{"paper_id":"731052c3-786a-4cde-adf6-2598fc3513d2","body_text":"Copyright@ Bhuchitra Singh | Biomed J Sci & Tech Res | BJSTR. MS.ID.003636.\n16044\nResearch Article\nISSN: 2574 -1241\nMatrix Metalloproteinases as Biomarkers of \nEndometriosis and the Role of Progesterone Receptors\nIsabelle Baptista1, Ping Xia2 and Bhuchitra Singh1*\n1Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology & Obstetrics, Johns Hopkins  \nUniversity, USA\n2Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, USA\n*Corresponding author: Bhuchitra Singh, Division of Reproductive Sciences & Women’s Health Research, Department of \nGynecology & Obstetrics, USA\n      DOI: 10.26717/BJSTR.2019.21.003636\nIntroduction\nEndometriosis is a gynecological disorder that affects around \n10% of reproductive aged women. It occurs when endometrial \ntissue grows outside the uterus, and as the tissue thickens, sheds, \nand bleeds along with all endometrial tissue during menstruation, \nit cannot exit the body due to its displacement. Some women \ndevelop cysts (endometriomas). These symptoms can cause pain \nespecially during menstruation and excessive bleeding. Women \nwith endometriosis sometimes develop problems with fertility. \nThere have been a multitude of research studies done in an effort to \nidentify the biomolecules associated with this disease. The plethora \nof studies conducted have led to the recognition of biomolecules \nwith abnormal expression levels in women with endometriosis, \nbut they have also led to the scattering of different biomolecules \namong papers and the indecisive correlations between specific \nbiomarkers and the disease [1]. There has been a failure to identify \nnovel biomarkers that can be utilized in confidently identifying \nendometriosis. This hinders the ability to make a diagnosis non-\ninvasively since the current methods to identify endometriosis \ninclude pelvic exams to locate cysts or scars. Recent research \nstudies suggest a correlation between abnormal expression of \nMatrix Metallo Proteinases (MMPs) and endometriosis. MMPs  \n \nare “enzymes that mediate normal tissue turnover including \nendometrial breakdown at menstruation” [1]. The aim of this review \nis to discuss the results of these studies regarding the association \nbetween MMP expression and the pathogenesis of endometriosis \nto provide a starting point for further research in developing a \nnon-invasive approach to recognizing endometriosis. Additionally, \nthere is currently no reliable cure for the disease since surgical \napproaches may still cause recurrence. With the advances of the \nmedical knowledge regarding the role of MMPs in endometriosis, \nit may become more feasible to start considering non-invasive \ntreatments such as pharmacological approaches that target the \nfactors mechanistically responsible for the unusual expression of \nthese proteins.\nMaterials and Methods\nA number of studies that investigated the role of MMPs in \nendometriosis were identified by searching for the keywords \n“MMPs” and “endometriosis” on pubmed.gov. This review addresses \nthe results of these studies in order to explore the role of MMPs \nin the development of endometriosis and the possibility of using \nMMPs as non-invasive diagnostic biomarkers of endometriosis. \nAdditional literature search was conducted via Pubmed utilizing the \nReceived: \n  September 20, 2019\nPublished: \n  September 30, 2019\nCitation: Isabelle B, Ping X, Bhuchitra S. \nMatrix Metalloproteinases as Biomarkers of \nEndometriosis and the Role of Progesterone \nReceptors. Biomed J Sci & Tech Res 21(4)-\n2019. BJSTR. MS.ID.003636.\nARTICLE INFO Abstract\nEndometriosis is a prevalent gynecological disorder that affects around 1 in 10 \nwomen during their reproductive years. Typically, it is diagnosed by means of a pelvic \nexam due to the lack of a non-invasive diagnostic method. However, in recent years, there \nhave been several research studies which explore matrix metalloproteinases as potential \nbiomarkers of endometriosis. The aim of this review is to identify studies which reported \nfindings regarding the correlation between MMP expression and the pathogenesis of \nendometriosis. Additionally, differential expression of two progesterone receptors may \nbe responsible for these abnormal expression of specific matrix metalloproteinases, \nthus leading to the discussion of drug therapy as a possible treatment method of \nendometriosis.