Preventive effects of Cetrorelix on the changes induced by Cisplatin on spermatogenic and myoid cells and basal lamina of seminiferous ducts in the testis of Balb/C mouse

Subject Areas : Veterinary Clinical Pathology

dariyoush mohammadneja ¹ , jafar soleymanirad ² , ameneh mohammadiroshandeh ³

1 - مرکز تحقیقات کار بردی دارویی، استادیار دانشگاه علوم پزشکی تبریز، تبریز، ایران
2 - گروه علوم تشریح، دانشکده پزشکی، استاد دانشگاه علوم پزشکی تبریز، تبریز، ایران
3 - گروه علوم تشریح، دانشکده پزشکی، استادیار دانشگاه علوم پزشکی همدان، همدان، ایران

Received: 2012-09-15 Accepted : 2013-01-30 Published : 2013-02-19

Keywords: Cisplatin, Cetrorelix, Spermatogenes, Myoid cell, Basal lamina,

Abstract :

Cisplatin used in chemotherapy can have side effect on spermatogenesis. As it is known Gonadotropine hormones (LH, FSH) affect spermatogenesis. It seems by suppressing secretion of LH and FSH during chemotherapy, spermatogenesis could stopped which could result in protection of the cells from cisplatin side effects. The aim of the present study is to investigate the preventive effect of cetrorelix (GnRH antagonist) on spermatogenic defect produced by Cisplatin. In the present study thirty adult male mice aging 6-8 weeks were divided into 3 groups as: Control, Experimental 1 and Experimental 2. Experimental 1 received Cisplatin for 5 days as 2.5 mg/kg intraperitoneally and Experimental 2 received 0.25 mg/kg cetrorelix (GnRH antagonist) one week before cisplatin treatment and continued for 3 weeks. After 35 days from last injection, testicular specimens were removed and prepared for light and electron microscopic study. The data were analyzed using ANOVA (Tukey) in all 3 groups. Histological results showed that nucleus of spermatogonia cells were more condensed and diameter of seminiferous tubules were reduced, in the group which received cisplatin in comparison with the control group. Histochemical studies showed an increase of apoptotic cells in the group which received cisplatin. Electron microscopy showed that in Experimental 1 group basment membrane was morphologically irregular and wavey and Myoid cells were thickened and contracted, but in Experimental 2 group the condition was similar to the control group. These results showed that injection of cetrorelix with cisplatin can protect spermatogenic cells against the side effects of cisplatin.

References:

• Aminsharifi, A., Shakeri, S., Ariafar, A., Moeinjahromi, B., Kumar, P.V. and Karbalaeedoost, S. (2010). Preventive role of exogenous testosterone on cisplatin-induced gonadal toxicity an experimental placebo-controlled prospective trial. Fertility and Sterility, 93:1388-1393.


• Andreson, Ph.O., Knoben, J.E. and Troutman, W.G. (2002). Handbook of Clinical Data, 10th Edition, Mc Grow Hill, New York, pp. 136-140.


• Bakalska, M., Atanassova, N., Koeva, Y., Nikolov, B. and Davidoff, M. (2004). Induction of male germ cell apoptosis by testosterone withdrawal after ethane dimethanesulfonate treatment in adult rats. Endocrine Regulations, 38:103-110.


• Bar-Shira Maymon, B., Yogev, L., Marks, A., Hauser, R. and Botchan, A. (2004). Sertoli cell inactivation damage to the human testis after cancer chemotherapy. Fertility and Sterility, 81:1391-1394.


• Behre, H.M., Nashan, D., Hubert, W. and Nieschlag, E. (1992). Depot Gonadotropin releasing hormone against blunts the androgen induced suppression of spermatogenesis in a clinical trial of male contraception. Journal of Clinical Endocrinology and Metabolism, 74:84-90.


• Bibin Bibin, A., Tatwei, T., Ishii, M., Mohammad, A. and Yoshiakira K.  (2004). An ultra structural study on cytotoxic effect of mono (2-ethlyhexyl) phthalate (MEHP) on testes in Shiba goat in vitro. Journal of Veterinary Science, 5:235-240.


• Bieber A.M., Marcon L., Hales B.F., Robaire B. (2006). Effects of chemoth apeutic agents for testicular cancer on the male rat reproduct system, spermatozoa, and fertility. Journal of  Andrology,  27: 189–200.


• Brinkworth, M.H. and Nieschlag E. (2000). Association of cyclophosphamide induced male mediated, foetal abnormalities with reduced paternal germ cell apoptosis. Mutation Research, 447:149-154.


• Cook, T. and Sheridan W.P. (2000). Development of GnRH antagonists or prostate cancer: new approaches to treatment. Oncologist, 5:162-168.


