Mode of suppression of pituitary and gonadal function after acute or prolonged administration of a luteinizing hormone-releasing hormone antagonist in normal men.

LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadotropin secretion and, consequently, gonadal function. We studied the pituitary and gonadal suppression following single doses and short term administration (1-3 weeks) of a recently developed LHRH antagonist in normal men. First, the antagonist Nal-Glu ([Ac-D2Nal1, D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),DAla10]LHRH ), was given as a single sc injection to five normal men at three dose levels of 1, 5, and 20 mg (study I). Serum FSH, immunoreactive LH (IR-LH), bioactive LH (bio-LH), testosterone, and estradiol were measured before and at frequent intervals for 48 h after Nal-Glu administration. Mean serum FSH decreased (P less than 0.001) by 28.9 +/- 5.4% (+/- SE), 38.2 +/- 7.9%, and 44.5 +/- 3.6% after the 1-, 5-, and 20-mg doses, respectively. Mean serum IR-LH decreased (P less than 0.001) by 39.0 +/- 13.8%, 53.2 +/- 10.0%, and 53.1 +/- 14.4% after the three doses. Serum bio-LH levels and the ratio of bio-LH/IR-LH decreased (P less than 0.001) after the 20-mg dose by 87.8% and 78.5%, respectively. Serum testosterone levels decreased (P less than 0.001) more than 78.5% after all Nal-Glu doses. The duration of testosterone suppression, but not the nadir reached, was dose dependent (P = 0.012). Serum estradiol levels also decreased (P less than 0.001), but the rate of decrease was slower than that of serum testosterone. The apparent plasma disappearance half-life of Nal-Glu after administration of 5 mg was 12.8 +/- 2.7 h. The Nal-Glu antagonist also was given daily as a single sc injection of 5 mg to eight normal men for 21 days (study II) or twice daily to five men for 7 days (study III). In study II, serum FSH, IR-LH, bio-LH, testosterone, estradiol, and 17-hydroxy-progesterone were measured daily, immediately before the next injection, and on days 1, 7, and 21 in frequent blood samples drawn for 24 h. The mean serum testosterone level in study II decreased (P less than 0.001) from 17.6 +/- 2.2 to 4.1 +/- 1.0 nmol/L on day 1, increased (P less than 0.05) between days 2 and 8, and then progressively decreased to below 2 nmol/L from day 18 until 24 h after the end of the study. Serum FSH, IR-LH, and bio-LH levels paralleled those of testosterone.(ABSTRACT TRUNCATED AT 400 WORDS)