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Shafie, A., Kianian, F., Ashabi, G., Kadkhodaee, M., Ranjbaran, M., Hajiaqaei, M., Lorian, K., Abdi, A., & Seifi, B. (2022). Beneficial effects of combination therapy with testosterone and hydrogen sulfide by reducing oxidative stress and apoptosis: Rat experimental varicocele model. International Journal of Reproductive BioMedicine (IJRM), 20(11), 941–954. https://doi.org/10.18502/ijrm.v20i11.12362
https://doi.org/10.18502/ijrm.v20i11.12362
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authors
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Anahid Shafie
Anahid Shafie
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Farzaneh Kianian
Farzaneh Kianian
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Ghorbangol Ashabi
Ghorbangol Ashabi
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Mehri Kadkhodaee
Mehri Kadkhodaee
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Mina Ranjbaran
Mina Ranjbaran
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Mahdi Hajiaqaei
Mahdi Hajiaqaei
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Keivan Lorian
Keivan Lorian
Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
-
Arash Abdi
Arash Abdi
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
-
Behjat Seifi
Behjat Seifi
Department of Physiology, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran.
Published Date
- Dec 12, 2022
Beneficial effects of combination therapy with testosterone and hydrogen sulfide by reducing oxidative stress and apoptosis: Rat experimental varicocele model
Abstract
Background: Despite the effectiveness of testosterone therapy in conditions associated with testosterone deficiency, including varicocele, several dose-dependent side effects limit the clinical use of testosterone therapy. Hydrogen sulfide, a toxic gas in high concentrations but a beneficial molecule in low concentrations, acts as both a major effector and an important inducer of testosterone.
Objective: This study investigated whether a subeffective dose of testosterone combined with a subeffective dose of hydrogen sulfide donor sodium hydrosulfide (NaHS) can be effective in an experimental varicocele model through a possible additive effect.
Materials and Methods: Thirty Wistar rats weighing 200-250 gr were divided into 5 groups as (n = 6/each): sham, varicocele, testosterone (200 μg/kg, 5 times per wk for 4 consecutive wk), NaHS (15 μmol/L, daily for 4 consecutive wk) and testosterone + NaHS (200 μg/kg, 5 times per wk + 15 μmol/L, daily, both for 4 consecutive wk). All animals, except in the sham group, underwent varicocele induction.
Results: The coadministration of testosterone and NaHS significantly increased serum testosterone (10.23 ± 0.95, p = 0.01), testicular H2S levels (608.94 ± 21.09, p < 0.001), and testicular superoxide dismutase activity (66.14 ± 1.56, p < 0.001), decreased malondialdehyde levels (0.77 ± 0.52, p < 0.001), and B-cell lymphoma 2-associated X protein to B-cell lymphoma 2 (0.16 ± 0.01, p < 0.001) protein expression ratio in the testicular tissues and improved sperm parameters and testicular histopathology compared to the varicocele group.
Conclusion: The combination therapy of subeffective doses of testosterone and NaHS can attenuate the varicocele-induced damages by reducing testicular oxidative stress and apoptosis and thus can be considered an effective approach with fewer side effects.
Key words: Apoptosis genes, Hydrogen sulfide, Oxidative stress, Sperm count, Testosterone, Varicocele.
References
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[2] Ohlander SJ, Lindgren MC, Lipshultz LI. Testosterone and male infertility. Urol Clin North AM 2016; 43: 195-202.
[3] Çayan S, Akbay E, Saylam B, Kadioglu A. Effect of varicocele and its treatment on testosterone in hypogonadal men with varicocele: Review of the literature. Balkan Med J 2020; 37: 121-124.
[4] Panach-Navarrete J, Morales-Giraldo A, Ferrandis-Cortes C, Garcia-Morata F, Pastor-Lence JC, Martinez-Jabaloyas JM. Is there a relationship between varicocele and testosterone levels? The Aging Male 2020; 23: 592-598.
[5] Bernie HL, Goldstein M. Varicocele repair versus testosterone therapy for older hypogonadal men with clinical varicocele and low testosterone. European Urology Focus 2018; 4: 314-316.
