help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2104
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alexopoulou, O.
Right arrow Articles by Maiter, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alexopoulou, O.
Right arrow Articles by Maiter, D.
Related Collections
Right arrow Neuroendocrinology and Pituitary
Right arrow Endocrine Oncology
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 4 1324-1330
Copyright © 2008 by The Endocrine Society

Divergence between Growth Hormone and Insulin-Like Growth Factor-I Concentrations in the Follow-Up of Acromegaly

Orsalia Alexopoulou, Marie Bex, Roger Abs, Guy T’Sjoen, Brigitte Velkeniers and Dominique Maiter

Department of Endocrinology (O.A., D.M.), St. Luc University Hospital, Université Catholique de Louvain, B-1200 Brussels, Belgium; Department of Endocrinology (M.B.), Gasthuisberg University Hospital, Gasthuisberg, Katholieke Universiteit Leuven, B-3000, Leuven, Belgium; Department of Endocrinology (R.A.), University of Antwerp, B-2610 Antwerp, Belgium; Department of Endocrinology (G.T.), University Hospital of Gent, B-9000 Gent, Belgium; and Department of Endocrinology (B.V.), Academic Hospital Free University of Brussels, B-1090 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. O. Alexopoulou, Service d’Endocrinologie et Nutrition, Cliniques Universitaires St. Luc, Avenue Hippocrate 54, UCL 54.74, B-1200 Brussels, Belgium. E-mail: orsalia.alexopoulou{at}diab.ucl.ac.be.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Divergence between GH and IGF-I values is regularly observed in treated acromegalic patients, and its significance is unclear.

Objectives: The objective of the study was to explore the frequency and identify potential determinants of discordant serum GH and IGF-I concentrations in noncured acromegalic patients.

Patients: Two hundred twenty-nine noncured acromegalic patients of the Belgian acromegaly registry (AcroBel) were grouped according to their mean GH level (≤ or > 2 µg/liter) and IGF-I z-score (≤ 2 or > 2). Clinical and metabolic parameters were compared between groups with active disease (high GH and IGF-I; n=81),high GH (with normal IGF-I; n=25), high IGF-I (with normal GH; n=55), and controlled disease (GH and IGF-I normal; n=68).

Results: Compared with the high IGF-I group, the high GH group was characterized by younger age (52 vs. 58 yr, P < 0.05), female predominance (72 vs. 36%, P < 0.01), and lower body mass index (25 vs. 31 kg/m2; P < 0.001), fasting glucose (91 vs. 99 mg/dl; P < 0.05), and glycated hemoglobin levels (5.7 vs. 6.1%; P < 0.01). There was no difference among the groups regarding baseline characteristics of pituitary adenoma, current medical treatment, or symptom score.

Conclusions: Thirty-five percent of noncured acromegalic patients exhibit a discordant GH and IGF-I pattern. The high GH phenotype was found predominantly in younger estrogen-sufficient females, implying a possible role for age, gender, and estrogens in this biochemical divergence. The high IGF-I phenotype was associated with a worse metabolic profile, suggesting that high IGF-I, rather than high GH, is indicative of persistently active disease.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Acromegaly is associated with significant morbidity and mortality due to prolonged exposure to excessive amounts of GH and IGF-I (1, 2, 3). Transsphenoidal adenomectomy is the first choice therapy, but about 50% of patients are not cured by surgery (1, 2) and require long-term medical treatment with dopamine agonists, somatostatin analogs, and/or the GH receptor antagonist pegvisomant (1, 4). Both random GH and IGF-I measurements are routinely used to monitor disease activity, and a normal age-related serum IGF-I level and a GH concentration lower than 2.0 or 2.5 µg/liter are the currently accepted criteria to define biochemical control in noncured patients (5).

Controversy persists regarding the relative importance of these two markers in predicting normalization of morbidity and mortality (5, 6, 7, 8, 9). Several studies have reported a discrepancy between GH and IGF-I status in up to 40% of treated acromegalic patients (3, 10, 11, 12). The mechanisms underlying this discordance have not been clearly defined and, in addition to the known variability of GH and IGF-I assays (13, 14), might involve factors such as gender, age, or prior radiotherapy, which are all known to modify the relationship between GH and IGF-I (15, 16, 17).

