Umbilical cord mesenchymal stem cell-derived exosomes inhibits fibrosis in human endometrial stromal cells via miR-140-3p/FOXP1/Smad axis.

Endometrial fibrosis is the histologic appearance of intrauterine adhesion (IUA). Emerging evidences demonstrated umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-exo) could alleviate endometrial fibrosis. But the specific mechanism is not clear. In this study, we explored the effect of UCMSC-exo on endometrial fibrosis, and investigated the possible role of miR-140-3p/FOXP1/Smad axis in anti-fibrotic properties of UCMSC-exo. UCMSC-exo were isolated and identified. Transforming growth factor-ß (TGF-ß) was used to induce human endometrial stromal cell (HESC) fibrosis. Dual luciferase assay was performed to verify the relationship between miR-140-3p and FOXP1. The expressions of fibrotic markers, SIP1, and p-Smad2/p-Smad3 in HESCs stimulated with UCMSC-exo were detected by western blot. In addition, the effects of miR-140-3p mimic, miR-140-3p inhibitor and FOXP1 over-expression on endometrial fibrosis were assessed. The isolated UCMSC-exo had a typical cup-shaped morphology and could be internalized into HESCs. The expressions of fibrotic markers were significantly increased by TGF-ß, which was reversed by UCMSC-exo. MiR-140-3p in UCMSC-exo ameliorated TGf-ß-induced HESCs fibrosis. FOXP1 was identified as the direct target of miR-140-3p, which could inversely regulate miR-140-3p's function on HESCs fibrosis. Furthermore, we demonstrated that miR-140-3p in UCMSC-exo regulated Smad signal pathway to exert the anti-fibrotic effect in HESCs. The anti-fibrotic effect of UCMSC-derived exosomes against HESC fibrosis was at least partially achieved by miR-140-3p/FOXP1/Smad axis.

Intrauterine interventions options for preventing recurrence after hysteroscopic adhesiolysis: a systematic review and network meta-analysis of randomized controlled trials.

PURPOSE: Recurrence of adhesions after hysteroscopic adhesiolysis is a challenging clinical problem without a unified management approach. Therefore, we conducted a network meta-analysis that considered both direct and indirect comparisons between interventions to identify optimal strategies for preventing recurrence. METHODS: We searched for research trials published up to July 2023 from PubMed, Embase and the Cochrane Database. We selected randomized controlled trials comparing the use of different interventions for the prevention of adhesion recurrence, with no language or regional restrictions. We used random-effects models to assess odds ratios (OR) and mean difference (MD) with 95% confidence intervals (CI). Adverse events associated with the interventions were also assessed. This study was registered on PROSPERO, CRD42023449068. RESULTS: Data from 21 randomized controlled trials involving 2406 patients were synthesized, including interventions with balloon, amnion, platelet-rich plasma (PRP), intrauterine device (IUD), hyaluronic acid (HA), platelet-rich fibrin (PRF), and granulocyte colony-stimulating factor (G-CSF). The top 5 interventions for change in AFS scores were: PRP + Balloon (MD = 5.44; 95% CI, 2.63-8.25), Amnion + Balloon (MD = 5.08; 95% CI, 2.71-7.44), IUD + Balloon (MD = 4.89; 95% CI, 2.49-7.30), HA + Balloon (MD = 3.80; 95% CI, 1.78-5.82), and G-CSF + Balloon (MD = 3.84; 95% CI, 1.05-6.63). There were no statistically significant differences between interventions in the recurrence rate of moderate-to-severe uterine adhesions and the clinical pregnancy rate. Most interventions were safe. CONCLUSIONS: To our knowledge, this is the most comprehensive network meta-analysis to date of interventions for preventing postoperative intrauterine adhesion recurrence. Our results indicate that PRP + Balloon seems to be the most effective approach.

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.

Transcriptomic Analysis Reveals Intrinsic Abnormalities in Endometrial Polyps.

