Irreversible increase of serum IGF-1 and IGFBP-3 levels in GnRH-dependent precocious puberty of different etiologies: implications for the onset of puberty

Abstract

In normal puberty, as well as in precocious puberty, serum GH, IGF-1 and IGFBP-3 are increased as a consequence of the increase in sex hormone secretion. However, the effect of suppressing sex hormones on serum GH and IGF-1 in precocious puberty is controversial. On the other hand, the interest in the interaction between the GH-IGF-1 system and the hypothalamic-pituitary gonadal axis has been reinforced by experimental evidence which indicates that IGF-1 might be involved in the regulation of the onset of puberty. We have studied 11 girls with GnRH-dependent precocious puberty (Gr1), before and during treatment with GnRH analog for 1.43+/-0.81 years, and 4 children (3 boys and 1 girl) with GnRH-dependent precocious puberty secondary to congenital adrenal hyperplasia (Gr2), before and during treatment with hydrocortisone (HC) alone 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 astrocytoma). During follow-up, clinical status as well as gonadotropin suppression, tested with the acute GnRH test, was checked every 3 months. Peptides and steroid hormones were determined by radioimmunoassay. Normal values for serum IGF-1 and serum IGFBP-3 were established in our laboratory 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 treatment, all patients had a pubertal type of response to the acute GnRH test which was suppressed during combination treatment. In Gr1, serum IGF-1 SDS for chronological age (CA), but not IGFBP-3 SDS CA, was significantly high before GnRH analog treatment (mean+/-SD 1.33+/-1.84 and -0.68+/-1.55, p < 0.05 and p = NS, respectively). IGF-1 SDS CA remained 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 were 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 SDS BA levels were similar to control subjects before and during treatments. In Gr1, mean serum dehydroepiandrosterone sulfate (DS) was within prepubertal preadrenarche values but serum androstenedione (delta4) was significantly higher (6.35+/-3.45 nmol/l) than in our own normal control group (1.84+/-1.18, n = 20), both before and during treatment (p < 0.02). In Gr2, serum DS and serum delta4 were high before treatment but they decreased to prepubertal values during combined treatment. It is concluded that (1) the CNS maturational events which change the regulation of serum IGF-1 and IGFBP-3 are induced by the pubertal increase in sex steroids in a nonreversible way and (2) the high adrenal steroid levels present in CAH induce a nonreversible activation of the GH-IGF-1 axis and of the GnRH pulse generator.