In the present study, data retrieved from AcroBel, the Belgian Registry on Acromegaly, were used to explore the frequency of discrepancy between serum GH and IGF-I concentrations in the follow-up of noncured acromegalic patients and to identify possible determinants accounting for this divergence. We also examined the possible relationships between divergent patterns of biochemical markers and clinical surrogates of disease activity.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
All endocrinologists involved in the care of patients with acromegaly in Belgium and in the Grand Duchy of Luxembourg were invited to participate in this nationwide survey and to include all acromegalic patients seen between January 1, 2000, and September 30, 2004. The survey design and the main demographic, epidemiological and outcome results have been recently reported in detail (18). Of the 418 patients registered in AcroBel, 316 had fasting blood sampling for local determinations of glucose, glycated hemoglobin (HbA1c), and lipid profile and measurements of GH and IGF-I in a central laboratory (St. Luc University Hospital, Brussels, Belgium). GH values were recorded as the mean of three serum samples taken at 15-min intervals.

We excluded patients considered cured (n = 73) on the basis of their disease status reported by the referring physician and both a normal IGF-I for age and gender (z-score ≤ 2 SD) and a mean GH value of 2.0 µg/liter or less in the absence of any current treatment (18). This group included a few operated patients with a normal IGF-I and a mean GH greater than 2 µg/liter due to one high value but with previous documentation of a GH nadir after oral glucose tolerance test less than 1 µg/liter or a random GH at least once below the detection limit of 0.5 µg/liter. The median GH (P5-P95) was low at 0.7 (0.2–3.4) µg/liter, and the IGF-I z-score was 0.08 ± 1.55 (mean ± SD). There were no significant differences in clinical and biochemical parameters between this group and the medically controlled patients, except for a lower IGF-I z-score in cured patients. Acromegalics under GH replacement therapy (n = 10) and patients under pegvisomant treatment (n = 4) were also excluded from the study.

Thus, 229 noncured patients (age 54 ± 14 yr, mean ± SD; 124 men) were included. A clinical symptom score was derived from the sum of the scores of five classical symptoms of acromegaly (headache, perspiration, asthenia, soft tissue swelling, joint pain) as self-evaluated by the patients using a four-point rating scale (0, none; 1, mild; 2, moderate; 3, severe). Informed consent was obtained from all patients, and the survey protocol was approved by a central Ethics Committee at the University Hospital of Leuven.

Assays

Serum GH and IGF-I concentrations were measured by automated, two-site chemiluminescence immunoassays (Nichols Advantage IGF-I assay and Nichols Advantage HGH assay; Nichols Institute Diagnostics, San Juan Capistrano, CA). Sensitivity of the GH assay was 0.1 µg/liter, and the intra- and interassay coefficients of variation were 4.8 and 5.8%, respectively. GH values are still expressed in terms of the first World Health Organization international standard 80/505 for pituitary-derived GH, which was used at that time of the assays (conversion factor for expression in terms of the new World Health Organization international standard 98/574 = GH concentration x 0.56). The sensitivity of the IGF-I assay was 6 µg/liter and the intra- and interassay coefficients of variation were 5.2 and 5.7%, respectively. All determinations were made in consecutive runs at the end of the survey, in singlicates for GH and duplicates for IGF-I. IGF-I values were compared with age- and gender-specific normal values (19) and were expressed as a z-score (normal range –2 to + 2).

Definitions

Controlled disease was defined by the same strict biochemical criteria used to define cure, when obtained under medical therapy, irrespective of previous pituitary surgery or radiotherapy. Active disease was defined as both an IGF-I z-score greater than 2 and a mean GH value greater than 2.0 µg/liter in treated and untreated patients. Patients with discordant IGF-I and GH values were considered as not controlled and were categorized as follows: patients with a mean GH greater than 2.0 µg/liter and an IGF-I z-score of 2 SD or less constituted the high GH group (n = 25) and patients with a mean GH of 2.0 µg/liter or less and an IGF-I z-score greater than 2 SD formed the high IGF-I group (n = 55).

