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Kucukakcali Z, Akbulut S, Colak C. Prediction of genomic biomarkers for endometriosis using the transcriptomic dataset. World J Clin Cases 2025; 13:104556. [DOI: 10.12998/wjcc.v13.i20.104556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/03/2025] [Accepted: 03/13/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Endometriosis is a clinical condition characterized by the presence of endometrial glands outside the uterine cavity. While its incidence remains mostly uncertain, endometriosis impacts around 180 million women worldwide. Despite the presentation of several epidemiological and clinical explanations, the precise mechanism underlying the disease remains ambiguous. In recent years, researchers have examined the hereditary dimension of the disease. Genetic research has aimed to discover the gene or genes responsible for the disease through association or linkage studies involving candidate genes or DNA mapping techniques.
AIM To identify genetic biomarkers linked to endometriosis by the application of machine learning (ML) approaches.
METHODS This case-control study accounted for the open-access transcriptomic data set of endometriosis and the control group. We included data from 22 controls and 16 endometriosis patients for this purpose. We used AdaBoost, XGBoost, Stochasting Gradient Boosting, Bagged Classification and Regression Trees (CART) for classification using five-fold cross validation. We evaluated the performance of the models using the performance measures of accuracy, balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value and F1 score.
RESULTS Bagged CART gave the best classification metrics. The metrics obtained from this model are 85.7%, 85.7%, 100%, 75%, 75%, 100% and 85.7% for accuracy, balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value and F1 score, respectively. Based on the variable importance of modeling, we can use the genes CUX2, CLMP, CEP131, EHD4, CDH24, ILRUN, LINC01709, HOTAIR, SLC30A2 and NKG7 and other transcripts with inaccessible gene names as potential biomarkers for endometriosis.
CONCLUSION This study determined possible genomic biomarkers for endometriosis using transcriptomic data from patients with/without endometriosis. The applied ML model successfully classified endometriosis and created a highly accurate diagnostic prediction model. Future genomic studies could explain the underlying pathology of endometriosis, and a non-invasive diagnostic method could replace the invasive ones.
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Affiliation(s)
- Zeynep Kucukakcali
- Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
| | - Sami Akbulut
- Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
| | - Cemil Colak
- Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
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Bhamidipaty-Pelosi S, Kyei-Barffour I, Volpert M, O'Neill N, Grimshaw A, Eriksson L, Vash-Margita A, Pelosi E. Müllerian anomalies and endometriosis: associations and phenotypic variations. Reprod Biol Endocrinol 2024; 22:157. [PMID: 39702195 DOI: 10.1186/s12958-024-01336-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 12/13/2024] [Indexed: 12/21/2024] Open
Abstract
Müllerian anomalies are congenital conditions characterized by the incomplete development of the female reproductive tract. Women affected by Müllerian anomalies often display additional malformations of the renal, skeletal, and cardiovascular system, and are at a higher risk for infertility and adverse pregnancy outcomes. Several Müllerian anomalies have been reported in association with endometriosis, but it is unclear if all classes or anatomical variations are associated with the disease. Most importantly, both Müllerian anomalies and endometriosis can manifest with a wide degree of variability, adding further complexity to their poorly defined relationship. Retrograde menstruation occurring in obstructive Müllerian anomalies is a well-accepted mechanism for the development of endometriosis. However, endometriosis can occur following surgical correction of the anomaly or in the absence of obstruction. This suggests that other mechanisms may be involved, although the specific pathogenesis remains elusive. This review provides a comprehensive summary of the current state of clinical research on endometriosis in Müllerian anomalies. This review also highlights research and knowledge gaps, informing the development of future experimental designs to address current limitations including heterogeneity of phenotypes, variable comorbidities, and lack of genetic information.
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Affiliation(s)
- Surya Bhamidipaty-Pelosi
- Department of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA
- Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD, Australia
| | - Isaac Kyei-Barffour
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Marianna Volpert
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Nora O'Neill
- Division of Pediatric and Adolescent Gynecology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
| | - Alyssa Grimshaw
- Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA
| | - Lars Eriksson
- Herston Health Sciences Library, The University of Queensland, Brisbane, QLD, Australia
| | - Alla Vash-Margita
- Division of Pediatric and Adolescent Gynecology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
| | - Emanuele Pelosi
- Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
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3
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Encalada Soto D. Navigating towards precision: evaluating the clinical value of non-invasive biomarkers for the diagnosis of endometriosis. Minerva Obstet Gynecol 2024; 76:564-577. [PMID: 38576337 DOI: 10.23736/s2724-606x.23.05313-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]
Abstract
INTRODUCTION Endometriosis is a chronic disease that affects millions of women worldwide, causing dysmenorrhea, chronic pain, and infertility, and has a significant impact on the healthcare system. Despite efforts to understand its pathogenesis, endometriosis is a disease with heterogeneous presentations and phenotypes which is manifested in part by the lack of a non-invasive biomarker available for its diagnosis. This review aims to bridge the gap between theory and practice by summarizing the most promising areas of study for developing a reliable biomarker or combination of biomarkers for the non-invasive diagnosis of endometriosis. EVIDENCE ACQUISITION We conducted a comprehensive literature search using the electronic databases PubMed and MEDLINE. EVIDENCE SYNTHESIS This review summarizes the potential biomarkers for endometriosis, including glycoproteins, inflammatory markers, immunologic markers, angiogenic cytokines, micro RNAs and the microbiome. Each of these biomarkers' role in the development and progression of endometriosis, and their diagnostic potential are discussed in detail. CONCLUSIONS Endometriosis is a complex and underdiagnosed disease with significant health impact. The development of non-invasive biomarkers for its diagnosis would be immensely valuable, and promising research is being done in this area. While no single biomarker has yet emerged as a reliable diagnostic tool, this review highlights the potential of several biomarkers and the importance of continued research in this field. By improving the diagnosis of endometriosis, we can improve the lives of millions of women worldwide.
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Affiliation(s)
- Diana Encalada Soto
- Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL, USA -
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Shim JY. Dysmenorrhea and Endometriosis in Adolescents. Obstet Gynecol Clin North Am 2024; 51:651-661. [PMID: 39510736 DOI: 10.1016/j.ogc.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Endometriosis is a chronic disorder often beginning in adolescence. Despite the high prevalence of the disease and the symptom burden, adolescents may experience suboptimal management and a delay in diagnosis. The symptoms and laparoscopic findings in adolescents with endometriosis may differ from that of adults. This article aims to equip readers with the tools necessary to diagnose and manage endometriosis in adolescents.
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Affiliation(s)
- Jessica Y Shim
- Division of Gynecology, Department of Surgery, Boston Children's Hospital, Boston, MA, USA; Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
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5
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Rempert AN, Rempert TH, Liu A, Hernández A, Blanck J, Segars J, Singh B. A Systematic Review of the Psychosocial Impact of Endometriosis before and after Treatment. Reprod Sci 2024; 31:1828-1860. [PMID: 38512699 PMCID: PMC11216884 DOI: 10.1007/s43032-024-01515-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 02/28/2024] [Indexed: 03/23/2024]
Abstract
While endometriosis is a common gynecologic disease associated with infertility, the psychosocial impact of endometriosis has not been evaluated against various quality of life (QoL) instruments and compared with other chronic illnesses. We rigorously analyzed the psychosocial burden of endometriosis in adult women and compared standardized and validated QoL scores of women with and without endometriosis, before and following treatment, and against other chronic illnesses. We searched PubMed, PsychINFO Embase, and Cochrane Reviews and ClinicalTrials.gov from January 1990 to December 2022 for publications using a detailed list of search terms related to QoL, endometriosis, and questionnaires. Only English-language publications that evaluated the association between Endometriosis and QoL using standardized and validated questionnaires measured at baseline and following treatment were considered. Four reviewers first performed a title and abstract screening followed by full text-review to finalize included articles. QoL scores of women with endometriosis were measured at baseline and analyzed against women without endometriosis and women with endometriosis who had undergone treatment. Additionally, baseline endometriosis scores were assessed against the published QoL scores of populations with other chronic conditions. Assessment of risk of bias was performed in accordance with Cochrane and Newcastle-Ottawa Scale guidelines. A total of 30 articles were included in this review: 4 randomized trials and 26 observational studies. The diagnosis and experience of women with symptomatic endometriosis had an equal or worse QoL score than that of other chronic conditions including heart disease, diabetes, and breast cancer when compared using the 36-Item Short Form Survey and World Health Organization Quality of Life questionnaires. Evidence showed association between low QoL and infertility, sexual dysfunction, mental health struggles, physical pain, poor sleep and fatigue. QoL scores were lower at baseline compared to following treatment in the majority of these domains. Endometriosis is associated with significant psychosocial burden and impaired QoL scores across baseline measurements in comparison to controls and other chronic illnesses. Medical and surgical interventions significantly decreased experienced burdens and improved QoL of women with endometriosis.
