Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Liver

Year 2024, Volume: 10 Issue: 1, 1 - 7, 15.03.2024

Seval Türk , Alexandra Cernomorcenco , Esma Kırımlıoğlu

https://doi.org/10.30934/kusbed.1281214

Abstract

Objective: We aimed to evaluate the effects of combined oral contraceptive active ingredients ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone for histopathological changes, and endoplasmic reticulum stress levels in the liver.

Methods: In the study, 37 to 8-week-old Balb/c female mice were used. Mice were randomly divided into the control, sham, ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone groups. Experimental groups were administered ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone with gavage for 35 days. In liver tissue sections, histopathological changes were detected with hematoxylin&eosin, orcein, Mallory's Azan, and periodic acid-Schiff, and the presence of endoplasmic reticulum stress was detected by Chop and Grp78 immunostaining.

Results: The ethinylestradiol+drospirenone group showed significant histopathological changes compared to the control group. Some degenerative changes were noted such as swelling and size differences in hepatocytes in the ethinylestradiol+drospirenone group. When compared to the control group, an increased collagen and elastic fibers density around the vena centralis was observed in the ethinylestradiol+drospirenone group. The expression level of Grp78 protein in female mice given ethinylestradiol+drospirenone was statistically significantly increased compared to the control group. The expression level of Chop protein was significantly increased in the ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone groups.

Conclusion: We concluded that the use of combined oral contraceptives increases endoplasmic reticulum stress in mouse liver tissue, and as a result, it may cause liver histopathological disorders by promoting cell death.

Keywords

Combined oral contraceptive, drospirenone, ethinylestradiol, liver, Grp78, Chop

Supporting Institution

yok

Project Number

yok

Thanks

Necdet Demir was the thesis advisor of Alexandra Cernomorcenco. And his vast knowledge was consulted when performing the Combined Oral Contraceptives Method on mice. Necdet Demir died on 21.12.2022. We would like to express our gratitude to Necdet Demir for his contributions, guidance, and support in our research life.

