Cortisol-producing Tumors Research Articles

Hormone Receptor Abnormalities in Adrenal Cushing's Syndrome

Cortisol secretion in ACTH-independent primary adrenal Cushing's syndromes was previously believed to be autonomous. In most cases, the pathophysiology of the disease was largely unknown. However, recent work by our group and others have shown that these cortisol-producing adrenocortical tumors may be under the control of inappropriate, illicit or ectopic hormone receptors. This review provides a rapid overview of the physiology of the normal adrenal cortex and outlines recent findings supporting the hypothesis that cortisol production may be regulated by a diversity of abnormal or ectopic hormone receptors in primary adrenal Cushing's syndrome.

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors.

Regulatory actions of angiotensin II (AngII), which is involved in the pathophysiology of hypertension and also participates in cell proliferation and cell differentiation, are mainly mediated by AngII type 1 (AT1) receptor. Recently, activating mutations of receptors causing hyperfunctioning endocrine diseases have been described in the case of the TSH and LH receptors, implicating that such mutations might occur in other G-protein-coupled receptors. Furthermore it seems to be possible that genetic variations of AT1 receptor have an influence upon the action of AngII. Therefore, we searched by sequence analysis of the coding region of AT1 receptor gene for activating mutations and genetic polymorphisms in 56 human adrenal tumors (16 aldosterone-producing adenomas, 10 cortisol-producing adenomas, 1 aldosterone-producing carcinoma, and 29 incidentalomas). We were not able to identify any activating mutation in the coding region of AT1 receptor gene. We conclude that activating mutations of the AT1 receptor are not a major cause of the development of adrenal adenomas, if at all. In addition, polymorphic subtypes of AT1 receptor do not seem to play a major role in the pathogenesis of these tumors, even though a tendency towards a higher frequency of the polymorphic base substitution at position 573 (T573-->C) in cortisol-producing tumors needs to be further evaluated.

Adrenal Incidentalomas: Diagnostic Workup of the Incidentally Discovered Adrenal Mass

The incidentally discovered adrenal mass is a diagnostic dilemma veterinarians are likely to face with increasing frequency in the coming years. Dogs and cats may be more prone to functional adrenal lesions than are humans. Most adrenal tumors are benign, but a significant number of adrenocortical carcinomas (approximately 12%) and metastatic lesions within the adrenal glands (3% to 34%) do occur. Evaluation for hypertension, hypokalemia, and loss of hypothalamic-pituitary-adrenal responsiveness to a low dose of dexamethasone is appropriate for all patients with adrenal incidentalomas. The value of clinical and historical signs of hormonal overexpression should not be underestimated. More invasive or expensive diagnostic testing should be predicted on suspicions raised by the history and clinical signs. New diagnostic clinicopathologic tests, including plasma CgA and serum DHEAS, should be investigated in veterinary patients. Advanced diagnostic imaging using nuclear scintigraphy and chemical-shift MRI may offer veterinarians sensitive and specific noninvasive tools to consider for the evaluation of these patients. Patients with large masses, tumors with signs of malignancy, or productive adrenal tumors (plus or minus cortisol-producing tumors in which chemical ablation with mitotane can be attempted) should be considered candidates for exploratory surgery.

A clinical case of Cushing’s syndrome caused by an ectopic cortisol-producing tumor

It is known a surgeon operating on the adrenal glands, should be aware of the possibility of the presence of ectopic adrenal tissue. According to the literature, there are relapses of Cushing's disease due to hyperfunction of adrenal accessory tissue. Its location may be the perinephric tissue, testicles, mediastinum, kidneys, urinary tract, broad ligament of the uterus, vagina, scrotum. The inclusion of adrenal tissue in the ovaries, liver, pancreas is also described. There is some evidence that additional adrenal tissue can be a source of tumors, including hormonal-active ones. O. I. Nikolaev (1970) cites a case of ectopia of a tumor in the kidney, 4 cases of ectopia in one of the ovaries, which, in addition to symptoms of hypercorticism, was accompanied by severe virilization. However, this pathology is extremely rare, therefore, there are few publications in the literature. In this regard, it seems appropriate to us to make such an observation.

Chromosomal aberrations in two adrenocortical tumors, one with a rearrangement at 11p15

Adrenocortical tumors are detected with increasing frequency, but symptomatic cases with excessive hormone production are rare. We investigated cytogenetically one benign aldosterone-producing tumor (Conn Syndrome)(case 1) and one malignant cortisol-producing tumor (Cushing Syndrome)(case 2). Radioimmunoassay of cell culture supernatant of case 2 detected cortisol secretion during 2 months in culture. Flow cytometry of spill-out cells from case 2 showed a bimodal pattern (DNA Index 1.0, 1.4). Case 1 revealed a marker chromosome in 4 25 cells analyzed; the marker was a long acrocentric partially derived from chromosome 2,der(2q). In case 2, a cytogenetic harvest was achieved after prolonged culture time (6 weeks) and a marker chromosome, add(11)(p15), was detected in 16 22 cells. A breakpoint of 11p13, as well as loss of heterozygosity of alleles on 11p15, has been reported in the literature for other malignant adrenocortical cancers.

Preclinical Cushing's syndrome in adrenal "incidentalomas": comparison with adrenal Cushing's syndrome.

