%. Conclusions: The risk factors for URSA included the number of SAs, the levels of autoantibodies and TNF‐α, and the MTHFR C677T T allele; 25‐(OH)D was a protective factor. We recommend that women diagnosed with URSA receive intervention as soon as possible so as to actively reduce the incidence of recurrent SA. [ABSTRACT FROM AUTHOR]

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level. Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing. Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit. Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics. [ABSTRACT FROM AUTHOR]

Abstract Background Impaired spermatozoa immunogenicity can result in pregnancy complications such as recurrent spontaneous abortion (RSA). Given that spermatozoa contact with microbiota, it is possible that inappropriate microbiota composition in the reproductive tract could result in the alteration of spermatozoa antigenicity. Probiotics, as a representative of microbiota, may therefore have a beneficial effect on this altered immunogenicity. The objective of this study was to determine the effect of probiotics on spermatozoa immunogenicity. Methods Twenty-five fertile couples and twenty-five RSA couples were included in this study. Spermatozoa were purified and treated with probiotics. Untreated and probiotic treated spermatozoa were evaluated for human leukocyte antigen (HLA) class I & II expression by flow cytometry. Untreated and probiotic treated spermatozoa were also cocultured with the wife’s peripheral blood mononuclear cells (PBMC) for 12 days. Then, the supernatant was assessed for IgG and APCA by enzyme-linked immunosorbent assay (ELISA) and complement-dependent cytotoxicity (CDC) assay respectively. Results Probiotic treatment of spermatozoa leads to an increase of HLA class I & II expression in both the fertile and RSA groups. The probiotic treatment resulted in a decrease in both IgG and APCA in the fertile group, but an increase in both IgG and APCA in the RSA group. Conclusions The results of this study suggest that a supplementary probiotic treatment may be useful in couples suffering from RSA with an immunologic cause, because it improves disturbed HLA expression on spermatozoa and improves disturbed APCA and IgG production in the presence of spermatozoa.

Recurrent spontaneous abortion (RSA) is defined as two or more pregnancy loss, affecting the happiness index of fertility couples. The mechanisms involved in the occurrence of RSA are not clear to date. The primary problem for the maternal immune system is how to establish and maintain the immune tolerance to the semi-allogeneic fetuses. During the pregnancy, decidual macrophages mainly play an important role in the immunologic dialogue. The purpose of this study is to explore decidual macrophages, and to understand whether there is a connection between these cells and RSA by analyzing their phenotypes and functions. Pubmed, Web of Science and Embase were searched. The eligibility criterion for this review was evaluating the literature about the pregnancy and macrophages. Any disagreement between the authors was resolved upon discussion and if required by the judgment of the corresponding author. We summarized the latest views on the phenotype, function and dysfunction of decidual macrophages to illuminate its relationship with RSA.

Background & Objective: One of the major genetic causes of recurrent spontaneous abortions is parental chromosomal abnormalities. The objectives of the study were to determine, compare and analyze the incidence and distribution of chromosomal abnormalities in couples with recurrent miscarriages from Northeastern Iran.Methods: This study was conducted at Ghaem Hospital, Mashhad, Iran. We evaluated karyotype results of 608 couples with history of recurrent spontaneous abortion. The standard method was used for culturing peripheral venous blood lymphocytes.Results: Chromosome aberrations were detected in 43 patients (3.54%), including 25 females and 18 males. Structural chromosomal abnormality was detected in 40 cases, including balanced translocations (25 cases), robertsonian translocations (4 cases), inversions (10 cases) and numerical chromosome aberrations (3 cases). Polymorphic variants were observed in 22 individuals.Conclusion: The frequency of chromosomal abnormalities in couples with Recurrent Spontaneous Abortion (RSA) in our study is 3.54%. Reciprocal translocation, pericentric inversions, robertsonian translocations, and numerical abnormality observed among couples who had experienced recurrent spontaneous abortions and that these couples might benefit from cytogenetic analysis.

Background: Impaired spermatozoa immunogenicity can result in pregnancy complications such as recurrent spontaneous abortion (RSA). Given that spermatozoa contact with microbiota, it is possible that inappropriate microbiota composition in the reproductive tract could result in the alteration of spermatozoa antigenicity. Probiotics, as a representative of microbiota, may therefore have a beneficial effect on this altered immunogenicity. The objective of this study was to determine the effect of probiotics on spermatozoa immunogenicity. Methods: Twenty-five fertile couples and twenty-five RSA couples were included in this study. Spermatozoa were purified and treated with probiotics. Untreated and probiotic treated spermatozoa were evaluated for human leukocyte antigen (HLA) class I & II expression by flow cytometry. Untreated and probiotic treated spermatozoa were also cocultured with the wife's peripheral blood mononuclear cells (PBMC) for 12 days. Then, the supernatant was assessed for IgG and APCA by enzyme-linked immunosorbent assay (ELISA) and complement-dependent cytotoxicity (CDC) assay respectively. Results: Probiotic treatment of spermatozoa leads to an increase of HLA class I & II expression in both the fertile and RSA groups. The probiotic treatment resulted in a decrease in both IgG and APCA in the fertile group, but an increase in both IgG and APCA in the RSA group. Conclusions: The results of this study suggest that a supplementary probiotic treatment may be useful in couples suffering from RSA with an immunologic cause, because it improves disturbed HLA expression on spermatozoa and improves disturbed APCA and IgG production in the presence of spermatozoa. [ABSTRACT FROM AUTHOR]

