Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist cetrorelix (SB-75) in normal men.
In rats and nonhuman primates the new GnRH antagonist cetrorelix (SB-75; [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]GnR H) has been shown to suppress testosterone secretion effectively and persistently. A clinical phase I study was performed to assess the hormonal effects of this highly potent antagonist in normal men. After 2 control examinations 30 young male volunteers were randomly assigned to 6 treatment groups (n = 5/group), and single doses of 0 (placebo), 0.25, 0.5, 1.0, 2.0, and 5.0 mg cetrorelix were administered sc. Blood samples were obtained over the course of 7 days postinjection. After maximal cetrorelix serum levels were achieved 1 h postinjection, the GnRH antagonist serum levels decreased with a terminal t1/2 of 29.8 +/- 4.2 h (mean +/- SE). LH secretion was suppressed dose- and time-dependently; maximal suppression occurred 4-6 h postinjection. Suppression of FSH did not reach statistical significance. Doses of 1.0, 2.0, and 5.0 mg cetrorelix significantly suppressed testosterone secretion compared to that in the placebo group. After the administration of 1.0 mg cetrorelix, maximal suppression was seen 8 h after injection, with testosterone levels of 7.5 +/- 1.1 nmol/L compared to 15.8 +/- 2.2 nmol/L in the placebo group. Maximal testosterone suppression by 2.0 and 5.0 mg cetrorelix occurred 12 h after injection, with testosterone concentrations of 4.9 +/- 0.5 and 2.2 +/- 0.4 nmol/L, respectively, compared to 16.5 +/- 1.7 nmol/L in the placebo group. Twenty-four hours after the injection of 1.0 and 2.0 mg cetrorelix, testosterone values were no longer significantly different from those in the placebo group, whereas in the 5.0-mg dose group testosterone concentrations increased slightly and reached serum concentrations in the lower normal range after 48 h. The only side-effect observed after the administration of cetrorelix was a transient local erythema at the injection site that disappeared within 30 min. No local induration or pruritus, or any adverse systemic side-effect occurred in any volunteer. In conclusion, the new GnRH antagonist cetrorelix effectively decreases serum LH and testosterone concentrations in a dose- and time-dependent manner and, therefore, has potential for treatment of sex hormone-dependent diseases and male contraception.
Behre
H M
HM
Institute of Reproductive Medicine, The University, Münster, Germany.
Klein
B
B
Steinmeyer
E
E
McGregor
G P
GP
Voigt
K
K
Nieschlag
E
E
D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors* / Q000097:blood; D008297:Male; D012016:Reference Values; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000097:blood
D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C062876:cetrorelix