Statistics

Comparisons between categorical variables were performed by {chi}2 tests and, for normally distributed continuous variables, by one-way ANOVA, followed by Student-Newman-Keuls tests when P < 0.05. For nonnormally distributed parameters, Kruskal-Wallis tests were used. Correlations between variables were derived from Spearman correlation tests. Factors related to diabetes within the studied population were investigated using a logistic regression analysis, whereas multiple regression analysis was used to evaluate the influence of different parameters on fasting glucose and on HbA1c values. Statistical analysis was performed using the SPSS 13.0 software (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Serum GH and IGF-I levels

As expected, the IGF-I z-score significantly correlated with the mean GH concentration expressed on a log scale, although this correlation was not very strong (r = 0.556; P < 0.001; Fig. 1Go). Interestingly enough, an IGF-I z-score of + 2 corresponded to a serum GH concentration of 1.1 µg/liter [regression analysis equation: IGF-I z-score = 2.19 log (GH) + 1.93]. Of note, the correlation between IGF-I and log GH was clearly different between women with a normal gonadotrophic axis or estrogen substitution (n = 58 estrogen sufficient women; serum GH corresponding to IGF-I z-score of 2 = 2.8 µg/liter) and men or estrogen-deprived women (corresponding serum GH concentrations = 0.8 and 1.1 µg/liter, respectively).


Figure 1
View larger version (32K):
[in this window]
[in a new window]

  		FIG. 1. Serum GH and IGF-I concentrations in the noncured acromegalic patients (n = 229). The regression line between log GH and IGF-I z-score is shown. The horizontal and vertical lines delineate the four groups of patients according to their GH (≤ or > 2 µg/liter) and IGF-I concentrations (z-score ≤ or > 2).

 
Based on the previously described criteria, 68 of the 229 noncured patients (30%) were considered as adequately controlled for both GH and IGF-I [median GH (P5-P95): 0.7 (0.2–2.0) µg/liter; IGF-I z-score: 0.64 ± 1.04, mean ± SD]. Of the remaining patients, 81 (35% of the total population) had obvious active disease with both increased GH concentration [4.3 (2.2–25.0) µg/liter] and IGF-I z-score (4.2 ± 1.5), and 80 (35% of the patients) exhibited discordant concentrations of IGF-I and GH, with a 2-fold higher prevalence of a high IGF-I, normal GH pattern (n = 55; 24%) [GH: 1.2 (0.4–2.0) µg/liter; IGF-I z-score: 3.20 ± 0.86], compared with a high GH, normal IGF-I pattern (n = 25; 11%) [GH: 4.0 (2.1–15.2) µg/liter; IGF-I z-score: 0.99 ± 0.78].

Patient characteristics

The main characteristics of the four groups of patients are shown in Table 1Go. Patients of the high IGF-I group were older than those of the high GH and the active disease groups (P < 0.05), whereas the men to women ratio was significant lower in the high GH group, compared with the high IGF-I and the active disease groups (P < 0.01). Moreover, there were significantly less estrogen-sufficient women in the high IGF-I group (18%), compared with the three other groups (high GH 69%; P < 0.01, controlled disease 48%; P < 0.05, active disease 46%; P < 0.05).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Characteristics of the patients and previous and current treatments in the active disease, high GH, high IGF-I, and controlled groups

 
Estimated duration of the disease was shorter in the patients with active disease, compared with patients with controlled disease or the high IGF-I pattern (P < 0.05), whereas no difference was evidenced between the high GH and high IGF-I groups. No differences were found among all groups, regarding characteristics of the pituitary tumor, such as size, invasiveness, and prolactin cosecretion. The numbers of patients with partial or total pituitary deficiency were not different between the various groups of patients (data not shown).

Previous and current treatment

A large majority of the patients had previously been operated in the controlled disease (73%) and high GH groups (72%) (Table 1Go), whereas this was the case in only 52 and 56% of patients in the active disease and high IGF-I groups, respectively (P < 0.05). The mean time since the last surgery was, however, not different between the groups. On the other hand, radiotherapy had been used less frequently in the high GH group (20%), compared with the high IGF-I (31%) and controlled groups (40%), although these differences did not reach statistical significance. Although more frequently used in controlled patients at the time of evaluation (79%; P < 0.001), somatostatin analogs (SSAs) were administered in a similar proportion of patients in the other groups (between 56 and 60%), and no difference was evidenced regarding the type of SSA used (data not shown). Current treatment with dopamine agonists was also equally observed in a similar proportion of patients among the different groups.

