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Mesenchymal stem cells play important roles in repairing injured endometrium. However, the molecular targets and potential mechanism of the endometrial recipient cells for stem cell therapy in intrauterine adhesion (IUA) are poorly understood. In this study, umbilical cord mesenchymal stem-cell-conditioned medium (UCMSCs-CM) produced positive effects on a Transforming growth factor beta (TGF-β) induced IUA cell model. RNA-sequencing was performed on clinical IUA tissues, and the top 40 upregulated and top 20 downregulated mRNAs were selected and verified using high-throughput (HT) qPCR in both tissues and cell models. Based on a bioinformatic analysis of RNA-sequencing and HT-qPCR results, 11 mRNAs were uncovered to be the intervention targets of UCMSCs-CM on IUA endometrium cell models. Among them, IGFBP3 was striking as a key pathogenic gene and a potential diagnostic marker of IUA, which exhibited the area under the curve (AUC), sensitivity, specificity were 0.924, 93.1% and 80.6%, respectively in 60 endometrial tissues. The silencing of IGFBP3 exerted positive effects on the IUA cell model through partially upregulating MMP1 and KLF2. In conclusion, RNA-sequencing combined with HT qPCR based on clinical tissues and IUA cell models were used in IUA research and our results may provide some scientific ideas for the diagnosis and treatment of IUA., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Intrauterine adhesion (IUA), a major cause of uterine infertility, is pathologically characterized by endometrial fibrosis. Current treatments for IUA have poor efficacy with high recurrence rate, and restoring uterine functions is difficult. We aimed to determine the therapeutic efficacy of photobiomodulation (PBM) therapy on IUA and elucidate its underlying mechanisms. A rat IUA model was established via mechanical injury, and PBM was applied intrauterinely. The uterine structure and function were evaluated using ultrasonography, histology, and fertility tests. PBM therapy induced a thicker, more intact, and less fibrotic endometrium. PBM also partly recovered endometrial receptivity and fertility in IUA rats. A cellular fibrosis model was then established with human endometrial stromal cells (ESCs) cultured in the presence of TGF-β1. PBM alleviated TGF-β1-induced fibrosis and triggered cAMP/PKA/CREB signaling in ESCs. Pretreatment with the inhibitors targeting this pathway weakened PBM's protective efficacy in the IUA rats and ESCs. Therefore, we conclude that PBM improved endometrial fibrosis and fertility via activating cAMP/PKA/CREB signaling in IUA uterus. This study sheds more lights on the efficacy of PBM as a potential treatment for IUA., (© 2023 American Society for Photobiology.)

Aim: To assess, from a United States (US) payer's perspective, the cost-effectiveness of gels designed to separate the endometrial surfaces (intrauterine spacers) placed following intrauterine surgery., Materials and Methods: A decision tree model was developed to estimate the cost-effectiveness of intrauterine spacers used to facilitate endometrial repair and prevent the formation (primary prevention) and reformation (secondary prevention) of intrauterine adhesions (IUAs) and associated pregnancy- and birth-related adverse outcomes. Event rates and costs were extrapolated from data available in the existing literature. Sensitivity analyses were conducted to corroborate the base case results., Results: In this model, using intrauterine spacers for adhesion prevention led to net cost savings for US payers of $2,905 per patient over a 3.5-year time horizon. These savings were driven by the direct benefit of preventing procedures associated with IUA formation ($2,162 net savings) and the indirect benefit of preventing pregnancy-related complications often associated with IUA formation ($3,002). These factors offset the incremental cost of intrauterine spacer use of $1,539 based on an assumed price of $1,800 and the related increase in normal deliveries of $931. Model outcomes were sensitive to the probability of preterm and normal deliveries. Budget impact analyses show overall cost savings of $19.96 per initial member within a US healthcare plan, translating to $20 million over a 5-year time horizon for a one-million-member plan., Limitations: There are no available data on the effects of intrauterine spacers or IUAs on patients' quality of life. Resultingly, the model could not evaluate patients' utility related to treatment with or without intrauterine spacers and instead focused on costs and events avoided., Conclusion: This analysis robustly demonstrated that intrauterine spacers would be cost-saving to healthcare payers, including both per-patient and per-plan member, through a reduction in IUAs and improvements to patients' pregnancy-related outcomes.

Intrauterine adhesions (IUA), characterized by endometrial fibrosis, is a challenging clinical issue in reproductive medicine. We previously demonstrated that epithelial-mesenchymal transition (EMT) and fibrosis of endometrial stromal cells (HESCs) played a vital role in the development of IUA, but the precise pathogenesis remains elucidated. Ferroptosis has now been recognized as a unique form of oxidative cell death, but whether it is involved in endometrial fibrosis remains unknown. In the present study, we performed an RNA-seq of the endometria from 4 severe IUA patients and 4 normal controls. Enrichment analysis and protein-protein interactions (PPIs) network analysis of differentially expressed genes (DEGs) were conducted. Immunohistochemistry was used to assess ferroptosis levels and cellular localization. The potential role of ferroptosis for IUA was investigated by in vitro and in vivo experiments. Here, we demonstrated that ferroptosis load is increased in IUA endometria. In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs). Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05). In vivo experiments suggested that elevation of ferroptosis level in mice by erastin led to mild endometrial EMT and fibrosis. Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model. Overall, our findings revealed that ferroptosis may serve as a potential therapeutic target for endometrial fibrosis in IUA., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The study aimed to establish a stable and effective animal model for the experimental study of intrauterine adhesion (IUA) by evaluating various mechanical injury methods., Methods: A total of 140 female rats were divided into four groups according to the extent and area of endometrial injury: group A (excision area: 2.0 × 0.5 cm 2 ), group B (excision area: 2.0 × 0.25 cm 2 ), group C (endometrial curettage) and group D (sham operation). On the 3rd, 7th, 15th and 30th day after the operation, the tissue samples of each group were collected, and the uterine cavity stenosis and histological changes were recorded by HE and Masson staining. Immunohistochemistry of CD31 was applied to visualize microvessel density (MVD). The pregnancy rate and the number of gestational sacs were used to evaluate the reproductive outcome., Results: The results showed that endometrium injured by small-area endometrial excision or simple curettage could be repaired. The ratio of fibrosis in groups A and B was higher than that in groups C and group D 30 days after modeling (P < 0.001). The number of endometrial glands and MVD in group A was significantly lower than those in groups B, C and D (P < 0.05). The pregnancy rate in group A was 20%, which was lower than that in groups B (33.3%), C (89%) and D (100%) (P < 0.05)., Conclusion: Full-thickness endometrial excision has a high rate of success in constructing stable and effective IUA models in rats., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Good endometrium is the prerequisite and guarantee for reproduction and maternal and child health. Endometrial injury caused by operation or non-operation can lead to menstrual irregularities, amenorrhea, abortion, infertility, and other gynecological diseases to bother women. Intrauterine adhesions (IUA) and thin endometrium are common diseases caused by abnormal repair after endometrium damage. The incidence of IUA is not low after uterine operative surgery, and the recurrence is pretty high after uterine adhesiolysis. At present, there were many methods for endometrial repair in clinic or in the laboratory, but the efficacy was different from methods to methods. They are mainly including estrogen therapy, stem cell therapy, complementary medicine therapy, and some physical barrier therapy. In order to guide the effective repair and regeneration of endometrium in clinic, this paper reviews the merit and demerit of these methods for endometrium regeneration and repair that have been proved to be effective in experiments and clinical in recent years., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Intrauterine adhesion (IUA), a leading cause of uterine infertility, is characterized by endometrial fibrosis. Implementing an appropriate animal model is essential for the research on the mechanisms of IUA. In the present study, we established and evaluated different intrauterine adhesion modeling procedures in rats to provide a reference for researchers. Rat IUA models were established by mechanical injury, 95% ethanol injection, and dual (mechanical injury with infection) injury. After two estrus cycles, the female rats were mated with sexually mature male rats, and uterine tissues were obtained on the 5th day of pregnancy. Hematoxylin and eosin staining and immunohistochemical detection of cytokeratin 19 and vimentin were performed to assess the morphology of the endometrium. Masson's trichrome staining and the expression of transforming growth factor-β1 and collagen I were used to assess the endometrium fibrosis. The expression of integrin avβ3, leukemia inhibitory factor, and homeobox gene A10 in the rat endometrium was used to evaluate the endometrial receptivity. In addition, the efficiency of embryo implantation was examined in the uterus on the 8th day of pregnancy. Our study found that mechanical injury caused by a curette can be completely repaired after two estrus cycles. However, dual injury and 95% ethanol injection can be used to establish an IUA rat model, and the dual injury is closer to the clinicpathological characteristics of IUA.

