E. Glaz

Adrenal cortex - a newly recognized peripheral site of action of enkephalins.

Summary Two naturally occuring enkephalins, Leu- and Met-enkephalin, were shown to inhibit adrenal corticosteroid biosynthesis. In isolated rat adrenal cell system corticosterone, desoxycorticosterone and aldosterone, and in isolated bovine adrenal cells cortisol, corticosterone and aldosterone production were markedly depressed in a dose-dependent fashion, both under basal conditions and following stimulation with ACTH 1–24 . The inhibitory action of enkephalins on corticosteroid synthesis could be augmented by increasing the Ca 2+ -concentration in the cell-containing medium. The demonstration that opioid peptides interfere with corticosteroidogenesis directly at the adrenal level points to the existence of a peripheral neuroendocrine relationship.

Skeletal differences in bone mineral area and content before and after cure of endogenous Cushing's syndrome

SummaryWe examined bone densitometric data in a four-year follow-up period before and after the cure of CS. Plasma cortisol concentrations were similar, but the duration of estimated glucocorticoid excess was longer in patients with prevalent bone fractures compared to those without fractures. After therapy of CS, bone area, BMC and BMD increased significantly at the LS and femur during follow-up, but they decreased at the forearm, suggesting redistribution of bone minerals from the peripheral to the axial skeleton.IntroductionOnly a few studies report the changes in bone mineral density (BMD) after the cure of Cushing’s syndrome (CS).MethodsForty-one patients with Cushing’s disease, 21 patients with adrenal CS and 6 patients with ectopic CS were prospectively enrolled. BMD, bone mineral content (BMC) and bone area were measured by DXA.ResultsNo significant correlations were found between serum cortisol concentrations and baseline bone densitometric data. After successful therapy of CS, bone area and BMD increased significantly at the lumbar spine (LS) and femur during follow-up, but they decreased at the forearm. The progressive increase in BMC at the LS had a significant negative correlation with the change of the BMC of radius in the first and second follow-up years. The change in the body mass index was an independent predictor for changes in BMC both at the LS and at the forearm at the second year of remission.ConclusionsThe regional differences and the time-dependent changes of BMC suggest that the source of marked increase in axial BMC after the cure of CS is, at least partly, due to the redistribution of bone minerals from the peripheral to the axial skeleton.

Clinical and biochemical features of sporadic and hereditary phaeochromocytomas: an analysis of 41 cases investigated in a single endocrine centre

The aims of this study were to estimate the prevalence of phaeochromocytomas among adrenal tumours and to analyse the clinical and biochemical features of sporadic and hereditary tumours. Our series of 609 adrenal tumours evaluated between January 1995 and July 2003 was reviewed. Catecholamine content in phaeochromocytoma tissues was also determined and correlated with clinical behaviour and biochemical parameters of patients. Forty-one (6.7%) of the 609 patients had phaeochromocytomas, of which 28 were sporadic (25 benign and three malignant) and 13 (all benign) were associated with hereditary diseases (multiple endocrine neoplasia type 2A in seven cases from four unrelated families carrying mutations of the RET gene, von Hippel–Lindau disease in two unrelated cases with mutations of the VHL gene, and type 1 neurofibromatosis in four unrelated cases). Bilateral tumours were found in three patients with hereditary syndromes and in one sporadic case. Tumour diameter was slightly but not significantly greater in patients with hereditary than in those with sporadic tumours. Systolic but not diastolic blood pressure was significantly higher in patients with sporadic compared with those with hereditary tumours, but comparison of other clinical data and biochemical parameters indicated an absence of significant differences in the mean age, presenting symptoms, heart rate, or fasting serum glucose levels. Tissue catecholamine content measured in 8 sporadic and 5 hereditary phaeochromocytomas was highly variable and it failed to show significant differences between hereditary and sporadic tumours. These results indicate a high proportion of hereditary diseases among patients with phaeochromocytomas. Genetic and clinical testing for hereditary diseases may be of great help to offer an appropriate treatment, follow-up and family screening for these patients.

Comparative analysis of plasma 17-hydroxyprogesterone and cortisol responses to ACTH in patients with various adrenal tumors before and after unilateral adrenalectomy

