Therapeutic potentials of the caffeine in polycystic ovary syndrome in a rat model: Via modulation of proinflammatory cytokines and antioxidant activity
Main Article Content
Keywords
Polycystic ovary syndrome, Ovarian structure, caffeine, apoptosis, inflammation, rat
Abstract
Recent studies have shown that polycystic ovary syndrome (PCOS) affects about 6% of women worldwide. It is associated with reproductive and metabolic dysfunction. Caffeine is naturally found in tea, cocoa, and coffee. It has been shown that caffeine can change hormonal profiles, stimulate ovulation, and enhance fertility. Therefore, in this study, the effects of caffeine on rats with PCOS were investigated. For this purpose, 40 female rats were divided into five groups: (1) control group (without any intervention), (2) sham group (administration of olive oil as a caffeine solvent), (3) PCOS group (injection of 2 mg of estradiol valerate for each rat), (4) caffeine group (administration of 37.5 mg/kg caffeine for each rat), and (5) PCOS + caffeine group. After 21 days of treatment, the ovaries of rats were removed and prepared for further evaluations, including hematoxylin and eosin staining, TUNEL assay, real-time PCR, and biochemical analysis. Administration of caffeine in PCOS mice considerably reduced both the volume of the ovary (P < 0.05) and follicular clusters (P < 0.01). However, superoxide dismutase and glutathione peroxidase were dramatically active in the PCOS + caffeine group compared to others (P < 0.05). Besides, caffeine treatment in PCOS mice led to Bax reduction and increased Bcl-2 expression. On the other hand, the expression of IL-6 and TNF-α in PCOS + caffeine group was high compared to other groups. We found that caffeine can reduce apoptosis and inflammation in PCOS ovaries and enhance the unpleasant symptoms of PCOS.
References
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21. Schliep KC, Schisterman EF, Mumford SL, Pollack AZ, Zhang C, Ye A, et al. Caffeinated beverage intake and reproductive hormones among premenopausal women in the BioCycle Study. Am J Clin Nutr. 2012;95(2):488–97. 10.3945/ajcn.111.021287
22. Fernandez M, Lopez A, Santa-Maria A. Apoptosis induced by different doses of caffeine on Chinese hamster ovary cells. J Appl Toxicol. 2003;23(4):221–4. 10.1002/jat.910
23. Raoofi A, Amini A, Farahani RM. The synergistic effect of curcumin and ziziphora extract due to their anti-inflammatory and antioxidant properties on ovarian tissue follicles. J Pharmaceutical Res Int. 2018;24(3):1–11. 10.9734/JPRI/2018/45124
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25. Nasiry D, Khalatbary AR, Ahmadvand H, Amiri FBT. Effects of Juglans regia L. leaf extract supplementation on testicular functions in diabetic rats. Biotech Histochem. 2020;96(1):1–7. 10.1080/10520295.2020.1755893
26. Duleba AJ, Dokras A. Is PCOS an inflammatory process? Fertil Steril. 2012;97(1):7–12. 10.1016/j.fertnstert.2011.11.023
27. Zirlik A, Abdullah SM, Gerdes N, MacFarlane L, Schönbeck U, Khera A, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: Results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007;27(9):2043–9. 10.1161/ATVBAHA.107.149484
28. Furtado MV, Rossini APW, Campani RB, Meotti C, Segatto M, Vietta G, et al. Interleukin-18: An independent predictor of cardiovascular events in patients with acute coronary syndrome after 6 months of follow-up. Coron Artery Dis. 2009;20(5):327–31. 10.1097/mca.0b013e32832e5c73
29. Hulsmans M, Holvoet P. The vicious circle between oxidative stress and inflammation in atherosclerosis. J Cell Mol Med. 2010;14(1–2):70–8. 10.1111/j.1582-4934.2009.00978.x
30. Sabuncu T, Vural H, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. Clin Biochem. 2001;34(5):407–13. 10.1016/s0009-9120(01)00245-4
31. Kuşçu NK, Var A. Oxidative stress but not endothelial dys-function exists in non-obese, young group of patients with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2009;88(5):612–7. 10.1080/00016340902859315
