scholarly journals Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing's syndrome

2010 ◽  
Vol 163 (2) ◽  
pp. 293-299 ◽  
Author(s):  
J W B de Groot ◽  
T P Links ◽  
A P N Themmen ◽  
L H Looijenga ◽  
R R de Krijger ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Immunohistochemical Analysis ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
Aberrant Expression ◽  
Adrenal Tissue ◽  
The Individual

ObjectiveAberrant adrenal expression of various hormone receptors has been identified in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing cortisol hypersecretion regulated by hormones other than ACTH. We aimed to determine aberrant expression of multiple hormone receptors in vivo and in vitro in adrenal tissue of a patient with AIMAH.DesignThe design of the study includes clinical case description, and biochemical and immunohistochemical analysis to demonstrate aberrant expression of multiple hormone receptors in AIMAH.MethodsThe subject of the study is a male diagnosed with Cushing's syndrome because of AIMAH. Directly after laparoscopic removal of the adrenals, adrenal tissue was incubated with and without test substances (ACTH, forskolin, arginine vasopressin (AVP), desmopressin, epinephrine, norepinephrine, purified human chorionic gonadotropin (hCG), metoclopramide and the combinations of AVP with ACTH, epinephrine and metoclopramide). LH/hCG-receptor (hCG-R) immunohistochemistry and RT-PCR analyses were performed to demonstrate aberrant expression of LH/hCG-R and V1–3-AVPR.ResultsAIMAH was characterized by in vivo cortisol responsiveness to AVP and in vitro cortisol responses to AVP, hCG, epinephrine, and norepinephrine suggesting aberrant adrenal expression of the receptors for AVP (the V1–3-AVPRs), catecholamines (the β-AR), and LH (the LH/hCG-R). Incubation with combinations of AVP and ACTH and of AVP with epinephrine induced a stronger cortisol response compared with incubation with the individual agents. Moreover, we demonstrated adrenal V1–3-AVPR and LH/hCG-R expression.ConclusionsAIMAH tissue may simultaneously express multiple aberrant hormone receptors, and individual ligands may potentiate each other regarding cell proliferation and cortisol production.

scholarly journals Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome

2010 ◽  
Vol 163 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Rossella Libé ◽  
Joël Coste ◽  
Laurence Guignat ◽  
Frédérique Tissier ◽  
Hervé Lefebvre ◽  
...  
Keyword(s):  
Functional Status ◽  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Cushing's Syndrome ◽  
Receptor Expression ◽  
Adrenal Hyperplasia ◽  
Cortisol Responses ◽  
A Prospective Study ◽  
Underlying Pathophysiology

ContextACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors.ObjectiveA large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status.Design and patientsThirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS).MethodsA baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed.ResultsAt least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS.ConclusionsCortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.

scholarly journals Cushing’s Syndrome in a Patient with Bilateral Macronodular Adrenal Hyperplasia Responding to Cisapride: An in Vivo and in Vitro Study

2003 ◽  
Vol 88 (10) ◽  
pp. 4616-4622 ◽  
Author(s):  
Massimo Mannelli ◽  
Pietro Ferruzzi ◽  
Paola Luciani ◽  
Clara Crescioli ◽  
Lisa Buci ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
In Vitro Study ◽  
Cushing's Syndrome ◽  
Vitro Study ◽  
Adrenal Hyperplasia

scholarly journals Are Ectopic or Abnormal Membrane Hormone Receptors Frequently Present in Adrenal Cushing’s Syndrome?1

2000 ◽  
Vol 85 (10) ◽  
pp. 3531-3536 ◽  
Author(s):  
Hortensia Mircescu ◽  
Jose Jilwan ◽  
Nina N′Diaye ◽  
Isabelle Bourdeau ◽  
Johanne Tremblay ◽  
...  
Keyword(s):  
Medical Therapy ◽  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Gastric Inhibitory Polypeptide ◽  
Cushing's Syndrome ◽  
Adrenergic Agonists ◽  
Adrenal Hyperplasia ◽  
Clinical Screening ◽  
Adrenal Hormone

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),β -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.

scholarly journals Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

2007 ◽  
Vol 51 (8) ◽  
pp. 1226-1237 ◽  
Author(s):  
Marcia Helena Soares Costa ◽  
André Lacroix
Keyword(s):  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
Sexual Steroids ◽  
Acth Receptor ◽  
The Family ◽  
Cycle Regulation ◽  
G Protein Coupled

ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS), in which clinical features usually become apparent only after several decades of life. This form of adrenal hyperplasia typically produces excess cortisol with overt or subclinical CS, but concurrent secretion of mineralocorticoids or sexual steroids can also occur. The diagnosis is suspected by bilateral adrenal nodules larger than 1 cm on incidental imaging studies or following the demonstration of ACTH-independent hormonal hypersecretion. The pathophysiology of this entity is heterogeneous and has been intensely explored in recent years. Several G-protein coupled receptors aberrantly expressed in the adrenal cortex have been implicated in the regulation of steroidogenesis and in the initial cell proliferation in AIMAH. Several familial cases of AIMAH have been recently described with the same pattern of aberrant hormone receptors in all affected members of the family. It is probable that additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition over time in the various nodules; other mechanisms, as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion have been rarely identified as the molecular mechanism in some cases. When systematically screened, most patients with AIMAH exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. The identification of these receptors creates the possibility of a specific pharmacological treatment isolated or associated with adrenalectomy.

