D-Tryptophan-6 analog of luteinizing hormone-releasing hormone as a protective agent against testicular damage caused by cyclophosphamide in baboons.

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Abstract
Possible protective effects of the agonist [D-Trp6]LH-RH (the 6-D-tryptophan analog of LHRH) against testicular damage caused by cyclophosphamide (Cytoxan) were investigated in subhuman primates. Three adult male baboons (P. anubis) were first subjected to normal semen evaluation by using electroejaculation. The average baseline count for the animals ranged from 95.7 .times. 106 to 585.7 .times. 106 sperm/ml with 90% normal forms and 85% motility with excellent rapid forward progression. After baseline evaluations, 2 of the animals were treated with daily s.c. injections of 0.5 mg of the agonist [D-Trp6]LHRH. There was an initial rise in serum testosterone after 1 wk, but testosterone fell to castration values at 1 mo. and continued at these levels during treatment with the agonist. There was also an initial rise in sperm concentration 2 mo. after treatment was started, but after 2 mo. the animals were azoospermic. After 13 wk of therapy with [D-Trp6]LHRH, these 2 baboons and a third untreated control animal were given cyclophosphamide at a dose of about 3 mg/kg of body weight per day for 4 mo. The 2 animals pretreated with [D-Trp6]LHRH, continued to receive this agonist until 1 wk after the last dose of Cytoxan. In 1 of the 2 baboons treated with Cytoxan and the LHRH agonist, the white blood count fell below 4000/.mu.l, and the dose of Cytoxan had to be reduced to 1.5 mg/kg per day for 12 days. The control animal developed azoospermia after 4 mo. of treatment with cyclophosphamide, and serum testosterone increased while sperm count decreased. Four wk after the agonist was stopped, serum testosterone in both animals pretreated with [D-Trp6]LHRH returned to normal levels. The control animal showed a small amount of nonmotile sperm 2.5 mo. after cessation of treatment, but after 9 mo. remains oligospermic with poor sperm motility. In one of the animals treated with LHRH agonist, semen analysis returned to normal pretreatment values 8 mo. after withdrawal of treatment. The other animal remains oligospermic 10 mo. after therapy, but the motility is improving. Treatment with LHRH agonist might decrease the gonadal damage caused by some chemotherapeutic agents.