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Yang X, Xue X, Zhu Y, Zhang Z. Correlation between lipid metabolism and endometriosis: a meta-analysis. Gynecol Endocrinol 2025; 41:2500459. [PMID: 40343766 DOI: 10.1080/09513590.2025.2500459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 12/25/2024] [Accepted: 04/17/2025] [Indexed: 05/11/2025] Open
Abstract
To analyze and evaluate the correlation between different lipid metabolism levels and endometriosis. The literatures on lipid metabolism and endometriosis published in databases were searched and collected. The search was conducted up to December 2023. The meta-analysis was conducted using Review Manager 5.4.1 software, with odds ratios (ORs) or standardized mean difference (SMD), confidence intervals (CIs), and heterogeneity (I2) being calculated. The literature bias was evaluated by drawing funnel plot. Five hundred and eighty-four literatures were retrieved, and finally, 7 literatures were included in this study. Meta-analysis showed that the level of total cholesterol (TC) in endometriosis groups was higher than control group [SMD = 1.70, 95%CI (0.60-2.80), p = 0.003], while triglyceride (TG) [SMD=-0.24, 95%CI (-0.68-0.21), p = 0.300], low-density lipoprotein (LDL) [SMD = 0.22, 95%CI (-0.34 - 0.78), p = 0.440] and high-density lipoprotein (HDL) [SMD = 0.06, 95%CI (-0.14 - 0.25), p = 0.550] was not statistically significant. Sensitivity analysis indicated that the combined effect size results were stable and reliable [SMD = 1.70, 95%CI (0.60-2.80), p = 0.030]. Funnel plot results showed publication bias. Patients with endometriosis have abnormal blood lipid level, and higher TC level may be a risk factor for endometriosis. The impact of blood lipid metabolism on endometriosis may provide new insights into the pathogenesis and treatment prognosis of endometriosis.
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Affiliation(s)
- Xuanru Yang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Dongcheng District, Beijing, China
| | - Xiaoou Xue
- Department of Gynecology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Dongcheng District, Beijing, China
| | - Yuying Zhu
- Department of Gynecology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Dongcheng District, Beijing, China
| | - Zhihang Zhang
- Department of Gynecology, Hepingli Hospital, Dongcheng District, Beijing, China
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Lv SJ, Yuan Q, Zong SS, Ye L. Dissecting the causal effects of interleukin receptor-related factors and the risk of developing endometriosis: a two-sample Mendelian randomization study. Gynecol Endocrinol 2025; 41:2512837. [PMID: 40448966 DOI: 10.1080/09513590.2025.2512837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/23/2025] [Accepted: 05/23/2025] [Indexed: 06/02/2025] Open
Abstract
This study investigates the causal associations between interleukin receptor-related factors and the development of endometriosis, as their etiology and pathophysiology remain largely unknown. A two-sample Mendelian randomization (MR) approach was employed to analyze genetic variants associated with interleukin receptor related factors as instrumental variables (IVs). The F-values have to be > 10 to exclude weak instrumental bias. The primary analysis was conducted using the inverse variance weighted (IVW) method, with confirmation using the MR-Egger, weighted median (WM), simple mode, and weighted mode methods. Sensitivity analyses were performed to ensure robustness, including tests for heterogeneity, pleiotropy, and leave-one-out. Multivariable MR (MVMR) analysis was used to assess the direct and mediated effects of immune cells. The results indicated significant causal associations between interleukin receptor factors prot-a-1542 (IL-6Rβ), prot-a-1530 (IL-3Rα), and prot-b-38 (IL-1RL1) and endometriosis. Reverse MR analysis showed that endometriosis did not significantly affect prot-a-1530 or prot-b-38. After adjusting for confounders like body mass index and smoking, these factors retained their significance. Additionally, immune cells(ebi-a-GCST90001951) were found to mediate the relationship between prot-b-38 and endometriosis, with an indirect effect accounting for approximately 6.38% of the total effect. This study provides new insights into endometriosis mechanisms involving specific interleukin receptor factors.
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Affiliation(s)
- Si-Ji Lv
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qing Yuan
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shan-Shan Zong
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lei Ye
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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Rahimi M, Kariminezhad Z, Rondon EP, Fahmi H, Fernandes JC, Benderdour M. Chitosan nanovectors for siRNA delivery: New horizons for nonviral gene therapy. Carbohydr Polym 2025; 360:123581. [PMID: 40399008 DOI: 10.1016/j.carbpol.2025.123581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/25/2025] [Accepted: 04/04/2025] [Indexed: 05/23/2025]
Abstract
The growing interest in RNA-based therapeutics has positioned small interfering RNA (siRNA) as a promising tool for gene silencing with high specificity and efficacy. However, the successful clinical application of siRNA therapies requires efficient delivery systems to overcome extracellular and intracellular barriers. Chitosan, a naturally derived polysaccharide, has gained significant attention as a non-viral vector due to its biodegradability, biocompatibility, mucoadhesive properties, and capacity to enhance cellular uptake. These attributes make chitosan an attractive alternative to lipid-based nanoparticles, which currently dominate siRNA delivery platforms. Recent advancements in chitosan-based nanoformulations, including chemical modifications and functionalization strategies, have improved siRNA stability, targeting efficiency, and transfection potential, addressing key limitations such as low bioavailability and immunogenicity. Despite these advances, challenges remain in achieving optimal release kinetics, scalability, and consistent therapeutic efficacy. Future research efforts will focus on engineering chitosan derivatives with enhanced physicochemical properties, integrating multifunctional nanocarriers, and refining formulation strategies to bridge the gap between preclinical research and clinical translation. The continued development of chitosan-based siRNA therapeutics holds significant potential for advancing precision medicine and expanding treatment options for a variety of diseases, including cancer, metabolic disorders, and inflammatory conditions.
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Affiliation(s)
- Mahdi Rahimi
- Orthopedics Research Laboratory, Research Center, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Québec H4J 1C5, Canada
| | - Zahra Kariminezhad
- Orthopedics Research Laboratory, Research Center, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Québec H4J 1C5, Canada; Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Elsa-Patricia Rondon
- Orthopedics Research Laboratory, Research Center, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Québec H4J 1C5, Canada; Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Hassan Fahmi
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Julio C Fernandes
- Orthopedics Research Laboratory, Research Center, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Québec H4J 1C5, Canada; Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Mohamed Benderdour
- Orthopedics Research Laboratory, Research Center, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Québec H4J 1C5, Canada.
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Scovazzi U, Xholli A, Schiaffino MG, Molinari F, Perugi I, Primizia E, Cagnacci A, Londero AP. Pilot Clinical and Radiomic Analysis of Deep Infiltrating Endometriosis of the Parametrium Using Shannon Entropy: A Retrospective Cohort Study. ULTRASOUND IN MEDICINE & BIOLOGY 2025; 51:1078-1083. [PMID: 40221222 DOI: 10.1016/j.ultrasmedbio.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/12/2025] [Indexed: 04/14/2025]
Abstract
OBJECTIVE Ultrasound techniques for diagnosing deep infiltrating endometriosis (DIE) currently lack a quantitative method to assess microstructural heterogeneity in relation to diagnosis and clinical symptoms. This study evaluates Shannon entropy-based radiomics for differentiating DIE lesions from adjacent tissue and correlating these features with pain severity. METHODS In this retrospective cohort study (2020-2024), fertile women with histologically confirmed parametrial endometriosis and high-quality ultrasound images were evaluated. Pain was measured using a 10-cm visual analog scale. Two 25 mm² regions of interest (ROIs) were defined: one within the DIE nodule and one in the adjacent perilesional tissue. Each ROI was analyzed with the Shannon entropy algorithm to assess tissue heterogeneity. RESULTS In this study, 148/663 women (22.3%) were diagnosed with parametrial DIE, of whom 52 underwent surgery and were included in the study. DIE was localized in 92.3% in the posterior, in 5.8% in both posterior and anterior, and in 2% in the anterior parametrium. Primary symptoms were menstrual pain (88%) and pain at intercourse (63%). ROI entropy of DIE lesion was lower than that of the perilesional ROI (p = 0.05). The area-under-the-curve (AUC) of Shannon entropy for endometriotic vs. adjacent tissue was 91.36% (95% CI: 84.5%-98.21%). The ROI entropy of the DIE lesion exhibited an inverse correlation with menstrual pain (rho -0.46, CI 95% -0.74/-0.12, p = 0.025), and that of perilesional tissue with chronic pelvic pain (rho -0.41, 95% CI -0.73/- 0.04; p = 0.072). CONCLUSION Entropy analysis distinguishes DIE lesion from perilesional tissue and significantly correlates with menstrual pain.
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Affiliation(s)
- Umberto Scovazzi
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy
| | - Anjeza Xholli
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy.
| | - Maria Giulia Schiaffino
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy
| | - Filippo Molinari
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy
| | - Isabella Perugi
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy
| | - Elvira Primizia
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy
| | - Angelo Cagnacci
- Academic Unit of Obstetrics and Gynecology, IRCCS San Martino Hospital, Genoa, Italy; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy
| | - Ambrogio Pietro Londero
- Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal, and Infant Health (DiNOGMI), IRCCS San Martino Hospital, Genoa, Italy; Obstetrics and Gynaecology Unit, IRCCS Ospedale Pediatrico Giannina Gaslini, Genoa, Italy
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Du X, Yang H, Kang X, Fu C, Yang T. Blocking GATA6 Alleviates Pyroptosis and Inhibits Abdominal Wall Endometriosis Lesion Growth Through Inactivating the PI3K/AKT Pathway. Cell Biochem Biophys 2025; 83:1757-1770. [PMID: 39365516 DOI: 10.1007/s12013-024-01583-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2024] [Indexed: 10/05/2024]
Abstract
Endometriosis is a benign gynecological disorder characterized by the abnormal presence of endometrium-like cells, referred to as ectopic tissue, located outside the uterine cavity. Beyond the abnormal proliferation of endometrium-like tissues within and beyond the pelvic cavity, compelling scientific evidence underscores the crucial involvement of the NOD-like receptor NLRP3 inflammasome and pyroptosis in the pathogenesis of EMS. Our investigation has revealed a striking upregulation of the endogenous protein GATA-binding protein 6 (GATA6) in abdominal wall EMS. Notably, the knockdown of GATA6 significantly impaired the viability and migratory potential of primary ectopic endometrial stromal cells (EESCs) while also inhibiting crucial markers of pyroptosis, such as NLRP3, the gasdermin D N-terminal fragment (GSDMD-N), and reactive oxygen species (ROS) levels within these cells. Delving deeper into the underlying mechanisms, we discovered that suppressing GATA6 mitigated the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in EESCs. The administration of 740 Y-P, an agonist of the PI3K/AKT pathway, mitigated the inhibitive actions of GATA6 knockdown on EESCs' growth, migration, and pyroptosis, highlighting the intricate crosstalk between GATA6 and this intricate signaling cascade. In vivo experiments corroborated these findings, demonstrating that reduced GATA6 expression effectively restrained the growth of endometrial lesions and concurrently suppressed pyroptosis, accompanied by a dampening of PI3K/AKT signaling within these lesions. In summary, our study underscores the pivotal role of GATA6 in modulating the growth and pyroptosis of abdominal wall EMS through its regulation of the PI3K/AKT signaling pathway. Silencing GATA6 emerges as a promising approach to alleviate pyroptosis and potentially offers a novel therapeutic angle for managing abdominal wall EMS.
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Affiliation(s)
- Xiufang Du
- Department of Women's Group Health, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, 050000, Hebei, China.
| | - Hongjie Yang
- Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, 050000, Hebei, China
| | - Xiaobei Kang
- Department of Women's Group Health, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, 050000, Hebei, China
| | - Changna Fu
- Blood Collection Room, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, 050000, Hebei, China
| | - Tao Yang
- The Second Department of Obstetrics and Gynecology, Shijiazhuang Maternal and Child Health Hospital, Shijiazhuang, 050000, Hebei, China
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Røssell EL, Melgaard A, Saraswat L, Horne AW, Josiasen M, Rytter D. Sociodemographic characteristics of women with endometriosis: A Danish register-based case-control study. Eur J Obstet Gynecol Reprod Biol 2025; 310:113968. [PMID: 40209486 DOI: 10.1016/j.ejogrb.2025.113968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/12/2025]
Abstract
OBJECTIVE To describe sociodemographic characteristics of women with hospital diagnosed endometriosis in Denmark and compare them with women without endometriosis. STUDY DESIGN Case-control study using Danish national registers. Cases were identified as women aged 14-84 years receiving a first-time hospital-based diagnosis of endometriosis in 1991-2021 (n = 37.709). Each case was matched based on date of diagnosis and birth year to five controls without endometriosis (n = 188.545). Information on diagnosis of endometriosis and sociodemographic factors was obtained from Danish registers. Descriptive statistics and unadjusted and adjusted conditional logistic regression analyses were used to investigate the association between a diagnosis of endometriosis and sociodemographic factors. RESULTS For family-based socioeconomic status, women in all groups other than the employed category (both higher and lower socioeconomic status) had lower odds of receiving a diagnosis (ORs ranging from 0.78 to 0.91). Women with primary education, master or equivalent, and PhD had lower odds of a diagnosis (ORs 0.79-0.93) compared to upper secondary education. Compared to couples, singles and "other" had slightly lower odds of a diagnosis (ORs 0.91-0.94). Women of Danish origin and immigrants had similar odds of a diagnosis whereas descendants had lower odds (0.85 (95% CI: 0.76-0.95)) when compared to the two other groups. CONCLUSION Sociodemographic factors were found to be associated with receiving a hospital diagnosis of endometriosis. However, only smaller differences and a mixed pattern were found.
