Control of follicle-stimulating hormone and luteinizing hormone release by hypothalamic peptides

Lesion, stimulation, and pharmacological studies point to separate hypothalamic control of pulsatile FSH and LH secretion. LH release is controlled by a region extending from the preoptic area to the anterior and mid-median eminence, whereas FSH release is controlled by a region extending from the dorsal anterior hypothalamic area to the caudal median eminence. We have separated an FSH-releasing factor from LHRH by gel-filtration on Sephadex G-25, confirming results obtained over 25 years ago; and we are attempting its isolation in collaboration with Vale and River. In the meantime, reasoning that FSH-releasing factor might be related to LHRH, we tested many analogs of LHRH and found one that has selective FSH-releasing activity over a 50-fold dose range; however, it is relatively weak. This led us to the possibility that the GAP might be FSH-RF. Indeed, GAP1-13 has FSH but no LH-releasing activity over a 100-fold dose range; however, it is less potent than we would expect of the natural product. Substituting D-Trp-9 into the molecule to inhibit enzymatic degradation yielded a more potent and completely selective FSH-releasing peptide,24 which could be clinically useful. Alpha-inhibin-92 of Li et al. has been shown to have a highly selective dose-related suppressive action on FSH release in castrate male rats.25 Smaller fragments (35-65 and 66-92) of this molecule also possess the activity, albeit at higher doses. That this molecule may be physiologically significant is indicated by elevations in plasma FSH in immature rats obtained following intravenous injection of antisera raised against the peptide. Because of its much smaller size than that of 32-kDa alpha, beta inhibins and the lack of carbohydrate in the molecule, this can be relatively easily synthesized and might have clinical utility as an FSH release-inhibiting peptide.