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Free Insulin-Like Growth Factor I Serum Levels in 1430 Healthy Children and Adults, and Its Diagnostic Value in Patients Suspected of Growth Hormone Deficiency¹

Department of Growth and Reproduction, National University Hospital (A.J., K.H., J.M., N.E.S.), the Center of Preventive Medicine, Glostrup County Hospital, University of Copenhagen (S.R.), and the Department of Pediatrics, Glostrup Amtssygehus (K.W.K.), Copenhagen; the Department of Pediatrics, Hvidovre Hospital (S.A.P.), Hvidovre; the Research Department of Human Nutrition, Royal Veterinary and Agricultural University (K.F.M.), Frederiksberg; and the Department of Biostatistics, Panum Institute (T.S.), Copenhagen, Denmark

Address all correspondence and requests for reprints to: Anders Juul, M.D., Ph.D., Department of Growth and Reproduction, GR 5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-I circulates in its free form, which is believed to be the biologically active form. However, our knowledge of the clinical or physiological value of determination of free IGF-I in serum is limited at present. In adults, the diagnostic value of total IGF-I and IGFBP-3 determinations in patients suspected of GHD has only been reported in a few studies, whereas no previous reports on the diagnostic value of free IGF-I levels in adults suspected of GHD exist.

Serum levels of free IGF-I were determined in 1430 healthy children, adolescents, and adults by a newly developed, commercially available immunoradiometric assay (Diagnostic Systems Laboratories) to establish valid normative data for this analysis. We studied the diagnostic value of free IGF-I in relation to total IGF-I and IGFBP-3 determinations in adults who were suspected of GHD. A GH provocative test, using oral clonidine, was performed in 108 adult patients who had previously been treated with GH in childhood.

In healthy subjects, free IGF-I levels increased during childhood, with the highest mean values during puberty. After puberty, a subsequent decline in serum levels of free IGF-I was apparent. We found unmeasurable free IGF-I values in 34 of the prepubertal children (3.3%). All individuals over 8 yr of age had measurable free IGF-I levels that amounted to approximately 1% of the total IGF-I concentrations. Free IGF-I levels were below -2 SD in 56 of 79 GHD patients (sensitivity, 71%) and above -2 SD in 24 of 29 patients with a normal GH response (specificity, 83%). Multiple linear regression analysis demonstrated that free IGF-I was significantly dependent on peak GH levels, duration of the disease, and number of other pituitary axes affected.

We conclude that free IGF-I serum levels increase during childhood with a peak in puberty, whereafter free IGF-I levels return to prepubertal levels. Three percent of healthy prepubertal children had unmeasurable free IGF-I levels using this assay. We found that determination of the free IGF-I serum concentration may predict the outcome of a GH provocative test in adults suspected of GHD, but that a single determination of free IGF-I offered no significant advantage compared to determination of total IGF-I or IGFBP-3 serum levels.

	Introduction

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PULSATILE GH secretion stimulates GH-responsive tissues to produce insulin-like growth factor I (IGF-I). IGF-I in plasma is primarily derived from the liver (1, 2), and virtually all IGF-I and -II circulate bound to specific IGF-binding proteins (IGFBPs), six of which have been characterized (3). When performing size-exclusion chromatography on serum, two fractions elute: a major fraction (80%) of approximately 150 kDa made of IGF in a ternary complex with IGFBP-3 and the acid-labile subunit, and a minor fraction of 30–50 kDa made of binary IGF-IGFBP complexes. The free IGF-I (7.5-kDa) fraction is barely detectable by this technique. Consequently, extraction of all interfering IGFBPs is mandatory before determination of the total IGF concentration in serum. It is very likely that the total IGF-I concentration does not reflect the IGF-mediated bioactivity of the serum entirely, as IGFBP concentrations as well as IGFBP proteolytic activity may modify the bioavailability of IGF to the tissues. Consequently, the free unbound IGF-I may represent the biologically active fraction of the total circulating IGF in analogy with thyroid and sex steroid hormones, but this hypothesis remains speculative at present. It is, however, noteworthy, that almost all previous studies of circulating IGF levels have been based on measurements of total extractable concentrations of IGF-I in serum, which evidently requires some reservations. With the recent advent of assays to determine free IGF-I concentrations, a new era of IGF research has begun that may enable further understanding of the complexity of the IGF system. At present, very little is known about the clinical or physiological value of determination of free IGF-I in serum. Free IGF-I serum levels increase in puberty in boys, and boys with precocious puberty have increased free IGF-I concentrations compared to prepubertal boys (4). In adults, an inverse relation between free IGF-I levels and age was shown in 49 subjects (5), and increased free IGF-I levels were demonstrated in obese adults, which may explain the low GH levels seen in obesity by a negative feedback mechanism (6).

