Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty

Background: Dosing of monthly depot leuprolide ( DL) in central precocious puberty ( CPP) varies considerably. U. S. practitioners use 7.5 - 15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3- month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses. Objectives: In an open 12- month protocol, we tested the efficacy of three DL doses ( 7.5 mg- and 3.75 mg- 1 month and 11.25 mg- 3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin ( Gn) levels at 12- wk intervals. The null hypothesis was no difference among doses. Methods: Both existing and new patients with CPP received our standard therapy ( DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL- stimulated LH 2 IU/ liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria ( < 4.5 IU/ liter) on 3.75 mg then received a single dose of 11.25 mg- 3 month and were reevaluated 12 wk later. Serum LH/ FSH and sex steroids were obtained 40 min after DL injection. Results: Thirty subjects were enrolled ( 20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL- stimulated LH levels ( mean +/- SD) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg- 3 month, respectively ( 7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg- 3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively ( 7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg- 3 month, P = 0.020). No differences were detected in mean sex steroid levels. Conclusions: Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg- 3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low- dose 1- and 3- month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/ FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long- term therapeutic differences remains to be determined.