Treatment Of Intrauterine Adhesions Research Articles

Advances in Clinical Diagnosis and Treatment of Intrauterine Adhesions

Intrauterine adhesion is a kind of high incidence disease caused by many pathogenic factors, which damages the endometrial basal layer and affects the menstruation and fertility of women. In recent years, due to artificial abortion and other types of increased uterine cavity surgery, the incidence of the disease gradually increased. Hysteroscopy is the main method to diagnose intrauterine adhesion. Combining with ultrasound, it can determine the range and degree of intrauterine adhesion and guide the choice of treatment. But it cannot find small changes in the uterine cavity, and for serious adhesions and endometrial injury in patients, hysteroscopy examination results are not good. Accurate assessment of recurrence risk and individualized diagnosis and treatment are important prerequisites to reduce the high recurrence rate and improve the low pregnancy rate. This article reviews the research on clinical diagnosis and treatment of intrauterine adhesions in order to enhance and improve the understanding of the disease and provide a new clinical thinking.

Novel therapeutic targets, including IGFBP3, of umbilical cord mesenchymal stem-cell-conditioned medium in intrauterine adhesion.

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.

Mesenchymal Stem Cell Derived Exosomes Repair Uterine Injury by Targeting Transforming Growth Factor-β Signaling.

Intrauterine adhesions (IUA) refer to adhesions within the uterine cavity and cervix caused by injuries from uterine surgery. They are a significant cause of female infertility. Exosomes derived from mesenchymal stem cells (MSCs) play an active role in the treatment of IUA. However, the mechanism by which they reduce fibrosis in the damaged endometrium remains unclear. In this paper, we demonstrate that exosomes derived from placental mesenchymal stem cells (PMSCs) can restore uterine functions and improve the fertility rate of injured animals. This is achieved by promoting cell proliferation, increasing endometrial thickness, and reversing fibrosis. Regarding the molecular mechanism behind these therapeutic effects, we identify three specific miRNAs, namely, miR-125b-5p, miR-30c-5p, and miR-23a-3p, enriched in PMSC-exosomes, as the key players in the treatment of IUA. Specifically, miR-125b-5p/miR-30c-5p and miR-23a-3p inhibit the expression of smad2 and smad3 by targeting their 3'-untranslated regions, resulting in the downregulation of the transforming growth factor-β (TGF-β)/smad signaling pathway and the reversal of fibrosis. Notably, the safety of PMSC-exosomes in intrauterine treatment was also been confirmed. In conclusion, we illustrate that exosomes derived from PMSCs possess the capability to repair endometrial damage and enhance fertility in injured animals by regulating the TGF-β/smad pathway via miR-125b-5p, miR-30c-5p, and miR-23a-3p. This provides insights into the precision treatment of IUA through exosome-based cell-free therapy.

Janus adhesive microneedle patch loaded with exosomes for intrauterine adhesion treatment.

Intrauterine adhesions (IUAs) are common sequelae of cervical mucosa damage caused by uterine curettage. Establishing an anti-adhesion barrier between the damaged endometrium with a sustained-release drug capability and hence promoting endogenous regeneration of the endometrium is an available treatment for IUA. However, current therapy lacks long-term intracavitary residence, drug-delivery permeability, and tissue anti-adhesion to the endometrium. Here, we report the design of a Janus microneedle patch consisting of two layers: an adhesive inner layer with an exosomes-loaded microneedle, which endows the patch with a tissue adhesive capability as well as transdermal drug-delivery capability; and an anti-adhesion outer layer, which prevents the intrauterine membrane from postoperative adhesion. This Janus adhesive microneedle patch firmly adhered to uterine tissue, and sustainedly released ∼80% of the total loaded exosomes in 7 days, hence promoting the expression of vascular- and endothelial-related cell signals. Furthermore, the anti-adhesive layer of the microneedle patch exhibited low cell and protein adhesion performance. In rats, the microneedle patch successfully prevented uterine adhesions, improved endometrial angiogenesis, proliferation, and hormone response levels. This study provides a stable anti-adhesion barrier as well as efficient drug-release capability treatment for intrauterine adhesion treatment.

