Protective effects of analogs of luteinizing hormone-releasing hormone against chemotherapy-induced testicular damage in rats.

Possible protective effects of analogs of luteinizing hormone-releasing hormone (LH-RH) against testicular damage caused by various cytotoxic agents were investigated in rats. The agonist [D-Trp6]LH-RH (in which Gly-6 is replaced by D-tryptophan) and the antagonist N-Ac-[D-Phe(pCl)1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH were administered for 12 weeks: [D-Trp6]LH-RH was given once a month in the form of long-acting microcapsules liberating 25 micrograms of agonist per day, and the antagonist was injected s.c. at a dose of 1000 micrograms per kg of body weight per day for the first 3 weeks and, thereafter, at a dose of 500 micrograms per kg of body weight per day. After a recovery period of 3 months, most seminiferous tubules in the antagonist-treated group showed a normal morphology, while patches of tubules in the agonist-treated group continued to show some suppression of spermatogenesis. Administration of busulfan, cisplatin, or cyclophosphamide produced only a reversible testicular injury, and pretreatment with LH-RH analogs seemed to temporarily enhance the tubular damage. Administration of procarbazine (200 mg per kg of body weight per week for 6 weeks) resulted in decreased testicular weights and increased serum LH levels 1 and 3 months after the discontinuation of treatment. The histology showed severe diffuse damage to seminiferous tubules. The germinal cells completely disappeared and the Sertoli cells were markedly degenerated. This damage was not restored even after a recovery period of 5 months. Some animals were pretreated for 6 weeks with the agonist or antagonist and then received procarbazine for 6 weeks while administration of analogs was continued. In these animals, the decrease in testicular weights and increase in serum LH levels after procarbazine were less marked than in the group not pretreated with the analogs. Three and 5 months after cessation of treatment, a large number of tubules showed a complete restoration of structural morphology in 30-45% of the animals that received procarbazine and the LH-RH agonist or antagonist. These results indicate that pretreatment with LH-RH analogs may protect testes against damage caused by some cytotoxic agents.