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Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency. | LitMetric

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency.

Am J Physiol Endocrinol Metab

Institut National de la Santé et de la Recherche Médicale, Le Kremlin-Bicêtre, France.

Published: February 2020

AI Article Synopsis

  • 21-Hydroxylase deficiency (21OHD) leads to salt-wasting syndrome by preventing the production of cortisol and aldosterone, affecting 75% of those affected by the condition.
  • Recent advancements in mass spectrometry have allowed researchers to identify 21-deoxysteroids like 17OHP, 21DF, and 21DB, which may disrupt mineralocorticoid signaling and fludrocortisone therapy in congenital adrenal hyperplasia (CAH) patients.
  • The study measured levels of these steroids in a pediatric CAH cohort and found that elevated concentrations can impair mineralocorticoid receptor activation, indicating the need for careful monitoring and adjustment of steroid levels to improve patient management.

Article Abstract

21-Hydroxylase deficiency (21OHD) is a rare genetic disorder in which salt-wasting syndrome occurs in 75% of cases, due to inability to synthesize cortisol and aldosterone. Recent mass spectrometry progress allowed identification of 21-deoxysteroids, i.e., 17-hydroxyprogesterone (17OHP), 21-deoxycortisol (21DF), and 21-deoxycorticosterone (21DB). We hypothesized that they may interfere with mineralocorticoid signaling and fludrocortisone therapy in patients with congenital adrenal hyperplasia (CAH) without effective glucocorticoid replacement and ACTH suppression. Our goal was to quantify circulating 21-deoxysteroids in a pediatric cohort with CAH related to 21OHD and to examine their impact on mineralocorticoid receptor (MR) activation. Twenty-nine patients with salt-wasting phenotype were classified in two groups according to their therapeutic control. During routine follow-up, 17OHP, 21DF, 21DB, and cortisol levels were quantified by liquid chromatography with tandem mass spectrometry before hydrocortisone intake and 1 and 2.5 h following treatment administration. Luciferase reporter gene assays were performed on transfected HEK293T cells while in silico modeling examined structural interactions between these steroids within ligand-binding domain of MR. Plasma 17OHP, 21DF, and 21DB accumulate in uncontrolled patients reaching micromolar concentrations even after hydrocortisone intake. 21DF and 21DB act as partial MR agonists with antagonist features similar to 17OHP, consistent with altered anchoring to Asn and unfavorable contact with Ala in ligand-binding pocket of MR. Our results demonstrate a complex interaction between all accumulating 21-deoxysteroids in uncontrolled 21OHD patients and mineralocorticoid signaling and suggest that appropriate steroid profiling should optimize management and follow-up of such patients, as keeping those steroids to low plasma levels should attest therapeutic efficacy and prevent interference with MR signaling.

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Source
http://dx.doi.org/10.1152/ajpendo.00368.2019DOI Listing

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