Endometriosis (EMs) is a disease that adversely affects women's health. Immune imbalance is an important factor contributing to EMs, and exosomes (Exo) play an important role in immunomodulation. The purpose of this study was to investigate the effect of exosomes derived from the blood of patients with EMs on macrophage polarization and elucidate the underlying mechanisms. Exosomes were isolated from the serum of healthy controls (control exosomes) and patients with EMs (EMs exosomes). Macrophage polarization levels were detected using flow cytometry (FCM), RT-qPCR, and Western blot. Subsequently, we used RNA sequencing to analyze differential microRNAs (miRNA) and associated pathways. Electroporation techniques were used to modify the exosomes. The associated pathways were analyzed by Western blot. Finally, 12Z cells were co-cultured with macrophages of different polarizations, and the viability and metastasis of 12Z cells were calculated by cell counting kit-8 (CCK-8), scratch, and Transwell. EMs exosomes induced M2-type polarization in macrophages. RNA sequencing results showed that miR-196a-5p was dramatically decreased in EMs exosomes, whereas overexpression of miR-196a-5p in EMs exosomes could inhibit the M2-type polarization of macrophages and activate the Hippo pathway. In addition, M2-type macrophages promoted 12Z cell proliferation and metastasis. These findings suggest that serum-derived exosomes encapsulating miR-196a-5p alleviate endometriosis by promoting M1-type macrophage polarization via Hippo pathway activation.

Numerous previous studies have suggested dyslipidemia is possibly linked to endometriosis (EMs). The connection between endometriosis and NHHR remains largely unexplored. Thus, this investigation examined whether NHHR is correlated with endometriosis development among adult women in the United States of America.

Data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) were analyzed in a cross-sectional study, with a final sample of 4,990 participants. To investigate the potential association between NHHR and the likelihood of developing endometriosis, we employed two statistical models: a weighted multivariate logistic regression model and a restricted cubic spline model. Data visualization included scatter plots with locally estimated scatterplot smoothing (LOESS) curves to illustrate the relationship between NHHR and the probability of endometriosis. To ensure the reliability of our findings, we subsequently conducted subgroup analyses and interaction tests to assess their stability.

In this study, after accounting for all potential confounders, it was found that for every one-point elevation in NHHR, the risk of developing endometriosis increased by 17% (95% CI: 1.05-1.35, p = 0.04). A linear dose-response association was identified that connected NHHR with the risk of endometriosis (P for nonlinear = 0.1315). Interaction results from subgroup analyses suggested that an association between NHHR and risk of endometriosis was largely unaffected by race, educational background, or marital status, among others.

NHHR and the probability of developing endometriosis are significantly correlated in the U.S. population, suggesting that further research on NHHR could assist in non-invasive diagnosis of endometriosis.

Fertility is a dynamic, multifactorial process governed by hormonal, immune, metabolic, and environmental factors. Recent evidence highlights the gut microbiota as a key systemic regulator of reproductive health, with notable impacts on endometrial function, implantation, pregnancy maintenance, and the timing of birth. This review examines the gut-endometrial axis, focusing on how gut microbial communities influence reproductive biology through molecular signaling pathways. We discuss the modulatory roles of microbial-derived metabolites-including short-chain fatty acids, bile acids, and tryptophan catabolites-in shaping immune tolerance, estrogen metabolism, and epithelial integrity at the uterine interface. Emphasis is placed on shared mechanisms such as β-glucuronidase-mediated estrogen recycling, Toll-like receptor (TLR)-driven inflammation, Th17/Treg cell imbalance, and microbial translocation, which collectively implicate dysbiosis in the etiology of gynecological disorders including endometriosis, polycystic ovary syndrome (PCOS), recurrent implantation failure (RIF), preeclampsia (PE), and preterm birth (PTB). Although most current evidence remains correlational, emerging insights from metagenomic and metabolomic profiling, along with microbiota-depletion models and Mendelian randomization studies, underscore the biological significance of gut-reproductive crosstalk. By integrating concepts from microbiology, immunology, and reproductive molecular biology, this review offers a systems-level perspective on host-microbiota interactions in female fertility.

This study aimed to identify and validate potential immune-related genes in endometriosis (Ems) through comprehensive bioinformatics analysis and immunohistochemistry (IHC) verification.

Using data from the GEO database, single-cell RNA sequencing (scRNA) data and traditional bulk RNA sequencing data were analyzed to identify differentially expressed genes related to the immune system. Immunological analysis confirmed alterations in immune cells associated with Ems. Machine learning techniques were employed to identify characteristic immune genes of eutopic and ectopic endometria, which were then validated through IHC experiments.

Immunological analysis revealed distinct variations in the enrichment of macrophages and NK cells in Ems. Functional enrichment analysis revealed a decrease in NK cell toxicity in both ectopic and eutopic endometria, activation of M2 macrophages in the ectopic endometrium supporting the survival of ectopic endothelial cells, and the presence of lipid antigens and signaling between immune cells facilitating the development of Ems. Machine learning algorithms revealed that TGFBR1 is a characteristic immune gene associated with the eutopic endometrium and that GIMAP4 is associated with the ectopic endometrium; this conclusion was also confirmed by IHC.

Macrophage and NK cell enrichment was significantly increased in endometria from patients with Ems. TGFBR1 is a characteristic immune gene associated with the eutopic endometrium, whereas GIMAP4 is associated with the ectopic endometrium.

These findings provide new insights for the clinical diagnosis and selection of immune-related targets for Ems.

Does the restoration of regulatory T cells (Tregs) suppress the progression of endometriosis?

Adoptive transfer of Tregs suppresses the progression of endometriosis and reduces the levels of helper T (Th)-cell-related and proinflammatory cytokines in mice.

Endometriosis is a chronic inflammatory gynecological disease, which involves multiple immune components. Activated Treg counts decrease in the endometrioma and endometrium of patients with endometriosis, and depletion of Tregs exacerbates endometriosis in mice.

We evaluated the effects of adoptive transfer of Tregs on the progression of endometriosis in mice. We used Foxp3tm3Ayr/J (Foxp3DTR) mice with temporarily ablated Tregs by injecting diphtheria toxin to develop an endometriosis model, which was generated by ovariectomy, estradiol administration and transplantation of uterine fragments from donor mice. Foxp3DTR mice were randomly divided into Treg adoptive transfer (n = 12) and control (n = 11) groups. Tregs were isolated from lymph nodes and spleens of wild-type (WT) mice and were adoptively transferred into mice that were temporarily Treg-depleted. Control mice were injected with vehicle. Treg adoptive transfer was performed on the day of uterine implantation, and a second adoptive transfer was performed after 14 days. Mice were euthanized 28 days after uterine implantation, and blood, peritoneal fluid, spleen, and endometriosis-like lesion samples were collected.

Foxp3DTR mice were intravenously injected with Tregs isolated from WT mice. The number, total weight, and total volume of the endometriosis-like lesions were evaluated on Day 28 following implantation of uterine fragments. The proportion of Tregs in endometriosis-like lesions, ascites, and peripheral blood was analyzed by flow cytometry. Inflammation in lesions and serum was examined using real-time PCR and ELISA.

Injection of Tregs increased their total count and decreased the number (P < 0.0001), weight (P = 0.0021), and volume (P = 0.0010) of endometriosis-like lesions in Foxp3DTR Treg-depleted mice. Furthermore, injection of Tregs decreased the mRNA expression of Th 1-, 2-, and 17-related cytokines, including interferon gamma (P = 0.0101), interleukin (IL)-4 (P = 0.0051), and IL-17 (P = 0.0177), as well as the levels of the proinflammatory cytokine IL-6 (P = 0.0002), in endometriosis-like lesions of Foxp3DTR Treg-depleted mice.

N/A.

Treg-related immune mechanisms in mice may not precisely reflect those in humans.