• da Cunha, M.F., Meistrich, M.L. and Nader S. (1987). Absence of testicular protection by a gonadotropin-    releasing hormone analog against cyclophosphamide-induced testicular cytotoxicity in the mouse. Cancer Research, 47:1093-1097.


• Francavilla, S., D'Abrizio, P., Cordeschi, G., Pelliccione, F., Necozione, S., Ulisse, S., Properzi, G. and Francavilla, F. (2002). Fas Expression correlates with human germ cell degeneration in meiotic and post-meiotic arrest of spermatogenesis. Molecular Human Reproduction, 8:213-220.


• Glode, L.M., Robinson, J. and Gould, S.F. (1981). Protection from cyclophosphamide inuced testicular damage with an analogue of gonadotropin releasing hormone. The Lancet, 23:1132-1134.


• Giri, A., Khynriam, D. and Prasad, S.B. (1998).Vitamin C mediated protection on cisplatin induced mutagenicity in mice. Mutation Research, 421:139-48.


• Grundker, C., Schlotawa, L., Viereck, V., Eick, N., Horst, A. and Kairies, B.  (2004). Anti proliferative effects of the GnRH antagonist cetrorelix and of GnRH ІІ on human endometrial and ovarian cancer cells are not mediated through the GnRH type І receptor. European Journal of Endocrinology, 151:141-149.


• Habermehl, D., Kammerer, B., Handrick, R., Eldh, Th., Gruber, Ch., Cordes, N., Daniel, P.T., Plasswilm, L., Bamberg, M., Belka, C. and Jendrossek, V. (2006). Proapoptotic activity of ukrain is mitochondrial death pathway. BioMed Central Cancer, 6:14-41.


• Helm, C.W. and States, J.C. (2009). Enhancing the efficacy of cisplatin in ovarian cancer treatment could Arsenic have a role. Journal Ovarian Research, 2:2.


• Hou, M., Chrysis, D., Nurmio, M., Parvinen, M., Eksborg, S., Söder, O. and Jahnukainen, K. (2005). Doxorubicin induces apoptosis in germ line stem cells in the immature rat testis and amifostin cannot protect against this cytotoxicity. Cancer Research, 65:9999-10005.


• Howell, S.J. and Shalet, S.M. (2005). Spermatogenesis after cancer treatment: Damage and Recovery. Journal of the National Cancer  Institute  Monographs, 34:12-17


• Kasper, D.L., Braunwald, E., Fauci, A.S., Hauser, S.L., Longo, D.L. and Jameson, J.L. (2005). Harrisons Principles of Internal Medicine. 16th ed. McGraw Hill, Medical Publishing Division, New York, pp. 114-118.


• Kazumasa, N., Yutaka, N., Masaaki, K., Shunichi, N., Takahiko, S., Akira, Y., Masahiro, F., Kiyoshi M.,  Koshiro W., Tomohide T., Seiichiro Y. and Nagahiro S. (2002). Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. New England Journal of Medicine, 346:85-91.


• Köberle, B., Tomicic, M., Usanova, S. and Kaina, B.  (2010). Cisplatin resistance: preclinical findings and clinical implications. Biochemica et Biophysica Acta, 1806:172-182.


• Maekawa, M., Kamimura, K. and Nagano, T.  (1996). Peritubular myoid cells in the testis: their structure and function. Archives of Histology and cytology, 59:1-13.


• Meistrich, M.L. (1998). Hormonal stimulation of the recovery of spermatogenesis following chemo-or radiotherapy. Acta Pathologica Microbiologia et Immunologia Scandinavica, 106:37-46.


• Meistrich M.L. and Kangasniemi, M. (1997). Hormone treatment after irradiation stimulates recovery of rat spermatogenesis from surviving spermatogonia. Journal of Andrology, 18:80-87.


• Meistrich, M.L., Parchuri, N., Wilson, G., Kurdogluy, B. and Kangasniemi, M.  (1995). Hormonal protection from cychlophosphamide induced inactivation of rat stem spermatogonia. Journal of Andrology 16:334-341.


• Meistrich, M.L. and Shetty, G.  (2003). Inhibition of spermatogonial differentiation by testosterone. Journal of Andrology, 24(2):135-148.


• Meistrich, M.L., Wilson, G. and Huhtaniemi, I. (1999). Hormonal treatment after cytotoxic therapy stimulates recovery of spermatogenesis. Cancer Research, 59:3557-3560.


• Meistrich, M.L., Wilson, G., Shuttlesworth, G., Huhtaniemi, I. and Reissmann, T.  (2001). GnRH agonists and antagonists stimulate recovery of fertility in irradiated LBNF1 rats. Journal of Andrology, 22:809-817.