[6] Agarwal A, Sharma R, Harlev A, Esteves SC. Effect of varicocele on semen characteristics according to the new 2010 world health organization criteria: A systematic review and meta-analysis. Asian J Androl 2016; 18: 163-170.
[7] Birowo P, Rahendra Wijaya J, Atmoko W, Rasyid N. The effects of varicocelectomy on the DNA fragmentation index and other sperm parameters: A meta-analysis. Basic and Clinical Andrology 2020; 30: 1-9.
[8] Jangkhah M, Farrahi F, Gilani MAS, Hosseini SJ, Dadkhah F, Salmanyazdi R, et al. Effects of varicocelectomy on serum testosterone levels among infertile men with varicocele. Int J Fertil Steril 2018; 12: 169-172.
[9] An Q, Zhang K, Fu L, Guo Y, Zhang C, Ge Z, et al. The impact of exogenous testosterone supplementation on spermatogenesis in a rat model of oligoasthenospermia. Int J Clin Exp Pathol 2020; 13: 1287-1299.
[10] Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to testosterone therapy: A review. Sex Med Rev 2018; 6: 106- 113.
[11] Fusco F, Verze P, Capece M, Napolitano L. Suppression of spermatogenesis by exogenous testosterone. Curr Pharm Des 2021; 27: 2750-2753. [12] Aroca A, Gotor C, Bassham DC, Romero LC. Hydrogen sulfide: From a toxic molecule to a key molecule of cell life. Antioxidants 2020; 9: 621.
[13] Wang J, Wang J, Shen T, Hong R, Tang S, Zhao X. H2S catalysed by CBS regulates testosterone synthesis through affecting the sulfhydrylation of PDE. J Cell Mol Med 2021; 25: 3460-3468.
[14] Azarbarz N, Shafiei Seifabadi Z, Moaiedi MZ, Mansouri E. Assessment of the effect of sodium hydrogen sulfide (hydrogen sulfide donor) on cisplatin-induced testicular toxicity in rats. Environ Sci Pollut Res Int 2020; 27: 8119-8128.
[15] Kang J, Jia Zh, Ping Y, Liu Z, Yan X, Xing G, et al. Testosterone alleviates mitochondrial ROS accumulation and mitochondria-mediated apoptosis in the gastric mucosa of orchiectomized rats. Arch Biochem Biophys 2018; 649: 53-59.
[16] Kianian F, Seifi B, Kadkhodaee M, Sajedizadeh A, Ahghari P. Protective effects of celecoxib on ischemia reperfusion-induced acute kidney injury: Comparing between male and female rats. Iran J Basic Med Sci 2019; 22: 43-48.
[17] Siregar S, Noegroho BS, Adriansjah R, Mustafa A, Bonar A. The effect of intratesticular injection of human adipose-derived mesenchymal cell on testicular oxidative stress and spermatogenesis process in the varicocele rat model. Res Rep Urol 2021; 13: 759-765.
[18] Turner TT. The study of varicocele through the use of animal models. Hum Reprod Update 2001; 7: 78-84.
[19] Fu L, Liu Y, Wang J, Sun Y, Zhang L, Wu T, et al. Cardioprotection by low-dose of estrogen and testosterone at the physiological ratio on ovariectomized rats during ischemia/reperfusion injury. J Cardiovas Pharmacol 2017; 70: 87-93.
[20] Khosravanian N, Razi M, Farokhi F, Khosravanian H. Testosterone and vitamin E administration up-regulated varicocele-reduced Hsp70-2 protein expression and ameliorated biochemical alterations. J Assist Reprod Genet 2014; 31: 341-354.
[21] Lorian K, Kadkhodaee M, Kianian F, Abdi A, Seifi B. Administration of sodium hydrosulfide reduces remote organ injury by an anti-oxidant mechanism in a rat model of varicocele. Iran J Basic Med Sci 2020; 23: 236-243.
[22] Hedayati Emami N, Mahmoudi Lafout F, Mohammadghasemi F. Administration of melatonin protects against acetylsalicylic acid-induced impairment of male reproductive function in mice. Iran J Basic Med Sci 2018; 21: 124-129.
[23] Boitrelle F, Shah R, Saleh R, Henkel R, Kandil H, Chung E, et al. The sixth edition of the WHO manual for human semen analysis: A critical review and SWOT analysis. Life (Basel) 2021; 11: 1368.
