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Division of Endocrinology (R.A.F., J.A.M.J.L.J., P.U., L.J.H., S.W.J.L., A.J.v.d.L., W.W.d.H.), Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; Neuroendocrine Unit (M.B.), Innenstadt University Hospital, 80336 Munich, Germany; and Division of Clinical Endocrinology (C.J.S.), Department of Medicine, Charite Campus Mitte, 10117 Berlin, Germany
Address all correspondence and requests for reprints to: R. A. Feelders, M.D., Ph.D., Erasmus Medical Center Rotterdam, Department of Internal Medicine, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: r.feelders{at}erasmusmc.nl.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective of this study was to define the optimal time point of postoperative evaluation by serial measurements of glucose-suppressed GH levels [oral glucose tolerance test (OGTT)] and the GH-dependent parameters IGF-I, free IGF-I, acid labile subunit (ALS), and GH-binding protein (GHBP).
Design: We describe a prospective study with 1-yr follow-up.
Setting: The study was conducted at a university hospital.
Patients: Seventeen patients with acromegaly were included in the study.
Main Outcome Measures: The main outcome measures were OGTT results at 1, 2, 3, 8, and 12 wk after TA; weekly measured GH, (free) IGF-I, ALS, and GHBP levels up to 12 wk; and total IGF-I levels measured at 52 wk.
Results: Postoperatively, nine patients were in remission with an OGTT GH nadir of less than 0.5 µg/liter and normalized IGF-I levels, whereas eight patients had persistent acromegaly. In both cured and noncured patients, OGTT results at 1 wk after TA were highly reproducible over time. In contrast, early postoperative IGF-I levels fluctuated and only stabilized at 12 wk. In all cured patients, free IGF-I levels rapidly normalized within 2 wk after TA (specificity, 100%). Preoperative ALS levels were elevated in all patients and normalized only in the cured patients after TA (specificity, 89%). Preoperative GHBP levels were low and increased from 2 wk after surgery.
Conclusions: We show that in the postoperative evaluation of patients with acromegaly, already 1 wk after surgery, an OGTT using 0.5 µg as the GH nadir cutoff value has a high predictive value for cure, whereas early IGF-I levels show varying patterns toward stabilization. Therefore, IGF-I should be measured as a predictive parameter not within 3 months after surgery. Free IGF-I and ALS levels may have an additional value in the postoperative assessment of disease activity.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The optimal postoperative timing for assessment of disease activity using these criteria has not, however, been established. Only a limited number of studies have repeatedly examined glucose-suppressed GH levels and/or IGF-I levels after pituitary surgery. Available data are contradictory with respect to the predictive value of an early-performed OGTT (4, 5, 6, 7). Furthermore, little data exist on when IGF-I levels stabilize after pituitary surgery. IGF-I levels can normalize early after successful adenomectomy, i.e. within 1 wk (5), but late stabilization, up to 12 months, has also been reported (5, 6, 8). Generally, it is recommended to measure IGF-I levels around 3 months after surgery (2). However, no prospective studies with serial postoperative IGF-I measurements have been performed.
Only a limited number of studies have addressed other GH-dependent parameters for the (postoperative) evaluation of the GH-IGF-I axis in acromegaly, including free IGF-I, IGF-BP3, acid labile subunit (ALS), and GH binding protein (GHBP). In circulation, the majority of IGF-I is bound in a 150- to 200-kDa ternary complex to the GH-dependent BPs IGF-BP3 and ALS (9). In active acromegaly, IGF-BP3 levels show a considerable variance with a significant overlap between controls and patients (10, 11). ALS levels, however, are elevated in most patients with active acromegaly (12, 13, 14, 15), and in one study, ALS levels showed a sensitivity and specificity comparable to IGF-I in the postoperative assessment of disease activity (14).