Human uterine stromal cell undergoes decidualization for pregnancy establishment and maintenance, which involved extensive proliferation and differentiation. Increasing studies have suggested that recurrent spontaneous abortion (RSA) may result from defective endometrial stromal decidualization. However, the critical molecular mechanisms underlying impaired decidualization during RSA are still elusive. By using our recently published single-cell RNA sequencing (scRNA-seq) atlas, we found that MYC-associated factor X (MAX) was significantly downregulated in the stromal cells derived from decidual tissues of women with RSA, followed by verification with immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). MAX knockdown significantly impairs human endometrial stromal cells (HESCs) proliferation as determined by MTS assay and Ki67 immunostaining, and decidualization determined by F-actin, and decidualization markers. RNA-seq together with chromatin immunoprecipitation sequencing (ChIP-seq) and cleavage under targets and release using nuclease sequencing (CUT&RUN-seq) analysis were applied to explore the molecular mechanisms of MAX in regulation of decidualization, followed by dual-luciferase reporter assay to verify that MAX targets to (odd-skipped related transcription factor 2) OSR2 directly. Reduced expression of OSR2 was also confirmed in decidual tissues in women with RSA by IHC and qRT-PCR. OSR2 knockdown also significantly impairs HESCs decidualization. OSR2-overexpression could at least partly rescue the downregulated insulin-like growth factor binding protein 1 (IGFBP1) expression level in response to MAX knockdown. Collectively, MAX deficiency observed in RSA stromal cells not only attenuates HESCs proliferation but also impairs HESCs decidualization by downregulating OSR2 expression at transcriptional level directly. [ABSTRACT FROM AUTHOR]

Human amniotic epithelial cells (hAECs) are originated from the innermost layer of the amniotic membrane and derivated from the inner cell mass of the blastocyst. hAECs are easily isolated from amniotic membrane, which possess characteristics of embryonic stem cells (ESCs) and can differentiate into the three germ layers under specific culture conditions. hAECs also have many excellent properties such as low immunogenicity, immunomodulatory and non-tumorigenicity. Moreover, hAECs can secrete a wide spectrum of cytokine, including growth factors, neurotrophic factors and anti-inflammatory factors. A growing body of research indicates that hAECs can help to restore the function of damaged tissues and organs. Therefore, hAECs have broad application prospects. This review focuses on the current research advances of the application of hAECs in obstetrics and gynecology-related diseases, including premature ovarian insufficiency, endometrial injury, gynecologic malignancies, and recurrent spontaneous abortion. [ABSTRACT FROM AUTHOR]

Background & Objective: One of the major genetic causes of recurrent spontaneous abortions is parental chromosomal abnormalities. The objectives of the study were to determine, compare and analyze the incidence and distribution of chromosomal abnormalities in couples with recurrent miscarriages from Northeastern Iran. Methods: This study was conducted at Ghaem Hospital, Mashhad, Iran. We evaluated karyotype results of 608 couples with history of recurrent spontaneous abortion. The standard method was used for culturing peripheral venous blood lymphocytes. Results: Chromosome aberrations were detected in 43 patients (3.54%), including 25 females and 18 males. Structural chromosomal abnormality was detected in 40 cases, including balanced translocations (25 cases), robertsonian translocations (4 cases), inversions (10 cases) and numerical chromosome aberrations (3 cases). Polymorphic variants were observed in 22 individuals. Conclusion: The frequency of chromosomal abnormalities in couples with Recurrent Spontaneous Abortion (RSA) in our study is 3.54%. Reciprocal translocation, pericentric inversions, robertsonian translocations, and numerical abnormality observed among couples who had experienced recurrent spontaneous abortions and that these couples might benefit from cytogenetic analysis. [ABSTRACT FROM AUTHOR]

