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Endocrine Care |
Division of Endocrinology, Departments of Medicine (A.C.F.C., A.R., A.C.M.), Pediatrics (C.E.M.), and Surgery (H.R.M.), School of Medicine of Ribeirão Preto-Universidade de São Paulo, Ribeirão Preto 14049-900, Brazil
Address all correspondence and requests for reprints to: Prof. Ayrton C. Moreira, Department of Medicine, School of Medicine of Ribeirão Preto Universidade de São Paulo, 14049-900, Ribeirão Preto, São Paulo, Brazil.
Abstract
The definition of a cure for acromegaly is controversial in the absence of a well-defined clinical end-point. Therefore, cure in acromegaly may be arbitrarily defined as a normalization of biochemical parameters. The accepted normal GH levels have been modified over time with the improved sensitivity of GH assays. The objective of the present study was to investigate the suppression of GH levels in the oral glucose tolerance test (oGTT) using a sensitive GH immunoassay in a large group of normal adult subjects and treated acromegalic patients. We evaluated these results in conjunction with IGF-I and IGF binding protein 3 (IGFBP-3) levels. Nadir GH levels after the ingestion of 75 g of glucose, as well as baseline IGF-I and IGFBP-3 levels, were evaluated in 56 normal adult subjects and 32 previously treated acromegalic patients. GH was assayed by an immunofluorometric assay. Normal controls had a mean GH nadir of 0.07 ± 0.09 µg/liter. Their mean basal IGF-I and IGFBP-3 levels were 160 ± 58 µg/liter and 1926 ± 497 µg/liter, respectively. Acromegalic patients had mean GH nadir, IGF-I, and IGFBP-3 levels higher than those of normal subjects (2.6 ± 7.6 µg/liter, 313 ± 246 µg/liter, and 2625 ± 1154 µg/liter, respectively). Considering a GH cut-off value of 0.25 µg/liter, as the normalized postglucose GH upper limit (mean + 2 SD) and, therefore, the target for treated patients, only five patients (15.6%) would have been considered cured. These results suggest that the strict physiological normalization of GH levels after oGTT is not often achieved as a therapeutic endpoint in acromegaly.
In addition to the refinement of GH assays, epidemiological studies have suggested that the mean basal GH levels (<2.5 µg/liter) or oGTT-derived GH levels < 2 µg/liter (RIA), or the normalization of IGF-I levels, appear to reduce morbidity and mortality in treated acromegaly. Using this epidemiologically based definition of cure for acromegaly, we reviewed our results obtained with a sensitive GH assay. Twenty-five patients (78%) had oGTT nadir GH < 2 µg/liter. Nineteen subjects had normal age-related IGF-I levels. When the GH nadir cut-off was reduced to 1 µg/liter or less, there was a cure rate of 59.4%. IGF-I and IGFBP-3 levels were normal in 16 and 15 of these 19 patients, respectively. Furthermore, 59.4% of these 32 patients were in remission when age-normalized IGF-I levels were used as a criterion for inactive disease. All but three had GH nadir of 1 µg/liter or less. Finally, the definition of cure may be contradictory in a subgroup (9.4%) of patients with a GH nadir less than 1 µg/liter despite high-for-age IGF-I levels.
In conclusion, using a sensitive GH assay it can be seen that the strictly normal postglucose GH values less than 0.25 µg/liter required for biochemical control of acromegaly are not often achieved. Furthermore, the cut-off of GH nadir 1 µg/liter or less is more closely related to normal for age serum IGF-I levels in treated acromegalic patients than 0.25 µg/liter or 2 µg/liter cut-offs. According to previous epidemiological reports, a GH level less than 2.5 µg/liter, determined by RIA, is associated with a reduction of morbidity and mortality. Therefore, our data lead us to postulate that the biochemical criterion of oGTT GH levels 1 µg/liter or less, determined by immunofluorometric assay, is a useful and accurate marker of safe GH secretion in treated acromegaly.
