{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:26:10Z","timestamp":1787023570901,"version":"build-2736575974"},"reference-count":39,"publisher":"Knowledge E DMCC","issue":"11","content-domain":{"domain":["knepublishing.com"],"crossmark-restriction":true},"short-container-title":["IJRM"],"abstract":"<jats:p>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.\r\nObjective: 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.\r\nMaterials and Methods: Thirty Wistar rats weighing 200-250 gr were divided into 5 groups as (n = 6\/each): sham, varicocele, testosterone (200 \u03bcg\/kg, 5 times per wk for 4 consecutive wk), NaHS (15 \u03bcmol\/L, daily for 4 consecutive wk) and testosterone + NaHS (200 \u03bcg\/kg, 5 times per wk + 15 \u03bcmol\/L, daily, both for 4 consecutive wk). All animals, except in the sham group, underwent varicocele induction.\r\nResults: The coadministration of testosterone and NaHS significantly increased serum testosterone (10.23 \u00b1 0.95, p = 0.01), testicular H2S levels (608.94 \u00b1 21.09, p &lt; 0.001), and testicular superoxide dismutase activity (66.14 \u00b1 1.56, p &lt; 0.001), decreased malondialdehyde levels (0.77 \u00b1 0.52, p &lt; 0.001), and B-cell lymphoma 2-associated X protein to B-cell lymphoma 2 (0.16 \u00b1 0.01, p &lt; 0.001) protein expression ratio in the testicular tissues and improved sperm parameters and testicular histopathology compared to the varicocele group.\r\nConclusion: 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.\r\nKey words: Apoptosis genes, Hydrogen sulfide, Oxidative stress, Sperm count, Testosterone, Varicocele.<\/jats:p>","DOI":"10.18502\/ijrm.v20i11.12362","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T01:37:26Z","timestamp":1670895446000},"page":"941-954","update-policy":"https:\/\/doi.org\/10.18502\/knecrossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Beneficial effects of combination therapy with testosterone and hydrogen sulfide by reducing oxidative stress and apoptosis: Rat experimental varicocele model"],"prefix":"10.18502","volume":"20","author":[{"given":"Anahid","family":"Shafie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzaneh","family":"Kianian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghorbangol","family":"Ashabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehri","family":"Kadkhodaee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Ranjbaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdi","family":"Hajiaqaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keivan","family":"Lorian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arash","family":"Abdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behjat","family":"Seifi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"7770","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"245231","doi-asserted-by":"crossref","unstructured":"Hassanin AM, Ahmed HH, Kaddah AN. A global view of the pathophysiology of varicocele. Andrology 2018; 6: 654-661.","DOI":"10.1111\/andr.12511"},{"key":"245232","doi-asserted-by":"crossref","unstructured":"Ohlander SJ, Lindgren MC, Lipshultz LI. Testosterone and male infertility. Urol Clin North AM 2016; 43: 195-202.","DOI":"10.1016\/j.ucl.2016.01.006"},{"key":"245233","doi-asserted-by":"crossref","unstructured":"\u00c7ayan 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.","DOI":"10.4274\/balkanmedj.galenos.2020.2020.1.85"},{"key":"245234","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1080\/13685538.2018.1550745"},{"key":"245235","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1016\/j.euf.2018.09.017"},{"key":"245236","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.4103\/1008-682X.172638"},{"key":"245237","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1186\/s12610-020-00112-6"},{"key":"245238","unstructured":"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."},{"key":"245239","unstructured":"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."},{"key":"245240","doi-asserted-by":"crossref","unstructured":"Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to testosterone therapy: A review. Sex Med Rev 2018; 6: 106- 113.","DOI":"10.1016\/j.sxmr.2017.09.004"},{"key":"245241","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.2174\/1381612826666201207104340"},{"key":"245242","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1111\/jcmm.16428"},{"key":"245243","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1007\/s11356-019-07266-5"},{"key":"245244","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1016\/j.abb.2018.05.002"},{"key":"245245","unstructured":"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."