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Departments of Pediatrics, Oregon Health Sciences University (P.M., K.L.P., R.G.R.), Portland, Oregon 97201; Molecular and Clinical Endocrinology and Oncology, University Federico II (P.M., C.D.S., G.L., A.C.), Naples I-80131, Italy; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto (J.K.), Toronto, Ontario, Canada; and Diagnostics Systems Laboratories, Inc. (J.K., A.D.), Toronto, Ontario, Canada
Address all correspondence and requests for reprints to: Paolo Marzullo, M.D., Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Via S. Pasini 5, Naples I-80131, Italy. E-mail: marzullo{at}ohsu.edu
Abstract
The diagnostic approach to acromegaly and GH deficiency frequently includes measurement of several components of the insulin-like growth factor (IGF) system. IGF-I levels are reported to be good predictors of active and cured acromegaly, but are commonly found within the normal age-adjusted range in adult GH-deficient (GHD) patients. Circulating concentrations of IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and free IGF-I reflect the GH secretory status, but their diagnostic accuracy is still debated. In this study serum levels of total and free IGF-I, IGFBP-3, ALS, and IGFBP-3-IGF-I and IGFBP-3-ALS complexes were determined in patients previously diagnosed with active (n = 67) or inactive (n = 16) acromegaly and adult GHD (n = 34) and compared with results obtained in 58 healthy controls.
In healthy subjects, IGF-I, IGFBP-3, ALS, and both IGFBP-3 complexes declined with age; a correlation was found between IGF-I and IGFBP-3 (r = 0.59; P < 0.001), ALS (r = 0.67; P < 0.001), and free IGF-I (r = 0.40; P < 0.05). Active acromegalic patients showed a significant increase in all parameters tested. IGF-I concentrations were above +2 SD in 100% of patients, whereas slightly lower sensitivities were shown for IGFBP-3 (85%), ALS (88%), and free IGF-I (94%). In this group, IGF-I exhibited a slightly higher correlation with IGFBP-3 (r = 0.83; P < 0.001) than with ALS levels (r = 0.78; P < 0.001). In cured acromegalic patients, we observed the normalization of all parameters but free IGF-I levels.
Adult GHD patients showed a significant reduction of all hormones. Unlike active acromegalic patients, all parameters had only a modest sensitivity in GHD; suppression below –2 SD was observed in 41% of GHD patients for IGF-I, 47% for IGFBP-3, 32% for ALS, and 35% for free IGF-I measurements. Previous radiotherapy and GH peak response below 3 µg/L were associated with significantly lower IGF-I, IGFBP-3, and ALS levels. IGF-I levels were significantly correlated to ALS (r = 0.68; P < 0.001) and IGFBP-3 (r = 0.64; P < 0.001) as well as with free IGF-I (r = 0.67; P < 0.001) levels. By multiple regression analysis, the number of anterior pituitary hormones impaired was the most predictive indicator of IGF-I, IGFBP-3, and free IGF-I levels in GHD patients; conversely, the GH peak response better anticipated ALS concentrations.
The pattern of IGFBP-3 complexes paralleled previous hormonal findings. In active acromegalic patients, IGFBP-3-IGF-I levels were 5.4-fold higher than in controls and were above +2 SD in 95% of patients, whereas IGFBP-3-ALS levels were elevated in 15% of cases. On the other hand, both IGFBP-3 complexes were able to predict GHD in only a minority of cases.
Taken together, these data support the diagnostic role of IGF-I in acromegaly and suggest that free IGF-I and the IGFBP-3-IGF-I complex can assist diagnostic strategies in this condition. All markers are of limited predictive value in adult GHD, as hormonal values are commonly found within the normal limits. In these patients, low IGFBP-3 and IGF-I concentrations can add further clinical information on the residual GH activity.