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Affiliation(s)
- Eeva-Liisa Røssell
- Department of Public Health, Aarhus University, Bartholins Allé 2, Aarhus C, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Palle Juul-Jensens Boulevard 11, Aarhus N, Denmark
| | - Anna Melgaard
- Department of Public Health, Aarhus University, Bartholins Allé 2, Aarhus C, Denmark
| | - Lucky Saraswat
- Centre for Research on Women's Health, University of Aberdeen, Cornhill Road, Aberdeen, Scotland, United Kingdom
| | - Andrew W Horne
- Centre for Reproductive Health, University of Edinburgh, 4-5 Little France Drive, Edinburgh, Scotland, United Kingdom
| | - Marie Josiasen
- Department of Public Health, Aarhus University, Bartholins Allé 2, Aarhus C, Denmark.
| | - Dorte Rytter
- Department of Public Health, Aarhus University, Bartholins Allé 2, Aarhus C, Denmark
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Born T, Krejci K, Rauh M, Cole G, Kappelmeyer M, Vural M, Köninger A. Extragenital endometriosis associated with uterine scar defects. Eur J Obstet Gynecol Reprod Biol X 2025; 26:100386. [PMID: 40236503 PMCID: PMC11999306 DOI: 10.1016/j.eurox.2025.100386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 03/22/2025] [Accepted: 03/29/2025] [Indexed: 04/17/2025] Open
Abstract
Introduction Uterine scar defects result from poor healing of the hysterotomy after cesarean sections (CS), in multiple cases leading to retroflexio uteri and retrograde menstruation. Endometriosis is the probable consequence. Patients often experience overlapping symptoms such as dysmenorrhea, dyspareunia, and infertility. Material and methods This study analysed cases of sonographically detected uterine scar defects, subsequently undergoing laparoscopy at the University Clinic St. Hedwig, in Regensburg, between 2020 and 2024. Herefore, surgery reports were reviewed, focusing on extragenital endometriosis, symptoms of Cesarean Scar Disorder (CSD), niche morphology, uterine position, and endometriosis localisation using the #Enzian classification. Results Extragenital endometriosis was histologically confirmed in 45 of 94 patients (47.9 %) with symptomatic or large uterine niches. A significant association was found between endometriosis and heavy menstrual bleeding (HMB) (p < 0.001) as well as retroflexio uteri (p = 0.036). Symptoms related to CSD did not differ in patients with or without Endometriosis. Endometriotic implants were primarily located in the peritoneum behind the uterus and sacrouterine ligaments, supporting the hypothesis of retrograde menstruation. Conclusion There is significant overlap between the symptoms of endometriosis and CSD. Almost half of the patients with a symptomatic niche were found to have endometriosis, whereby the location of endometriosis supports the hypothesis of retrograde menstruation. However, the patient´s history of complaints is not indicative of the diagnosis of endometriosis. Therefore, all patients with CSD should be offered a laparoscopy and endometriosis surgery. All patients with a previous caesarean section presenting with symptoms of endometriosis should be offered standardised and high-quality niche diagnosis and treatment.
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Affiliation(s)
- Tilman Born
- Department of Gynecology and Obstetrics, University of Regensburg, Clinic St. Hedwig, Steinmetzstrasse 1-3, Regensburg 93049, Germany
| | - Katrin Krejci
- Department of Gynecology and Obstetrics, University of Regensburg, Clinic St. Hedwig, Steinmetzstrasse 1-3, Regensburg 93049, Germany
| | - Maximilian Rauh
- Department of Gynecology and Obstetrics, University of Regensburg, Clinic St. Hedwig, Steinmetzstrasse 1-3, Regensburg 93049, Germany
| | - Georgia Cole
- Department of Gynecology and Obstetrics, University of Regensburg, Clinic St. Hedwig, Steinmetzstrasse 1-3, Regensburg 93049, Germany
| | - Maurice Kappelmeyer
- Department of Gynecology and Obstetrics, University of Regensburg, Clinic St. Hedwig, Steinmetzstrasse 1-3, Regensburg 93049, Germany
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Allen CL, Banerjee S, Karoshi M, Humaidan P, Tahmasebi F. The efficacy of progestins in managing pain associated with endometriosis, fibroids and pre-menstrual syndrome: a systematic review. Arch Gynecol Obstet 2025; 311:1511-1533. [PMID: 40067480 PMCID: PMC12055938 DOI: 10.1007/s00404-025-07957-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/12/2025] [Indexed: 05/07/2025]
Abstract
PURPOSE Alongside being contraceptives, progestins have been investigated as potential anti-inflammatory and analgesic therapies for use in painful gynaecological conditions. This review aims to synthesise evidence pertaining to the efficacy of progestins as analgesics for use in endometriosis, fibroids and pre-menstrual syndrome (PMS). METHODS We conducted a systematic review of the extant literature investigating the analgesic efficacy of progestins compared to any comparator interventions for individuals with the three specified gynaecological conditions. The search was carried out across the PubMed and CENTRAL databases on 7 April 2024 for randomised control trials (RCTs) published in the peer-reviewed literature from 2000 onwards. Data pertaining to analgesic efficacy, assessed by changes in pain indices/scores before and after treatment, were synthesised narratively. Data pertaining to adverse effect frequency and changes in bone mineral density (BMD) were also synthesised narratively. Risk of bias was assessed using the Cochrane risk of bias 2 tool. RESULTS The primary search identified 1220 potentially eligible RCTs of which 21 were ultimately included; 19 RCTs related to endometriosis, two related to fibroids and zero related to PMS. Quality assessment identified nine studies to be at a low risk of bias, nine studies with some concerns surrounding bias and three studies to be at a high risk of bias. The included studies represented a total of 2745 participants of whom 1317 were treated with a progestin and 1428 received a comparator intervention. In 18 of the 19 studies concerning endometriosis, progestins produced a statistically significant reduction in pain, further, in five instances progestins were more efficacious in reducing pain than comparator interventions. In both studies on fibroids, progestins produced significant reductions in pain, however, statistically significant differences compared to comparator interventions were not demonstrated. The most frequently cited adverse effect of progestins was spotting/irregular bleeding whilst those receiving comparator interventions most often reported hot flushes; cited in 12 and seven studies respectively. Five studies assessed the impact of progestins and comparators on BMD. Three studies found progestins significantly reduced BMD, however, in these instances reductions were significantly lower than those produced by comparator interventions and in two studies were not statistically significant after 12 months of follow-up. CONCLUSION Our review demonstrates the potential scope for the use of progestins as analgesics in the management of pain associated with endometriosis. Further research will need to be conducted to identify their efficacy in the management of pain associated with fibroids and PMS.
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Affiliation(s)
- Connor Luke Allen
- Department of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
- Western Health, Melbourne, Australia.
| | | | | | - Peter Humaidan
- The Fertility Clinic, Skive Regional Hospital, Skive, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Zhang Y, Yang H. Silencing of FZD7 Inhibits Endometriotic Cell Viability, Migration, and Angiogenesis by Promoting Ferroptosis. Cell Biochem Biophys 2025; 83:2471-2480. [PMID: 39797998 DOI: 10.1007/s12013-024-01656-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Endometriosis (EMS) is a difficult gynecological disease to cure. Frizzled-7 (FZD7) has been shown to be associated with the development of EMS, but its specific mechanism remains unclarified. This study aims to explore the role of FZD7 in EMS. METHODS RT-qPCR and western blot were used to detect the expression level of FZD7 in human endometrial stromal cells (hESCs) and human ectopic endometrial stromal cell line hEM15A. The interfering plasmid of FZD7 was established. CCK-8, EdU, wound healing, transwell invasion, and cytoskeletal staining assays were applied to evaluate the role of FZD7 silencing in hEM15A cell proliferation, invasion, and migration. Tube forming ability of cells was evaluated by tube formation assay. Cellular VEGF, GSH, and MDA levels were measure by kits. Intracellular lipid ROS and Fe2+ levels were tested using C11-BODIPY (581/591) and FeRhoNox-1 probes, respectively. The ferroptosis-related protein SLC7A11, GPX4, and ACSL4 expressions were analyzed using western blot. The effects of ferroptosis on endometriotic cell viability, migration, and angiogenesis were further analyzed with the addition of an ferroptosis inhibitor (Fer-1). RESULTS FZD7 was upregulated in hEM15A cells, and silencing of FZD7 inhibited cell proliferation, migration, invasion, and angiogenesis abilities. Downregulation of FZD7 decreased cellular GSH level and elevated MDA level. Knockdown of FZD7 also caused an increase in intracellular ROS and Fe2+ levels, as well as the downregulation of SLC7A11 and GPX4 levels and the upregulation of ACSL4 level, which are hallmarks of ferroptosis. However, the inhibitory effects of FZD7 knockdown on hEM15A cell progression were reversed when ferroptosis inhibitor Fer-1 added. CONCLUSION The above indices suggest that FZD7 knockdown regulates endometriotic cell proliferation, invasion, migration, and angiogenesis via ferroptosis.
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Affiliation(s)
- Yi Zhang
- Department of Obstetrics and Gynecology, The Affiliated Women and Children's Hospital of Ningbo University, Ningbo, Zhejiang, 315012, China
| | - Huifen Yang
- Department of Obstetrics and Gynecology, Lishui Municipal Central Hospital, Lishui, Zhejiang, 323000, China.
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Lu B, Huang Q, Zhong Y. Endometriosis-derived exosomes encapsulated miR-196a-5p mediate macrophage polarization through regulation of the Hippo pathway. J Cell Commun Signal 2025; 19:e70020. [PMID: 40416727 PMCID: PMC12103834 DOI: 10.1002/ccs3.70020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/13/2025] [Accepted: 05/16/2025] [Indexed: 05/27/2025] Open
Abstract
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.
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Affiliation(s)
- Bin Lu
- Department of GynecologyWuhu No.1 People's HospitalWuhu CityChina
| | - Qixiang Huang
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yanyu Zhong
- Reproductive Medicine CentreThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
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11
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Dridi D, Ottolini FL, Ambruoso D, Bandini V, Chiaffarino F, Cetera GE, Barbara G. Clinical features and management of thoracic endometriosis: a 20-year monocentric retrospective study. Arch Gynecol Obstet 2025; 311:1733-1742. [PMID: 40158040 PMCID: PMC12055912 DOI: 10.1007/s00404-025-08006-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/09/2025] [Indexed: 04/01/2025]
Abstract
PURPOSE Although thoracic endometriosis (TE) represents the most common manifestation of extra-pelvic endometriosis, it is a rare condition and currently there is no established clinical guideline for the management of this condition. The study's primary objective was to assess patient satisfaction with the treatment provided. A secondary objective was to investigate the efficacy of different treatment modalities in terms of symptom and lesion recurrence. METHODS A retrospective review of the clinical records of all women with TE who had been referred to our institution, a tertiary referral center, was conducted between January 2000 and September 2021. A frequency analysis was performed for all the variables examined in the study. The Kaplan-Meier method was adopted to analyse the time from thoracic surgery to PNX recurrence. Lastly, an intention-to-treat analysis was performed. RESULTS Regarding clinical presentation, 50% of women (30/60; 95% CI 36.8-63.2) experienced at least one episode of pneumothorax (PNX). A total of 61.7% of the women in the study underwent surgical intervention, while 36.6% received pharmacological treatment. The cumulative recurrence rate of the first PNX following surgery was 0.26 (0.13-0.41) and 0.82 (0.44-0.95) at six months and 240 months, respectively. At the follow-up assessment, regardless of the administered treatment modality, over half of the women included in the study reported being satisfied with their treatment (PGIC). Additionally, most of them described their overall condition as having improved since the onset of the treatment (PGIS). CONCLUSION Both surgical and pharmacological treatments are valuable options for TE. Rather than being considered mutually exclusive, these approaches should be viewed as complementary.
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Affiliation(s)
- Dhouha Dridi
- Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy.
| | | | - Deborah Ambruoso
- Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
| | - Veronica Bandini
- Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
| | - Francesca Chiaffarino
- Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy.
- Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy.
| | - Giulia Emily Cetera
- Academic Center for Research on Adenomyosis and Endometriosis, Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
| | - Giussy Barbara
- Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
- Academic Center for Research on Adenomyosis and Endometriosis, Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
- Obstetric & Gynecological Emergency Unit and Service for Sexual and Domestic Violence, SVSeD, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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12
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Tang L, Li X, Zhu SY, Wan YK, Zhang SK, Ma JZ, Yang Y, Chen AW, Luo L, Cao LY. 6PPD and 6PPD Quinone Induce Endometrial Cell Dysfunction via Activating ERα and GPER at Human-Relevant Levels. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:9918-9929. [PMID: 40364734 DOI: 10.1021/acs.est.4c13961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
The widespread environmental prevalence of tire-derived N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and 6PPD-quinone (6PPD-Q) has provoked public concern about their health risks. This study aimed to investigate the potential of 6PPD and 6PPD-Q to induce endometrial cell dysfunction through nuclear estrogen receptor (ER) and G-protein-coupled estrogen receptor (GPER) signaling pathways. Fluorescence competitive binding and reporter gene assays revealed that 6PPD and 6PPD-Q selectively bound to ERα (not ERβ) and activated ER transcriptional activity, with the lowest observed effective concentrations (LOECs) of 500 and 10 nM, respectively. Calcium mobilization assays further demonstrated that both 6PPD and 6PPD-Q activated the GPER nongenomic pathway in a concentration-dependent manner (LOEC = 1 nM). 6PPD-Q exhibited stronger ERα and GPER activation potency than 6PPD, which was explained well by molecular dynamics simulation. 6PPD and 6PPD-Q stimulated endometrial cell proliferation via ERα/GPER signaling pathways, mechanistically linked to Cyclin D1/Ki67 upregulation. Furthermore, 6PPD/6PPD-Q promoted endometrial cell migration through an ERα/GPER-regulated epithelial-mesenchymal transition and inflammatory responses. Notably, the LOECs for these functional disruptions reached nanomolar levels relevant to human exposure. Collectively, we elucidated the molecular initial events and downstream key events of 6PPD/6PPD-Q-induced endometrial cell dysfunction, which implied their threat to the reproductive system and provided novel perspectives for their health risk evaluation.
