Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery

in European Journal of Endocrinology
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  • The Medical Research Laboratories, Department of Endocrinology and Internal Medicine, Clinical Institute, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark

Context

Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial.

Objective

To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA).

Design and methods

Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)).

Results

Total and bioactive IGF1 (μg/l) levels were similar (total: 185±10 (SA) versus 171±8 (surgery) (P=0.28); bioactive: 1.9±0.2 vs 1.9±0.1 (P=0.70)). Suppression of total and free GH (μg/l) during OGTT was blunted in the SA group (total GHnadir: 0.59±0.08 (SA) versus 0.34±0.06 (surgery) (P=0.01); free GHnadir: 0.43±0.06 vs 0.19±0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02).

Conclusions

i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

Abstract

Context

Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial.

Objective

To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA).

Design and methods

Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)).

Results

Total and bioactive IGF1 (μg/l) levels were similar (total: 185±10 (SA) versus 171±8 (surgery) (P=0.28); bioactive: 1.9±0.2 vs 1.9±0.1 (P=0.70)). Suppression of total and free GH (μg/l) during OGTT was blunted in the SA group (total GHnadir: 0.59±0.08 (SA) versus 0.34±0.06 (surgery) (P=0.01); free GHnadir: 0.43±0.06 vs 0.19±0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02).

Conclusions

i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

Introduction

Acromegaly is a rare condition caused by excessive production of GH usually from a benign pituitary adenoma. The diagnosis is based on clinical symptoms, elevated serum levels of GH and/or insulin-like growth factor 1 (IGF1), and a magnetic resonance imaging (MRI) of the pituitary region. Surgery has stood the test of time as primary therapy, but not all patients are eligible and surgery by itself provides sufficient disease control in only 60% (1). Medical treatment, in particular slow-release formulations of somatostatin analog (SA), therefore plays an important role. With this treatment, prompt and sustained symptom relief (2, 3) as well as functional improvement (4) is usually obtained. In contrast to surgery, it remains to be consistently documented that SA treatment also improves the survival rate, even though two recent meta-analyses indeed point in that direction (5, 6).

The biochemical definition of remission or control with either treatment is far from trivial, and no uniform consensus exists (7). Complete restoration of the normal pulsatile GH secretory pattern would be ideal, but this is not feasible in clinical practice. Normalization of IGF1 levels or achievement of a certain nadir GH value, preferably during an oral glucose tolerance test (OGTT), is used in most studies, but the exact definitions of a normal IGF1 level and a nadir GH level vary considerably and depend on the assay and the quality of the reference values (7). Moreover, discordant results of IGF1 and GH levels are frequently observed (8), which may be caused by several factors. GH levels are influenced not only by the disease and its treatment, but also by chronological age, gender, and body composition (9). In addition, slightly elevated GH levels in the presence of normalized IGF1 levels may be an early predictor of disease recurrence (10), but cases of persistent disease despite very low GH levels (and elevated IGF1 levels) also exist (7, 11). Furthermore, somatostatin acts not only at the pituitary level to suppress GH release, but also exhibits inhibitory effects on GH signaling and thus GH receptor (GHR)-mediated clearance of GH (12). In addition, somatostatin suppresses insulin secretion (13), which may lower hepatic IGF1 production and hence also the circulating levels of IGF1 (14). It has also been reported that SA treatment may impact the GH response to oral glucose (8).

In this study, we compared pertinent markers of GH status in acromegalic patients who were considered in long-term remission based on normalized IGF1 levels either after surgery alone or during SA treatment respectively. This included mean GH curves, nadir GH levels during an OGTT, as well as an assessment of bioactive IGF1 and free GH levels using novel assays. In addition, self-reported health status was assessed in the same patients by means of generic- and disease-specific questionnaires.

Patients and methods

Patients

All patients were diagnosed and treated at the neuroendocrine unit of Aarhus University Hospital and were followed on an outpatient basis (Tables 1 and 2). Serum IGF1 measurements were not available before 1989, and pituitary MRI was not a routine practice until 1992. The inclusion criteria were the following: i) clinical remission for >6 months at the time of follow-up as defined by IGF1 levels within the normal range for age; ii) treatment with either surgery alone or a slow-release formulation of an SA (i.e. Sandostatin LAR (Novartis) or Lanreotide Autogel (Ipsen, Paris, France)); iii) available serum samples at the time of follow-up. Of the 125 acromegalic patients followed, 62 were excluded from the analysis because of i) treatment with pegvisomant (n=8); ii) being recently diagnosed (n=10); iii) lack of available serum samples for analysis (n=7); 4) non-normalized IGF1 levels (n=37).