DIAGNOSIS OF GH-RELATED disorders usually requires stimulatory testing to allow for the variability in determinations of spontaneous GH secretion (1, 2). Measurement of insulin-like growth factor I (IGF-I) has been proposed as an appropriate first-line investigation for diagnostic and therapeutic monitoring of acromegaly (1, 3, 4, 5). In pediatric GHD, approximately 80% of patients are expected to have IGF-I levels below –2 SD, for the age-related mean values (2, 6), but the relationship existing between IGF-I and both spontaneous and stimulated GH secretion is arguable in adult patients.
IGF-I circulates predominantly associated with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS) in a ternary complex, which constitutes both a reservoir and a carrier system for IGF-I (7). Although GH is known to regulate the hepatic synthesis of these peptides, IGFBP-3 and ALS concentrations do not reflect the 24-h spontaneous GH secretion as accurately as IGF-I does. It is well established that both IGFBP-3 and ALS are increased in acromegaly and reduced in GH deficiency, but results can be paradoxically normal in both diseases (8, 9, 10, 11, 12, 13). An altered status of GH secretion may be also reflected in a decreased free fraction of IGF-I, reported to be normally only 1% of the total IGF-I present in the circulation. Free IGF-I concentrations are elevated in the majority of patients with untreated acromegaly (14, 15, 16). In adult GHD, multiple regression analysis showed a significant correlation among free IGF-I concentrations and peak GH levels, disease duration, and residual pituitary function (17, 18). Nevertheless, the sensitivity of this marker seems to be affected by overlaps with normal levels both in acromegaly and GHD (16, 17, 18, 19).
Until recently, the possibility of detecting immunocomplexes involving combined components of the IGF system had not been investigated (20). The determination of combined multiple markers potentially improves the accuracy of IGF axis immunoassays, as IGF-I, IGFBP-3, and ALS are all individually GH dependent. Two novel assays, capable of detecting IGFBP-3 complexed with IGF-I or ALS, showed these complexes to be significantly correlated to other markers of the GH/IGF-I axis (20).
Our study aimed at determining the usefulness of multiple IGF markers in the diagnostic approach to GH-related disorders. To achieve this goal, we assessed the circulating levels of GH, total and free IGF-I, IGFBP-3, ALS, and IGFBP-3-IGF-I and IGFBP-3-ALS complexes in a population of acromegalic and adult GHD patients.
Subjects and Methods
Healthy controls
Blood samples were obtained from 58 subjects (34 women and 24 men; age, 18–74 yr) working in or referred to the Department of Endocrinology, University of Naples. All participants were reportedly free from any endocrine or nonendocrine disease.
Acromegalic patients
Eighty-three patients (47 women and 36 men; age, 22–73 yr) were diagnosed with acromegaly on the basis of signs and symptoms of disease, elevated GH levels (>2.5 µg/L) unsuppressed below 1 µg/L during an oral glucose tolerance test, high IGF-I concentrations, and radiological detection of pituitary adenoma. Patients were classified according to disease status: 67 patients (35 women and 32 men) were recruited at the time of diagnosis and were in the active disease stage. The remaining 16 (6 women and 10 men) were considered cured after pituitary surgery (all patients) and radiotherapy (n = 3): all exhibited normal GH levels in basal (<2.5 µg/L) and glucose-stimulated (<1 µg/L) conditions and the absence of residual tumor tissue on pituitary imaging.
Adult GHD patients
Thirty-four hypopituitary subjects (19 women and 15 men; age, 18–60 yr) had been previously subjected to transsphenoidal and/or transcranial surgery for pituitary tumor, craniopharyngioma, or meningioma, except for 2 patients affected with idiopathic GHD. Eight of 32 patients previously operated on had been also subjected to external radiotherapy. Diagnosis of GHD was based on the GH peak response to the provocative test with arginine plus GHRH below 9 µg/L, as previously described (21). Six patients suffered from diabetes insipidus. Twenty-three patients were suffering from other anterior pituitary deficiencies in addition to GH: ACTH in 2; FSH and LH in 8; ACTH, FSH, and LH in 9; and FSH, LH, ACTH, and TSH in 4. All patients with multiple deficits were undergoing adequate replacement therapy at the time of testing.
