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Nezhat CR, Oskotsky TT, Robinson JF, Fisher SJ, Tsuei A, Liu B, Irwin JC, Gaudilliere B, Sirota M, Stevenson DK, Giudice LC. Real world perspectives on endometriosis disease phenotyping through surgery, omics, health data, and artificial intelligence. NPJ WOMEN'S HEALTH 2025; 3:8. [PMID: 39926583 PMCID: PMC11802455 DOI: 10.1038/s44294-024-00052-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 12/31/2024] [Indexed: 02/11/2025]
Abstract
Endometriosis is an enigmatic disease whose diagnosis and management are being transformed through innovative surgical, molecular, and computational technologies. Integrating single-cell and other omic disease data with clinical and surgical metadata can identify multiple disease subtypes with translation to novel diagnostics and therapeutics. Herein, we present real-world perspectives on endometriosis and the importance of multidisciplinary collaboration in informing molecular, epidemiologic, and cell-specific data in the clinical and surgical contexts.
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Affiliation(s)
- Camran R. Nezhat
- Center for Special Minimally Invasive and Robotic Surgery, Camran Nezhat Institute, Stanford University Medical Center, University of California, San Francisco, Woodside, CA 94061 USA
| | - Tomiko T. Oskotsky
- Bakar Computational Health Sciences Institute, University of California San Francisco, 490 Illinois St, Floor 2, San Francisco, CA 94158 USA
| | - Joshua F. Robinson
- Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 513 Parnassus Ave, Rm. 1621, San Francisco, CA 94143 USA
| | - Susan J. Fisher
- Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, 35 Medical Center Way, Box 0665, San Francisco, CA 94143 USA
| | - Angie Tsuei
- Center for Special Minimally Invasive and Robotic Surgery, Camran Nezhat Institute, Woodside, CA 94061 USA
| | - Binya Liu
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, 513 Parnassus Avenue Room 1600 HSE, San Francisco, CA 94143 USA
| | - Juan C. Irwin
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, 513 Parnassus Avenue Room 1600 HSE, San Francisco, CA 94143 USA
| | - Brice Gaudilliere
- Department of Anesthesiology, Pain, and Perioperative Medicine, and (courtesy) Pediatrics, Stanford University, 3174 Porter Dr, Palo Alto, CA 94304 USA
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, University of California San Francisco, 490 Illinois St, Floor 2, San Francisco, CA 94158 USA
| | - David K. Stevenson
- Department of Pediatrics, Stanford University, 453 Quarry Rd, Palo Alto, CA 94304 USA
| | - Linda C. Giudice
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, 513 Parnassus Avenue Room 1600 HSE, San Francisco, CA 94143 USA
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Turčić M, Matušan Ilijaš K, Rajković Molek K, Valković Zujić P. Rectus Abdominis Muscle Endometriosis: A Unique Case Report with a Literature Review. Curr Issues Mol Biol 2025; 47:47. [PMID: 39852162 PMCID: PMC11763801 DOI: 10.3390/cimb47010047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/03/2025] [Accepted: 01/08/2025] [Indexed: 01/26/2025] Open
Abstract
Introduction and importance: Extrapelvic endometriosis, confined exclusively to the body of the rectus abdominis muscle, is a rare form of abdominal wall endometriosis. While its etiopathology remains unclear, it is often diagnosed in healthy women who present with atypical symptoms and localization unrelated to any incision site, or in the absence of a history of endometriosis or previous surgery. Presentation of the case: Here, we describe a unique case of intramuscular endometriosis of the rectus abdominis muscle in a healthy 39-year-old Caucasian woman. The condition was located away from any prior incisional scars and presented without typical symptoms or concurrent pelvic disease, making diagnostic imaging unclear. After partial surgical resection of the endometriotic foci, the diagnosis was confirmed histologically. Progestogen-based supportive medication was initiated to prevent the need for additional surgeries and to reduce the risk of recurrence. After 6 years of follow-up and continued progestogen treatment, the patient remains symptom-free and has shown no recurrence of the disease. Clinical discussion: Endometriosis of the rectus abdominis muscle exhibits specific characteristics in terms of localization, etiopathology, symptomatology, and diagnostic imaging, suggesting that it should be considered a distinct clinical entity. Conclusions: Although rare, primary endometriosis of the rectus abdominis muscle should be included in the differential diagnosis for women of childbearing age. Early diagnosis is essential to avoid delayed recognition, tissue damage, and to minimize the risk of recurrence or malignant transformation. Given the increasing frequency of gynecologic and laparoscopic surgeries worldwide, it is crucial to establish standardized reporting protocols, follow-up timelines, and imaging assessments during specific phases of the menstrual cycle. Standardization will help raise awareness of this disease, and further our understanding of its pathogenesis, risk factors, recurrence patterns, and potential for malignant transformation-factors that are still not fully understood.
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Affiliation(s)
- Marijana Turčić
- Faculty of Biotehnology and Drug Research, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
| | - Koviljka Matušan Ilijaš
- Clinical Department of Pathology and Cytology, Clinical Hospital Centre Rijeka, Krešimirova 42, 51000 Rijeka, Croatia;
| | - Koraljka Rajković Molek
- Clinical Department of Pathology and Cytology, Clinical Hospital Centre Rijeka, Krešimirova 42, 51000 Rijeka, Croatia;
| | - Petra Valković Zujić
- Department of Diagnostic and Interventional Radiology, Clinical Hospital Centre Rijeka, Krešimirova 42, 51000 Rijeka, Croatia;
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Vissers G, Giacomozzi M, Verdurmen W, Peek R, Nap A. The role of fibrosis in endometriosis: a systematic review. Hum Reprod Update 2024; 30:706-750. [PMID: 39067455 PMCID: PMC11532625 DOI: 10.1093/humupd/dmae023] [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: 03/15/2024] [Revised: 06/04/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis. OBJECTIVE AND RATIONALE This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis. SEARCH METHODS A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included. OUTCOMES Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells. WIDER IMPLICATIONS This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases. REGISTRATION NUMBER N/A.
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Affiliation(s)
- Guus Vissers
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maddalena Giacomozzi
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wouter Verdurmen
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ron Peek
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Annemiek Nap
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
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Neme GL, Guimarães CTS, Dantas PP, Santana DDB, Yamauchi FI, Filho HML, Bittencourt LK, Pereira RMA, Mattos LA. Postoperative Imaging of Endometriosis. Radiographics 2024; 44:e230159. [PMID: 38512726 DOI: 10.1148/rg.230159] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
Endometriosis is a highly prevalent disease that affects 10%-15% of women of reproductive age worldwide and is mainly associated with chronic pelvic pain and infertility. With the widespread use of imaging for the diagnosis and monitoring of endometriosis, combined with the ability of surgery to eradicate the disease and address infertility, there has been a significant increase in recent years in imaging examinations for postoperative evaluation of endometriosis. US and MRI are used not only to help diagnose and map endometriosis but also to evaluate refractory symptoms, residual lesions, and complications at posttreatment assessment. Knowledge of surgical techniques and recognition of expected postoperative imaging findings are crucial to differentiate postoperative changes from residual disease and/or recurrence. The authors discuss imaging aspects of postoperative endometriosis, with an emphasis on the imaging approach, comprehension of surgical techniques, recognition of the expected findings, possible complications, and analysis of residual disease or recurrence. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by VanBuren in this issue. The slide presentation from the RSNA Annual Meeting is available for this article.
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Affiliation(s)
- Glaucy L Neme
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Cassia T S Guimarães
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Patricia P Dantas
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Daniel D B Santana
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Fernando I Yamauchi
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Hilton M Leão Filho
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Leonardo K Bittencourt
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Ricardo M A Pereira
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
| | - Leandro A Mattos
- From the Department of Radiology, Diagnósticos da América SA (DASA), Av Juruá 434, Alphaville Industrial, Barueri, SP 06455-010, Brazil (G.L.N., C.T.S.G., D.D.B.S., F.I.Y., H.M.L.F., L.A.M.); Department of Radiology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil (P.P.D.); Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (L.K.B.); and Center of Endometriosis, Santa Joana Hospital, São Paulo, Brazil (R.M.A.P.)
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Colgrave EM, Keast JR, Nowell CJ, Healey M, Rogers PAW, Holdsworth-Carson SJ, Girling JE. Distribution of smooth muscle actin and collagen in superficial peritoneal endometriotic lesions varies from the surrounding microenvironment. Reprod Biomed Online 2024; 48:103610. [PMID: 38241767 DOI: 10.1016/j.rbmo.2023.103610] [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: 07/02/2023] [Revised: 09/26/2023] [Accepted: 10/09/2023] [Indexed: 01/21/2024]
Abstract
RESEARCH QUESTION Do different subtypes of superficial peritoneal endometriotic lesions exist, based on the presence and morphology of smooth muscle, collagen fibres and immune cell populations? DESIGN A retrospective cohort study of 24 patients, from across the menstrual cycle, with surgically and histologically confirmed endometriosis. Immunofluorescence was used to delineate the CD10 stromal area of lesions (n = 271 lesions from 67 endometriotic biopsies), and then smooth muscle actin (SMA) positive tissue and immune cell populations (CD45+ and CD68+) were quantified within and adjacent to these lesions. Second harmonic generation microscopy was used to evaluate the presence and morphology of type-1 collagen fibres within and surrounding lesions. RESULTS Overall, immune cell numbers and the area of SMA and collagen within endometriotic lesions tended to be low, but a spectrum of presentations significantly varied, particularly in the adjacent tissue microenvironment, based on lesion locations, the morphology of endometriotic gland profiles, or both. Lesions in which collagen fibres formed well aligned capsules around the CD10+ stromal border were identified compared with lesions in which collagen fibre distribution was random. Considerable inter- and intra-patient variability in the morphology of SMA and collagen was observed within and surrounding lesions. CONCLUSION These data demonstrate considerable diversity in the presence of immune cells and morphology of SMA and collagen within, but even more so, surrounding endometriotic lesions, even within individual patients. This heterogeneity, especially within individual patients, presents a challenge to incorporating these cell and tissue types into any new endometriosis classification systems or prognostic approaches.
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Affiliation(s)
- Eliza Morgan Colgrave
- Department of Obstetrics and Gynaecology, The University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Janet R Keast
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Cameron J Nowell
- Imaging, FACS and Analysis Core, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
| | - Martin Healey
- Department of Obstetrics and Gynaecology, The University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Peter A W Rogers
- Department of Obstetrics and Gynaecology, The University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Sarah J Holdsworth-Carson
- Department of Obstetrics and Gynaecology, The University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia; The Julia Argyrou Endometriosis Centre, Epworth HealthCare, Richmond, Victoria, Australia
| | - Jane E Girling
- Department of Obstetrics and Gynaecology, The University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia; Department of Anatomy, School of Biomedical Sciences, The University of Otago, Dunedin, Aotearoa New Zealand.