Table 1

Patient characteristics at baseline. Data are presented as mean±s.e.m.

SA treatmentSurgeryP value
Number2736
Sex (male/female)11/1615/211.00
Age at diagnosis, years44.5±2.747.0±1.90.44
Duration of symptoms (years)7.2±1.25.6±0.80.24
Adenoma size (micro/macro)7/1715/210.48
GH nadir (μg/l)28.0±6.913.9±3.00.20
IGF1 (μg/l)751±69724±490.75
Diabetes mellitus (yes/no)2/252/341.00
Deficiency (%)630.43
 ACTH (no./total)1/271/36
 TSH (no./total)0/270/36
 FSH/LH (no./total)4/272/36
Table 2

Patient characteristics at follow-up. Data are presented as mean±s.e.m.

SA treatmentSurgeryP value
Number2736
Sex (male/female)11/1615/211.00
Age (years)58.4±2.758.8±1.90.91
Surgery (yes/no)21/636/0
Radiation therapy (yes/no)2/251/35
Time since treatment start (years)10.7±1.59.9±1.20.64
Time since surgery (years)13.9±1.89.9±1.20.06
Diabetes mellitus (yes/no)5/224/320.48
Deficiency (%)11110.82
 ACTH (no./total)3/277/36
 TSH (no./total)3/273/36
 FSH/LH (no./total)3/272/36

Sixty-three patients (37F/26M, mean±s.e.m. age 59±2 years) were included, of whom 36 had been treated with surgery alone (surgery) and 27 were on current treatment with SA. The patients were diagnosed between 1967 and 2008 at a mean age of 45.9±1.6 years (Table 1). Twenty-one patients in the SA group had initially undergone transsphenoidal surgery. All operations after 1987 (n=54) were performed by two dedicated neurosurgeons. The mean duration of SA treatment was 10.7±1.4 years (range: 0.6–23 years). Three patients had received conventional radiation therapy 2 years after surgery (one in the surgery group and two in the SA group). Eighteen patients received Sandostatin LAR (mean dose: 19±2 mg/4 weeks), and nine patients were treated with Lanreotide Autogel (mean dose: 66±4 mg/4 weeks). Twenty-seven of 37 female patients were considered postmenopausal at the time of follow-up based on either retrievable gonadotropin measurements or chronological age (>55 years); four female patients received oral estrogen treatment. At the time of follow-up, nine patients (SA: 5 and surgery: 4) were diagnosed with type 2 diabetes, of whom one received insulin treatment (SA treatment).

Methods

The follow-up was performed between 2005 and 2009. The patients were studied after an overnight hospital stay in the fasting and supine state. Blood was sampled from an antecubital vein for 3 h at 10-min intervals for the first hour (‘spontaneous profile’) after which an oral glucose load (75 g) was given (t=0) followed by sampling at t=30, 45, 60, 90, and 120 min. The standard measurements included total GH in all samples, a single total IGF1, and blood glucose during the OGTT. For the purpose of this study, free GH, GH binding protein (GHBP), bioactive IGF1, IGF-binding protein (IGFBP)-1, -2, -3, and insulin were measured from serum samples stored at −20 °C (mean storage time: 13±1 months).

Assays

Total IGF1 levels were measured by a validated, in-house time-resolved immunofluorometric assay (TR-IFMA) after acid–ethanol extraction of the IGFBPs, using recombinant human (rh) IGF1 as standard (Austral Biologicals, San Ramon, CA, USA). Intra- and inter-assay coefficient of variation (CV) averaged 5 and 10% respectively (15). Bioactive IGF1 was determined by a cell-based kinase receptor activation assay (KIRA) based on human embryonic cells transfected with the human IGF1 receptor (IGF1R) gene (16). The bioassay determines the ability of serum IGF to phosphorylate the IGF1R in vitro, and takes into account the presence of the IGFBPs and their ability to modify IGF1R activation. The signal obtained in serum was compared to a serial dilution of rh IGF1 (same as in the IGF1 TR-IFMA). As in in vivo, the bioassay detects IGF2- and pro-IGF2-mediated activation of the IGF1R with a cross-reactivity of 12 and 2% respectively, whereas insulin and its analogs barely cross react (<1%). Mean intra- and inter-assay CV of the KIRA averaged 10 and 15% respectively (16). IGFBP1 was determined by an in-house RIA using an MAB that recognizes all phosphoforms of IGFBP1 (MAB 6303, Medix Biochemica, Kauniainen, Finland). The IGFBP1 was calibrated against highly purified amnion IGFBP1 (HyTest Ltd, Turku, Finland) and had intra- and inter-assay CV values averaging 5 and 12% respectively (17). IGFBP2 was determined by a validated in-house TR-IFMA, based on commercial reagents from R&D Systems (Abingdon, UK). Intra- and inter-assay CV of the IGFBP2 assayed averaged 5 and 12% respectively (17). IGFBP3 was determined by a commercial IRMA (BioSource Inc., Nivelle, Belgium) according to the instructions by the manufacturer. For all data on IGF1, bioactive IGF1, and IGFBP1 to -3, the obtained measurements were within the operational range of the respective assays.

