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The Acid-Labile Subunit of Human Ternary Insulin-Like Growth Factor-Binding Protein Complex in Girls with Central Precocious Puberty before and during Gonadotropin-Releasing Hormone Analog Therapy

Department of Pediatrics, IRCCS Policlinico S. Matteo, University of Pavia (M.C., M.D.), 27100 Pavia, Italy; Department of Pediatrics, University of Parma (S.B.), 43100 Parma, Italy; Department of Biomedicine of Developing Age, University of Bari (L.C.), 70100 Bari, Italy; Institute of Pediatrics, University of Messina (F.D.L.), 98100 Messina, Italy; Exacta Central Laboratories (A.L.) 37100 Verona, Italy; and Department of Pediatrics, Policlinico University of Verona (S.L., D.S., L.T.), 37100 Verona, Italy

Address all correspondence and requests for reprints to: Mariangela Cisternino, M.D., Department of Pediatrics, IRCCS Policlinico S. Matteo, Piazzale Golgi 5, 27100 Pavia, Italy. E-mail: m.cisternino{at}smatteo.pv.it.

Abstract

The aim of the study was to evaluate serum acid-labile subunit (ALS) concentrations and their relationship with other parameters of the human ternary IGF-I-binding protein (IGFBP) complex in girls with central precocious puberty (CPP) before and after pharmacological arrest of puberty. We studied serum ALS, free IGF-I, total IGF-I, IGFBP-3 levels and IGFBP-3 protease activity in 13 girls, aged 1.6–7.8 yr (mean, 5.9 ± 2.2), diagnosed as having CPP before and after 6 and 12 months of GnRH analog (GnRHa) therapy. The ALS SD score before treatment was high (1.4 ± 0.72) and decreased significantly after 6 and 12 months of GnRHa therapy [0.4 ± 0.54 (P < 0.01) and -0.4 ± 0.61 (P < 0.01), respectively]. Serum IGF-I and IGFBP-3 were also increased before treatment, but both of these factors remained elevated after 6 and 12 months of GnRH-A therapy [IGF-I SD score, 3.20 ± 1.64, 2.92 ± 1.82, and 3.68 ± 1.94 (P = NS), respectively; IGFBP-3 SD score, 1.02 ± 0.53, 0.94 ± 0.68, and 1.22 ± 0.87 (P = NS), respectively]. Serum free IGF-I levels and IGFBP-3 proteolytic activity did not vary significantly from their pretreatment values during GnRHa therapy. In conclusion, serum ALS levels were elevated in girls with CPP and decreased significantly during the first year of GnRHa therapy. Serum IGF-I and IGFBP-3 levels were also increased before therapy, but their levels were not influenced by treatment. The ALS decrease seems to be the sole GH-dependent factor that parallels the decreases in steroid levels and growth velocity during GnRHa therapy.

CENTRAL PRECOCIOUS PUBERTY (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. The growth spurt in CPP, like that in normal puberty, is determined by the gonadal hormones that stimulate spontaneous GH secretion, which, in turn, activates the IGF-I axis (1, 2).

Treatment of CPP with GnRH analogs (GnRHa) halts puberty and slows growth velocity. GH secretion was found to decrease with the fall in gonadal steroids (1, 3, 4, 5). However, a lack of suppression of IGF-I and IGF-binding protein-3 (IGFBP-3) levels has been observed in more recent studies (6, 7, 8). Indeed, serum IGFBP-3 was found to increase during GnRHa gonadal suppression (7). After GnRHa treatment in boys with CPP, total and dissociable free IGF-I levels decreased concomitantly with the height velocity decrease (7, 9).

IGF-I circulates in the plasma as part of a 150-kDa stable ternary complex because of its binding with two glycoproteins, IGFBP-3 and the acid-labile subunit (ALS). The ternary complex has a high molecular mass due to the 85-kDa ALS and modulates the bioavailability of IGF-I, prolonging the biological half-life and preventing cross-endothelial transport of IGF-I (10). GH appears to be the main regulator of ALS, increasing ALS gene transcription, secretion by hepatocytes, and blood levels (11, 12, 13, 14).

Serum ALS levels were found to increase gradually throughout childhood, with maximal levels reached in puberty (11, 15, 16). This was demonstrated to be due to the increasing GH secretion in puberty, although ALS levels were not correlated with 24-h endogenous GH secretion in children.

