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 (Δ4) 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 Δ4 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.

Keywords:
IGF-1, IGFBP-3, Precocious puberty, Sex steroids, Congenital adrenal hyperplasia
1.
Wiedemann E, Schwartz E, Frantz AG: Acute and chronic estrogen effect upon serum somatomedin activity, growth hormone, and prolactin in man. J Clin Endocrinol Metab 1976;42:942–952.
2.
Rosenfield RI, Furlanetto R, Bock D: Relationship of somatomedin-C concentrations to pubertal changes. J Pediatr 1983;103:723–728.
3.
Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL, Thorner MO: Effects of sex and age on the 24-hour profile of growth hormone secretion in man: Importance of endogenous estradiol concentration. J Clin Endocrinol Metab 1987;64:51–58.
4.
Zadik Z, Chalew SA, McCorter RJ Jr, Meistas M, Kowarski AA: The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab 1985;60:513–516.
5.
Harris DA, Van Vliet G, Egli CA, Grumbach MM, Kaplan SL, Styne DM, Vainsel M: Somatomedin-C in normal puberty and in true precocious puberty before and after treatment with a potent luteinizing hormone-releasing hormone agonist. J Clin Endocrinol Metab 1985;61:152–159.
6.
Pescovitz OH, Rosenfeld RG, Hintz RL, Barnes K, Hench K, Comité F, Loriaux D, Cutler GB Jr: Somatomedin-C in accelerated growth of children with precocious puberty. J Pediatr 1985;107:20–25.
7.
Mansfield MJ, Rudlin CR, Crigler JF Jr, Karol KA, Crawford JD, Boepple PA, Crowley WF Jr: Changes in growth, serum growth hormone, and plasma somatomedin-C levels during suppression of gonadal sex steroid in girls with central precocious puberty. J Clin Endocrinol Metab 1988;66:3–9.
8.
Kreiter M, Burstein S, Rosenfield RL, Moll GW Jr, Cara JD, Yousefzadeh DK, Cuttler L, Levitsky LL: Preserving adult height potential in girls with idiopathic true precocious puberty. J Pediatr 1990;117:364–370.
9.
Juul A, Scheike T, Nielsen CT, Krabbe S, Müller J, Skakkebæk NE: Serum insulin-like growth factor (IGF-1) and IGF binding protein-3 levels are increased in central precocious puberty: Effects of two different treatment regimes with gonadotropin-releasing hormone agonists, without or in combination with an antiandrogen (cyproterone acetate). J Clin Endocrinol Metab 1995;80:3059–3067.
10.
Sklar ChA, Rothenberg S, Blumberg D, Oberfield ShE, Levine LS, David R: Suppression of the pituitary-gonadal axis in children with central precocious puberty: Effects on growth, growth hormone, insulin-like growth factor-1, and prolactin secretion. J Clin Endocrinol Metab 1991;73:734–738.
11.
Kanety H, Karasik A, Pariente C, Kauschansky A: Insulin-like growth factor-1 and IGF binding protein-3 remain high after GnRH analogue therapy in girls with central precocious puberty. Clin Endocrinol 1996;45:7–12.
12.
Hiney JK, Ojeda SR, Les Dees W: Insulin-like growth factor 1: A possible metabolic signal involved in the regulation of female puberty. Neuroendocrinology 1991;54:420–423.
13.
Cameron JL: Modulation of reproductive function by metabolic signals: A role in the initiation of puberty? In Bergadá C, Moguilevsky JA (eds): Puberty. Basic and Clinical Aspects. Rome, Ares Serono Symposia, 1995, pp 333–342.
14.
Aubert ML, Gruaz NM, D’Alleves V, Pierroz DD, Arsenijevic V, Sizonenko PC: Body weight, growth hormone, insulin-like growth factors, and neuropeptide Y as potential factors for the control of the initiation of sexual maturation; in Bergadá C, Moguilevsky JA (eds): Puberty. Basic and Clinical Aspects. Rome, Ares Serono Symposia, 1995, pp 343–356.
15.
