Hormonal responses to the new potent GnRH antagonist Cetrorelix

GnRH antagonists, unlike the GnRH agonists, immediately suppress gonadotropins and testosterone secretion without initial stimulatory effect. We report here on a single-dose study with the new GnRH antagonist Cetrorelix (Ac-D-Nal(2)1, D-Phe(4C1)2, D-Pal3, D-Cit6, D-Alal0) in 25 normal men. The study involved five different dose groups (0.25, 0.5, 1.0, 1.5 or 3.0 mg) and subjects were observed over a 40 h period. Five men served as controls. Serum levels of LH, FSH and testosterone decreased rapidly with a dose-related decline for testosterone of 25%, 24%, 41%, 53% and 72%, respectively, for testosterone within the first 8 h of antagonist administration. All effects were reversible and no serious side effects were observed. Thus, this GnRH antagonist is active in men even in small doses and could become a new therapeutic tool for sex hormone-dependent diseases. Cetrorelix seems to have the highest suppressive rate per mg peptide of all other antagonists from the literature, such as Nal-Glu (Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal3, Arg5, D-Glu6(AA), D-Alal0), Detirelix (Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Alal0) or 4F (Ac-delta 3Prol, 4F-D-Phe2, D-Trp3,6). During the time of suppression after a dose of 3 mg there was an LH and testosterone peak in the early morning coinciding with the testosterone peak in untreated men. The GnRH antagonist seems to unmask the circadian rhythm of LH secretion.