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Salamonsen LA. Menstrual Fluid Factors Mediate Endometrial Repair. FRONTIERS IN REPRODUCTIVE HEALTH 2021; 3:779979. [PMID: 36304016 PMCID: PMC9580638 DOI: 10.3389/frph.2021.779979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Menstruation is a process whereby the outer functionalis layer of the endometrium is shed each month in response to falling progesterone and estrogen levels in a non-conception cycle. Simultaneously with the tissue breakdown, the surface is re-epithelialized, protecting the wound from infection. Once menstruation is complete and estrogen levels start to rise, regeneration progresses throughout the proliferative phase of the cycle, to fully restore endometrial thickness. Endometrial repair is unique compared to tissue repair elsewhere in the adult, in that it is rapid, scar-free and occurs around 400 times during each modern woman's reproductive life. The shedding tissue and that undergoing repair is bathed in menstrual fluid, which contains live cells, cellular debris, fragments of extracellular matrix, activated leukocytes and their products, soluble cellular components and extracellular vesicles. Proteomic and other analyses have revealed some detail of these components. Menstrual fluid, along with a number of individual proteins enhances epithelial cell migration to cover the wound. This is shown in endometrial epithelial and keratinocyte cell culture models, in an ex vivo decellularized skin model and in pig wounds in vivo. Thus, the microenvironment provided by menstrual fluid, is likely responsible for the unique rapid and scar-free repair of this remarkable tissue. Insight gained from analysis of this fluid is likely to be of value not only for treating endometrial bleeding problems but also in providing potential new therapies for poorly repairing wounds such as those seen in the aged and in diabetics.
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Barbe AM, Berbets AM, Davydenko IS, Koval HD, Yuzko VO, Yuzko OM. Expression and Significance of Matrix Metalloproteinase-2 and Matrix Metalloproteinas-9 in Endometriosis. J Med Life 2020; 13:314-320. [PMID: 33072202 PMCID: PMC7550149 DOI: 10.25122/jml-2020-0117] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Endometriosis is a chronic benign hormone-dependent condition when the endometrial tissue, identical with the endometrium by its morphological and functional properties, grows outside the borders of the uterine mucous membrane. Recent studies have pointed to the possible role of matrix metalloproteinases (MMPs) in the pathogenesis of endometriosis. We suggested a hypothesis that increased expression of MMPs activity in eutopic and ectopic endometrium of patients with endometriosis might correlate with the presence of endometriotic lesions. The aim of the study was to evaluate the level of MMP-2 and MMP-9 expression in the ectopic endometrium of women with visible endometriotic lesions and eutopic endometrium in patients with no signs of endometriosis. The study was conducted on 43 patients. They were divided into two groups. Group 1 included 31 patients with peritoneal/ovarian endometriosis who had undergone laparoscopy and hysteroscopy. Group 2 consisted of 12 patients with leiomyoma, endometrial polyps or relatively healthy patients who had undergone hysterectomy or polypectomy and endometrial curettage. This study showed statistically higher expression of MMP-2 (1.7783 ± 0.22 immunohistochemistry (IHC) optical density score compared to the control group – 1.41± 0.34, p = 0.0017) and MMP-9 (1.352 ± 0.067 versus 1.85 ± 0.26 in the control group, p = 0.001) in ectopic and eutopic endometrium samples from patients with endometriosis compared to samples taken from patients without endometriosis. A strong correlation between expression of the above-mentioned MMPs (r=0.74 for MMP-2 and r=0.88 for MMP-9) in ectopic and eutopic endometrium might be of promising diagnostic value.
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Affiliation(s)
| | | | | | - Halyna Danylivna Koval
- Department of Clinical Immunology, Allergology and Endocrinology, Bukovinian State Medical University, Chernivtsi, Ukraine
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Critchley HOD, Babayev E, Bulun SE, Clark S, Garcia-Grau I, Gregersen PK, Kilcoyne A, Kim JYJ, Lavender M, Marsh EE, Matteson KA, Maybin JA, Metz CN, Moreno I, Silk K, Sommer M, Simon C, Tariyal R, Taylor HS, Wagner GP, Griffith LG. Menstruation: science and society. Am J Obstet Gynecol 2020; 223:624-664. [PMID: 32707266 PMCID: PMC7661839 DOI: 10.1016/j.ajog.2020.06.004] [Citation(s) in RCA: 158] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/13/2020] [Accepted: 06/03/2020] [Indexed: 12/11/2022]
Abstract
Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation-a fast, scarless healing process in healthy individuals-will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, "Menstruation: Science and Society" with an aim to "identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field." Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration-and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids-to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent "menstrual equity" and "period poverty" movements spreading across high-income countries.
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Affiliation(s)
- Hilary O D Critchley
- Medical Research Council Centre for Reproductive Health, The University of Edinburgh, United Kingdom.
