Protective effects of analogs of luteinizing hormone-releasing hormone against chemotherapy-induced testicular damage in rats (luteLnizing hormone-releasing hormone agonists and antagonists/gonadal chemoprotectors)

Possible protective effects of analogs of lu- teinizing hormone-releasing hormone (LH-RH) against testic- ular damage caused by various cytotoxic agents were investi- gated in rats. The agonist (D-Trp6)LH-RH (in which Gly-6 is replaced by D-tr1Iptophan) and the antagonist N-Ac-(D- Phe(pCI).2',D-Trp ,D-Arg6,D-AIaJ)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 pg of agonist per day, and the antagonist was injected s.c. at a dose of 1000 pg per kg of body weight per day for the first 3 weeks and, thereafter, at a dose of 500 pg 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 spermatogene- sis. Administration of busulfan, cisplatin, or cyclophospha- mide produced only a reversible testicular inJury, and pre- treatment with LH-RH analogs seemed to temporarily en- hance 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 tu- bules. 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 cessa- tion of treatment, a large number of tubules showed a com- plete restoration of structural morphology in 3045% 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.