Suppression of Pituitary-Gonadal Function by a Potent New Luteinizing Hormone-Releasing Hormone Antagonist in Normal Men*

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Abstract
LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadal function by suppressing gonadotropin secretion. Westudied the effects of a recently developed LHRH antagonist on the pituitary-gonadal axis in man. The antagonist Detirelix ([N-Ac-D-Nal(2)1) D-pCl-Phe2)D-Trp3, D-hArg(Et2)6, D-Ala10] LHRH) was given as a single sc injection to nine normal men at three dose levels (5, 10, and 20mg) at intervals of at least 7 days. Serum FSH, LH, and testosterone levels were measured before treatment, at frequent intervals for 48 h, and 72, 96, and 168 h after administration of the antagonist. Mean serum FSH levels decreased (P < 0.001) from 6.9 ± 0.5 (±SEM) mlU/mL to nadirs of 4.4 ± 1.1, 3.6 ± 0.9, and 4.1 ± 0.9 after the 5-, 10-, and 20-mg doses, respectively. Serum LH levels decreased (P < 0.001) from 6.2 ± 0.3 mlU/mL to nadirs of 3.3 ± 0.4, 2.8 ± 0.3, and 2.7 ± 0.3 after all three doses. Serumtestosterone levels decreased (P < 0.001) in a dose-dependent fashion from 5.1 ± 0.2 ng/mL to nadirs of 1.3 ± 0.3, 0.9 ± 0.3, and 0.6 ±0.1 after the same doses. After the initial testosterone decrease, however, escape occurred 12-28 h after the lower doses. The area under the response curve, describing hormone concentrations as a function of time during the study, diminished by 23 ± 2%, 36 ± 4%, and 36 ± 3% for FSH, by 14 ± 6%, 30 ± 6%, and 34 ± 5% for LH, and by 41 ± 5%, 58 ± 6%, and 68 ± 4% for testosterone with the same doses, respectively. The apparent plasma disappearance half-life of Detirelix by RIA was at least 41 h after all three doses. Detirelix elicited only a minor local reaction; no systemic side-effects were observed within the dose range used. These results indicate that this LHRH antagonist is a safe, highly potent inhibitor of the human pituitary-gonadal axis with an exceptionally long duration of action.