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

Year 2024, Volume: 19 Issue: 1, 8 - 15, 27.02.2024

Abstract

Objective: This study aimed to analyze the effects of combined oral contraceptive active ingredients,
Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone, on liver histopathological
changes and endoplasmic reticulum stress levels.
Material and Methods: In the study, 37 Balb/c female mice were used. Mice were randomly divided
into the Control, Sham, Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone
groups. The experimental groups were administered with gavage to 8-week-old female mice for
35 days. Kidney tissue sections were applied with Hematoxylin&Eosin, Orcein, Mallory’s Azan,
and Periodic Acid-Schiff to detect histopathological changes, and Chop and Grp78 were used to
detect Endoplasm Reticulum Stress.
Results: Significant loss of microvilli and a decrease in glycogen accumulation were observed
in the apical part of some of the proximal tubules of animals in the Drospirenone and Ethinyl
Estradiol+Drospirenone groups. The amount of collagen fiber stained with Mallory’s Azan
increased in the parietal layer of Bowman’s capsule of the kidney tissues of the Drospirenone and
Ethinyl Estradiol+Drospirenone applied groups, but no difference was observed in elastic fibers in
all groups. The expression level of Grp78 and Chop proteins in the kidney tubules of female mice
given Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone was significantly
higher compared to the control group.
Conclusion: In this study, it was shown that the expression of Grp78 and Chop markers detected
in the mouse kidney increased as a result of Drospirenone, Ethinyl Estradiol and Ethinyl Estradiol
+ Drospirenone administration, thus causing kidney cell apoptosis by inducing ER-dependent
death pathway activity.

