Evidence that gonadotropin-releasing hormone II is not a physiological regulator of gonadotropin secretion in mammals.
Gonadotropin-releasing hormone (GnRH)-II stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion when administered at high doses in mammals, and this effect has been assumed to be mediated through the GnRH-II receptor expressed on gonadotropes. This study used two selective GnRH-I receptor antagonists to test the alternative hypothesis that GnRH-II acts through the GnRH-I receptor to elicit gonadotropin secretion. The antagonist, antide, was used to characterize the receptor-relay because it was a pure antagonist in vitro based on inositol phosphate responses in COS-7 cells transfected with either mammalian GnRH-I and GnRH-II receptors and, in vivo, potently antagonized the gonadotropin-releasing effect of a single injection of 250 ng GnRH-I in our sexually inactive sheep model. In a series of studies in sheep, antide (i). blocked the acute LH response to a single injection of GnRH-II (20 microg antide: 10 microg GnRH-II); (ii). blocked both the acute, pulsatile LH response and the FSH priming response to 2-hourly injections of GnRH-II over 36 h (100 microg antide/8 h: 4 microg GnRH-II/2 h); and (iii). chronically blocked both the pulsatile LH response and the marked FSH priming response to 4-hourly injections of GnRH-II over 10 days (75 microg antide/8 h: 4 microg GnRH-II/4 h). In two final experiments, the GnRH-I antagonist 135-18, shown previously to agonize the mammalian GnRH-II receptor, blocked the gonadotropin-releasing effects of GnRH-I (250 ng) but failed to elicit an LH response when given alone, and simultaneous administration of GnRH-II (250 ng) failed to alter the LH-releasing effect of GnRH-I (50-500 ng). These data thus support our hypothesis. Based on additional literature, it is unlikely that the GnRH-II decapeptide is a native regulator of the gonadotrope in mammals.
Gault
P M
PM
Medical Research Council Human Reproductive Sciences Unit, University of Edinburgh, Chancellor's Building, Edinburgh, UK.
Maudsley
S
S
Lincoln
G A
GA
D000818:Animals; D019556:COS Cells; D004347:Drug Interactions; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D006062:Gonadotropins / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors; D012756:Sheep
D006062:Gonadotropins; D006727:Hormone Antagonists; D009842:Oligopeptides; D020033:Protein Isoforms; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C057022:iturelix