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Ducreux B, Patrat C, Firmin J, Ferreux L, Chapron C, Marcellin L, Parpex G, Bourdon M, Vaiman D, Santulli P, Fauque P. Systematic review on the DNA methylation role in endometriosis: current evidence and perspectives. Clin Epigenetics 2025; 17:32. [PMID: 39985111 PMCID: PMC11846336 DOI: 10.1186/s13148-025-01828-w] [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: 10/28/2024] [Accepted: 01/30/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Endometriosis appears to have a multilayered etiology, with genetic and epigenetic factors each contributing half of the pathogenesis. The molecular processes that underlie the onset of endometriosis are yet unclear, but it is assumed that an important contributor in the etiopathology of the disease is DNA methylation. METHODS We conducted a systematic review of the literature regarding DNA methylation in endometriosis following PRISMA guidelines. Records were obtained from PubMed and Web of Science on May 31, 2024. Original research articles analyzing regional or genome-wide DNA methylation in patients with confirmed endometriosis (by surgery and/or histological examination) were given consideration for inclusion. Only human studies were included, and there were no restrictions on the types of tissue that was analyzed (i.e., endometrium, blood, or fetal tissue). The study selection process was run by two manual reviewers. In parallel, an adapted virtual artificial intelligence-powered reviewer operated study selection and results were compared with the manual reviewers' selection. Studies were divided into targeted (e.g., single gene or region level) and epigenome-wide association studies. For each, we extracted a list of genes studied with precise location of CpGs analyzed and the DNA methylation status according to the groups compared. Quality assessment of studies was performed following the Newcastle-Ottawa scale. Quality of evidence was graded following the Grading of Recommendations Assessment, Development and Evaluation. RESULTS A total of 955 studies were screened, and 70 were identified as relevant for systematic review. Our analyses displayed that endometriosis could be polyepigenetic and with alterations in specific genes implicated in major signaling pathways contributing to the disease etiopathology (cell proliferation, differentiation, and division [PI3K-Akt and Wnt-signaling pathway], cell division [MAPK pathway], cell adhesion, cell communication, developmental processes, response to hormone, apoptosis, immunity, neurogenesis, and cancer). CONCLUSION Our systematic review indicates that endometriosis is associated with DNA methylation modifications at specific genes involved in key endometrial biological processes, particularly in the ectopic endometrium. As DNA methylation appears to be an integral component of the pathogenesis of endometriosis, the identification of DNA methylation biomarkers would likely help better understand its causes and aggravating factors as well as potentially facilitate its diagnosis and support the development of new therapeutic approaches.
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Affiliation(s)
- Bastien Ducreux
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Centre Hospitalier Universitaire (CHU), Faculty of Medicine, INSERM 1231, Université de Bourgogne-Europe, Dijon, France
| | - Catherine Patrat
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Julie Firmin
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Lucile Ferreux
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Charles Chapron
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Louis Marcellin
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Guillaume Parpex
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Mathilde Bourdon
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Daniel Vaiman
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
| | - Pietro Santulli
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Patricia Fauque
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France.
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France.
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Zanon P, Terraciano PB, Quandt L, Palma Kuhl C, Pandolfi Passos E, Berger M. Angiotensin II - AT1 receptor signalling regulates the plasminogen-plasmin system in human stromal endometrial cells increasing extracellular matrix degradation, cell migration and inducing a proinflammatory profile. Biochem Pharmacol 2024; 225:116280. [PMID: 38735446 DOI: 10.1016/j.bcp.2024.116280] [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: 02/13/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/14/2024]
Abstract
The pivotal role of human endometrial stromal cells (hESCs) in the development of endometriosis lies in their ability to adopt a pro-invasive and proinflammatory profile upon migration to areas outside the uterus. However, the molecular mechanisms involved in these events remain unclear. In this study, we investigated how angiotensin II (Ang II) affects the plasminogen-plasmin system in hESCs, and the mechanisms underlying cell proliferation, migration, matrix degradation, and inflammation. Precursors, receptors, and peptidases involved in angiotensin metabolism increased significantly in Ang II-treated hESCs. The expression and activity of tissue (tPA)- and urokinase (uPA)- type plasminogen activators and the receptor for uPA (uPAR) were induced in the presence of Ang II. The up-regulation of tPA-uPA/uPAR pathway significantly contributes to heightened plasmin production both on the surface of hESCs and in their conditioned media. As a result, the plasmin generation induced by Ang II enhances the degradation of fibrin and matrix proteins, while also boosting hESC viability, proliferation, and migration through the up-regulation of growth factor expression. Notably, Ang II-induced hESC migration was dependent on the generation of active plasmin on cell surface. Ang II regulates oxidative and inflammatory signalling in hESCs primarily via NADPH oxidase and through the up-regulation of proinflammatory cytokines and adhesion molecules. Interestingly, Ang II receptor (AT1R) blockage, decreased plasmin generation, tPA-uPA/uPAR expression and hESC migration. Our results suggest that Ang II/AT1R axis regulates hESC proliferation and migration through tPA-uPA/uPAR pathway activation and plasmin generation. We propose the Ang II/AT1R axis as a potential target for endometriosis treatment.
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Affiliation(s)
- Pamela Zanon
- Grupo de Reprodução e Farmacologia Celular, Laboratório de Bioquímica Farmacológica, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Paula Barros Terraciano
- Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Grupo de Reprodução e Farmacologia Celular, Laboratório de Embriologia e Diferenciação Celular, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil
| | - Letícia Quandt
- Grupo de Reprodução e Farmacologia Celular, Laboratório de Bioquímica Farmacológica, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Cristiana Palma Kuhl
- Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Grupo de Reprodução e Farmacologia Celular, Laboratório de Embriologia e Diferenciação Celular, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil
| | - Eduardo Pandolfi Passos
- Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Grupo de Reprodução e Farmacologia Celular, Laboratório de Embriologia e Diferenciação Celular, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil; Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Centro de Fertilidade, Hospital Moinhos de Vento, Porto Alegre, RS, Brazil
| | - Markus Berger
- Grupo de Reprodução e Farmacologia Celular, Laboratório de Bioquímica Farmacológica, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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Omidvar-Mehrabadi A, Ebrahimi F, Shahbazi M, Mohammadnia-Afrouzi M. Cytokine and chemokine profiles in women with endometriosis, polycystic ovary syndrome, and unexplained infertility. Cytokine 2024; 178:156588. [PMID: 38555853 DOI: 10.1016/j.cyto.2024.156588] [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: 01/10/2024] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 04/02/2024]
Abstract
Numerous factors (including immunological, congenital, hormonal, and morphological disorders) can lead to infertility. In this regard, 3 specific diseases associated with infertility are discussed in this review study (i.e., polycystic ovary syndrome [PCOS], endometriosis [EMS], and unexplained infertility [UI]). PCOS is a common endocrine disorder characterized by chronic low-grade inflammation, and EMS is a benign disease characterized by the presence of ectopic endometrial tissue. UI refers to couples who are unable to conceive for no known reason. Conception and pregnancy are significantly affected by the immune system; in this regard, chemokines and cytokines play important roles in the regulation of immune responses. Patients with PCOS, EMS, and UI have altered cytokine and chemokine profiles, suggesting that dysregulation of these molecules may contribute to infertility in these conditions. Accordingly, the issue of infertility is addressed in this review study, a condition that affects approximately 16% of couples worldwide.
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Affiliation(s)
| | - Fateme Ebrahimi
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Shahbazi
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Laudański P, Rogalska G, Warzecha D, Lipa M, Mańka G, Kiecka M, Spaczyński R, Piekarski P, Banaszewska B, Jakimiuk A, Issat T, Rokita W, Młodawski J, Szubert M, Sieroszewski P, Raba G, Szczupak K, Kluz T, Kluza M, Neuman T, Adler P, Peterson H, Salumets A, Wielgos M. Autoantibody screening of plasma and peritoneal fluid of patients with endometriosis. Hum Reprod 2023; 38:629-643. [PMID: 36749097 DOI: 10.1093/humrep/dead011] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 11/26/2022] [Indexed: 02/08/2023] Open
Abstract
STUDY QUESTION Are there specific autoantibody profiles in patients with endometriosis that are different from those in controls? SUMMARY ANSWER This study did not reveal a significantly higher prevalence of autoantibodies in the studied groups of patients. WHAT IS KNOWN ALREADY Various inflammatory factors are postulated to be involved in the pathomechanisms of endometriosis, and a potential link exists with autoimmune diseases, which may also play an important role. As the diagnosis of endometriosis remains invasive, it can only be confirmed using laparoscopy with histopathological examination of tissues. Numerous studies have focused on identifying useful biomarkers to confirm the disease, but without unequivocal effects. Autoantibodies are promising molecules that serve as potential prognostic factors. STUDY DESIGN, SIZE, DURATION A multicentre, cross-sectional study was conducted over 18 months (between 2018 and 2019), at eight Departments of Obstetrics and Gynaecology in several cities across Poland on 137 patients undergoing laparoscopic examination for the diagnosis of endometriosis. PARTICIPANTS/MATERIALS, SETTINGS, METHODS During laparoscopy, we obtained plasma samples from 137 patients and peritoneal fluid (PF) samples from 98 patients. Patients with autoimmune diseases were excluded from the study. Autoantibody profiling was performed using HuProt v3.1 human proteome microarrays. MAIN RESULTS AND THE ROLE OF CHANCE We observed no significant differences in the expression of autoantibodies in the plasma or PF between the endometriosis and control groups. The study revealed that in the PF of women with Stage II endometriosis, compared with other stages, there were significantly higher reactivity signals for ANAPC15 and GABPB1 (adj. P < 0.016 and adj. P < 0.026, respectively; logFC > 1 in both cases). Comparison of the luteal and follicular phases in endometriosis patients revealed that levels of NEIL1 (adj. P < 0.029), MAGEB4 (adj. P < 0.029), and TNIP2 (adj. P < 0.042) autoantibody signals were significantly higher in the luteal phase than in the follicular phase in PF samples of patients with endometriosis. No differences were observed between the two phases of the cycle in plasma or between women with endometriosis and controls. Clustering of PF and plasma samples did not reveal unique autoantibody profiles for endometriosis; however, comparison of PF and plasma in the same patient showed a high degree of concordance. LIMITATIONS, REASONS FOR CAUTION Although this study was performed using the highest-throughput protein array available, it does not cover the entire human proteome and cannot be used to study potentially promising post-translational modifications. Autoantibody levels depend on numerous factors, such as infections; therefore the autoantibody tests should be repeated for more objective results. WIDER IMPLICATIONS OF THE FINDINGS Although endometriosis has been linked to different autoimmune diseases, it is unlikely that autoimmune responses mediated by specific autoantibodies play a pivotal role in the pathogenesis of this inflammatory disease. Our study shows that in searching for biomarkers of endometriosis, it may be more efficient to use higher-throughput proteomic microarrays, which may allow the detection of potentially new biomarkers. Only research on such a scale, and possibly with different technologies, can help discover biomarkers that will change the method of endometriosis diagnosis. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by a grant from the Polish Ministry of Health (grant no. 6/6/4/1/NPZ/2017/1210/1352). It was also funded by the Estonian Research Council (grant PRG1076) and the Horizon 2020 Innovation Grant (ERIN; grant no. EU952516), Enterprise Estonia (grant no. EU48695), and MSCA-RISE-2020 project TRENDO (grant no. 101008193). The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Piotr Laudański
