title: 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).
abstract: 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.
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, PA 15261, and Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Pohl
authors.forename: Meloni J
authors.initials: MJ
authors.lastname: DiPietro
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
authors.forename: Tony M
authors.initials: TM
authors.lastname: Plant
mesh_terms: D000818:Animals; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007262:Infusions, Intravenous; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins; D013739:Testosterone; D007986:Luteinizing Hormone