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6
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Watanabe M. Discordance in Histopathological versus Clinical Diagnosis of a Paracolpium Endometrioma - A Diagnostic Challenge. Gynecol Minim Invasive Ther 2024; 13:64-65. [PMID: 38487603 PMCID: PMC10936722 DOI: 10.4103/gmit.gmit_48_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 10/09/2023] [Accepted: 11/10/2023] [Indexed: 03/17/2024] Open
Affiliation(s)
- Masahiro Watanabe
- Department of Obstetrics and Gynecology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
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Proestling K, Husslein H, Hudson QJ, Witzmann-Stern M, Widmar B, Bagó-Horváth Z, Sandrieser L, Perricos A, Wenzl R, Yotova I. MLLT11 Regulates Endometrial Stroma Cell Adhesion, Proliferation and Survival in Ectopic Lesions of Women with Advanced Endometriosis. Int J Mol Sci 2023; 25:439. [PMID: 38203610 PMCID: PMC10778601 DOI: 10.3390/ijms25010439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
MLLT11 is a gene implicated in cell differentiation and the development and progression of human cancers, but whose role in the pathogenesis of endometriosis is still unknown. Using quantitative RT-PCR and immunohistochemistry, we analyzed 37 women with and 33 women without endometriosis for differences in MLLT11 expression. We found that MLLT11 is reduced in the ectopic stroma cells of women with advanced stage endometriosis compared to women without endometriosis. MLLT11 knockdown in control stroma cells resulted in the downregulation of their proliferation accompanied by G1 cell arrest and an increase in the expression of p21 and p27. Furthermore, the knockdown of MLLT11 was associated with increased apoptosis resistance to camptothecin associated with changes in BCL2/BAX signaling. Finally, MLLT11 siRNA knockdown in the control primary stroma cells led to an increase in cell adhesion associated with the transcriptional activation of ACTA2 and TGFB2. We found that the cellular phenotype of MLLT11 knockdown cells resembled the phenotype of the primary endometriosis stroma cells of the lesion, where the levels of MLLT11 are significantly reduced compared to the eutopic stroma cells of women without the disease. Overall, our results indicate that MLLT11 may be a new clinically relevant player in the pathogenesis of endometriosis.
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Affiliation(s)
- Katharina Proestling
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Heinrich Husslein
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Quanah James Hudson
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Matthias Witzmann-Stern
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Barbara Widmar
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Zsuzsanna Bagó-Horváth
- Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria;
| | - Lejla Sandrieser
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Alexandra Perricos
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - René Wenzl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
| | - Iveta Yotova
- Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; (K.P.); (H.H.); (Q.J.H.); (M.W.-S.); (B.W.); (L.S.); (A.P.); (R.W.)
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8
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Blontzos N, Mavrogianni D, Ntzeros K, Kathopoulis N, Moustogiannis A, Philippou A, Koutsilieris M, Protopapas A. Differential Expression of Insulin Growth Factor 1 (IGF-1) Isoforms in Different Types of Endometriosis: Preliminary Results of a Single-Center Study. Biomolecules 2023; 14:7. [PMID: 38275748 PMCID: PMC10813029 DOI: 10.3390/biom14010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 12/09/2023] [Accepted: 12/13/2023] [Indexed: 01/27/2024] Open
Abstract
Endometriosis is a benign, estrogen-dependent gynecological condition with an uncertain exact pathogenetic mechanism. The aim of this study was to evaluate the potential differential expression of Insulin Growth Factor 1 (IGF-1) isoforms in deeply infiltrating endometriotic (DIE) lesions, in ovarian endometriomas, and in the eutopic endometrium of the same endometriosis patients and to compare their expression with that in the eutopic endometrium of women without endometriosis. A total of 39 patients were included: 28 with endometriosis, of whom 15 had endometriomas only, 7 had DIE nodules only, and 6 had both DIE and endometriomas, and 11 without endometriosis served as controls. We noticed a similar pattern of expression between IGF-1Ea and IGF-1Ec, which differed from that of the IGF-1Eb isoform, possibly implying differential biological actions of different isoforms in DIE subtypes. We observed a tendency of lower expression of IGF-1Ea and IGF-1Ec in endometriomas without DIE compared to endometriomas with concurrent DIE or in DIE nodules. In conclusion, differential expression of IGF-1 isoforms may indicate that DIE with its associated ovarian lesions and simple ovarian endometriosis should be considered as two forms of the disease developing under different molecular pathways.
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Affiliation(s)
- Nikolaos Blontzos
- Endoscopic Surgery Unit, 1st Department of Obstetrics Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.B.); (A.P.)
- Experimental Laboratory, 1st Department of Obstetrics Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (D.M.); (K.N.)
| | - Despoina Mavrogianni
- Experimental Laboratory, 1st Department of Obstetrics Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (D.M.); (K.N.)
| | - Konstantinos Ntzeros
- Experimental Laboratory, 1st Department of Obstetrics Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (D.M.); (K.N.)
| | - Nikolaos Kathopoulis
- Endoscopic Surgery Unit, 1st Department of Obstetrics Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.B.); (A.P.)
| | - Athanasios Moustogiannis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.M.); (A.P.); (M.K.)
| | - Anastassios Philippou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.M.); (A.P.); (M.K.)
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.M.); (A.P.); (M.K.)
| | - Athanasios Protopapas
- Endoscopic Surgery Unit, 1st Department of Obstetrics Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.B.); (A.P.)
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9
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Bernacchioni C, Rossi M, Vannuzzi V, Prisinzano M, Seidita I, Raeispour M, Muccilli A, Castiglione F, Bruni P, Petraglia F, Donati C. Sphingosine-1-phosphate receptor 3 is a non-hormonal target to counteract endometriosis-associated fibrosis. Fertil Steril 2023:S0015-0282(23)02074-5. [PMID: 38072366 DOI: 10.1016/j.fertnstert.2023.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 12/05/2023] [Accepted: 12/05/2023] [Indexed: 12/31/2023]
Abstract
OBJECTIVE To study the molecular mechanisms responsible for fibrosis in endometriosis by investigating whether the protein expression levels of sphingosine-1-phosphate receptor 3 (S1PR3), one of the five specific receptors of the bioactive sphingolipid sphingosine-1-phosphate (S1P), correlate with fibrosis extent in endometriotic lesions and which are the cellular mechanisms involved in this process. DESIGN Case-control laboratory study and cultured endometriotic cells. SETTING University research institute and university hospital. PATIENT(S) A total of 33 women, with and without endometriosis, were included in the study. INTERVENTIONS(S) Endometriotic lesions were obtained from women with endometriosis (ovarian endometrioma, n = 8; deep infiltrating endometriosis, n = 15; [urological n = 5, gastrointestinal n = 6, and posterior n = 4]) and control endometrium from healthy women, n = 10, by means of laparoscopic and hysteroscopic surgery. The expression of S1PR3 was evaluated using immunohistochemistry and the extent of fibrosis was assessed using Masson's trichrome staining. Human-cultured epithelial endometriotic 12Z cells were used to evaluate the mechanisms involved in the profibrotic effect of S1PR3 activation. MAIN OUTCOME MEASURE(S) The expression of S1PR3 in endometriotic lesions is positively correlated with endometriosis-associated fibrosis. In addition, S1P induced epithelial-mesenchymal transition (EMT) and fibrosis in epithelial endometriotic cells. Using RNA interference and pharmacological approaches, the profibrotic effect of S1P was shown to rely on S1PR3, thus unveiling the molecular mechanism implicated in the profibrotic action of the bioactive sphingolipid. RESULT(S) The protein expression levels of S1PR3 were significantly augmented in the glandular sections of endometrioma and deep infiltrating endometriosis of different localizations with respect to the control endometrium and positively correlated with the extent of fibrosis. Sphingosine-1-phosphate was shown to have a crucial role in the onset of fibrosis in epithelial endometriotic cells, stimulating the expression of EMT and fibrotic markers. Genetic approaches have highlighted that S1PR3 mediates the fibrotic effect of S1P. Downstream of S1PR3, ezrin and extracellular-signal-regulated kinases 1 and 2 signaling were found to be critically implicated in the EMT and fibrosis elicited by S1P. CONCLUSION(S) Sphingosine-1-phosphate receptor 3 may represent a possible innovative pharmacological target for endometriosis.
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Affiliation(s)
- Caterina Bernacchioni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy.
| | - Margherita Rossi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | | | - Matteo Prisinzano
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Isabelle Seidita
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Maryam Raeispour
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Angela Muccilli
- Histopathology and Molecular Diagnostics, Careggi University Hospital, Florence, Italy
| | - Francesca Castiglione
- Histopathology and Molecular Diagnostics, Careggi University Hospital, Florence, Italy
| | - Paola Bruni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Felice Petraglia
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy; Obstetrics and Gynecology, Careggi University Hospital, Florence, Italy
| | - Chiara Donati
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
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10
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Garcia Garcia JM, Vannuzzi V, Donati C, Bernacchioni C, Bruni P, Petraglia F. Endometriosis: Cellular and Molecular Mechanisms Leading to Fibrosis. Reprod Sci 2023; 30:1453-1461. [PMID: 36289173 PMCID: PMC10160154 DOI: 10.1007/s43032-022-01083-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/09/2022] [Indexed: 10/31/2022]
Abstract
Endometriosis is a chronic inflammatory condition affecting women of reproductive age. A relevant feature of endometriosis is the presence of fibrotic tissue inside and around the lesions, thus contributing to the classic endometriosis-related symptoms, pain, and infertility. The molecular mechanisms responsible for the development of fibrosis in endometriosis are not yet defined. The present review aimed to examine the biological mechanisms and signalling pathways involved in fibrogenesis of endometriotic lesions, highlighting the difference between deep infiltrating and ovarian endometriosis. The main cell types involved in the development of fibrosis are platelets, myofibroblasts, macrophages, and sensory nerve fibers. Members of the transforming growth factor (TGF) -β family, as well as the receptor Notch, or the bioactive sphingolipid sphingosine 1-phosphate (S1P), play a role in the development of tissue fibrosis, resulting in their metabolism and/or their signalling pathways altered in endometriotic lesions. It is relevant the knowledge of the molecular mechanisms that guide and support fibrosis in endometriosis, to identify new drug targets and provide new therapeutic approaches to patients.
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Affiliation(s)
- Jose Manuel Garcia Garcia
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Valentina Vannuzzi
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Chiara Donati
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Caterina Bernacchioni
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Paola Bruni
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Felice Petraglia
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy.
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11
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Tan Z, Gong X, Li Y, Hung SW, Huang J, Wang CC, Chung JPW. Impacts of endometrioma on ovarian aging from basic science to clinical management. Front Endocrinol (Lausanne) 2023; 13:1073261. [PMID: 36686440 PMCID: PMC9848590 DOI: 10.3389/fendo.2022.1073261] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/08/2022] [Indexed: 01/06/2023] Open
Abstract
Endometriosis is a common reproductive disorder characterized by the presence of endometrial implants outside of the uterus. It affects ~1 in 10 women of reproductive age. Endometriosis in the ovary, also known as endometrioma (OMA), is the most frequent implantation site and the leading cause of reproductive failure in affected women. Ovarian aging is one of the characteristic features of OMA, however its underlying mechanism yet to be determined. Accumulated evidence has shown that pelvic and local microenvironments in women with OMA are manifested, causing detrimental effects on ovarian development and functions. Whilst clinical associations of OMA with poor ovarian reserve, premature ovarian insufficiency, and early menopause have been reported. Moreover, surgical ablation, fenestration, and cystectomy of OMA can further damage the normal ovarian reservoir, and trigger hyperactivation of primordial follicles, subsequently resulting in the undesired deterioration of ovarian functions. Nevertheless, there is no effective treatment to delay or restore ovarian aging. This review comprehensively summarised the pathogenesis and study hypothesis of ovarian aging caused by OMA in order to propose potential therapeutic targets and interventions for future studies.