SEVERAL DIFFERENT THERAPEUTIC approaches are currently available to treat acromegaly, of which transsphenoidal surgery is the main option (1, 2). Morbidity and mortality rates increase among patients who undergo surgery but fail to achieve a cure (3, 4, 5, 6). Therefore, a second treatment modality needs to be established for these patients. The main problem in the assessment of disease activity in acromegaly is that no sensitive clinical parameters are available, other than biochemical ones. Epidemiological studies have shown that in acromegaly the most important determinant of outcome, in terms of morbidity and mortality, is the final serum GH level after treatment (4, 5, 6, 7, 8).
The biochemical criteria for the cure of acromegaly have been changed over time. With the advent, in the 1960s, of the first RIAs to determine plasma GH levels, various cut-off limits were suggested as a criterion for cure of the disease (9, 10, 11, 12, 13). In recent years, this limit has progressively decreased, either under basal conditions or by suppression with glucose. The classic method used to assess the cure of acromegaly is the suppression of GH after the oral glucose tolerance test (oGTT) (1, 7, 14, 15, 16). However, the availability of new and sensitive GH immunoassays (ELISA, immunoradiometric, immunofluorometric and chemiluminescence assays), some with a sensitivity up to 100 times higher than that of RIA, has led to more stringent criteria for the establishment of the normal limits of GH suppression (17, 18, 19). The development of assays for the determination of serum levels of IGF-I and its main binding protein, IGF binding protein 3 ( IGFBP-3), has also brought new controversy to the assessment of acromegaly activity (20, 21, 22, 23, 24, 25, 26, 27, 28, 29).
The aim of this study was to compare oGTT-suppressed GH levels in a large group of normal adult subjects and treated acromegalic patients through a sensitive immunoassay. In addition, we assessed the levels of GH-dependent circulating molecules such as IGF-I and IGFBP-3. Our data were also compared with epidemiological criteria for cure reported in the literature.
Subjects and Methods
Normal subjects
The study included 56 normal adult subjects (30 women and 26 men; mean age ± SD, 40.1 ± 11.7 yr) with a mean body mass index of 25.6 ± 3.9 kg/m2. These subjects showed no clinical evidence of acute or chronic disease and were not taking any medications. Neither the phase of the menstrual cycle nor estrogen status were standardized.
Treated acromegalic patients
We studied 32 treated acromegalic patients (15 women and 17 men; age, 51.7 ± 15.5 yr and body mass index, 27.9 ± 4.0 kg/m2). Acromegaly was diagnosed on the basis of clinical features and by insufficient suppression of serum GH concentration during oGTT together with the presence of a pituitary adenoma confirmed by imaging studies. These patients had been previously submitted to different treatment modalities (surgery and/or radiotherapy) at different times before the study. In approximately 85% of patients, the tumor was a macroadenoma. All of the 28 patients who had undergone pituitary transsphenoidal surgery as primary therapy were operated by the same neurosurgeon (H.R.M.). None of the patients had been taking GH-suppressive medications.
Study design
All subjects were ambulatory. After an overnight fast, two blood samples were drawn between 0830 and 0900 h, to determine basal GH, glucose, IGF-I and IGFBP-3 levels. The subjects drank a solution containing 75 g of glucose and blood samples were drawn within 30, 60, 90, and 120 min for GH and glucose assays. All samples were analyzed in duplicate. This protocol was approved by the University Hospital Ethics Committee and informed consent was obtained from all subjects.
Assays
GH. Serum GH levels were measured by solid phase immunofluorometric assay (IFMA) (30, 31). The standard reference used was the AFP-4793B (NIDDK-NIH-USA). The biological potency of this preparation is 2.2 IU/mg. The two monoclonal antibodies used—E9P5 (capture) and D11P6 (labeled with Europium)—were produced by Dr. J. G. H. Vieira (Fleury Laboratories, São Paulo, Brazil). The antibodies show less than 0.1% cross-reactivity with other pituitary peptides and 100% cross reactivity with the 22-kDa and 20-kDa GH proteins. The sensitivity of the method was 0.06 µg/liter. The intraassay coefficient of variation (CV) was 5%. The mean interassay CV was 14%. This method had previously shown a high correlation (r = 0.99) with serum GH determined by a commercial IFMA (Delfia hGH, Wallac Oy, Turku, Finland) (32).
