{"paper_id":"a1fa7a51-6336-4665-8306-d2cf5f5d479f","body_text":"Abstract\nTo assess the potential therapeutic role of antilipidemic ezetimibe on endometriosis in an experimental rat model. A standard experimental endometriosis model was created with 18 Whistar-Albino rats, and after 1 month, the sizes of the endometriotic explants were measured. The rats were randomized as study and control groups. A total of 1 mg/kg/day ezetimibe and 1 ml/kg/day saline were administered orally to the study and control groups respectively for 28 days. At the end of 28 days, the explants were measured again, excised, and sent for histopathologic assessment for expression of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) and number of mast cells. At the end of the study period, the size of the endometriotic explants decreased significantly in the study group; but not in the control group (from 145.3 ± 120.5 to 89.8 ± 60.1 vs 174.72 ± 88.3 to 87.65 ± 27.1 cm3 respectively); however, the amount of post- and pretreatment differences in explant sizes was similar in the groups. The median TNF-α and VEGF levels were significantly lower in the ezetimibe group when compared to the control group (4 [3–4] vs 2 [1–3], p 0.029; 4 [3–4] vs 2 [2–3], p 0.002; respectively). And numbers of mast cells in all uterine layers were also lower in the ezetimibe group. Ezetimibe decreased the size of the endometriotic explants with its anti-inflammatory and anti-angiogenic properties. This agent alone or with combination of other agents may have a potential role in the treatment of endometriosis.\nSimilar content being viewed by others\nData availability\nThe data that support the findings of this study are available from the corresponding author (HA) upon request.\nReferences\nAytan H, Caliskan AC, Demirturk F, Aytan P, Koseoglu DR (2007a) Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces the size of experimental endometriosis in the rat model. Aust N Z J Obstet Gynaecol 47:321–325\nAytan H, Caglar P, Uygur D, Zergeroglu S, Batioglu S (2007b) Effect of the immunomodulator leflunomide on the induction of endometriosis in an experimental rat model. Fertil Steril 87:698–701\nBurney RO, Giudice LC (2012) Pathogenesis and pathophysiology of endometriosis. Fertil Steril 98:511–519\nDolezelova E, Stein E, Derosa G, Maffioli P, Nachtigal P, Sahebkar A (2017) Effect of ezetimibe on plasma adipokines: a systematic review and meta-analysis. Br J Clin Pharmacol 83:1380–1396\nEfstathiou JA, Sampson DA, Levine Z et al (2005) Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. Fertil Steril 83:171–181\nEzzet F, Krishna G, Wexler DB, Statkevich P, Kosoglou T, Batra VK (2001) A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther 23:871–885\nFerrero S, Abbamonte LH, Anserini P, Remorgida V, Ragni N (2005) Future perspectives in the medical treatment of endometriosis. Obstet Gynecol Surv 60:817–826\nHull ML, Charnock-Jones DS, Chan CL et al (2003) Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab 88:2889–2899\nKim HO, Park CW, Hong SR (2003) Expression of CD44s, Ki-67, VEGF, and MMP-2 according to morphology of pelvic endometriosis. Fertil Steril 80(suppl):S224–S225\nKosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB (2005) Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 44:467–494\nLaschke MW, Elitzsch A, Scheuer C, Holstein JH, Vollmar B, Menger MD (2006) Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation. Br J Pharmacol 149:137–144\nLi XX, Zhao L, Chang Y et al (2018) Ezetimibe prevents myocardial remodeling in an obese rat model by inhibiting inflammation. Acta Biochim Pol 65:465–470\nMachado DE, Perini JA, de Mendonça EM, Branco JR, Rodrigues-Baptista KC, Alessandra-Perini J et al (2018) Clotrimazole is effective for the regression of endometriotic implants in a Wistar rat experimental model of endometriosis. Mol Cell Endocrinol 476:17–26\nMiura K, Ohnishi H, Morimoto N et al (2019) Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet. Cancer Sci 110:771–783\nNap AW, Dunselman GA, Griffioen AW, Mayo KH, Evers JL, Groothuis PG (2005) Angiostatic agents prevent the development of endometriosis-like lesions in the chicken chorioallantoic membrane. Fertil Steril 83:793–795\nNisolle M, Casanas-Roux F, Anaf V, Mine JM, Donnez J (1993) Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril 59:681–684\nOeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1(4):a000034. https://doi.org/10.1101/cshperspect.a000034\nRafique S, Decherney AH (2017) Medical management of endometriosis. Clin Obstet Gynecol 60:485–496\nSantulli P, Marcellin L, Noël J-C et al (2012) Sphingosine pathway deregulation in endometriotic tissues. Fertil Steril 97:904–911\nShibuya M (2006) Differential roles of vascular en dothelial growth factor receptor-1 and recep tor-2 in angiogenesis. J Biochem Mol Biol 39:469–478\nShibuya M (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153:13–19\nTaylor HS, Alderman Iii M, D’Hooghe TM, Fazleabas AT, Duleba AJ (2017) Effect of simvastatin on baboon endometriosis. Biol Reprod 97:32–38\nVallée A, Lecarpentier Y (2020) Curcumin and endometriosis. Int J Mol Sci 21:2440\nVernon MW, Wilson EA (1985) Studies on the surgical induction of endometriosis in the rat. Fertil Steril 44:684–694\nvon Rokitansky KF. Ueber uterusdrüsen-neubildung in uterus-und ovarial-sarcomen. Druck von Carl Ueberreuter; 1860. 6 p\nYilmaz B, Sucak A, Kilic S et al (2010a) 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):e1-8. https://doi.org/10.1016/j.ajog.2009.10.873\nYilmaz B, Ozat M, Kilic S et al (2010b) Atorvastatin causes regression of endometriotic implants in a rat model. Reprod Biomed Online 20:291–299\nZhou WJ, Yang HL, Shao J, Mei J, Chang KK, Zhu R, Li MQ (2019) Anti-inflammatory cytokines in endometriosis. Cell Mol Life Sci 76:2111–2132\nFunding\nThis work was supported by Mersin University Department of Scientific Research Projects (grant number: 2019–3-TP3-3810).\nAuthor information\nAuthors and Affiliations\nContributions\nR. Tapdıgova: project development, data collection, assessment of the explants, manuscript writing.\nG. Bayrak: ımmunohistochemical assessment.\nB. Coşkun Yılmaz: ımmunohistochemical assessment.\nH. Aytan: project development, data collection, surgical induction of endometriosis, statistical analysis, manuscript writing, editing.\nThe authors declare that all data were generated in-house and that no paper mill was used.\nCorresponding author\nEthics declarations\nEthics approval\nThe study was approved by Mersin University’s local animal experiments ethics committee (approval number: 992903).\nConsent to participate\nThis is an experimental animal study.\nConsent for publication\nThis is an experimental animal study.\nConflict of interest\nThe authors declare no competing interests.\nAdditional declarations for articles in life science journals that report the results of studies involving humans and/or animals\nAll processes were carried out in accordance with the National Institute of Health “Guide for the care and Use of Laboratory Animals” rules.\nAdditional information\nPublisher's note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nRights and permissions\nAbout this article\nCite this article\nTapdıgova, R., Bayrak, G., Yılmaz, B.C. et al. Antilipidemic ezetimibe induces regression of endometriotic explants in a rat model of endometriosis with its anti-inflammatory and anti-angiogenic effects. Naunyn-Schmiedeberg's Arch Pharmacol 395, 673–680 (2022). https://doi.org/10.1007/s00210-022-02226-2\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s00210-022-02226-2","source_license":"CC0","license_restricted":false}