ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2019; pii: jc.2019–00563.

Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, affecting ~6% of the adult general hypertensive population. Patients with PA are at increased risk of cerebrovascular and cardiovascular morbidity, renal abnormalities and metabolic syndrome. The activity of mTORC1 (mammalian target of rapamycin complex 1) is increased in the adrenal glands of patients with PA.

The current study analyzed the expression of mTORC1 components in aldosterone-producing adenomas (APA) in mice and in patients with PA, and investigated whether mTORC1 inhibition affects aldosterone levels, blood pressure and renin levels. Six pairs of APA and matched control adrenal cortex samples were subjected to deep quantitative mass spectrometry analysis. The expression of mTORC1 components was unchanged in APA and thus does not explain the increased mTORC1 activity observed in APAs. Systemic inhibition of mTORC1 using rapamycin in mice decreased plasma aldosterone levels but the changes were not significant and were independent of Angiotensin II. Whether the effect is direct on aldosterone synthesis or indirect via paracrine factors regulating aldosterone metabolism remains to be investigated.

To assess the systemic mTORC1 effect in human PA, 14 patients with PA were treated with everolimus for two weeks. Ten patients reported some type of adverse event, 1 patient developed pancreatitis (serious adverse event), and 4 patients were defined as treatment responders (>=30% reduction in aldosterone levels), although the aldosterone levels were returned to baseline after two weeks of wash-out period. Other steroid hormone levels did not differ between the treatment and non-treatment phase. Furthermore, 24-h steroid metabolome profiles of the patients responding to everolimus treatment suggested that everolimus affects aldosterone synthesis specifically since both aldosterone levels and its major metabolite tetrahydroaldosterone were reduced, but no change was observed in the levels of other steroids with mineralocorticoid action. Patients with PA treated with everolimus showed significant reductions in blood pressure and lowered the renin suppression. The effect was independent of heart rate, urine volume, and ADH.

The above results in mice and patients with PA suggest that increased mTORC1 activity in APA most likely depends on downstream signaling changes rather than overexpression of its components. mTORC1 inhibition is a potential therapy for hypertension in PA, however, further studies are needed to identify potential responders, and to define the most appropriate dose and safety and efficacy profiles.