Previous studies have reported the involvement of γδ T cells in recurrent spontaneous abortion (RSA); however, both pathogenic and protective effects were suggested. To interrogate the role of γδ T cells in RSA, peripheral blood from RSA patients and healthy women with or without pregnancy were analyzed for γδ T cells by flow cytometry (n = 9–11 for each group). Moreover, the decidua from pregnant RSA patients and healthy controls (RSA-P and HC-P group, respectively) was simultaneously stained for γδ T cells by immunohistochemistry (IHC) and bulk sequenced for gene expression. Our results demonstrated that the frequencies of peripheral γδ T cells and their subpopulations in RSA patients were comparable to that in healthy subjects, but the PD1 expression on Vδ2+ cells was increased in pregnant patients. Furthermore, peripheral Vδ2+ cells in RSA-P patients demonstrated significantly increased expression of CD107a, as compared to that in pregnant healthy controls. In addition, RSA-P patients had higher proportion of IL-17A-secreting but not IL-4-secreting Vδ2+ cells compared to the control groups. In decidua, an inflammatory microenvironment was also evident in RSA-P patients, in which CCL8 expression and the infiltration of certain immune cells were higher than that in the HC-P group, as revealed by transcriptional analysis. Finally, although the presence of γδ T cells in decidua could be detected during pregnancy in both RSA patients and healthy subjects by multicolor IHC analysis, the expression of CD107a on γδ T cells was markedly higher in the RSA-P group. Collectively, our results indicated that the increased activation, cytotoxicity, and inflammatory potential of peripheral and/or local γδ T cells might be responsible for the pathogenesis of RSA. These findings could provide a better understanding of the role of γδ T cells in RSA and shed light on novel treatment strategies by targeting γδ T cells for RSA patients.

Previous studies have reported the involvement of γδ T cells in recurrent spontaneous abortion (RSA); however, both pathogenic and protective effects were suggested. To interrogate the role of γδ T cells in RSA, peripheral blood from RSA patients and healthy women with or without pregnancy were analyzed for γδ T cells by flow cytometry (n = 9–11 for each group). Moreover, the decidua from pregnant RSA patients and healthy controls (RSA-P and HC-P group, respectively) was simultaneously stained for γδ T cells by immunohistochemistry (IHC) and bulk sequenced for gene expression. Our results demonstrated that the frequencies of peripheral γδ T cells and their subpopulations in RSA patients were comparable to that in healthy subjects, but the PD1 expression on Vδ2+ cells was increased in pregnant patients. Furthermore, peripheral Vδ2+ cells in RSA-P patients demonstrated significantly increased expression of CD107a, as compared to that in pregnant healthy controls. In addition, RSA-P patients had higher proportion of IL-17A-secreting but not IL-4-secreting Vδ2+ cells compared to the control groups. In decidua, an inflammatory microenvironment was also evident in RSA-P patients, in which CCL8 expression and the infiltration of certain immune cells were higher than that in the HC-P group, as revealed by transcriptional analysis. Finally, although the presence of γδ T cells in decidua could be detected during pregnancy in both RSA patients and healthy subjects by multicolor IHC analysis, the expression of CD107a on γδ T cells was markedly higher in the RSA-P group. Collectively, our results indicated that the increased activation, cytotoxicity, and inflammatory potential of peripheral and/or local γδ T cells might be responsible for the pathogenesis of RSA. These findings could provide a better understanding of the role of γδ T cells in RSA and shed light on novel treatment strategies by targeting γδ T cells for RSA patients. [ABSTRACT FROM AUTHOR]

Purpose: Vitamin D (VD) deficiency seems to be associated with the risk of recurrent spontaneous abortion (RSA). Vitamin D receptor (VDR) and cytochrome P450 family 2 subfamily R member 1 (CYP2R1) are two genes which are vital for VD metabolism and actions. However, whether single-nucleotide polymorphisms (SNPs) in these genes are correlated with the risk of RSA are poorly understood. Therefore, we aimed to characterize the relationships among VDR SNPs, CYP2R1 SNPs and RSA.Methods: This case-control study enrolled 75 RSA patients and 83 controls. Serum VD and some cytokines were detected with LC-MS/MS and flow cytometry, respectively. Genotyping for three SNPs of CYP2R1 (rs10741657, rs10766197 and rs12794714) and five SNPs of VDR (rs7975232, rs1544410, rs2189480, rs2228570 and rs2239179) was done with polymerase chain reaction (PCR) and high-throughput sequencing. All the data were analyzed with appropriate methods and in different models.Results: The results revealed a significant correlation between the AG genotype of CYP2R1 rs12794714 and VD levels (OR 0.686; 95% CI 0.49-0.96; p = 0.028). Besides, the AG and GG genotypes of CYP2R1 rs12794714 were markedly related to the risk of RSA (OR 52.394, 59.497; 95% CI 2.683-1023.265, 3.110-1138.367; p = 0.009, 0.007, respectively).Conclusion: Our results indicate that CYP2R1 rs12794714 might be a risk factor for RSA. Hence, early screening of pregnant women for CYP2R1 rs12794714 is necessary to warrant proactive counseling and treatment against RSA. [ABSTRACT FROM AUTHOR]