IGF-I. Serum IGF-I levels were determined by RIA after extraction from serum (33, 34). The standard reference was obtained from Sigma (St. Louis, MO). The anti-IGF-I antibody BPL-M23 was provided by Dr. C. Camacho-Hübner (Saint Bartholomew’s Hospital, London, UK). The assay sensitivity was 0.1 µg/liter. The intra and interassay CV were 5% and 10.5%, respectively. The normal ranges for this assay, compiled by Dr. Camacho-Hübner, are as follows: age 19–29 yr, 125–329 µg/liter; 30–39 yr, 120–330 µg/liter; 40–49 yr, 126–369 µg/liter; 50–59 yr, 108–263 µg/liter; and over 60 yr, 108–229 µg/liter.
IGFBP-3. Serum IGFBP-3 levels were measured by immunoradiometric assay (IRMA) (Diagnostics Systems Laboratories, Inc., Webster, TX). The assay sensitivity was 0.5 µg/liter and the intra and interassay CV were 3% and 14%, respectively.
Glucose. Glucose was determined by the glucose-oxidase method.
Statistical analysis. The serum GH nadir was defined as the lowest value at any time point after oGTT. GH values below the sensitivity of the assay were considered to be 0.06 µg/liter. Baseline serum IGF-I and IGFBP-3 levels were calculated as the mean of the 15- and 0-min concentrations. The values were expressed as means ± SD. The Wilcoxon-Mann-Whitney test and the Spearman correlation test were used where appropriate. Significance was assumed when P < 0.05. In the assessment of disease activity in the treated acromegalic patients, the normalization of these biochemical parameters was arbitrarily defined as the upper limit of GH nadir established according to the value 2 SD above the mean concentrations (mean + 2 SD) from our healthy controls. IGF-I levels in all acromegalic patients and control subjects were compared with their age-appropriate absolute values normal ranges. IGF-I values were also expressed as percentages of the upper limit of normal range for age (% ULNR; normal <100% ULNR). IGFBP-3 levels were considered normal when levels were below the upper limit of control subjects. The analysis was performed using the GraphPad Prism program (GraphPad Software, Inc., San Diego, CA).
Results
Normal subjects
GH nadir.
Healthy subjects had a mean GH nadir after oGTT of 0.07 ± 0.09 µg/liter (range: 0.06 to 0.7 µg/liter). The GH nadir was undetectable (
0.06 µg/liter) in 70% and 0.1 µg/liter in 93% of subjects. Three female subjects (28–33 yr) had a GH nadir of 0.2 µg/liter, and in a 29-yr-old female the value was 0.7 µg/liter. On average, women had GH nadir levels higher than those of men (0.1 ± 0.12 vs. 0.06 ± 0.02 µg/liter, P < 0.01). No significant difference was observed between subjects less than 40 yr and 40 yr or older (0.11 ± 0.13 vs. 0.07 ± 0.01) in each group. However, when sex was considered, females younger than 40 yr had higher GH nadir than older women (0.15 ± 0.17 vs. 0.07 ± 0.02, P < 0.0001). Male subjects presented no age-related difference in GH nadir (0.07 ± 0.01 vs. 0.06 ± 0.01 µg/liter).
IGF-I. Healthy subjects had basal serum IGF-I levels of 160 ± 58 µg/liter (range: 66–382 µg/liter); levels for all subjects but one were below the upper limit of their age-appropriate normal ranges. No significant difference was observed between female and male subjects (163 ± 60 vs. 157 ± 55 µg/liter).
IGFBP-3. Healthy subjects had basal serum IGFBP-3 levels of 1926 ± 497 µg/liter (range: 1003–3343 µg/liter). No significant sex or age differences were observed.
