P. Colombo

Failure of somatostatin and octreotide to acutely affect the hypothalamic-pituitary-adrenal function in patients with corticotropin hypersecretion

Although somatostatin inhibits a variety of pituitary and non-pituitary hormones, not univocal data on its effects on ACTH release have been reported so far. In this study we investigated the effects of somatostatin or octreotide on ACTH levels of patients with corticotropin hypersecretion: 7 patients with Addison’s disease, 2 patients previously adrenalectomized for Cushing’s disease, 4 patients with Cushing’s disease and 3 patients with ectopic ACTH syndrome. Plasma ACTH and Cortisol levels were determined after somatostatin (500μg over 60 min) infusion or octreotide (100μg sc) injection. In 5 other patients with Cushing’s disease ACTH and Cortisol responses to CRH (1 μ/kg iv) were evaluated in basal conditions and after octreotide acute administration. In no patients with Addison’s disease any inhibitory influence of somatostatin (Δ % = −21, −25) or octreotide (Δ % = −38 ± 12 vs −39 ± 12 after saline) on plasma ACTH was found. Somatostatin did not significantly inhibit plasma ACTH in the two patients previously adrenalectomized for Cushing’s disease and in 3 patients with Cushing’s syndrome; in other 4 patients with Cushing’s syndrome octreotide did not affect plasma ACTH levels. In 5 patients with Cushing’s disease the plasma ACTH and Cortisol responses to CRH were similar both before (ACTH from 9.9 ± 1.7 pmol/L to 19.4 ± 6.1 pmol/L; Cortisol from 496 ± 43.9 nmol/L to 923 ± 355 nmol/L) and after octreotide injection (ACTH from 8.8 ± 2.4 pmol/L to 19.1 ± 8.2 pmol/L; Cortisol from 510 ± 54.6 nmol/L to 735 ± 220 nmol/L). In conclusion, the acute administration of somatostatin or octreotide is not able to modify ACTH levels in patients with corticotropin hypersecretion either due to hypo-cortisolemic state or consequent to ACTH-secret-ing pituitary or ectopic tumors; moreover, octreotide does not affect the pituitary-adrenal responsiveness to CRH in patients with Cushing’s disease.

Effect of desmopressin on ACTH and cortisol secretion in states of ACTH excess.

To assess the ability of desmopressin administration to stimulate ACTH/cortisol secretion in patients with Cushings disease, either before or after surgery, and in patients with other states characterized by ACTH hypersecretion, and to compare the results with those obtained after CRH testing.

The silent corticotropinoma: is clinical diagnosis possible?

Up to now, the diagnosis of silent corticotropin cell pituitary adenomas has been made only on histopathological basis. In this paper we describe 6 women affected with pituitary adenomas, without evident clinical features of hypercortisolism, in whom retrospective data suggested the possibility of clinically diagnosing silent corticotropinomas in vivo. In all patients basal ACTH and Cortisol levels were normal, and the low-dose dexamethasone test constantly suppressed serum Cortisol and urinary 17-hydroxycorti-costeroid levels. The CRH and/or lysine-vasopressin tests, performed in five patients, always induced exaggerated ACTH/cortisol rises. In three cases the response to the opiate agonist loperamide was assessed and no inhibition of ACTH/cortisol levels was found. All patients underwent pituitary surgery. In five cases evidence of corticotropinoma was obtained by immunohistochemistry or immunofluorescence studies; moreover, in one adenoma ACTH was secreted into the culture medium, and in another one CRH and arginine-vasopressin induced a marked intracellular [Ca++] rise. Electron microscopy study of the adenoma, removed from three patients, showed the presence of adenomatous corticotropin cells. Finally, in another woman no hormonal abnormalities were initially observed and she was operated for a “nonfunctioning” pituitary adenoma, but four years later an overt Cushing’s disease appeared, suggesting that a silent corticotropinoma subsequently became functional, although the formation of a different adenoma cannot be excluded. In conclusion, the occurrence of ACTH/cortisol hyperresponsiveness to CRH and/or lysine-vasopressin and the lack of suppression of ACTH/cortisol secretion to opioid agonists in patients with apparently “nonfunctioning” pituitary tumors might allow the in vivo recognition of silent corticotropinomas.

Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism

In the present work the possible use of loperamide, an opiate agonist, in the dynamic evaluation of patients with suspected hypercortisolism was investigated. The effects of loperamide on plasma ACTH and Cortisol levels were evaluated in normal subjects and in 58 patients with suspected Cushing’s syndrome. The results were compared to those obtained after the overnight dexamethasone suppression test. In normal subjects plasma ACTH and Cortisol levels were significantly (p < 0.005) suppressed by both loperamide (16 mg po) and dexamethasone (1 mg po). In 17 patients, in whom the diagnosis of Cushing’s syndrome was confirmed by subsequent investigations, neither loperamide or dexamethasone inhibited Cortisol (from a baseline of 606 ± 55 nmol/L) to a nadir of 502 ± 43 nmol/L and 539 ± 50 nmol/L, respectively) and ACTH concentration (from a basal level of 70.1 +11.8 pg/ml to a nadir of 46.0 ± 8.6 pg/ml and 54.3 ± 7.5 pg/ml, respectively). In 34 patients, in whom the suspect of hypercortisolism was ruled out, either loperamide or dexamethasone suppressed the pituitary-adrenal axis: Cortisol and ACTH levels significantly fell from 417 ± 24 nmol/L and 28.3 ± 3.5 pg/ml to 60 ± 6 nmol/L and 14.4 ± 1.4 pg/ml after loperamide and to 26 ± 4 nmol and 16.4 ± 1.7 pg/ml after dexamethasone. In 7 patients discordant responses were observed. In 3 patients treated with antiepileptic drugs ACTH and Cortisol levels were inhibited by loperamide, but not by dexamethasone. In 4 other patients a normal suppression was induced by dexamethasone, but not by loperamide: in 2 cases the suspected hypercortisolism was definitely ruled out while in the other two no definitive diagnosis could be established. In these series of patients, the loperamide test equals the 1 mg dexamethasone suppression test in terms of sensitivity, specificity, diagnostic accuracy and predictive value. In conclusion: i) Loperamide administration is practical and reliable in testing the pituitary-adrenal function; ii) The procedure needs only three and half h to be completed and thus it is suitable and compliant to outpatients; iii) Loperamide might be useful in patients in some conditions (drug interference), in which the low-dose dexamethasone test has some limitations.

Effect of atrial natriuretic factor infusion on basal and CRH-stimulated ACTH, cortisol and aldosterone levels in patients with Cushing's or Addison's disease

OBJECTIVES While it has been shown that atrial natriuretic factor (ANF) is able to inhibit CRH‐stimulated ACTH secretion in vitro, in normal men conflicting results on its effect on ACTH/cortisol responses to insulin and CRH have been reported. Since no data are available concerning the possible influence of ANF on the hypothalamic‐pituitary‐adrenal axis in states of ACTH hypersecretion, the effect of ANF on pituitary‐adrenal function in basal conditions and after CRH stimulation has been investigated in patients with Cushings (n= 4) and Addisons disease (n= 4).