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Affiliation(s)
- Zhouyurong Tan
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xue Gong
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yiran Li
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Sze Wan Hung
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jin Huang
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen, China
| | - Chi Chiu Wang
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Reproduction and Development, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jacqueline Pui Wah Chung
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
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12
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Leyendecker G, Wildt L, Laschke MW, Mall G. Archimetrosis: the evolution of a disease and its extant presentation : Pathogenesis and pathophysiology of archimetrosis (uterine adenomyosis and endometriosis). Arch Gynecol Obstet 2023; 307:93-112. [PMID: 35596746 PMCID: PMC9836992 DOI: 10.1007/s00404-022-06597-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/27/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE This article presents a novel concept of the evolution and, thus, the pathogenesis of uterine adenomyosis as well as peritoneal and peripheral endometriosis. Presently, no unifying denomination of this nosological entity exists. METHODS An extensive search of the literature on primate evolution was performed. This included comparative functional morphology with special focus on the evolution of the birthing process that fundamentally differs between the haplorrhine primates and most of the other eutherian mammals. The data were correlated with the results of own research on the pathophysiology of human archimetrosis and with the extant presentation of the disease. RESULTS The term Archimetrosis is suggested as a denomination of the nosological entity. Archimetrosis occurs in human females and also in subhuman primates. There are common features in the reproductive process of haplorrhine primates such as spontaneous ovulation and corpus luteum formation, spontaneous decidualization and menstruation. These have fused Müllerian ducts resulting in a uterus simplex. Following a usually singleton pregnancy, the fetus is delivered in the skull position. Some of these features are shared by other mammals, but not in that simultaneous fashion. In haplorrhine primates, with the stratum vasculare, a new myometrial layer has evolved during the time of the Cretaceous-Terrestrial Revolution (KTR) that subserves expulsion of the conceptus and externalization of menstrual debris in non-conceptive cycles. Hypercontractility of this layer has evolved as an advantage with respect to the survival of the mother and the birth of a living child during delivery and may be experienced as primary dysmenorrhea during menstruation. It may result in tissue injury by the sheer power of the contractions and possibly by the associated uterine ischemia. Moreover, the lesions at extra-uterine sites appear to be maintained by biomechanical stress. CONCLUSIONS Since the pathogenesis of archimetrosis is connected with the evolution of the stratum vasculare, tissue injury and repair (TIAR) turns out to be the most parsimonious explanation for the development of the disease based on clinical, experimental and evolutionary evidence. Furthermore, a careful analysis of the published clinical data suggests that, in the risk population with uterine hypercontractility, the disease develops with a yet to be defined latency phase after the onset of the biomechanical injury. This opens a new avenue of prevention of the disease in potentially affected women that we consider to be primarily highly fertile.
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Affiliation(s)
| | | | - Matthias W. Laschke
- Institut für Klinisch-Experimentelle Chirurgie, Universität des Saarlandes, 66421 Homburg, Germany
| | - Gerhard Mall
- Wiesenbacher Str. 10, 69151 Neckargemünd, Germany
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13
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Huang Q, Liu X, Guo SW. Higher fibrotic content of endometriotic lesions is associated with diminished prostaglandin E2 signaling. Reprod Med Biol 2021; 21:e12423. [PMID: 34938147 PMCID: PMC8656679 DOI: 10.1002/rmb2.12423] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/12/2021] [Accepted: 10/21/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose While the prevailing view holds that the prostaglandin E2 (PGE2) signaling plays a vital role in endometriosis, PGE2 also is known to be anti-fibrotic. We investigated the immunostaining of COX-2, EP2, and EP4, along with fibrotic content in ovarian endometrioma (OE) and deep endometriosis (DE) lesions, and in OE lesions from adolescent and adult patients. In addition, we evaluated the effect of substrate stiffness on the expression of COX-2, EP2, and EP4 in endometrial stromal cells. Methods Immunohistochemistry analysis of COX-2, EP2, and EP4, along with the quantification of lesional fibrosis, was conducted for OE and DE lesion samples and also OE lesion samples from adolescent and adult patients. The effect of substrate rigidity on fibroblast-to-myofibroblast transdifferentiation (FMT) and the expression of COX-2, EP2, and EP4, with or without TGF-β1 stimulation, were investigated. Results The immunostaining of COX-2, EP2, and EP4 was substantially reduced in endometriotic lesions as lesions became more fibrotic. Both TGF-β1 stimulation and stiff substrates induced FMT and reduced the expression of COX-2, EP2, and EP4. Conclusions Since fibrosis is a common feature of endometriosis, our results thus cast doubts on the use of therapeutics that suppresses the PGE2 signaling pathway, either by inhibiting COX-2 or EP2/EP4.
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Affiliation(s)
- Qingqing Huang
- Shanghai OB/GYN Hospital Fudan University Shanghai China.,The Third Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
| | - Xishi Liu
- Shanghai OB/GYN Hospital Fudan University Shanghai China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases Fudan University Shanghai China
| | - Sun-Wei Guo
- Shanghai OB/GYN Hospital Fudan University Shanghai China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases Fudan University Shanghai China
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14
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Kusama K, Fukushima Y, Yoshida K, Azumi M, Yoshie M, Mizuno Y, Kajihara T, Tamura K. PGE2 and Thrombin Induce Myofibroblast Transdifferentiation via Activin A and CTGF in Endometrial Stromal Cells. Endocrinology 2021; 162:6380884. [PMID: 34606582 DOI: 10.1210/endocr/bqab207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Indexed: 12/20/2022]
Abstract
Endometriosis is characterized by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal hemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, menstruation-related factors, PGE2 and thrombin (P/T), a PAR1 agonist induced epithelial-mesenchymal transition (EMT) of endometrial cells under hypoxia. However, the molecular mechanisms by which P/T induce development of endometriosis have not been fully characterized. To investigate the effects of P/T, RNA extracted from endometrial stromal cells (ESCs) treated with P/T were subjected to RNA sequence analysis, and identified activin A, FOS, and GATA2 as upregulated genes. Activin A increased the expression of connective tissue growth factor (CTGF) and mesenchymal marker genes in ESCs. CTGF induced the expression of fibrosis marker type I collagen, fibronectin, and α-smooth muscle actin (αSMA), indicating fibroblast to myofibroblast transdifferentiation (FMT) of ESCs. In addition, activin A, FOS, GATA2, CTGF, and αSMA were localized in endometriosis lesions. Taken together, our data show that P/T induces changes resembling EMT and FMT in ectopic ESCs derived from retrograde menstruation, and that these are associated with fibrotic changes in the lesions. Pharmacological means that block P/T-induced activin A and CTGF signaling may be strategies to inhibit fibrosis in endometriotic lesions.
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Affiliation(s)
- Kazuya Kusama
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | - Yuta Fukushima
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | - Kanoko Yoshida
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | - Mana Azumi
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | - Mikihiro Yoshie
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | - Yumi Mizuno
- Department of Obstetrics and Gynecology, Saitama Medical University, Saitama 350-0495, Japan
| | - Takeshi Kajihara
- Department of Obstetrics and Gynecology, Saitama Medical University, Saitama 350-0495, Japan
| | - Kazuhiro Tamura
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
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15
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Colgrave EM, Keast JR, Bittinger S, Healey M, Rogers PAW, Holdsworth-Carson SJ, Girling JE. Comparing endometriotic lesions with eutopic endometrium: time to shift focus? Hum Reprod 2021; 36:2814-2823. [PMID: 34535995 DOI: 10.1093/humrep/deab208] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 08/02/2021] [Indexed: 12/23/2022] Open
Abstract
Endometriosis is a heterogeneous disease in terms of patient symptoms, treatment responsiveness and the presentation of endometriotic lesions. This article explores the histological features of endometriotic lesions, highlighting their sometimes underappreciated heterogeneity. We note the variability in evidence for and against the menstrual cycle responsiveness of lesions and consider the utility of drawing parallels between endometriotic lesions and eutopic endometrium. We ask whether histopathologic features beyond just the presence/absence of endometrial-like glands and/or stroma could help improve disease stratification. At the same time, we acknowledge the desire of many clinicians and patients to avoid invasive surgery thereby limiting the ability to histologically phenotype lesions. The ability to derive clinically useful histological information from endometriotic lesions, in association with patient data, would be invaluable to clinicians to help improve treatment options in such a diverse group of patients. However, in suggesting that a shift in focus may enable the development of a better patient stratification system, we recognise that our wish for a single comprehensive stratification system may be beyond reach for a disease of such diverse presentation.
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Affiliation(s)
- Eliza M Colgrave
- Department of Obstetrics and Gynaecology, University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Australia
| | - Janet R Keast
- Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
| | - Sophie Bittinger
- Department of Pathology, Royal Women's Hospital, Melbourne, Australia
| | - Martin Healey
- Department of Obstetrics and Gynaecology, University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Australia
| | - Peter A W Rogers
- Department of Obstetrics and Gynaecology, University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Australia
| | - Sarah J Holdsworth-Carson
- Department of Obstetrics and Gynaecology, University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Australia
| | - Jane E Girling
- Department of Obstetrics and Gynaecology, University of Melbourne and Gynaecology Research Centre, Royal Women's Hospital, Melbourne, Australia.,Department of Anatomy, University of Otago, Dunedin, New Zealand
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16
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Figuier C, Montoriol PF, Pereira B, Chauvet P, Bourdel N, Canis M. Abdominal wall endometriosis: Is structure in imaging related to nodule localisation? A retrospective study. JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2021. [DOI: 10.1177/22840265211009643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Objective: Investigate the relationship between the structure of abdominal wall endometriotic nodules in MRI and their localisation in abdominal wall layers in order to better understand nodule origins. Design: Women who had an MRI prior to surgical treatment of an abdominal wall endometriotic nodule between 2005 and 2016. Population: Thirty-six patients including four patients with two nodules. Methods: MRI images were reviewed. Each nodule was analysed according to its structure (fibrous, cystic, mixed), localisation (subcutaneous fat, intra muscular, intermediary position), and size. Results: Forty nodules were analysed in MRI with no relationship found between localisation and nodule structure ( p = 0.48). 87.5% of mixed nodules were revealed to have a cystic superficial rim extending towards the subcutaneous fat layer. This finding suggests that the glandular part of the nodule is the active part of the disease from which nodule progression occurs. Intermediary and intramuscular nodules were respectively statistically larger than subcutaneous fat nodules indicating a relationship between nodule size and localisation (35 mm (22–53) vs 17 mm (17–23)) ( p = 0.03). Conclusion: Despite differences in environments surrounding the nodules, no significant relationship between nodule structure in imaging and abdominal wall localisation was found. Data from mixed nodules indicate however the possible role of nodule environment on structure and that the mechanism of nodule growth may be linked to development of cystic superficial rims, at the forefront of disease progression, abdominal wall nodules growing from deep to superficial. Studies are required to further investigate our findings and enable greater understanding of the origins of AWE.
