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Lourenço Reis J, Martins C, Ângelo-Dias M, Rosa NN, Borrego LM, Lima J. TIM-3 Expression in Endometriosis. Am J Reprod Immunol 2024; 91:e13887. [PMID: 38924299 DOI: 10.1111/aji.13887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/29/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
PROBLEM Endometriosis is a prevalent chronic gynecological disease linked to immune dysfunction. The protein T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) plays a crucial role in immune system balance. Malfunction of TIM-3 may result in excessive immune activation and inflammatory tissue damage. Given TIM-3's established role in the development of cancer and autoimmune diseases, we decided to study its role in women suffering from endometriosis. STUDY METHOD We included a total of 62 female patients, all of whom had undergone laparoscopic surgery. Of these, 47 had endometriosis and 15 did not. During surgery, we collected peritoneal fluid (PF) and peripheral blood (PB) samples from every patient for analysis using flow cytometry. To mark the samples, we used a panel of monoclonal antibodies and examined TIM-3 expression in their immune cells. RESULTS Endometriosis patients in PB demonstrated a significantly lower percentage of CD56+ T cells with TIM-3 expression. As endometriosis progressed through its stages, this expression lessened. This decrease was particularly notable in women with stage III/IV endometriosis. Additionally, both women diagnosed with intestinal endometriosis and those with recent endometriosis diagnoses showed a significantly reduced percentage of CD56+ T cells expressing TIM-3. CONCLUSIONS Patients with endometriosis exhibit diminished TIM-3 expression within circulating T cells. This warrants further investigation to discern whether it contributes to the progression of endometriosis, potentially through the amplification of autoreactive T cells and inflammation.
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Affiliation(s)
- José Lourenço Reis
- Department of Obstetrics and Gynecology, LUZ SAÚDE, Hospital da Luz Lisboa, Lisboa, Portugal
| | - Catarina Martins
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
- Immunology Department, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Miguel Ângelo-Dias
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
- Immunology Department, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
| | | | - Luís Miguel Borrego
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
- Immunology Department, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
- Department of Imunoallergy, LUZ SAÚDE, Hospital da Luz, Lisboa, Portugal
| | - Jorge Lima
- Department of Obstetrics and Gynecology, LUZ SAÚDE, Hospital da Luz Lisboa, Lisboa, Portugal
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
- Immunology Department, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
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Kisovar A, Becker CM, Granne I, Southcombe JH. The role of CD8+ T cells in endometriosis: a systematic review. Front Immunol 2023; 14:1225639. [PMID: 37497226 PMCID: PMC10366819 DOI: 10.3389/fimmu.2023.1225639] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023] Open
Abstract
Background Endometriosis is a chronic disease affecting 6-10% of women of reproductive age. It is an important cause of infertility and chronic pelvic pain with poorly understood aetiology. CD8+ T (CD8 T) cells were shown to be linked to infertility and chronic pain and play a significant role in lesion clearance in other pathologies, yet their function in endometriosis is unknown. We systematically evaluated the literature on the CD8 T in peripheral blood and endometriosis-associated tissues to determine the current understanding of their pathophysiological and clinical relevance in the disease and associated conditions (e.g. infertility and pelvic pain). Methods Four databases were searched (MEDLINE, EMBASE, Web of Science, CINAHL), from database inception until September 2022, for papers written in the English language with database-specific relevant terms/free-text terms from two categories: CD8 T cells and endometriosis. We included peer-reviewed papers investigating CD8 T cells in peripheral blood and endometriosis-associated tissues of patients with surgically confirmed endometriosis between menarche and menopause, and animal models with oestrous cycles. Studies enrolling participants with other gynaecological pathologies (except uterine fibroids and tubal factor infertility used as controls), cancer, immune diseases, or taking immune or hormonal therapy were excluded. Results 28 published case-control studies and gene set analyses investigating CD8 T cells in endometriosis were included. Data consistently indicate that CD8 T cells are enriched in endometriotic lesions in comparison to eutopic endometrium, with no differences in peripheral blood CD8 T populations between patients and healthy controls. Evidence on CD8 T cells in peritoneal fluid and eutopic endometrium is conflicting. CD8 T cell cytotoxicity was increased in the menstrual effluent of patients, and genomic analyses have shown a clear trend of enriched CD8 T effector memory cells in the eutopic endometrium of patients. Conclusion Literature on CD8 T cells in endometriosis-associated tissues is inconsistent. Increased CD8 T levels are found in endometriotic lesions, however, their activation potential is understudied in all relevant tissues. Future research should focus on identifying clinically relevant phenotypes to support the development of non-invasive diagnostic and treatment strategies. Systematic Review Registration PROSPERO identifier CRD42021233304.
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Affiliation(s)
| | | | | | - Jennifer H. Southcombe
- Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Balunathan N, Rani G U, Perumal V, Kumarasamy P. Single nucleotide polymorphisms of Interleukin - 4, Interleukin-18, FCRL3 and sPLA2IIa genes and their association in pathogenesis of endometriosis. Mol Biol Rep 2023; 50:4239-4252. [PMID: 36905404 DOI: 10.1007/s11033-023-08316-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/31/2023] [Indexed: 03/12/2023]
Abstract
BACKGROUND Endometriosis is a complex gynaecological disorder that contributes to infertility, dysmenorrhea, dyspareunia, and other chronic issues. It is a multifactorial disease involving genetic, hormonal, immunological and environmental components. Endometriosis's pathogenesis remains unclear. AIM OF THE STUDY was to analyse the polymorphisms in Interleukin 4, Interleukin 18, FCRL3 and sPLA2IIa genes to identify any significant association with the risk of endometriosis. MATERIAL AND METHODS This study evaluated the polymorphism of -590 C/T in interleukin- 4(IL-4) gene, C607A in Interleukin - 18(IL-18) gene, -169T > C in FCRL3 gene and 763 C > G in sPLA2IIa gene in women with endometriosis. The case-control study included 150 women with endometriosis and 150 apparently healthy women as control subjects. DNA was extracted from peripheral blood leukocytes and endometriotic tissue of cases and blood samples for controls and further analysed by PCR amplification and then sequencing was carried out to find the allele and genotypes of the subjects and then to analyse the relationship between the gene polymorphisms and endometriosis. To evaluate the association of the different genotypes, 95% confidence intervals (CI) were calculated. RESULTS Interleukin - 18 and FCRL3 gene polymorphisms of endometriotic tissue and blood samples of endometriosis (cases) showed significantly associated (OR = 4.88 [95% CI = 2.31-10.30], P > 0.0001) and (OR = 4.00 [95% CI = 2.2-7.33], P > 0.0001) when compared with normal blood samples. However, there was no significant difference in Interleukin - 4 and sPLA2IIa gene polymorphisms between control women and patients with endometriosis. CONCLUSIONS The present study suggests that the IL-18 and FCRL3 gene polymorphisms are associated with a higher risk for endometriosis, which delivers valuable knowledge of endometriosis's pathogenesis. However, a larger sample size of patients from various ethnic backgrounds is necessary to evaluate whether these alleles have a direct effect on disease susceptibility.
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Affiliation(s)
- Nandhini Balunathan
- Department of Human Genetics, Faculty of Biomedical sciences & technology, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University, Porur, Chennai, India.
| | - Usha Rani G
- Department of Obstetrics & Gynaecology, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University, Porur, Chennai, India
| | - Venkatachalam Perumal
- Department of Human Genetics, Faculty of Biomedical sciences & technology, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University, Porur, Chennai, India
| | - P Kumarasamy
- Controller of examinations, Tamilnadu Veterinary and Animal sciences university, Chennai, India
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Heidari S, Kolahdouz-Mohammadi R, Khodaverdi S, Tajik N, Delbandi AA. Expression levels of MCP-1, HGF, and IGF-1 in endometriotic patients compared with non-endometriotic controls. BMC Womens Health 2021; 21:422. [PMID: 34930225 PMCID: PMC8686524 DOI: 10.1186/s12905-021-01560-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/02/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND To study the concentrations of monocyte chemoattractant protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) in peritoneal fluid (PF) and serum, and to evaluate their expressions by PF and peripheral blood mononuclear cells (PFMCs and PBMCs, respectively), and ectopic and eutopic endometrial stromal cells of patients with endometriosis (EESCs and EuESCs, respectively) compared with controls. METHODS The concentrations of mentioned cytokines in serum and PF, as well as their expression in PBMCs, PFMCs, EuESCs and EESCs from endometriosis patients and controls were assessed. RESULTS The levels of MCP-1, HGF, and IGF-1 in serum and PF in women with endometriosis were significantly higher than the controls (P < 0.05-P < 0.001). Gene expression of MCP-1 and IGF-1 in the PFMCs, PBMCs and EESCs also showed an increased level compared to controls (P < 0.05-P < 0.01). The protein expression of MCP-1 and IGF-1 by PFMCs was statistically higher in endometriotic women (P < 0.05 and P < 0.01, respectively). The gene and protein expression of HGF in PFMCs and its gene expression by EESCs were significantly higher in endometriotic women compared to controls (P < 0.05-P < 0.01). CONCLUSIONS The higher concentrations of mentioned cytokines in serum and PF and their higher expression by PFMCs and EESCs in endometriosis patients may contribute to the development of endometriosis.
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Affiliation(s)
- Sahel Heidari
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Roya Kolahdouz-Mohammadi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Khodaverdi
- Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nader Tajik
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran. .,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Meligy FY, Elgamal DA, Abdelzaher LA, Khashbah MY, El-Mokhtar MA, Sayed AA, Refaiy AM, Othman ER. Adipose tissue-derived mesenchymal stem cells reduce endometriosis cellular proliferation through their anti-inflammatory effects. Clin Exp Reprod Med 2021; 48:322-336. [PMID: 34875740 PMCID: PMC8651762 DOI: 10.5653/cerm.2021.04357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 06/23/2021] [Indexed: 12/29/2022] Open
Abstract
Objective Endometriosis is a chronic debilitating inflammatory condition characterized by the presence of endometrial tissues outside the uterine cavity. Pelvic soreness and infertility are the usual association. Due to the poor effectiveness of the hormone therapy and the high incidence of recurrence following surgical excision, there is no single effective option for management of endometriosis. Mesenchymal stem cells (MSCs) are multipotent stromal cells studied for their broad immunoregulatory and anti-inflammatory properties; however, their efficiency in endometriosis cases is still a controversial issue. Our study aim was to evaluate whether adipose tissue-derived MSCs (AD-MSCs) could help with endometriosis through their studied anti-inflammatory role. Methods Female Wistar rats weighting 180 to 250 g were randomly divided into two groups: group 1, endometriosis group; established by transplanting autologous uterine tissue into rats’ peritoneal cavities and group 2, stem cell treated group; treated with AD-MSCs on the 5th day after induction of endometriosis. The proliferative activity of the endometriosis lesions was evaluated through Ki67 staining. Quantitative estimation of interferon γ, tumor necrosis factor-α, interleukin (IL)-6, IL-1β, IL-10, and transforming growth factor β expression, as well as immunohistochemical detection of CD68 positive macrophages, were used to assess the inflammatory status. Results The size and proliferative activity of endometriosis lesions were significantly reduced in the stem cell treated group. Stem cells efficiently mitigated endometriosis associated chronic inflammatory reactions estimated through reduction of CD68 positive macrophages and the expression of the proinflammatory cytokines. Conclusion Stem cell therapy can be considered a novel remedy in endometriosis possibly through its anti-inflammatory and antiproliferative properties.
