{"paper_id":"cdd4319e-fae3-4e72-b203-d198108fd870","body_text":"Abstract\nPurpose\nThe aim of this study was to test if melatonin causes regression of endometriotic implants and whether it influences implant levels of superoxide dismutase (SOD), malondialdehyde (MDA), vascular endothelial growth factor (VEGF), tissue inhibitor of metalloproteinase (TIMP)-2 and matrix metalloproteinase (MMP)-9 in rats.\nMethods\nEndometriotic implants were introduced surgically to 20 female Wistar albino rats, which were either treated with melatonin via intraperitoneal injection for four weeks (melatonin group, n = 10) or with saline (control group, n = 10) after a second-look laparotomies. The main outcome measures included volume (mm3) and weight (mg) of explants and tissue levels of SOD, MDA, VEGF, TIMP-2 and MMP-9.\nResults\nBefore and after treatment implant volumes of the melatonin group were decreased significantly (P < 0.01) while there was no significant difference between the pretreatment and posttreatment implant volumes of the control group. Moreover, weight (P < 0.05) and histologic score (P < 0.05) of implants of the melatonin-treated rats were significantly lower than controls. Activity of SOD and TIMP-2 staining in melatonin group was significantly higher (both P < 0.01) while there were significant reductions in implant levels of VEGF and MMP-9 in melatonin group (both P < 0.01) than controls.\nConclusions\nMelatonin induces the regression of endometriotic implants in rats by modulating implant levels of SOD, MDA, VEGF, MMP-9 and TIMP-2.\nSimilar content being viewed by others\nReferences\nTamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ (2009) Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril 92:328–343\nSampson JA (1927) Peritoneal endometriosis is due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 4:433–469\nVan Langendonckt A, Casanas-Roux F, Donnez J (2002) Oxidative stress and peritoneal endometriosis. Fertil Steril 77:861–870\nDizerega GS, Barber DL, Hodgen GD (1980) Endometriosis:role of ovarian steroids in initiation, maintenance and suppression. Fertil Steril 33:649–653\nGupta S, Agarwal A, Krajcir N, Alvarez JG (2006) Role of oxidative stress in endometriosis. Reprod Biomed Online 13:126–134\nHalliwell B, Gutteridge JMC (1999) Free radicals, other reactive species and disease. In: Halliwell B, Gutteridge JMC (eds) Free radicals in biology and medicine, 3rd edn. Oxford University Press, Oxford, pp 639–645\nMatrisian LM (1990) Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6:121–125\nChung HW, Lee JY, Moon HS, Hur SE, Park MH, Wen Y, Polan ML (2002) Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil Steril 78:787–795\nRajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS (1996) Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98:2572–2579\nCollette T, Bellehumeur C, Kats R, Maheux R, Mailloux J, Villeneuve M, Akoum A (2004) Evidence for an increased release of proteolytic activity by the eutopic endometrial tissue in women with endometriosis and for involvement of matrix metalloproteinase-9. Hum Reprod 19:1257–1264\nPaul S, Sharma AV, Mahapatra PD, Bhattacharya P, Reiter RJ, Swarnakar S (2008) Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis. J Pineal Res 44:439–449\nPaul S, Bhattacharya P, Das Mahapatra P, Swarnakar S (2010) Melatonin protects against endometriosis via regulation of matrix metalloproteinase-3 and an apoptotic pathway. J Pineal Res 49:156–168\nBruner KL, Matrisian LM, Rodgers WH, Gorstein F, Osteen KG (1997) Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nüde mice. J Clin Invest 99:2851–2857\nSevket O, Sevket A, Molla T, Sevket O, Sevket A, Molla T, Buyukpınarbasılı N, Uysal O, Yılmaz B, Dane B, Kelekcı S (2013) Somatostatin analogs regress endometriotic implants in rats by decreasing implant levels of vascular endothelial growth factor and matrix metaloproteinase 9. Reprod Sci 20:639–645\nErgenoglu AM, Yeniel AO, Erbas O, Aktuğ H, Yildirim N, Ulukuş M, Taskiran D (2013) Regression of endometrial implants by resveratrol in an experimentally induced endometriosis model in rats. Reprod Sci 20:1230–1236\nReiter RJ, Tan DX, Maldonado MD (2005) Melatonin as an antioxidant: physiology versus pharmacology. J Pineal Res 39:215–216\nGalano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J Pineal Res 54:245–257\nGüney M, Oral B, Karahan N, Mungan T (2008) Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Fertil Steril 89:934–942\nKoc O, Gunduz B, Topcuoglu A, Bugdayci G, Yilmaz F, Duran B (2010) Effects of pinealectomy and melatonin supplementation on endometrial explants in a rat model. Eur J Obstet Gynecol Reprod Biol 153:72–76\nYildirim G, Attar R, Ozkan F, Kumbak B, Ficicioglu C, Yesildaglar N (2010) The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. Fertil Steril 93:1787–1792\nVernon MW, Wilson EA (1985) Studies on the surgical induction of endometriosis in the rat. Fertil Steril 44:684–694\nLebovic DI, Kir M, Casey CL (2004) Peroxisome proliferator–activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril 82:1008–1013\nOktem M, Esinler I, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu HB (2007) High-dose atorvastatin causes regression of endometriotic implants: a rat model. Hum Reprod 