IRREVERSIBLE INCREASE OF SERUM IGF-1 AND IGFBP-3 LEVELS IN GNRH-DEPENDENT PRECOCIOUS PUBERTY OF DIFFERENT ETIOLOGIES - IMPLICATIONS FOR THEONSET OF PUBERTY

In normal puberty, as well as in precocious puberty, serum GH, IGF-1 a nd IGFBP-3 are increased as a consequence of the increase in sex hormo ne secretion. However, the effect of suppressing sex hormones on serum GH and IGF-1 in precocious puberty is controversial. On the other han d, the interest in the interaction between the GH-IGF-1 system and the hypothalamic-pituitary gonadal axis has been reinforced by experiment al evidence which indicates that IGF-1 might be involved in the regula tion of the onset of puberty. We have studied 11 girls with GnRH-depen dent precocious puberty (Gr1), before and during treatment with GnRH a nalog for 1.43 +/- 0.81 years, and 4 children (3 boys and 1 girl) with GnRH-dependent precocious puberty secondary to congenital adrenal hyp erplasia (Gr2), before and during treatment with hydrocortisone (HC) a lone for 0.32 +/- 0.23 years, and during combined treatment with GnRH analog, for 1.87 +/- 1.43 additional years. The etiology of precocious puberty in Gr1 was either idiopathic or associated with several brain lesions (hydrocephalia, hypothalamic hamartoma, suprasellar astrocyto ma). During follow-up, clinical status as well as gonadotropin suppres sion, tested with the acute GnRH test, was checked every 3 months. Pep tides and steroid hormones were determined by radioimmunoassay. Normal values for serum IGF-1 and serum IGFBP-3 were established in our labo ratory from a population of 165 clinically controlled subjects, aged 0 .5-15 years. In Gr1, treatment arrested breast development and blunted LH and FSH response to GnRH in all subjects. In Gr2, during HC treatm ent, all patients had a pubertal type of response to the acute GnRH te st which was suppressed during combination treatment. In Gr1, serum IG F-1 SDS for chronological age (CA), but not IGFBP-3 SDS CA, was signif icantly high before GnRH analog treatment (mean +/- SD 1.33 +/- 1.84 a nd -0.68 +/- 1.55, p < 0.05 and p = NS, respectively). IGF-1 SDS CA re mained high and IGFBP-3 SDS CA remained normal during treatment (1.34 +/- 2.0 and 0.73 +/- 1.93). In Gr2, serum IGF-1 and IGFBP-3 SDS CA wer e high before treatment (3.11 +/- 0.74 and 1.31 +/- 1.43, p < 0.02 and p < 0.05, respectively), and they remained high during HC or combined treatment. In the two groups, serum IGF-1 SDS BA and serum IGFBP-3 SD S BA levels were similar to control subjects before and during treatme nts. In Gr1, mean serum dehydroepiandrosterone sulfate (DS) was within prepubertal preadrenarche values but serum androstenedione (Delta(4)) was significantly higher (6.35 +/- 3.45 nmol/l) than in our own norma l control group (1.84 +/- 1.18, n = 20), both before and during treatm ent (p < 0.02). In Gr2, serum DS and serum Delta(4) were high before t reatment but they decreased to prepubertal values during combined trea tment. It is concluded that (1) the CNS maturational events which chan ge the regulation of serum IGF-1 and IGFBP-3 are induced by the pubert al increase in sex steroids in a nonreversible way and (2) the high ad renal steroid levels present in CAH induce a nonreversible activation of the GH-IGF-1 axis and of the GnRH pulse generator.