Correlation between GH nadir, IGF-I, IGFBP-3, and age in normal subjects. There was a negative correlation between age and basal IGF-I levels (r = -0.60, P < 0.0001), GH nadir (r = -0.35, P < 0.01) and basal serum IGFBP-3 levels (r = -0.30, P < 0.05). There was a positive correlation between IGF-I levels and GH nadir (r = 0.38, P < 0.001) and between IGF-I and IGFBP-3 (r = 0.48, P < 0.001). No correlation was observed between GH nadir and IGFBP-3 or between IGF-I levels and GH nadir in the 0.07 or greater and 1 µg/liter or less GH range.
Treated acromegalic patients
Table 1
shows the individual basal and nadir GH levels after oGTT, and baseline IGF-I and IGFBP-3 values, of 32 patients with treated acromegaly. These patients had higher mean basal GH (3.8 ± 9.5 µg/liter) and oGTT GH nadir levels (2.6 ± 7.7 µg/liter) than controls. They had mean basal serum IGF-I levels of 313 ± 246 µg/liter (range: 53–1313 µg/liter). These absolute values and their age-corrected IGF-I levels, expressed as percentage of ULNR, were higher than controls (110 ± 80% vs. 48.5 ± 18%, P < 0.0001). The mean basal serum IGFBP-3 levels in this group were 2625 ± 1154 µg/liter (range: 699-5833 µg/liter). IGFBP-3 levels were higher in acromegalic patients than in controls.
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), as well as between GH nadir and IGFBP-3 (r = 0.53, P < 0.002, Fig. 2). Positive correlations were also observed between IGF-I and IGFBP-3 (r = 0.76, P < 0.0001) and between serum IGF-I levels and GH nadir in the 
0.07 and 1 µg/liter GH range (r = 0.49, P < 0.04).
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Based on the postglucose GH nadir cut-off value of 0.25 µg/liter, which corresponds to the mean + 2 SD of the values obtained for normal subjects, only 5 acromegalic patients (4F/1M) would be considered to have been cured, i.e. only 15.6% of patients had GH suppression similar to that of normal subjects (Fig. 1
). On average, these 5 patients had basal serum IGF-I and IGFBP-3 levels below those of normal subjects (89 ± 24 vs. 160 ± 58 µg/liter, and 1375 ± 526 vs. 1926 ± 497 µg/liter, P < 0.05, respectively). Four of these 5 patients had hypopituitarism. If we adopt the GH nadir limit of 1 µg/liter, 19 (59.4%) of our patients would be considered cured. Sixteen of these subjects had IGF-I levels within the normal range for age. In addition, 15 of these patients had normal IGFBP-3 levels (Fig. 2). Of the 14 treated patients who had a GH nadir between 0.25 and 1 µg/liter, only 4 had deficiency of one or more pituitary hormones. If we adopt the GH nadir of less than 2 µg/liter, 25 patients (78%) would be considered cured, and 19 of these subjects had IGF-I levels within the normal range.
IGF-I levels as a criterion for acromegaly remission
Based on the age-adjusted IGF-I cut-offs, expressed either as absolute values or as % ULNR, 19 acromegalic patients (59.4%) would be considered cured. On average, these patients had a GH nadir above that of normal subjects (0.58 ± 0.42 vs. 0.07 ± 0.09 µg/liter, P < 0.001). All but three of these patients had a GH nadir of 1 µg/liter or less. Among the 13 patients with active disease, defined by elevated IGF-I levels, none had a GH nadir lower than 0.25 µg/liter (GH nadir: 2.6 ± 1.8 µg/liter), and three of them presented a GH nadir between 0.25 and 1 µg/liter.
IGFBP-3 levels as a criterion for acromegaly remission
Based on the cut-off value of 3343 µg/liter, 27 patients (84.4%) would be considered cured. These 27 patients had a GH nadir above that of normal subjects (1.3 ± 1.5 vs. 0.07 ± 0.09 µg/liter, P < 0.001), with 10 of 27 patients having a GH nadir greater than 1 µg/liter. Seven of these 10 patients had also increased IGF-I values (146 ± 19% ULNR).