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Affiliation(s)
- Claire Figuier
- Department of Gynecological Surgery, Clermont Ferrand University Hospital, Clermont Ferrand, France
| | | | - Bruno Pereira
- Department of Clinic Research and Innovation, Clermont-Ferrand University Hospital, Clermont Ferrand, France
| | - Pauline Chauvet
- Department of Gynecological Surgery, Clermont Ferrand University Hospital, Clermont Ferrand, France
| | - Nicolas Bourdel
- Department of Gynecological Surgery, Clermont Ferrand University Hospital, Clermont Ferrand, France
| | - Michel Canis
- Department of Gynecological Surgery, Clermont Ferrand University Hospital, Clermont Ferrand, France
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17
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Ersoy B, Hey-Cunningham AJ, Lindsay L, Varol N, Markham R. Altered immune environment in peritoneal endometriotic lesions: relationship to lesion appearance. F&S SCIENCE 2021; 2:207-218. [PMID: 35559754 DOI: 10.1016/j.xfss.2020.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To study the localization of and quantify different immune cell populations in red, black, and white peritoneal endometriotic lesions and compare immune cell densities between lesions and the surrounding tissue. DESIGN Cross-sectional study. SETTING Teaching hospital, university research laboratory. PATIENT(S) Participants undergoing laparoscopic excision of endometriosis were recruited from gynecological operating theaters at Royal Prince Alfred Hospital, Sydney (n = 28). INTERVENTION(S) Immunohistochemical staining for and quantification of dendritic cells (mature and immature), T cells (effector, cytotoxic, and regulatory), B cells, and macrophages in endometriotic peritoneal lesions and the surrounding tissue. MAIN OUTCOME MEASURE(S) Immune cell densities and aggregates were quantified. RESULT(S) Red and black lesions are significantly more likely to be surrounded by immune cell aggregates than white lesions (P=.036). In the tissue surrounding the peritoneal endometriotic lesions, there was a consistent pattern of greater and more variable density of immune cell populations for red lesions than black or white lesions and a range of significant positive correlations between densities of different immune populations (all P≤.004; not observed within the lesion stroma). CONCLUSION(S) There is a greater presence of immune cells in the tissue surrounding earlier/red and black lesions than older scarred white lesions, particularly in the form of immune cell aggregates, indicating an immunologic response in close proximity to the adjacent lesion. The relationship between densities of immune populations in the tissue surrounding the lesions suggests complementary recruitment and local interactions between cells. Categorizing immune cell populations in proximity to peritoneal endometriotic lesions may improve the understanding of lesion persistence and transition to older white appearances. Early (red) peritoneal endometriotic lesions are surrounded by a greater density of immune cells, including immune aggregates, than later (black or white) lesions. These immune cells may support lesion persistence.
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Affiliation(s)
- Burcu Ersoy
- Obstetrics, Gynaecology and Neonatology, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Alison J Hey-Cunningham
- Obstetrics, Gynaecology and Neonatology, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Laura Lindsay
- Discipline of Anatomy and Histology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
| | - Nesrin Varol
- Obstetrics, Gynaecology and Neonatology, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Obstetrics and Gynaecology, Royal Prince Alfred Hospital, Camperdown, Australia
| | - Robert Markham
- Obstetrics, Gynaecology and Neonatology, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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18
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Aleksandrov A, Meshulam M, Smith AV, Chauvet P, Canis M, Bourdel N. Fluorescence-guided management of deep endometriosis. Fertil Steril 2020; 114:1116-1118. [PMID: 32907747 DOI: 10.1016/j.fertnstert.2020.07.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To demonstrate the advantages of the fluorescence-guided surgery using indocyanine green (ICG) in the management of deep endometriotic nodules toward more complete and safe excision of the disease in cases when rectal shaving is performed. DESIGN Surgical video demonstrating the result of the application of a fluorescent dye (ICG) during deep endometriosis surgery. The local institutional review board was consulted and ruled that approval was not required for this video article because the video describes a technique and the patient cannot be identified. SETTING Tertiary-care university hospital. PATIENT(S) The patient underwent rectal shaving due to a deep endometriotic nodule located at the level of the rectovaginal septum. INTERVENTION(S) The procedure started with exploration of the lesion and the anatomical structures. The nodule is approached using the "reverse technique." As the nodule is infiltrating the vagina, complete resection of the posterior vaginal wall is performed. At the start of the rectal shaving, ICG is injected and its fluorescence effect is used to provide navigation for the surgeon during the excision. At the end of the procedure the vascularization of the bowel wall and the vagina are evaluated with the help of the ICG. MAIN OUTCOME MEASURE(S) Visual assessment and distinction between the borders of the endometriotic nodule and the rectal wall as a result of the fluorescence effect of the ICG. RESULT(S) After injection of the ICG, the borders of the healthy rectum are delineated and a clear distinction between the endometriotic nodule and the bowel wall is demonstrated. In addition, the effect of the ICG was used to assess the vascularization of the infiltrated organs (vagina and rectal wall). CONCLUSION(S) Deep endometriosis at the level of the rectum usually represents a solid fibrotic nodule. The fibrosis plays a major role in the development of the disease. Indocyanine green is a fluorescent contrast agent, routinely used in a wide range of specialties to assess the blood supply and vascularization of different organs and tissues. Based on the fibrotic nature of the disease, the fluorescence could facilitate the distinction between healthy vascularized tissues and the endometriotic nodule. In the presented case, using ICG, a clear difference between the nodule and the rectum is demonstrated, as well as the vascularization of the bowel wall and the vagina. The implementation of ICG during endometriosis surgery could provide navigation for the surgeon toward a more complete and safer treatment of the disease, reducing the risk of complications and reinterventions. Additional studies are needed to further evaluate ICG fluorescence-guided surgery in the management of deep endometriosis.
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Affiliation(s)
- Atanas Aleksandrov
- Department of Gynecological Surgery, Clermont-Ferrand University Hospital Estaing, Clermont-Ferrand, France; Specialised Hospital for Obstetrics and Gynecology SBAGAL Pr. Dimitar Stamatov, Medical University Varna, Varna, Bulgaria
| | - Moshe Meshulam
- Department of Gynecological Surgery, Clermont-Ferrand University Hospital Estaing, Clermont-Ferrand, France; Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Pauline Chauvet
- Department of Gynecological Surgery, Clermont-Ferrand University Hospital Estaing, Clermont-Ferrand, France; EnCoV, IP, UMR 6602 CNRS, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Michel Canis
- Department of Gynecological Surgery, Clermont-Ferrand University Hospital Estaing, Clermont-Ferrand, France; EnCoV, IP, UMR 6602 CNRS, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Nicolas Bourdel
- Department of Gynecological Surgery, Clermont-Ferrand University Hospital Estaing, Clermont-Ferrand, France; EnCoV, IP, UMR 6602 CNRS, Université Clermont Auvergne, Clermont-Ferrand, France.
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19
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Maruyama S, Imanaka S, Nagayasu M, Kimura M, Kobayashi H. Relationship between adenomyosis and endometriosis; Different phenotypes of a single disease? Eur J Obstet Gynecol Reprod Biol 2020; 253:191-197. [PMID: 32877772 DOI: 10.1016/j.ejogrb.2020.08.019] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/10/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023]
Abstract
Adenomyosis and endometriosis are common gynecological disorders, but their pathophysiology is still under debate. The aim of this review is to discuss whether adenomyosis and endometriosis represent two different entities or different phenotypes of a single disease. We searched PubMed electronic databases published between January 2000 and April 2020. Endometriosis is classified into three phenotypes; superficial peritoneal disease (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) lesions. Adenomyosis presents several different subtypes, including intrinsic adenomyosis, extrinsic adenomyosis, adenomyosis externa and focal adenomyosis located in the outer myometrium (FAOM). Human uterus is embryologically composed of archimetra, originating from the Müllerian duct, and neometra, arising from the non-Müllerian duct, and adenomyosis and endometriosis are diseases of archimetra. The outer myometrial layer of the uterus is composed of highly differentiated smooth muscle cells (SMCs), while the inner myometrial cells are immature. Inappropriate uterine contractions can cause retrograde menstruation and chronic inflammation in the pelvic cavity, then influencing the development of pelvic endometriosis. Furthermore, hyperperistalsis results in physiological and pathological changes to the endometrial-myometrial junctional barrier, allowing invagination of the normal endometrial tissue into the inner myometrial layer. This can trigger the development of intrinsic adenomyosis. There are insufficient data available to draw conclusions, but extrinsic adenomyosis may result from pelvic endometriosis and FAOM from rectal and bladder DIE/adenomyosis externa. In conclusions, this paper contributes to the debate in the possibility that adenomyosis and endometriosis represent different phenotypes of a single disease.
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Affiliation(s)
- Sachiyo Maruyama
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 634-8522, Japan
| | - Shogo Imanaka
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 634-8522, Japan; Department of Gynecology and Infertility, Ms.Clinic MayOne, Kashihara, 634-0813, Japan
| | - Mika Nagayasu
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 634-8522, Japan
| | - Mai Kimura
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 634-8522, Japan
| | - Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 634-8522, Japan; Department of Gynecology and Infertility, Ms.Clinic MayOne, Kashihara, 634-0813, Japan.
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20
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Vercellini P, Sergenti G, Buggio L, Frattaruolo MP, Dridi D, Berlanda N. Advances in the medical management of bowel endometriosis. Best Pract Res Clin Obstet Gynaecol 2020; 71:78-99. [PMID: 32680785 DOI: 10.1016/j.bpobgyn.2020.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 12/29/2022]
Abstract
Endometriosis infiltrating the bowel can be treated medically in accurately selected women not seeking conception and without overt obstructive symptomatology. When the rectosigmoid junction is involved, the probabilities of intestinal symptoms relief, undergoing surgery after treatment failure, and developing bowel obstruction during hormonal treatment are around 70%, 10%, and 1-2%, respectively. When the lesion infiltrates exclusively the mid-rectum, thus in cases of true rectovaginal endometriosis, the probabilities of intestinal symptoms relief and undergoing surgery are about 80% and 3%, respectively. Endometriotic obstructions of the rectal ampulla have not been reported. A rectosigmoidoscopy or colonoscopy should be performed systematically before starting medical therapies, also to rule out malignant tumours arising from the intestinal mucosa. Progestogens are safe, generally effective, well-tolerated, inexpensive, and should be considered as first-line medications for bowel endometriosis. Independently of symptom relief, intestinal lesions should be checked periodically to exclude nodule progression during hormonal treatment.
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Affiliation(s)
- Paolo Vercellini
- Department of Clinical Sciences and Community Health, Università degli Studi, Via Commenda, Milan, Italy; Fondazione Ca' Granda Ospedale Maggiore Policlinico, Via Commenda, 12-20122, Milan, Italy.
| | - Greta Sergenti
- Department of Clinical Sciences and Community Health, Università degli Studi, Via Commenda, Milan, Italy
| | - Laura Buggio
- Fondazione Ca' Granda Ospedale Maggiore Policlinico, Via Commenda, 12-20122, Milan, Italy
| | - Maria Pina Frattaruolo
- Fondazione Ca' Granda Ospedale Maggiore Policlinico, Via Commenda, 12-20122, Milan, Italy
| | - Dhouha Dridi
- Department of Clinical Sciences and Community Health, Università degli Studi, Via Commenda, Milan, Italy; Fondazione Ca' Granda Ospedale Maggiore Policlinico, Via Commenda, 12-20122, Milan, Italy
| | - Nicola Berlanda
- Fondazione Ca' Granda Ospedale Maggiore Policlinico, Via Commenda, 12-20122, Milan, Italy
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21
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Xu Z, Zhang L, Yu Q, Zhang Y, Yan L, Chen ZJ. The estrogen-regulated lncRNA H19/miR-216a-5p axis alters stromal cell invasion and migration via ACTA2 in endometriosis. Mol Hum Reprod 2020; 25:550-561. [PMID: 31323679 DOI: 10.1093/molehr/gaz040] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 06/27/2019] [Accepted: 07/10/2019] [Indexed: 12/11/2022] Open
Abstract
Fibrotic tissue may contribute to the origin of some endometriosis-related symptoms, such as chronic pelvic pain and infertility. Alterations in the H19/miR-216a-5p/ACTA2 pathway may mediate the regulation of eutopic endometrial stromal cell (euESC) invasion and migration and may represent a potential mechanism underlying fibrous tissue formation or fibrosis in women with endometriosis. In this study, we aimed to determine the expression of H19 and ACTA2 in endometrial tissues of women with endometriosis. Two groups of 23 infertile women with endometriosis and 23 matched infertile women without endometriosis were investigated. Primary cultured cells of endometrial tissues were analyzed using RT-PCR and western blotting (WB) to determine expression of H19 and ACTA2. 5-Ethyl-2'-deoxyuridine, CCK8 and Transwell assays were used to study the functions of H19 and ACTA2. Human embryonic kidney 293 cells were used for luciferase assays to study miR-216a-5p binding sites with H19 and ACTA2. We found that H19 and ACTA2 levels were significantly higher in endometriosis euESCs than in control euESCs (P < 0.05) and were positively correlated in endometriosis euESCs. Luciferase assays indicated that H19 regulates ACTA2 expression via competition for inhibitory miR-216a-5p binding sites. Our results indicate that alterations in the estrogen/H19/miR-216a-5p/ACTA2 pathway regulated endometriosis euESC invasion and migration. Downregulation of H19 or ACTA2 inhibited endometriosis euESC invasion and migration; however, estrogen promoted endometriosis euESC invasion and migration via H19. The main limitation of our study was that experiments were conducted in vitro and further in vivo studies are required in the future. However, our study showed that primary cultured cells represented endometriosis cells more clearly than cell lines.
