Objective: To observe the difference of testosterone levels in adult male Sprague Dawley rats treated with combination of cisplatin and vitamin E compared to those treated with cisplatin only. Material & Methods: We used 24 adult male Sprague Dawley rats weight 200–300 grams and randomly assigned into 4 groups (n=6). Rats in negative control group (NC) were given intraperitoneal normal saline injection, while the positive control (PC) group were injected with cisplatin 5 mg/kgBW at the end of the 3rd week. Two other groups, P1 and P2, were injected with cisplatin 5 mg/kgBW and given vitamin E orally 50 mg/kgBW and 200 mg/kgBW, respectively. Cardiac blood was aspirated at the end of the 7th week and processed for analysis of testosterone levels. Results: We recorded a significantly lower testosterone levels in rats treated only with cisplatin 5 mg/kgBW (CP) compared to those in CN group (p=0.006), and those receiving combination of cisplatin and vitamin E 50 mg/kgBW (p=0.003) and 200 mg/kgBW (p=0.001). Though not significant, testosterone levels were higher in P2 group than in P1 group (p=0.702). Conclusion: Exposure to cisplatin can lower testosterone levels in white rats, and the administration of vitamin E gives protection against such effect.
Cisplatin, chemotherapy, Vitamin E, antioxidant, testosterone, testis
Torre LA, Bray F, Siegel RL. Global cancer statistics 2012. CA Cancer J Clin. 2015; 65: 87–108.
Ward E, DeSantis C, Robbins A. Childhood and adolescent cancer statistics. CA Cancer J Clin. 2014; 64: 83–103.
Riddell Imogen A, Lippard Stephen J. Cisplatin and oxaliplatin: Our current understanding of their actions. In Sigel Astrid, Sigel Helmut, Freisinger Eva, Sigel Roland KO. Metallo-Drugs: Development and Action of Anticancer Agents. Berlin: de Gruyter GmbH; 2018. p. 1–42.
Mieog JSD, van der Hage JA, van de Velde CJH. Neoadjuvant chemotherapy for operable breast cancer. British Journal of Surgery. 2007; 94(10): 1189–200.
Jafri SH, Mills G. Neoadjuvant chemotherapy in lung cancer. Therapy. 2011; 8(1): 23–31.
Barabas K, Milner R, Lurie D. Cisplatin: a review of toxicities and therapeutic applications. Vet. Comp. Oncol. 2008; 6: 1–18.
Hoff PM, Saad ED, Costa F. Literature review and practical aspects on the management of oxaliplatin-associated toxicity. Clin Colorectal Cancer. 2012; 11(2): 93–100.
Howell SJ, Shalet SM. Testicular function following chemotherapy. Hum Reprod Updat. 2001; 7: 363–9.
Colpi GM, Contalbi GF, Nerva F. Testicular function following chemo-radiotherapy. Eur J Obstet Gynecol Reprod Biol. 2004; 113(Suppl. 1): S2–6.
Kilarkaje N. Effects of combined treatment of α‑tocopherol, l‑ascorbic acid, selenium and zinc on bleomycin, etoposide and cisplatin‑induced alterations in testosterone synthesis pathway in rats. Cancer Chemother Pharmacol; 2014. DOI 10.1007/s00280-014-2592-8
Agarwal A, Makker K, Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update. Am J Hum Reprod Immunol. 2008; 59: 2–11.
Ishikawa T, Fujioka H, Fujisawa M. Clinical and hormonal findings in testicular maturation arrest. BJU Int. 2004; 94: 1314–6.
Soni KK, Kim HK, Choi BR, Karna KK, You JH, Cha JS, et al. Dose-dependent effects of cisplatin on the severity of testicular injury in sprague dawley rats: reactive oxygen species and endoplasmic reticulum stress. Drug Des Devel Ther. 2016; 10: 3959–68.
Strumberg D, Brugge S, Korn MW. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer.
Sprauten M, Brydey M, Haugnes HS. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol. 32: 571-8.
Bandak M. Longitudinal changes in serum levels of testosterone and luteinizing hormone in testicular cancer patients after orchiectomy alone or bleomycin, etoposide, and cisplatin. Eur Urol Focus; 2016. http:// dx.doi.org/10.1016/j.euf.2016.11.018
Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radical Biology & Medicine. 2011; 51: 1000–13.
Yamauchi R, Miyake N, Kato K, Ueno Y. Reaction of c!-tocopherol with alkyl and alkylperoxyl radicals of methyl linoleate. Lipids. 1993; 2(8): 201-6.
Gevrek F, Erdemir F. Investigation of the effects of curcumin, vitamin E and their combination in cisplatin-induced testicular apoptosis using immunohistochemical technique. Türk Üroloji Dergisi/Turkish J Urol. 2018; 44: 16–23.
Cepeda V, Fuertes M, Castilla J, Alonso C, Quevedo C, Pere, J. Biochemical mechanisms of cisplatin cytotoxicity. Anticancer: Agents Med Chem. 2007; 7: 3–18.
Pisano C, Pratesi G, Laccabue D. Paclitaxel and cisplatin-induced neurotoxicity: a protective role of acetyl-l-carnitine. Clin Cancer Res. 2003; 9: 5756–67.
Ciftci Osman. Comparison of reproductive toxicity caused by cisplatin and novel platinum-n-heterocyclic carbene complex in male rats. Basic Clin Pharmacol Toxicol; 2011. p. 328–33.
Martins NM, Santos NA, Curti C, Bianchi ML, Santos AC. Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. J Appl Toxicol. 2008; 28(3): 337–44.
Vawda AI. Effect of testosterone on cisplatin-induced testicular damage. Arch Androl. 1994; 32(1): 53–57.
Azouri H, Bidartt JM, Bohuon C. In vivo toxicity of cisplatin and carboplatin on the leydig cell function and effect of the human choriogonadotropin. Biochem Pharmacol. 1989; 38: 567–71.
Aydiner A, Aytekin Y, Topuz E. Effects of cisplatin on testicular tissue and the leydig cell-pituitary axis. Oncology. 1997; 54: 74–78.
Maines MD, Sluss PM, Iscan M. Cis-platinum-mediated decrease in serum testosterone is associated with depression of luteinizing hormone receptors and cytochrome P-450scc in rat testis. Endocrinology. 1990; 126: 2398–406.
Garcia MMS, Acquier A, Suarez G, Gomez NV. Cisplatin inhibits testosterone synthesis by a mechanism that includes the action of reactive species oxygen (ROS) at the level of P450scc. Chemico-Biological Interactions. 2012; 199: 185-91.
Terao J, Matsushita S. The peroxidizing effect of α-tocopherol on autoxidation of methyl linoleate in bulk phase. Lipids. 1986; 21: 255-60.
Akazawa N, Mikami S, Kimura S. Effects of vitamin E deficiency on the hormone secretion of the pituitary-gonadal axis of the rat. Tohoku J Exp Med. 1987; 152(3): 221-9.
Umeda F. Functional and morphological studies on pituitary-gonadal, and adrenal axes in vitamin E deficient and supplemented male rats. Fukuoka Acta Med. 1978; 69: 327-37.
Umeda F, Kato K, Muta K, Ibayashi H. Effect of vitamin E on function of pituitary-gonadal axis in male rats and human subjects. Endocrinol Jpn. Jun 1982; 29(3): 287-92.