The effect of [D-Trp6]LHRH, a potent agonist of LHRH, on pituitary-testicular responses was investigated in male rhesus monkeys. Acute administration of 5, 25, or 500 micrograms [D-Trp6]LHRH produced dose-related increases in serum testosterone and bioassayable LH levels. The administration of 500 micrograms [D-Trp6]LHRH twice weekly for 12 weeks led to a 75% decrease in the LH responses to successive doses of this peptide; testosterone responses in these animals were unchanged, however. The lack of any change in the motility or sperm number in semen obtained by electroejaculation suggested that there was no effect on spermatogenesis during the twice weekly administration. These animals were then treated with [D-Trp6]LHRH (500 micrograms daily) for 16 weeks. This caused dramatic decreases in the LH responses to the agonist in all four animals. The testosterone response was reduced in two and abolished in two animals. These latter two animals also lost their electroejaculatory response. During the recovery period following the cessation of treatment, these two animals produced ejaculates with no sperm, indicating that a transient period of azoospermia was achieved. The results of these studies suggest that 1) the responsiveness of the pituitary is more susceptible to desensitization by [D-Trp6]LHRH than that of the testes; and 2) even though chronic administration of [D-Trp6]LHRH suppressed the pituitary-Leydig cell axis in all monkeys, seminiferous tubular function was reduced only in those animals with very low androgen levels.