Endometrial polyps (EPs) are benign overgrowths of the endometrial tissue lining the uterus, often causing abnormal bleeding or infertility. This study analyzed gene expression differences between EPs and adjacent endometrial tissue to elucidate intrinsic abnormalities promoting pathological overgrowth. RNA sequencing of 12 pairs of EPs and the surrounding endometrial tissue from infertile women revealed 322 differentially expressed genes. Protein-protein interaction network analysis revealed significant alterations in specific signaling pathways, notably Wnt signaling and vascular smooth muscle regulation, suggesting these pathways play critical roles in the pathophysiology of EPs. Wnt-related genes DKK1 and DKKL1 were upregulated, while GPC3, GREM1, RSPO3, SFRP5, and WNT10B were downregulated. Relevant genes for vascular smooth muscle contraction were nearly all downregulated in EPs, including ACTA2, ACTG2, KCNMB1, KCNMB2, MYL9, PPP1R12B, and TAGLN. Overall, the results indicate fundamental gene expression changes promote EP formation through unrestrained growth signaling and vascular defects. The intrinsic signaling abnormalities likely contribute to clinical symptoms of abnormal uterine bleeding and infertility common in EP patients. This analysis provides molecular insights into abnormal endometrial overgrowth to guide improved diagnostic and therapeutic approaches for this troublesome women's health condition. Confirmation of expanded cohorts and further investigations into implicated regulatory relationships are warranted.

Manually driven versus motor driven hysteroscopic tissue removal system for polypectomy: Long-term results.

OBJECTIVE: The aim of this follow-up study is to compare a manually driven hysteroscopic tissue removal system (ResectrTM 9 Fr) with a motor driven system (TruclearTM) in terms of long-term clinical outcomes such as abnormal uterine bleeding and polyp recurrence. STUDY DESIGN: This is a follow-up of a multicenter randomized controlled trial comparing a manually and motor driven hysteroscopic tissue removal system for polypectomy. This prospective cohort study was performed at Ghent University Hospital (Ghent, Belgium) and Catharina Hospital Eindhoven (Eindhoven, the Netherlands). The trial was registered at Clinicaltrials.gov (Trial ID = NCT05337605, April 2022). Seventy-five women with abnormal uterine bleeding who participated in the randomized controlled trial and had pathological confirmation of the diagnosis of an endometrial polyp, were contacted. Fifty-five women (70.67 %) were willing to participate in this follow-up study. The primary outcome was the recurrence and/or persistence of abnormal uterine bleeding and the time to the recurrence of abnormal uterine bleeding. Secondary outcomes were polyp recurrence and time to polyp recurrence, symptom relief, satisfaction score regarding symptom relief and general satisfaction score regarding the surgical procedure. RESULTS: In the manually driven group, the mean time to the recurrence or persistence of abnormal uterine bleeding was 26 months (95 % CI 20 - 32). In the motor driven group, the mean time to the recurrence or persistence of abnormal uterine bleeding was 29 months (95 % CI 23- 34). A log-rank test showed a non-significant difference between both groups (P =.77). There was no significant difference in polyp recurrence (P =.22) or symptom relief between the two groups (P =.67). Additionally, the groups did not differ in satisfaction scores regarding symptoms or polypectomy (P =.16 and P =.61, respectively). CONCLUSION: This long-term follow-up study showed no statistically significant difference in the recurrence and persistence of abnormal uterine bleeding between a manually and motor driven hysteroscopic tissue removal system for polypectomy.

Impaired fertility in adenomyosis: a murine model reveals endometrial receptivity and progesterone resistance imbalances.

In brief: The impact of adenomyosis on reproductive health needs to be fully understood. By using a murine model, this study provides novel insights into the nuanced mechanisms associated with fertility challenges and offers a foundation for targeted interventions. Abstract: This study investigates the intricate relationship between adenomyosis and reproductive health using a murine model, offering novel insights into this prevalent gynecological disorder. Adenomyosis, characterized by the invasive growth of endometrial tissue into the myometrium, is believed to negatively impact fertility. However, the challenge lies in disentangling this influence, as adenomyosis often coexists with other gynecological diseases. A tamoxifen-induced mice model presents a significant advantage by enabling the specific study of adenomyosis, devoid of confounding influences of concurrent gynecological diseases such as endometriosis. Focusing exclusively on adenomyosis, our study aims to elucidate pathogenic mechanisms underlying fertility issues, focusing on estrous cyclicity, ovarian follicle development, and overall fertility. Our findings uncover disruptions in estrous cyclicity, characterized by an increased duration of time spent in the estrus phase in adenomyosis-induced mice. These disturbances are potentially linked to observed compromised folliculogenesis and the remarkable reduction in litter number and size in mice affected by adenomyosis. Moreover, this study unveils potential drivers of subfertility such as progesterone resistance and altered endometrial receptivity. Within the uteri of mice with adenomyosis, reduced expression of the progesterone receptor and a decreased expression of two implantation-related markers (HoxA10 and integrin ß3) were observed. This comprehensive examination sheds light on the nuanced complexities of adenomyosis-associated reproductive challenges, providing a foundation for targeted interventions in addressing fertility issues related to this disease.