Circulating GH levels were measured using a commercial 22 kDa-specific GH TR-IFMA (Delfia, Perkin Elmer Life Sciences, Turku, Finland), calibrated against the international standard WHO 80/505. Total GH was measured in unprocessed serum according to the recommendations from the manufacturer, with one exception: to reduce the impact of GHBP on the readings of the assay, all samples were incubated overnight rather than for 2 h (18). Free GH levels, i.e. GH not associated with GHBP (identical to the truncated, extracellular domain of the GHR), were determined by a novel, validated in-house ultrafiltration assay that allows separation of free from bound GH at approached in vivo-like conditions. The separation procedure was performed as described recently (18). The obtained ultrafiltrates were assayed for GH using the GH Delfia, performed according to the instructions by the manufacturer, with overall intra- and inter-assay CV values averaging 7 and 11% respectively, i.e. slightly higher than the corresponding CV values of total GH. The detection limit of the GH assay was 0.033 μg/l (18). GHBP was determined by an in-house TR-IFMA with intra- and inter-assay CV values averaging 5 and 12% respectively (19). Glucose was determined by the glucose oxidase method, and insulin was determined by a commercial TR-IFMA (Delfia, Perkin Elmer Life Sciences).

Health status

The generic EuroQoL/EQ-5D health questionnaire evaluates general health status and consists of two parts. The first part comprises five questions regarding mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each answer corresponds to either no problems (1 point), some problems (2 points) or extreme problems (3 points). The second part is a rating scale from 0 to 100 evaluating general health status, where 100 represents the best possible state. The disease-specific questionnaire PASQ from Acrostudy consists of six questions rating 0–8 yielding a maximum of 48 points, and a seventh question based on the first six questions evaluating overall health status rating 0–10. The first six questions evaluate disease-specific symptoms including headache, excessive sweating, joint pain, fatigue, soft tissue swelling, and numbness and tingling of the extremities. In this questionnaire, a score of 0 to the first six questions indicates no symptoms; likewise, in the overall health status, 0 is the best possible. Fifty-seven patients completed the questionnaires, of whom 55 were eligible for the analysis. Eight patients (four from each group) did not contribute any data.

Ethics

The protocol had the consent of the Danish Ethical Committee of Region Midtjylland, and was also registered with the Danish Data Protection Agency.

Statistical analysis

Data were expressed as means±s.e.m. Student's t-test was performed when data were normally distributed. Otherwise a non-parametric Mann–Whitney rank sum test was used. The χ2-test was performed to compare categorical variables. Area under the curve (AUC) during the OGTT was calculated for total GH, free GH, glucose, and insulin using the trapezoid rule (SigmaPlot 11). The levels of insulin, glucose, total GH, and free GH during the OGTT were evaluated according to treatment group by two-way ANOVA. Levels of IGF1 were correlated to log10-transformed GH data using Pearson's correlation analysis. Multiple linear regression analysis was performed to evaluate predictors of IGF1 levels in women at follow-up. The Statistical software SigmaPlot 11 (Systat Software Inc., San Jose, CA, USA) and SPSS 17.0 (SPSS Inc., Chicago, IL, USA) were employed. A P value <0.05 was considered statistically significant.

Results

Patient characteristics

Patient characteristics at baseline and follow-up are provided in Tables 1 and 2 respectively. We recorded no differences in pertinent clinical variables between the groups at either time of diagnosis or follow-up. When comparing time since surgery for the two groups, the difference approached statistical significance (P=0.06), but the time since surgery (in the surgery only group) versus the time since start of SA treatment did not differ (P=0.64).

