Regulatory role of MRTF-A in macrophage polarization and the therapeutic mechanism of Bushen Wenyang Huayu decoction in endometriosis.

Endometriosis (EMS) is a prevalent gynecological condition, and its diagnosis remains challenging. Hematological indicators such as platelet count (PLT), mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) have recently received attention for their potential diagnostic value in EMS. To assess the association of PLT, MPV, and PLR in EMS by a meta-analysis. We systematically searched Embase, PubMed, Cochrane Library, and Web of Science up to June 2025 for studies on the association of platelet-related parameters (PLT, MPV, and PLR) with EMS. Standardized mean difference (SMD) with 95% confidence interval (CI) was calculated for PLT, MPV, and PLR using a random-effects model. All statistical analyses were performed using Stata16.0. Nineteen studies with 5675 subjects were included. Overall pooled analyses showed no statistically significant differences in PLT (SMD 0.35 [- 0.02, 0.71], I²=97.6%, P = 0.063) and PLR (SMD 0.24 [- 0.16, 0.64], I²=96.6%, P = 0.224) between EMS and non-EMS populations. However, MPV was significantly elevated in EMS compared with non-EMS populations (SMD 0.30 [0.09, 0.52], I²=82.7%, P = 0.006). Subgroup analyses by control group type revealed context-dependent associations. Compared with benign gynecological conditions (e.g., ovarian cysts, uterine fibroids), EMS showed significantly elevated PLT (SMD 0.20 [0.01, 0.38], I²=53.7%, P = 0.042) and PLR (SMD 0.33 [0.22, 0.43], I²=0.0%, P < 0.01). PLT was significantly lower in EMS than in ovarian cancer (SMD - 0.56 [- 0.81, - 0.32], I²=0.0%, P < 0.001). MPV was significantly elevated in EMS compared with healthy individuals (SMD 0.46 [0.11, 0.81], I²=84.7%, P = 0.010), whereas no significant difference was observed between EMS and other benign gynecological conditions (SMD 0.04 [- 0.10, 0.19], I²=0.0%, P = 0.547). MPV shows potential as an adjunctive marker for EMS, while PLT and PLR have limited independent diagnostic value but may be useful in specific clinical contexts.

Endometriosis (EM) is a common gynecological disorder imposing a considerable burden on the quality of life of women through chronic pain, infertility, and other clinical manifestations. The effectiveness of management options for EM is limited by substantial side effects associated with current treatment options, including hormonal therapies and surgery, increasing the need for an alternative approach associated with fewer adverse effects. Polyphenols, a wide class of naturally occurring bioactive compounds, have generated considerable attention due to their antioxidant, anti-inflammatory, and anti-proliferative properties. This structured narrative review highlights the therapeutic potential of polyphenols, focusing on their ethnopharmacological relevance and providing valuable insights into these natural compounds to be used as an alternative therapeutic approach for managing endometriosis. A comprehensive literature search was conducted across databases, including PubMed, Web of Science, and Scopus, with studies on polyphenol interventions in EM models. Data were analyzed for mechanisms such as antioxidant, anti-proliferative, anti-inflammatory, apoptotic effects, and others associated with endometriosis pathology. The existing evidence indicates that polyphenols can mitigate endometriosis-related outcomes, including inflammation, pain, lesion growth, and invasion in experimental models of endometriosis. However, the majority of the evidence available comes from rodent models, high-dose in vitro research, and immortalized cell lines, all of which have significant translational constraints and might not accurately represent the complexity of human disease. Additionally, there are very few clinical trials assessing the safety and effectiveness of polyphenols in endometriosis patients. In our opinion, polyphenols hold significant promise as adjunct therapies for EM. However, further large-scale clinical trials are essential to validate efficacy, optimize dosing, and establish safety profiles in diverse patient populations.

ABSTRACTUterine leiomyomas are common benign tumors, but their clinical presentation can be misleading. We report two unusual cases of pedunculated uterine masses presenting with heavy vaginal bleeding. In the first case, a woman in her 40s underwent urgent resection of a prolapsing mass after acute hemorrhage; histopathological examination demonstrated a mature cystic teratoma containing a leiomyomatous component, an exceptionally rare finding. In the second case, a woman in her late 40s presented with a pedunculated cervical mass initially considered to be a leiomyoma; histopathology instead showed an endometriotic cyst with no definitive evidence of leiomyoma. These cases emphasize that apparently typical prolapsing uterine masses may conceal rare pathological entities and highlight the importance of comprehensive histopathological assessment for accurate diagnosis, counseling, and management.