Comparison of microbial abundance and diversity in uterine and peritoneal fluid in infertile patients with or without endometriosis.

INTRODUCTION: Endometriosis (EM) is a multifactorial disease that affects 10 - 15% of women of reproductive age. Additionally, 30-50% of women with EM suffer from infertility. The mechanism of infertility caused by EM has not yet been consistently explained. In recent years, studies have shown a link between infertility associated with EM and changes in the reproductive tract microbiota. METHODS: In this study, we involved 26 EM patients (8 cases of stage I-II and 18 cases of stage III-IV) and 31 control subjects who were tubal obstruction-related infertility (TORI). The samples from peritoneal fluid (PF) and uterine fluid (UF) were collected and sequenced by 16 S rRNA amplicon. RESULTS: In the comparison of microbial diversity, we found no significant differences in the microbial diversity of PF and UF between patients with stage I-II EM and those with TORI. However, there was a significant difference in microbial diversity among patients with stage III-IV EM compared to the previous two groups. Lactobacillus decreased in PF of EM compared to the control group, while it increased in UF. In PF, the abundance of Pseudomonas, Enterococcus, Dubosiella and Klebsiella was significantly higher in patients with stage III-IV compared to TORI patients. And in UF, the main differences existed between stage I-II EM compared to the other two groups. The abundance of pontibacter, aquabacterium, Rikenellaceae and so on at the genus level was significantly enriched in the EM patients with stage I-II. In the analysis based on KEGG database, EM may affect the receptivity related pathways of the endometrium by influencing changes in the uterine microbiota. CONCLUSION: Our results indicated that as EM progresses, the microorganisms in UF and PF keep changing. These changes in the microbiota, as well as the resulting alternations in gene functional classification, may play an important role in the infertility associated with EM.

Intrauterine adhesion in ultrasound-guided manual vacuum aspiration (USG-MVA) versus electric vacuum aspiration (EVA): a randomised controlled trial.

BACKGROUND: Intrauterine adhesion (IUA) can arise as a potential complication following uterine surgery, as the surgical procedure may damage the endometrial stratum basalis. The objective of this study was to assess and compare the occurrence of IUA in women who underwent ultrasound-guided manual vacuum aspiration (USG-MVA) versus electric vacuum aspiration (EVA) for managing first-trimester miscarriage. METHODS: This was a prospective, single-centre, randomised controlled trial conducted at a university-affiliated tertiary hospital. Chinese women aged 18 years and above who had a delayed or incomplete miscarriage of ≤ 12 weeks of gestation were recruited in the Department of Obstetrics and Gynaecology at the Prince of Wales. Recruited participants received either USG-MVA or EVA for the management of their miscarriage and were invited for a hysteroscopic assessment to evaluate the incidence of IUA between 6 and 20 weeks after the surgery. Patients were contacted by phone at 6 months to assess their menstrual and reproductive outcomes. RESULTS: 303 patients underwent USG-MVA or EVA, of whom 152 were randomised to 'USG-MVA' and 151 patients to the 'EVA' group. Out of the USG-MVA group, 126 patients returned and completed the hysteroscopic assessment, while in the EVA group, 125 patients did the same. The incidence of intrauterine adhesion (IUA) was 19.0% (24/126) in the USG-MVA group and 32.0% (40/125) in the EVA group, showing a significant difference (p < 0.02) between the two groups. No significant difference in the menstrual outcomes at 6 months postoperatively between the two groups but more patients had miscarriages in the EVA group with IUA. CONCLUSIONS: IUAs are a possible complication of USG-MVA. However, USG-MVA is associated with a lower incidence of IUA postoperatively at 6-20 weeks. USG-MVA is a feasible, effective, and safe alternative surgical treatment with less IUA for the management of first-trimester miscarriage. TRIAL REGISTRATION: The study was registered with the Centre for Clinical Research and Biostatics- Clinical Trials Registry (CCRBCTR), which is a partner registry of the WHO Primary Registry-Chinese Clinical Trials Registry (ChiCTR) (Unique Trial Number: ChiCTR1900023198 with the first trial registration date on 16/05/2019).

Endometrial mesenchymal stromal/stem cells improve regeneration of injured endometrium in mice.

