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  • Author: Steven WJ Lamberts x
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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.

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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.

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Steven W.J. Lamberts, Jan G. M. Klijn, Frank H. de Jong and Jan C. Birkenhäger

Abstract.

The recovery of the hypothalamo-pituitary-adrenal axis after selective transsphenoidal adenomectomy was studied in 3 patients with Cushing's disease by measuring basal plasma ACTH and cortisol concentrations, cortisol secretion rate, the diurnal rhythm of cortisol, and the reaction of cortisol to lysine vasopressin (LVP), of compound S to metyrapone and of cortisol and growth hormone to an insulin-induced hypoglycaemia. The third patient had been treated previously by external pituitary irradiation. In 2 patients basal plasma ACTH levels returned within normal values before plasma cortisol, but no supra-physiological plasma concentrations of ACTH were seen as has been observed after withdrawal of exogenous glucocorticoids. With regard to the different stimulation tests: at first the normal reaction of plasma cortisol to LVP returned after 3 months, at the same time as the restoration of growth hormone secretion in response to hypoglycaemia. A normalization of the reaction to metyrapone was seen thereafter while finally the reaction of cortisol to an insulin-induced hypoglycaemia and the diurnal rhythm of plasma cortisol returned 15 to 18 months after operation in the first patient and after 12 months in the second patient. Selective adenomectomy had also been carried out in the third patient, as evidenced by normal TSH, LH and FSH secretion. Hypocortisolism, and a deficient ACTH and growth hormone secretion in response to the stimuli mentioned, however, did not normalize up till 22 months after operation. The restoration of the hypothalamo-pituitary-adrenal axis after selective pituitary adenomectomy in Cushing's disease was prevented in this patient by prior external pituitary irradiation.

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Marloes Louwerens, Wouter W de Herder, Pieter TE Postema, Hervé LJ Tanghe and Steven WJ Lamberts

Louwerens M, de Herder WW, Postema PTE, Tanghe HLJ, Lamberts SWJ. Pituitary insufficiency and regression of acromegaly caused by pituitary apoplexy following cerebral angiography. Eur J Endocrinol 1996;134:737–40. ISSN 0804–4643

Pituitary apoplexy as a complication of cerebral angiography has been described in only a few case reports. Some studies have reported the clinical resolution of active acromegaly after pituitary apoplexy. We present a patient with active acromegaly due to a growth hormone (GH)-secreting pituitary macroadenoma, who developed anterior and posterior pituitary insufficiency following cerebral angiography. Furthermore, a significant reduction in tumour size was accompanied by normalization of mean 24 h in GH insulin-like growth factor I (IGF-I) and IGF binding protein 3 levels.

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

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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.

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Frank RE Nobels, Wouter W de Herder, Dik J Kwekkeboom, Willy Coopmans, Andries Mulder, Roger Bouillon and Steven WJ Lamberts

Nobels FRE, de Herder WW, Kwekkeboom DJ, Coopmans W, Mulder A, Bouillon R, Lamberts SWJ. Serum chromogranin A in the differential diagnosis of Cushing's syndrome. Eur J Endocrinol 1994:131:589–93. ISSN 0804–4643

We evaluated whether measuring serum levels of chromogranin A, a marker of neuroendocrine tumours, could be useful in the differential diagnosis between pituitary, adrenal and ectopic causes of Cushing's syndrome. Thirty patients with Cushing's syndrome were studied. The localization of the tumours responsible was pituitary in 15, adrenal in 5 and ectopic in 10 patients. Serum concentrations of chromogranin A were measured in all patients. Petrosal sinus sampling for chromogranin A was performed in the cases with pituitary-dependent Cushing's syndrome. Immunohistochemical staining for chromogranin A was carried out on part of the tumour specimens. Slightly elevated serum levels of chromogranin A (range 223–262 μg/1) were detected in inferior petrosal sinus and peripheral venous samples from three patients with pituitary-dependent Cushing's syndrome. Serum chromogranin A showed no significant pituitary to peripheral gradient in these patients. Chromogranin A levels were not elevated in cases of adrenal Cushing's syndrome. Markedly elevated concentrations (range 270–13900 μg/1) were shown in seven of 10 patients with neuroendocrine tumours with ectopic adrenocorticotrophin (ACTH) and/or corticotrophin-releasing hormone (CRH) production. Widespread metastasis was present in all these cases. Subjects with "occult" carcinoid tumours, with limited spread, had normal chromogranin A levels Immunohistochemical staining for chromogranin A was positive in three out of five pituitary adenomas and in all neuroendocrine tumours with ectopic ACTH and/or CRH production, while it was negative in all adrenocortical tumour specimens. It is concluded that elevated serum levels of chromogranin A can serve as markers of neuroendocrine tumours with ectopic ACTH and/or CRH production. The circulating levels are dependent mainly on the size of the tumours. Serum chromogranin A is not useful in the diagnosis of so-called occult Cushing's syndrome, caused by ectopic ACTH and/or CRH secretion by small neuroendocrine tumours.

F Nobels, Department of Endocrinology, Onze Lieve Vrouw Hospital, 164 Moorselbaan, 9300 Aalst, Belgium

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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