References

• Brynhildsen J. Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks. Ther Adv Drug Saf. 2014;5(5):201-213. doi: 10.1177/2042098614548857.
• Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update. 2006;12(2):169-178. doi:10.1093/humupd/dmi046.
• Sitruk-Ware R, Nath A. The characteristics and metabolic effects of estrogen and progestin in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab. 2013;27(1):13-24. doi: 10.1016/j.beem.2012.09.004.
• Sherif K. Benefits and risks of oral contraceptives. Am J Obstet Gynecol. 1999;180(6 Pt 2):S343-348. doi: 10.1016/S0002-9378(99)70694-0.
• Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190(4 Suppl):S5-22. doi:10.1016/j.ajog.2004.01.061.
• Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ. 2009;339:b3914. doi:10.1136/bmj.b3914.
• Yang L, Kuper H, Sandin S, et al. Reproductive history, oral contraceptive use, and the risk of ischemic and hemorrhagic stroke in a cohort study of middle-aged Swedish women. Stroke. 2009;40(4):1050-1058. doi: 10.1161/STROKEAHA.108.531913.
• Margolis KL, Adami HO, Luo J, Ye W, Weiderpass E. A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women. Fertil Steril. 2007;88(2):310-316. doi: 10.1016/j.fertnstert.2006.11.206.
• Dinger J, Assmann A, Mohner S, Minh TD. Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care. 2010;36(3):123-129. doi: 10.1783/147118910791749416.
• Plu-Bureau G, Hugon-Rodin J, Maitrot-Mantelet L, Canonico M. Hormonal contraceptives and arterial disease: an epidemiological update. Best Pract Res Clin Endocrinol Metab. 2013;27(1):35-45. doi: 10.1016/j.beem.2012.11.003.
• Peck R, Norris CW. Significant Risks of Oral Contraceptives (OCPs): Why This Drug Class Should Not Be Included in a Preventive Care Mandate. Linacre Q. 2012;79(1):41-56. doi: 10.1179/002436312803571447.
• Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6):396-402.doi: 10.1016/j.contraception.2020.08.015.
• Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology. 2011;53(5):1752-1763. doi: 10.1002/hep.24279.
• Kierszenbaum AL, Tres LL. Histology and Cell Biology An Introduction to Pathology.4th ed. New York, NY:Elsevier; 2021.
• Ji C, Kaplowitz N. ER stress: can the liver cope? J Hepatol. 2006;45(2):321-333.
• Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM. Role of endoplasmic reticulum stress in the pathogenesis of the nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(7):1768-1776.
• Ji C, Kaplowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J Gastroenterol. 2004;10(12):1699-1708. doi: 10.3748/wjg.v10.i12.1699.
• Benali-Furet NL, Chami M, Houel L, et al. The Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene. 2005;24(31):4921-4933. doi: 10.1038/sj.onc.1208673.
• Kaplowitz N, Ji C. Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum. J Gastroenterol Hepatol. 2006;21 Suppl 3:S7-9. doi: 10.1111/j.1440-1746.2006.04581.x.
• Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002;110(10):1389-1398.doi: 10.1172/JCI16886.
• Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol. 2008;3:399-425. doi: 10.1146/annurev.pathmechdis.3.121806.151434.
• Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35(4):373-381. doi: 10.1016/j.ymeth.2004.10.010.
• Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519-529. doi: 10.1038/nrm2199.
• Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18(24):3066-3077. doi: 10.1101/gad.1250704.
• Oliveira CAR, Dos Reis Araujo T, Aguiar GS, et al. Combined oral contraceptive in female mice causes hyperinsulinemia due to beta-cell hypersecretion and reduction in insulin clearance. J Steroid Biochem Mol Biol. 2019;190:54-63. doi: 10.1016/j.jsbmb.2019.03.018.
• El Amki M, Binder N, Steffen R, et al. Contraceptive drugs mitigate experimental stroke-induced brain injury. Cardiovasc Res. 2019;115(3):637-646. doi: 10.1093/cvr/cvy248.
• Tarantino G, Di Minno MN, Capone D. Drug-induced liver injury: is it somehow foreseeable? World J Gastroenterol. 2009;15(23):2817-2833. doi: 10.3748/wjg.15.2817.
• Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54(4):795-809. doi: 10.1016/j.jhep.2010.11.005.
• Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity, and diabetes. Trends Mol Med. 2012;18(1):59-68. doi:10.1016/j.molmed.2011.07.010.
• Zhou H, Liu R. ER stress and hepatic lipid metabolism. Front Genet. 2014;5:112.doi: 10.3389/fgene.2014.00112.
• Liu X, Green RM. Endoplasmic reticulum stress and liver diseases. Liver Res. 2019;3(1):55-64. doi: 10.1016/j.livres.2019.01.002.
• Porto LC, Chevallier M, Peyrol S, Guerret S, Grimaud JA. Elastin in human, baboon, and mouse liver: an immunohistochemical and immunoelectron microscopic study. Anat Rec. 1990;228(4):392-404. doi: 10.1002/ar.1092280405.
• Yurdakul U, Uçankuş NL, Ömeroğlu S, Hatipoğlu MT. Değişik yaş gruplarındaki sıçan karaciğer dokusunda bağ dokusu liflerinin dağılımı. Düzce Tıp Fak Derg. 2005;3:15-20. https://dergipark.org.tr/tr/pub/dtfd/issue/48257/610917
• Nacar A, Karaboga I, Okuyan HM, Kaplan Sefil N, Nacar E. Investigation of the protective effect of erdosteine against cyclosporine-induced injury in rat liver with histological and biochemical methods. Turk J Med Sci. 2015;45(6):1390-1395. doi: 10.3906/sag-1404-6.
• Mescher AL. Junqueira's Basic Histology Text&Atlas. 5th ed. US: Mc Graw Hill Education; 2018.
• Klipping C, Duijkers I, Mawet M, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021;103(4):213-221.doi: 10.1016/j.contraception.2021.01.001.
• Steingold KA, Cefalu W, Pardridge W, Judd HL, Chaudhuri G. Enhanced hepatic extraction of estrogens used for replacement therapy. J Clin Endocrinol Metab. 1986;62(4):761-766. doi: 10.1210/jcem-62-4-761.
• Foufelle F, Girard J, Ferre P. Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: a review of the potential cellular and molecular mechanisms. Adv Enzyme Regul. 1996;36:199-226. doi: 10.1016/0065-2571(95)00010-0.
• Gaspard U, Scheen A, Endrikat J, et al. A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism. Contraception. 2003;67(6):423-429. doi: 10.1016/S0010-7824(02)00537-1.
• Crook D, Godsland IF, Worthington M, Felton CV, Proudler AJ, Stevenson JC. A comparative metabolic study of two low-estrogen-dose oral contraceptives containing desogestrel or gestodene progestins. Am J Obstet Gynecol. 1993;169(5):1183-1189. doi: 10.1016/0002-9378(93)90279-R.
• Ni M, Zhang Y, Lee AS. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signaling, and therapeutic targeting. Biochem J. 2011;434(2):181-188. doi:10.1042/BJ20101569.
• Pfaffenbach KT, Lee AS. The critical role of GRP78 in physiologic and pathologic stress. Curr Opin Cell Biol. 2011;23(2):150-156. doi: 10.1016/j.ceb.2010.09.007.
• Nishitoh H. CHOP is a multifunctional transcription factor in the ER stress response. J Biochem. 2012;151(3):217-219. doi: 10.1093/jb/mvr143.
• Taneepanichskul S, Jaisamrarn U, Phupong V. Effect of a new oral contraceptive with drospirenone on vital signs, complete blood count, glucose, electrolytes, renal, and liver function. J Med Assoc Thai. 2007;90(3):426-431. http://www.jmatonline.com/index.php/jmat/article/view/8774.
• Kang MH, Katsuzaki H, Osawa T. Inhibition of 2,2'-azobis(2,4-dimethylvaleronitrile)-induced lipid peroxidation by sesaminols. Lipids. 1998;33(10):1031-1036. doi: 10.1007/s11745-998-0302-y.
• Crews C, Hough P, Godward J, et al. Quantitation of the main constituents of some authentic grape-seed oils of different origin. J Agric Food Chem. 2006;54(17):6261-6265. doi: 10.1021/jf060338y.
• Chavali SR, Utsunomiya T, Forse RA. Increased survival after cecal ligation and puncture in mice consuming diets enriched with sesame seed oil. Crit Care Med. 2001;29(1):140-143. doi: 10.1097/00003246-200101000-00028.
• Akimoto K, Kitagawa Y, Akamatsu T, et al. Protective effects of sesamin against liver damage caused by alcohol or carbon tetrachloride in rodents. Ann Nutr Metab. 1993;37(4):218-224. doi: 10.1159/000177771.
• Hsu DZ, Liu MY. Sesame oil protects against lipopolysaccharide-stimulated oxidative stress in rats. Crit Care Med. 2004;32(1):227-231. doi: 10.1097/01.CCM.0000104947.16669.29.
• Abdou HM, Hussien HM, Yousef MI. Deleterious effects of cypermethrin on rat liver and kidney: protective role of sesame oil. J Environ Sci Health B. 2012;47(4):306-314. doi: 10.1080/03601234.2012.640913.