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Affiliation(s)
- Lei Tang
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Xin Li
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Shi-Ye Zhu
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Yu-Ke Wan
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Shi-Ke Zhang
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Jie-Zhi Ma
- Department of Obstetrics and Gynecology, Xiangya Third Hospital, Central South University, Changsha 410013, China
| | - Yuan Yang
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - An-Wei Chen
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Lin Luo
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
| | - Lin-Ying Cao
- College of Environment and Ecology, Hunan Agricultural University, 1 Nongda Road, Furong District, Changsha 410128, China
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13
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Liang Y, Lu Q, Chen M, Zhao X, Chu C, Zhang C, Yuan J, Liu H, Lash GE. Impact of endocrine disrupting chemicals (EDCs) on epigenetic regulation in the uterus: a narrative review. Reprod Biol Endocrinol 2025; 23:80. [PMID: 40420228 PMCID: PMC12105221 DOI: 10.1186/s12958-025-01413-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Accepted: 05/08/2025] [Indexed: 05/28/2025] Open
Abstract
Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and have been shown to interfere with the endocrine system, leading to adverse effects on reproductive health. In females, EDC exposure has been linked to menstrual irregularities, infertility, and pregnancy complications. Epigenetic regulation, which involves modifications to DNA and histones that do not alter the underlying genetic code, plays a crucial role in female reproduction. EDCs have been shown to disrupt epigenetic mechanisms, leading to changes in gene expression that can have long-term effects on reproductive outcomes. Several EDCs, including bisphenol A (BPA) and phthalates, dioxins, and polychlorinated biphenyls (PCBs), have been shown to alter DNA methylation patterns and histone modifications in female reproductive tissues. These changes can lead to altered expression of genes involved in ovarian function, implantation, and placental development. Here, we integrate epidemiological and experimental evidence from the last 20 years to profile the types of diseases that EDCs trigger in the female reproductive system in relation to the uterus, and the corresponding molecular mechanisms that have been studied. In addition, this review will outline the state of knowledge of EDC epigenetic regulation in the uterus and how it impacts reproductive health, as well as identify areas for future research.
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Affiliation(s)
- Yinjing Liang
- Division of Uterine Vascular Biology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, 9 Jinsui Road, Tianhe District, Guangzhou, 510623, China
| | - Qinsheng Lu
- Division of Uterine Vascular Biology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, 9 Jinsui Road, Tianhe District, Guangzhou, 510623, China
| | - Miaojuan Chen
- Division of Uterine Vascular Biology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, 9 Jinsui Road, Tianhe District, Guangzhou, 510623, China
| | - Xiaomiao Zhao
- Department of Reproductive Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Chu Chu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Chaofan Zhang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Jianhuan Yuan
- Department of Gynecology, The First Huizhou Affiliated Hospital of Guangdong Medical University, Huizhou, China
| | - Huimin Liu
- Department of Gynecology, The First Huizhou Affiliated Hospital of Guangdong Medical University, Huizhou, China
| | - Gendie E Lash
- Division of Uterine Vascular Biology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, 9 Jinsui Road, Tianhe District, Guangzhou, 510623, China.
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14
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Zhe J, Cai Y, Bi Y. Association between lipid accumulation product and endometriosis: A cross-sectional study from NHANES 1999-2006. PLoS One 2025; 20:e0323932. [PMID: 40373106 PMCID: PMC12080788 DOI: 10.1371/journal.pone.0323932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 04/16/2025] [Indexed: 05/17/2025] Open
Abstract
The association of lipid accumulation product (LAP) and the likelihood of endometriosis prevalence has not been previously mentioned. The research aimed to assess the possible potential association between LAP and endometriosis in nationwide research. This cross-sectional analysis was conducted on 2,216 participants selected from the National Health and Nutrition Examination Survey (NHANES) in the 1999-2006 cycles. Logistic regression and stratified analysis by age, race, level of education, BMI, marital status, PIR, glycohemoglobin, drinking, and smoking status were used to analyze the association of the LAP index and odds of endometriosis prevalence. Moreover, smoothed curve fitting was used to evaluate the relevancy of LAP and endometriosis. The multivariate logistic regression model showed a positive association between ln LAP and endometriosis. This trend remained after a full adjustment (odds ratio = 1.37, 95% confidence interval:1.08-1.75, P = 0.010). Compared to the minimum ln LAP quartile, participants in the highest ln LAP had a 93% higher chance of endometriosis incidence (odds ratio = 1.93, 95% confidence interval: 1.08-3.46, P = 0.027). After conducting subgroup analysis and interaction testing, it was found that this positive association was most prominent among women aged 35 years and above and participants with glycohemoglobin≥6%. This nationwide study suggested that an elevated ln LAP was related to an increased endometriosis prevalence. Therefore, LAP may be a valuable tool for predicting the occurrence of endometriosis. Follow-up studies are critical to assess the association between LAP and odds of endometriosis prevalence and explain the potential mechanisms of this relationship.
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Affiliation(s)
- Jing Zhe
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Guiyang, China
| | - Yanxing Cai
- Department of Clinical Laboratory, Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Guiyang, China
| | - Yakun Bi
- Science and Technology Management Center, Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Guiyang, China
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15
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Kou L, Huang C, Xiao D, Liao S, Li Y, Wang Q. Pharmacologic Interventions for Endometriosis-Related Pain: A Systematic Review and Meta-analysis. Obstet Gynecol 2025:00006250-990000000-01271. [PMID: 40373315 DOI: 10.1097/aog.0000000000005923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 02/13/2025] [Indexed: 05/17/2025]
Abstract
OBJECTIVE To evaluate the effectiveness of various medications for the treatment of endometriosis-related pain through a network meta-analysis. DATA SOURCES A comprehensive search was conducted in PubMed, Embase, Web of Science, and the Cochrane Controlled Trials Register until July 22, 2024. We also searched ClinicalTrials.gov for additional data on recently completed trials or potentially eligible randomized controlled trials (RCTs) but found nothing. METHODS OF STUDY SELECTION The analysis included randomized RCTs that used pharmacologic interventions for managing endometriosis-related pain. The primary efficacy outcome was endometriosis-associated pelvic pain, which included dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain. The analysis adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. TABULATION, INTEGRATION, AND RESULTS A total of 31 RCTs involving 8,665 patients were included in the analysis. In terms of endometriosis-associated pelvic pain, four interventions demonstrated significantly greater efficacy compared with placebo: leuprolide combined with combined oral contraceptive pills (OCPs) (standardized mean difference [SMD] -1.40, 95% CI, -2.41 to -0.38), dienogest (SMD -1.20, 95% CI, -1.78 to -0.61), leuprolide alone (SMD -1.05, 95% CI, -1.64 to -0.45), and combined OCP (SMD -0.67, 95% CI, -1.25 to -0.09). Leuprolide combined with combined OCP emerged as the most effective treatment modality. In addition, elagolix and the combination of vitamin C and vitamin E were identified as the most effective interventions for dysmenorrhea and dyspareunia. For nonmenstrual pelvic pain, gestrinone demonstrated superior efficacy compared with placebo and all other interventions. CONCLUSION This network meta-analysis indicates that leuprolide in combination with combined OCP, elagolix, vitamins C and E, and gestrinone may represent the most effective therapeutic options for alleviating endometriosis-associated pelvic pain, dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain. These findings enhance our understanding of the relative efficacy of treatment strategies for pain associated with endometriosis. Future research should focus on conducting larger-scale and rigorously designed clinical trials within the target patient populations to further validate these results.
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Affiliation(s)
- Liqiu Kou
- Department of Pharmacy, Zigong Maternal and Child Health Care Hospital, Zigong, and the Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, and the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
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16
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Ozkan HD, Ozkan MA, Filiz AA, Karakaya ME, Engin-Ustun Y. The Effect of Ovarian Endometriosis on Pregnancy Outcomes in Spontaneous Pregnancies. J Clin Med 2025; 14:3468. [PMID: 40429462 PMCID: PMC12112524 DOI: 10.3390/jcm14103468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Background: This study investigates the impact of ovarian endometriosis on pregnancy outcomes. Methods: A retrospective analysis was conducted at Etlik Zübeyde Hanım Women's Diseases Training and Research Hospital between January 2019 and December 2024, including 1127 pregnant women-170 with ovarian endometriosis and 957 healthy controls. Pregnancies achieved via assisted reproductive techniques were excluded. Statistical analyses were performed using appropriate tests, and a p-value < 0.05 was considered significant. Results: Women with ovarian endometriosis had higher rates of miscarriage (21.8% vs. 7.5%), preterm birth (15.0% vs. 8.8%), and placenta previa (4.7% vs. 0.6%), with adjusted odds ratios (OR) of 3.41, 1.84, and 7.82, respectively. No significant differences were observed in terms of gestational diabetes, hypertensive disorders, fetal growth restriction (FGR), intrahepatic cholestasis of pregnancy (ICP), placental abruption, or preterm premature rupture of membranes (PPROM). Cyst size and bilaterality were not associated with complications. Conclusions: Spontaneously conceiving women with ovarian endometriosis are at increased risk for miscarriage, placenta previa, and preterm birth. Prospective randomized studies are warranted to validate these findings.
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Affiliation(s)
- Halis Dogukan Ozkan
- Department of Obstetrics and Gynecology, Lösante Children and Adults Hospital, Ankara 06830, Turkey
| | - Merve Ayas Ozkan
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara 06710, Turkey; (M.A.O.); (A.A.F.)
| | - Ahmet Arif Filiz
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara 06710, Turkey; (M.A.O.); (A.A.F.)
| | - Muhammed Enes Karakaya
- Department of Obstetrics and Gynecology, Etlik Zübeyde Hanım Women’s Diseases Training and Research Hospital, Ankara 06010, Turkey; (M.E.K.); (Y.E.-U.)
| | - Yaprak Engin-Ustun
- Department of Obstetrics and Gynecology, Etlik Zübeyde Hanım Women’s Diseases Training and Research Hospital, Ankara 06010, Turkey; (M.E.K.); (Y.E.-U.)
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Torraco A, Di Nicolantonio S, Cardisciani M, Ortu E, Pietropaoli D, Altamura S, Del Pinto R. Meta-Analysis of 16S rRNA Sequencing Reveals Altered Fecal but Not Vaginal Microbial Composition and Function in Women with Endometriosis. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:888. [PMID: 40428846 PMCID: PMC12112980 DOI: 10.3390/medicina61050888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 04/29/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025]
Abstract
Background and Objectives: Dysbiosis of the oral-gut axis is related to several extraintestinal inflammatory diseases, including endometriosis. This study aims to assess the microbial landscape and pathogenic potential of distinct biological niches during endometriosis. Materials and Methods: A microbiome meta-analysis was conducted on 182 metagenomic sequences (79 of fecal and 103 of vaginal origin) from women with and without endometriosis. Fecal and vaginal microbial diversity, differential abundance, and functional analysis based on disease status were assessed. Random forest, gradient boosting, and generalized linear modeling were used to predict endometriosis based on differentially enriched bacteria. Results: Only intestinal microbes displayed distinctive taxonomic and functional characteristics in women with endometriosis compared to control women. Taxonomic differences were quantified using the microbial endometriosis index (MEI), which effectively distinguished between individuals with and without the disease. The observed functional enrichment pointed to proinflammatory pathways previously related to endometriosis development. Conclusions: Dysbiosis in the oral-gut microbial community appears to play a prevalent role in endometriosis. Our findings pave the ground for future studies exploring the potential mechanistic involvement of the oral-gut axis in disease pathogenesis.
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Affiliation(s)
- Astrid Torraco
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.T.); (S.D.N.); (M.C.); (E.O.)
| | - Sara Di Nicolantonio
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.T.); (S.D.N.); (M.C.); (E.O.)
| | - Martina Cardisciani
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.T.); (S.D.N.); (M.C.); (E.O.)
| | - Eleonora Ortu
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.T.); (S.D.N.); (M.C.); (E.O.)
| | - Davide Pietropaoli
- Department of Physical and Chemical Science, University of L’Aquila, 67100 L’Aquila, Italy
| | - Serena Altamura
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.T.); (S.D.N.); (M.C.); (E.O.)
| | - Rita Del Pinto
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.T.); (S.D.N.); (M.C.); (E.O.)
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Stieger A, Asadauskas A, Luedi MM, Andereggen L. Women's Pain Management Across the Lifespan-A Narrative Review of Hormonal, Physiological, and Psychosocial Perspectives. J Clin Med 2025; 14:3427. [PMID: 40429422 PMCID: PMC12112123 DOI: 10.3390/jcm14103427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/29/2025] [Accepted: 05/02/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction: Pain perception and management differ by sex, with women frequently experiencing more acute and chronic pain and greater disability than men. Yet, anesthesiology and pain control often overlook the physiological, hormonal, and psychological factors shaping women's pain. Methods: This narrative review explores essential considerations from current literature to optimize pain management in women. We examine evidence about the impact of hormonal changes, reproductive transitions, and psychosocial factors on pain perception and responses to analgesics. By highlighting key insights and practical strategies, we aim to support the development of personalized pain management approaches tailored to women's unique needs. Results: Hormonal changes, including variations in estrogen and progesterone levels, significantly influence pain thresholds and the effectiveness of analgesics and anesthetics. The menstrual cycle, menopausal transitions, and pregnancy each alter pain responses, necessitating personalized approaches to pain management. Postmenopausal women are particularly vulnerable to chronic pain conditions, such as those associated with osteoporosis, which require adjustments in long-term treatment strategies. Furthermore, psychosocial factors like anxiety and emotional distress can intensify pain, highlighting the need for holistic, integrative care. Conclusions: The existing gaps in women's pain management across the lifespan highlight the need to revise both anesthesia and pain management protocols to better account for sex-specific biological and psychosocial factors. Addressing the unique biological and psychosocial factors that influence pain in women can enhance both the effectiveness and equity of care. By tailoring treatment strategies in women, clinicians can not only enhance pain management but also greatly improve their overall quality of life.
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Affiliation(s)
- Andrea Stieger
- Department of Anaesthesiology, Rescue- and Pain Medicine, Cantonal Hospital of St. Gallen, 9007 St. Gallen, Switzerland; (A.S.)
| | - Auste Asadauskas
- Department of Neurology, University Hospital of Bern, Inselspital Bern, 3010 Bern, Switzerland
| | - Markus M. Luedi
- Department of Anaesthesiology, Rescue- and Pain Medicine, Cantonal Hospital of St. Gallen, 9007 St. Gallen, Switzerland; (A.S.)