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.,OVIklinika Infertility Center, Warsaw, Poland.,Women's Health Research Institute, Calisia University, Kalisz, Poland.,Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Gabriela Rogalska
- Clinic of Gynecology, Oncological Gynecology and Obstetrics, Municipal Polyclinical Hospital in Olsztyn, Olsztyn, Poland
| | - Damian Warzecha
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | - Michał Lipa
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | | | | | - Robert Spaczyński
- Center for Gynecology, Obstetrics and Infertility Treatment Pastelova, Poznan, Poland
| | - Piotr Piekarski
- Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Beata Banaszewska
- Chair and Department of Laboratory Diagnostics, Poznan University of Medical Sciences, Poznan, Poland
| | - Artur Jakimiuk
- Department of Obstetrics and Gynecology, Institute of Mother and Child, Warsaw, Poland.,Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland
| | - Tadeusz Issat
- Department of Obstetrics and Gynecology, Institute of Mother and Child, Warsaw, Poland
| | - Wojciech Rokita
- Collegium Medicum Jan Kochanowski University in Kielce, Kielce, Poland.,Clinic of Obstetrics and Gynecology, Provincial Combined Hospital in Kielce, Kielce, Poland
| | - Jakub Młodawski
- Collegium Medicum Jan Kochanowski University in Kielce, Kielce, Poland.,Clinic of Obstetrics and Gynecology, Provincial Combined Hospital in Kielce, Kielce, Poland
| | - Maria Szubert
- Department of Gynecology and Obstetrics Medical, University of Lodz, Lodz, Poland.,Department of Surgical Gynecology and Oncology, Medical University of Lodz, Lodz, Poland
| | - Piotr Sieroszewski
- Department of Gynecology and Obstetrics Medical, University of Lodz, Lodz, Poland.,Department of Fetal Medicine and Gynecology, Medical University of Lodz, Lodz, Poland
| | - Grzegorz Raba
- Clinic of Obstetric and Gynecology in Przemysl, Przemysl, Poland.,University of Rzeszow, Rzeszow, Poland
| | - Kamil Szczupak
- Clinic of Obstetric and Gynecology in Przemysl, Przemysl, Poland.,University of Rzeszow, Rzeszow, Poland
| | - Tomasz Kluz
- Department of Gynecology, Gynecology Oncology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Marek Kluza
- Department of Gynecology, Gynecology Oncology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | | | - Priit Adler
- Institute of Computer Science, University of Tartu, Tartu, Estonia
| | - Hedi Peterson
- Institute of Computer Science, University of Tartu, Tartu, Estonia
| | - Andres Salumets
- Competence Centre on Health Technologies, Tartu, Estonia.,Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.,Division of Obstetrics and Gynaecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Miroslaw Wielgos
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
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Fiorentino G, Cimadomo D, Innocenti F, Soscia D, Vaiarelli A, Ubaldi FM, Gennarelli G, Garagna S, Rienzi L, Zuccotti M. Biomechanical forces and signals operating in the ovary during folliculogenesis and their dysregulation: implications for fertility. Hum Reprod Update 2023; 29:1-23. [PMID: 35856663 DOI: 10.1093/humupd/dmac031] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 05/12/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting from the interplay between mechanical forces and molecular signals. Morphological and functional changes to the growing follicle and to the surrounding tissue are required to produce oocytes capable of supporting preimplantation development to the blastocyst stage. OBJECTIVE AND RATIONALE This review will summarize the ovarian morphological and functional context that contributes to follicle recruitment, growth and ovulation, as well as to the acquisition of oocyte developmental competence. We will describe the changes occurring during folliculogenesis to the ovarian extracellular matrix (ECM) and to the vasculature, their influence on the mechanical properties of the ovarian tissue, and, in turn, their influence on the regulation of signal transduction. Also, we will outline how their dysregulation might be associated with pathologies such as polycystic ovary syndrome (PCOS), endometriosis or premature ovarian insufficiency (POI). Finally, for each of these three pathologies, we will highlight therapeutic strategies attempting to correct the altered biomechanical context in order to restore fertility. SEARCH METHODS For each area discussed, a systematic bibliographical search was performed, without temporal limits, using PubMed Central, Web of Science and Scopus search engines employing the keywords extracellular matrix, mechanobiology, biomechanics, vasculature, angiogenesis or signalling pathway in combination with: ovary, oogenesis, oocyte, folliculogenesis, ovarian follicle, theca, granulosa, cumulus, follicular fluid, corpus luteum, meiosis, oocyte developmental competence, preimplantation, polycystic ovary syndrome, premature ovarian insufficiency or endometriosis. OUTCOMES Through search engines queries, we yielded a total of 37 368 papers that were further selected based on our focus on mammals and, specifically, on rodents, bovine, equine, ovine, primates and human, and also were trimmed around each specific topic of the review. After the elimination of duplicates, this selection process resulted in 628 papers, of which 287 were cited in the manuscript. Among these, 89.2% were published in the past 22 years, while the remaining 8.0%, 2.4% or 0.3% were published during the 1990s, 1980s or before, respectively. During folliculogenesis, changes occur to the ovarian ECM composition and organization that, together with vasculature modelling around the growing follicle, are aimed to sustain its recruitment and growth, and the maturation of the enclosed oocyte. These events define the scenario in which mechanical forces are key to the regulation of cascades of molecular signals. Alterations to this context determine impaired folliculogenesis and decreased oocyte developmental potential, as observed in pathological conditions which are causes of infertility, such as PCOS, endometriosis or POI. WIDER IMPLICATIONS The knowledge of these mechanisms and the rules that govern them lay a sound basis to explain how follicles recruitment and growth are modulated, and stimulate insights to develop, in clinical practice, strategies to improve follicular recruitment and oocyte competence, particularly for pathologies like PCOS, endometriosis and POI.
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Affiliation(s)
- Giulia Fiorentino
- Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.,Center for Health Technologies, University of Pavia, Pavia, Italy
| | | | | | - Daria Soscia
- Clinica Valle Giulia, GeneraLife IVF, Rome, Italy
| | | | | | - Gianluca Gennarelli
- Obstetrics and Gynecology, Physiopathology of Reproduction and IVF Unit, Department of Surgical Sciences, Sant'Anna Hospital, University of Torino, Turin, Italy.,Livet, GeneraLife IVF, Turin, Italy
| | - Silvia Garagna
- Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.,Center for Health Technologies, University of Pavia, Pavia, Italy
| | - Laura Rienzi
- Clinica Valle Giulia, GeneraLife IVF, Rome, Italy.,Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - Maurizio Zuccotti
- Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.,Center for Health Technologies, University of Pavia, Pavia, Italy
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Matsuzaki S, Pouly JL, Canis M. IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis: IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression. Hum Reprod 2023; 38:14-29. [PMID: 36413036 DOI: 10.1093/humrep/deac248] [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: 08/01/2022] [Revised: 10/25/2022] [Indexed: 11/23/2022] Open
Abstract
STUDY QUESTION Is interleukin-10 (IL-10) anti-fibrotic in endometriosis? SUMMARY ANSWER IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis, because IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression. WHAT IS KNOWN ALREADY We previously showed that persistent activation of signal transducer and activator of transcription 3 (STAT3) via IL-6 trans-signaling promotes fibrosis of endometriosis. Studies showed marked anti-fibrotic effects of IL-10 via the STAT3 signaling pathway, which is generally considered to be anti-inflammatory, in various organs. STUDY DESIGN, SIZE, DURATION Endometrial and/or endometriotic samples of 54 patients who had histological evidence of deep endometriosis, and endometrial samples from 30 healthy fertile women were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS The effects of IL-10/STAT3 signaling as well as inhibition of STAT3 activation by knockdown of STAT3 gene on the pro-fibrotic phenotype in endometrial and endometriotic stromal cells in vitro were investigated. Then, the effects of various time points of IL-10 treatment in combination with transforming growth factor (TGF)-β1 and/or IL-6/soluble IL-6 receptor (sIL-6R) on the profibrotic phenotype of endometrial and endometriotic stromal cells were investigated. MAIN RESULTS AND THE ROLE OF CHANCE IL-10 induced pro-fibrotic phenotype (cell proliferation, collagen type I synthesis, α-smooth muscle actin positive stress fibers and collagen gel contraction) of endometriotic stromal cells. Knockdown of STAT3 gene decreased the IL-10 induced pro-fibrotic phenotype of endometriotic stromal cells. In contrast, IL-10 had no significant effects on pro-fibrotic phenotype of endometrial stromal cells of healthy women. Sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R induced persistent activation of STAT3 and significantly increased proliferation of myofibroblasts (cells with α-smooth muscle actin positive stress fibers) and protein expression of collagen type I in endometriotic stromal cells. TGF-β1 and/or IL-6/sIL6RIL-6/sIL6R treatment significantly increased tissue inhibitor of metalloproteinase 1 (TIMP1) protein expression, whereas IL-10 had no significant effects. Knockdown of STAT3 gene significantly decreased the TGF-β1 and/or IL-6/sIL6R induced TIMP1 protein expression. In contrast, pre-treatment with IL-10 before TGF-β1 and/or IL-6/sIL-6R treatment and sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R significantly decreased proliferation of fibroblasts (cells without α-smooth muscle actin positive stress fibers) and collagen type I protein expression in endometrial stromal cells of healthy women. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Given the large number of complex interactions and signaling pathways of pro- and anti-inflammatory mediators that are involved in the pathophysiology of endometriosis, the present study investigated only a very small portion of the whole. Further in vivo studies are required to validate the present findings. WIDER IMPLICATIONS OF THE FINDINGS Inflammatory mediators in the pathophysiology of endometriosis have been extensively investigated as potential therapeutic targets. However, the present study showed that anti-inflammatory signals of IL-10 and IL-6 through persistent STAT3 activation may promote endometriosis fibrosis. Therapeutic strategies, such as suppression of 'inflammation', might dysregulate the cross-regulation of 'pro- and anti-inflammatory mediators', leading to detrimental effects in patients with endometriosis, such as fibrosis. To develop new, but not deleterious, therapeutic strategies, studies are required to investigate whether, how and what 'anti-inflammatory mediators' along with pro-inflammatory mediators are involved in individual patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by KARL STORZ SE & Co. KG (Tuttlingen, Germany). The authors have no conflict of interest to disclose.