},{"key":"245246","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.2147\/RRU.S330634"},{"key":"245247","doi-asserted-by":"crossref","unstructured":"Turner TT. The study of varicocele through the use of animal models. Hum Reprod Update 2001; 7: 78-84.","DOI":"10.1093\/humupd\/7.1.78"},{"key":"245248","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1097\/FJC.0000000000000497"},{"key":"245249","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1007\/s10815-013-0165-0"},{"key":"245250","unstructured":"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."},{"key":"245251","unstructured":"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."},{"key":"245252","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.3390\/life11121368"},{"key":"245253","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1111\/and.13496"},{"key":"245254","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1002\/9781118904398.ch114"},{"key":"245255","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1080\/10641963.2018.1445752"},{"key":"245256","doi-asserted-by":"crossref","unstructured":"Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4- hydroxynonenal. Methods in Enzymology 1990; 186: 407-421.","DOI":"10.1016\/0076-6879(90)86134-H"},{"key":"245257","doi-asserted-by":"crossref","unstructured":"Kianian F, Seifi B, Kadkhodaee M, Sadeghipour HR, Ranjbaran M. Nephroprotection through modifying the apoptotic tnf-\u03b1\/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.","DOI":"10.1080\/08820139.2020.1858860"},{"key":"245258","unstructured":"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."},{"key":"245259","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1038\/s41598-021-86586-4"},{"key":"245260","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.3892\/mmr.2018.8753"},{"key":"245261","doi-asserted-by":"crossref","unstructured":"Miller WL. Steroidogenesis: Unanswered questions. Trends Endocrinol Metab 2017; 28: 771-793.","DOI":"10.1016\/j.tem.2017.09.002"},{"key":"245262","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1016\/j.urology.2014.05.029"},{"key":"245263","doi-asserted-by":"crossref","unstructured":"Wang K, Gao Y, Wang Ch, Liang M, Liao Y, Hu K. Role of oxidative stress in varicocele. Front Genet 2022; 13: 850114.","DOI":"10.3389\/fgene.2022.850114"},{"key":"245264","doi-asserted-by":"crossref","unstructured":"Nishimura H, L\u2019Hernault SW. Spermatogenesis. Curr Biol 2017; 27: R988-R994.","DOI":"10.1016\/j.cub.2017.07.067"},{"key":"245265","doi-asserted-by":"crossref","unstructured":"Hayden RP, Tanrikut C. Testosterone and varicocele. Urol Clin North Am 2016; 43: 223-232.","DOI":"10.1016\/j.ucl.2016.01.009"},{"key":"245266","unstructured":"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."},{"key":"245267","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1007\/s00345-009-0462-5"},{"key":"245268","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1111\/and.14033"},{"key":"245269","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.15252\/embj.2021108690"}],"container-title":["International Journal of Reproductive BioMedicine (IJRM)"],"original-title":[],"link":[{"URL":"https:\/\/knepublishing.com\/index.php\/ijrm\/article\/download\/12362\/20098","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/knepublishing.com\/index.php\/ijrm\/article\/download\/12362\/20099","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/knepublishing.com\/index.php\/ijrm\/article\/download\/12362\/20098","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T05:32:06Z","timestamp":1737437526000},"score":1,"resource":{"primary":{"URL":"https:\/\/knepublishing.com\/index.php\/ijrm\/article\/view\/12362"},"secondary":[{"URL":"https:\/\/ijrm.ssu.ac.ir\/article-1-2423-en.html","label":"UNIVERSITY"},{"URL":"https:\/\/knepublishing.com\/index.php\/ijrm\/article\/view\/12362","label":"PUBLISHER"}]},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,12]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,12,12]]}},"URL":"https:\/\/doi.org\/10.18502\/ijrm.v20i11.12362","relation":{},"ISSN":["2476-3772","2476-4108"],"issn-type":[{"value":"2476-3772","type":"electronic"},{"value":"2476-4108","type":"print"}],"subject":[],"published":{"date-parts":[[2022,12,12]]}}}