Sustained Inhibitory Actions of a Potent Antagonist of Gonadotropin-Releasing Hormone in Postmenopausal Women*

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Abstract
The inhibitory time course and dose-related characteristics of a new potent GnRH antagonist peptide, [N-acetyl-d-pCl-Phe1,2-d-Trp3-d-Lys6-d-Ala10]GnRH, on gonadotropin secretion were studied in nine postmenopausal women. Effective suppression of gonadotropin secretion was correlated with increased circulating concentrations of immunoassayable GnRH antagonist. Inhibition of gonadotropin secretion was achieved by a parenteral dose of 300 μg/kg GnRH antagonist. This dose reduced plasma bioactive LH concentrations by 49–59%, immunoactive LH by 41–46%, and immunoactive FSH by 25–40%. Blockade of gonadotropin secretion was sustained for 10–28 h after a single injection of the synthetic decapeptide. This prolonged action was associated with significant plasma protein binding of the GnRH antagonist and mean plasma half-times of disappearance of 1.5 and 21 h for the fast and slow components, respectively. In summary, we have described the biological actions of a potent GnRH antagonist that binds avidly to serum proteins, has a prolonged plasma residence time, and exerts sustained inhibitory effects on bio- and immunoactive LH release in man. The extended duration of action of this compound may reflect in part its significant binding to circulating plasma proteins.

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