\n\nCopyright@ Bhuchitra Singh | Biomed J Sci & Tech Res | BJSTR. MS.ID.003636.\nVolume 21- Issue 4\nDOI: 10.26717/BJSTR.2019.21.003636\n16045\nkeywords “progesterone receptors,” “SPRMs,” and “endometriosis” \nin order to find the association of progesterone receptor expression \nwith the disease’s pathogenesis, as well as research done on class \nof, specific progesterone receptor modulators, and its potential in \ntreating endometriosis. \nResults\nMMPs and Invasion of Endometrium Tissues \nA review by Balkowiec et al. stated that “aberrant regulation \nof matrix metalloproteinases may be the primary cause of \nendometrial lesion formation” since their abnormal expression \ncan lead to “adhesion formation, ovulatory disfunction and fertility \nimpairment” [2]. Normally, Reversion-inducing-cysteine-rich \nprotein with Kazal motifs (RECK) and Tissue Inhibitors of Metallo \nProteinases (TIMPs) are responsible for regulating MMP activity, \nforming inhibitory complexes with specific catalytic regions on \nMMPs to contribute in Extra Cellular Matrix (ECM) remodeling, \nregulating angiogenesis and inflammatory reactions [2]. Table 1 \nsummarizes all the studies.\nTable 1: Endometriosis and MMP Levels.\nStudy Year Ethnicity MMP\nExperimental \nGroup Sample \nSize\nControl \nGroup \nSample Size\nSample Type\nExperimental \nGroup MMP \nLevels\nControl Group \nMMP Levels\nSzamatowicz 2002 Caucasian MMP-9 22 21 Serum 6.2 +/- 1.8 ng/\nmL\n2.9 +/- 2.6 ng/\nmL\nHaiping 2015 Asian MMP-9 100 50 Serum 6.42 +/- 0.53 \nmM\n1.21 +/- 0.51 \nmM\nBostanci 2019 Caucasian MMP-9 60 31 Serum 15.0 pg/mL 12.0 pg/mL\nHuang 2004 Asian MMP-2 40 18 Serum 38.5 +/- 4.0 pg 19.8 +/- 4.7 pg\nMalvezzi 2013 Multi-Ethnic MMP-2 10 10 Serum\nMMP-2 levels \nhigher in stages \nIII/IV vs stages \nI/II\nN/A\nGilabert-\nEstellés 2007 Caucasian MMP-3 111 50 Tissue-\nExtracts\n.078 +/- .058 \n(MMP-3 mRNA)\n.018 +/- .006 \n(MMP-3 mRNA)\nOne study by Szamatowicz et al. set out to explore variations \nin MMP and TIMP levels in the peritoneal fluid of women \nwith endometriosis. Women with endometriosis associated \ninfertility were compared to a control group of infertile patients, \nand there was a concentration of 6.2 +/- 1.8 ng/ml in patients \nwith endometriosis as compared to 2.9 +/- 2.6 ng/ml in the \ncontrol group [3]. Furthermore, TIMP-1 levels in patients with \nendometriotic peritoneal fluids were found to have a statistically \nlower concentration than in the samples collected from the women \nin the control group. The lab concluded that “these results suggest \nthat a disturbed equilibrium exists between MMP-9 and TIMP-1 \nin peritoneal fluid of women with endometriosis” which may be a \ncontributing factor to the development of the disease [3]. \nLiu et al. also tested the levels of MMP-9 in serum and ascites \nsamples of 100 patients and compared these levels to those of a \ncontrol group. It was found that the endometriosis patients had \na significant elevation in MMP-9 levels in both of these samples. \nAdditionally, individuals with more advanced stages of the disease \nhad even higher levels of MMP-9. The lab concluded that expression \nlevels had a correlation with proliferation, endometrium site, and \nclinical stage of the disease. It is suggested that MMPs are “involved \nin the ectopic implantation and invasion of endometrium tissues, \nas it can facilitate the degradation of extracellular matrix and help \nthe penetration of basal membrane” [4]. MMP-9, the member of \nthe protein family studied by Liu et al. specifically degrades type \nIII, type IV, and type V collagen and elastin along with allowing for \nneo-angiogenesis and an increase in blood flow which contribute \nto the “invasive growth of ectopic endometrium” [4].  