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Affiliation(s)
- Sachiko Matsuzaki
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Jean-Luc Pouly
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Michel Canis
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
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7
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The role of plasminogen activator inhibitor-1 in gynecological and obstetrical diseases: an update review. J Reprod Immunol 2022; 150:103490. [DOI: 10.1016/j.jri.2022.103490] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 11/21/2022]
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8
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Morris SA, Korach KS, Burns KA. Unique Sensitivity of Uterine Tissue and the Immune System for Endometriotic Lesion Formation. Front Physiol 2021; 12:805784. [PMID: 34975547 PMCID: PMC8719640 DOI: 10.3389/fphys.2021.805784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 11/23/2021] [Indexed: 12/04/2022] Open
Abstract
Endometriosis is a debilitating disease that affects about 10% of reproductive-aged adolescents and women. The etiology of the disease is unknown; however, a prevailing hypothesis is that endometriosis develops from retrograde menstruation, where endometrial tissue and fluids flow back through the oviducts into the peritoneal cavity. There is no cure for endometriosis, and symptoms are treated palliatively. Despite the advances in knowledge, the complexity of endometriosis etiology is still unknown. Recent work by our group suggests that the initiation of endometriosis is immune-dependent. Using a mouse model of endometriosis, we hypothesized the initiation of endometriosis is immune regulated and uterine endometrium specific. In the absence of a functional immune system non-obese diabetic/severe combined immunodeficiency (NOD/SCID mice), endometriotic lesions did not form. Uterine endometrial tissue forms endometriotic lesions, whereas tissues with differing basal expression levels of estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), similar cellular composition to uterus (i.e. bladder, mammary gland, and lung), and treated with estradiol did not form lesions. As MMP7 is known to play a major role in the organization/reorganization of the endometrium during the menstrual cycle, blocking metalloproteinase (MMP) activity significantly decreased the invasive properties of these cells. Together, these findings suggest that endometriosis is immune and uterine specific and that MMP7 likely plays a role in the ability of uterine tissue and the innate immune system to establish and maintain endometriotic lesions.
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Affiliation(s)
- Stephanie A. Morris
- Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Kenneth S. Korach
- Receptor Biology Group, Reproductive, and Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, NC, United States
| | - Katherine A. Burns
- Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- *Correspondence: Katherine A. Burns
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9
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Yang B, Gu N, Shi S, Zhang C, Chen L, Ouyang J, Lin Y, Sun F, Xu H. Immunoreactivity of Plasminogen Activator Inhibitor 1 and Its Correlation with Dysmenorrhea and Lesional Fibrosis in Adenomyosis. Reprod Sci 2021; 28:2378-2386. [PMID: 33683668 PMCID: PMC8289782 DOI: 10.1007/s43032-021-00513-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 02/21/2021] [Indexed: 12/29/2022]
Abstract
Adenomyosis is associated with dysmenorrhea, infertility, and lesional fibrosis. The pathogenesis of adenomyosis is still unclear. Plasminogen activator inhibitor 1 (PAI-1) plays important roles in pathological activities like tumor metastasis and endometriosis. Our objective was to investigate the expression and localization of PAI-1 in eutopic and ectopic endometrium with adenomyosis and in endometrium without adenomyosis. We also sought to determine the relationship between PAI-1 immunoreactivity and the severity of dysmenorrhea and the extent of lesional fibrosis in adenomyosis. PAI-1 expression was significantly higher in the ectopic endometrium of patients with adenomyosis than in both the eutopic endometrium of patients with adenomyosis and the endometrium of controls. Ectopic PAI-1 expression correlated positively with dysmenorrhea visual analog scale (VAS) scores and the extent of lesional fibrosis in adenomyosis. High PAI-1 expression increased the likelihood of moderate to severe dysmenorrhea in adenomyosis. These results suggest that PAI-1 is involved in the adenomyosis-associated dysmenorrhea and lesional fibrosis, which provide a potential target in treating symptomatic adenomyosis.
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Affiliation(s)
- Bingxin Yang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Nihao Gu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Shu Shi
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
| | - Chen Zhang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Lan Chen
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Jing Ouyang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
| | - Yu Lin
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Feng Sun
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
| | - Hong Xu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
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CLTA-4 Expression is Associated with the Maintenance of Chronic Inflammation in Endometriosis and Infertility. Cells 2021; 10:cells10030487. [PMID: 33668701 PMCID: PMC7996292 DOI: 10.3390/cells10030487] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Altered immune mechanisms are implicated in the pathogenesis of endometriosis. CTLA-4 is a membrane receptor that favors the anergic state of lymphocytes, which may disrupt the immune system response in the endometriotic environment. In this study, we examined the expression of CTLA-4 on T and B cells by flow cytometry and its levels in blood serum and peritoneal fluid by ELISA. Levels of CTLA-4+ T cells were significantly higher in patients with more advanced endometriosis than in those with less advanced disease. Additionally, the negative correlation of CTLA-4+ T lymphocytes and the percentage of NK and NKT-like cells in women with endometriosis and infertility may indicate a different etiopathogenesis of endometriosis accompanying infertility. Our findings shed light on the potential of CTLA-4 in developing new diagnostic and therapeutic approaches in endometriosis management.
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11
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Wilson MR, Reske JJ, Holladay J, Neupane S, Ngo J, Cuthrell N, Wegener M, Rhodes M, Adams M, Sheridan R, Hostetter G, Alotaibi FT, Yong PJ, Anglesio MS, Lessey BA, Leach RE, Teixeira JM, Missmer SA, Fazleabas AT, Chandler RL. ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation. Cell Rep 2020; 33:108366. [PMID: 33176148 PMCID: PMC7682620 DOI: 10.1016/j.celrep.2020.108366] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/16/2020] [Accepted: 10/16/2020] [Indexed: 12/12/2022] Open
Abstract
Endometriosis affects 1 in 10 women and is characterized by the presence of abnormal endometrium at ectopic sites. ARID1A mutations are observed in deeply invasive forms of the disease, often correlating with malignancy. To identify epigenetic dependencies driving invasion, we use an unbiased approach to map chromatin state transitions accompanying ARID1A loss in the endometrium. We show that super-enhancers marked by high H3K27 acetylation are strongly associated with ARID1A binding. ARID1A loss leads to H3K27 hyperacetylation and increased chromatin accessibility and enhancer RNA transcription at super-enhancers, but not typical enhancers, indicating that ARID1A normally prevents super-enhancer hyperactivation. ARID1A co-localizes with P300 at super-enhancers, and genetic or pharmacological inhibition of P300 in ARID1A mutant endometrial epithelia suppresses invasion and induces anoikis through the rescue of super-enhancer hyperacetylation. Among hyperactivated super-enhancers, SERPINE1 (PAI-1) is identified as an essential target gene driving ARID1A mutant endometrial invasion. Broadly, our findings provide rationale for therapeutic strategies targeting super-enhancers in ARID1A mutant endometrium.
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Affiliation(s)
- Mike R Wilson
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Jake J Reske
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Jeanne Holladay
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Subechhya Neupane
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Julie Ngo
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Nina Cuthrell
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Marc Wegener
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Mary Rhodes
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Marie Adams
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Rachael Sheridan
- Flow Cytometry Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Galen Hostetter
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Fahad T Alotaibi
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Physiology, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Paul J Yong
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
| | - Michael S Anglesio
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, BC, Canada
| | - Bruce A Lessey
- Department of Obstetrics and Gynecology, Wake Forest Baptist Health, Winston-Salem, NC 27157, USA
| | - Richard E Leach
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Jose M Teixeira
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Stacey A Missmer
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Asgerally T Fazleabas
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Ronald L Chandler
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
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12
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Ding S, Lin Q, Zhu T, Li T, Zhu L, Wang J, Zhang X. Is there a correlation between inflammatory markers and coagulation parameters in women with advanced ovarian endometriosis? BMC WOMENS HEALTH 2019; 19:169. [PMID: 31888633 PMCID: PMC6937785 DOI: 10.1186/s12905-019-0860-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 11/29/2019] [Indexed: 12/13/2022]
Abstract
Background Endometriosis is defined as a chronic inflammatory disease. Recent studies have shown that increased coagulation parameters including fibrinogen and platelets are associated with endometriosis. The objective of this study was to determine the levels of inflammatory markers and coagulation parameters and their correlations in women with endometriomas compared to those with benign ovarian cysts or normal pelvic anatomy. Methods Between June 2015 and June 2017, a total of 548 women who underwent laparoscopic/laparotomic surgery for ovarian endometriomas (OMA group, n = 226), non-endometriosis benign ovarian cysts (Cyst group, n = 210) and tubal reanastomosis (Control group, n = 112) were recruited in this study. Inflammatory markers including c-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and coagulation parameters including platelet count, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time, and plasma fibrinogen as well as CA-125 were determined. Results Compared with Cyst group and Control group, TT and PT in OMA group were significantly shorter and plasma fibrinogen levels were significantly higher (P < 0.05). Moreover, the levels of plasma fibrinogen were positively correlated with CRP, NLR and PLR (P < 0.05). In addition, the confidence intervals for the area under the curve (AUC) for CA-125 × fibrinogen were significantly higher than those for CA-125 (0.904–0.952 vs. 0.899–0.949) in the diagnosis of endometrioma. Conclusions These results indicate that women with endometriomas demonstrate a hypercoagulable status due to the inflammatory nature of endometriosis. The combined determination for CA-125 and fibrinogen demonstrate a higher area under the curve than the single detection of CA-125 in those with endometriomas compared to these with benign ovarian cysts. Trial registration This study was approved by the Human Ethics Committee of the Women’s Hospital, School of Medicine, Zhejiang University (No.20170174) and all women provided written informed consent.
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Affiliation(s)
- Shaojie Ding
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Qiao Lin
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Tianhong Zhu
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Tiantian Li
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Libo Zhu
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Jianzhang Wang
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Xinmei Zhang
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, People's Republic of China.
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13
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Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M, Tayade C. The Immunopathophysiology of Endometriosis. Trends Mol Med 2018; 24:748-762. [PMID: 30054239 DOI: 10.1016/j.molmed.2018.07.004] [Citation(s) in RCA: 298] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/02/2018] [Accepted: 07/05/2018] [Indexed: 12/14/2022]
Abstract
Endometriosis is a chronic, inflammatory, estrogen-dependent disease characterized by the growth of endometrial tissue outside of the uterine cavity. Although the etiology of endometriosis remains elusive, immunological dysfunction has been proposed as a critical facilitator of ectopic lesion growth following retrograde menstruation of endometrial debris. However, it is not clear whether this immune dysfunction is a cause or consequence of endometriosis. Thus, here we provide in-depth insights into our current understanding of the immunopathophysiology of endometriosis and highlight challenges and opportunities for future research. With the explosion of successful immune-based therapies targeting various chronic inflammatory conditions, it is crucial to determine whether immune dysfunction can be therapeutically targeted in endometriosis.
