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Pourheydar, B., Azarm, F., Farjah, G., Karimipour, M., & Pourheydar, M. (2022). Effect of silymarin and metformin on the sperm parameters and histopathological changes of testes in diabetic rats: An experimental study. International Journal of Reproductive BioMedicine (IJRM), 19(12), 1091-1104. https://doi.org/10.18502/ijrm.v19i12.10060
https://doi.org/10.18502/ijrm.v19i12.10060
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- Cited by 5 articles
authors
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Bagher Pourheydar
Bagher Pourheydar
Department of Anatomical Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
-
Fatemeh Azarm
Fatemeh Azarm
Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
-
Gholamhossein Farjah
Gholamhossein Farjah
Department of Anatomical Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
-
Mojtaba Karimipour
Mojtaba Karimipour
Department of Anatomical Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
-
Maryam Pourheydar
Maryam Pourheydar
Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
Published Date
- Jan 12, 2022
Effect of silymarin and metformin on the sperm parameters and histopathological changes of testes in diabetic rats: An experimental study
Abstract
Background: Oxidative stress is a major contributor to diabetes, which can lead to testicular damage and infertility.
Objective: This study aimed to compare the effects of metformin as a chemical drug with silymarin as an herbal agent on the sperm parameters and histopathological changes of testes in diabetic rats.
Materials and Methods: Thirty-two male Wistar rats (250-270 gr) were randomly divided into four groups: 1) control; 2) diabetic; 3) diabetic+metformin 200 mg/kg; and 4) diabetic+silymarin 100 mg/kg. Daily injections were administered intraperitoneally for 56 days. At the end of the treatment, blood sampling was performed for biochemical assessment. Then, the rats were sacrificed and their left testis and epididymis were cut for sperm analysis as well as histopathology and morphometric evaluation.
Results: Diabetes was associated with a reduced sperm count, motility, viability, maturity, and chromatin quality of sperm (p ≤ 0.001). It was also associated with a higher malondialdehide level and lower total antioxidant capacity level of serum in comparison with the control group (p ≤ 0.001). There was a significant difference in the seminiferous tubule diameter, germinal epithelium height, and testicular histopathological alterations in the diabetic rats compared with the control rats (p ≤ 0.001). Treatment with metformin and silymarin improved the above-mentioned parameters and this improvement was more substantial in silymarin-treated animals (p ≤ 0.001).
Conclusion: In diabetic rats, metformin and silymarin improved sperm parameters, sperm DNA integrity, seminiferous tubule diameter, germinal epithelium thickness, and testicular histopathological complications; this improvement was more substantial in the silymarin-treated group. So, the findings of this study suggest that silymarin is more effective than metformin in treating diabetic-induced infertility.
Key words: Diabetes, DNA damage, Metformin, Silymarin, Sperm, Testis.
References
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[15] Shokri S, Hemadi M, Bayat G, Bahmanzadeh M, Jafari-Anarkooli I, Mashkani B. Combination of running exercise and high dose of anabolic androgenic steroid, nansrolone decanoate, increases protamine deficiency and DNA damage in rat spermatozoa. Andrologia 2014; 46: 184–190.
[16] Ghanbari M, Mortazavi SB, Khavanin A, Khazaei M. Simultaneus effects of exposure to microwaves and noise on male rat sperm parameters and total antioxidant capacity. Health Scope 2013; 1: 178–184.
[17] Momeni HR, Eskandari N. Effect of vitamin E on sperm parameters and DNA integrity in sodium arsenite-induced rats. Iran J Reprod Med 2012; 10: 249–256.
[18] Kazerooni T, Asadi N, Jadid L, Kazerooni M, Ghanadi AR, Ghaffarpasand F, et al. Evaluation of sperm’s chromatin quality with acridine orange test, chromomycin A3 and anilin blue staining in couples with unexplained recurrent abortion. J Assist Reprod Genet 2009; 26: 591–596.
[19] Ognjanovic BI, Markovic SD, Dordevic NZ, Trbojevic IS, Stajn AS, Saicic ZS. Cadmium-induced lipid peroxidation and changes antioxidant defense system in the rat testes: Protective role of coenzyme Q10 and vitamin E. Reprod Toxicol 2010; 29: 191–197.
