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Original Article |
Department of Endocrinology and Metabolism (S.G., M.S., F.M., A.B.) and Centre of Excellence for Biomedical Research (F.M., A.B.), University of Genova, Genova I-16132; and Department of Pediatrics (G.R.), Hospital of Bolzano, and Department of Pediatrics (M.B.), University of Pavia, I-27100 Pavia, Italy
Address all correspondence and requests for reprints to: Antonina Barreca, M.D., Ph.D., Cattedra di Endocrinologia, Department of Endocrinology and Metabolism, University of Genova, Viale Benedetto XV, no 6, I-16132 Genova, Italy. E-mail: barreca{at}unige.it.
Abstract
The height of subjects with constitutionally tall stature (CTS) is at least 2 SD above the mean of subjects of the same age and sex. Apart from a few discordant data on the role of GH and its direct mediator, IGF-I, no studies have been conducted on other components of the IGF system, which also condition the bioavailability and activity of IGF-I. We, therefore, investigated the possibility that other components of the IGF system might play a role in determining the increased growth velocity seen in CTS. To this end, we evaluated the behavior not only of IGF-I but also of IGF-II, IGF-binding protein (IGFBP)-3, and acid-labile subunit, the subunits that constitute the main IGF complex in circulation (150-kDa complex), as well as of IGFBP-1 and IGFBP-2, which are negatively regulated by GH and, like IGFBP-3, able to influence the bioavailability of the IGFs. The study was performed on 22 prepubertal subjects affected by CTS (16 males and 6 females), aged 2.8–13.3 yr (6.8 ± 0.5 yr, mean ± SEM). Thirty-seven normal prepubertal subjects (16 males and 21 females) aged between 2.2 and 13.3 yr (6.7 ± 0.5 yr), who were comparable in socioeconomic and nutritional terms, served as controls. From the auxological point of view, subjects with CTS differed significantly from controls only in terms of growth velocity (HV-SD score; CTS, 1.8 ± 0.3; controls, 0.4 ± 0.2; P < 0.0001) and height (H-SD score; CTS, 3.1 ± 0.1; controls, 0.4 ± 0.2; P < 0.0001). The results demonstrated that the concentrations of IGF-I (27.3 ± 2.0 nmol/liter), IGFBP-3 (66.9 ± 3.8), and acid-labile subunit (216.8 ± 13.6) in CTS-affected subjects were not significantly different from those determined in controls (25.0 ± 2.9, 74.4 ± 4.1, and 241.0 ± 11.9, respectively). By contrast, IGF-II levels proved significantly higher in CTS subjects (IGF-II: 87.2 ± 3.4 vs. 52.4 ± 2.3, P < 0.0001). Chromatographic analysis, performed after acid treatment of pooled sera, showed only the presence of normal 7.5-kDa IGF-II in both CTS subjects and controls. In comparison with controls, CTS children showed a lower concentration of IGFBP-1 (1.6 ± 0.3 vs. 4.1 ± 0.7, P = 0.03) and a higher concentration of IGFBP-2 (14.3 ± 1.8 vs. 9.6 ± 1.1, P = 0.03). The IGFs (IGF-I and -II)/IGFBPs (-1 + -2 + -3) molar ratio was significantly higher (P < 0.0001) in CTS children than in controls. In particular, the IGF-II/IGFBP ratio (P < 0.0001) was responsible for the excess of the IGF peptide in relation to the concentrations of IGFBPs and, therefore, for the increase in the potentially bioactive free form of the IGFs. Moreover, the IGFBP-3/IGF molar ratio was significantly reduced, being less than 1 in CTS subjects (0.6 ± 0.1 vs. 1.1 ± 0.1), so that a quantity of IGF peptides lack sufficient IGFBP-3 to form the 150-kDa complex with which are normally sequestered in the vascular compartment. The data show that in CTS: 1) the most GH-dependent components of the IGF system are normal, consistent with the finding of a normal GH secretory state; 2) the less GH-dependent IGF-II is significantly increased, in agreement with the finding of a relationship between high levels of IGF-II and overgrowth in some syndromes; and 3) the IGF/IGFBP molar ratio is increased, and, therefore, a greater availability of free IGF for target tissues may be responsible for overgrowth in CTS.
