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Activation of the hypothalamic-pituitary-adrenal axis in adults with mineralocorticoid receptor haploinsufficiency

Lookup NU author(s): Professor Brian WalkerORCiD


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Context: Mineralocorticoid receptors (MRs) contribute to the negative feedback of the hypothalamic- pituitary-adrenal (HPA) axis in rodents. Studies with MR antagonists suggest a similar role in humans. Objective: The objective of the studywasto establish whether loss-of-function mutations inNR3C2, encoding MR, cause activation of the HPA axis. Design and Setting: This was a case-control study in members of pedigrees from the PHA1.NET cohort, comprising patients with pseudohypoaldosteronism type 1 (PHA1) who are heterozygous for loss-of-function mutations in NR3C2 and healthy controls who are unaffected family members. Participants: Twelve adult patients with PHA1 (six men, six women) and 20 age-matched healthy controls (seven men, 13 women) participated in the study. Results: Patients with PHA1 had higher morning plasma cortisol (816 ± 85 vs 586 ± 50 nmol/L, P ± .02)andincreased 24-hour urinary excretion of cortisol metabolites (985±150 vs 640±46μg/mmol creatinine, P = .03), independently of gender. After adjustment for gender, age, PHA1 diagnosis, and percentage body fat, higher plasma cortisol was associated with higher plasma renin, lower serum high-density lipoprotein-cholesterol, and higher waist circumference but not with blood pressure, carotid intima-media thickness, or echocardiographic parameters. Conclusions: Haploinsufficiency of MR in PHA1 causes HPA axis activation, providing genetic evidence that MR contributes to negative feedback in the human HPA axis. With limited sample size, initial indications suggest the resulting hypercortisolemia is related to the severity ofMRdeficiency and has adverse effects mediated by glucocorticoid receptors on liver lipid metabolism and adipose tissue distribution but does not adversely affect cardiac and vascular remodeling in the absence of normal signaling through the MR. Copyright © 2014 by the Endocrine Society.

Publication metadata

Author(s): Walker BR, Andrew R, Escoubet B, Zennaro M-C

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2014

Volume: 99

Issue: 8

Pages: E1586–E1591

Print publication date: 01/08/2014

Online publication date: 01/08/2014

Acceptance date: 01/04/2014

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Endocrine Society


DOI: 10.1210/jc.2014-1420

PubMed id: 24712576


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