Study procedure
All subjects were included in the study after informed consent to participate and approval by the local ethics committee had been obtained. Subjects were analyzed under fasting conditions, while seated or recumbent. After blood drawing, samples were allowed to clot at room temperature and then were centrifuged, aliquoted, and stored at -80 C. Samples from each subject were run in duplicate. For GH measurements, individual values were calculated as follows: in normal subjects and acromegalic patients, the mean of three consecutive blood samples each drawn at 15-min intervals; in GHD patients, the maximal peak GH response to provocative tests (21).
Hormonal assays
All measurements were performed using assays provided by Diagnostics Systems Laboratories, Inc. (Webster, TX), except for the GH assay.
Serum GH levels were measured by immunoradiometric assay (IRMA; HGH-CTK, Sorin, Italy). The assay sensitivity was 0.15 µg/L; the intra- and interassay coefficients of variation (CVs) were 4.5% and 7.9%, respectively. Total and free IGF-I, IGFBP-3, and ALS levels were measured with noncompetitive sandwich-type assays. Total IGF-I IRMA was performed after extraction; the assay sensitivity was 0.8 µg/L; intra- and interassay CVs for the low, medium, and high points of the curve were 3.4%, 3%, and 1.5% and 8.2%, 1.5%, and 3.7%, respectively. IGF-I reference concentrations were 101–503, 100–494, 101–303, and 78–258 µg/L for ages of less than 30, 30–40, 40–50, and above 50 yr, respectively. The free IGF-I IRMA was performed without extraction; the assay sensitivity was 0.03 µg/L, and the intra- and interassay CVs for the low, medium, and high points of the curve were 10.3%, 5.1%, and 3.3% and 7.7%, 3.6%, and 10.7%, respectively. The IGFBP-3 IRMA had a sensitivity of 0.5 µg/L; the intra- and interassay CVs for the low, medium, and high points of the curve were 1.8%, 3.2%, and 3.9% and 1.9%, 0.5%, and 0.6%, respectively. IGFBP-3 reference values were 2000–7290, 1730–7260, 2080–4310, and 2020–3990 µg/L for ages of less than 30, 30–40, 40–50, and over 50 yr, respectively. The ALS enzyme-linked immunosorbent assay (ELISA) (11) had a sensitivity of 0.07 µg/mL; the intra- and interassay CVs for the low, medium, and high points of the curve were 6.1%, 7.5%, and 3.8% and 8.6%, 2.8%, and 8.9%, respectively. The serum concentrations of the IGFBP-3-IGF-I and IGFBP-3-ALS complexes were measured by two ELISAs, recently described (20). Results were expressed as arbitrary units (AU) per L, calculated from a pool of 10 normal human sera, which were assigned a value of 100 AU/L. The sensitivity of the IGFBP-3-IGF-I assay was 0.12 AU/L; the intra- and interassay CVs were 3.5–6.6% and 4.8–9.7%, respectively. The IGFBP-3-ALS assay sensitivity was 1.13 AU/L; the intra- and interassay CVs were 4.3–7.6% and 5.3–10.6%, respectively.
Data analysis
For each group, results are presented as the mean ± SEM. For statistical analysis, data from acromegalic and GHD patients were compared with the age-distributed ranges for healthy subjects, calculated by the simple least linear regression analysis, to express individual hormonal values as SD scores. The regression line represents the mean, and the prediction interval is represented by ±2 SD (residual deviation of the regression errors). To approximate a normal (Gaussian) distribution, data were introduced in the statistical analysis as log transformed. Unpaired Student’s t test or Mann-Whitney rank-sum test was used for comparisons. Correlation coefficients were determined from simple and multiple least linear regression analysis. The test sensitivity was estimated from the percentage of acromegalic patients with hormonal concentrations above +2 SD and from the percentage of GHD patients with hormonal concentrations lower than –2 SD for the normal values for age. Significance was set at P < 0.05. Statistical analyses were performed with SPSS 10.0 (SPSS, Inc., Chicago, IL).
