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Aart Jan van der Lely, Peter Jönsson, Patrick Wilton, Ann-Charlotte Åkerblad, José Cara and Ezio Ghigo

Objective

To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I.

Design

ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the ‘high’-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35–60 (10–90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the ‘low’-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3–10 (10–90%)).

Results

Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m2). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups.

Conclusions

Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

Free access

Aart-Jan van der Lely, Ignacio Bernabeu, Jan Cap, Philippe Caron, Annamaria Colao, Josef Marek, Sebastian Neggers and Pascal Birman

Objective

To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40–120 mg/week) in acromegaly.

Design

This is a 28-week, multicenter, open-label, single-arm sequential study.

Methods

Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40–80 mg once weekly or 40 or 60 mg twice weekly).

Results

In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (−0.6±1.6) and soft tissue swelling (−0.6±1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related – thrombocytopenia, urticaria; not treatment related – abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5×upper limit of normal with normalization after withdrawal).

Conclusions

In patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

Restricted access

Wouter W de Herder, Piet Uitterlinden, Aart-Jan van der Lely, Leo J Hofland and Steven WJ Lamberts

de Herder WW, Uitterlinden P, van der Lely A-J, Hofland LJ. Lamberts SWJ. Octreotide, but not bromocriptine, increases circulating insulin-like growth factor binding protein 1 levels in acromegaly. Eur J Endocrinol 1995;133:195–9. ISSN 0804–4643

Twenty-three patients with active acromegaly underwent serum sampling for growth hormone (GH), insulin and insulin-like growth factor binding protein 1 (IGFBP-1) after placebo or single doses of octreotide or bromocriptine. Integrated 24-h serum GH levels decreased by 90% after octreotide and 49% after bromocriptine. A statistically significant correlation between the course of GH levels after octreotide and bromocriptine was observed (p < 0.001). Octreotide, but not bromocriptine, induced a significant increase in integrated 24-h serum IGFBP-1 levels to 37.4 times the baseline values. Bromocriptine caused a non-significant increase in integrated 24-h serum IGFBP-1 levels, which argues against a direct regulatory effect of GH on IGFBP-1 production in acromegaly. In conclusion, octreotide induces in acromegaly the production of IGFBP-1, which occurs independently of the number of somatostatin receptors on the GH-secreting pituitary adenoma. The supposed inhibitory effect of IGFBP-1 on the biological effect of IGF-I might result in an additional clinical benefit in acromegalic patients as compared to treatment directed at the pituitary level.

WW de Herder, Department of Internal Medicine III and Clinical Endocrinology, University Hospital Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

Restricted access

Annewieke W van den Beld, Olga D Carlson, Maire E Doyle, Dimitris Rizopoulos, Luigi Ferrucci, Aart Jan van der Lely and Josephine M Egan

Objective

Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality.

Design and Participants

BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years.

Results

IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P < 0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43 (95% CI: 0.3–2.6). This accounted for both baseline (P = 0.02) as well as serial (P < 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P < 0.001).

Conclusion

This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.

Open access

Wouter W de Herder, Ambroos E M Reijs, Richard A Feelders, Maarten O van Aken, Eric P Krenning, Aart-Jan van der Lely and Dik J Kwekkeboom

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using 123I-S-(−)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide (123I-IBZM) and 123I-epidepride. 123I-epidepride is generally superior to 123I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, 123I-IBZM and 123I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with 11C-N-raclopride and 11C-N-methylspiperone.

Free access

Wouter W de Herder, H Rob Taal, Piet Uitterlinden, Richard A Feelders, Joop A M J L Janssen and Aart-Jan van der Lely

Objectives: To study whether the growth hormone (GH) response after the subcutaneous administration 50 μg of octreotide (acute octreotide test) has any predictive value for long-term IGF-I normalization with Sandostatin LAR.

Design: Twenty four therapy-naive patients with active acromegaly were studied.