Approximately 1% of total IGF-I in serum is present in an unbound form, and this free IGF-I fraction may represent the biologically active fraction, analogous to free thyroid and steroid hormone concentrations (16). In the majority of acromegalic patients, free IGF-I levels are elevated (17, 18, 19). However, the postoperative kinetics of free IGF-I and its predictive value for cure are unknown.
Finally, measurement of GHBP levels may be useful to assess disease activity in acromegaly. GHBP is the soluble extracellular part of the GH receptor, and GHBP levels are inversely related to GH secretion (20). Indeed, GHBP levels are low in acromegaly (21, 22, 23). The time course and diagnostic value of GHBP after pituitary surgery have not, however, been extensively investigated.
We have conducted a prospective study in surgically treated patients with acromegaly with serial measurements of glucose-suppressed GH concentrations and IGF-I levels to define optimal timing for postoperative assessment of cure. Secondly, we investigated the postoperative kinetics and the diagnostic potentials of free IGF-I, IGF-BP3, ALS, and GHBP.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Seventeen patients with newly diagnosed acromegaly were included, 11 male and 6 female, with a mean age of 53.7 ± 2.9 yr (range, 35–72 yr). Twelve patients had microadenoma, whereas five patients had macroadenoma. All patients were treated by transsphenoidal adenomectomy, and no patient was pretreated with somatostatin analogs or dopamine agonists. Perioperatively, patients were treated with hydrocortisone (100 mg/24 h), which was tapered and subsequently stopped at the fourth day after surgery. Female subjects did not use oral contraceptives or estrogen substitution during the entire study period. No patient had overt diabetes mellitus. Preoperatively, two patients with a macroadenoma had pan-hypopituitarism, which was treated by hydrocortisone-, thyroxine-, and testosterone-replacement therapy. Postoperatively, secondary hypogonadism occurred in three male patients and secondary hypothyroidism developed in one female patient, with all patients being treated from wk 2. All studies were performed according to the rules of the hospital medical ethics committee. Informed consent was obtained from all patients.
Test protocol
Blood was sampled at baseline and postoperatively every week until 12 wk for measurement of GH, IGF-I, free IGF-I, IGF-BP3, ALS, and GHBP concentrations. IGF-I levels were also measured at 1 yr after surgery. Each patient underwent OGTT at baseline and postoperatively at 1, 2, 3, 8, and 12 wk. OGTT was performed as follows: after an overnight fast and while seated, 100 g of glucose was administrated orally, and blood was sampled at baseline and at 30, 60, 90, 120, 150, 180, and 240 min for GH measurement. Postoperatively, patient groups were defined as follows: group 1 included patients who were in remission, defined by a GH nadir in the OGTT of less than 1 µg/liter. According to IGF-I levels, patients in group 1 were arbitrarily subdivided into those with IGF-I levels of less than 0.8x the upper limit of the age- and gender-normalized range (ULN) (1A) and those with high-normal IGF-I levels between 0.8 and 1.2x ULN (1B) at 12 wk postoperatively; group 2 included patients with active acromegaly with a GH nadir of more than 1 µg/liter and/or IGF-I levels of more than 1.2x ULN.
Assays
GH levels were determined using a nonisotopic, automatic chemiluminescence immunoassay system (Immulite; Diagnostic Products Corp., Los Angeles, CA) with an analytical sensitivity of 0.01 µg/liter. The normal range in healthy adults was 0.06–5.0 µg/liter. The intra- and interassay coefficients of variation (CV) of this assay are 6.0 and 5.7%, respectively.
