Suppression of bioactive and immunoreactive follicle-stimulating hormone and luteinizing hormone levels by a potent gonadotropin-releasing hormone antagonist: pharmacodynamic studies.

Dose-dependent gonadotropin suppression by a potent gonadotropin-releasing hormone (GnRH) antagonist, Nal1 Glu6 [( Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,DGlu(AA)6,- DAla10]GnRH), was determined in five postmenopausal women by frequent sampling for immunoreactive luteinizing hormone (I-LH) and immunoreactive follicle stimulating hormone (I-FSH) for 72 hours after single intramuscular (IM) injections of 10, 50, 150, and 300 micrograms/kg. Bioactive (B) LH and B-FSH also were measured after the IM administration of the 50-micrograms/kg dose. Serum levels of Nal1 Glu6 were determined by a radioreceptor assay for the first 24 hours after the 50-micrograms/kg IM dose and in three women after a 10-micrograms/kg intravenous (IV) dose. While the disappearance rate of serum Nal1 Glu6 after a 10-micrograms/kg IV injection was rapid, gonadotropin suppression persisted longer than detectable serum levels. In contrast, after a 50-micrograms/kg IM injection, the decline from peak circulating levels was slower, contributing to its longer duration of action (greater than 24 hours). All IM doses tested resulted in a similar 51% to 63% decrease in I-LH, which was maximal by 8 hours. The duration of action was dose-dependent, with decreased levels lasting up to 72 hours at the 300-micrograms/kg dose. While decline of I-FSH was smaller (14% to 33%), the duration of suppression was also dose-dependent, although the nadir occurs later (8 to 9 hours after administration) and suppression lasted longer (72 hours at the 150-micrograms/kg dose). The reduction of B-LH was greater than that of I-LH and the suppression of B-FSH also was greater than that of I-FSH.(ABSTRACT TRUNCATED AT 250 WORDS)