COMPARATIVE EFFECTS OF 2 DIFFERENT DELIVERY SYSTEMS ON GONADOTROPIN-RELEASING-HORMONE (GNRH) ANTAGONIST-INDUCED SUPPRESSION OF GONADOTROPINS AND TESTOSTERONE IN MAN

The Nal-Glu gonadotropin-releasing hormone (GnRH) antagonist, when giv en in daily subcutaneous (SC) doses of 5 mg or higher, maximally suppr esses serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to near undetectable levels and induces azoospermia in no rmal men; lower doses (1.5 and 3.0 mg) are less effective. Cost and co nvenience are important considerations in contraceptive development. S tudies with GnRH agonists suggest that constant delivery is more effec tive in suppressing gonadal function than equal doses by single daily injection. In this study, we examined whether the constant infusion (C I) of a submaximal suppressive dose (1.5 mg) of Nal-Glu would be more effective in suppressing the pituitary-gonadal axis than its repeated single daily injections (SDI). This (1.5 mg) dose was selected because the 5 mg dose given once daily SC for 21 days led to maximal suppress ion of LH, FSH, and testosterone m levels, whereas 1.5 mg once daily f or 21 days gave only partial suppression. It was felt that if continuo us infusion was considerably more effective than intermittent administ ration of this submaximal dose, then the development of long-acting su stained release delivery systems for contraceptives based on GnRH anta gonist analogs would allow both reduced cost and enhanced convenience. One and a half mg of Nal-Glu was administered SC either as a SDI or C I over 24 hours for 21 days to two groups of five normal men. Three me asurements of serum LH, FSH, and T were performed before antagonist in jection and 1, 2, 4, 8, 12, 16, and 24 hours after Nal-Glu infection o n days 0, 1, 7, 21. Frequent blood sampling at 10-minute intervals ove r an 8-hour period was carried out for analysis of immunoreactive LH ( iLH) pulses on day 0 (control day) and the last treatment day (day 21) . In addition, pooled samples for LH, FSH, and T were obtained on days 0, 1, 4, 7, 10, 14, 16, and 21. The SDI regimen suppressed mean serum iLH to a nadir of 6.2 +/- 1.3 IU/L (mean +/- SEM) on day 1, and serum T to 14.4 +/- 3.9 nmol/L (mean +/- SEM) on day 7. Detailed sampling o n subsequent days revealed that the suppressive effect on iLH lasted f or a limited number of hours. There was no significant suppression of serum iFSH. The CI regimen did not suppress serum iLH, iFSH, or T on a ny of the days sampled. These data do not support the contention that constant delivery of the Nal-Glu antagonist is more effective in suppr essing the hypothalamic pituitary-gonadal axis (HPG) than its daily in jection. Although small differences in the efficacy of the two regimen s may not have been detected because of relatively small sample sire, it is unlikely that these small differences would have any practical s ignificance in terms of the cost or the amount of antagonist needed to be loaded into a long-term sustained release delivery system.