22:1474–1480\nKeenan JA, Williams-Boyce PK, Massey PJ, Chen TT, Caudle MR, Bukovsky A (1999) Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil Steril 72:135–141\nBradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254\nMihara M, Uchiyama M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278\nYilmaz B, Ozat M, Kilic S, Gungor T, Aksoy Y, Lordlar N, Sut N, Aksakal O (2010) Atorvastatin causes regression of endometriotic implants in a rat model. Reprod Biomed Online 20:291–299\nYilmaz B, Sucak A, Kilic S, Aksakal O, Aksoy Y, Lortlar N, Sut N, Gungor T (2010) Metformin regresses endometriotic implants in rats by improving implant levels of superoxide dismutase, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinase-9. Am J Obstet Gynecol 202:368.e1–368.e8\nMccarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr (1985) Estrogen receptor analyses: correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721\nBudwit-Novotny DA, Mccarty KS, Cox EB, Vandekerckhove P (1986) Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res 46:5419–5425\nCulley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, Raine-Fenning N (2013) The social and psychological impact of endometriosis on women’s lives: a critical narrative review. Hum Reprod Update 19:625–639\nRocha AL, Reis FM, Petraglia F (2012) New trends for the medical treatment of endometriosis. Expert Opin Investig Drugs 21:905–919 Review\nDogan E, Saygili U, Posaci C (2004) Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril 82:1115–1120\nHughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekerckhove P (2007) Ovulation suppression for endometriosis. Cochrane Database Syst Rev 3:CD000155\nErcan CM, Kayaalp O, Cengiz M, Keskin U, Yumusak N, Aydogan U, Ide T, Ergun A (2014) Comparison of efficacy of bromocriptine and cabergoline to GnRH agonist in a rat endometriosis model. Arch Gynecol Obstet. Nov 4. (Epub ahead of print)\nCetinkaya N, Attar R, Yildirim G, Ficicioglu C, Ozkan F, Yilmaz B, Yesildaglar N (2014) The effects of different doses of melatonin treatment on endometrial implants in an oophorectomized rat endometriosis model. Arch Gynecol Obstet. Sep 16. (Epub ahead of print)\nSimsek Y, Gul M, Yilmaz E, Ozerol IH, Ozerol E, Parlakpinar H (2014) Atorvastatin exerts anti-nociceptive activity and decreases serum levels of high-sensitivity C-reactive protein and tumor necrosis factor-α in a rat endometriosis model. Arch Gynecol Obstet 290:999–1006\nOnalan G, Gulumser C, Mulayim B, Dagdeviren A, Zeyneloglu H (2014) Effects of amifostine on endometriosis, comparison with N-acetyl cysteine, and leuprolide as a new treatment alternative: a randomized controlled trial. Arch Gynecol Obstet 289:193–200\nAzimirad A, Alborzi S, Kumar PV, Zarei A, Azimirad M (2013) The effects of levamisole on experimental endometriosis: a randomized controlled trial in a rat model. Arch Gynecol Obstet 288:1301–1308\nSimsek Y, Celik O, Karaer A, Gul M, Yılmaz E, Koc O, Colak C, Zengin S, Aydin NE (2013) Therapeutic efficiency of Atosiban, an oxytocin receptor blocking agent in the treatment of experimental endometriosis. Arch Gynecol Obstet 286:777–783\nHu L, Li LA, Li Y (2012) Preliminary study on the effects of carbon dioxide and nitrogen pneumoperitoneums on endometriotic lesions. Arch Gynecol Obstet 286:389–393\nBourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M (2006) The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction 132:501–509\nBruner-Tran KL, Eisenberg E, Yeaman GR, Anderson TA, McBean J, Osteen KG (2002) Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab 87:4782–4791\nRudra DS, Pal U, Maiti MC, Reiter RJ, Swarnakar S (2013) Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res 54:398–405\nSchwertner A, Conceição Dos Santos CC, Deitos A, de Souza A, de Souza IC, Torres IL, da Cunha Filho JS, Caumo W (2013) Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain 154:874–881\nAlvarez-García V, González A, alonso-González C, Martínez-Campa C, Cos S (2013) Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res 54:373–380\nCarbajo-Pescador S, Ordoñez R, Benet M, Jover R, García-Palomo A, Mauriz JL, González-Gallego J (2013) Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells. Br J Cancer 109:83–91\nGanguly K, Sharma AV, Reiter RJ, Swarnakar S (2010) Melatonin promotes angiogenesis during protection and healing of indomethacin-induced gastric ulcer: role of matrix metaloproteinase-2. J Pineal Res 49:130–140\nGanguly K, Kundu P, Banerjee A, Reiter RJ, Swarnakar S (2006) Hydrogen peroxide-mediated downregulation of matrix metalloprotease-2 in indomethacin-induced acute gastric ulceration is blocked by melatonin and other antioxidants. Free Radic Biol Med 41:911–925\nConflict of interest\nThe authors report no financial or commercial conflicts of interest.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nYilmaz, B., Kilic, S., Aksakal, O. et al. Melatonin causes regression of endometriotic implants in rats by modulating angiogenesis, tissue levels of antioxidants and matrix metalloproteinases. Arch Gynecol Obstet 292, 209–216 (2015). https://doi.org/10.1007/s00404-014-3599-4\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s00404-014-3599-4","source_license":"CC0","license_restricted":false}