The follicular fluid (FF) microenvironment plays a critical role in oocyte maturation and embryo development, reflecting local ovarian activity and systemic metabolic status. While metabolic alterations in FF have been described in different diseases, comparative analyses across different infertility-related disorders remain limited. This study aimed to characterize and compare amino acid profiles in FF from patients undergoing in vitro fertilization (IVF) with insulin resistance (IR), endometriosis (EM), thyroid dysfunction (TD) and to identify disease-specific metabolic signatures. We analyzed 171 FF samples using targeted ultra-high-performance liquid chromatography. The twenty proteogenic amino acids were quantified and analyzed using univariate and multivariate statistical analyses, including Kruskal-Wallis testing with post-hoc correction, generalized linear modeling adjusted for BMI, principal component analysis (PCA) and pathway enrichment analysis. PCA revealed that the global amino acid composition of FF was largely conserved across all groups. However, disease status had a statistically significant but moderate effect on the overall amino acid profile (PERMANOVA, R²=0.081, p = 0.001). After adjusting for BMI, IR was associated with decreased glycine and arginine levels and TD was associated with lower histidine, tryptophan and lysine concentrations. In contrast, EM was characterized by a selective increase in the histidine content. Pathway analysis revealed alterations in branched-chain amino acid (BCAA) metabolism in IR group and broader disruptions in central amino acid metabolism in TD group. Multivariate and ROC analyses indicated limited discriminative performance of individual amino acids (AUC ≤ 0.71), suggesting that metabolic alterations are subtle and distributed across multiple pathways. FF amino acid composition is tightly regulated but distinct disease-specific metabolic alterations can be detected in IR, EM and TD. These changes are independent of BMI and reflect coordinated alterations in the metabolism of different amino acids rather than strong individual biomarkers. These results show the sensitivity of the follicular environment to overall metabolic health and support the idea of using multivariable metabolic patterns to better understand reproductive dysfunction.

Objectives This meta-analysis aimed to evaluate the association between endometriosis (EM) and cardiovascular disease (CVD) risk by synthesizing evidence from large-scale cohort studies, with emphasis on subtype-specific risks and geographic disparities. Methods We systematically searched PubMed, Embase, and Cochrane Library for cohort studies published until December 2024. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analyses stratified CVD subtypes (e.g. ischemic heart disease, atrial fibrillation), continents, and country development levels. Heterogeneity and publication bias were assessed via I2 statistics, sensitivity analyses, and Egger’s test. Results Eleven cohort studies (n = 3,100,610 participants) were included. EM was associated with a 22% increased risk of all-cause CVD (HR = 1.22; 95% CI: 1.08–1.38; I 2 = 94.6%). Subgroup analyses revealed elevated risks for myocardial infarction (HR = 1.29; 95% CI: 1.10–1.50), coronary artery disease (HR = 1.47; 95% CI: 1.29–1.67), and cerebrovascular events (HR = 1.18; 95% CI: 1.12–1.25), but not heart failure. Geographic disparities were significant, with higher CVD risks in Asian (HR = 1.36; 95% CI: 1.25–1.48) and North American cohorts (HR = 1.37; 95% CI: 1.16–1.61) compared to European populations (HR = 0.93; 95% CI: 0.64–1.34). Conclusions EM is independently associated with an elevated risk of CVD, particularly for coronary artery disease and myocardial infarction. These findings underscore the need for targeted cardiovascular monitoring in EM patients, particularly in high-risk populations.