The serum ALS concentration has not been studied in CPP to date. We therefore measured serum concentrations of ALS and other parameters of the IGF-I axis in patients with CPP before and during the first year of GnRHa therapy to evaluate the effect of therapy-induced gonadal suppression on the components of the IGF-I human ternary complex.

Subjects and Methods

Patients

Thirteen girls with idiopathic CPP were studied. They all had clinical onset of pubertal development before the age of 8 yr, pubertal response of LH to GnRH stimulation test, uterine length greater than 38 mm by pelvic ultrasound, and advanced bone age. All patients had a magnetic resonance imaging examination at the time of diagnosis, which did not show central nervous system alterations in any patients. The clinical and hormonal characteristics of the patients are shown in Table 1.

The age at the initiation of treatment was 1.6–7.8 yr (mean, 5.9 ± 2.2 yr). Patients were treated with depot leuprorelin (Enantone Depot, Takeda, Italia Farmaceutici, Rome, Italy) im injections; the dose was 3.75 mg in children weighing over 20 kg and 1.875 mg in those weighing less than 20 kg. The first two doses were injected 21 d apart, and then the next doses were given every 28 d up to the end of the 1-yr treatment period. To counteract the flare-up phenomenon, all girls received oral cyproterone acetate in a daily dose of 100 mg/m² (maximum, 100 mg/d) for 20 d before and after the first injection.

Fasting blood samples were collected for measurements of basal and GnRH-stimulated FSH and LH levels and serum estradiol (E2) levels before and after 3, 6, and 12 months of GnRHa treatment. ALS, IGF-I, free IGF-I, IGFBP-3, and IGFBP-3 protease activity were measured before and after 6 and 12 months of GnRHa treatment. Pelvic ultrasound was performed before treatment and at 3, 6, and 12 months. Left hand x-ray for bone age assessment was performed before treatment and at 6 and 12 months of therapy.

All girls had their heights measured using a Harpenden stadiometer. Body mass index was calculated as weight (kilograms) divided by height (meters) squared. Pubertal development was recorded according to Tanner’s classification (17).

Methods

Serum ALS levels were determined by ELISA (Diagnostic Systems Laboratories, Inc., Webster, TX). The sensitivity was 1.1 nmol/liter, and the intra- and interassay coefficients of variation were 5.8% and 6.8%, respectively.

Serum total IGF-I levels were measured by immunoradiometric assay after acid extraction with a commercial kit (Diagnostic Systems Laboratories, Inc.). The sensitivity was 0.9 nmol/liter; the intra- and interassay coefficients of variation were 7.2% and 9.8%, respectively. Serum free IGF-I levels were also measured by immunoradiometric assay with a commercial kit (Diagnostic Systems Laboratories, Inc.). In this case the sensitivity was 0.004 nmol/liter, and the intra- and interassay coefficients of variation were 6.1% and 8.6%, respectively. Serum IGFBP-3 levels were determined by RIA with a commercial kit (Diagnostic Systems Laboratories, Inc.). The sensitivity was 0.9 mg/liter; the intra- and interassay coefficients of variation were 5.8% and 8.2%, respectively.

IGFBP-3 proteolytic activity was studied using the Lamson method (18) with minor modifications (19): ¹²⁵I-labeled human recombinant glycosylated IGFBP-3 was provided by Diagnostic Systems Laboratories, Inc. Labeled [¹²⁵I]IGFBP-3 (50,000 cpm) was incubated with 5 µl serum in a total volume of 20 µl PBS (pH 7.4) containing 1 mM CaCl₂. After 8 h at 37 C, reactions were stopped by adding 20 ml nonreducing sample buffer. The mixtures were subjected to 15% SDS-PAGE. Bands were visualized by autoradiography. The relative OD of autoradiographic bands was measured with an Ultrascan densitometer (LKB, Rockville, MD). To estimate the extent of [¹²⁵I]IGFBP-3 degradation, the areas under the OD peaks from intact and degraded IGFBP-3 were integrated with a computer program (LKB GelScan software). The amount of proteolysis was calculated as the ratio of the absorbance of fragmented [¹²⁵I]IGFBP-3 over the sum of all [¹²⁵I]IGFBP-3-related OD in that line; to be precise, the integrated peaks of the relative ODs from cleavage product bands were expressed as a percentage of the total OD from all bands in each line.

Serum E2 levels were measured using a commercial RIA kit (Diagnostic Systems Laboratories, Inc.). The sensitivity of the assay was 2.2 pg/ml; the intra- and interassay coefficients of variation were 7.5% and 9.3%, respectively. Serum FSH and LH levels were measured by immunoenzymatic assay (FSH, Abbott Laboratories, Rome, Italy; LH, Dade Behring, Milan, Italy). The sensitivity of the assay was 0.2 U/liter; the intra- and interassay coefficients of variation were: FSH, 4.7% and 8.9%, respectively; and LH, 3.1% and 4.0%, respectively.

Statistical analysis

To facilitate comparisons among children of various ages, parameters (ALS, IGF-I, free IGF-I, and IGFBP-3) were standardized by computing an SD score based on individual chronological age. Reference data for these parameters were obtained from 50 healthy school children in our normal control population. Results are expressed as the mean ± SD. Statistical analysis was performed using unpaired and paired two-tailed t tests with the Bonferroni method. The significance of changes after therapy was analyzed using ANOVA for repeated measurements. Correlations were calculated by linear regression analyses. Data analysis was carried out using the BMDP system (BMDP Statistical Software, Inc., Los Angeles, CA).

Results

Sexual maturation and serum gonadotropins

GnRHa therapy induced an arrest or regression of breast development in all girls. From the third month of treatment both uterine and ovarian volumes decreased compared with pretreatment values. Basal and GnRH-stimulated LH and FSH values declined to prepubertal levels in all girls by month 3 and remained suppressed thereafter. Similarly, E2 levels declined to within the normal prepubertal range during therapy (Table 1).

The auxological characteristics of the girls are shown in Table 2. Growth velocity decreased from 11.5 ± 4.82 cm/yr during the pretreatment year to 6.74 ± 2.89 and 6.15 ± 2.88 during 6 and 12 months of therapy (P < 0.001), respectively. The ratios of bone age increment over height age increment (BA/HA) and of chronological age increment over bone age increment (CA/BA) did not change significantly during therapy; the height SD score for BA and predicted adult height improved slightly at the end of the first year of therapy (Table 2).

The serum ALS mean (±SD) values in CPP girls compared with those in age-matched control girls are presented in Table 3. Before treatment, ALS concentrations in CPP girls were higher than those in controls, and the difference was statistically significant (P < 0.001) for the group of patients, aged 7–7.8 yr. During GnRHa therapy, ALS levels decreased in 12 patients and did not change in one girl; the mean ALS values in CPP girls aged 7–7.8 yr decreased significantly (P < 0.01) after 6 and 12 months of therapy. The ALS SD score before treatment was high (1.4 ± 0.72) and decreased significantly after 6 and 12 months of GnRHa therapy [0.4 ± 0.54 (P < 0.01) and -0.4 ± 0.61, (P < 0.01), respectively; Fig. 1].

View larger version (14K): [in this window] [in a new window]   Figure 1. ALS SD score for chronological age before and during treatment with GnRHa in girls with CPP. The means are indicated by the horizontal solid bars.

View larger version (11K): [in this window] [in a new window]   Figure 2. IGF-I SD score for chronological age before and during treatment with GnRHa in girls with CPP. The means are indicated by the horizontal solid bars.

View larger version (12K): [in this window] [in a new window]   Figure 3. IGFBP-3 SD score for chronological age before and during treatment with GnRHa in girls with CPP. The means are indicated by the horizontal solid bars.

Free IGF-I SD score before treatment was high (3.5 ± 2.2) and remained elevated after 6 and 12 months of GnRHa therapy (2.5 ± 1.5 and 4.0 ± 2.6, respectively; P = NS). The mean values of free-IGF-I are shown in Table 4. Free IGF-I accounted for 1.6% of the total IGF-I before treatment; this percentage rose to 1.9% at month 12 of therapy.

Serum IGFBP-3 proteolytic activity did not vary significantly during GnRHa therapy, remaining similar to pretreatment values (Table 4).

Discussion

In the present study we measured serum ALS concentrations in girls with CPP before and during GnRHa therapy. The relationship between ALS and other parameters of the IGF-I axis was also investigated. Serum ALS levels were increased in these girls with CPP and decreased, concomitantly with the growth velocity decrease, during the gonadal suppression induced by GnRHa therapy. IGF-I and IGFBP-3 serum levels were also increased before treatment, but unlike ALS, both of these factors remained elevated during the first year of GnRHa therapy.