Belgorosky A, Rivarola MA: Role of sex steroids in the mechanism of the onset of puberty. Front Endocrinol 1995;10:267–279.
16.
Stratakis CA, Brodie A, De Atkine D, Vottero A, Yue W, Flor AW, Garnica A, Mitsiadis CS, Chrousos GP: The syndrome of increased aromatase activity causes isosexual precocious puberty in girls and prepubertal gynecomastia in boys: Diagnosis, biochemical and molecular investigation in two generations’ treatment. 10th International Congress of Endocrinology, San Francisco 1996, p 587.
17.
Belgorosky A, Rivarola MA: Progressive increase in non-sex hormone-binding globulin-bound testosterone from infancy to late prepuberty in boys. J Clin Endocrinol Metab 1987;64:482–485.
18.
Belgorosky A, Rivarola MA: Progressive increase in non-sex hormone-binding globulin-bound testosterone and estradiol from infancy to late prepuberty in girls. J Clin Endocrinol Metab 1988;67:234–237.
19.
Belgorosky A, Ferraris JR, Ramirez JA, Jasper H, Rivarola MA: Serum sex hormone-binding globulin and serum non-sex hormone-binding globulin-bound testosterone fractions in prepubertal boys with chronic renal insufficiency. J Clin Endocrinol Metab 1991;73:107–110.
20.
Belgorosky A, Martinez A, Domené H, Heinrich JJ, Bergadá C, Rivarola MA: High serum sex hormone-binding globulin and low serum non-sex hormone-binding globulin-bound testosterone during prepuberty in boys with idiopathic hypopituitarism and the effect of recombinant hGH. J Clin Endocrinol Metab 1987;65:1107–1111.
21.
Ciaccio M, Belgorosky A, Rivarola MA: Differences in serum IGF-1 and SHBG levels between early and late puberty in patients with idiopathic and organic growth hormone deficiency. Acta Endocrinol 1993;129:419–423.
22.
Belgorosky A, Chahin S, Chaler E, Maceiras M, Rivarola MA: Serum concentrations of FSH and LH in normal girls and boys during prepuberty and at early puberty. J Endocrinol Invest 1996;19:88–91.
23.
Belgorosky A, Rivarola MA: Determination of sex hormone binding globulin in human serum. Medicina (Buenos Aires) 1982;42:141.
24.
Forest MG: Physiological changes in circulating androgens; in Forest MG (ed): Androgens in Childhood. Pediatr Adolesc Endocrinol. Basel, Karger, 1989, vol 19, pp 104–129.
25.
Jansson JO, Edén S, Isaksson O: Sexual dimorphism in the control of growth hormone secretion. Endocr Rev 1985;6:128–150.
26.
Devesa J, Lois N, Arve V, Diaz MJ, Lima L, Tresguerres JAF: The role of sexual steroids in the modulation of growth hormone secretion in humans. J Steroid Biochem Mol Biol 1993;40:165–173.
27.
Hiney JK, Srivastava V, Nyberg ChL, Ojeda SR, Le Dees W: Insulin-like growth factor 1 of peripheral origin acts centrally to accelerate the initiation of female puberty. Endocrinology 1996;137:3717–3728.
28.
Ojeda SR, Ma YJ, Rage F: A role of TGFα in the neuroendocrine control of female puberty; in Plant TM, Lee PA (eds): The Neurobiology of Puberty. Bristol, Journal of Endocrinology, Ltd., 1995, pp 103–117.
29.
Berg-von der Emde K, Ma YJ, Costa ME, Ojeda SR: Hypothalamic astrocytomas respond to transforming growth factor alpha with prostaglandin L (PGE2) release (abstract). 23rd Annual Meeting of the Society of Neuroscience, Washington 1993, p 1682.
30.
Plant TM, Perera AD: Is puberty in primates triggered by a structural reorganization of the neuronal network governing pulsatile GnRH release? In Bergadá C, Moguilevsky JA (eds): Puberty: Basic and Clinical Aspects. Rome, Ares-Serono Symposia, 1995, pp 13–19.
1998
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