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Endocrinology Unit, Department of Medicine, Hospital T Alvarez (H.R.B., P.G.V.S., H.L.F., A.M.S., A.V.G., M.G.S., G.F.R.), Buenos Aires C1406FWY, Argentina; and Department of Endocrinology, Hospital de Niños (M.M.), Córdoba, Argentina X 5000 ANM
Address all correspondence and requests for reprints to: H. L. Fideleff, M.D., Ph.D., Hospital T. Alvarez, Endocrinology Unit. Aranguren 2701, Buenos Aires C1406FWY, Argentina. E-mail: .
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To gain more insight into the value of IGF-I and IGFBP-3 measurements in the screening for GHD in children and adults, we assessed their concentrations in GHD children, idiopathic short stature children (ISS), adults with GHD (AGHD), and healthy adult volunteers. To establish the best cut-off line we used an appropriate statistical methodology, receiver operating characteristic (ROC) plots (11), to be able to evaluate the diagnostic efficiency (DEf) of IGF-I and IGFBP-3 in patients with GHD.
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Subjects and Methods |
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Our data originally consisted of 158 measurements of IGF-I and 102 measurements of IGFBP-3 in serum from 66 children, aged 1.3–15 yr, and 92 adults, aged 18–70 yr. Thirty-four children (12 females and 22 males) were GHD patients, with a height of -6.4 to -1.0 SD score (SDS) and a body mass index (BMI) between the 3rd and 97th percentiles. As there is no general consensus on the most appropriate poststimulation GH cut-off for the diagnosis of GHD in children, we, like other researchers (12, 13), have characterized our patients by a GH peak below 7 µg/liter (<0.33 pmol/liter) in two stimulation tests (exercise-propranolol or clonidine and arginine). Eleven of them had multiple pituitary hormone deficiencies (MPHD), and 23 had isolated GH deficiency (IGHD). The primary pathological process resulting in GHD was idiopathic (n = 16); pituitary hypoplasia (n = 6); pituitary stalk disruption syndrome (n = 3); empty sella (n = 2); craniopharyngioma, midline syndrome, hydrocephalus, and pituitary stalk cyst (n = 1 each); and posttherapy for rhabdomyosarcoma, retinoblastoma, and acute lymphoblastic leukemia (n = 1 each). Thirty-two subjects (16 females and 16 males) were ISS, characterized by a height less than -2.0 SDS, a growth velocity below the 10th percentile, BMI between the 10th and 75th percentiles, and a GH peak greater than 10 µg/liter (>0.47 pmol/liter) in 2 stimulation tests. In male patients with bone age of 12 yr or more and Tanner stage less than III and in girls with bone age of 10 yr or more and Tanner stage I, GH stimulation tests were performed after priming (17ß-estradiol, 1 mg/m2 of body surface for 3 d). This methodology was used for both GHD patients and ISS children (14). Of the 92 adults, 72 had GHD, and 20 were healthy subjects. Of the 72 GHD adults, 34 (12 females and 22 males) had acquired GHD during prepuberty [childhood onset (AGHD-CO)], and 38 (16 females and 22 males) had acquired GHD when they were older than 18 yr [adult onset (AGHD-AO)]. In AGHD-CO patients, the BMI was 16.0–42.2 kg/m2 and in AGHD-AO patients, the BMI was 19.0–43.0 kg/m2. AGHD was confirmed according to Consensus Guidelines 1997 (2) as a GH response below 3 µg/liter (<0.14 pmol/liter) to an insulin tolerance test. When an insulin tolerance test was contraindicated, especially in elderly patients (n = 7), an arginine stimulation test was performed using the same cut-off line (2, 15). The etiologies of GHD for AGHD-CO were idiopathic (n = 21); craniopharyngioma (n = 6); perinatal trauma or asphyxia (n = 2); and meningitis, oligodendroglioma, cholesteatoma, empty sella, and pinealoma (n = 1 each). Etiologies for AGHD-AO were nonfunctioning pituitary tumor (n = 14); prolactinoma (n = 5); Sheehan’s syndrome (n = 4); Cushing’s disease (n = 3); pituitary epidermoid cyst (n = 2); and pituitary granuloma, hypophysitis, empty sella, myoblastoma, dysgerminoma, and idiopathic (n = 1 each). Twenty-nine AGHD-CO patients and 37 AGHD-AO patients had MPHD. The study also enrolled 20 healthy adult volunteers belonging to the medical and biochemical staff of the Endocrinology Unit (9 females and 11 males) with BMI of 25 kg/m2 or less, who had GH peak greater than 3 µg/liter (>0.14 pmol/liter) in 2 arginine stimulation tests and whose data have been previously published (15). In all subjects, children and adults, the presence of other pathological conditions that may affect serum IGF-I and IGFBP-3 levels was ruled out. None of the patients evaluated had diabetes mellitus. All patients, both children and adults, were receiving desmopresin, corticosteroid, or thyroid hormone replacement therapy, as clinically required. Eleven of 12 AGHD-CO females had estrogen deficiency; one of them was receiving estrogens transdermally, and the others orally. All AGHD-AO had estrogen deficiency, six of them were not receiving replacement therapy (four were menopausal, and estrogen therapy was contraindicated in the other two); two patients were receiving estrogens transdermally, and the others orally.