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Affiliation(s)
- Zhen Xu
- School of Medicine, Shandong University, 44 Wenhua West Road, Jinan, China.,Reproductive Hospital Affiliated to Shandong University, 157 Jingliu Road, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, 157 Jingliu Road, Jinan, China.,Shandong Provincial Key Laboratory of Reproductive Medicine, 157 Jingliu Road, Jinan, China
| | - Liping Zhang
- School of Medicine, Shandong University, 44 Wenhua West Road, Jinan, China.,Reproductive Hospital Affiliated to Shandong University, 157 Jingliu Road, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, 157 Jingliu Road, Jinan, China.,Shandong Provincial Key Laboratory of Reproductive Medicine, 157 Jingliu Road, Jinan, China
| | - Qian Yu
- School of Medicine, Shandong University, 44 Wenhua West Road, Jinan, China.,Reproductive Hospital Affiliated to Shandong University, 157 Jingliu Road, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, 157 Jingliu Road, Jinan, China.,Shandong Provincial Key Laboratory of Reproductive Medicine, 157 Jingliu Road, Jinan, China
| | - Yanan Zhang
- School of Medicine, Shandong University, 44 Wenhua West Road, Jinan, China.,Reproductive Hospital Affiliated to Shandong University, 157 Jingliu Road, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, 157 Jingliu Road, Jinan, China.,Shandong Provincial Key Laboratory of Reproductive Medicine, 157 Jingliu Road, Jinan, China
| | - Lei Yan
- School of Medicine, Shandong University, 44 Wenhua West Road, Jinan, China.,Reproductive Hospital Affiliated to Shandong University, 157 Jingliu Road, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, 157 Jingliu Road, Jinan, China.,Shandong Provincial Key Laboratory of Reproductive Medicine, 157 Jingliu Road, Jinan, China
| | - Zi-Jiang Chen
- School of Medicine, Shandong University, 44 Wenhua West Road, Jinan, China.,Reproductive Hospital Affiliated to Shandong University, 157 Jingliu Road, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, 157 Jingliu Road, Jinan, China.,Shandong Provincial Key Laboratory of Reproductive Medicine, 157 Jingliu Road, Jinan, China.,Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, 845 Lingshan Road, Shanghai, China
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22
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Agely A, Bolan C, Metcalfe A, VanBuren W, Menias C. Genitourinary manifestations of endometriosis with emphasis on the urinary tract. Abdom Radiol (NY) 2020; 45:1711-1722. [PMID: 31919646 DOI: 10.1007/s00261-019-02383-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Endometriosis is a common benign condition affecting women. The disease has a broad spectrum of presentations from incidental lesions in asymptomatic women to causing significant and debilitating morbidity in others. Ectopic endometrial glands are located in predictable locations throughout the pelvis, including implantation on the ovaries and in the rectouterine cul-de-sac. Less commonly, the urinary tract may be involved. As genitourinary manifestations may remain symptomatically occult or masquerade as other diagnoses, it is essential for the radiologist to be aware of the imaging features, consider this diagnosis, and potentially save the patient from delayed treatment.
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Affiliation(s)
- A Agely
- Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA
| | - C Bolan
- Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA.
| | - A Metcalfe
- Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA
| | - W VanBuren
- Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA
| | - C Menias
- Department of Radiology, Mayo Clinic Arizona, Scottsdale, AZ, USA
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23
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Ganieva U, Nakamura T, Osuka S, Bayasula, Nakanishi N, Kasahara Y, Takasaki N, Muraoka A, Hayashi S, Nagai T, Murase T, Goto M, Iwase A, Kikkawa F. Involvement of Transcription Factor 21 in the Pathogenesis of Fibrosis in Endometriosis. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:145-157. [DOI: 10.1016/j.ajpath.2019.09.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 09/03/2019] [Accepted: 09/12/2019] [Indexed: 12/26/2022]
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24
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Greaves E, Rosser M, Saunders PTK. Endometriosis-Associated Pain - Do Preclinical Rodent Models Provide a Good Platform for Translation? ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2020; 232:25-55. [PMID: 33278006 DOI: 10.1007/978-3-030-51856-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pelvic pain is a common symptom of endometriosis. Our understanding of its etiology remains incomplete and medical management is limited by poor translation from preclinical models to clinical trials. In this review, we briefly consider the evidence, or lack thereof, that different subtypes of lesion, extra-uterine bleeding, and neuropathic pathways add to the complex and heterogeneous pain experience of women with the condition. We summarize the studies in rodent models of endometriosis that have used behavioral endpoints (evoked and non-evoked) to explore mechanisms of endometriosis-associated pain. Lesion innervation, activation of nerves by pronociceptive molecules released by immune cells, and a role for estrogen in modulating hyperalgesia are key endometriosis-associated pain mechanisms replicated in preclinical rodent models. The presence of ectopic (full thickness uterus or endometrial) tissue may be associated with changes in the spinal cord and brain, which appear to model changes reported in patients. While preclinical models using rats and mice have yielded insights that appear relevant to mechanisms responsible for the development of endometriosis-associated pain, they are limited in scope. Specifically, most studies are based on models that only resulted in the formation of superficial lesions and use induced (evoked) behavioral 'pain' tests. We suggest that translation for patient benefit will be improved by new approaches including models of ovarian and deep infiltrating disease and measurement of spontaneous pain behaviors. Future studies must also capitalize on new advances in the wider field of pain medicine to identify more effective treatments for endometriosis-associated pain.
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Affiliation(s)
- Erin Greaves
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
| | - Matthew Rosser
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Philippa T K Saunders
- Centre for Inflammation Research, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
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25
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Viganò P, Ottolina J, Bartiromo L, Bonavina G, Schimberni M, Villanacci R, Candiani M. Cellular Components Contributing to Fibrosis in Endometriosis: A Literature Review. J Minim Invasive Gynecol 2019; 27:287-295. [PMID: 31785417 DOI: 10.1016/j.jmig.2019.11.011] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/31/2019] [Accepted: 11/21/2019] [Indexed: 12/17/2022]
Abstract
Endometriosis-related fibrosis represents a complex phenomenon with underlying mechanisms yet to be clarified. Fibrosis is consistently present in all disease forms and contributes to classic endometriosis-related symptoms of pain and infertility. The purpose of this literature review was to examine the role of various cellular populations and biologic mechanisms and signaling pathways in inducing fibrogenesis of endometriotic lesions. A search was performed through PubMed and MEDLINE for animal and human studies published in English in the last 23 years that examined fibrosis in superficial, ovarian, and deep infiltrating endometriosis. The main cell types found to be involved in the development of fibrosis were platelets, macrophages, ectopic endometrial cells, and sensory nerve fibers. Interactions among each of the cell types contribute to the production of fibrosis through the production of soluble factors, mostly transforming growth factor-β but also other cytokines and neuropeptides. Cell types known to be critical to the pathophysiology of endometriosis also contribute to fibrogenesis, thus supporting the theory that fibrosis is an inherent part of endometriosis.
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Affiliation(s)
- Paola Viganò
- Reproductive Sciences Lab, Division of Genetics and Cell Biology (Dr. Vigano).
| | - Jessica Ottolina
- Gynecology/Obstetrics Unit (Drs. Ottolina, Bartiromo, Bonavina, Schimberni, Villanacci, and Candiani), San Raffaele Scientific Institute, Milan, Italy
| | - Ludovica Bartiromo
- Gynecology/Obstetrics Unit (Drs. Ottolina, Bartiromo, Bonavina, Schimberni, Villanacci, and Candiani), San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Bonavina
- Gynecology/Obstetrics Unit (Drs. Ottolina, Bartiromo, Bonavina, Schimberni, Villanacci, and Candiani), San Raffaele Scientific Institute, Milan, Italy
| | - Matteo Schimberni
- Gynecology/Obstetrics Unit (Drs. Ottolina, Bartiromo, Bonavina, Schimberni, Villanacci, and Candiani), San Raffaele Scientific Institute, Milan, Italy
| | - Roberta Villanacci
- Gynecology/Obstetrics Unit (Drs. Ottolina, Bartiromo, Bonavina, Schimberni, Villanacci, and Candiani), San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Candiani
- Gynecology/Obstetrics Unit (Drs. Ottolina, Bartiromo, Bonavina, Schimberni, Villanacci, and Candiani), San Raffaele Scientific Institute, Milan, Italy
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26
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Marcellin L, Leconte M, Gaujoux S, Santulli P, Borghese B, Chapron C, Dousset B. Associated ileocaecal location is a marker for greater severity of low rectal endometriosis. BJOG 2019; 126:1600-1608. [PMID: 31407476 DOI: 10.1111/1471-0528.15901] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2019] [Indexed: 12/23/2022]
Affiliation(s)
- L Marcellin
- Département de Gynécologie Obsétrique II et Médecine de la Reproduction (Professeur Chapron) Assistance Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire Paris Centre (HUPC) Paris France
- Université Paris Descartes Sorbonne Paris Cité Paris France
| | - M Leconte
- Université Paris Descartes Sorbonne Paris Cité Paris France
- Service de Chirurgie Digestive Hépato‐biliaire et Endocrinienne Assistance, Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire, Paris Centre (HUPC) Paris France
| | - S Gaujoux
- Université Paris Descartes Sorbonne Paris Cité Paris France
- Service de Chirurgie Digestive Hépato‐biliaire et Endocrinienne Assistance, Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire, Paris Centre (HUPC) Paris France
| | - P Santulli
- Département de Gynécologie Obsétrique II et Médecine de la Reproduction (Professeur Chapron) Assistance Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire Paris Centre (HUPC) Paris France
- Université Paris Descartes Sorbonne Paris Cité Paris France
| | - B Borghese
- Département de Gynécologie Obsétrique II et Médecine de la Reproduction (Professeur Chapron) Assistance Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire Paris Centre (HUPC) Paris France
- Université Paris Descartes Sorbonne Paris Cité Paris France
| | - C Chapron
- Département de Gynécologie Obsétrique II et Médecine de la Reproduction (Professeur Chapron) Assistance Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire Paris Centre (HUPC) Paris France
- Université Paris Descartes Sorbonne Paris Cité Paris France
| | - B Dousset
- Université Paris Descartes Sorbonne Paris Cité Paris France
- Service de Chirurgie Digestive Hépato‐biliaire et Endocrinienne Assistance, Publique‐Hôpitaux de Paris (AP‐HP) Centre Hospitalier Universitaire (CHU) Cochin Hôpital Universitaire, Paris Centre (HUPC) Paris France
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27
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Endometriotic Peritoneal Fluid Promotes Myofibroblast Differentiation of Endometrial Mesenchymal Stem Cells. Stem Cells Int 2019; 2019:6183796. [PMID: 31281378 PMCID: PMC6589313 DOI: 10.1155/2019/6183796] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 01/14/2019] [Accepted: 02/10/2019] [Indexed: 02/06/2023] Open
Abstract
During the development of endometriosis, the presence of fibrotic tissues in and surrounding endometriotic lesions may lead to subsequent adhesion, anatomic distortion, and chronic pain. Therefore, studies aimed at clarifying the underlying mechanisms of fibrogenesis in endometriosis could potentially provide a novel strategy for effective treatment. Mesenchymal stem cells (MSCs) play a key role in fibrotic diseases by differentiating into myofibroblasts in appropriate microenvironment. In this study, we collected endometrial and endometriotic tissues from patients with endometriosis (n = 32) and control patients without endometriosis (n = 20) to compare the expression of fibrotic proteins and investigate the effect of endometriotic peritoneal fluid (PF) on myofibroblast differentiation of endometrial MSCs. We found that the expression of fibrotic proteins, including alpha-smooth muscle actin (α-SMA), type I collagen (collagen I), connective tissue growth factor (CTGF), and fibronectin, and the extent of fibrosis extremely enhanced in ectopic endometria compared with eutopic endometria from the same patients with endometriosis and normal endometria from patients without endometriosis. We next isolated and identified endometrial MSCs and found that treatment with endometriotic PF strongly induced endometrial MSCs to differentiate into myofibroblasts concomitant with the activation of Smad2/3. Moreover, ectopic endometrial MSCs expressed elevated collagen I, α-SMA, fibronectin, and CTGF. Sushi domain containing-2 (SUSD2), a marker of endometrial MSCs, and α-SMA, a well-recognized marker for myofibroblasts, colocalized extensively in ectopic endometria while seldom in normal and eutopic endometria. These findings suggest that ectopic endometrial MSCs are probably more susceptible to myofibroblast differentiation because of the long-term influence of endometriotic PF. All together, we report for the first time that endometriotic PF promotes myofibroblast differentiation of endometrial MSCs. This understanding will greatly improve our understanding of the pathophysiology of endometriosis and help design better therapeutics.