Results
Healthy subjects
Mean and age-distributed hormonal values for all groups are
presented in Table 1
and Fig. 1. Total IGF-I (r = -0.54;
P < 0.001), ALS (r = -0.37; P <
0.01), IGFBP-3-IGF-I (r = -0.52; P < 0.001), and
IGFBP-3-ALS (r = -0.41; P < 0.01) concentrations
declined with age. IGF-I levels were higher in females than in males
(214 ± 19 vs. 177 ± 11 µg/L; P
< 0.05) and were positively correlated to both IGFBP-3 and ALS levels
(r = 0.59 and r = 0.67; P < 0.001 in both
cases). A positive correlation also existed between free IGF-I and
both total IGF-I (r = 0.40; P < 0.01) and the
IGF-I/IGFBP-3 molar ratio (r = 0.38; P < 0.01).
The free/total IGF-I ratio was below 1% in 48 subjects (83%). No
gender-related differences were observed for IGFBP-3 complexes.
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Active acromegaly. As expected, all IGF parameters tested
measured higher than those in controls (Tables 1
and 2, and Figs. 1 and 2). As in healthy subjects, age was
associated with a decline in serum IGF-I (r = -0.43;
P < 0.001), IGFBP-3 (r = -0.44;
P < 0.001), ALS (r = -0.40; P <
0.01), and IGFBP-3-ALS levels (r = -0.37; P <
0.01; Fig. 1). IGF-I and IGFBP-3 concentrations were above +2
SD, respectively, in all and in 57 of 67 patients
(sensitivities, 100% and 85%, respectively). A positive correlation
existed between these 2 markers (r = 0.83; P <
0.001). The IGF-I/IGFBP-3 ratio was higher than that in control
subjects (P < 0.001; Fig. 3).
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Inactive acromegaly. A progressive reduction of total (r
= -0.56; P < 0.001) and free IGF-I levels (r =
-0.51; P < 0.001) occurred with age (Fig. 1). In this
subgroup we observed the normalization of total IGF-I, IGFBP-3, ALS,
and IGFBP-3-IGF-I (sensitivity, 100% for all markers). In contrast,
free IGF-I levels remained above +2 SD in 11 of
16 cases (sensitivity, 31%), and the free/total IGF-I ratio was,
consequently, more than 1% in 6 cases. IGFBP-3-ALS levels were
normalized in 13 cases and were below -2 SD in
the 3 remaining patients (sensitivity, 81%; Table 1 and Figs. 1 and 2). We observed a significant correlation of free IGF-I with total
IGF-I (r = 0.60; P < 0.001), but not with the
IGF-I/IGFBP-3 ratio.
Adult GHD
All IGF parameters tested were significantly lower than those in
normal subjects (Tables 1 and 2, and
Figs. 1 and 2). Total (r = -0.34; P < 0.05) and
free IGF-I levels (r = -0.35; P < 0.05) declined
with increasing age (Fig. 1). IGF-I and IGFBP-3 concentrations were
below –2 SD in 14 and 16 patients
(sensitivities, 41% and 47%, respectively), 13 of whom had reached a
GH peak response in the combined stimulatory test below 3 µg/L (Table 3). As expected, a positive correlation
existed between IGF-I and IGFBP-3 concentrations (r = 0.64;
P < 0.001), and both markers were negatively
correlated to the number of anterior pituitary hormones impaired
(r = -0.57 and r = -0.51, respectively; P
< 0.01 in both cases). ALS concentrations were below –2
SD in 11 cases (sensitivity, 32%) and were well
correlated to both IGFBP-3 and IGF-I levels (r = 0.85 and r =
0.68; P < 0.001 in both cases). Overall, IGF-I
SD score, IGFBP-3 SD score,
and ALS SD score were significantly reduced in
patients with GH peak responses below 3 µg/L (Table 3) as well as in
patients previously irradiated (P < 0.05).
