Evidence That Gonadotropin‐Releasing Hormone II Is Not a Physiological Regulator of Gonadotropin Secretion in Mammals

Abstract

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.

Role of gonadotropin-releasing hormone II in the mammalian nervous system

“…This conjecture has been supported recently by studies in shrews, sheep and primates. Although Type-2 GnRH receptors are reportedly present in mammalian gonadotropes, GnRH II stimulation of pituitary gonadotropins is completely blocked with administration of Type-1 GnRH receptor antagonists, both in vitro and in vivo [65][66][67]. Likewise, similar blocking effects of Type-1 receptor antagonists were found on GnRH II-induced ovulation in female musk shrews (TABLE 2) [68].…”

“…More recent evidence contradicts these earlier findings; in vitro studies using rat hemi-pituitaries found that GnRH II had no significant FSH-or LH-releasing ability, except at very high doses, and no selective releasing activity for FSH [73,74]. Likewise, in vivo studies in sheep and rhesus monkeys, as well as an in vitro investigation using cultured primate pituitaries, have reported no selective FSH-releasing activity for GnRH II [65][66][67]. Collectively, the data indicate that GnRH II has only weak actions as a selective FSH-RF, if at all.…”

“…These findings indicate that GnRH II's actions on behavior are probably mediated via the Type-2 GnRH receptor or other, as-yet unidentified, GnRH receptors. By contrast, GnRH II's stimulation of gonadotropin release in mammals is probably mediated via Type-1 GnRH receptor pathways, as blocking this receptor prevents any GnRH II-induced LH release and ovulation [65,66,68]. Intriguingly, the Type-2 GnRH receptor, in contrast to the Type-1 receptor, possesses a cytoplasmic C-terminal tail, which allows for fast desensitization …”

Gonadotropin-releasing hormone antagonists

“…GnRH-II was found to induce expression of LH and FSH in sheep but not in the presence of antide, a specific GnRH-I receptor antagonist [60]. GnRH-II did little to augment the activity of GnRH-I on gonadotropin secretion.…”

Conserved Amino Acid Residues that Are Important for Ligand Binding in the Type I Gonadotropin-Releasing Hormone (GnRH) Receptor Are Required for High Potency of GnRH II at the Type II GnRH Receptor

“…Genes for a type II GnRH receptor (nomenclature of Ref. 13) have been identified in several mammals (14,16,18,19). Type II GnRH receptors have high affinity for GnRH II and much lower affinity for GnRH I (14,16).…”