BACKGROUND: The monthly regeneration of human endometrial tissue is maintained by the presence of human endometrial mesenchymal stromal/stem cells (eMSC), a cell population co-expressing the perivascular markers CD140b and CD146. Endometrial regeneration is impaired in the presence of intrauterine adhesions, leading to infertility, recurrent pregnancy loss and placental abnormalities. Several types of somatic stem cells have been used to repair the damaged endometrium in animal models, reporting successful pregnancy. However, the ability of endometrial stem cells to repair the damaged endometrium remains unknown. METHODS: Electrocoagulation was applied to the left uterine horn of NOD/SCID mice causing endometrial injury. Human eMSC or PBS was then injected into the left injured horn while the right normal horn served as controls. Mice were sacrificed at different timepoints (Day 3, 7 and 14) and the endometrial morphological changes as well as the degree of endometrial injury and repair were observed by histological staining. Gene expression of various inflammatory markers was assessed using qPCR. The functionality of the repaired endometrium was evaluated by fertility test. RESULTS: Human eMSC successfully incorporated into the injured uterine horn, which displayed significant morphological restoration. Also, endometrium in the eMSC group showed better cell proliferation and glands formation than the PBS group. Although the number of blood vessels were similar between the two groups, gene expression of VEGF-α significantly increased in the eMSC group. Moreover, eMSC had a positive impact on the regeneration of both stromal and epithelial components of the mouse endometrium, indicated by significantly higher vimentin and CK19 protein expression. Reduced endometrial fibrosis and down-regulation of fibrosis markers were also observed in the eMSC group. The eMSC group had a significantly higher gene expression of anti-inflammatory factor Il-10 and lower mRNA level of pro-inflammatory factors Ifng and Il-2, indicating the role of eMSC in regulation of inflammatory reactions. The eMSC group showed higher implantation sites than the PBS group, suggesting better endometrial receptivity with the presence of newly emerged endometrial lining. CONCLUSIONS: Our findings suggest eMSC improves regeneration of injured endometrium in mice.

Histological study of telocytes in mice intrauterine adhesion model and their positive effect on mesenchymal stem cells in vitro.

Intrauterine adhesions (IUA), the main cause of secondary infertility in women, result from irreversible fibrotic repair of the endometrium due to inflammation or human factors, accompanied by disruptions in the repair function of endometrial stem cells. This significantly impacts the physical and mental health of women in their childbearing years. Telocytes (TCs), a distinctive type of interstitial cells found in various tissues and organs, play diverse repair functions due to their unique spatial structure. In this study, we conduct the inaugural exploration of the changes in TCs in IUA disease and their potential impact on the function of stem cells. Our results show that in vivo, through double immunofluorescence staining (CD34+/Vimentin+; CD34+/CD31-), as endometrial fibrosis deepens, the number of TCs gradually decreases, telopodes shorten, and the three-dimensional structure becomes disrupted in the mouse IUA mode. In vitro, TCs can promote the proliferation and cycle of bone mesenchymal stem cells (BMSCs) by promoting the Wnt/ß-catenin signaling pathway, which were inhibited using XAV939. TCs can promote the migrated ability of BMSCs and contribute to the repair of stem cells during endometrial injury. In addition, TCs can inhibit the apoptosis of BMSCs through the Bcl-2/Bax pathway. In conclusion, our study demonstrates, for the first time, the resistance role of TCs in IUA disease, shedding light on their potential involvement in endometrial repair through the modulation of stem cell function.

The risk factors for premalignant and malignant endometrial polyps in premenopausal and postmenopausal women and trends over the past decade: A retrospective study in a single center, South Korea.

OBJECTIVES: To assess the prevalence and risk factors for premalignancy and malignancy in endometrial polyps and to evaluate trends over the past decade. STUDY DESIGN: This was a retrospective study of patients who underwent hysteroscopic polypectomy at Inha University Hospital, South Korea between January 2013 and June 2023. The demographic and clinical characteristics of the patients reviewed to identify risk factors for premalignancy and malignancy in endometrial polyps included the following: age, parity, body mass index, menopausal status, abnormal uterine bleeding symptoms, diabetes mellitus, hypertension, polycystic ovarian syndrome, use of menopausal hormonal therapy or oral contraceptives, tamoxifen treatment in patients with breast cancer, and the number of polyps. RESULTS: In total, 725 patients were enrolled, among whom 52 (7.2 %) had premalignant and malignant lesions. In logistic regression analysis, menopause (OR: 8.37, 95 % CI [3.33-21.04]), abnormal uterine bleeding (OR: 7.42, 95 % CI [2.13-25.86]), obesity (OR: 3.22, 95 % CI [1.53-6.77]), multiple polyps (OR: 2.86, 95 % CI [1.39-5.88]) and nulliparity (OR: 2.64, 95 % CI [1.13-6.19]) were significantly associated with premalignancy and malignancy in polyps. Annual trends during the study period showed an increase in the number of patients with three of the five risk factors (obesity, multiple polyps, and nulliparity) and an increase in the prevalence of premalignancy and malignancy in polyps. CONCLUSIONS: Menopause, abnormal uterine bleeding, obesity, multiple polyps, and nulliparity increase the risk of premalignancy and malignancy in endometrial polyps. The prevalence of premalignant and malignant polyps has been increasing over the past decade. The risk factors that have contributed to this trend were obesity, nulliparity, and multiple polyps.