Cardiovascular and metabolic risk parameters and other comorbidities

As shown in Table 2Go, patients of the high GH group had lower body mass index (BMI) and diastolic blood pressure, compared with patients of the three other groups (P < 0.05). They also exhibited a better metabolic profile than patients of the active disease and high IGF-I groups. Figure 2AGo shows indeed that fasting glucose concentrations were similar in the controlled and high GH groups (median 91 and 91 mg/dl, respectively) and lower than in the active disease and high IGF-I groups (100 and 99 mg/dl, P < 0.05). Similar differences, although of lesser amplitude, were observed for HbA1c, which is known to be a less sensitive measure of glucose tolerance (5.8 and 5.7% vs. 5.9 and 6.1%, respectively, Fig. 2BGo). Interestingly, in the whole study population, glucose and HbA1c were not associated with GH concentration, but both parameters were positively correlated with IGF-I (r = 0.215; P < 0.001 for glucose and r = 0.233; P < 0.001 for HbA1c). In multiple regression analysis, age (P < 0.001), BMI (P < 0.05), the use of somatostatin analogs (P < 0.01), and the IGF-I z-score (P < 0.001) were independent predictors of HbA1c, whereas only age (P < 0.001) predicted fasting glucose values. Both univariate and multivariate analyses also showed that IGF-I, but not GH, was a significant predictor of diabetes mellitus (Table 3Go). This effect was independent of age, BMI, and the use of somatostatin analogs, which were also found to be predictors of diabetes mellitus. Similar results were obtained when statistical analyses were restricted to the subgroup of patients on current medical treatment (data not shown).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Clinical parameters and prevalence of current and past complications in the active disease, high GH, high IGF-I, and controlled groups

 

Figure 2
View larger version (12K):
[in this window]
[in a new window]

  		FIG. 2. A, Serum glucose concentrations in the active disease, high GH, high IGF-I, and controlled disease groups as defined according to their GH (≤ or > 2 µg/liter) and IGF-I concentrations (z-score ≤ or > 2). Data are presented as median, the interquartile range, and the fifth and 95th percentiles. B, Serum HbA1c concentrations in the active disease, high GH, high IGF-I, and controlled disease groups as defined according to their GH (≤ or > 2 µg/liter) and IGF-I concentrations (z-score ≤ or > 2). Data are presented as median, the interquartile range, and the fifth and 95th percentiles.

 

View this table:
[in this window]
[in a new window]

  		TABLE 3. Predictive factors for diabetes according to univariate and multivariate analyses

 
The lowest clinical symptom score was observed in the high GH group, but the differences between groups did not reach significance (Table 2Go). Whereas there was a tendency of less frequent occurrence of diabetes mellitus and arthrosis in the high GH group, compared with the high IGF-I group (P = 0.07), no difference was observed in the prevalence of other acromegaly-related comorbidities between the four groups of patients (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Although some controversy persists regarding criteria defining strict biochemical control of acromegaly, data from epidemiologic studies have demonstrated that increased mortality can be diminished when treatment is successful in reducing GH concentrations to less than 2.0 or 2.5 µg/liter (3, 7, 8, 9, 20, 21). In addition, some studies have shown that patients with a normal IGF-I have a mortality rate similar to that of the general population, whereas those with persistently elevated IGF-I have a reduced life expectancy (2, 8). Therefore, measurements of both serum GH and IGF-I levels are most often used to monitor treated acromegalic patients, as advised by the most recent consensus statement (5).