All subjects gave written informed consent. The study was approved by the Alvarez Hospital research and ethical committee. The study was conducted according to the Declaration of Helsinski II and the Guidelines for Good Clinical Practice.
Assays
Samples for the measurement of IGF-I and IGFBP-3 were taken in the morning after an overnight fast in all subjects. IGF-I was determined by immunoradiometric assay (IRMA) after acid-ethanol extraction (Diagnostics Systems Laboratories, Webster, TX). Standards for IGF-I were calibrated against WHO International Reference Preparation 87/518. The detection limit was 3.6 µg/liter (0.47 nmol/liter), and the intra- and interassay coefficients of variation (CVs) were less than 5.3% for a dose of 64 µg/liter (8.32 nmol/liter) and less than 5.4% for a dose of 157 µg/liter (20.41 nmol/liter). IGFBP-3 was determined in serum by IRMA (Diagnostics Systems Laboratories), and the standards for this assay were calibrated against recombinant IGFBP-3 MN 28.75 KDA expressed in Escherichia coli obtained from Celtrix Pharmaceuticals, Inc. (Palo Alto, CA). The detection limit was 1.8 µg/liter (0.06 nmol/liter), and the intra- and interassay CVs were less than 5% for a dose of 6.1 µg/liter (0.21 nmol/liter) and less than 10.5% for a dose of 21 µg/liter (0.74 nmol/liter).
Two different assays were used to determine plasma levels of GH. First, an IRMA-Magnetic Solid Phase was used (Serono Maia Clone, Milan, Italy). The standards for this assay were calibrated against First International Reference Preparation 66/217. The detection limit was 0.23 µg/liter (0.01 pmol/liter); the intra- and interassay CVs were less than 4% for a dose of 1.3 µg/liter (0.06 pmol/liter) and less than 4.2% for a dose of 13.4 µg/liter (0.62 pmol/liter). Then a two-site chemiluminescent enzyme immunometric assay (Immulite, Diagnostic Products, Los Angeles, CA) was used, calibrated against WHO International Reference Preparation 80/505. The detection limit was 0.08 µg/liter (0.004 pmol/liter), and the intra- and interassay CVs were less than 3% for a dose of 1.8 µg/liter (0.08 pmol/liter) and less than 5% for a dose of 9.6 µg/liter (0.45 pmol/liter). The equation for the linear regression line comparing the two methods was: log y = 1.03. log x - 0.09, where x was the IRMA, and y was the chemiluminescent enzyme immunometric assay (r = 0.97; SE of the estimate = 0.11).
Reference values
IGF-I and IGFBP-3 reference values for the pediatric population were obtained from serum samples from 212 children and adolescents (133 males and 79 females) who attended our hospital for health examinations. Consent from the child and parental approval were always obtained. All of them had normal weight, height, growth velocity, and bone age (within 2 SD for the normal age-corresponding mean), with an age range between 1–13.2 yr in prepubertal children and between 9.1–17 yr in pubertal subjects. Values obtained according to Tanner stage and sex are shown in Table 1
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. As IGF-I levels in the 21–25 yr age range were significantly higher than those found in the 26–30 yr age range, the 21–30 yr decade was subdivided into 5-yr periods. This finding was not observed in subsequent decades. Data analysis
Data were analyzed following the logarithmically transformed IGF-I and IGFBP-3 values. The values were converted into SDS using the corresponding reference values (children or adults) according to the following formula: x - average x/SD, where x is the actual log IGF-I or log IGFBP-3 of the patient, average x is the mean log IGF-I or log IGFBP-3 at the corresponding Tanner stage and gender (in children) or age (in adults), and SD is the SD from the mean.
