INTRODUCTION<\/strong><\/p>\n Clinical symptoms of Cushing\u2019s syndrome are known to be closely associated with the enhanced secretion of hormones synthesized by the adrenal cortex, mainly cortisol. The most common cause of ACTH-dependent hypercortisolism is Cushing\u2019s disease [(CD) about 80%], ACTH producing extrapituitary tumour (ECT) being a less frequent form (15%). ACTH-independent Cushing\u2019s syndrome is rare and is due to a tumour or micronodular hyperplasia of the adrenal cortex (ACTH-ind).1<\/sup> The incidence rate of Cushing\u2019s syndrome caused by unilateral adrenal adenoma is estimated at 2 cases per 1,000,000 population per year. The incidence of CD is 3 times more frequent than primary adrenal lesion, i.e. 5-6 cases per 1,000,000 per year (9-10 cases together with ECT). There are large gender differences in the incidence of adrenal adenoma, which occurs 4 times more frequently in women than in men.1<\/sup><\/p>\n Vasopressin (VP), like corticotropin-releasing hormone (CRH), is an important regulator of pituitary ACTH secretion. After binding of CRH and VP to their respective receptors in corticotrophs (R1 for CRH and V3 for VP), the synthesis of proopiomelanocortin (POMC), a precursor of ACTH, is stimulated.2<\/sup> Moreover, VP has been reported to exert direct action on neoplasias of the adrenal cortex where it activates the so-called \u201cectopic receptors\u201d.3<\/sup><\/p>\n The present study was designed to elucidate the direct effect of the VP agonist desmopressin (DM) on each of the three functional zones of the human adrenal cortex. To this end, we evaluated pituitary response (by measuring ACTH level) and the response of the zona glomerulosa, zona fasciculate, and zona reticularis (by measuring aldosterone, cortisol, and dehydroepiandrosterone-sulfate concentrations, respectively) to the action of DM in patients with different forms of hypercortisolism (Endogenous Cushing\u2019s Syndrome). The study group included 43 patients with hypercortisolism and 11 healthy individuals who served as controls.<\/p>\n Three groups of patients with hypercortisolism, aged 22-49 years, were studied during the active phase of the disease: 21 patients had Cushing\u2019s disease (CD, 14 females and 7 males), 11 had ectopic (pulmonary), ACTH-producing tumour (ECT, 5 females and 6 males), and 11 had cortisol secreting adrenal tumour (ACTH-ind, 6 females and 5 males). In all patients the diurnal rhythm of ACTH and cortisol surges were examined (blood samples were taken at 08:00, 12:00, 16:00, and 23:00). Based on the 4 individual values the mean daily value was calculated.<\/p>\n The presence of pituitary adenomas and adrenal tumours was confirmed by magnetic resonance imaging (MRI), and the ectopic pulmonary ACTH-producing tumour by computed tomography (CT). After the surgical removal, the type of the tumours was confirmed histologically and immunochemically with antibodies to ACTH, where appropriate.<\/p>\n The control group consisted of 11 healthy subjects, aged 22 to 49 years: 7 females in the follicular phase of the menstrual cycle, and 4 males. In the controls, the diurnal rhythm of ACTH and of steroids was studied.<\/p>\n After low-dose dexamethasone suppression, the cortisol level was not significantly inhibited (less than 50%) in all patients, thus confirming the presence of Cushing\u2019s syndrome. Two weeks before the DM test, all drug therapy was discontinued in all patients. The DM test was carried out in the morning after overnight fasting. ACTH, cortisol (Cort), dehydroepiandrosterone-sulfate (DHEAS), and aldosterone (Ald) were measured in blood samples taken before and 15, 30, 60, 90, and 120 min after intravenous injection of 10 \u03bcg of DM. During the test the patients were supine and NaCl solution was infused.<\/p>\n Plasma ACTH was measured with commercial kits (CIS-bio International, France) and Cort by a Vitros ECI automatic analyzer (UK); aldosterone and dehydroepiandrosterone were determined using WHO-standardized radioimmunoassay kits.4<\/sup><\/p>\n A 30% rise in steroid levels above the initial values was regarded as significant.5,6<\/sup><\/p>\n The data are expressed as median values and interpercentile amplitude between 10% and 90% percentiles. Comparison between groups was carried out using the Mann-Whitney test. The level of significance was set at p<0.05. Statistical analysis was made using STATISTICA 6.0 software package for Windows, Statsoft Inc (1999).