Patients with non-hyperfunctioning adrenal adenomas often have an increased plasma 17-hydroxyprogesterone response to ACTH stimulation. The effects of adrenal surgery on this abnormality have rarely been investigated. One hundred and sixty-one patients with unilateral adrenal tumors (non-hyperfunctioning adenomas, 78; cortisol-producing adenomas, 8; aldosteroneproducing adenomas, 37; adrenal cysts, 12; pheochromocytomas, 26) were studied. Patients before and after adrenal surgery as well as 60 healthy subjects underwent an ACTH stimulation test using 2 mg synthetic ACTH1-24 (Cortrosyn Depot, Organon). Basal and ACTH-stimulated plasma 17- hydroxyprogesterone and cortisol concentrations are reported. Before adrenal surgery, the basal plasma 17-hydroxyprogesterone concentrations were normal in patients with all types of tumors. However, the ACTH-stimulated plasma 17-hydroxyprogesterone levels were abnormally increased in 53% and 31% of patients with non-hyperfunctioning adenomas and aldosterone-producing adenomas, respectively. In addition, a few patients with adrenal cysts and pheochromocytomas also showed an increased ACTH-stimulated 17- hydroxyprogesterone response. After unilateral adrenalectomy, this hormonal abnormality disappeared in most, although not all patients with adrenal tumors. In patients with non-hyperfunctioning adrenal tumors, ACTH-stimulated plasma 17-hydroxyprogesterone and cortisol concentrations significantly correlated with the size of the tumors. These results firmly indicate that the tumoral mass itself may be responsible for the increased plasma 17-hydroxyprogesterone and cortisol responses after ACTH stimulation in patients with non-hyperfunctioning and hyperfunctioning adrenal adenomas.

Corticosteroidogenesis by isolated human adrenal cells: effect of serotonin and serotonin antagonists.

The direct effect of serotonin and antiserotonin agents on adrenal steroid biosynthesis was studied in isolated adrenal cells derived from patients with Cushings syndrome. The results indicate that serotonin increases corticosterone production, while the serotonin antagonists cyproheptadine and methysergide depress adrenal steroid-particularly cortisol and aldosterone-biosynthesis.

Acth sensitivity of isolated human pathological adrenocortical cells: Variability of responses in aldosterone, corticosterone, deoxycorticosterone and cortisol production

In vitro aldosterone, deoxycorticosterone, corticosterone and cortisol production of human adrenocortical cells derived from adenomas (Conns syndrome, Cushings syndrome), from hyperplastic adrenals (Cushings syndrome) and from adrenals surrounding aldosteronoma are described. Cells from adenomas causing either Cushings syndrome or Conns syndrome harboured the highest basal and ACTH-stimulated corticosteroid production. Adrenocortical cells derived from micronodular hyperplasia causing Cushings syndrome and cells from cortisol producing adenoma displayed predominantly cortisol and corticosterone secretion both under basal conditions and following stimulation with ACTH. Aldosteronoma cells showed highly variable aldosterone, deoxycorticosterone, corticosterone and cortisol response to ACTH. However, in aldosteronoma cell suspensions, the basal and ACTH-stimulated ratios of aldosterone to cortisol were increased when compared to ratios of steroids produced by cells from other adrenal tissues. Chronic treatment with spironolactone of patients with Conns syndrome before surgery was associated with a decreased ratio of aldosterone to corticosterone, revealing that 18-hydroxylase in aldosteronoma cells may be inhibited during long-term therapy. Non-tumorous cells isolated from adrenals surrounding aldosteronoma displayed less aldosterone prior to and after stimulation with ACTH than aldosteronoma cells.

A iatrogén cushing-szindróma kezelése: A glükokortikoid terápia leépitésének kérdései

Iatrogenic Cushings syndrome is the most common form of hypercortisolism. Glucocorticoids are widely used for the treatment of various diseases, often in high doses that may lead to the development of severe hypercortisolism. Iatrogenic hypercortisolism is unique, as the application of exogenous glucocorticoids leads to the simultaneous presence of symptoms specific for hypercortisolism and the suppression of the endogenous hypothalamic-pituitary-adrenal axis. The principal question of its therapy is related to the problem of glucocorticoid withdrawal. There is considerable interindividual variability in the suppression and recovery of the hypothalamic-pituitary-adrenal axis, therefore, glucocorticoid withdrawal and substitution can only be conducted in a stepwise manner with careful clinical follow-up and regular laboratory examinations regarding endogenous hypothalamic-pituitary-adrenal axis activity. Three major complications which can be associated with glucocorticoid withdrawal are: i. reactivation of the underlying disease, ii. secondary adrenal insufficiency, iii. steroid withdrawal syndrome. Here, the authors summarize the most important aspects of this area based on their clinical experience and the available literature data.

Laterality disturbance and hypopituitarism. A case report of co-existing situs inversus totalis and combined pituitary hormone deficiency