References

  • 1. Dragoman MV. The combined oral contraceptive pill-recent developments, risk and benefits. Best Pract Res Clin Obstet Gynaecol. 2014; 825-834. doi.org/10.1016/j.bpobgyn.2014.06.003
  • 2. Foidart JM, Danielsson KG, Kubba A, et al. The benefits of estetrol addition to drospirenone for contraception. AJOG Global Reports. 2023, in press. https://doi.org/10.1016/j.xagr.2023.100266
  • 3. Sitruk Ware R, Nath A. Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab. 2013;27:13-24. https://doi.org/10.1016/j.beem.2012.09.004
  • 4. Brynhildsen J. Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks. Ther Adv Drug Saf. 2014;5(5):201-213. https://doi.org/10.1177/2042098614548857
  • 5. Lundin C, Wikman A, Wikman P, et al. Hormonal Contraceptive use and risk of depression among young women with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2023;62(6): 665-674. https://doi.org/10.1016/j.jaac.2022.07.847
  • 6. Purohit R, Soni S. A review on oral contraception and breast cancer. SFS. 2023;10(2): 34-50.
  • 7. Lahoti D, Bhople N, Kumar S, et al. Porto-mesenteric venous thrombosis and extrahepatic portal venous obstruction in association with oral contraceptives: An often unsuspected cause. Indian J Gastroenterol. 2023; 42(4): 582-584. https://doi.org/10.1007/s12664-023-01379-z
  • 8. Cameron NA, Byler CA, Bello A. Oral Contraceptive pills and hypertension: a review of current evidence and recommendations. Hypertension. 2023;80:924-935. https://doi.org/10.1161/HYPERTENSIONAHA.122.20018
  • 9. Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contracept. 2020;102:396-402. https://doi.org/10.1016/j.contraception.2020.08.015
  • 10. Uutela A, Hughes M. Benign liver lesions. Surgery. 2023;41(6):359-370. https://doi.org/10.1016/j.mpsur.2023.02.020
  • 11. Trepiccione F, Capasso G, Unwin R. Electrolytes and acid-base: common fluid and electrolyte disorders. Medicine. 2023;51(2):102-109. https://doi.org/10.1016/j.mpmed.2022.11.001 12. Garibotto G, Sofia A, Saffioti S, et al. Amino acid and protein metabolism in the human kidney and in patients with chronic kidney disease. Clin Nutr. 2010;29:424-433. https://doi.org/10.1016/j.clnu.2010.02.005
  • 13. Zhang R, Bian C, Gao J, et al. Endoplasmic reticulum stress in diabetic kidney disease: adaptation and apoptosis after three UPR pathways. Apoptosis. 2023;28:977-996. https://doi.org/10.1007/s10495-023-01858-w
  • 14. Zhu G, Lee AS. Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. J Cell Physiol. 2015;230:1413-1420. https://doi.org/10.1002/jcp.24923
  • 15. Gallazzini M, Pallet N. Endoplasmic reticulum stress and kidney dysfunction. Biol Cell. 2018;110:205-216. https://doi.orf/10.1111/boc.201800019
  • 16. 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. https://doi.org/10.1016/j.jsbmb.2019.03.018
  • 17. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contracept. 2000;62:29-38. https://doi.org/10.1016/S0010-7824(00)00133-5
  • 18. Schurmann R, Blode H, Benda N, et al. Effect of drospirenone on serum potassium and drospirenone pharmacokinetics in women with normal or impaired renal function. J Clin Pharmacol. 2006;46:867-875. https://doi.org/10.1177/0091270006289973
  • 19.Gatea EA, Kbyeh FR, Jasim HM. Influence of the combined oral and injectable contraceptives on the level of creatinine, urea, and some electrolyte. JGPT. 2019;11:09,144-147. 20. Ransome DI, Tamuno-Boma O, Barizoge LC, et al. Effects of selected oral contraceptives on the kidney functionality. GSCBPS. 2022;18(3):242-249. https://doi.org/10.30574/gscbps.2022.18.3.0114
  • 21. Fenton C, Wellington K, Moen MD, et al. Drospirenone/ethinylestradiol 3mg/20microg (24/4 day regimen): a review of its use in contraception, premenstrual dysphoric disorder and moderate acne vulgaris. Drugs. 2007;67:1749-1765. https://doi.org/10.2165/00003495-200767120-00007
  • 22. Abdel Kader DH, Gabri, M.S., Ibrrahim, M.A., et al. Histological and Immunohistochemical study on the Changes Induced by Contraceptive pills in the female rabbit’s kidney. Egypt J Hosp Med. 2012;46:47-63. https://doi.org/10.21608/ejhm.2012.16357
  • 23. Sitruk Ware R, Nath, A. The use of newer progestins for contraception. Contracept. 2010;82:410-417. https://doi.org/10.1016/j.contraception.2010.04.004
  • 24. 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;90:426-431.
  • 25. Al Jomard SA, Al-Youzbaki, WB. Effect of combined oral contraceptive pills on renal function tests. Iraqi J Comm Med. 2012;4:314-319.
  • 26. Al Ani IM, Noor Al-Deen, JA, Kashmola, MA. Light and transmission electron microscopic study on the effect of contraceptive pills on the glomerulus and juxtaglomerular apparatus in mice. Annal Micro. 2009;9:63-72.
  • 27. Kareem IN, Mustafa EM, Toama FN. Study of physiological changes induced by therapeutic dose of contraceptive pills (yasmin) in the liver and kidneys of albino mice. JSFS. 2023;10:3S,2662-2666. https://doi.org/10.17762/sfs.v10i3S.976
  • 28. Li K, Li Y, Ding H, et al. Metal-binding proteins cross-linking with endoplasmic reticulum stress in cardiovascular diseases. J Cardiovasc DevDis. 2023;10(171):1-21. https://doi.org/10.3390/jcdd10040171
  • 29. Fujimoto D, Kuwabara T, Hata Y, et al. Suppressed ER-associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease. Faseb j, 2020;34(11):15577–15590. https://doi.org/10.1096/fj.202000078RR
  • 30. Wu L, Wang Q, Guo F, et al. Involvement of miR-27a-3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress. J Cell Physiol. 2021;236(2):1454–1468. https://doi.org/10.1002/jcp.29951