32. Fenkci V, Fenkci S, Yilmazer M, Serteser M. Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril. 2003;80(1):123–7. 10.1016/s0015-0282(03)00571-5
33. Dinger Y, Akcay T, Erdem T, Saygili EI, Gundogdu S. DNA damage, DNA susceptibility to oxidation and glutathione level in women with polycystic ovary syndrome. Scand J Clin Lab Invest. 2005;65(8):721–8. 10.1080/00365510500375263
34. Insenser M, Martínez-García MA, Montes R, San-Millán JL, Escobar-Morreale HF. Proteomic analysis of plasma in the polycystic ovary syndrome identifies novel markers involved in iron metabolism, acute-phase response, and inflammation. J Clin Endocrinol Metab. 2010;95(8):3863–70. 10.1210/jc.2010-0220
35. Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: A systematic review and metaanalysis. Fertil Steril. 2011;95(3):1048–58. 10.1016/j.fertnstert.2010.11.036
36. Bas D, Abramovich D, Hernandez F, Tesone M. Altered expression of Bcl-2 and Bax in follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Cell Biol Int. 2011;35(5):423–29. 10.1042/CBI20100542
37. Tilly JL, Tilly K. Inhibitors of oxidative stress mimic the ability of follicle-stimulating hormone to suppress apoptosis in cultured rat ovarian follicles. Endocrinology. 1995;136(1):242–52. 10.1210/endo.136.1.7828537
38. Tilly JL. Apoptosis and ovarian function. Rev Reproduction. 1996;1(3):162–72. 10.1530/ror.0.0010162
39. Shah KN, Patel SS. Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome. Pharm Biol. 2016;54(6):975–83. 10.3109/13880209.2015.1091482
40. Kafali H, Iriadam M, Ozardali I, Demir N. Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease. Arch Med Res. 2004;35(2):103–8. 10.1016/j.arcmed.2003.10.005
41. Xu F, Liu P, Pekar JJ, Lu H. Does acute caffeine ingestion alter brain metabolism in young adults? Neuroimage. 2015;110:39–47. 10.1016/j.neuroimage.2015.01.046
42. Kolahdouzan M, Hamadeh MJ. The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther. 2017;23(4):272–90. 10.1111/cns.12684
43. Devasagayam T, Kamat JP, Mohan H, Kesavan PC. Caffeine as an antioxidant: Inhibition of lipid peroxidation induced by reactive oxygen species. Biochim Biophys Acta. 1996;1282(1):63–70. 10.1016/0005-2736(96)00040-5
44. Mishra J, Kumar A. Improvement of mitochondrial NAD+/ FAD+-linked state-3 respiration by caffeine attenuates quinolinic acid-induced motor impairment in rats: Implications in Huntington’s disease. Pharmacol Rep. 2014;66(6):1148–55. 10.1016/j.pharep.2014.07.006
45. Carelli-Alinovi C, Ficarra S, Russo AM, Giunta E, Barreca D, Galtieri A, et al. Involvement of acetylcholinesterase and protein kinase C in the protective effect of caffeine against β-amyloid-induced alterations in red blood cells. Biochimie. 2016;121:52–9. 10.1016/j.biochi.2015.11.022
46. Ullah F, Ali T, Ullah N, Kim MO. Caffeine prevents d-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain. Neurochem Int. 2015;90:114–24. 10.1016/j.neuint.2015.07.001
2. Sanchez-Garrido MA, Tena-Sempere M. Metabolic dys-function in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937. 10.1016/j.molmet.2020.01.001
3. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370(9588):685–97. 10.1016/S0140-6736(07)61345-2
4. Rothenberg SS, Beverley R, Barnard E, Baradaran-Shoraka M, Sanfilippo JS. Polycystic ovary syndrome in adolescents. Best Pract Res Clin Obstet Gynaecol. 2018;48:103–14. 10.1016/j.bpobgyn.2017.08.008
5. Ainehchi N, Khaki A, Farshbaf-Khalili A, Hammadeh M, Ouladsahebmadarek E. The effectiveness of herbal mixture supplements with and without clomiphene citrate in comparison to clomiphene citrate on serum antioxidants and glycemic biomarkers in women with polycystic ovary syndrome willing to be rregnant: A randomized clinical trial. Biomolecules. 2019;9(6):215. 10.3390/biom9060215