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By multiple regression analysis, the number of anterior pituitary
hormones impaired constituted the best predictive indicator of low
IGF-I, IGFBP-3, free IGF-I, IGFBP-3-IGF-I, and IGFBP-3-ALS values; in
contrast, ALS concentrations appeared to depend mostly on the GH peak
response to the provocative test (Table 4).
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The present study was designed to elucidate the diagnostic potential of the IGF system in adult GH disorders and to test the diagnostic accuracy of two combined GH-dependent markers recently developed. Our results show that all parameters tested were significantly increased in active acromegaly and reduced in GHD. There was a significant correlation among IGF-I, IGFBP-3, ALS ,and IGFBP-3-IGF-I concentrations in all groups evaluated, whereas total and free IGF-I were correlated only in the group of adult GHD patients. We observed that IGF-I measurements were highly reliable in the diagnosis of acromegaly. Conversely, the diagnostic significance of both IGF-I and IGFBP-3 measurements in adult GH deficiency was lower than that of the GH stimulatory testing. Finally, the concentrations of IGBP-3-IGF-I complex, free IGF-I, and ALS were more sensitive to GH excess than to GHD.
Acromegaly
The most accurate method for diagnosing acromegaly is a GH response greater than 1 µg/L to a glucose load (1, 3, 4, 5, 22). The employment of ultrasensitive assays allows discrimination of a lower GH threshold and optimizes diagnostic accuracy (23, 24, 25). However, postglucose suppression of GH levels seems not to definitely exclude active acromegaly (26). The diagnostic role played by IGF-I in acromegaly is well established (3, 4, 5, 25, 26) and was confirmed in the present study in both active and cured patients. Conversely, IGFBP-3 results were diagnostically unsuccessful in 10 active cases. Given the evidence that the measurement of IGFBP-3 concentrations, formerly proposed as a discriminatory indicator of acromegaly, can overlap normal levels in a considerable proportion of patients (9, 16, 26, 27), our results are in line with these observations.
One of our most striking observations was ALS and free IGF-I sensitivity in active acromegaly. ALS has been shown to reach concentrations 2.5-fold higher than those in controls (28) and to better predict the postoperative recurrence of acromegaly than does IGF-I (13). Some patients, however, can present with inappropriately normal ALS concentrations (11). In this study ALS sensitivity was generally lower than that of IGF-I in active acromegaly. This discrepancy could not be attributed to individual differences in age, disease duration, or GH levels. Conflicting results also exist regarding the usefulness of free IGF-I in acromegaly. Basal free IGF-I levels are usually elevated and generally correlate with both baseline and glucose-suppressed GH levels (14, 15, 16). Overlap with normal free IGF-I values has been reported in up to 73% of unsuccessfully treated acromegalic patients (16). In the current study a significant elevation of free IGF-I levels was found in as many as 94% of active patients, and as previously reported by van der Lely and co-workers (15), no correlation existed between free and total IGF-I levels. Despite these observations in active acromegaly, the utility of free IGF-I assays may be blunted by the persistence of high concentrations in the group of inactive acromegalic patients.
Adult GHD
Data analysis in GHD patients showed a greater variability of results. To date, no definitive conclusion exists on the reliability of the IGF system in diagnosing adult GHD. IGF-I is significantly decreased in childhood-onset GHD patients, and IGF-I reduction is generally greater in the case of organic pituitary disease, multiple hormonal insufficiencies, and younger onset age of GHD (29, 30, 31, 32, 33, 34). However, the occurrence of normal IGF-I values can occur in 34–70% of adult-onset GHD patients (30, 34, 35, 36, 37), and this result is confirmed in the present study. The diagnostic accuracy of IGFBP-3 measurements was slightly greater than that of IGF-I. In other studies, IGFBP-3 was shown to be more sensitive than IGF-I measurements in idiopathic GHD (38), but a comparison between the sensitivities of GH peak response and IGFBP-3 levels in short children did not confirm such a finding (39). Furthermore, up to 72% of adult-onset GHD patients can exhibit false negative IGFBP-3 results (18, 35, 37).