[24] Lorian K, Kadkhodaee M, Kianian F, Abdi A, Ranjbaran M, Ashabi G, et al. Long-term NaHS administration reduces oxidative stress and apoptosis in a rat model of left-side varicocele. Andrologia 2020; 52: e13496.
[25] Cecere JT. Eosin-Nigrosin staining in the evaluation of sperm. In: Dascanio J, McCue P. Equine reproductive procedures. 2nd Ed. USA: John Wiley & Sons Inc; 2014: 373- 376.
[26] Seifi B, Sajedizadeh A, Kadkhodaee M, Ranjbaran M. Longterm exercise restores hydrogen sulfide in the kidney and contributes to exercise benefits in 5/6 nephrectomized rats. Clin Exp Hypertens 2019; 41: 87-91.
[27] Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4- hydroxynonenal. Methods in Enzymology 1990; 186: 407-421.
[28] Kianian F, Seifi B, Kadkhodaee M, Sadeghipour HR, Ranjbaran M. Nephroprotection through modifying the apoptotic tnf-α/erk1/2/bax signaling pathway and oxidative stress by long-term sodium hydrosulfide administration in ovalbumin-induced chronic asthma. Immunol Invest 2022; 51: 602-618.
[29] Pourmirzaei F, Ranjbaran M, Kadkhodaee M, Kianian F, Lorian K, Abdi A, et al. Sperm and testicular dysfunction during cecal ligation and puncture-induced sepsis in male rats and effects of tannic acid through reducing testicular oxidative stress and inflammation. Iran J Basic Med Sci 2021; 24: 1554-1560.
[30] Talebi H, Farahpour MR, Hamishehkar H. The effectiveness of rutin for prevention of surgical induced endometriosis development in a rat model. Sci Rep 2021; 11: 7180.
[31] Zhang J, Jin PP, Gong M, Yi QT, Zhu RJ. Role of leptin and the leptin receptor in the pathogenesis of varicocele-induced testicular dysfunction. Mol Med Rep 2018; 17: 7065- 7072.
[32] Miller WL. Steroidogenesis: Unanswered questions. Trends Endocrinol Metab 2017; 28: 771-793.
[33] Abdel-Meguid TA, Farsi HM, Al-Sayyad A, Tayib A, Mosli HA, Halawani AH. Effects of varicocele on serum testosterone and changes of testosterone after varicocelectomy: A prospective controlled study. Urology 2014; 84: 1081-1087.
[34] Wang K, Gao Y, Wang Ch, Liang M, Liao Y, Hu K. Role of oxidative stress in varicocele. Front Genet 2022; 13: 850114.
[35] Nishimura H, L’Hernault SW. Spermatogenesis. Curr Biol 2017; 27: R988-R994.
[36] Hayden RP, Tanrikut C. Testosterone and varicocele. Urol Clin North Am 2016; 43: 223-232.
[37] Lorian K, Kadkhodaee M, Kianian F, Abdi A, Sadeghipour H, Seifi B. Oxidative stress, nitric oxide and inflammation in the pathophysiology of varicocele and the effect of hydrogen sulfide as a potential treatment. Physiol Pharmacol 2019; 23: 249-260.
[38] Shiraishi K, Takihara H, Matsuyama H. Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis. World J Urol 2010; 28: 359-364.
[39] Gur FM, Timurkaan S, Taskin E, Guven C, Gur HE, Senturk M, et al. Thymoquinone improves testicular damage and sperm quality in experimentally varicocele-induced adolescent rats. Andrologia 2021; 53: e14033.
[40] Flores-Romero H, Hohorst L, John M, Albert MC, King LE, Beckmann L, et al. BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. EMBO J 2022; 41: e108690.
[2] Ohlander SJ, Lindgren MC, Lipshultz LI. Testosterone and male infertility. Urol Clin North AM 2016; 43: 195-202.
[3] Çayan S, Akbay E, Saylam B, Kadioglu A. Effect of varicocele and its treatment on testosterone in hypogonadal men with varicocele: Review of the literature. Balkan Med J 2020; 37: 121-124.