Intrauterine adhesion (IUA) is one of the principal causes of secondary infertility in women of reproductive age, which seriously affects female reproductive function and quality of life. In recent years, the incidence of IUA has been increasing year by year, but its pathological mechanism has not yet been clarified. This study intended to reveal the pathogenesis of IUA and find new therapeutic targets by analyzing the proteomic differences between intrauterine adhesion tissues and normal human endometrial tissues. In the label-free quantitative proteomics, we identified 789 up-regulated differentially expressed proteins (DEPs) and 539 down-regulated DEPs. These DEPs were further analyzed by Gene Ontology (GO) annotation and enrichment analysis, Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis to preliminarily clarify the biomarkers involved in the pathogenesis of the IUA. The DEPs were further verified by parallel reaction monitoring (PRM) to confirm the results of proteomics. Finally, 7 target proteins may be candidates for treatment and elucidating the pathophysiology of IUA. SIGNIFICANCE: IUA is a fertility complication, which has increasing incidence recently. Until now, only a little research paid attention to the proteomic changes of IUA. This is the first study focused on the comparative analysis of endometrial tissue between IUA patients and normal women. We found 7 key proteins that may become the potential biomarkers of IUA., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients., (© The Author(s) 2023. Published by Oxford University Press.)

Iatrogenic injury to endometrial tissue is the main cause of intrauterine adhesions (IUA) and infection can also damage the endometrium. The microbiota plays an important role in the health of the female reproductive tract. However, the mechanism is still unclear. In total, 908 patients with IUA and 11,389 healthy individuals were retrospectively selected for this clinical study. Participant information including vaginal microecological results and human papillomavirus (HPV) status were collected. Univariate and multivariate logistic regression analyses were used to identify the factors related to IUA. Next, animal experiments were performed in a curettage-induced IUA rat model. After the procedure, rats in the experimental group received a vaginal infusion of a Candida albicans (C. albicans) fungal solution. On days 3, 7, and 14 after curettage and infusion, the expression levels of IL-6, fibrotic pathway-related factors (TGF-β1, Smad 2, and COL1), and estrogen receptor (ER) and progesterone receptor (PR) in rat endometrial tissues were assessed. Fungal infection of the reproductive tract was found to be an independent risk factor for IUA (P < 0.05). The inflammatory response and degree of fibrosis were greater in rats infected with C. albicans than in the controls. The levels of IL-6, TGF-β1, Smad 2, and COL1 expression in endometrial tissues were significantly higher in the experimental group than in the control group (P < 0.05). However, the ER and PR levels were lower in the IUA group than in the non-IUA group (P < 0.05). C. albicans infection may be related to IUA. C. albicans elicits a strong inflammatory response that can lead to more severe endometrial fibrosis., (© 2023. The Author(s).)

Introduction: Human umbilical cord mesenchymal stem cells (UCMSCs) play an important role in repairing the damaged endometrium of intrauterine adhesion (IUA). Meanwhile, exosomes released by UCMSCs can mediate intercellular communication by delivering miRNAs. It has been shown that miR-543 level was reduced in IUA tissues. However, the role of miR-543 in the progression of IUA remains largely unknown. Therefore, we investigated the role of UCMSCs-derived exosomal miR-543 in IUA., Methods: In this study, human endometrial epithelial cells (hEECs) were treated with TGF-β1 for mimicking endometrial fibrosis in vitro. In addition, the IUA-like mouse model in vivo was established by a dual damage method of curettage and LPS infection., Results: The level of miR-543 was markedly reduced in hEECs exposed to TGF-β1 and in endometrium tissues of IUA mice. Additionally, miR-543 could be transferred from UCMSCs to hEECs via exosomes. Meanwhile, exosomal miR-543-derived from UCMSCs significantly reduced the expressions of N-cadherin, α-SMA, fibronectin 1 and elevated the expression of E-cadherin in TGF-β1-treated hEECs. Furthermore, UCMSCs-derived exosomal miR-543 attenuated IUA-induced endometrial fibrosis in vivo, as shown by the decreased N-cadherin, α-SMA and fibronectin 1 protein expressions., Discussion: Collectively, UCMSCs-derived exosomal miR-543 was able to prevent endometrial fibrosis both in vitro and in vivo via downregulating N-cadherin. These results may provide an insight into the clinical treatment for IUA., Competing Interests: Declaration of competing interest The authors declare there is no competing financial interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intrauterine adhesion (IUA), resulting from pregnancy or nonpregnant uterine trauma, is one of the major causes of abnormal menstruation, infertility, or repeated pregnancy loss. Although a few methods, including hysteroscopy and hormone therapy, are routinely used for its diagnosis and treatment, they cannot restore tissue regeneration. Stem cells, which have self-renewal and tissue regeneration abilities, have been proposed as a promising therapy for patients with severe IUAs. In this review, we summarize the origin and features of endometrium-associated stem cells and their applications in the treatment of IUAs based on animal models and human clinical trials. We expect that this information will help to elucidate the underlying mechanism for tissue regeneration and to improve the design of stem cell-based therapies for IUAs.

Background: Intrauterine adhesion (IUA) is a condition caused due to damage or infection of the endometrium. It is characterized by continuous inflammation and following fibrosis and dysfunction. However, the current animal IUA models have several disadvantages, including complex operation, high mortality, and many extra distractions owing to opening of the abdominal cavity to expose the uterus. Mesenchymal stem cells (MSCs), which have been used in treatment of IUA, are heterogeneous and immunosuppressive. However, their therapeutic effect is not as good as expected., Methods: Here, we successfully built a new murine IUA model, called electric tool-scratching IUA model, and applied it in our experiments to investigate the efficacy of tumor necrosis factor-α (TNF-α) primed MSCs (T-MSCs). In the new model, we used a self-made electric tool that can cause mechanical damage to the endometrium without opening the abdominal cavity. ELISA and histological staining analysis were performed to evaluate pathological features of IUA. qRT-PCR, flow cytometry and immunofluoresence staining were performed to detect the phenotypes of macrophages. TMT proteomics quantification and western blotting assay were performed to analyze the differentially expressed proteins of MSC exosomes., Results: Based on the new IUA model, we found TNF-α pretreatment could enhance the ability of MSCs to relieve inflammation and reduce endometrium fibrosis. Mechanistically, T-MSC promoted macrophage polarization to M2 phenotype through exosomes. Subsequently, we found the expression of Galectin-1 was increased in T-MSC exosomes. Finally, we analyzed the gene expression pattern of Galectin-1 treated macrophages and found Galectin-1 promoted macrophage polarization to M2 phenotype mainly through the Jak-STAT signaling pathway., Conclusions: Our studies proposed an innovative mouse model and a better MSC treatment strategy for IUA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Pan, Yang, Wang, Jiang, Dou and Hou.)