Restoration of Tregs may be a useful therapeutic strategy for inhibiting the progression of endometriosis in cases where the decrease in the Treg population is an exacerbating factor.

This study was partially supported by the Grants-in-Aid for Scientific Research (grant numbers 18K16808 and 20K22983) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The sponsor had no role in the study design, collection, analysis and interpretation of data, writing of the report, and decision to submit the article for publication. The authors have no conflicts of interest to disclose.

Previous studies have suggested that aging may influence reproductive functions of female. Nonetheless, the causal relationship between aging and endometriosis has yet to be completely understood.

This study aims to determine whether aging had a causal association with the incidence of endometriosis.

We conducted bidirectional MR analyses to evaluate the causal relationship between aging biomarkers, particularly leukocyte telomere length (LTL), and endometriosis risk. Instrumental variables for LTL were derived from the UK Biobank GWAS, while endometriosis-associated variants were obtained from the FinnGen GWAS dataset. Subgroup analyses were performed to investigate the association between LTL and endometriosis subtypes. Additionally, validation was performed using independent GWAS meta-analysis datasets.

Inverse variance-weighted (IVW) analysis revealed a significant association between longer LTL and an increased risk of endometriosis (OR-IVW = 1.276, 95% CI: 1.143 to 1.424, FDR-adjusted P = 7.00E-5), with consistent findings across multiple MR methods. Sensitivity analysis using an independent GWAS meta-analysis dataset did not confirm the LTL-endometriosis association (OR-IVW = 1.128, 95% CI: 0.140 to 9.115, P = 0.910). Bidirectional MR analysis found no causal relationship between endometriosis and LTL. Subgroup analyses indicated that longer LTL was significantly associated with endometriosis of the ovary (OR-IVW = 1.343, 95% CI: 1.143 to 1.577, P = 3.00E-4) and endometriosis of the rectovaginal septum and vagina (OR-IVW = 1.336, 95% CI: 1.064 to 1.676, P = 0.013), while no significant association was found with endometriosis of the pelvic peritoneum.

Our findings suggest that longer LTL may contribute to an increased risk of endometriosis, particularly in ovarian and rectovaginal subtypes. However, no causal effect of endometriosis on aging was observed. The lack of replication in independent datasets highlights the potential influence of population heterogeneity and dataset-specific factors, warranting further validation in diverse cohorts.

Investigate the association between endometriosis and the incidence of age-related macular degeneration.

This study used data from Taiwan's National Health Insurance Research Database (2000-2018) to examine the link between endometriosis and age-related macular degeneration. The endometriosis cohort included women diagnosed with the condition, with the index date set as their first diagnosis. A control group of women without endometriosis was matched using propensity score matching based on age, year of the index date, and comorbidities. The primary outcome was the occurrence of age-related macular degeneration during the study period. The incidence of age-related macular degeneration was compared between the two cohorts using a Cox regression model, and the risk of developing age-related macular degeneration was estimated with the Kaplan-Meier method.

The study included 53,993 individuals per group, with no significant differences in age or comorbidities. The mean follow-up duration was significantly longer for the endometriosis cohort (10.18 years) than the non-endometriosis cohort (9.96 years). Patients with endometriosis exhibited a significantly higher risk of age-related macular degeneration (adjusted hazard ratio = 1.43, 95 % confidence interval: 1.26-1.63, p < 0.001) after adjusting for age and comorbidities. The Kaplan-Meier curves confirmed an increased cumulative incidence of age-related macular degeneration in the endometriosis cohort. Subgroup analysis revealed a higher risk of age-related macular degeneration in patients with endometriosis across various age groups and in those without comorbidities.

This study demonstrated a significant association between endometriosis and the risk of developing age-related macular degeneration in women.

Endometriosis is a common gynecological disease that causes severe pain and infertility. However, the available treatments for EMS are limited. SCM-198, a synthetic form of leonurine, possesses various abilities, including anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and anti-proliferative effects. Previous studies have shown that SCM-198 can inhibit the growth of ectopic lesions, but the specific mechanism remains unknown. The results of our studies indicate that SCM-198 significantly suppresses the endometriotic growth of EMS mice. Enrichment analysis of RNA-seq indicates that SCM-198 is involved in T cell differentiation, activation, cytokine production, stimulation of chemotaxis, and migration. Flow cytometry reveals that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells in ectopic lesions. RNA-seq analysis shows that SCM-198 enhances the expression of CCL5 in the ectopic lesions, and western blot is conducted to verify this conclusion both in vivo and in vitro. These findings demonstrate that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells, alleviating the growth of mouse ectopic lesions, and the changes in CCR5 + T cells are likely due to the reduced expression of CCL5.

Endometriosis is a complex gynecological disorder characterized by endometrial-like tissue growing outside the uterus, leading to chronic pain, infertility, and reduced quality of life. Its pathophysiology involves genetic, epigenetic, immune, and molecular factors. Theories such as retrograde menstruation, coelomic metaplasia, and stem cell involvement explain lesion formation. Endometrial mesenchymal stem cells (eMSCs) and epithelial progenitors (eEPs) contribute to lesion establishment by adhering to peritoneal surfaces, proliferating, and differentiating into ectopic tissue. Aberrant adhesion molecules, inflammatory cytokines, and molecular pathways like PI3K/Akt and Wnt/β-catenin drive proliferation, angiogenesis, and resistance to apoptosis. Elevated estrogen levels and progesterone resistance further promote lesion growth and immune evasion. Immune dysfunction, including altered macrophage activity and reduced natural killer (NK) cell function, contributes to inflammation and lesion persistence. Pain is linked to prostaglandin E2 (PGE2) and nerve infiltration, emphasizing the need for targeted pain management. Current therapies, such as GnRH agonists, suppress ovarian hormone production but face limitations in long-term efficacy and side effects. Integrating molecular insights into clinical practice may advance diagnostics and treatment, with emerging approaches focusing on molecular pathways, immune modulation, and hormonal regulation for more effective, personalized therapies. Future research should unravel the complex mechanisms driving endometriosis to improve patient outcomes.

Early diagnosis and treatment of endometriosis (EM) remain challenging because of the lack of knowledge about EM development. While oxidative stress (OS) has been associated with EM, the link is unclear. We explored OS-related genes (OSRGs) and their role in EM pathogenesis.

We combined two ectopic endometrium (EC) and eutopic endometrium (EU) datasets (GSE11691 and GSE25628) into a dataset for analysis. Bioinformatic analyses were used to identify differentially expressed genes (DEGs), OS-related genes (OSRGs), enriched pathways, competitive endogenous RNA network, and immune cell infiltration. Finally, real time-quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) were used to validate the expression of key OSRGs in clinical patient samples.

Bioinformatic analysis identified 459 DEGs between EC and EU samples, including 67 OSRGs. A ceRNA network was established, encompassing 28 DE-OSRGs, 32 miRNAs, and 53 lncRNAs. Four key OSRGs (CYP17A1, NR3C1, ENO2, and NGF) were selected from protein-protein interaction network analysis. The RT-qPCR and WB analysis showed that these genes' abnormal changes in RNA and protein levels were consistent with data in public databases. Weighted gene co-expression network analysis identified three immune-related OSRGs (CYP17A1, NR3C1, and NGF) and 20 lncRNAs that may regulate NR3C1 through 10 miRNAs.

The key OSRGs may function via multilayered networks in EM. We provide insights into EM and underscore the potential significance of OSRGs and the immune environment for diagnostic and prognosis evaluation.