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Lukas Andereggen
- Department of Neurosurgery, Kantonsspital Aarau, 5001 Aarau, Switzerland
- Faculty of Medicine, University of Bern, 3010 Bern, Switzerland
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19
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Yadav SS, Nair RR. Ethyl Pyruvate as a Potential Therapeutic Agent for Endometriosis: A Perspective. Reprod Sci 2025:10.1007/s43032-025-01875-x. [PMID: 40360949 DOI: 10.1007/s43032-025-01875-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025]
Abstract
Endometriosis is a disease where vascularised tissue similar to endometrium (the lining of the uterus) grows outside of the uterus. Its pathogenesis involves a complex interplay of inflammation, angiogenesis, cellular proliferation, reactive oxygen species (ROS) production, altered energy metabolism, and epithelial-to-mesenchymal transition (EMT).Even though endometriosis was described more than 150 years ago, we have been unable to find its effective therapy. Conservative treatment approaches like non-steroidal anti-inflammatory drugs or hormone therapy are available to date for the treatment of endometriosis. Anti-angiogenic inhibitors and immunomodulators like IFN-α, β, and TNF-α inhibitors are also potential treatment options. These treatments are inadequate as they either affect the symptoms only of endometriosis or target only one pathological pathway involved. Surgical excision of the endometriotic lesion is also possible, however, recurrence of the disease is reported in several cases. A single therapeutic agent targeting several pathological processes in endometriosis would always be a better option. Here we present our perspective on the pharmacological potential of Ethyl pyruvate and also propose it as a promising therapeutic agent for endometriosis as it inhibits inflammation, cell proliferation, angiogenesis, aerobic glycolysis, EMT, and ROS activity together.
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Affiliation(s)
- Suresh Singh Yadav
- Department of Molecular Biology & Biochemistry, Guru Nanak Dev University, Amritsar, 143005, Punjab, India
| | - Rohini Ravindran Nair
- Department of Medical Biotechnology, Gujrat Biotechnology University, Gandhinagar, 382355, Gujrat, India.
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20
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Karunadhas NS, Catherwood M, Stringfellow H, Arora R, McCluggage WG. "Early" Clear Cell Proliferations (Clear Cell Carcinoma in Situ) in Ovarian Endometriotic Cysts: Report of a Case Series With Recommendations for Terminology. Am J Surg Pathol 2025:00000478-990000000-00517. [PMID: 40326407 DOI: 10.1097/pas.0000000000002415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Clear cell carcinoma (CCC) is an uncommon malignancy accounting for ∼12% of ovarian carcinomas. Most cases arise from endometriosis, frequently an endometriotic cyst. We report a series of 6 cases where clear cell proliferations, morphologically, and immunophenotypically consistent with CCC, involve the epithelial lining of an endometriotic cyst without invasion into the surrounding stroma. The patients were aged 29 to 63 years (mean 45). In all cases, epithelial proliferations composed of cells with atypical nuclei, sometimes with a hobnail morphology, and clear or eosinophilic cytoplasm involved the epithelial lining of an ovarian endometriotic cyst. In areas, the proliferations comprised a monolayer, but in all cases, there was also significant epithelial stratification and multilayering, sometimes with a pseudopapillary architecture. There was no invasion of the atypical cells into the surrounding ovarian stroma. The proliferations were positive for Napsin A (6 of 6; 4 diffuse, 2 focal), racemase (5 of 5; 3 diffuse, 2 focal), hepatocyte nuclear factor 1-beta (5 of 5; all diffuse), oestrogen receptor (5 of 6; 2 diffuse, 3 focal), and PAX8 (3 of 3; all diffuse). p53 was wild-type in all 6 cases and WT1 and progesterone receptor were negative in the 4 and 6 cases tested, respectively. Mismatch repair immunohistochemistry was retained in the 3 cases tested. Next-generation sequencing was performed in 2 cases. In 1 case, a sole pathogenic MSH6 variant (p.Ser65fs) was identified. Follow-up (2 to 24 months) was available in 5 cases and there was no tumour recurrence. In reporting these "early" clear cell proliferations in endometriotic cysts, we provide recommendations for the reporting pathologist regarding the most appropriate terminology, which is important in patient management. We suggest that these proliferations be termed "CCC in situ" and that identification of such a lesion should prompt extensive sampling in order to exclude an invasive CCC component within the stroma outside the endometriotic cyst lining. We also stress the importance of close dialogue between the pathologist and the clinician and between the clinician and the patient in order to avoid overtreatment in such cases.
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Affiliation(s)
| | - Mark Catherwood
- Regional Molecular Diagnostics Service, Belfast Health and Social Care Trust, Belfast, Northern Ireland
| | | | - Rupali Arora
- Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
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21
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Hong Y. Prioritization of potential drug targets in ovarian-related diseases: Mendelian randomization and colocalization analyses. F&S SCIENCE 2025; 6:164-176. [PMID: 39988236 DOI: 10.1016/j.xfss.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 02/25/2025]
Abstract
OBJECTIVE To identify key genes and potential drug targets for ovarian-related diseases through genome-wide Mendelian randomization (MR) and colocalization analyses. DESIGN We conducted a comprehensive two-sample MR analysis to estimate the causal effects of blood expression quantitative trait loci (eQTLs) on ovarian-related diseases, followed by colocalization analyses to verify the robustness of the expression instrumental variables (IVs). Phenome-wide association studies (PheWAS) were also performed to evaluate the horizontal pleiotropy of potential drug targets and possible side effects. SUBJECTS Large cohorts of European ancestry. EXPOSURE The exposure in this study was the genetic variants (eQTLs) associated with gene expression levels, considered a form of lifelong exposure. Expression quantitative trait loci data were obtained from the eQTLGen Consortium, encompassing 16,987 genes and 31,684 cis-eQTLs derived from blood samples of healthy individuals of European ancestry. MAIN OUTCOME MEASURES The primary outcome measures were the identification of genes causally associated with ovarian-related diseases and the validation of these genes as potential therapeutic targets. RESULTS Our study revealed that specific genes such as CD163L1, PPP3CA, MTAP, F12, NRM, BANK1, ZNF66, GNA15, and SLC6A9 were associated with ovarian endometriosis, ovarian cysts, and polycystic ovarian syndrome. Through MR and colocalization analyses, we identified potential drug targets, including CTNNB1, PTPN7, and ABCB4, with strong evidence of colocalization with ovarian-related diseases. Sensitivity analyses confirmed the robustness of our findings, showing no evidence of horizontal pleiotropy or heterogeneity. CONCLUSION This research highlights the significance of precision medicine approaches in identifying genetic factors underlying ovarian-related diseases and provides a foundation for developing targeted therapies, enhancing diagnostic accuracy, and improving treatment strategies for ovarian-related diseases.
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Affiliation(s)
- Yanggang Hong
- The Second School of Medicine, Wenzhou Medical University, Zhejiang, China.
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22
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Kaveh M, Moghadam MN, Safari M, Chaichian S, Kashi AM, Afshari M, Sadegi K. The impact of early diagnosis of endometriosis on quality of life. Arch Gynecol Obstet 2025; 311:1415-1421. [PMID: 40188403 PMCID: PMC12033121 DOI: 10.1007/s00404-025-07999-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/03/2025] [Indexed: 04/08/2025]
Abstract
BACKGROUND Endometriosis is one of the most common chronic diseases in women, with a prevalence of up to 10%. The disease particularly affects women of reproductive age. Endometriosis has a significant impact on the patient's quality of life (QoL). In the current study, we aimed to evaluate the role of early diagnosis of endometriosis on patients' QoL. METHODS In this longitudinal prospective study, 205 women with endometriosis who were referred to the gynecology department of Amir al-Mominin Hospital (Zabol-Iran) in 2021 were evaluated. Patients were divided into two groups based on the time of diagnosis, including early diagnosis and late diagnosis. An Endometriosis Health Profile (EHP) questionnaire was used to collect information about QoL before and 18 months after treatment. Data were analyzed using SPSSv.26 software and significance level was considered less than 0.05. RESULTS In both groups with early and late diagnosis, the QoL scores improved without significant difference (p = 0.303). There was a significant difference between lower stages (1 and 2) and higher stages (3 and 4) in terms of treatment effects on patients' QoL, and higher stages of endometriosis affected patients' QoL before and after treatment more than lower stages (P values < 0.05). CONCLUSION Early or late diagnosis of endometriosis doesn't affect patients' QoL and patients benefit from treatment regardless of the time of diagnosis.
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Affiliation(s)
- Mania Kaveh
- Department of Obstetrics and Gynecology, School of Medicine, Amir Al Momenin Hospital, Zabol University of Medical Sciences, Zabol, Iran
- Iranian Scientific Society of Minimally Invasive Gynecology, Tehran, Iran
| | - Maryam Nakhaee Moghadam
- Department of Obstetrics and Gynecology, School of Medicine, Amir Al Momenin Hospital, Zabol University of Medical Sciences, Zabol, Iran
| | - Mojtaba Safari
- School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Shahla Chaichian
- Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Mehdizadeh Kashi
- Department of Obstetrics and Gynecology, School of Medicine, Endometriosis Research Center, Hazrat-e Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Afshari
- Department of Community Medicine, School of Medicine, Pediatric Gastroenterology and Hepatology Research Center, Zabol University of Medical Sciences, Zabol, Iran
| | - Kambiz Sadegi
- Department of Anesthesiology, School of Medicine, Amir Al Momenin Hospital, Zabol University of Medical Sciences, Zabol, Iran.
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Fan W, Zhang Y, Dai Y, Ma H, Zhao R, Liu Y. Creation of a rat model of ovarian endometriosis: a novel and easy approach to simulating chocolate cysts. Exp Cell Res 2025; 448:114553. [PMID: 40216010 DOI: 10.1016/j.yexcr.2025.114553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 04/15/2025]
Abstract
Ovarian endometriosis(OEM) is the most common type of endometriosis, but there is still a lack of simple and easy-to-promote animal models. Therefore, it is necessary to establish a feasible animal model of OEM and analyze its pathogenesis. In this study, a novel insertional surgical method was used to construct the OEM rat model. The rat model group's morphology and HE staining revealed a close relationship between the transplanted ectopic tissue and the ovary. Compared to the surgery group and the normal group, the bilateral OEM group's level of Anti-mullerian hormone(AMH) was noticeably lower. There was no discernible difference in the unilateral OEM group's AMH level between the normal and sham operation groups. Serum interleukin-1beta(IL-1β) levels in four groups of rats showed bilateral OEM had the greatest level, followed by unilateral OEM. Compared to the normal group, the two model groups had greater serum levels of IL-1β. According to immunohistochemistry, unilateral OEM had higher Intercellular adhesion molecule 1(ICAM1), Matrix metalloproteinase-9(MMP9), Tumor necrosis factor-α(TNF-a), and IL-1β expression levels than the normal rat endometrium. WB revealed that bilateral and unilateral ectopic tissues had higher levels of MMP9, TNF-a, Vascular endothelial growth factor D and IL-1β expression than normal tissues. Transcriptome research revealed that ectopic tissues had higher pro-inflammatory, immunological, and ectopic endometrial proliferation pathways than normal tissues. The ovaries of unilateral OEM have down-regulated immune and inflammation-related pathways and up-regulated steroid hormones compared to normal ovarian tissue. GSEA enrichment analysis comparisons between rat and human endometriotic tissue revealed that Janus kinase-signal transducer and activator of transcription(JAK-STAT), Nuclear factor-kappa B(NFκB), and Toll-like receptors were up-regulated. The intercalation approach of OEM building used in this work is more akin to the human OEM lesion type. It deserves promotion that modeling is more straightforward and has a higher success rate than the suture approach.
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Affiliation(s)
- Weisen Fan
- Department of Gynecology, Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
| | - Yingjie Zhang
- School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250013, China
| | - Yuanquan Dai
- Department of Gynecology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250013, China
| | - Haotian Ma
- Department of Gynecology, Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Ruihua Zhao
- Department of Gynecology, Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yong Liu
- Department of Gynecology, Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
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Eubanks AA, Combs JC. Reassessing endometriosis as a heterogeneous condition in assisted reproductive technology outcomes. Fertil Steril 2025; 123:790-791. [PMID: 39954981 DOI: 10.1016/j.fertnstert.2025.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Affiliation(s)
- Allison A Eubanks
- Department of Reproductive Endocrinology and Infertility, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Joshua C Combs
- Department of Reproductive Endocrinology and Infertility, Naval Medical Center Portsmouth, Portsmouth, Virginia
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Mostafa J, Volodarsky-Perel A, Altshuler H, Doron A, Burke YZ, Elizur SE, Berkowitz E. The impact of war situation on endometriosis patients: Evaluating physical and mental health outcomes. J Health Psychol 2025; 30:1177-1188. [PMID: 39394790 DOI: 10.1177/13591053241288963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2024] Open
Abstract
To investigate the impact of war situation on physical functioning, mental health status, and disease manifestations among endometriosis patients. Questionnaire-based study analyzing physical and psychosocial well-being. The study includes 50 endometriosis patients at Sheba Medical Center who completed a detailed questionnaire before and after the onset of the October 7, 2023, War in Israel. Significant deterioration in physical and mental health after the onset of war (pain score 6 vs 7; p < 0.001). Although having a first-degree relative affected by the war was associated with health deterioration (OR, 5.44; p = 0.02), similar pattern of health status aggregation was observed also in a subgroup of 19 women without family involvement, suggesting the general war situation as a likely cause. Starting new anti-anxiety or antidepressant medications and psychological therapy had a protective effect (OR, 0.21; p = 0.05). War situation exacerbates endometriosis symptoms, highlighting the importance of early psychological interventions to mitigate negative impacts.
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Türkoğlu İ, Sacinti KG, Panattoni A, Namazov A, Sanlier NT, Sanlier N, Cela V. Eating for Optimization: Unraveling the Dietary Patterns and Nutritional Strategies in Endometriosis Management. Nutr Rev 2025; 83:869-879. [PMID: 39225782 DOI: 10.1093/nutrit/nuae120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
Endometriosis is a chronic gynecological disorder affecting millions of women worldwide, causing chronic pelvic pain, dyspareunia, dysmenorrhea, and infertility, and severely impacting their quality of life. Treatment primarily involves hormonal therapies and surgical excision, but high recurrence rates and the economic burden are substantial. With these challenges, significant discussion surrounds the potential role of dietary patterns in managing endometriosis, making it necessary to bridge this critical gap. This review investigates the current scientific evidence on the dietary patterns (eg, Mediterranean, vegetarian, anti-inflammatory, low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols [low-FODMAP], and Western-style diets) associated with endometriosis and provides a concise, yet thorough, overview on the subject. In addition, antioxidants, microbiota, and artificial intelligence (AI) and their potential roles were also evaluated as future directions. An electronic-based search was performed in MEDLINE, Embase, Cochrane Library, CINAHL, ClinicalTrials.gov, Scopus, and Web of Science. The current data on the topic indicate that a diet based on the Mediterranean and anti-inflammatory diet pattern, rich in dietary fiber, omega-3 fatty acids, plant-based protein, and vitamins and minerals, has a positive influence on endometriosis, yielding a promising improvement in patient symptoms. Preclinical investigations and clinical trials indicate that dietary antioxidants and gut microbiota modulation present potential new approaches in managing endometriosis. Also, AI may offer a promising avenue to explore how dietary components interact with endometriosis. Ultimately, considering genetic and lifestyle factors, a healthy, balanced, personalized approach to diet may offer valuable insights on the role of diet as a means of symptom improvement, facilitating the utilization of nutrition for the management of endometriosis.
