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Effect of Continuous Intravenous Administration of Human Metastin 45–54 on the Neuroendocrine Activity of the Hypothalamic-Pituitary-Testicular Axis in the Adult Male Rhesus Monkey (Macaca mulatta)

Department of Cell Biology and Physiology (S.R., M.J.D., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit of the Department of Medicine (S.B.S., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Physical Therapy (C.R.P.), School of Health Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282

Address all correspondence and requests for reprints to: Prof. Tony M. Plant, Ph.D., Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, S828A Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261. E-mail: plant1{at}pitt.edu.

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 µg/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 µg) 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 µg). 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.