| | - Elnur Babayev
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Serdar E Bulun
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | | | - Iolanda Garcia-Grau
- Igenomix Foundation-Instituto de Investigación Sanitaria Hospital Clínico, INCLIVA, Valencia, Spain; Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, Spain
| | - Peter K Gregersen
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY
| | | | | | | | - Erica E Marsh
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI
| | - Kristen A Matteson
- Division of Research, Department of Obstetrics and Gynecology, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI
| | - Jacqueline A Maybin
- Medical Research Council Centre for Reproductive Health, The University of Edinburgh, United Kingdom
| | - Christine N Metz
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY
| | - Inmaculada Moreno
- Igenomix Foundation-Instituto de Investigación Sanitaria Hospital Clínico, INCLIVA, Valencia, Spain
| | - Kami Silk
- Department of Communication, University of Delaware, Newark, DE
| | - Marni Sommer
- Department of Sociomedical Sciences, Columbia University Mailman School of Public Health, New York, NY
| | - Carlos Simon
- Igenomix Foundation-Instituto de Investigación Sanitaria Hospital Clínico, INCLIVA, Valencia, Spain; Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, Spain; Beth Israel Deaconess Medical Center, Harvard University, Boston, MA; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX
| | | | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT
| | - Günter P Wagner
- Department of Ecology and Evolutionary Biology, Department of Obstetrics, Gynecology and Reproductive Sciences, Systems Biology Institute, Yale University, New Haven, CT; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Linda G Griffith
- Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, MA
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Mousazadeh S, Ghaheri A, Shahhoseini M, Aflatoonian R, Afsharian P. The Effect of Imbalanced Progesterone Receptor-A/-B Ratio on Gelatinase Expressions in Endometriosis. INTERNATIONAL JOURNAL OF FERTILITY & STERILITY 2019; 13:127-134. [PMID: 31037923 PMCID: PMC6500082 DOI: 10.22074/ijfs.2019.5604] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 10/29/2018] [Indexed: 12/25/2022]
Abstract
Background Gelatinases degrade extracellular matrix (ECM) components to allow for physiological remodeling and contribute to pathological tissue destruction in endometriosis. It is known that the function of gelatinases is resistant to suppression by progesterone in endometriosis. The ability of progesterone to impact gene expression depends on the progesterone receptor-A/-B(PR-A/PR-B) ratio. An imbalanced PR-A/PR-B ratio in endometriotic tissue may be the result of the differential expression of MMP-2 and MMP-9, which could be important in the etiology and pathogenesis of the disease. Hence, we decided to study the association of PR-A/PR-B ratio and gelatinases expression in endometriosis. Materials and Methods In this prospective case-control study, we enrolled 40 women, 20 in the case group who were diagnosed with stage III/IV endometriosis and 20 normal subjects without endometriosis (controls) who referred to Royan Institute, Tehran, Iran during 2013-2014. We obtained 60 tissue samples [ectopic (n=20), eutopic (n=20), and normal endometrium (n=20)]. RNA was extracted from the tissue samples in order to analyze PR-A, PR-B, MMP-2, and MMP-9 mRNA levels through real-time polymerase chain reaction (PCR). Results There was significantly lower expression of the PR-B isoform in ectopic tissues compared to the control (P=0.002) and eutopic endometrium (P=0.006) tissues. PR-A expression was higher, but not significantly so, in the same ectopic and eutopic endometrium tissues compared to the control tissues (P=0.643). There was significant overexpression of MMP-9 in ectopic samples compared to control (P=0.014) and eutopic endometrium (P=0.012) samples. The PR-A/PR-B ratio was not significantly higher in either eutopic or ectopic samples compared to the control samples (P=0.305). Conclusion Our findings support an altered PR-B expression in endometriosis, which may be associated with MMP-9 overexpression. This finding can be important for disease pathogenesis.
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Affiliation(s)
- Sepideh Mousazadeh
- Department of Genetics, School of Natural Sciences, University of Tabriz, Tabriz, Iran.,Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Azadeh Ghaheri
- Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Maryam Shahhoseini
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Parvaneh Afsharian
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. Electronic Address:
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Pro-endometriotic niche in endometriosis. Reprod Biomed Online 2019; 38:549-559. [DOI: 10.1016/j.rbmo.2018.12.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/31/2018] [Accepted: 12/11/2018] [Indexed: 12/11/2022]
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Christodoulidis G, Tsilioni I, Spyridakis ME, Kiropoulos T, Oikonomidi S, Koukoulis G, Tepetes K. Matrix metaloproteinase-2 and -9 serum levels as potential markers of intraperitoneal adhesions. J INVEST SURG 2013; 26:134-140. [PMID: 23514055 DOI: 10.3109/08941939.2012.730599] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To assess the value of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) as prognostic serum markers for intraperitoneal adhesions. BACKGROUND Postoperative adhesions are associated with serious complications responsible for increased patient's morbidity. METHODS Forty-eight rabbits were used and randomized into groups A, B, C, and D. Abdominal laparotomy and experimental adhesion formation model was carried out. In group A, 60 mL of N/S 0.9% were instilled intraperitoneally, in group B 60 mL of icodextrin 4% were instilled intraperitoneally, in group C 0.1 mL/kg of dimetindene maleate were administered intravenously, and in group D both agents were administered. Prior to euthanasia 0.5 mL of blood was obtained. The type, the surface area of adhesions, and serum concentration of MMPs were assessed. RESULTS The mean surface area and Zuhlke classification of adhesions of groups B, C, and D has been proved to be significantly lower compared to group A. Serum MMP-2 levels were significantly higher in groups B and D than in group A, while group D was higher when compared to group C. Serum MMP-9 levels were significantly higher in group D compared to groups A, B, and C. Serum MMP-9 was the most accurate test to differentiate between animals with and without adhesions with a sensitivity of 81.8% and a specificity of 100% at a cut-off point of 21.5 (AUC = 0.934). CONCLUSIONS The administration of icodextrin 4% and dimetindene maleate seems to prevent postoperative adhesion formation. Serum levels of MMP-2 and MMP-9 may serve as prognostic markers to identify postoperative adhesions.
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Henriet P, Gaide Chevronnay HP, Marbaix E. The endocrine and paracrine control of menstruation. Mol Cell Endocrinol 2012; 358:197-207. [PMID: 21820486 DOI: 10.1016/j.mce.2011.07.042] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Revised: 07/19/2011] [Accepted: 07/20/2011] [Indexed: 01/29/2023]
Abstract
During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis).
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Affiliation(s)
- Patrick Henriet
- Cell Biology Unit, de Duve Institute, Université catholique de Louvain, avenue Hippocrate, 75, B-1200 Bruxelles, Belgium.
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Guo Y, Wu XQ, Zhang C, Liao ZX, Wu Y, Wang H. Protective effect of sodium ferulate on acetaldehyde-treated precision-cut rat liver slices. J Med Food 2012; 15:557-62. [PMID: 22404575 DOI: 10.1089/jmf.2011.1915] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis, and inhibition of HSC activation may prevent liver fibrosis. Acetaldehyde, the most deleterious metabolite of alcohol, triggers HSC activation in alcoholic liver injury. In the present study, we investigated the protective effect of sodium ferulate (SF), a sodium salt of ferulic acid that is rich in fruits and vegetables, on acetaldehyde-stimulated HSC activation using precision-cut liver slices (PCLSs). Rat PCLSs were co-incubated with 350 μM acetaldehyde and different concentrations of SF. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde content in tissue. α-Smooth muscle actin, transforming growth factor-β(1), and hydroxyproline were determined to assess the activation of HSCs. In addition, matrix metalloproteinase (MMP)-1 and the tissue inhibitor of metalloproteinase (TIMP-1) were determined to evaluate collagen degradation. SF prominently prevented the enzyme leakage in acetaldehyde-treated slices and also inhibited HSC activation and collagen production stimulated by acetaldehyde. In addition, SF increased MMP-1 expression and decreased TIMP-1 expression. These results showed that SF protected PCLSs from acetaldehyde-stimulated HSC activation and liver injury, which may be associated with the attenuation of oxidative injury and acceleration of collagen degradation.
