We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.
J Feenstra, M O van Aken, W W de Herder, R A Feelders and A J van der Lely
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
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.
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.
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.
Leo J Hofland, Joost van der Hoek, Richard Feelders, Maarten O van Aken, Peter M van Koetsveld, Marlijn Waaijers, Diana Sprij-Mooij, Christian Bruns, Gisbert Weckbecker, Wouter W de Herder, Albert Beckers and Steven W J Lamberts
Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing’s disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst1, sst2, sst3 and sst5 was recently introduced. We compared the in vitro effects of the sst2-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells.
Methods: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied.
Results: Corticotroph adenomas expressed predominantly sst5 mRNA (six out of six adenomas), whereas sst2 mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range −30 to −40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (− 28%). In AtT20 cells, expressing sst2, sst3 and sst5, SOM230 inhibited ACTH secretion with high potency (IC50 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst5 is relatively resistant to negative control by glucocorticoids.
Conclusions: The selective expression of sst5 receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing’s disease.
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.
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.
S M Webb, X Badia, M J Barahona, A Colao, C J Strasburger, A Tabarin, M O van Aken, R Pivonello, G Stalla, S W J Lamberts and J E Glusman
Chronic exposure to hypercortisolism has significant impact on patient's health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a disease-generated questionnaire to evaluate HRQoL in patients with Cushing's syndrome (CS; CushingQoL).
Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions.
Observational, international, cross-sectional study.
A total of 125 patients were recruited by 14 investigators from Spain, France, Germany, The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 36 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score.
A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females, mean age 45 years (range 20–73 years); 39 (31%) were currently hypercortisolemic; and 47 (38%) adrenal insufficient. In clinical practice, CushingQoL was feasible (117; 94% of patients fully responded to the questionnaire in a mean time of 4 min), reliable (Crohnbach's α=0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P<0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson's correlation coefficient ≥0.597). Patients with current hypercortisolism scored worse (lower) than those without (44±22 vs 56±21, P=0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL.
CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters.