Comparison of the antigonadotropic activity of three GnRH antagonists (Nal-Glu, Antide and Cetrorelix) in a non-human primate model (Macaca fascicularis)

Summary. We compared the antigonadotropic activity of the GnRH antagonists Nal-Glu, Antide and Cetrorelix in a non-human primate model (Macaca fascicularis). Orchidectomized animals received a single subcutaneous injection at doses of 250 μg kg−1 (n = 4), 625 μg kg−1 (n = 4) and 1250 μg kg−1 (n = 3) of the compounds Nal-Glu ([Ac-D-Nal (2)1, D-4-Cl-Phe2, D-Pal3, Arg5, D-Glu(AA)6, D-Ala10]-GnRH), Antide (Nal-Lys, [Ac-D-Nal1, D-4-Cl-Phe2, D-Pal3, Nic-Lys5, D-Nic-Lys6, Ip-Lys8, D-Ala10]-GnRH) or Cetrorelix ([Ac-D-Nal1, D-4-Cl-Phe2, D-Pal3, D-Cit6, D-Ala10]-GnRH). Blood samples were collected before and 3, 6, 12, 24, 48, 72, and 96 h after GnRH antagonist administration. Serum was analysed for concentrations of bioactive LH and immunoactive LH and FSH. All three compounds decreased LH secretion within 3–12 h (P<0.05) and FSH secretion within 12–48 h (P<0.05) after injection. Major differences between the GnRH antagonists were observed with regard to the effective dose and duration of action. At a dose of 250 μg kg−1 Nal-Glu and Antide only transiently suppressed LH and FSH release, whereas Cetrorelix induced complete inhibition (P<0.05) which lasted for the entire observation period. At a dose of 625 μg kg−1 Cetrorelix exhibited the longest duration of action and Nal-Glu the shortest. At the highest dose of 1250 μg kg−1 Nal-Glu, Antide and Cetrorelix markedly inhibited LH and FSH secretion throughout the entire study period. With Nal-Glu (625 and 1250 μg kg−1) bioactive LH secretion appeared more reduced compared to immunoactive LH. In conclusion, Nal-Glu, Antide and Cetrorelix are potent inhibitors of LH and FSH secretion. In terms of the effective dose and duration of action Cetrorelix appeared most active, followed by Antide and Nal-Glu in this experimental model. Thus, Antide and Cetrorelix are highly interesting for clinical use.