Efficient management of acromegalic patients may, however, become puzzling when divergent values of GH and IGF-I are observed during follow-up. Our data from AcroBel show indeed that up to 35% of treated acromegalic patients exhibit discordant GH and IGF-I concentrations, confirming results from previous studies (3, 10, 12). The high IGF-I, normal GH pattern was more frequently observed in our population (24%) than the high GH, normal IGF-I paradigm (11%), whereas conflicting results have been reported previously (10, 21, 22). Espinosa-de-Los-Monteros et al. (22) found more frequently elevated GH with normal IGF-I (22%) rather than the opposite pattern (4%) in 126 operated acromegalic patients not receiving any further therapy. However, these authors applied a more stringent criterion to define normalized GH (postglucose GH nadir < 0.3 µg/liter). Using an ultrasensitive GH assay, Freda et al. (23) found that up to 50% of patients with an active disease on the basis of elevated IGF-I levels had nadir GH values less than 1.0 µg/liter after an oral glucose tolerance test, whereas 39% of the patients with apparent remission (normal IGF-I) failed to adequately suppress GH. Thus, differences in the definition of cure or remission and in the type of GH and IGF-I assays used in previous studies make it hard to draw firm conclusions concerning the relative frequency of discordant GH/IGF-I patterns.

The underlying mechanisms accounting for this divergence between GH and IGF-I have not been fully explored. It has been proposed that an enhanced tissue sensitivity to GH could account for high IGF-I concentrations and the presence of clinical symptoms, despite apparently normal GH concentrations (24). However, in acromegalic patients with high IGF-I and normal GH levels, removal of the GH-producing tumor is usually followed by normalization of IGF-I, improvement of clinical symptoms, and a decline in GH levels, implying that a true elevation of GH output was likely causing acromegaly in these patients (25). It has also been suggested that integrated GH secretion does not determine alone circulating IGF-I levels and that characteristics of GH pulsatility are also important. Patients with acromegaly have indeed a reduced proportion of GH secreted as pulses and persistently high GH values throughout the day (26). Thus, continuous exposure of peripheral tissues to minimally elevated GH levels, less than 2.0 µg/liter, seems to be sufficient to increase IGF-I levels above normal values (27).

Whereas IGF-I concentrations are analyzed according to age-adjusted normal values, the GH cut-off value (2.0–2.5 µg/liter) is usually defined independent of age. Recently Colao et al. (28) suggested that for older patients, lower thresholds for fasting GH should be used (i.e. 1.4 µg/liter). This could explain part of the discrepancy observed between GH and IGF-I results. Interestingly, by applying the above mentioned criterion, 10 of the 55 patients within the high IGF-I group would now belong to the active disease group, but six of the 68 patients previously classified within the controlled disease group would now have a high GH, normal IGF-I pattern. Of note, another study does not support the adoption of an age-related GH threshold criterion in acromegaly (29).

We found a much higher percentage of women in the high GH group, compared with the high IGF-I group, and more specifically a higher proportion of women under estrogen exposure, related to either replacement therapy or to a normal gonadotrophic axis. This suggests that circulating estrogens may also be involved in the GH/IGF-I divergence. Indeed, we observed a clear gender difference in the relationship between GH and IGF-I concentrations as it has been reported previously in both healthy subjects and patients with acromegaly (15, 16). Thus, normal premenopausal women secrete much more GH than normal men or postmenopausal women to achieve similar IGF-I levels (30). This relative GH resistance is due to direct effects of estrogens on hepatic IGF-I production because oral but not transdermal estrogen replacement therapy lowers IGF-I levels (31). Despite this known gender difference, most commercially available GH and IGF-I assays do not usually report sex-adjusted normal values, and similar cutoffs are still used in acromegalic men and women. Our data suggest, however, that different GH thresholds should be used to monitor acromegaly in estrogen-exposed women, compared with male or estrogen-deprived female patients.

External radiotherapy is considered as a moderately effective treatment for the long-term control of GH hypersecretion, resulting in a progressive decrease of basal GH levels (17), with less obvious effects on plasma IGF-I levels (17, 32). Peacey et al. (27) found that in contrast to surgically treated patients, none of the radiotherapy-treated patients displayed a normal GH profile, despite reaching GH levels less than 2.0 µg/liter. This again suggests that a sustained slight elevation of GH release may increase IGF-I levels in these patients. In agreement with these findings, our results showed that only a minority of irradiated patients (7%) was in the high GH group and much more (24%) in the high IGF-I group, thus evoking a possible role for radiotherapy on some divergent GH/IGF-I profiles.