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28
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Barra F, Scala C, Biscaldi E, Vellone VG, Ceccaroni M, Terrone C, Ferrero S. Ureteral endometriosis: a systematic review of epidemiology, pathogenesis, diagnosis, treatment, risk of malignant transformation and fertility. Hum Reprod Update 2019; 24:710-730. [PMID: 30165449 DOI: 10.1093/humupd/dmy027] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 08/03/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The ureter is the second most common site affected by urinary tract endometriosis, after the bladder. Optimal strategies in the diagnosis and treatment of ureteral endometriosis (UE) are not yet well defined. OBJECTIVE AND RATIONALE The aim of this study was to systematically review evidence regarding the epidemiology, pathophysiology, diagnosis, medical and surgical treatment, impact on fertility and risk of malignant transformation of UE. SEARCH METHODS A systematic literature review, by searching the MEDLINE and PUBMED database until April 2018, was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and was registered in the PROSPERO registry (www.crd.york.ac.uk/PROSPERO CRD42017060065). A total of 67 articles were selected to be included in this review. OUTCOMES The involvement of the ureter by endometriosis is often asymptomatic or leads to non-specific symptoms. When the diagnosis is delayed, UE may lead to persistent hydronephrosis and eventually loss of renal function. Ultrasonography is the first-line technique for the assessment of UE; alternatively, magnetic resonance imaging provides an evaluation of ureteral type involvement. The surgical treatment of UE aims to relieve ureteral obstruction and avoid disease recurrence. It includes conservative ureterolysis or radical approaches, such as ureterectomy with end-to-end anastomosis or ureteroneocystostomy performed in relation to the type of ureteral involvement. Fertility and pregnancy outcomes are in line with those observed after surgical treatment of deep infiltrating endometriosis (DIE). Current evidence does not support the potential risk of malignant transformation of UE. WIDER IMPLICATIONS In this article, we review available evidence on ureteral endometriosis, providing a useful tool to guide physicians in the management of this disease. Diagnosis and management of UE remain a challenge. In relation to the degree of ureteral involvement and the association with other DIE implants, the surgical approach should be planned and carried out in an interdisciplinary collaboration between gynecologist and urologist.
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Affiliation(s)
- Fabio Barra
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy.,Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genova, Italy
| | - Carolina Scala
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy.,Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genova, Italy
| | - Ennio Biscaldi
- Department of Radiology, Galliera Hospital, Genova, Italy
| | - Valerio Gaetano Vellone
- Department of Surgical and Diagnostic Sciences, Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Marcello Ceccaroni
- Department of Obstetrics and Gynecology, Gynecologic Oncology and Minimally Invasive Pelvic Surgery, International School of Surgical Anatomy, 'Sacro Cuore - Don Calabria' Hospital, Negrar, Verona, Italy
| | - Carlo Terrone
- Department of Urology, Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Simone Ferrero
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy.,Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genova, Italy
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29
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Yan D, Liu X, Guo SW. Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis. Sci Rep 2019; 9:2698. [PMID: 30804432 PMCID: PMC6389969 DOI: 10.1038/s41598-019-39170-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023] Open
Abstract
Endometriotic lesions are known to be hyperinnervated, especially in lesions of deep endometriosis (DE), which are frequently in close proximity to various nerve plexuses. DE lesions typically have higher fibromuscular content than that of ovarian endometriomas (OE) lesions, but the underlying reason remains elusive. Aside from their traditional role of pain transduction, however, whether or not sensory nerves play any role in the development of endometriosis is unclear. Here, we show that, thorough their respective receptors neurokinin receptor 1 (NK1R), calcitonin receptor like receptor (CRLR), and receptor activity modifying protein 1 (RAMP-1), neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT) and further turn stromal cells into smooth muscle cells (SMCs) in endometriotic lesions, resulting ultimately in fibrosis. We show that SP and CGRP, or the rat dorsal root ganglia (DRG) supernatant, through the induction of NK1R and CGRP/CRLR/RAMP-1 signaling pathways, promoted EMT, FMT and SMM in endometriosis, resulting in increased migratory and invasive propensity, cell contractility, production of collagen, and eventually to fibrosis. Neutralization of NK1R and/or CGRP/CRLR/RAMP-1 abrogated these processes. Extended exposure of endometriotic stromal cells to SP and/or CGRP or the DRG supernatant induced increased expression of α-SMA, desmin, oxytocin receptor, and smooth muscle myosin heavy-chain. Finally, we show that DE lesions had significantly higher nerve fiber density, increased staining levels of α-SMA, NK1R, CRLR, and RAMP-1, concomitant with higher lesional fibrotic content than that of OE lesions. The extent of lesional fibrosis correlated positively with the staining levels of NK1R, CRLR, and RAMP-1, as well as the nerve fiber density in lesions. Thus, this study provides another piece of evidence that sensory nerves play an important role in promoting the development and fibrogenesis of endometriosis. It explains as why DE frequently have higher fibromuscular content than that of OE, highlights the importance of lesional microenvironment in shaping the lesional fate, gives more credence to the idea that ectopic endometrium is fundamentally wounds that go through repeated tissue injury and repair, and should shed much needed light into the pathophysiology of endometriosis.
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Affiliation(s)
- Dingmin Yan
- Shanghai OB/GYN Hospital, Fudan University, Shanghai, 200011, China
| | - Xishi Liu
- Shanghai OB/GYN Hospital, Fudan University, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
| | - Sun-Wei Guo
- Shanghai OB/GYN Hospital, Fudan University, Shanghai, 200011, China. .,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
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Ibrahim MG, Sillem M, Plendl J, Taube ET, Schüring A, Götte M, Chiantera V, Sehouli J, Mechsner S. Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFβ1) in myofibroblastic metaplasia. Arch Gynecol Obstet 2018; 299:489-499. [PMID: 30523440 DOI: 10.1007/s00404-018-4995-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 11/24/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Superficial peritoneal endometriotic (pEM) lesions are composed of endometrial glands and stroma, in addition to a third component-myofibroblasts and smooth muscles (SM)-like cells. The latter develops secondary to a metaplasia. In this study, we characterised the third component cells in pEM according to differentiation markers in different micro-compartments. Furthermore, a possible effect of TGFβ1 on myofibroblastic metaplasia in endometriotic epithelial cells was studied. METHODS Seventy-six premenopausal patients were included. Peritoneal biopsies were excised from EM patients (n = 23), unaffected peritoneum (peritoneum from EM patients but without EM components, n = 5/23) and non-EM patients (n = 10). All peritoneal biopsies were immunolabeled for ASMA, calponin, collagen I, desmin, TGFß receptor 1 (R1), R2 and R3 in addition to ultrastructure examination by transmission electron microscopy (TEM) (n = 1). TGFß1 level was measured in peritoneal fluid (PF) (EM, n = 19 and non-EM, n = 13) collected during laparoscopy. Furthermore, TGFß1 effect on myofibroblastic metaplasia was studied in vitro. RESULTS At the centre of pEM lesions, calponin immunolabeling outweighs the collagen I while in the periphery the reverse occurs. SM-like cells expressing desmin predominate at the periphery, while ASMA immunolabeling was detectable in all micro-compartments. Both indicate an abundance of myofibroblasts at the centre of pEM lesions and SM-like cells in the periphery. Although activated TGFß1 in PF did not differ between EM and non-EM, it inhibited the cell proliferation of the endometriotic epithelial cells and induced an upregulation in ASMA and collagen IA2 expression as well. CONCLUSION The abundance of the myofibroblasts and SM-like cells points to a myofibroblastic metaplasia in pEM. Both cells are differentially arranged in the different micro-compartments of pEM lesions, with increasing cell maturity towards the periphery of the lesion. Furthermore, TGFß1 may play a role in the myofibroblastic metaplasia of the endometriotic epithelial cells. These findings provide a better insight in the micro-milieu in EM lesions, where most of the disease dynamics occur.
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Affiliation(s)
- Mohamed Gamal Ibrahim
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany
- Department of Gynecology and Obstetrics, UKM Fertility Center, University Hospital of Muenster, Domagkstr. 11, 48149, Münster, Germany
| | - Martin Sillem
- Universitäts-Frauenklinik Homburg/Saar und Praxisklinik am Rosengarten, Augustaanlage 7-11, 68165, Mannheim, Germany
| | - Johanna Plendl
- Department of Veterinary Medicine, Institute of Veterinary Anatomy, Free University of Berlin, Berlin, Germany
| | - Eliane T Taube
- Institute for Pathology, Charité University of Medicine, Charitéplatz 1, 10117, Berlin, Germany
| | - Andreas Schüring
- Department of Gynecology and Obstetrics, UKM Fertility Center, University Hospital of Muenster, Domagkstr. 11, 48149, Münster, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, UKM Fertility Center, University Hospital of Muenster, Domagkstr. 11, 48149, Münster, Germany
| | - Vito Chiantera
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Jalid Sehouli
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Sylvia Mechsner
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany.
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Koninckx PR, Ussia A, Adamyan L, Wattiez A, Gomel V, Martin DC. Pathogenesis of endometriosis: the genetic/epigenetic theory. Fertil Steril 2018; 111:327-340. [PMID: 30527836 DOI: 10.1016/j.fertnstert.2018.10.013] [Citation(s) in RCA: 226] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To study the pathophysiology of endometriosis. DESIGN Overview of observations on endometriosis. SETTING Not applicable. PATIENT(S) None. INTERVENTIONS(S) None. MAIN OUTCOME MEASURE(S) The hypothesis is compatible with all observations. RESULT(S) Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases. CONCLUSION(S) The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.
