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)

Endocrinology. 2007 Jul;148(7):3364-70. doi: 10.1210/en.2007-0207. Epub 2007 Apr 5.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects*
  • Hypothalamo-Hypophyseal System / metabolism
  • Infusions, Intravenous
  • Kisspeptins
  • Luteinizing Hormone / blood
  • Luteinizing Hormone / metabolism
  • Macaca mulatta
  • Male
  • Neurosecretory Systems / drug effects*
  • Neurosecretory Systems / metabolism
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology*
  • Receptors, G-Protein-Coupled / metabolism
  • Testosterone / blood
  • Testosterone / metabolism
  • Time Factors
  • Tumor Suppressor Proteins / administration & dosage
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / pharmacology*


  • KISS1 protein, human
  • Kisspeptins
  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • Tumor Suppressor Proteins
  • Testosterone
  • Luteinizing Hormone