The objective of this study is to evaluate the predictive value of sperm DNA fragmentation Index (DFI) in unexplained recurrent spontaneous abortion (RSA) and to investigate its correlation with conventional sperm parameters. Besides, we aimed to reveal the necessity of establishing a DFI clinical threshold of each laboratory for the prognostic diagnosis of RSA and establish our own DFI threshold. Semen samples were collected from male partners of RSA patients (n = 139) and healthy recent fathers (control, n = 200). DFI was tested using SCSA and conventional semen analysis was performed using an automatic semen analyzer. The DFI value and distribution were compared between the two groups using corresponding statistical software. The diagnostic threshold value was established by ROC curve. The correlation between DFI and the conventional semen parameters of the 139 cases was further analyzed using Student's t test and Mann-Whitney U test. Our result showed that DFI was significantly higher in RSA patients compared with normal donor controls. We established our own DFI threshold at 13.59%. There was only a weak partial correlation between DFI values and conventional sperm analysis parameters. Our present study suggested that DFI might be used as a valuable predictor for RSA independent of conventional sperm parameters. Additionally, we recommend that each laboratory should establish its own clinical DFI threshold for more precise prediction of RSA and we recommend that sperm DNA fragmentation test should be included in complete sperm quality assessment in addition to conventional semen analysis for RSA male partners. [ABSTRACT FROM AUTHOR]

Until recently, trophoblast invasion during human placentation was characterized by and restricted to invasion into uterine connective tissues and the uterine spiral arteries. The latter was explained to connect the arteries to the intervillous space of the placenta and to guarantee the blood supply of the mother to the placenta. Today, this picture has dramatically changed. Invasion of endoglandular trophoblast into uterine glands, already starting at the time of implantation, enables histiotrophic nutrition of the embryo prior to perfusion of the placenta with maternal blood. This is followed by invasion of endovenous trophoblasts into uterine veins to guarantee the drainage of fluids from the placenta back into the maternal circulation throughout pregnancy. In addition, invasion of endolymphatic trophoblasts into the lymph vessels of the uterus has been described. Only then, invasion of endoarterial trophoblasts into spiral arteries takes place, enabling hemotrophic nutrition of the fetus starting with the second trimester of pregnancy. This new knowledge paves the way to identify changes that may occur in pathological pregnancies, from tubal pregnancies to recurrent spontaneous abortions. [ABSTRACT FROM AUTHOR]

Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor β (TGF-β), VDR and 1-α-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-β were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA.

Recurrent spontaneous abortion (RSA) is a multifactorial disease of which the exact causes are still unknown. In the current study, we aimed to analyze the distribution of abnormal embryonic karyotypes in RSA. 781 RSA patients of 17 hospitals in Shanghai from January 2014 to September 2016 were enrolled. Fetal villus tissues were collected during uterine curettage and then cultured in situ for karyotyping. All of the 781 cases were successfully cultured. There were 393 cases of abnormal karyotypes, accounting for 50.3% of the total cases. Women with abnormal embryonic karyotype were significantly older compared to those with normal karyotype (P < 0.001). The majority of patients with abnormal karyotype fell among age groups of 25-29 and 30-34. There were 247 cases of aneuploidy, accounting for 62.8% of the total abnormal karyotype cases. Autosomal trisomy was the primary form of aneuploidy (189/247, 76.5%), and the most common types were trisomy-16 (n = 69), trisomy-22 (n = 28), trisomy-21 (n = 21), trisomy-15 (n = 15), and trisomy-13 (n = 10). Abnormal karyotype is a major factor related to RSA. Further studies are needed to elucidate the etiology of RSA in order to achieve more effective prevention and treatment. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) is an unknown aetiology common disease troubled women all over the world. Recent studies of circular RNAs (circRNAs) in gynecology and obstetrics area have sprung up. Our purpose in this study was to investigate the expression of circRNAs in chorionic villi from patients with RSA versus corresponding healthy gravidas, and to infer the potential role of these circRNAs in RSA occurrence. We selected 35 pairs of RSA patients and healthy control subjects, and analyzed the aberrant circRNA expression in three pairs of villi samples from each group using circRNA microarray. Altogether, including 335 up-regulated and 259 down-regulated circRNAs, 594 aberrant expressed circRNAs (FC ≥ 2.0, P ≤ 0.05) were found. Considering the raw content of each circRNAs, fold change differences and the restriction of the divergent primers, four down-regulated circRNAs (hsa_circRNA_104948, 104547, 101319 and 104938) and four up-regulated (hsa_circRNA_102116, 100709, 102424 and 103102) were selected as validation genes, using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Paired t -test and receiver operating characteristic (ROC) curves were also established. The result of content verification was accordant exactly with the microarray chip outcome (P ≤ 0.05 in all validation circRNAs). The area under the ROC curves (AUCs) of these eight circRNAs were all greater than 0.5. Further function analysis of circRNAs in RSA patients was performed by paper comparison. Taken together, aberrant villi circRNA expression in RSA played a vital role in its nosogenesis possibly via miRNA sponge function of circRNAs. Deeper analysis of the detailed mechanisms will be worthwhile. [ABSTRACT FROM AUTHOR]