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Affiliation(s)
- Yu Guo
- Department of Pharmacology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, China
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Guo Y, Wu XQ, Zhang C, Liao ZX, Wu Y, Xia ZY, Wang H. Effect of indole-3-carbinol on ethanol-induced liver injury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cut rat liver slices. Clin Exp Pharmacol Physiol 2011; 37:1107-13. [PMID: 20880187 DOI: 10.1111/j.1440-1681.2010.05450.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
1. Indole-3-carbinol (I3C), a major indole compound found in high levels in cruciferous vegetables, shows a broad spectrum of biological activities. However, few studies have reported the effect of I3C on alcoholic liver injury. In the present study, we investigated the protective effect of I3C on acute ethanol-induced hepatotoxicity and acetaldehyde-stimulated hepatic stellate cells (HSC) activation using precision-cut liver slices (PCLS). 2. Rat PCLS were incubated with 50 mmol/L ethanol or 350 μmol/L acetaldehyde, and different concentrations (100-400 μmol/L) of I3C were added into the culture system of these two liver injury models, respectively. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde (MDA) content in tissue. Activities of alcoholic enzymes were also determined. α-Smooth muscle actin (α-SMA), transforming growth factor (TGF-β(1) ) and hydroxyproline (HYP) were used as indices to evaluate the activation of HSC. In addition, matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase (TIMP-1) were observed to estimate collagen degradation. 3. I3C significantly reduced the enzyme leakage in ethanol-treated slices. In I3C groups, cytochrome P450 (CYP) 2E1 activities were inhibited by 40.9-51.8%, whereas alcohol dehydrogenase (ADH) activity was enhanced 1.6-fold compared with the ethanol-treated group. I3C also showed an inhibitory effect against HSC activation and collagen production stimulated by acetaldehyde. After being incubated with I3C (400 μmol/L), the expression of MMP-1 was markedly enhanced, whereas TIMP-1 was decreased. 4. These results showed that I3C protected PCLS against alcoholic liver injury, which might be associated with the regulation of ethanol metabolic enzymes, attenuation of oxidative injury and acceleration of collagen degradation.
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Affiliation(s)
- Yu Guo
- Department of Pharmacology, School of Basic Medical Science, Wuhan University, Wuhan, China
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Juhasz-Böss I, Hofele A, Lattrich C, Buchholz S, Ortmann O, Malik E. Matrix metalloproteinase messenger RNA expression in human endometriosis grafts cultured on a chicken chorioallantoic membrane. Fertil Steril 2010; 94:40-5. [DOI: 10.1016/j.fertnstert.2009.02.052] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Revised: 02/14/2009] [Accepted: 02/18/2009] [Indexed: 01/09/2023]
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Zhang H, Li M, Wang F, Liu S, Li J, Wen Z, Zhao X. Endometriotic epithelial cells induce MMPs expression in endometrial stromal cells via an NFkappaB-dependent pathway. Gynecol Endocrinol 2010; 26:456-67. [PMID: 19903119 DOI: 10.3109/09513590903366988] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To explore the stroma-epithelium interactions in endometriosis and to identify the possible signalling pathways involved in this cross-talk. DESIGN Laboratory study via primary cultured endometrial stromal and epithelial cells. SETTING University Hospital. PATIENTS Fifteen patients with endometriosis confirmed by histopathology were recruited in the study, and 12 women free of endometriosis were used as control group. INTERVENTION(S) Specific NFkappaB inhibitor 1-Pyrrolidinecarbodithioic acid ammonium salt (PDTC) was used in cell cultures. MAIN OUTCOME MEASURE(S) The expression and secretion of MMP-2, MMP-9, TIMP-1, TIMP-2 and the DNA-binding activity of NFkappaB in normal endometrial stromal cells or in co-cultures with normal or endometriotic epithelial cells from patients with endometriosis. RESULT(S) Endometrial epithelial cells induced MMP-9 and MMP-2 expression in normal stromal cells in vitro. In co-cultures with endometriotic epithelial cells, normal endometrial stromal cells expressed and secreted higher MMP-2 (p < 0.05) and MMP-9 (p < 0.05). Specific inhibition of NFkappaB pathway in stromal cells abolished this induction effect by epithelial cells. CONCLUSION(S) Endometriotic epithelial cells induce MMPs expression and secretion in normal endometrial stromal cells via an NFkappaB-dependent pathway in vitro. This cross-talk between epithelial cells and stromal cells may facilitate the implantation and extension of the ectopic foci and favour the development of the disease.
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Affiliation(s)
- Hui Zhang
- Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Shandong, People's Republic of China
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Pitsos M, Kanakas N. The role of matrix metalloproteinases in the pathogenesis of endometriosis. Reprod Sci 2009; 16:717-26. [PMID: 19351962 DOI: 10.1177/1933719109333661] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Endometriosis is a benign, estrogen-dependent disease with an obscure etiology. Even the most widely accepted theory of retrograde menstruation cannot satisfactorily explain the development of endometriosis due to the many gaps in our understanding of its pathophysiology. Although most women have retrograde menstruation; only some develop endometriosis. Apart from simply being present in the peritoneal cavity, the endometrial cells are able to attach to, invade the peritoneum, and proliferate to create and maintain an endometriotic lesion. Matrix metalloproteinases (MMPs) are a group of enzymes that degrade the extracellular matrix. These enzymes participate in the histologic changes of the endometrium during the menstrual cycle with generally a higher expression during the menstrual and proliferative phase of the endometrium and a decreased expression during the secretory phase. As noted above, not only do these enzymes play a crucial factor in the cycling endometrium but the degradation of extracellular matrix is essential for the endometrial cells to invade the peritoneum and to develop an endometriotic lesion as well. The aim of this review is to describe the altered expression of MMPs in the development of endometriosis.