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Affiliation(s)
- Fatma Y Meligy
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Dalia A Elgamal
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Lobna A Abdelzaher
- Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Maha Y Khashbah
- Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ayat A Sayed
- Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Abeer M Refaiy
- Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Essam R Othman
- Reproductive Science Research Center, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University, Assiut, Egypt
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Osuchowska-Grochowska I, Blicharska E, Gogacz M, Nogalska A, Winkler I, Szopa A, Ekiert H, Tymczyna-Borowicz B, Rahnama-Hezavah M, Grochowski C. Brief Review of Endometriosis and the Role of Trace Elements. Int J Mol Sci 2021; 22:11098. [PMID: 34681755 PMCID: PMC8540211 DOI: 10.3390/ijms222011098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/13/2022] Open
Abstract
Endometriosis is a chronic, estrogen-dependent, inflammatory condition that is defined as the presence of endometrial glands and stroma outside the uterine cavity. Despite the progress in research into the mechanisms leading to the development of endometriosis, its cause has not yet been established. It seems to be possible that the formation of oxidative stress may be one of the main causes of the development of endometriosis. There is much research that studies the potential role of trace elements in the appearance of endometrial-like lesions. Most studies focus on assessing the content of selected trace elements in the blood, urine, or peritoneal fluid in women with endometriosis. Meanwhile, little is known about the content of these elements in endometrial-like implants, which may be helpful in developing the theory of endometriosis. Investigations that are more comprehensive are needed to confirm a hypothesis that some trace elements play a role in the pathomechanism of endometriosis.
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Affiliation(s)
| | - Eliza Blicharska
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland;
| | - Marek Gogacz
- 2nd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland;
| | - Agata Nogalska
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Izabela Winkler
- 2nd Department of Gynecology, St John’s Center Oncology, 20-090 Lublin, Poland;
| | - Agnieszka Szopa
- Department of Pharmaceutical Botany, Jagielonian University, Collegium Medicum, 30-688 Kraków, Poland; (A.S.); (H.E.)
| | - Halina Ekiert
- Department of Pharmaceutical Botany, Jagielonian University, Collegium Medicum, 30-688 Kraków, Poland; (A.S.); (H.E.)
| | - Barbara Tymczyna-Borowicz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-439 Lublin, Poland;
| | | | - Cezary Grochowski
- Laboratory of Virtual Man, Medical University of Lublin, 20-439 Lublin, Poland;
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Simopoulou M, Rapani A, Grigoriadis S, Pantou A, Tsioulou P, Maziotis E, Tzanakaki D, Triantafyllidou O, Kalampokas T, Siristatidis C, Bakas P, Vlahos N. Getting to Know Endometriosis-Related Infertility Better: A Review on How Endometriosis Affects Oocyte Quality and Embryo Development. Biomedicines 2021; 9:273. [PMID: 33803376 PMCID: PMC7998986 DOI: 10.3390/biomedicines9030273] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 12/20/2022] Open
Abstract
Endometriosis-related infertility describes a case of deteriorated fecundity when endometriosis is diagnosed. Numerous mechanisms have been proposed in an effort to delineate the multifaceted pathophysiology that induces impairment of reproductive dynamics in patients with endometriosis. In this critical analysis, authors present the plethora of molecular events that are entailed and elaborate on how they potentially impair the oocyte's and embryo's competence in patients with endometriosis. Reactive oxygen species, dysregulation of the immune system and cellular architectural disruption constitute the crucial mechanisms that detrimentally affect oocyte and embryo developmental potential. The molecular level impairment of the reproductive tissue is discussed, since differentiation, proliferation and apoptosis constitute focal regulatory cellular functions that appear severely compromised in cases of endometriosis. Mapping the precise molecular mechanisms entailed in endometriosis-related infertility may help delineate the complex nature of the disorder and bring us a step closer to a more personalized approach in understanding, diagnosing and managing endometriosis-related infertility.
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Affiliation(s)
- Mara Simopoulou
- Laboratory of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527 Athens, Greece; (A.R.); (S.G.); (A.P.); (P.T.); (E.M.)
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Anna Rapani
- Laboratory of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527 Athens, Greece; (A.R.); (S.G.); (A.P.); (P.T.); (E.M.)
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Sokratis Grigoriadis
- Laboratory of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527 Athens, Greece; (A.R.); (S.G.); (A.P.); (P.T.); (E.M.)
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Agni Pantou
- Laboratory of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527 Athens, Greece; (A.R.); (S.G.); (A.P.); (P.T.); (E.M.)
- Centre for Human Reproduction, Genesis Athens Clinic, 14-16, Papanikoli, 15232 Athens, Greece
| | - Petroula Tsioulou
- Laboratory of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527 Athens, Greece; (A.R.); (S.G.); (A.P.); (P.T.); (E.M.)
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Evangelos Maziotis
- Laboratory of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527 Athens, Greece; (A.R.); (S.G.); (A.P.); (P.T.); (E.M.)
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Despina Tzanakaki
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Olga Triantafyllidou
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Theodoros Kalampokas
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Charalampos Siristatidis
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Panagiotis Bakas
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
| | - Nikolaos Vlahos
- Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528 Athens, Greece; (D.T.); (O.T.); (T.K.); (C.S.); (P.B.); (N.V.)
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Hemoglobin-induced continuous activation of macrophages in endometriotic cysts: a potential mechanism of endometriosis development and carcinogenesis. Med Mol Morphol 2021; 54:122-132. [PMID: 33392726 DOI: 10.1007/s00795-020-00272-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 11/26/2020] [Indexed: 10/22/2022]
Abstract
Endometriosis is a chronic inflammatory disease. Endometriotic cysts contain hemoglobin (Hb) and infiltrated macrophages, indicating that the metabolism of Hb by macrophages may play an important role in the inflammation of endometriotic cysts. In this study, we investigated the distribution of immune cells and CD163 (Hb receptor)-positive cells in the endometriotic cyst wall using immunohistochemistry. We also examined the role of macrophage activation by Hb on the pathogenesis of endometriotic cysts by measuring the cytokine concentration in the cystic fluids and macrophage-culture supernatant using ELISA. Macrophages were the most prominent immune cells observed in the endometriotic cysts and were differentially distributed in the different histological areas of the cyst wall. The localization of CD163-positive macrophages was restricted to the hemorrhagic and outer areas in the cyst wall. High concentrations of IL-6 and CCL2 were found in the cystic fluids, and inflammatory cytokines (IL-6, TNF-α, and CCL2) were secreted from macrophages on stimulation by Hb. IL-6 is a promotional factor for endometriotic stromal cells and ovarian clear cell carcinoma, the most common histological subtype of endometriosis-related ovarian cancer, hence, the continuous activation of macrophages by Hb could be a potential mechanism underlying endometriosis development and carcinogenesis.
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9
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Freitag N, Pour SJ, Fehm TN, Toth B, Markert UR, Weber M, Togawa R, Kruessel JS, Baston-Buest DM, Bielfeld AP. Are uterine natural killer and plasma cells in infertility patients associated with endometriosis, repeated implantation failure, or recurrent pregnancy loss? Arch Gynecol Obstet 2020; 302:1487-1494. [PMID: 32666129 PMCID: PMC7584523 DOI: 10.1007/s00404-020-05679-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/03/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE Infertility is a debilitating situation that millions of women around the world suffer from, but the causal relationship between infertility and endometriosis is still unclear. We hypothesize that the immune cell populations of uterine natural killer cells (uNK) and plasma cells (PC) which define chronic endometritis could differ in patients with or without endometriosis and therefore be the link to endometriosis-associated infertility. METHODS Our retrospective study includes 173 patients that underwent an endometrial scratching in the secretory phase of the menstrual cycle and subsequently immunohistochemical examination for uNK cells and PC. Sixty-seven patients were diagnosed with endometriosis, 106 served as the control cohort. RESULTS The risk for an elevated number of uNK cells in women with endometriosis is not increased as compared to the control group. Our findings suggest that patients with endometriosis are 1.3 times more likely to have chronic endometritis (CE) as compared to those without and that the treatment with doxycycline might increase pregnancy rates. Endometriosis and an increased number of uNK cells seem to be unrelated. CONCLUSIONS In contrast to the lately published connection between endometriosis, infertility and increased uNK cells, we could not find any evidence that patients with endometriosis are more prone to elevated uterine uNK cells. Counting of PC in endometrial biopsies might be a new approach in the search of biomarkers for the nonsurgical diagnosis of endometriosis since our findings suggest a connection.