The impact of low GH levels on ALS and free IGF-I concentrations was even less clear. The age of onset and the severity of GHD have been proposed as determinant factors in reducing ALS levels (40, 41, 42). Despite the finding of low ALS levels in up to 72% of childhood-onset GHD patients (12), ALS concentrations in adult GHD have been found to overlap both normal and acromegalic values (11). We observed reduced ALS levels in only one third of cases; stratification of patients for GH peak response below 3 µg/L increased this percentage to 43% of cases. Similar figures were obtained for free IGF-I measurements. There is circumstantial evidence indicating that free IGF-I results vary depending on the assay techniques. Therefore, the reproducibility of data might depend on the methodology employed. By means of direct IRMA measurements, free IGF-I levels have been reported to be significantly reduced in over 70% of childhood-onset adult GHD patients (17) and to be below the lower normal limits in 52% of adult-onset GHD patients (18). Other researchers have reported results comparable to ours using ultrafiltration techniques (43).
IGFBP-3 complexes in acromegaly and adult GHD
One unique feature of the present study is the extensive evaluation of two novel immunoassays, recently generated by pairwise combination of anti-IGFBP-3 with anti-IGF-I (IGFBP-3-IGF-I complex) or anti-ALS (IGFBP-3-ALS complex) antibodies (20). The theoretical advantage of these assays resides in the ability of directly measuring the combined levels of several GH-dependent molecules in a single assay as well as reducing the effect of IGFBP-3 fragments and other IGFBPs. The present data confirm and extend previous findings. IGFBP-3-IGF-I levels appeared to be a reliable marker of acromegaly and reached mean concentrations 5.4-fold higher than those in controls; they were above +2 SD in 95% of patients. A lower sensitivity was shown for IGFBP-3-ALS complex. On the other hand, neither marker accurately distinguished adult GHD. The IGFBP-3-IGF-I ELISA is capable of quantifying any ALS-IGFBP-3-IGF-I ternary complex and any binary IGFBP-3-IGF-I complex that could be present in the circulation; the IGFBP-3-ALS ELISA interacts with both IGF-I- and IGF-II-based ternary complexes and, potentially, with any IGFBP-3-ALS combination. We cannot exclude, therefore, that the intrinsic immunoreactivity of the IGFBP-3-ALS ELISA as well as the dynamics of the ternary and binary complex in this condition (10) might contribute to the high IGFBP-3-IGF-I accuracy in acromegaly.
In conclusion, our data support the strong diagnostic role of IGF-I as marker of GH excess. IGFBP-3, ALS, and free IGF-I values provide complementary information, which can assist decision-making procedures in acromegaly. In agreement with previous studies, our findings in adult GHD patients indicate that a single ALS and free IGF-I determination does not offer significant diagnostic advantage over IGF-I and IGFBP-3 measurements. However, in the absence of a generally accepted gold standard test, it remains difficult to assess whether any marker can predict GHD better than the GH peak response to provocative testing. Finally, the results on IGFBP-3 complexes suggest that these markers, particularly the complex of IGFBP-3-IGF-I, can offer relevant information in diagnostic strategies for GH disorders and potentially open new diagnostic perspectives in conditions associated with GH/IGF-I alterations.
Footnotes
1 This work was supported in part by NIH Grants CA-58110 and
DK-51513. 
Received January 5, 2001.
Revised March 21, 2001.
Revised March 21, 2001.
Accepted April 5, 2001.
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), active (AA; •), and cured
(CA; 
) acromegalic patients and GH-deficient patients (GHD; 
).