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Affiliation(s)
- Ashley N Rempert
- Department of Biology, Johns Hopkins University, Baltimore, MD, USA
| | - Trevor H Rempert
- Department of Physiology and Biophysics, Casewestern Reserve University, Cleveland, OH, USA
| | - Amy Liu
- Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA
| | - Ana Hernández
- Department of Biology, Johns Hopkins University, Baltimore, MD, USA
| | - Jaime Blanck
- Informationist Services, Welch Medical Library, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James Segars
- Department of Gynecology and Obstetrics, Division of Reproductive Sciences &, Women's Health Research, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 624, Baltimore, MD, USA
| | - Bhuchitra Singh
- Department of Gynecology and Obstetrics, Division of Reproductive Sciences &, Women's Health Research, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 624, Baltimore, MD, USA.
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Liu M, Peng R, Tian C, Shi J, Ma J, Shi R, Qi X, Zhao R, Guan H. Effects of the gut microbiota and its metabolite short-chain fatty acids on endometriosis. Front Cell Infect Microbiol 2024; 14:1373004. [PMID: 38938880 PMCID: PMC11208329 DOI: 10.3389/fcimb.2024.1373004] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 05/31/2024] [Indexed: 06/29/2024] Open
Abstract
In recent years, a growing body of research has confirmed that the gut microbiota plays a major role in the maintenance of human health and disease. A gut microbiota imbalance can lead to the development of many diseases, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome, endometriosis, and cancer. Short-chain fatty acids are metabolites of specific intestinal bacteria and are crucial for maintaining intestinal homeostasis and regulating metabolism and immunity. Endometriosis is the result of cell proliferation, escape from immune surveillance, and invasive metastasis. There is a strong correlation between the anti-proliferative and anti-inflammatory effects of short-chain fatty acids produced by gut microbes and the development of endometriosis. Given that the mechanism of action of gut microbiota and Short-chain fatty acids in endometriosis remain unclear, this paper aims to provide a comprehensive review of the complex interactions between intestinal flora, short-chain fatty acids and endometriosis. In addition, we explored potential microbial-based treatment strategies for endometriosis, providing new insights into the future development of diagnostic tests and prevention and treatment methods for endometriosis.
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Affiliation(s)
- Menghe Liu
- College of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Ru Peng
- Department of Obstetrics and Gynecology, Hohhot Maternal and Child Health Care Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Chunfang Tian
- Department of Oncology, Inner Mongolia Traditional Chinese Medicine Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Jianping Shi
- College of Traditional Chinese Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Jiannan Ma
- College of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Ruiwen Shi
- College of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Xiao Qi
- College of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Rongwei Zhao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Haibin Guan
- College of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
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Zyguła A, Sankiewicz A, Sakowicz A, Dobrzyńska E, Dakowicz A, Mańka G, Kiecka M, Spaczynski R, Piekarski P, Banaszewska B, Jakimiuk A, Issat T, Rokita W, Młodawski J, Szubert M, Sieroszewski P, Raba G, Szczupak K, Kluza T, Kluza M, Pierzyński P, Wojtyla C, Lipa M, Warzecha D, Wielgos M, Cendrowski K, Gorodkiewicz E, Laudanski P. Is the leptin/BMI ratio a reliable biomarker for endometriosis? Front Endocrinol (Lausanne) 2024; 15:1359182. [PMID: 38567305 PMCID: PMC10985179 DOI: 10.3389/fendo.2024.1359182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
Background The aim of this study was to analyze the concentration of leptin in peritoneal fluid and plasma and to assess their role as potential biomarkers in the diagnosis of endometriosis. Materials & methods Leptin adjusted for BMI (leptin/BMI ratio) was measured using surface plasmon resonance imaging (SPRI) biosensors. Patients with suspected endometriosis were included in the study. Plasma was collected from 70 cases, and peritoneal fluid from 67 cases. Based on the presence of endometriosis lesions detected during laparoscopy, patients were divided into a study group and a control group (patients without endometriosis). Results Leptin/BMI ratio in plasma did not differ between women with endometriosis and the control group (0.7159 ± 0.259 vs 0.6992 ± 0.273, p= 0,7988). No significant differences were observed in peritoneal leptin/BMI ratio levels in patients with and without endometriosis (0.6206 ± 0.258 vs 0.6215 ± 0.264, p= 0,9896). Plasma and peritoneal leptin/BMI ratios were significantly lower in women with endometriosis - related primary infertility compared to women with endometriosis without primary infertility (0.640 ± 0.502 vs 0.878 ± 0.623, p < 0.05). The difference was observed in case of primary infertility, but not in terms of the secondary one. No significant differences were noted between leptin/BMI ratio in the proliferative phase and the secretory phase (0.716 ± 0.252 vs 0.697 ± 0.288, p= 0,7785). Conclusion The results of present study do not support the relevance of leptin concentration determination as a biomarker of the endometriosis. Due to the limited number of samples in the tested group, further studies are needed to confirm its role.
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Affiliation(s)
| | - Anna Sankiewicz
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Bialystok, Poland
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland
| | - Ewa Dobrzyńska
- Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Dakowicz
- Department of Rehabilitation, Medical University of Bialystok, Bialystok, Poland
| | | | | | - Robert Spaczynski
- Center for Gynecology, Obstetrics and Infertility Treatment Pastelova, Poznan, Poland
- Collegium Medicum, University of Zielona Gora, Zielona Gora, Poland
| | - Piotr Piekarski
- Gynecological Obstetric Clinical Hospital of Poznan University of Medical Sciences, Minimally Invasive Gynecological Surgery, Poznan, Poland
| | - Beata Banaszewska
- Chair and Department of Laboratory Diagnostics, Poznan University of Medical Sciences, Poznan, Poland
| | - Artur Jakimiuk
- Department of Reproductive Health, Institute of Mother and Child in Warsaw, 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 in Warsaw, 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
- Medical College of Rzeszow University, Rzeszow, Poland
| | - Kamil Szczupak
- Clinic of Obstetric and Gynecology in Przemysl, Przemysl, Poland
- Medical College of Rzeszow University, Rzeszow, Poland
| | - Tomasz Kluza
- 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
| | | | - Cezary Wojtyla
- OVIklinika Infertility Center, Warsaw, Poland
- Women’s Health Research Institute, Calisia University, Kalisz, Poland
| | - Michal Lipa
- Departament of Obstetrics and Perinatology National Medical Institute of the Ministry of Interior and Administration, Warsaw, Poland
| | - Damian Warzecha
- OVIklinika Infertility Center, Warsaw, Poland
- City South Hospital, Warsaw, Warsaw, Poland
- Department of Biomedical Fundamentals of Development and Sexology, Faculty of Education, University of Warsaw, Warsaw, Poland
| | - Miroslaw Wielgos
- Departament of Obstetrics and Perinatology National Medical Institute of the Ministry of Interior and Administration, Warsaw, Poland
- Premium Medical Clinic, Warsaw, Poland
- Medical Faculty, Lazarski University, Warsaw, Poland
| | - Krzysztof Cendrowski
- Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Gorodkiewicz
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Bialystok, Poland
| | - Piotr Laudanski
- OVIklinika Infertility Center, Warsaw, Poland
- Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland
- Women’s Health Research Institute, Calisia University, Kalisz, Poland
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8
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Vallée A, Ceccaldi PF, Carbonnel M, Feki A, Ayoubi JM. Pollution and endometriosis: A deep dive into the environmental impacts on women's health. BJOG 2024; 131:401-414. [PMID: 37814514 DOI: 10.1111/1471-0528.17687] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND The interaction between pollution and endometriosis is a pressing issue that demands immediate attention. The impact of pollution, particularly air and water pollution, or occupational hazards, on hormonal disruption and the initiation of endometriosis remains a major issue. OBJECTIVES This narrative review aims to delve into the intricate connection between pollution and endometriosis, shedding light on how environmental factors contribute to the onset and severity of this disease and, thus, the possible public health policy implications. DISCUSSION Endocrine-disrupting chemicals (EDCs) in pollutants dysregulate the hormonal balance, contributing to the progression of this major gynaecological disorder. Air pollution, specifically PM2.5 and PAHs, has been associated with an increased risk of endometriosis by enhancing chronic inflammation, oxidative stress, and hormonal imbalances. Chemical contaminants in water and work exposures, including heavy metals, dioxins, and PCBs, disrupt the hormonal regulation and potentially contribute to endometriosis. Mitigating the environmental impact of pollution is required to safeguard women's reproductive health. This requires a comprehensive approach involving stringent environmental regulations, sustainable practices, responsible waste management, research and innovation, public awareness, and collaboration among stakeholders. CONCLUSION Public health policies have a major role in addressing the interaction between pollution and endometriosis in a long-term commitment.
