Abstract. Natural Somatostatin has a short half-life (3 min), is only active after intravenous administration and causes a rebound hypersecretion of hormones after discontinuation of administration. Recently a longacting powerful Somatostatin analog was developed (SMS 201-995; Sandostatin) which has a half-life of 113 min after subcutaneous administration. After administration of this analog no rebound hypersecretion of hormones was observed. In the present review the effects of the acute administration and of long-term treatment with SMS 201-995 in acromegalic patients is discussed. In addition the potential role of therapy with Somatostatin analogs and the preliminary effects of Somatostatin and/or SMS 201-995 are discussed in disorders of gastro-intestinal function (haemorrhages, diarrhoea, pancreatitis and endocrine pancreatic tumours), diabetes mellitus, central nervous system disturbances and oncology. Finally, several aspects of the tolerance, tachyphylaxis and side effects of SMS 201-995 are discussed.
Steven W.J. Lamberts
Abstract. SMS 201-995 (Sandostatin) is an octapeptide which differs in its action from native somatostatin in four ways: 1) it inhibits GH hormone secretion in preference to insulin secretion; 2) it can be administered subcutaneously or even orally; 3) it is long-acting (t1/2 after sc administration 113 min), and 4) there is no rebound hypersecretion of hormones when the effect of the analogue lingers off. In this paper a guide is offered for the use of Sandostatin in the treatment of acromegaly (after unsuccessful operation and/or radiotherapy) and of metastatic endocrine pancreatic tumours and carcinoids. A dose regimen for these two types of patients is suggested and the adverse reactions which can be expected are summarized. In addition, preliminary data are shown and the limitations are discussed of possible future indications of the analogue in the treatment of cancer, diabetes mellitus and gastrointestinal diseases.
TheoJ. Visser and Steven W. J. Lamberts
In 15 untreated patients with Cushing's disease the regulation of TSH secretion and thyroid function were evaluated. The maximal increment of plasma TSH to TRH was 3.8 ± 2.2 vs 8.7 ± 2.9 μU/ml (patients with Cushing's disease vs controls; mean ± sd; P < 0.001). Free thyroxine-index was 21.8 ± 5.2 vs 27.7 ± 5.0 (P < 0.001). Plasma T3 1.45 ± 0.24 vs 1.96 ± 0.32 nmol/1 (P < 0.001) and reverse T3 0.22 ± 0.05 vs 0.20 ± 0.08 nmol/l (N.S.). The maximal TSH increase in response to TRH was inversely correlated with plasma cortisol (P < 0.05).
The maximal increment of TSH to TRH and plasma T4, free T4 index and T3 are reduced in patients with Cushing's disease due to an impaired thyrotroph function. Plasma reverse T3, however, is normal which may be due to a simultaneous decrease in production and degradation.
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.
Steven W.J. Lamberts, Piet Uitterlinden and Jan M. G. Klijn
Abstract. Chronic therapy of a patient with Nelson's syndrome for 2 years with 300 μg SMS 201–995 per day resulted in a significant decrease in circulating ACTH levels, normalization of the visual field defect and of loss of visual acuity of one eye, and stabilization of tumour growth, without radiological evidence of shrinkage of the pituitary tumour. In two other patients with Nelson's syndrome, SMS 201–995 acutely inhibited circulating ACTH levels. This effect could be shown best if cortisol replacement was temporarily withheld. SMS 201–995 did not affect plasma ACTH and cortisol levels in three patients with untreated Cushing's disease.
Richard J. Krieg Jr, Steven W.J. Lamberts and Robert M. MacLeod
Abstract. Prolactin (Prl) secretion is normally elevated on the afternoon of pro-oestrus in the rat. Studies have shown that ether stress caused a 'paradoxical inhibiting effect' on these high Prl levels. The present study was designed to investigate whether the paradoxical suppression of Prl was mediated by the central nervous system or the adrenal glands. Plasma was obtained from adult female rats after sampling via intra-atrial catheters from 16.25–18.45 h on the afternoon of pro-oestrus. Restraint stress administered between 16.45–17.00 h induced the expected precipitous decrease in plasma Prl in intact animals. Pre-treatment of intact animals with the catecholamine receptor blocking agent haloperidol (1.0 mg/kg at 13.00 h) resulted in a further elevation of plasma Prl levels as compared with untreated controls, but eliminated the decrease of Prl in response to restraint stress. Although acutely adrenalectomized (ADX) animals proved to be highly sensitive to the bleeding procedures, initial Prl levels on the afternoon of pro-oestrus were not different from those of intact animals. Restraint stress under conditions of acute ADX was not found to induce the expected suppression of high Prl levels. Rather, the response was opposite to that which occurred in intact animals. These results indicate that the paradoxical suppression of Prl by restraint stress was mediated by catecholaminergic mechanisms, and that the adrenal gland was essential for the effect.
Leo J. Hofland, Peter M. van Koetsveld, Theo M. Verleun and Steven W. J. Lamberts
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.
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.
Leo J. Hofland, Peter M. van Koetsveld, Theo M. Verleun and Steven W. J. Lamberts
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.
Annie H. Wagenaar, Alan G. Harris, Aart J. van der Lely and Steven W. J. Lamberts
The separate and combined GH-lowering effects of single doses of octreotide and bromocriptine were assessed in 51 acromegalic patients on 4 occasions each 2 days apart. Patients received sequentially: placebo sc (N=51), 50 μg octreotide sc (N=51), 2.5 mg bromocriptine po (N=40) or a combination of both drugs (N=25). With octreotide, in 28 patients (55%) GH levels were suppressed to less than 5 μg/l and 39 of them (76.5%) had a 50% or greater decrease of their basal GH level from 2 to 6 h. During bromocriptine, GH values were suppressed to below 5 μg/l in 11 patients (27.5%) and reduced by 50% or more in 21 (52.5%). The combination of both drugs acutely suppressed GH levels to less than 2 μg/l in 32%, to less than 5 μg/l in 56%, and by more than 50% in 84% of patients. Octreotide produced a stronger and faster suppression of GH levels than bromocriptine in most patients. The combination of both drugs had an additive effect on the lowering of GH levels, especially between 7 and 10 h after drug administration. These results suggest that chronic therapy with a combination of both drugs may be as effective as therapy with higher doses of either compound alone. Albeit transient, octreotide caused a rapid near total suppression of insulin release in the morning, 15 to 45 min after administration. Postprandial glucose rise, between 2 and 3.5 h after breakfast was significantly higher during octreotide than on the control day.