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Original Studies |
Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore Istituto Ricovero e Cura a Carattere Scientifico (M.A., G.F.), I-20122 Milan; and Department of Endocrinology and Metabolism, University of Genova (S.G., A.C., F.M., A.B.), and Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research (P.B.), I-16132 Genova, Italy
Address all correspondence and requests for reprints to: Dr. A. Barreca, Department of Endocrinology and Metabolism, University of Genova, Viale Benedetto XV, no 6. I-16132 Genova, Italy. E-mail: barreca{at}unige.it
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Abstract |
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The results demonstrated that in acromegaly before treatment all parameters (ALS, 523 ± 26; IGF-I, 129 ± 6; IGFBP-1, 0.7 ± 0.1; IGFBP-3, 234 ± 21; nmol/L; mean ± SEM) but IGFBP-2 were significantly different (P < 0.0001) from those in healthy subjects (ALS, 281 ± 4; IGF-I, 22 ± 1; IGFBP-1, 1.6 ± 0.1; IGFBP-3, 91 ± 3). IGF-I was more sensitive (100%) than ALS (89%), and both were more predictive of disease status than IGFBP-3, in that 27% of the patients had IGFBP-3 levels within the normal range. Considering the ALS/IGFBP-3 molar ratio, almost 55% of ALS circulated in a free form in active acromegaly. Before treatment, the IGF-I/IGFBPs (-1 + -2 + -3) molar ratio, which can be regarded as free, biologically active, IGF-I, was greatly increased (0.77 ± 0.06; P < 0.0001) compared with that in control subjects (0.23 ± 0.01).
After surgery, all 10 patients with controlled disease showed normalization of ALS (100% sensitivity), whereas 9 of them had normal IGFBP-3; reevaluation after varying lengths of time showed all these parameters within the normal range. In the 27 patients with active disease, IGF-I and ALS were more predictive of disease status (91% and 83% negative predictive values, respectively) than IGFBP-3 (53%).
The basal ALS concentration correlated only with IGFBP-3 (r = 0.70; P < 0.001). In postsurgery samples (first control) a statistically significant (P < 0.001) correlation was found between mean GH values as well as minimum GH after oral glucose tolerance test and ALS (r = 0.72 and 0.83, respectively), IGF-I (r = 0.69 and 0.77), IGFBP-3 (r = 0.50 and 0.72), and IGFBP-2 (r = -0.36 and -0.63). Similarly, IGF-I, IGFBP-3, and ALS were positively correlated among themselves and negatively correlated with IGFBP-2 (P < 0.001).
In conclusion, in the diagnosis of acromegaly, the measurement of total IGF-I appears to be the most sensitive parameter among the subunits of the 150K complex, and IGFBP-3 the least sensitive. For ALS, this subunit is quite sensitive and appears to be a useful parameter in reassessment after surgical treatment.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite the recognized GH dependence of the ALS and the stability of its circulating concentration, few data are currently available with regard to its reliability as a parameter of GH secretory status, and these are often conflicting (13, 14, 15). Experimental and clinical data demonstrate that the ALS, like IGF-I, is primarily under the control of GH (16, 17, 18). Except in critically ill patients (19, 20, 21), the ALS is relatively independent of mechanisms known to influence IGF-I and IGFBP-3 secretion (22), thus suggesting that it might be a more specific parameter of GH secretory status. Moreover, as its measurement is unaffected by IGFBPs, which may interfere in many conventional IGF-I assays (23), it could offer several advantages over IGF-I in monitoring the activity of acromegalic disease. However, ALS measurement is relatively recent, and data on ALS concentrations in acromegaly are very scarce (23, 24, 25).