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Affiliation(s)
- Nadine Freitag
- Department of Obstetrics, Gynecology and REI (UniKiD), Medical Faculty, Medical Center University of Düsseldorf, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany
| | - Sarah J Pour
- Department of Obstetrics, Gynecology and REI (UniKiD), Medical Faculty, Medical Center University of Düsseldorf, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany
| | - Tanja N Fehm
- Department of Obstetrics and Gynecology, Medical Center University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany
| | - Bettina Toth
- Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Innsbruck, Austria
| | - Udo R Markert
- Placenta Lab, Department of Obstetrics, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
| | - Maja Weber
- Placenta Lab, Department of Obstetrics, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
| | - Riku Togawa
- Department of Gynecological Endocrinology and Fertility Disorders, Karls-Ruprecht University, Heidelberg, Germany
| | - Jan-Steffen Kruessel
- Department of Obstetrics, Gynecology and REI (UniKiD), Medical Faculty, Medical Center University of Düsseldorf, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany
| | - Dunja M Baston-Buest
- Department of Obstetrics, Gynecology and REI (UniKiD), Medical Faculty, Medical Center University of Düsseldorf, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
| | - Alexandra P Bielfeld
- Department of Obstetrics, Gynecology and REI (UniKiD), Medical Faculty, Medical Center University of Düsseldorf, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany
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Koninckx PR, Ussia A, Adamyan L, Tahlak M, Keckstein J, Wattiez A, Martin DC. The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear. Best Pract Res Clin Obstet Gynaecol 2020; 71:14-26. [PMID: 32978068 DOI: 10.1016/j.bpobgyn.2020.08.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022]
Abstract
As the diagnosis requires a laparoscopy, we only have data in women with pain and/or infertility. Endometriosis has been considered to be a single disease defined as 'endometrium like glands and stroma outside the uterus'. However, subtle, typical, cystic ovarian and deep endometriosis lesions should be considered to be different pathologies which occur in all combinations and with different severities. All large datasets, especially those based on hospital discharge records, consider endometriosis to be a single disease without taking into account severity. In particular, the variable prevalence and recognition of subtle lesions is problematic. Reliable surgical data are small series not permitting multivariate analysis. Endometriosis is a hereditary disease. The oxidative stress of heavy menstrual bleeding with retrograde menstruation and an altered pelvic microbiome are probably associated with increasingly severe endometriosis. Whether the prevalence is increasing, or whether endometriosis is associated with fat intake or an increased risk of cardiovascular disease is unclear.
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Affiliation(s)
- Philippe R Koninckx
- Latifa Hospital, Dubai, United Arab Emirates; Professor Emeritus OBGYN, KULeuven Belgium; University of Oxford-Hon Consultant, UK; University Cattolica, Roma, Moscow State Univ. Italy; Gruppo Italo Belga, Villa Del Rosario Rome Italy.
| | - Anastasia Ussia
- University Cattolica, Roma, Moscow State Univ. Italy; Gruppo Italo Belga, Villa Del Rosario Rome 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, Moscow, Russia; Department of Reproductive Medicine and Surgery, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Muna Tahlak
- Latifa Hospital, Dubai, United Arab Emirates
| | - Jörg Keckstein
- Endometriosis Centre, Dres. Keckstein Villach, Austria; University Ulm, Ulm, Germany
| | - Arnaud Wattiez
- Latifa Hospital, Dubai, United Arab Emirates; University of Strassbourg, France
| | - Dan C Martin
- Professor Emeritus School of Medicine, University of Tennessee Health Science Centre, Memphis, TN, USA; Institutional Review Board, Virginia Commonwealth University, Richmond, VA, USA.
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11
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Noh EJ, Kim DJ, Lee JY, Park JH, Kim JS, Han JW, Kim BC, Kim CJ, Lee SK. Ureaplasma Urealyticum Infection Contributes to the Development of Pelvic Endometriosis Through Toll-Like Receptor 2. Front Immunol 2019; 10:2373. [PMID: 31636643 PMCID: PMC6788432 DOI: 10.3389/fimmu.2019.02373] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/23/2019] [Indexed: 12/29/2022] Open
Abstract
Endometriosis is a chronic gynecological disorder, characterized by the presence of ectopic endometrial tissue outside the uterine cavity. Among several hypotheses, Sampson's theory of retrograde menstruation is still applicable. Recent studies have reported the importance of inflammation among endometrial tissue, the peritoneum, and immune cells. However, less is known regarding the role of bacterial infection in the pathophysiology of endometriosis. We hypothesized that Ureaplasma urealyticum infection might contribute to the development of endometriosis by inducing the production of inflammatory mediators by peritoneal mesothelial cells (PMCs), possibly through TLR2. Hence, our objective was to reveal whether PMC infection by U. urealyticum is associated with endometriosis. Moreover, we aimed to demonstrate the molecular mechanism involved in this relationship. We developed a new infection-induced mouse model of endometriosis with wild type and Tlr2-deficient mice. Based on the in vivo mouse model, U. urealyticum-infected mice showed significantly increased numbers and sizes of ectopic endometriotic lesions. U. urealyticum upregulated not only the production of IL-6, CXCL1, and CCL2, but also the expression of ICAM-1, VCAM-1, and MMP2 in murine PMCs. Similarly, endometrial stromal cells dose-dependently produced IL-6, CXCL1, and CCL2 in response to U. urealyticum infection. The series of inflammatory responses in PMCs was mediated mainly through TLR2. The phosphorylation of ERK and JNK was observed when U. urealyticum was added to PMCs and knock out of Tlr2 inhibited these MAPKs phosphorylation. Based on our co-culture study, U. urealyticum-infected PMCs exhibited significantly increased attachment to ESCs compared with uninfected PMCs. Collectively, U. urealyticum infection promotes the development of endometriosis by increasing inflammatory mediators, adhesion molecules, and MMP-2 expression in PMCs through TLR2 signaling. Through our results, we present a theory that infection-induced pelvic inflammation contributes to the initiation and progression of endometriosis. Appropriate treatment of reproductive tract infection may decrease the prevalence of endometriosis.
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Affiliation(s)
- Eui Jeong Noh
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Dong Jae Kim
- Laboratory Animal Resource Centre, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu, South Korea
| | - Jun Young Lee
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Jong Hwan Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
| | - Jong-Seok Kim
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, South Korea
| | - Jae Won Han
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Byoung Chan Kim
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Chul Jung Kim
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Sung Ki Lee
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea.,Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, South Korea
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Bouquet de Joliniere J, Major A, Ayoubi JM, Cabry R, Khomsi F, Lesec G, Frydman R, Feki A. It Is Necessary to Purpose an Add-on to the American Classification of Endometriosis? This Disease Can Be Compared to a Malignant Proliferation While Remaining Benign in Most Cases. EndoGram® Is a New Profile Witness of Its Evolutionary Potential. Front Surg 2019; 6:27. [PMID: 31231658 PMCID: PMC6566301 DOI: 10.3389/fsurg.2019.00027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/29/2019] [Indexed: 12/22/2022] Open
Abstract
Endometriosis is a curious pathology that has been the topic of many international publications. Its etiology remains mysterious but seems to have multiple causes. It is a complex disease whose lesions are very heterogeneous in where they can occur (deep endometriosis, superficial, ovarian cyst), extent, associated symptoms, evolution or aggressiveness of the disease, and response to treatments. Furthermore, it evolves in pushes, remains autonomous, and is responsible for both superficial and deep lesions that explain its two most well know challenges: pain and infertility. It has always been classified by the size of its anatomical lesions—Acosta classification (1), revised by the American fertility society (AFS) (2), and the American society of reproductive medicine (ASRM) classification with a description of the disease at different stages: minimal (score of 1 to 5), mild (3–12), moderate (16 to 40), and severe (>40) (13). If this classification provides a complete repertoire of implants (anatomic) (10), the attribution of points is arbitrary. In fact, the size of the lesions is not synonymous with the difficulty to treat them surgically. Their location, if deep, is larger than the size of ovarian endometriomas. In addition, small anatomical but evaluative lesions will have a larger impact than big fibrous and stable lesions (Figure 1). Thus, attempts to explain their inflammatory side effects have been proposed (14, 15). The French classification nodule, ovaries, adhesions, tube, and inflammation (FOATI) (10) has had the merit of taking this phenomenon into account. In our opinion, we must go much further and propose an amendment in this classification, taking into account the evolution of the lesions and their deep molecular biology because in reality, the lesions are not at the same stage.
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Affiliation(s)
| | - Attila Major
- Department of Gynecology and Obstetrics, HFR, Fribourg Cantonal Hospital, Friborg, Switzerland
| | - Jean Marc Ayoubi
- Department of Gynecology and Obstetrics, Foch Hospital, Suresnes, France
| | - Rosalie Cabry
- Department of Gynecology and Obstetrics, HFR, Fribourg Cantonal Hospital, Friborg, Switzerland
| | - Fathi Khomsi
- Department of Gynecology and Obstetrics, HFR, Fribourg Cantonal Hospital, Friborg, Switzerland
| | - Guy Lesec
- Department of Anatomopathology, Unilabs, Lausanne, Switzerland
| | - René Frydman
- Department of Gynecology and Obstetrics, Foch Hospital, Suresnes, France
| | - Anis Feki
- Department of Gynecology and Obstetrics, HFR, Fribourg Cantonal Hospital, Friborg, Switzerland
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13
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Vassiliadis S. Premature Immunosenescence Impairs Immune Surveillance Allowing the Endometriotic Stem Cell to Migrate: The Cytokine Profile as a Common Denominator. ACTA ACUST UNITED AC 2018. [DOI: 10.1177/228402651000200103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
While endometriosis, one of the most common reasons for infertility, remains a multifactorial condition and its exact cause highly speculative, there are data pointing to novel pathways of disease initiation which involve a stem cell and its ability to migrate and implant after it differentiates into an endometriotic stem cell. Thus, the mechanisms conferring immune surveillance, which would also normally expel the mesenchymal endometriotic cell, impairing its migration and implantation, appear to be negatively influenced by a state of endometriotic premature immunosenescence. This interplay between the two immunological mechanisms and endometriosis is influenced by a number of common factors having an active role in the host's protection process that inhibits harmful diseases and maintains cellular homeostasis. It appears more than coincidental that production/inhibition of IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IL-18, TNF-α, VEGF, ICAM-1, and the number of Tolllike receptors is the same in immunosenescent states and in conditions with reduced immune surveillance, while the same variations are recorded in endometriotic patients. It is probable that these are common to all process signals, guide the endometriotic stem cell and dictate its fate according to the stochastic, transdifferentiation (plasticity) or deterministic model to become capable of migration and tissue invasion. It is currently unknown whether the pathway taken by the hemopoietic stem cell to become endometriotic represents a normal or aberrant route of development. This prompts research into its isolation and in vitro study of its behavior in order to reveal its potential function and role in endometriosis. (Journal of Endometriosis 2010; 2: 7–18)
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14
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Brubel R, Bokor A, Pohl A, Schilli GK, Szereday L, Bacher-Szamuel R, Rigo J, Polgar B. Serum galectin-9 as a noninvasive biomarker for the detection of endometriosis and pelvic pain or infertility-related gynecologic disorders. Fertil Steril 2017; 108:1016-1025.e2. [PMID: 29202955 DOI: 10.1016/j.fertnstert.2017.09.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 09/05/2017] [Accepted: 09/06/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the usefulness of soluble galectin-9 (Gal-9) in the noninvasive laboratory diagnosis of endometriosis and various gynecologic disorders. DESIGN Prospective case-control study. SETTING University medical centers. PATIENT(S) A total of 135 women of reproductive age were involved in the study, 77 endometriosis patients, 28 gynecologic controls, and 30 healthy women. INTERVENTION(S) Diagnostic laparoscopy and collection of tissue biopsies, peritoneal cells, and native peripheral blood from different case groups of gynecology patients and healthy women. MAIN OUTCOME MEASURE(S) The expression of mRNA and serum concentration of Gal-9. RESULT(S) Semiquantitative reverse transcription-polymerase chain reaction analysis and serum soluble Gal-9 ELISA were performed on three different cohorts of patients: those with endometriosis, those with benign gynecologic disorders, and healthy controls. Differences in the Gal-9 concentrations between the investigated groups and the stability of Gal-9 in the serum and diagnostic characteristics of Gal-9 ELISA were determined by statistical evaluation and receiver operating characteristic (ROC) curve analysis. Significantly elevated Gal-9 levels were found in both minimal-mild (I-II) and moderate-severe (III-IV) stages of endometriosis in comparison with healthy controls. At a cutoff of 132 pg/mL, ROC analysis revealed an excellent diagnostic value of Gal-9 ELISA in endometriosis (area under the curve = 0.973) with a sensitivity of 94% and specificity of 93.75%, indicating better diagnostic potential than that of other endometriosis biomarkers. Furthermore, various pelvic pain or infertility-associated benign gynecologic conditions were also associated with increased serum Gal-9 levels. CONCLUSION(S) Our results suggest that Gal-9 could be a promising noninvasive biomarker of endometriosis and a predictor of various infertility or pelvic pain-related gynecologic disorders.