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Affiliation(s)
- Lindsey K Symons
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Jessica E Miller
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Vanessa R Kay
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Ryan M Marks
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Kiera Liblik
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Madhuri Koti
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada; Department of Obstetrics and Gynecology, Kingston General Hospital, Kingston, Ontario, K7L 2V7, Canada; Division of Cancer Biology and Genetics, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Chandrakant Tayade
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
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Bałkowiec M, Maksym RB, Włodarski PK. The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review). Mol Med Rep 2018; 18:3123-3136. [PMID: 30066912 PMCID: PMC6102659 DOI: 10.3892/mmr.2018.9303] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/19/2018] [Indexed: 11/06/2022] Open
Abstract
Aberrant regulation of matrix metalloproteinases (MMPs) may be the primary cause of endometrial lesion formation in a group of predisposed women. Prospect for the genuine origin of endometriosis is ongoing, since retrograde menstruation leads to presence of endometrial debris in peritoneal cavity of many women, which do not experience endometriosis. Tissue remodeling is regulated precisely by a balance of MMPs and their inhibitors. Interplay between factors enhancing and suppressing matrix turnover is crucial for cyclic preparation of endometrium for embryo implantation, and endometrial shedding and renewal in physiology of primates. Disorders of the regulation of matrix remodeling leads to augmentation of implantation and invasive growth of ectopic endometrial tissue. Moreover, endometriosis-induced changes in the matrix balance leads to adhesion formation, ovulatory dysfunction and fertility impairment. The review summarizes the current knowledge regarding the regulation of extracellular matrix turnover in the physiology of the endometrial cycle and in the development of endometriosis, as well as the pathophysiology of ovulatory dysfunction in endometriotic women. Therapeutic modalities utilizing modulation of tissue remodeling were discussed.
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Affiliation(s)
- Magdalenia Bałkowiec
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Radosław B Maksym
- Center for Preclinical Research, Department of Methodology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Paweł K Włodarski
- Center for Preclinical Research, Department of Methodology, Medical University of Warsaw, 02-097 Warsaw, Poland
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Haikalis ME, Wessels JM, Leyland NA, Agarwal SK, Foster WG. MicroRNA expression pattern differs depending on endometriosis lesion type†. Biol Reprod 2018; 98:623-633. [DOI: 10.1093/biolre/ioy019] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 01/23/2018] [Indexed: 12/11/2022] Open
Affiliation(s)
- Maria E Haikalis
- Department of Obstetrics & Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Jocelyn M Wessels
- Department of Obstetrics & Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Nicholas A Leyland
- Department of Obstetrics & Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Sanjay K Agarwal
- Center for Endometriosis Research and Treatment, University of California, San Diego, La Jolla, California, USA
| | - Warren G Foster
- Department of Obstetrics & Gynecology, McMaster University, Hamilton, Ontario, Canada
- Center for Endometriosis Research and Treatment, University of California, San Diego, La Jolla, California, USA
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Bashti O, Noruzinia M, Garshasbi M, Abtahi M. miR-31 and miR-145 as Potential Non-Invasive Regulatory Biomarkers in Patients with Endometriosis. CELL JOURNAL 2017; 20:84-89. [PMID: 29308623 PMCID: PMC5759684 DOI: 10.22074/cellj.2018.4915] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 02/18/2017] [Indexed: 12/19/2022]
Abstract
Objective Endometriosis is a prevalent gynecologic disease affecting 10% of women in reproductive age. Endometriosis
is diagnosed by laparoscopy that was followed by histologic confirmation. Early diagnosis will lead to a more effective
treatment with much less morbidity. As miR-31 and miR-145 are shown to be directly or indirectly correlated to biological
processes involved in endometriosis, the aim of this study was to examine the association of miR-31 and miR-145
expression in plasma with the presence of endometriosis.
Materials and Methods In this case control study, the plasma samples of 55 patients with endometriosis and 23
women without endometriosis were collected, extracted and analyzed by real time quantitative polymerase chain
reaction (qPCR) for the expression of miR-145 and miR-31.
Results Our findings showed that miR-31 expression levels in stage 3 or 4 and stage 1 or 2 were significantly down-
regulated (less than 0.01-fold, P<0.05), while the expression level of miR-145 was significantly up-regulated in women
with endometriosis in stage 1 or 2.
Conclusion Different cellular biological processes, such as differentiation, proliferation, mitochondrial function,
reactive oxygen species (ROS) production, invasion and decidualization, are deregulated in endometriosis. miR-31
and miR-145 are microRNAs (miRNAs) with potential roles, as shown in pathologies like cancers. We found that miR-
31 was under-expressed in patients with endometriosis, while miR-145 was over-expressed in stage 1 or 2, indicating
that they were relatively down-regulated in the more severe forms. Our findings suggested that these two miRNAs may
be considered as potential biomarkers with probable implications in early diagnosis and even follow-up of patients with
endometriosis.
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Affiliation(s)
- Oranous Bashti
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehrdad Noruzinia
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Masoud Garshasbi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Mackawy AM, Megahed O. Significance of matrix metalloproteinase-1 and -3 gene polymorphisms and their expression in normal and neoplastic endometrium. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Riccio LGC, Baracat EC, Chapron C, Batteux F, Abrão MS. The role of the B lymphocytes in endometriosis: A systematic review. J Reprod Immunol 2017; 123:29-34. [PMID: 28910679 DOI: 10.1016/j.jri.2017.09.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 08/01/2017] [Accepted: 09/06/2017] [Indexed: 01/06/2023]
Abstract
The physiopathology of endometriosis is not completely understood and its progression is associated with a local and systemic inflammatory reaction. It is important to clarify the potential role of the immune system to better understand its implication in the pathogenesis of endometriosis, which includes the study of the role of B cells and antibodies. The aim of this study was to review the literature about the role of B lymphocytes in endometriosis. A search for "endometriosis", "B cells" and "B lymphocytes" in databases resulted in 140 citations; after applying inclusion and exclusion criteria, a total of 22 studies were assessed. The analyzed samples in the studies varied and different markers and techniques were used by the authors to evaluate the direct or indirect role of B lymphocytes in endometriosis. Most studies demonstrated increased number and/or activation of B cells while seven studies found no difference and two studies showed decreased number of B cells. Increased B lymphocytes and excessive production of autoantibodies in endometriosis have been described in the literature, but their role in the development of the disease is not well understood. Moreover, the association of these factors with clinical symptoms, location and severity of the disease has not been investigated. Further studies are necessary to clarify the role of B cells in the development of endometriosis and propose new therapeutic strategies such as the use of drugs that target these cells.
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Affiliation(s)
- L G C Riccio
- School of Medicine, University of São Paulo, Endometriosis Division, Obstetrics and Gynecology Department, São Paulo, Brazil; Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016-Batteux, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
| | - E C Baracat
- School of Medicine, University of São Paulo, Endometriosis Division, Obstetrics and Gynecology Department, São Paulo, Brazil.
| | - C Chapron
- Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Université Paris Descartes, Paris, France; Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016-Batteux, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
| | - F Batteux
- Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016-Batteux, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Immunology, Hôpital Cochin, AP-HP, Paris, France.
| | - M S Abrão
- School of Medicine, University of São Paulo, Endometriosis Division, Obstetrics and Gynecology Department, São Paulo, Brazil.
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Ye Y, Vattai A, Zhang X, Zhu J, Thaler CJ, Mahner S, Jeschke U, von Schönfeldt V. Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases. Int J Mol Sci 2017; 18:ijms18081651. [PMID: 28758928 PMCID: PMC5578041 DOI: 10.3390/ijms18081651] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 07/24/2017] [Accepted: 07/27/2017] [Indexed: 01/13/2023] Open
Abstract
Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.
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Affiliation(s)
- Yao Ye
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Aurelia Vattai
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Xi Zhang
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Junyan Zhu
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Christian J Thaler
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Sven Mahner
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Udo Jeschke
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
| | - Viktoria von Schönfeldt
- Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, 80337 Munich, Germany.
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Xu X, Li Z, Liu J, Yu S, Wei Z. MicroRNA expression profiling in endometriosis-associated infertility and its relationship with endometrial receptivity evaluated by ultrasound. JOURNAL OF X-RAY SCIENCE AND TECHNOLOGY 2017; 25:523-532. [PMID: 28506024 DOI: 10.3233/xst-17286] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To investigate the microRNA expression profiling in endometriosis-associate infertility, and relationship between the microRNA expression and endometrial receptivity evaluated by ultrasound. METHODS First, miRNA expression profiling difference of ectopic endometrium between 8 endometriosis patients and 6 endometriosis-free patients were compared. Bioinformatics analyses detected 61 differentially expressed (DE) known miRNAs and 57 DE novel miRNAs. Next, other 24 patients were selected for checking the microRNAs in differential expression by RT-PCR. Among them, case and control groups include 14 endometriosis and 10 endometriosis-free infertility patients, respectively. Last, endometrial receptivity of other 20 endometriosis patients was evaluated by ultrasound. In this group of patients, 12 had high endometrial receptivity, in which infertility is caused by fallopian tube occlusion, and 8 had low endometrial receptivity. The study compared endometrial miRNAs expression between two groups, and also evaluated the relationship between the endometrial miRNAs expression and the endometrial receptivity. RESULTS First, study indicated that "proteinaceous extracellular matrix," "laminin binding" and "extracellular matrix binding" were enriched in 6 up-regulated miRNA targets, while "cell proliferation" was enriched in the 4 down-regulated miRNA targets. Second, 10 miRNAs in different expression (miR-1304- 3p, miR-544b, miR-3684, miR-494-5p, miR-4683, miR-6747-3p; miR-3935, miR-4427, miR-652-5p, miR-205-5p) were detected by RT-PCR, and the results showed statistically significant differences between 2 groups in all 10 miRNAs. Third, the expression levels of miR-1304-3p, miR-494-5p, and miR-4427 were different between the two groups with different endometrial receptivity. But for the miR-544b, there was no statistically significant difference between two groups. CONCLUSIONS The study provided a comprehensive understanding to the current knowledge in the field of miRNAs in endometriosis and the relationship between them and the endometrial receptivity. miRNAs could be used as diagnostic biomarkers and therapeutic agents for this disease. The combination of ultrasound and miRNAs detection could be a better choice for the diagnosis of infertility in the future.