Considering \nthe finding that patients in the proliferative stage of the disease \nhad significantly higher levels of MMP-9 expression compared \nto those in the beginning stages of endometriosis, this further \nexemplifies the role of the enzyme in allowing for the progression \nof endometriosis. This increase in MMP-9 levels has been found \nto have a correlation with pelvic inflammation since “the elevated \nMMP-9 levels in the patients’ peritoneal fluids is mainly due to the \nhigh percentage of local macrophages” which are responsible for \nthe inflammation [4]. \nA similar study by Durmus et al. explored the levels of MMP-9 \nin women with endometriosis. Serum MMP-9 levels were measured \nin a group of 60 patients and were compared to a control group \nconsisting of 31 women. It was found that “MMP-9 levels were \nsignificantly higher in the study group compared to the controls,” \nand additionally, “MMP-9 might be a potential predictive marker \nfor advanced stages of the disease” [5]. The lab notes that MMP-\n9 levels are higher in eutopic/ectopic endometrial tissue and they \npromote the invasion of endometriotic lesions. It also appears that \nanother protein, NGAL, forms a complex with MMP-9 to inhibit \nantidegradation. The authors stated that the “MMP-9 cut-off level \nfor prediction of severe endometriosis is a novel finding obtained \nfrom this study with acceptable sensitivity and specificity” [5]. \nStudies have also been done regarding the expression of \nMMP-2. It has been found that women with endometriosis have \nhigher levels of MMP-2 [6]. This study by Huang et al. found that \n\nCopyright@ Bhuchitra Singh | Biomed J Sci & Tech Res | BJSTR. MS.ID.003636.\nVolume 21- Issue 4\nDOI: 10.26717/BJSTR.2019.21.003636\n16046\nin a group of 40 patients with endometriosis, peritoneal fluid and \nserum levels of MMP-2 were elevated and levels of progesterone \nwere lower as compared to a control group, and these “results \ndemonstrated a correlation between MMP-2 concentrations and \nsteroid hormones in sera and peritoneal fluids of the patients with \nendometriosis-associated infertility.” Moreover, it is suggested \nthat progesterone is responsible for the downregulation of MMP-\n2 “to inhibit the formation and development of endometriosis” \n[6]. Malvezzi et al. note in their study that “levels of MMP-2 were \nsignificantly higher in the serum of infertile women with advanced \nstages of endometriosis,” so this may indicate that “advanced pelvic \nendometriosis severity is related to higher serum MMP-2 levels” \n[7]. \nAnother lab which studied the MMP-3 expression levels in \nwomen with endometriosis compared 71 samples to 50 controls \nand found a positive correlation between elevated MMP-3 levels \nand endometriosis [8]. They conclude that “the development of \nendometriotic implants at ectopic sites may be facilitated” by this \nelevation in MMP-3, “promoting the progress of the endometriosis” \n[8]. Sayantan et al. studied the specific mechanism of MMP-3 in \nthe progression of endometriosis by focusing on MMP-3 and the \napoptotic pathway. They “speculate that increased MMP-3 activity \nmight be involved in the Fas mediated apoptosis” [9]. They utilized \nthe mouse model and found “endometriotic developments” with \n“increased MMP-3 expression” as well as “TUNEL positive cells” \nwhich “might have resulted from destruction of local immune cells” \n[9]. \nProgesterone Resistance and MMPs\nIn the review by Balkowiec et al. it was found that although \nMMP expression is controlled by various inhibitors such as RECK \nand TIMP , “steroid hormones were described as main agents, that \nhave an influence on MMPs activity, especially in endometriosis and \nendometrial tissue turnover” [11]. A recent study published in 2019 \nfound that an imbalance in the ratio of two different progesterone \nreceptors, PR-A and PR-B, may affect the gene expression of MMP-2 \nand MMP-9 which could lead to the development of endometriosis. \nNormally, these MMPs allow for degradation of ECM for menstrual \nendometrial remodeling, but with this overexpression in women \nwith endometriosis and a decreased amount of their inhibitors, \nTIMPs, “tumor invasion, fibrosis, and endometriosis” are likely \nto occur [10]. In women without endometriosis, progesterone is \nresponsible for preventing the breakdown of the endometrium by \ninhibiting MMPs, but in women with endometriosis, it has been \nfound that the endometrium is resistant to the normal effects \nof progesterone. These enzymes are resistant to suppression by \nprogesterone in endometriosis, and therefore, this study aimed \nto find an association between the progesterone receptor ratio \nand MMP expression. The study determined that women with \nendometriosis have a statistically significant lower expression \nof PR-B as well as an over-expression of MMP-9. The researchers \nfurther