Endometriosis (EM) is a chronic inflammatory disease that is one of the most common causes of gynecological systemic lesions in women before menopause. The most representative histological feature of EM is that the endometrium appears outside of the uterine cavity, often in the ovary. Although it is generally accepted that the epithelial and stromal cells of the ectopic endometrium are not malignant, they still have numerous similarities to malignant tumors, including considerable changes to the immune microenvironment (immune monitoring disorder), the creation of a specific hormone environment, high levels of oxidative stress, chronic inflammation and abnormal immune cell regulation. The pathogenesis of EM is not fully understood, which makes it difficult to identify specific biomarkers and potential therapeutic targets for early disease diagnosis and effective treatment. However, considerable progress has been made in this field over the past few decades. The purpose of the present review is to summarize the confirmed and potential biomarkers for EM, and to identify potential therapeutic targets based on changes in immunological factors (including natural killer cells, macrophages, the complement system, miRNA and P‑selectin) in the ectopic endometrial tissue. It is hoped that this work can be used as the basis for identifying accurate diagnostic markers for EM and developing personalized immune‑targeted therapy.

Ovarian cancer is the fifth leading cause of cancer-related death among women, which is one of the most common gynecological cancers worldwide. Although several cytoreductive surgeries and chemotherapies have been attempted to address ovarian cancer, the disease still shows poor prognosis and survival rates due to prevalent metastasis. Peritoneal metastasis is recognized as the primary route of metastatic progression in ovarian cancer. It causes severe symptoms in patients, but it is generally difficult to detect at an early stage. Current anti-cancer therapy is insufficient to completely treat metastatic ovarian cancer due to its high rates of recurrence and resistance. Therefore, developing strategies for treating metastatic ovarian cancer requires a deeper understanding of the tumor microenvironment (TME) and the identification of effective therapeutic targets through precision oncology. Given that various signaling pathways, including TGF-β, NF-κB, and PI3K/AKT/mTOR pathways, influence cancer progression, their activity and significance can vary depending on the cancer type. In ovarian cancer, these pathways are particularly important, as they not only drive tumor progression but also impact the TME, which contributes to the metastatic potential. The TME plays a critical role in driving metastatic features in ovarian cancer through altered immunologic interactions. Recent therapeutic advances have focused on targeting these distinct features to improve treatment outcomes. Deciphering the complex interaction between signaling pathways and immune populations contributing to metastatic ovarian cancer provides an opportunity to enhance anti-cancer efficacy. Hereby, this review highlights the mechanisms of signaling pathways in metastatic ovarian cancer and immunological interactions to understand improved immunotherapy against ovarian cancer.

Do activated fibroblasts expressing fibroblast activation protein-α (FAP) - which is traceable in positron emission topography/computed topography (PET/CT) - play a role in the microenvironment of endometriosis?

Activated fibroblasts expressing FAP are detectable in endometriotic lesions and correlate with iron and collagen content and infiltrating CD8-positive cytotoxic T cells and CD68-positive macrophages in the microenvironment endometriotic lesions.

FAP-positive activated fibroblasts are found in various fibrosis-related pathologies and in the desmoplastic stroma of solid tumours; they can be traced in PET/CT but have not been investigated in the context of endometriosis, a chronic disease involving hormone-mediated repetitive tissue remodelling and fibrosis.

We analysed a cohort of endometriosis patients (n = 159) who had undergone surgery with removal of endometriotic foci at our University Hospital (tertiary care centre) between 2018 and 2024. All patients provided written informed consent. The median age of the patients was 34 years. In total, 245 samples from different locations were analysed retrospectively.

We investigated the expression of FAP and its relation to stroma composition and the immune microenvironment of endometriosis in 245 specimens from peritoneal lesions, ovarian endometriomas, deep infiltrating endometriosis, and extra-abdominal lesions using conventional histology and immunohistochemistry followed by digital image analysis. Tissue within a radius of 500 µm of ectopic endometrium-like epithelium was analysed. To measure FAP expression in the perilesional stroma, a histoscore (H-score) was calculated. Masson trichrome staining was used to determine collagen content. Prussian blue staining for iron was used for age-dating of lesions. The abundance of CD68-positive macrophages and CD8-positive cytotoxic T cells within the microenvironment of ectopic endometriotic glands was analysed. Extra-lesional tissue served as controls.

Distinct FAP expression (H-score >10) was observed in 84% of endometriotic lesions and in only 4% of extra-lesional controls. FAP expression was significantly higher in endometriotic lesions (mean H-score 61.8) than in extra-lesional tissue (mean H-score 3.8, P < 0.0001). There was a significant (P < 0.05) association with collagen content when comparing samples with low (H-score <100) and high (H-score ≥100) FAP expression, and a significant difference in FAP expression correlating with the tissue iron content when comparing strong staining intensity and negative samples (P < 0.0005) or samples with weak staining intensity (P < 0.005). Moreover, the abundance of CD8-positive and CD68-positive cells was significantly higher (P < 0.0001) in samples with high FAP expression (H-score ≥100).

N/A.

This study proves the presence of FAP-positive fibroblasts in endometriosis by immunohistological methods. However, to translate targeting FAP into endometriosis diagnostics, these results have to be compared to imaging data and FAP inhibitor (FAPi) PET/CT has to be validated in a structured way on a large patient cohort. Moreover, we show that FAP expression is intertwined with the immune cell infiltrate in the microenvironment of endometriosis. To explore and understand mechanisms contributing to chronic inflammation, immune evasion, and fibrosis, more studies including more immune cell subtypes and functional experiments are needed.

FAP-positive activated fibroblasts not only impact the immune microenvironment of endometriosis and are linked to increased macrophage and cytotoxic T-cell infiltration, as we showed, but could also provide new options for non-invasive diagnostic methods and an improvement of the diagnostic workup prior to surgery. FAPi PET/CT should be considered when exploring new diagnostic options in endometriosis.

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) 'Clinician Scientist Program in Evolutionary Medicine' (project number 413490537 to F.K.). We acknowledge financial support by Land Schleswig-Holstein within the funding programme 'Open Access Publikationsfonds'. The authors declare that they have no conflicts of interest related to this work.

Endometriosis (EMS) is a benign gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Evidence shows that the survival of patients with ectopic endometrial implants is associated with a dysregulated immune microenvironment. CD4 + T cells can regulate EMS through diverse cytokines, the inflammatory response, and angiogenesis. CCR5 +CD4 + T cells exhibit increased cellular immunogenicity and play a role in infectious diseases, host defense, and cancer progression. However, the specific mechanisms of CCR5 +CD4 + T cells in EMS remain unknown. In the present study, flow cytometry and RNA-seq are utilized to assess the proportions and features of CCR5 +CD4 + T cells in EMS patients, RT-PCR and ELISA are used to assess the production of CCL5 by ectopic endometrial stromal cells (ecESCs). Two EMS models are established through C57B6 wild-type and CCL5 ‒/‒ mice and utilized to explore the in vivo effects of CCR5 +CD4 + T cells on ectopic lesions. Compared with CCR5 ‒CD4 + T cells, CCR5 +CD4 + T cells display a more activated and cytotoxic phenotype. Diminished CCR5 +CD4 + T cells and their impaired ability to produce IFN-γ are observed in the ectopic lesions of EMS patients and in murine EMS models. Impaired production of CCL5 has been detected in human ecESCs. Moreover, endometria stripped from CCL5 ‒/‒ mice are more likely to generate ectopic lesions in the peritoneum of recipient mice. These findings demonstrate that the attenuated recruitment of CCR5 + CD4 + T cells in ectopic lesions caused by decreased production of CCL5 in ecESCs may facilitate the progression of EMS.