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Collette T, Maheux R, Mailloux J, Akoum A. Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis. Hum Reprod 2006; 21:3059-67. [PMID: 16880228 DOI: 10.1093/humrep/del297] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Endometriosis is a disease where endometrial tissue implants in ectopic locations. Remodelling of the extracellular matrix (ECM) is a prerequisite for the implantation of this tissue to be possible. METHODS In this study, we detected immunoreactive matrix metalloproteinase-9 (MMP-9) throughout endometrial tissue and identified von Willebrand factor (vWF)-positive endothelial cells, CD45-positive leukocytes, CD3-positive T lymphocytes and CD68-positive macrophages as cells expressing MMP-9 in the stroma. RESULTS We found an increased expression of MMP-9 in the uterine endometrial tissue of women with endometriosis, as assessed by zymography and enzyme-linked immunosorbent assay (ELISA) (P < 0.05). However, RT-PCR did not show a statistically significant increase in MMP-9 mRNA expression in these tissues (P = 0.14). There was no significant difference between women with and without endometriosis in the expression of tissue inhibitor of MMPs (TIMP)-1, a known natural inhibitor of the pro- and active forms of MMP-9, whether tested by ELISA or by RT-PCR (P = 0.46 and 0.37, respectively). Interestingly, the ratio of MMP-9/TIMP-1 expression was significantly higher in women with endometriosis than in normal women both at the protein and the mRNA levels (P < 0.05). CONCLUSION These findings make plausible the involvement of MMP-9/TIMP-1 imbalance in the invasiveness of the endometrial tissue of patients with endometriosis and the ectopic development of the disease.
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Affiliation(s)
- T Collette
- Centre de Recherche, Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Canada
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Abdallah MA, Kang S, Nakajima ST, Gercel-Taylor C. Matrix metalloproteinase-9 activity in the plasma of patients after surgical resection of endometriomas. Fertil Steril 2006; 85:1847-8. [PMID: 16674956 DOI: 10.1016/j.fertnstert.2005.11.043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2005] [Revised: 11/08/2005] [Accepted: 11/08/2005] [Indexed: 10/24/2022]
Abstract
Matrix metalloproteinases (MMPs) may have a role in the pathogenesis of endometrioma. The level of MMP was lower compared to the level taken after resection of endometrioma.
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Affiliation(s)
- Maher Ali Abdallah
- Department of Obstetrics, Gynecology and Women's Health, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
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Malik S, Day K, Perrault I, Charnock-Jones DS, Smith SK. Menstrual effluent in endometriosis shows no difference in volume, VEGF-A, MMP2 and MMP9 or sFLT. Reprod Biomed Online 2006; 12:174-81. [PMID: 16478582 DOI: 10.1016/s1472-6483(10)60858-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Since retrograde menstruation is considered a key event in the aetiology of endometriosis, this study sought to determine whether the menstrual effluent of women with this condition is different from that of those with a normal pelvis. As the amount of blood lost during menstruation is thought to be higher in this group, measured objective menstrual blood loss (MBL) was measured. In addition, factors enhancing both ectopic implantation of endometrium and its subsequent growth (by establishing a neo-vasculature) were chosen for study. Our hypothesis was that they are increased in the menstrual effluent of women with endometriosis. The study showed that at the time of menstruation, there is no difference in MBL or in the volume of menstrual effluent between women with endometriosis and those with a normal pelvis at laparoscopy. In addition, vascular endothelial growth factor-A (VEGF-A) message and protein, soluble truncated receptor sVEGF-R1 (sFLT), matrix metalloproteinase (MMP) 2 and MMP9 activities were also shown to be similar between the two groups. It is concluded that the enhanced expression of VEGF-A and MMP in the peritoneal fluid and ectopic lesions of endometriotic patients may be a secondary event, resulting from an innate difference in peritoneal and systemic factors rather than in the endometrium, causing an abnormal peritoneal response to menstrual debris and facilitating its ectopic implantation.
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Affiliation(s)
- Shazia Malik
- Reproductive Medicine Unit, The Elizabeth Garrett Anderson and Obstetric Hospital, Huntley Street, London, WCIE 6DH, UK.
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Demir AY, Groothuis PG, Dunselman GAJ, Schurgers L, Evers JLH, de Goeij AFPM. Molecular characterization of soluble factors from human menstrual effluent that induce epithelial to mesenchymal transitions in mesothelial cells. Cell Tissue Res 2005; 322:299-311. [PMID: 16082522 DOI: 10.1007/s00441-005-0002-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2004] [Accepted: 05/02/2005] [Indexed: 10/25/2022]
Abstract
We have studied menstrual effluent in order to identify soluble menstrual factors that induce epithelial to mesenchymal transitions (EMT) in mesothelial cells. A variety of molecules, such as nitric oxide and its reaction products, proteases (i.e. matrix metalloproteinases, plasmin) and proteins and/or peptides (i.e. growth factors: b-fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, transforming growth factor-beta; cytokines: interleukin 1 beta, tumour necrosis factor-alpha [TNF-alpha]) may be involved in this process. We have demonstrated that TNF-alpha is involved in EMT, whereas the other molecules are not. Biochemical analysis has shown that the inducing menstrual factors are heat-labile molecules, are uncharged at neutral pH, have a molecular weight between 50-70 kDa (or are bound in complexes of that size) and are eluted in the albumin fraction during gel filtration chromatography. Further analysis of this fraction by using proteomics and mass spectrometry has led to the identification of alpha-enolase and haemoglobin whose inhibition partially prevents EMT. When antibodies against TNF-alpha, alpha-enolase and haemoglobin are combined, EMT is almost completely inhibited. Thus, the candidates for soluble menstrual factors that induce mesothelial EMT are TNF-alpha, alpha-enolase and haemoglobin.
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Affiliation(s)
- Ayşe Y Demir
- Research Institute Growth and Development (GROW), Academic Hospital and Maastricht University, Maastricht, The Netherlands.
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Groothuis PG, Nap AW, Winterhager E, Grümmer R. Vascular development in endometriosis. Angiogenesis 2005; 8:147-56. [PMID: 16211360 DOI: 10.1007/s10456-005-9005-x] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2004] [Accepted: 01/26/2005] [Indexed: 01/17/2023]
Abstract
Endometriosis, defined as the presence of endometrial tissue outside the uterus, is an estrogen-dependent disease which causes pelvic pain and subfertility in women of reproductive age. The condition has a dramatic impact on the professional, social and marital life of sufferers. Direct and indirect evidence suggests that angiogenesis is required for the development and persistence of endometriosis. In this review the state-of-the-art with regard to our understanding of the role of angiogenesis in the ectopic implantation and survival of menstrual endometrial tissue will be discussed.
