Institute National Of La Sante Et Of La Recherche Medicale Unite 567

Paris, France

Institute National Of La Sante Et Of La Recherche Medicale Unite 567

Paris, France
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Assie G.,University of Paris Descartes | Assie G.,Institute National Of La Sante Et Of La Recherche Medicale Unite 567 | Louiset E.,University of Rouen | Sturm N.,Center Hospitalier University Albert Michallon | And 22 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Stimulation of cortisol secretion through abnormally expressed G protein-coupled receptors (GPCRs) is a frequent feature of ACTH-independent macronodular adrenal hyperplasia (AIMAH). This has opened a pharmacological strategy that targets GPCRs for the treatment of Cushing's syndrome in AIMAH. However, only few drugs are available for the presently described GPCRs. Objective: The objective of the study was to identify new GPCR targets for the pharmacological treatment of adrenal Cushing's syndrome. Design and Patients: We designed a cDNA chip containing 865 nucleotidic sequences of GPCRs. mRNAs were extracted from three normal adrenals, 18 AIMAHs, four adrenals from Cushing's disease patients, and 13 cortisol-secreting adenomas. A set of GPCR mRNAs that showed significantly higher or lower expression in AIMAH than in normal adrenal were studied by quantitative RT-PCR analysis. Analysis of protein expression and function were performed on selected GPCRs. Setting: The study was conducted at a tertiary care center and basic research laboratories. Results: The ACTH MC2 receptor showed a low expression in 15 of 18 AIMAHs samples, whereas several previously undescribed GPCR genes were found highly expressed in a subset of AIMAH, such as the receptors for motilin (MLNR; three of 18 AIMAHs) and γ-aminobutyric acid (GABBR1; five of 18 AIMAHs), and the α2A adrenergic receptor (ADRA2A; 13 of 18 AIMAHs), on which we focused our attention. Western blot and immunochemistry analyses showed expression of ADRA2A protein in AIMAH but not in normal adrenal cortex. The ADRA2A agonist clonidine enhanced both basal and stimulated cortisol production. Clonidine-induced increase in basal cortisol levels was blocked by the ADRA2A antagonist yohimbine. Conclusion: ADRA2A is a potential target for pharmacological treatment of Cushing's syndrome linked to AIMAH. Copyright © 2010 by The Endocrine Society.


PubMed | Institute National Of La Sante Et Of La Recherche Medicale Unite 567
Type: Journal Article | Journal: European journal of endocrinology | Year: 2010

ACTH-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.A 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.Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushings syndrome (CS), and 22 had a subclinical CS (SCS).A 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.At 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.Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.


Libe R.,Institute National Of La Sante Et Of La Recherche Medicale Unite 567 | Coste J.,University of Paris Descartes | Coste J.,Biostatistics Unit | Guignat L.,Center for Rare Adrenal Diseases | And 17 more authors.
European Journal of Endocrinology | Year: 2010

Context: ACTH-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. Objective: A 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 patients: Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS). Methods: A 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. Results: At 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. Conclusions: Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology. © 2010 European Society of Endocrinology.

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