IRREVERSIBLE INCREASE OF SERUM IGF-1 AND IGFBP-3 LEVELS IN GNRH-DEPENDENT PRECOCIOUS PUBERTY OF DIFFERENT ETIOLOGIES - IMPLICATIONS FOR THEONSET OF PUBERTY
A. Belgorosky et Ma. Rivarola, IRREVERSIBLE INCREASE OF SERUM IGF-1 AND IGFBP-3 LEVELS IN GNRH-DEPENDENT PRECOCIOUS PUBERTY OF DIFFERENT ETIOLOGIES - IMPLICATIONS FOR THEONSET OF PUBERTY, Hormone research, 49(5), 1998, pp. 226-232
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.