Minimally invasive delivery of human umbilical cord-derived mesenchymal stem cells by an injectable hydrogel via Diels-Alder click reaction for the treatment of intrauterine adhesions.

Intrauterine adhesions (IUA) are the most common cause of uterine infertility, and conventional treatments have not consistently achieved satisfactory pregnancy rates. Stem cell therapy shows promising potential for the clinical treatment of IUA. Although various advanced biomaterials have been designed for delivering stem cells to the uterine cavity, there remain significant challenges, particularly in devising therapeutic strategies for clinical application that minimize surgical incisions and conform to the intricate structure of uterine cavity. Herein, an injectable hydrogel loaded with human umbilical cord-derived mesenchymal stem cells (UCMSCs) was synthesized via the Diels-Alder click reaction for endometrial regeneration and fertility restoration, exhibiting suitable mechanical properties, good biocompatibility, and desirable degradation properties. Notably, this hydrogel permitted minimally invasive administration and integrated seamlessly with surrounding tissue. Our study revealed that the UCMSCs-laden injectable hydrogel enhanced cell proliferation, migration, angiogenesis, and exhibited anti-fibrotic effects in vitro. The implantation of this hydrogel significantly facilitated endometrium regeneration and restored fertility in a rat endometrial damage model. Mechanistically, in vivo results indicated that the UCMSCs-laden injectable hydrogel effectively promoted macrophage recruitment and facilitated M2 phenotype polarization. Collectively, this hydrogel demonstrated efficacy in regenerating damaged endometrium, leading to the restoration of fertility. Consequently, it holds promise as a potential therapeutic strategy for endometrial damage and fertility decline arising from intrauterine adhesions. STATEMENT OF SIGNIFICANCE: Severe endometrial traumas frequently lead to intrauterine adhesions and subsequent infertility. Stem cell therapy shows promising potential for the clinical treatment of IUA; however, challenges remain, including low delivery efficiency and compromised stem cell activity during the delivery process. In this study, we fabricated an injectable hydrogel loaded with UCMSCs via the Diels-Alder click reaction, which exhibited unique bioorthogonality. The in situ-gelling hydrogels could be introduced through a minimally invasive procedure and adapt to the intricate anatomy of the uterus. The UCMSCs-laden injectable hydrogel promoted endometrial regeneration and fertility restoration in a rat endometrial damage model, efficaciously augmenting macrophage recruitment and promoting their polarization to the M2 phenotype. The administration of UCMSCs-laden injectable hydrogel presents a promising therapeutic strategy for patients with severe intrauterine adhesion.

Ultrasound finding of endometrial polyp and factors increasing risk of malignancy.

This article presents a comprehensive review of factors that increase the risk of malignancy in ultrasound findings of an endometrial polyp. We collected original studies, reviews, and meta-analyses that dealt with the topic of endometrial polyps and the risk of developing endometrial cancer. Each presumed risk factor was analysed individually. According to searched studies, abnormal uterine bleeding, old age, and body mass index are valid risk factors for developing endometrial cancer in endometrial polyps. Lynch syndrome patients are also in a high-risk group for endometrial cancer. On the other hand, the number of polyps, their size, diabetes mellitus, hypertension, and positive family history are factors with inconclusive results. There are either not enough data or different results among several studies.

Uterovesical fistula and its treatment in Sub-Saharan Africa.