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Affiliation(s)
- Reka Brubel
- First Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary
| | - Attila Bokor
- First Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary
| | - Akos Pohl
- First Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary
| | - Gabriella Krisztina Schilli
- Department of Medical Microbiology and Immunology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Centre, Pecs, Hungary
| | - Laszlo Szereday
- Department of Medical Microbiology and Immunology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Centre, Pecs, Hungary
| | - Reka Bacher-Szamuel
- Department of Medical Microbiology and Immunology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Centre, Pecs, Hungary
| | - Janos Rigo
- First Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary
| | - Beata Polgar
- Department of Medical Microbiology and Immunology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Centre, Pecs, Hungary.
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15
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Cicinelli E, Trojano G, Mastromauro M, Vimercati A, Marinaccio M, Mitola PC, Resta L, de Ziegler D. Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link. Fertil Steril 2017. [DOI: 10.1016/j.fertnstert.2017.05.016] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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16
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Chen H, Qin S, Lei A, Li X, Gao Q, Dong J, Xiao Q, Zhou J. Expansion of monocytic myeloid-derived suppressor cells in endometriosis patients: A pilot study. Int Immunopharmacol 2017; 47:150-158. [PMID: 28407569 DOI: 10.1016/j.intimp.2017.03.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 03/25/2017] [Accepted: 03/27/2017] [Indexed: 11/20/2022]
Abstract
Endometriosis is a chronic inflammation disease and is closely associated with immune dysregulation. Myeloid-derived suppressor cells (MDSCs) are a negative regulator of the immune system. The aim of this study was to evaluate the possible role of MDSCs in endometriosis patients. We collected the peripheral blood and peritoneal fluid from endometriosis patients and controls and analyzed M-MDSCs level using specific monoclonal antibodies recognizing HLA-DR, CD33, CD11b, CD14 markers by flow cytometry. We found that there existed abnormal expansion of monocytic MDSCs (M-MDSCs) (HLA-DR-/lowCD33+CD11b+ CD14+) in peripheral blood and peritoneal fluid of patients with endometriosis. Functional studies revealed that M-MDSCs from endometriosis patients significantly suppressed T-cell responses and produced high level of reactive oxygen species (ROS). The elevation of M-MDSCs from endometriosis patients may contribute to the disease progression.
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Affiliation(s)
- Haiwen Chen
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Shuang Qin
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China
| | - Aihua Lei
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xing Li
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qi Gao
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China
| | - Jingyin Dong
- Zhejiang University City College, Hangzhou 310015, Zhejiang, China.
| | - Qing Xiao
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China.
| | - Jie Zhou
- Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou 510623, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou 510080, China.
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17
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Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/s10397-016-0970-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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18
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Marí-Alexandre J, Barceló-Molina M, Olcina-Guillem M, García-Oms J, Braza-Boïls A, Gilabert-Estellés J. MicroRNAs: New players in endometriosis. World J Obstet Gynecol 2016; 5:28-38. [DOI: 10.5317/wjog.v5.i1.28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/14/2015] [Accepted: 01/07/2016] [Indexed: 02/05/2023] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disorder that limits the quality of life of affected women. This pathology affects 10% of reproductive-age women, although the prevalence in those patients experiencing pain, infertility or both is as high as 35%-50%. Endometriosis is characterized by endometrial-like tissue outside the uterus, primarily on the pelvic peritoneum, ovaries and the pouch of Douglas. Despite extensive research endeavours, a unifying theory regarding the exact etiopathogenic mechanism of this high prevalent and incapacitating condition is still lacking, although it has been suggested that epigenetics could be involved. MicroRNAs (miRNAs), one of the epigenetic players, are small non-coding RNAs that can act as post-transcriptional regulators of gene expression, reducing the expression of their target mRNAs either inhibiting its translation or promoting its degradation. MiRNA expression profiles are specific of tissue and cell type. Abnormal miRNA expression has been described in different pathological conditions, such as a myriad of oncological, cardiovascular and inflammatory diseases and gynecological pathologies. In endometriosis, miRNA expression patterns of eutopic endometrium from patients and control women and from different endometriotic lesions have been described. These small non-coding molecules have become attractive candidates as novel biomarkers for an early non-invasive diagnosis of the disease, which could suppose a valuable benefit to the patients in terms of improvement of prognosis and reduction of the ratio of recurrence. In this systematic review we will focus on the role of miRNAs in the pathophisiology of endometriosis.
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19
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Zhang H, Zhang Z, Li G, Wang S, Zhang S, Xie B. Association of FCRL3 Genetic Polymorphisms With Endometriosis-Related Infertility Risk: An Independent Study in Han Chinese. Medicine (Baltimore) 2015; 94:e1168. [PMID: 26334889 PMCID: PMC4616513 DOI: 10.1097/md.0000000000001168] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The Fc receptor-like 3 (FCRL3) gene was reported to be linked to a variety of autoimmune diseases, including endometriosis-related infertility. However, this linkage has not been studied in Chinese population and there has been no meta-analysis on the interrelationship of FCRL3 gene and endometriosis-related infertility. The aim of the study was to investigate the association between FCRL3 genetic polymorphisms and the risk of endometriosis-related infertility in Han Chinese, and a further meta-analysis was conducted to confirm our results.Four single nucleotide polymorphisms (SNPs) (rs7528684 [FCRL3_3], rs11264799 [FCRL3_4], rs945635 [FCRL3_5], and rs3761959 [FCRL3_6]) on FCRL3 gene were genotyped in a case-control cohort composed of 217 patients suffering from endometriosis-related infertility and 220 healthy controls using cleaved amplification polymorphism sequence-tagged sites (polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP). Odds ratio (OR) and its 95% confidence interval (CI) was used to evaluate the association quantitatively. Furthermore, a meta-analysis of previous studies including the present study was implemented through Stata 11.0 (Stata Corporation, College Station, TX).We found an approximately 1.4-fold significantly increased frequency of the FCRL3_3 variant in women with endometriosis-related infertility over the controls (OR = 1.41 [95% CI = 1.08-1.84], P = 0.013). However, no significant difference was found between women with endometriosis-related infertility and controls for FCRL3_4, FCRL3_5, and FCRL3_6. Regardless of the symptoms and the revised classification of the American Society of Reproductive Medicine (rASRM) stage of endometriosis, there was a significant association between FCRL3_3 variant and an increased risk of endometriosis-related infertility. Meta-analysis of previous studies combined with the present study further confirmed the association between FCRL3_3 and the risk of endometriosis-related infertility.In summary, the present study suggested that FCRL3_3 variant was associated with an increased risk of endometriosis-related infertility, regardless of symptoms, and rASRM stage of the patients. Meta-analysis of previous studies combined with the present study further confirmed our results. Further large-scale studies in the future are warranted to explore the association between FCRL3 genetic polymorphisms and endometriosis-related infertility, as well as other human diseases, in Asian and other ethnicities.
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Affiliation(s)
- Haiyan Zhang
- From the Department of Gynecology, Affiliated Qilu Hospital of Shandong University, Jinan, China (HZ) and Gynecology Ward-1 (HZ, ZZ, BX); Department of Gastrointestinal Surgery (GL), and Gynecology Ward-3 (SW), Linyi City People's Hospital, Shandong Province, China
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Santoro L, D’Onofrio F, Flore R, Gasbarrini A, Santoliquido A. Endometriosis and atherosclerosis: what we already know and what we have yet to discover. Am J Obstet Gynecol 2015; 213:326-31. [PMID: 25935777 DOI: 10.1016/j.ajog.2015.04.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 04/08/2015] [Accepted: 04/23/2015] [Indexed: 12/21/2022]
Abstract
The possible association between endometriosis and atherosclerosis represents an emerging topic in the field of women's health. In this Clinical Opinion paper, we analyze this theme focusing on the pathogenetic mechanisms of both diseases, deeply discussing about what is already known about this association and producing starting points about what we consider suitable to research in the near future with regard to cardiovascular involvement in women affected by endometriosis. We have identified 5 reports specifically carried out to investigate the relationship between atherosclerosis and endometriosis; these studies show the presence of subclinical atherosclerosis in women affected by endometriosis, susceptible of regression after surgical removal of endometriosis, with a possible prognostic relevance for variations of cardiovascular risk in these women. However, to date, no studies in literature have been carried out to investigate the real incidence of cardiovascular events in women with endometriosis.