6. Hadi A, Moradi S, Ghavami A, Khalesi S, Kafeshani M. Effect of probiotics and synbiotics on selected anthropometric and biochemical measures in women with polycystic ovary syndrome: A systematic review and meta-analysis. Eur J Clin Nutr. 2020;74(4):1–5. 10.1038/s41430-019-0434-9
7. Heidari B, Lerman A, Lalia AZ, Lerman LO, Chang AY. Effect of metformin on microvascular endothelial function in polycystic ovary syndrome. Mayo Clin Proc. 2019;94(12):2455–66. 10.1016/j.mayocp.2019.06.015
8. Lingaiah S, Morin-Papunen L, Risteli J, Tapanainen JS. Metformin decreases bone turnover markers in polycystic ovary syndrome: A post hoc study. Fertil Steril. 2019;112(2):362–70. 10.1016/j.fertnstert.2019.04.013
9. Meier RK. Polycystic ovary syndrome. Nurs Clin North Am. 2018;53(3):407–20. 10.1016/j.cnur.2018.04.008
10. Dumesic D, Hoyos LR, Chazenbalk GD, Naik R, Padmanabhan V, Abbott DH. Mechanisms of intergenerational transmission of polycystic ovary syndrome. Reproduction. 2020;159(1):R1–R13. 10.1530/REP-19-0197
11. Ostadmohammadi V, Jamilian M, Bahmani M, Asemi Z. Vitamin D and probiotic co-supplementation affects mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome. J Ovarian Res. 2019;12(1):5. 10.1186/s13048-019-0480-x
12. Wu PF, Li RZ, Zhang W, Hu HY, Wang W, Lin Y. Polycystic ovary syndrome is causally associated with estrogen receptor-positive instead of negative breast cancer: A Mendelian randomization study. Am J Obstet Gynecol. 2020;223(4):583–5. 10.1016/j.ajog.2020.05.016
13. Fett CA, Aquino NM, Junior JS, Brandão CF, Cavalcanti JDD, Fett WC. Performance of muscle strength and fatigue tolerance in young trained women supplemented with caffeine. J Sports Med Phys Fitness. 2018;58(3):249–55. 10.23736/S0022-4707.17.06615-4
14. Lane J, Steege JF, Rupp SL, Kuhn CM. Menstrual cycle effects on caffeine elimination in the human female. Eur J Clin Pharmacol. 1992;43(5):543–46. 10.1007/BF02285099
15. Fenster L, Quale C, Waller K, Windham GC, Elkin EP, Benowitz N, et al. Caffeine consumption and menstrual function. Am J Epidemiol. 1999;149(6):550–7. 10.1093/oxford-journals.aje.a009851
16. Wesselink AK, Wise LA, Rothman KJ, Hahn KA, Mikkelsen EM, Mahalingaiah S, et al. Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort. Reprod Toxicol. 2016;62:39–45. 10.1016/j.reprotox.2016.04.022
17. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Caffeinated and alcoholic beverage intake in relation to ovulatory disorder infertility. Epidemiology. 2009;20(3):374–81. 10.1097/EDE.0b013e31819d68cc
18. Caan B, Quesenberry CPJr, Coates AO. Differences in fertility associated with caffeinated beverage consumption. Am J Public Health. 1998;88(2):270–4. 10.2105/ajph.88.2.270.
19. Schliep KC, Schisterman EF, Wactawski-Wende J, Perkins NJ, Radin RG, Zarek SM, et al. Serum caffeine and paraxanthine concentrations and menstrual cycle function: Correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study. Am J Clin Nutrition. 2016;104(1):155–63. 10.3945/ajcn.115.118430
20. Kwak Y, Choi H, Bae J, Choi YY, Roh J. Peri-pubertal high caffeine exposure increases ovarian estradiol production in immature rats. Reprod Toxicol. 2017;69:43–52. 10.1016/j.reprotox.2017.01.007
21. Schliep KC, Schisterman EF, Mumford SL, Pollack AZ, Zhang C, Ye A, et al. Caffeinated beverage intake and reproductive hormones among premenopausal women in the BioCycle Study. Am J Clin Nutr. 2012;95(2):488–97. 10.3945/ajcn.111.021287
22. Fernandez M, Lopez A, Santa-Maria A. Apoptosis induced by different doses of caffeine on Chinese hamster ovary cells. J Appl Toxicol. 2003;23(4):221–4. 10.1002/jat.910
23. Raoofi A, Amini A, Farahani RM. The synergistic effect of curcumin and ziziphora extract due to their anti-inflammatory and antioxidant properties on ovarian tissue follicles. J Pharmaceutical Res Int. 2018;24(3):1–11. 10.9734/JPRI/2018/45124
24. Howard V, Reed M. Unbiased stereology: Three-dimensional measurement in microscopy. 2nd ed. London, UK: Garland Science; 2004. 277 p.