[20] Mirzaei Khorramabadi Kh, Talebi AR, Abbasi Sarcheshmeh A, Mirjalili A. Protective effect of vitamin E on oxidative stress and sperm apoptosis in diabetic mice. Int J Reprod Biomed 2019; 17: 127–134.
[21] Mortazavi M, Salehi I, Alizade Z, Vahabian M, Mohammadi Roushandeh A. Protective effects of antioxidants on sperm parameters and seminiferous tubules epithelium in high fat-fed rats. J Reperod Infertil 2014; 15: 22–28.
[22] Mardanshahi T, Rezaei N, Zare Z, Malekzadeh Shafaroudi M, Mohammadi HR. Effect of L-carnitine on the sperm parameters, apoptosis of spermatogenic cells and testis histopathology in diabetic rats. Int J Reprod Biomed 2018; 17: 325–336.
[23] Mahmoud YK, Saleh ShY, El Ghannam AERA, Ibrahim IA. Biochemical efficacy of Nigella sativa oil and metformin on induced diabetic male rats. Am J Anim Vet Sci 2014; 9: 277–284.
[24] El-Far M, Negm A, Wahdan M. Promising biopharmaceutical use of silymarin and silibinin as anti-diabetic natural agents in streptozotocin-induced diabetic rats: First comparative assessment. World J Pharm Pharmaceut Sci 2015; 4: 7–28.
[25] Yaman T, Uyar A, Salih Kaya M, Faruk Keles O, Atalay Uslu B, Yener Z. Protective effects of silymarin on methotrexateinduced damages in rat testis. Braz J Pharm Sci 2018; 54: e17529.
[26] Omolaoye Temidayo S, du Plessis Stefan S. Diabetes mellitus and male infertility. Asian Pac J Reprod 2018; 7: 6–14.
[27] Eskenazi B, Kidd SA, Marks AR, Sloter E, Block G, Wyrobek AJ. Antioxidant intake is associated with semen quality in healthy men. Hum Reorod 2005; 20: 1006–1012.
[28] Wang X, Hai CX. ROS act as a double-edged sword in the pathogenesis of type-2 diabetes: Is Nrf2 a potential target for the treatment? Mini Rev Med Chem 2011; 11: 1082–1092.
[29] Farjad E, Momeni HR. Silymarin ameliorates oxidative stress and enhances antioxidant defense system capacity in cadmium-treated mice. Cell J 2018; 20: 422–426.
[30] Surui PF. Silymarin as a natural antioxidant. An overview of the current evidence and perspectives. Antioxidants (Basel) 2015; 4: 204–247.
[31] Azad F, Nejati V, Shalizar-Jalali A, Najafi GhR, Rahmani F. Royal jelly protects male mice against nicotine-induced reproductive failure. Vet Res Forum 2018; 9: 231–238.
[32] Cho Ch, Jung-Ha H, Willis WD, Goulding EH, Stein P, Xu Zh, et al. Protamin 2 deficiency leads to sperm DNA damage and embryo death in mice. Biol Reprod 2003; 69: 211–217.
[33] Sadeghi MR, Hodjat M, Lakpour N, Arefi S, Amirjanatti N, Modarresi T, et al. Effect of sperm chromatin integrity oh fertilization rate and embryo quality following intracytoplasmic sperm injection. Avicenna J Med Biotechnol 2009; 1: 173–180.
[34] Jalili C, Kamani M, Roshankhah Sh, Sadeghi H, Salahshoor MR. Effects of Falcaria vulgaris extracts on sperm parameters in diabetic rats. Andrologia 2018; 50: e13130.
[35] Yaman O, Topcu-Tarladacalisir Y. L-carnitine counteracts prepubertal exposure to cisplatin induced improved sperm in adult rats by preventing germ cells apoptosis. Biotech Histochem 2018; 93: 157–167.
[36] Shahreari Sh, Khaki A, Ahmadi-Ashtiani HR, Rezazadeh Sh, Hajiaghaei R. Effects of Danae racemosa on testosterone hormone in experimental diabetic rats. J Med Plants 2010; 9: 114–119.
[37] Asadi S, Goodarzi MT, Karimi J, Hashemnia M, Khodadadi I. Does curcumin or metformin attenuate oxidative stress and diabetic nephropathy in rats? J Nephropathol 2019; 8: e08.