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21
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Ziętek A, Futyma K, Nowakowski Ł, Gogacz M, Rechberger T. Progress on macrophage's proinflammatory products as markers of acute endometriosis. JOURNAL OF ACUTE DISEASE 2015. [DOI: 10.1016/j.joad.2015.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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22
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González-Foruria I, Santulli P, Chouzenoux S, Carmona F, Batteux F, Chapron C. Soluble ligands for the NKG2D receptor are released during endometriosis and correlate with disease severity. PLoS One 2015; 10:e0119961. [PMID: 25775242 PMCID: PMC4361401 DOI: 10.1371/journal.pone.0119961] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 01/18/2015] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Endometriosis is a benign gynaecological disease. Abundant bulk of evidence suggests that patients with endometriosis have an immunity dysfunction that enables ectopic endometrial cells to implant and proliferate. Previous studies show that natural killer cells have a pivotal role in the immune control of endometriosis. METHODS AND FINDINGS This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n= 202) during surgery for benign gynaecological conditions. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free controls women were enrolled. Patients with endometriosis were classified according to a surgical classification in three different types of endometriosis: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE). Peritoneal fluid samples were obtained from all study participants during the surgery in order to detect soluble NKG2D ligands (MICA, MICB and ULBP-2). When samples with undetectable peritoneal fluid levels of MICA, MICB and ULBP-2 were excluded, MICA ratio levels were significantly higher in endometriosis patients than in controls (median, 1.1 pg/mg; range, 0.1-143.5 versus median, 0.6 pg/mg; range, 0.1-3.5; p=0.003). In a similar manner peritoneal fluid MICB levels were also increased in endometriosis-affected patients compared with disease-free women (median, 4.6 pg/mg; range, 1.2-4702 versus median, 3.4 pg/mg; range, 0.7-20.1; p=0.001). According to the surgical classification, peritoneal fluid soluble MICA, MICB and ULBP-2 ratio levels were significantly increased in DIE as compared to controls (p=0.015, p=0.003 and p=0.045 respectively). MICA ratio levels also correlated with dysmenorrhea (r=0.232; p=0.029), total rAFS score (r=0.221; p=0.031) and adhesions rAFS score (r=0.221; p=0.031). CONCLUSIONS We demonstrate a significant increase of peritoneal fluid NKG2D ligands in women with endometriosis especially in those cases presenting DIE. This study suggests that NKG2D ligands shedding is a novel pathway in endometriosis complex pathogenesis that impairs NK cell function.
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Affiliation(s)
- Iñaki González-Foruria
- Département Développement, Reproduction et Cancer, Institut Cochin, INSERM, Paris, France
- Université Paris Descartes, Sorbone Paris Cité, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France
- Institut Clinic of Gynecology, Obstetrics and Neonatology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine-University of Barcelona, Barcelona, Spain
| | - Pietro Santulli
- Département Développement, Reproduction et Cancer, Institut Cochin, INSERM, Paris, France
- Université Paris Descartes, Sorbone Paris Cité, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France
| | - Sandrine Chouzenoux
- Département Développement, Reproduction et Cancer, Institut Cochin, INSERM, Paris, France
| | - Francisco Carmona
- Institut Clinic of Gynecology, Obstetrics and Neonatology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine-University of Barcelona, Barcelona, Spain
| | - Frédéric Batteux
- Département Développement, Reproduction et Cancer, Institut Cochin, INSERM, Paris, France
- Service d’immunologie biologique, Hôpital Cochin, Paris cedex 14, France
- DHU Risque et grossesse, Hôpital Cochin, Paris cedex 14, France
| | - Charles Chapron
- Département Développement, Reproduction et Cancer, Institut Cochin, INSERM, Paris, France
- Université Paris Descartes, Sorbone Paris Cité, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France
- DHU Risque et grossesse, Hôpital Cochin, Paris cedex 14, France
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Dutta M, Subramani E, Taunk K, Gajbhiye A, Seal S, Pendharkar N, Dhali S, Ray CD, Lodh I, Chakravarty B, Dasgupta S, Rapole S, Chaudhury K. Investigation of serum proteome alterations in human endometriosis. J Proteomics 2014; 114:182-96. [PMID: 25449831 DOI: 10.1016/j.jprot.2014.10.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 10/23/2014] [Accepted: 10/29/2014] [Indexed: 12/26/2022]
Abstract
UNLABELLED Endometriosis is a common benign gynecological disease, characterized by proliferation of functional endometrial glands and stroma outside the uterine cavity. The present study involves investigation of alterations in the serum proteome of endometriosis patients compared to healthy controls using 2DE and 2D-DIGE combined with MALDI TOF/TOF-MS. Comparison of serum proteome of endometriosis patients and healthy subjects revealed 25 significant differentially expressed proteins. Gene ontology and network analysis, performed using PANTHER, DAVID, WebGestalt and STRING, revealed that the differentially expressed proteins are majorly involved in response to stimulus, immune system, metabolic, localization and cellular processes. For serum diagnostic marker identification, several robust statistical screening procedures were applied to identify the set of the most significant proteins responsible for successful diagnosis of different endometriosis stages. Partial least squares (PLS) based marker selection tool and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to identify the most significant proteins for disease prediction. Western blotting validation in a separate cohort of patients revealed that haptoglobin (HP), Ig kappa chain C region (IGKC), alpha-1B-glycoprotein (A1BG) can be considered effective serum protein markers for the diagnosis of Stage II, III and IV endometriosis. For diagnosis of Stage I, only IGKC and HP seemed promising. BIOLOGICAL SIGNIFICANCE Globally, about 12 in 100 women of reproductive age are diagnosed with endometriosis. The pathogenesis of the disease still remains unclear, leading to non-specific therapeutic approaches for disease management. Moreover, there is a delay of 8-12years in correct diagnosis after the initial onset of symptoms leading to a considerable impact on the woman's lifestyle. Also, the gold standard for diagnosis of endometriosis, laparoscopy, is an invasive procedure. The value of a noninvasive or semi-invasive diagnostic test for endometriosis with easily accessible fluids such as plasma, serum, urine, and saliva is, therefore, rightfully recognized. The present study is expected to considerably improve the understanding of the disease pathogenesis along with improved diagnostics and therapeutic approaches leading to better management of the disease.
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Affiliation(s)
- Mainak Dutta
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India
| | - Elavarasan Subramani
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India
| | - Khushman Taunk
- Proteomics Lab, National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India
| | - Akshada Gajbhiye
- Proteomics Lab, National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India
| | | | - Namita Pendharkar
- Proteomics Lab, National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India
| | - Snigdha Dhali
- Proteomics Lab, National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India
| | - Chaitali Datta Ray
- Institute of Post Graduate Medical Education & Research, Obstetrics & Gynecology, Kolkata, West Bengal, India
| | - Indrani Lodh
- Institute of Reproductive Medicine, Sector-III, Kolkata, West Bengal, India
| | | | - Swagata Dasgupta
- Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal, India
| | - Srikanth Rapole
- Proteomics Lab, National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India
| | - Koel Chaudhury
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India.
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Abstract
Most of the key physiological processes in the human reproductive tract involve a significant inflammatory component. These processes include follicle development, ovulation, implantation, pregnancy, labor, postpartum, remodeling and menstruation. In this context, the term 'inflammation' usually means an influx of leukocytes ('immune cells'), often of different types, into a reproductive tract tissue. These examples of inflammation are not overtly associated with any infective process. There may also be evidence that these invading leukocytes have altered their functions to take on specific and relevant local regulatory roles. Specific sequential changes in different leukocytes can be demonstrated within human endometrium during the different phases of the normal menstrual cycle. Leukocytes are fairly sparse in numbers through the proliferative phase, but increase substantially into and through the secretory phase, so much so that around 40% of all stromal cells in the premenstrual phase are leukocytes, mainly uterine natural killer cells, a large granulated lymphocyte. Other leukocytes which play key roles in menstruation appear to be macrophages, mast cells, dendritic cells, neutrophils, eosinophils and regulatory T cells. Premenstrual withdrawal of progesterone increases the endometrial expression of inflammatory mediators, including IL-8 and MCP-1, which are believed to drive endometrial leukocyte recruitment at this time. Macrophages and neutrophils are rich sources of defensins and whey acid protein motif proteins, which play important roles in ensuring microbial protection while the epithelial barrier is disrupted. Mast cells are increasingly activated as the menstrual phase approaches, and leukocyte proteases trigger a cascade of matrix metalloproteinases and degradation of extracellular matrix. Dendritic cells and other antigen-presenting cells (e.g. macrophages) almost certainly facilitate clearance of cellular debris from the uterine cavity, and reduce the amount of viable cellular material transiting the Fallopian tubes. All of these processes are influenced or controlled by regulatory T cells. Many of these leukocytes also have the potential to release regulatory molecules which stimulate endometrial repair mechanisms. Increasing recent evidence also implicates disturbances of immune cells and their cytokine mediators in contributing to symptoms of abnormal uterine bleeding and pelvic pain. These recent findings all point towards the importance of the 'inflammatory process' in both normal and abnormal endometrial bleeding.
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Affiliation(s)
- M Berbic
- Queen Elizabeth II Research Institute for Mothers and Infants, Department of Obstetrics, Gynaecology and Neonatology, The University of Sydney , Sydney , Australia
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Gogacz M, Winkler I, Bojarska-Junak A, Tabarkiewicz J, Semczuk A, Rechberger T, Adamiak A. T regulatory lymphocytes in patients with endometriosis. Mol Med Rep 2014; 10:1072-6. [PMID: 24889795 DOI: 10.3892/mmr.2014.2294] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 03/25/2014] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to investigate the presence of T regulatory cells (Tregs) in the peripheral blood (PB) and peritoneal fluid (PF) in females with endometriosis. The present study included 42 patients who underwent laparoscopy between 2010 and 2011. Flow cytometry was used to determine the percentage of Tregs in the PF and PB of the patients. No significant difference was observed in the percentage of Tregs in the patients in the endometriosis group compared with those in the control group in the PF (9.1±5.4 vs. 9.1±3.8%) or the PB (6.5±3.2 vs. 6.5±3.7%). However, the percentage of Tregs was found to be higher in the PF compared with the PB in the patients in the endometriosis and control groups, but significance was found only in those in the control group. Furthermore, no significant difference was observed in the Treg concentration in the patients with early stage (I/II) endometriosis compared with those with late stage (III/IV) endometriosis. Moreover, no significant correlation was found between the percentage of Tregs and the white blood cell count, lymphocyte count or CA125 concentration in the patients. These findings suggest that the local host‑defense mechanism is deficient in patients with endometriosis, thus endometriosis should not be treated as an autoimmune condition.