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Affiliation(s)
- İnci Türkoğlu
- Department of Nutrition and Dietetics, Hacettepe University School of Health Sciences, Ankara 06100, Turkey
| | - Koray Gorkem Sacinti
- Department of Obstetrics and Gynecology, Aksaray University Training and Research Hospital, Aksaray 68200, Turkey
- Division of Epidemiology, Department of Public Health, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| | - Andrea Panattoni
- Division of Obstetrics and Gynecology, Department of Clinical and Reproductive Medicine, University of Pisa, Pisa 56126, Italy
| | - Ahmet Namazov
- Department of Obstetrics and Gynecology, Barzilai University Medical Center, Ashkelon 7830604, Israel
- Faculty of Health Sciences, Ben-Gurion University of Negev, Beer-Sheva 8410501, Israel
| | - Nazlı Tunca Sanlier
- Department of Obstetrics and Gynecology, Turkish Ministry of Health, Ankara City Hospital, Ankara 06800, Turkey
| | - Nevin Sanlier
- Department of Nutrition and Dietetics, Ankara Medipol University School of Health Sciences, Ankara 06050, Turkey
| | - Vito Cela
- Division of Obstetrics and Gynecology, Department of Clinical and Reproductive Medicine, University of Pisa, Pisa 56126, Italy
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27
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Liu L, Ge D, Lin Y, Han Z, Zhao H, Cao L, Wu X, Ma G. Epigenetic regulation in oogenesis and fetal development: insights into m6A modifications. Front Immunol 2025; 16:1516473. [PMID: 40356909 PMCID: PMC12066277 DOI: 10.3389/fimmu.2025.1516473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
The unique physiological structure of women has led to a variety of diseases that have attracted the attention of many people in recent years. Disturbances in the reproductive system microenvironment lead to the progression of various female tumours and pregnancy disorders. Numerous studies have shown that epigenetic modifications crucially influence both oogenesis and foetal development. m6A, a modification at the mRNA level, consists of three parts, namely, writers, erasers, and readers, which are involved in several biological functions, such as the nucleation and stabilisation of mRNAs, thereby regulating the development of reproductive system diseases. In this manuscript, we delineate the constituents of m6A, their biological roles, and advancements in understanding m6A within the maternal-foetal immunological context. In addition, we summarise the mechanism of m6A in gynaecological diseases and provide a new perspective for targeting m6A to delay the progression of reproductive system diseases in clinical practice.
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Affiliation(s)
- Lusheng Liu
- Department of Acupuncture and Moxibustion, Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Clinical Medical College of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Danxia Ge
- Department of Critical Care Medicine, Traditional Chinese Medicine Hospital of, Ningbo, Zhejiang, China
| | - Yumeng Lin
- Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhongyu Han
- Department of Acupuncture and Moxibustion, Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Heng Zhao
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liqin Cao
- Department of Gynecology, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xi Wu
- Department of Gynecology, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guizhi Ma
- Department of Acupuncture and Moxibustion, Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Mallis P. Hypoxic endometrial epithelial cell-derived microRNAs effectively regulate the regenerative properties of mesenchymal stromal cells. World J Stem Cells 2025; 17:102482. [PMID: 40308881 PMCID: PMC12038455 DOI: 10.4252/wjsc.v17.i4.102482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/06/2025] [Accepted: 03/05/2025] [Indexed: 04/23/2025] Open
Abstract
Endometrial thickness plays an important role in successful embryo implantation and normal pregnancy achievement. However, a thin endometrial layer (≤ 7 mm) may have a significant effect on microenvironment tolerance, which is further related to successful embryo implantation or conception, either naturally or after assisted reproductive technology. Moreover, this microenvironment tolerance shift induces hypoxic damage to endometrial epithelial cells (EECs), which results in altered signaling biomolecule secretion, including exosome content. In the context of endometrium regeneration, mesenchymal stromal cells (MSCs) and umbilical cord (UC)-derived stem cells have been applied in clinical trials with promising results. It has been recently shown that exosomes derived from hypoxic damaged EECs directly contribute to the increased migratory and regenerative abilities of UCs and MSCs. Specifically, microRNAs in exosomes secreted by the hypoxic damaged EECs, such as miR-214-5p and miR-21-5p, play a crucial role in the migratory capacity and differentiation ability of MSCs to EECs mediated through the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Taking into consideration the above information, UC-MSCs may be considered as a modern intervention for endometrial regeneration.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Attikí, Greece.
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29
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Valihora HP. Experiences of disempowerment amongst endometriosis patients: Toward comprehensive care to address the psychosocial impact of chronic illness. J Health Psychol 2025:13591053251331279. [PMID: 40257283 DOI: 10.1177/13591053251331279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2025] Open
Abstract
Endometriosis is a devastating chronic condition with significant physical and social implications. This research focused on two questions: 1) how do endometriosis patients experience healthcare in Canada, and 2) how can the healthcare encounter effectively address the psychosocial burden of disease that patients bear? This study examines the psychosocial implications of endometriosis diagnosis and treatment. Data was obtained through semi-structured interviews with nine people diagnosed with endometriosis. Interview questions centering patient perceptions of care were thematically analyzed utilizing reflexive thematic analysis. Analyzing participant narratives and drawing upon Kleinman's concepts of illness experiences and slow medicine, this article underlines the urgency of moving toward a deeper ethics of care for endometriosis patients, wherein the patient is understood and advocated for within the Canadian healthcare system. Drawing upon participant experiences, the present research calls for the widespread availability of a comprehensive healthcare model for the treatment of endometriosis.
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Colombo GE, Makieva S, Somigliana E, Schoretsanitis G, Leeners B, Polli C, Salmeri N, Kalaitzopoulos DR, Vigano' P. The association between endometriosis and migraine: a systematic review and meta-analysis of observational studies. J Headache Pain 2025; 26:82. [PMID: 40247158 PMCID: PMC12007130 DOI: 10.1186/s10194-025-02020-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Accepted: 04/01/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Endometriosis affects women of reproductive age. Increasing attention is being given to the characterization of comorbidities in endometriosis to enhance clinical phenotyping. Among these comorbidities, migraine has been reported to be significantly more common in individuals with endometriosis compared to the general population. However, the true epidemiological burden remains uncertain, and no conclusive evidence links specific subtypes of endometriosis to migraine. MAIN BODY Seven electronic databases were searched from inception until July 22nd, 2024, using combinations of relevant keywords. PROSPERO Registration CRD42023449492. Two independent reviewers screened the records according to inclusion/exclusion criteria and abstracted data. The risk of bias assessment was undertaken using the ROBINS-E tool. Random effects models were implemented to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between endometriosis and migraine. Fourteen studies were included in the qualitative synthesis, and 13 in the meta-analysis, accounting for a total of 331,655 individuals (32,489 with endometriosis vs. 299,166 controls). There was a serious risk of bias in the majority of the included studies, with 50% being at very high risk of bias. The risk of migraine was higher in individuals with endometriosis compared to those without (OR 2.25, 95%CI = 1.85-2.72; n = 13 studies; I2 = 81%). This association remained significant in the sensitivity analyses: (i) when excluding studies at very high or high risk of bias (OR 2.64; 95%CI = 1.62-4.31; n = 4 studies; I2 = 77%), (ii) when including only risk estimates adjusted for clinically relevant confounders (OR 2.35; 95%CI = 1.77-3.13; n = 6 studies; I2 = 88%), and (iii) when including only risk estimates adjusted for hormonal therapy (OR 1.95; 95%CI = 1.42-2.66; n = 3; I2 = 92%). Endometriosis was significantly associated with migraine without aura (OR 2.64, 95%CI 1.89-3.69; n = 3 studies; I2 = 0%), but not migraine with aura (OR 3.47, 95%CI = 0.53-22.89; n = 3, I2 = 73%). CONCLUSION This meta-analysis highlights the high prevalence of migraine in patients with endometriosis. However, due to observed high heterogeneity and risk of bias, caution is advised when interpreting and applying these findings in clinical practice. Future research should address these issues by limiting variations in diagnostic criteria, stratifying study populations, accounting for key confounders, and investigating potential underlying pathophysiological mechanisms to enhance understanding of the endometriosis-migraine relationship.
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Affiliation(s)
- Giorgia Elisabeth Colombo
- Department of Obstetrics and Gynaecology, Chelsea and Westminster NHS Foundation Trust, London, SW10 9NH, UK.
- Endometriosis Center, Department of Obstetrics and Gynecology, Ospedale Regionale di Lugano, Ente Ospedaliero Cantonale (EOC), Via Tesserete 46, Lugano, 6900, Switzerland.
| | - Sofia Makieva
- Klinik für Reproduktions-Endokrinologie, Universitätsspital Zürich, Frauenklinikstrasse 10, Kinderwunschzentrum, Zürich, 8091, Switzerland
| | - Edgardo Somigliana
- Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 28, 20122, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Commenda 19, 20122, Milan, Italy
| | - Georgios Schoretsanitis
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, 75-59 263rd St, Glen Oaks, NY, 11004, USA
- Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, 11549, USA
- Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Lenggstrasse 31, Zürich, 8008, Switzerland
| | - Brigitte Leeners
- Klinik für Reproduktions-Endokrinologie, Universitätsspital Zürich, Frauenklinikstrasse 10, Kinderwunschzentrum, Zürich, 8091, Switzerland
| | - Christian Polli
- Endometriosis Center, Department of Obstetrics and Gynecology, Ospedale Regionale di Lugano, Ente Ospedaliero Cantonale (EOC), Via Tesserete 46, Lugano, 6900, Switzerland
| | - Noemi Salmeri
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Commenda 19, 20122, Milan, Italy
| | | | - Paola Vigano'
- Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 28, 20122, Milan, Italy.
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Abhang A, Burgess DJ. Recent advancements and future applications of intrauterine drug delivery systems. Expert Opin Drug Deliv 2025:1-16. [PMID: 40193227 DOI: 10.1080/17425247.2025.2490266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 04/03/2025] [Indexed: 04/10/2025]
Abstract
INTRODUCTION Intrauterine devices (IUDs) are drug-device combination products that are placed inside the uterus above the endometrium. IUDs contain a therapeutic agent used for contraception and have been shown to have other therapeutic benefits. Over the past century, intrauterine drug delivery systems (IUDDS) have revolutionized women's health, and they hold immense growth potential in the future for new developments in the therapeutic areas beyond contraception. AREAS COVERED The aim of this review is to offer a comprehensive description of the history, development, and current state of IUDDS, next-generation IUDDS, and future applications of IUDDS in therapeutic areas beyond contraception such as multi-purpose prevention technologies, hormone replacement therapy, endometriosis, uterine fibroids, and endometrial cancer. EXPERT OPINION The uterus's unique features make it an ideal site for controlled, prolonged, and localized delivery of drugs, ensuring maximum concentration at the target site. Currently, IUDs are the most widely used contraceptive method. Future IUDDS hold the potential to deliver therapeutic agents for broader therapeutic areas for women's health, potentially aiding in the treatment of various diseases and disorders of the female reproductive system. Further research in development, characterization, and translation is warranted to ensure IUDDS reach their potential in many areas of women's health.
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Affiliation(s)
- Ashwin Abhang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA
| | - Diane J Burgess
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA
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Jung GS, Lee JH, Lee MJ, Lee I, Park H, Kim N, Kim JY, Im W, Cho S, Choi YS. Effects of chronic particulate matter exposure on endometriosis-associated signaling pathways and disease progression. Mol Hum Reprod 2025; 31:gaaf013. [PMID: 40233240 DOI: 10.1093/molehr/gaaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/06/2025] [Indexed: 04/17/2025] Open
Abstract
Exposure to PM2.5 (particulate matter <2.5 μm) has been implicated in increasing the risk of endometriosis and worsening its symptoms. However, the molecular mechanisms and direct associations remain unclear. This study explored whether PM2.5 contributes to the onset or progression of endometriosis using in vitro and in vivo models. Endometrial (EM) cells from women without endometriosis were cultured to the second passages (P2) with or without exposure to PM2.5 at a concentration of 200 µg/ml (N = 5 for each group). Z-stack confocal imaging confirmed PM accumulation in the nucleus and cytoplasm of exposed EM cells. Initial PM exposure at the primary passage (P0) led to decreased proliferation, migration, anti-apoptosis, and oxidative stress, accompanied by downregulation of associated pathways. However, repeated PM exposure during subculturing to P2 led to increased proliferation, enhanced anti-apoptotic activity, and elevated oxidative stress. Given the similarity of these gene expression alterations to those observed in endometriosis, an endometriosis-induced mouse model was established to assess the potential of repeated PM exposure to exacerbate the condition in vivo. To investigate the in vivo effects, an endometriosis-induced mouse model was developed using female C57BL/6 mice exposed to low (10 mg/kg/day) or high (20 mg/kg/day) doses of PM2.5 for 4 weeks (n = 6 for each group). PM exposure significantly enlarged endometriotic lesions compared to controls (no PM exposure). Upregulated gene expression in endometriotic lesions included anti-apoptotic (Bcl2/Bax), proliferative (p-ERK), inflammatory (p-NF-κB, p-c-jun, IL-6, IL-1β), and migration (MMP-2, MMP-9) markers. PM exposure altered estrogen receptor (ER) expression, resulting in a decreased ERα/ERβ ratio in both dose groups. The control group exhibited a ratio of 1.03 ± 0.09, while the low-dose and high-dose mice had ratios of 0.57 ± 0.08 (P = 0.02) and 0.46 ± 0.26 (P = 0.03), respectively. In conclusion, PM2.5 exposure alters gene expression related to cell growth, survival, oxidative stress, and migration in EM cells and exacerbates endometriotic lesions in vivo, likely through ER modulation. These findings suggest PM2.5 may contribute to other estrogen-dependent conditions, such as leiomyoma or adenomyosis, by influencing ER pathways.
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Affiliation(s)
- Gee Soo Jung
- Department of Integrative Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Lee
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Min Jung Lee
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Inha Lee
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyemin Park
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Nara Kim
- Department of Medical Device Engineering and Management, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji-Ye Kim
- Department of Pathology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang-Si, Gyeonggi-Do, Republic of Korea
| | - Wooseok Im
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - SiHyun Cho
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Sik Choi
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Ge L, Yang Y, Xiao T, Gao Y, Chang W, Du F, Yu M, Zhang JV. Ovarian Endometriosis Accelerates Premature Ovarian Failure and Contributes to Osteoporosis and Cognitive Decline in Aging Mice. Int J Mol Sci 2025; 26:3313. [PMID: 40244208 PMCID: PMC11989598 DOI: 10.3390/ijms26073313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/23/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
Ovarian endometriosis (OEM) is a chronic inflammatory condition that impairs ovarian function. While its effects on ovarian reserve are well established, the long-term consequences of OEM on ovarian dysfunction, premature ovarian failure (POF), and systemic health, particularly in the context of accelerated aging, remain insufficiently studied. In this study, we employed an OEM mouse model and bulk RNA sequencing to investigate the underlying mechanisms. Our results show that OEM accelerates primordial follicle depletion and upregulates mTOR signaling pathway gene expression, along with mechanical stress and paracrine signaling via the Hippo and Myc pathways. OEM also induces irregular estrus and ovarian fibrosis in aging mice, decreases serum AMH levels, and increases FSH levels. Systemically, elevated serum IgG levels contribute to osteoporosis and cognitive decline, both linked to ovarian dysfunction and POF in OEM. These findings elucidate the mechanisms driving premature ovarian reserve depletion in OEM and highlight its broader systemic effects. This study emphasizes the importance of monitoring ovarian health and ectopic tissue to safeguard ovarian reserves and mitigate long-term risks such as osteoporosis and cognitive decline.
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Affiliation(s)
- Lei Ge
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- University of Chinese Academy of Sciences, Beijing 100049, China
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
| | - Yali Yang
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
| | - Tianxia Xiao
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
| | - Yuqing Gao
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Wakam Chang
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Feifei Du
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
| | - Ming Yu
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
| | - Jian V. Zhang
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (L.G.); (M.Y.)
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen 518000, China
- Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen 518028, China
- Sino-European Center of Biomedicine and Health, Shenzhen 518000, China
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Yi Y, Nie J, Liu X, Guo SW. Progressively Diminished Prostaglandin E2 Signaling in Concordance with Increasing Fibrosis in Ectopic Endometrium. Reprod Sci 2025; 32:1271-1286. [PMID: 39174854 DOI: 10.1007/s43032-024-01658-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/13/2024] [Indexed: 08/24/2024]
Abstract
The prostaglandin E2 (PGE2) signaling has traditionally been viewed to play a pivotal role in endometriosis, linking inflammation and hyperestrogenism. We have previously reported that asectopic endometrium becomes more fibrotic, the expression of both COX-2 and PGE2 receptors (EP2 and EP4) are reduced. This study further investigatedwhether the expression levels of genes involved in the biosynthesis and metabolism of PGE2in ectopic endometrium diminish in concordance with increasing lesional fibrosis. We performed immunohistochemistry analyses of COX-2, mPGES-1, mPGES-2, cPGES, 15-PGDH, EP2 and EP4 and Masson trichrome staining for ovarian endometrioma (OE), adenomyosis (AD), and deep endometriosis (DE) tissue samples and control endometrial tissue samples (CT). Gene and protein expression analyses were performed by real-time RT-PCR and Western blotting, respectively. We found that as the extent of lesional fibrosis increased, immunoexpression of COX-2, mPGES-1/2, cPGES, EP2 and EP4 in OE lesions was increased but no change in these genes/proteins in DE lesions as compared with CT. Immunoexpression of COX-2 was found to be reduced while that of 15-PGDH was found to be elevated in DE lesions. In AD lesions, only EP2 and COX-2 were overexpressed. Thus, our data indicate that when the extent of lesional fibrosis is high, the PGE2 signaling pathway is depressed, manifesting as reduced COX-2 expression and elevated expression of 15-PGDH. They underscore the fact that not all ectopic endometria are the same and equal, and highlight the importance of the extracellular matrix in shaping the lesional behavior and response to drug treatment.
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Affiliation(s)
- Yunhua Yi
- Dept. of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Jichan Nie
- Dept. of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Xishi Liu
- Dept. of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
| | - Sun-Wei Guo
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
- Research Institute, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
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Xu Y, Li Y, Zhang J, Cai P. Hua Yu Xiao Zheng decoction induces ectopic endometrial stromal cell senescence via inhibiting the PI3K/AKT signaling. Tissue Cell 2025; 93:102763. [PMID: 39914108 DOI: 10.1016/j.tice.2025.102763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/17/2025] [Accepted: 01/25/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Our purpose is to explore the influence of Hua Yu Xiao Zheng (HYXZ) decoction on the senescence of ectopic endometrial stromal cells (ESCs) in endometriosis as well as its relevant mechanisms. METHODS The proliferation, apoptosis, migration, and invasion of primary ectopic ESCs was assessed utilizing EdU assay, flow cytometry, and transwell assays. Moreover, the effects of HYXZ decoction on oxidative stress were evaluated using DCFH-DA probe and via measuring MDA, GSH, SOD and GPx levels. The function of HYXZ decoction on cell senescence were explored through utilizing SA-β-gal staining and measuring the cumulative population doubling level and the average telomere length. The protein expression was measured using western blotting analysis. Endometriosis in rats was surgically induced, and the efficacy and mechanism of HYXZ decoction were determined in vivo. RESULTS HYXZ decoction inhibited the growth, migration, and invasion of ectopic ESCs, but induced oxidative stress and senescence. HYXZ decoction inhibited PI3K/AKT signaling in ectopic ESCs. PI3K-AKT signaling pathway activator (740Y-P) significantly reversed the inhibitory effects of HYXZ decoction on ectopic ESCs. In rats with endometriosis, oral administration of HYXZ decoction inhibited lesion volume alone with the increased oxidative stress and cell senescence, as well as the decreased PI3K/AKT activity. CONCLUSION HYXZ decoction might repress the growth and migration of ectopic ESCs, and induce oxidative stress and senescence through suppressing PI3K/AKT signaling. This finding indicates that HYXZ decoction may be a potential therapeutic drug against endometriosis.
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Affiliation(s)
- Yuan Xu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, PR China; Traditional Chinese Medicine Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China
| | - Yuhui Li
- Medical Equipment Department, Shandong Cancer Hospital, Jinan, Shandong 250117, PR China
| | - Jingyong Zhang
- Vascular Surgery Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China
| | - Pingping Cai
- Traditional Chinese Medicine Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China.
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Oliveira IJ, Pinto PV, Bernardes J. Noninvasive Diagnosis of Endometriosis in Adolescents and Young Female Adults: A Systematic Review. J Pediatr Adolesc Gynecol 2025; 38:124-138. [PMID: 39098544 DOI: 10.1016/j.jpag.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 06/14/2024] [Accepted: 07/26/2024] [Indexed: 08/06/2024]
Abstract
STUDY OBJECTIVES Our aim was to review the evidence concerning the noninvasive diagnosis of endometriosis in adolescents. METHODS A systematic review was written following the SWiM reporting guidelines. The study research was made across three databases (MEDLINE/PubMed, Scopus, and Web of Science) to identify articles about the adolescent population and the diagnosis of endometriosis through noninvasive methods. The search included the keywords "endometriosis," "adolescents," "diagnosis," "ultrasound," and "MRI." Only English-language articles were considered, and those published prior to 2000 were excluded. The established outcomes focused on clinical symptoms, ultrasound (US), and magnetic resonance imaging (MRI) findings suggestive of endometriosis. RESULTS We included 26 articles, mostly comprising case series and cross-sectional studies. The pooled analysis involved 2,299 female adolescents (age range 8-25 years old) with clinically suspected, imaged, and/or surgically confirmed endometriosis. The most frequently reported symptom was dysmenorrhea, followed by chronic pelvic pain. Among adolescents clinically suspected of endometriosis undergoing ultrasound (US), 32.8% exhibited at least one sign of endometriosis. Of the 167 patients with ultrasound-diagnosed endometriosis, 48.5% had deep infiltrating endometriosis (DIE), and 45.5% had an endometrioma detected. Three studies assessed MRI findings, revealing that 49.8% presented with signs of endometriosis. CONCLUSIONS Dysmenorrhea and chronic pelvic pain stand out as key symptoms of adolescent endometriosis. Although their diagnostic accuracy varies, US and MRI have emerged as valuable tools for diagnosing the disease. While the US may have limitations, especially in detecting subtle lesions, MRI shows promise, even in cases with normal previous ultrasounds. Early recognition and proactive diagnosis are crucial for improving the management of endometriosis in adolescents.
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Affiliation(s)
- Inês Jerónimo Oliveira
- Mestrado Integrado em Medicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
| | - Pedro Viana Pinto
- Serviço de Anatomia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Serviço de Ginecologia, Centro Hospitalar e Universitário de São João, Porto, Portugal
| | - João Bernardes
- Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Serviço de Ginecologia, Centro Hospitalar e Universitário de São João, Porto, Portugal; Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS@RISE), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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Wang T, Ji M, Yang P, Zhang J, Peng X, Miao Y, Liu W, Sun J. Cyclooxygenase 2 overexpression suppresses Smad3 and augments ERK1/2 signaling activated by TGFβ1 in endometrial stromal cells: A novel insight into endometriosis pathogenesis. Mol Cell Endocrinol 2025; 599:112470. [PMID: 39864487 DOI: 10.1016/j.mce.2025.112470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 01/15/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
RESEARCH QUESTION To investigate the underlying mechanisms driving the opposing effects of transforming growth factor-beta 1 (TGFβ1) on the proliferation of control (CESCs) and ectopic (EESCs) endometrial stromal cells. DESIGN Cell proliferation assays (CCK-8 and colony formation) were employed to assess the effects of TGFβ1 on CESC and EESC proliferation. An immortalized human endometrial stromal cell line (HESC) was used to elucidate the mechanisms behind cytostatic effect of TGFβ1 and the potential role of cyclooxygenase (COX)-2 in mediating the modulation of TGFβ1 signaling. RESULTS This study demonstrated that TGFβ1 inhibited the proliferation of CESCs and HESCs while significantly promoting the proliferation of EESCs. In both CESCs and HESCs, TGFβ1-induced growth arrest was primarily mediated by cell cycle arrest rather than apoptosis. Mechanistically, TGFβ1 activated both Smad3 and ERK1/2 signaling pathways, with Smad3 acting to inhibit proliferation and ERK1/2 to promote it. Notably, overexpression of COX-2 in HESCs abolished the cytostatic effect of TGFβ1 by enhancing ERK1/2 signaling and decreasing Smad3 protein levels and its nuclear translocation. Similar effects were observed following prostaglandin E2 (PGE2) treatment. In contrast, inhibition of COX-2 activity in EESCs resulted in increased Smad3 expression, reduced ERK1/2 activation, and a restoration of the cytostatic effect of TGFβ1. CONCLUSION COX-2 modulates the effects of TGFβ1 on endometrial stromal cells by altering the balance between the Smad3 and ERK1/2 signaling pathways, thereby converting TGFβ1 from a growth inhibitor to a proliferation stimulator.
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Affiliation(s)
- Tao Wang
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Mei Ji
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Pusheng Yang
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jiaxin Zhang
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xiaotong Peng
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yaxin Miao
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Wenwen Liu
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jing Sun
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
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Josiasen M, Røssell EL, Zhu T, Melgaard A, Saraswat L, Horne AW, Hansen KE, Rytter D. Prevalence and sociodemographic distribution of endometriosis symptoms and indicators in Denmark. Eur J Obstet Gynecol Reprod Biol 2025; 307:109-120. [PMID: 39908742 DOI: 10.1016/j.ejogrb.2025.01.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION Endometriosis is characterized by a range of non-specific symptoms which may contribute to the significant delay in diagnosis. Knowledge about the distribution of endometriosis symptoms across different geographical regions as well as other sociodemographic factors could add knowledge and guide initiatives to reduce this underdiagnosis. This study aims to explore how the prevalence of endometriosis symptoms and indicators are linked to the different sociodemographic factors. STUDY DESIGN The study used data from the CYKLUS-survey; a women's health survey sent to 63,199 Danish women aged 16 to 51 in 2023. Self-reported information on endometriosis symptoms and indicators was linked to Danish register data on sociodemographic factors. Age-standardized prevalence of six endometriosis symptoms and indicators were estimated for each of the nine different regions of residence and for the whole country. In addition, logistic regression analysis was used to estimate the association between sociodemographic factors and the six endometriosis symptoms and indicators. RESULTS 11,407 women were included in the study. Age-standardized prevalence of symptoms showed little variation across Danish regions. However, younger age, lower socioeconomic status, and non-Danish origin were found to be associated with higher prevalences, and higher education was found to be associated with lower prevalences. CONCLUSION No major regional differences in endometriosis symptoms and indicators were found. However, associations were found between several sociodemographic factors and endometriosis symptoms and indicators, suggesting disparities in the burden of symptoms. These findings call for further investigation into factors causing these disparities in Denmark.