<\/p>\n RESULTS<\/strong><\/p>\n In patients with various forms of Cushing\u2019s syndrome, Cort values were high and the diurnal rhythm was impaired (Table 1<\/a> ). The mean ACTH levels significantly differ (p <0.001) among the various patients groups (median, 10-90 percentiles): 74.9 (43.2-111.8) pg\/ml) in CD, 6.3 (1.5-10.2) pg\/ml in ACTH-ind, and 127.3 (79.8-286.5) pg\/ml in ECT (Table 1<\/a>, Figure 1). In the controls, the mean daily ACTH and Cort levels were 31.0 (16.0-38.0) pg\/ml and 208.5 (189.8-309.5) nmol\/l, respectively.<\/p>\n Patients with CD (Figure 2) showed a significant rise in ACTH concentration following DM administration: it was 3-9 times the initial ACTH level with a maximum at 15 min after injection (266%; 134-890%), gradually decreasing within the next 90-120 min.<\/p>\n No significant increase of ACTH levels in response to DM was documented in ACTH-ind and ECT patients (Figure 2). The highest ACTH concentration in patients with ECT was 1.5 times (75.0%; 45-117%) the initial level at 15 minutes, whereas in ACTH-ind patients there was practically no response to DM stimulation, [a maximum rise of only 18% (16-50%)] occuring at 30 minutes.<\/p>\n The response of adrenal steroids and ACTH to DM stimulation was not uniform in all patients even in the same group.<\/p>\n The variable secretory responses to DM injections are depicted in Table 2<\/a> and are exemplified below.<\/p>\n (1)\u00a0\u00a0 \u00a0Variant 1: DM stimulated ACTH secretion and increased the production of steroids by all three zones of the adrenal gland (6 patients with CD). 4a- stimulation of all studied steroids (1 patient with ACTH-ind) (5)\u00a0\u00a0 \u00a0Variant 5: DM did not stimulate the adrenal cortex (2 patients with CD, 6 patients with ECT and 5 patients with ACTH-ind).<\/p>\n It follows from Table 2<\/a> that the majority of CD patients (16 of the 21) responded to the administration of DM by increased secretion of ACTH and one or more steroids of the adrenal cortex. In contrast, the adrenal cortex of patients with ACTH-ind and ECT (10 of the 22) responded to DM without a concomitant rise of ACTH. One patient with ECT was an exception. In this patient a rise in Cort followed ACTH elevation.<\/p>\n Figure 2.<\/strong> Variations of plasma ACTH level in patients with hypercortisolism in response to desmopressin (median+3rd<\/sup> quartile). Percent (%) rise from baseline<\/p>\n Variant 1. Administration of DM to patients with CD triggered a good ACTH surge at 15 minutes after injection with a 342% rise (134-854%) over the initial level. It should be emphasized that these patients showed the most pronounced response to DM compared with patients of the other groups (Figure 2). An increased level of ACTH in CD patients was associated with a 95.5% (34-180%), 84.5% (45-160%), and 81% (18-110%) rise in Cort, DHEAS, and Ald concentrations, respectively. Maximum values of these steroids were observed within 30-60 min after the rise of plasma ACTH concentration (Table 3<\/a> ).<\/p>\n
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\nSUBJECTS AND METHODS<\/strong><\/p>\n![\"](\"\/wp-content\/uploads\/images\/dyn\/243-250_01.jpg\")
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\nFigure 1<\/strong>. Mean daily concentrations of ACTH and cortisol in patients with hypercortisolism (median+3rd<\/sup> quartile). To convert to SI units for ACTH multiply by 0.22.<\/p>\n
\n(2)\u00a0\u00a0 \u00a0Variant 2: DM induced secretion of ACTH and Cort but had no effect on Ald and DHEAS secretion (5 patients with CD and 1 with ECT).
\n(3)\u00a0\u00a0 \u00a0Variant 3: DM induced secretion of ACTH and Cort in association with either Ald or DHEAS; 5 patients with CD, [1 with increased Cort and DHEAS (3a) and 4 (3b) with increased Cort and Ald levels].
\n(4)\u00a0\u00a0 \u00a0Variant 4: Administration of DM resulted in an increased secretion of Cort, Ald, and DHEAS in various combinations without a rise in ACTH:<\/p>\n
\n4b- stimulation of Cort + Ald (1 patient with ACTH-ind)
\n4c- stimulation of Cort + DHEAS (2 patients with ACTH-ind)
\n4d- stimulation of Cort secretion (1 patient with ACTH-ind)
\n4e- stimulation of Ald + DHEAS secretion (1 patient with CD and 1 patient with ECT)
\n4f- stimulation of DHEAS secretion (2 patients with CD, 1 with ECT and 1 with ACTH-ind)
\n4g- stimulation of Ald secretion (2 patients with ECT).<\/p>\n![\"](\"\/wp-content\/uploads\/images\/dyn\/243-250_02.jpg\")
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