The aim of the present study is to compare ALS levels in a group of healthy subjects with those of a group of patients with active acromegaly. The effects of both successful and unsuccessful pituitary surgery on ALS levels, as judged by GH suppression during an oral glucose tolerance test (OGTT), are also reported. The reliability of the ALS in acromegaly will be considered in comparison with other components of the GH-IGF-I axis: GH, IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty-five acromegalic patients (23 women and 22 men; age, 21–64 yr) who had undergone adenomectomy were included in this study. Acromegaly was diagnosed on the basis of clinical features, high serum IGF-I concentrations compared with the age-adjusted normal range, and elevated GH levels that were not suppressible to less than 1 µg/L during an OGTT (26). The duration of the acromegalic disease ranged from 1–20 yr (median, 6 yr). All patients were off medical therapy for acromegaly, two were receiving replacement therapy with T4, and none was taking glucocorticoids. Most patients had been newly diagnosed. Four patients who had received octreotide therapy (300 µg/day, sc) were assessed at least 1 month after therapy discontinuation. GH concentrations (mean of at least four fasting samples) were 23.6 ± 3.2 µg/L (±SEM), ranging from 2.6–78. 5 µg/L. In 37 patients PRL levels were within the normal range (<20 µg/L in women and <15 µg/L in men), whereas 8 patients had elevated PRL levels ranging from 23–108 µg/L. Gonadal function was normal in 15 men and 16 women. Six women were in the menopause and were not receiving hormone replacement therapy; 1 was amenorrheic. Seven men had reduced testosterone levels ranging from 2.4–9.1 nmol/L (normal range, 13–42). Two patients had diabetes mellitus: 1 was treated with insulin, and 1 with oral antidiabetic agents. In all patients the presence of a GH-secreting tumor was confirmed by immunohistochemical studies of surgically removed tissue.
Thirty-seven patients were reevaluated 1–6 months after surgery (first control). None of them had undergone medical therapy. Ten patients were considered controlled on the basis of GH suppression to less than 1 µg/L after OGTT and normal IGF-I concentrations compared with the age-adjusted normal range. In these 10 patients, the abnormal GH responses present before surgery (to TRH in 7, to sulpiride injected during dopamine infusion in 2, and to GnRH in 1) had also disappeared. One patient presenting with IGF-I level above the 97th percentile of the control group and nadir GH after OGTT below 1 µg/L was considered to have persistent disease. Two other patients, in whom GH decreased to 1 µg/L and not less than 1 after OGTT while abnormal GH responses were maintained, were not considered cured (27). Gonadal function normalized in 3 men and worsened in 2; all other anterior pituitary functions were unchanged. Antidiabetic therapies were unmodified.
In 4 of 10 patients with controlled disease and in 21 of 27 with active disease, further evaluation (second control) was performed 12–36 months after surgery. The uncontrolled group of patients was assessed while off medical therapy. Seven of these patients had undergone radiotherapy in the meantime.
One hundred age- and sex-matched healthy blood donors volunteered as
controls (Table 1
).
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Analytical methods
Serum GH levels were determined by an immunofluorimetric assay (AutoDelfia hGH, Wallac, Inc., Turku, Finland). The sensitivity of the assay was 0.01 µg/L; the intra- and interassay coefficients of variation were 2.6% and 3.9%, respectively.
IGF-I was measured by RIA using immunochemicals and tracer provided by Medgenix (Fleurus, Belgium). The sensitivity of the assay was 1.2 nmol/L; the intra- and interassay coefficients of variation were 6% and 7.5%, respectively. To avoid interference from binding proteins, single plasma ethylenediamine tetraacetate samples were treated with acid-ethanol according to the method of Daughaday et al. (28).
Serum total ALS was measured by means of specific two-site sandwich enzyme-linked immunosorbent assay, using anti-ALS antibodies raised against synthetic amino-terminal and carboxyl-terminal ALS peptides, and reagents and tracer provided by Diagnostics Systems 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/L; the intra- and interassay coefficients of variation were 5.5% and 7.2%, respectively. Recovery of human serum-derived glycosylated ALS [purified as described previously (6)] was 75% for the lower concentration added (1 µg) and 95% for the higher concentration added (60 µg).
IGFBP-1 was measured by immunoradiometric assay, using reagents and tracer provided by Diagnostics Systems Laboratories, Inc. The sensitivity of the assay was 0.05 nmol/L; 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, as described by Clemmons et al. (29). 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/L; 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 Diagnostics Systems Laboratories, Inc. All samples were diluted appropriately so as to reach a point in the curve where there is parallelism among unglycosylated Escherichia coli-derived IGFBP-3, glycosylated Chinese hamster ovary-derived IGFBP-3, and serum (%B/B0, 70–85%). The sensitivity of the assay was 0.04 nmol/L; the intra- and interassay coefficients of variation were 3.25% and 5.6%, respectively.