• Nejad, M.D., Rad, S.J., Roshankar, L., Karimpor, M., Ghanbari, A.A., Azami, A. and Valilou, M.R. (2008). Effect of Thiotepa on mice Spermatogenesis using light and electronic microscope. Pakistan Journal of Biology Sciences, 11:1929-1934.


• Pelletier, G., Labrie, C. and Labrie, F.  (2000). Localization of oestrogen receptor alpha, oestrogen receptor beta and androgen receptors in the rat reproductive organs. Journal of Endocrinology, 165:359-370.


• Print, C.G. and Loveland, K.L. (2000). Germ Cell Suicide: new insight in to apoptosis during spermatogenesis. BioEssays, 22:423-430.


• Richardson, L.L., Kleinman, H.K. and Dym, M. (1998). Altered basement membrane synthesis in the testis after tissue injury. Journal of Andrology, 19:145-155.


• Roberts, R.  (200). Apoptosis in toxicology. Taylor and Francies, London, pp. 130-204.


• Sawada, H. and Esaki, M. (2003). Electron microscopic observation of 137Cs-irradiated rat testis: production of basal laminae for germ cells, despite their absence. Journal of Electron Microscopy (Tokyo), 52:391-397.


• Sawhney, P., Giammona, C.J., Meistrich, M.L. and Richburg, J.H. (2005). Cisplatin-induced long-term failure of spermatogenesis in adult C57/Bl/6J mice. Jouanal of Andrology, 26:136-145.


• Seaman, F., Sawhney, P., Giammona, C.J. and Richburg, J.H. (2003). Cisplatin-induced pulse of germ cell apoptosis precedes long-term elevated apoptotic rates in C57/BL/6 mouse testis. Apoptosis, 8:101-108.


• Shapiro, E., Huang, H., Masch, R.J., Mcfadden, D.E. and Wu, X.R. (2005). Immunolocalization of androgen receptor and estrogen receptors alpha and beta in human fetal testis and epididymis. Journal of Urology, 174:1695-1698.


• Shetty, G. and Meistrich, M.L.  (2005). Hormonal approaches to preservation and restoration of male fertility after cancer treatment. Journal of the National Cancer Institute Monographs, 34:36-39.


• Shetty, G., Wilson, G., Hardy, M.P., Niu, E., Huhtaniemi, I. and Meistrich, M.L. (2002). Inhibition of recovery of spermatogenesis in irradiated rats by different androgens. Endocrinology, 143:3385-3396.


• Shetty, G., Wilson, G., Huhtaniemi, I., Shuttlesworth, G.A., Reissmann, T. and Meistrich, M.L. (2000). Gonadotropin-releasing hormone analogs stimulate and testosterone inhibits the recovery of spermatogenesis in irradiated rats. Endocrinology, 141:1735-1745.


• Spermon, J.R., Ramos, L., Wetzels,  A.M.M. , Sweep,  C.G.J.,  Braat, D.D.M. , Kiemeney,  L.A.L.M. and Witjes, J.A. (2006). Sperm integrity pre- and post-chemotherapy in men with testicular germ cell cancer. Human Reproduction, 21:1781-1786.


• Tevor, A.J., Katzung, B.G. and Masters, S.B. (2002). Katzung and Trevoor's Pharmacology. 6th Edition, McGraw Hill, Philadelphia, pp. 206-208.


• Tohda, A., Matsumiya, K., Tadokoro, Y.,Yomogida, K., Miyagawa, Y., Dohmae, K., Okuyama, A. and Nishimune,  Y. (2001). Testosterone suppresses spermatogenesis in juvenile spermatogonial depletion (jsd) mice. Biology of Reproduction, 65:532-537.


• Turk, G., Atessahin, A., Sonmes, M., Yuce, A. and Ceribasi, A.O. (2007). Lycopene protects against cyclosporine a induced testicular toxicity in rats. Theriogenology, 67:778 -785.


• Udagawa, K., Ogawa, T., Watanabe, T., Yumura, Y., Takeda, M. and Hosaka, M. (2001). GnRH analog, leuprorelin acetate, promotes regeneration of rat spermatogenesis after severe chemical damage. International Journal of Urology, 8:615-622.


• Velasquez, W.S., Cabanillas, F., Salvador, P., Mclaughlin, P., Fridrik, M., Tucker, S., Jagannath, S., Hagemeister, F.B., Redman, J.R. and Swan, F.  (1988). Effective salvage therapy for lymphoma with cisplatin in combination with high-dose ara-c and dexamethasone (DHAP), Blood, 71:117-12.             


• Virtanen, I., Kallojoki, M. and Narvanen, O. (1986). Peritubular myoid cells of human and rat testis are smooth muscle cells that contain desmin-type intermediate filaments. Journal of Anatomy Research, 215:10-20.