INHIBITION OF LUTEINIZING-HORMONE, FOLLICLE-STIMULATING-HORMONE AND SEX-STEROID LEVELS IN MEN AND WOMEN WITH A POTENT ANTAGONIST ANALOG OF LUTEINIZING-HORMONE-RELEASING HORMONE, CETRORELIX (SB-75)

Cetorelix (SB-75;[Ac-D-Nal(2)(1), D-Phe(4Cl)(2), D-Pal(3)(3). D-Cit(6), D-Ala(10)]luteinizing hormone-releasing hormone (LHRH)) is a new highly potent antagonist analog of LHRH containing the D-ureidoalkyl amino acid D-citrulline at position 6 and is free of allergenic effects. This study shows the inhibition of LH and follicle-stimulating hormone (FSH) release in normal men, postmenopausal women and patients with gonadal dysgenesis, using different doses and im. sc and iv routes of administration of SB-75. The mean serum levels of LH and FSH in normal men who received one single dose of 300 mu g of SB-75 sc started to decline rapidly 1 h after its administration; the LH suppression was sustained for 14 h and that of FSH up to 24 h or longer as the samples were obtained only up to this time. The nadir for LH was reached at 14 h and that for FSH at 24 h or later after administration of the antagonist (p < 0.05). Serum levels of total and free testosterone decreased after the first hour and this inhibition was maintained for up to 14 h. The nadir for total testosterone was at 6 h and that for free testosterone was at X h (p < 0.001), corresponding to 56% and 60% of inhibition, respectively. In postmenopausal. women, inhibition of the elevated basal serum LH and FSH levels occurred after a single injection of the antagonist analog SB-75 in doses of 75, 150, 300, 600 and 1200 mu g using im, sc and iv routes of administration. The mean resting levers of serum LH and FSH showed a significant decrease for all doses and routes of administration of SB-75 (p < 0.01). Maximal inhibition was observed 6-12 h after administration. After administration of 300 mu g of SB-75 sc every 12 h for 3 days, serum LH and FSH continued to be secreted but a marked decrease in the basal levels of both gonadotropins was observed. A fall in LH and FSH also was produced in patients with gonadal dysgenesis who were given 300 mu g of SB-75. The nadir of serum LH was 61 +/- 9.6% for the iv route and 58.5 +/- 7.5% for the sc route (p < 0.01): for serum FSH it was 51 +/- 7.5% and 48.5 +/- 7.5% (p < 0.01), respectively, of the baseline levels. These results show that the antagonistic analog SB-75 is devoid of allergenic effects, extremely active in small doses and can be administered safely to humans. The development of sustained delivery systems for SB-75 should facilitate the clinical use of this powerful LHRH antagonist.