In the present study we have measured serum levels of free IGF-I in a cross-sectional study of 1430 healthy children, adolescents, and adults to describe valid normal ranges for this analysis. Subsequently we have evaluated the diagnostic value of free IGF-I determinations in relation to the outcome of GH provocative testing and total IGF-I and IGFBP-3 in 108 adults suspected of GH deficiency (GHD).

	Subjects and Methods

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Healthy subjects

Children (n = 1063; 0–5 yr). Fifty-one healthy infants participated in a longitudinal study and were examined with blood sampling four times: at birth (cord blood) and at 2, 6, and 9 months of age. Additionally, blood samples were drawn from 43 boys before herniotomy or circumcision and from 3 girls who underwent herniotomy.

Children and adolescents (5–20 yr). Children and their parents in 4 different primary schools and 1 grammar school in the Copenhagen area were asked to complete a questionnaire and provide their medical records and consent to participate in the study. Fifty-six children were excluded due to chronic disease (e.g. asthma and diabetes) or acute disease (within the last 2 weeks) or because of medication (including oral contraception). Another 31 children were excluded due to the fact that they were of non-Caucasian origin. All had heights and weights within the normal ranges of Danish children. Total IGF-I and IGFBP-3 levels have previously been reported in these children (7, 8).

Adults (n = 367). As part of a large cohort study (DAN-MONICA) in the Copenhagen area, serum was taken from 190 adults, aged 40, 50, 60, or 70 yr. Furthermore, 177 hospital employees and medical students participated as controls in the age group 20–40 yr. None had acute or chronic diseases, and none was taking any medication (including oral contraceptives).

Patients

One hundred and eight patients who were previously treated with GH during childhood were included in this study. They were studied to evaluate the consequences of childhood-onset GHD in adults as well as to select patients for GH replacement therapy. GH secretion was reevaluated in adulthood by provocative testing and grouped according to the peak GH response as either GHD (peak GH, <7.5 µg/L) or as having a normal GH response (peak GH, >7.5 µg/L). GH provocative testing was performed using oral clonidine (75 µg/m² Catapressan, Boehringer Ingelheim, Ingelheim, Germany), with blood sampling at -30, 0, 30, 60, 90, and 120 min. We have previously described the results of the retesting as well as the diagnostic value of total IGF-I and IGFBP-3 in these patients (9).

Blood sampling

Serum levels of free IGF-I were determined on a basal blood sample from all 1538 individuals and compared to the peak GH value during the GH provocative test in the 108 patients. Blood samples were drawn from an antecubital vein and centrifuged, and serum was stored at -20 C until analysis.

Serum analyses

Free IGF-I. Free IGF-I was determined by a commercially available immunoradiometric assay using coated tubes (Diagnostic System Laboratories, Webster, TX) that we have described previously (4). Briefly, this immunoradiometric assay is a noncompetitive assay in which the analyte is sandwiched between two antibodies. It is a direct assay of the dissociable fraction of IGF-I. Initially, 100 µL sample, controls, and standards are added to antibody-coated tubes, incubated for 120 min at 2–8 C, and washed with 2 mL deionized water. Hereafter, 200 µL of the radiolabeled antibody mixture are added to the tubes, and the tubes are incubated for 120 min at room temperature on a shaker set at 180 rpm. After incubation, the tubes are washed three times with 3 mL deionized water and decanted before counting. Cross-reactivity was reported to be undetectable at 0.2 µg/tube for IGF-II, insulin, proinsulin, and GH. Addition of pure IGFBP-1 or IGFBP-3 caused a dose-dependent decrease in measurable free IGF-I (10). Sensitivity, defined as repeated measures of the zero standard, was 0.03 µg/L. Intraassay coefficients of variation (CVs) were 10.3% (at 0.3 µg/L), 5.1% (at 5.5 µg/L), and 3.3% (at 14.2 µg/L; n = 8), according to the manufacturer. Interassay CVs were 7.7% (at 0.26 µg/L), 3.6% (at 5.52 µg/L), and 10.7% (at 13.87 µg/L), respectively. In our hands, intraassay CVs were 14.7% (at 0.7 µg/L), 10.1% (at 4.3 µg/L), and 13.4% (at 5.3 µg/L), respectively (all n = 12). Interassay CVs were 14.1% (at 1.9 µg/L), 9.9% (at 6.9 µg/L), and 21.6% (at 10.7 µg/L; n = 71), respectively.