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Affiliation(s)
- Xianfeng Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China
- Department of Obstetrics and Gynecology, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, P. R. China
| | - Zhenzhou Li
- Department of Ultrasound, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, P. R. China
| | - Jin Liu
- Department of Obstetrics and Gynecology, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, P. R. China
| | - Sha Yu
- Department of Obstetrics and Gynecology, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, P. R. China
| | - Zhaolian Wei
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China
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Effect of matrix metalloproteinase promoter polymorphisms on endometriosis and adenomyosis risk: evidence from a meta-analysis. J Genet 2016; 95:611-9. [DOI: 10.1007/s12041-016-0675-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Gupta D, Hull ML, Fraser I, Miller L, Bossuyt PMM, Johnson N, Nisenblat V, Cochrane Gynaecology and Fertility Group. Endometrial biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 2016; 4:CD012165. [PMID: 27094925 PMCID: PMC6953323 DOI: 10.1002/14651858.cd012165] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND About 10% of reproductive-aged women suffer from endometriosis, which is a costly, chronic disease that causes pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but it is expensive and carries surgical risks. Currently, there are no non-invasive tests available in clinical practice that accurately diagnose endometriosis. This is the first diagnostic test accuracy review of endometrial biomarkers for endometriosis that utilises Cochrane methodologies, providing an update on the rapidly expanding literature in this field. OBJECTIVES To determine the diagnostic accuracy of the endometrial biomarkers for pelvic endometriosis, using a surgical diagnosis as the reference standard. We evaluated the tests as replacement tests for diagnostic surgery and as triage tests to inform decisions to undertake surgery for endometriosis. SEARCH METHODS We did not restrict the searches to particular study designs, language or publication dates. To identify trials, we searched the following databases: CENTRAL (2015, July), MEDLINE (inception to May 2015), EMBASE (inception to May 2015), CINAHL (inception to April 2015), PsycINFO (inception to April 2015), Web of Science (inception to April 2015), LILACS (inception to April 2015), OAIster (inception to April 2015), TRIP (inception to April 2015) and ClinicalTrials.gov (inception to April 2015). We searched DARE and PubMed databases up to April 2015 to identify reviews and guidelines as sources of references to potentially relevant studies. We also performed searches for papers recently published and not yet indexed in the major databases. The search strategies incorporated words in the title, abstract, text words across the record and the medical subject headings (MeSH). SELECTION CRITERIA We considered published peer-reviewed, randomised controlled or cross-sectional studies of any size that included prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). DATA COLLECTION AND ANALYSIS Two authors independently extracted data from each study and performed a quality assessment. For each endometrial diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis and calculated the estimates of sensitivity and specificity. We considered two or more tests evaluated in the same cohort as separate data sets. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient data were available. The predetermined criteria for a clinically useful test to replace diagnostic surgery was one with a sensitivity of 94% and a specificity of 79%. The criteria for triage tests were set at sensitivity at or above 95% and specificity at or above 50%, which in case of negative results rules out the diagnosis (SnOUT test) or sensitivity at or above 50% with specificity at or above 95%, which in case of positive result rules in the diagnosis (SpIN test). MAIN RESULTS We included 54 studies involving 2729 participants, most of which were of poor methodological quality. The studies evaluated endometrial biomarkers either in specific phases of the menstrual cycle or outside of it, and the studies tested the biomarkers either in menstrual fluid, in whole endometrial tissue or in separate endometrial components. Twenty-seven studies evaluated the diagnostic performance of 22 endometrial biomarkers for endometriosis. These were angiogenesis and growth factors (PROK-1), cell-adhesion molecules (integrins α3β1, α4β1, β1 and α6), DNA-repair molecules (hTERT), endometrial and mitochondrial proteome, hormonal markers (CYP19, 17βHSD2, ER-α, ER-β), inflammatory markers (IL-1R2), myogenic markers (caldesmon, CALD-1), neural markers (PGP 9.5, VIP, CGRP, SP, NPY, NF) and tumour markers (CA-125). Most of these biomarkers were assessed in single studies, whilst only data for PGP 9.5 and CYP19 were available for meta-analysis. These two biomarkers demonstrated significant diversity for the diagnostic estimates between the studies; however, the data were too limited to reliably determine the sources of heterogeneity. The mean sensitivities and specificities of PGP 9.5 (7 studies, 361 women) were 0.96 (95% confidence interval (CI) 0.91 to 1.00) and 0.86 (95% CI 0.70 to 1.00), after excluding one outlier study, and for CYP19 (8 studies, 444 women), they were were 0.77 (95% CI 0.70 to 0.85) and 0.74 (95% CI 0.65 to 84), respectively. We could not statistically evaluate other biomarkers in a meaningful way. An additional 31 studies evaluated 77 biomarkers that showed no evidence of differences in expression levels between the groups of women with and without endometriosis. AUTHORS' CONCLUSIONS We could not statistically evaluate most of the biomarkers assessed in this review in a meaningful way. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Although PGP 9.5 met the criteria for a replacement test, it demonstrated considerable inter study heterogeneity in diagnostic estimates, the source of which could not be determined. Several endometrial biomarkers, such as endometrial proteome, 17βHSD2, IL-1R2, caldesmon and other neural markers (VIP, CGRP, SP, NPY and combination of VIP, PGP 9.5 and SP) showed promising evidence of diagnostic accuracy, but there was insufficient or poor quality evidence for any clinical recommendations. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and using any non-invasive tests should only be undertaken in a research setting. We have also identified a number of biomarkers that demonstrated no diagnostic value for endometriosis. We recommend that researchers direct future studies towards biomarkers with high diagnostic potential in good quality diagnostic studies.
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Affiliation(s)
| | - M Louise Hull
- The University of AdelaideDiscipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research InstituteKing William RoadAdelaideSouth AustrailaAustralia
| | - Ian Fraser
- University of New South WalesSchool of Women's and Children's Health, Royal Hospital for WomenBarker StSydneyNSWAustralia2131
| | - Laura Miller
- Fertility PlusDepartment of Obstetrics and GynaecologyAuckland District Health BoardAucklandNew Zealand1142
| | - Patrick MM Bossuyt
- Academic Medical Center, University of AmsterdamDepartment of Clinical Epidemiology, Biostatistics and BioinformaticsRoom J1b‐217, PO Box 22700AmsterdamNetherlands1100 DE
| | - Neil Johnson
- The University of AdelaideDiscipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research InstituteKing William RoadAdelaideSouth AustrailaAustralia
| | - Vicki Nisenblat
- The University of AdelaideDiscipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research InstituteKing William RoadAdelaideSouth AustrailaAustralia
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Marí-Alexandre J, Barceló-Molina M, Olcina-Guillem M, García-Oms J, Braza-Boïls A, Gilabert-Estellés J. MicroRNAs: New players in endometriosis. World J Obstet Gynecol 2016; 5:28-38. [DOI: 10.5317/wjog.v5.i1.28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/14/2015] [Accepted: 01/07/2016] [Indexed: 02/05/2023] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disorder that limits the quality of life of affected women. This pathology affects 10% of reproductive-age women, although the prevalence in those patients experiencing pain, infertility or both is as high as 35%-50%. Endometriosis is characterized by endometrial-like tissue outside the uterus, primarily on the pelvic peritoneum, ovaries and the pouch of Douglas. Despite extensive research endeavours, a unifying theory regarding the exact etiopathogenic mechanism of this high prevalent and incapacitating condition is still lacking, although it has been suggested that epigenetics could be involved. MicroRNAs (miRNAs), one of the epigenetic players, are small non-coding RNAs that can act as post-transcriptional regulators of gene expression, reducing the expression of their target mRNAs either inhibiting its translation or promoting its degradation. MiRNA expression profiles are specific of tissue and cell type. Abnormal miRNA expression has been described in different pathological conditions, such as a myriad of oncological, cardiovascular and inflammatory diseases and gynecological pathologies. In endometriosis, miRNA expression patterns of eutopic endometrium from patients and control women and from different endometriotic lesions have been described. These small non-coding molecules have become attractive candidates as novel biomarkers for an early non-invasive diagnosis of the disease, which could suppose a valuable benefit to the patients in terms of improvement of prognosis and reduction of the ratio of recurrence. In this systematic review we will focus on the role of miRNAs in the pathophisiology of endometriosis.
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Marí-Alexandre J, Sánchez-Izquierdo D, Gilabert-Estellés J, Barceló-Molina M, Braza-Boïls A, Sandoval J. miRNAs Regulation and Its Role as Biomarkers in Endometriosis. Int J Mol Sci 2016; 17:ijms17010093. [PMID: 26771608 PMCID: PMC4730335 DOI: 10.3390/ijms17010093] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 01/05/2016] [Accepted: 01/08/2016] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs (18-22 nt) that function as modulators of gene expression. Since their discovery in 1993 in C. elegans, our knowledge about their biogenesis, function, and mechanism of action has increased enormously, especially in recent years, with the development of deep-sequencing technologies. New biogenesis pathways and sources of miRNAs are changing our concept about these molecules. The study of the miRNA contribution to pathological states is a field of great interest in research. Different groups have reported the implication of miRNAs in pathologies such as cancer, diabetes, cardiovascular, and gynecological diseases. It is also well-known that miRNAs are present in biofluids (plasma, serum, urine, semen, and menstrual blood) and have been proposed as ideal candidates as disease biomarkers. The goal of this review is to highlight the current knowledge in the field of miRNAs with a special emphasis to their role in endometriosis and the newest investigations addressing the use of miRNAs as biomarkers for this gynecological disease.
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Affiliation(s)
- Josep Marí-Alexandre
- Unit of Hemostasia, Thrombosis, Atherosclerosis and Vascular Biology, Health Research Institute La Fe, Valencia 46026, Spain.
| | | | | | - Moisés Barceló-Molina
- Unit of Hemostasia, Thrombosis, Atherosclerosis and Vascular Biology, Health Research Institute La Fe, Valencia 46026, Spain.
| | - Aitana Braza-Boïls
- Unit of Hemostasia, Thrombosis, Atherosclerosis and Vascular Biology, Health Research Institute La Fe, Valencia 46026, Spain.
| | - Juan Sandoval
- Epigomics Unit, Health Research Institute La Fe, Valencia 46026, Spain.
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Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and Immune Dysfunction in Endometriosis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:795976. [PMID: 26247027 PMCID: PMC4515278 DOI: 10.1155/2015/795976] [Citation(s) in RCA: 213] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/18/2014] [Indexed: 12/30/2022]
Abstract
Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis.
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Affiliation(s)
- Soo Hyun Ahn
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6
| | - Stephany P. Monsanto
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6
| | - Caragh Miller
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6
| | - Sukhbir S. Singh
- Department of Obstetrics and Gynecology, University of Ottawa, The Ottawa Hospital, ON, Canada K1H 7W9
| | - Richard Thomas
- Department of Obstetrics and Gynecology, Kingston General Hospital, Kingston, ON, Canada K7L 3N6
| | - Chandrakant Tayade
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6
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Fortin CN, Saed GM, Diamond MP. Predisposing factors to post-operative adhesion development. Hum Reprod Update 2015; 21:536-51. [PMID: 25935859 DOI: 10.1093/humupd/dmv021] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Accepted: 04/07/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Adhesion development is the most common sequelae of intra-abdominal and pelvic surgery and represents a significant, yet poorly understood, cause of morbidity among post-operative patients. It remains unclear, for example, exactly why adhesions form more frequently in certain tissues and/or patients, or at specific locations within them, as opposed to others. This review contributes to the growing knowledge pool by elucidating factors that potentially predispose to the development of adhesions. Given the strong correlation between a hypofibrinolytic state and adhesion formation, this review article will examine not only those factors that have been shown to directly predispose to adhesion development, but also those that are likely do so indirectly by means of altering the coagulation/fibrinolytic profile. METHODS A literature search was performed using the PubMed database for all relevant English language articles up to February 2014. All of the identified articles were reviewed with particular attention to predisposing factors to post-operative adhesion development. In addition, the reference lists of each article were reviewed to identify additional relevant articles. RESULTS Various factors have been shown to directly increase the risk of post-operative adhesion development; namely, certain genetic polymorphisms in the interleukin-1 receptor antagonist, increased estrogen exposure, and endometriosis. In addition, numerous factors are known to increase the risk of fibrosis, therefore likely increasing the risk of adhesion development indirectly. These factors include genetic polymorphisms in plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, diabetes mellitus, metabolic syndrome, hyperglycemia, obesity, depression, binge alcohol consumption, anti-Parkinsonian medications, oral hormone therapy, pregnancy, and cancer. CONCLUSIONS The literature reviewed in this paper will help to direct future research aimed at understanding the mechanisms that underlie the association of certain factors with adhesion development. This information will be crucial in the creation of adequate preventative and treatment strategies.