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Affiliation(s)
- Alexandre Vallée
- Department of Epidemiology and Public Health, Foch Hospital, Suresnes, France
| | - Pierre-François Ceccaldi
- Department of Obstetrics, Gynaecology and Reproductive Medicine, Foch Hospital, Suresnes, France
- Medical School, University of Versailles, Saint-Quentin-en-Yvelines (UVSQ), Versailles, France
| | - Marie Carbonnel
- Department of Obstetrics, Gynaecology and Reproductive Medicine, Foch Hospital, Suresnes, France
- Medical School, University of Versailles, Saint-Quentin-en-Yvelines (UVSQ), Versailles, France
| | - Anis Feki
- Department of Gynaecology and Obstetrics, University Hospital of Fribourg, Fribourg, Switzerland
| | - Jean-Marc Ayoubi
- Department of Obstetrics, Gynaecology and Reproductive Medicine, Foch Hospital, Suresnes, France
- Medical School, University of Versailles, Saint-Quentin-en-Yvelines (UVSQ), Versailles, France
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9
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Cook CJ, Wiggin N, Fogg KC. Characterizing the Extracellular Matrix Transcriptome of Endometriosis. Reprod Sci 2024; 31:413-429. [PMID: 37789126 PMCID: PMC10827821 DOI: 10.1007/s43032-023-01359-w] [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: 03/13/2023] [Accepted: 09/12/2023] [Indexed: 10/05/2023]
Abstract
In recent years, the matrisome, a set of proteins that make up the extracellular matrix (ECM) or are closely involved in ECM behavior, has been shown to have great importance for characterizing and understanding disease pathogenesis and progression. The matrisome is especially critical for examining diseases characterized by extensive tissue remodeling. Endometriosis is characterized by the extrauterine growth of endometrial tissue, making it an ideal condition to study through the lens of matrisome gene expression. While large gene expression datasets have become more available and gene dysregulation in endometriosis has been the target of several studies, the gene expression profile of the matrisome specifically in endometriosis has not been well characterized. In our study, we explored four Gene Expression Omnibus (GEO) DNA microarray datasets containing eutopic endometrium of people with and without endometriosis. After batch correction, menstrual cycle phase accounted for 53% of variance and disease accounted for 23%; thus, the data were separated by menstrual cycle phase before performing differential expression analysis, statistical and machine learning modeling, and enrichment analysis. We established that matrisome gene expression alone can effectively differentiate endometriosis samples from healthy ones, demonstrating the potential of matrisome gene expression for diagnostic applications. Furthermore, we identified specific matrisome genes and gene networks whose expression can distinguish endometriosis stages I/II from III/IV. Taken together, these findings may aid in developing future in vitro models of disease, offer insights into novel treatment strategies, and advance diagnostic tools for this underserved patient population.
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Affiliation(s)
- Carson J Cook
- Bioengineering, Oregon State University, Corvallis, OR, 97331, USA
| | - Noah Wiggin
- Computer Science, Oregon State University, Corvallis, OR, 97331, USA
| | - Kaitlin C Fogg
- Bioengineering, Oregon State University, Corvallis, OR, 97331, USA.
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10
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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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11
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Szaflik T, Romanowicz H, Szyłło K, Smolarz B. Long Non-Coding RNA SNHG4 Expression in Women with Endometriosis: A Pilot Study. Genes (Basel) 2023; 14:152. [PMID: 36672893 PMCID: PMC9859099 DOI: 10.3390/genes14010152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Endometriosis is a chronic disease of the genital organs that mainly affects women of reproductive age. The analysis of long non-coding RNA (lncRNA) in endometriosis is a novel field of science. Recently, attention has been drawn to SNHG4, which is incorrectly expressed in various human diseases, including endometriosis. AIM The aim of this pilot study was to analyze the expression of lncRNA small nucleolar RNA host gene 4 (SNHG4) and to investigate its significance in endometriosis. MATERIAL AND METHODS LncRNA SNHG4 expression was investigated in paraffin blocks in endometriosis patients (n = 100) and in endometriosis-free controls (n = 100) using a real-time PCR assay. RESULTS This study revealed a higher expression of SNHG4 in endometriosis patients than in controls. A statistically significant relationship between expression level and SNHG4 was found in relation to The Revised American Society for Reproductive Medicine classification of endometriosis, 1996, in the group of patients with endometriosis. CONCLUSION This pilot study has revealed that gene expression in SNHG4 plays an important role in the pathogenesis of endometriosis.
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Affiliation(s)
- Tomasz Szaflik
- Department of Gynaecology, Oncological Gynaecology and Endometriosis Treatment, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
| | - Hanna Romanowicz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Krzysztof Szyłło
- Department of Gynaecology, Oncological Gynaecology and Endometriosis Treatment, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
| | - Beata Smolarz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
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12
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Xie C, Lu C, Liu Y, Liu Z. Diagnostic gene biomarkers for predicting immune infiltration in endometriosis. BMC Womens Health 2022; 22:184. [PMID: 35585523 PMCID: PMC9118874 DOI: 10.1186/s12905-022-01765-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 05/06/2022] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To determine the potential diagnostic markers and extent of immune cell infiltration in endometriosis (EMS). METHODS Two published profiles (GSE7305 and GSE25628 datasets) were downloaded, and the candidate biomarkers were identified by support vector machine recursive feature elimination analysis and a Lasso regression model. The diagnostic value and expression levels of biomarkers in EMS were verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, then further validated in the GSE5108 dataset. CIBERSORT was used to estimate the composition pattern of immune cell components in EMS. RESULTS One hundred and fifty-three differential expression genes (DEGs) were identified between EMS and endometrial with 83 upregulated and 51 downregulated genes. Gene sets related to arachidonic acid metabolism, cytokine-cytokine receptor interactions, complement and coagulation cascades, chemokine signaling pathways, and systemic lupus erythematosus were differentially activated in EMS compared with endometrial samples. Aquaporin 1 (AQP1) and ZW10 binding protein (ZWINT) were identified as diagnostic markers of EMS, which were verified using qRT-PCR and western blotting and validated in the GSE5108 dataset. Immune cell infiltrate analysis showed that AQP1 and ZWINT were correlated with M2 macrophages, NK cells, activated dendritic cells, T follicular helper cells, regulatory T cells, memory B cells, activated mast cells, and plasma cells. CONCLUSION AQP1 and ZWINT could be regarded as diagnostic markers of EMS and may provide a new direction for the study of EMS pathogenesis in the future.
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Affiliation(s)
- Chengmao Xie
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
| | - Chang Lu
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Yong Liu
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Zhaohui Liu
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
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13
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Alkattan A, Alkhalifah A, Alsalameen E, Alghanim F, Radwan N. Polymorphisms of genes related to phase II metabolism and resistance to clopidogrel. Pharmacogenomics 2021; 23:61-79. [PMID: 34866404 DOI: 10.2217/pgs-2021-0092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Clopidogrel is an antiplatelet drug commonly used to prevent coagulation. This review aimed to investigate the effect of polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK and GLRX genes on clopidogrel during phase II metabolism through exploring previous studies. The results revealed that low glutathione plasma levels caused by several alleles related to these genes could affect the bioactivation process of the clopidogrel prodrug, making it unable to inhibit platelet aggregation perfectly and thus leading to severe consequences in patients with a high risk of blood coagulation. However, the study recommends platelet reactivity tests to predict clopidogrel efficacy rather than studying gene mutations, as most of these mutations are rare and other nongenetic factors could affect the drug's efficacy.
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Affiliation(s)
- Abdullah Alkattan
- Planning and Research Department, General Directorate of School Health, Ministry of Health, Riyadh 11176, Saudi Arabia
| | - Ahmed Alkhalifah
- Department of Sales, Fresenius Kabi, Alhaya Medical Company, Riyadh, Saudi Arabia
| | - Eman Alsalameen
- Department of Pharmacy, King Khalid University Hospital, Medical City King Saud University, Riyadh, Saudi Arabia
| | - Fatimah Alghanim
- Department of General Medicine, Faculty of Medicine, Imam Abdulrahman bin Faisal University
| | - Nashwa Radwan
- Department of Public Health & Community Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt.,Department of Research, Assisting Deputyship for Primary Health Care, Ministry of Heath, Riyadh, Saudi Arabia
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14
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Salliss ME, Farland LV, Mahnert ND, Herbst-Kralovetz MM. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain. Hum Reprod Update 2021; 28:92-131. [PMID: 34718567 DOI: 10.1093/humupd/dmab035] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 08/25/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Endometriosis is a chronic, burdensome condition that is historically understudied. Consequently, there is a lack of understanding of the etiology of the disease and its associated symptoms, including infertility and chronic pelvic pain (CPP). Endometriosis development is influenced by estrogen metabolism and inflammation, which are modulated by several factors including the microbiome and the estrobolome (the collection of genes encoding estrogen-metabolizing enzymes in the gut microbiome). Therefore, there is increasing interest in understanding the role of microbiota in endometriosis etiology. OBJECTIVE AND RATIONALE To date, there is no cure for endometriosis and treatment options often are ineffective. This manuscript will review the potential relationship between the microbiome and endometriosis, infertility and CPP and highlight the available data on the microbiome in relation to endometriosis and its related symptoms. The overarching goal of this manuscript is to inform future microbiome research that will lead to a deeper understanding of the etiology of the disease and possible diagnostic modalities and treatments. The potential impact of the microbiome on estrogen regulation modulated by the estrobolome, as well as inflammation and other endometriosis-promoting mechanisms within the genital tract, will be reviewed. The methodological limitations of microbiome-related studies will be critically assessed to provide improved guidelines for future microbiome and clinical studies. SEARCH METHODS PubMed databases were searched using the following keywords: endometriosis AND microbiome, infertility AND microbiome, pelvic pain AND microbiome, IVF (in-vitro fertilization) AND microbiome, endometriosis AND infertility. Clinical and preclinical animal trials that were eligible for review, and related to microbiome and endometriosis, infertility or CPP were included. All available manuscripts were published in 2002-2021. OUTCOMES In total, 28 clinical and 6 animal studies were included in the review. In both human and animal studies, bacteria were enriched in endometriosis groups, although there was no clear consensus on specific microbiota compositions that were associated with endometriosis, and no studies included infertility or CPP with endometriosis. However, bacterial vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority (23/28) of studies. Interpretation of endometrial studies is limited owing to a variety of methodological factors, discussed in this review. In addition, metadata outlining antibiotic usage, age, race/ethnicity, menopausal status and timing of sample collection in relation to diagnosis of endometriosis was not consistently reported. Animal studies (6/6) support a bidirectional relationship between the gut microbiota and endometriosis onset and progression. WIDER IMPLICATIONS There is evidence that a dysbiotic gut or genital microbiota is associated with multiple gynecologic conditions, with mounting data supporting an association between the microbiome and endometriosis and infertility. These microbiomes likely play a role in the gut-brain axis, which further supports a putative association with the spectrum of symptoms associated with endometriosis, including infertility and CPP. Collectively, this review highlights the demand for more rigorous and transparent methodology and controls, consistency across the field, and inclusion of key demographic and clinical characteristics of disease and comparison participants. Rigorous study designs will allow for a better understanding of the potential role of the microbiome in endometriosis etiology and the relationship to other disorders of the female reproductive tract.