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.

scholarly journals Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

2007 ◽  
Vol 51 (9) ◽  
pp. 1452-1462 ◽  
Author(s):  
Tânia L. Mazzuco ◽  
Michaël Thomas ◽  
Monique Martinie ◽  
Nadia Cherradi ◽  
Nathalie Sturm ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cultured Cells ◽  
Cushing's Syndrome ◽  
Screening Tests ◽  
Adrenal Hyperplasia ◽  
Hormone Production ◽  
Autocrine Loop ◽  
Molecular Alterations ◽  
Molecular Abnormalities

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a b-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.

scholarly journals TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover

2012 ◽  
Vol 166 (6) ◽  
pp. 1039-1048 ◽  
Author(s):  
Tove Lekva ◽  
Thor Ueland ◽  
Hege Bøyum ◽  
Johan Arild Evang ◽  
Kristin Godang ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Cushing’S Syndrome ◽  
Bone Cells ◽  
Cushing's Syndrome ◽  
Gene Encoding ◽  
Osteoclast Activity ◽  
Bone Biopsies ◽  
Before And After

ObjectivePatients with endogenous Cushing's Syndrome (CS), as long-time treated patients with exogenous glucocorticoids (GCs), have severe systemic manifestations including secondary osteoporosis and low-energy fractures. The aim of the present study was to investigate the functional role ofTXNIPin bone with focus on osteoblast (OB) differentiation and OB-mediated osteoclast activity and functionin vitro.Design and methodsNine bone biopsies from CS before and after surgical treatment were screened for expressional candidate genes. Microarray analyses revealed that the gene encodingTXNIPranked among the most upregulated genes. Subsequentin vitroandin vivostudies were performed.ResultsWe found thatTXNIPgene in bone is downregulated in CS following surgical treatment. Furthermore, ourin vivodata indicate novel associations between thioredoxin andTXNIP. Ourin vitrostudies showed that silencingTXNIPin OBs was followed by increased differentiation and expression and secretion of osteocalcin as well as enhanced activity of alkaline phosphatase. Moreover, treating osteoclasts with silenced TXNIP OB media showed an increased osteoclast activity.ConclusionsTXNIPexpression in bone is highly regulated during the treatment of active CS, and by GC in bone cellsin vitro. Our data indicate that TXNIP may mediate some of the detrimental effects of GC on OB function as well as modulate OB-mediated osteoclastogenesis by regulating the OPG/RANKL ratio.

CONCURRENT 3β-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY IN ADRENAL AND SCLEROCYSTIC OVARY

1965 ◽  
Vol 48 (3) ◽  
pp. 392-412 ◽  
Author(s):  
Leonard R. Axelrod ◽  
Joseph W. Goldzieher ◽  
S. David Ross
Keyword(s):  
Cushing’S Syndrome ◽  
Dehydrogenase Deficiency ◽  
Clinical Manifestations ◽  
Regulatory System ◽  
Hydroxysteroid Dehydrogenase ◽  
Cushing's Syndrome ◽  
Hypothalamic Pituitary Adrenal ◽  
Relative Deficiency

ABSTRACT In vivo and in vitro studies were performed in a virilized patient with enlarged sclerocystic ovaries, in whom urinary corticoid excretion was not suppressed by dexamethasone. Both ovarian and adrenal tissues were incubated with 5-pregnenolone-4-14C and the metabolites isolated and definitively identified. Both tissues showed a relative deficiency of 3β-hydroxysteroid dehydrogenase. The ovarian aromatizing mechanism was intact. 5-Androstene-3β,17β-diol was the major adrenal biosynthetic product, and its metabolites were identified in the urine. The abnormality of the hypothalamic-pituitary-adrenal regulatory system resembled that seen in Cushing's syndrome, but the clinical manifestations were altered by the steroid enzyme abnormality.

scholarly journals IN VIVO AND IN VITRO STUDIES OF ADRENAL SECRETIONS IN CUSHING'S SYNDROME AND PRIMARY ALDOSTERONISM*

1963 ◽  
Vol 42 (4) ◽  
pp. 516-524 ◽  
Author(s):  
Edward G. Biglieri ◽  
Satoshi Hane ◽  
Paul E. Slaton ◽  
Peter H. Forsham
Keyword(s):  
Cushing’S Syndrome ◽  
Primary Aldosteronism ◽  
Cushing's Syndrome ◽  
In Vitro Studies
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