AIM:  Aim of the study to summarize the current information on diagnostic and treatment options for uterovesical fistula as a consequence of iatrogenic complication. Methods: Literature review of available information on surgical treatment options for uterovesical fistula resulting from previous caesarean section and comparison with our own experience in the developing world. Conclusion: Uterovesical fistula is an abnormal communication between the bladder and uterus. The cause of this pathology in most cases is an iatrogenic complication, most commonly arising after a caesarean section. The incidence of this pathology varies significantly geographically. In developed countries, these fistulas are rather rare. On the other hand, in developing countries, uterovesical fistulas are more common with a significant impact on the subsequent life of the patient due to generally inaccessible health care.

Key drivers of hysterectomy among women of reproductive age in three states in India: comparative evidence from NFHS-4 and NFHS-5.

PURPOSE: According to the 4th and 5th rounds of National Family Health Survey (NFHS), there is high prevalence of hysterectomies in the three states of Andhra Pradesh Telangana and Bihar. The three said states have more than double the number of hysterectomies taking place than the national average. Our purpose is to analyse whether these rates are increasing, decreasing or have stabilized and their reasons thereof. Such an analyses will help the policy makers in recommending good clinical practices within their states. MATERIAL AND METHODS: We used data from NFHS-4 (2015-16) and NFHS-5 (2019-2021) rounds. We calculated the differences in predicted probabilities for various factors, performed a Fairlie Decomposition analyses to quantify the positive and negative contributors in the prevalence of hysterectomy across the three states over two time points, and assessed the association of various socio-demographic characteristics to hysterectomy through a multilevel logistic regression model. RESULTS AND CONCLUSION: The results show that out of a total of 80,976 eligible respondents from the states under study, 5826 respondents self-reported that they had a hysterectomy done. It was found that older age, living in rural areas, belonging to other backward classes and higher wealth quintile, and higher parity positively contributed to the increased prevalence of hysterectomies in the three states. Higher educational attainment and previous use of family planning methods acted as protective factors. Characteristics at the household level had the highest intra-class correlation value in the prevalence of hysterectomy among women, followed by the Primary Sampling Unit and District levels, indicating high clustering in the prevalence of hysterectomy at the household level in all three states. Heavy menstrual bleeding/pain was the leading cause of hysterectomies in all three states, followed by fibroids/cysts in Andhra Pradesh and Telangana and Uterine disorder/ prolapse in Bihar. Over 80% of hysterectomies took place in the private hospitals. RECOMMENDATIONS: The study recommends better, more efficient and accountable hysterectomy surveillance to ensure more sustainable woman's reproductive health services in India. Government should adopt and implement standard regulatory guidelines to prevent provider-driven avoidable hysterectomies. Moreover, we recommend informing primary care professionals about the long-term health effects of hysterectomy and promoting alternate therapies for treating uterine fibroids and heavy bleeding.

The adenomyosis/endometriosis IVF patient - call for clinical focus.

Endometriosis and adenomyosis are distinct clinical conditions that carry the same pathophysiological features. In recent years the clinical focus on assisted reproductive technology patients with either condition (E/A) has increased, in the recognition that this subgroup of patients might need special attention to obtain reproductive success. Endometriosis and adenomyosis are characterized by a disruption of progesterone and oestrogen signalling pathways, resulting in local oestrogen dominance and progesterone resistance at the receptor level. Recent scientific evidence suggests that the endometrial progesterone receptor resistance encountered in E/A patients can be overcome by a freeze-all policy, followed by down-regulating circulating oestradiol concentrations prior to frozen embryo transfer (FET), in combination with an increase in exogenous luteal phase progesterone supplementation in hormonal replacement therapy (HRT) FET cycles. Specifically, for adenomyosis patients who do not respond to gonadotrophin-releasing hormone agonist down-regulation in terms of a decrease in circulating oestradiol concentrations, a small case series has suggested that the addition of an aromatase inhibitor for 21 days prior to HRT-FET is a valid option. Endometriosis and adenomyosis are hormonally active diseases, which need to be treated by controlling local hyperoestrogenism and progesterone resistance. Based on physiology and recent preliminary clinical data, the authors of this opinion paper wish to stimulate discussion and spark interest in research in E/A patients.

Uterine wound healing after caesarean section: A systematic review.