Results: >75% GH decrease in the acute octreotide test predicted long-term IGF-I normalization with Sandostatin LAR in 8/11 (73%) of patients. 3/13 (23%) patients with <75% GH decrease in the acute octreotide test were long-term biochemically controlled with Sandostatin LAR. Using the >75% GH reduction criterion, the sensitivity and specificity of this test for predicting long-term normalization of serum IGF-I with Sandostatin LAR treatment were 73% and 77%, respectively (positive and negative predictive values: 73% and 77%, respectively). 6/8 (75%) patients with GH suppression to levels <1.1 μg/l and 9/16 (56%) patients with GH suppression to levels <2 μg/l in the acute octreotide test showed normalization of serum IGF-I with long-term Sandostatin LAR treatment. The sensitivity and specificity of GH suppression <1.1 μg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 55% and 85%, respectively (positive and negative predictive values: 75% and 69%, respectively). The sensitivity and specificity of GH suppression <2 μg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 82% and 46%, respectively (positive and negative predictive values: 56% and 75%, respectively).

Conclusion: The acute octreotide is not recommended for clinical decision making with regard to long-term treatment using the long-acting somatostatin analog Sandostatin LAR in acromegaly.

Free access

Rosalie M Kiewiet, Maarten O van Aken, Kim van der Weerd, Piet Uitterlinden, Axel P N Themmen, Leo J Hofland, Yolanda B de Rijke, Patric J D Delhanty, Ezio Ghigo, Thierry Abribat and Aart Jan van der Lely

Objective

To investigate the effects of unacylated ghrelin (UAG) and co-administration of acylated ghrelin (AG) and UAG in morbid obesity, a condition characterized by insulin resistance and low GH levels.

Design and method

Eight morbidly obese non-diabetic subjects were treated with either UAG 200 μg, UAG 100 μg in combination with AG 100 μg (Comb) or placebo in three episodes of 4 consecutive days in a double-blind randomized crossover design. Study medication was administered as daily single i.v. bolus injections at 0900 h after an overnight fast. At 1000 h, a standardized meal was served. Glucose, insulin, GH, free fatty acids (FFA) and ghrelin were measured up to 4 h after administration.

Results

Insulin concentrations significantly decreased after acute administration of Comb only, reaching a minimum at 20 min: 58.2±3.9% of baseline versus 88.7±7.2 and 92.7±2.6% after administration of placebo and UAG respectively (P<0.01). After 1 h, insulin concentration had returned to baseline. Glucose concentrations did not change after Comb. However, UAG administration alone did not change glucose, insulin, FFA or GH levels.

Conclusion

Co-administration of AG and UAG as a single i.v. bolus injection causes a significant decrease in insulin concentration in non-diabetic subjects suffering from morbid obesity. Since glucose concentration did not change in the first hour after Comb administration, our data suggest a strong improvement in insulin sensitivity. These findings warrant studies in which UAG with or without AG is administered for a longer period of time. Administration of a single bolus injection of UAG did not influence glucose and insulin metabolism.

Free access

Mark Wijnen, Daniel S Olsson, Marry M van den Heuvel-Eibrink, Casper Hammarstrand, Joseph A M J L Janssen, Aart-Jan van der Lely, Gudmundur Johannsson and Sebastian J C M M Neggers

Objective

Patients with craniopharyngioma are at an increased risk for cardio- and cerebrovascular mortality. The metabolic syndrome (MetS) is an important cardiometabolic risk factor, but barely studied in patients with craniopharyngioma. We aimed to investigate the prevalence of and risk factors for the MetS and its components in patients with craniopharyngioma.

Design

Cross-sectional study with retrospective data.

Methods

We studied the prevalence of and risk factors for the MetS and its components in 110 Dutch (median age 47 years, range 18–92) and 68 Swedish (median age 50 years, range 20–81) patients with craniopharyngioma with ≥3 years of follow-up (90 females (51%); 83 patients with childhood-onset craniopharyngioma (47%); median follow-up after craniopharyngioma diagnosis 16 years (range 3–62)). In Dutch patients aged 30–70 years and Swedish patients aged 45–69 years, we examined the prevalence of the MetS and its components relative to the general population.