Total and free GH levels

Total GH (GHtotal) levels (μg/l) were comparable in the two groups in the fasting condition (1.3±0.2 (SA) versus 1.2±0.2 (surgery), P=0.53; Table 3 and Figs 1–3). The nadir level of GHtotal during the OGTT, however, was lower after surgery as compared with SA treatment, and the same difference was recorded in the mean levels of GHtotal during the OGTT (0–120 min) (0.92±0.13 (SA) versus 0.58±0.07 (surgery) (P=0.04)). The relative decrease in GHtotal (%) during the OGTT was also more pronounced in the surgery group (43.0±4.7 vs 59.9±4.9 (P=0.01)). This pattern was also evident when comparing the changes in GH levels with time and treatment by means of ANOVA (P=0.045; Fig. 1).

Table 3

Summary of results presented as mean±s.e.m.

SA treatmentSurgeryP value
Total GH (g/l)
 Nadir0.59±0.080.34±0.060.01
 Mean1.12±0.150.89±0.130.26
 Decrease, mean-nadir (%)43.0±4.759.9±4.90.01
Free GH (μg/l)
 Nadir0.43±0.060.19±0.040.002
 Mean0.57±0.080.36±0.040.04
 Decrease, mean-nadir (%)31.7±4.457.9±5.10.001
IGF1 (μg/l)185±9.7171±8.10.28
Bioactive IGF1 (μg/l)1.9±0.21.9±0.10.70
GHBP (nmol/l)1.5±0.11.6±0.10.44
IGFBP1 (μg/l)66.3±6.561.8±6.20.46
IGFBP2 (μg/l)315±31328±390.86
IGFBP3 (μg/l)3852±1413764±980.60
GH:IGF1 ratio (×100)0.3±0.050.2±0.040.02
Glucose (mmol/l)
 FPG5.4±0.24.9±0.10.01
 2 h glc8.5±0.76.8±0.50.02
 AUC during OGTT (area)1112±46902±48<0.001
Insulin
 Cmax (pmol/l)281±39241±310.28
 Tmax (min)88±5.466±4.70.004
 AUC during OGTT (area)18 158±228717 879±24880.84
Figure 1
Figure 1

Total serum GH levels (mean±s.e.m.) before and during the OGTT (0–120 min). The oral glucose load (75 g) is given at time 0.

Citation: European Journal of Endocrinology 163, 5; 10.1530/EJE-10-0640

Figure 2
Figure 2

Free serum GH levels (mean±s.e.m.) during the OGTT (0–120 min). The oral glucose load is given at time 0.

Citation: European Journal of Endocrinology 163, 5; 10.1530/EJE-10-0640

Figure 3
Figure 3

(A) Total GH and total IGF1 levels (mean±s.e.m.) after somatostatin analog (SA) treatment (open bars) versus surgical treatment (black bars). (B) Corresponding levels of free GH and bioactive IGF1.

Citation: European Journal of Endocrinology 163, 5; 10.1530/EJE-10-0640

The levels of free GH (GHfree) during the OGTT (0–120 min) showed responses similar to GHtotal in both the treatment groups, with a more pronounced suppression after surgery (P<0.001; Fig. 2). During the OGTT, both nadir GHfree and mean GHfree were higher in the SA group (Fig. 3B). Moreover, the ratio of free to total nadir GH was higher in the SA group (0.66±0.04 (SA) versus 0.50±0.04 (surgery), P=0.02).

Females had higher levels of GHtotal (μg/l) irrespective of treatment as compared with males (0.57±0.07 vs 0.27±0.05 (P=0.01)), despite similar levels of IGF1 (μg/l) (174±9 vs 181±9, (P=0.57)) (Fig. 4). Among the female patients, we could not detect a significant effect of estrogen status on either nadir GHtotal or IGF1 levels (GH (μg/l): 0.56±0.09 (deplete) versus 0.58±0.13 (replete), (P=0.93); IGF1 (μg/l): 163±7 (deplete) versus 201±23 (replete), (P=0.07)), and the gender difference in nadir GHtotal also did not depend on the estrogen status of the female patients (data not shown). Multiple linear regression analysis was performed with IGF1 as dependent variable, and treatment modality, age, estrogen status and nadir GHtotal as independent variables. Only age appeared to be a significant and negative predictor of IGF1 (P=0.012).

Figure 4
Figure 4

Total serum GH nadir levels (mean±s.e.m.) at the time of follow-up in female versus male patients.

Citation: European Journal of Endocrinology 163, 5; 10.1530/EJE-10-0640

IGF1, bioactive IGF1, and GH:IGF1 ratio

As expected, no difference was found between the treatment groups regarding IGF1 levels (P=0.28; Table 3 and Figs 3 and 5). Likewise, bioactive IGF1 levels were identical in the two groups. The ratio between nadir GHtotal and total IGF1 was significantly higher in the SA group compared with the surgery group (P=0.02; Fig. 3).

