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Submitted on December 6, 2005
Accepted on January 27, 2006
Reproductive Endocrinology Unit (S.B.S., W.F.C.,Jr.), Massachusetts General Hospital, Boston, MA, Department of Cell Biology and Physiology (M.J.DiP., S.R., T.M.P.), University of Pittsburgh, Pittsburgh, PA
* To whom correspondence should be addressed. E-mail: plant1{at}pitt.edu.
The effect of continuous administration of the C-terminal fragment of metastin, the ligand for the G protein-coupled receptor, GPR54, on GnRH-induced LH secretion was examined in 3 agonadal, juvenile male monkeys whose responsiveness to GnRH was heightened by pretreatment with a chronic pulsatile iv infusion of synthetic GnRH. After bolus injection of 10 µg human (hu) metastin 45-54 (equivalent to kisspeptin 112-121), the GPR54 agonist was infused continuously at a dose of 100 µg/h and elicited a brisk LH response for approximately 3 h. This rise was then followed by a precipitous drop in LH despite continuous exposure of GPR54 to metastin 45-54. On day 4, during the final 3 h of the infusion, single boluses of hu metastin 45-54 (10 µg), NMDA (10 µg/kg) and GnRH (0.3 µg) were administered to interrogate each element of the metastin-GPR54-GnRH-GnRH receptor cascade. Although the NMDA and GnRH boluses were able to elicit LH pulses, that of hu metastin 45-54 was not, demonstrating functional integrity of GnRH neurons (NMDA) and GnRH receptors (NMDA and GnRH), but desensitization of GPR54. The desensitization of GPR54 by continuous hu metastin 45-54 administration has therapeutic implications for a variety of conditions currently being treated by GnRH and its analogs, including restoration of fertility in patients with abnormal GnRH secretion (i.e. idiopathic hypogonadotropic hypogonadism, hypothalamic amenorrhea), and selective, reversible suppression of the pituitary-gonadal axis to achieve suppression of gonadal steroids (i.e. precocious puberty, endometriosis, uterine fibroids, and prostate cancer).
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