Although both GH and IGF-I levels have been implicated as indicators of mortality, IGF-I is currently considered as the best biochemical marker of clinical disease activity. In a study of postoperative acromegalic patients (6), IGF-I was a very strong predictor of abnormal glucose tolerance, in contrast to GH levels. Likewise, Puder et al. (33) found that in patients with normal serum IGF-I levels, abnormalities of GH suppression were not predictive of insulin resistance, whereas insulin sensitivity was reduced in patients with elevated IGF-I, regardless of whether GH was suppressed or not after oral glucose tolerance test. Our data extend these results because we have been able to show that patients with a mean GH greater than 2.0 µg/liter but a normal IGF-I exhibit a better metabolic profile, compared with patients with a mean GH of 2.0 µg/liter or less and still elevated IGF-I levels. Indeed, in the high GH group, patients had lower fasting glucose and HbA1c levels, and the prevalence of diabetes tended to be lower, compared with the high IGF-I group. Furthermore, IGF-I, but not GH, was a strong predictor of diabetes in our study population, independent of BMI or other factors.

Albeit of small amplitude, the differences observed in fasting glucose and HbA1c between the high GH and the high IGF-I groups may be clinically meaningful because a continuous and graded relationship between these parameters and cardiovascular disease mortality has been observed in several epidemiological studies (34). In contrast, we failed to demonstrate any difference among the four groups of patients regarding the clinical symptoms of acromegaly, in agreement with previous cross-sectional studies, which showed no relation between the sign and symptom score and biochemical measures of disease control (35).

Our study has certain limitations. Although most data regarding outcome were collected prospectively, some information on diagnosis and criteria for cure were not available in the registry. We had also to rely on the quality of reporting by the referring physician, and selection and diagnosis bias are always possible in such a large multicenter study. It is also likely that a small subset of patients considered cured on the basis of normal baseline IGF-I and GH concentrations would not show complete suppression after a glucose load, as reported previously (23). On the other hand, the high number of acromegalics included in this study and the use of central well-validated GH and IGF-I assays in all patients constitute important strengths that allow confident interpretation of our main findings.

In conclusion, our data from AcroBel show that 35% of noncured acromegalic patients exhibit discordant GH and IGF-I results. The high GH phenotype was found predominantly in younger female patients, with some degree of estrogen exposure and having been less frequently irradiated, implying a possible role of age, gender, and radiotherapy on this biochemical divergence. Although there was no difference regarding clinical symptoms of acromegaly, patients with high IGF-I but normal GH showed a worse metabolic profile, compared with patients with the high GH, normal IGF-I pattern. Moreover, IGF-I but not GH was a strong independent predictor of diabetes mellitus. These data suggest that a high IGF-I concentration is indicative of persistently active disease, even though mean GH levels are within the currently admitted safe interval.


   Footnotes
 
This work was supported by an unrestricted grant from Novartis for this study through the Belgian Endocrine Society (to O.A., M.B., R.A., G.T., B.V., and D.M.).

Disclosure Statement: M.B. has received consulting fees from Ipsen. R.A. has received lecture fees from Pfizer and Novartis.

First Published Online January 29, 2008

Abbreviations: BMI, Body mass index; HbA1c, glycated hemoglobin; SSA, somatostatin analog.

Received September 19, 2007.