concluded that this altered PR-B expression may be \ncorrelated with this MMP-9 overexpression. \nMoreover, high levels of MMP-2 and MMP-9 along with \nlow levels of TMP-1 may be responsible for “low production of \nmature oocytes and subsequent decreased quality of embryos in \nendometriosis patients,” so these expression levels are potential \ncauses of the infertility often associated with the disease. PR-B \nhad a significantly decreased expression level in the experimental \ngroup, and when the ratio of the receptors is higher in PR-A, then \nthere is an increase in expression of pro-inflammatory genes. \nThus, the inflammatory symptoms of endometriosis may be due \nto this change in ratio of progesterone receptors. The lab’s data \nalso showed that the alteration in the PR-A/PR-B ratio may lead to \nMMP-9 overexpression. \nAdditionally, MMP-1, -2, -3, -11, -13, -15, and -23 have \nbeen experimentally found to be expressed at higher levels in \nwomen with endometriosis. A 2004 study by Nap et al. used a \nchicken Cholorio Allantoic Membrane (CAM) model with human \nendometrium transplanted onto the CAM to study the levels MMP \nactivity, and all of these MMPs had high expression profiles [11]. \nWhen these MMPs were inhibited, this “led to significant inhibition \nof endometriosis-like lesion formation in CAMs” which “indicates \nthat MMPs are involved in endometriosis-like lesion development \nand that the CAM model is a useful tool to evaluate the involvement \nof MMPs in the initial steps of lesion formation and endometrial \ntissue” [11]. Before this study, it was not reported that MMP-8, -13, \n-10, -15, -16, and -23 were correlated to endometriosis. Therefore, \nit is possible that many subclasses of MMPs are responsible for \nthe pathogenesis of this disease, however, the “results indicate \nfunctional involvement of MMP-1, -2, -3, -7 and -13 in this process,” \nbut other “MMPs or mechanisms cannot be excluded” [11]. \nSelective Progesterone Receptor Modulators (SPRMs): \nPotential Treatment Option\nSelective progesterone receptor modulators (SPRMs) are a \nclass of drugs which target progesterone receptors and can affect \ntheir expression. In 2018, a study concerning the effectiveness of \nvarious selective progesterone receptor modulators was published. \nAll of these drugs have controversial usage and recurrence of \nendometriosis after use of these drugs were not studied before \nthis experiment [12]. The study utilized mouse endometriosis \nmodels, and it was found that the drugs all “effectively limit the \nendometriotic lesion growth and development” by “inhibition \nof progesterone receptor and cell proliferation and activation of \napoptosis mechanisms” [12]. It was also concluded that the side \neffects of the Dienogest in particular were not significant, indicating \na wide safety margin. \nThere are additional types of SPRMs which have been reported \nto treat the symptoms associated with endometriosis. Mifepristone \nand asoprisnil “have been shown to significantly reduce menstrual \nblood loss in association with fibroids but do not increase \nproliferation,” and the administration of these drugs in patients \nwith endometriosis resulted in a reported decrease in symptoms. A \nclinical study involved the administration of Asoprisnil in patients \n\nCopyright@ Bhuchitra Singh | Biomed J Sci & Tech Res | BJSTR. MS.ID.003636.\nVolume 21- Issue 4\nDOI: 10.26717/BJSTR.2019.21.003636\n16047\nwith endometriosis resulted in a decrease in non-menstrual pelvic \npain as well as dysmenorrhea as compared to a group that received \na placebo [13]. With the administration of mifepristone, it was \nfound that patients also reported a decrease in their symptoms \nincluding pelvic pain and uterine cramping [13]. \nConclusion\nMMPs have been found to have an association with the \npathogenesis of endometriosis which shed light on narrowing \nthe scope of future endometriosis research. Studies can begin to \nfocus on specific the genes responsible for MMP expression and \nfactors that may affect their abnormal expression in order to better \nunderstand the mechanisms of the disease [14]. This will aid in \nthe development of a novel method for non-invasively identifying \nendometriosis as well as serve as a starting point for the potential \nuse of drugs like SPRMs as treatment methods [15]. \nSome limitations of the studies mention include the unknown \ninvolvement of other classes of MMPs as well as the lack of larger \nexperimental groups or the use of animal models when studying \nthe use of SPRMs which may not reflect certain side effects in \nhumans. Therefore, although these experimental findings provide \nfor a good starting point for further research concerning MMPs and \ntheir role in endometriosis as well as the potential use of SPRMs, \nmore research must be done in order to solidify the knowledge \nsurrounding MMPs and the pathogenesis of endometriosis as well \nas to determine the safety of using these drug treatments.