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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)

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)

Suresh Ramaswamy, Stephanie B Seminara, Clifford R Pohl, Meloni J DiPietro, William F Crowley Jr, Tony M Plant

Endocrinology. 2007 Jul;148(7):3364-70.

PMID: 17412800

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4249363	Metastin (45-54)			Price

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