[Treatment of intrauterine adhesions in rats with hypoxia-cultured BMSC-derived exosomes].

Objective: To perform intrauterine adhesion modeling, and to investigate the repair effect of hypoxic treated bone marrow mesenchymal stem cells (BMSC) and their derived exosomes (BMSC-exo) on endometrial injury. Methods: BMSC and their exosomes BMSC-exo extracted from rats' femur were cultured under conventional oxygen condition (21%O2) or hypoxia condition (1%O2). Intrauterine adhesion modeling was performed on 40 healthy female SD rats by intrauterine injection of bacterial lipopolysaccharide after curettage. On the 28th day of modeling, 40 rat models were randomly divided into five groups, and interventions were performed: (1) NC group: 0.2 ml phosphate buffered solution was injected into each uterine cavity; (2) BMSC group: 0.2 ml BMSC (1×106/ml) with conventional oxygen culture was injected intrauterine; (3) L-BMSC group: 0.2 ml of hypoxic cultured BMSC (1×106/ml) was injected intrauterine; (4) BMSC-exo group: 0.2 ml of BMSC-exo cultured with conventional oxygen at a concentration of 500 μg/ml was injected into the uterine cavity; (5) L-BMSC-exo group: 0.2 ml hypoxic cultured BMSC-exo (500 μg/ml) was injected intrauterine. On the 14th and 28th day of treatment, four rats in each group were sacrificed by cervical dislocation after anesthesia, and endometrial tissues were collected. Then HE and Masson staining were used to observe and calculate the number of glands and fibrosis area in the endometrium. The expressions of angiogenesis related cytokines [vascular endothelial growth factor A (VEGFA) and CD31], and fibrosis-related proteins [collagen-Ⅰ, collagen-Ⅲ, smooth muscle actin α (α-SMA), and transforming growth factor β1 (TGF-β1)] in endometrial tissues were detected by western blot. Results: (1) HE and Masson staining showed that the number of endometrial glands in L-BMSC group, BMSC-exo group and L-BMSC-exo group increased and the fibrosis area decreased compared with NC group on the 14th and 28th day of treatment (all P<0.05). Noteworthily, the changes of L-BMSC-exo group were more significant than those of BMSC-exo group (all P<0.05), and the changes of BMSC-exo group were greater than those of BMSC group (all P<0.05). (2) Western blot analysis showed that, compared with NC group, the expressions of collagen-Ⅲ and TGF-β1 in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group decreased on the 14th and 28th day of treatment (all P<0.05). As the treatment time went on, the expressions of fibrosis-related proteins were different. Compared with BMSC group, the expressions of collagen-Ⅲ, α-SMA and TGF-β1 in the BMSC-exo group and L-BMSC group decreased on the 28th day (all P<0.05). Moreover, the expressions of collagen-Ⅲ and TGF-β1 in L-BMSC-exo group were lower than those in BMSC-exo group on the 28th day (all P<0.05). And the expressions of collagen-Ⅰ, α-SMA and TGF-β1 in L-BMSC-exo group were lower than those in L-BMSC group on the 28th day (all P<0.05). (3) The results of western blot analysis of VEGFA and CD31 showed that, the expressions of VEGFA and CD31 in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group increased on the 14th and 28th day of treatment compared with NC group (all P<0.05). Treatment for 28 days, the expressions of VEGFA and CD31 in BMSC-exo group and CD31 in L-BMSC group were higher than those in BMSC group (all P<0.05). Moreover, the expressions of VEGFA and CD31 in L-BMSC-exo group were higher than those in BMSC-exo group and L-BMSC group on the 28th day (all P<0.05). Conclusions: Treatment of BMSC and their exosomes BMSC-exo with hypoxia could promote endometrial gland hyperplasia, inhibit tissue fibrosis, and further repair the damaged endometrium in rats with intrauterine adhesion. Importantly, hypoxic treatment of BMSC-exo is the most effective in intrauterine adhesion rats.