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Affiliation(s)
- Mary E Salliss
- Department of Obstetrics and Gynecology, University of Arizona-College of Medicine, Phoenix, AZ, USA.,Department of Biology and Biochemistry, Bath University, Bath, UK
| | - Leslie V Farland
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.,Department of Obstetrics and Gynecology, University of Arizona-College of Medicine Tucson, Tucson, AZ, USA
| | - Nichole D Mahnert
- Department of Obstetrics and Gynecology, University of Arizona-College of Medicine, Phoenix, AZ, USA.,Department of Obstetrics and Gynecology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA
| | - Melissa M Herbst-Kralovetz
- Department of Obstetrics and Gynecology, University of Arizona-College of Medicine, Phoenix, AZ, USA.,Department of Basic Medical Sciences, University of Arizona-College of Medicine, Phoenix, AZ, USA
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15
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Novel diagnostic options for endometriosis - Based on the glycome and microbiome. J Adv Res 2021; 33:167-181. [PMID: 34603787 PMCID: PMC8463906 DOI: 10.1016/j.jare.2021.01.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/10/2020] [Accepted: 01/24/2021] [Indexed: 01/09/2023] Open
Abstract
Background Endometriosis is a chronic gynaecological disease whose aetiology is still unknown. Despite its prevalence among women of reproductive age, the pathology of the disease has not yet been elucidated and only symptomatic treatment is available. Endometriosis has high latency and diagnostic methods are both limited and invasive. Aim of review The aim of this review is to summarise minimally invasive or non-invasive diagnostic methods for endometriosis and their diagnostic efficiencies. Furthermore, we discuss the identification and diagnostic potential of novel disease biomarkers of microbial or glycan origin. Key scientific concepts of review Great efforts have been made to develop minimally invasive or non-invasive diagnostic methods in endometriosis. The problem with most potential biomarker candidates is that they have high accuracy only in cases of severe disease. Therefore, it is necessary to examine other potential biomarkers more closely. Associations between gastrointestinal and genital tract microbial health and endometriosis have been identified. For instance, irritable bowel syndrome is more common in women with endometriosis, and hormonal imbalance has a negative impact on the microbiome of both the genital tract and the gastrointestinal system. Further interrogation of these associations may have potential diagnostic significance and may identify novel therapeutic avenues. Glycomics may also be a potent source of biomarkers of endometriosis, with a number of glyco-biomarkers already approved by the FDA. Endometriosis-associated microbial and glycomic profiles may represent viable targets for development of innovative diagnostics in this debilitating disease.
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16
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Kim HJ, Lee HS, Kazmi SZ, Hann HJ, Kang T, Cha J, Choi S, Swan H, Kim H, Lee YS, Ahn HS. Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings. BJOG 2021; 128:1938-1948. [PMID: 34028167 DOI: 10.1111/1471-0528.16769] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI). DESIGN, SETTING AND POPULATION Population-based nationwide cohort study. METHODS Using data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2 109 288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale. MAIN OUTCOME MEASURES IRR of endometriosis among women with and without affected siblings. RESULTS From 19 195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10 000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25-3.36), and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19-11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43-7.55), 3.47 (95% CI 2.82-4.26) and 3.09 (95% CI 2.68-3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant. CONCLUSION Genetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene-environment interaction exists between family history and smoking or early menarche.
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Affiliation(s)
- H J Kim
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
| | - H-S Lee
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
| | - S Z Kazmi
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
| | - H J Hann
- Medical Research Institute, College of Medicine, Ewha Womans University, Seoul, Korea
| | - T Kang
- Health and Wellness College, Sungshin Women's University, Seoul, Korea
| | - J Cha
- Department of Public Health, Korea University, Seoul, Korea
| | - S Choi
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
| | - H Swan
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
| | - H Kim
- Department of Obstetrics and Gynaecology, Seoul National University Hospital, Seoul, Korea
| | - Y S Lee
- Department of Health Informatics and Management, College of Medicine, Chungbuk National University, Cheongju, Korea
| | - H S Ahn
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
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17
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Benagiano G, Bianchi P, Guo SW. Endometriosis in adolescent and young women. Minerva Obstet Gynecol 2021; 73:523-535. [PMID: 33876904 DOI: 10.23736/s2724-606x.21.04764-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Endometriosis in adolescence represents a specific variant of the disease with its own characteristics and, in some cases, even a possibly different pathogenesis. It has its own clinical presentation, diagnostic and therapeutic modalities. The condition is not rare as once thought and certainly deserves attention in view of increasing evidence of its likely progressive nature. Numerous theories for Its pathogenesis have been formulated and they have been divided into two main categories: the 'in-situ' and the 'transplantation' hypotheses. Clinical manifestations include as the prevailing symptom a persistent chronic pelvic pain, despite medical treatment, manifested under various forms: dysmenorrhea, acyclic chronic pain, acute abdominal pain and migraines. These symptoms can substantially affect the quality of life on an adolescent. At histopathology, adolescent endometriosis is characterized by a high proportion of subtle, clear, red or vesicular implants and by the rarity of deep nodules. Frequently, the picture includes ovarian endometriomas. In some adolescent girls, lesions may regress or even disappear, probably through immune suppression; in others, chronic stress, unhealthy diet or lifestyle such as high-fat diet, may accelerate lesional progression and cause symptoms. Classically, management of adolescent endometriosis has been centered on attempts to treat dysmenorrhea; today both medical and surgical modalities have the potential to improve quality of life, alleviate symptoms, prevent the development of more severe disease and minimize risks for future fertility in adolescents. Nonetheless, at present, medical treatments are considered the first line of interventions in treating young women.
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Affiliation(s)
- Giuseppe Benagiano
- Department of Maternal and Child Health, Gynecology and Urology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy -
| | - Paola Bianchi
- Department of Medico-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Sun-Wei Guo
- Shanghai Obstetrics & Gynecology Hospital, Fudan University, Shanghai, China
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Chou YC, Chen MJ, Chen PH, Chang CW, Yu MH, Chen YJ, Tsai EM, Tsai SF, Kuo WS, Tzeng CR. Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes. Sci Rep 2021; 11:478. [PMID: 33436679 PMCID: PMC7803948 DOI: 10.1038/s41598-020-79515-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023] Open
Abstract
To determine whether genetic predisposition to endometriosis varies depending on ethnicity and in association with expression quantitative trait loci (eQTL) in a Taiwanese population. We conducted a genome-wide association study (GWAS) and replicated it in 259 individuals with laparoscopy-confirmed stage III or IV endometriosis (cases) and 171 women without endometriosis (controls). Their genomic DNA was extracted from blood and evaluated by the GWAS of Taiwan Biobank Array. Novel genetic variants that predispose individuals to endometriosis were identified using GWAS and replication, including rs10739199 (P = 6.75 × 10-5) and rs2025392 (P = 8.01 × 10-5) at chromosome 9, rs1998998 (P = 6.5 × 10-6) at chromosome 14, and rs6576560 (P = 9.7 × 10-6) at chromosome 15. After imputation, strong signals were exhibited by rs10822312 (P = 1.80 × 10-7) at chromosome 10, rs58991632 (P = 1.92 × 10-6) and rs2273422 (P = 2.42 × 10-6) at chromosome 20, and rs12566078 (P = 2.5 × 10-6) at chromosome 1. We used the Genotype-Tissue Expression (GTEx) database to observe eQTL. Among these SNPs, the cis-eQTL rs13126673 of inturned planar cell polarity protein (INTU) showed significant association with INTU expression (P = 5.1 × 10-33). Moreover, the eQTL analysis was performed on endometriotic tissues from women with endometriosis. The expression of INTU in 78 endometriotic tissue of women with endometriosis is associated with rs13126673 genotype (P = 0.034). To our knowledge, this is the first GWAS to link endometriosis and eQTL in a Taiwanese population.
