Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension

J Clin Endocrinol Metab. 2015 Aug;100(8):2857-64. doi: 10.1210/jc.2015-1268. Epub 2015 May 14.


Context: Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA).

Objective: We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT).

Patients and methods: One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs.

Results: Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group.

Conclusions: A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / complications
  • Adenoma / genetics
  • Adenoma / metabolism
  • Adrenal Gland Neoplasms / complications
  • Adrenal Gland Neoplasms / genetics
  • Adrenal Gland Neoplasms / metabolism
  • Adrenocorticotropic Hormone / blood
  • Aldosterone / blood
  • Aldosterone / metabolism*
  • Case-Control Studies
  • Cytochrome P-450 CYP11B2 / genetics
  • Essential Hypertension
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • Humans
  • Hydrocortisone / blood
  • Hyperaldosteronism / complications
  • Hyperaldosteronism / genetics
  • Hyperaldosteronism / metabolism*
  • Hypertension / complications
  • Hypertension / genetics
  • Hypertension / metabolism*
  • Middle Aged
  • Mutant Chimeric Proteins / genetics
  • Renin / blood
  • Steroid 11-beta-Hydroxylase / genetics
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism*


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNJ5 protein, human
  • Mutant Chimeric Proteins
  • Aldosterone
  • Adrenocorticotropic Hormone
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase
  • Renin
  • Hydrocortisone