Total IGF-I. IGF-I was determined in all subjects with a RIA using truncated IGF-I [des(1, 2, 3)-IGF-I] as radioligand, as originally described (11), modified by the use of a monoiodinated isomer as tracer [Tyr³¹-des(1, 2, 3)-IGF-I] (12). Serum was extracted by acid-ethanol and cryoprecipitated before analysis to remove interfering binding proteins. Intraassay CVs (n = 15) were 5.4% [at a bound/free ratio (B/B₀) of 0.20], 3.9% (at a B/B₀ of 0.4), and 10.3% (at a B/B₀ of 0.7), respectively. Interassay CVs (n = 45) were 10.4% (at a B/B₀ of 0.2), 8.7% (at a B/B₀ of 0.4), and 14.1% (at a B/B₀ of 0.7), respectively.

IGFBP-3. Serum concentrations of IGFBP-3 were measured by RIA, as previously described by Blum et al. (13). Reagents for the IGFBP-3 RIA were obtained from Mediagnost (Tubingen, Germany). Intraassay CVs (n = 17) were 2.3% (at a B/B₀ of 0.3), 2.4% (at a B/B₀ of 0.4), and 5.9% (at a B/B₀ of 0.8), respectively. Interassay CVs (n = 144) were 10.7% (at a B/B₀ of 0.5) and 7.6% (at a B/B₀ of 0.8), respectively.

Serum GH. Serum GH was determined using a commercially available RIA (Pharmacia, Uppsala, Sweden).

Statistical procedures

Construction of reference ranges (95% confidence bounds) was performed using a smoothing spline on transformed residuals for free IGF-I (due to non-Gaussian distribution of the data). The transformation, x^0.25, gave an approximation to a normal distribution of the data. From these curves age- and sex-related z-scores [i.e. number of SDs from an age- and sex-related mean (SD score)] were calculated for each transformed value (i.e. free IGF-I^0.25). The sensitivity of the parameters was defined as the percentage of GHD patients with a value below -2 SD. The specificity was defined as the percentage of patients with a normal GH response who had a value above -2 SD. The predictive value of positive test was defined as the percentage of values below -2 SD that represent GHD patients. The predictive value of a negative test was defined as percentage of values above -2 SD that represent patients with normal GH response. Test accuracy was defined as the number of GHD patients with a subnormal value plus the number of patients with a normal GH response who had a normal value divided by total number of patients. Results are expressed as means (±SE) unless otherwise stated. P < 0.05 was considered statistically significant.

Ethical considerations

All children and their parents gave their informed consent. The study was in accordance with the Helsinki II declaration and was approved by the local ethical committee of Copenhagen, Denmark (approval V200.1996/90).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum levels of free IGF-I in healthy subjects

Free IGF-I serum levels increased during childhood, with highest values in puberty. A 95% prediction interval based on transformed free IGF-I levels is shown in Fig. 1 and Table 1). We found unmeasurable free IGF-I values in 34 of the prepubertal children (3.2% of all children). All individuals more than 8 yr of age had measurable free IGF-I levels that amounted to approximately 1% of the total IGF-I concentrations. There was a significant difference in free IGF-I levels according to gender; free IGF-I levels increased 1–2 yr earlier in girls than in boys (Fig. 2).

View larger version (30K): [in this window] [in a new window]   Figure 1. Serum levels of free IGF-I in 1430 healthy children and adults according to age (males in upper panel). The lines represent the mean value and upper and lower limits, respectively (equal to -2 and +2 SD).

View larger version (15K): [in this window] [in a new window]   Figure 2. Mean serum levels of free IGF-I (top panel), total IGF-I (middle panel), and height velocity (bottom panel) according to sex. Data on total IGF-I and height velocities are derived from Refs. 7 and 14.