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Affiliation(s)
- P G Groothuis
- Research Institute GROW, Department of Obstetrics and Gynaecology, University Hospital Maastricht, Maastricht, The Netherlands.
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Abstract
AIM: The aim of this study was to observe the effect of a Chinese medicine compound Changtong oral liquid (CT) on tissue plasminogen activity (t-PA), plasminogen activator inhibitor (PAI), TGF-β1 and hydroxyproline (OHP).
METHODS: Two sets of animal experiments were performed in the present study. Forty New Zealand rabbits and 48 Sprague-Dawley (SD) rats were assigned randomly to one of the five groups: sham adhesion, adhesion with saline, adhesion with low dosage of the CT, adhesion with middle dosage of the CT and adhesion with high dosage of the CT. t-PA and PAI activity in plasma, OHP and TGF-β1 expression in adhesion were investigated. Analysis of variance was used to test differences among groups.
RESULTS: CT treatment increased plasma t-PA activity in rabbits but decreased TGF-β1 activity in rats. The data were expressed from low to high dose respectively as follows: t-PA, 46.1±8.6 μkat/L, 59.6±10.1 μkat/L, 64.0±11.5 μkat/L; TGF-β1 28±7.23%, 31±3.05%, 30±4.04%. There were significant differences compared with saline-treated animals (t-PA 26.4±5.1 μkat/L, TGF-β1 54±5.51%). OHP content in cecum of rabbits from middle and high but not low dose of CT lowered significantly as compared with saline-treated rabbits, 0.3641±0.1373, 0.3348±0.0321, 0.2757±0.0497 mg/g vs 0.4183±0.0883 mg/g of protein, P>0.05, P<0.05, P<0.05 respectively. The rabbit plasma PAI activity and OHP content in abdominal wall had no difference in all groups.
CONCLUSION: CT treatment significantly enhanced t-PA activity in rabbits, but decreased TGF-β1 content in rats, OHP content in cecum of rabbits, and failed to affect the activity of PAI and OHP content in abdominal wall in rabbits, compared with saline group. The result suggests that CT could effectively prevent adhesions without interfering wound healing.
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Affiliation(s)
- Xi-Xiao Yang
- Department of Pharmacy, Nanfang Hospital, The First Military Medical University, Guangzhou 510515, Guangdong Province, China.
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Shan K, Ying W, Jian-Hui Z, Wei G, Na W, Yan L. The function of the SNP in the MMP1 and MMP3 promoter in susceptibility to endometriosis in China. ACTA ACUST UNITED AC 2005; 11:423-7. [PMID: 15879464 DOI: 10.1093/molehr/gah177] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Matrix metalloproteinases (MMPs) may contribute to the development of endometriosis. Genetic variations in several MMP promoters may influence the transcription and expression of MMPs. The purpose of the present study was to assess how gene polymorphisms in the MMP1 and MMP3 promoters affect the risk of development of endometriosis. We genotyped 100 women with endometriosis and 150 control subjects in North China. There was a significant difference in frequency of the MMP1 genotype between cases and controls (P=0.03). The 2G homozygote in endometriosis and controls was significantly different (P=0.02). The frequency of the 2G allele among affected women (79%) was significantly higher than among the healthy controls (66.9%; P=0.003). However, the overall genotype and allelotype distribution of the MMP3 single nucleotide polymorphism (SNP) in patients was not different from that of controls (P> or =0.05). MMP1 and MMP3 polymorphisms were in linkage disequilibrium in cases and controls (D'=0.47; P=0.00). The haplotype frequency distribution derived from these two polymorphisms was significantly different between cases and controls (P=0.00). The haplotype analysis suggested an implication of both MMP1 and MMP3 polymorphisms in the susceptibility to endometriosis. We conclude that the MMP1 promoter SNP and MMP 2G/6A haplotype may modify susceptibility to endometriosis, but that the MMP3 promoter SNP is unlikely to be associated with endometriosis in the population of North China.
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Affiliation(s)
- Kang Shan
- Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital and Department of Molecular Biology, Hebei Cancer Institute, Shijiazhuang, China
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20
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Chegini N, Rhoton-Vlasak A, Williams RS. Expression of matrix metalloproteinase-26 and tissue inhibitor of matrix metalloproteinase-3 and -4 in endometrium throughout the normal menstrual cycle and alteration in users of levonorgestrel implants who experience irregular uterine bleeding. Fertil Steril 2003; 80:564-70. [PMID: 12969699 DOI: 10.1016/s0015-0282(03)00797-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To determine the expression of matrix metalloproteinase (MMP-26) and tissue inhibitor of MMP (TIMP) in the endometrium of women with normal menstrual cycles compared with users of levonorgestrel implants. DESIGN Prospective observational study. SETTING Academic research center. PATIENT(S) Fifty patients with normal menstrual cycles who requested permanent surgical sterilization (tubal ligation) and 35 users of levonorgestrel implants. INTERVENTION(S) Endometrial biopsy. MAIN OUTCOME MEASURE(S) Expression of MMP-26, TIMP-3, and TIMP-4 by immunohistochemistry and semiquantitative analysis of staining intensity by using the H score. RESULT(S) Endometrium from women with a normal menstrual cycle and users of levonorgestrel implants expresses MMP-26, TIMP-3, and TIMP-4. These substances are present in various types of endometrial cells; expression is strongest in surface and glandular epithelial cells, followed by vascular endothelial and endometrial stromal cells. Inflammatory and immune-related cells also stained strongly for MMP-26 and TIMPs. Semiquantitative analysis of the staining intensity of endometrial epithelial and stromal cells indicated that expression of MMP-26, TIMP-3, and TIMP-4 peaks during the early to mid-luteal phase. Expression of MMP-26 is elevated in users of levonorgestrel implants who experienced irregular uterine bleeding. CONCLUSION(S) Endometrial expression of MMP-26 and TIMP-4 is present throughout the menstrual cycle and is elevated during the early to mid-luteal phase in normally cycling women. Further elevations in MMP-26 are seen in users of levonorgestrel implants who experience irregular uterine bleeding. These substances thus seem to play a role in hormonal regulation and endometrial tissue remodeling.
