Abstract 547 Poster Session I, Saturday, 5/1 (poster 312)

GnRH analogs are standard therapy for central precocious puberty (CPP), but reported clinical trials have not assessed gonadotropin suppression using highly sensitive gonadotropin assays. 139 children with precocious puberty (B2 before 8 years in girls and G2/P2 by 9 y in boys) were screened for CPP at 9 centers. Fifty-five subjects (49 F, 6 M) met enrollment criteria including GnRH-stimulated LH≥10U/L by double antibody immunofluorometric assay (DELFIA). Mean age was 7.2±2.0 years (range 1.1-8.9), and mean BA was 10±2.2 years (range 2.5±13.2). Depot leuprolide acetate 7.5-1.5 mg was administered IM every 4 weeks. IV GnRH stimulation tests with serum samples at -20, 0, 20, 40, 60, and 90 min were repeated at 4, 12, 24, 36, and 48 weeks, and every 6 months. One female subject was excluded due to non-compliance. All 54 remaining subjects received at least two years of therapy and almost all have completed treatment. Per protocol, the dose was increased in 6 girls with follow-up GnRH-stimulated LH> 1.75 IU/L or bleeding after the first month. Mean Tanner stage did not change during therapy. Growth rate declined from 10.8 cm/yr pretreatment to 5.9 cm/yr in the first year. After an initial lag in bone age deceleration, delta BA/ delta CA fell to 0.63 in the second year. Final height data will be reported separately.

In 48 females, peak GnRH-stimulated LH levels fell from 36.8±21.7 to 0.76±0.60 IU/L after a single dose, and peak serum FSH levels declined from 14.3±5.2 to 0.90±0.45 IU/L. Basal LH levels fell from 2.30±3.89 to 0.47±0.28 at 4 weeks, and basal FSH declined from 4.18±1.72 to 0.78±0.30 IU/L. Basal and peak LH levels further declined as treatment progressed. In contrast, basal and GnRH-stimulated FSH levels gradually increased during long term therapy. In females, mean serum estradiol was 15.5±16 pg/ml before therapy; and none of the 48 girls had a detectable estradiol (5 pg/ml) at any time during therapy. In boys, serum testosterone was 205±162 ng/dl before treatment and 19.8±15 ng/dl at 4 weeks, as 4 out of 6 males continued to have detectable testosterone levels during therapy. At cessation of therapy, gonadotropin and sex steroid levels returned to pubertal levels by the 6 month follow-up. In summary, peak LH and basal and peak FSH levels measured by immunofluorometric assay were immediately suppressed by depot leuprolide to levels below prepubertal norms; basal LH was suppressed, but not to prepubertal levels. LH and FSH levels followed opposite trends over multiple years of therapy.

Supported by TAP Pharmaceuticals