Aberrant hormone receptors in primary aldosteronism.

The mechanisms involved in the renin-independent regulation of aldosterone secretion in primary aldosteronism are poorly understood. In ACTH-independent Cushing's syndrome, cortisol secretion can be regulated by the aberrant expression of G-protein coupled receptors (GPCRs) in unilateral tumors and bilateral macronodular adrenal hyperplasia. By analogy, some recent studies identified overexpression or function of several GPCR as a potential cause for excess aldosterone production in some aldosteronomas and in bilateral idiopathic hyperaldosteronism. Initial studies have used in vitro techniques, while the clinical aldosterone responses were not assessed. More recently, several receptors have been shown to be expressed in aldosterone-producing adrenal tumors in vitro and to regulate aberrantly renin-independent aldosterone secretion in vivo. The prevalence of aberrant hormone receptors in primary aldosteronism could be elevated, but larger systematic studies are required to establish its true frequency. The identification of aberrant adrenal GPCRs by in vivo functional studies offers the potential for novel pharmacological therapies that either suppress the endogenous ligands or block the receptor with specific antagonists.

Clinical and biochemical features of seven adult adrenal ganglioneuromas.

BACKGROUND: Adrenal ganglioneuroma (GN) is seldom considered in the differential diagnosis of adrenal lesions, and its clinical presentation is not well known. OBJECTIVE: Our aim was to describe the clinical, biochemical, and radiological features of adrenal GNs in adults. METHODS: Seven adults underwent endocrine investigation for adrenal lesions that were confirmed to be adrenal GNs. RESULTS: Mean age of the seven patients was 49 yr (range, 23 to 71 yr). Average tumor diameter was 5.0 cm (range, 1.5 to 10.4 cm). In five patients, the adrenal lesions were found incidentally. A 49-yr-old female carried a germline mutation in MSH2 gene. A 57-yr-old female presented with mild virilization and increased testosterone levels. Bilateral adrenal venous sampling revealed testosterone production from her right adrenal lesion. All tumors showed nonenhanced attenuation between 25 and 40 Hounsfield units on computed tomography scan. Magnetic resonance imaging revealed low- to iso-signal intensity on T1-weighted imaging and high-signal intensity on T2-weighted imaging. [(18)F]-2-Fluoro-deoxy-d-glucose-positron emission tomography scan (n = 5) disclosed a mean standard uptake value of 2.4. Three tumors were composite pheochromocytoma-GN. Microsatellite instability study and immunohistochemical analysis of MSH2 protein in a patient carrying a MSH2 mutation showed normal MSH2 protein expression and low microsatellite instability, indicating that the adrenal GN was not related to the patient's MSH2 germline defect. CONCLUSIONS: We describe one of the largest series of adult adrenal GNs. Adrenal GNs may secrete testosterone or be part of a composite tumor with pheochromocytoma. The association of adrenal GN with MSH2 mutation seems to be a coincidental finding.

A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.

BACKGROUND: Inactivation of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours. METHODS AND RESULTS: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes. CONCLUSION: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIalpha as a candidate tumour suppressor gene.

A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus.

Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)i-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections (negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIA(i) locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas.

Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome.

Cortisol secretion in adrenal Cushing's syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin. Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing's syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH. A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 microg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female. This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.

Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome?

Twenty consecutive patients with adrenal Cushing's syndrome were studied with an in vivo protocol to determine the prevalence and diversity of the presence of ectopic or abnormal hormone receptors in their adrenal tissues. All six patients with bilateral ACTH-independent macronodular adrenal hyperplasia were found to have one or two abnormal adrenal receptors, including those for gastric inhibitory polypeptide, vasopressin (V1-vasopressin), beta-adrenergic agonists, LH/human CG, or serotonin 5-HT4. The presence of abnormal hormone receptors was found to be less frequently present in unilateral adenomas or carcinomas (3 of 14). The identification of abnormal adrenal hormone receptors can allow new pharmacological therapies of hypercortisolism. We suggest that the clinical screening for the presence of abnormal hormone receptors should be conducted in patients with adrenal Cushing's syndrome and, more particularly, in those with ACTH-independent macronodular adrenal hyperplasia, in the hope of offering medical therapy as an alternative to bilateral adrenalectomy.