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Affiliation(s)
- Philippe R Koninckx
- Obstetrics-Gynecology, KU Leuven, Bierbeek, Belgium; Gruppo Italo Belga, Rome, Italy; Latiffa Hospital, Dubai, United Arab Emirates; Università Cattolica, Roma, Italy.
| | - Anastasia Ussia
- Gruppo Italo Belga, Rome, Italy; Università Cattolica, Roma, Italy
| | - Leila Adamyan
- Department of Operative Gynecology, Federal State Budget Institution V. I. Kulakov Research Centre for Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, and Department of Reproductive Medicine and Surgery, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Arnaud Wattiez
- Latiffa Hospital, Dubai, United Arab Emirates; Department of Obstetrics and Gynecology, University of Strasbourg, Strasbourg, France
| | - Victor Gomel
- Department of Obstetrics and Gynecology, University of British Columbia and Women's Hospital, Vancouver, British Columbia, Canada
| | - Dan C Martin
- School of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, and Virginia Commonwealth University, Richmond, Virginia
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Seminal plasma (SP) induces a rapid transforming growth factor beta 1 (TGFβ1)—independent up-regulation of epithelial–mesenchymal transdifferentiation (EMT) and myofibroblastic metaplasia-markers in endometriotic (EM) and endometrial cells. Arch Gynecol Obstet 2018; 299:173-183. [DOI: 10.1007/s00404-018-4965-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 11/08/2018] [Indexed: 10/27/2022]
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Manconi F, Fazleabas AT, Markham R, Fraser IS. Nerve fibre infiltration and expression in peritoneal lesions of endometriosis in a nonhuman primate model of endometriosis. JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2018. [DOI: 10.1177/2284026518810594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Baboon ( Papio anubis) models of endometriosis are thought to mimic the early stages of spontaneous human peritoneal endometriotic disease. The objective of this study was to investigate the presence and course of nerve fibre ingrowth during peritoneal lesion formation in specimens collected at 3 months (early stage of lesion development) and 15 months (late stage of lesion development) after disease initiation compared to pelvic peritoneum (control). Five-micron sections of paraffin-embedded peritoneal lesions were obtained from normally cycling baboons with 3-month (n = 12), 15-month (n = 12) induced endometriosis and pelvic peritoneum (n = 10) from baboons with no endometriosis. Immunohistochemical staining was performed with specific antibodies: protein gene product 9.5 – broad marker of nerve fibres and neurones, neuropeptide Y – sympathetic neurones, substance P – sensory neurones, vasoactive intestinal peptide – parasympathetic neurones, nerve growth factor – development of new neurones and high-affinity receptor for nerve growth factor (tropomyosin receptor kinase A) – neuronal differential. Significantly, more nerve fibres were identified in peritoneal endometriotic lesions collected 15 months after the initiation of experimental protocols compared with 3-month and control samples (p < 0.001). Nerve fibres were immunoreactive for all the tested markers – protein gene product 9.5, neuropeptide Y, substance P, vasoactive intestinal peptide, nerve growth factor and tropomyosin receptor kinase A – indicating the presence of different types of nerve fibres. In conclusion, peritoneal lesions of endometriosis in a nonhuman primate model of endometriosis were found to be progressively and spontaneously innervated by both myelinated and unmyelinated sensory nerve fibres, parasympathetic and sympathetic neurones. These nerve fibres may play an important role in the mechanisms of pain generation in this condition.
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Affiliation(s)
- Frank Manconi
- Queen Elizabeth II Research Institute for Mothers and Infants, Department of Obstetrics, Gynaecology and Neonatology, The University of Sydney, Camperdown, NSW, Australia
| | - Asgi T Fazleabas
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Robert Markham
- Queen Elizabeth II Research Institute for Mothers and Infants, Department of Obstetrics, Gynaecology and Neonatology, The University of Sydney, Camperdown, NSW, Australia
| | - Ian S Fraser
- School of Women’s and Children’s Health and Royal Hospital for Women, University of New South Wales, Randwick, NSW, Australia
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Vercellini P, Buggio L, Borghi A, Monti E, Gattei U, Frattaruolo MP. Medical treatment in the management of deep endometriosis infiltrating the proximal rectum and sigmoid colon: a comprehensive literature review. Acta Obstet Gynecol Scand 2018; 97:942-955. [DOI: 10.1111/aogs.13328] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 02/06/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Paolo Vercellini
- Department of Clinical Sciences and Community Health; University of Milan; Milan Italy
- IRCCS Ca ‘Granda Foundation - Maggiore Policlinico Hospital; Milan Italy
| | - Laura Buggio
- IRCCS Ca ‘Granda Foundation - Maggiore Policlinico Hospital; Milan Italy
| | - Alessandra Borghi
- Department of Clinical Sciences and Community Health; University of Milan; Milan Italy
| | - Ermelinda Monti
- IRCCS Ca ‘Granda Foundation - Maggiore Policlinico Hospital; Milan Italy
| | - Umberto Gattei
- IRCCS Ca ‘Granda Foundation - Maggiore Policlinico Hospital; Milan Italy
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Viganò P, Somigliana E, Gentilini D, Benaglia L, Vercellini P. Back to the Original Question in Endometriosis: Implantation or Metaplasia? ACTA ACUST UNITED AC 2018. [DOI: 10.1177/228402650900100102] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The pathogenesis of some forms of endometriosis is still controversial. Different research approaches have been used to clarify this issue and an intense debate has derived over the years among scientists. This paper presents and discusses aged and modern ideas derived from various observations in different research areas on this specific topic. More specifically, data derived from histological results, animal studies, anatomical findings and basic research activity are presented. Although an increasing body of evidence tends to support the implantation theory, which currently represents the most recognized pathogenic model for endometriosis, some aspects of this disease remain obscure and the scientific and medical communities have still not made significant progress in terms of completely elucidating the histogenesis of some forms of the disease.
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Affiliation(s)
- Paola Viganò
- A.O. Sant'Anna, Como and Center for Research in Obstetrics and Gynecology (CROG), Milan
- Department of Obstetrics and Gynecology, University of Milan, Milan - Italy
| | - Edgardo Somigliana
- Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan
| | | | - Laura Benaglia
- Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan
| | - Paolo Vercellini
- Department of Obstetrics and Gynecology, University of Milan, Milan - Italy
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36
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Ganewatta SP, Berbic M, Luscombe G, Markham R, Fraser IS. The Characteristic Expression of CD3+ T Cells, CD8+ T Cells and CD57+ NK Cells in Distinct Zones of Peritoneal Endometriotic Lesions. ACTA ACUST UNITED AC 2018. [DOI: 10.1177/228402651000200403] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Endometriosis is a benign gynecological condition, associated with a dysfunctional immune response that facilitates progression of peritoneal lesions. Specific immune cells are hypothesized to be recruited to peritoneal endometriotic lesions; though little is known about the significance of specific T and NK cell expression and the microanatomical zoning of lesions. This study aimed to characterize the zoning of T and NK cell populations in endometriotic peritoneal lesions compared to histologically normal peritoneum. Methods and Results: Immunohistochemical analysis of CD3+ and CD8+ T cells and CD57+ NK cells in 18 peritoneal endometrial lesions and 20 normal peritoneal biopsies revealed greatly increased expression of these immune cells in women with confirmed endometriosis. Alpha-smooth muscle actin (α-SMA) antibody was used to detect the reactive a-SMA zone surrounding the core glands and stroma. CD57+ NK cells and CD3+ and CD8+ T cells were significantly over-expressed (p<0.01) throughout the peritoneal endometriotic lesions compared to normal peritoneum (in women without endometriosis) and these cells were highly expressed in the core lesion zone compared to expression in the adjacent α-SMA zone and surrounding peritoneum. Conclusions: Our observations support the concept that immune cell populations are recruited into developing endometriotic lesions. We have for the first time shown that NK and T immune cells are distributed differentially across various microanatomical zones of peritoneal lesions. Such understanding of zone specific immune-cell expression is crucial for better defining the roles these immune cells play in endometriotic lesion establishment and progression.
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Affiliation(s)
- Subha P. Ganewatta
- Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Sydney - Australia
| | - Marina Berbic
- Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Sydney - Australia
| | - Georgina Luscombe
- Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Sydney - Australia
| | - Robert Markham
- Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Sydney - Australia
| | - Ian S. Fraser
- Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Sydney - Australia
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Vigano P, Candiani M, Monno A, Giacomini E, Vercellini P, Somigliana E. Time to redefine endometriosis including its pro-fibrotic nature. Hum Reprod 2017; 33:347-352. [DOI: 10.1093/humrep/dex354] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/08/2017] [Indexed: 01/28/2023] Open
Affiliation(s)
- P Vigano
- Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - M Candiani
- Obstetrics and Gynaecology Department, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - A Monno
- Innate immunity and Tissue Remodelling Unit, Regenerative Medicine Division, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - E Giacomini
- Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - P Vercellini
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via della Commenda 12, Milan 20122, Italy
| | - E Somigliana
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via della Commenda 12, Milan 20122, Italy
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38
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Role of medical therapy in the management of deep rectovaginal endometriosis. Fertil Steril 2017; 108:913-930. [DOI: 10.1016/j.fertnstert.2017.08.038] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/29/2017] [Accepted: 08/30/2017] [Indexed: 12/17/2022]
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Pathogenesis of deep endometriosis. Fertil Steril 2017; 108:872-885.e1. [DOI: 10.1016/j.fertnstert.2017.08.036] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 08/22/2017] [Accepted: 08/28/2017] [Indexed: 12/16/2022]
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40
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Marcellin L, Santulli P, Chouzenoux S, Cerles O, Nicco C, Dousset B, Pallardy M, Kerdine-Römer S, Just PA, Chapron C, Batteux F. Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis. Free Radic Biol Med 2017; 110:1-10. [PMID: 28457937 DOI: 10.1016/j.freeradbiomed.2017.04.362] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 04/10/2017] [Accepted: 04/19/2017] [Indexed: 01/24/2023]
Abstract
The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes' transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2-/-) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes.
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Affiliation(s)
- L Marcellin
- Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France.
| | - P Santulli
- Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France
| | - S Chouzenoux
- Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France
| | - O Cerles
- Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France
| | - C Nicco
- Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France
| | - B Dousset
- Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Service de Chirurgie Digestive, 75679 Paris, France
| | - M Pallardy
- UMR996 - Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France; Université Paris Sud, INSERM UMR 996, Faculté de Pharmacie, Université Paris-Saclay, Châtenay-Malabry 92290, France
| | - S Kerdine-Römer
- UMR996 - Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France; Université Paris Sud, INSERM UMR 996, Faculté de Pharmacie, Université Paris-Saclay, Châtenay-Malabry 92290, France
| | - P A Just
- Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Service de pathologie, CAncer Research for PErsonalized Medicine (CARPEM), Paris, France
| | - C Chapron
- Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France
| | - F Batteux
- Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France
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Liu X, Zhang Q, Guo SW. Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis. Reprod Sci 2017; 25:329-340. [PMID: 28718381 DOI: 10.1177/1933719117718275] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) have long been recognized to have different histology and, as such, postulated to be 2 separate disease entities. Few studies, however, have attempted to elucidate the causes for their differences. Making use of ectopic endometrial tissue samples from 25 and 20 women with OMA and DIE, respectively, and control endometrial tissue samples from 25 women without endometriosis, we conducted an immunohistochemical analysis to evaluate the expression of a group of carefully chosen markers for epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM), fibrosis, vascularity, hormonal receptors, and proteins involved in epigenetic modifications. We found that both OMA and DIE lesions exhibited the same cellular changes consistent with EMT, FMT, SMM, and fibrosis as already shown in animal models. Compared to OMA, DIE lesions underwent more thorough and extensive EMT, FMT, and SMM and, consequently, displayed significantly higher fibrotic content but less vascularity. The 2 conditions also showed different expression levels of hormonal receptors. Both OMA and DIE lesions, especially the latter, showed significantly higher staining of enhancer of zeste homolog 2, H3K9me3, and H3K27me3 than that of control endometrium, suggesting progressive epigenetic changes concomitant with cellular ones. Finally, proteins that are known to be involved in fibrogenesis, such as thymocyte differentiation antigen 1 and peroxisome proliferator-activated receptor γ , were also aberrantly expressed under both conditions. The many similarities shared by both OMA and DIE indicate that the 2 conditions may actually share the same pathogenesis/pathophysiology. Their differences, however, suggest that the source of these differences may result from the different lesional microenvironments.