Adrenal tumors are usually diagnosed by clinical symptoms of hormone excess. The increasing use of ultrasound and computed tomography results in the detection of a substantial number of incidentally discovered adrenal tumors. Most of these tumors are nonfunctional adrenocortical adenomas, but a few cases of subclinical cortisol production in "incidentalomas" have been reported. We investigated prospectively the prevalence of autonomous cortisol production in 68 patients (44 females and 24 males, aged 25-90 yr) with adrenal incidentalomas at our institution. As a screening procedure all patients with incidentalomas underwent an overnight dexamethasone suppression test (1 mg). Patients who failed to suppress serum cortisol below 140 nmol/L (5 micrograms/dL) underwent more comprehensive studies (prolonged dexamethasone suppression test, determination of the diurnal rhythm of cortisol secretion in saliva, and CRH stimulation test). Eight patients (12% of all patients with incidentalomas; 5 females and 3 males, aged 25-71 yr) were finally identified as having cortisol-producing tumors, and the findings in these patients were compared with those of overt Cushing's syndrome in 8 patients (8 females, aged 26-50 yr) suffering from cortisol-producing adrenal adenomas. The tumor size of patients with cortisol-producing incidentalomas ranged from 2-5 cm. No specific signs and symptoms of hypercortisolism were present, but arterial hypertension (seven of eight subjects), diffuse obesity (four of eight subjects), and noninsulin-dependent diabetes mellitus (NIDDM; two of eight subjects) were frequently observed. Baseline cortisol levels were in the normal to upper normal range, whereas baseline ACTH levels were suppressed in five of the eight patients. In none of the patients was serum cortisol suppressible by low dose or high dose dexamethasone. The ACTH and cortisol responses to CRH were normal in two, blunted in one, and suppressed in four patients. Unilateral adrenalectomy was performed in seven patients and resulted in temporary adrenal insufficiency in four of them. After surgery, improvement of arterial hypertension, a permanent weight loss in obese subjects, and a better metabolic control of NIDDM were noted in the majority of patients. The following conclusions were reached. Incidentally diagnosed adrenal tumors with pathological cortisol secretion in otherwise clinically asymptomatic patients are more frequently observed than previously assumed. Adrenocortical insufficiency is a major risk in these patients after adrenalectomy. After surgery, hypertension, obesity, and NIDDM may improve. Patients with asymptomatic adrenal incidentalomas, therefore, should be screened for cortisol production by means of an overnight dexamethasone suppression test.

Angiotensin II receptors of human and primate adrenal fasciculata and glomerulosa: Correlations of binding and steroidogenesis

Subcellular fraction and collagenase-dispersed isolated adrenal fasciculata and glomerulosa cells from human and primate adrenal glands and cortisol-producing tumors have been utilized to study angiotensin II (Ang II) receptors and steroid biosynthesis. The receptor density of glomerulosa was threefold higher than that of fasciculata. A benign cortisol-producing adenoma did not differ from normal fasciculata, but a malignant tumor had significantly lower affinity binding. Agonist and antagonist analogues of Ang II competed for binding sites commensurate with known biologic activity. The K d of binding to fasciculata (2 nmol/L) correlated well with the ED 50 of cortisol biosynthesis in normal and adenomatous tissue. Analogue binding also had corresponding changes in cortisol biosynthesis. The ED 50 for aldosterone biosynthesis by glomerulosa cells was significantly lower at 55 pmol/L. Fewer receptors in human fasciculata as compared to glomerulosa and a less sensitive response to Ang II are consistent with previous in vitro observations in other species. These studies suggest that there may be a biologically relevant Ang II receptor of human and primate adrenal fasciculata that share many characteristics with the receptor of the glomerulosa.

Application of ACTH Stimulation to Adrenal Imaging with Radioiodocholesterol

ACTH-stimulation adrenal imaging (ACTH-I) was performed in 14 patients after baseline imaging (B-I) was performed. In six patients with no adrenal diseases in whom the findings of B-I were equivocal, morphologic normality of the adrenals was confirmed by ACTH-I because of increased adrenal uptake of radioiodocholesterol. In three patients with cortisol-producing tumors, visualization of contralateral glands by ACTH-I provided indirect evidence for autonomous cortisol secretion of the tumors. In three patients with pheochromocytoma or cyst, ACTH-I increased adjacent cortical radioactivity to more clearly delineate the lesions. In two patients with primary adrenocortical insufficiency, exogenous ACTH had no effect on adrenal uptake of the tracer. Correlation was observed between response of the adrenal net counts and urinary excretion of 17-OHCS and 17-KS. ACTH-I is useful when B-I does not provide sufficient diagnostic information or further information is needed due to low or absent radioiodocholesterol uptake by the adrenal gland(s).

Observations on the cortisol content of human adrenal venous blood.

ABSTRACT Cortisol levels in 101 blood samples obtained during diagnostic adrenal venography from 62 patients, ranged from 0 to 1700 μg/100 ml. The cortisol levels in the two contralateral adrenal veins of 34 patients without cortisol producing tumors differed on average by 3-fold. The adrenal cortisol levels of 20 patients with Cushing's syndrome were not significantly elevated. This was at least in part explained by the fact that their adrenal blood flow was increased. In 8 patients serial adrenal blood samples were obtained during periods of up to 30 min.