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Objective: Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA(L206R) mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone., Design, Patients, and Methods: In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone., Results: Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA(L206R) mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions., Conclusions: PRKACA(L206R) is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations., (© 2015 European Society of Endocrinology.)

Adrenal adenomas producing both aldosterone and cortisol (A/CPAs) have been described in only a few cases. Correct subtype classification is necessary for making therapeutic decisions in primary aldosteronism (PA). Therefore, we studied in detail the clinical, hormonal and histological features of this entity in two patients with A/CPAs. We describe two patients with A/CPA and present their endocrine evaluations at baseline, after suppression with fludrocortisone and dexamethasone, after therapy with spironolactone and after unilateral adrenalectomy. Moreover, the expression of corticotropin (MC2R) and angiotensin II type 1 (AT1R) receptors and 17alpha-hydroxylase in the tumors of these two patients was analyzed by immunohistochemistry. Aldosterone, 18-hydroxycorticosterone (18-OH-B) and 18-hydroxycortisol (18-OH-F) were not suppressible with fludrocortisone in either patient and were partly suppressible with dexamethasone in one of the patients. Adrenal insufficiency developed in both patients after operation and lasted for more than 6 months. Aldosterone and hybrid corticosteroids returned to normal 8 weeks after adrenalectomy. In both cases, immunostaining showed weak expression of AT1R and MC2R but strong expression of 17alpha-hydroxylase. The most common germline mutations in the aldosterone synthase gene and the aldosterone synthase/11beta-hydroxylase hybrid gene were absent. These two cases document the fact that sporadic A/CPA is a subtype of PA. The presence of an A/CPA should be considered if a patient has both PA and hypercortisolism.

We asked whether plasma concentrations of endothelin-1 (ET-1) or adrenomedullin (ADM) are altered by different activity states of the renin-angiotensin-aldosterone system (RAAS). Levels of ET-1 and ADM were studied in patients with primary aldosteronism ( n = 15), essential hypertension ( n = 15), and adrenal insufficiency ( n = 7). Effects of fludrocortisone, dexamethasone, or spironolactone treatment on ET-1 and ADM levels were also analyzed. Plasma ET-1 and ADM concentrations did not differ significantly between the patient groups. After fludrocortisone, dexamethasone, or spironolactone treatment, both ET-1 and ADM did not change significantly. The data support the hypothesis that the RAAS is not directly linked with the ET-1/ADM system. [ABSTRACT FROM AUTHOR]

The serum sodium to urinary sodium ratio divided by the (serum potassium)2 to urinary potassium ratio (SUSPPUP formula) reflects aldosterone action. We here prospectively investigated into the usefulness of the SUSPPUP ratio as a diagnostic tool in primary hyperaldosteronism. Parallel measurements of serum and urinary sodium and potassium concentrations (given in mmol/L) in the fasting state were done in 225 patients. Of them, 69 were diagnosed with primary aldosteronism (PA), 102 with essential hypertension (EH), 26 with adrenal insufficiency (AI) and 28 did not suffer from the above-mentioned disorders and were assigned to the reference group (REF). The result of the SUSPPUP formula was highest in the PA group (7.4, 4.2–12.3 L/mmol), followed by EH (3.2, 2.3–4.3 L/mmol), PA after surgery (3.9, 3.0–6.0 L/mmol), REF (3.4 ± 1.4 L/mmol) and AI (2.9 +/− 1.2 L/mmol). The best sensitivity in distinguishing PA from EH was reached by multiplication of the aldosterone to renin-ratio (ARR) with the SUSPPUP formula (92.7% at a cut off > 110 L/mmol), highest specificity was reached by the SUSPPUP determinations (87.2%). The integration of the SUSPPUP ratio into the ARR helps to improve the diagnosis of hyperaldosteronism substantially. [ABSTRACT FROM AUTHOR]

Endothelial cell-derived products influence the synthesis of aldosterone and cortisol in human adrenocortical cells by modulating proteins such as steroidogenic acute-regulatory (StAR) protein, steroidogenic factor (SF)-1 and CITED2. However, the potential endothelial cell-derived factors that mediate this effect are still unknown. The current study was perfomed to look into the control of β -catenin activity by endothelial cell-derived factors and to identify a mechanism by which they affect β -catenin activity in adrenocortical NCI H295R cells. Using reporter gene assays and Western blotting, we found that endothelial cell-conditioned medium (ECCM) led to nuclear translocation of β -catenin and an increase in β -catenin-dependent transcription that could be blocked by U0126, an inhibitor of the mitogen-activated protein kinase pathway. Furthermore, we found that a receptor tyrosin kinase (RTK) was involved in ECCM-induced β -catenin-dependent transcription. Through selective inhibition of RTK using Su5402, it was shown that receptors responding to basic fibroblast growth factor (bFGF) mediate the action of ECCM. Adrenocortical cells treated with bFGF showed a significant greater level of bFGF mRNA. In addition, HUVECs secrete bFGF in a density-dependent manner. In conclusion, the data suggest that endothelial cells regulate β -catenin activity in adrenocortical cells also via secretion of basic fibroblast growth factor. [ABSTRACT FROM AUTHOR]