Statistical analysis
Statistical analysis was performed by nonparametric test on paired (Wilcoxon signed rank test) and unpaired (Mann-Whitney test) observations. P < 0.05 was considered significant. Results are expressed as the mean ± SEM. The correlations among all parameters studied were evaluated using Spearman rank order statistics and linear regression analysis models. For this purpose, log-transformed values of GH and IGFBP-3, which showed a log normal distribution, were used. The 97th percentile of the normal distribution calculated for each age group in the healthy subjects was chosen as the cut-off point for normal serum levels of all parameters of the IGF system. Because normal levels are largely arbitrary and vary according to laboratory, we investigated the diagnostic accuracy of each parameter at different cut-off points by determination of the receiver-operating characteristic (ROC). All statistical analyses were made using SPSS statistical software (SPSS, Inc., Chicago, IL).
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Results |
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The mean concentrations of the different parameters are shown in
Table 1
and Fig. 1. Analytical
distribution of age and single values of IGF-I, IGFBP-3, and ALS are
shown in Fig. 2.
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Acromegalic patients: before surgery
In the group of acromegalic patients ALS levels were elevated
before transsphenoidal surgery (Table 1 and Figs. 1 and 2). ALS levels
were higher than the 97th percentile of healthy subjects in 40 patients
(89%). One of the 5 patients in whom ALS levels were below the 97th
percentile of healthy controls also showed the lowest concentration of
GH (mean value, 2.6 µg/L) and response after OGTT (1.4 µg/L). IGF-I
concentration, although always above the normal range for age, tended
to be lower in these patients than in patients with high ALS levels.
All 5 also showed IGFBP-3 below the 97th percentile and IGFBP-2 levels
in the higher range concentration. The basal ALS concentration
correlated with IGFBP-3 (r = 0.70; P < 0.001). No
correlation with age, GH, IGF-I, IGFBP-1, IGFBP-2, or tumor size was
observed in untreated acromegalic patients. No differences according to
gender, PRL levels, or gonadal status were observed.
IGF-I levels were elevated in all patients compared with those in
normal controls (Table 1 and Figs. 1 and 2), ranging from 60–197
nmol/L. The IGF-I/IGFBPs (-1 + -2 + -3) molar ratio was
significantly (P < 0.001) higher (0.77 ± 0.1)
than that in normal subjects (0.23 ± 0.01). In contrast with
healthy subjects, the IGF-I concentration did not decrease with age. A
significant correlation was found between IGF-I and GH mean
concentrations and nadir value after OGTT (r = 0.44 and 0.59;
P < 0.01).
IGFBP-3 levels ranged from 67–717 nmol/L (Table 1 and Figs. 1 and 2).
About two thirds of the patients showed high IGFBP-3 concentrations,
whereas 12 (27%) had IGFBP-3 levels in the normal range. No
correlations were found with the parameters evaluated, apart from
ALS.
IGFBP-1 concentrations ranged from 0.08–2.46 nmol/L and were
significantly lower than IGFBP-1 levels in normal controls (Table 1 and
Fig. 1).
IGFBP-2 levels ranged from 1.44–26.37 nmol/L and were not
statistically different from those in controls (Fig. 1). However, with
regard to the IGFBP-2/IGF-I molar ratio, 95% of patients showed a
value below the third percentile of that in healthy subjects.
None of the parameters considered, apart from GH concentration (P < 0.01), correlated with the size of the adenoma.
Information on the discriminatory ability of each parameter evaluated
by ROC curve analysis (Fig. 3) was in
close agreement with the estimates obtained using the cut-off points
from normal controls (97th percentile).
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Acromegalic patients: reevaluation after surgery
Thirty-seven patients were reevaluated after transsphenoidal
surgery. Mean levels of the different parameters before and after
surgery are shown in Fig. 1. All parameters showed the expected
modifications after removal or reduction of the adenoma; GH, IGF-I, and
IGFBP-3 decreased, whereas IGFBP-1 and IGFBP-2 increased. The
sensitivity, specificity, and positive and negative predictive values
of ALS, IGF-I, and IGFBP-3 in identifying patients with controlled and
active disease are shown in Table 2.