The present study aimed to diagnose uterine adhesion using ultrasonography to decide the treatment approach for better survival of buffaloes suffering from uterine torsion. The peculiar visceral slide against the other abdominal organs induced by breathing was considered an absence of uterine adhesion, while the total absence of visceral slide was considered the presence of uterine adhesions on ultrasonographic examination. The 59 Mehsana buffaloes suffering from uterine torsion were divided into two groups based on the presence (Group I; n = 27) or absence (group II; n = 32) of adhesions. The mean pixel values (MPV) and thickness of uterine wall were also quantified in both the groups. In group I, severe type adhesions (n = 16/27) were directly subjected to caesarean section (CS), while fibrinous adhesions (n = 11/27) were subject to rolling by Sharma's modified Schaffer's method, and if rolling failed were further, subjected to CS and adhesions were confirm during CS. In Group II, 28 buffaloes were subjected to rolling by Sharma's modified Schaffer's method and 4 buffaloes were directly subjected to CS because of longer duration of illness (≥3 days), higher degree (≥180°) and previous field handling. The incidence of adhesions was 45.76 per cent (27/59) in buffaloes with uterine torsion. The degenerative changes such as oedematous (hyperoedema-hypoechoic with anechoic trabeculae) or thin (homogenous hypoechoic), sloughing of serosa and wall separation were observed in the uterine wall. The significantly thinner uterine wall (p = .017) and higher MPV (p = .001) were evident in group I than in group II. The weak negative non-significant correlation between uterine wall thickness and MPV was observed in group I (r = -.250, p = .147) and group II (r = -.235, p = .089). The dam survival rate was 48.15 per cent (13/27) in group I and 81.25% (26/32) in group II. There was a significant (p = .04) association between the treatment approach and dam survival. Ultrasonography has synergistic diagnostic value for uterine adhesions by evaluating uterine surfaces beyond the reach of obstetricians during a manual clinical examination. Thereby, avoiding futile efforts to relieve uterine torsion by rolling might help to improve dam survival by planning a better obstetrical manoeuvre to salvage buffaloes suffering from uterine torsion., (© 2022 Wiley-VCH GmbH.)

Intrauterine adhesion (IUA) is a gynaecological disease caused by uterine cavity surgeries and infections that leads to partial or total occlusion of the uterine cavity. However, the underlying mechanism(s) and progression of the disease have not yet been identified. IUA has a high recurrence rate and poor prognosis, and effective drugs to prevent adhesion are lacking. Therefore, establishing an effective animal model of IUA is of great significance for revealing the pathogenesis of IUA and the mechanism(s) governing drug effects. Rats, mice, rabbits, and other animals are currently used to establish intrauterine adhesion models. The IUA induction methods include chemical, thermal, or mechanical damage and mechanical damage combined with an infective method. We analysed the advantages and disadvantages of various models and their clinical simulations in order to provide a precise animal model for exploring the pathogenesis, treatment strategies, and prevention of IUA.

Intrauterine adhesion (IUA) refers to injury to the basal layer of the endometrium, which can be caused by various factors. It is often accompanied by clinical symptoms such as abnormal menstruation, infertility, recurrent abortion, and periodic abdominal pain. In recent years, a number of studies have reported the effects of β-Klotho (KLB) on the occurrence and development of human tumors and fibrotic diseases, but its relationship with endometrial fibroblasts and endometrial fibrosis has not been elucidated. In this study, we compared the expression of KLB in endometrial stromal cells (ESCs) from patients with IUA and normal controls. We constructed animal and cell models of IUA and conducted expression verification and functional experiments on KLB. We found that the expression of KLB was significantly increased in the ESCs of IUA patients and rat models compared with the controls. The overexpression of KLB could promote the proliferation and fibrosis of ESCs. In addition, the overexpression of KLB activated the PI3K/AKT signaling pathway in ESCs. Our study shows that KLB protein is highly expressed in the ESCs of patients with IUA and can enhance stromal cell proliferation and cell fibrosis by activating the PI3K/AKT pathway, thus promoting the development of IUA.

Background: Endometrial fibrosis caused by intrauterine adhesion (IUA) can lead to hypomenorrhea, amenorrhea, and even infertility and abortion. The postoperative recurrence rate of severe IUA remains high, giving rise to low pregnancy rates. An extracellular matrix (ECM) scaffold, a new biological material that can promote cell proliferation and differentiation at lesions, has been widely used in general surgery and neurosurgery. The present study applied ECM scaffolds in obstetrics and gynecology for the first time to improve endometrial fibrosis, repair severe IUA, and improve pregnancy outcomes for infertile patients., Methods: This paper presents a prospective randomized single-blind controlled superiority study of infertile women aged ≤40 years with IUA. According to the scoring criteria for IUA established by the American Fertility Society, patients with moderate or severe IUA were randomized into two groups at a ratio of 1:1; patients in the experimental group were treated with an ECM scaffold (small intestinal submucosa [SIS]) + intrauterine balloon, while patients in the control group were treated with an intrauterine balloon only. A hysteroscopic examination of adhesion repair was performed again after 2 months of postoperative hormone replacement therapy. Endometrial tissue was sampled during the two operations, and immunohistochemistry was used to observe endometrial and microvascular proliferation. After thawing and resuscitation, a postoperative frozen embryo transfer was performed on the participants in both groups, and their endometrial thickness, intrauterine volume, endometrial vascularization flow index, endometrial flow index, and uterine artery blood flow resistance were evaluated by 3D ultrasonography. The rates of embryo implantation, clinical pregnancy, and early spontaneous abortion were observed., Discussion: The ECM scaffold (SIS) + intrauterine balloon method was able to repair endometrial fibrosis and improve IUA. This new technique represents a novel treatment method for improving the pregnancy outcome of infertile patients with moderate/severe IUA., Trial Registration: Chinese Clinical Trial Register ChiCTR2100052027 . Registered on October 14, 2021., (© 2022. The Author(s).)

Background: There is unmet need for effective therapies of intrauterine adhesions (IUAs) that are common cause of menstrual disturbance and infertility, since current clinical procedures do not improve prognosis for patients with moderate to severe IUA, with a recurrence rate of 23-50%. Stem cell-based therapy has emerged as a therapeutic option with unsolved issues for IUA patients in the past few years. Primary endometrial epithelial cells for cell therapy are largely hampered with the extremely limited proliferation capacity of uterine epithelial cells. This study was to evaluate whether IUA is curable with conditionally reprogrammed (CR) endometrial epithelial cells., Methods: Mouse endometrial epithelial cells (MEECs) were isolated from C57BL female mice, and long-term cultures of MEECs were established and maintained with conditional reprogramming (CR) method. DNA damage response analysis, soft agar assay, and matrigel 3D culture were carried out to determine the normal biological characteristics of CR-MEECs. The tissue-specific differentiation potential of MEECs was analyzed with air-liquid interface (ALI) 3D culture, hematoxylin and eosin (H&E) staining, Masson's trichrome and DAB staining, immunofluorescence assay. IUA mice were constructed and transplanted with CR-MEECs. Repair and mechanisms of MEECs transplantation in IUA mice were measured with qRT-PCR, Masson's trichrome, and DAB staining., Results: We first successfully established long-term cultures of MEECs using CR approach. CR-MEECs maintained a rapid and stable proliferation in this co-culture system. Our data confirmed that CR-MEECs retained normal biological characteristics and endometrium tissue-specific differentiation potential. CR-MEECs also expressed estrogen and progesterone receptors and maintained the exquisite sensitivity to sex hormones in vitro. Most importantly, allogeneic transplantation of CR-MEECs successfully repaired the injured endometrium and significantly improved the pregnancy rate of IUA mice., Conclusions: Conditionally reprogrammed physiological endometrial epithelial cells provide a novel strategy in IUA clinics in a personalized or generalized manner and also serve as a physiological model to explore biology of endometrial epithelial cells and mechanisms of IUA., (© 2022. The Author(s).)