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

Year 2024, Volume: 19 Issue: 1, 8 - 15, 27.02.2024

Abstract

Objective: This study aimed to analyze the effects of combined oral contraceptive active ingredients,
Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone, on liver histopathological
changes and endoplasmic reticulum stress levels.
Material and Methods: In the study, 37 Balb/c female mice were used. Mice were randomly divided
into the Control, Sham, Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone
groups. The experimental groups were administered with gavage to 8-week-old female mice for
35 days. Kidney tissue sections were applied with Hematoxylin&Eosin, Orcein, Mallory’s Azan,
and Periodic Acid-Schiff to detect histopathological changes, and Chop and Grp78 were used to
detect Endoplasm Reticulum Stress.
Results: Significant loss of microvilli and a decrease in glycogen accumulation were observed
in the apical part of some of the proximal tubules of animals in the Drospirenone and Ethinyl
Estradiol+Drospirenone groups. The amount of collagen fiber stained with Mallory’s Azan
increased in the parietal layer of Bowman’s capsule of the kidney tissues of the Drospirenone and
Ethinyl Estradiol+Drospirenone applied groups, but no difference was observed in elastic fibers in
all groups. The expression level of Grp78 and Chop proteins in the kidney tubules of female mice
given Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone was significantly
higher compared to the control group.
Conclusion: In this study, it was shown that the expression of Grp78 and Chop markers detected
in the mouse kidney increased as a result of Drospirenone, Ethinyl Estradiol and Ethinyl Estradiol
+ Drospirenone administration, thus causing kidney cell apoptosis by inducing ER-dependent
death pathway activity.

Ethical Statement

Permission was obtained from The Institutional Animal Ethical Committee of Akdeniz University (Antalya, Türkiye) approved the study. (Authorization reference number: 2022.01.009).

Thanks

This study was presented at the International Congress on Natural & Medical Sciences as an oral presentation.

