Inhibition of endopeptidase 24.15 greatly increases the release of luteinizing hormone and follicle stimulating hormone in response to luteinizing hormone/releasing hormone.

Inhibitors of endopeptidase (EP) 24.15, an enzyme cleaving the Tyr5-Gly6 bond of LHRH, greatly increase the half-life of i.v. or i.c.v. administered luteinizing hormone-releasing hormone (LHRH) (Lasdun et al., J. Pharmacol. Exp. Ther. 251: 439-447, 1989). Concentrations of plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured in rats after i.c.v. and i.v. administration of LHRH alone or in conjunction with inhibitors of EP 24.15. In animals treated with two potent EP 24.15 inhibitors, i.v. and i.c.v. LHRH injections induced a much greater and longer-lasting increase of plasma LH and FSH concentrations than in controls Two and 4 hr after administration of the inhibitors and LHRH, hormone concentrations were one order of magnitude greater than in controls. The magnitudes and durations of the increases were similar to those after administration of [D-Trp6]-LHRH or [D-Leu6, Des-Gly-NH2(10)]-LHRH ethylamide, two "superactive" analogs of LHRH, which are resistant to degradation by EP 24.15, due to the presence of a D-amino acid in position 6. It is concluded that LHRH degradation by EP 24.15 limits the magnitude and duration of the response of the pituitary to LHRH, and that increases in plasma LH and FSH similar to those obtained after administration of superactive analogs can be also obtained with the natural hormone, provided that its degradation is prevented by EP 24.15 inhibitors. Accordingly, the increased in vivo activity of the superactive LHRH analogs can be largely attributed to their resistance to degradation by EP 24.15.