We reported previously that after a single injection of a gonadotrophin-releasing hormone (GnRH) antagonist to male monkeys, exogenous GnRH stimulated LH secretion in a time- and dose-dependent manner, indicating that GnRH antagonist-induced blockade of LH secretion resulted from pituitary GnRH receptor occupancy. The present study was performed to investigate whether GnRH can also restore a blockade of LH and testosterone secretion during chronic GnRH antagonist administration. Four adult male cynomolgus monkeys (Macaca fascicularis) received daily s.c. injections of the GnRH antagonist [N-Ac-D-pCl-Phe1,2,D-TRP3,D-Arg6-D-Ala10]-GnRH (ORG 30276) at a dose of 1400-1600 micrograms/kg for 8 weeks. Before the GnRH antagonist was given and during weeks 3 and 8 of treatment, pituitary stimulation tests were performed with 0.5, 5, 50 and 500 micrograms synthetic GnRH, administered in increasing order at intervals of 24 h. At 8 weeks, a dose of 1000 micrograms GnRH was also given. All doses of GnRH significantly (P less than 0.05) stimulated serum concentrations of bioactive LH (3- to 8-fold) and testosterone (2.6- to 3.8-fold) before the initiation of GnRH antagonist treatment. After 3 weeks of GnRH antagonist treatment, only 50 and 500 micrograms GnRH doses were able to increase LH and testosterone secretion. Release of LH was significantly (P less than 0.05) more elevated with 500 micrograms compared with 50 micrograms GnRH. After 8 weeks, only the highest dose of 1000 micrograms elicited a significant (P less than 0.05) rise in LH secretion. Basal hormone levels just before the bolus injection of GnRH were similar (P greater than 0.10-0.80).(ABSTRACT TRUNCATED AT 250 WORDS)