CONSTITUTIONALLY TALL STATURE (CTS) is a condition in which the subject’s height reaches the upper limit of the normal growth pattern. Although its prevalence is comparable with that of constitutionally short stature, CTS is a far less serious medical problem in that tall stature is not normally a cause for concern either to the patient or their parents, except in the case of girls, particularly during adolescence. Genetic and familial factors underlie CTS; almost always one or both of the subject’s parents are tall and have followed a similar growth pattern. The organism functions normally and there are no endocrine disorders, although enhanced 24-h GH secretion (1, 2, 3) and a paradoxical response of the hormone both to glucose loading and TRH stimulation (4, 5) have been reported. Similar responses, however, have also been recorded in adolescents of normal or short stature and have, therefore, been regarded as being linked to the stage of pubertal development (6, 7). Increased levels of IGF-I have also been found (8). The height of subjects with CTS is at least 2 SD above the mean of subjects of the same age and sex (9). Birth length is generally normal, although in the first few months of life growth velocity increases markedly; the growth curve climbs toward the highest percentiles and exceeds the 97th percentile around the age of 4 yr, at which time the individual’s excessive height becomes evident (10). Subsequently, growth slows down and the curve begins to parallel that of normal subjects. Body proportions are harmonious and puberty occurs normally in terms of both timing and sequence of its progression. Bone age generally corresponds to chronological age, presenting a variability that is not significantly different from that of subjects of normal height (11). Diagnosis is based on the family history of the parents or other tall relatives; characteristic growth curve; harmony of body proportions; lack of dysmorphism; normality of bone age; and, finally, the exclusion of the various causes, especially endocrinological, of pathologically tall stature.
In a previous study (12), we excluded the existence of alterations in basal and stimulated (with arginine, insulin, and levodopa) GH secretion as well as alterations in the biological activity of the GH molecule or GH receptors (evaluated as GH-binding protein). Apart from a few discordant data on the role of GH and its direct mediator, IGF-I, no studies have been conducted on other components of the IGF system, which also condition the bioavailability and activity of IGF-I. We, therefore, investigated the behavior of the IGF-binding proteins (IGFBPs) and acid-labile subunit (;l) in this condition. Moreover, we extended our study to another important IGF peptide, IGF-II, which does not depend directly on GH but interacts with high affinity with the IGF-I receptor and appears to be implicated in syndromes characterized by macrosomia, such as Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes (13, 14, 15).
Patients and Methods
Patients
We evaluated 22 prepubertal subjects (16 males and 6 females), aged 2.8–13.3 yr (6.8 ± 0.5, mean ± SEM), referred to our Pediatric Departments for tall stature (Tables 1
and 2). Mean height SD score (16) was 3.1 ± 0.1 (range, 2–4) and height velocity SD was 1.8 ± 0.2 (range, 0.1–3.6). Body mass index SD score (17) was 0.3 ± 0.4. Bone age ranged from 3.9–14 yr (8.1 ± 0.5), according to the method of Greulich and Pyle (18). At least one parent was of tall stature. As reported previously (12), alterations in basal or stimulated GH secretion in these CTS-affected subjects were excluded. None of the patients had chromosomal abnormalities, dysmorphic syndromes, homocystinuria, endocrine or metabolic diseases, and/or other disorders associated with tall stature. Normal thyroid and adrenal functions were observed on evaluating serum total and free T4 and TSH and morning and evening serum cortisol concentrations, respectively. Thirty-seven normal prepubertal subjects (16 males and 21 females) aged between 2.2 and 13.3 yr (6.7 ± 0.5), who were comparable in socioeconomic and nutritional terms, served as controls (Table 1).
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Analytical methods
IGF-I was measured by RIA using immunochemicals and tracer provided by Medgenix (Fleurus, Belgium). The sensitivity of the assay was 0.2 nmol/liter; the intra- and interassay coefficients of variation were 6% and 7.5%, respectively. IGF-II was measured by double-antibody RIA using a monoclonal antibody provided by Sera-Lab (Techno-genetics, Trezzano, Italy) and 125I-IGF-II provided by Amersham (Aylesbury, Buckinghamshire, United Kingdom). The standard curve was performed using recombinant IGF-II. The sensitivity of the assay was 0.12 nmol/liter; the intra- and interassay coefficients of variation were 6% and 9%, respectively. No cross-reactivity could be evidenced between IGF-I and IGF-II with the respective antibodies used in the assays up to concentrations of 500 ng/ml of both peptides. To avoid interference from binding proteins, single plasma EDTA samples were treated with acid ethanol, according to Daughaday et al. (19).