Chorionic villi-derived nanofibers enhanced mesenchymal stem cell extracellular vesicle secretion and bioactivity for endometrium regeneration toward intrauterine adhesion treatment

Intrauterine adhesion (IUA) is one of the main causes of female infertility. Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs), are consisted of a complete lipid bilayer structure, rich in multiple factors and miRNAs related to tissue regeneration, which are the main effective paracrine components of MSCs to treat IUA. However, the poor secretion and bioactivity of EVs leading to the unexpected therapeutic efficacy of MSC-EVs, have been obstacles to their widespread use in clinical practice. Here, we developed human chorionic villi (CV)-derived nanofibers that mimic the tissue-specific ECM microenvironment of CV-derived MSCs, maintain the stemness of MSCs for a long time, and are rich in apolipoproteins, HSP90, ANXA1-A6, etc., which can enhance EV secretion and bioactivity. Then, the CV-nanofiber bionic culture system for mesenchymal stem cells was constructed to achieve large-scale cultivation of MSCs for continuous collection of high-concentration EVs enrichment supernatant. Additionally, EVs obtained by this system were encapsulated with CV-nanofibers to form EVs-ECM aggregate, which can effectively promote endometrium regeneration toward supporting fetal development and live births. Our study provides a new idea for enhancing EV secretion and bioactivity, and a cell-free therapy for treating IUA by EVs, thus promoting the potential of clinical application.

Melatonin-pretreated human umbilical cord mesenchymal stem cells improved endometrium regeneration and fertility recovery through macrophage immunomodulation in rats with intrauterine adhesions†.

Intrauterine adhesions (IUA) are a common gynecological problem. Stem cell therapy has been widely used in the treatment of IUA. However, due to the complex and harsh microenvironment of the uterine cavity, the effectiveness of such therapy is greatly inhibited. This study aimed to investigate whether melatonin pretreatment enhances the efficacy of human umbilical cord mesenchymal stem cells (HucMSCs) in IUA treatment in rats. First, we explored the effect of melatonin on the biological activity of HucMSCs in vitro through a macrophage co-culture system, Cell Counting Kit 8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry, immunofluorescence staining, and qRT-PCR. Subsequently, we established the IUA rat model and tracked the distribution of HucMSCs in this model. In addition, we observed the number of M1 and M2 macrophages through immunofluorescence staining and detected the levels of inflammatory cytokines. Four weeks after cell transplantation, HE, Masson, and immunohistochemical staining were performed. In vitro experiments showed that melatonin pretreatment of HucMSCs promoted proliferation, reduced apoptosis, up-regulated the stemness gene, and regulated macrophage polarization. In vivo, melatonin pretreatment caused more HucMSCs to remain in the uterine cavity. Melatonin-pretreated HucMSCs recruited more macrophages, regulated macrophage polarization, and reduced inflammation. Melatonin-pretreated HucMSCs relieved fibrosis, increased endometrium thickness, and up-regulated CD34, vimentin, proliferating cell nuclear antigen (PCNA), and alpha small muscle antigen (α-SMA) expression. Fertility tests showed that melatonin-pretreated HucMSCs increased the number of embryos. In summary, pretreatment with melatonin was beneficial for HucMSC treatment because it enhanced the cell's ability to recruit macrophages and regulate macrophage polarization, which led to the regeneration of the endometrium and improved pregnancy outcomes.

Treatment strategies for intrauterine adhesion: focus on the exosomes and hydrogels.

Intrauterine adhesion (IUA), also referred to as Asherman Syndrome (AS), results from uterine trauma in both pregnant and nonpregnant women. The IUA damages the endometrial bottom layer, causing partial or complete occlusion of the uterine cavity. This leads to irregular menstruation, infertility, or repeated abortions. Transcervical adhesion electroreception (TCRA) is frequently used to treat IUA, which greatly lowers the prevalence of adhesions and increases pregnancy rates. Although surgery aims to disentangle the adhesive tissue, it can exacerbate the development of IUA when the degree of adhesion is severer. Therefore, it is critical to develop innovative therapeutic approaches for the prevention of IUA. Endometrial fibrosis is the essence of IUA, and studies have found that the use of different types of mesenchymal stem cells (MSCs) can reduce the risk of endometrial fibrosis and increase the possibility of pregnancy. Recent research has suggested that exosomes derived from MSCs can overcome the limitations of MSCs, such as immunogenicity and tumorigenicity risks, thereby providing new directions for IUA treatment. Moreover, the hydrogel drug delivery system can significantly ameliorate the recurrence rate of adhesions and the intrauterine pregnancy rate of patients, and its potential mechanism in the treatment of IUA has also been studied. It has been shown that the combination of two or more therapeutic schemes has broader application prospects; therefore, this article reviews the pathophysiology of IUA and current treatment strategies, focusing on exosomes combined with hydrogels in the treatment of IUA. Although the use of exosomes and hydrogels has certain challenges in treating IUA, they still provide new promising directions in this field.