The rate of caesarean section (CS) is increasing worldwide. Defects in uterine healing have a major gynaecological and obstetric impact (uterine rupture, caesarean scar defect, caesarean scar pregnancy, placenta accreta spectrum). The complex process of cellular uterine healing after surgery, and specifically after CS, remains poorly understood in contrast to skin wound healing. This literature review on uterine wound healing was mainly based on histological observations, particularly after CS. The primary objective of the review was to examine the effects of CS on uterine tissue at the cellular level, based on histological observations. The secondary objectives were to describe the biomechanical characteristics and the therapies used to improve scar tissue after CS. This review was performed using PRISMA criteria, and PubMed was the data source. The study included all clinical and animal model studies with CS and histological analysis of the uterine scar area (macroscopic, microscopic, immunohistochemical and biomechanical). Twenty studies were included: 10 human and 10 animal models. In total, 533 female humans and 511 female animals were included. Review articles, meeting abstracts, case series, case reports, and abstracts without access to full-text were excluded. The search was limited to studies published in English. No correlation was found between cutaneous and uterine healing. The histology of uterine scars is characterized by disorganized smooth muscle, fibrosis with collagen fibres and fewer endometrial glands. As for skin healing, the initial inflammation phase and mediation of some growth factors (particularly connective tissue growth factor, vascular endothelial growth factor, platelet-derived growth factor, tumour necrosis factor α and tumour necrosis factor ß) seem to be essential. This initial phase has an impact on the subsequent phases of proliferation and maturation. Collagen appears to play a key role in the initial granulation tissue to replace the loss of substance. Subsequent maturation of the scar tissue is essential, with a decrease in collagen and smooth muscle restoration. Unlike skin, the glandular structure of uterine tissue could be responsible for the relatively high incidence of healing defects. Uterine scar defects after CS are characterized by an atrophic disorganized endometrium with atypia and a fibroblastic highly collagenic stromal reaction. Concerning immunohistochemistry, one study found a decrease in tumour necrosis factor ß in uterine scar defects. No correlation was found between biomechanical characteristics (particularly uterine strength) and the presence of a collagenous scar after CS. Based on the findings of this review, an illustration of current understanding about uterine healing is provided. There is currently no validated prevention of caesarean scar defects. Various treatments to improve uterine healing after CS have been tested, and appeared to have good efficacy in animal studies: alpha lipoic acid, growth factors, collagen scaffolds and mesenchymal stem cells. Further prospective studies are needed.

Hypoxic bone marrow mesenchymal stem cell exosomes promote angiogenesis and enhance endometrial injury repair through the miR-424-5p-mediated DLL4/Notch signaling pathway.

Background: Currently, bone marrow mesenchymal stem cells (BMSCs) have been reported to promote endometrial regeneration in rat models of mechanically injury-induced uterine adhesions (IUAs), but the therapeutic effects and mechanisms of hypoxic BMSC-derived exosomes on IUAs have not been elucidated. Objective: To investigate the potential mechanism by which the BMSCS-derived exosomal miR-424-5p regulates IUA angiogenesis through the DLL4/Notch signaling pathway under hypoxic conditions and promotes endometrial injury repair. Methods: The morphology of the exosomes was observed via transmission electron microscopy, and the expression of exosome markers (CD9, CD63, CD81, and HSP70) was detected via flow cytometry and Western blotting. The expression of angiogenesis-related genes (Ang1, Flk1, Vash1, and TSP1) was detected via RT‒qPCR, and the expression of DLL4/Notch signaling pathway-related proteins (DLL4, Notch1, and Notch2) was detected via Western blotting. Cell proliferation was detected by a CCK-8 assay, and angiogenesis was assessed via an angiogenesis assay. The expression of CD3 was detected by immunofluorescence. The endometrial lesions of IUA rats were observed via HE staining, and the expression of CD3 and VEGFA was detected via immunohistochemistry. Results: Compared with those in exosomes from normoxic conditions, miR-424-5p was more highly expressed in the exosomes from hypoxic BMSCs. Compared with those in normoxic BMSC-derived exosomes, the proliferation and angiogenesis of HUVECs were significantly enhanced after treatment with hypoxic BMSC-derived exosomes, and these effects were weakened after inhibition of miR-424-5p. miR-424-5p can target and negatively regulate the expression of DLL4, promote the expression of the proangiogenic genes Ang1 and Flk1, and inhibit the expression of the antiangiogenic genes Vash1 and TSP1. The effect of miR-424-5p can be reversed by overexpression of DLL4. In IUA rats, treatment with hypoxic BMSC exosomes and the miR-424-5p mimic promoted angiogenesis and improved endometrial damage. Conclusion: The hypoxic BMSC-derived exosomal miR-424-5p promoted angiogenesis and improved endometrial injury repair by regulating the DLL4/Notch signaling pathway, which provides a new idea for the treatment of IUAs.