One milliliter of plasma obtained from patients presenting with CTS and 1 ml of a pool of sera from 15 age-matched controls were acidified by dialysis at 4 C against three changes of 0.5 mol/liter acetic acid in Spectra-Por 6 membranes (molecular weight cut-off, 1000), lyophilized, resuspended with 0.1 mol/liter acetic acid-0.15 mol/liter NaCl (pH of the mixture <3), and gel filtrated on fast protein liquid chromatography Superdex-75 and Superdex-Peptides columns (Pharmacia, Uppsala, Sweden) connected in series, equilibrated with 0.1 mol/liter acetic acid-0.15 mol/liter NaCl (pH 2.75). Fractions were pooled at 0.02 Kav intervals, lyophilized, reconstituted in PBS, and analyzed for IGF-II.
Serum total ALS was measured by means of specific two-site sandwich ELISA, using anti-ALS antibodies raised against synthetic amino-terminal and carboxy-terminal ALS peptides, reagents, and tracer provided by Diagnostic System Laboratories, Inc. (Webster, TX.). All samples were pretreated to dissociate the complexed ALS and enhance ALS immunoreactivity. The sensitivity of the assay was 4.7 nmol/liter; the intra- and interassay coefficients of variation were 5.5% and 7.2%, respectively. Recovery of human serum-derived glycosylated ALS, purified as described (20), was 75% for the lowest concentration added (1 µg) and 95% for the highest concentration added (60 µg).
IGFBP-1 was measured by means of immunoradiometric assay, using reagents and tracer provided by Diagnostic Systems Laboratories, Inc.. The sensitivity of the assay was 0.02 nmol/liter; the intra- and interassay coefficients of variation were 2.5% and 4.6%, respectively.
IGFBP-2 levels were determined by double-antibody RIA using a nonequilibrium technique. Specific IGFBP-2 antiserum was purchased from Upstate Biotechnology, Inc. (Lake Placid, NY), and the standard was a pure IGFBP-2 preparation obtained by DNA recombinant technology (ImmunoKontact, Frankfurt, Germany). The sensitivity of the assay was 0.01 nmol/liter; the intra- and interassay coefficients of variation were 6% and 9.5%, respectively.
IGFBP-3 was measured by immunoassay, using reagents and tracer provided by Diagnostic Systems Laboratories, Inc.. All samples were diluted appropriately to reach a point in the curve at which there is parallelism among unglycosylated Escherichia coli-derived IGFBP-3, glycosylated Chinese hamster ovary-derived IGFBP-3 and serum (%B/Bo: 70–85). The sensitivity of the assay was 0.04 nmol/liter; the intra- and interassay coefficients of variation were 3.25% and 5.6%, respectively.
Statistical analysis
Statistical analysis was performed by nonparametric test on unpaired (Mann-Whitney test) observations. A P value less than 0. 05 was considered significant. Results are expressed as mean ± SEM. The correlations among all parameters studied were calculated as Spearman rank-order correlation coefficients. All statistical analyses were done using SPSS Statistical Software (SPSS, Inc., Chicago, IL).
Results
From the auxological point of view, subjects with CTS differed significantly from the controls only in terms of growth velocity and height (Tables 1
and 2).
Evaluation of the IGF system components directly regulated by GH and present in circulation in the form of the 150-kDa complex confirmed the absence of an altered secretion of the hypophyseal hormone most strongly implicated in forms of endocrine-linked pathologically tall stature. Indeed, determination of the concentrations of IGF-I, IGFBP-3, and ALS in CTS-affected subjects revealed no statistically significant difference from the concentrations determined in control subjects of comparable age (Table 2 and Fig. 1).
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and Figs. 1 and 2). IGF-II levels were higher in almost all subjects than in controls of comparable age and were 2 SD scores above the mean of normal subjects (2.45 ± 0.24). Because some reports have shown that IGF-II overexpression in various cancers is often associated with pro-IGF-II forms, we investigated this aspect in our patients. The chromatographic profile of IGF-II showed only the presence of normal 7.5-kDa IGF-II in both CTS and normal serum pools (data not shown).