Biomedical patches are considered as a promising strategy to help tissue repair and regeneration, prevent tissue adhesion, and reduce neighboring friction. Here, novel arrowhead composite microneedle patches (MNPs) are presented with anisotropic surface adhesion and growth factor encapsulation using a heterogeneous template replication approach for endometrium repair and intrauterine adhesions (IUAs) prevention. The arrowhead structures bring about interlocking between the microneedle (MN) tips and tissues, allowing these MNPs to steadily adhere to the tissues. Besides, benefitting from the cytoadhesive needle-tip material and the antiadhesive base material, these MNPs possess anisotropic surface adhesion and can facilitate cell adhesion on one surface to repair damaged tissues while restrain tissue contact on the other to prevent adverse adhesion. In the meanwhile, the encapsulated growth factor can be delivered through the MNs to the deep tissue, further accelerating tissue repair. Additionally, as the bases are soft and their patterns are highly tunable, the MNPs can change their shapes flexibly to adjust to the irregular morphology of uteri. It is demonstrated that these MNPs show good performances in treating injured endometrium and preventing IUAs of a rat model, indicating their great potential in versatile postoperative adhesion prevention and other clinical applications., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Menstrual blood mesenchymal stem cell (MBMSC) is a potential cell source for effective therapy for intrauterine adhesion (IUA). Collagen scaffold (CS) loaded with mesenchymal stem cells promotes endometrial regeneration in IUA model animals. However, role of combination of MBMSCs and CS in IUA therapy remains elusive. In particular, transplantation of MBMSCs over a long period of time requires more in-depth research. Here in this study, transplantation of human MBMSCs loaded on CS was applied for therapy for a long term rat IUA model. A rat IUA model characterized by lower number of endometrial glands and increased fibrosis was established. At 90 days after transplantation of the human MBMSC-loaded CS, expression of HuNu, a human protein, was identified in the uteri of the transplanted IUA model rats. The transplantation increased the number of endometrial glands and decreased the fibrotic areas significantly. Moreover, transplantation of the human MBMSC-loaded CS decreased the Collagen I and increased the CK 18 significantly. Immunoblotting assay results further proved the downregulation of Collagen I and the upregulation of CK 18. Together, endometrium regeneration promoted by human MBMSC-loaded CS was demonstrated in a long term rat model of IUA, shedding a new light on the role of human MBMSCs in the therapy for IUA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Intrauterine adhesions (IUAs) caused by mechanical damage or infection increase the risk of infertility in women. Although numerous physical barriers such as balloon or hydrogel are developed for the prevention of IUAs, the therapeutic efficacy is barely satisfactory due to limited endometrial healing, which may lead to recurrence. Herein, a second near-infrared (NIR-II) light-responsive shape memory composite based on the combination of cuprorivaite (CaCuSi 4 O 10 ) nanosheets (CUP NSs) as photothermal conversion agents and polymer poly(d,l-lactide-co-trimethylene carbonate) (PT) as shape memory building blocks is developed. The as-prepared CUP/PT composite possesses excellent shape memory performance under NIR-II light, and the improved operational feasibility as an antiadhesion barrier for the treatment of IUAs. Moreover, the released ions (Cu, Si) can stimulate the endometrial regeneration due to the angiogenic bioactivity. This study provides a new strategy to prevent IUA and restore the injured endometrium relied on shape memory composite with enhanced tissues reconstruction ability., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: Intrauterine adhesion (IUA) is one of the major causes of refractory secondary infertility, especially in regions and countries with high abortion rates. In this study, we used the mouse IUA model to evaluate the feasibility of the organoids, a 3D cell structure derived from endometrial tissue, as grafts for the treatment of post-traumatic endometrial regeneration disorders., Methods: The isolated and cultured endometrial organoid was transplanted into the model IUA uterus by the hydrogel scaffold method., Results: The cultured endometrial organoids were transplanted into the basal layer of the damaged endometrium for 28 days. They were completely implanted and grew normally. They not only reconstructed the structural integrity of the endometrial epithelium but also realized the functional repair of the endometrium through differentiation cultures and secretory functions., Conclusion: For severe IUA, this method may be better than stem cell transplantation. These findings provide useful insights into the use of endometrial organoid regeneration in the treatment of injury repair., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Huang, Zhao, Chen, Lin and Shi.)

Intrauterine adhesion refers to endometrial repair disorders which are usually caused by uterine injury and may lead to a series of complications such as abnormal menstrual bleeding, recurrent abortion and secondary infertility. At present, therapeutic approaches to intrauterine adhesion are limited due to the lack of effective methods to promote regeneration following severe endometrial injury. Therefore, to develop new methods to prevent endometrial injury and intrauterine adhesion has become an urgent need. For severely damaged endometrium, the loss of stem cells in the endometrium may affect its regeneration. This article aimed to discuss the characteristics of various stem cells and their applications for uterine tissue regeneration., (© 2021. The Author(s).)

Intrauterine adhesion (IUA) formation and the resulting Asherman's syndrome (AS) is an unfortunate clinical condition that occurs when the endometrium is damaged as a consequence of trauma, such as vigorous curettage, infection, or some Müllerian anomaly. The most frequent symptoms include hypo/amenorrhea, infertility, and adverse reproductive outcomes. Prevention of IUA formation is essential; however, when present, accurate diagnosis and surgical intervention (hysteroscopic adhesiolysis) are required. The outcome of this treatment is based on the technique and the extent of surgery performed which depends on the severity and complexity of the disease. Hence its classification becomes particularly important to determine a standardized therapy for each case and patient counseling regarding the prognosis. In this article, we aim to describe the IUAs classification systems that have been proposed comparing the merits and demerits of each one.

Intrauterine adhesion is a major cause of menstrual irregularities, infertility, and recurrent pregnancy losses and the progress towards its amelioration and therapy is slow and unsatisfactory. We aim to summarize and evaluate the current treatment progress and research methods for intrauterine adhesion. We conducted literature review in January 2020 by searching articles at PubMed on prevention and treatment, pathogenesis, the repair of other tissues/organs, cell plasticity, and the stem cell-related therapies for intrauterine adhesion. A total of 110 articles were selected for review. Uterine cell heterogeneity, expression profile, and cell-cell interaction were investigated based on scRNA-seq of uterus provided by Human Cell Landscape (HCL) project. Previous knowledge on intrauterine adhesion (IUA) pathogenesis was mostly derived from correlation studies by differentially expressed genes between endometrial tissue of intrauterine adhesion patients/animal models and normal endometrial tissue. Although the TGF-β1/SMAD pathway was suggested as the key driver for IUA pathogenesis, uterine cell heterogeneity and distinct expression profile among different cell types highlighted the importance of single-cell investigations. Cell-cell interaction in the uterus revealed the central hub of endothelial cells interacting with other cells, with endothelial cells in endothelial to mesenchymal transition and fibroblasts as the strongest interaction partners. The potential of stem cell-related therapies appeared promising, yet suffers from largely animal studies and nonstandard study design. The need to dissect the roles of endometrial cells, endothelial cells, and fibroblasts and their interaction is evident in order to elucidate the molecular and cellular mechanisms in both intrauterine adhesion pathogenesis and treatment.

