ESPE2015 Poster Category 3 Late Breaking Posters (15 abstracts)
Adrenal Steroid Precursors Accumulating in Congenital Adrenal Hyperplasia lead to Transactivation of the Glucocorticoid Receptor
Karijn Pijnenburg-Kleizen a , Manon Engels a, , Christiaan Mooij a , Aliesha Griffin c , Nils Krone c , Paul Span d , Antonius van Herwaarden b , Fred Sweep b & Hedi Claahsen-van der Grinten a
aDepartment of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands; bDepartment of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; cCentre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; dDepartment of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
Background: Congenital adrenal hyperplasia (CAH) patients are clinically often less severely affected by cortisol deficiency than anticipated from their enzymatic defect.
Objective and hypotheses: We hypothesize that adrenal steroid hormone precursors that accumulate in untreated or poorly controlled CAH have glucocorticoid activity and partially compensate for cortisol deficiency. We aimed to determine the in vitro binding, translocation and transactivation potential of the steroid hormone precursors 21-deoxycortisol, 17-hydroxyprogesterone, progesterone, and androstenedione on the human glucocorticoid receptor (hGR).
Method: Competitive binding assays were performed in HeLa cells. Nuclear translocation of the hGR was studied by transfection of COS-7 cells with a GFP-tagged hGR and fluorescence microscopy. Transactivation assays were performed in COS-7 cells and repeated in HEK 293 cells using a dual luciferase assay after co-transfection of the cells with the hGR and luciferase reporter vectors.
Results: 21-Deoxycortisol, 17-hydroxyprogesterone, and progesterone are able to bind to the hGR with binding affinities of 24–43% compared to cortisol. Androstenedione has a low binding affinity. Incubation with 21-deoxycortisol led to complete nuclear translocation of the hGR, whereas treatment with 17-hydroxyprogesterone or progesterone resulted in partial nuclear translocation. 21-Deoxycortisol transactivated the hGR with an EC50 approximately sixfold the EC50 of cortisol. 17-Hydroxyprogesterone and progesterone transactivated the hGR with EC50s of more than 100 times the EC50 of cortisol. No hGR transactivation was detected after incubation with androstenedione.
Conclusion: 21-Deoxycortisol, 17-hydroxyprogesterone, and progesterone are able to bind, translocate and transactivate the hGR in vitro and thus may have glucocorticoid activity. Mainly 21-deoxycortisol might have a clinically relevant agonistic effect on the hGR and could potentially partially compensate the cortisol deficiency in CAH patients.
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