ABSTRACT
BACKGROUND: Cyclophosphamide (Cy), a widely used anticancer drug, is associated with significant testicular damage and sterility. Co-administration of the immunomodulating compound AS101 during chemotherapy treatments was previously shown to protect organs against cytotoxic damage, without attenuating the drug's anticancer effect. In this animal study, we investigated the effect of AS101 on testicular damage, sperm DNA damage and infertility induced by Cy. Akt and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation were investigated as a possible chemoprotective mechanism. METHODS: Mature male mice, 10 in each group, were injected intraperitoneally with 200 mg/kg Cy once a week for 5 weeks, with or without concurrent treatment with 10 microg per mouse AS101 three times per week. Damage to testicular tubules and sperm production was determined, sperm chromatin damage was analyzed and fertility was gauged. Akt and GSK-3beta phosphorylation were evaluated. RESULTS: Co-treatment with AS101 during the course of Cy administration significantly reduced the percentage of damaged seminiferous tubules (76.0 +/- 10.8% versus 40.3 +/- 2.6%), and reduced sperm DNA fragmentation (%DFI) from 44.7 +/- 1.0% to 25 +/- 6.5%. Co-treatment with AS101 also partially protected against the decrease in numbers of impregnated females and litter size. AS101 increased Akt and GSK-3beta phosphorylation. CONCLUSIONS: Our results indicate that AS101 can significantly protect against Cy-induced testicular damage and sperm DNA damage, probably by acting through Akt/GSK-3beta phosphorylation.
Subject(s)
Adjuvants, Immunologic/pharmacology , Antineoplastic Agents, Alkylating/toxicity , Cyclophosphamide/toxicity , Ethylenes/pharmacology , Infertility, Male/prevention & control , Testis/drug effects , Animals , DNA Fragmentation/drug effects , Drug Interactions , Female , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Infertility, Male/chemically induced , Infertility, Male/pathology , Male , Mice , Mice, Inbred BALB C , Organ Size/drug effects , Phosphorylation/drug effects , Pregnancy , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Sperm Count , Spermatozoa/drug effects , Spermatozoa/pathology , Testis/pathologyABSTRACT
BACKGROUND: Storage of embryos for fertility preservation before chemotherapy is widely practiced. For multiple oocyte collection, the ovaries are hyperstimulated with gonadotrophins that significantly alter ovarian physiology. The effects of ovarian stimulation prior to chemotherapy on future ovarian reserve were investigated in an animal model. METHODS: Cyclophosphamide (Cy) in doses of 0, 50 or 100 mg/kg was administered to 38 adult mice (control, unstimulated). A second group of 12 mice were superovulated with equine chorionic gonadotrophin (eCG, 10 IU on Day 0) before Cy administration; hCG (10 IU) was administered (Day 2) followed by 0, 50 or 100 mg/kg Cy (Day 4). In both groups ovaries were removed, serially sectioned (7-day post-Cy), primordial follicles were counted and differences between groups evaluated. RESULTS: Follicle number dropped from 469 +/- 24 (mean +/- SE) to 307 +/- 27 and 234 +/- 19 with 50 or 100 mg/kg Cy, respectively (P < 0.0001). In the eCG pretreated group, follicle count dropped from 480 +/- 31 to 345 +/- 16 and 211 +/- 26 when 50 or 100 mg/kg Cy were administered (P < 0.0001). There were no significant differences in follicle count between the pretreated eCG group and controls for each chemotherapy dose. CONCLUSIONS: This animal study indicates that ovarian stimulation before administration of Cy does not adversely affect ovarian reserve post-treatment. These results provide support for the safety of fertility preservation using ovarian stimulation and IVF-embryo cryopreservation procedures prior to chemotherapy.