Background: Rumex crispus L. (Polygonaceae), known as "Labada" in Turkey, was reported to be used for the treatment of gynecological diseases such as postpartum complications and infertility in folk medicine. Earlier studies on R. crispus have shown that leaf, fruit and root extracts have anti-inflammatory and antioxidant activities and are used for the treatment of tumors in the uterus. The hypothesis of this study is that R. crispus may generate potential anti-adhesive activity against complex factors such as inflammation, oxidation and fibrosis., Objectives: We aimed to investigate the potential anti-adhesive activity of aqueous methanol extracts of leaves, fruits and roots of R. crispus., Methods: Abdominal adhesion model was performed in 72 female Wistar Albino rats. In the first step of the experiment, the rats were divided into six groups namely, Sham, Control, Reference and Experimental Groups (consisting of three sub-groups in which R. crispus leaf, fruit and root extracts were applied at 100 mg/kg dose). The test samples were administered once to the peritoneal cavity and the rats were sacrificied at the end of the 14th day. Root extract showed prominent activity, therefore this extract was subjected to fractionation to obtain 3 fractions (30-60-100% methanol fractions) by using vacuum-liquid chromatography. In the second stage, animals were divided into 6 groups as Sham, Control, Reference and Experimental Groups (R30, R60, R100 at 100 mg/kg dose). Adhesion scoring, tissue total antioxidant and oxidant levels, histopathological and immunohistochemical (TNF-α, IL-6 and IL-8) analyzes were performed., Results and Conclusion: Adhesion scores, inflammatory cytokines and inflammation cells decreased by the application of R. crispus root extract. The fractions also showed similar anti-inflammatory effects, but R60 was found to be more effective in prevention of intra-abdominal adhesions and uterine fibrosis. R60 fraction, possessing potential bioactivity, was investigated in terms of phenolic composition by HPLC.

Background: Intrauterine adhesion seriously affects reproductive health in women. Hysteroscopic adhesiolysis using cold scissors or electrosurgery is the main treatment, although there is no consensus on the preferable method. This review aimed to compare the efficacy and safety of these methods for treating moderate to severe intrauterine adhesion., Methods: PubMed, EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Web of Science, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure were searched on April 30, 2020. Randomized controlled trials and observational studies that were published in all languages (must contain English abstracts) and compared hysteroscopic cold scissors with electrosurgery for the treatment of intrauterine adhesion were included. Mean differences, odds ratios, and 95% confidence intervals (CIs) were reported. Bias was evaluated using the Cochrane Risk of Bias assessment tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. Data were analyzed using RevMan software (Review Manager version 5.3, The Cochrane Collaboration, 2014). Two researchers independently extracted data and assessed the quality of the included studies. If a consensus was not reached, a third researcher was consulted., Results: Nine studies (n = 761; 6 randomized controlled trials and 3 retrospective studies) were included. The intrauterine adhesion recurrence rate with second look hysteroscopy was significantly lower (odds ratio = 0.30, 95% CI = 0.16-0.56; P = .0002) with hysteroscopic cold scissors than with electrosurgery. The total operation time was significantly shorter (mean difference = -7.78, 95% confidence interval = -8.50 to -7.07; P < .00001), intraoperative blood loss was significantly lower (mean difference = -9.88, 95% CI = -11.25 to -8.51; P < .00001), and the menstrual flow rate was significantly higher (odds ratio = 4.36, 95% confidence interval = 2.56-7.43; P < .00001) with hysteroscopic cold scissors than with electrosurgery. There were no significant differences in the pregnancy rate. One complication (1 perforation case, hysteroscopic cold scissors group) was reported., Conclusions: Hysteroscopic cold scissors is more efficient in preventing intrauterine adhesion recurrence, increasing the menstrual flow, reducing intraoperative blood loss, and shortening the operation time., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

We previously reported that transplantation of menstrual blood-derived stromal cells (MenSCs) significantly improved fertility restoration in intrauterine adhesion (IUA). However, it is difficult to obtain menstrual blood samples in some severe IUA patients who have amenorrhea or oligomenorrhea. Thus, a safe and effective stem cell replacement therapy is necessary to promote endometrial regeneration. Recent studies demonstrated that the effects of MenSCs are partly mediated in a paracrine manner via small extracellular vesicles (sEVs). To explore this possibility, we performed a pre-clinical study to investigate whether concentrated MenSC-derived sEVs (MenSCs-sEVs) are sufficient to repair IUA and the mechanisms underlying their action. Rat IUA models were established by mechanical injury, followed by the administration of MenSCs or MenSCs-sEVs through intrauterine transplantation. Consistent with the efficacy of MenSCs, MenSCs-sEVs effectively recovered the morphology, promoted regeneration of the glands and angiogenesis, and reversed endometrial fibrosis in the IUA uterus. The endometrial receptivity and pregnancy outcome significantly improved after repeated MenSCs-sEVs transplantations. In addition, all rats in the MenSCs-sEVs group had no hematological or biochemical abnormalities. Three-dimensional fluorescence imaging suggested that MenSCs tended to migrate through the bloodstream, whereas MenSCs-sEVs had a better localized therapeutic effect. Moreover, MenSCs and MenSCs-sEVs inhibited the TGFβ1/SMAD3 pathway in the IUA endometrium, while promoting the phosphorylation of SMAD1/5/8 and ERK 1/2 and upregulating the expression of BMP7. Thus, MenSCs-sEVs safely and effectively enhanced endometrial restoration, suggesting a promising non-cellular therapy for endometrial regeneration and a key role in MenSC-mediated IUA treatment.

Objective: C-X-C motif chemokine ligand 5 (CXCL5), a member of the chemokine family, is associated with remodeling of connective tissues. However, its role in formation of intrauterine adhesions (IUA) remains unclear. We aimed to investigate the expression and mechanism underlying the role of CXCL5 in IUA., Methods: Expression of CXCL5 in IUA was detected by immunohistochemistry in a rat model of IUA and by real-time PCR and western blotting in patients with IUA. The protein levels of matrix metalloproteinase 9 (MMP9) and transcription factor p65 in human endometrial cells were assessed by western blotting after CXCL5 overexpression., Results: Protein expression of CXCL5 was significantly decreased in the endometria of IUA rats compared with that of control and sham-operated rats. Real-time PCR and western blotting in patients with IUA showed similar results to those from the rat model. After overexpression, CXCL5 significantly upregulated expression of MMP9 and slightly upregulated expression of p65 in human endometrial cells., Conclusions: CXCL5 plays an important role in IUA formation after endometrial injury. We propose a molecular mechanism to explain formation of IUA, including downregulation of MMP9 by low CXCL5 expression. These findings provide valuable information for the prevention and targeted therapy of IUA.