IGF-I levels were measured by two assays. The first assay concerns a commercially available nonextraction immunoradiometric assay (IRMA) supplied by Diagnostic Systems Laboratories, Inc. (Webster, TX). The intra- and interassay CV for this assay amounted to 3.9 and 4.2%, respectively. Age- and gender-adjusted reference ranges were provided by the manufacturer, and the ULN was defined as mean + 2 SD. Secondly, IGF-I levels were measured by the automated Advantage chemiluminescent IGF-I assay system (Nichols Diagnostics Institute, Bad Nauheim, Germany). For this method, samples are acidified to separate IGF-I from its BP, IGF-BP3. To prevent reaggregation of IGF-I and IGF-BP3, and thus to exclude interference of IGF-BP 3, the acidified samples are incubated with an excess of IGF-II. The intraassay CV was 11.5, 5.1, and 3.5% at concentrations of 42, 262, and 522 ng/ml, respectively. At the same concentrations, between-assay CV was 10.6, 10.6, and 10.2%. The lower limit of quantification was 17 ng/ml, and the linear range was 17–1000 ng/ml. The ULN was defined as mean + 2 SD of the age- and gender-adjusted reference ranges as published by Brabant et al. (24).
Free IGF-I levels were measured with a commercially available IRMA (Diagnostic Systems Laboratories). This assay was carried out in a blinded manner, and quality control samples were included within assay runs. Interassay and intraassay CV for free IGF-I were 10.3 and 10.7%, respectively. Age- and gender-adjusted reference ranges were adapted from those of reported in Ref.25 .
IGF-BP3 levels were measured by IRMA (Diagnostic Systems Laboratories). Interassay and intraassay CV for IGF-BP3 were 1.0 and 3.0%, respectively. Age- and gender-adjusted reference ranges were provided by the manufacturer.
Serum ALS levels (milliunits per liter) were measured in duplicate by sandwich immunometric assay using monoclonal antibodies directed against specific N- and C-terminal oligopeptides (26). A serum pool of healthy male volunteers was used for calibration and assigned 1000 U/liter. The assay range is 500-5000 U/liter, and the intra- and interassay CV were less than 9%. All samples from an individual subject were analyzed in one run.
Serum GHBP levels (picomoles per liter) were measured by a modification of the ligand immunofunctional assay (27) with an in-house monoclonal anti-GHBP antibody. Within-assay CV were 9.4% at 115 pmol/liter and 6.1% at 1550 pmol/liter. At the same concentrations, between-assay CV were 8.5 and 10.9%, respectively. The lower limit of quantification was 19 pM, and the linear range was 19–3500 pM. All samples from an individual subject were analyzed in one run. The reference range was established by GHBP measurement in serum samples from 234 healthy subjects, 101 males and 133 females, with an age range from 20–89 yr. The 5th and 95th percentile were used as lower and upper limits of normal and were 303 and 2249 pmol/liter for males and 455 and 2633 pmol/liter for females.
Statistics
Data are presented as mean ± SEM. Statistical analysis was performed by the Mann-Whitney U test for comparison of parameters between groups or between different time points. Correlations between parameters were evaluated by Spearman rank correlation.
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Results |
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Mean GH nadir in the preoperative OGTT was 8.5 ± 1.8 µg/liter. According to the postoperative GH nadir, patients were classified into two groups using 1 µg/liter as the cutoff value. Group 1 consisted of nine patients with a GH nadir of less than 1 µg/liter. Based on weekly measured IGF-I concentrations, two subgroups were arbitrarily defined with IGF-I levels of less than 0.8x ULN (group 1A, n = 4) and with high-normal IGF-I levels, i.e. between 0.8 and 1.2x ULN (group 1B, n = 5), at 12 wk postoperatively (Fig. 1
). In all patients, the GH nadir was less than 1 µg/liter from the first postoperative OGTT at 1 wk after surgery, with a low intraindividual variation during the study period. Mean GH nadir at all time points was 0.3 ± 0.1 µg/liter. At 12 wk, the GH nadir was 0.2 µg/liter or less in all but two patients, who had a GH nadir of 0.5 µg/liter. Shown in Fig. 2 are basal GH levels, which were less than 1 µg/liter from 1 wk postadenomectomy in all patients.