Oestrogen receptors are implicated in the pathogenesis of recurrent spontaneous abortion (RSA). Non-genomic oestrogen responses can be mediated by GPER. The prevalence of polymorphisms in GPER1 gene in RSA was assessed in 747 Chinese women from Yunnan province (171 Bai, 258 Chinese Han, 234 Dai, 33 Achang and 51 Jingpo patients). Snapshot technology was used for genotyping the polymorphisms of the GPER1 gene. The rs4265085G was significantly increased in the Dai and Bai groups versus controls (Dai: P < 0.0001, P adj < 0.0001, OR 95% CI 2.34 [1.79 to 3.05]; Bai: P = 0.0004, P adj = 0.0012, OR 95% CI 1.71 [1.27 to 2.31]); recessive model of rs4265085 in the Dai ( P = 0.003, P adj = 0.009, OR 95% CI 2.71 [1.38 to 5.30]); Bai ( P < 0.0001, P adj < 0.0001, OR 95% CI 3.37 [1.93 to 5.91]). Haplotype frequencies containing rs10269151G-rs4265085G-rs11544331C were separately significantly different in Dai and Bai ethnic groups (Dai: P = 0.0002, P adj = 0.001, OR 95% CI = 2.12 [1.43 to 3.17]; Bai: P = 0.005, P adj = 0.025, OR 95% CI = 1.82 [1.18 to 2.78]) compared with controls. The intron variant rs4265085 may confer risk for RSA in Dai and Bai ethnic groups. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) is a disturbing pregnancy disorder experienced by ~2.5% of women attempting to conceive. The pathogenesis of RSA is still unclear. Previous findings revealed that transcription factor YIN-YANG 1(YY1) was related to the pathogenesis of RSA by influence trophoblastic cell invasion ability. Present study aimed to investigate more specific molecular mechanism of YY1 playing in trophoblastic cells. In our research, RNA-seq and Chip-seq were used to find significant changed genes between si-YY1(Knock down of YY1) HTR-8/SVneo cells(n = 3) and HTR-8/SVneo cells(n = 3). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results suggested that Integrins related pathway maybe necessary to biological functions of trophoblastic cells. Chip-seq dataset analysis results predict YY1 can regulate ITGA3/7 expression by binding to the promoter region of ITGA3/7. Furthermore, results from chip experiment, RT-PCR, Dual-luciferase reporter gene assay showed that YY1 was able to bind to the promoter region of ITGA3 and regulate ITGA3 mRNA and protein expression. However, ITGA7 could not be significant influenced by YY1. Besides, gene silencing experiment, Western blot and Immunofluorescence assay confirmed that both YY1 and ITGA3 can accelerate phosphorylation focal adhesion kinase and affect cytoskeleton formation in HTR-8/SVneo cells. In conclusion, YY1/ITGA3 play a critical role in trophoblast invasion ability by regulating cytoskeleton formation. • YY1 as a transcription factor can transcriptionally regulate the expression of ITGA3. • YY1 and ITGA3 can accelerate p-FAK level and affect cell skeletal formation of HTR-8/SVneo cells. • YY1/ITGA3 may be involved in the pathogenesis of RSA by decreasing cell skeletal formation. [ABSTRACT FROM AUTHOR]

Abstract: Natural killer (NK) cells play a fundamental role in maintaining pregnancy. Based on the availability and non-invasive method of collection of menstrual blood (MB), here we investigated for the first time a comparative analysis of NK cell subsets in MB and peripheral blood (PB) of women with recurrent spontaneous abortion (RSA) and fertile women. PB and MB of healthy fertile (n =15) and RSA women (n =15) were sampled simultaneously on the second day of the menstrual cycle. Proportions of CD56+CD3−CD16+/−, CD56+CD3−CCR7+/−, and CD56+CD3−CD45RO+/− cells were analyzed using flow cytometry. In the MB of both groups, proportions of CD16+ and CD45RO− NK cells were significantly lower than in the PB. In parallel, CD56+CD16+CCR7− and CCR7+ cells were present in significantly smaller amounts in MB than in PB. However, the amounts of CD56+CD16−CCR7− and CCR7+ cells were greater in MB. In comparison to the fertile group, the percentage of MB CD45RO+ NK cells was significantly lower and frequencies of PB CD16−, CD45RO− and CD56+CD16+CCR7+ subsets were significantly higher in RSA patients. Different subsets of NK cells are differentially distributed in MB in comparison with PB in women with RSA and fertile subjects. Population differences of NK cell subsets in RSA patients and normal controls were more clearly reflected at the systemic level. [Copyright &y& Elsevier]

Abstract: Aim: The aim of this study was to investigate the association of microRNA polymorphisms (miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G) in Korean patients with recurrent spontaneous abortion (RSA). Methods: We conducted a case–control study of 564 Korean women: 330 patients with at least two unexplained consecutive pregnancy losses and 234 healthy controls with at least one live birth and no history of pregnancy loss. Results: RSA patients exhibited significantly different frequencies of the miR-196a2CC (TT+TC vs. CC; adjusted odds ratio [AOR], 1.587; 95% confidence interval [CI], 1.042–2.417) and miR-499AG+GG genotypes (AOR, 1.671; 95% CI, 1.054–2.651) compared with the control group. The combination of miR-196a2CC and miR-499AG+GG showed synergistic effects (AOR, 3.541; 95% CI, 1.645–7.624). Conclusion: miR-196a2CC, miR-499AG+GG, and the miR-196a2CC/miR-499AG+GG combination are significantly associated with idiopathic RSA in Korean women. [Copyright &y& Elsevier]

