DOI: https://doi.org/10.14710/jbtr.v6i2.8113

Effect of Metformin on Bcl-2/Bax Expression Ratio and Endometrial Implants: A Mouse Model in Endometriosis Study

1Diponegoro University, Indonesia

2Airlangga University, Indonesia

Received: 12 Jun 2020; Revised: 28 Aug 2020; Accepted: 18 Aug 2020; Available online: 31 Aug 2020; Published: 31 Aug 2020.
Open Access Copyright (c) 2020 Journal of Biomedicine and Translational Research

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Abstract

Background: Endometriosis is a gynaecological disorder characterised by the presence of endometrial tissue outside the uterine cavity. Apoptosis, regulated by the balance of Bcl-2/Bax, plays an important role in the endometrial improvement. Metformin, an insulin sensitizer that is known to have beneficial effect in the endometriosis treatment, is expected to lower Bcl-2/Bax expression ratio and reduce endometrial implants.

Objective: To explore the effect of metformin on the Bcl-2/Bax expression ratio and endometrial implant area of endometriosis-induced mice.

Methods: This experimental study used 3-month old 33 BALB/c mice of endometriosis that were randomly and equally divided into three groups (P0, P1, and P2). On the 15th day, the P0 group was first terminated for Bcl-2/Bax examination and the size of endometrial implants. The P1 group was given aquabidest, whereas the P2 group was given metformin 4 mg/day for 14 days. The immunohistochemistry of Bcl-2/Bax expression were performed from cavum abdomen and pelvis peritoneal tissues of the mice and measured by the Remmele Scale Index, whereas the extracted mice’ endometrial implants were analysed with computer tracing method. All data normality test was calculated with Shapiro-Wilk test. The mean difference test of all groups was analysed using the one-way ANOVA test, whereas the mean difference test between groups was completed using the Unpaired T-test (LSD/Least Significance Difference).

Results: The Bcl-2/Bax expression ratio and endometrial implant area in the P2 group were significantly lower compared to P0 and P1 (p<0.001). There were no significant differences in the Bcl-2/Bax expression ratio or endometrial implant area in P0 and P1 (p>0.05)

Conclusion: Metformin may be a potential effective drug treatment for endometriosis by decreasing Bcl-2/Bax expression ratio and endometrial implants.

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Keywords: Metformin; endometriosis, Bcl-2/Bax ratio, endometriosis implants
Funding: Diponegoro University; Airlangga University

