Aberrant Hormone Receptors in Primary Aldosteronism

Abstract

The mechanisms involved in the renin-independent regulation of aldosterone secretion in primary aldosteronism are poorly understood. In ACTH-independent Cushing's syndrome, cortisol secretion can be regulated by the aberrant expression of G-protein coupled receptors (GPCRs) in unilateral tumors and bilateral macronodular adrenal hyperplasia. By analogy, some recent studies identified overexpression or function of several GPCR as a potential cause for excess aldosterone production in some aldosteronomas and in bilateral idiopathic hyperaldosteronism. Initial studies have used in vitro techniques, while the clinical aldosterone responses were not assessed. More recently, several receptors have been shown to be expressed in aldosterone-producing adrenal tumors in vitro and to regulate aberrantly renin-independent aldosterone secretion in vivo. The prevalence of aberrant hormone receptors in primary aldosteronism could be elevated, but larger systematic studies are required to establish its true frequency. The identification of aberrant adrenal GPCRs by in vivo functional studies offers the potential for novel pharmacological therapies that either suppress the endogenous ligands or block the receptor with specific antagonists.

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…In almost all cases, this has appeared to involve increased expression of receptors normally found in the adrenal (eutopic receptors) rather than expression of receptors not normally expressed in the adrenal (ectopic receptors) (320). Examples of the former (some of which have been discussed earlier in this section) include receptors for ACTH (24), serotonin (277), somatostatin (312), vasopressin (395), glucose-dependent insulinotropic peptide (GIP) (274), gonadotropin releasing and luteinizing hormones (320), and thyroid stimulating hormone (596).…”

Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism

“…APAs can be distinguished by their size, cell types, hormone oversecretion, and responsiveness to angiotensin 2. In addition, in vitro molecular and immunohistochemistry studies as well as clinical studies with infusion of various compounds in vivo showed that in patients with APA, aldosterone secretion may be regulated also by multiple other factors, mainly arginine, vasopressin, and serotonin (64). However, they can also be differentiated by the extent of hormone suppression by dexamethasone and by the secretion of hybrid steroids, as 18-hydroxy-cortisol (18-OH-F) (65)(66)(67).…”

Comparison of the Saline Infusion Test and the Fludrocortisone Suppression Test for the Diagnosis of Primary Aldosteronism

“…Therefore, blood aldosterone concentrations that are elevated in relation to a low renin level, which is refl ected by an increase in the aldosterone-to-renin ratio (ARR), do not necessarily prove autonomous aldosterone secretion, being the reason for primary aldosteronism (PA) [ 4 ] . In addition, overexpression of G-protein-coupled membrane receptors is observed in a high proportion of cases with PA and may lead to oversensitivities of aldosteroneproducing adenomas (APAs) to stimuli with an otherwise physiological concentration in the blood [ 5 ] . To circumvent the uncertainties associated with ARR determinations, there is now consensus that the diagnosis of PA be built on the results of confi rmatory testing [ 6 ] .…”