A comparison of special intrauterine balloons and intrauterine contraceptive devices in the treatment of intrauterine adhesions

PurposeThis study aimed to compare the efficacy of a special kind of intrauterine balloon (IUB) and that of an intrauterine contraception device (IUD) for patients with intrauterine adhesions (IUAs) after transcervical resection of adhesion (TCRA).MethodsIn this retrospective cohort study, after TCRA, 31 patients received a special IUB, and 38 patients received an IUD. The Fisher exact test, logistic regression method, Kaplan–Meier method and Cox proportional hazards regression model were used for statistical analysis. A two-sided value of P < 0.05 was considered statistically significant.ResultsThe readhesion rate significantly differed between the IUB group and IUD group, at 15.39% and 54.06%, respectively (P = 0.002). For recurrent moderate IUA, patients in the IUB group had lower scores than patients in the IUD group (P = 0.035). There was a significant difference in the intrauterine pregnancy rate of IUA patients in the IUB group and IUD group after treatment, with rates of 55.56% and 14.29%, respectively (P = 0.015).ConclusionPatients in the special IUB group had better outcomes than those in the IUD group, which has a certain guiding significance for clinical work.

Cost savings analysis of routine hysteroscopy for early detection and treatment of intrauterine adhesions

Cost savings analysis of routine hysteroscopy for early detection and treatment of intrauterine adhesions

Platelet-Rich Plasma Improves Pregnancy Outcomes in Moderate to Severe Intrauterine Adhesion: A Retrospective Cohort Study.

The purpose of the present study was to investigate the therapeutic effects of platelet-rich plasma (PRP) in women with moderate to severe intrauterine adhesion (IUA). A retrospective cohort study was conducted at a reproductive medical center between July 2020 and June 2021 to compare the clinical pregnancy rate of two groups (PRP and non-PRP groups) after hysteroscopic adhesiolysis. A multivariate logistic regression analysis and propensity score matching (PSM) were performed to minimize potential bias. According to our inclusion and exclusion criteria, 133 patients were finally enrolled and divided into the PRP group (n = 48) and non-PRP group (n = 85). In the primary comparison, the clinical pregnancy rate in the PRP group was higher than that in the non-PRP group (41.7% vs. 28.2%, p = 0.114), albeit without statistical significance. Multivariate logistic regression analysis was performed, and the results of the adjusted model showed that PRP treatment significantly improved the clinical pregnancy rate (adjusted OR = 3.00, 95% CI = 1.22-7.38, p = 0.017). After PSM, the clinical pregnancy rate was higher in the PRP group than that in the non-PRP group (46.2% vs. 20.5%, p = 0.031). Based on the present study, we concluded that intrauterine perfusion of PRP had great potential in improving the clinical pregnancy rate in patients with moderate to severe IUA. Therefore, we recommend the application of PRP in the treatment of IUA.

Tumor necrosis factor-α-primed mesenchymal stem cell-derived exosomes promote M2 macrophage polarization via Galectin-1 and modify intrauterine adhesion on a novel murine model.

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. 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. 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. Our studies proposed an innovative mouse model and a better MSC treatment strategy for IUA.

Efficacy of electrical stimulation combined with ultrasound acupuncture therapy on treatment in patients with intrauterine adhesions: Study protocol for a placebo-controlled, single-blind, single-center, randomized trial.