Accepted January 23, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Melmed S 2006 Medical progress: acromegaly. N Engl J Med 355:2558–2573[Free Full Text]
  2. Swearingen B, Barker FG, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83:3419–3426[Abstract/Free Full Text]
  3. Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS 2004 Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab 89:1613–1617[Abstract/Free Full Text]
  4. Clemmons DR, Chihara K, Freda PU, Ho KK, Klibanski A, Melmed S, Shalet SM, Strasburger CJ, Trainer PJ, Thorner MO 2003 Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. J Clin Endocrinol Metab 88:4759–4767[Abstract/Free Full Text]
  5. 2004 Biochemical assessment and long-term monitoring in patients with acromegaly: statement from a joint consensus conference of the Growth Hormone Research Society and the Pituitary Society. J Clin Endocrinol Metab 89:3099–3102
  6. Serri O, Beauregard C, Hardy J 2004 Long-term biochemical status and disease-related morbidity in 53 postoperative patients with acromegaly. J Clin Endocrinol Metab 89:658–661[Abstract/Free Full Text]
  7. Biermasz NR, Dekker FW, Pereira AM, van Thiel SW, Schutte PJ, van Dulken H, Romijn JA, Roelfsema F 2004 Determinants of survival in treated acromegaly in a single center: predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab 89:2789–2796[Abstract/Free Full Text]
  8. Holdaway IM, Rajasoorya RC, Gamble GD 2004 Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 89:667–674[Abstract/Free Full Text]
  9. Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Niskanen L, Markkanen H, Loyttyniemi E, Ebeling T, Jaatinen P, Laine H, Nuutila P, Salmela P, Salmi J, Stenman UH, Viikari J, Voutilainen E 2005 A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 90:4081–4086[Abstract/Free Full Text]
  10. Kaltsas GA, Isidori AM, Florakis D, Trainer PJ, Camacho-Hubner C, Afshar F, Sabin I, Jenkins JP, Chew SL, Monson JP, Besser GM, Grossman AB 2001 Predictors of the outcome of surgical treatment in acromegaly and the value of the mean growth hormone day curve in assessing postoperative disease activity. J Clin Endocrinol Metab 86:1645–1652[Abstract/Free Full Text]
  11. Damjanovic SS, Neskovic AN, Petakov MS, Popovic V, Macut D, Vukojevic P, Joksimovic MM 2005 Clinical indicators of biochemical remission in acromegaly: does incomplete disease control always mean therapeutic failure? Clin Endocrinol (Oxf) 62:410–417[CrossRef][Medline]
  12. Bates AS, Evans AJ, Jones P, Clayton RN 1995 Assessment of GH status in acromegaly using serum growth hormone, serum insulin-like growth factor-1 and urinary growth hormone excretion. Clin Endocrinol (Oxf) 42:417–423[Medline]
  13. Bidlingmaier M, Strasburger CJ 2007 Growth hormone assays: current methodologies and their limitations. Pituitary 10:115–119[CrossRef][Medline]
  14. Clemmons DR 2007 IGF-I assays: current assay methodologies and their limitations. Pituitary 10:121–128[CrossRef][Medline]
  15. Parkinson C, Ryder WD, Trainer PJ 2001 The relationship between serum GH and serum IGF-I in acromegaly is gender-specific. J Clin Endocrinol Metab 86:5240–5244[Abstract/Free Full Text]
  16. Freda PU 2003 Pitfalls in the biochemical assessment of acromegaly. Pituitary 6:135–140[CrossRef][Medline]
  17. Barkan AL, Halasz I, Dornfeld KJ, Jaffe CA, Friberg RD, Chandler WF, Sandler HM 1997 Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 82:3187–3191[Abstract/Free Full Text]
  18. Bex M, Abs R, T’sjoen G, Mockel J, Velkeniers B, Muermans K, Maiter D 2007 AcroBel, the Belgian registry on acromegaly: a survey of the ‘real-life’ outcome in 418 acromegalic subjects. Eur J Endocrinol 157:399–409[Abstract/Free Full Text]
  19. Brabant G, von zur MA, Wuster C, Ranke MB, Kratzsch J, Kiess W, Ketelslegers JM, Wilhelmsen L, Hulthen L, Saller B, Mattsson A, Wilde J, Schemer R, Kann P 2003 Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study. Horm Res 60:53–60[CrossRef][Medline]
  20. Orme SM, McNally RJ, Cartwright RA, Belchetz PE 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 83:2730–2734[Abstract/Free Full Text]
  21. Abosch A, Tyrrell JB, Lamborn KR, Hannegan LT, Applebury CB, Wilson CB 1998 Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:3411–3418[Abstract/Free Full Text]