Figure 5
Figure 5

Correlations between IGF1 and GH after treatment. (A and C) Somatostatin analog (SA) treatment. (B and D) Surgery alone.

Citation: European Journal of Endocrinology 163, 5; 10.1530/EJE-10-0640

At baseline levels, log(nadir GHtotal) was positively correlated to IGF1 level (all: r=0.605, P<0.001; SA: r=0.631, P=0.007; surgery: r=0.619, P<0.001), whereas at follow-up, a significant correlation was found only in the surgery group (Fig. 5) (SA: r=−0.20, P=0.32; surgery: r=0.39, P=0.02). The same pattern was observed for log(nadir GHfree) versus bioactive IGF1 (Fig. 5C and D).

GH- and IGFBPs

Serum levels of GHBP and IGFBP1, -2, and -3 were identical in the two groups. Nadir GHfree levels were negatively correlated to GHBP levels (r=−0.35, P=0.005; Table 3). Total IGF1 levels were negatively correlated to IGFBP1 (r=−0.25, P=0.046) and positively to IGFBP3 (r=0.43, P<0.001). In neither operated nor SA-treated patients, we observed correlations between bioactive IGF1 and the molar ratio of IGF1 to IGFBP3 (r<0.06, P>0.80).

Glucose tolerance and insulin secretion

Glucose levels during the OGTT (fasting, 2 h, and AUC) were more elevated in the SA group (Table 3). The peak insulin concentration measured during the OGTT (Cmax) did not differ significantly between the two groups, but the peak was significantly delayed (Tmax) in the SA group (P=0.004). The AUC for insulin during the OGTT did not differ between the two groups (P=0.84).

Health status

The general health status assessed by the EuroQoL/EQ-5D health questionnaire did not differ between the two groups (Table 4). By contrast, the disease-specific health status (PASQ) was significantly reduced in the SA-treated patients.

Table 4

Self-reported health status (see text). Data are presented as mean±s.e.m.

SA treatmentSurgeryP value
EuroQoL: EQ-5D
 Mobility1–31.39±0.11.19±0.10.10
 Self-care1–31.13±0.11.13±0.10.96
 Usual activities1–31.39±0.11.31±0.10.56
 Pain/discomfort1–31.70±0.11.47±0.10.14
 Anxiety/depression1–31.26±0.11.25±0.10.78
EQ-5D overall health status0–10072.52±4.077.09±3.80.29
Acrostudy: PASQ
 Headache0–82.20±0.50.88±0.30.01
 Excessive sweating0–82.05±0.61.44±0.30.46
 Joint pain0–83.70±0.62.28±0.40.049
 Fatique0–83.15±0.52.47±0.40.18
 Soft tissue swelling0–81.95±0.51.16±0.30.12
 Numbness or tingling0–82.15±0.51.56±0.40.29
PASQ total0–4815.20±2.59.78±1.90.04
PASQ overall health status0–103.81±0.52.47±0.40.02

EQ-5D: 1, no problems; 2, some problems; 3, extreme problems. EQ-5D VAS: 100 corresponds to the best imaginable health status and 0 to the worst imaginable. PASQ: 0, no symptoms; 8, invalidating symptoms. Overall PASQ: 0, best possible health status; 10, worst possible.

Discussion

This study was undertaken to compare novel and conventional biomarkers of treatment outcome in acromegalic patients with normalized IGF1 levels after surgery alone versus SA treatment. Moreover, self-reported health status was also assessed by means of generic as well as disease-specific questionnaires. Our main finding is that patients treated with SA exhibit elevated nadir GH levels as compared with patients treated with surgery alone. This was associated with a reduced disease-specific health status in patients treated with SA.

Our study design has limitations. First, the study was not randomized, so even though the two groups did not differ significantly at the time of diagnosis with regard to demographic variables and disease activity, the majority of patients on SA treatment were by definition selected on the basis that they had not responded successfully to initial surgery. In this regard, it is worth noting that the SA group exhibited numerically higher GH levels at the time of diagnosis, although it did not reach statistical significance. We could not record a difference in adenoma size between the two groups, but this most likely reflects that the imaging data were limited and based on routine measurements. The outcome of surgery depends strongly on tumor size and localization (1, 20), and it is probable that the true prevalence of large and/or invasive adenomas was higher in the patients on SA treatment as compared with the patients treated with surgery only. Secondly, our inclusion criterion for all patients was achievement of a normalized serum IGF1 level at the time of follow-up. A normalized IGF1 level is an accepted definition of disease control (21), and IGF1 has also proven a reliable predictor of mortality in acromegaly (6, 22, 23). But the patients represent a selected group since we did not include those with predefined ‘normal’ or ‘safe’ GH levels and elevated IGF1 levels. However, with these limitations in mind, we believe that our study has provided new and interesting information.

