In agonadal juvenile male monkeys, continuous administration of human metastin 45-54 (hu metastin 45-54) leads to desensitization of its receptor, G protein-coupled receptor 54 (GPR54), and decreased LH. The present study extended this observation to the adult male monkey, a more preclinically relevant model in which robust activity in the hypothalamic-pituitary-testicular axis is present. Continuous iv infusion of hu metastin 45-54 at either 200 or 400 microg/h elicited a marked rise in circulating LH that peaked 2-3 h after initiation of treatment. Thereafter, levels declined, and by 24 h, LH in metastin 45-54-infused animals was similar to control. LH release in response to an iv bolus of hu metastin 45-54 (10-30 microg) during the final 3 h of continuous infusion was truncated or abolished (low and high peptide dose, respectively). GPR54 desensitization by the high-dose metastin 45-54 infusion was associated with compromised pituitary response to a bolus GnRH injection (0.3 microg). LH pulse amplitude and pulse frequency were markedly suppressed during high-dose metastin 45-54 treatment. Surprisingly, the fidelity of the relationship between circulating testosterone (T) and LH was distorted during the high-dose peptide infusion. Thus, for a given concentration of LH, T levels were invariably higher during the high-dose metastin 45-54 infusion than during vehicle, suggesting that the peptide may exert direct actions on the testis to amplify T production. These findings support the notion that GPR54 is desensitized by continuous exposure to ligand, and they raise the possibility of an intratesticular role of GPR54.