\nReferences\n1. Osteen KG, Yeaman GR, Bruner-Tran KL (2003) Matrix metalloproteinases \nand endometriosis. Thieme 2(21): 155-164. \n2. Bałkowiec M, Maksym RB, Włodarski PK (2018) The bimodal role \nof matrix metalloproteinases and their inhibitors in etiology and \npathogenesis of endometriosis (Review). Mol Med Rep 18(3): 3123-\n3136. \n3. Szamatowicz J, Lauda ński P , Tomaszewska I (2002) Matrix \nmetalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1: \na possible role in the pathogenesis of endometriosis. Hum Reprod 17(2): \n284-288. \n4. Liu H, Wang J, Wang H, Tang N, Li Y, et al.  (2015) Correlation between \nMatrix Metalloproteinase-9 and Endometriosis. Int J Clin Exp Pathol \n8(10): 13399-13404. \n5. Durmus BA, Cengiz DS, Yilmaz H, Candar T , Gursoy AY, et al. (2019) \nThe levels of matrix metalloproteinase-9 and neutrophil gelatinase-\nassociated lipocalin in different stages of endometriosis. J Obstet \nGynaecol 39(7): 991-995. \n6. Huang HF, Hong LH, Tan Y, Sheng JZ (2004) Matrix metalloproteinase 2 is \nassociated with changes in steroid hormones in the sera and peritoneal \nfluid of patients with endometriosis. Fertil Steril 81(5): 1235-1239. \n7. Malvezzi H, Aguiar VG, Paz CC, Tanus-Santos JE, Penna IA, et al. (2012) \nIncreased Circulating MMP-2 Levels in Infertile Patients with Moderate \nand Severe Pelvic Endometriosis. Sage Journals 20(5): 557-562. \n8. Gilabert-Estellés J, Ram ón LA, Espa ña F, Gilabert J, Vila V, et al. (2007) \nExpression of angiogenic factors in endometriosis: Relationship to \nfibrinolytic and metalloproteinase systems. Hum Reprod 22(8): 2120-\n2127.\n9. Jana S, Paul S, Swarnakar S (2012) Curcumin as Anti-endometriotic \nagent: implication of mmp-3 and intrinsic apoptotic pathway. Biochem \nPharmacol 83(6): 797-804.\n10. Mousazadeh S, Ghaheri A, Shahhoseini M, Aflatoonian R, Afsharian P \n(2019) The Effect of Imbalanced Progesterone Receptor-A/-B Ratio on \nGelatinase Expressions in Endometriosis. Int J fertil steril 13(2): 127-\n134. \n11. Nap AW, Dunselman GA, de Goeij AF, Evers JL, Groothuis PG (2004) \nInhibiting MMP activity prevents the development of endometriosis in \nthe chicken chorioallantoic membrane model. Human Reproduction \n19(10): 2180-2187. \n12. Liang B, Wu L, Xu H, Cheung CW, Fung WY, et al. (2018) Efficacy, safety \nand recurrence of new progestins and selective progesterone receptor \nmodulator for the treatment of endometriosis: A comparison study in \nmice. Reprod Biol Endocrinol 16(1): 32. \n13. Chwalisz K, Perez MC, DeManno D, Winkel C, Schubert G, et al. (2005) \nSelective Progesterone Receptor Modulator Development and Use in the \nTreatment of Leiomyomata and Endometriosis. Endocr Rev 26(3): 423-\n438.\n14. Cardoso JV, Machado DE, da Silva MC, Berardo PT , Ferrari R, et al. \n(2019) Matrix metalloproteinases 3 polymorphism increases the risk of \ndeveloping advanced endometriosis and infertility: A case-control study. \nEur J Obstet Gynecol Reprod Biol X 3: 10041. \n15. Wagenfeld A, Saunders PT , Whitaker L, Critchley HO (2016) Selective \nprogesterone receptor modulators (SPRMs): Progesterone receptor \naction, mode of action on the endometrium and treatment options in \ngynecological therapies. Expert opin ther targets 20(9): 1045-1054.\nSubmission Link: https://biomedres.us/submit-manuscript.php\nAssets of Publishing with us\n• Global archiving of articles\n• Immediate, unrestricted online access\n• Rigorous Peer Review Process\n• Authors Retain Copyrights\n• Unique DOI for all articles\nhttps://biomedres.us/\nThis work is licensed under Creative\nCommons Attribution 4.0 License\nISSN: 2574-1241\nDOI: 10.26717/BJSTR.2019.21.003636\nBhuchitra Singh. 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