Results

Sixty-nine (46%) of 149 patients with complete data demonstrated the MetS. Prevalence of the MetS was significantly higher in patients with craniopharyngioma compared with the general population (40% vs 26% (P < 0.05) for Dutch patients; 52% vs 15% (P < 0.05) for Swedish patients). Multivariable logistic regression analysis identified visual impairment as a borderline significant predictor of the MetS (OR 2.54, 95% CI 0.95–6.81; P = 0.06) after adjustment for glucocorticoid replacement therapy and follow-up duration. Age, female sex, tumor location, radiological hypothalamic damage, 90Yttrium brachytherapy, glucocorticoid replacement therapy and follow-up duration significantly predicted components of the MetS.

Conclusions

Patients with craniopharyngioma are at an increased risk for the MetS, especially patients with visual impairment.

Free access

Wouter W de Herder, Ambroos E M Reijs, Richard A Feelders, Maarten O van Aken, Eric P Krenning, Hervé L J Tanghe, Aart-Jan van der Lely and Dik J Kwekkeboom

Objective: Clinically non-functioning pituitary adenomas (NFPAs) can express functional dopamine D2 receptors. Therapy with dopamine (DA) agonists may result in a NFPA size reduction. However, DA agonist-sensitive and -resistant NFPAs are clinically indistinguishable. We have studied the correlation between in vivo imaging of D2 receptors using 123I-epidepride and the radiological response of NFPA to DA in 18 patients.

Methods: Patients were treated with either cabergoline (1–2 mg/week) or quinagolide (150–300 μg/day) for a mean period of 89.7 months (range, 34–187 months).

Results: Pituitary uptake of 123I-epidepride varied from slight uptake classified as grade 0 to very high classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three; grade 2 in ten, and grade 3 in one. NFPA stabilization or shrinkage with DA agonist therapy showed no significant difference between grade 0, 1, and 2 tumors (mean tumor stabilization or shrinkage: 31, 30, and 36% respectively). However, when we considered a decrease in tumor size ranging from 0 to 20% as tumor stabilization and >20% decrease in tumor size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three with grade 1 uptake, and eight out of ten with grade 2 uptake showed tumor shrinkage.

Conclusion: In conclusion, there is limited clinical usefulness of dopamine D2 receptor imaging for predicting the clinical efficacy of DA agonist in selected patients with NFPAs. DA agonist therapy in NFPAs can result in tumor stabilization and shrinkage.

Free access

Ingrid E Bonapart, Ron van Domburg, Saskia M T H ten Have, Wouter W de Herder, Ruud A M Erdman, Joop A M J L Janssen and Aart Jan van der Lely

Objectives: To investigate the quality of life (QoL) in acromegalic patients in relation to biochemical parameters.

Design and methods: Single-center, open label study in 14 acromegalic patients (eight woman and six men, age 33–77 years), with normal serum IGF-I levels during long-term treatment with monthly injections of 20 mg of long-acting octreotide. We investigated which biochemical parameter might reflect optimal QoL, using the SF-36 questionnaire.

Results: We observed that six patients had a low QoL score at baseline in the same range as observed in cancer patients. The other eight patients had a normal QoL. GH, IGF-I nor free IGF-I could discriminate these two subgroups at baseline. After skipping one monthly injection, all six subjects with the low QoL escaped in their free IGF-I concentrations. Also total IGF-I concentrations escaped in four of these six. In the subjects with normal QoL, free IGF-I levels remained normal in all, while total IGF-I levels only escaped in one.

Conclusions: This study tells us that the currently used biochemical criteria for disease control in acromegaly might be sufficient in assessing long-term mortality and morbidity, but they are insufficient in addressing the most important parameter from the patient’s perspective – QoL.