[4] Panach-Navarrete J, Morales-Giraldo A, Ferrandis-Cortes C, Garcia-Morata F, Pastor-Lence JC, Martinez-Jabaloyas JM. Is there a relationship between varicocele and testosterone levels? The Aging Male 2020; 23: 592-598.
[5] Bernie HL, Goldstein M. Varicocele repair versus testosterone therapy for older hypogonadal men with clinical varicocele and low testosterone. European Urology Focus 2018; 4: 314-316.
[6] Agarwal A, Sharma R, Harlev A, Esteves SC. Effect of varicocele on semen characteristics according to the new 2010 world health organization criteria: A systematic review and meta-analysis. Asian J Androl 2016; 18: 163-170.
[7] Birowo P, Rahendra Wijaya J, Atmoko W, Rasyid N. The effects of varicocelectomy on the DNA fragmentation index and other sperm parameters: A meta-analysis. Basic and Clinical Andrology 2020; 30: 1-9.
[8] Jangkhah M, Farrahi F, Gilani MAS, Hosseini SJ, Dadkhah F, Salmanyazdi R, et al. Effects of varicocelectomy on serum testosterone levels among infertile men with varicocele. Int J Fertil Steril 2018; 12: 169-172.
[9] An Q, Zhang K, Fu L, Guo Y, Zhang C, Ge Z, et al. The impact of exogenous testosterone supplementation on spermatogenesis in a rat model of oligoasthenospermia. Int J Clin Exp Pathol 2020; 13: 1287-1299.
[10] Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to testosterone therapy: A review. Sex Med Rev 2018; 6: 106- 113.
[11] Fusco F, Verze P, Capece M, Napolitano L. Suppression of spermatogenesis by exogenous testosterone. Curr Pharm Des 2021; 27: 2750-2753. [12] Aroca A, Gotor C, Bassham DC, Romero LC. Hydrogen sulfide: From a toxic molecule to a key molecule of cell life. Antioxidants 2020; 9: 621.
[13] Wang J, Wang J, Shen T, Hong R, Tang S, Zhao X. H2S catalysed by CBS regulates testosterone synthesis through affecting the sulfhydrylation of PDE. J Cell Mol Med 2021; 25: 3460-3468.
[14] Azarbarz N, Shafiei Seifabadi Z, Moaiedi MZ, Mansouri E. Assessment of the effect of sodium hydrogen sulfide (hydrogen sulfide donor) on cisplatin-induced testicular toxicity in rats. Environ Sci Pollut Res Int 2020; 27: 8119-8128.
[15] Kang J, Jia Zh, Ping Y, Liu Z, Yan X, Xing G, et al. Testosterone alleviates mitochondrial ROS accumulation and mitochondria-mediated apoptosis in the gastric mucosa of orchiectomized rats. Arch Biochem Biophys 2018; 649: 53-59.
[16] Kianian F, Seifi B, Kadkhodaee M, Sajedizadeh A, Ahghari P. Protective effects of celecoxib on ischemia reperfusion-induced acute kidney injury: Comparing between male and female rats. Iran J Basic Med Sci 2019; 22: 43-48.
[17] Siregar S, Noegroho BS, Adriansjah R, Mustafa A, Bonar A. The effect of intratesticular injection of human adipose-derived mesenchymal cell on testicular oxidative stress and spermatogenesis process in the varicocele rat model. Res Rep Urol 2021; 13: 759-765.
[18] Turner TT. The study of varicocele through the use of animal models. Hum Reprod Update 2001; 7: 78-84.
[19] Fu L, Liu Y, Wang J, Sun Y, Zhang L, Wu T, et al. Cardioprotection by low-dose of estrogen and testosterone at the physiological ratio on ovariectomized rats during ischemia/reperfusion injury. J Cardiovas Pharmacol 2017; 70: 87-93.
[20] Khosravanian N, Razi M, Farokhi F, Khosravanian H. Testosterone and vitamin E administration up-regulated varicocele-reduced Hsp70-2 protein expression and ameliorated biochemical alterations. J Assist Reprod Genet 2014; 31: 341-354.
[21] Lorian K, Kadkhodaee M, Kianian F, Abdi A, Seifi B. Administration of sodium hydrosulfide reduces remote organ injury by an anti-oxidant mechanism in a rat model of varicocele. Iran J Basic Med Sci 2020; 23: 236-243.
