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: 4.07). 04/2010; 163(1):129-38. DOI: 10.1530/EJE-10-0195
Source: PubMed


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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    • "In addition, no cut-off values of diagnostic tests have been established that define subclinical hypercortisolism. The findings on in vivo responsiveness to hormonal stimuli are a confirmation of an earlier study [16], in which it was postulated that clinical and subclinical CS represent a continuum of disease rather than two separate entities. This hypothesis is supported by the smaller adrenal sizes detected in subclinical CS patients; these patients could progress into clinical CS when adrenal size and coupled steroidogenic capacity increase. "
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    ABSTRACT: Adrenal Cushing's syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro. In vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues. Positive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1. Multiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression.
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    ABSTRACT: Subclinical hypercortisolism (SH) is a condition of biochemical cortisol excess without the classical signs or symptoms of overt hypercortisolism. It is thought to be present in the 5-30% of patients with incidentally discovered adrenal mass (adrenal incidentalomas), which in turn are found in 4-7% of the adult population. Therefore, SH has been suggested to be present in 0.2-2.0% of the adult population. Some studies suggested that this condition is present in 1-10% of patients with diabetes or established osteoporosis. The present manuscript reviews the literature on diagnostic procedures and the metabolic effect of the recovery from SH. A PubMed search was used to identify the available studies. The most relevant studies from 1992 to November 2010 have been included in the review. The available data suggest that SH may be associated with chronic complications, such as hypertension, diabetes mellitus, overweight/obesity, and osteoporosis. The available intervention studies suggest that the recovery from SH may lead to the improvement of hypertension and diabetes mellitus. A retrospective study suggests that this beneficial effect could be predicted before surgery. SH is suggested to be associated with some chronic complications of overt cortisol excess. Recovery from this condition seems to improve these complications. However, a large, prospective, randomized study is needed to confirm this hypothesis and to establish the best diagnostic approach to identify patients with adrenal incidentalomas who can benefit from surgery.
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