Endometriosis is a gynecologic condition characterized by the growth of endometrium-like stroma and glandular elements outside of the uterine cavity. The involvement of hormonal dysregulation, specifically estrogen, is well established in the initiation, progression, and maintenance of the condition. Evidence also highlights the association between endometriosis and altered immune states. The human endometrium is a highly dynamic tissue that undergoes frequent remodeling in response to hormonal regulation during the menstrual cycle. Similarly, endometriosis shares this propensity, compounded by unclear pathogenic mechanisms, presenting unique challenges in defining its etiology and pathology. Here, we provide a lens to understand the interplay between estrogen and innate and adaptive immune systems throughout the menstrual cycle in the pathogenesis of endometriosis. Estrogen is closely linked to many altered inflammatory and immunomodulatory states, affecting both tissue-resident and circulatory immune cells. This review summarizes estrogenic interactions with specific myeloid and lymphoid cells, highlighting their implications in the progression of endometriosis.

Endometriosis is a complex gynecological condition characterized by abnormal immune responses. This study aims to explore the immunomodulatory effects of monoterpene glycosides from Paeonia lactiflora on endometriosis. Using the ssGSEA algorithm, we assessed immune cell infiltration levels between normal and endometriosis groups. Key targets were identified through differential expression analysis of the GSE51981 dataset. Potential immunomodulatory targets of Paeonia lactiflora compounds were identified through Venn diagram analysis, followed by enrichment and machine learning analyses. A nomogram was developed for predicting endometriosis, while molecular docking explored compound-target interactions. Significant differences in immune cell infiltration were observed, with increased CD8 T cells, cytotoxic cells, and others in endometriosis. Differential expression analysis identified 43 potential targets. Enrichment analysis highlighted pathways involved in immune and inflammatory responses. Machine learning identified SSTR5, CASP3, FABP2, and SYK as critical targets, contributing to a nomogram that demonstrated good predictive performance for endometriosis risk. Molecular docking revealed strong interactions between Paeoniflorigenone and CASP3. Our findings suggest that monoterpene glycosides have therapeutic effects on endometriosis by modulating key immune-related targets and pathways, providing a basis for further investigation into Paeonia lactiflora's potential as a treatment for this condition.

Ovarian endometrioma (OE), also known as "chocolate cysts," is a cystic mass that develops in the ovaries due to endometriosis and is a common gynecological condition characterized by the growth of endometrial tissue outside the uterus, leading to symptoms such as dysmenorrhea, pelvic pain, and infertility. However, the precise molecular and cellular mechanisms driving this pathophysiology remain largely unknown, posing challenges for diagnosis and treatment. Here, we employed integrated single-cell transcriptomic profiling of over 52,000 individual cells from endometrial tissues of OE patients and healthy donors and identified twelve major cell populations. We identified notable alterations in cell type-specific proportions and molecular signatures associated with OE. Notably, the activation of IGFBP5+ macrophages with pro-inflammatory properties, NK cell exhaustion, and aberrant proliferation of IQCG+ and KLF2+ epithelium are key features and may be the potential mechanisms underlying the pathogenesis of OE. Collectively, our data contribute to a better understanding of OE at the single cell level and may pave the way for the development of novel therapeutic strategies.

This study aims to investigate alterations in immune cell counts within preovulatory follicles of patients with poor ovarian response (POR) during assisted reproductive technology (ART), classified according to the POSEIDON criteria.

This single-centre cross-sectional study included 543 women undergoing IVF/ICSI treatment, selected based on specific inclusion and exclusion criteria: 292 with normal ovarian response and 251 with poor response. Follicular fluid (FF) was collected on the day of oocyte retrieval and analysed by flow cytometry to determine the proportions of macrophages (Mφs), M1 and M2 Mφs, T cells (CD4 and CD8 T cells), dendritic cells (DCs), including type 1 conventional dendritic cells (cDC1) and type 2 conventional dendritic cells (cDC2), and neutrophils. Multivariable logistic regression assessed the relationship between immune cell counts and POR, Pearson correlation determined associations with the number of retrieved oocytes, and receiver operating characteristic (ROC) curves evaluated the predictive power of immune cell counts for POR.

Immune cells accounted for 52.57% (±23.90%) of the total cell population in the follicular microenvironment, which was approximately equal to that of granulosa cells, with Mφs being the most abundant, followed sequentially by T cells, DCs, and neutrophils. In patients with POR, overall Mφs infiltration in the follicular microenvironment decreased, whereas M1 and M2 polarization increased. T cell infiltration increased, with a decrease in the CD4/CD8 ratio. Both cDC1 and cDC2 were significantly elevated. Moreover, multivariable logistic regression revealed that the total macrophage count, CD4 T cell count, and cDC2 count were independent predictors of POR. Notably, cDC2 showed the largest area under the ROC curve, suggesting its strong potential as a biomarker for predicting POR.

The proportion of immune cells in preovulatory follicles were significantly altered in patients with POR. These findings suggest that immune cell dynamics in the follicular microenvironment may play a crucial role in determining ovarian response and prognosis, indicating that targeted immunomodulatory strategies could be considered in future therapeutic approaches.

Pathogenesis of endometriosis (EN) is still unknown, but growing evidence suggests that immune regulation may be important, and the pattern of peripheral immune changes in reproductive women with EN has yet to be fully explored. In this study, we conducted a comprehensive and systematic analysis of immune cell subsets within T cells, B cells, NK cells, and γδ T cells in peripheral blood (PB) samples from women with EN, women with uterine fibroids (UF) but without EN (UF-alone), and healthy controls using multi-parameter flow cytometry. Our findings revealed that UF, a common comorbidity of EN, exhibited similar peripheral immune features to EN, particularly in T cell and B cell immunity. Compared to healthy controls, we constructed the peripheral immune profile of EN. This profile highlighted that the immunopathogenic factors in EN predominantly relate to the immune disorder of B cells and their subsets, as well as the functional abnormalities within immune cell subsets of CD4+ T cells, CD8+ T cells, and γδ T cells. Moreover, using the random forest (RF) machine-learning method, we developed a diagnostic model that can effectively identify the patients with EN from healthy controls. The immune factors identified within this model could be pivotal for unraveling the immune pathogenic mechanisms of EN. Our study is the first to present a comprehensive depiction of the circulating immune features in EN, although the detailed roles and underlying mechanisms of these immune factors in the context of EN require further investigation.

Endometriosis is an oestrogen-dependent inflammatory disease affecting menstruating women, with varying levels of severity. Oestrogen dysregulation is responsible for chronic inflammation, angiogenesis, endometrial lesion development, progression, and infertility during menarche in afflicted women. The inflammatory mediators associated with this chronic painful disease have been established, with research also indicating the relationship between dysbiosis and disease manifestation. Endometriosis is also present with several painful comorbidities, including endometrial cancer, cardiovascular disease, and autoimmunity. The lack of specific and sensitive non-invasive diagnostic procedures, coupled with poor response to current therapeutic approaches, means that treatment needs remain unmet. Surgical procedures are performed to remove endometriosis ectopic lesions, for which the recurrence rate of disease is up to 50%, with certain patients exhibiting no alleviation of symptoms. This review aims to outline the aetiology of endometriosis, detailing novel diagnostic approaches and potential therapeutic approaches, namely advanced therapeutic medical products (ATMPs), including stem cell therapy and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing. This timely review also provides novel insights into the important recent modalities which may be applied for the diagnosis and therapeutic response of endometriosis, including biomarkers, microfluidic platforms, and organoid systems. Undoubtedly, reliable, reproducible, sensitive, and specific models of endometriosis in humans are urgently needed to investigate and detail the aetiology of this debilitating disease.