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Affiliation(s)
- Marek Gogacz
- Second Department of Gynaecology, Medical University of Lublin, Lublin 20‑954, Poland
| | - Izabela Winkler
- Second Department of Gynaecology, Medical University of Lublin, Lublin 20‑954, Poland
| | | | - Jacek Tabarkiewicz
- Department of Clinical Immunology, Medical University, Lublin 20‑093, Poland
| | - Andrzej Semczuk
- Second Department of Gynaecology, Medical University of Lublin, Lublin 20‑954, Poland
| | - Tomasz Rechberger
- Second Department of Gynaecology, Medical University of Lublin, Lublin 20‑954, Poland
| | - Aneta Adamiak
- Second Department of Gynaecology, Medical University of Lublin, Lublin 20‑954, Poland
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26
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Takebayashi A, Kimura F, Kishi Y, Ishida M, Takahashi A, Yamanaka A, Takahashi K, Suginami H, Murakami T. The association between endometriosis and chronic endometritis. PLoS One 2014; 9:e88354. [PMID: 24558386 PMCID: PMC3928198 DOI: 10.1371/journal.pone.0088354] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 01/12/2014] [Indexed: 01/27/2023] Open
Abstract
Objective To evaluate the association between endometriosis and chronic endometritis. Methods Endometrial specimens were obtained from 71 patients, 34 with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group), who underwent hysterectomy, and the specimens were immunostained for the plasmacyte marker CD138. The rate of chronic endometritis was compared between the endometriosis group and the non-endometriosis group. Furthermore, the 71 patients were also divided into two groups, 28 with chronic endometritis (chronic endometritis group) and 43 without chronic endometritis (non-chronic endometritis group). Logistic regression analysis was performed with variables including age, body mass index (BMI), gravidity and parity, and diagnoses of leiomyoma, adenomyosis, and endometriosis on pathology to examine the independent effect of each variable on chronic endometritis. Patients suffering from cervical invasive carcinoma, endometrial carcinoma, and endometrial polyps or treated with gonadotropin-releasing hormone agonists, progestins, or oral contraceptives before surgery were excluded. Results Chronic endometritis was identified in 52.94% of the endometriosis group and 27.02% of the non-endometriosis group (p<0.05). Logistic regression analysis revealed that endometriosis was associated with chronic endometritis. Conclusions This result suggests a strong association between endometriosis and chronic endometritis.
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Affiliation(s)
- Akie Takebayashi
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
- * E-mail:
| | - Fuminori Kimura
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Yohei Kishi
- Department of Obstetrics and Gynecology, Takanohara Central Hospital, Nara-shi, Nara, Japan
| | - Mitsuaki Ishida
- Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Akimasa Takahashi
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Akiyoshi Yamanaka
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Kentaro Takahashi
- Department of Community Perinatal Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Hiroshi Suginami
- Department of Obstetrics and Gynecology, Takanohara Central Hospital, Nara-shi, Nara, Japan
| | - Takashi Murakami
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
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27
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Al-Jefout M, Tokushige N, Hey-Cunningham AJ, Manconi F, Ng C, Schulke L, Berbic M, Markham R, Fraser IS. Microanatomy and function of the eutopic endometrium in women with endometriosis. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17474108.4.1.61] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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28
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Li X, Large MJ, Creighton CJ, Lanz RB, Jeong JW, Young SL, Lessey BA, Palomino WA, Tsai SY, Demayo FJ. COUP-TFII regulates human endometrial stromal genes involved in inflammation. Mol Endocrinol 2013; 27:2041-54. [PMID: 24176914 DOI: 10.1210/me.2013-1191] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis.
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Affiliation(s)
- Xilong Li
- Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
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29
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Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update 2013; 19:406-18. [PMID: 23539633 DOI: 10.1093/humupd/dmt010] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena. METHODS We searched Pubmed for items published in English between September 1991 and September 2011 and selected the studies evaluating the effects of hormones on chemokines or apoptosis in normal human endometrium and endometriosis. RESULTS Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to be exacerbated in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2. The main effect of progestogens is to inhibit interleukin-8 and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is also effective in inducing apoptosis in endometrial and endometriotic cells through the inhibition of Bcl-2 and nuclear factor-κB. CONCLUSIONS Estrogens and progestogens modulate chemotaxis and apoptosis in human endometrium and endometriotic cells and tissues. These endocrine and paracrine pathways are perturbed in women with endometriosis, contributing to inflammatory responses, abnormal tissue remodeling, therapeutic refractoriness and disease persistence. Ultimately, they promote adhesion formation and the clinical symptoms of pelvic pain and infertility. A more detailed understanding of the molecular mechanisms involved will offer new opportunities for novel pharmacological strategies to diagnose and treat endometriosis.
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Affiliation(s)
- Fernando M Reis
- Department of Obstetrics and Gynecology, University of Minas Gerais, Belo Horizonte, Brazil
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30
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Kokcu A. Possible effects of endometriosis-related immune events on reproductive function. Arch Gynecol Obstet 2013; 287:1225-33. [DOI: 10.1007/s00404-013-2767-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 02/12/2013] [Indexed: 02/02/2023]
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31
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Olkowska-Truchanowicz J, Bocian K, Maksym RB, Bialoszewska A, Wlodarczyk D, Baranowski W, Zabek J, Korczak-Kowalska G, Malejczyk J. CD4+ CD25+ FOXP3+ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Hum Reprod 2012; 28:119-24. [DOI: 10.1093/humrep/des346] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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32
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Kokcu A, Yavuz E, Celik H, Bildircin D. A panoramic view to relationships between reproductive failure and immunological factors. Arch Gynecol Obstet 2012; 286:1283-9. [DOI: 10.1007/s00404-012-2480-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Accepted: 07/12/2012] [Indexed: 10/28/2022]
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Marci R, Lo Monte G, Soave I, Bianchi A, Patella A, Wenger JM. Rectus abdominis muscle endometriotic mass in a woman affected by multiple sclerosis. J Obstet Gynaecol Res 2012; 39:462-5. [DOI: 10.1111/j.1447-0756.2012.01933.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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34
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Canet B, Pons C, Espinosa I, Prat J. CDC42-positive macrophages may prevent malignant transformation of ovarian endometriosis. Hum Pathol 2011; 43:720-5. [PMID: 21944080 DOI: 10.1016/j.humpath.2011.06.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 06/20/2011] [Accepted: 06/22/2011] [Indexed: 12/27/2022]
Abstract
It is currently thought that most clear cell and endometrioid carcinomas arise from ovarian endometriosis. We recently suggested that, besides their origin in the ovary, reduction of CDC42 messenger RNA (a member of the RHO GTPase family) may contribute to explain why clear cell carcinomas are not uncommonly found limited to the ovary (stage I). On the other hand, little is known about the expression of CDC42 in ovarian endometriosis with and without carcinoma. Twenty-two endometriotic cysts not associated with carcinoma, 19 endometriotic cysts associated with carcinoma (contiguous endometriosis), as well as the 19 corresponding tumors (11 clear cell, 4 endometrioid, and 4 mixed-clear cell and endometrioid-carcinomas) were investigated. We analyzed CDC42 expression both by real-time polymerase chain reaction and immunohistochemistry. Endometriotic cysts not associated with carcinoma showed higher expression of CDC42 messenger RNA than cysts associated with carcinoma (P = .002). Immunohistochemically, CDC42 was exclusively expressed by macrophages. CDC42-positive macrophages were present in most of the endometriotic cysts not associated with carcinoma (11/19, or 58%). In contrast, only 5 endometriotic cysts containing carcinoma (contiguous endometriosis) (5/18, or 28%) and 1 ovarian carcinoma arising from endometriosis (1/18, or 5%) had CDC42-positive macrophages (58% versus 28%, P = .065; 28% versus 5%, P = .046). Our results raise the possibility that CDC42-positive macrophages may prevent the development of endometrioid and clear cell carcinomas.
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Affiliation(s)
- Belen Canet
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, Institute of Biomedical Research (IIB Sant Pau), Autonomous University of Barcelona, Barcelona -08041, Spain
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35
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Bianco B, Teles JS, Lerner TG, Vilarino FL, Christofolini DM, Barbosa CP. Association of FCRL3 −169T/C polymorphism with endometriosis and identification of a protective haplotype against the development of the disease in Brazilian population. Hum Immunol 2011; 72:774-8. [DOI: 10.1016/j.humimm.2011.05.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2011] [Revised: 05/04/2011] [Accepted: 05/13/2011] [Indexed: 10/18/2022]
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36
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Laschke M, Giebels C, Menger M. Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update 2011; 17:628-636. [DOI: 10.1093/humupd/dmr023] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Caccavo D, Pellegrino NM, Totaro I, Vacca MP, Selvaggi L, Depalo R. Anti-laminin-1 antibodies in sera and follicular fluid of women with endometriosis undergoing in vitro fertilization. Int J Immunopathol Pharmacol 2011; 24:481-8. [PMID: 21658322 DOI: 10.1177/039463201102400221] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
There is increasing evidence that autoimmune phenomena, including auto-antibody production, may affect fertility in women with endometriosis. The aims of this study are to evaluate anti-laminin-1 antibody (aLN-1) presence in sera and in follicular fluids (FF) of women with endometriosis undergoing IVF and its impact on oocyte maturation and IVF outcome. aLN-1 were measured by a home-made enzyme linked immunosorbent assay in sera and FF obtained from 35 infertile women with endometriosis and in sera from 50 fertile controls and 27 infertile women without endometriosis (IWWE). aLN-1 serum levels were significantly higher in women with endometriosis in comparison with both fertile controls and IWWE (P<0.001 and P<0.05, respectively) and a positive correlation was found between serum- and FF-aLN-1 (r=0.47, P=0.004). According to the cut-off (mean+3 SD of fertile controls), 31% of women with endometriosis were aLN-1 positive. Metaphase II oocyte counts showed inverse correlation with FF-aLN-1 levels (r=-0.549, P=0.0006). Ongoing pregnancy (i.e pregnancy progressing beyond the 12th week of gestation) occurred in 4/11 aLN-1 positive patients and in 7/24 aLN-1 negative with no significant difference (P=0.7). In conclusion, our results highlight that aLN-1 are increased in women with endometriosis and their presence in FF may affect oocyte maturation leading to a reduced fertility. However, aLN-1 seem to have no effect on IVF outcome.
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Affiliation(s)
- D Caccavo
- Department of Clinical Medicine, Immunology and Infectious Diseases, University of Bari Aldo Moro, Bari, Italy.