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Affiliation(s)
- Marie Josiasen
- Department of Public Health, Research unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark.
| | - Eeva-Liisa Røssell
- Department of Public Health, Research unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark
| | - Tong Zhu
- Department of Public Health, Research unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark
| | - Anna Melgaard
- Department of Public Health, Research unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark
| | - Lucky Saraswat
- Aberdeen Centre of Women's Health Research, University of Aberdeen, Aberdeen AB25 2ZN, UK; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZN, UK
| | - Andrew W Horne
- Centre for Reproductive Health, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, 4-5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Karina Ejgaard Hansen
- Department of Public Health, Research unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark
| | - Dorte Rytter
- Department of Public Health, Research unit for Epidemiology, Aarhus University, 8000 Aarhus C, Denmark
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Ge L, Yang Y, Gao Y, Xiao T, Chang W, Wang H, Xiao Z, Chen J, Li M, Yu M, Jin P, Zhang JV. Ovarian Endometrioma Disrupts Oocyte-Cumulus Communication and Mitochondrial Function, With Melatonin Mitigating the Effects. Cell Prolif 2025; 58:e13800. [PMID: 39837534 PMCID: PMC11969245 DOI: 10.1111/cpr.13800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
Ovarian endometrioma (OEM), a particularly severe form of endometriosis, is an oestrogen-dependent condition often associated with pain and infertility. The mechanisms by which OEM impairs fertility, particularly through its direct impact on oocyte-cumulus cell (CC) communication and related pathways, remain poorly understood. This study investigates the impact of OEM on oocyte-CC communication and explores melatonin's therapeutic potential. We used a mouse model of OEM and employed ovarian transcriptome and gene set enrichment analyses to identify disrupted gene pathways, alongside phalloidin staining for cytoskeletal analysis, gap junction coupling analysis for intercellular communication, and mitochondrial function assessments for cellular metabolism. Our results showed that OEM significantly impairs steroidogenesis and cumulus cell function, leading to increased apoptosis, disrupted transzonal projections (TZPs), and impaired antioxidant transfer to oocytes. This culminates in oxidative stress, mitochondrial dysfunction, and compromised ATP production. OEM oocytes also exhibited severe abnormalities, including DNA damage, maturation defects, spindle assembly disruptions, and increased aneuploidy. This study identifies disrupted TZPs as a key pathological feature in OEM and highlights melatonin's potential to restore intercellular communication, mitigate oxidative damage, and improve reproductive outcomes.
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Affiliation(s)
- Lei Ge
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- University of Chinese Academy of SciencesBeijingChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Yali Yang
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Yuqing Gao
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
- Department of Biomedical Sciences, Faculty of Health SciencesUniversity of MacauMacauChina
| | - Tianxia Xiao
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Wakam Chang
- Department of Biomedical Sciences, Faculty of Health SciencesUniversity of MacauMacauChina
| | - Hefei Wang
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Zhonglin Xiao
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
- Faculty of Data ScienceCity University of MacauMacauChina
| | - Jie Chen
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Mengxia Li
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Ming Yu
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
| | - Ping Jin
- Shenzhen Maternity and Child Healthcare HospitalShenzhenGuangdongChina
- The First School of Clinical MedicineSouthern Medical UniversityShenzhenGuangdongChina
| | - Jian V. Zhang
- Center for Energy Metabolism and ReproductionShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenGuangdongChina
- Shenzhen Key Laboratory of Metabolic HealthShenzhenGuangdongChina
- Faculty of Pharmaceutical SciencesShenzhen University of Advanced TechnologyShenzhenGuangdongChina
- Sino‐European Center of Biomedicine and HealthShenzhenGuangdongChina
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Marino Y, Inferrera F, Genovese T, Cuzzocrea S, Fusco R, Di Paola R. Mitochondrial dynamics: Molecular mechanism and implications in endometriosis. Biochimie 2025; 231:163-175. [PMID: 39884375 DOI: 10.1016/j.biochi.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 02/01/2025]
Abstract
Endometriosis affects about 10 % of women of reproductive age, leading to a disabling gynecologic condition. Chronic pain, inflammation, and oxidative stress have been identified as the molecular pathways involved in the progression of this disease, although its precise etiology remains uncertain. Although mitochondria are considered crucial organelles for cellular activity, their dysfunction has been linked to the development of this disease. The purpose of this review is to examine the functioning of the mitochondrion in endometriosis: in particular, we focused on the mitochondrial dynamics of biogenesis, fusion, and fission. Since excessive mitochondrial activity is reported to affect cell proliferation, we also considered mitophagy as a mechanism involved in limiting disease development. To better understand mitochondrial activity, we also considered alterations in circadian rhythms, the gut microbiome, and estrogen receptors: indeed, these mechanisms are also involved in the development of endometriosis. In addition, we focused on recent research about the impact of numerous substances on mitochondrial activity; some of them may offer a future breakthrough in endometriosis treatment by acting on mitochondria and inhibiting cell proliferation.
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Affiliation(s)
- Ylenia Marino
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy.
| | - Francesca Inferrera
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy.
| | - Tiziana Genovese
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy.
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy; Link Campus University, Via del Casale di San Pio V, 44, Italy.
| | - Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy.
| | - Rosanna Di Paola
- Department of Veterinary Sciences, 98168, University of Messina, Messina, Italy.
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Chadha S. A transcriptomic analysis of the interplay of ferroptosis and immune filtration in endometriosis and identification of novel therapeutic targets. Comput Biol Chem 2025; 115:108343. [PMID: 39798208 DOI: 10.1016/j.compbiolchem.2025.108343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 12/31/2024] [Accepted: 01/03/2025] [Indexed: 01/15/2025]
Abstract
Endometriosis is an inflammatory disease, involving immune cell infiltration and production of inflammatory mediators. Ferroptosis has recently been recognized as a mode of controlled cell death and the iron overload and peroxidative environment prevailing in the ectopic endometrium facilitates the occurrence of ferroptosis. In the current investigation, gene expression data was obtained from the dataset GSE7305.The variation in infiltration of immune cells amongst the samples with endometriosis and normal tissue was analysed using the CIBERSORTx tool which revealed higher infiltration of T cells gamma delta, macrophages M2, B cells naïve, T cells CD4 memory resting cells, plasma cells, T cells CD8 and mast cells activated in the tissue samples with endometriosis. An overlap of the differentially expressed genes (DEGs) and ferroptosis related genes revealed 32 ferroptosis related DEGs (FR-DEGs). GO and KEGG pathway analysis showed the FR-DEGs to be enriched in ferroptosis. The PPI network of the FR-DEGs was constructed and TP53, HMOX1, CAV1, CDKN1A, CD44, EPAS1, SLC2A1, MAP3K5, GCLC and FANCD2 were identified as the hub genes. Pearson correlation revealed significant correlation between the hub genes and infiltrating immune cells in endometriosis, thereby suggesting existence of a regulatory crosstalk between immune responses and ferroptosis in endometriosis. Hub gene- miRNA network analysis revealed that 7 of the 10 hub genes were targets of 3 miRNAs -hsa-miR-20a-5p, hsa-miR-16-5p and hsa-miR-17-5p, thereby providing further insight into the regulatory mechanisms underlying disease progression. Predictive analysis and cross validation studies revealed TP53 and CDKN1A as common targets of hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-20a-5p, thereby revealing their regulatory roles in ferroptosis and immune modulatory pathways relevant to endometriosis. The present study indicates an important role of both immune dysregulation and ferroptosis in the pathogenesis of endometriosis and identifies ferroptosis related hub genes and their miRNA regulators as favourable novel targets for further studies and therapeutic interventions.
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Affiliation(s)
- Sonia Chadha
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, Uttar Pradesh, India.
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Yang Y, Du Y, Ma X, Yuan G, Li G, Zhang Q, Zhou S. Transcription factor addictions: exploring the potential Achilles' Heel of endometriosis. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2832-8. [PMID: 40163264 DOI: 10.1007/s11427-024-2832-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/15/2024] [Indexed: 04/02/2025]
Abstract
A considerable number of women of reproductive age suffer from endometriosis worldwide. There is a significant physical, mental, and financial burden on patients affected by this condition in terms of pelvic pain, either continuously or intermittently, dysmenorrhea, infertility, and a higher risk of certain types of cancer. Several treatments available in clinical settings for endometriosis management do not provide adequate efficacy and have undesirable side effects. Transcription factors (TFs) are crucial regulators of key biological processes involved in endometriosis. Here, we elaborated on the research progress regarding the crucial roles of TFs in endometriosis, emphasizing their implications for clinical outcomes and critical therapeutic contributions. By delving into their involvement in key processes, such as cell proliferation and apoptosis, we revealed the multifaceted role of key TFs in disease progression. We aimed to provide a systemic understanding of TFs regulation in endometriosis pathogenesis, establishing a foundation for innovative treatment approaches.
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Affiliation(s)
- Yang Yang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Yi Du
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Gang Yuan
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Guobo Li
- Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Qian Zhang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China.
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China.
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Blanco LP, Salmeri N, Temkin SM, Shanmugam VK, Stratton P. Endometriosis and autoimmunity. Autoimmun Rev 2025; 24:103752. [PMID: 39828017 DOI: 10.1016/j.autrev.2025.103752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Endometriosis is a female-specific chronic condition that affects 1 in 10 women and other individuals with a uterus worldwide with common symptoms that include pelvic pain and infertility. Reliable and effective non-invasive biomarkers for endometriosis do not exist, and therefore currently a diagnosis of endometriosis requires direct visualization of lesions at surgery. Similarly, few safe and effective management strategies exist for endometriosis, with hormonal interventions and surgery only providing temporary symptom control. The development of endometriosis involves the implantation and proliferation of ectopic endometrial cells which triggers local and systemic inflammation and fibrosis. While multiple genetic, environmental, and lifestyle factors appear to influence the natural history of endometriosis, chronic inflammation is a hallmark feature associated with development and progression of the disease. Data further shows that endometriosis commonly co-occurs with autoimmune diseases, adding evidence that immune dysfunction likely contributes to the pathogenesis of this disorder. Specific innate and adaptive immune system drivers of endometriosis remain to be identified and additional research is needed to elucidate the mechanistic underpinnings of this debilitating disease. In this narrative review, we discuss the shared biological mechanisms and plausible immune-related connections between endometriosis and autoimmunity.
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Affiliation(s)
- Luz P Blanco
- National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Noemi Salmeri
- Office of Research on Women's Health, Office of the Director, National Institutes of Health, Bethesda, MD, United States of America
| | - Sarah M Temkin
- Office of Research on Women's Health, Office of the Director, National Institutes of Health, Bethesda, MD, United States of America
| | - Victoria K Shanmugam
- Office of Autoimmune Disease Research, Office of Research on Women's Health, Office of the Director, National Institutes of Health, Bethesda, MD, United States of America
| | - Pamela Stratton
- Office of Research on Women's Health, Office of the Director, National Institutes of Health, Bethesda, MD, United States of America; Scientific Consulting Group, Gaithersburg, MD, United States of America.
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Gupta S, Tripathi R, Kawale AK, Sarkar S, Singh A, Verma RK, Sankhwar PL, Sharma V, Jha RK. PARP-2 acts on ILK signaling and pharmacological targeting of PARP-2 ameliorate endometriosis in a mouse model. Biochem Biophys Res Commun 2025; 754:151509. [PMID: 40036901 DOI: 10.1016/j.bbrc.2025.151509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/21/2025] [Accepted: 02/17/2025] [Indexed: 03/06/2025]
Abstract
Endometriosis, an endocrine disorder in reproductive-aged women with an occurrence of ∼10 %, gives rise to inflammation, pelvic pain, menstrual irregularity, infertility, etc. One study demonstrated the elevated plasma level of PARP during endometriosis. Thus, we studied the role of PARP-2 during endometriosis using human endometriotic tissue and cells along with an endometriosis mouse model. We found an increased expression level of PARP-2 in the endometriotic tissue from human endometriosis patients, likewise in the endometriotic cells, 12Z and mouse model. The expression level of PARP-2 was suppressed by progesterone (P4) in the immortalized human endometriotic cells (IHECs). However, the danazol (100 mg/kg body weight) treatment reduced the lesion size, but not the expression level of PARP-2 in the endometriotic lesion from the mouse model. PARP-2 inhibition by UPF-1069 (5 mg/kg b. wt.) treatment in the mouse model of endometriosis reduced the endometriotic lesion area. During ovulation and letrozole (1 mg/kg b.wt.) treatment in the endometriosis SD rat model, the expression level of PARP-2 was high. The cell aggregation, a spheroid formation assay using IHECs was reduced by PARP-2 inhibition. The inflammatory chemokines, CCL-11 and -22, GSK-3beta and ILK were downregulated in IHECs by PARP-2 inhibitor (10 μM). Transient overexpression of ILK in endometriotic cells showed reduced levels of PARP-2 and GSK-3beta. In conclusion, PARP-2 is upregulated in the endometriotic tissue in response to estradiol (E2) and inhibition of it pharmacologically reduced the IHECs congregation and the endometriotic lesion, possibly affecting the inflammatory response via ILK-GSK-3beta, in the mouse model and human endometriotic cells.
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Affiliation(s)
- Satish Gupta
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rupal Tripathi
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ajay K Kawale
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India
| | - Sudarsan Sarkar
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Akanksha Singh
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Raj Kumar Verma
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Pushp Lata Sankhwar
- Department of Gynecology and Obstetrics, King George's Medical University, Shah Mina Road, Chowk, Lucknow, Uttar Pradesh, 226003, India
| | - Vanisha Sharma
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India
| | - Rajesh Kumar Jha
- Endocrinology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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Lu Y, Li Y, Li Y, Lin Y, Wang X, Zhu Y, Wang B, Du M. SCM-198 Inhibits EMS Development by Reversing Decreased Proportions of IFN-γ +T Cells and CCR5 +T Cells. Reprod Sci 2025:10.1007/s43032-025-01823-9. [PMID: 40113654 DOI: 10.1007/s43032-025-01823-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 02/13/2025] [Indexed: 03/22/2025]
Abstract
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.
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Affiliation(s)
- Yewei Lu
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, SAR, China
- Department of Obstetrics and Gynecology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- Laboratory of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital and Institute, Fudan University Shanghai Medical College, Shanghai, China
- Department of Obstetrics, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng, Jiangsu, 224001, PR China
| | - Yunyun Li
- Department of Reproductive Medical Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - Yue Li
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, SAR, China
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City, Longgang Maternity Child Institute of Shantou University Medical College, Shenzhen, 518172, China
| | - Yikong Lin
- Laboratory of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital and Institute, Fudan University Shanghai Medical College, Shanghai, China
| | - Xiaolin Wang
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, SAR, China.
| | - Yizhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, SAR, China.
| | - Beihua Wang
- Department of Obstetrics and Gynecology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Meirong Du
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, SAR, China.