[2] Nasrolahi O, Khaneshi F, Rahmani F, Razi M. Honey and metformin ameliorated diabetes-induced damages in testes of rat: Correlation with hormonal changes. Iran J Reprod Med 2013; 11: 1013–1020.
[3] Ghanbari E, Nejati V, Azadbakht M. Protective effect of royal jelly against renal damage in streptozotocin-induced diabetic rats. Iran J Toxicol 2015; 9: 1258–1263.
[4] Kim SH, Kim SC, Ku JL. Metformin increases chemosensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. Oncotarget 2017; 8: 56546–56557.
[5] Zhang S, Xu H, YU X, Wu Y, Sui D. Metformin ameliorated diabetic nephropathy in a rat model of lowdose streptozotocin-induced diabetes. Exp Ther Med 2017; 14: 383–390.
[6] Tan MH, Alquaini H, Mizokami-Stout K, MacEachern M. Metformin: From research to clinical practice. Endocrinol Metab Clin North Am 2016; 45: 819–843.
[7] Saisho Y. Metformin and inflammation: Its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 2015; 15: 196–205.
[8] Park MJ, Lee SY, Moon SJ, Son HJ, lee SH, Kim EK, et al. Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription3 and promoting adenosine monophosphate-activated protein kinase
-autophagy for the balance between T helper 17 and Treges. Transl Res 2016; 173: 115–130.
[9] Fatima M, Sadeeqa S, Nazir SUR. Metformin and its gastrointestinal problems: A review. Biomed Res 2018; 29: 2285–2289.
[10] Taghiabadi E, Imenshahidi M, Abnous Kh, Mosafa F, Sankian M, Memar B, et al. Protective effect of silymarin against acrolein-induced cardiotoxicity in mice. Evid Based Complement Altern Med 2012; 2012: 352091.
[11] Darbandi M, Darbandi S, Agrawal A, Sengupta P, Durairajanayagam D, Henkel R, et al. Reactive oxygen species and male reproductive hormones. Reprod Biol Endocrinol 2018; 16: 87.
[12] Sing BK, Sing A, Kumar V. Ameliorative effect of adjunct therapy of metformin with atorvastatin on streptozotocininduced diabetes mellitus in rats. Drug Res (Stuttg) 2016; 66: 28–32.
[13] Mousavi F, Eidi A, Khalili M, Roghani M. Metformin ameliorated learning and memory deficits in streptozotocin-induced diabetes rats. J Basic Clin Pathophysiol 2018; 6: 17–22.
[14] Baluchnejadmojarad T, Roghani M, Homayonfar H, Khaste Khodaei Z. [Protective effect of chronic administration of silymarin on blood glucose and lipids and oxidative stress in diabetic rats]. Koomesh 2009; 10: 143–150. (in Persian)
[15] Shokri S, Hemadi M, Bayat G, Bahmanzadeh M, Jafari-Anarkooli I, Mashkani B. Combination of running exercise and high dose of anabolic androgenic steroid, nansrolone decanoate, increases protamine deficiency and DNA damage in rat spermatozoa. Andrologia 2014; 46: 184–190.
[16] Ghanbari M, Mortazavi SB, Khavanin A, Khazaei M. Simultaneus effects of exposure to microwaves and noise on male rat sperm parameters and total antioxidant capacity. Health Scope 2013; 1: 178–184.
[17] Momeni HR, Eskandari N. Effect of vitamin E on sperm parameters and DNA integrity in sodium arsenite-induced rats. Iran J Reprod Med 2012; 10: 249–256.
[18] Kazerooni T, Asadi N, Jadid L, Kazerooni M, Ghanadi AR, Ghaffarpasand F, et al. Evaluation of sperm’s chromatin quality with acridine orange test, chromomycin A3 and anilin blue staining in couples with unexplained recurrent abortion. J Assist Reprod Genet 2009; 26: 591–596.
[19] Ognjanovic BI, Markovic SD, Dordevic NZ, Trbojevic IS, Stajn AS, Saicic ZS. Cadmium-induced lipid peroxidation and changes antioxidant defense system in the rat testes: Protective role of coenzyme Q10 and vitamin E. Reprod Toxicol 2010; 29: 191–197.