Abstract: Objectives: To find the association between recurrent spontaneous abortion (RSA)/early embryo growth arrest and Y chromosome polymorphism. Study design: Peripheral blood samples of the male patients of big Y chromosome, small Y chromosome and other male patients whose partners suffered from unexplained RSA/early embryo growth arrest were collected. PCR and real-time fluorescent quantitative PCR were used to test the deletion and the copy number variation of DYZ1 region in Y chromosome of the patients. A total of 79 big Y chromosome patients (48 of whose partners suffered from RSA or early embryo growth arrest), 7 small Y chromosome patients, 106 other male patients whose partners had suffered from unexplained RSA or early embryo growth arrest, and 100 normal male controls were enrolled. Results: There was no fraction deletion of DYZ1 detected both in big Y patients and in normal men. Of RSA patients, 1 case showed deletion of 266bp from the gene locus 25–290bp, and 2 cases showed deletion of 773bp from 1347 to 2119bp. Of only 7 small Y chromosome patients, 2 cases showed deletion of 266bp from 25 to 290bp, and 4 cases showed deletion of 773bp from 1347 to 2119bp and 275bp from 3128 to 3420bp. The mean of DYZ1 copies was 3900 in normal control men; the mean in big Y patients was 5571, in RSA patients was 2655, and in small Y patients was 1059. All of the others were significantly different (P <0.01) compared with normal control men, which meant that DYZ1 copy number in normal control men was less than that of big Y chromosome patients, and was more than that of unexplained early RSA patients and small Y patients. Conclusions: The integrity and copy number variation of DYZ1 are closely related to the Y chromosome length under microscope. The cause of RSA/early embryo growth arrest in some couples may be the increase (big Y patients) or decrease of DYZ1 copy number in the husbands’ Y chromosome. [Copyright &y& Elsevier]

Abstract: Objectives: The objective of this study was to determine whether or not the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensin II type 1 receptor (AT1R), and angiotensinogen (AGT) gene polymorphisms are associated with idiopathic recurrent spontaneous abortions (RSAs) in Korean women. Study design: A total of 251 patients with unexplained consecutive pregnancy losses, and 126 healthy controls with at least one live birth and no history of pregnancy loss. Result: The odds ratios (ORs) of the ACE ID (OR=2.423; 95% confidence interval (CI)=1.417–4.142; p =0.001) and the ACE II (OR=2.050; 95% CI=1.143–3.675; p =0.018) for the ACE DD genotype were significantly different between patients with idiopathic RSA and controls; however, there were no significant differences between patients and controls with respect to the AT1R 1166A>C and AGT M235T polymorphisms. In a haplotype-based analysis of I-A (p =0.010), D-A (p =0.004), I-A-T (p =0.033), D-A-T (p =0.0005), and D-C-T (p =0.013) polymorphism pairs with synergistic effects derived by the MDR method in patients and in controls showed significant results. Conclusion: This study suggests that ACE, AT1R and AGT polymorphisms and haplotypes are a genetic determinant for the risk of idiopathic RSA in Korean women. [Copyright &y& Elsevier]

Abstract: Indoleamine 2,3-dioxygenase (INDO) catalyzes degradation of the indole ring of indoleamines and locally depletes tryptophan. INDO expression suppresses T cell proliferation and activation. Genetic variation in the INDO gene may contribute to the variable INDO enzyme expression, activity and severity of some diseases. Recurrent spontaneous abortion (RSA) is a common pregnancy complication and the exact causes of RSA are not yet known. We performed an association study between INDO single nucleotide polymorphisms (SNPs) and RSA. To identify INDO SNPs we sequenced DNA samples for ten exons and adjacent intronic regions from 111 RSA patients. Consequently 10 SNPs were detected; four in exons (one in exon 4, two in exon 9 and one in exon 10) and six in intronic regions (one in intron 3, three in intron 6, one in intron 8 and one in intron 9). Three (IVS3+562 del C, IVS8+116 T→G and IVS9+2431 G→A) of these ten SNPs have been registered at the NCBI SNP database. Statistical analysis of allele, genotype and haplotype frequency distribution in the three most frequent SNPs (IVS3+562 del C, IVS6+61 G→A and IVS9+2431 G→A) showed no significant differences between the 111 RSA and 105 matched control women. CGA and CGG were the most frequent haplotypes in both the RSA and control groups. We conclude that there is no association between INDO polymorphisms and susceptibility of Iranian women to RSA. [Copyright &y& Elsevier]

