The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice

BACKGROUND: It has remained controversial whether and in what way suppression of the pituitary-gonadal axis using GnRH analogues can reduce the destructive effects of chemotherapy on ovarian primordial follicles and thus prevent ovarian failure. GnRH antagonists suppress gonadotrophin levels immediately after administration. In this study we determined whether administration of the GnRH antagonist cetrorelix before exposure to increasing doses of cyclophosphamide (Cy) affected the number of surviving primordial follicles (PMF) in the mice ovary. METHODS: Highly inbred young Balb/c mice (114 females) were injected with 0, 50 and 75 mg/kg of Cy. In each treatment group, half of the females were injected daily with cetrorelix starting 9 days before and 7 days post-administration of Cy. In serial sequential ovarian sections the total number of PMF in both ovaries was counted. RESULTS: Ovaries exposed to Cy at doses of 50 and 75 mg/kg had significantly fewer PMF than those in the control group (P < 0.01). In each of the Cy groups used, pretreatment with cetrorelix resulted in significantly higher numbers of PMF: in the 50 mg/kg Cy group only 14% were destroyed (cetrorelix group) versus 53% (P < 0.001), while in the 75 mg/kg Cy group only 35% of PMF were destroyed versus 54% in animals treated only with Cy (P < 0.004). The interaction between the effect of cetrorelix and the different doses of Cy did not reach statistical significance (P = 0.089, two-way ANOVA). CONCLUSIONS: Administration of the GnRH antagonist cetrorelix to mice significantly decreases the extent of ovarian damage induced by the chemotherapeutic agent Cy. The use of different substerilizing doses of Cy suggested that the extent of protection achieved by the antagonist is dose-dependent and decreases with increasing Cy doses. The results of this study may suggest a possible similar beneficial effect in women undergoing chemotherapy, can explain the discrepancy in results of existing clinical studies and indicate possible pathways for ovarian GnRH agonist protection. Further research and clinical studies are needed in order to confirm these results.