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Affiliation(s)
- Chelsea N Fortin
- Wayne State University, School of Medicine, Detroit, MI 48201, USA
| | - Ghassan M Saed
- Department of Obstetrics and Gynecology, CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Michael P Diamond
- Department of Obstetrics and Gynecology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA
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Marí-Alexandre J, García-Oms J, Barceló-Molina M, Gilabert-Aguilar J, Estellés A, Braza-Boíls A, Gilabert-Estellés J. MicroRNAs and angiogenesis in endometriosis. Thromb Res 2015; 135 Suppl 1:S38-40. [PMID: 25903532 DOI: 10.1016/s0049-3848(15)50439-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
miRNAs function as important regulators of a wide range of cellular processes, such as angiogenesis and fibrinolysis, by postranscriptional modulation of gene expression. We present a review on the role of miRNAs and angiogenesis in endometriosis. Endometriosis, defined as the implantation of endometrial tissue outside the uterine cavity, is one of the most frequent benign gynecological diseases and it has important consequences on the quality of life and fertility of patients. Similarly to tumor metastasis, the ectopic endometrium acquires the capability to adhere, proliferate and infiltrate the extracellular matrix. Endometriosis is a multifactorial and polygenic disease in which angiogenesis and proteolysis may be involved, and emerging data provide evidence that a dysregulation of miRNA expression may be implicated in these processes. The detection of circulating miRNAs in plasma and other body fluids and their relative stability has raised the possibility that they might serve as non-invasive biomarkers for the diagnosis of the disease. On the other hand, the development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for the treatment of endometriosis.
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Affiliation(s)
- Josep Marí-Alexandre
- Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Javier García-Oms
- Area Maternoinfantil, Hospital General Universitario, Valencia, Spain
| | - Moisés Barceló-Molina
- Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | | | - Amparo Estellés
- Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Aitana Braza-Boíls
- Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain
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Effect of Three Dimensional Culture of Porcine Endometrial Cells on Their Plasminogen Activity and Pre-implantation Embryo Development after Co-culture. JOURNAL OF ANIMAL REPRODUCTION AND BIOTECHNOLOGY 2014. [DOI: 10.12750/jet.2014.29.2.207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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29
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Braza-Boïls A, Marí-Alexandre J, Gilabert J, Sánchez-Izquierdo D, España F, Estellés A, Gilabert-Estellés J. MicroRNA expression profile in endometriosis: its relation to angiogenesis and fibrinolytic factors. Hum Reprod 2014; 29:978-88. [PMID: 24608518 DOI: 10.1093/humrep/deu019] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
STUDY QUESTION Could an aberrant microRNA (miRNA) expression profile be responsible for the changes in the angiogenic and fibrinolytic states observed in endometriotic lesions? SUMMARY ANSWER This study revealed characteristic miRNA expression profiles associated with endometriosis in endometrial tissue and endometriotic lesions from the same patient and their correlation with the most important angiogenic and fibrinolytic factors. WHAT IS ALREADY KNOWN?: An important role for dysregulated miRNA expression in the pathogenesis of endometriosis is well documented. However, to the best of our knowledge, there are no reports of the relationship between angiogenic and fibrinolytic factors and miRNAs when endometrial tissue and different types of endometriotic lesions from the same patient are compared. STUDY DESIGN, SIZE, DURATION Case-control study that involved 51 women with endometriosis and 32 women without the disease (controls). PARTICIPANTS/MATERIALS, SETTING, METHODS The miRNA expression profiles were determined using the GeneChip miRNA 2.0 Affymetrix array platform, and the results were analysed using Partek Genomic Suite software. To validate the obtained results, 12 miRNAs differentially expressed were quantified by using miRCURY LNA™ Universal RT microRNA PCR. Levels of vascular endothelial growth factor (VEGF-A), thrombospondin-1 (TSP-1), urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) proteins were quantified by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE Patient endometrial tissue showed significantly lower levels of miR-202-3p, miR-424-5p, miR-449b-3p and miR-556-3p, and higher levels of VEGF-A and uPA than healthy (control) endometrium. However, tissue affected by ovarian endometrioma showed significantly lower expression of miR-449b-3p than endometrium from both controls and patients, and higher levels of PAI-1 and the angiogenic inhibitor TSP-1. A significant inverse correlation between miR-424-5p and VEGF-A protein levels was observed in patient endometrium, and an inverse correlation between miR-449b-3p and TSP-1 protein levels was observed in ovarian endometrioma. Peritoneal implants had significantly higher levels of VEGF-A than ovarian endometrioma samples. LIMITATIONS, REASONS FOR CAUTION Functional studies are needed to confirm the specific targets of the miRNAs differently expressed. WIDER IMPLICATIONS OF THE FINDINGS Differences in miRNA levels could modulate the expression of VEGF-A and TSP-1, which may play an important role in the pathogenesis of endometriosis. The higher angiogenic and proteolytic activities observed in eutopic endometrium from patients might facilitate the implantation of endometrial cells at ectopic sites. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by research grants from ISCIII-FEDER (PI11/0091, Red RIC RD12/0042/0029), Consellería de Educación-Generalitat Valenciana (PROMETEO/2011/027), Beca de Investigación Fundación Dexeus para la Salud de la Mujer (2011/0469), and by Fundación Investigación Hospital La Fe (2011/211). A.B-B. has a Contrato Posdoctoral de Perfeccionamiento Sara Borrell-ISCIII (CD13/00005). J.M-A. has a predoctoral grant PFIS-ISCIII (FI12/00012). The authors have no conflicts of interest to declare.
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Affiliation(s)
- Aitana Braza-Boïls
- Grupo de Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto Investigación Sanitaria Hospital La Fe (IIS La Fe), Valencia, Spain
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30
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Machairiotis N, Stylianaki A, Dryllis G, Zarogoulidis P, Kouroutou P, Tsiamis N, Katsikogiannis N, Sarika E, Courcoutsakis N, Tsiouda T, Gschwendtner A, Zarogoulidis K, Sakkas L, Baliaka A, Machairiotis C. Extrapelvic endometriosis: a rare entity or an under diagnosed condition? Diagn Pathol 2013; 8:194. [PMID: 24294950 PMCID: PMC3942279 DOI: 10.1186/1746-1596-8-194] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 11/23/2013] [Indexed: 12/16/2022] Open
Abstract
Endometriosis is a clinical entity characterized by the presence of normal endometrial mucosa abnormally implanted in locations other than the uterine cavity. Endometriosis can be either endopelvic or extrapelvicdepending on the location of endometrial tissue implantation. Despite the rarity of extrapelvic endometriosis, several cases of endometriosis of the gastrointestinal tract, the urinarytract, the upper and lower respiratory system, the diaphragm, the pleura and the pericardium, as well as abdominal scars loci have been reported in the literature. There are several theories about the pathogenesis and the pathophysiology of endometriosis. Depending on the place of endometrial tissue implantation, endometriosis can be expressed with a wide variety of symptoms. The diagnosis of this entity is neither easy nor routine. Many diagnostic methods clinical and laboratory have been used, but none of them is the golden standard. The multipotent localization of endometriosis in combination with the wide range of its clinical expression should raise the clinical suspicion in every woman with periodic symptoms of extrapelvic organs. Finally, the therapeutic approach of this clinical entity is also correlated with the bulk of endometriosis and the locum that it is found. It varies from simple observation, to surgical treatment and treatment with medication as well as a combination of those.
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Affiliation(s)
| | | | | | - Paul Zarogoulidis
- Pulmonary Department, "G, Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Exohi 1100, 57010 Thessaloniki, Greece.
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Braza-Boïls A, Gilabert-Estellés J, Ramón LA, Gilabert J, Marí-Alexandre J, Chirivella M, España F, Estellés A. Peritoneal fluid reduces angiogenesis-related microRNA expression in cell cultures of endometrial and endometriotic tissues from women with endometriosis. PLoS One 2013; 8:e62370. [PMID: 23620826 PMCID: PMC3631199 DOI: 10.1371/journal.pone.0062370] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 03/20/2013] [Indexed: 02/06/2023] Open
Abstract
Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent gynecological diseases. It has been suggested that modifications of both endometrial and peritoneal factors could be implicated in this disease. Endometriosis is a multifactorial disease in which angiogenesis and proteolysis are dysregulated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the protein expression and may be the main regulators of angiogenesis. Our hypothesis is that peritoneal fluid from women with endometriosis could modify the expression of several miRNAs that regulate angiogenesis and proteolysis in the endometriosis development. The objective of this study has been to evaluate the influence of endometriotic peritoneal fluid on the expression of six miRNAs related to angiogenesis, as well as several angiogenic and proteolytic factors in endometrial and endometriotic cell cultures from women with endometriosis compared with women without endometriosis.
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Affiliation(s)
- Aitana Braza-Boïls
- Grupo de Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto Investigación Sanitaria Hospital La Fe, Valencia, Spain
| | | | - Luis A. Ramón
- Grupo de Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto Investigación Sanitaria Hospital La Fe, Valencia, Spain
| | - Juan Gilabert
- Servicio de Ginecología, Hospital Arnau de Vilanova, Valencia, Spain
| | - Josep Marí-Alexandre
- Grupo de Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto Investigación Sanitaria Hospital La Fe, Valencia, Spain
| | - Melitina Chirivella
- Departamento de Anatomopatología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Francisco España
- Centro de Investigación, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Amparo Estellés
- Centro de Investigación, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- * E-mail:
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32
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Adammek M, Greve B, Kässens N, Schneider C, Brüggemann K, Schüring AN, Starzinski-Powitz A, Kiesel L, Götte M. MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of an in vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors. Fertil Steril 2013; 99:1346-1355.e5. [PMID: 23312222 DOI: 10.1016/j.fertnstert.2012.11.055] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 11/15/2012] [Accepted: 11/30/2012] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To study the function of miR-145, known to be dysregulated in endometriosis, and to identify its target genes in an in vitro endometriosis model. DESIGN Experimental laboratory study. SETTING University medical centers. PATIENT(S) Primary endometrial stroma cells were derived from eutopic endometrium of three American Society for Reproductive Medicine stage III endometriosis patients and from ectopic lesions of four patients with deep infiltrating endometriosis. INTERVENTION(S) The human endometriotic cell line 12Z and primary eutopic and ectopic endometrial stroma cells were transiently transfected with miR-145 precursors or anti-miR-145 inhibitors and investigated for posttranscriptional regulation of predicted target genes and changes in cell behavior. MAIN OUTCOME MEASURE(S) Predicted target expression was measured by quantitative reverse transcription-polymerase chain reaction and Western blotting, and altered cell behavior was monitored by cell proliferation assays. The 12Z cells were additionally investigated by Matrigel invasion assays, cell cycle analysis, side population analysis, and aldehyde dehydrogenase activity assays. RESULT(S) In all cells investigated, miR-145 overexpression inhibited cell proliferation and induced down-regulation of FASCIN-1, SOX2, and MSI2. In 12Z cells miR-145 upregulation increased Matrigel invasiveness and reduced side population and aldehyde dehydrogenase-1 activity. Additional down-regulated targets in 12Z cells included OCT4, KLF4, PODXL, JAM-A, and SERPINE1/PAI-1. ACTG2 and TAGLN were up-regulated upon pre-miR-145 transfection. JAM-A, FASCIN-1, and PAI-I down-regulation in 12Z cells were confirmed by Western blotting. CONCLUSION(S) miR-145 inhibits endometriotic cell proliferation, invasiveness, and stemness by targeting multiple pluripotency factors, cytoskeletal elements, and protease inhibitors.
