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Endocrine Abstracts (2019) 63 OC10.2 | DOI: 10.1530/endoabs.63.OC10.2

ECE2019 Oral Communications Adrenal 2 (5 abstracts)

Glucocorticoid resistance patients exhibit defective cortisol metabolism, responsible for functional hypermineralocorticism

Géraldine Vitellius 1 , Brigitte Delemer 2 , Olivier Chabre 3 , Philippe Caron 4 , Eric Pussard 1, , Jerome Bouligand 1, , Séverine Trabado 1, & Marc Lombès 1


1INSERM UMR_S U1185, Le Kremlin Bicetre, France; 2Service d’endocrinologie-Diabète-Nutrition, Hôpital Robert Debré, Reims, France; 3Endocrinologie, pavillon des Écrins, CHU Grenoble, Grenoble, France; 4Service d’Endocrinologie, Pôle Cardio-Vasculaire et Métabolique, CHU Larrey, Toulouse, France; 5Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris Sud, AH-HP, CHU Bicêtre, Le Kremlin Bicetre, France.

Glucocorticoid resistance syndrome, a rare genetic disease, is often associated with glucocorticoid receptor (GR) loss-of-function mutations. Six patients carrying heterozygous mutations of NR3C1 gene encoding GR, either missense R477S, Q501H, L672P or non-sense R469X, R491X, Y660X mutations were studied. Surprisingly, NR3C1 mutation carriers presented with low kalemia, low plasma renin and aldosterone levels associated or not with arterial hypertension, consistent with functional hypermineralocorticism. Importantly, circulating corticosterone or 11-deoxycorticosterone levels, when measured in these patients, were in the normal range, excluding the involvement of these mineralocorticoid agonist compounds in the pathogenesis of pseudohypermineralocorticism, as initially suggested. In this context, we hypothesize that the clinical and biological features of glucocorticoid resistant patients might be secondary to a partial impairment of GR regulation of HSD11B2, leading to an enzymatic defect of the renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), considered as a major MR-protecting mechanism, and thus responsible for an illicit cortisol activation of the mineralocorticoid receptor (MR). The 11β-HSD2 catalyzes the conversion of cortisol into cortisone, unable to bind MR. HSD11B2 promoter presented with putative glucocorticoid response elements. Transient transfections of plasmid expressing the wild-type GR and HSD11B2 promoter-luciferase construct in HEK293T cells, disclosed a dexamethasone-dependent increase of reporter gene activity that was totally inhibited by cotreatment with the GR antagonist RU486, indicating a GR-mediated transactivation of HSD11B2 gene. Likewise, a defective GR Q501H mutant fails to stimulate luciferase activity. In the absence of human renal model endogenously expressing 11β-HSD2, we demonstrate a 3-fold increase in DXM-induced HSD11B2 mRNA levels in human breast cancer MCF7 cells, which was abolished by RU486 or by the transcription inhibitor Actinomycin D, further supporting a GR-dependent transactivation. The 11β-HSD2 activity, evaluated by cortisone/cortisol ratio quantified by LC-MS/MS, was 10-fold higher in the supernatant of DXM-treated cells than controls, strongly suggesting a GR-dependent stimulation of 11β-HSD2 catalytic activity. Collectively, we provide evidence that 11β-HSD2 expression is transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings bring additional support for a reduced HSD11B2 transcription and 11β-HSD2 activity, driven by GR signaling defect. Thus, patients carrying heterozygous loss-of-function NR3C1 mutations exhibited an impaired 11β-HSD2 enzymatic activity, leading to a functional pseudohypermineralocorticism. These findings call for a careful monitoring of such patients to prevent or adequately control the hypertension and its associated cardiovascular consequences.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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