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). In particular, the IGF-II/IGFBP ratio (1.1 ± 0.1 vs. 0.62 ± 0.03, P < 0.0001) was responsible for the excess of the IGF peptide in relation to the concentrations of IGFBPs and, therefore, for the increase in the potentially bioactive free form of the IGFs (Fig. 2). Moreover, it is noteworthy that, although the ALS/IGFBP-3 ratio was normal, the ratio between the molar concentrations of IGFBP-3 and the concentration of the two IGFs was significantly reduced, being less than 1 in subjects with CTS (0.59 ± 0.04; control subjects, 1.06 ± 0.08; Fig. 2).
In comparison with controls, children with CTS showed lower concentration of IGFBP-1 and higher concentration of IGFBP-2 (Table 2 and Fig. 1). The ratio between the molar concentrations of IGFBP-2 and IGFs (0.13 ± 0.02) proved to be similar to that seen in controls (0.15 ± 0.02). We analyzed serum IGFBP-1 proteolytic activity by Western immunoblot after incubation at 37 C in the absence or presence of 10 mmol EDTA and 1 mmol CaCl2. Moreover, we also evaluated the presence and amount of serum metalloproteinase by gelatin zymogram The results demonstrated that the IGFBP-1 proteolytic activity is limited in both groups and that the amount and activity of metalloproteinase-9 and -2 were not increased in CTS-affected children in comparison with control serum (data not shown).
As in the normal subjects, IGF-I, IGFBP-3, and ALS in the children with CTS were seen to correlate positively. Unlike the control subjects, however, in whom IGF-I correlated positively with IGF-II (P < 0.0001) and negatively with IGFBP-1 (P = 0.013) and IGFBP-2 (P = 0.015), the children with CTS showed no significant correlation either between the IGF peptides themselves or between these and IGFBP-1 or IGFBP-2.
Discussion
The possible role of the GH-IGF-I axis in giving rise to CTS is still under discussion (7, 12, 20, 21, 22, 23). With regard to GH secretion, both a lack of suppression on glucose loading and paradoxical response to TRH have been documented. Because similar phenomena are observed in acromegaly, CTS has been likened to gigantism. However, it has been widely acknowledged that similar anomalous responses of GH may also be encountered in normal adolescents (5, 6, 24). Moreover, in a large population of subjects with CTS, considerable variability in spontaneous and stimulated GH secretion has been recorded, with some subgroups characterized by high circadian integrated secretion and others actually by lower-than-normal secretion (6). It is, therefore, possible that several causes act differentially on different populations and that CTS is a heterogeneous condition in which a preacromegalic status or disorder of hypothalamo-pituitary regulation of GH secretion should be investigated. In a previous study, we excluded the existence of alterations in basal or stimulated GH secretion as well as in the biological activity of the GH molecule or its receptors (12) in our population of prepubertal constitutionally tall children. However, apart from GH regulation, there are many variables that modulate the synthesis, circulating levels, and biological activity of IGF-I. The present study, therefore, aimed to investigate the possibility that other components of the IGF system might play a role in determining the increased growth velocity seen in CTS. To this end, we evaluated the behavior not only of IGF-I but also of IGF-II, IGFBP-3, and ALS, that is to say, the subunits that constitute the main somatomedin complex in circulation, as well as of IGFBP-1 and IGFBP-2, which are negatively regulated by GH and, like IGFBP-3, able to influence the bioavailability of the IGFs.
In agreement with our previous data, IGF-I levels in subjects with CTS were not significantly different from those seen in normal subjects. Moreover, further confirmation of the substantial normality of GH secretion and normal biological activity of GH itself is provided by the fact that ALS and IGFBP-3 concentrations proved to be comparable with those recorded in control subjects.