Endometriosis is a multifactorial gynecological disease, with angiogenesis as a key hallmark. The role of exosomal microRNAs (miRNAs) in endometriosis is not well understood. This study investigates differentially expressed exosomal miRNAs linked to angiogenesis in endometriosis, clarifies their molecular mechanisms, and identifies potential targets. Primary endometrial stromal cells (ESCs) were cultured, and exosomes were extracted. In a co-culture system, ESC-derived exosomes were taken up by human umbilical vein endothelial cells (HUVECs). Endometriosis implant-ESC-derived exosomes (EI-EXOs) significantly promoted HUVEC proliferation, migration and tube formation compared to normal endometrium-exosomes (NE-EXOs), a finding consistent in vivo in mice. MiRNA sequencing and bioinformatics identified differentially expressed miR-21-5p from EI-EXOs, confirmed by RT-qPCR. The miR-21-5p inhibitor or GW4869 attenuated EI-EXO-induced HUVEC proliferation, migration, and tube formation. TIMP3 overexpression diminished the pro-angiogenic effect of EI-EXOs, which was reversed by adding EI-EXOs or upregulating miR-21-5p. These findings validate the crosstalk between ESCs and HUVECs mediated by exosomal miR-21-5p, and confirm the miR-21-5p-TIMP3 axis in promoting angiogenesis in endometriosis. KEY MESSAGES: ESC-derived exosomes were found to be taken up by recipient cells, i.e. HUVECs. Functionally, endometriosis implant-ESC-derived exosomes (EI-EXOs) could significantly promote the proliferation, migration and tube formation of HUVECs compared to normal endometrium-exosomes (NE-EXOs). Through miRNA sequencing and bioinformatics analysis, differentially expressed miR-21-5p released by EI-EXOs was chosen, as confirmed by qRT-PCR. miR-21-5p inhibitor or GW4869 was found to attenuate the proliferation, migration, and tube formation of HUVECs induced by EI-EXOs. In turn, TIMP3 overexpression diminished the pro-angiogenic effect of EI-EXOs, and this angiogenic phenotype was reversed once EI-EXOs were added or miR-21-5p was upregulated.

Endometriosis, a prevalent chronic condition, afflicts approximately 10% of women in their reproductive years. Emerging evidence implicates immune cells in the pathogenesis of endometriosis, particularly in angiogenesis, tissue proliferation, and lesion invasion. This investigation employs two-sample Mendelian Randomization (MR) to dissect the bidirectional causal relationships between immune cell profiles and endometriosis.

We leveraged publicly available genome-wide association study (GWAS) data to elucidate the causal interplay between immune cell traits and endometriosis. Utilizing GWAS summary statistics ranging from accession numbers GCST90001391 to GCST90002121 and endometriosis data from the FinnGen study GWAS (8,288 endometriosis cases and 68,969 controls), we adopted stringent criteria for instrumental variable selection. We applied MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods to derive causal estimates. To address potential heterogeneity and pleiotropy, Cochran's Q test, MR-Egger intercept, and leave-one-out analyses were executed. Reverse-direction MR and bidirectional MR analyses evaluated potential reciprocal causation and the influence of endometriosis on immune cell composition.

Our analysis identified five immune phenotypes inversely associated with endometriosis risk. These phenotypes comprise: a percentage of CD11c + HLA-DR + + monocytes, CD25 expression on CD39 + CD4 + T cells, elevated CD25 on CD45RA + CD4 + non-regulatory T cells, HLA-DR intensity on HLA-DR + CD8 bright (CD8br) T cells, and the proportion of naïve double-negative (CD4 - CD8- %DN) T cells. In contrast, eleven phenotypes were positively correlated with endometriosis risk, including: CD127 expression on T cells, the proportion of CD24 + CD27 + B cells within lymphocytes, CD25 expression on CD28 + CD4 + T cells, CD28 expression on CD39 + activated regulatory T cells (activated Tregs), the frequency of bright CD33 HLA-DR + CD14 - cells within the CD33br HLA-DR + compartment, CD45 expression on lymphocytes and natural killer (NK) cells, activation status of central memory CD8 bright (CM CD8br) T cells, CX3CR1 expression on monocytes, and the percentage of HLA-DR + NK cells within the NK cell subset. Sensitivity assessments that excluded significant heterogeneity and pleiotropy confirmed the stability of these associations, thereby reinforcing the validity of our findings.

This study provides novel evidence of the potential causal impact of specific immune cells on the risk of developing endometriosis. These findings enhance our understanding of endometriosis pathophysiology and may inform innovative approaches for its diagnosis and management. While our findings provide novel insights, limitations such as potential horizontal pleiotropy and reliance on European ancestry data should be considered. Future research should expand to diverse populations and incorporate individual-level data to refine these findings.

Background: Inflammation and immune cell dysfunction are critical facilitators of endometriosis pathophysiology. Macrophages are renowned for stimulating lesion growth, vascularization, innervation, and pain generation. By combining macrophages and endometriotic cells, we determined if resveratrol and its natural analogs can target the immune dysregulation and oxidative imbalance in endometriosis. Methods: After treatment with compounds (5, 10, 25 µM), we evaluated the expression of key inflammatory and oxidative stress markers, cytokines release, and ROS production by applying q-PCR, ELISA, Cytometric Beads Array, and multiplexed fluorogenic staining and flow cytometry analysis with bioimaging. Results: The results showed that endometriosis-related macrophages treated with stilbenes have impaired expression of pro-inflammatory markers (IL6, IL8, IL1B, TNF, CCL2, CXCL10, PTGS2). The effect of resveratrol, pterostilbene, and piceatannol was observed, especially in reducing IL1B, CCL2, and CXCL10 genes up to 3.5-, 5-, and 7.7-fold at 25 µM, respectively. Also, with piceatannol or polydatin exposure, the IL-6 decrease was noticeable. This study reported an antioxidant effect by reducing ROS-positive cells from 96% to 48% by pterostilbene. Results from flow cytometry correlated with the transcript activation of detoxification enzymes (SOD, GPX). Conclusions: Prospects for potential therapy based on regulating the immune microenvironment and reducing the accumulation of free radicals with stilbenes application were described in the article.

Endometriosis is a chronic, estrogen-dependent, proinflammatory disease that can cause various dysfunctions. The main clinical manifestations of endometriosis include chronic pelvic pain and impaired fertility. The disease is characterized by a spectrum of dysfunctions spanning hormonal signaling, inflammation, immune dysregulation, angiogenesis, neurogenic inflammation, epigenetic alterations, and tissue remodeling. Dysregulated hormonal signaling, particularly involving estrogen and progesterone, drives abnormal growth and survival of endometrial-like tissue outside the uterus. Chronic inflammation, marked by immune cell infiltration and inflammatory mediator secretion, perpetuates tissue damage and pain. Altered immune function, impaired ectopic tissue clearance, and dysregulated cytokine production contribute to immune dysregulation. Enhanced angiogenesis promotes lesion growth and survival. Epigenetic modifications influence gene expression patterns, e.g., HSD11B1 gene, affecting disease pathogenesis. Endometriosis related changes and infertility lead to depression in diagnosed women. Depression changes lifestyle and induces physiological and immunological changes. A higher rate of depression and anxiety has been reported in women diagnosed with endometriosis, unleashing physiological, clinical and immune imbalances which further accelerate chronic endometriosis or vice versa. Thus, both endometriosis and depression are concomitantly part of a vicious cycle that enhance disease complications. A multidimensional treatment strategy is needed which can cater for both endometrial disease and depression and anxiety disorders.