References

  • 1. Dragoman MV. The combined oral contraceptive pill-recent developments, risk and benefits. Best Pract Res Clin Obstet Gynaecol. 2014; 825-834. doi.org/10.1016/j.bpobgyn.2014.06.003
  • 2. Foidart JM, Danielsson KG, Kubba A, et al. The benefits of estetrol addition to drospirenone for contraception. AJOG Global Reports. 2023, in press. https://doi.org/10.1016/j.xagr.2023.100266
  • 3. Sitruk Ware R, Nath A. Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab. 2013;27:13-24. https://doi.org/10.1016/j.beem.2012.09.004
  • 4. Brynhildsen J. Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks. Ther Adv Drug Saf. 2014;5(5):201-213. https://doi.org/10.1177/2042098614548857
  • 5. Lundin C, Wikman A, Wikman P, et al. Hormonal Contraceptive use and risk of depression among young women with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2023;62(6): 665-674. https://doi.org/10.1016/j.jaac.2022.07.847
  • 6. Purohit R, Soni S. A review on oral contraception and breast cancer. SFS. 2023;10(2): 34-50.
  • 7. Lahoti D, Bhople N, Kumar S, et al. Porto-mesenteric venous thrombosis and extrahepatic portal venous obstruction in association with oral contraceptives: An often unsuspected cause. Indian J Gastroenterol. 2023; 42(4): 582-584. https://doi.org/10.1007/s12664-023-01379-z
  • 8. Cameron NA, Byler CA, Bello A. Oral Contraceptive pills and hypertension: a review of current evidence and recommendations. Hypertension. 2023;80:924-935. https://doi.org/10.1161/HYPERTENSIONAHA.122.20018
  • 9. Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contracept. 2020;102:396-402. https://doi.org/10.1016/j.contraception.2020.08.015
  • 10. Uutela A, Hughes M. Benign liver lesions. Surgery. 2023;41(6):359-370. https://doi.org/10.1016/j.mpsur.2023.02.020
  • 11. Trepiccione F, Capasso G, Unwin R. Electrolytes and acid-base: common fluid and electrolyte disorders. Medicine. 2023;51(2):102-109. https://doi.org/10.1016/j.mpmed.2022.11.001 12. Garibotto G, Sofia A, Saffioti S, et al. Amino acid and protein metabolism in the human kidney and in patients with chronic kidney disease. Clin Nutr. 2010;29:424-433. https://doi.org/10.1016/j.clnu.2010.02.005
  • 13. Zhang R, Bian C, Gao J, et al. Endoplasmic reticulum stress in diabetic kidney disease: adaptation and apoptosis after three UPR pathways. Apoptosis. 2023;28:977-996. https://doi.org/10.1007/s10495-023-01858-w
  • 14. Zhu G, Lee AS. Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. J Cell Physiol. 2015;230:1413-1420. https://doi.org/10.1002/jcp.24923
  • 15. Gallazzini M, Pallet N. Endoplasmic reticulum stress and kidney dysfunction. Biol Cell. 2018;110:205-216. https://doi.orf/10.1111/boc.201800019
  • 16. 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. https://doi.org/10.1016/j.jsbmb.2019.03.018
  • 17. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contracept. 2000;62:29-38. https://doi.org/10.1016/S0010-7824(00)00133-5
  • 18. Schurmann R, Blode H, Benda N, et al. Effect of drospirenone on serum potassium and drospirenone pharmacokinetics in women with normal or impaired renal function. J Clin Pharmacol. 2006;46:867-875. https://doi.org/10.1177/0091270006289973
  • 19.Gatea EA, Kbyeh FR, Jasim HM. Influence of the combined oral and injectable contraceptives on the level of creatinine, urea, and some electrolyte. JGPT. 2019;11:09,144-147. 20. Ransome DI, Tamuno-Boma O, Barizoge LC, et al. Effects of selected oral contraceptives on the kidney functionality. GSCBPS. 2022;18(3):242-249. https://doi.org/10.30574/gscbps.2022.18.3.0114
  • 21. Fenton C, Wellington K, Moen MD, et al. Drospirenone/ethinylestradiol 3mg/20microg (24/4 day regimen): a review of its use in contraception, premenstrual dysphoric disorder and moderate acne vulgaris. Drugs. 2007;67:1749-1765. https://doi.org/10.2165/00003495-200767120-00007
  • 22. Abdel Kader DH, Gabri, M.S., Ibrrahim, M.A., et al. Histological and Immunohistochemical study on the Changes Induced by Contraceptive pills in the female rabbit’s kidney. Egypt J Hosp Med. 2012;46:47-63. https://doi.org/10.21608/ejhm.2012.16357
  • 23. Sitruk Ware R, Nath, A. The use of newer progestins for contraception. Contracept. 2010;82:410-417. https://doi.org/10.1016/j.contraception.2010.04.004
  • 24. 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;90:426-431.
  • 25. Al Jomard SA, Al-Youzbaki, WB. Effect of combined oral contraceptive pills on renal function tests. Iraqi J Comm Med. 2012;4:314-319.
  • 26. Al Ani IM, Noor Al-Deen, JA, Kashmola, MA. Light and transmission electron microscopic study on the effect of contraceptive pills on the glomerulus and juxtaglomerular apparatus in mice. Annal Micro. 2009;9:63-72.
  • 27. Kareem IN, Mustafa EM, Toama FN. Study of physiological changes induced by therapeutic dose of contraceptive pills (yasmin) in the liver and kidneys of albino mice. JSFS. 2023;10:3S,2662-2666. https://doi.org/10.17762/sfs.v10i3S.976
  • 28. Li K, Li Y, Ding H, et al. Metal-binding proteins cross-linking with endoplasmic reticulum stress in cardiovascular diseases. J Cardiovasc DevDis. 2023;10(171):1-21. https://doi.org/10.3390/jcdd10040171
  • 29. Fujimoto D, Kuwabara T, Hata Y, et al. Suppressed ER-associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease. Faseb j, 2020;34(11):15577–15590. https://doi.org/10.1096/fj.202000078RR
  • 30. Wu L, Wang Q, Guo F, et al. Involvement of miR-27a-3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress. J Cell Physiol. 2021;236(2):1454–1468. https://doi.org/10.1002/jcp.29951
There are 28 citations in total.

Details

Primary Language English
Subjects Urology
Journal Section Research Article
Authors

Esma Kırımlıoğlu 0000-0002-5689-5670

Seval Türk This is me 0000-0002-0850-4671

Alexandra Cernomorcenco This is me 0000-0003-3882-426X

Publication Date February 27, 2024
Published in Issue Year 2024 Volume: 19 Issue: 1

Cite

Vancouver Kırımlıoğlu E, Türk S, Cernomorcenco A. Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Kidney. New J Urol. 2024;19(1):8-15.