The most important finding to emerge from our study is that IGF-II levels are significantly higher in CTS-affected subjects than in individuals of normal height. In actual fact, a 1984 study of tall subjects in various stages of puberty had already documented increased IGF peptide levels and reduced IGFBP levels, as assessed by means of radioligand assays (8). In that study, however, the assay system used was unable to distinguish between IGF-I and IGF-II. Our study identifies IGF-II as the IGF peptide that may be responsible for overgrowth of children with CTS. Indeed, though not strictly GH dependent, this peptide, like IGF-I, promotes cell proliferation and differentiation with similar potency, particularly in human fetal growth. High circulating levels of IGF-II might be responsible for increased growth velocity, especially in early childhood, when the still immature GH-IGF-I axis has not yet fully assumed its predominant role in body growth. The increased IGF-II levels observed in almost all subjects with CTS in comparison with control subjects involve a significantly higher IGF/IGFBP molar ratio in children with CTS than in controls and, therefore, an increase in the potentially bioactive free form of the IGFs. Moreover, it should be underlined that, although the concentrations of IGFBP-3 and ALS are comparable with those seen in controls so that their molar ratio is normal, the IGFBP-3/IGFs molar ratio, which is physiologically equal to 1, proves to be significantly reduced in subjects with CTS. This means that in children with CTS, unlike normal subjects, considerable amounts of IGF peptides lack sufficient IGFBP-3 to form the 150-kDa complex, with which they are characteristically sequestered in the vascular compartment. Thus, they can more easily cross the capillary endothelial barrier and reach the target tissue in which they exert their proliferating and differentiating actions. In particular, in the absence of IGFBP-3 and reduced formation of the ternary complex, IGFBP-2, which shows greater binding affinity for IGF-II, might assume a vicarious role, protecting the peptide from enzymatic degradation and conducting it intact to the target tissue. The increased IGF peptide concentration and bioavailability present in the CTS-affected subjects could be the cause of the lower IGFBP-1 (25, 26) as well as higher IGFBP-2 (27) values in comparison with those of control subjects.
It remains to be established whether the increased concentration of IGF-II, in concomitance with normal concentrations of the other GH-dependent components of the system, is caused by increased stimulation of its gene expression (or processes downstream of its expression) or reduced degradation and elimination from circulation on the part of the IGF-II receptor. Indeed, although it is acknowledged that expression of the IGF-I gene is regulated primarily by GH, the primary regulator of IGF-II gene transcription remains unclear. Nevertheless, expression of both IGF peptides is also influenced by nutritional status and dietary energy intake and various hormones, such as sex steroids and pituitary hormones, as well as by other growth factors, such as platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor (28, 29, 30). On the other hand, a contribution to the maintenance of circulating levels of IGF-II can be attributed to the IGF-II receptor, which mainly performs a scavenger function for circulating IGF-II (31, 32), as demonstrated by the finding that, upon proteolytic cleavage, the extracellular domain of the receptor is dissociated from the cell membrane as a soluble fragment that circulates in the blood with the ability to bind to IGF-II and facilitate its degradation (33, 34, 35). In our prepubertal study population, we can exclude environmental, socioeconomic, and nutritional factors, although these factors play an important role both in regulating IGF synthesis and determining an individual’s stature.
A close correlation between increased IGF-II expression and body growth accompanied by a greater risk of neoplasia has been demonstrated in many syndromes, such as Beckwith-Wiedeman and Simpson Golabi Behmel (13, 15, 32). Moreover, increased IGF-II expression has been associated with neoplastic growth in a certain number of tumors, including Wilms’ tumors, rhabdomyosarcoma, gliomas, and lung cancer (36, 37). Because some important epidemiological studies (38, 39) have found a high correlation between tall stature during childhood and the incidence of neoplasms in adulthood, the involvement of IGF-II in CTS appears of concern. In this regard, the chromatographic profile of IGF-II in CTS-affected children excluded the presence of the 10- to 20-kDa pro-IGF-II, which is characteristic of many tumors (40). However, although the link between circulating IGF levels and the risk of cancer is inconclusive, it seems that individuals with a lower IGFBP-3/IGF ratio have a higher cancer risk (41, 42). The therapeutic use of IGFBP-3 may be able to redress the molar ratios. This approach could be more appropriate in protecting the organism from hyperstimulation than current therapies, especially those involving sex steroids, which appear to engender several side effects and an unknown risk of thromboembolic problems and carcinoma of the breast, ovary, and uterus (43).
In conclusion, the results of the present study reveal an alteration in the concentration of IGF-II, involving an increase in the free form of the IGF peptides because of a relative lack of IGFBP-3. This may induce an increase in their growth activity on target tissues, particularly at the level of cartilaginous and bone tissue.
Acknowledgments
Footnotes
This work was supported by Research Grant 9906153187-005 from Ministero dell’Università e della Ricerca Scientifica (MURST, Roma).
Abbreviations: ALS, Acid-labile subunit; CTS, constitutionally tall stature; IGFBP, IGF-binding protein.
Received April 22, 2002.
Accepted August 26, 2002.
References
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