Recurrence of postoperative adhesions is one of the most important factors for poor reproductive outcomes after hysteroscopic surgery, particularly in cases diagnosed with severe intrauterine adhesions (IUAs), where the recurrence rate is significantly higher. This study aims to explore the effectiveness of the electrical muscle stimulation combined with ultrasound acupuncture therapy in preventing the recurrence of IUAs and improving reproductive outcomes after operative hysteroscopy. This study is a single-center, randomized controlled trial. A total of 210 patients with IUAs will be randomly assigned into 2 groups according to the ratio of 1:1, as the treatment group and the control group. Participants will receive the electrical muscle stimulation combined with ultrasound acupuncture therapy and oral hormone supplementation or receive oral hormone supplementation only. The primary outcome was the clinical response rate. There were 3 menstrual cycles of treatment and 3 menstrual cycles of follow-up in this study. This study protocol was approved by the Ethics Committee of the Reproductive Hospital of Guangxi Zhuang Autonomous Region (approval number: KY-LL-2022-06). This trial will be conducted in accordance with the principles of the Declaration of Helsinki as well as Good Clinical Practice. Study results will be disseminated at academic presentations and publications in peer-reviewed journals. Registry name: Clinical value of electroultrasonic instrument in the treatment of IUAs and changes of related protein expression; Registry number: ChiCTR2200058901; registration date: April 19th, 2022; http://www.chictr.org.cn/showproj.aspx?proj=166155.

Cost-Savings Analysis of Routine Hysteroscopy for Early Detection and Treatment of Intrauterine Adhesions

Cost-Savings Analysis of Routine Hysteroscopy for Early Detection and Treatment of Intrauterine Adhesions

Application of genipin-crosslinked small intestine submucosa and urine-derived stem cells for the prevention of intrauterine adhesion in a rat model

As a major cause for recurrent miscarriage and secondary infertility, intrauterine adhesion (IUA) is characterized by partial or total obliteration of the uterine cavity and/or cervical canal due to injuries to the basal layer of endometrium caused by improper intrauterine operation and/or infection. While various treatments have been used to prevent the occurrence of IUA, these approaches have shown limited therapeutic efficiency. As a promising bio-engineering method, tissue engineering technology may be used for enhancing endometrial regeneration. Extracellular matrix such as small intestine submucosa (SIS) may provide a favorable microenvironment, whilst stem cells can promote the endometrial regenerative capacity. In this study, genipin-crosslinked SIS (GP-SIS) loaded with urine-derived stem cells (USCs) has been applied for the regeneration of endometrium. The GP-SIS scaffolds have demonstrated sound mechanical properties and excellent biocompatibility and promoted epithelial migration and angiogenesis in vitro. In a rat model for IUA caused by endometrial damage, transplantation of the GP-SIS/USCs has maintained normal luminal structure, promoted endometrial and glandular regeneration, vascularization, inhibited fibrogenesis and improved endometrial receptivity. Our research has therefore provided a new strategy for promoting the recovery of endometrial structure and function, which may be beneficial for the prevention and treatment of IUA in the clinics.

Effect of growth hormone on endometrium growth of intrauterine adhesion and the underlying mechanism.