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Affiliation(s)
- Marlene Adammek
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
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Schneider C, Kässens N, Greve B, Hassan H, Schüring AN, Starzinski-Powitz A, Kiesel L, Seidler DG, Götte M. Targeting of syndecan-1 by micro-ribonucleic acid miR-10b modulates invasiveness of endometriotic cells via dysregulation of the proteolytic milieu and interleukin-6 secretion. Fertil Steril 2012. [PMID: 23206733 DOI: 10.1016/j.fertnstert.2012.10.051] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To study the function of syndecan-1 (SDC1) and its potential regulator miR-10b in endometriosis. DESIGN Experimental laboratory study. SETTING University medical center. PATIENT(S) Not applicable. INTERVENTION(S) The human endometriotic cell line 12Z was transiently transfected with SDC1 small interfering RNA or miR-10b precursors and investigated for changes in cell behavior and gene expression. 12Z and primary eutopic endometrial stroma cells of two American Society for Reproductive Medicine class III endometriosis patients were transfected with miR-10b precursors to investigate posttranscriptional regulation of SDC1. MAIN OUTCOME MEASURE(S) Quantitative polymerase chain reaction, Western blotting, flow cytometry, 3' untranslated region luciferase assays, and zymography were used to measure miR-10b-dependent targeting of SDC1 and SDC1-dependent expression changes of proteases and interleukin-6. Altered cell behavior was monitored by Matrigel invasion assays, cell viability assays, and mitogen-activated protein kinase activation blots. RESULT(S) Knockdown of SDC1 inhibited Matrigel invasiveness by >60% but did not affect cell viability. Interleukin-6 secretion, matrix metalloproteinase-9 expression, and matrix metalloproteinase-2 activity were reduced, whereas plasminogen activator inhibitor-1 protein expression was up-regulated. miR-10b overexpression significantly down-regulated SDC1, reduced Matrigel invasiveness by 20% and cell viability by 14%, and decreased mitogen-activated protein kinase activation in response to hepatocyte growth factor. CONCLUSION(S) Syndecan-1, a target of miR-10b, inhibits epithelial endometriotic cell invasiveness through down-regulation of metalloproteinase activity and interleukin-6.
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Affiliation(s)
- Cornelia Schneider
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
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Chen CH, Miller MA, Sarkar A, Beste MT, Isaacson KB, Lauffenburger DA, Griffith LG, Han J. Multiplexed protease activity assay for low-volume clinical samples using droplet-based microfluidics and its application to endometriosis. J Am Chem Soc 2012; 135:1645-8. [PMID: 23157326 DOI: 10.1021/ja307866z] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
As principal degrading enzymes of the extracellular matrix, metalloproteinases (MPs) contribute to various pathologies and represent a family of promising drug targets and biomarker candidates. However, multiple proteases and endogenous inhibitors interact to govern MP activity, often leading to highly context-dependent protease function that unfortunately has impeded associated clinical utility. We present a method for rapidly assessing the activity of multiple specific proteases in small volumes (<20 μL) of complex biological fluids such as clinical samples that are available only in very limited amounts. It uses a droplet-based microfluidic platform that injects the sample into thousands of picoliter-scale droplets from a barcoded droplet library (DL) containing mixtures of unique, moderately selective FRET-based protease substrates and specific inhibitors and monitors hundreds of the reactions thus initiated simultaneously by tracking these droplets. Specific protease activities in the sample are then inferred from the reaction rates using a deconvolution technique, proteolytic activity matrix analysis (PrAMA). Using a nine-member DL with three inhibitors and four FRET substrates, we applied the method to the peritoneal fluid of subjects with and without the invasive disease endometriosis. The results showed clear and physiologically relevant differences with disease, in particular, decreased MMP-2 and ADAM-9 activities.
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Affiliation(s)
- Chia-Hung Chen
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
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35
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Trovó de Marqui AB. Polimorfismos genéticos e endometriose: A contribuição dos genes que regulam a função vascular e o remodelamento de tecidos. Rev Assoc Med Bras (1992) 2012; 58:620-32. [DOI: 10.1590/s0104-42302012000500022] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 05/11/2012] [Indexed: 01/11/2023] Open
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Trovó de Marqui AB. Polimorfismos genéticos e endometriose: A contribuição dos genes que regulam a função vascular e o remodelamento de tecidos. Rev Assoc Med Bras (1992) 2012. [DOI: 10.1016/s0104-4230(12)70259-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Ramón LA, Braza-Boïls A, Gilabert J, Chirivella M, España F, Estellés A, Gilabert-Estellés J. microRNAs related to angiogenesis are dysregulated in endometrioid endometrial cancer. Hum Reprod 2012; 27:3036-45. [DOI: 10.1093/humrep/des292] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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38
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Gilabert-Estellés J, Ramón LA, Braza-Boïls A, Gilabert J, Chirivella M, España F, Estellés A. Plasminogen activator inhibitor-1 (PAI-1) 4 G/5 G polymorphism and endometrial cancer. Influence of PAI-1 polymorphism on tissue PAI-1 antigen and mRNA expression and tumor severity. Thromb Res 2012; 130:242-7. [DOI: 10.1016/j.thromres.2011.10.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 09/16/2011] [Accepted: 10/10/2011] [Indexed: 01/08/2023]
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Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration. Fertil Steril 2012; 97:1380-6.e1. [PMID: 22542989 DOI: 10.1016/j.fertnstert.2012.03.057] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2011] [Revised: 03/25/2012] [Accepted: 03/30/2012] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To evaluate inflammatory/angiogenic cytokines-interleukin-1β (IL-1β), IL-6, IL-8, IL-12, interferon-γ (IFN-γ), tumor necrosis factor (TNF), and vascular endothelial growth factor A (VEGF-A)-in the peritoneal fluid of patients with endometriosis in relation to the occurrence and severity of pelvic adhesions and in control women without pelvic pathology. DESIGN Case-control study. SETTING University research institution and hospital. PATIENT(S) Sixty-five women with laparoscopically and histopathologically confirmed endometriosis, including 40 women with pelvic adhesions, and 37 control women without pelvic pathology. INTERVENTION(S) Peritoneal fluid aspirated during routine diagnostic laparoscopic examination. MAIN OUTCOME MEASURE(S) Cytokines evaluated in the peritoneal fluid via specific enzyme-linked immunosorbent assays. RESULT(S) Endometriosis and the revised American Fertility Society score of this disease were associated with statistically significantly increased levels of peritoneal IL-6 and IL-8 whereas the incidence and score of endometriosis-related pelvic adhesions were negatively associated with increased levels of VEGF-A. Notably, the concentration of VEGF-A predicted adhesion development and severity after adjustment for endometriosis severity. The adhesion score also correlated with increased levels of IL-6; however, after adjustment for endometriosis severity, the effect of this cytokine was no longer statistically significant. CONCLUSION(S) Increased levels of VEGF-A may be associated with a decreased rate of pelvic adhesion formation in the course of endometriosis.
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Abstract
Matrix metalloproteinases (MMPs) were originally identified as matrixin proteases that act in the extracellular matrix. Recent works have uncovered nontraditional roles for MMPs in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized matrixins participate in many physiological and pathological cellular processes, in which they can act as both degradative and regulatory proteases. In this review, we discuss the transcriptional and translational control of matrixin expression, their regulation of intracellular sorting, and the structural basis of activation and inhibition. In particular, we highlight the emerging roles of various matrixin forms in diseases. The activity of matrix metalloproteinases is regulated at several levels, including enzyme activation, inhibition, complex formation and compartmentalization. Most MMPs are secreted and have their function in the extracellular environment. MMPs are also found inside cells, both in the nucleus, cytosol and organelles. The role of intracellular located MMPs is still poorly understood, although recent studies have unraveled some of their functions. The localization, activation and activity of MMPs are regulated by their interactions with other proteins, proteoglycan core proteins and / or their glycosaminoglycan chains, as well as other molecules. Complexes formed between MMPs and various molecules may also include interactions with noncatalytic sites. Such exosites are regions involved in substrate processing, localized outside the active site, and are potential binding sites of specific MMP inhibitors. Knowledge about regulation of MMP activity is essential for understanding various physiological processes and pathogenesis of diseases, as well as for the development of new MMP targeting drugs.
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Affiliation(s)
- Ferdinando Mannello
- Department of Biomolecular Sciences, Section of Clinical Biochemistry, Unit of Cell Biology, University Carlo Bo of Urbino, Via O. Ubaldini 7, 61029 Urbino (PU), Italy.
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Mabrouk M, Elmakky A, Caramelli E, Farina A, Mignemi G, Venturoli S, Villa G, Guerrini M, Manuzzi L, Montanari G, De Sanctis P, Valvassori L, Zucchini C, Seracchioli R. Performance of peripheral (serum and molecular) blood markers for diagnosis of endometriosis. Arch Gynecol Obstet 2011; 285:1307-12. [PMID: 22065163 DOI: 10.1007/s00404-011-2122-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2011] [Accepted: 10/17/2011] [Indexed: 11/26/2022]
Abstract
PURPOSE To quantify the mRNA levels of MMP-3, MMP-9, VEGF and Survivin in peripheral blood and the serum levels of CA-125 and Ca19-9 in women with and without endometriosis and to investigate the performance of these markers to differentiate between deep and ovarian endometriosis. METHODS A case control study enrolled a series of 60 patients. Twenty controls have been matched with 20 cases of ovarian and 20 cases of deep endometriosis. Univariable and multivariable performance of serum CA125 and CA19-9, mRNA for Survivin, MMP9, MMP3 and VEGF genes have been evaluated by means of ROC curves and logistic regression, respectively. RESULTS No difference in markers' concentration was detected between ovarian and deep endometriosis. In comparison with controls, serum CA125 and CA19 yielded the better sensitivity followed by mRNA for Survivin gene (81.5, 51.9 and 7.5% at 10% false positive rate, respectively). Multivariable estimated odds of endometriosis yielded a sensitivity of 87% at the same false positive rate. CONCLUSIONS A combination of serum and molecular markers could allow a better diagnosis of endometriosis.