To evaluate the diagnostic capacity of IGF-I and IGFBP-3 SDS in the characterization of GHD, various cut-off lines were analyzed using ROC methodology (11). We considered as true positive the values corresponding to patients with a diagnosis of GHD and as true negative the values corresponding to patients with ISS in the pediatric group and the values corresponding to healthy subjects in adults. DEf was defined as: (true positive + true negative)/total of cases.
The Spearman rank order correlation test was used to correlate IGF-I SDS and IGFBP-3 SDS with BMI (16). All results are expressed as the median and range.
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Results |
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Children. IGF-I SDS levels were: GHD patients (n = 34), -2.25 (-4.80 to 0.87); and ISS (n = 32), -0.17 (-1.80 to 2.17).
In GHD children, no correlation was found between BMI (expressed as a percentile) and IGF-I SDS (r = -0.09; P = 0.62), whereas in ISS, a slight correlation was found between BMI and IGF-I SDS (r = 0.54; P = 0.021).
The ROC plot analysis showed that the best cut-off line for IGF-I SDS was -1.65 to discriminate between both conditions, with a S of 68%, a Sp of 97%, and a DEf of 81% (Fig. 1A). Twelve children with GHD had an SDS above -1.65, and the etiologies of their deficiency were seven idiopathic, two pituitary hypoplasias, one empty sella, one pituitary stalk cyst, and one posttherapy for acute lymphoblastic leukemia. Of these 12 patients, nine had IGHD, and three had MPHD. Only one patient with ISS had IGF-I SDS below -1.65 (Fig. 2A).
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No correlation was found between the BMI and IGF-I SDS in patients with AGHD-CO or in patients with AGHD-AO (r = 0.15; P = 0.37 and r =0.12; P = 0.49, respectively). No correlation was found in healthy volunteers (r = 0.22; P = 0.29).
The ROC plot analysis in AGHD-CO patients showed that the best cut-off line was -1.65, with an S of 91%, an Sp of 100%, and a DEf of 94% (Fig. 1A). Three patients had an SDS above -1.65 (one craniopharyngioma, one oligodendroglioma, and one idiopathic GHD). Of these three patients, only one had IGHD. None of the healthy volunteers had an SDS below -1.65 (Fig. 2B).
The ROC plot analysis in AGHD-AO showed that the best cut-off line was -1.80, with an S of 81%, an Sp of 100%, and a DEf of 88% (Fig. 1A). Six patients had an SDS above -1.80, and the etiologies of their deficiency were three craniopharyngiomas, two nonsecreting pituitary adenomas, and one epidermoid cyst. All of these patients had MPHD. None of the healthy volunteers had an SDS below -1.80 (Fig. 2C).
IGFBP-3 data
Children. IGFBP-3 SDS levels were: GHD patients (n = 20), -2.90 (-7.20 to 0.80); and ISS (n = 30), -0.21 (-2.60 to 1.60).
In GHD children and in children with ISS no correlation was found between the BMI (expressed as a percentile) and the IGFBP-3 SDS (r = 0.02; P = 0.93 and r = -0.037; P = 0.89, respectively).
The ROC plot analysis showed that the best cut-off line for IGFBP-3 SDS was -1.80 to discriminate between the two conditions, with an S of 90%, an Sp of 60%, and a DEf of 78% (Fig. 1B). Eight GHD children (seven IGHD and one MPHD) had an SDS above -1.80, and the etiologies were two idiopathic, two pituitary hypoplasias, one empty sella, one pituitary stalk cyst, two posttherapy (acute lymphoblastic leukemia and rhabdomyosarcoma; Fig. 3A). Of these eight patients, two had IGF-I SDS levels below the previously established cut-off line. In the ISS group, only three patients had an IGFBP-3 SDS below -1.80, and none of the patients in this group had IGF-I SDS below their respective cut-off lines.
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No correlation was found between the BMI and the IGFBP-3 SDS in AGHD-CO patients or in AGHD-AO patients (r = 0.12; P = 0.57 and r =0.09; P = 0.63, respectively). No correlation was found in healthy volunteers (r = -0.34; P = 0.09).
The ROC plot analysis in AGHD-CO patients showed that the best cut-off line was -1.45, with an S of 90%, an Sp of 75%, and a DEf 82% (Fig. 1B). Six patients had an SDS above -1.45 (five idiopathic AGHD and one perinatal trauma), of whom only one had IGHD (Fig. 3B). Of these six patients, five had IGF-I SDS below the cut-off line. Two healthy volunteers had an IGFBP-3 SDS below -1.45.