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and Table 2). In 4 controlled patients, reevaluation after
varying lengths of time (control 2) showed IGF-I, IGFBP-3, and ALS
concentrations in the normal range.
Twenty-six of the 27 patients in whom surgery was unsuccessful had
elevated IGF-I concentrations, whereas 2 (7%) and 8 (30%) showed
normal ALS and IGFBP-3, respectively (Fig. 2 and Table 2). Reevaluation
of the only patient who had presented with IGF-I, IGFBP-3, and ALS
concentrations at the upper end of the normal range at the first
control revealed increased concentrations of IGF-I and ALS, but not
IGFBP-3. The other patient with ALS below the normal range, but IGF-I
above the 97th percentile of the control group, showed a nadir GH less
than 1 µg/L after an OGTT and normal IGFBP-3. Reevaluation of this
patient showed normalization of all parameters, including IGF-I
concentration. Therefore, in 20 of 21 patients who were reevaluated
(control 2), elevated concentrations of IGF-I and ALS persisted,
ranging from 60–120 and from 382–976 nmol/L, respectively, whereas
IGFBP-3 levels were normal in 5 patients.
IGFBP-1 levels increased slightly, although not significantly, in both
controlled and uncontrolled patients (Fig. 1).
IGFBP-2 levels and IGFBP-2/IGF-I ratio increased significantly only in
the group of controlled patients (Table 1 and Fig. 1). All patients
with controlled disease showed a significantly increased
(P < 0.001) IGFBP-2/IGF-I ratio in both postsurgical
follow-up examinations, whereas 23 of 26 patients with active disease
showed a ratio lower than the third percentile of that of the normal
population.
In postsurgery samples (first control) a statistically significant
(P < 0.001) correlation was found between mean GH
values (Fig. 4) as well as minimum GH
after OGTT and ALS (r = 0.72 and 0.83, respectively), IGF-I
(r = 0.69 and 0.77), IGFBP-3 (r = 0.46 and 0.67), and IGFBP-2
(r = -0.36 and -0.63). Similarly, IGF-I, IGFBP-3, and ALS
were positively correlated among themselves and negatively correlated
with IGFBP-2 (P < 0.001).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study, carried out by comparing a large number of acromegalic patients with 100 healthy adults, shows that active acromegaly is characterized by elevated ALS concentrations. Previous data are concordant with our finding that ALS levels in acromegalic patients are about twice those present in normal subjects. Indeed, using an antibody raised against serum-derived glycosylated ALS, Baxter (24) first showed that ALS levels were elevated in acromegalic patients and, using the same RIA, Hoffman et al. (15) reported mean ALS levels 2.5-fold above the normal mean and 91% of patients with values above the normal range. More recently, using the same two-site sandwich enzyme-linked immunosorbent assay as we used, Khosravi et al. (25) found mean ALS levels in 20 acromegalics about 1.6-fold above the mean of control value, and 80% of patients above the normal range. In the 45 acromegalic patients evaluated in this study, pathological ALS levels were found in 89% of patients before treatment. In the remaining 5 patients, we could not find any known cause shared by all to justify ALS levels within the normal range. However, we cannot exclude that the complex regulatory mechanisms modulating the circulating levels of the 150K complex (16, 17, 18, 19, 20, 21, 22) might differently affect the synthesis of each subunit, at least in some patients. Nevertheless, in this subset of patients GH levels and IGF-I concentrations tended to be lower, and IGFBP-2 levels higher, than in patients with pathological ALS levels. The finding that all of them also showed IGFBP-3 below the normal range confirms the close association of these two components of the 150K complex. Indeed, the findings that multiple linear regression analysis indicates that ALS is the factor most closely associated with IGFBP-3 concentration (P < 0.005) and that ALS/IGFBP-3 molar ratio found in acromegalic patients does not differ significantly from that seen in normal subjects are in agreement with the hypothesis that much of the apparent GH dependency of serum IGFBP-3 might be secondary to its stabilization by ALS (32). Considering the ALS/IGFBP-3 molar ratio, almost 55% of ALS should circulate in a free form in acromegaly. In agreement with data reported by Juul et al. (33), not only the IGF-I/IGFBP-3 molar ratio but also the IGF-I/IGFBPs (-1 + -2 + -3) ratio, which can be regarded as free, biologically active, IGF-I, was greatly increased in patients with active acromegaly. This increase was more closely related to the increased IGF-I synthesis and the elevated IGF-I/IGFBP-3 molar ratio than to the reduction of the IGFBPs negatively regulated by GH. Indeed, IGFBP-2 was unchanged, and IGFBP-1 was, on the average, only half that seen in control subjects.