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). Postoperatively, a GH nadir of less than 1 µg/liter was measured in two patients, with mean values of 0.6 and 0.9 µg/liter, respectively. Mean basal GH levels varied between 3 and 5 µg/liter after surgery (Fig. 2). During postoperative OGTTs, the GH nadir occurred between 60 and 120 min in all patients. Therefore, 120 min, instead of 240 min, seems to be an adequate test duration. Postoperatively, a correlation was found between GH nadir values and IGF-I levels in all patients (r = 0.76, P < 0.0001).
Stabilization of IGF-I and individual IGF-I profiles
The postoperative time course of IGF-I levels in groups 1A and 1B (postoperative GH nadir of less than 1 µg/liter) was characterized by a marked decrease in the first week after transsphenoidal adenomectomy, followed by a gradual stabilization to the defined values of less than 0.8x ULN and between 0.8 and 1.2x ULN respectively (Fig. 1). In nearly all patients, these IGF-I levels were reached at 12 wk, which were lower compared with those measured at 1 wk (P < 0.01). After 1-yr follow-up, IGF-I levels in groups 1A and 1B did not change significantly, with mean values of 0.7x ULN and 1.0x ULN, respectively. In patients with persistent acromegaly, mean IGF-I levels initially decreased and stabilized from 2 wk after surgery. However, in both cured and noncured patients, individual IGF-I profiles showed a considerable variation. For each group, Fig. 3 shows three examples of individual IGF-I patterns with early, intermediate, and late stabilization.
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The correlation between IGF-I measurements performed by the IRMA-Diagnostic Systems Laboratories (DSL) and the Nichols assay is shown in Fig. 4. The obtained IGF-I results from both assays were strongly correlated (r = 0.90, P < 0.0001), in particular in the range up to 1000 ng/ml.
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Free IGF-I concentrations are shown in Fig. 5. Preoperatively, free IGF-I concentrations were elevated in 15 of 17 patients (sensitivity, 88%). In all patients with a postoperative GH nadir of less than 1 µg/liter, free IGF-I levels showed an acute fall into the normal range in the first week after surgery and were less than 80% of ULN at 12 wk postsurgery (specificity, 100%). In patients with persistent acromegaly, mean free IGF-I levels initially decreased postoperatively toward the ULN but subsequently increased to levels above normal from wk 8 and onwards, which were higher compared with group 1 (P < 0.01). At 12 wk, two patients had free IGF-I values of less than 80% ULN (sensitivity, 75%). Correlations between free IGF-I and total IGF-I, IGF-BP3, and ALS are shown in Fig. 6.
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Preoperative and postoperative IGF-BP3 levels are shown in Fig. 7. At baseline, IGF-BP3 levels were elevated in 14 of 17 patients (sensitivity, 82%). Postoperatively, IGF-BP3 levels decreased in all patients and were slightly higher in group 2.
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ALS levels were elevated in all patients at baseline (sensitivity, 100%) (Fig. 8) and showed a sharp decrease in the first week after transsphenoidal adenomectomy. In patients with a postoperative GH nadir of less than 1 µg/liter, ALS levels stabilized from wk 9 and onwards at levels just below the ULN in all but one patient (specificity, 89%). In patients with persistent acromegaly, ALS levels showed an initial decrease, without reaching the normal range, followed by a sustained increase to 197 ± 29% of ULN at 12 wk (P < 0.001 compared with group 1). At 12 wk, ALS levels were above the ULN in all noncured patients (sensitivity, 100%).
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Preoperative and postoperative GHBP levels are shown in Fig. 9. Before treatment, GHBP levels were in the lower segment of the normal range in most patients. In group 1, mean postoperative GHBP levels showed a gradual increase to approximately 50% of the ULN, stabilized after 6 wk, and were higher compared with group 2 (P < 0.05). There was, however, a considerable overlap between cured and noncured patients. In all patients, an inverse relation was found between GHBP and GH concentrations (r = –0.59, P < 0.0001).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Postoperative evaluation of patients with acromegaly by combined assessment of glucose-suppressed GH levels and IGF-I levels is considered to be the most comprehensive approach (1). However, definite biochemical criteria for remission have not been fully established and are still evolving by fine tuning of analytical methods, normative data, etc. As a result, discrepancies in test results can be anticipated, with patients showing either persistent GH dysregulation but normalized IGF-I levels or adequate GH suppression but elevated IGF-I levels (1, 8, 28, 29, 30).
