Interactions between adrenal-regulatory and calcium-regulatory hormones in human health

Abstract

Purpose of review: To summarize the evidence characterizing the interactions between adrenal-regulating and calcium-regulating hormones, and the relevance of these interactions to human cardiovascular and skeletal health.

Recent findings: Human studies support the regulation of parathyroid hormone (PTH) by the renin-angiotensin-aldosterone system (RAAS): angiotensin II may stimulate PTH secretion via an acute and direct mechanism, whereas aldosterone may exert a chronic stimulation of PTH secretion. Studies in primary aldosteronism, congestive heart failure, and chronic kidney disease have identified associations between hyperaldosteronism, hyperparathyroidism, and bone loss, which appear to improve when inhibiting the RAAS. Conversely, elevated PTH and insufficient vitamin D status have been associated with adverse cardiovascular outcomes, which may be mediated by the RAAS. Studies of primary hyperparathyroidism implicate PTH-mediated stimulation of the RAAS, and recent evidence shows that the vitamin D-vitamin D receptor complex may negatively regulate renin expression and RAAS activity. Ongoing human interventional studies are evaluating the influence of RAAS inhibition on PTH and the influence of vitamin D receptor agonists on RAAS activity.

Summary: Although previously considered independent endocrine systems, emerging evidence supports a complex web of interactions between adrenal-regulating and calcium-regulating hormones, with implications for human cardiovascular and skeletal health.

Figure 1. Interactions between Calcium-Regulatory Hormones and the Renin-Angiotensin-Aldosterone System

Increasing evidence supports multiple, complex interactions between the calcium-regulatory system and the RAAS, and these interactions are relevant to both cardiovascular and skeletal disease. Shown on the left is a simplified diagram of the key components of the calcium-regulating system, and on the right, from bottom to top, is a simplified schematic of the RAAS. Solid arrows denote established interactions within the calcium- and adrenal-regulatory hormone systems, respectively. Dashed arrows indicate newly appreciated interactions between the two systems. Black arrows indicate a stimulatory relationship, whereas grey lines terminating in a bar indicate an inhibitory relationship. Arrows A and B depict RAAS-mediated stimulation of the calcium-regulatory system. (A) Chronic exposure to aldosterone stimulates PTH, possibly secondary to urinary calcium loss, though the mineralocorticoid receptor is expressed in the parathyroid [14**,15**,16*]. (B) AngII acutely stimulates PTH, and the angiotensin type 1 receptor is expressed in parathyroid tissue [17**]. Arrows C-F show Ca-, PTH-, and Vitamin D-mediated control of the RAAS. (C) Ca acutely inhibits renin release, but chronic elevations in Ca may stimulate renin production [18]. (D) PTH augments the aldosterone response to AngII [19], and PTH receptors are expressed in aldosterone-producing cells [20]. (E) PTH directly stimulates renin in vitro [21], and PTH infusion results in increased AngII levels [22]. (F) The 1,25(OH)₂D-Vitamin D Receptor complex inhibits renin expression in vitro [23**], insufficient Vitamin D status has been associated with increased plasma renin activity [24], and Vitamin D supplementation can downregulate the RAAS [25**]. RAAS, renin-angiotensin-aldosterone system; PTH, parathyroid hormone; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; Ca, calcium; AGT, angiotensinogen; AngI, angiotensin I; ACE, angiotensin converting enzyme; AngII, angiotensin II.