Introduction: intrauterine pathologies were traditionally evaluated by blind dilatation and curettage along with hysterosalpingography. Hysteroscopy is a veritable tool for evaluation of uterine cavity pathologies with an increasing availability in Nigeria. The study aims to report the diagnostic yield and therapeutic outcome of hysteroscopy in women with infertility from a Nigerian metropolis., Methods: a retrospective cross-sectional study of consecutive cases of infertile women referred for hysteroscopy to an ambulatory care endoscopy facility in Port Harcourt, Nigeria. The variables collated included age, parity, past gynaecological history, indication, hysteroscopy findings and interventions. Statistical analysis was performed using SPSS version 25., Results: included in study were 75 patients undergoing a total of 124 hysteroscopic procedures. The age range of patients was 25 to 56 years (mean 40.7 ± 5.9 years). A positive diagnostic yield of 93.3% with non-visualization of intracavitary uterine pathology in 5 patients was recorded. The most common pathologies were submucous myoma-25(31.3%), endometrial polyps- 18(22.5%) and intrauterine adhesions-18(22.5%). There was no statistical difference between the mean age of patients with or without polyp, myoma and intrauterine adhesions (P = 0.185, P = 0.510 and P = 0.619 respectively) but a non-linear relationship between age and polyp detection (Eta2 = 0.024). Operative hysteroscopies were all performed on out- patient basis but staged in 30(40.0%) patients., Conclusion: benign uterine growths and intrauterine adhesions are frequent causes of uterine factor infertility. A high successful completion rate of hysteroscopic interventions was achieved., Competing Interests: The authors declare no competing interests., (Copyright: Emeka Ray-Offor et al.)

Objective: To evaluate the rate of pregnancy following hysteroscopic management of intrauterine adhesions., Design: Retrospective study., Setting: From June 2009 to December 2014 in a teaching hospital., Patients: Women treated by operative hysteroscopy for intrauterine adhesions., Intervention: Operative hysteroscopy to manage intrauterine adhesions., Main Outcome Measure: rate of intrauterine pregnancy after hysteroscopic management of intrauterine adhesions., Results: Out of the 202 women whom benefit from hysteroscopic adhesiolysis, 112(55%) had an effective pregnancy desire. Among them, an intrauterine pregnancy was obtained for 58 women (52%) with a trend to a lower rate for type IV and Vb intrauterine adhesions management (40.5%, p = 0.09). Pregnancy rates were similar for women undergoing one or more procedures., Conclusion: Hysteroscopic management of intrauterine adhesions seems useful as it leads to a pregnancy rate of 52%. However, this rate is lower in case of type IV and Vb intrauterine adhesions. Repeated procedures don't seem to lead to less pregnancy; however, a more powerful prospective study should be performed to answer this specific question., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Intrauterine adhesion (IUA) caused by endometrial injury is one of the important causes of infertility in women of reproductive age and requires advanced treatment strategies. Increasing evidence suggests that the therapeutic effects of mesenchymal stem cells (MSC) mainly depend on their capacity to secrete paracrine factors and are mediated by MSC-derived exosomes. This study aimed to identify exosomes derived from adipose-derived mesenchymal stem cells (ADSC-exo) and explore the therapeutic potential in IUA rat models. ADSC-exo exhibited classic cup-shaped morphology with a positive expression of Alix and CD63 and were mainly concentrated at 109.5 nm. In IUA model, treatment with ADSC-exo maintained normal uterine structure, promoted endometrial regeneration and collagen remodeling, and enhanced the expression of integrin-β3, LIF, and VEGF. An improved receptivity of the regenerated endometrium was confirmed. Our findings demonstrated that ADSC-exo promoted endometrial regeneration and fertility restoration. It suggested that topical administration of ADSC-exo in uterus could be a promising strategy for patients suffering severe intrauterine adhesions and infertility.

The replacement of normal endometrial epithelium by fibrotic tissue is the pathological feature of intrauterine adhesion (IUA), which is caused by trauma to the basal layer of the endometrium. COL5A2 is a molecular subtype of collagen V that regulates collagen production in fibrotic tissue. Here, we investigated the roles of Foxf2 and Smad6 in regulating the transcription of COL5A2 and their involvement in the pathogenesis of IUA. Small interference-mediated Foxf2 (si-Foxf2) silencing and pcDNA3.1-mediated Smad6 (pcDNA3.1-Smad6) up-regulation were performed in a TGF-β1-induced human endometrial stromal cell line (HESC) fibrosis model. Assessment of collagen expression by Western blotting, immunofluorescence and qRT-PCR showed that COL5A2, COL1A1 and FN were significantly down-regulated in response to si-Foxf2 and pcDNA3.1-Smad6. Transfection of lentivirus vector-Foxf2 (LV-Foxf2) and pcDNA3.1-Smad6 into HESCs and qRT-PCR showed that Foxf2 promoted COL5A2 expression and Smad6 inhibited Foxf2-induced COL5A2 expression. Co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays to detect the interaction between Foxf2 and Smad6 and their role in COL5A2 transcription showed that Foxf2 interacted with Smad6 and bond the same promoter region of COL5A2. In a rat IUA model, injection of ADV2-Foxf2-1810 and ADV4-Smad6 into the uterine wall showed that Foxf2 down-regulation and Smad6 up-regulation decreased fibrosis and the expression of COL5A2 and COL1A1, as detected by haematoxylin/eosin, Masson trichrome staining and immunohistochemistry. Taken together, these results suggested that Foxf2 interacted with Smad6 and co-regulated COL5A2 transcription in the pathogenesis of IUA, whereas they played opposite roles in fibrosis., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

This network meta-analysis was conducted to compare the efficacy of six interventions, including anti-blocking agents, intrauterine contraceptive devices (IUDs), estrogens, intrauterine balloon, Foley catheter, and amnion graft for the prevention of intrauterine adhesions (IUAs). We searched PubMed, Embase, and Cochrane Library from inception to December 2016. Cohort studies meeting these six interventions in the prevention of IUAs were included. The combination of direct and indirect evidence was conducted to assess the odds ratio (OR) or weighted mean differences and surface under the cumulative ranking curves of the six interventions in the prevention of postoperative IUAs. Finally, 12 eligible cohort studies were included in this network meta-analysis. The results of this network meta-analysis demonstrated that during 1 to 2 months after operation, compared with the surgical group, anti-blocking agent, and estrogens presented with relatively low ratios of postoperative IUAs (OR = 0.30 95% confidence interval (CI) = 0.10-0.67; OR = 0.12, 95% CI = 0.01-0.78, respectively). Compared with IUDs, estrogens exerted comparatively low ratio of postoperative IUAs (OR = 0.10, 95% CI = 0.01-0.90), which indicated that anti-blocking agent and estrogens had relatively better prevention efficacy. The cluster analysis showed that estrogens had relatively better efficacy in the prevention postoperative IUAs. Overall, our findings support that estrogens had relatively better efficacy in the prevention of postoperative IUAs., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The aim of this study was to investigate the role of kinase-insert domain-containing receptor (KDR) in intrauterine adhesions (IUA) and its mechanism. The Case group consisted of 92 patients diagnosed with IUA, and the Control group included 86 patients with uterine septum who had normal endometrium verified with an uteroscope. In addition, 50 rats were randomly assigned into Control, Sham, Model, NC-siRNA, and KDR-siRNA groups. Rats in the Model, NC-siRNA, and KDR-siRNA groups were induced by uterine curettage and lipopolysaccharide (LPS) treatment to establish the IUA model. Then, immunohistochemistry was applied for detection of VEGF and KDR expression, HE staining was used for observation of the endometrial morphology and gland counting, Masson staining for measurement of the degree of endometrial fibrosis, and qRT-PCR and western blot for the expression of KDR, VEGF, MMP-9, as well as TGF-β1/Smads pathway-related proteins. Compared with the Control group, the mRNA and protein expressions of KDR were significantly higher in IUA endometrial tissues, and the expression of KDR was positively correlated to the severity of IUA. In addition, the injection of si-KDR increased the number of endometrial glands, reduced the area of fibrosis, inhibited mRNA and protein expression of KDR and VEGF, up-regulated the expression of MMP-9 and Smad7, and decreased the expression level of TGF-β1, p-Smad2, p-Smad3, and Smad4 in rats with IUA. Highly-expressed KDR was related to patients' severity of IUA, and silencing KDR may prevent the occurrence and development of IUA via TGF-β1/Smads signaling pathway and up-regulating the expression of MMP-9.

