Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism

Nada El Ghorayeb,André Lacroix,Isabelle Bourdeau

doi:10.3389/fendo.2016.00072

Abstract

The major physiological regulators of aldosterone production from the adrenal zona glomerulosa are potassium and angiotensin II; other acute regulators include adrenocorticotropic hormone (ACTH) and serotonin. Their interactions with G-protein coupled hormone receptors activate cAMP/PKA pathway thereby regulating intracellular calcium flux and CYP11B2 transcription, which is the specific steroidogenic enzyme of aldosterone synthesis. In primary aldosteronism (PA), the increased production of aldosterone and resultant relative hypervolemia inhibits the renin and angiotensin system; aldosterone secretion is mostly independent from the suppressed renin–angiotensin system, but is not autonomous, as it is regulated by a diversity of other ligands of various eutopic or ectopic receptors, in addition to activation of calcium flux resulting from mutations of various ion channels. Among the abnormalities in various hormone receptors, an overexpression of the melanocortin type 2 receptor (MC2R) could be responsible for aldosterone hypersecretion in aldosteronomas. An exaggerated increase in plasma aldosterone concentration (PAC) is found in patients with PA secondary either to unilateral aldosteronomas or bilateral adrenal hyperplasia (BAH) following acute ACTH administration compared to normal individuals. A diurnal increase in PAC in early morning and its suppression by dexamethasone confirms the increased role of endogenous ACTH as an important aldosterone secretagogue in PA. Screening using a combination of dexamethasone and fludrocortisone test reveals a higher prevalence of PA in hypertensive populations compared to the aldosterone to renin ratio. The variable level of MC2R overexpression in each aldosteronomas or in the adjacent zona glomerulosa hyperplasia may explain the inconsistent results of adrenal vein sampling between basal levels and post ACTH administration in the determination of source of aldosterone excess. In the rare cases of glucocorticoid remediable aldosteronism, a chimeric CYP11B2 becomes regulated by ACTH activating its chimeric CYP11B1 promoter of aldosterone synthase in bilateral adrenal fasciculate-like hyperplasia. This review will focus on the role of ACTH on excess aldosterone secretion in PA with particular focus on the aberrant expression of MC2R in comparison with other aberrant ligands and their GPCRs in this frequent pathology.

Highlights

Primary aldosteronism (PA) was first described in patients with unilateral aldosterone-producing adenomas [1]
Renin is an enzyme produced primarily by the juxtaglomerular apparatus of the kidney and its release is the rate-limiting step in the regulation of the rennin–angiotensin system (RAS) [19, 20]; it is controlled by four factors: [1] the macula densa comprises chemoreceptors for monitoring the sodium and chloride loads present in the distal tubule, [2] juxtaglomerular cells acting as pressure transducers that sense stretch of the afferent arteriolar wall and renal perfusion pressure, [3] the sympathetic nervous system (SNS), which increases the release of renin, in response to upright posture, in addition to [4] inhibiting factors, including K+, Ca++, angiotensin II, and atrial natriuretic peptides [19]
No mutations of any of the above ion channel genes were found in bilateral adrenal hyperplasia (BAH) or in zona glomerulosa (ZG) hyperplasia adjacent to the dominant aldosteronomas [26, 29, 32, 33]; these findings suggest that nodule formation and excess aldosterone production are two dissociated events, implying a two-hit hypothesis for aldosterone-producing adenoma (APA) formation [16, 34]