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Abstract
Endometriosis is a common cause of pelvic pain and infertility, affecting ∼10% of reproductive-age women. Annual costs for medical and surgical care in the United States exceed $20 billion. The disorder is characterized by implants of endometrial tissue outside the uterine cavity. Endometriotic lesions induce a state of chronic peritoneal inflammation, accompanied by elevated prostaglandin, cytokine, and growth factor concentrations. The current therapy is surgical ablation of ectopic implants and hormones that block the hypothalamic-pituitary-ovarian axis, but these approaches are expensive, carry perioperative risks, or have unpleasant side effects of hypoestrogenism. Recent evidence indicates that ectopic endometriotic implants recruit their own unique neural and vascular supplies through neuroangiogenesis. It is believed that these nascent nerve fibers in endometriosis implants influence dorsal root neurons within the central nervous system, increasing pain perception in patients. We consider the mechanisms and therapeutic implications of neuroangiogenesis in these lesions and propose potential treatments for the control or elimination of endometriosis-associated pain.
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Affiliation(s)
- Albert Asante
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Vilarino FL, Bianco B, Lerner TG, Teles JS, Mafra FA, Christofolini DM, Barbosa CP. Analysis of vitamin D receptor gene polymorphisms in women with and without endometriosis. Hum Immunol 2011; 72:359-63. [DOI: 10.1016/j.humimm.2011.01.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 12/09/2010] [Accepted: 01/13/2011] [Indexed: 02/08/2023]
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Marino G, Piras D, Pedalino M, Di Primio O, Velia R, Vercesi E. Indications and Limits to Endourologic Procedures for Endometriosis of the Urinary Tract. Urologia 2010. [DOI: 10.1177/0391560310077017s03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Introduction The incidence of Urinary tract endometriosis (UTE) ranges from 1% to 3%; bladder is the most affected organ (85% of UTE), followed by ureter (12–14% of UTE), for which we distinguish an intrinsic very rare form and an extrinsic variety most frequently occurring in advanced pelvic endometriosis. Materials and Methods. From 1997 to 2010, 33 surgical procedures for urologic endometriosis were performed, involving the urinary tract, in 28 patients with mean age of 31 years (25–43). The localization of endometriosis were: 7 cases in the bladder, 2 cases in the vesicoureteral tract, and 19 cases of ureteral tract only. Of these, two cases were diagnosed with an intrinsic localization. Results Overall, we performed 3 TURB, 5 partial cystectomies (2 with open surgical approach and 3 by laparoscopy procedure), 12 laparoscopic ureterolysis and simultaneous protection of the upper urinary tract with stent, 9 cases of ureterocystoneostomy (UCNS) according to Lich-Gregoire procedure, and 3 according to Boari–Kuess procedure. Of the 12 patients who underwent ureterolysis with laparoscopic and stenting procedure, five cases required a UCNS according to Lich-Gregoire technique for persistent ureteral obstruction. Conclusions The limits of endoscopic procedures in endometriosis of the urinary tract are correlated both to the degree of extension and the localization of the disease. It is mandatory to achieve an interdisciplinary consensus in order to ensure the disease removal and the simultaneous functional results of the upper urinary tract.
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Affiliation(s)
- G. Marino
- S.C. Urologia - S.C. Anatomia Patologica ASL TO 5 Chieri (Torino) - Italy
| | - D. Piras
- S.C. Urologia - S.C. Anatomia Patologica ASL TO 5 Chieri (Torino) - Italy
| | - M. Pedalino
- S.C. Urologia - S.C. Anatomia Patologica ASL TO 5 Chieri (Torino) - Italy
| | - O.G. Di Primio
- S.C. Urologia - S.C. Anatomia Patologica ASL TO 5 Chieri (Torino) - Italy
| | - R. Velia
- S.C. Urologia - S.C. Anatomia Patologica ASL TO 5 Chieri (Torino) - Italy
| | - E. Vercesi
- S.C. Urologia - S.C. Anatomia Patologica ASL TO 5 Chieri (Torino) - Italy
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Sharpe-Timms KL, Nabli H, Zimmer RL, Birt JA, Davis JW. Inflammatory cytokines differentially up-regulate human endometrial haptoglobin production in women with endometriosis. Hum Reprod 2010; 25:1241-50. [PMID: 20176595 PMCID: PMC2902841 DOI: 10.1093/humrep/deq032] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2008] [Revised: 01/08/2010] [Accepted: 01/25/2010] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Evidence suggests that eutopic endometrium from women with endometriosis (US-E) has intrinsic functional anomalies compared with women without endometriosis (US-C). We hypothesized that differences in endometrial haptoglobin (eHp) mRNA and protein levels exist between eutopic endometrium from US-E and US-C and that inflammatory mediators may be involved. METHODS Endometrial stromal cells and tissue explants from US-E (n = 18) and US-C (n = 18) were cultured (24 h/48 h for cells/explants) with interleukin (IL)-1alpha, -1beta, -6, -8 or tumor necrosis factor-alpha (TNF-alpha) at 0-100 ng/ml. eHp protein in media and mRNA levels were quantified by enzyme-linked immunosorbent assay and quantitative PCR. RESULTS In eutopic endometrial stromal cells from US-E, IL-1beta, IL-6 and TNF-alpha (10 ng/ml) increased eHp mRNA levels (P = 0.002, P < 0.001 and P < 0.001, respectively) and eHp protein (P = 0.023, 0.031 and 0.006, respectively) versus control. In endometrial tissues from US-E, IL-1beta, IL-6 and TNF-alpha increased eHp mRNA (P < 0.001, P = 0.017 and P < 0.001, respectively) and eHp protein (P < 0.001, P = 0.007 and 0.039, respectively) versus control. IL-1alpha and IL-8 had small or no effects on isolated endometrial cells or tissues. In US-C, IL-1beta, IL-8 and TNF-alpha each reduced eHp mRNA in endometrial stromal cells (all P < 0.001) versus control; IL-1alpha and IL-6 had no effect. eHp mRNA increased in endometrial tissues from US-C in response to IL-1beta (P = 0.008), IL-6 (P = 0.015) and TNF-alpha (P = 0.031) versus control; IL-1alpha or IL-8 had no effect. CONCLUSIONS Endometrium from US-E differentially responds to specific inflammatory cytokines by production of eHp. We propose that up-regulation of endometrial eHp by inflammatory mediators disrupts normal endometrial function and may facilitate the pathogenesis of endometriosis.
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Affiliation(s)
- K L Sharpe-Timms
- Department of Obstetrics, Gynecology and Women's Health, The University of Missouri-Columbia, 1 Hospital Drive, N 625 HSC, Columbia, MO 65212, USA.
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González-Ramos R, Van Langendonckt A, Defrère S, Lousse JC, Colette S, Devoto L, Donnez J. Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis. Fertil Steril 2010; 94:1985-94. [PMID: 20188363 DOI: 10.1016/j.fertnstert.2010.01.013] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2009] [Revised: 01/05/2010] [Accepted: 01/08/2010] [Indexed: 10/19/2022]
Abstract
OBJECTIVE To evaluate the role of nuclear factor-κB (NF-κB) in the pathogenesis of endometriosis. DESIGN A literature search was conducted in PubMed to identify all relevant citations. RESULT(S) Our findings highlight the important role of NF-κB in the pathophysiology of endometriosis. In vitro and in vivo studies show that NF-κB-mediated gene transcription promotes inflammation, invasion, angiogenesis, and cell proliferation and inhibits apoptosis of endometriotic cells. Constitutive activation of NF-κB has been demonstrated in endometriotic lesions and peritoneal macrophages of endometriosis patients. Agents blocking NF-κB are effective inhibitors of endometriosis development and some drugs with known NF-κB inhibitory properties have proved efficient at reducing endometriosis-associated symptoms in women. Iron overload activates NF-κB in macrophages. NF-κB activation in macrophages and ectopic endometrial cells stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-κB pathway and promoting endometriotic lesion establishment, maintenance and development. CONCLUSION(S) NF-κB transcriptional activity modulates key cell processes contributing to the initiation and progression of endometriosis. Because endometriosis is a multifactorial disease, inhibiting NF-κB appears to be a promising strategy for future therapies targeting different cell functions involved in endometriosis development, such as cell adhesion, invasion, angiogenesis, inflammation, proliferation, and apoptosis. Upcoming research will elucidate these hypotheses.
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Affiliation(s)
- Reinaldo González-Ramos
- Instituto de Investigaciones Materno Infantil, Departamento de Obstetricia y Ginecología, Hospital Clínico San Borja-Arriarán, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
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Machado DE, Berardo PT, Palmero CY, Nasciutti LE. Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2010; 29:4. [PMID: 20085636 PMCID: PMC2826344 DOI: 10.1186/1756-9966-29-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 01/19/2010] [Indexed: 12/27/2022]
Abstract
Background Endometriosis is a common disease characterized by the presence of a functional endometrium outside the uterine cavity, causing pelvic pain, dysmenorrheal, and infertility. This disease has been associated to development of different types of malignancies; therefore new blood vessels are essential for the survival of the endometrial implant. Our previous observations on humans showed that angiogenesis is predominantly found in rectosigmoid endometriosis, a deeply infiltrating disease. In this study, we have established the experimental model of rat peritoneal endometriosis to evaluate the process of angiogenesis and to compare with eutopic endometrium. Methods We have investigated the morphological characteristics of these lesions and the vascular density, VEGF and its receptor Flk-1 and MMP-9 expression, and activated macrophage distribution, using immunohistochemistry and RT-PCR. Results As expected, the auto-transplantation of endometrium pieces into the peritoneal cavity is a well-established method for endometriosis induction in rats. The lesions were cystic and vascularized, and demonstrated histological hallmarks of human pathology, such as endometrial glands and stroma. The vascular density and the presence of VEGF and Flk-1 and MMP-9 were significantly higher in endometriotic lesions than in eutopic endometrium, and confirmed the angiogenic potential of these lesions. We also observed an increase in the number of activated macrophages (ED-1 positive cells) in the endometriotic lesions, showing a positive correlation with VEGF. Conclusion The present endometriosis model would be useful for investigation of the mechanisms of angiogenesis process involved in the peritoneal attachment of endometrial cells, as well as of the effects of therapeutic drugs, particularly with antiangiogenic activity.