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Affiliation(s)
- Nasser Chegini
- Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida 32610, USA.
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21
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Curry TE, Osteen KG. The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 2003; 24:428-65. [PMID: 12920150 DOI: 10.1210/er.2002-0005] [Citation(s) in RCA: 432] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The ovary and uterus undergo extensive tissue remodeling throughout each reproductive cycle. This remodeling of the extracellular environment is dependent upon the cyclic hormonal changes associated with each estrous or menstrual cycle. In the ovary, tissue remodeling is requisite for growth and expansion of the follicle, breakdown of the follicular wall during the ovulatory process, transformation of the postovulatory follicle into the corpus luteum, as well as the structural dissolution of the corpus luteum during luteal regression. In the uterus, there is extraordinary turnover of the endometrial connective tissue matrix during each menstrual cycle. This turnover encompasses the complete breakdown and loss of this layer, followed by its subsequent regrowth. With implantation, extensive remodeling of the uterus occurs to support placentation. These dynamic changes in the ovarian and uterine extracellular architecture are regulated, in part, by the matrix metalloproteinase (MMP) system. The MMP system acts to control connective tissue remodeling processes throughout the body and is comprised of both a proteolytic component, the MMPs, and a regulatory component, the associated tissue inhibitors of metalloproteinases. The current review will highlight the key features of the MMPs and tissue inhibitors of metalloproteinases, focus on the changes and regulation of the MMP system that take place throughout the estrous and menstrual cycles, and address the impact of the dynamic tissue remodeling processes on ovarian and uterine physiology.
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Affiliation(s)
- Thomas E Curry
- Department of Obstetrics and Gynecology (T.E.C.), University of Kentucky, Lexington, Kentucky 40536, USA
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Cheong YC, Shelton JB, Laird SM, Li TC, Ledger WL, Cooke ID. Peritoneal fluid concentrations of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and transforming growth factor-beta in women with pelvic adhesions. Fertil Steril 2003; 79:1168-75. [PMID: 12738513 DOI: 10.1016/s0015-0282(03)00079-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE To establish whether the concentration of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-beta (TGF-beta) is influenced by the presence or absence of adhesions, and whether the concentration of these mediators vary throughout the menstrual cycle. DESIGN Prospective case-control study. SETTING Women undergoing laparoscopy in a university hospital in the United Kingdom. PATIENT(S) Women undergoing laparoscopy for benign gynecological conditions. INTERVENTION(S) Samples of peritoneal fluid were collected at diagnostic laparoscopy in one group, and at laparoscopy and serially during the first 48 hours after laparoscopic adhesiolysis in a second group. We correlated the concentrations of mediators in serially sampled peritoneal fluid during the 48 hours following laparoscopic adhesiolysis to the adhesion formation and reformation found during second-look laparoscopy. MAIN OUTCOME MEASURE(S) The concentrations of MMP-9, TIMP-1, and TGF-beta in peritoneal fluid. RESULT(S) MMP-9 concentration was lower in the follicular phase than the luteal phase of the menstrual cycle. MMP-9 concentration was significantly lower in women with pelvic adhesions than in women with a normal pelvis. The MMP-9/TIMP-1 ratio is significantly higher in women with significant adhesions at second-look laparoscopy compared to women with minimal or no adhesions. CONCLUSION(S) The components of extracellular matrix remodeling may play an important part in the adhesion formation/reformation process.
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Affiliation(s)
- Ying C Cheong
- Department of Obstetrics and Gynaecology, St. Mary's Hospital, Milton Road, Portsmouth, Hampshire, United Kingdom.
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Wolber EM, Kressin P, Meyhöfer-Malik A, Diedrich K, Malik E. Differential induction of matrix metalloproteinase 1 and 2 in ectopic endometrium. Reprod Biomed Online 2003; 6:238-43. [PMID: 12676008 DOI: 10.1016/s1472-6483(10)61716-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
According to the transplantation theory, endometriosis develops from endometrial fragments that are retrogradely menstruated into the peritoneal cavity. In order to develop into endometriotic lesions, they have to connect to the vascular system by angiogenesis, probably involving matrix metalloproteinases (MMP) as key enzymes in extracellular matrix remodelling. A model of endometriosis using the chorioallantoic membrane (CAM) of chick embryos was established. Eutopic endometrium from healthy women was transferred to the CAM and cultivated ectopically for up to 3 days. Before transplantation and after 24, 48 and 72 h of culture on the CAM, total RNA was extracted and reverse transcribed. Human MMP-1 (interstitial collagenase) and MMP-2 (gelatinase A) mRNA expression was assessed by competitive PCR. Results were normalized to the content of human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA. In eutopic endometrium, 0.29 amol MMP-1 mRNA and 0.42 fmol MMP-2 mRNA per fmol GAPDH mRNA were found. Relative MMP-1 mRNA concentrations increased strongly after culture on the CAM, while MMP-2 mRNA levels were nearly unaltered. This differential regulation suggests different roles of these enzymes in the angiogenesis of ectopic endometrial fragments and during the development of endometriosis.
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Affiliation(s)
- Eva-Maria Wolber
- Beth Israel Deaconess Medical Center, Cancer Biology Program, Harvard Institutes of Medicine, Boston, MA, USA.
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24
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Abstract
Endometriosis is a common gynecologic disorder characterized by the presence of endometrial tissue outside the uterine cavity. Various theories have been put forth to explain the mechanisms for the development of this disease. Although no single theory can explain all cases of endometriosis, the retrograde menstruation theory has gained the widest acceptance. This theory proposes that viable endometrial tissue is refluxed through the fallopian tubes during menstruation and implants on peritoneal surface or pelvic organs. Retrograde menstruation occurs in 76% to 90% of women. The much lower prevalence of endometriosis suggests that additional factors determine susceptibility to endometriosis. Once in the peritoneal cavity, the survival and implantation of endometrial cells seem to be mediated by abnormal MMP and TIMP expression, altered immune milieu, aberrant local aromatase activity, and genetic and environmental factors.
