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

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

References

1. 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.
2. Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update. 2006;12(2):169-178. doi:10.1093/humupd/dmi046.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.

9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Kierszenbaum AL, Tres LL. Histology and Cell Biology An Introduction to Pathology.4th ed. New York, NY:Elsevier; 2021.
15. Ji C, Kaplowitz N. ER stress: can the liver cope? J Hepatol. 2006;45(2):321-333.
16. 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.
17. 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.
18. 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.
19. 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.
20. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002;110(10):1389-1398.doi: 10.1172/JCI16886.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. Zhou H, Liu R. ER stress and hepatic lipid metabolism. Front Genet. 2014;5:112.doi: 10.3389/fgene.2014.00112.
31. 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.
32. 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.
33. 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
34. 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.
35. Mescher AL. Junqueira's Basic Histology Text&Atlas. 5th ed. US: Mc Graw Hill Education; 2018.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.