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Affiliation(s)
- Ya-Ching Chou
- Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.,Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, Hsinchu, Taiwan.,Center for Reproductive Medicine and Sciences, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan.,Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ming-Jer Chen
- Department of Obstetrics and Gynecology and Women's Health, Taichung Veterans General Hospital, Taichung, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Pi-Hua Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ching-Wen Chang
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Mu-Hsien Yu
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Jen Chen
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Eing-Mei Tsai
- General Research Centers of R&D Office, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Shih-Feng Tsai
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Wun-Syuan Kuo
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chii-Ruey Tzeng
- Center for Reproductive Medicine and Sciences, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan. .,Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Vignali M, Pisoni S, Gentilini D, Spada E, Solima E, Viganò P, Candiani M, Busacca M, DI Blasio AM. Hormonal therapy potentiates the effect of surgery on gene expression profile of peripheral blood mononuclear cells in patients affected by endometriosis. Minerva Endocrinol (Torino) 2020; 46:90-98. [PMID: 33269572 DOI: 10.23736/s2724-6507.20.03298-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Combined oral contraceptives (COCs) represent a common pharmacological approach for endometriosis. They have been demonstrated to mitigate painful symptoms in patients and are considered the first line therapy for symptomatic disease. The goal of this study was to evaluate whether the presence of pelvic endometriotic lesions can exert a systemic effect on PBMC gene expression and to investigate whether hormonal treatment may restore a normal gene expression profile. METHODS Forty women, with endometriosis at stage III-IV, were enrolled in the study. After surgery, 20, randomly chosen, were treated with COC for six months and 20 did not receive hormonal therapy. Blood samples were obtained few days before surgery and six months after surgery. Gene expression profile of PBMC was studied by microarray. Gene expression levels before surgery and post-surgery, in presence and absence of COC, were compared. RESULTS Nine genes previously reported to be overexpressed by endometriosis, were confirmed to be significantly downregulated after surgery. COC treatment lead to a greater down-regulation of these genes and to a significant down-regulation of 3 additional genes. 145 genes resulted downregulated and 28 upregulated by comparing gene expression before surgery with that 6 months after surgery in the presence of COC therapy. CONCLUSIONS Results support the concept that a systemic chronic inflammatory status is among the mechanisms underlying endometriosis. Moreover, they shed light into the mechanisms of action of COCs and strength the rationale for their use to improve quality of life of women affected by the disease.
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Affiliation(s)
- Michele Vignali
- Department of Biomedical Health Sciences, M. Melloni Hospital, University of Milan, Milan, Italy
| | - Serena Pisoni
- Laboratory of Molecular Biology, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Davide Gentilini
- Laboratory of Molecular Biology, IRCCS Istituto Auxologico Italiano, Milan, Italy.,Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - Elena Spada
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | | | - Paola Viganò
- Division of Genetics and Cell Biology, Laboratory of Reproductive Sciences, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Candiani
- Unit of Obstetrics and Gynecology, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Mauro Busacca
- Department of Biomedical Health Sciences, M. Melloni Hospital, University of Milan, Milan, Italy
| | - Anna M DI Blasio
- Laboratory of Molecular Biology, IRCCS Istituto Auxologico Italiano, Milan, Italy -
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20
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Serum Leptin as a Marker for Severity of Endometriosis. Obstet Gynecol Int 2020; 2020:6290693. [PMID: 32963544 PMCID: PMC7492927 DOI: 10.1155/2020/6290693] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 12/01/2022] Open
Abstract
Background Endometriosis a disease of theories, and one of the important causes of chronic pelvic pain, dysmenorrhea, dyspareunia, and subfertility. Surgery is the mainstay step for the diagnosis; noninvasive test is the goal in the future. Aim of Study. To test the role of serum leptin in determination of severity of endometriosis. Study Design. A cross-sectional study done in Al-Yarmouk Teaching Hospital from 1st of January 2018 to 1st of January 2019. Methods 60 BMI-matched patients were involved in the study. A study group of 30 patients were operated either by laparoscopy or laparotomy for many reasons diagnosed as endometriosis by histopathology, and 30 normal women as a control group underwent elective surgery. Blood sample was taken from all patients in the theater room when laparoscopy finding went with endometriosis, and classifying according to surgical staging of endometriosis, the level of serum leptin was measured by ELISA using Human LEP (Leptin) ELISA Kit. The recording of finding of laparoscopy after conforming of diagnosis by histopathology was compared with the result of serum leptin. Result The result shows no significant difference between the two groups regarding parity and age; however, the level of serum leptin was significantly high in the endometriosis group than in the control group. The P value was less than 0.05. Also, the result shows no significant differences between serum leptin in both groups according to the symptom but there was a significant difference with surgical staging. The mean of the level of serum leptin in stage 1 was 214.8, while it was 340.3 in stage 4. Conclusion Serum leptin can be used as a marker of severity of endometriosis.
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Ghafouri-Fard S, Shoorei H, Taheri M. Role of Non-coding RNAs in the Pathogenesis of Endometriosis. Front Oncol 2020; 10:1370. [PMID: 32850438 PMCID: PMC7417625 DOI: 10.3389/fonc.2020.01370] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/29/2020] [Indexed: 12/23/2022] Open
Abstract
Endometriosis is a disorder characterized by the presence of endometrial glands and stroma like lesions outside of the uterus. Although several hypothesis have tried to explain the underlying cause of endometriosis, yet the main cause remained obscure. Recent studies have shown contribution of non-coding RNAs in the pathogenesis of endometriosis. Two classes of these transcripts namely long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have mostly attracted attention of researchers. Several studies have reported aberrant expression of these transcripts in affected tissues from patients as well as animal models. Modulation of important signaling pathways such as PI3K/AKT, P38-MAPK, ERK1/2-MAPK and Wnt-β catenin by miRNAs and lncRNAs have potentiated these molecules as biomarkers or therapeutic agents in endometriosis. Single nucleotide polymorphisms with miR-126, miR-143 and miR-146b have been associated with risk of endometriosis. Moreover, miRNAs and lncRNAs control inflammatory responses, cell proliferation, angiogenesis and tissue remodeling, thus understanding the role of these transcripts in endometriosis is a possible way to develop novel diagnostic tests and therapeutic targets for this disorder.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zubrzycka A, Zubrzycki M, Perdas E, Zubrzycka M. Genetic, Epigenetic, and Steroidogenic Modulation Mechanisms in Endometriosis. J Clin Med 2020; 9:E1309. [PMID: 32370117 PMCID: PMC7291215 DOI: 10.3390/jcm9051309] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/24/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Endometriosis is a chronic gynecological disease, affecting up to 10% of reproductive-age women. The exact cause of the disease is unknown; however, it is a heritable condition affected by multiple genetic, epigenetic, and environmental factors. Previous studies reported variations in the epigenetic patterns of numerous genes known to be involved in the aberrant modulation of cell cycle steroidogenesis, abnormal hormonal, immune and inflammatory status in endometriosis, apoptosis, adhesion, angiogenesis, proliferation, immune and inflammatory processes, response to hypoxia, steroidogenic pathway and hormone signaling are involved in the pathogenesis of endometriosis. Accumulating evidence suggest that various epigenetic aberrations may contribute to the pathogenesis of endometriosis. Among them, DNA methyltransferases, histone deacetylators, and non-coding microRNAs demonstrate differential expression within endometriotic lesions and in the endometrium of patients with endometriosis. It has been indicated that the identification of epigenetic differences within the DNA or histone proteins may contribute to the discovery of a useful prognostic biomarker, which could aid in the future earlier detection, timely diagnosis, and initiation of a new approach to the treatment of endometriosis, as well as inform us about the effectiveness of treatment and the stage of the disease. As the etiology of endometriosis is highly complex and still far from being fully elucidated, the presented review focuses on different approaches to identify the genetic and epigenetic links of endometriosis and its pathogenesis.
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Affiliation(s)
- Anna Zubrzycka
- Department of Biomedicine and Genetics, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland; Poland;
- Department of Operative and Conservative Gynecology, K. Jonscher Memorial Hospital, Milionowa 14, 93-113 Lodz, Poland
| | - Marek Zubrzycki
- Department of Cardiac Surgery and Transplantology, The Cardinal Stefan Wyszynski Institute of Cardiology, Alpejska 42, 04-628 Warsaw, Poland;
| | - Ewelina Perdas
- Department of Cardiovascular Physiology, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland;
| | - Maria Zubrzycka
- Department of Cardiovascular Physiology, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland;
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Abstract
Endometriosis is a disease of reproductive age women that is commonly characterized by symptoms that often negatively impact quality of life. The clinical management of endometriosis remains highly variable and mostly influenced by geographic location, practice patterns, and breadth of clinician experience. This variability in treatment has inspired a trend towards multidisciplinary and specialized care of patients suffering from this disease. Surgical sampling, followed by histologic confirmation of endometrial-like tissue, remains the standard for the definitive diagnosis of endometriosis. However, the high sensitivity and specificity of MRI and ultrasound has shed light on the path towards non-surgical diagnosis of deep infiltrating endometriosis. Molecular variability and intricacy of this disease has limited the development of biologic markers to target for non-invasive diagnosis and pharmacologic therapies. Surgical management of advanced-stage endometriosis can be difficult, mostly secondary to the invasive nature of the disease, and anatomical distortion requiring advanced surgical skills to manage. The high prevalence of chronic pelvic pain and other complex pain syndromes in patients with endometriosis also requires knowledge in the management of these types of issues in order to provide comprehensive care. Menopausal endometriosis, extrapelvic presentation, and potential malignant transformation of lesions are infrequent, requiring a high index of suspicion for timely diagnosis and treatment.