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Section: Original Research Articles
Language : EN
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  1. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–98
  2. Pabona JMP, Simmen FA, Nikiforov MA, Zhuang D, Shankar K, Velarde MC, et al. Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2012;97(3):E376-92
  3. Harada T, Kaponis A, Iwabe T, Taniguchi F, Makrydimas G, Sofikitis N, et al. Apoptosis in human endometrium and endometriosis. Hum Reprod Update. 2004;10(1):29–38
  4. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327–46
  5. Reed JC. Mechanism of Apoptosis. Am J Pathol. 2000;157(5):1415–30
  6. Poeta G Del, Venditti A, Principe MI Del, Maurillo L, Buccisano F, Tamburini A, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2003;101(6):125–31
  7. Omer NA, Taher MA, Aljebory HDS. Effect of Metformin Treatment on some Blood Biomarkers inWomen with Endometriosis. Iraqi J Pharm Sci. 2016;25(1):28–36
  8. Bedaiwy MA, Barker NM. Evidence based surgical management of endometriosis. Middle East Fertil Soc J. 2012;17(1):57–60
  9. Dunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400–12
  10. Elnashar A. Emerging treatment of endometriosis. Middle East Fertil Soc J. 2015;20(2):61–9
  11. Rizk B, Fischer AS, Lotfy HA, Turki R, Zahed HA, Malik R, et al. Recurrence of endometriosis after hysterectomy. Facts, Views Vis ObGyn. 2014;6(4):219–27
  12. Bozdag G. Recurrence of Endometriosis: Risk Factors, Mechanisms and Biomarkers. Women’s Heal. 2016;11(5):693–9
  13. Selçuk I, Bozdağ G. Recurrence of endometriosis; risk factors, mechanisms and biomarkers; review of the literature. J Turkish Ger Gynecol Assoc. 2013;14(2):98–103
  14. Cakmak H, Guzeloglu-Kayisli O, Kayisli UA, Arici A. Immune-endocrine interactions in endometriosis. Front Biosci. 2009;1:429–43
  15. Leyendecker G, Wildt L, Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet. 2009;280(4):529–38
  16. Yang L, Ma B, Sun G, Dong C, Ma B. Antiproliferative and antiangiogenic effects of metformin on multidrug-resistant MCF-7 cells. Int J Clin Exp Med. 2018;11(7):6776–83
  17. Gong L, Goswami S, Giaomini KM, Altman RB, Klein TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22(11):820–7
  18. Song R. Mechanism of Metformin: A Tale of Two Sites. Diabetes Care. 2016;39:187–9
  19. Foda AA, Aal IAA. Metformin as a new therapy for endometriosis, its effects on both clinical picture and cytokines profile. Middle East Fertil Soc J. 2012;17:262–7
  20. Duque JE, López C, Cruz N, Samudio I. Antitumor mechanisms of metformin: Signaling, metabolism, immunity and beyond. Univ Sci. 2010;15(2):122–9
  21. Gargett CE, Schwab KE, Deane JA. Endometrial stem/progenitor cells: the first 10 years. Hum Reprod Update. 2016;22(2):137–63
  22. Wu J, Xie H, Yao S, Liang Y. Macrophage and nerve interaction in endometriosis. J Neuroinflammation. 2017;14(53):1–11
  23. Yilmaz B, Sucak A, Kilic S, Lortlar N, Sut N, Gungor T. 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. Res Reprod Endocrinol Infertil. 2009;202(4):368 E1-8
  24. Oner G, Ozcelik B, Ozgun MT, Serin IS, Ozturk F, Basbug M. The effects of metformin and letrozole on endometriosis and comparison of the two treatment agents in a rat model. Hum Reprod. 2010;25(4):932–7
  25. Takahashi A, Kimura F, Yamanaka A, Takebayashi A, Kita N, Takahashi K, et al. Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int. 2014;14(53):1–12
  26. Trisetyono Y, Widjiati W, Hidayat ST, Pramono N. Antioxidant Herbs Supplementation Inhibits Endometriosis Extension in Mice. J Biomed Transl Res. 2019;5(2):53–61
  27. Glamour S, Hidayat ST, Prianto AS, Widjiati W. The Differences of Integrin ανβ3, Leukemia Inhibitory Factors Expression and Superoxide Dismutase Serum Concentration in the Provision of Kebar Extract (Biophytum petersianum Klotczh), Metformin, and Their Combination to Mouse models of Endometriosis. 2018. 2018;4(1):1–8
  28. Hapsari A, Hendarto H, Widjiati. Hylocereus Polyrhizus Peel Ethanol Extract- the Potential Effect to Tumor Necrosis Factor-Α, Macrophage, and Matrix Metalloproteinase-9 in Endometriosis Mice. J Int Dent Med Res. 2017;10(3):1070–3
  29. Nasu K, Yuge A, Tsuno A, Nishida M, Narahara M. Involvement of resistance to apoptosis in the pathogenesis of endometriosis. Histol Histopathol. 2009;24:1181–92
  30. Tian C, Chen S, Tong L. Induction of Ectopic Endometrial Apoptosis by Metformin in Endometriosis. J Pract Obstet Gynecol. 2012;6:28
  31. Kinaan M, Ding H, Triggle CR. Metformin: An Old Drug for the Treatment of Diabetes but a New Drug for the Protection of the Endothelium. Med Princ Pract. 2015;24(5):401–15
  32. Xu J-N, Zeng C, Zhou Y, Peng C, Zhou Y-F, Xue Q. Metformin inhibits StAR expression in human endometriotic stromal cells via AMPK-mediated disruption of CREB-CRTC2 complex formation. J Clin Endocrinol Metab. 2014;99(8):2795–803
  33. Petchsila K, Prueksaritanond N, Insin P, Yanaranop M, Chotikawichean N. Effect of Metformin For Decreasing Proliferative Marker in Women with Endometrial Cancer: A Randomized Double-Blind Placebo-Controlled Trial. Asian Pacific J Cancer Prev. 2020;21(3):733–41

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