The main treatment for intrauterine adhesion (IUA) is hysteroscopic adhesiolysis (HA), which most of treatment frequently employs estrogen and progesterone cycle therapy. The growth and coverage of endometrium after operation is a difficult problem, and several hospitals in China have performed growth hormone (GH) in empirically treating IUA, which has achieved excellent curative effects. Unfortunately, the mechanism of action has not yet been clearly elucidated. In previous study, an IUA animal model after surgical abortion and curettage in pregnant rats has been successfully established. In this experiment, the IUA animal model after surgical abortion and curettage in pregnant rats, which is more in line with the mechanism of human intrauterine adhesion, was used for the first time to investigate the therapeutic effect of GH on IUA in the pregnant rat curettage model. The expression of signal transducers and activators of transcription 3(STAT3), phosphorylated STAT3 (p-STAT3), STAT5 and p-STAT5 content were detected by immunohistochemistry to preliminarily explore the possible mechanism of GH involving in promoting endometrial growth of IUA, and to provide a theoretical basis for clinical medication and treatment. Pregnant rats were anesthetized, and the bilateral embryos were removed completely. Then the rat endometrium was scraped with a curette in 4 different directions (front, back, left, and right). After the IUA animal model was established, the rats were randomly divided into 3 groups (n=5): a control group, a GH group, and a GH + AG490 group. Normal saline (0.4 mL/100 g) was injected subcutaneously at the 7th day after curettage in the control group；0.15 U/100 g of GH was injected subcutaneously at the 7th day after curettage in the GH group; 0.15 U/100 g of GH was injected subcutaneously and 1 mg/100 g AG490 was injected intraperitoneally at the 7th day after curettage in the GH+ AG490 group. All the rats were injected continuously for 5 days. The rats in each group were sacrificed at the 14th day. The uterus of rats in each group was stained with HE staining to explore the endometrial morphology and the number of endometrial glands in each group, and Masson staining was utilized to observe the degree of endometrial fibrosis. The levels of STAT3, p-STAT3, STAT5 and p-STAT5 were detected by immunohistochemistry. 1) The number of glands in the GH group was more than that in the control group on the 14th day, with statistical difference (P<0.05). However, the number of endometrial glands in the AG490+GH group was decreased compared with the GH group on the 14th day (P<0.05). 2) The fibrosis ratio in the GH group was less than that in the control group at the 14th day after operation (P<0.05). However, the area of endometrial interstitial fibrosis in the AG490+GH group was much higher than that in the GH group 14 days after operation (P<0.05). 3) Compared with the control group, there was not significant difference in the levels of STAT3 and STAT5 in GH group (both P>0.05), while the levels of protein p-STAT3 and p-STAT5 were increased in the GH group (both P<0.05). Compared with the GH group, there was not significant difference in the levels of STAT3 and STAT5 in the AG490+GH group (both P>0.05), while the levels of p-STAT3 and p-STAT5 were decreased in the AG490+GH group (both P<0.05). GH can not only promote the growth of endometrial glands in the IUA model, but also reduce the degree of fibrosis and play a role in the treatment of IUA, which may be related to the activation of the Janus kinase (JAK), JAK/STAT3 and STAT5 signaling pathways.

Role of noncoding RNA in the pathophysiology and treatment of intrauterine adhesion.

Intrauterine adhesion (IUA) is one of the most common diseases of the reproductive system in women. It is often accompanied by serious clinical problems that damage reproductive function, such as menstrual disorder, infertility, or recurrent abortion. The clinical effect of routine treatment is not ideal, and the postoperative recurrence rate is still very high. Therefore, exploring the pathological mechanism of IUA and finding new strategies for the effective prevention and treatment of IUA are needed. The main pathological mechanism of IUA is endometrial fibrosis and scar formation. Noncoding RNA (ncRNA) plays an important role in the fibrosis process, which is one of the latest research advances in the pathophysiology of IUA. Moreover, the exosomal miRNAs derived from mesenchymal stem cells can be used to improve IUA. This paper reviewed the role of ncRNAs in IUA pathogenesis, summarized the core pathways of endometrial fibrosis regulated by ncRNAs, and finally introduced the potential of ncRNAs as a therapeutic target.

CircPTP4A2-miR-330-5p-PDK2 Signaling Facilitates In Vivo Survival of HuMSCs on SF-SIS Scaffolds and Improves the Repair of Damaged Endometrium.