FUT2 is an autosomal gene that controls the secretion of the ABH blood group antigens in organic fluids. The secretor gene plays an important role during intrauterine life. The aim of this study is to investigate a possible association between the ABH system and reproductive success in couples with primary repeated spontaneous abortion (RSA). Sixty-six couples with primary repeated spontaneous abortion and 356 consecutive healthy puerperae with their newborn infants from the white population of Rome were studied. All couples were seen at the Center for Reproductive Disorders of the Institute of Obstetrics and Gynecology of the University of Rome, La Sapienza. Secretor phenotype was determined by saliva in all subjects by laboratory standard procedures. In couples with primary RSA, the frequency of non-secretor phenotype of both husbands and wives (37.9%) were significantly higher than those of newborns from other couples (21.4% for male newborns and 29.4% for female newborns). In husbands, but not in wives, of the couples with primary RSA succeeding in having at least a live born infant after 5 years of follow up, the frequency of non-secretor phenotype was significantly lower than those without a liveborn infant (22.8% vs 54.8%). The presence of joint secretor phenotype in both husband and wife was positively associated with having a liveborn infant after 5 years of follow up (odds ratio = 4.57, 95% C.I.1.39-15.6). Secretor phenotype of couples with RSA, especially of the husband, could facilitate 'reproductive success'. [ABSTRACT FROM AUTHOR]

Background: Th1-type cytokines secretion such as IFN-γ, and Th2 cytokines such as IL-10, have been shown to exert deleterious effects on pregnancy, inhibiting fetal growth and development . Aim: Measurement of the locally concentrations of selected Th1 and Th2 cytokines in women with a history of recurrent spontaneous abortion (RSA) at the time of abortion using in situ hyperdization technique. Methods: A total of one hundred and nineteen women, ranged from the mean age (23.9 - 28.5)years, were enrolled in the current study and were further classified into three categories: Group A- Recurrent spontaneous abortion (RSA): n= 62 women, with a mean age of (28.5 + 0.68);Group B- non- recurrent spontaneous abortion (non-RSA): n= 34 women, with a mean age of (26.4 ± 0.85)and group C- Control (successful pregnancy): n= 23 women, with a mean age of (23.9 ± 0.88). From each patient and control, placental tissues were collected. Trophoblasts tissues (an image for the local microenvironment) were screened to determine their in situ levels of IL-10 and IFN-γ based on cDNA probes (for in-situ hybridization, ISH). Results: There was a significant increase in the level of IL-10 within trophoblast tissues biopsies exclusively from women with successful pregnancies (group C) (p < 0.001). On the other hand, IFN-γ was found predominantly expressed in trophoblast tissue biopsies of patients with RSA whether IHC or ISH were conducted (p< 0.05). Accordingly, only trophoblast tissues biopsies from patients with RSA revealed a significant increase in the ratio of IFN-γ/IL-10 levels expressed as determined by in situ hybridization in comparison to the same ration calculated from trophoblasts tissues of women with successful pregnancies (group C) (p< 0.001). as marker for Th2 immune response, during successful pregnancies. Furthermore, the current study failed to demonstrate a significant difference in the tissue levels of IL-8 between RSA and control group (p> 0.05) and no significant different between non-RSA and control (p>0.05) , (always p < 0.05). Conclusion: These outcomes may further support the possible exisance of an immune response that orchestrates abortive phenomena and the possible protective role of IL-10. Keywords: Recurrent spontaneous abortion (RSA), in-situ hybridization, ISH, cytokine,IL- 8,IL-10,IFN γ. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Methylenetetrahydrofolate reductase (MTHFR) mutations known to be associated with hyperhomocysteinemia may be a risk factor for recurrent spontaneous abortion. Recently 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) was reported to affect plasma homocysteine level. We investigated the association between plasma homocysteine level and MTHFR and TSER genotypes. Methods: Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutations (C677T and A1298C) were identified by PCR-restriction fragment length polymorphism assay. TSER mutation was analyzed by PCR method. Results: Average homocysteine level was significantly higher in MTHFR 677TT genotype (9.80±3.87 μmol/L) than in MTHFR 677CT (7.04±1.99 μmol/L) in MTHFR 677CC genotype (8.14±1.74 μmol/L) in Korean patients with unexplained recurrent spontaneous abortion (p =0.0143). While MTHFR 1298AA showed the highest level, plasma homocysteine levels were not significantly different among MTHFR 1298AA (8.42±2.65 μmol/L), 1298AC (6.98±2.44 μmol/L) and 1298CC (6.09±0.32 μmol/L) (p =0.2058). There was no significant difference among TSER genotypes (2R2R, 8.61±1.68 μmol/L; 2R3R, 7.84±2.16 μmol/L; 3R3R, 8.05±2.81 μmol/L; p =0.9319). Among the combined genotypes of MTHFR C677T and TSER, 677TT-3R3R genotype had the highest homocysteine level (11.47±4.66 μmol/L). 1298AA-3R3R had the highest level (8.54±3.05 μmol/L) among the combined genotypes of MTHFR A1298C and TSER. Conclusion: Although there was no significant difference found among combined genotypes, 3R3R showed elevated homocysteine levels in MTHFR 677TT and 1298AA in Korean patients with unexplained recurrent spontaneous abortion. Thus TSER polymorphism may be a genetic determinant of plasma homocysteine level in Korean patients as well as MTHFR C677T polymorphism. [Copyright &y& Elsevier]