The ROC plot analysis in AGHD-AO patients showed that the best cut-off line was -0.90, with an S of 90%, an Sp of 68%, and a DEf of 77% (Fig. 1B). Nine patients had an SDS above -0.90, and the etiologies of their deficiency were three nonsecreting pituitary adenomas, two craniopharyngiomas, two Sheehan’s syndrome, one dysgerminoma, and one prolactinoma. All patients had MPHD (Fig. 3C). Six of these nine patients had IGF-I SDS below the previously established cut-off line. Two healthy volunteers had an IGFBP-3 SDS below -0.90.
IGF-I and IGFBP-3: diagnostic accuracy
Children. The correct diagnosis of ISS could be made in 26 of 30 cases (87%) using the above-described cut-off lines for IGF-I SDS and IGFBP-3 SDS together (above -1.65 and -1.80, respectively). When the IGF-I SDS was used alone, 29 of 30 children (97%) could be characterized, and when the IGFBP-3 SDS was used alone, it was possible to characterize 27 of 30 children (90%).
In GHD patients, the correct diagnosis could be made in 12 of 20 patients (60%) using the IGF-I SDS and the IGFBP-3 SDS together (below -1.65 and -1.80, respectively). When the IGF-I SDS was used alone, 13 of 20 children (65%) were characterized, and when using the IGFBP-3 SDS alone, 12 of 20 children (60%) were characterized.
Adults. The correct diagnosis of AGHD-CO could be made in 17 of 24 patients (71%) using the above-described cut-off lines for IGF-I SDS and IGFBP-3 SDS together (below -1.65 and -1.45, respectively). When the IGF-I SDS was used alone, 22 of 24 adults (92%) could be characterized, and when the IGFBP-3 SDS was used alone, 18 of 24 patients (75%) could be characterized.
In AGHD-AO patients, the correct diagnosis could be made in 18 of 28 patients (64%) using the IGF-I SDS and the IGFBP-3 SDS together (below -1.80 and -0.90, respectively). When the IGF-I SDS was used alone, 24 of 28 patients (86%) were characterized, and when the IGFBP-3 SDS was used alone, 19 of 28 adults (68%) were characterized.
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Discussion |
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Two of the peptides most widely used for evaluation of the somatotropic axis have been IGF-I and IGFBP-3. For a correct interpretation of results, it has been pointed out that it is necessary to use reference values specific for each population (7, 8); however, there are still doubts about which is the most appropriate cut-off line in the characterization of pediatric and adult patients with GHD. Moreover, it should be noted that misclassification of subjects cannot be excluded, taking into account false positive and false negative results during GH stimulation tests. Different researchers have used cut-off lines based on standard criteria, such as the 5th percentile, the 10th percentile, or 2 SD in relation to the mean. Based on these criteria, a performance of IGF-I has been reported in children in the diagnosis of GHD with an S of 47–100% and an Sp of 50–98% (7, 17, 18, 19, 20, 21), whereas for IGFBP-3, S was 31–97%, and Sp was 57–98% (17, 20, 21, 22, 23, 24). In adults, the performance of IGF-I showed an S of 41–86%, and Strasburger et al. (8) found an Sp of 89%, whereas for IGFBP-3 an S of 47–90% and an Sp of 81% were described (25, 26, 27). Many researchers suggest a greater DEf for both parameters in AGHD-CO patients than in patients with AGHD-AO and with more limitations in patients over 60 yr of age (9).
To resolve the discrepancy among the various cut-off lines and their limitations, in this study we used ROC methodology. ROC plots provide a pure index of accuracy by demonstrating the limits of a test’s ability to discriminate between alternative states of health over the complete spectrum of operating conditions. The use of this methodology enabled us to set a cut-off limit with a higher S and Sp as well as to visualize the test’s ability to discriminate between GHD subjects and non-GHD subjects, allowing for a comparison of various parameters. There is scarce experience in the use of ROC methodology to determine the best diagnostic cut-off line for IGF-I and/or IGFBP-3 (28). The aim of our study, which involves both GHD children and adults (CO and AO subjects), has been to find the appropriate cut-off line for IGF-I and IGFBP-3, in terms of SDS, that makes it possible to attain the higher S and Sp and, therefore, the higher DEf. Nevertheless, the final decision on the best cut-off lines always involves a more or less subjective decision on whether the selected cut-off line should give a high S at the expense of Sp or vice versa. Additionally, we preferred to express the values of both peptides in terms of SDS to be able to compare patients of various ages and results from different laboratories. This would also allow the monitoring of the long-term GH treatment of patients with GHD (29).