Serum free IGF-I levels in 79 patients with GHD and in 29 patients with a normal GH response are shown in Fig. 3. Free IGF-I decreased significantly with increasing degree of hypopituitarism (Table 2; P < 0.001).

View larger version (53K): [in this window] [in a new window]   Figure 3. Serum levels of free IGF-I in patients with a normal GH response (peak GH, >7.5 µg/L; top panels) and patients with GHD (peak GH, <7.5 µg/L; bottom panels). Males are shown to the left, females to the right. The shaded area represents the 95% prediction intervals for free IGF-I based on 1430 healthy individuals.

Free IGF-I levels were below -2 SD in 56 of 79 GHD patients and were above the cut-off value in 24 of 29 patients with normal GH response. Sensitivities and specificities are given in Table 3. Free IGF-I correlated significantly with peak GH levels (r = 0.46; P < 0.001). The combined use of free and total IGF-I as well as free IGF-I and IGFBP-3 improved the diagnostic value, as shown in Fig. 4.

View larger version (18K): [in this window] [in a new window]   Figure 4. Comparison of the diagnostic value of free IGF-I vs. total IGF-I (top panel) and free IGF-I vs. IGFBP-3 (bottom panel). The lines represent the lower limit (-2 SD) for the analyses. The dots represent values from patients with GHD (•) and those from patients with a normal GH response ().

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

We have previously shown that the molar ratio between total IGF-I and IGFBP-3 increases in puberty concomitant with a decrease in IGFBP-1, suggesting that free, biologically active IGF-I increases in normal puberty when growth velocity is high (8). The free IGF-I determination is not trivial due to methodological problems, and other methods, such as urinary IGF-I and salivary IGF-I measurements, have, therefore, been used to express free IGF-I levels (12, 15, 16, 17). Previous attempts to isolate the free unbound fractions of IGF-I in serum have used high pressure liquid chromatography (11, 18), reverse phase chromatography (13), and ultracentrifugation (5), which give varying results, possibly due to the induction of disequilibrium between free and bound IGF by the various techniques. Direct determination of free IGF-I was initially reported by Takada et al. (19), and this technique offers another methodological reservation; the amount of free IGF-I determined will depend on the affinities of the IGFBPs vs. the affinities of the IGF antibodies used in the assay. On the other hand, one could argue that the free IGF-I fraction that is available (or dissociable) to the antibody in this assay may represent the free IGF-I fraction that is available to the tissues. The present assay also measures free IGF-I by direct determination, which enables us to study the possible clinical use of free (or dissociable) IGF-I concentrations. Hasegawa et al. (20) recently demonstrated similar clinical utility of free IGF-I compared to total IGF-I in the evaluation of GHD in children. However, the diagnostic value of free IGF-I levels in adults suspected of GHD has not previously been studied. We found that the diagnostic sensitivity of the free IGF-I determination was 70.9% in 108 adults with childhood-onset GHD, giving a predictive value of a positive test (ability to correctly identify patients with GHD) of 91.8% for free IGF-I, which is slightly higher than the predictive values for total IGF-I and IGFBP-3, respectively.

We conclude that a subnormal free IGF-I concentration predicts a subnormal GH response to provocative testing in patients who are suspected of GHD. On the other hand, normal levels of free IGF-I do not exclude GHD. In adults with GHD, free IGF-I levels were dependent on the duration of GHD, the number of additional hormonal deficits, and the peak GH levels. We believe that free IGF-I determination offered no major advantage in the evaluation of adult GHD compared to total IGF-I or IGFBP-3 measurement. However, in children, the diagnostic value of free IGF-I determination in subjects suspected of GHD remains to be seen.

	Acknowledgments

 
We are grateful to Ulla Højelse, Brian Vendelboe, and Kirsten Jørgensen for their skilled technical assistance. Drs. Knut Borch-Johnsen and Phillip D. K. Lee are acknowledged for their assistance. We are grateful to the 1430 healthy children and adults who volunteered to participate in this study.

	Footnotes

 
¹ This work was supported by the Michaelsen Foundation (to A.J.) and the Danish Medical Research Council (Grants 12–9361 and 12–1376).

Received January 2, 1997.

Revised March 19, 1997.

Accepted April 24, 1997.

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