PTH Modulation by Aldosterone and Angiotensin II is Blunted in Hyperaldosteronism and Rescued by Adrenalectomy

Abstract

Context Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathyroid gland through mechanisms that remain unexplored. Objectives To test the hypothesis that in vivo angiotensin II blockade affects PTH secretion in patients with hypertension and that aldosterone and angiotensim II directly stimulate PTH secretion ex vivo. Design and Setting We investigated the changes of serum PTH levels induced by oral captopril (50 mg) administration in patients with primary essential hypertension (EH) and with primary aldosteronism (PA) caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), the latter before and after adrenalectomy. We also exposed primary cultures of human parathyroid cells from patients with primary hyperparathyroidism to angiotensin II (10−7 M) and/or aldosterone (10−7 M). Results Captopril lowered PTH levels (in nanograms per liter) both in patients with EH (n = 63; 25.9 ± 8.3 baseline vs 24.4 ± 8.0 postcaptopril, P < 0.0001) and in patients with APA after adrenalectomy (n = 27; 26.3 ± 11.6 vs 24.0 ± 9.7 P = 0.021). However, it was ineffective in patients with full-blown PA caused by APA and BAH. In primary culture of human parathyroid cells, both aldosterone (P < 0.001) and angiotensin II (P = 0.002) markedly increased PTH secretion from baseline, by acting through mineralocorticoid receptor and angiotensin type 1 receptor, as these effects were abolished by canrenone and irbesartan, respectively. Conclusion These results collectively suggest an implication of the renin-angiotensin-aldosterone system in PTH regulation in humans, at least in PTH-secreting cells obtained from parathyroid tumors. Moreover, they further support the concept that mild hyperparathyroidism is a feature of human PA that is correctable with adrenalectomy.

Primary and Secondary Hyperparathyroidism in Patients with Primary Aldosteronism – Findings From the German Conn’s Registry

“…Brown et al could demonstrate a 2-to 4-fold increase of mineralocorticoid and angiotensin II type 1 receptors in adenomatous tissue of the parathyroid gland [19]. A recent study of Lenzini et al in primary culture of human parathyroid cells showed that both aldosterone and angiotensin II increased PTH secretion, by acting through MR and angiotensin II type 1 receptors, respectively [8].…”

“…with normal aldosterone levels demonstrated that six weeks of treatment with the mineralocorticoid receptor antagonist spironolactone resulted in a relative decrease in PTH compared to placebo [19]. Recently, the study of Lenzini et al showed that the inhibition of angiotensin II with captopril lowered PTH levels both in essential hypertension and in APA patients after adrenalectomy [8]. Interestingly, captopril had no effect on the elevated PTH levels in PA patients, suggesting that the parathyroid gland loses its ability to respond to acute angiotensin II inhibition when hyperaldosteronism coexists with hyperparathyroidism.…”

“…The role of parathyroid hormone (PTH) and its influence on aldosterone secretion as well as the effect of aldosterone excess on the calcium phosphate homeostasis are so far not clearly understood. Recent studies support a bidirectional interaction between the two hormonal systems [6][7][8]. Increased levels of PTH have been demonstrated in PA patients, possibly triggered through aldosterone-mediated tubular calcium and magnesium losses [9][10][11][12].…”

The Interplay Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone

“…The relationship between the RAAS and PTH is significantly positive, as patients with PA exhibit higher PTH levels compared to secondary aldosteronism and primary hypertension patients (2,17,77). Recent studies have suggested that mild hyperparathyroidism is a characteristic of PA (80), irrespective of the subtype of PA (81). Furthermore, PA may even contribute to secondary hyperparathyroidism (77).…”

“…Aldosteronoma resection decreases the PTH level (83). Adrenalectomy not only cures hyperaldosteronism but also corrects hyperparathyroidism (17,80). Compared with MRA, surgical treatment reduces PTH levels more obviously in PA patients (77).…”