In both GHD children and AGHD-CO patients, the best cut-off line for IGF-I SDS was -1.65, with DEf values of 81% and 94%, respectively, whereas for AGHD-AO patients, the best cut-off line was -1.80, with a DEf of 88%. Interestingly, these cut-off lines do not coincide with the traditionally used cut-off lines of -2 SDS, as in the three groups evaluated they were above those values. It should be noted that although the cut-off lines obtained were above -2 SDS, the Sp for the diagnosis of GHD was 97% in children and 100% in adults. The lower S found might be correlated with the fact that plasma levels of IGF-I appear to be regulated by multiple factors, and for this reason a variable percentage of GHD patients have completely normal results. Different researchers have reported high Sp and lower DEf with the use of IGF-I (21, 28, 30), in agreement with our finding. However, other groups recommending the use of IGF-I in the evaluation of children with short stature, reported lower Sp and higher S (4, 31). These discrepancies could be partly attributed to methodological differences or to the fact that reference values may differ significantly, possibly because of genetic or environmental factors (31). In our report to avoid a potential overlap with increasing age, we expressed IGF-I values in terms of SDS.
With regard to IGFBP-3, the best cut-off line for GHD children was -1.80 (78% DEf), that for AGHD-CO was -1.45 (82% DEf), and that for AGHD-AO was -0.90 (77% DEf). Paradoxically, in contrast with the findings for IGF-I, the best cut-off line for IGFBP-3 showed good S and poor Sp in the three groups. In practice, this might mean considering as GH deficient a relatively large percentage of non-GHD subjects. IGFBP-3 results might be correlated with the fact that this peptide reflects total levels of IGFs, a parameter that is less GH dependent than IGF-I alone, as IGF-II has little GH dependency (32).
In our experience the joint use of IGF-I and IGFBP-3 allowed for the correct diagnosis of only 60% of GHD children, 71% of AGHD-CO subjects, and 64% of AGHD-AO subjects and did not prove to be more useful than the use of IGF-I alone. We decided to calculate diagnostic accuracy based on both markers being below the respective cut-off lines, instead of one of the two markers being below the respective cut-off line, to avoid a lower Sp.
The BMI does not appear to influence the cut-off lines established for IGF-I and IGFBP-3 in GHD subjects, although this cannot be fully asserted given the limited number of cases evaluated. Biller et al. (28) reported that the BMI did not affect the GH cut-off points of the model they had described. IGF-I has been reported to be dependent on different variables (age, sex, and pubertal development), but not on BMI in normal subjects (33, 34).
In the group with AGHD-AO, patients with IGF-I and/or IGFBP-3 values above the respective cut-off lines were in all cases MPHD and of organic etiology. This might be attributed to the fact that this was a very homogenous group with regard to clinical features (37 of 38 were MPHD and of organic etiology). In all other groups for both IGF-I and IGFBP-3, levels were above the cut-off lines reported in IGHD and MPHD as well as in idiopathic and organic GHD. Hartman et al. (30) also reported IGF-I levels above the cut-off line established by them in a variable number of patients with IGHD as well as in patients with 1–4 additional pituitary hormone deficiencies.
In conclusion, our findings further support the need to use cut-off lines expressed in SDS obtained using an appropriate statistical methodology for a better characterization of the various clinical presentations. IGF-I proved to be more useful because of its good DEf in both children and adults, whereas IGFBP-3 did not significantly contribute to the diagnosis of GHD patients.
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Acknowledgments |
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Footnotes |
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Abbreviations: AGHD-AO, Adults with GH deficiency of adult onset; AGHD-CO, adults with GH deficiency of childhood onset; BMI, body mass index; CV, coefficient of variation; DEf, diagnostic efficiency; GHD, GH deficiency; IGFBP-3, IGF-binding protein-3; IGHD, isolated GH deficiency; IRMA, immunoradiometric assay; ISS, idiopathic short stature; MPHD, multiple pituitary hormone deficiencies; ROC, receiver operating characteristic; S, sensitivity; SDS, SD score; Sp, specificity.
Received March 10, 2003.
Accepted July 14, 2003.
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, multiple pituitary hormone deficiency; 
, healthy volunteers; 
, ISS.