This research has suggested a link between major depressive disorder (MDD) and infertility, with interleukin-18 (IL-18) being proposed as a potential mediator due to its connections to both conditions. A Mendelian randomization (MR) approach was utilized in this study, which drew on genetic data from 500,199 European participants studied for MDD, along with additional IL-18 and reproductive health data from the FinnGen consortium and GWAS datasets. Single nucleotide polymorphisms were employed as instrumental variables to examine the causal relationships between MDD, genetically predicted IL-18 levels, and infertility. In our study, bidirectional MR analysis revealed a significant inverse causal relationship between MDD and genetically predicted IL-18 levels, with a higher genetic predisposition to MDD, correlating with reduced IL-18 levels (β: -0.40; 95% confidence interval (CI): -0.69 to -0.11; P = 7.09 × 10-3). Additionally, MDD is found to significantly increase the risk of female infertility. Notably, genetically predicted IL-18 levels demonstrated a protective effect against female infertility (odds ratio (OR): 0.92; 95% CI: 0.86-0.98; P = 1.17 × 10-2). Mediation analysis indicated that genetically predicted IL-18 levels partially mediated the impact of MDD on female infertility associated with cervical, vaginal, other or unspecified origin, accounting for up to 14.61% of this effect. No evidence of pleiotropy or heterogeneity was detected. The role of genetic predispositions to MDD in influencing genetically predicted IL-18 levels, and subsequently, female infertility, was highlighted by our study, offering insights into the complex interplay between mental health and reproductive biology. These findings contribute to a deeper understanding of the genetic and molecular pathways influencing these conditions, suggesting new directions for research and potential therapeutic interventions.

Endometriosis is a prevalent gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterus. This condition poses significant challenges due to its chronic nature, debilitating symptoms such as pelvic pain and infertility, and substantial impact on quality of life. Central to the pathogenesis of endometriosis are inflammatory mechanisms that perpetuate tissue proliferation, adhesion formation, and immune dysregulation within the pelvic cavity. Inflammation plays a pivotal role in the development and progression of endometriosis, influencing the severity of symptoms and complications associated with the disease. Dysregulated immune responses contribute to the persistence of ectopic endometrial implants, exacerbating pelvic pain and other symptoms experienced by affected individuals. Moreover, the inflammatory milieu created by endometriotic lesions disrupts normal ovarian function, impairs follicular development, and compromises reproductive outcomes, thereby posing challenges to fertility. This review comprehensively explores the inflammatory mechanisms underlying endometriosis and their implications for fertility. Synthesizing current research and clinical insights elucidates the intricate interplay between inflammation, disease progression, and reproductive health outcomes. Understanding these complex interactions is essential for developing targeted diagnostic strategies and optimizing therapeutic approaches tailored to alleviate symptoms and improve fertility outcomes in individuals with endometriosis. Ultimately, this review aims to enhance the understanding of endometriosis pathophysiology, inform clinical practice, and stimulate further research to advance personalized care and management strategies for this challenging condition.

Endometriosis is one of the most common gynaecological diseases, yet it lacks efficient biomarkers for early detection and unravels disease mechanisms. Proteomic profiling has revealed diverse patterns of protein changes in various clinical samples. Integrating and systematically analysing proteomics data can facilitate the development of biomarkers, expediting diagnosis and providing insights for potential clinical and therapeutic applications. Hence, this systematic review and meta-analysis aimed to explore potential non-invasive diagnostic biomarkers in various biological samples and therapeutic targets for endometriosis.

Online databases, including Scopus, PubMed, Web of Science, MEDLINE, Embase via Ovid, and Google Scholar, were searched using MeSH terms. Two independent authors screened the articles, extracted the data, and assessed the methodological quality of the included studies. GO and KEGG analyses were performed to identify the pathways that were significantly enriched. Protein‑protein interaction and hub gene selection analyses were also conducted to identify biomarker networks for endometriosis.

Twenty-six observational studies with a total of 2,486 participants were included. A total of 644 differentially expressed proteins (180 upregulated and 464 downregulated) were identified from 9 studies. Proteins in peripheral blood exhibited a sensitivity and specificity of 38-100% and 59-99%, respectively, for detecting endometriosis, while proteins in urine had a sensitivity of 58-91% and specificity of 76-93%. Alpha-1-antitrypsin, albumin, and vitamin D binding proteins were significantly DEPs in both serum and urine. Complement C3 is commonly expressed in serum, menstrual blood, and cervical mucus. Additionally, S100-A8 is commonly expressed in both menstrual blood and cervical mucus. Haptoglobin is commonly detected in both serum and plasma, whereas cathepsin G is found in urine, serum, and plasma. GO and KEGG enrichment analyses revealed that proteoglycans in cancer pathways, which regulate cell-to-cell interactions, modulate the extracellular matrix, and promote the proliferation and invasion of endometrial cells, are commonly enriched in serum and urine.

This comprehensive study revealed potential proteomes that were significantly differentially expressed in women with endometriosis utilizing various non-invasive clinical samples. Exploring common differentially expressed proteins in various biological samples provides insights into the diagnosis and pathophysiology of endometriosis, as well as potential clinical and therapeutic applications.

Patients of ovary endometriosis have an abnormal immune micro-environment, leading to endometrial tissue that from retrograde menstruation evade immune surveillance and subsequently develop into ectopic lesions.

This study aims to elucidate the crucial immune cells and molecular pathways that are associated with an aberrant immune micro-environment of endometriosis.

In this study, we identified differentially expressed genes between ovarian ectopic endometrial tissue (OVE) and eutopic endometrial tissue from patients with endometriosis (PE) and non-endometriosis patients (CON) by analyzing the mRNA sequencing data. Additionally, we used WGCNA(Weighted Gene Co-expression Network Analysis) to screen for key genes related to immune cell infiltration and compared the sub-types of infiltrating immune cells using CIBERSORT(cell-type identification by estimating relative subsets of RNA transcript). Subsequently, we conducted a single-cell analysis on the identified key genes. Furthermore, we analyzed potential drugs suitable for ovarian endometriosis treatment using pRRophertic.

Seven key genes associated with immune cell infiltration were screened out. The expression of these genes in OVE was significantly lower than that in PE and CON. These key genes were mainly enriched in the NK cell-mediated cytotoxicity pathway, especially for CD16 + CD56dim NK. Moreover, NK cells infiltration in ovarian endometriosis was significantly reduced compared with PE and CON, while M2 macrophage shown the opposite. Results of the single-cell analysis showed that the expression of the seven key genes in NK cells and monocyte-macrophages in OVE was significantly lower than that in PE or CON. Additionally, we identified potential drugs suitable for ovarian endometriosis treatment.

The decreased infiltration of NK cells and increased infiltration of M2 macrophages contribute to the evasion of immune surveillance against endometrial tissue, promoting the progression of OVE. Therefore, potential strategies for the treatment of OVE include increasing NK cell activation and decreasing M2 macrophage polarization.

In recent years, a growing body of research has confirmed that the gut microbiota plays a major role in the maintenance of human health and disease. A gut microbiota imbalance can lead to the development of many diseases, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome, endometriosis, and cancer. Short-chain fatty acids are metabolites of specific intestinal bacteria and are crucial for maintaining intestinal homeostasis and regulating metabolism and immunity. Endometriosis is the result of cell proliferation, escape from immune surveillance, and invasive metastasis. There is a strong correlation between the anti-proliferative and anti-inflammatory effects of short-chain fatty acids produced by gut microbes and the development of endometriosis. Given that the mechanism of action of gut microbiota and Short-chain fatty acids in endometriosis remain unclear, this paper aims to provide a comprehensive review of the complex interactions between intestinal flora, short-chain fatty acids and endometriosis. In addition, we explored potential microbial-based treatment strategies for endometriosis, providing new insights into the future development of diagnostic tests and prevention and treatment methods for endometriosis.