The authors present the case history of a 52-yr-old male patient with a unique association of combined pituitary hormone deficiency (CPHD) and situs inversus totalis. Except for signs and symptoms of pituitary hormone deficiency, the patient had no dysmorphic features, and hearing impairment, primary mental or neurologicaldefects were also absent. Pituitary magnetic resonance imaging (MRI) scan showed hypoplasia of the anterior lobe of the pituitary gland and an ectopic posterior pituitary lobe. Despite the presence of situs inversus totalis, thepatient was right-handed and functional MRI demonstrated left-hemisphere activation during language tests. Kartagener syndrome was considered, but immunofluorescence analysis showed normal localization of the outer dynein arm protein in respiratory epithelial cells obtained from the nasal mucosa. Direct DNA sequencing of all coding exons of the pituitary transcription factor 1 (PIT1) and prophet of PIT1 (PROP1) genes failed to detect disease-causing mutations, suggesting that these genes were not involved in the development of CPHD in our patient. More interestingly, the potential role of the paired like homeodomain transcription factor 2 (PITX2) gene, which has been implicated not only in CPHD, but also in left-right patterning in animal models, was also excluded, as sequencing showed the absence of mutations in coding exons of this gene. To our knowledge, PITX2 gene mutations have not been investigated in CPHD patients who had situs inversus totalis. We conclude that in contrast to animal models, the PITX2 gene is not involved in the development of situs inversus totalis, at least not in our CPHD patient.

Effect of single doses of dexamethasone and adrenocorticotrop hormone on serum bone markers in healthy subjects and in patients with adrenal incidentalomas and Cushing’s syndrome

The aim of the present study was to explore whether short-term changes in glucocorticoid activity which occur during dynamic testing of the pituitary adrenal axis with dexamethasone, ACTH, or metyrapone could have an effect on serum osteocalcin (OC) and β-crosslaps (β-CTx) concentrations in healthy subjects, in patients with adrenal incidentalomas and in those with Cushing’s syndrome. The study included 40 healthy subjects (35 women and 5 men, age range 18–69 yr), 49 patients with adrenal incidentalomas (34 women and 15 men, age range 19–77 yr) and 8 patients with Cushing’s syndrome (5 cortisol-producing adenomas and 3 pituitary-dependent Cushing’s syndrome, 3 women and 5 men, age range 19–70 yr). Serum OC and β-CTx concentrations were determined with electrochemoluminescent immunoassays at midnight, after an overnight fast between 08:00 and 09:00 h, after an overnight dexamethasone test (1 mg, orally) and after a single dose of metyrapone (30 mg/kg, orally). In healthy subjects and in patients with adrenal incidentalomas, serum bone marker concentrations were also measured after a single dose of ACTH injection (Cortrosyn depot, 1 mg im). Patients with Cushing’s syndrome, but not those with adrenal incidentalomas, showed significantly lower serum OC at midnight (18.5±12 ng/ml, mean±SD) and between 08:00 and 09:00 h (17.7±9.6 ng/ml) compared to corresponding values obtained in healthy subjects (24.5±7.0 and 28.3±12.2 ng/ml, respectively). Serum OC concentrations were significantly decreased after a single dose of 1-mg dexamethasone in healthy subjects (from 28.3±12.2 to 21.8±9.5 ng/ml) and in patients with adrenal incidentalomas (from 29.8±15.9 to 24.1±14.1 ng/ml), whereas serum OC concentrations remained unchanged in patients with Cushing’s syndrome. In addition, serum OC concentrations were even more markedly decreased after a single dose of ACTH injection in both healthy subjects (12.5±4.6 ng/ml) and in patients with adrenal incidentalomas (12.2±6.5 ng/ml). By contrast, metyrapone administration failed to induce significant changes in OC levels. There were no significant differences in β-CTx concentrations between the three groups or after drug treatments. Thus, serum OC levels should be interpreted with caution when obtained during testing of the pituitaryadrenal axis with dexamethasone or ACTH.

P53 protein and its messenger ribonucleic acid in human adrenal tumors

The role of p53 tumor suppressor gene in the pathomechanism of adrenal tumors was investigated by measuring p53 protein and its messenger ribonucleic acid (mRNA) in 12 normal human adrenals as well as in 56 adrenal tumors (7 aldosterone-producing adenomas, 5 adrenocortical adenomas causing Cushing’s syndrome, 19 non-hyperfunctioning adrenocortical adenomas, 5 adrenocortical carcinomas, 12 pheochromocy-tomas, 3 myelolipomas, 4 ganglioneuromas and 1 hemangioma). The p53 protein concentration was significantly increased in aldosterone-producing adenomas (394±36 pg/mg cytosolic protein, mean±SE, vs 266±18 in normal human adrenals), whereas the concentration of this protein in Cushing’s adenomas, non-hyperfunctioning adrenocortical adenomas, pheochromocytomas, and in all but one adrenocortical carcinomas was similar to that measured in normal human adrenal tissues. One adrenocortical carcinoma tissue showed very high p53 protein content (3000 pg/mg cytosolic protein). By contrast, myelolipomas (23±20) ganglioneuromas (43±15) and a hemangioma (11 pg/mg cytosolic protein) had very low p53 protlein content. Northern blot analysis revealed the presence of p53 mRNA in each adrenal tissue examined with highest levels in aldosterone-producing and Cushing’s adenomas. It is possible that the differences in p53 protein and/or mRNA contents reflect corresponding differences in the pathogenetic importance of p53 alterations in these types of adrenal tumors.