scholarly journals PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

2015 ◽  
Vol 172 (6) ◽  
pp. 677-685 ◽  
Author(s):  
Anne Thiel ◽  
Anna-Carinna Reis ◽  
Matthias Haase ◽  
Gerald Goh ◽  
Matthias Schott ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Somatic Mutations ◽  
Germline Mutations ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Genetic Studies ◽  
Younger Age ◽  
Single Center Study ◽  
Autonomous Cortisol Secretion

ObjectiveCortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACAL206R 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 methodsIn 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.ResultsAmong 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 PRKACAL206R 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.ConclusionsPRKACAL206R 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.

scholarly journals Food-Dependent Cushing’s Syndrome: Possible Involvement of Leptin in Cortisol Hypersecretion*

1999 ◽  
Vol 84 (10) ◽  
pp. 3817-3822 ◽  
Author(s):  
François P. Pralong ◽  
Fulgencio Gomez ◽  
Louis Guillou ◽  
François Mosimann ◽  
Sebastiano Franscella ◽  
...  
Keyword(s):  
Food Intake ◽  
Cushing’S Syndrome ◽  
Adrenal Adenoma ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Adrenal Cells ◽  
Patient Reported ◽  
Stimulation Of

Abstract Stimulation of cortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing’s syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing’s syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing’s syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing’s syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing’s syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

scholarly journals The role of high performance liquid chromatography in the functional state of the adrenal glands before and after surgical treatment for corticosteroma

2020 ◽  
Vol 11 (2) ◽  
pp. 30-37
Author(s):  
M. O. Buinova ◽  
N. V. Vorokhobina ◽  
L. I. Velikanova ◽  
E. G. Strelnikova ◽  
V. L. Baranov
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Adrenal Cortex ◽  
Cushing’S Syndrome ◽  
Postoperative Period ◽  
High Performance ◽  
Cushing's Syndrome ◽  
Early Postoperative Period ◽  
Cortisol Secretion ◽  
Autonomous Cortisol Secretion

Objective: It is to evaluate the functional state of the adrenal cortex after surgical treatment in patients with corticosteromas for optimize of tactic of postoperative management.Materials and methods: We examined 143 patients (43 men and 100 women) aged 51.3 ± 10.1 years with incidentaloma of adrenal glands and 27 healthy peopels (control group) aged 45.5 ± 5.7 years. Cushing's syndrome was detected in 22 patients, autonomous cortisol secretion was detected in 43. All patients had an analysis of the complaints, objective, laboratory and instrumental data in the preoperative and early postoperative periods. Assessment of levels glucocorticoid and mineralocorticoid hormones in biological fluids was carried out by immunoassay and high performance liquid chromatography.Results: The signs of adrenal cortex insufficiency in the early postoperative period were obtained in 77.3% of patients with Cushing's syndrome and in 25% of patients with autonomous cortisol secretion according to immunoassay and high performance liquid chromatography. An increase of level of corticosterone in the serum of blood in the preoperative period indicate the possibility development of adrenal insufficiency in the early postoperative period in all patients. Аn increase of levels of 11-deoxycortisol and 18-OH-corticosteronein in the serum of blood аnd urinary excretion of free cortisone, 18-OH-corticosterone and 6β-hydroxycortisol indicate the possibility development of adrenal insufficiency in the early postoperative period in patients with Cushing's syndrome.Conclusions: The determination of cortisol and aldosterone precursors by high performance liquid chromatography increases the accuracy of the diagnosis of glucocorticoid and mineralocorticoid function of the adrenal cortex in patients with Cushing's syndrome and with autonomous cortisol secretion in the early postoperative period.

scholarly journals Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing’s Syndrome

2001 ◽  
Vol 86 (11) ◽  
pp. 5534-5540 ◽  
Author(s):  
Isabelle Bourdeau ◽  
Pierre D’Amour ◽  
Pavel Hamet ◽  
Jean-Marie Boutin ◽  
André Lacroix
Keyword(s):  
Cushing’S Syndrome ◽  
Plasma Cortisol ◽  
Hormone Receptors ◽  
Gastric Inhibitory Polypeptide ◽  
Urinary Free Cortisol ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Free Cortisol ◽  
Cortisol Levels

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 μg 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.

scholarly journals Irregular and Frequent Cortisol Secretory Episodes with Preserved Diurnal Rhythmicity in Primary Adrenal Cushing’s Syndrome

2005 ◽  
Vol 90 (3) ◽  
pp. 1570-1577 ◽  
Author(s):  
M. O. van Aken ◽  
A. M Pereira ◽  
S. W. van Thiel ◽  
G. van den Berg ◽  
M. Frölich ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Approximate Entropy ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Age And Gender ◽  
Pulsatile Secretion ◽  
Event Frequency ◽  
And Gender ◽  
Diurnal Rhythmicity