Discussion
Ideally, cure of acromegaly should be defined as a complete remission of signs and symptoms, return of normal GH secretion, reversal of the tumor mass effects, and preservation of other anterior pituitary functions (1, 2). However, the definition of cure for acromegaly is controversial in the absence of a well-defined and reliable clinical parameter through which to compare pretreatment and posttreatment disease activity. In the absence of such clinical criteria, most centers evaluate residual disease activity by performing biochemical tests. Therefore, cure in acromegaly may be arbitrarily defined as a normalization of biochemical parameters. The biochemical markers that have been used for this purpose include basal GH and mean serum GH from a four-point GH day curve, oGTT GH nadir levels, and measurement of circulating molecules reflecting GH secretion, such as IGF-I levels or, more recently, IGFBP-3 levels (9, 10, 11, 12, 13, 14, 15, 16, 28, 29). These previous studies usually determined GH levels using RIA or IRMA. Established treatment goals were basal serum GH levels less than 5 µg/liter, a mean GH of less than 2.5 µg/liter during a day profile, or GH nadir after oGTT of less than 2 µg/liter. However, early GH assays were insufficiently sensitive to measure the extent of normal suppression using oGTT. Recently, the availability of highly sensitive immunoassays has made it possible to establish postglucose GH values in normal subjects (17, 18). Despite this, to our knowledge only one study has compared more sensitive GH assays with IGF-I and IGFBP-3 levels in a group of normal adults and treated acromegalic patients (19).
We used one of these immunoassays (IFMA) to standardize the GH levels after a glucose load in 56 healthy adult subjects of both sexes. Our findings confirm previous results (18) showing a lower postglucose GH nadir in men compared with women. The GH nadir was 0.1 µg/liter or less for most normal subjects. This indicates that the strictest criteria for GH normalization are required for use in acromegaly. In this study, the GH cut-off value of 0.25 µg/liter corresponded to the mean plus 2 SD value obtained for our healthy control group. If this is taken as the target value for the normalized postglucose GH upper limit in the treated acromegalic patients, only 5 patients (15.6%) would be considered cured. We found that these patients had low serum IGF-I and IGFBP-3 levels, and 4 patients had hypopituitarism. All patients had received two different forms of therapy. Recently, Freda et al. (19) found normal GH suppression (nadir GH <0.14 µg/liter by IRMA) in 38% of treated acromegalic patients with normal IGF-I levels. These results, taken together with ours, suggest that the normalization of GH levels after oGTT is not often achieved as the therapeutic endpoint in acromegaly. In addition, our data suggest an increased risk of hypopituitarism in these patients resulting from the additional treatment, such as radiotherapy, which aimed for complete normalization of GH nadir levels (GH nadir <0.25 µg/liter).
In addition to the refinement of GH assays, epidemiological studies have raised another pertinent issue: is it necessary to meet absolute biochemical cure targets to achieve clinical remission and to reduce morbidity and mortality in acromegaly? Four studies (4, 5, 6, 7, 8) related serum GH levels to morbidity and mortality rates among treated acromegalics, whereas a further study (6) used serum IGF-I levels as the criterion for remission. These studies clearly suggested that mean basal GH levels less than 2.5 µg/liter, oGTT-derived GH levels less than 2 µg/liter by RIA or the normalization of IGF-I levels appear to reduce mortality to that of age-matched controls. In addition, restoration of the normal body composition is associated with mean GH levels less than 2.5 µg/liter (RIA) after treatment (35). Therefore, regardless of the treatment mode, these target values for GH and IGF-I would not be defined as cure but rather as safe values, which is a more realistic concept.
Using the epidemiological definition of cure for acromegaly, as stated above, we reviewed our results obtained with a sensitive GH assay. Twenty-five (78%) patients had oGTT GH nadir less than 2 µg/liter. Among this group 76% (19 of 25) of patients had normal age-related IGF-I levels. However, using a more strict criterion (GH nadir 1 µg/liter), as was recommended by a recent consensus statement (1), based on GH measurement with more sensitive assays (17, 18), the cure rate was reduced to 59.4% (19 of 32 patients). Of these cured patients, defined by this lower cut-off, 84% (16 of 19) showed normal age-related IGF-I levels. The incidence of posttreatment hypopituitarism was 28.5% in the group of acromegalics whose GH nadir was between 0.25 and 1 µg/liter. Our results are similar to those reported by Sheaves et al. in 1996 (36) who found postoperative hypopituitarism in 21% of patients who achieved a mean basal GH level less than 2.5 µg/liter (IRMA).