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Affiliation(s)
- Miguel A Luna Russo
- Section of Benign Gynecology, Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH, USA -
| | - Julia N Chalif
- Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I-II and III-IV endometriosis independently of hormonal milieu. Sci Rep 2020; 10:313. [PMID: 31941945 PMCID: PMC6962450 DOI: 10.1038/s41598-019-57207-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023] Open
Abstract
Eutopic endometrium appears to be crucial for endometriosis development. Despite of the evident importance, data regarding the cellular microenvironment remain unclear. Our objective was to explore the tissue microenvironment heterogeneity, transcripts, and pathways that are enriched in all phases of the menstrual cycle by analysing publicly deposited data derived from whole transcriptome microarrays of eutopic endometria of women with and without endometriosis. A meta-analysis of the transcriptome microarrays was performed using raw data available from a public database. Eligibility criteria included eutopic endometrium samples from women with endometriosis and healthy controls without any pathological condition reported the presence of an adequately reported normal menstrual phase, and samples containing both glandular and stromal components. Raw data were processed using a robust multiarray average method to provide background correction, normalisation, and summarisation. The batch effect was estimated by principal variant component analysis and removed using an empirical Bayes method. Cellular tissue heterogeneity was inferred using the xCell package. Differentially expressed genes were identified based on a 5% adjusted p value and a 2.0-fold change. Pathways were identified by functional enrichment based on the Molecular Signatures Database, a p value of < 5%, and an FDR q value of ≤ 25%. Genes that were more frequently found in pathways were identified using leading edge analysis. In a manner independent of cycle phase, the subpopulations of activated dendritic cells, CD4 T effector memory phenotype cells, eosinophils, macrophages M1, and natural killer T cells (NKT) were all higher in stage I-II endometriosis compared to those in healthy controls. The subpopulations of M2 macrophages and natural killer T cells were elevated in eutopic endometriums from women with stage III-IV endometriosis, and smooth muscle cells were always more prevalent in healthy eutopic endometriums. Among the differently expressed genes, FOS, FOSB, JUNB, and EGR1 were the most frequently mapped within the interaction networks, and this was independent of stage and cycle phase. The enriched pathways were directly related to immune surveillance, stem cell self-renewal, and epithelial mesenchymal transition. PI3K AKT mTOR, TGF signalling, and interferon alpha/gamma responses were enriched exclusively in stage III-IV endometriosis. The cellular microenvironments and immune cell profiles were different between eutopic endometriums from women with stage I-II and stage III-IV endometriosis, and these differences were independent of the hormonal milieu. Specifically, a pro-inflammatory profile was predominant in stage I-II endometriosis, and M1-M2 polarization into eutopic endometrium may be crucial for the progression of the disease. The higher prevalence of NKT cells in eutopic endometriums from women with endometriosis that was independent of cycle phase or staging suggested a sustained stress and/or damage to these eutopic endometriums. Based on this, the results of this meta-analysis are important for identifying challenges and opportunities for future research.
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Cipollini M, Luisi S, Piomboni P, Luddi A, Landi D, Melaiu O, Figlioli G, Garritano S, Cappelli V, Viganò P, Gemignani F, Petraglia F, Landi S. Functional polymorphism within NUP210 encoding for nucleoporin GP210 is associated with the risk of endometriosis. Fertil Steril 2019; 112:343-352.e1. [PMID: 31256999 DOI: 10.1016/j.fertnstert.2019.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To investigate whether nucleoporin 210 (GP210, encoded by NUP210 gene) is involved in endometriosis. DESIGN Immunohistofluorescence analysis for assessing whether GP210 is expressed in endometrial tissues from patients and controls; genotyping and case-control study for assessing the association between rs354476 within NUP210 and risk of endometriosis; in vitro luciferase assay for assessing the functional activity of rs354476. SETTING University. PATIENT(S) Histologically diagnosed cases (n = 175) of endometriosis: minimal or mild (stage I-II) in 48 cases (28%), moderate (stage III) in 69 cases (39%), and severe (stage IV) in 58 cases (33%). Controls (n = 557) were female blood donors collected at Meyer Hospital of Florence. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) GP210 tissue expression; genotype distribution and risk of endometriosis; in vitro gene expression measurements. RESULT(S) GP210 had positive nuclear immunohistofluorescence staining in endometrial glandular epithelium. Carriers of the variant allele were associated with increased risks: C/T, odds ratio (OR) 1.83, 95% confidence interval (CI) 1.04-3.21; T/T, OR 2.55, 95% CI 1.36-4.80. In vitro, luciferase assay showed that rs354476 is a bona fide target for hsa-miR-125b-5p. CONCLUSION(S) Nucleoporin GP210 is involved in endometriosis. Rs354476 polymorphism affects the regulation of NUP210 gene expression by altering the binding with hsa-miR-125b-5p, a microRNA already known as playing an important role for endometriosis. This provides the rationale for the observed increased risk of endometriosis in carriers of the variant allele.
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Affiliation(s)
| | - Stefano Luisi
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Paola Piomboni
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Alice Luddi
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Debora Landi
- Department of Biology, University of Pisa, Pisa, Italy
| | | | | | - Sonia Garritano
- Centre for Integrated Biology, University of Trento, Trento, Italy
| | - Valentina Cappelli
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Paola Viganò
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | | | - Felice Petraglia
- Obstetrics and Gynecology, Department of Biomedical, Experimental and Clinical Sciences "Mario Serio" University of Florence, Florence, Italy
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
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KOUKOURA OURANIA, SIFAKIS STAVROS, SPANDIDOS DEMETRIOSA. DNA methylation in endometriosis (Review). Mol Med Rep 2016; 13:2939-48. [PMID: 26934855 PMCID: PMC4805102 DOI: 10.3892/mmr.2016.4925] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/22/2016] [Indexed: 12/01/2022] Open
Abstract
Endometriosis is defined by the presence and growth of functional endometrial tissue, outside the uterine cavity, primarily in the ovaries, pelvic peritoneum and rectovaginal septum. Although it is a benign disease, it presents with malignant characteristics, such as invasion to surrounding tissues, metastasis to distant locations and recurrence following treatment. Accumulating evidence suggests that various epigenetic aberrations may play an essential role in the pathogenesis of endometriosis. Aberrant DNA methylation represents a possible mechanism repsonsible for this disease, linking gene expression alterations observed in endometriosis with hormonal and environmental factors. Several lines of evidence indicate that endometriosis may partially be due to selective epigenetic deregulations influenced by extrinsic factors. Previous studies have shed light into the epigenetic component of endometriosis, reporting variations in the epigenetic patterns of genes known to be involved in the aberrant hormonal, immunologic and inflammatory status of endometriosis. Although recent studies, utilizing advanced molecular techniques, have allowed us to further elucidate the possible association of DNA methylation with altered gene expression, whether these molecular changes represent the cause or merely the consequence of the disease is a question which remains to be answered. This review provides an overview of the current literature on the role of DNA methylation in the pathophysiology and malignant evolution of endometriosis. We also provide insight into the mechanisms through which DNA methylation-modifying agents may be the next step in the research of the pharmaceutical treatment of endometriosis.
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Affiliation(s)
- OURANIA KOUKOURA
- Department of Obstetrics and Gynecology, University Hospital of Larissa, Larissa 41500, Greece
| | - STAVROS SIFAKIS
- Department of Obstetrics and Gynecology, University Hospital of Heraklion, Heraklion 71003, Greece
| | - DEMETRIOS A. SPANDIDOS
- Laboratory of Clinical Virology, University of Crete Medical School, Heraklion 71409, Greece
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Abstract
INTRODUCTION Endometriosis affects 10% of women of reproductive age. It is defined as the presence of implanted active endometrial tissue outside the uterine cavity. The exact pathophysiology of endometriosis is still uncertain, although several optional etiological theories have been suggested. Being so common, a novel treatment for endometriosis is widely quested. Recent studies addressing the pathological characteristics of endometriosis have revealed a vicious cycle in which oxidative stress (OS) is generated, which in turn facilitates the implantation of the ectopic endometrium. At the same time, the generation of high amounts of reactive oxygen species further triggers a state of OS. AREAS COVERED The author examined the evidence associating OS and endometriosis. After establishing an association, a search for antioxidant agents that were investigated specifically on endometriosis patients are described including Vitamins C and E, melatonin, resveratrol, xanthohumol and epigallocatechin-3-gallate. A significant effect of all the reviewed antioxidants on endometriosis is reported. EXPERT OPINION Aiming for the reduction of OS as the treatment goal for endometriosis looks promising. However, since most of the studies are either in vitro or are animal based, further studies on human subjects are deemed necessary to elucidate the impact of OS reduction on patients with endometriosis.