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Affiliation(s)
- Emre Seli
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8063, USA
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25
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Nap AW, Groothuis PG, Demir AY, Maas JWM, Dunselman GAJ, de Goeij AFPM, Evers JLH. Tissue integrity is essential for ectopic implantation of human endometrium in the chicken chorioallantoic membrane. Hum Reprod 2003; 18:30-4. [PMID: 12525437 DOI: 10.1093/humrep/deg033] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Not all women with patent tubes develop clinically manifest endometriosis. Quality and quantity of endometrium in retrograde menstruation may be the determining factor in the development of the disease. We hypothesize that retrograde shedding of endometrial fragments with preserved integrity facilitates implantation of endometrium in ectopic locations, resulting in endometriotic lesion development. We evaluate the impact of tissue integrity on the success of endometriosis-like lesion development in the chicken embryo chorioallantoic membrane (CAM) model. METHODS Menstrual and non-menstrual (cyclic) endometrium were collected by biopsy, and either minced or enzymatically dispersed. Spontaneously shed menstrual effluent was collected by a menstrual cup, and cells and tissue were isolated. We evaluated whether infiltration or lesion formation in the CAM occurred after transplantation of endometrium onto the CAM. RESULTS Transplantation of biopsied menstrual and cyclic endometrium fragments, and of endometrium fragments >1 mm(3) isolated from menstrual effluent, resulted in lesion formation. Transplantation of endometrial cells isolated from menstrual effluent did not lead to lesion formation. After transplantation of digested biopsied cyclic endometrium, infiltration in the CAM but no lesions were observed. CONCLUSION In the CAM assay, integrity of tissue architecture determines success of implantation of human endometrium in ectopic locations.
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Affiliation(s)
- Annemiek W Nap
- Departments of Obstetrics and Gynaecology, Academisch ziekenhuis Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
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26
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Chao-Hsi L, Ching-Chung L. Hymen re-formation after hymenotomy associated with pregnancy. Aust N Z J Obstet Gynaecol 2002; 42:559-60. [PMID: 12495114 DOI: 10.1111/j.0004-8666.2002.548_8.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Lee Chao-Hsi
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Toa Yuan, Taiwan, Republic of China
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27
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Sharpe-Timms KL, Cox KE. Paracrine regulation of matrix metalloproteinase expression in endometriosis. Ann N Y Acad Sci 2002; 955:147-56; discussion 157-8, 396-406. [PMID: 11949944 DOI: 10.1111/j.1749-6632.2002.tb02775.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Following retrograde menstruation, shed endometrial tissue fragments attach to and invade the peritoneal surface to form established endometriotic lesions. With disease progression, the biochemically active lesions undergo remodeling and become fibrotic. Matrix metalloproteinase enzymes (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a significant role in normal endometrial remodeling during menses. Anomalous expression of MMPs and TIMPs has been identified in endometriotic lesions as compared to their highly regulated expression in eutopic endometrium. The paracrine mechanisms regulating misexpression of MMPs and TIMPs by endometriotic lesions are, however, not well defined. Misexpression of the MMPs and TIMPs may be due to innate anomalies in the eutopic endometrium from women with endometriosis, in the resident immune cells and peritoneal cells that juxtapose the ectopic endometrium, and/or numerous substances present in peritoneal fluid of women with endometriosis. The majority of MMPs are under strict transcriptional regulation. Steroid hormones and cytokines appear to act on the MMP promoter, either independently or in consort, to provide both positive and negative regulation of these genes. Misregulated expression of MMPs and TIMPs is associated with a more aggressive phenotype and a cascade of events facilitating peritoneal extracellular matrix degradation and establishment or remodeling of endometriotic lesions. The mechanisms by which MMP and TIMP expression are misregulated warrant further investigation as such information may provide insight into novel therapeutic modalities for endometriosis.
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Affiliation(s)
- Kathy L Sharpe-Timms
- Department of Obstetrics and Gynecology, University of Missouri-Columbia, 65212, USA.
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28
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Henriet P, Cornet PB, Lemoine P, Galant C, Singer CF, Courtoy PJ, Eeckhout Y, Marbaix E. Circulating ovarian steroids and endometrial matrix metalloproteinases (MMPs). Ann N Y Acad Sci 2002; 955:119-38; discussion 157-8, 396-406. [PMID: 11949942 DOI: 10.1111/j.1749-6632.2002.tb02773.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Recent studies strongly suggest that matrix metalloproteinases (MMPs) play a key role in the initiation of menstrual bleeding in the human endometrium upon the fall of ovarian steroid serum concentrations by inducing the degradation of the extracellular matrix of this mucosa. MMPs are also involved in abnormal endometrial bleeding and have been identified in endometriotic foci. In all cases, they are associated with areas of extracellular matrix breakdown. This paper reviews the literature on the regulation by estradiol and progesterone of the expression and activation of MMPs, and of the expression of their tissue inhibitors (TIMPs), (i) in the endometrium in situ during normal cycle, (ii) during artificial cycles in spayed monkeys, and (iii) in cultures of endometrial explants or purified cells. Whereas progesterone consistently decreases the activity of endometrial MMPs, its effects vary in intensity, duration, and pattern between MMPs as well as among experimental systems. The contribution and limitations of the various investigations are therefore discussed. The focal heterogeneity points to additional local controls of the expression and activation of MMPs in human endometrium, acting beyond the general inhibitory role of progesterone, for example, by cytokines. Focal changes in type or abundance of sex steroid receptors also could be responsible for spatial variation in the expression of MMPs in the endometrium and endometriotic lesions.
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Affiliation(s)
- Patrick Henriet
- Cell Biology Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Brussels, Belgium
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29
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Sharpe-Timms KL. Using rats as a research model for the study of endometriosis. Ann N Y Acad Sci 2002; 955:318-27; discussion 340-2, 396-406. [PMID: 11949958 DOI: 10.1111/j.1749-6632.2002.tb02792.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Although there are disadvantages of extrapolating data across species, the rat model may be used to study events involved in the pathogenesis and pathophysiologies of endometriosis or novel therapeutic approaches for this disorder that are not accessible in humans. Rat endometriotic tissues are similar to human lesions in vivo, and rat endometriotic tissues and cells perform in a similar manner as human endometriotic tissues and cells in organ explant culture and isolated cell culture. The rat model permits studies of mechanisms and regulators in a controlled manner free from confounding influences such as individual patient variation and environmental influences. The primary method used for induction of endometriosis in rats has been autotransplantation of uterine squares (implants) into the peritoneal cavity. Beyond mere growth of endometrium in ectopic locations, rats with endometriosis display similar symptoms, including a reduction in fertility and fecundity, and the endometriotic implants react similarly to therapeutics as those of humans with the disease. Similar alterations in gene expression and protein production have been observed in endometriotic tissues from rats and humans that may, in part, be causative agents involved in the pathogenesis or pathophysiologies of endometriosis.
