Pretreatment with gonadotropin-releasing hormone antagonist protects against chemotherapy-induced testicular damage in mice
Open Access
- 1 January 2022
- journal article
- research article
- Published by SAGE Publications in Therapeutic Advances in Medical Oncology
Abstract
Background: Testicular toxicity following chemotherapy is of increasing importance with the continuous improvement of survival rates. Gonadotropin-releasing hormone (GnRH) was suggested to protect testis against such toxicity; however, its suppressive quality and mechanism of action are still unclear. We examined whether and how pretreatment with GnRH antagonist protects against the testicular damage caused by chemotherapy. Methods: Mature male mice were injected subcutaneously eight times in 2-day intervals with either saline or GnRH antagonist (Cetrotide; 1 g/mg), followed by an intraperitoneal injection with either saline or cyclophosphamide (CTX;100 mg/kg BW) and sacrificed 2 weeks or 3 months later. Testicular weight, epididymis weight, epididymal sperm count and sperm motility were measured. Serum anti-Mullerian hormone (AMH) was measured by enzyme-linked immunosorbent assay. Immunohistochemistry (Ki-67), immunofluorescence (PCNA, CD34), terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling (TUNEL) and computerized analysis were performed to examine testicular proliferation, apoptosis and vascularization. Quantitative real-time PCR was used to assess the amount of spermatogonial reserve (Id4 and Gfra1 mRNAs). Results: Pretreatment with GnRH antagonist transiently reduced testicular weight, epididymal weight, germinal proliferation and sperm count; it also abolished the permanent long-term effect of CTX on these parameters and prevented cyclophosphamide-induced testicular toxicity characterized by apoptosis and serum AMH increase and irreversible loss of spermatogonial reserve. Conclusions: Our findings imply that pretreatment with GnRH antagonist temporarily reduces spermatogenesis and may be used as pretreatment for reducing chemotherapeutic testicular toxicity.Funding Information
- Israel Science Foundation (grant number 1816/13 to IBA)
This publication has 45 references indexed in Scilit:
- Hormonal suppression for fertility preservation in males and femalesReproduction, 2008
- Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonistsApoptosis, 2007
- Regulation of Mouse Spermatogonial Stem Cell Self-Renewing Division by the Pituitary Gland1Biology of Reproduction, 2004
- Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal1Biology of Reproduction, 2003
- Effect of local heating of rat testes after suppression of spermatogenesis by pretreatment with a GnRH agonist and an anti-androgenReproduction, 2002
- Effect of the GnRH-agonist leuprolide on colonization of recipient testes by donor spermatogonial stem cells after transplantation in miceTissue and Cell, 2001
- Stage Specific Identification of the Expression of GnRH mRNA and Localization of the GnRH Receptor in Mature Rat and Adult Human TestisJournal of Urology, 1995
- Does a gonadotropin-releasing hormone analogue prevent cisplatin-induced spermatogenic impairment?Urological Research, 1991
- Testicular GnRH-Receptors and Direct Effects of a GnRH-Agonist on Human Testicular SteroidogenesisScandinavian Journal of Urology and Nephrology, 1989
- PROTECTION FROM CYCLOPHOSPHAMIDE-INDUCED TESTICULAR DAMAGE WITH AN ANALOGUE OF GONADOTROPIN-RELEASING HORMONEThe Lancet, 1981