Additional information may be obtained by comparing the value for the restoration of age-normalized serum IGF-I levels to the oGTT GH levels, as measured by IFMA as a therapeutic goal. A linear relationship has been demonstrated between serum GH and IGF-I levels when the former is between 1 and 15 µg/liter (24). Although this fact is well known, information on the possible extension of this relationship below the nadir GH levels less than 1 µg/liter is scant (19). Our data showed a positive relationship between IGF-I levels and GH nadir within the GH range 0.07 and 1 µg/liter in treated acromegaly. The sensitive GH assay permitted observation of the fine-tuning of the GH-IGF-I relationship. Furthermore, using an approach based on age-normalized IGF-I as a criterion for acromegaly cure, 59.4% of the patients had normal IGF-I levels. All but three of these 19 patients had GH nadir of 1 µg/liter or less. However, the definition of cure may be contradictory in a subgroup of 3 patients with postglucose GH suppression of less than 1 µg/liter, despite high-for-age IGF-I levels. Even in successfully treated patients, IGF-I levels may not fall for a period of several months (2). In addition, IGF-I may also be affected by factors other than GH alone. Finally, we cannot rule out the possibility that the failure of treatment to effectively normalize IGF-I levels may indicate persistent, albeit low, levels of dysregulated 24-h GH (19). Clinical judgement must balance the burden of additional treatment against the possible reduction in morbidity and mortality afforded by the strictest biochemical control in these borderline cases. Epidemiological data are still needed to clarify the significance of this marginal situation in treated acromegaly.
Recently, several contradictory reports have evaluated the utility of determining GH-dependent IGFBP-3, the major serum carrier of IGF peptides, for the assessment of clinical activity in treated acromegaly (25, 26, 27, 28). We showed a positive correlation between IGFBP-3 levels and IGF-I and oGTT GH in our acromegalic group, although 37% of the patients with normal IGFBP-3 levels had GH nadir greater than 1 µg/liter and high mean IGF-I levels. Thus, the value of IGFBP-3 measurements for follow-up of acromegaly may be limited. Further studies are required to correlate posttreatment IGFBP-3 levels with survival rates in acromegaly.
In conclusion, the strictest criterion for the normalization of postglucose GH levels (GH nadir <0.25 µg/liter), and biochemical control of acromegaly is not often achieved. Furthermore, using a sensitive GH assay, the cut-off of GH nadir of 1 µg/liter or less is more closely related to normal age-appropriate IGF-I levels in treated acromegalic patients than 0.25 µg/liter or 2 µg/liter cut-offs. According to the epidemiological reports, GH levels less than 2.5 µg/liter, determined by RIA, are associated with a reduction in morbidity and mortality. Therefore, our data lead us to postulate that the biochemical criterion of an oGTT GH nadir level of 1 µg/liter or less, as determined by IFMA, is a useful and accurate indicator of safe GH secretion in treated acromegaly.
Acknowledgments
We thank Drs. J. G. H. Vieira and C. Camacho-Hübner for the gift of antibodies used in this study. Normal ranges for the IGF-I assay were compiled by Dr. C. Camacho-Hübner. We also thank Dr. Gareth Cuttle for revision of the English text, and Drs. Margaret Castro and Lucila K. Elias for helpful discussions.
Footnotes
This work was supported in part by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (Grant 350 987/94-7) and Fundação de Apoio au Hospital das Clinicas (HCFMRP-FAEPA).
Present address for A.C.F.C.: School of Medicine, University of Brasília, 70919-970, Distrito Federal, Brazil.
Abbreviations: CV, Coefficient(s) of variation; IFMA, immunofluorometric assay; IGFBP-3, IGF binding protein 3; IRMA, immunoradiometric assay; oGTT, oral glucose tolerance test; ULNR, upper limit of normal range for age.
Received May 23, 2001.
Accepted March 19, 2002.
References
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