SERUM INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) AND IGF-BINDING PROTEIN-3 LEVELS ARE INCREASED IN CENTRAL PRECOCIOUS PUBERTY - EFFECTS OF 2 DIFFERENT TREATMENT REGIMENS WITH GONADOTROPIN-RELEASING-HORMONE AGONISTS, WITHOUT OR IN COMBINATION WITH AN ANTIANDROGEN (CYPROTERONE-ACETATE)

Central precocious puberty (CPP) is characterized by early activation of the pituitary gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed th;at gonadal sex steroids stimulate pulsatile GH secretion, which, in)turn, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term treatment with GnRH in combination with an antiandrogen (cyproterone acetate) to block the possible effect of adrenal androgens has not previously been evaluated. We, therefore, studied 40 patients with ere treated for 24 months with either GnRH with (Buserelin) in combination with cyproterone acetate (Androcur; n = 23) or with long acting GnRH analog (Decapeptyl Depot; n = 17). We found that serum IGF-I levels were increased before treatment in both groups (mean +/- SE, 446 +/- 35 and 391 +/- 35 mu g/L; P < 0.0001, respectively) compared to those sin normal age-matched prepubertal children. Similarly, IGFBP-3 levels were significantly elevated (4675 +/- 209 and 4305 +/- 162 mu g/L, respectively; P < 0.0001) in the two groups. Treatment with GnRH analog in combination with cyproterone acetate significantly decreased height velocity and serum IGF-I and IGFBP-3 levels to normal levels after 2 yr of treatment (P < 0.0001). Serum IGF-I levels remained unchanged during monthly im treatment with long acting GnRH analog, whereas IGFBP-3 levels significantly increased during the first year of this treatment despite unmeasurable estradiol levels. Thus, in both groups, the molar ratio between IGF-I and IGFBP-3 (i.e. free biologically active IGF-I) declined concomitantly with a decrease in growth velocity. Serum levels of IGF-I and IGFBP-3 (expressed as the SD score for bone age), but not those of estradiol, correlated with height velocity before and during treatment (r = 0.34; P < 0.0001 and r = 0.24; P = 0.003, respectively). Six of the patients with a subnormal GH response to clonidine had similar IGF-I and IGFBP-3 serum levels and growth velocity compared to the other 34 girls with CPP and a normal GH response. We conclude that circulating IGF-I and IGFBP-3 levels are involved in the increased growth in precocious puberty and that the inverse effect on IGF-I and IGFBP-3 of gonadal suppression with long-acting GnRH analog suggests a differential regulation of serum IGF-I and IGFBP-3.