A high prevalence of elevated GH levels during the OGTT in the presence of normalized IGF1 levels during SA treatment has previously been observed (8). Other studies using spontaneous GH levels have recorded either the same pattern (24), a higher prevalence of elevated IGF1 levels (25), or no apparent discordance (26). This study, however, is the first to provide serum profiles of GH before and after an OGTT in combination with analysis of novel biomarkers.

Our observation regarding GH levels during SA treatment is in agreement with the data from Biermasz et al. (27), who recorded elevated non-pulsatile GH secretion in seven acromegalic patients with normalized IGF1 levels during SA treatment. That study was based on frequent blood sampling during 24 h, which is not a feasible option in daily clinical practice. Our study indicates that information of a similar nature can be obtained with measurements during an oral glucose load. We consider this observation of potential clinical relevance and suggest that assessment of treatment outcome includes measurement of GH during an OGTT also in SA-treated patients.

The possible mechanisms whereby SA treatment normalizes IGF1 levels despite relatively elevated GH levels are several. It is known that co-administration of octreotide reduces serum IGF1 levels in GH-substituted adult hypopituitary patients (28, 29), which supports a pituitary-independent effect of somatostatin that is not restricted to patients with acromegaly. Moreover, the suppressive effect of somatostatin on insulin secretion (13) may result in reduced hepatic IGF1 production, and hence lower serum IGF1 levels, in as much as insulin stimulates hepatic GHR synthesis and activity (30). Moreover, data from rodent studies show that somatostatin directly suppresses hepatic IGF1 production and possibly also the receptor-mediated clearance of GH (12), and a study in healthy human subjects indicates that somatostatin exerts GH-antagonistic effects directly in skeletal muscle in vivo(31). It has also been suggested that somatostatin may antagonize the suppressive effect of oral glucose on GH secretion (8), and it is worth noting that the difference in GH levels in our study was mainly present during the OGTT. The elevation in GH relative to IGF1 observed in the SA group was even more pronounced when free GH levels were measured, which is compatible with the observation that GHBP levels were comparable in the two groups. At present, however, the precise role of free GH measurements in clinical practice remains to be defined, and the same applies to bioactive IGF1.

Somatostatin-induced suppression of portal insulin levels may also impact circulating IGF1 levels indirectly via effects on IGFBPs, particularly IGFBP1 (32). We did, however, not detect any differences in the levels of either IGFBPs or bioactive IGF1 in our two patient groups. SA treatment is associated with an increase in IGFBP1 levels, which may be a combination of a direct stimulatory effect of SA and suppression of insulin secretion (33). In addition, there are several lines of evidence to suggest that GH per se suppresses IGFBP1 (34, 35), and we have observed that surgically cured acromegalic patients exhibit supranormal IGFBP1 levels (36). So it could be argued that IGFBP1 levels are expected to increase after both types of therapy albeit perhaps via different mechanisms. Glucose tolerance was significantly impaired in the SA group, which is compatible with most albeit not all studies (37). The mechanism is readily explained by the inhibition of stimulated insulin secretion since insulin sensitivity has been shown to improve during SA treatment (38). We also recorded higher fasting levels of plasma glucose in the SA group, which contrasts with the average outcome of 31 trials (37).

Our observation of a positive correlation between serum levels of IGF1 and GH (log10-transformed) in newly diagnosed acromegaly is in accordance with the literature (39), and it is interesting that this correlation is preserved after surgery and lost after SA treatment. It supports the notion that the effect of SA treatment is not restricted to suppression of GH secretion and as such differs from surgery alone.

It has previously been recorded that serum GH levels are higher in female as compared with male patients with acromegaly (9, 40, 41, 42), and our study demonstrates that this difference prevails during SA treatment. It is also interesting that the gender difference in our study was more pronounced when basal GH levels were compared. This gender-specific difference in GH levels is also observed in healthy subjects and seems to represent a relative GH resistance in females as compared with males. This notion is supported by the fact that GH dose requirements are higher in females as compared with male patients with adult GH deficiency (43). Several lines of evidence suggest that the elevated GH levels in females represent an increase in GH secretion to compensate for a suppressive effect of estrogen on hepatic IGF1 production (44, 45), but the gender-specific difference in patients with acromegaly is also reported in elderly subjects and is not fully accounted for by estrogen status (9). The observation made from that study, which did not include patients on medical treatment, was replicated in our population, and both dataset suggest that additional factors such as abdominal adiposity may contribute to the relative increase in GH levels in females as compared with males (46).