Endometriosis (EMs) is a prevalent gynecological disorder affecting reproductive-age women. Exosomes secreted by peripheral blood macrophages may participate in EMs progression. In this pilot translational study, exosomes from peripheral blood macrophages obtained from patients with EMs (n = 3) and control patients (n = 3) were isolated by ultracentrifugation, identified by transmission electron microscopy and exosomal markers, and cocultured with endometrial stromal cells. Quantitative reverse transcription polymerase chain reaction was used to detect long noncoding RNA zinc finger antisense 1 (ZFAS1) expression in macrophage-derived exosomes. Cell proliferation, migration, invasion, and apoptosis were evaluated using Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine, wound healing, transwell, and flow cytometry assays. Gain- and loss-of-function experiments were performed in stromal cells to examine the biological role of ZFAS1. EMs-derived macrophage exosomes promoted endometrial stromal-cell proliferation, migration, and invasion and inhibited apoptosis compared with the blank and control-exosome groups. long noncoding RNA ZFAS1 expression was higher in EMs-derived exosomes than in control exosomes. In stromal cells, ZFAS1 overexpression enhanced proliferation, migration, and invasion and reduced apoptosis, whereas ZFAS1 knockdown produced the opposite effects. Macrophage-derived exosomes were associated with an aggressive stromal-cell phenotype, and exosomal ZFAS1 may contribute to this process. Because of the very small patient sample size and limited exosome characterization, these findings should be considered preliminary and hypothesis-generating.

Ceramide, a central hub in sphingolipid metabolism, serves as a critical bioactive signalling mediator that integrates lipid metabolism with multiple signalling pathways, primarily promoting autophagy and apoptosis. It influences female reproductive homeostasis and pathophysiology through multiple dimensions: altered ceramide levels have been observed in various reproductive disorders-such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and endometriosis (EM)-as well as across the female lifespan. These changes impact key processes including gonadotropin release, follicular development, and uterine microenvironment homeostasis. This review systematically summarizes the effects of ceramide on female fertility, highlighting its role as a pivotal entry point for understanding reproductive endocrine disorders in women. Modulating ceramide levels may represent a promising therapeutic strategy to enhance fertility and promote female reproductive health.

A transdiagnostic cognitive model of depression and anxiety in chronic inflammatory disease: Evidence from multiple sclerosis and endometriosis.

Research on the association between urinary heavy metals, phthalates, phytoestrogens (PEs), polycyclic aromatic hydrocarbons (PAHs), and endometriosis (EM) is limited. Data were from the National Health and Nutrition Examination Survey 1999 to 2016. Logistic regression models were used for analysis. In addition, qgcomp and Bayesian kernel machine regression models were employed to evaluate the effects of mixed exposures. After adjusting for covariates, compared with the first quartile (Q1), the fourth quartile (Q4) of urinary cobalt (95% confidence interval [CI] = 1.3–3.9) and urinary lead (95% CI = 1.0–3.1) were significantly associated with an increased risk of EM. Conversely, 1-naphthol (95% CI = 0.3–0.9), 2-fluorene (2-Flu; 95% CI = 0.3–0.9), 3-phenanthrene (95% CI = 0.3–1.0), and 2-phenanthrene (95% CI = 0.3–0.9) were negatively correlated with EM risk. When concentrations exceeded the 50th percentile, elevated levels of urinary heavy metal mixtures and PAH mixtures were positively associated with EM. In the Bayesian kernel machine regression mixture analysis, 2-Flu showed a positive association with EM, while 1-pyrene was negatively correlated, although the direction for 2-Flu differed from single-pollutant logistic regression. Analyses of chemical mixtures suggested possible associations for specific substances, including the PAH 2-Flu, the phthalate monobutyl phthalate, and the PEs enterodiol and enterolactone; however, the overall phthalate and PE mixtures were not significantly associated with EM, and these findings require further confirmation. Heavy metals (cobalt and lead) were consistently associated with increased EM risk.

Luoshi Neiyi prescription mitigates endometriosis by modulating nuclear receptor subfamily 5 group A member 1 methylation.

Human Phospholipase A2 Group V (hPLA2-G5) is elevated in inflammatory conditions and promotes neutrophil and macrophage recruitment. Its enzymatic activity activates lipid receptors and cytosolic phospholipase A2 (cPLA2), leading to arachidonic acid release and PGE2 production─key mediators of chronic inflammation. Thus, hPLA2-G5 represents a promising therapeutic target for diseases with inflammatory pain, such as in endometriosis─a highly debilitating disease characterized by the ectopic growth of endometriotic cells in the abdominal cavity. High-throughput and fragment-based screening identified structurally related small molecule hits. Optimization of the physicochemical and pharmacokinetic properties of the HTS hit led to the identification of BAY-439, a potent and selective hPLA2-G5 inhibitor with single-digit nanomolar activity. Accepted as a donated chemical probe by the Structural Genomics Consortium, both BAY-439 and the inactive negative probe BAY-163 are freely available as valuable pharmacological tools to investigate the role of hPLA2-G5 both under physiological and pathological conditions.

Objective: To investigate the burden of endometriosis (EMs)-related and polycystic ovary syndrome (PCOS)-related infertility among women aged 15-49 years in China and globally, and to project trends over the next 15 years. Methods: Data were sourced from the 2021 Global Burden of Disease (GBD) database. Disease burden indicators, including the age-standardized prevalence rate (ASPR) and age-standardized years lived with disability rate (ASYR) for EMs- and PCOS-related infertility, were calculated and analyzed among women aged 15-49 years in China and globally. Linear regression models and Joinpoint regression analysis were used to further analyze the trend changes in disease burden in China and globally. The Bayesian age-period-cohort (BAPC) model was employed to predict disease trends over the next 15 years. Results: From 1990 to 2021, ASPR and ASYR of EMs-related infertility among women aged 15-49 years in China and globally showed a declining trend. The ASPR of EMs-related infertility declined faster in China than globally, with an average annual percentage change (AAPC) of -1.42% in China and -0.95% globally. By 2021, the ASPR and ASYR for EMs-related infertility in Chinese women aged 15-49 years were lower than the global average and those of all sociodemographic index (SDI) regions. In 2021, the highest ASPR and ASYR were observed in Chinese women aged 40-44 years, while globally, the highest rates were in the 25-29 age group. From 1990 to 2021, the ASPR and ASYR of PCOS-related infertility among women aged 15-49 years showed an increasing trend in both China and globally. The increase in ASPR among Chinese women aged 15-49 years was significantly higher than the global average and that of all SDI regions, with an AAPC of 1.93% in China and 0.99% globally. In 2021, the highest ASPR for PCOS-related infertility in China was observed in women aged 25-29 years, while the fastest increases in ASPR and ASYR both globally and in China occurred in women aged 20-24 years. The BAPC model predicts that by 2036, the ASPR and ASYR of EMs-related infertility among women aged 15-49 years will decrease to 32.98 per 100 000 and 0.21 per 100 000 in China, and to 55.57 per 100 000 and 0.33 per 100 000 globally, respectively. In contrast, the ASPR and ASYR of PCOS-related infertility among women aged 15-49 years will increase to 620.39 per 100 000 and 3.46 per 100 000 in China, and to 774.34 per 100 000 and 4.45 per 100 000 globally, respectively. Conclusions: The ASPR and ASYR for EMs-related infertility among women aged 15-49 years are declining in China and globally, with China's burden lower than the global average, and this trend is expected to continue over the next 15 years. In contrast, the ASPR and ASYR for PCOS-related infertility among women aged 15-49 years are increasing persistently, with a faster increase in China than globally and across all SDI regions. This indicates that PCOS has become a key priority for the prevention and management of infertility among women aged 15-49 years in China, with particular attention needed for women aged 20-29 years, and underscoring the need for targeted interventions addressing age-specific and socioeconomic disparities.

Endometriosis (EMs) is an estrogen-dependent inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, yet its precise pathogenesis remains incompletely elucidated. TICAM1, a key adaptor protein in the Toll-like receptor (TLR) signaling pathway, is known to be involved in inflammatory responses; however, its specific role in EMs has not been defined. This study integrated evidence from clinical tissue samples of patients with ovarian endometriomas, in vitro studies, and in vivo models to explore the role of TICAM1 in EMs. TICAM1 expression was significantly upregulated in both eutopic and ectopic endometrium, with the highest levels observed in ectopic lesions, where it was primarily localized to stromal and glandular epithelial cells. Functional experiments showed that TICAM1 overexpression promoted the proliferation, migration, and invasion of human endometrial stromal cells (hESCs), while TICAM1 knockdown suppressed these activities. Concurrently, TLR3 and TLR4 were also upregulated in EMs tissues, and their activation increased TICAM1 expression. Knockdown of TICAM1 attenuated the enhanced cellular activities induced by TLR3/TLR4 activation. Mechanistically, IRF3 and IFN-β levels were elevated in both EMs tissues and TICAM1-overexpressing hESCs, while TICAM1 knockdown inhibited TLR3/TLR4-induced IRF3 phosphorylation and subsequent IFN-β production. These findings were further corroborated in a mouse model of EMs. Together, our findings suggest that TICAM1 may enhance the proliferation, migration, and invasion of hESCs by mediating TLR3/TLR4 signaling and promoting IRF3 phosphorylation and subsequent IFN-β production, thereby potentially contributing to EMs progression. Therefore, targeting TICAM1 may represent a potential therapeutic direction for ovarian endometrioma-associated EMs, while its relevance to superficial peritoneal and deep infiltrating EMs requires further investigation.

We aimed to explore shared genetic architectures and potential causal associations between inflammatory bowel disease (IBD) and gynecological diseases, including ovarian cysts (OC), pelvic inflammatory disease (PID), and endometriosis (EMs), and to evaluate whether the findings are consistent with a gut-reproductive connection. We used genome-wide association study (GWAS) data to assess genetic correlation between IBD and gynecological diseases. Cross-trait pleiotropic loci and genes were identified using PLACO, colocalization, and functional annotation analyses. Stratified LDSC and HyPrColoc were applied to explore immune-related enrichment and colocalized immune traits. Mendelian randomization (MR) was used to assess bidirectional causal effects, and UK Biobank cohort data were analyzed using Cox proportional hazards models. Genetic correlation analyses supported shared genetic architecture between IBD and gynecological diseases. Pleiotropy and colocalization analyses highlighted representative loci including 6q22.33, 9q34, 1q21.3, 16q12.1, 6q27, and 1q32.1, with enrichment of immune-related pathways such as IL-23 and JAK-STAT signaling, particularly in the colon, small intestine, and spleen. Colocalization signals involving Ruminococcus gauvreauii suggested overlap with microbial abundance traits. MR analyses provided the most consistent evidence for directional associations from IBD and CD to PID, whereas UK Biobank analyses supported broader bidirectional associations, particularly for OC and PID. This study identifies shared genetic loci, immune-related pathways, and complementary causal and observational associations between IBD and gynecological conditions. These findings support the gut-reproductive axis as a conceptual framework for future mechanistic investigation.

Endometriosis (EMs) is characterized by dysregulated persistence and enhanced invasiveness of ectopic endometrial cells. Current treatment strategies remain limited by high recurrence rates and considerable adverse effects. Although iron overload is a recognized feature of EMs, ectopic lesions paradoxically demonstrate resistance to ferroptosis, an iron-dependent cell death mechanism. The mechanistic involvement of microsomal glutathione S-transferase 3 (MGST3) in this process remains to be clarified. This study examined MGST3 expression and its functional role in EMs using in vitro assays and an in vivo murine model. MGST3 expression was markedly increased in ectopic endometrial cells compared with controls. Functional analyses indicated that MGST3 enhances the invasive phenotype of immortalized human ectopic endometrial stromal cells while concurrently inhibiting apoptosis. Furthermore, treatment with GSTO-IN-2 in the mouse model attenuated ectopic lesion growth and significantly altered ferroptosis-associated markers. However, due to the lack of specificity of GSTO-IN-2 for MGST3, these in vivo findings cannot be directly attributed to an MGST3-specific effect. Collectively, these results indicate that MGST3 may play a role in the regulation of ferroptosis in EMs, with its overexpression contributing to ferroptosis-associated survival phenotypes in endometrial stromal cells. MGST3 may therefore serve as a potential biomarker and requires further investigation as a therapeutic target in EMs.

In brief: Iron overload-induced ferroptosis contributes to ovarian damage in endometriosis, yet effective interventions are lacking. This study shows that electroacupuncture preserves ovarian function by activating the nuclear factor erythroid 2-related factor 2 antioxidant pathway to inhibit ferroptosis. Abstract: Endometriosis (EMs) is a common cause of ovarian dysfunction and infertility, closely linked to iron overload-induced oxidative stress and ferroptosis. While electroacupuncture (EA) has shown promise in treating reproductive disorders, its role in regulating ovarian ferroptosis in EMs remains unclear. This study aimed to investigate the protective effects and underlying mechanisms of EA on ovarian function in a mouse model of EMs, which simulated the chronic pelvic hemorrhage observed in patients. Comprehensive evaluations were performed using hematoxylin-eosin staining, quantitative real-time PCR, western blot, immunohistochemistry, immunofluorescence, and biochemical assays to assess ovarian function, iron metabolism, oxidative stress, and ferroptosis-related markers. The results demonstrated that EA treatment significantly restored estrous cyclicity, increased ovarian weight and index, improved serum hormone levels, promoted multi-stage follicular development, and reduced follicular atresia. EA also alleviated ovarian iron overload and oxidative stress. Mechanistically, EA activated the nuclear factor erythroid 2-related factor 2 pathway and its downstream targets, upregulated the anti-ferroptotic protein glutathione peroxidase 4, suppressed the pro-ferroptotic factor long-chain acyl-CoA synthetase 4, and consequently reduced lipid peroxidation. In conclusion, this study reveals that EA mitigates granulosa cell ferroptosis and ameliorates EMs-induced ovarian injury by activating nuclear factor erythroid 2-related factor 2 to enhance glutathione peroxidase 4 activity and inhibit long-chain acyl-CoA synthetase 4-mediated lipid peroxidation. These findings provide experimental evidence supporting EA as a potential complementary therapy for EMs-related infertility.

UCA1 facilitates endometriosis progression through EIF4A3-mediated stabilization of E2F1 mRNA and enhanced glycolysis.

To investigate the association between delivery/abortion methods, allergy history, and endometriosis (EM) risk. This prospective case-control study was conducted at the First Affiliated Hospital of Naval Medical University (Shanghai Changhai Hospital), China, from 2018 to 2024. We enrolled 1498 EM patients and 452 non-EM controls. Associations between clinical variables (delivery modes, abortion, allergy history) and EM incidence were analyzed using multivariate logistic regression to adjust for confounders. Cesarean section increased EM risk approximately 2-fold (OR 2.043, 95% CI: 1.489-2.804); this risk remained significant after excluding scar EM (OR 1.944, 95% CI: 1.414-2.674). Induced abortion also correlated with a 2-fold increased risk of EM (OR 2.262, 95% CI: 1.529-3.347). Furthermore, allergic patients with a history of induced abortion had a significantly higher likelihood of developing deep infiltrating endometriosis (DIE). Cesarean section and induced abortion independently increase EM risk. Moreover, induced abortion combined with an allergy history elevates the risk of developing DIE, highlighting the synergistic effect of surgical trauma and immune status on EM pathogenesis.

Endometriosis (EMS) is a gynecological condition that is associated with chronic pelvic pain and inflammation. Evidence supports the idea that natural killer (NK) cell dysfunction contributes to EMS pathogenesis; nevertheless, the role of T cell immunoreceptors with Ig and ITIM domains (TIGIT) and lymphocyte activation gene 3 (LAG3) in the development of endometriosis-associated immunological abnormalities is not yet reported. The present study used multicolor flow cytometry to compare the frequency of NK cells expressing TIGIT and LAG3 in the peripheral blood (PB) and peritoneal fluid (PF) of women with and without endometriosis. The levels of soluble form of LAG3 (sLAG3) were compared between EMS and non-EMS participants in both PB and PF. The number of NK cells expressing TIGIT increased in the PF of EMS compared to the other benign gynecological conditions (OBGC) (Pv=0.0089); however, this difference was not statistically significant in PB. In contrast, an increased frequency of LAG3+NK cells was detected in both PF and PB in EMS compared to the controls. Additionally, a higher level of sLAG3 was stated in both the PB and PF of EMS patients. An impaired number of TIGIT+ and LAG3+NK cells was detected in the peritoneal microenvironment of EMS, which may be responsible for impaired immune surveillance, promoting the survival of ectopic lesions, and contributing to the evolution of EMS.