Objective: To compare the efficacy of intermittent intrauterine balloon dilatation versus standard care in the prevention of adhesion reformation., Design: Single-blind randomised controlled trial., Setting: Hysteroscopic Centre of a tertiary University Hospital., Population: Two hundred patients with moderate to severe (European Society for Gynaecological Endoscopy Grade ≥II) intrauterine adhesions who underwent hysteroscopic adhesiolysis., Methods: All participants were randomised to a balloon group or a control group postoperatively. The balloon group received intrauterine balloon dilatation therapy at 2 weeks and 6 weeks after surgery, whereas the control group did not. All patients underwent follow-up hysteroscopy at 4 and 8 weeks postoperatively., Main Outcome Measures: The adhesion reformation rate and the Pictorial Blood Loss Assessment Chart scores were analysed., Results: A total of 191 patients successfully completed the study protocol (94 cases for the balloon group and 97 cases for the control group). According to hysteroscopic evaluation at the 8th week, the overall adhesion reformation rate was significantly lower in patients in the balloon group than patients in the control group (20.2% versus 40.2%, respectively; P < 0.05). There was also a significant increase in menstruation flow, as assessed by the Pictorial Blood Loss Assessment Chart score (30 versus 9, respectively; P < 0.001)., Conclusions: Postoperative intermittent intrauterine balloon dilatation therapy can significantly reduce postoperative adhesion reformation and significantly increase menstruation flow., Tweetable Abstract: RCT: Postoperative intermittent intrauterine balloon therapy can prevent adhesion reformation after hysteroscopic adhesiolysis., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Background: Intrauterine adhesion (IUA) is an adhesion of the uterine cavity or cervical canal resulting from damage to the basal layer of the endometrium; this condition is usually accompanied by fibrosis of the endometrium. Previous studies have demonstrated that human amniotic epithelial cells (hAECs) have stem cell characteristics; however, it is unclear whether hAECs have the therapeutic potential to restore fertility after IUA., Methods: A murine IUA model was established by mechanical injury to the uterus. Then, 10 6 hAECs were transplanted by intraperitoneal injection. The endometrium thickness, number of glands, and fibrosis area were measured by hematoxylin and eosin (H&E) staining and Masson staining. Molecules (including vWF, VEGF, PCNA, ER, PR, LC3, and p62) related to endometrial angiogenesis, cell proliferation, and autophagy were assayed by IHC staining. Pregnancy outcomes were also evaluated. Finally, hAECs were cocultured with human endometrial mesenchymal stem cells (hEnSCs) damaged by H 2 O 2 to verify the paracrine effect on endometrial stromal cells in vitro., Results: The IUA uterine cavity presented with adhesion and even atresia, accompanied by a thinner endometrium, fewer glands, increased fibrosis area, and fewer microvessels. However, hAECs significantly improved the uterine structure after IUA. After hAEC treatment, the endometrium was thicker, the number of endometrial glands was increased, fibrosis was reduced, and more microvessels were generated. The expression levels of VEGF, PCNA, and ER were increased in the hAEC-treated endometrium, indicating improvements in angiogenesis and stromal cell proliferation. hAECs also increased pregnancy outcomes in IUA mice, and the pregnancy rate and fetus number increased. Furthermore, we observed altered autophagy in the IUA uterine model, and hAEC transplantation upregulated autophagy. An in vitro study showed that hAECs activated autophagy in (hEnSCs) treated with H 2 O 2 in a paracrine manner., Conclusions: Our results demonstrated that hAECs have the potential to repair the uterus after injury, providing a new strategy for the prevention and treatment of Asherman syndrome.

Competing Interests: There are no conflicts of interest

The pathogenesis and therapeutic treatment of intrauterine adhesions (IUAs) remain unsolved, highlighting the need for stable and effective experimental animal models. In this study, uterine electrocoagulation of twenty-one female New Zealand White rabbits was carried out to establish an IUA model. As rabbits have two completely separate uterine horns, each rabbit had its own internal control: one uterine horn was given an electrothermal injury (Group A, n=21), and the contralateral uterine horn received no treatment and served as the control (Group B, n=21). The endometrial morphology, number of endometrial glands, area of endometrial fibrosis, and number of implanted fetuses were compared between the two groups. In Group A, the numbers of endometrial glands on Days 7 and 14 and the number of implanted fetuses were significantly lower than those in Group B (P<0.05, P<0.05, and P<0.01, respectively), while the ratio of the area with endometrial stromal fibrosis to the total endometrial area was significantly increased (P<0.01). These results suggest that this method of electrothermal injury is effective for the establishment of a rabbit IUA model between 7 and 14 d after surgery.

Intrauterine adhesions (IUA) are associated with the loss of stem cells in the endometrium. Menstrual blood‑derived stem cells (MenSCs) can be isolated from the menstrual blood and differentiated into endometrial cells. To check the transplantation feasibility of MenSCs for the treatment of severe IUA, MenSCs were isolated from menstrual blood, cultured in Dulbecco's modified Eagle's medium (DMEM), identified by immunocytochemistry and flow cytometry, differentiated into endometrial cells in vitro, and finally transplanted into the axillary subcutaneous tissue of non‑obese diabetic/severe combined immunodeficiency (NOD‑SCID) mice to create endometrial tissue. Additionally, the cloning efficiency and POU domain class 5 transcription factor 1 (OCT‑4) positivity of MenSCs from patients with severe IUA were compared with those from healthy women. Immunocytochemistry and flow cytometry results showed that 95.1±0.8% cells were OCT‑4‑positive, 0.9±0.4% were cluster of differentiation (CD)45‑positive, 1.8±0.9% were STRO‑1‑positive and 1.0±0.4% were human leukocyte antigen‑antigen D related‑positive. Following differentiation in vitro, the results of immunocytochemistry, reverse transcription‑polymerase chain reaction and western blot analysis showed that the expression of cytokeratin (CK) and vimentin (VIM) was increased in MenSCs compared with that in control subjects. Subsequent to transplantation in mice administered with sequential 17β‑estradiol and progesterone, CK, VIM, estrogen receptor and progesterone receptor were expressed in the transplantation regions, suggesting that MenSCs could differentiate into endometrial tissues in vivo. The cloning efficiency and OCT‑4 positivity of MenSCs from patients with severe IUA was significantly decreased. In conclusion, to the best of our knowledge, this is the first study in which MenSCs could differentiate into endometrial cells in vitro and create endometrial tissue in NOD‑SCID mice in vivo, with impaired cloning efficiency and OCT‑4 expression of MenSCs from patients with IUA. This study will provide a theoretical basis for the treatment of IUA with MenSCs.

