To study the dose response characteristics of a gonadotropin-releasing hormone (GnRH) antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5,dGlu6 (AA), d-Ala10] GnRH; Nal-Glu), 1.5 or 5.0 mg of Nal-Glu were administered to two groups of five normal men by daily subcutaneous injection for 21 days. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) were determined on multiple occasions before, during, and after the antagonist treatment. Five milligrams Nal-Glu markedly suppressed mean serum immunoreactive LH to a mean of 1.5 +/- 0.4 IU/L (+/- SEM), immunoreactive FSH to the limit of assay detection (1 IU/L), and lowered basal mean serum T to castrate range (less than 2 nmol/L). Serum bioactive LH levels also showed a marked decrease in the 5.0-mg group similar to that seen in immunoreactive LH levels. Amplitude of immunoreactive LH pulses was markedly reduced in the 5.0-mg group on day 21. A 1.5-mg dose of Nal-Glu transiently suppressed serum immunoreactive LH levels on day 1. There was a subsequent escape on the rest of the days sampled. Serum immunoreactive FSH levels were not significantly changed over the 21-day treatment period. Serum T levels were transiently suppressed only on day 1 paralleling immunoreactive LH suppression. No adverse systemic side effects occurred. Thus, the 5.0-mg dose of this GnRH antagonist provides a pharmacological means of markedly suppressing the hypothalamic-pituitary-gonadal axis and, therefore, has potential as a male contraceptive.