Abstract
BackgroundAdrenal 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.MethodsIn 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.ResultsPositive 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.ConclusionsMultiple 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.
Highlights
Adrenal Cushing’s syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli
Aberrant hormonal responses and the presence of hormone receptors in AIMAH have been well documented for glucose-dependent insulinotropic polypeptide (GIP) receptor [3,4,5], α4, β1- and β2-adrenergic receptor (AR) [6,7], arginine-vasopressin (AVP) type 1a and 2 receptors (AVPR1A/2) [8,9], luteinizing hormone receptor (LHR) [10,11] and serotonin (5-HT) type 4 receptor (5HT4R) [12,13]
We evaluated the effects of the hormonal stimuli on mRNA levels of steroid acute regulatory protein (STAR) and the steroidogenic enzymes involved in cortisol synthesis (Figure 2)
Summary
Adrenal Cushing’s syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. Cushing’s syndrome (CS) can be divided into adrenocorticotropin (ACTH)-dependent and ACTH-independent disease [1]. The latter can in rare cases result from ACTHindependent macronodular adrenocortical hyperplasia (AIMAH). The hypercortisolism in AIMAH patients is caused by an exaggerated or ectopic response to stimulation by hormonal signals. Receptors for these hormones, eutopically or ectopically expressed on adrenocortical cells and activated by endogenous hormones, stimulate intracellular pathways leading to (sub-)clinical CS [2]. Other possible aberrantly expressed receptors include the AngII type I receptor (AT1R) [14] and glucagon receptor [15,16]
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