Objective: To study whether small intestine submucosa (SIS) could be a treatment option for preventing the formation of intrauterine adhesions (IUAs)., Methods: The IUAs model was established by mechanical curettage and infectious injury in a rat model. One uterine horn of the rat model was treated with the transplantation of SIS (SIS group) and the other one was left without any treatment (control group). The endometrium was evaluated with endometrial thickness, number of glands and fibrosis area. The endometrial receptive factors were detected by quantitative real-time polymerase chain reaction The number and location of embryos were documented to assess the function of endometrium., Results: In the SIS group, endometrial thickness was significantly thicker than that in the control group on the 14th and 21st day and the percentage of fibrosis area was significantly lower during the entire observation process (p < 0.05). The number of glands was similar between the 2 groups (p > 0.05). Receptive factors changed as follows: in the SIS group, the expression of uteroglobin was higher and peaked on the 21st day (3.42-fold, p < 0.05); the HOXA10 level was significantly higher on the 10th day (2.16-fold, p < 0.05), and it then decreased. More embryos were seen in SIS horns (5.13 vs. 1.25, p < 0.05)., Conclusions: SIS could be a potential physical barrier for the formation of IUAs. It contributes to the regeneration of and improvement of the receptivity of endometrium, and helps in the implantation and development of embryos in a rat model., (© 2017 S. Karger AG, Basel.)

Objective: The study was to evaluate whether fibrotic markers, endometrial receptivity markers and SDF-1/CXCR4 had been changed in the treatment of intrauterine adhesions (IUAs) by different dosages of estrogen., Study Design: A total of 39 patients with IUAs were treated with EV 4 mg or 9 mg randomly post-surgery. TGF-β1/MMP-9, VEGF/αvβ3 and SDF-1/CXCR4 were detected in endometrial tissue before and after treatment by real-time PCR and Western blot., Results: TGF-β1 and MMP-9 expression significantly decreased after treatment for 3 months than before (p < .05), the falling range was larger with EV 4 mg than 9 mg in the mild-moderate degree IUAs (p < .05); Integrin avβ3 expression significantly increased after treatment for 3 months than before (p < .05), the variation range was larger with EV 4 mg than 9 mg (p < .05); CXCR4 expression had no significant change after treatment 3 months compared to that before treatment (p > .05). SDF-1 presented an upward tendency at early phase, and it came back to the level of pre-surgery. But there were no significant difference between treatment with 4 mg and 9 mg in the rate of menstrual restoration and pregnancy follow-up 3 months after the treatment., Conclusions: Endometrium fibrosis may be inhibited and endometrium receptivity may be improved by estrogen with moderate dosage therapy. Compared to the large one, it seems to be advantageous.

Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E 2 ) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat's endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E 2 -HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E 2 -HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E 2 -HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E 2 -HP hydrogel showed a prolonged release of E 2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E 2 -HP hydrogel group. We also demonstrated that E 2 -HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E 2 into the injured endometrium. Therapeutic strategies targeting ER stress using E 2 -HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This study aimed to investigate the effects of estrogen in combination with aspirin and intrauterine balloon on the uterine endometrial repair and reproductive prognosis in patients after surgery for severe intrauterine adhesion (sIUA). We prospectively recruited 114 patients with sIUA. Intrauterine device (IUD) was placed and oral estrogen was administered after surgery. Patients were divided into control group and aspirin group. In addition, patients in aspirin group were subdivided into nonballoon group and balloon group. Results showed that, after therapy, the increase in endometrial thickness of aspirin groups was superior to control group ( P < 0.05). The scores of intrauterine adhesion and menstruation were significantly improved in balloon group as compared to nonballoon group and control group, and significant differences were also observed between nonballoon group and control group ( P < 0.05). Of 97 patients, 44.3% became pregnant after surgery, the live birth rate was 27.8%, and the miscarriage rate was 37.2%, but there were no significant differences among three groups ( P > 0.05). Thus, aspirin may promote the uterine endometrial growth and repair after surgery for sIUA, and IUD in combination with intrauterine balloon may reduce the recurrence of intrauterine adhesion, but their effect on the reproductive prognosis is required to be further studied., Competing Interests: The authors declare that they have no competing interests.

Objective: To investigate the recurrence potential of intrauterine adhesions after hysteroscopic adhesiolysis., Design: Retrospective observational study., Setting: Tertiary university hospital., Population: This study included 115 women who had intrauterine adhesions completely separated during hysteroscopic surgery. The treated adhesions were classified into four groups according to their location and extent: Group 1, central type (i.e. intervening space between the adhesions and both lateral uterine sidewalls) at the middle area of uterine cavity; Group 2, central type at uterine cornua; Group 3, cervico-isthmic; and Group 4, extensive if the adhesions were dense with occlusion of part of the uterine cavity other than cervico-isthmic region., Methods: Postoperative outpatient hysteroscopic adhesiolysis was scheduled 10-14 days after the initial hysteroscopic surgery and procedures were repeated every 10-14 days until no reformed adhesions were detected. Multivariate logistic regression models were built to examine initial adhesion characteristics and other factors associated with adhesion reformation and need for subsequent outpatient adhesiolysis. Categorical data were compared using Fisher's exact test., Main Outcome Measures: Number of postoperative outpatient hysteroscopic adhesiolysis procedures., Results: The location and extent of adhesions according to the allocated group was the only parameter independently related to the number of postoperative outpatient adhesiolysis procedures (P = 0.0004). Women with Group 1 adhesions underwent a lower number of postoperative interventions compared with those with Group 2, 3 and 4 adhesions (P = 0.0355, P = 0.0004 and P = 0.0087, respectively)., Conclusions: There is an increased likelihood of intrauterine adhesion recurrence when successfully divided adhesions were originally located at the uterine cornua, the cervico-isthmic region or involved a large portion of the uterine cavity., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Background: Assisted reproduction technology (ART) has become a standard treatment for infertile couples. Increased success rates obtained over the years have resulted primarily from improved embryo quality, but implantation rates still remain lower than expected. The uterus, an important player in implantation, has been frequently neglected. While a number of uterine pathologies have been associated with decreased natural fertility, less information exists regarding the impact of these pathologies in ART. This report reviews the evidence to help clinicians advise ART patients., Methods: An electronic search of PubMed and EMBASE was performed to identify articles in the English, French or Spanish language published until May 2014 which addressed uterine pathology and ART. Data from natural conception were used only in the absence of data from ART. Studies were classified in decreasing categories: RCTs, prospective controlled trials, prospective non-controlled trials, retrospective studies and experimental studies. Studies included in lower categories were only used if insufficient evidence was available. Pooled data were obtained from systematic reviews with meta-analyses when available. The summary of the evidence for the different outcomes and the degree of the recommendation for interventions were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) statement recommendations., Results: There is strong evidence that surrogacy is effective for uterine agenesia. For the remaining pathologies, however, there is very little evidence that the established treatments improve outcomes, or that these pathologies have a negative effect on ART. In the presence of an apparently normal uterus, assessing endometrial receptivity (ER) is the goal; however diagnostic tests are still under development., Conclusions: The real effect of different uterine/endometrial integrity pathologies on ART is not known. Moreover, currently proposed treatments are not based on solid evidence, and little can be done to assess ER in normal or abnormal conditions. No strong recommendations can be given based on the published experience, bringing an urgent need for well-designed studies. In this context, we propose algorithms to study the uterus in ART., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)