[20] Mirzaei Khorramabadi Kh, Talebi AR, Abbasi Sarcheshmeh A, Mirjalili A. Protective effect of vitamin E on oxidative stress and sperm apoptosis in diabetic mice. Int J Reprod Biomed 2019; 17: 127–134.
[21] Mortazavi M, Salehi I, Alizade Z, Vahabian M, Mohammadi Roushandeh A. Protective effects of antioxidants on sperm parameters and seminiferous tubules epithelium in high fat-fed rats. J Reperod Infertil 2014; 15: 22–28.
[22] Mardanshahi T, Rezaei N, Zare Z, Malekzadeh Shafaroudi M, Mohammadi HR. Effect of L-carnitine on the sperm parameters, apoptosis of spermatogenic cells and testis histopathology in diabetic rats. Int J Reprod Biomed 2018; 17: 325–336.
[23] Mahmoud YK, Saleh ShY, El Ghannam AERA, Ibrahim IA. Biochemical efficacy of Nigella sativa oil and metformin on induced diabetic male rats. Am J Anim Vet Sci 2014; 9: 277–284.
[24] El-Far M, Negm A, Wahdan M. Promising biopharmaceutical use of silymarin and silibinin as anti-diabetic natural agents in streptozotocin-induced diabetic rats: First comparative assessment. World J Pharm Pharmaceut Sci 2015; 4: 7–28.
[25] Yaman T, Uyar A, Salih Kaya M, Faruk Keles O, Atalay Uslu B, Yener Z. Protective effects of silymarin on methotrexateinduced damages in rat testis. Braz J Pharm Sci 2018; 54: e17529.
[26] Omolaoye Temidayo S, du Plessis Stefan S. Diabetes mellitus and male infertility. Asian Pac J Reprod 2018; 7: 6–14.
[27] Eskenazi B, Kidd SA, Marks AR, Sloter E, Block G, Wyrobek AJ. Antioxidant intake is associated with semen quality in healthy men. Hum Reorod 2005; 20: 1006–1012.
[28] Wang X, Hai CX. ROS act as a double-edged sword in the pathogenesis of type-2 diabetes: Is Nrf2 a potential target for the treatment? Mini Rev Med Chem 2011; 11: 1082–1092.
[29] Farjad E, Momeni HR. Silymarin ameliorates oxidative stress and enhances antioxidant defense system capacity in cadmium-treated mice. Cell J 2018; 20: 422–426.
[30] Surui PF. Silymarin as a natural antioxidant. An overview of the current evidence and perspectives. Antioxidants (Basel) 2015; 4: 204–247.
[31] Azad F, Nejati V, Shalizar-Jalali A, Najafi GhR, Rahmani F. Royal jelly protects male mice against nicotine-induced reproductive failure. Vet Res Forum 2018; 9: 231–238.
[32] Cho Ch, Jung-Ha H, Willis WD, Goulding EH, Stein P, Xu Zh, et al. Protamin 2 deficiency leads to sperm DNA damage and embryo death in mice. Biol Reprod 2003; 69: 211–217.
[33] Sadeghi MR, Hodjat M, Lakpour N, Arefi S, Amirjanatti N, Modarresi T, et al. Effect of sperm chromatin integrity oh fertilization rate and embryo quality following intracytoplasmic sperm injection. Avicenna J Med Biotechnol 2009; 1: 173–180.
[34] Jalili C, Kamani M, Roshankhah Sh, Sadeghi H, Salahshoor MR. Effects of Falcaria vulgaris extracts on sperm parameters in diabetic rats. Andrologia 2018; 50: e13130.
[35] Yaman O, Topcu-Tarladacalisir Y. L-carnitine counteracts prepubertal exposure to cisplatin induced improved sperm in adult rats by preventing germ cells apoptosis. Biotech Histochem 2018; 93: 157–167.
[36] Shahreari Sh, Khaki A, Ahmadi-Ashtiani HR, Rezazadeh Sh, Hajiaghaei R. Effects of Danae racemosa on testosterone hormone in experimental diabetic rats. J Med Plants 2010; 9: 114–119.
[37] Asadi S, Goodarzi MT, Karimi J, Hashemnia M, Khodadadi I. Does curcumin or metformin attenuate oxidative stress and diabetic nephropathy in rats? J Nephropathol 2019; 8: e08.