Background and Objectives: Oral contraceptives (OCs) are usually used to treat endometriosis; however, the evidence is inconsistent about whether OC use in the past, when given to asymptomatic women, is protective against the development of future disease. We aimed to assess the relationship between the use of OCs and the likelihood of discovering endometriosis, considering the length of time under OCs during their fertile age. Materials and Methods: This was a monocentric retrospective cohort study in a tertiary-care University Hospital (Department of Human Reproduction, Division of Gynaecology and Obstetrics, University Medical Centre Ljubljana, Slovenia) carried out from January 2012 to December 2022. Reproductive-aged women scheduled for laparoscopic surgery for primary infertility and subsequent histopathological diagnosis of endometriosis were compared to women without an endometriosis diagnosis. They were classified based on the ratio of years of OC use to fertile years in four subgroups: never, <25%, between 25 and 50%, and >50. Results: In total, 1923 women (390 with and 1533 without endometriosis) were included. Previous OC use was higher in those with endometriosis than controls (72.31% vs. 58.64%; p = 0.001). Overall, previous OC usage was not related to histopathological diagnosis of endometriosis (aOR 1.06 [95% CI 0.87-1.29]). Women who used OCs for less than 25% of their fertile age had reduced risk of rASRM stage III endometriosis (aOR 0.50 [95% CI 0.26-0.95]; p = 0.036) or superficial implants (aOR 0.88 [95% CI 0.58-0.95]; p = 0.040). No significant results were retrieved for other rASRM stages. Using OCs for <25%, between 25 and 50%, or >50% of fertile age did not increase the risk of developing superficial endometriosis, endometriomas, or DIE. Conclusions: When OCs are used at least once, histological diagnoses of endometriosis are not increased. A protective effect of OCs when used for less than 25% of fertile age on superficial implants may be present. Prospective research is needed to corroborate the findings due to constraints related to the study's limitations.

To compare survival outcomes and patterns of recurrence between endometriosis-associated ovarian cancer patients and non-endometriosis-associated ovarian cancer patients.

This retrospective study included data of consecutive patients with endometrioid or clear cell ovarian cancer treated at the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano between January 2010 and June 2021. Patients were assigned to one of two groups according to the absence or presence of endometriosis together with ovarian cancer at final histological examination. Survival outcomes were assessed using Kaplan-Meier and Cox hazard models. Proportions in recurrence rate and pattern of recurrence were evaluated using the Fisher exact test.

Overall, 83 women were included in the endometriosis-associated ovarian cancer group and 144 in the non-endometriosis-associated ovarian cancer group, respectively. Patients included in the non- endometriosis-associated ovarian cancer group had a shorter disease-free survival than those in the endometriosis-associated ovarian cancer group (23.4 (range 2.0-168.9) vs 60.9 (range 4.0-287.8) months; p<0.001). Univariable and multivariable analyses showed that the association with endometriosis, previous hormonal treatment, early stage at presentation, and endometrioid histology were related to better disease-free survival in the entire study population. Similarly, patients in the non-endometriosis-associated ovarian cancer group had a shorter median (range) overall survival than those in the endometriosis-associated ovarian cancer group (54.4 (range 0.7-190.6) vs 77.6 (range 4.5-317.8) months; p<0.001). Univariable and multivariable analyses showed that younger age at diagnosis, association with endometriosis, and early stage at presentation were related to better overall survival. The recurrence rate was higher in the non-endometriosis-associated ovarian cancer group (63/144 women, 43.8%) than in the endometriosis-associated ovarian cancer group (17/83 women, 20.5%; p<0.001).

Endometriosis-associated ovarian cancer patients had significantly longer disease-free survival and overall survival than non-endometriosis-associated ovarian cancer patients, while the recurrence rate was higher in non-endometriosis-associated ovarian cancer patients.

Endometriosis is a frequent, estrogen-dependent, chronic disease, characterized by the presence of endometrial glands and stroma outside of the uterine cavity. Although it is not considered a precursor of cancer, endometriosis is associated with ovarian cancer. In this review, we summarized the evidence that clear-cell and endometrioid ovarian carcinomas (endometriosis-associated ovarian carcinoma-EAOC) may arise in endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interaction domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in phosphatidylinositol 3-kinase (PI3K) which frequently coexist. Recent studies have also suggested the simultaneous role of the PTEN tumor-suppressor gene in the early malignant transformation of endometriosis and the contribution of deficient MMR (mismatch repair) protein status in the pathogenesis of EAOC. In addition to activating and inactivating mutations in cancer driver genes, the complex pathogenesis of EAOC involves multiple other mechanisms such as the modulation of cancer driver genes via the transcriptional and post-translational (miRNA) modulation of cancer driver genes and the interplay with the inflammatory tissue microenvironment. This knowledge is being translated into the clinical management of endometriosis and EAOC. This includes the identification of the new biomarkers predictive of the risk of endometriosis and cancer, and it will shape the precision oncology treatment of EAOC.

Background/Objectives: Endometriosis represents substantial direct and indirect healthcare costs impacted by an absence of uniformly accurate, non-invasive diagnostic tools. We endeavored to demonstrate gastrointestinal myoelectrical activity (GIMA) biomarkers, unique to endometriosis, will allow non-invasive, uniformly accurate diagnosis or exclusion of endometriosis. Methods: Prospective open-label comparative study of 154 patients, age ≥ 18, with or without diagnosed endometriosis. Population included 62 non-endometriosis controls (Cohort 1), 43 subjects with surgically/histologically confirmed endometriosis (Cohort 2), and 49 subjects with abdominal pain and negative imaging (Cohort 3). Non-invasive electroviscerography (EVG) recorded GIMA biomarkers from three abdominal electrodes before and 30 min post water load protocol. Cohort 2 had postoperative EVG and Cohort 3 had preoperative EVG. Calculated specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV), and predictive probability or C-statistic used univariate, multivariate, linear, and logistical regression analyses of the area under the curve (AUC) at all frequency and time points, including age and pain covariants. Results: The non-endometriosis cohort differed significantly from the endometriosis cohorts (p < 0.001) for median (IQR) and AUC percent frequency distribution of power at baseline, 10 min, 20 min, and 30 min post water load at all frequency ranges: 15-20 cpm, 30-40 cpm, and 40-50 cpm. The endometriosis cohorts were statistically similar (p > 0.05). GIMA biomarker threshold scoring demonstrated 95%/91% sensitivity and PPV, 96%/95% specificity and NPV, and a C-statistic of >99%/98%, respectively, for age subsets. GIMA biomarkers in Cohort 3 predicted 47/49 subjects positive and 2/49 negative for endometriosis, confirmed surgically. Hormonal therapy, surgical stage, nor pain score affected diagnostic accuracy. Conclusions: EVG with GIMA biomarker detection distinguished participants with and without endometriosis based upon endometriosis-specific GIMA biomarkers threshold scoring.

Vitamin D is a fat-soluble steroid hormone that was initially known only for regulating calcium and phosphorus levels and maintaining bone health. However, it was later discovered that many organs express vitamin D metabolizing enzymes and have a ligand for vitamin D, which regulates the expression of an extensive assortment of genes. As a result, vitamin D is indispensable for the proper function of organs, and its deficiency is believed to be a critical factor in symptoms and disorders such as cardiovascular diseases, autoimmune diseases, and cancers. The significance of vitamin D in reproductive tissues was recognized later, and studies have revealed its crucial role in male and female fertility, as well as proper reproductive function during pregnancy. Vitamin D deficiency has been identified as a risk factor for infertility, gonadal cancers, pregnancy complications, polycystic ovary syndrome, and endometriosis. However, data investigating the association between vitamin D levels and reproductive disorders, including endometriosis, have encountered inconsistencies. Therefore, the present study aims to review existing research on the effect of vitamin D on proper reproductive function, and the role of deficiency in reproductive diseases and specifically focuses on endometriosis.

The objective of this study was to investigate the role of phase separation-related genes in the development of endometriosis (EMs) and to identify potential characteristic genes associated with the condition.

We used GEO database data, including 74 non-endometriosis and 74 varying-degree EMs patients. Our approach involved identifying significant gene modules, exploring gene intersections, identifying core genes, and screening for potential EMs biomarkers using weighted gene co-expression network analysis (WGCNA) and various machine learning approaches. We also performed gene set enrichment analysis (GSEA) to understand relevant pathways. This comprehensive approach helps investigate EMs genetics and potential biomarkers.