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Affiliation(s)
- Xishi Liu
- 1 Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- 2 Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Qi Zhang
- 1 Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Sun-Wei Guo
- 1 Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- 2 Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
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Ibrahim MG, Sillem M, Plendl J, Chiantera V, Sehouli J, Mechsner S. Myofibroblasts Are Evidence of Chronic Tissue Microtrauma at the Endometrial–Myometrial Junctional Zone in Uteri With Adenomyosis. Reprod Sci 2017; 24:1410-1418. [DOI: 10.1177/1933719116687855] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Mohamed Gamal Ibrahim
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm, Berlin, Germany
| | - Martin Sillem
- Praxisklinik am Rosengarten, Augustaanlage, Mannheim, Germany
| | - Johanna Plendl
- Department of Veterinary Medicine, Institute of Veterinary Anatomy, Free University of Berlin, Berlin, Germany
| | - Vito Chiantera
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm, Berlin, Germany
| | - Jalid Sehouli
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm, Berlin, Germany
| | - Sylvia Mechsner
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm, Berlin, Germany
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Leone Roberti Maggiore U, Ferrero S, Candiani M, Somigliana E, Viganò P, Vercellini P. Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation. Eur Urol 2016; 71:790-807. [PMID: 28040358 DOI: 10.1016/j.eururo.2016.12.015] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 12/15/2016] [Indexed: 02/03/2023]
Abstract
CONTEXT The bladder is the most common site affected in urinary tract endometriosis. There is controversy regarding the pathogenesis, clinical management (diagnosis and treatment), impact on fertility, and risk of malignant transformation of bladder endometriosis (BE). OBJECTIVE To systematically evaluate evidence regarding the pathogenesis, diagnosis, medical and surgical treatment, impact on female fertility, and risk of malignant transformation of BE. EVIDENCE ACQUISITION A systematic review of PubMed/Medline from inception until October 2016 was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and was registered in the PROSPERO registry (www.crd.york.ac.uk/prospero; CRD42016039281). Eighty-seven articles were selected for inclusion in this analysis. EVIDENCE SYNTHESIS BE is defined as the presence of endometrial glands and stroma in the detrusor muscle. Ultrasonography is the first-line technique for assessment of BE owing to its accuracy, safety, and cost. Clinical management can be conservative, using hormonal therapies, or surgical. When conservative treatment is preferred, estrogen-progestogen combinations and progestogens should be chosen because of their favorable profile that allows long-term therapy. Surgery should guarantee complete removal of the bladder nodule to minimize recurrence, so transurethral surgery alone should be avoided in favor of segmental bladder resection. There is not a strong rationale for hypothesizing a detrimental impact of BE per se on fertility. Furthermore, current evidence does not support the removal of bladder endometriotic lesions because of the potential risk of malignant transformation since this phenomenon is exceedingly rare. CONCLUSIONS BE is a challenging condition, and the common coexistence of other types of endometriosis means that clinical management of BE should involve collaboration between gynecologists and urologists. PATIENT SUMMARY In this article we review available knowledge on bladder endometriosis. The review provides a useful tool to guide physicians in the management of this complex condition.
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Affiliation(s)
- Umberto Leone Roberti Maggiore
- Academic Unit of Obstetrics and Gynecology, IRCCS AOU San Martino, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Simone Ferrero
- Academic Unit of Obstetrics and Gynecology, IRCCS AOU San Martino, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
| | - Massimo Candiani
- Department of Obstetrics and Gynecology, Vita Salute San Raffaele University School of Medicine, IRCCS, Ospedale San Raffaele, Milan, Italy
| | - Edgardo Somigliana
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano and Department of Obstet-Gynecol, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Viganò
- Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Vercellini
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano and Department of Obstet-Gynecol, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Zhang Q, Duan J, Liu X, Guo SW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol 2016; 428:1-16. [PMID: 26992563 DOI: 10.1016/j.mce.2016.03.015] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 03/11/2016] [Accepted: 03/12/2016] [Indexed: 12/15/2022]
Abstract
Smooth muscle metaplasia (SMM) and fibrotic tissues are frequently seen in endometriotic lesions, yet the mechanisms underlying their formation are poorly understood. In this study, we investigated the roles of activated platelets in driving epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in endometriosis. Through in vitro experimentations, we found that activated platelets, through the release of TGF-β1 and the induction of TGF-β/Smad signaling pathway, promoted EMT and FMT in endometriosis, resulting in increased cell contractility, collagen production, and ultimately to fibrosis. TGF-β blockade reversed these processes. Prolonged exposure of endometriotic stromal cells to activated platelets induced increased expression of α-SMA as well as markers of differentiated smooth muscle cells. Consequently, endometriotic lesions and their microenvironment contain all the necessary molecular machinery to promote SMM and fibrogenesis. Our results suggest that endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.
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Affiliation(s)
- Qi Zhang
- Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China
| | - Jie Duan
- Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China
| | - Xishi Liu
- Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
| | - Sun-Wei Guo
- Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
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Benagiano G, Petraglia F, Gordts S, Brosens I. A new approach to the management of ovarian endometrioma to prevent tissue damage and recurrence. Reprod Biomed Online 2016; 32:556-62. [DOI: 10.1016/j.rbmo.2016.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 03/01/2016] [Accepted: 03/02/2016] [Indexed: 01/08/2023]
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MRI technique for the preoperative evaluation of deep infiltrating endometriosis: current status and protocol recommendation. Clin Radiol 2016; 71:179-94. [DOI: 10.1016/j.crad.2015.09.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 08/20/2015] [Accepted: 09/16/2015] [Indexed: 12/31/2022]
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Anaf V, Gocevska S, Lemoine O, El Nakadi I, Buggenhout A, Zalcman M, Noël JC. The Problem of Anastomotic Stricture After Rectosigmoid Resection in Deep Infiltrating Endometriosis. J Gynecol Surg 2016. [DOI: 10.1089/gyn.2015.0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Vincent Anaf
- Department of Gynecology, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Sashka Gocevska
- Department of Gynecology, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Olivier Lemoine
- Department of Gastroenterology, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Issam El Nakadi
- Department of Digestive Surgery, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Alexis Buggenhout
- Department of Digestive Surgery, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Marc Zalcman
- Department of Radiology, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Christophe Noël
- Department of Pathology, Academic Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
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Savelli L, Fabbri F, Zannoni L, De Meis L, Di Donato N, Mollo F, Seracchioli R. Preoperative ultrasound diagnosis of deep endometriosis: importance of the examiner's expertise and lesion size. Australas J Ultrasound Med 2015; 15:55-60. [PMID: 28191143 PMCID: PMC5025115 DOI: 10.1002/j.2205-0140.2012.tb00227.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Objectives: To evaluate the accuracy of transvaginal sonography (TVS) in the diagnosis of deep infiltrating endometriosis (DIE) of the posterior compartment (rectovaginal septum, uterosacral ligaments, rectosigmoid colon, vagina) when undertaken by physicians of varying experience and to investigate if size of the nodule is relevant in influencing diagnostic accuracy. Methods: 381 patients who were operated on between January 2007 and December 2010 for suspected pelvic endometriosis were prospectively recruited. Clinical, surgical and histopathologic data were collected and a preoperative TVS was carried out. Comparison was made between the diagnostic accuracy of TVS performed by two groups of physicians of different expertise. Results: One hundred and thirty-six patients underwent removal of deep endometriotic lesions of the posterior compartment. Sensitivity, specificity, positive and negative predictive value and the overall diagnostic accuracy of the expert operators were 77%, 95%, 90%, 87% and 88% respectively. Corresponding values for first-level operators were: 45%, 98%, 92%, 79% and 81%. In patients with positive findings at TVS, the mean diameter of the endometriotic nodule was of 4.7 ± 3.4 cm while, in cases with negative findings, the average diameter was 2.6 ± 1.1 cm (P < 0.05). Conclusions: TVS is accurate in detecting the presence of DIE. Accuracy is dependent on the experience of the physician and the size of the nodule.
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Affiliation(s)
- Luca Savelli
- Acute Gynecology Unit Gynaecology Department S Orsola-Malpighi Hospital University of Bologna Bologna Italy
| | - Federica Fabbri
- Acute Gynecology Unit Gynaecology Department S Orsola-Malpighi Hospital University of Bologna Bologna Italy
| | - Letizia Zannoni
- Acute Gynecology Unit Gynaecology Department S Orsola-Malpighi Hospital University of Bologna Bologna Italy
| | - Lucia De Meis
- Acute Gynecology Unit Gynaecology Department S Orsola-Malpighi Hospital University of Bologna Bologna Italy
| | - Nadine Di Donato
- Minimally Invasive Gynaecological Surgery Unit, Gynaecology Department S Orsola-Malpighi Hospital, University of Bologna Bologna Italy
| | - Francesco Mollo
- Acute Gynecology Unit Gynaecology Department S Orsola-Malpighi Hospital University of Bologna Bologna Italy
| | - Renato Seracchioli
- Minimally Invasive Gynaecological Surgery Unit, Gynaecology Department S Orsola-Malpighi Hospital, University of Bologna Bologna Italy
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Yang H, Lau WB, Lau B, Xuan Y, Zhou S, Zhao L, Luo Z, Lin Q, Ren N, Zhao X, Wei Y. A mass spectrometric insight into the origins of benign gynecological disorders. MASS SPECTROMETRY REVIEWS 2015; 36:450-470. [PMID: 26633258 DOI: 10.1002/mas.21484] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Accepted: 11/06/2015] [Indexed: 02/05/2023]
Abstract
Applications of mass spectrometry (MS) are rapidly expanding and encompass molecular and cellular biology. MS aids in the analysis of in vivo global molecular alterations, identifying potential biomarkers which may improve diagnosis and treatment of various pathologies. MS has added new dimensionality to medical research. Pioneering gynecologists now study molecular mechanisms underlying female reproductive pathology with MS-based tools. Although benign gynecologic disorders including endometriosis, adenomyosis, leiomyoma, and polycystic ovarian syndrome (PCOS) carry low mortality rates, they cause significant physical, mental, and social detriments. Additionally, some benign disorders are unfortunately associated with malignancies. MS-based technology can detect malignant changes in formerly benign proteomes and metabolomes with distinct advantages of speed, sensitivity, and specificity. We present the use of MS in proteomics and metabolomics, and summarize the current understanding of the molecular pathways concerning female reproductive anatomy. Highlight discoveries of novel protein and metabolite biomarkers via MS-based technology, we underscore the clinical application of these techniques in the diagnosis and management of benign gynecological disorders. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:450-470, 2017.
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Affiliation(s)
- Huiliang Yang
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.,Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Wayne Bond Lau
- Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, 19107
| | - Bonnie Lau
- Department of Surgery, Emergency Medicine, Kaiser Santa Clara Medical Center, Affiliate of Stanford University, Stanford, CA, 94305
| | - Yu Xuan
- The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Shengtao Zhou
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Linjie Zhao
- The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Zhongyue Luo
- College of Biological Sciences, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Qiao Lin
- College of Biological Sciences, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Ning Ren
- College of Biological Sciences, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Yuquan Wei
- The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
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Affiliation(s)
- Debra S. Heller
- Department of Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ
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