Background Human umbilical cord mesenchymal stem cells- (HuMSCs-) based therapy has shown promising results in the treatment of intrauterine adhesions (IUA). In this study, we aimed to construct a HuMSCs-seeded silk fibroin small-intestinal submucosa (SF-SIS) scaffold and evaluate its ability to repair the damaged endometrium in an IUA mouse model. Methods To identify the functional effect of HuMSCs-SF-SIS scaffolds on the repair of damaged endometrium, a mouse IUA model was established. Uterine morphology and fibrosis were evaluated by hematoxylin-eosin staining and Masson staining. CircRNA sequencing, real-time PCR, and RNA fluorescence in situ hybridization were used to screen and verify the potential circRNAs involved in the repair of damaged endometrium by HuMSCs. Real-time integrated cellular measurement of oxygen consumption rate was performed using the Seahorse XF24 Extracellular Flux Analyzer. The potential downstream miRNAs and proteins of circRNAs were analyzed by dual-luciferase reporter assay and western blot. Results HuMSCs-SF-SIS not only increased the number of glands but also reduced the ulcer area in the IUA model. circPTP4A2 was elevated in the HuMSCs seeded on the SF-SIS scaffolds and was targeted by miR-330-5p-PDK2. It also stabilized the mitochondrial metabolism of HuMSCs. Moreover, miR-330-5p was found to inhibit PDK2 expression through the 3′ UTR target region. A rescue experiment further showed that circPTP4A2-miR-330-5p-PDK2 signaling was critical to HuMSCs-SF-SIS in decreasing the fibrosis area and increasing the number of glands in the IUA model. Conclusion We demonstrated that circPTP4A2 was elevated in HuMSCs-seeded on SF-SIS scaffolds and stabilized the mitochondrial metabolism through miR-330-5p-PDK2 signaling, which contributes to endometrial repair progression. These findings demonstrate that HuMSCs-seeded SF-SIS scaffolds have potential for the treatment of IUA.

ASHERMAN SYNDROME TREATMENT METHODS TO RESTORE REPRODUCTIVE FUNCTION

Abstract. Asherman syndrome includes menstrual and childbearing disorders caused by the presence of intrauterine adhesions. Infertility and hypomenorrhea were found to be the most frequent clinical manifestations of Asherman syndrome (55.1% and 32.1% of cases). Diagnosis is difficult because the syndrome cannot be detected by standard methods of examination. In most cases, treatment leads to the recurrence of the disease, which is an aggravating factor for reproduction. The aim of the work is to identify optimal methods of Asherman syndrome treatment on the basis of scientific literature. The scientific literature on the restoration of reproductive function in women with Asherman syndrome was studied. An analytical review of clinical cases and a comparative analysis of the latest methods of treating this syndrome with solid and semi-solid barriers to form an artificial layer between the uterine walls and reduce adhesive changes, as well as hormonal treatment, intrauterine and anti-spastic gel based on hyaluronic acid gel was performed. The standard treatment of intrauterine adhesions is to dissect them, called hysteroscopic adhesiolysis, to restore the integrity of the uterine cavity and to further prevent their formation. Damage to the uterine tissue after hysteroscopic adhesiolysis can also cause new recurrences. To date, the introduction of multiple solid and semi-solid barriers to form an artificial layer between the uterine walls and reduce adhesion changes has been proposed. Intrauterine synechias and, as an extremely severe variant, Asherman syndrome are a multicomponent problem that requires a comprehensive approach. The prognosis depends on the degree of severity and etiology of Asherman syndrome. The following algorithm for the management of women with Asherman syndrome is possible: diagnostic module, sparing intrauterine surgery with subsequent insertion of antispastic barriers into the uterine cavity, postoperative rehabilitation aimed.

Decision tree model predicts live birth after surgery for moderate-to-severe intrauterine adhesions

BackgroundAfter treatment of intrauterine adhesions, the rate of re-adhesion is high and the pregnancy outcome unpredictable and unsatisfactory. This study established and verified a decision tree predictive model of live birth in patients after surgery for moderate-to-severe intrauterine adhesions (IUAs).MethodsA retrospective observational study initially comprised 394 patients with moderate-to-severe IUAs diagnosed via hysteroscopy. The patients underwent hysteroscopic adhesiolysis from January 2013 to January 2017, in a university-affiliated hospital. Follow-ups to determine the rate of live birth were conducted by telephone for at least the first postoperative year. A classification and regression tree algorithm was applied to establish a decision tree model of live birth after surgery.ResultsWithin the final population of 374 patients, the total live birth rate after treatment was 29.7%. The accuracy of the model was 83.8%, and the area under the receiver operating characteristic curve (AUC) was 0.870 (95% CI 7.699–0.989). The root node variable was postoperative menstrual pattern. The predictive accuracy of the multivariate logistic regression model was 70.3%, and the AUC was 0.835 (95% CI 0.667–0.962).ConclusionsThe decision tree predictive model is useful for predicting live birth after surgery for IUAs; postoperative menstrual pattern is a key factor in the model. This model will help clinicians make appropriate clinical decisions during patient consultations.