For the GH nadir in the OGTT, we used 1.0 µg/liter as the cutoff value according to the consensus article by Giustina et al. (2). It could be argued, however, that this cutoff value should be adjusted to a lower level, because several studies using sensitive GH assays have shown that in normal subjects, the mean GH nadir after an oral glucose load is less than 0.3 µg/liter, with upper limits ranging from 0.05–0.7 µg/liter (3, 29). Furthermore, in a subset of acromegalic patients, postglucose GH levels of less than 1.0 µg/liter can be measured (11, 31). However, in all cured patients, we measured values of 0.5 µg/liter or less, which would also fit an adjusted criterion for GH suppression. Two noncured patients had a GH nadir of less than 1.0 µg/liter but more than 0.5 µg/liter. Therefore, it seems rational to adjust the cutoff value to a lower level. However, this would require establishment of new normative data for glucose-suppressed GH levels by currently available GH assays.
Subsequently, based on IGF-I levels at 12 wk postoperatively, patients in our study were, arbitrarily, classified in a clear remission group, a clear active group, and a group representing a gray zone, with a GH nadir of less than 1 µg/liter and IGF-I levels that were around the ULN. The rationale of this classification is that, in our opinion, patients with IGF-I levels in the upper part of the normal range cannot simply be defined as cured or noncured. Firstly, we observed that IGF-I levels fluctuated in the early postoperative period around the ULN in this group, which implies that if the ULN is used strictly to assess disease activity, a patient would be alternately judged as cured or noncured. Secondly, the analytical precision should be implicated in the interpretation of IGF-I results. Most assays have intra- and interassay CV of less than 10%, but again, if the IGF-I level is just below the ULN, the value should be interpreted with a certain margin that can exceed the ULN.
How can the coexistence of apparently normal GH suppression and high-normal IGF-I levels be explained in the gray-zone group? On the one hand, two of five patients had a GH nadir of 0.5 µg/liter, which may indicate subtle GH hypersecretion considering GH nadir values in healthy controls. Indeed, Freda et al. (11) showed that in a cohort of postoperative patients with elevated IGF-I levels, GH nadir values were between 0.33 and 1.0 µg/liter in nearly 50%. On the other hand, we measured GH nadir levels of 0.2 µg/liter or less in the other patients and after 1-yr follow-up, IGF-I levels were still around the ULN in all patients, which would not point to late-disease recurrence. Furthermore, the age-adjusted normal range of IGF-I is wide, and the measured IGF-I levels around the ULN may represent the normal IGF-I level of the individual according to a personal set point.
Timing of postoperative assessment
No prospective studies have been performed on the optimal timing of postoperative assessment of acromegalic patients. With respect to the OGTT, available data are conflicting, because an early OGTT, i.e. performed within 4 wk postoperatively, was found to be less reliable to predict cure compared with an OGTT performed at 3 months in one study (7), whereas others showed that the early OGTT may have a high predictive value for long-term outcome (4, 5, 6). Limitations of these studies are the low number of OGTTs performed (4, 6, 7), i.e. only once or twice, and the absence of standardized time points of measurement within one study (4, 6, 8). With respect to IGF-I levels, reported postoperative stabilization periods range from 1 wk to 12 months (5, 6, 8). But again, studies with frequent IGF-I measurements are lacking.
We show that an OGTT performed at 1 wk after pituitary surgery is reproducible over time and is highly predictive for cure because in both cured and noncured patients, the initial postoperative pattern of GH suppression persisted during the entire study period. This indicates that neurohumoral GH regulation can recover rapidly after successful transsphenoidal adenomectomy. In contrast, postoperative individual IGF-I profiles did vary significantly until 12 wk, and in both cured and noncured patients, patterns with early, intermediate, and late stabilization could be recognized. Assessment of IGF-I levels to evaluate cure should, therefore, not be performed within 12 wk after pituitary surgery.
