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.

Department of Endocrinology, Metabolism and Cancer, Institut National de la Santé et de la Recherche Médicale Unité 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France.
European Journal of Endocrinology (Impact Factor: 3.14). 04/2010; 163(1):129-38. DOI: 10.1530/EJE-10-0195
Source: PubMed

ABSTRACT 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 Cushing's 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.

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    ABSTRACT: Primary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome and is more often diagnosed as bilateral adrenal incidentalomas with subclinical cortisol production. We summarize the recent insights concerning its epidemiology, diagnosis, genetics, pathophysiology, and therapeutic options. Recent publications have modified our notions on the genetics and pathophysiology of bilateral macronodular adrenal hyperplasia. Combined germline and somatic mutations of armadillo repeat containing 5 gene were identified in familial cases, in approximately 50% of apparently sporadic cases and in the relatives of index cases; genetic testing should allow early diagnosis in the near future. The recent finding of ectopic adrenocortical production of adrenocorticotropic hormone in clusters of bilateral macronodular adrenal hyperplasia tissues and its regulation by aberrant hormone receptors opens new horizons for eventual medical therapy using melanocortin-2 receptor and G-protein-coupled receptor antagonists. Finally, some medical and surgical treatments have been updated. Recent findings indicate that bilateral macronodular adrenal hyperplasia is more frequently genetically determined than previously believed. Considering the role of paracrine adrenocorticotropic hormone production on cortisol secretion, the previous nomenclature of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia appears inappropriate, and this disease should now be named primary bilateral macronodular adrenal hyperplasia.
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