  22. Espinosa-de-Los-Monteros AL, Sosa E, Cheng S, Ochoa R, Sandoval C, Guinto G, Mendoza V, Hernandez I, Molina M, Mercado M 2006 Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status. Clin Endocrinol (Oxf) 64:245–249[CrossRef][Medline]
  23. Freda PU, Post KD, Powell JS, Wardlaw SL 1998 Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly. J Clin Endocrinol Metab 83:3808–3816[Abstract/Free Full Text]
  24. Daughaday WH, Starkey RH, Saltman S, Gavin III JR, Mills-Dunlap B, Heath-Monnig E 1987 Characterization of serum growth hormone (GH) and insulin-like growth factor I in active acromegaly with minimal elevation of serum GH. J Clin Endocrinol Metab 65:617–623[Abstract/Free Full Text]
  25. Dimaraki EV, Jaffe CA, DeMott-Friberg R, Chandler WF, Barkan AL 2002 Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up. J Clin Endocrinol Metab 87:3537–3542[Abstract/Free Full Text]
  26. Ho KY, Weissberger AJ 1994 Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy. Clin Endocrinol (Oxf) 41:75–83[Medline]
  27. Peacey SR, Toogood AA, Veldhuis JD, Thorner MO, Shalet SM 2001 The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy. J Clin Endocrinol Metab 86:259–266[Abstract/Free Full Text]
  28. Colao A, Pivonello R, Cavallo LM, Gaccione M, Auriemma RS, Esposito F, Cappabianca P, Lombardi G 2006 Age changes the diagnostic accuracy of mean profile and nadir growth hormone levels after oral glucose in postoperative patients with acromegaly. Clin Endocrinol (Oxf) 65:250–256[CrossRef][Medline]
  29. Freda PU, Landman RE, Sundeen RE, Post KD 2001 Gender and age in the biochemical assessment of cure of acromegaly. Pituitary 4:163–171[CrossRef][Medline]
  30. Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL, Thorner MO 1987 Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 64:51–58[Abstract/Free Full Text]
  31. Weissberger AJ, Ho KK, Lazarus L 1991 Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 72:374–381[Abstract/Free Full Text]
  32. Jenkins PJ, Bates P, Carson MN, Stewart PM, Wass JA 2006 Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly. J Clin Endocrinol Metab 91:1239–1245[Abstract/Free Full Text]
  33. Puder JJ, Nilavar S, Post KD, Freda PU 2005 Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly. J Clin Endocrinol Metab 90:1972–1978[Abstract/Free Full Text]
  34. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N 2004 Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 141:413–420[Abstract/Free Full Text]
  35. Rowles SV, Prieto L, Badia X, Shalet SM, Webb SM, Trainer PJ 2005 Quality of life (QOL) in patients with acromegaly is severely impaired: use of a novel measure of QOL: acromegaly quality of life questionnaire. J Clin Endocrinol Metab 90:3337–3341[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
P. Kamenicky, C. Dos Santos, C. Espinosa, S. Salenave, F. Galland, Y. Le Bouc, P. Maison, P. Bougneres, and P. Chanson
D3 GH receptor polymorphism is not associated with IGF1 levels in untreated acromegaly
Eur. J. Endocrinol., August 1, 2009; 161(2): 231 - 235.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Bianchi, A. Giustina, V. Cimino, R. Pola, F. Angelini, A. Pontecorvi, and L. De Marinis
Influence of Growth Hormone Receptor d3 and Full-Length Isoforms on Biochemical Treatment Outcomes in Acromegaly
J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 2015 - 2022.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. D. Carmichael, V. S. Bonert, J. M. Mirocha, and S. Melmed
The Utility of Oral Glucose Tolerance Testing for Diagnosis and Assessment of Treatment Outcomes in 166 Patients with Acromegaly
J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 523 - 527.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
V J Moyes, K A Metcalfe, and W M Drake
Clinical use of cabergoline as primary and adjunctive treatment for acromegaly
Eur. J. Endocrinol., November 1, 2008; 159(5): 541 - 545.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alexopoulou, O.
Right arrow Articles by Maiter, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alexopoulou, O.
Right arrow Articles by Maiter, D.
Related Collections
Right arrow Neuroendocrinology and Pituitary
Right arrow Endocrine Oncology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals