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, Nal 1 Glu 6 ([Ac-D 2 Nal 1 , D 4 ClPhe 2 , D 3 Pal 3 , Arg 5 , DGlu(AA) 6 ,-DAla 10 ]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 μ g/kg. Bioactive (B) LH and B-FSH also were measured after the IM administration of the 50- μ g/kg dose. Serum levels of Nal 1 Glu 6 were determined by a radioreceptor assay for the first 24 hours after the 50- μ g/kg IM dose and in three women after a 10 -μ g/kg intravenous (IV) dose. While the disappearance rate of serum Nal 1 Glu 6 after a 10- μ g/kg IV injection was rapid, gonadotropin suppression persisted longer than detectable serum levels. In contrast, after a 50- μ g/kg IM injection, the decline from peak circulating levels was slower, contributing to its longer duration of action (>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- μ g/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- μ g/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. Thus, Nal 1 Glu 6 is a potent antagonist to GnRH action, with prompt and sustained suppression of pituitary gonadotropin secretion. It provides a useful tool for studies of GnRH-dependent events in humans.