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing’s syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

scholarly journals Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates

2007 ◽  
Vol 196 (1) ◽  
pp. 1-9 ◽  
Author(s):  
E Louiset ◽  
V Contesse ◽  
L Groussin ◽  
D Cartier ◽  
C Duparc ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cultured Cells ◽  
Cushing's Syndrome ◽  
Receptor Protein ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Rt Pcr ◽  
Vasopressin Receptors ◽  
Cell Incubation ◽  
Pharmacological Profiles

Cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome can be controlled by illegitimate receptors. The aim of the present study was to characterize the molecular, immunohistochemical, and pharmacological profiles of vasopressin receptors in cells derived from three patients with AIMAH (H1–H3), in order to evaluate the role of ectopic vasopressin receptors in the physiopathology of hypercortisolism. Expression of mRNAs encoding the vasopressin receptor types (V1a, V1b, and V2) were analyzed by RT-PCR in adrenal tissues. The presence of V1a and V2 receptors was studied by immunohistochemistry on adrenal sections. The pharmacological profiles of vasopressin receptors involved in the control of cortisol secretion were investigated using the V1a receptor antagonist SR49059 and the V2 receptor agonist [deamino-Cys1, Val4, d-Arg8]-vasopressin on cultured cells. The V1a receptor protein was present and functional in H1 and H3 tissues, whereas the V1b receptor was not expressed in any of the tissues. RT-PCR experiments revealed that V2 receptor mRNAs were detected in the three tissues. In contrast, immunohistochemical and cell incubation studies showed that the V2 receptor was involved in the stimulatory effect of AVP on cortisol secretion in H1 and H2, but not in H3 cells. Taken together, these data show that expression of functional ectopic V2 receptors and repression of eutopic V1a receptor can coexist in some hyperplastic corticosteroidogenic tissues. They also reveal that immunohistochemical and incubation studies are essential for the characterization of ectopic receptors actually involved in the control of cortisol secretion by AIMAHs.

scholarly journals In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

2005 ◽  
Vol 90 (3) ◽  
pp. 1302-1310 ◽  
Author(s):  
Jérôme Bertherat ◽  
Vincent Contesse ◽  
Estelle Louiset ◽  
Gaëlle Barrande ◽  
Céline Duparc ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Gastric Inhibitory Polypeptide ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Adrenocortical Cells ◽  
Normal Cells ◽  
H1 Cells

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing’s syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1–H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing’s syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.

QUANTITATIVE ESTIMATION OF URINARY PREGNANETRIOL, PREGNANETRIOLONE, TETRAHYDRO S AND Δ5-PREGNENETRIOL IN THE INVESTIGATION OF ADRENOCORTICAL FUNCTION

1969 ◽  
Vol 60 (4) ◽  
pp. 657-668 ◽  
Author(s):  
Frances J. Thomas ◽  
A. W. Steinbeck
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Cushing’S Syndrome ◽  
Adrenocortical Carcinoma ◽  
Quantitative Estimation ◽  
Cushing's Syndrome ◽  
Adrenocortical Function ◽  
Adrenal Hyperplasia ◽  
Ectopic Acth ◽  
Modified Method ◽  
Idiopathic Hirsutism

ABSTRACT A modified method for the estimation of urinary pregnanetriol, pregnanetriol, pregnanetriolone, Δ5-pregnenetriol and tetrahydro S was investigated. The steroids, separated by chromatography, were measured quantitatively, tetrahydro S by reaction with blue tetrazolium and the other three as acetaldehydogenic substances. The excretion of these steroids was studied in suspected instances of adrenal and/or ovarian disease. Urinary pregnanetriol and tetrahydro S levels were normal in Cushing's syndrome, secondary adrenocortical carcinoma, the Stein-Leventhal syndrome, idiopathic hirsutism and hypertension. Tetrahydro S was doubtfully elevated in an instance of ectopic ACTH Cushing's syndrome. Pregnanetriol excretion was elevated in untreated cases of congenital adrenal hyperplasia and after treatment in some. Pregnanetriolone was found in all patients with congenital adrenal hyperplasia, including those receiving cortisone. Pregnanetriolone was also detected in Cushing's syndrome, secondary adrenocortical carcinoma, the Stein-Leventhal syndrome, ectopic ACTH Cushing's syndrome and suspected congenital adrenal hyperplasia. Δ5-pregnenetriol was present as a glucuronide in the Stein-Leventhal syndrome and idiopathic hirsutism. The diagnostic implications of these results are discussed.

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