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Affiliation(s)
- Kathy L Sharpe-Timms
- Department of Obstetrics and Gynecology, University of Missouri-Columbia, 65212, USA.
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30
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Chegini N, Kotseos K, Bennett B, Diamond MP, Holmdahl L, Burns J. Matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP in peritoneal fluids and sera and correlation with peritoneal adhesions. Fertil Steril 2001; 76:1207-11. [PMID: 11730752 DOI: 10.1016/s0015-0282(01)02874-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To assess the presence of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP (TIMP-1) in peritoneal fluid and serum of subjects with and without adhesions. DESIGN Cross-sectional study. SETTING Academic research centers. PATIENT(S) Sixty-three patients who underwent abdominal/pelvic surgery. INTERVENTION(S) MMP-1, TIMP-1, and MMP-1-TIMP-1 complex content. MAIN OUTCOME MEASURE(S) ELISA. RESULT(S) Peritoneal fluids (PF) and sera of subjects with and without peritoneal adhesions contain MMP-1, TIMP-1, and MMP-1-TIMP-1 complex at varying levels with 10- to 100-fold higher TIMP-1 than MMP-1. Compared with serum, PF contains a lower level of MMP-1 in subjects with mild adhesions and without adhesions, higher TIMP-1 in subjects with extensive adhesions, and lower MMP-1-TIMP-1 complex in subjects with moderate adhesions. However, the serum and PF content of MMP-1, TIMP-1, and MMP-1-TIMP-1 complex was not statistically different among subjects with or without adhesions, with the exception of TIMP-1 in PF of subjects with extensive adhesions. MMP1-TIMP-1 ratio indicates that a major portion of MMP-1 is in complex with TIMP-1. There was no age- or gender-dependent difference in MMP-1 and TIMP-1 content in serum or PF. CONCLUSION(S) Despite differences in MMP-1 and TIMP-1 levels in serum and PF of subjects with extensive and moderate adhesions, there is no correlation between MMP-1 and TIMP-1, with the exception of higher TIMP-1 in PF of subjects with extensive adhesions.
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Affiliation(s)
- N Chegini
- Institute for Wound Research, Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida 32610-0294, USA.
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Chegini N, Kotseos K, Zhao Y, Ma C, McLean F, Diamond MP, Holmdahl L, Burns J. Expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP in serosal tissue of intraperitoneal organs and adhesions. Fertil Steril 2001; 76:1212-9. [PMID: 11730753 DOI: 10.1016/s0015-0282(01)02875-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE To compare expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP (TIMP-1) in serosal tissue of intraperitoneal organs and adhesions. DESIGN Prospective and cross-sectional study. SETTING Academic research centers. PATIENT(S) Patients undergoing abdominal or pelvic surgery. INTERVENTION(S) MMP-1 and TIMP-1 expression. MAIN OUTCOME MEASURE(S) Expression of messenger ribonucleic acid (mRNA) and protein was measured by using quantitative reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay. RESULT(S) Serosal tissue of intraperitoneal organs and adhesions express MMP-1 and TIMP-1 mRNA and protein at levels that are consistently varied with 10- to 10,000-fold and 2- to 10-fold higher TIMP, mRNA and protein, respectively. Parietal peritoneum, fallopian tubes and ovaries express higher MMP-1 mRNA levels compared with uterus and adhesions; the lowest expression is found in small and large bowels, subcutaneous tissue. and omentum. Expression of TIMP-1 mRNA was less variable; the highest level was found in the uterus and the lowest in subcutaneous tissue and small bowels. There was less variability in MMP-1 and TIMP-1 protein content than mRNA expression; ovaries and adhesions contained the highest MMP-1 and TIMP-1 levels, respectively, and peritoneum contained the lowest. The MMP-1 and TIMP-1 content and ratios further indicate limited MMP-1 proteolytic activity. Although tissues from premenopausal women express more MMP-1 and TIMP-1, expression did not differ by sex or age. CONCLUSION(S) Because MMP-1 and TIMP-1 expression varies consistently among the serosal tissues of peritoneal organs and adhesions, and because tissue injury alters their expression, site-specific variations in expression of these substances may predispose a particular organ to develop more adhesions.
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Affiliation(s)
- N Chegini
- Department of Obstetrics and Gynecology, Institute for Wound Research, University of Florida, Gainesville, Florida 32610-0294, USA.
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Cox KE, Piva M, Sharpe-Timms KL. Differential regulation of matrix metalloproteinase-3 gene expression in endometriotic lesions compared with endometrium. Biol Reprod 2001; 65:1297-303. [PMID: 11566756 DOI: 10.1095/biolreprod65.4.1297] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
In vivo levels of mRNA and the specificity of the extrauterine environment on matrix metalloproteinase (MMP)-3, MMP-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were evaluated in eutopic and ectopic endometrial tissue during the establishment of endometriosis in a rat model. Uteri and endometriotic implants were collected and frozen at 36 h, 2 wk, and 4 wk postsurgery to study in vivo mRNA levels. Intact uteri, uterine tissues implanted in the peritoneum or under the skin, and peritoneal adipose implants were collected at 2 wk, halved, and either frozen or cultured. Gene-specific reverse transcriptase-polymerase chain reaction was performed to detect and quantify MMP-2, MMP-3, and TIMP-1 mRNA levels. The peritoneal endometriotic implants progressed from avascularized implants, to vascularized red lesions, to well-established encapsulated cysts. In vivo, MMP-3 mRNA was detectable at all times in ectopic tissues but not in eutopic uterine tissues, whereas MMP-2 and TIMP-1 were ubiquitously expressed at all times in both tissues. In vitro, only MMP-3 mRNA levels were elevated in endometrial tissues collected from the intact uterine and from under the skin, at levels similar to in vivo endometriotic implant MMP-3. In conclusion, ectopic endometrial MMP-3 may participate in the process of invasion and tissue remodeling that is hypothesized to occur in the pathogenesis of endometriosis.
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Affiliation(s)
- K E Cox
- Department of Obstetrics and Gynecology, University of Missouri, Columbia, Missouri 65212, USA
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