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Affiliation(s)
- Avi Harlev
- a 1 American Center for Reproductive Medicine, Cleveland Clinic, Cleveland , OH, USA.,b 2 Ben-Gurion University of the Negev, Faculty of Health Sciences, Soroka University Medical Center, Fertility and IVF Unit, Department of Obstetrics & Gynecology , Israel
| | - Sajal Gupta
- a 1 American Center for Reproductive Medicine, Cleveland Clinic, Cleveland , OH, USA
| | - Ashok Agarwal
- c 3 American Center for Reproductive Medicine, Cleveland Clinic , Mail Code: X-11, 10681 Carnegie Avenue, Cleveland, OH 44195, USA +1 216 444 9485 ; +1 216 445 6049;
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Xie J, Kvaskoff M, Li Y, Zhang M, Qureshi AA, Missmer SA, Han J. Severe teenage acne and risk of endometriosis. Hum Reprod 2014; 29:2592-9. [PMID: 25139175 PMCID: PMC4191450 DOI: 10.1093/humrep/deu207] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 06/23/2014] [Accepted: 07/01/2014] [Indexed: 12/14/2022] Open
Abstract
STUDY QUESTION Is there a relationship between severe teenage acne and endometriosis? SUMMARY ANSWER Endometriosis is positively associated with severe teenage acne. WHAT IS KNOWN ALREADY No studies have specifically explored a possible association between severe acne in adolescence and risk of endometriosis. STUDY DESIGN, SIZE, DURATION This prospective cohort study used data collected from 88 623 female nurses from September 1989 to June 2009 as part of the Nurses' Health Study II (NHS II) cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS Regression models were used to calculate hazard ratios (HRs) and confidence intervals (CIs) for endometriosis among women with and without severe teenage acne. Multivariate models were adjusted for established risk factors of endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE A total of 4 382 laparoscopically confirmed endometriosis cases were documented during 1 132 272 woman-years of follow-up. Compared with women without a history of severe teenage acne, women who had severe teenage acne had a 20% increased risk of endometriosis (HR = 1.20, 95% CI: 1.08-1.32). The association was not affected by adjusting for use of tetracycline or isotretinoin. LIMITATIONS AND REASONS FOR CAUTION The HR is likely to be underestimated since we only included endometriosis cases confirmed by laparoscopy. Although geographically diverse, the NHS II cohort is primarily Caucasian, which may limit generalization to more ethnically diverse populations. WIDER IMPLICATIONS OF THE STUDY The results of this study suggest that severe teenage acne is associated with an increased risk of endometriosis. As a visible and non-invasive clinical indicator, severe teenage acne may be useful for early detection of endometriosis. We bring this counter-intuitive association to the attention of clinicians for the benefit of the patient and an early diagnosis of endometriosis. STUDY FUNDING/COMPETING INTEREST This study was funded by research grant CA176726 from the National Institute of Health. M.K. is supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078). The funding agencies had no role in the design of the study, in the analysis and interpretation of the data, in the writing of the report or in the decision to submit the paper for publication.
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Affiliation(s)
- Jing Xie
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Marina Kvaskoff
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Yunhui Li
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Mingfeng Zhang
- Clinical Research Program, Department of Dermatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Abrar A Qureshi
- Clinical Research Program, Department of Dermatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Stacey A Missmer
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Jiali Han
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA Clinical Research Program, Department of Dermatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA Department of Epidemiology, Fairbanks School of Public Health, Simon Cancer Center, Indiana University, Indianapolis, IN, USA
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Ser312Gly Polymorphism of the HSD17β1 Gene is not Associated with Endometriosis in Brazilian Patients. JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2014. [DOI: 10.5301/je.5000195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Purpose The aim of this study was to determine whether a polymorphism of the HSD17β1 gene (rs605059), involved in estrogen synthesis, is associated with endometriosis in Brazilian patients. Methods A case-control study was conducted in 231 women. All patients in the case group had a histopathological diagnosis of endometriosis. Genomic DNA was genotyped by nested-PCR, followed by digestion of the PCR product with the enzyme BstUI. Results The frequencies of the genotypes detected in the case and control groups were 22.4% GG, 52.2% AG and 25.4% AA; and 31.3% GG, 49.3% AG and 19.4% AA, respectively, with no significant difference between groups. The prevalence of the G allele was 48.5% and 56% in the case and control groups, respectively. No significant difference in genotype or allele frequency was detected between the different stages of endometriosis (p>0.05). Conclusions The results suggested that the Ser312Gly polymorphism of the HSD17β1 gene is not associated with endometriosis in Brazilian patients.
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Wang Y, Lin M, Weng H, Wang X, Yang L, Liu F. ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model. Am J Obstet Gynecol 2014; 210:531.e1-8. [PMID: 24495669 DOI: 10.1016/j.ajog.2014.01.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 12/11/2013] [Accepted: 01/28/2014] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Protease-activated receptor 2 plays an important role in the pathogenesis of endometriosis. We studied the effect of ENMD-1068, a protease-activated receptor 2 antagonist, on the development of endometriosis in a noninvasive fluorescent mouse model. STUDY DESIGN A red fluorescent protein-expressing xenograft model of human endometriosis was created in nude mice. After endometriosis induction, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 μL of the vehicle control daily for 5 days. The endometriotic lesions that developed in the mice were then counted, measured, and collected. The lesions were assessed for the production of interleukin 6 and monocyte chemotactic protein-1 by enzyme-linked immunosorbent assays and evaluated for the activation of nuclear factor-κB and the expression of vascular endothelial growth factor by immunohistochemical analyses. Cell proliferation and apoptosis were assessed by immunohistochemistry for Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively. RESULTS ENMD-1068 dose-dependently inhibited the development of endometriotic lesions (P < .05) without apparent toxicity to various organs of the treated mice. Consistently, ENMD-1068 dose-dependently inhibited the expression of interleukin 6 and nuclear factor-κB (P < .05) and cell proliferation (P < .05) in the lesions, as well as increased the percentage of apoptotic cells (P < .05). ENMD-1068 reduced the levels of monocyte chemotactic protein-1 and vascular endothelial growth factor in the lesions (P < .05), but not in a dose-dependent manner. CONCLUSION Our study suggests that ENMD-1068 is effective in suppressing the growth of endometriosis, which might be attributed to the drug's antiangiogenic and antiinflammatory activities.
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Affiliation(s)
- Yifeng Wang
- Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Min Lin
- Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Huinan Weng
- Department of Reproductive Center, GuangDong Women And Children Hospital, Guangzhou, China
| | - Xuefeng Wang
- Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Li Yang
- Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Fenghua Liu
- Department of Reproductive Center, GuangDong Women And Children Hospital, Guangzhou, China.
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Altmäe S, Esteban FJ, Stavreus-Evers A, Simón C, Giudice L, Lessey BA, Horcajadas JA, Macklon NS, D'Hooghe T, Campoy C, Fauser BC, Salamonsen LA, Salumets A. Guidelines for the design, analysis and interpretation of 'omics' data: focus on human endometrium. Hum Reprod Update 2014; 20:12-28. [PMID: 24082038 PMCID: PMC3845681 DOI: 10.1093/humupd/dmt048] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 08/04/2013] [Accepted: 08/19/2013] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND 'Omics' high-throughput analyses, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, are widely applied in human endometrial studies. Analysis of endometrial transcriptome patterns in physiological and pathophysiological conditions has been to date the most commonly applied 'omics' technique in human endometrium. As the technologies improve, proteomics holds the next big promise for this field. The 'omics' technologies have undoubtedly advanced our knowledge of human endometrium in relation to fertility and different diseases. Nevertheless, the challenges arising from the vast amount of data generated and the broad variation of 'omics' profiling according to different environments and stimuli make it difficult to assess the validity, reproducibility and interpretation of such 'omics' data. With the expansion of 'omics' analyses in the study of the endometrium, there is a growing need to develop guidelines for the design of studies, and the analysis and interpretation of 'omics' data. METHODS Systematic review of the literature in PubMed, and references from relevant articles were investigated up to March 2013. RESULTS The current review aims to provide guidelines for future 'omics' studies on human endometrium, together with a summary of the status and trends, promise and shortcomings in the high-throughput technologies. In addition, the approaches presented here can be adapted to other areas of high-throughput 'omics' studies. CONCLUSION A highly rigorous approach to future studies, based on the guidelines provided here, is a prerequisite for obtaining data on biological systems which can be shared among researchers worldwide and will ultimately be of clinical benefit.