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Affiliation(s)
- Mohamed Mabrouk
- Reproductive Medicine Unit, S. Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy
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Brandes A, Christofolini DM, Cavalheiro CM, Vilarino FL, André GM, Bianco B, Barbosa CP. Genetic variants in fibrinolytic system-related genes in infertile women with and without endometriosis. Genet Test Mol Biomarkers 2011; 16:54-7. [PMID: 21819230 DOI: 10.1089/gtmb.2011.0112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS The aim of this study was to evaluate urokinase-type plasminogen activator gene (uPA) and thrombin-activatable fibrinolysis inhibitor gene (TAFI) genotypes in a group of infertile women with and/or without endometriosis and controls. METHODS A case-control study comprising 180 infertile women with endometriosis, 68 women with idiopathic infertility, and 152 fertile women as controls was carried out. Detection of uPA (C422T/rs2227564) and TAFI (G438A/rs2146881) polymorphisms was performed by TaqMan polymerase chain reaction. The results were statistically analyzed and a p-value of <0.05 was considered significant. RESULTS We found no association among both uPA or TAFI polymorphisms and endometriosis-related infertility (p=0.920 and p=0.356, respectively) or idiopathic infertility (p=0.502 and p=0.392, respectively) comparing to controls, even considering minimal/mild and moderate/severe endometriosis separately. Both uPA and TAFI polymorphisms were in Hardy-Weinberg equilibrium for all studied groups. The combinatory analysis of both uPA and TAFI polymorphisms to endometriosis-related infertility, idiopathic infertility, and control group showed no statistical difference to any combination. CONCLUSION The data suggest that, in the Brazilian population, genetic variations in both uPA and TAFI were not relevant to endometriosis and/or infertility.
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Affiliation(s)
- Ariel Brandes
- Division of Human Reproduction and Genetics, Department of Gynecology and Obstetrics, Faculdade de Medicina do ABC , Santo André, Sao Paulo, Brazil
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Liu H, Lang JH. Is abnormal eutopic endometrium the cause of endometriosis? The role of eutopic endometrium in pathogenesis of endometriosis. Med Sci Monit 2011; 17:RA92-9. [PMID: 21455119 PMCID: PMC3539524 DOI: 10.12659/msm.881707] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Endometriosis (EM) is one of the most common diseases which severely affect the health and reproductive function of women of childbearing age. There are fundamental abnormal changes within the eutopic endometrium of women with endometriosis compared to normal endometrium of women without endometriosis. Eutopic endometrium shows enhanced ability of proliferation, implantation and angiogenesis, and greater probability of escaping the unfavorable conditions of the ectopic environment. Therefore, the character of eutopic endometrium determines the fate of the backward-flowing endometrial tissue – to live or to die. The abnormal endometrial tissue in EM patients flows backward to the pelvic cavity, completing a 3-step procedure of pathogenesis (attachment-aggression-angiogenesis), and ultimately develops into EM. Abnormal eutopic endometrium may also play important roles in endometriosis-associated infertility. This recognition regarding the pathogenesis of endometriosis ultimately will help to discover new methods for diagnosis and treatment. Endometrial markers for micro-invasive diagnosis and direct treatment of eutopic endometrium as the origin of the disease should be further investigated.
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Affiliation(s)
- Haiyuan Liu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, PR China
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44
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May K, Villar J, Kirtley S, Kennedy S, Becker C. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update 2011; 17:637-53. [DOI: 10.1093/humupd/dmr013] [Citation(s) in RCA: 168] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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45
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Ramon LA, Braza-Boils A, Gilabert-Estelles J, Gilabert J, Espana F, Chirivella M, Estelles A. microRNAs expression in endometriosis and their relation to angiogenic factors. Hum Reprod 2011; 26:1082-90. [DOI: 10.1093/humrep/der025] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Lee J, Banu SK, Subbarao T, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of human immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases. Mol Cell Endocrinol 2011; 332:306-13. [PMID: 21111772 DOI: 10.1016/j.mce.2010.11.022] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 11/16/2010] [Accepted: 11/18/2010] [Indexed: 01/10/2023]
Abstract
Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. We recently reported that inhibition of COX-2 decreased migration as well as invasion of human endometriotic epithelial and stromal cells. Results of the present study indicates that selective inhibition of PGE2 receptors EP2 and EP4 suppresses expression and/or activity of MMP1, MMP2, MMP3, MMP7 and MMP9 proteins and increases expression of TIMP1, TIMP2, TIMP3, and TIMP4 proteins and thereby decreases migration and invasion of human immortalized endometriotic epithelial and stromal cells into matrigel. The interactions between EP2/EP4 and MMPs are mediated through Src and β-arrestin 1 protein complex involving MT1-MMP and EMMPRIN in human endometriotic cells. These novel findings provide an important molecular and cellular framework for further evaluation of selective inhibition of EP2 and EP4 as potential nonsteroidal therapy for endometriosis in childbearing-age women.
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MESH Headings
- Cell Movement/physiology
- Cells, Cultured
- Dinoprostone/metabolism
- Endometriosis/metabolism
- Endometriosis/pathology
- Endometrium/cytology
- Epithelial Cells/metabolism
- Epithelial Cells/pathology
- Female
- Humans
- Matrix Metalloproteinase Inhibitors
- RNA, Small Interfering/metabolism
- Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors
- Receptors, Prostaglandin E, EP2 Subtype/genetics
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors
- Receptors, Prostaglandin E, EP4 Subtype/genetics
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Stromal Cells/metabolism
- Stromal Cells/pathology
- Tissue Inhibitor of Metalloproteinases/metabolism
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Affiliation(s)
- JeHoon Lee
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, United States
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Paul S, Bhattacharya P, Das Mahapatra P, Swarnakar S. Melatonin protects against endometriosis via regulation of matrix metalloproteinase-3 and an apoptotic pathway. J Pineal Res 2010; 49:156-68. [PMID: 20609072 DOI: 10.1111/j.1600-079x.2010.00780.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The role of matrix metalloproteinases (MMPs) in endometriosis, a gynecological disease of women, is unclear. The study investigated the activity of MMP-3 and its interplay with MMP-9 during the onset of endometriosis. Additionally, the importance of MMP-3 on the apoptotic pathway in endometriosis and effect of melatonin thereon were investigated. A Significant increase in the activity of MMP-3 with the severity of endometriosis in human was observed which was found similar in mice also. During the early phase of endometriosis, MMP-3 but not MMP-9 was increased and associated with the expression of transcription factor, c-Fos. Moreover, urokinase plasminogen activator and tissue inhibitor of metalloproteinase (TIMP)-3 were involved in MMP-3 regulation during endometriosis. Furthermore, MMP-3 activity that was parallel to c-Fos expression in endometriosis was reduced by melatonin pretreatment as characterized by diminished activator protein (AP)-1 DNA-binding activity. Because decreased apoptosis is an explanation for the perpetuation of endometriosis, we tested the role of melatonin on apoptotic pathway in preventing endometriosis. Significant regression of glandular epithelium was observed in melatonin-treated when compared to untreated mice. Melatonin treatment increased apoptotic cells in endometriotic zones. This was related to reduced Bcl-2 expression along with increased Bax expression and caspase-9 activation. In summary, early induction of MMP-3 was distinct from MMP-9 during endometriosis, which was regulated by c-Fos and TIMP-3. Melatonin suppressed MMP-3 activity and amplified apoptosis while regressing endometriosis through a caspase-3 mediated pathway. Thus, melatonin may be a therapeutic agent for resolving endometriosis.
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Affiliation(s)
- Sumit Paul
- Department of Physiology, Indian Institute of Chemical Biology, Kolkata, India
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Yang J, Fan XH, Guan YQ, Li Y, Sun W, Yang XZ, Liu R. MMP-2 gene polymorphisms in type 2 diabetes mellitus diabetic retinopathy. Int J Ophthalmol 2010; 3:137-40. [PMID: 22553537 PMCID: PMC3340781 DOI: 10.3980/j.issn.2222-3959.2010.02.10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Accepted: 05/26/2010] [Indexed: 11/02/2022] Open
Abstract
AIM To study the association between polymorphisms of the MMP-2 gene and diabetic retinopathy (DR). METHODS MMP-2 C-1306T and C-735T SNPs was genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis in 151 DR patients and 150 healthy individuals served as control. RESULTS There is no significant difference between the patient and control groups in allele or genotype distributions of MMP-2 C-735T (P=0.263 and P=0.248). Also, there is no significant difference between the patient and control in allele of MMP-2 C-1306T (P=0.03). However the result has significant deviation of C/C, C/T, T/T genotypic frequencies between the patient and control groups in MMP-2 C-1306T (P=0.008). We found that subjects with the MMP-2 C-1306T genotype had an overall 2-fold increase in the risk of developing DR [adjusted odds ratio (OR)=2.446; 95% confidence interval (CI)=1.239-4.829] compared with those with the T-1306T or C-1306T genotype. Stratification analysis showed that the MMP-2 -1306C/T and -735C/T SNPs are not associated with the development of NPDR to PDR of DR in North Chinese Han population. CONCLUSION MMP-2 C-1306T genotypes may be associated with DR development in the Chinese population. However, there is no relationship between the MMP-2 C-735T genotypes with the development of DR.
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Affiliation(s)
- Jie Yang
- Department of Ophthalmology, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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Immunohistochemical expression of matrix metalloproteinases, their tissue inhibitors, and cathepsin-D in ovarian endometriosis: correlation with severity of disease. Fertil Steril 2010; 94:2470-2. [PMID: 20385381 DOI: 10.1016/j.fertnstert.2010.03.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2009] [Revised: 02/07/2010] [Accepted: 03/03/2010] [Indexed: 11/24/2022]
Abstract
In this study the immunohistochemical expression of matrix metalloproteinases 1, 2, 3, and 9, tissue inhibitors (TIMPs) 1 and 2, and cathepsin-D in ovarian endometriomas were correlated with the clinical severity of endometriosis (i.e., presence of chronic pelvic pain [CPP] and American Society of Reproductive Medicine [ASRM] scores). Positive expression of proteases and their inhibitors was found more frequently in cases with low ASRM scores, whereas presence of CPP correlated significantly with absence of expression of TIMPs 1 and 2, indicating, first, that production of these enzymes is more active during the initial phases of the evolution of ovarian endometriosis, declining as fibrosis develops, and second, that expression of TIMPs seems to play a role in the development of CPP.
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Yi YC, Chou PT, Chen LY, Kuo WH, Shih-Chu Ho E, Han CP, Yang SF. Matrix metalloproteinase-7 (MMP-7) polymorphism is a risk factor for endometrial cancer susceptibility. Clin Chem Lab Med 2010; 48:337-44. [DOI: 10.1515/cclm.2010.082] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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