This is the first paper reporting changes in all components of the IGF-I ternary complex during GnRHa therapy in patients affected by CPP. Conflicting results regarding the effect of this therapy in CPP on IGF-I and IGFBP-3 serum levels have been reported, whereas ALS has not been studied previously, as far as we know.

Some studies reported high IGF-I levels in CPP patients, which decreased during GnRHa therapy (1, 2, 5), whereas other studies showed no change after pharmacological gonadal suppression (6, 7, 8, 20). IGFBP-3 serum levels were high in CPP before therapy (6, 7, 9) or normal (8) with no change (6, 8) or a further rise (7) during GnRHa therapy. The most important conclusion of these latter studies was that gonadal steroids induce an irreversible increase in IGF-I and IGFBP-3. Therefore, the decrease in growth velocity during GnRHa therapy seems to be independent of the IGF-I axis.

In one study (7) it was reported that the molar ratio between IGF-I and IGFBP-3 (i.e. free biologically active IGF-I) declined during GnRHa therapy in girls with CPP, thus suggesting that the decrease in free-IGF-I accounted for the decline in growth velocity. The same researchers found high free IGF-I levels in boys with CPP and that these levels decreased during GnRHa therapy (9). The free IGF-I concentration was not influenced by IGFBP-3 proteolysis. We, too, found high free IGF-I levels in our girls, but they were not altered by GnRHa therapy. Furthermore, no variations in IGFBP-3 proteolytic activity was observed. One explanation for the different results concerning free IGF-I levels during therapy could be the different gender of the patients. In fact, we observed a marked decrease in free IGF-I levels during GnRHa therapy in one boy with CPP.

Hormonal control of the growth spurt during puberty, either spontaneous or precocious, is complex. GH increases growth at puberty through stimulation of the IGF-I axis. Almost all IGF-I in the circulation is present as 150-kDa stable ternary complexes that contain IGFBP-3 and ALS. The components of the ternary complex are synthesized under GH control by different cell populations in the liver: IGF-I and ALS in hepatocytes, and IGFBP-3 in nonparenchymal Kupffer cells and sinusoidal endothelial cells (21, 22). Consequently, their regulation, dependence on nutritional status, and diagnostic utility may vary. In healthy children serum ALS levels were increased in puberty (11, 16, 23). ALS levels are positively correlated with IGF-I and IGFBP-3 levels (16).

GH is the most potent inducer of ALS mRNA in the liver and of ALS in plasma (11, 12, 13, 14). This is supported by the finding that ALS was almost completely absent in GH deficiency or GH resistance (24, 25, 26), and little IGF-I is present in the 150-kDa ternary complex, most being found in the lower molecular mass IGF-I-IGFBP-3 complex or bound by other IGFBPs. Furthermore, GH administration to GH-deficient patients shifts IGF from the 40- to 50-kDa low molecular mass peak to the 150-kDa high molecular mass peak, increasing ternary complex formation (25, 27, 28).

GH secretion is increased in precocious puberty and decreases with the fall in levels of gonadal steroids after treatment with GnRHa (1, 3, 4, 5). The ALS decrease in our girls during therapy reflects the GH decrease, although we would also have expected a decrease in the other components of the IGF-I axis. Several explanations for the different trends of these factors may be suggested. Firstly, as IGF-I levels remain elevated several years after peak height velocity (29), it may be that ALS precedes the decrease in IGF-I, representing the first indicator of the GH decrease. Secondly, the unsuppressed IGF-I and IGFBP-3 levels during therapy may reflect the persistence of elevated concentrations of binary complexes that are less effective on growth. Finally, IGF-I and IGFBP-3 levels are also dependent on metabolic and nutritional status, thus reflecting GH status less closely than do ALS levels.

In conclusion, serum ALS levels were elevated in girls with CPP and decreased significantly during the first year of GnRHa therapy. Serum IGF-I and IGFBP-3 levels were also increased before therapy, but their levels were not influenced by treatment. Therefore, the ALS decrease is the sole factor of the IGF-I ternary complex that parallels the steroid decrease and the growth velocity decrease during treatment with GnRHa therapy. The decrease in serum ALS suggests that IGF-I ternary complex formation is reduced during GnRHa therapy.

Acknowledgments

Footnotes

Abbreviations: ALS, Acid-labile subunit; CPP, central precocious puberty; E2, estradiol; GnRHa, GnRH analog; IGFBP, IGF-I-binding protein.

Received February 26, 2002.

Accepted June 23, 2002.

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