In the acromegalic patients before treatment, the levels of total IGF-I and IGFBP-3 were increased in 100% and 73% of patients, respectively. The finding regarding the poor reliability of IGFBP-3 in the diagnosis of acromegaly is in agreement with several previous reports showing that from 26–45% of patients have IGFBP-3 levels overlapping with those of healthy controls (11, 12, 34, 35), although in one study (36) elevated levels of IGFBP-3 were found in all 18 untreated acromegalic patients.
In postsurgical reassessment of the disease, it is noteworthy that ALS shows a positive predictive value equal to that of IGF-I (100%) and a negative predictive value slightly lower (83%) than that of IGF-I (91%), whereas IGFBP-3 again shows the lowest sensitivity and specificity.
Although GH exerts an inhibitory effect on the synthesis of IGFBP-1 as well as IGFBP-2 (29, 38), IGFBP-1 is not usually considered, because, unlike IGFBP-3 and IGFBP-2, it shows marked diurnal variations due to changes in metabolic status (38). Moreover, owing to its short half-life and lower circulating levels, IGFBP-1 does not usually play an important role in stabilizing circulating IGFs (39). The observation that IGFBP-1 levels were lower in acromegaly than in normal subjects is in agreement with previous reports (33, 40, 41) and with the known inhibition of this parameter by insulin (38). After surgery, IGFBP-1 levels increased, reaching statistical significance only in the group of controlled patients. Jørgensen et al. (41) found serum IGFBP-1 levels to be slightly supernormal after adenomectomy; this finding was not confirmed by our data, according to which IGFBP-1 only normalized.
Although IGFBP-2 levels significantly lower than those in healthy subjects have been reported in acromegalics (33, 41, 42), our data, in agreement with those reported by Clemmons et al. (29), showed IGFBP-2 concentrations not significantly different from those found in a large group of normal subjects. With regard to the IGFBP-2/IGF-I molar ratio, 94% of patients showed a ratio below the third percentile of healthy subjects, and this ratio normalized in controlled patients. After surgery, IGFBP-2 greatly increased in the group of controlled patients, without any significant change in not controlled patients, thus suggesting that elevated GH and IGF-I indeed have an effect on IGFBP-2.
In postoperative samples, GH secretion (mean values as well as nadir GH after OGTT) correlated mostly with ALS and IGF-I and to a lesser extent with IGFBP-3. Our previous finding of a log-linear correlation between GH and IGF-I (2) is further corroborated by this study and extended to the ALS subunit and to IGFBP-3.
In conclusion, our data show that active acromegaly is characterized by elevated ALS concentrations as well as elevated total and free IGF-I levels. Mean levels of IGFBP-3 were also higher, whereas levels of IGFBP-1 were lower than those in normal subjects. However, one quarter of the patients had IGFBP-3 levels in the normal range, and most of these showed normal IGFBP-1 and IGFBP-2 concentrations. These observations are equally true when considering newly diagnosed patients and patients with active disease after pituitary surgery. Therefore, in the diagnosis of acromegaly, the measurement of total IGF-I appears to be the most sensitive parameter among the subunits of the 150K complex, and IGFBP-3 the least sensitive. For what concerns ALS, this subunit is seen to be quite sensitive and appears to be a useful parameter in reassessment after surgical treatment.
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Footnotes |
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Received April 3, 2000.
Revised August 15, 2000.
Revised October 12, 2000.
Accepted November 22, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) subunit of the high molecular
weight insulin-like growth factor-binding protein complex. J Clin
Endocrinol Metab. 70:1347–1353.[Abstract]
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