Nine genes were identified at the intersection, suggesting their involvement in EMs. GSEA linked DEGs to pathways like complement and coagulation cascades, DNA replication, chemokines, apical plasma membrane processes, and diseases such as Hepatitis B, Human T-cell leukemia virus 1 infection, and COVID-19. Five feature genes (FOS, CFD, CCNA1, CA4, CST1) were selected by machine learning for an effective EMs diagnostic nomogram. GSEA indicated their roles in mismatch repair, cell cycle regulation, complement and coagulation cascades, and IL-17 inflammation. Notable differences in immune cell proportions (CD4 T cells, CD8 T cells, DCs, macrophages) were observed between normal and disease groups, suggesting immune involvement.

This study suggests the potential involvement of phase separation-related genes in the pathogenesis of endometriosis (EMs) and identifies promising biomarkers for diagnosis. These findings have implications for further research and the development of new therapeutic strategies for EMs.

Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.

We aimed to explore the relationship of adipose tissue concentrations of some persistent organic pollutants (POPs) with the risk of endometriosis and the endometriotic tissue expression profile of genes related to the endometriosis-related epithelial-mesenchymal transition (EMT) process. This case-control study enrolled 109 women (34 cases and 75 controls) between January 2018 and March 2020. Adipose tissue samples and endometriotic tissues were intraoperatively collected to determine concentrations of nine POPs and the gene expression profiles of 36 EMT-related genes, respectively. Associations of POPs with endometriosis risk were explored with multivariate logistic regression, while the relationship between exposure and gene expression profiles was assessed through Spearman correlation or Mann-Whitney U tests. After adjustment, increased endometriosis risk was associated with p,p'-DDT, PCB-180, and ΣPCBs. POP exposure was also associated with reduced gene expression levels of the CLDN7 epithelial marker and increased levels of the ITGB2 mesenchymal marker and a variety of EMT promoters (HMGA1, HOXA10, FOXM1, DKK1, CCR1, TNFRSF1B, RRM2, ANG, ANGPT1, and ESR1). Our findings indicate that exposure to POPs may increase the risk of endometriosis and might have a role in the endometriosis-related EMT development, contributing to the disease onset and progression. Further studies are warranted to corroborate these findings.

Endometriosis is a complex and chronic gynaecological disorder that affects millions of women worldwide, leading to significant morbidity and impacting reproductive health. This condition affects up to 10% of women of reproductive age and is characterised by the presence of endometrial-like tissue outside the uterus, potentially leading to symptoms such as chronic pelvic pain, dysmenorrhoea, dyspareunia, and infertility. The Montreux summit brought a number of experts in this field together to provide a platform for discussion and exchange of ideas. These proceedings summarise the six main topics that were discussed at this summit to shed light on future directions of endometriosis classification, diagnosis, and therapeutical management. The first question addressed the possibility of preventing endometriosis in the future by identifying risk factors, genetic predispositions, and further understanding of the pathophysiology of the condition to develop targeted interventions. The clinical presentation of endometriosis is varied, and the correlation between symptoms severity and disease extent is unclear. While there is currently no universally accepted optimal classification system for endometriosis, several attempts striving towards its optimisation - each with its own advantages and limitations - were discussed. The ideal classification should be able to reconcile disease status based on the various diagnostic tools, and prognosis to guide proper patient tailored management. Regarding diagnosis, we focused on future tools and critically discussed emerging approaches aimed at reducing diagnostic delay. Preserving fertility in endometriosis patients was another debatable aspect of management that was reviewed. Moreover, besides current treatment modalities, potential novel medical therapies that can target underlying mechanisms, provide effective symptom relief, and minimise side effects in endometriotic patients were considered, including hormonal therapies, immunomodulation, and regenerative medicine. Finally, the question of hormonal substitution therapy after radical treatment for endometriosis was debated, weighing the benefits of hormone replacement.

Endometriosis (EM) is one of the most common diseases among women of reproductive age. The etiology and pathogenesis of EM remain unclear and therefore there is a lack of effective treatment measures, which affects physical and mental health, as well as the quality of life of patients with EM. Angiogenesis has become a hotspot for research on the pathogenesis of EM; the role of angiogenesis‑related serological markers and anti‑angiogenic therapy in the diagnosis and treatment of EM is promising for early diagnosis and treatment of EM. Angiogenesis in EM is subject to complex regulation by hormones, immunity and associated cytokines. Therefore, novel targets for angiogenesis therapy are also being discovered and developed. The present review summarized the pathological mechanisms of angiogenesis and the value of relevant markers in pathogenesis and diagnosis of EM, along with the status of research on anti‑angiogenic drugs in the treatment of EM. The role of angiogenesis in EM provides an important reference for treatment and diagnosis, but there is no uniform non‑invasive diagnostic marker and proven strategy for anti‑angiogenesis.

This study is aimed at identifying variations in the effect of endometriosis on fecundity in a mouse model based on prior pregnancy experience. Endometriosis is one of the most prevalent gynecological diseases and is known to impact female fecundity adversely. In this study, an endometriosis mouse model was established by allografting uterine horn tissue using Pelch's method. The effect of endometriosis on fecundity was confirmed in primiparous and multiparous female mice. As fecundity indicators, the pregnancy rate, number of litters, pregnancy period, and survival rate of the pups were investigated. As a result of the experiment, the pregnancy rate decreased, and the pregnancy period tended to be shorter in primiparous female mice. However, there was no significant change in the multiparous mice. In addition, it has been established that correlations exist between the size of lesions and certain fecundity indicators of the lesion, even among primiparous and multiparous females with endometriosis. The study attempted to demonstrate a link between pregnancy experience and fecundity changes caused by endometriosis by experimentally reproducing clinical results using mouse models. These results suggest strategies for identifying several pathophysiological characteristics of endometriosis.

This study aimed to identify the key genes involved in the development of endometriosis and construct an accurate predictive model to provide new directions for the diagnosis and treatment of endometriosis. Using bioinformatics analysis, we employed the single-cell cell communication method to identify the key cell subtypes. By combining chip data and integrating differential analysis, WGCNA analysis, and the least absolute shrinkage and selection operator (LASSO) model, key genes were identified for immune infiltration and functional enrichment analyses. Cell communication analysis identified tissue stem cells as the key subtype. Differential analysis revealed 1879 differentially expressed genes, whereas WGCNA identified 357 module genes. The LASSO model further selects 4 key genes: Adipocyte Enhancer Binding Protein 1(AEBP1), MBNL1, GREM1, and DES. All 4 key genes showed significant correlations with immune cell content. Moreover, these genes were significantly expressed in single cells. The predictive model demonstrated good diagnostic performance. Through scRNA-seq, WGCNA, and LASSO methodologies, DES, GREM1, MBNL1, and AEBP1 emerged as crucial core genes linked to tissue stem cell markers in endometriosis. These genes have promising applications as diagnostic markers and therapeutic targets for endometriosis.

Association studies investigating miRNA in relation to diseases have consistently shown significant alterations in miRNA expression, particularly within inflammatory pathways, where they regulate inflammatory cytokines, transcription factors (such as NF-κB, STAT3, HIF1α), and inflammatory proteins (including COX-2 and iNOS). Given that endometriosis (EMS) is characterized as an inflammatory disease, albeit one influenced by estrogen levels, it is natural to speculate about the connection between EMS and miRNA. Recent research has indeed confirmed alterations in the expression levels of numerous microRNAs (miRNAs) in both endometriotic lesions and the eutopic endometrium of women with EMS, when compared to healthy controls. The undeniable association of miRNAs with EMS hints at the emergence of a new era in the study of miRNA in the context of EMS. This article reviews the advancements made in understanding the pathological role of miRNA in EMS and its association with EMS-associated infertility. These findings contribute to the ongoing pursuit of developing miRNA-based therapeutics and diagnostic markers for EMS.