Pregnancy is a unique physiologic condition that guarantees the survival of the semiallogenic embryo during the long period of gestation. The placenta plays a key role in the maintenance of local tolerance and allows the mother to accept the embryo until completion of pregnancy. The complex process of tolerance accompanying the survival of the foetus is controlled at the embryo-maternal interface by factors deriving from decidualized endometrium and from the trophoblast itself. Trophoblasts develop various strategies to evade the damaging attack by the maternal immune response including expression of non-classical MHC class I antigens and of complement regulatory proteins. Also, cytokines released at the feto-meternal interface play an important role in regulating embryo survival controlling not only the maternal immune response but also angiogenesis and vascular remodelling. The delicate equilibrium established between the mother and the foetus can be compromised in pathological condition of pregnancy as a result of humoral and/or cellular response of the mother against trophoblast antigens leading to sponstaneous miscarriage. Cytotoxic cells and antibodies to trophoblast and endothelial cells are frequently found in patients with recurrent spontaneous abortion. This review article focuses on the delicate equilibrium established at the feto-maternal interface during pregnancy examining the various strategies devised by the embryo to evade the maternal immune attack, and the pathological conditions in which this equilibrium is compromised leading to serious complications of pregnancy. [ABSTRACT FROM AUTHOR]

The efficacy of immunotherapy in the prevention of habitual abortion remains controversial. It has been suggested that the benefits are predominantly due to psychological factors. We have evaluated the success of pregnancy outcome following immunotherapy with allogeneic lymphocytes, in relation to the subsequent development of anti-paternal cytotoxic antibodies (APCA). It was observed that in women who developed an APCA titre of ≥ 1:16, live births occurred in 16 out of 21 cases (76%), while only two out of seven (28%) women who failed to achieve an APCA titre of ≥ 1:16 had successful pregnancies ( <0.05). In eight women who had an APCA titre of 1: 16 on initial screening, and were, therefore, excluded from the trial, successful pregnancy outcome was noted in 62.5% of cases. Although these results are based on a small sample and on an open, non-randomized trial, they show that the efficacy of immunotherapy is related to immune response to allogeneic lymphocytes, and is not simply a placebo effect. Measurement of APCA titre could serve as a marker for immunopotentiation. [ABSTRACT FROM PUBLISHER]

STOX1 is a transcription factor that is implicated in the high prevalence of human gestational diseases. It has been studied in various types of gestational diseases using different molecular and cellular biological technologies. However, the effect and detailed mechanism of storkhead box 1 (STOX1) in recurrent spontaneous abortion (RSA) remain unknown. This study aimed to explore the effect and detailed mechanism of STOX1 in human trophoblast cells. The result showed that downregulation of STOX1 by short hairpin RNA (shRNA) led to a decrease in proliferation and migration in HTR-8/SVneo cells, while it induced the apoptosis of HTR-8/SVneo cells. Moreover, the result showed that trophoblast cells expressed lower levels of pAKT and p85 subunits after treatment with STOX1 shRNA when compared with control. However, overexpression of STOX1 obviously increased the pAKT and p85 protein expressions. Transfection of pcDNA-AKT plasmid increased cell proliferation and migration in HTR-8/SVneo cells while suppressed the apoptosis of HTR-8/SVneo cells. Furthermore, inhibition of the PI3K/Akt pathway by a specific inhibitor promoted cell apoptosis and aggravatedly suppressed cell proliferation and migration of HTR-8/SVneo cells. On the other hand, upregulation of the PI3K/Akt pathway could increase the relative expression level of Bcl-2 and decrease the relative expression levels of Bax and Bim, while inhibition of the PI3K/Akt pathway led to adverse results. Our results demonstrated that inhibition of STOX1 could suppress trophoblast cell proliferation and migration, while promote apoptosis through inhibiting the PI3K/Akt signaling pathway. These findings might provide a new fundamental mechanism for regulating RSA and could be used to prevent and treat RSA in clinic., (© 2018 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.)

Granulocyte colony-stimulating factor (G-CSF) belongs to the family of colony-stimulating factors (CSF). As the name suggests, it was initially identified as being able to target and influence granulopoiesis, but was soon shown to be a ubiquitous growth factor, with synthesis and receptors, such as the related granulocyte macrophage colony-stimulating factor (GM-CSF), which is found in a wide variety of tissue types, including the organs and cell populations involved in reproduction. It must now be assumed that both G-CSF and GM-CSF control, or play a role in controlling, key processes in oocyte and sperm maturation, endometrial receptivity, implantation, and embryo and fetal development, possibly extending to birth. The following article offers an overview of the current findings with regard to animal experimental studies, initial clinical applications in reproductive medicine, and potential risks., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)