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Affiliation(s)
- Daniel E Machado
- Programa de Pesquisa em Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária-Ilha do Fundão, 21941-590 Rio de Janeiro, RJ Brazil
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Schulke L, Berbic M, Manconi F, Tokushige N, Markham R, Fraser IS. Dendritic cell populations in the eutopic and ectopic endometrium of women with endometriosis. Hum Reprod 2009; 24:1695-703. [PMID: 19321495 DOI: 10.1093/humrep/dep071] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
BACKGROUND Immune alterations may be involved in the pathogenesis and progression of endometriosis. Dendritic cells (DCs) are potent antigen presenting cells that are highly involved in the initiation of the immune response. The aim of this study was to investigate DC populations in the eutopic and ectopic endometrium of women with endometriosis compared with controls. METHODS Hysterectomy samples were obtained from premenopausal women with (n = 33) and without (n = 28) endometriosis. In addition, paired peritoneal endometriotic lesions and uterine curettings were collected from 32 women with endometriosis. Specimen sections were stained immunohistochemically using antibodies for monoclonal mouse antibodies directed against human CD1a and CD83, which are specific for immature and mature DCs, respectively. RESULTS The mean density of endometrial CD1a+ DCs in the basal layer was significantly increased in women with endometriosis compared with controls during the proliferative phase only (P = 0.001). There was a highly significant decrease in the density of endometrial CD83+ DCs in women with endometriosis compared with controls in both layers of the endometrium across all phases of the menstrual cycle (P = 0.001). The density of CD1a+ DCs was significantly increased in peritoneal endometriotic lesions (P = 0.003) and in the surrounding peritoneum (P = 0.001) compared with paired uterine curettings and peritoneum distant from the lesion. CONCLUSIONS Both CD1a+ and CD83+ DC populations were altered in the eutopic and ectopic endometrium of women with endometriosis compared with controls. Alterations in these cells, which play a crucial role in the coordination of the immune response, may be involved in pain generation and the pathogenesis of endometriosis.
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Affiliation(s)
- Lauren Schulke
- Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Sydney 2006, Australia
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Ngô C, Chéreau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:225-34. [PMID: 19498006 DOI: 10.2353/ajpath.2009.080804] [Citation(s) in RCA: 217] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Endometriosis is associated with chronic inflammation, and reactive oxygen species (ROS) are proinflammatory mediators that modulate cell proliferation. We have investigated whether the dysregulation of ROS production in endometriotic cells correlates with a pro-proliferative phenotype and can explain the spreading of this disease. Stromal and epithelial cells were purified from ovarian endometrioma and eutopic endometrium from 14 patients with endometriosis to produce four primary cell lines from each patient. ROS production, detoxification pathways, cell proliferation, and mitogen-activated protein kinase pathway activation were studied and compared with epithelial and stromal cell lines from 14 patients without endometriosis. Modulation of the proliferation of endometriosis by N-acetyl-cysteine, danazol, and mifepristone was tested in vitro and in 28 nude mice implanted with endometriotic tissue of human origin. Endometriotic cells displayed higher endogenous oxidative stress with an increase in ROS production, alterations in ROS detoxification pathways, and a drop in catalase levels, as observed for tumor cells. This increase in endogenous ROS correlated with increased cellular proliferation and activation of ERK1/2. These phenomena were abrogated by the antioxidant molecule N-acetyl-cysteine both in vitro and in a mouse model of endometriosis. Human endometriotic cells display activated pERK, enhanced ROS production, and proliferative capability. Our murine model shows that antioxidant molecules could be used as safe and efficient treatments for endometriosis.
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Affiliation(s)
- Charlotte Ngô
- Faculté de Médecine, Service de Gynécologie Obstétrique II et Médecine de la Reproduction, AP-HP Hôpital Cochin, Paris, France
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Berbic M, Schulke L, Markham R, Tokushige N, Russell P, Fraser IS. Macrophage expression in endometrium of women with and without endometriosis. Hum Reprod 2009; 24:325-32. [DOI: 10.1093/humrep/den393] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Haber E, Danenberg HD, Koroukhov N, Ron-El R, Golomb G, Schachter M. Peritoneal macrophage depletion by liposomal bisphosphonate attenuates endometriosis in the rat model. Hum Reprod 2008; 24:398-407. [PMID: 18948309 DOI: 10.1093/humrep/den375] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Activation of macrophages is central to the implantation of endometriosis (EM). We examined the hypothesis that macrophage depletion by intraperitoneal (IP) injection of liposomal alendronate (LA) could result in EM attenuation in a rat model, thus supporting the notion of the pivotal role of macrophages in EM pathology. METHODS In this study, 90 rats were subjected to an EM model and were divided randomly into seven groups: five groups were treated by 4x once-weekly IP injections of LA (0.02, 0.1, 1, 5 or 10 mg/kg) and the other two groups received saline injections (control) or empty liposomes. Sham-operated rats also received empty liposomes. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Four weeks after the initial surgery, the number, size and weight of implants were recorded, adhesions were graded, macrophage infiltration was assessed and the peritoneal fluid was analyzed for monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor alpha (TNFalpha). RESULTS Monocyte depletion following IP LA administration resulted in an inhibitory effect on the initiation and growth of EM implants, as expressed by implantation rate, adhesion scoring, implants' size and weight (>0.1 mg/kg LA, P < 0.05). Reduced numbers of infiltrating macrophages were observed in implants of the 1 mg/kg LA group. Peritoneal fluid MCP-1 levels were negatively correlated with LA dose (P < 0.001), whereas no significant correlation could be found for TNFalpha. CONCLUSIONS Macrophage depletion using IP LA has been shown to effectively inhibit the initiation and growth of EM implants, in a rat EM model. The clear dose-response effect may be viewed as a confirmation of the validity of the concept and encourages further study.
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Affiliation(s)
- E Haber
- Faculty of Medicine, Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel
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Nowak NM, Fischer OM, Gust TC, Fuhrmann U, Habenicht UF, Schmidt A. Intraperitoneal inflammation decreases endometriosis in a mouse model. Hum Reprod 2008; 23:2466-74. [PMID: 18653673 PMCID: PMC2569845 DOI: 10.1093/humrep/den189] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND The role of the immune system in the pathogenesis of endometriosis remains elusive. It has been shown that patients have an altered peritoneal environment with increased levels of inflammatory cytokines, activated macrophages and reduced clearance of retrogradely transported endometrial fragments. However, it is not known if this unique inflammatory situation is cause or consequence of endometriosis. This study investigates the impact of a pre-existing peritoneal inflammation on endometriosis establishment in a mouse model. METHODS Endometriosis was induced by intraperitoneal injection of enhanced green fluorescent protein (EGFP)-expressing endometrium in mice. In parallel, a peritonitis model was established via intraperitoneal injection of thioglycolate medium (TM). Finally, endometriosis was induced in the inflamed peritoneal cavity and lesion establishment as well as morphological and histological characteristics were analysed. RESULTS Induction of endometriosis in an inflamed peritoneal cavity resulted in fewer lesions and significantly lower sum of lesion surface area per mouse in the TM-treated group. Additionally, a higher amount of non-attached debris could be detected in the peritoneal cavity of TM-treated mice. CONCLUSIONS An intraperitoneal inflammation decreases endometriosis establishment in this mouse model. Thus, a pre-existing peritoneal inflammation might not be a factor favouring the development of endometriosis.
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Affiliation(s)
- N M Nowak
- GDD-TRG Women's Healthcare, Bayer Schering Pharma AG, Berlin, Germany
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Becker CM, D'Amato RJ. Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res 2007; 74:121-30. [PMID: 17574280 DOI: 10.1016/j.mvr.2007.04.008] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2007] [Revised: 04/25/2007] [Accepted: 04/26/2007] [Indexed: 11/26/2022]
Abstract
Endometriosis, the presence of endometrium-like tissue outside of the uterine cavity, is a common disease among women of reproductive age. Typical symptoms include abdominal pain and painful menstruation. In addition, endometriosis is associated with reduced fertility. Current treatment modalities, the surgical removal of endometriotic lesions and the hormonal suppression of estrogen are associated with significant morbidity, side-effects and recurrence rates. Despite uncertainties about the pathophysiology of the disease it has recently become apparent that angiogenesis plays a pivotal role in endometriosis. This review focuses on a multitude of factors involved in the angiogenic phenotype of endometriosis demonstrating that many biological systems such as the immune system and steroid hormones are closely connected to angiogenic pathways in this disease. In addition, experimental and clinical data are discussed that concentrate on the inhibition of angiogenesis as a novel therapeutic approach for endometriosis.
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Affiliation(s)
- Christian M Becker
- Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, UK
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Hever A, Roth RB, Hevezi P, Marin ME, Acosta JA, Acosta H, Rojas J, Herrera R, Grigoriadis D, White E, Conlon PJ, Maki RA, Zlotnik A. Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc Natl Acad Sci U S A 2007; 104:12451-6. [PMID: 17640886 PMCID: PMC1941489 DOI: 10.1073/pnas.0703451104] [Citation(s) in RCA: 165] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Endometriosis affects 10-20% of women of reproductive age and is associated with pelvic pain and infertility, and its pathogenesis is not well understood. We used genomewide transcriptional profiling to characterize endometriosis and found that it exhibits a gene expression signature consistent with an underlying autoimmune mechanism. Endometriosis lesions are characterized by the presence of abundant plasma cells, many of which produce IgM, and macrophages that produce BLyS/BAFF/TNFSF13B, a member of the TNF superfamily implicated in other autoimmune diseases. B lymphocyte stimulator (BLyS) protein was found elevated in the serum of endometriosis patients. These observations suggest a model for the pathology of endometriosis where BLyS-responsive plasma cells interact with retrograde menstrual tissues to give rise to endometriosis lesions.
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Affiliation(s)
- Aniko Hever
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Richard B. Roth
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Peter Hevezi
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Maria E. Marin
- School of Medicine, University of Baja California, 21100 Mexicali, Baja California, Mexico
| | - Jose A. Acosta
- School of Medicine, University of Baja California, 21100 Mexicali, Baja California, Mexico
| | - Hector Acosta
- School of Medicine, University of Baja California, 21100 Mexicali, Baja California, Mexico
| | - Jose Rojas
- School of Medicine, University of Baja California, 21100 Mexicali, Baja California, Mexico
| | - Rosa Herrera
- School of Medicine, University of Baja California, 21100 Mexicali, Baja California, Mexico
| | - Dimitri Grigoriadis
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Evan White
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Paul J. Conlon
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Richard A. Maki
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
| | - Albert Zlotnik
- *Neurocrine Biosciences, Department of Discovery Biology, San Diego, CA 92130; and
- To whom correspondence should be addressed. E-mail:
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