[22] Hedayati Emami N, Mahmoudi Lafout F, Mohammadghasemi F. Administration of melatonin protects against acetylsalicylic acid-induced impairment of male reproductive function in mice. Iran J Basic Med Sci 2018; 21: 124-129.
[23] Boitrelle F, Shah R, Saleh R, Henkel R, Kandil H, Chung E, et al. The sixth edition of the WHO manual for human semen analysis: A critical review and SWOT analysis. Life (Basel) 2021; 11: 1368.
[24] Lorian K, Kadkhodaee M, Kianian F, Abdi A, Ranjbaran M, Ashabi G, et al. Long-term NaHS administration reduces oxidative stress and apoptosis in a rat model of left-side varicocele. Andrologia 2020; 52: e13496.
[25] Cecere JT. Eosin-Nigrosin staining in the evaluation of sperm. In: Dascanio J, McCue P. Equine reproductive procedures. 2nd Ed. USA: John Wiley & Sons Inc; 2014: 373- 376.
[26] Seifi B, Sajedizadeh A, Kadkhodaee M, Ranjbaran M. Longterm exercise restores hydrogen sulfide in the kidney and contributes to exercise benefits in 5/6 nephrectomized rats. Clin Exp Hypertens 2019; 41: 87-91.
[27] Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4- hydroxynonenal. Methods in Enzymology 1990; 186: 407-421.
[28] Kianian F, Seifi B, Kadkhodaee M, Sadeghipour HR, Ranjbaran M. Nephroprotection through modifying the apoptotic tnf-α/erk1/2/bax signaling pathway and oxidative stress by long-term sodium hydrosulfide administration in ovalbumin-induced chronic asthma. Immunol Invest 2022; 51: 602-618.
[29] Pourmirzaei F, Ranjbaran M, Kadkhodaee M, Kianian F, Lorian K, Abdi A, et al. Sperm and testicular dysfunction during cecal ligation and puncture-induced sepsis in male rats and effects of tannic acid through reducing testicular oxidative stress and inflammation. Iran J Basic Med Sci 2021; 24: 1554-1560.
[30] Talebi H, Farahpour MR, Hamishehkar H. The effectiveness of rutin for prevention of surgical induced endometriosis development in a rat model. Sci Rep 2021; 11: 7180.
[31] Zhang J, Jin PP, Gong M, Yi QT, Zhu RJ. Role of leptin and the leptin receptor in the pathogenesis of varicocele-induced testicular dysfunction. Mol Med Rep 2018; 17: 7065- 7072.
[32] Miller WL. Steroidogenesis: Unanswered questions. Trends Endocrinol Metab 2017; 28: 771-793.
[33] Abdel-Meguid TA, Farsi HM, Al-Sayyad A, Tayib A, Mosli HA, Halawani AH. Effects of varicocele on serum testosterone and changes of testosterone after varicocelectomy: A prospective controlled study. Urology 2014; 84: 1081-1087.
[34] Wang K, Gao Y, Wang Ch, Liang M, Liao Y, Hu K. Role of oxidative stress in varicocele. Front Genet 2022; 13: 850114.
[35] Nishimura H, L’Hernault SW. Spermatogenesis. Curr Biol 2017; 27: R988-R994.
[36] Hayden RP, Tanrikut C. Testosterone and varicocele. Urol Clin North Am 2016; 43: 223-232.
[37] Lorian K, Kadkhodaee M, Kianian F, Abdi A, Sadeghipour H, Seifi B. Oxidative stress, nitric oxide and inflammation in the pathophysiology of varicocele and the effect of hydrogen sulfide as a potential treatment. Physiol Pharmacol 2019; 23: 249-260.
[38] Shiraishi K, Takihara H, Matsuyama H. Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis. World J Urol 2010; 28: 359-364.
[39] Gur FM, Timurkaan S, Taskin E, Guven C, Gur HE, Senturk M, et al. Thymoquinone improves testicular damage and sperm quality in experimentally varicocele-induced adolescent rats. Andrologia 2021; 53: e14033.
[40] Flores-Romero H, Hohorst L, John M, Albert MC, King LE, Beckmann L, et al. BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. EMBO J 2022; 41: e108690.