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Affiliation(s)
- Signe Altmäe
- Competence Centre on Reproductive Medicine and Biology, Tartu, Estonia
- School of Medicine, Department of Paediatrics, University of Granada, 18012 Granada, Spain
| | | | - Anneli Stavreus-Evers
- Department of Women's and Children's Health, Uppsala University, Akademiska Sjukhuset, 75185 Uppsala, Sweden
| | - Carlos Simón
- Fundación Instituto Valenciano de Infertilidad (FIVI) and Instituto Universitario IVI/INCLIVA, Valencia University, 46021 Valencia, Spain
| | - Linda Giudice
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143-0132, USA
| | - Bruce A. Lessey
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University Medical Group, Greenville Hospital System, Greenville, South Carolina, SC 29605, USA
| | - Jose A. Horcajadas
- Araid-Hospital Miguel Servet, 50004 Zaragoza, Spain
- Department of Genetics, Universidad Pablo de Olavide, 41013 Sevilla, Spain
| | - Nick S. Macklon
- Department of Obstetrics and Gynaecology, Division of Developmental Origins of Adult Disease, University of Southampton, Princess Anne Hospital, SO16 5YA Southampton, UK
- Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Thomas D'Hooghe
- Leuven University Fertility Center, Department of Obstetrics and Gynecology, University Hospital Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven (Leuven University), 3000 Leuven, Belgium
| | - Cristina Campoy
- School of Medicine, Department of Paediatrics, University of Granada, 18012 Granada, Spain
| | - Bart C. Fauser
- Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Lois A. Salamonsen
- Prince Henry's Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Andres Salumets
- Competence Centre on Reproductive Medicine and Biology, Tartu, Estonia
- Department of Obstetrics and Gynaecology, University of Tartu, 51014 Tartu, Estonia
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Developmental exposure of fetal ovaries and fetal germ cells to endometriosis in an endometriosis model causes differential gene expression in the preimplantation embryos of the first-generation and second-generation embryos. Fertil Steril 2013; 100:1436-43. [PMID: 23954358 DOI: 10.1016/j.fertnstert.2013.07.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 07/08/2013] [Accepted: 07/08/2013] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To characterize multigenerational gene expression anomalies in eight-cell stage embryos associated with developmental exposure to endometriosis. DESIGN Using an endometriosis model in rats (F0 founder generation) to evaluate gene expression in F1 (fetal exposure) and F2 (fetal germ cell exposure) generation eight-cell stage embryos. SETTING Laboratory. ANIMAL(S) Endometriosis model in rats (Endo) and controls (Sham). INTERVENTION(S) F0 Endo and Sham rats were bred; half the pregnant rats were killed on gestational day 3 to collect F1 eight-cell stage embryos and the others gestated to term (F1 females). Adult F1 females bred; F2 eight-cell embryos collected. MAIN OUTCOME MEASURE(S) Maintenance of differential gene expression in F1 and F2 generation eight-cell embryos in endometriosis. RESULT(S) Developmental exposure to endometriosis altered the gene signaling pathways, with changes found in apoptosis, the cell cycle process, the response to oxidative stress, negative regulation of molecular function, and RNA processing. The apoptotic genes Diablo, Casp3, Parp1, Cad, and Dnaja3 were increased and the Nfkbia transcripts were decreased in F1 Endo versus F1 Sham embryos. In F2 Endo versus Sham embryos, Casp3 and Cad were statistically significantly increased, and Parp1 and Nfkbia tended to be elevated. CONCLUSION(S) Fetal and germ cell exposure to endometriosis alters apoptotic gene expression in first- and second-generation eight-cell stage embryos, supporting the hypothesis of multigenerational inheritance resulting from exposure to endometriosis in utero.
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Genome-wide association study link novel loci to endometriosis. PLoS One 2013; 8:e58257. [PMID: 23472165 PMCID: PMC3589333 DOI: 10.1371/journal.pone.0058257] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Accepted: 02/01/2013] [Indexed: 12/17/2022] Open
Abstract
Endometriosis is a common gynecological condition with complex etiology defined by the presence of endometrial glands and stroma outside the womb. Endometriosis is a common cause of both cyclic and chronic pelvic pain, reduced fertility, and reduced quality-of-life. Diagnosis and treatment of endometriosis is, on average, delayed by 7–10 years from the onset of symptoms. Absence of a timely and non-invasive diagnostic tool is presently the greatest barrier to the identification and treatment of endometriosis. Twin and family studies have documented an increased relative risk in families. To identify genetic factors that contribute to endometriosis we conducted a two-stage genome-wide association study (GWAS) of a European cohort including 2,019 surgically confirmed endometriosis cases and 14,471 controls. Three of the SNPs we identify associated at P<5×10−8 in our combined analysis belong to two loci: LINC00339-WNT4 on 1p36.12 (rs2235529; P = 8.65×10−9, OR = 1.29, CI = 1.18–1.40) and RND3-RBM43 on 2q23.3 (rs1519761; P = 4.70×10−8, OR = 1.20, Cl = 1.13–1.29, and rs6757804; P = 4.05×10−8, OR = 1.20, Cl = 1.13–1.29). Using an adjusted Bonferoni significance threshold of 4.51×10−7 we identify two additional loci in our meta-analysis that associate with endometriosis:, RNF144B-ID4 on 6p22.3 (rs6907340; P = 2.19×10−7, OR = 1.20, Cl = 1.12–1.28), and HNRNPA3P1-LOC100130539 on 10q11.21 (rs10508881; P = 4.08×10−7, OR = 1.19, Cl = 1.11–1.27). Consistent with previously suggested associations to WNT4 our study implicate a 150 kb region around WNT4 that also include LINC00339 and CDC42. A univariate analysis of documented infertility, age at menarche, and family history did not show allelic association with these SNP markers. Clinical data from patients in our study reveal an average delay in diagnosis of 8.4 years and confirm a strong correlation between endometriosis severity and infertility (n = 1182, P<0.001, OR = 2.18). This GWAS of endometriosis was conducted with high diagnostic certainty in cases, and with stringent handling of population substructure. Our findings broaden the understanding of the genetic factors that play a role in endometriosis.
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Lee HJ, Kim H, Ku SY, Kim SH, Kim JG. Transforming growth factor-β1 gene polymorphisms in Korean women with endometriosis. Am J Reprod Immunol 2011; 66:428-434. [PMID: 21623988 DOI: 10.1111/j.1600-0897.2011.01009.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
PROBLEM To investigate the association between endometriosis, transforming growth factor-β1 (TGFB1) gene polymorphisms, and serum TGF-β1 levels in Korean women. METHOD OF STUDY The -509C/T, 868T/C, 913G/C and 979G/A polymorphisms of the TGFB1 gene were analyzed in women with (n = 131) and without (n = 107) endometriosis using restriction fragment length polymorphism (RFLP) analysis. Serum TGF-β1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS The 913G/C and 979G/A polymorphisms were not observed in the study participants. The genotype and allele distribution of the -509C/T and 868T/C polymorphisms in endometriosis were similar to those in controls. However, the -509T/868C (TC) haplotype allele was observed 4.55 times more frequently in early-stage endometriosis than in other haplotype alleles. Serum TGF-β1 levels were significantly higher in endometriosis than in controls. The single and haplotype genotype of -509C/T and 868T/C polymorphisms were not related with serum TGF-β1 levels. CONCLUSION The TC haplotype allele of TGFB1-509C/T and 868T/C polymorphisms may be associated with early-stage endometriosis in Korean women.
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Affiliation(s)
- Hye Jun Lee
- Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Korea
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Veiga-Castelli L, Rosa e Silva J, Meola J, Ferriani R, Yoshimoto M, Santos S, Squire J, Martelli L. Genomic alterations detected by comparative genomic hybridization in ovarian endometriomas. Braz J Med Biol Res 2010; 43:799-805. [DOI: 10.1590/s0100-879x2010007500072] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2010] [Accepted: 07/19/2010] [Indexed: 11/22/2022] Open
Affiliation(s)
| | | | - J. Meola
- Universidade de São Paulo; Universidade de São Paulo, Brasil
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Nouri K, Ott J, Krupitz B, Huber JC, Wenzl R. Family incidence of endometriosis in first-, second-, and third-degree relatives: case-control study. Reprod Biol Endocrinol 2010; 8:85. [PMID: 20618992 PMCID: PMC2911462 DOI: 10.1186/1477-7827-8-85] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Accepted: 07/11/2010] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Initial publications examining the hereditary aspects of endometriosis appeared in the early seventies and demonstrated an up to seven-fold risk for endometriosis in first-degree relatives of endometriosis patients. The aim was to evaluate the influence of hereditary aspects on the endometriosis risk in our patient collective. METHODS In a retrospective cohort study we evaluated the incidence of endometriosis among first-, second-, and third-degree relatives of endometriosis patients and compare it with its incidence among first-, second-, and third-degree relatives of patients without endometriosis. RESULT(S) Eighty patients in whom endometriosis had been confirmed laparoscopically and histologically by biopsy and 60 patients in whom no endometriosis had been found during laparoscopy were given a questionnaire about the presence of symptoms associated with endometriosis and its family incidence. Patients of both the endometriosis and the control group were 37.7 +/- 6.2 and 45.9 +/- 12.0 years of age at the time of the interview, respectively (p < 0.05). Information about the presence of endometriosis was more readily available for relatives of those in the endometriosis group than for those in the control group (325/749 [43.4%] vs. 239/425 [56.2%], p < 0.05). In 5/136 (3.7%) and 8/134 (6.0%) first-degree relatives of endometriosis patients and the control group, respectively, information about the presence of endometriosis was not available (p = 0.554). Endometriosis was found in 8/136 (5.9%) first-degree relatives of patients and in 4/134 (3.0%) first-degree relatives of controls in the real-case analysis (p = 0.248). When comparing endometriosis characteristics between endometriosis patients with and without a history of familial endometriosis, no significant differences were found. CONCLUSION(S) There is a trend toward an increased familial incidence of endometriosis. In contrast to the literature, we found a less dramatic increase in familial risk for the development of endometriosis.
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Affiliation(s)
- Kazem Nouri
- Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, Vienna, Austria
| | - Johannes Ott
- Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, Vienna, Austria
| | | | - Johannes C Huber
- Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, Vienna, Austria
| | - Rene Wenzl
- Department of Gynecology and Gynecologic Oncology, Medical University of Vienna, Vienna, Austria
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