0021-972X/91/7304-0734$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society

Vol. 73, No. 4 Printed in U.S.A.

Suppression of the Pituitary-Gonadal Axis in Children with Central Precocious Puberty: Effects on Growth, Growth Hormone, Insulin-Like Growth Factor-I, and Prolactin Secretion* CHARLES A. SKLAR, SAUL ROTHENBERG, DENISE BLUMBERG, SHARON E. OBERFIELD, LENORE S. LEVINE, AND RAPHAEL DAVID Departments of Pediatrics (C.A.S., D.B., R.D.) and Medicine (S.R.), New York University Medical Center, New York, New York 10016; and the Pediatric Service, St. Luke's-Roosevelt Hospital Center, and the Department of Pediatrics (S.O., L.L.), Columbia University College of Physicians and Surgeons, New York, New York 10025

ABSTRACT. To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factorI (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt, we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL, GH response to GH-releasing factor-(1-44), and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P < 0.01) and the plasma concentration of estradiol (P < 0.05). The patients' mean height velocity SD score for chronological age, initially 3.8 ± 1.9, decreased significantly to 0.9 ± 0.9 with treatment (P < 0.005). Nocturnal GH secretion

(mean GH concentration, sum of GH pulse areas, sum of GH pulse amplitudes, and GH pulse frequency) and mean IGF-I levels (1.38 ± 0.6 vs. 1.72 ± 0.34 U/mL) were not significantly altered by treatment. However, the mean peak GH response to GH-releasing factor-(l-44) was 29.2 ± 6.8 fig/L before treatment and declined significantly to 17.7 ± 3.4 ^g/L after gonadal suppression (P < 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth. (J Clin Endocrinol Metab 73: 734-738, 1991)

G

controls (10) and to have elevated plasma concentrations of IGF-I (11, 12). The relationship between the changes in sex steroids, GH, and IGF-I that occur at puberty and the accelerated growth velocity characteristic of both normal and precocious puberty remains controversial. Data exist to support both an indirect GH-dependent effect of sex steroids on linear growth (3, 5, 6, 9-12) as well as direct effects of sex steroids on bone growth (9,13-15). In the current study we have examined the impact of gonadal suppression on growth and GH, PRL, and IGF-I levels in children with precocious puberty.

ONADAL sex steroids are known to play an important role in the regulation of PRL secretion (1, 2) and in the control of the GH-insulin-like growth factorI (IGF-I) axis (2-4). Studies in children and adolescents have generally revealed an increase in both the physiological pulsatile release of GH (5,6) and the GH response to provocative stimuli (7, 8) in mid- to late puberty compared to the responses observed in prepubertal children. These changes in GH secretion are accompanied by a parallel increase in the plasma concentration of IGF-I (3), which appears to be mediated through the increased levels of GH (9). Children with precocious puberty, likewise, have been found to produce increased amounts of GH compared to age-matched prepubertal

Materials and Methods Patients

Received December 26, 1990. Address all correspondence and requests for reprints to: Charles A. Sklar, M.D., Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 * This work was supported in part by a grant (MOIRR-00096) from the NIH, USPHS.

We studied 11 children (10 girls and 1 boy) with central precocious puberty (CPP) defined as follows: 1) onset of breast development in a girl before the age of 8 yr or evidence of genital development/testicular enlargement in a boy before the 734

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GROWTH, GH, IGF-I, AND PRL IN CPP age of 9 yr, 2) pubertal LH/FSH response to GnRH, 3) elevated gonadal sex steroids, and 4) an advanced bone age (Table 1). All 10 girls exhibited bilateral ovarian enlargement, often with multiple small cysts, and an enlarged uterus on pelvic ultrasound. An organic cause of the precocious puberty was evident only in the male subject (no. 11), who had an optic glioma. He had been treated with surgery alone and never received cranial irradiation. The 10 girls had idiopathic precocity based on the results of a computed tomographic and/or magnetic resonance imaging scan of the brain. Three of the girls, however, had associated problems that might have contributed to their CPP (Table 1). Two patients (no. 4 and 10) had been treated previously with medroxyprogesterone acetate, which was discontinued at least 1 month before this study. As treatment with medroxyprogesterone acetate can alter growth velocity (16), the pretreatment growth velocities of patients 4 and 10 have been excluded from analysis. The patients ages ranged from 3.4-9.2 yr (median, 8 yr), and their bone ages ranged from 912 years (median, 11 years) at entry to the study (Table 1). Only patient 1 had experienced menarche. Study protocol The study was approved by the New York University Institutional Review Board. Informed written consent was obtained from the study subjects and/or their parents. Before the initiation of therapy, the subjects were admitted to the Clinical Research Center of New York University Medical Center. All subjects were admitted the evening before testing in order to adapt to the Sleep Laboratory. A standard GnRH (Factrel) stimulation test was performed at 0900 h, using a dose of 100 Hg administered iv. Nocturnal sampling commenced 2 h before the individual subject's normal bedtime and continued for a total of 10 h. Blood samples for GH and PRL were obtained at 30-min intervals during the 2 h before sleep, then at 20-min intervals during 8 h of polygraphically monitored sleep. The following morning at 0800 h after an overnight fast the patients underwent a GH-releasing factor (GRF) stimulation test with GRF-(l-44) (Hoffman-LaRoche, Nutley, NJ) administered iv TABLE

1. Clinical data

Patient S e x Associated diagn o no - " o s i s 1 2 3 4 5 6

F F F F F F

7 8 9 10 11

F F F F M

None None None None Neurofibromatosis Spina bifida/hydrocephalus None None None Down's syndrome Optic glioma/neurofibromatosis

CA/BA Ht

(SDS)

**""

Br/Gt Pubic hair 3.5/9 5/8.5 7/10 7.4/12 7.8/11 8/11

+4.7 +2.5 -0.8 +1.2 +0.2 +0.5

IV IV III IV III

II-III

III-IV

II

8.1/11 8.8/10.5 8.9/11 9/11.5 9.3/12.5

+1.5 +0.4 -0.6 -1.2 +1.7

IV II-III III III V

III II III IV IV

III III II III

CA, Chronological age; BA, bone age; Br, breast development; Gt, genitalia.

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at a dose of 1 Mg/kg. Blood for GH was drawn at 0, 15, 30, 60, 90, and 120 min. Single blood samples were obtained at 08000900 h for serum IGF-I, estradiol, and/or testosterone determinations. Radiological evaluation included an x-ray of the left hand and wrist for bone age and a pelvic ultrasound (female subjects). After the pretreatment testing, all subjects began therapy with the GnRH agonist leuprolide acetate (DLeu6,Des,GlyNH210-Proethylamide9 GnRH, TAP Pharmaceuticals, North Chicago, IL), given as a single daily sc injection. Patients were seen monthly for assessment of height, weight, Tanner stage, and baseline determinations of estradiol or testosterone. GnRH stimulation tests and pelvic ultrasonography were performed approximately every 3 months. Patients were considered to have achieved suppression of the pituitary-gonadal axis once the LH response was prepubertal (maximum increase in LH,

Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion.

To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factor-I (IGF-I) secretion and to help clarify th...
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