- Department of Obstetrics and Gynecology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
- Laboratory of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital and Institute, Fudan University Shanghai Medical College, Shanghai, China.
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Mei J, Jiang XY, Zhang B, Wang L, Zhang AX, Li JJ, Chen SX, Xu X, Hu J, Zhou SG. Unveiling Potential Blood Markers for Endometriosis Through the Integration and Experimental Validation of Immune Cell Traits Genome and Genome-Wide Associated Data. Int J Womens Health 2025; 17:845-853. [PMID: 40123754 PMCID: PMC11930248 DOI: 10.2147/ijwh.s509722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/06/2025] [Indexed: 03/25/2025] Open
Abstract
Background While endometriosis (EM) has been previously associated with multiple immune factors, the causal relationship underlying these associations remains unclear. Objective In this study, Two-sample Mendelian randomization (MR) method was employed to investigate the causal relationship between 731 immune cell traits and EM based on tabulated data from genome-wide association studies (GWAS). Methods MR method includes inverse variance weighting (IVW), the weighted median (WM), MR-Egger, the weighted model, and the simple model. IVW is used as the primary method for judging causal effects. Peripheral blood was obtained from EM patients, and the positive immune cell phenotype was confirmed using flow cytometry. Results After P-value correction, our two-sample MR showed that CD28 on CD28+ DN (CD4-CD8-) had a suggestive causal relationship with EM (β =0.040, 95% CI =1.02-1.06, P =0.00029, PFDR = 0.1984). The results of the other two main methods were similar: Weighted median (OR =1.031, 95% CI =1.00-1.07, P =0.082); MR-Egger (OR =1.032, 95% CI =1.10-1.06, P =0.044). The flow cytometry results indicated that the expression level of CD28 on CD28+ DN (CD4-CD-8) was significantly increased in the ectopic intima of EM patients. Conclusion Our study demonstrated a causal relationship between immune traits and EM, and the results were verified by clinical samples. The study may provide new biomarkers for the early diagnosis and immunotherapy of EM.
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Affiliation(s)
- Jie Mei
- Department of Gynecology, The Fifth Affiliated Clinical College of Anhui Medical University, Maternal and Child Health Center of Anhui Medical University, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Anhui Women and Children’s Medical Center, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Linquan Maternity and Child Healthcare Hospital, Fuyang, Anhui, 236400, People’s Republic of China
| | - Xi-Ya Jiang
- Department of Gynecology, The Fifth Affiliated Clinical College of Anhui Medical University, Maternal and Child Health Center of Anhui Medical University, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Anhui Women and Children’s Medical Center, Hefei, Anhui, 230001, People’s Republic of China
| | - Bin Zhang
- Department of Scientific Research, Hefei Maternity and Child Healthcare Hospital, Hefei, Anhui, 230001, People’s Republic of China
| | - Li Wang
- Department of Clinical Laboratory, Linquan Maternity and Child Healthcare Hospital, Fuyang, Anhui, 236400, People’s Republic of China
| | - Ai-Xi Zhang
- Department of Public Health, Linquan Maternity and Child Healthcare Hospital, Fuyang, Anhui, 236400, People’s Republic of China
| | - Jie-Jie Li
- Department of Gynecology, The Fifth Affiliated Clinical College of Anhui Medical University, Maternal and Child Health Center of Anhui Medical University, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Anhui Women and Children’s Medical Center, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Linquan Maternity and Child Healthcare Hospital, Fuyang, Anhui, 236400, People’s Republic of China
| | - Shun-Xia Chen
- Department of Gynecology, The Fifth Affiliated Clinical College of Anhui Medical University, Maternal and Child Health Center of Anhui Medical University, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Anhui Women and Children’s Medical Center, Hefei, Anhui, 230001, People’s Republic of China
| | - Xiao Xu
- Department of Gynecology, The Fifth Affiliated Clinical College of Anhui Medical University, Maternal and Child Health Center of Anhui Medical University, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Anhui Women and Children’s Medical Center, Hefei, Anhui, 230001, People’s Republic of China
| | - Jing‑Jing Hu
- Department of reproduction, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China
| | - Shu-Guang Zhou
- Department of Gynecology, The Fifth Affiliated Clinical College of Anhui Medical University, Maternal and Child Health Center of Anhui Medical University, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Anhui Women and Children’s Medical Center, Hefei, Anhui, 230001, People’s Republic of China
- Department of Gynecology, Linquan Maternity and Child Healthcare Hospital, Fuyang, Anhui, 236400, People’s Republic of China
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Arsalan HM, Mumtaz H, Lagana AS. Biomarkers of endometriosis. Adv Clin Chem 2025; 126:73-120. [PMID: 40185537 DOI: 10.1016/bs.acc.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2025]
Abstract
Endometriosis represents a diverse disease characterized by three distinct phenotypes: superficial peritoneal lesions, ovarian endometriomas, and deep infiltrating endometriosis. The most widely accepted pathophysiological hypothesis for endometriosis is rooted in retrograde menstruation, a phenomenon observed in most patients. Endometriosis is closely linked to infertility, but having endometriosis does not necessarily imply infertility. The disease can impact fertility through various mechanisms affecting the pelvic cavity, ovaries, and the uterus itself. MicroRNAs (miRNAs) indeed represent a fascinating and essential component of the regulatory machinery within cells. Discovered in the early 1990s, miRNAs have since been identified as critical players in gene expression control. Unfortunately, ovarian endometrioma is a common gynecologic disorder for which specific serum markers are currently lacking. Some have examined urocortin for its ability to differentiate endometriomas from other benign ovarian cysts. Another potential marker, Cancer Antigen 125 (CA-125) is a well-established indicator for epithelial cell ovarian cancer and its levels can be elevated in conditions such as endometriosis. CA-125 is derived from coelomic epithelia, including the endometrium, fallopian tube, ovary, and peritoneum. In this review we examine the pathophysiologic basis for endometriosis and highlight potential markers to more fully characterize the underlying biochemical processes linked to this multifaceted disease state.
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Affiliation(s)
- Hafiz Muhammad Arsalan
- Faculty of General Medicine, Altamimi International Medical University, Bishkek, Kyrgyzstan.
| | - Hina Mumtaz
- Department of Biochemistry, University of Central Punjab, Lahore, Pakistan.
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Chen CH, Lin YH, Lee CY, Shen H, Hsu YT, Wu PC. Long-term clinical outcomes of dienogest for perimenopausal women with symptomatic adenomyosis. Sci Rep 2025; 15:8174. [PMID: 40059225 PMCID: PMC11891300 DOI: 10.1038/s41598-025-93156-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 03/05/2025] [Indexed: 05/13/2025] Open
Abstract
We aimed to evaluate the successful long-term use of dienogest for the management of pelvic pain and bleeding control in perimenopausal women with symptomatic adenomyosis using real-world data. All women aged ≥ 40 years with adenomyosis who complained of dysmenorrhea and/or menorrhagia and received dienogest between September 2018 and December 2021 were retrospectively recruited. The primary outcome was successful long-term use of dienogest for pelvic pain and/or bleeding control. A total of 87 women were analyzed. Overall, forty-nine (56%) patients had excellent pain control, but 17 (20%) eventually underwent hysterectomy, while 21 (24%) received dienogest for over 24 months (mean 33.5 ± 8.5 months). According to subgroup analysis by age (≥ 45 vs. <45), older women easily discontinued dienogest due to side effects (51% vs. 30%, p = 0.047) but less frequently changed to surgery (11% vs. 30%, p = 0.012) than younger women. Older age, higher CA-125 value, and larger uterine size before treatment were linked to poorer long-term responses to dienogest. As risk factor, uterine volume > 352.7 cm3 reflects easier treatment failure (sensitivity = 65.4%, specificity = 66.7%, area = 0.68, p = 0.032). In perimenopausal women with symptomatic adenomyosis, nearly half of the treated patients benefitted from dienogest. Our informative findings can assist clinicians in pre-treatment counseling and identifying factors correlated with treatment effectiveness.
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Affiliation(s)
- Chi-Hau Chen
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, No. 8, Zhongshan S. Rd., Zhongzheng Dist, 100225, Taipei City, Taiwan (R.O.C.)
| | - Yi-Heng Lin
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, No. 8, Zhongshan S. Rd., Zhongzheng Dist, 100225, Taipei City, Taiwan (R.O.C.)
| | - Chia-Yi Lee
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Hsin-Chu Branch, No. 25, Ln. 442, Sec. 1, Jingguo Rd., North Dist, 300195, Hsinchu City, Taiwan (R.O.C.)
| | - Hung Shen
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Hsin-Chu Branch, No. 25, Ln. 442, Sec. 1, Jingguo Rd., North Dist, 300195, Hsinchu City, Taiwan (R.O.C.)
| | - Ya-Ting Hsu
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, No. 8, Zhongshan S. Rd., Zhongzheng Dist, 100225, Taipei City, Taiwan (R.O.C.)
| | - Pei-Chi Wu
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, No. 8, Zhongshan S. Rd., Zhongzheng Dist, 100225, Taipei City, Taiwan (R.O.C.).
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Hsin-Chu Branch, No. 25, Ln. 442, Sec. 1, Jingguo Rd., North Dist, 300195, Hsinchu City, Taiwan (R.O.C.).
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Zhang R, Lv H, Liu J, Yin J, Wu S, Xie Y, Xing H, Wang R, Zhao Z, Shi B, Yang X, Gao S. The impact of MTHFR and VDR polymorphisms on endometriosis susceptibility: Insights from a systematic review and meta-analysis. J Reprod Immunol 2025; 168:104449. [PMID: 39946760 DOI: 10.1016/j.jri.2025.104449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/29/2025] [Accepted: 02/03/2025] [Indexed: 03/10/2025]
Abstract
The VDR and MTHFR polymorphisms have been linked to many gynecological and obstetrical diseases. However, there is still a pressing need for a systematic review and meta-analysis to synthesize the current evidence on the association between these variants and endometriosis risk. English and Chinese literature databases were systematically retrieved to find relevant research published up to August 1, 2024. The meta-analytic calculations were implemented in the R language 4.4.1 environment. The odds ratios (ORs) with the corresponding 95 % confidence intervals (95 % CIs) were estimated to assess the magnitude of the effect. In total, 26 datasets comprising 9300 subjects were included. The pooled estimate demonstrated a significant association between the MTHFR C677T polymorphism and endometriosis susceptibility in the allele model (OR: 1.41, 95 % CI: 1.07-1.86, P = 0.01), homozygote model (OR: 2.09, 95 % CI: 1.56-2.79, P < 0.01), dominant model (OR: 1.48, 95 % CI: 1.06-2.07, P = 0.02), and recessive model (OR: 1.81, 95 % CI: 1.38-2.37, P < 0.01). However, the meta-analysis for the MTHFR A1298C polymorphism and the VDR FokI, TaqI, ApaI, and BsmI polymorphic variants did not find statistical significance. In conclusion, this meta-analysis suggests that the MTHFR C677T polymorphism might play a role in developing endometriosis disease. Meanwhile, further large-scale validations that consider multiple factors are warranted to confirm this finding.
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Affiliation(s)
- Ruting Zhang
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Hanxin Lv
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China; Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Jinghua Liu
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Jiashan Yin
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Shuang Wu
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Yuyang Xie
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Huihui Xing
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Rui Wang
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China; School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Zefan Zhao
- Suzhou International Academy of Beijing Foreign Studies University, Suzhou, Jiangsu Province, China
| | - Bimin Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215123, China.
| | - Xiaoqin Yang
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China.
| | - Shangshang Gao
- MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province 215123, China.
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de Souza Gaio G, Kemczenski F, Fernandes Oliveira Amador W, Farias CF, Chagas J. Clinical effectiveness of progestogens compared to combined oral contraceptive pills in the treatment of endometriosis: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2025; 306:219-225. [PMID: 39862640 DOI: 10.1016/j.ejogrb.2025.01.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/14/2025] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
OBJECTIVE Endometriosis involves the growth of endometrium-like cells outside the uterus, affecting reproductive-aged women. Symptoms such as dysmenorrhea, pelvic pain, and infertility significantly impair quality of life. Among therapeutic options, progestogens have demonstrated efficacy in managing pain and reducing recurrence rates. This study aimed to compare the clinical effectiveness of progestogens versus combined oral contraceptive pills in alleviating pelvic pain, dyspareunia, dysmenorrhea, and associated side effects. STUDY DESIGN A systematic review and meta-analysis were conducted by searching PubMed, Embase, and the Cochrane Central Register of Controlled Trials, with the last search conducted in October 2024. The review was registered under PROSPERO registration number CRD42024609658. Studies were included regardless of language, publication year, or country. Articles not comparing progestogens and combined oral contraceptives or lacking relevant outcomes were excluded, as were abstracts, theses, case reports, opinion pieces, and correspondence. Risk of bias was assessed using the modified Cochrane Risk of Bias tool 2.0 for randomized studies. RESULTS Seven studies, including 948 patients (476 receiving progestogens), met inclusion criteria. The meta-analysis found no significant differences between progestogens and COCPs for pelvic pain (SMD = 0.02; 95 % CI: -0.37 to 0.40; P = 0.04; I2 = 66.7 %), dysmenorrhea (SMD = 0.00; 95 % CI: -0.19 to 0.19), dyspareunia (SMD = 0.21; 95 % CI: -0.42 to 0.85; P = 0.02; I2 = 81.4 %), or psychological health (SMD = 0.01; 95 % CI: -0.21 to 0.23; P = 0.19; I2 = 39.1 %). Similarly, no significant differences were observed in side effects, including breast tenderness, weight gain, amenorrhea, and bleeding. CONCLUSION Progestogens and COCPs demonstrate comparable efficacy in managing pelvic pain, dysmenorrhea, dyspareunia, and psychological health, with similar side effect profiles. These findings suggest both treatments are equally effective options for symptom management in endometriosis.
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Affiliation(s)
- Giovana de Souza Gaio
- University of Joinville's Region, Department of Medicine Joinville Santa Catarina Brazil.
| | - Frederico Kemczenski
- University of Joinville's Region, Department of Medicine Joinville Santa Catarina Brazil
| | | | | | - Júnea Chagas
- Faculty of Medical Sciences of Minas Gerais Belo Horizonte Brazil
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