It is remarkable, however, that there is a discrepancy in time between normalization of GH regulation and stabilization of IGF-I levels. One possible explanation could be the recovery of GH sensitivity. We have observed that initially suppressed GHBP levels increase after surgery, reflecting an increase in hepatic GH-receptor expression (20). It might, therefore, be speculated that the transition from a relatively GH-resistant state toward normalization of GH sensitivity is accompanied by fluctuating IGF-I patterns until a new equilibrium between GH secretion and GH responsiveness is established.
Additional GH-dependent parameters
In line with previous studies (17, 18, 19), we found elevated free IGF-I levels in most untreated acromegalic patients. Interestingly, in all patients with a postoperative GH nadir of less than 1 µg/liter, including those with total IGF-I levels around the ULN, free IGF-I levels decreased rapidly, preceding normalization of total IGF-I levels. Measurement of free IGF-I levels can, therefore, be useful in the postoperative evaluation, in particular when OGTT and total IGF-I results are discordant.
With respect to IGF-I BPs, we found that IGF-BP3 levels did not sufficiently discriminate between remission and active disease, as has been shown before (10, 11). In contrast to this, using ALS levels, disease activity of acromegaly could biochemically be established in our patients, with a 100% sensitivity. Previous studies demonstrated that ALS levels are elevated in 80–90% of patients (12, 13, 14, 15). In one study, ALS levels were examined in the postoperative evaluation of disease activity and showed a sensitivity and specificity of 93 and 100%, respectively (14). We found that after pituitary surgery, ALS levels normalized in most patients in remission. In all noncured patients, ALS levels remained elevated, thus having a sensitivity of 100%. ALS, although not superior to IGF-I, can, therefore, be a useful parameter in the diagnosis and postoperative follow-up of acromegalic patients. It should be noted that we used an in-house assay for ALS measurement and that the reproducibility of these ALS results with commercial assays is currently unknown.
Finally, we examined pre- and postoperative GHBP levels in acromegalic patients. Because there is a close relationship between hepatic GH-receptor number and GHBP levels, GHBP is thought to reflect integrated tissue GH responsiveness (32). In addition, because both tissue GH receptor expression and GHBP levels are inversely related to GH pulsatility, GHBP may be an index of GH secretory status (20, 33). Indeed, we found low GHBP levels in active acromegaly that were negatively correlated with GH levels, presumably indicating down-regulation of tissue GH-receptor expression. After reversal of GH excess, GHBP levels increased and stabilized after 5–6 wk, reflecting recovery of GH sensitivity. Although the increase in GHBP levels was less pronounced in the patients with persistent acromegaly, a considerable overlap with cured patients limits the diagnostic value of GHBP in the assessment of disease activity.
Conclusion
We observed that in the postoperative evaluation of acromegaly, an early postoperative OGTT, performed within 1 wk, can reliably predict cure if a GH nadir cutoff level of 0.5 µg/liter is used. Early postoperative IGF-I levels are, however, highly variable and stabilize at approximately 12 wk, which should be the period after which definite postoperative assessment of IGF-I levels should be performed. Free IGF-I and ALS levels are elevated in acromegaly and may have an additional value in the postoperative evaluation of disease activity. GHBP levels are suppressed in active acromegaly, and the postoperative GHBP increase may indicate recovery of GH sensitivity.
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Acknowledgments |
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Footnotes |
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Abbreviations: ALS, Acid labile subunit; BP, binding protein; CV, coefficient(s) of variation; GHBP, GH binding protein; IRMA, immunoradiometric assay; OGTT, oral glucose tolerance test; ULN, upper limit of the age- and gender-normalized range.
Received April 25, 2005.
Accepted September 6, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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