Guideline No. 447: Diagnosis and Management of Endometrial Polyps.

OBJECTIVE: The primary objective of this clinical practice guideline is to provide gynaecologists with an algorithm and evidence to guide the diagnosis and management of endometrial polyps. TARGET POPULATION: All patients with symptomatic or asymptomatic endometrial polyps. OPTIONS: Options for management of endometrial polyps include expectant, medical, and surgical management. These will depend on symptoms, risks for malignancy, and patient choice. OUTCOMES: Outcomes include resolution of symptoms, histopathological diagnosis, and complete removal of the polyp. BENEFITS, HARMS, AND COSTS: The implementation of this guideline aims to benefit patients with symptomatic or asymptomatic endometrial polyps and provide physicians with an evidence-based approach toward diagnosis and management (including expectant, medical, and surgical management) of polyps. EVIDENCE: The following search terms were entered into PubMed/Medline and Cochrane: endometrial polyps, polyps, endometrial thickening, abnormal uterine bleeding, postmenopausal bleeding, endometrial hyperplasia, endometrial cancer, hormonal therapy, female infertility. All articles were included in the literature search up to 2021 and the following study types were included: randomized controlled trials, meta-analyses, systematic reviews, observational studies, and case reports. Additional publications were identified from the bibliographies of these articles. Only English-language articles were reviewed. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: Gynaecologists, family physicians, registered nurses, nurse practitioners, medical students, and residents and fellows. TWEETABLE ABSTRACT: Uterine polyps are common and can cause abnormal bleeding, infertility, or bleeding after menopause. If patients don't experience symptoms, treatment is often not necessary. Polyps can be treated with medication but often a surgery will be necessary. SUMMARY STATEMENTS: RECOMMENDATIONS.

Incidence, risk factors and maternal outcomes of unsuspected placenta accreta spectrum disorders: a retrospective cohort study.

BACKGROUND: To identify incidence and underlying risk factors for unsuspected placenta accreta spectrum (PAS) and compare the maternal outcomes between suspected and unsuspected cases in three large academic referral centers. METHODS: A retrospective cohort study was conducted in three university-based tertiary referral centers from Jan 1st, 2013, to Dec 31st, 2022. All cases of PAS confirmed by pathology were included in the study. Unsuspected PAS cases were diagnosed at the time of delivery, while suspected cases served as the control group. Potential risk factors were compared between the two groups. Multivariable regression model was also performed to identify risk factors. Maternal outcomes were also evaluated. RESULTS: A total of 339 pathology-confirmed PAS cases were included in the study out of 415,470 deliveries, of which 35.4% (n = 120) were unsuspected cases. Unsuspected PAS cases were 7.9 times more likely to have a history of intrauterine adhesions (adjusted odds ratio [aOR] 7.93; 95% confidence interval [CI] 2.35-26.81), 7.0 times more likely to have a history of clinically confirmed PAS (aOR, 6.99; 95% CI 2.85-17.18), 6.3 times more likely to have a posterior placenta (aOR, 6.30; 95% CI 3.48-11.40), and 3.4 times more likely to have a history of placenta previa (aOR, 3.41; 95% CI 1.18-9.82). On the other hand, cases with gravidity > 3, placenta previa, and/or a history of previous cesarean delivery were more likely to be diagnosed antenatally (aOR 0.40, 0.19, 0.36; 95% CI 0.22-0.74, 0.09-0.40, 0.19-0.70). Although the suspected PAS group had a higher proportion of invasive cases and abdominal and pelvic organ injuries (74.4% vs. 25.8%, p < 0.001; 6.8% vs. 1.7%, p = 0.037), the maternal outcomes were more favorable in the sPAS group, with a lower median volume of 24-hour blood loss and blood product transfusion (estimated blood loss in 24 h, 1000 [800-2000] vs. 2000 [1400-2400], p < 0.001; RBC unit transfusion, 0 [0-800] vs. 800 [600-1000], p < 0.001; fresh-frozen plasma transfusion, 0 [0-450] vs. 600 [400-800], p < 0.001). CONCLUSIONS: Our findings indicate that 35% of patients with PAS were unsuspected prior to delivery. Factors associated with PAS being unsuspected prior to delivery include a history of intrauterine adhesions, a history of clinically confirmed PAS, a posterior placenta, and a history of placenta previa. Additionally, gravidity > 3, a history of previous cesarean delivery, and placenta previa increase the likelihood of antenatal diagnosis.