It is generally appreciated that health-related quality of life is impaired in acromegaly, and that this impairment is only partially restored following treatment (47, 48, 49). It was, however, unexpected that the disease-specific health status of SA-treated patients was significantly poorer as compared with patients treated only with surgery. It is important to emphasize that our study – due to its design – is unable to investigate if surgical treatment per se is superior to SA treatment as regards health status. It is likely that the two groups differed at the time of diagnosis in terms of disease severity, and that this may have contributed to the health status at the time of follow-up. Our results also do not question the usefulness of SA treatment. What our results do question is whether a normalized serum IGF1 level is a sufficient biomarker of disease activity especially during SA treatment. In this regard, our data support the observation made by Neggers et al. (50) that disease-specific quality of life improved significantly in the SA-treated patients following placebo-controlled co-treatment with pegvisomant despite unaltered and normalized serum IGF1 levels. Both studies suggest that serum IGF1 levels may not adequately reflect disease activity during SA treatment. To test this hypothesis, a randomized study in the SA-treated patients is required comparing the impact of targeting either ‘safe’ GH levels or normalized IGF1 levels on disease-specific health status. Such a study is feasible and would be relevant.

In conclusion, this study reports that achievement of normal IGF1 levels in patients with acromegaly during SA treatment is accompanied by relatively elevated nadir GH levels as compared with patients who achieve normal IGF1 levels after surgery alone. This was associated with a poorer disease-specific health status in the SA group. The underlying mechanisms for this discordance remain to be clarified, but we hypothesize that SA treatment not only reduces GH secretion from the pituitary tumor or its remnant, but also exerts a specific suppressive effect on hepatic IGF1 production. The latter effect of SA treatment may therefore result in biochemical normalization – as defined by serum IGF1 – despite continued disease activity induced by circulating GH. This hypothesis should be tested in a randomized trial, but in the mean time, we suggest that assessment of treatment outcome in the SA-treated patients should include frequent measurements of serum GH during an OGTT in addition to a single IGF1 measurement.

Declaration of interest

J O L Jørgensen has received lecture fees and unrestricted research grants from Pfizer, Novartis, and Ipsen.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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  • View in gallery

    Total serum GH levels (mean±s.e.m.) before and during the OGTT (0–120 min). The oral glucose load (75 g) is given at time 0.

  • View in gallery

    Free serum GH levels (mean±s.e.m.) during the OGTT (0–120 min). The oral glucose load is given at time 0.

  • View in gallery

    (A) Total GH and total IGF1 levels (mean±s.e.m.) after somatostatin analog (SA) treatment (open bars) versus surgical treatment (black bars). (B) Corresponding levels of free GH and bioactive IGF1.

  • View in gallery

    Total serum GH nadir levels (mean±s.e.m.) at the time of follow-up in female versus male patients.

  • View in gallery

    Correlations between IGF1 and GH after treatment. (A and C) Somatostatin analog (SA) treatment. (B and D) Surgery alone.

  • 1

    Swearingen B, Barker FG II, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. Journal of Clinical Endocrinology and Metabolism 1998 83 34193426 doi:10.1210/jc.83.10.3419.

    • Search Google Scholar
    • Export Citation
  • 2

    Ch'ng LJ, Sandler LM, Kraenzlin ME, Burrin JM, Joplin GF, Bloom SR. Long term treatment of acromegaly with a long acting analogue of somatostatin. BMJ 1985 290 284285 doi:10.1136/bmj.290.6464.284-a.

    • Search Google Scholar
    • Export Citation
  • 3

    Chanson P, Borson-Chazot F, Kuhn JM, Blumberg J, Maisonobe P, Delemer B. Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly. Clinical Endocrinology 2008 69 299305 doi:10.1111/j.1365-2265.2008.03208.x.

    • Search Google Scholar
    • Export Citation
  • 4

    Maison P, Tropeano AI, Macquin-Mavier I, Giustina A, Chanson P. Impact of somatostatin analogs on the heart in acromegaly: a meta analysis. Journal of Clinical Endocrinology and Metabolism 2007 92 17431747 doi:10.1210/jc.2006-2547.

    • Search Google Scholar
    • Export Citation
  • 5

    Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP. Mortality in acromegaly: a meta analysis. Journal of Clinical Endocrinology and Metabolism 2008 93 6167 doi:10.1210/jc.2007-1191.

    • Search Google Scholar
    • Export Citation
  • 6

    Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. European Journal of Endocrinology 2008 159 8995 doi:10.1530/EJE-08-0267.

    • Search Google Scholar
    • Export Citation
  • 7

    Freda PU. Current concepts in the biochemical assessment of the patient with acromegaly. Growth Hormone and IGF Research 2003 13 171184 doi:10.1016/S1096-6374(03)00029-7.

    • Search Google Scholar
    • Export Citation
  • 8

    Carmichael JD, Bonert VS, Mirocha JM, Melmed S. The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 2009 94 523527 doi:10.1210/jc.2008-1371.

    • Search Google Scholar
    • Export Citation
  • 9

    Parkinson C, Ryder WD, Trainer PJ. The relationship between serum GH and serum IGF-I in acromegaly is gender-specific. Journal of Clinical Endocrinology and Metabolism 2001 86 52405244 doi:10.1210/jc.86.11.5240.

    • Search Google Scholar
    • Export Citation
  • 10

    Freda PU, Nuruzzaman AT, Reyes CM, Sundeen RE, Post KD. Significance of “abnormal” nadir growth hormone levels after oral glucose in postoperative patients with acromegaly in remission with normal insulin-like growth factor-I levels. Journal of Clinical Endocrinology and Metabolism 2004 89 495500 doi:10.1210/jc.2003-031316.

    • Search Google Scholar
    • Export Citation
  • 11

    Dimaraki EV, Jaffe CA, DeMott-Friberg R, Chandler WF, Barkan AL. Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up. Journal of Clinical Endocrinology and Metabolism 2002 87 35373542 doi:10.1210/jc.87.8.3537.

    • Search Google Scholar
    • Export Citation
  • 12

    Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis. Journal of Clinical Investigation 2004 114 349356 doi:10.1172/JCI19933.

    • Search Google Scholar
    • Export Citation
  • 13

    Alberti KG, Christensen NJ, Christensen SE, Hansen AP, Iversen J, Lundbaek K, Seyer-Hansen K, Orskov H. Inhibition of insulin secretion by somatostatin. Lancet 1973 2 12991301 doi:10.1016/S0140-6736(73)92873-0.

    • Search Google Scholar
    • Export Citation
  • 14

    Wurzburger MI, Prelevic GM, Sonksen PH, Balint-Peric LA, Wheeler M. The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes. Journal of Clinical Endocrinology and Metabolism 1993 77 267272 doi:10.1210/jc.77.1.267.

    • Search Google Scholar
    • Export Citation
  • 15

    Frystyk J, Dinesen B, Ørskov H. Non-competitive time-resolved immunofluorometric assays for determination of human insulin-like growth factor I and II. Growth Regulation 1995 5 169176.

    • Search Google Scholar
    • Export Citation
  • 16

    Chen JW, Ledet T, Ørskov H, Jessen N, Lund S, Whittaker J, De Meyts P, Larsen MB, Christiansen JS, Frystyk J. A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. American Journal of Physiology. Endocrinology and Metabolism 2003 284 E1149E1155 doi:10.1152/ajpendo.00410.2002.

    • Search Google Scholar
    • Export Citation
  • 17

    Jeyaratnaganthan N, Grønbaek H, Holland-Fischer P, Espelund U, Chen JW, Flyvbjerg A, Vilstrup H, Frystyk J. Ascites from patients with alcoholic liver cirrhosis contains higher IGF-I bioactivity than serum. Clinical Endocrinology 2010 72 625632 doi:10.1111/j.1365-2265.2009.03707.x.

    • Search Google Scholar
    • Export Citation
  • 18

    Frystyk J, Andreasen CM, Fisker S. Determination of free growth hormone. Journal of Clinical Endocrinology and Metabolism 2008 93 30083014 doi:10.1210/jc.2008-0375.

    • Search Google Scholar
    • Export Citation
  • 19

    Fisker S, Frystyk J, Skriver L, Vestbo E, Ho KK, Orskov H. A simple, rapid immunometric assay for determination of functional and growth hormone-occupied growth hormone-binding protein in human serum. European Journal of Clinical Investigation 1996 26 779785 doi:10.1046/j.1365-2362.1996.2010558.x.

    • Search Google Scholar
    • Export Citation
  • 20

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