25. Nasiry D, Khalatbary AR, Ahmadvand H, Amiri FBT. Effects of Juglans regia L. leaf extract supplementation on testicular functions in diabetic rats. Biotech Histochem. 2020;96(1):1–7. 10.1080/10520295.2020.1755893
26. Duleba AJ, Dokras A. Is PCOS an inflammatory process? Fertil Steril. 2012;97(1):7–12. 10.1016/j.fertnstert.2011.11.023
27. Zirlik A, Abdullah SM, Gerdes N, MacFarlane L, Schönbeck U, Khera A, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: Results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007;27(9):2043–9. 10.1161/ATVBAHA.107.149484
28. Furtado MV, Rossini APW, Campani RB, Meotti C, Segatto M, Vietta G, et al. Interleukin-18: An independent predictor of cardiovascular events in patients with acute coronary syndrome after 6 months of follow-up. Coron Artery Dis. 2009;20(5):327–31. 10.1097/mca.0b013e32832e5c73
29. Hulsmans M, Holvoet P. The vicious circle between oxidative stress and inflammation in atherosclerosis. J Cell Mol Med. 2010;14(1–2):70–8. 10.1111/j.1582-4934.2009.00978.x
30. Sabuncu T, Vural H, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. Clin Biochem. 2001;34(5):407–13. 10.1016/s0009-9120(01)00245-4
31. Kuşçu NK, Var A. Oxidative stress but not endothelial dys-function exists in non-obese, young group of patients with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2009;88(5):612–7. 10.1080/00016340902859315
32. Fenkci V, Fenkci S, Yilmazer M, Serteser M. Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril. 2003;80(1):123–7. 10.1016/s0015-0282(03)00571-5
33. Dinger Y, Akcay T, Erdem T, Saygili EI, Gundogdu S. DNA damage, DNA susceptibility to oxidation and glutathione level in women with polycystic ovary syndrome. Scand J Clin Lab Invest. 2005;65(8):721–8. 10.1080/00365510500375263
34. Insenser M, Martínez-García MA, Montes R, San-Millán JL, Escobar-Morreale HF. Proteomic analysis of plasma in the polycystic ovary syndrome identifies novel markers involved in iron metabolism, acute-phase response, and inflammation. J Clin Endocrinol Metab. 2010;95(8):3863–70. 10.1210/jc.2010-0220
35. Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: A systematic review and metaanalysis. Fertil Steril. 2011;95(3):1048–58. 10.1016/j.fertnstert.2010.11.036
36. Bas D, Abramovich D, Hernandez F, Tesone M. Altered expression of Bcl-2 and Bax in follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Cell Biol Int. 2011;35(5):423–29. 10.1042/CBI20100542
37. Tilly JL, Tilly K. Inhibitors of oxidative stress mimic the ability of follicle-stimulating hormone to suppress apoptosis in cultured rat ovarian follicles. Endocrinology. 1995;136(1):242–52. 10.1210/endo.136.1.7828537
38. Tilly JL. Apoptosis and ovarian function. Rev Reproduction. 1996;1(3):162–72. 10.1530/ror.0.0010162
39. Shah KN, Patel SS. Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome. Pharm Biol. 2016;54(6):975–83. 10.3109/13880209.2015.1091482
40. Kafali H, Iriadam M, Ozardali I, Demir N. Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease. Arch Med Res. 2004;35(2):103–8. 10.1016/j.arcmed.2003.10.005
41. Xu F, Liu P, Pekar JJ, Lu H. Does acute caffeine ingestion alter brain metabolism in young adults? Neuroimage. 2015;110:39–47. 10.1016/j.neuroimage.2015.01.046
42. Kolahdouzan M, Hamadeh MJ. The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther. 2017;23(4):272–90. 10.1111/cns.12684
43. Devasagayam T, Kamat JP, Mohan H, Kesavan PC. Caffeine as an antioxidant: Inhibition of lipid peroxidation induced by reactive oxygen species. Biochim Biophys Acta. 1996;1282(1):63–70. 10.1016/0005-2736(96)00040-5
44. Mishra J, Kumar A. Improvement of mitochondrial NAD+/ FAD+-linked state-3 respiration by caffeine attenuates quinolinic acid-induced motor impairment in rats: Implications in Huntington’s disease. Pharmacol Rep. 2014;66(6):1148–55. 10.1016/j.pharep.2014.07.006
45. Carelli-Alinovi C, Ficarra S, Russo AM, Giunta E, Barreca D, Galtieri A, et al. Involvement of acetylcholinesterase and protein kinase C in the protective effect of caffeine against β-amyloid-induced alterations in red blood cells. Biochimie. 2016;121:52–9. 10.1016/j.biochi.2015.11.022
46. Ullah F, Ali T, Ullah N, Kim MO. Caffeine prevents d-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain. Neurochem Int. 2015;90:114–24. 10.1016/j.neuint.2015.07.001
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Nov 1, 2022
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Raoofi, A., Rezaie, M. J., Delbari, A., Ghoreishi, S. A.-H., Sichani, P. H., Maleki, S., Nasiry, D., Akhlaghi, M., Ebrahimi, V., & Mousavi Khaneghah, A. (2022). Therapeutic potentials of the caffeine in polycystic ovary syndrome in a rat model: Via modulation of proinflammatory cytokines and antioxidant activity. Allergologia Et Immunopathologia, 50(6), 137-146. https://doi.org/10.15586/aei.v50i6.715
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How to Cite
Raoofi, A., Rezaie, M. J., Delbari, A., Ghoreishi, S. A.-H., Sichani, P. H., Maleki, S., Nasiry, D., Akhlaghi, M., Ebrahimi, V., & Mousavi Khaneghah, A. (2022). Therapeutic potentials of the caffeine in polycystic ovary syndrome in a rat model: Via modulation of proinflammatory cytokines and antioxidant activity. Allergologia Et Immunopathologia, 50(6), 137-146. https://doi.org/10.15586/aei.v50i6.715