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Steven W J Lamberts and Leo J Hofland

Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.

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Leo J. Hofland, Peter M. van Koetsveld, Theo M. Verleun and Steven W. J. Lamberts

Abstract.

Pituitary adenoma cells from 6 acromegalic patients were separated on continuous Percoll density gradients according to differences in their density. Two adenomas produced GH only in culture, the other 4 adenomas produced either GH and PRL (one adenoma) or GH and α-subunit (one adenoma) or GH, PRL and α-subunit (2 adenomas). The cell subpopulations obtained by this technique differed in the amount of hormone production per 105 cells: GH release decreased from the low density fractions to the higher density fractions in 5 of 6 adenomas. Intracellular GH levels completely followed this profile. In the mixed GH/α-subunit adenomas the α-subunit profile completely paralleled the GH profile, whereas in the mixed GH/PRL adenomas the PRL profile showed a pattern different from that of GH (and α-subunit). In neither of the adenomas did we find any differences between the subpopulations with respect to the responsiveness of GH, PRL or α-subunit release to GHRH, TRH and the somatostatin analogue SMS 201-995. Conclusions: 1. Within pituitary adenomas from acromegalic patients heterogeneity exists with respect to hormone production per cell. 2. The cell subpopulations obtained by density gradient centrifugation are not different in their responsiveness to SMS 201-995, GHRH or TRH. 3. Because GH and α-subunit release by the fractions from the mixed GH/α-subunit secreting adenomas were completely parallel, further evidence for co-release of GH and α-subunit by the same tumoural cells is provided.

Open access

Joost van der Hoek, Steven W J Lamberts and Leo J Hofland

The patho-physiological role of somatostatin receptor subtypes (sst) in neuro endocrine diseases has gained enhanced scientific interest in the past few years. The development of novel somatotropin-release inhibiting factor analogs, both sst-specific and universal ligands, seem promising as a tool to further increase fundamental insights in sst function. Eventually, this research should result in novel medical therapeutic opportunities in patients suffering from neuro-endocrine diseases. In the present review, the functional role of sst in all types of pituitary adenomas, based on recent preclinical and clinical studies, is being discussed.

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Leo J. Hofland, Peter M. van Koetsveld, Theo M. Verleun and Steven W. J. Lamberts

Abstract

Normal adult female rat mammotrope and somatotrope subpopulations were separated on continuous Percoll density gradients according to differences in their density. Viable cells were recovered in 16 fractions. The cells from each fraction were cultured during 7 days after which period 4-h incubations were performed. rPRL secretion per cell increased towards the higher density fractions. No major difference in TRH, dopamine and somatostatin responsiveness was observed between mammotropes that were recovered in the different gradient fractions. In addition, no differences in somatostatin responsiveness between the somatotrope cells in the different gradient fractions were observed. However, somatotropes that were recovered in the highest density region of the gradient appeared to be more responsive to GHRH than the lower density somatotropes. In the various gradient fractions there were no paradoxical effects of TRH and dopamine on rGH release and of GHRH on rPRL release. Conclusions: 1. In long-term cultures there is no evidence for functionally different subpopulations of mammotropes and somatotropes, separated according to differences in their density, with regard to dopamine and TRH responsiveness and with regard to somatostatin responsiveness, respectively. 2. There is no evidence for a (mammosomatotrope?) subpopulation of cells showing paradoxical responses of PRL or GH release to GHRH and dopamine or TRH, respectively.

Open access

Rosario Pivonello, Diego Ferone, Gaetano Lombardi, Annamaria Colao, Steven W J Lamberts and Leo J Hofland

The dopaminergic system has a pivotal role in the central nervous system but also plays important roles in the periphery, mainly in the endocrine system. Dopamine exerts its functions via five different receptors, named D1–D5, belonging to the category of G protein coupled membrane receptors. Dopamine receptors are heterogeneously expressed in different cells, tissues and organs, where they stimulate or inhibit different functions, including neurotransmission and hormone synthesis and secretion. In particular, the dopamineric system has a pivotal role in the physiological regulation of the hypothalamus–pituitary–adrenal axis. Recent data have demonstrated the expression and function of dopamine receptors not only in endocrine organs but also in endocrine tumors, mainly those belonging to the hypothalamus–pituitary–adrenal axis, and also in the so-called ‘neuroendocrine’ tumors. These data confirm the important role of the dopaminergic system in this endocrine axis, as well as in the neuroendocrine system. This review summarizes the main structural and functional characteristics of dopamine receptors, emphasizing the most recent novelties, and focused on the physiological and pathological regulation of the hypothalamus–pituitary–adrenal axis by the dopaminergic system. In addition, the recent findings on the relationship between dopamine receptors and neuroendocrine tumors are summarized.

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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

Free access

Aimee J Varewijck, Steven W J Lamberts, A J van der Lely, Sebastian J C M M Neggers, Leo J Hofland and Joseph A M J L Janssen

Context

Previously we demonstrated that IGF1 receptor stimulating activity (IGF1RSA) offers advantages in diagnostic evaluation of adult GH deficiency (GHD). It is unknown whether IGF1RSA can be used to monitor GH therapy.

Objective

To investigate the value of circulating IGF1RSA for monitoring GH therapy.

Design/methods

106 patients (54 m; 52 f) diagnosed with GHD were included; 22 were GH-naïve, 84 were already on GH treatment and discontinued therapy 4 weeks before baseline values were established. IGF1RSA was determined by the IGF1R kinase receptor activating assay, total IGF1 by immunoassay (Immulite). GH doses were titrated to achieve total IGF1 levels within the normal range.

Results

After 12 months, total IGF1 and IGF1RSA increased significantly (total IGF1 from 8.1 (95% CI 7.3–8.9) to 14.9 (95% CI 13.5–16.4) nmol/l and IGF1RSA from 115 (95% CI 104–127) to 181 (95% CI 162–202) pmol/l). After 12 months, total IGF1 normalized in 81% of patients, IGF1RSA in 51% and remained below normal in more than 40% of patients in whom total IGF1 had normalized.

Conclusions

During 12 months of GH treatment, changes in IGF1RSA did not parallel changes in total IGF1. Despite normalization of total IGF1, IGF1RSA remained subnormal in a considerable proportion of patients. At present our results have no short-term consequences for GH therapy of GHD patients. However, based on our findings we propose future studies to examine whether titrating GH dose against IGF1RSA results in a better clinical outcome than titrating against total IGF1.

Free access

Johannes Hofland, Wouter W de Herder, Lieke Derks, Leo J Hofland, Peter M van Koetsveld, Ronald R de Krijger, Francien H van Nederveen, Anelia Horvath, Constantine A Stratakis, Frank H de Jong and Richard A Feelders

Context

Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop.

Objective

Investigation of regulation of steroidogenesis in a case of PPNAD with virilization.

Materials and methods

A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues.

Results

Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue.

Conclusion

PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas.

Free access

Federico Gatto, Nienke R Biermasz, Richard A Feelders, Johan M Kros, Fadime Dogan, Aart-Jan van der Lely, Sebastian J C M M Neggers, Steven W J Lamberts, Alberto M Pereira, Diego Ferone and Leo J Hofland

Abstract

Objective

The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function.

Design

To investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands.

Methods

β-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients.

Results

β-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P = 0.024 and P = 0.047) and complete biochemical control (P = 0.047 and P = 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P = 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P = 0.011 and P = 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P = 0.045 and P = 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ = –0.69, P = 0.0011 and ρ = –0.67, P = 0.0016).

Conclusions

Low β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with 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.