Proof of concept for a superior therapeutic index of corticosterone compared with hydrocortisone in patients with congenital adrenal hyperplasia.

Autor:	Kyle CJ; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Boyle LD; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Nixon M; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Homer NZM; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Simpson JP; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Rutter A; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Ramage LE; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Kelman A; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Freel EM; Queen Elizabeth University Hospital, Glasgow, G51 4TF, United Kingdom., Andrew R; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom., Walker BR; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom.; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE4 5PL, United Kingdom., Stimson RH; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2024 Nov 27; Vol. 191 (6), pp. 535-544.
DOI:	10.1093/ejendo/lvae144
Abstrakt:	Objective: Outcomes are poor for patients with congenital adrenal hyperplasia (CAH), in part due to the supraphysiological glucocorticoid doses required to control adrenal androgen excess. Hydrocortisone (ie, cortisol) is the recommended glucocorticoid for treatment of CAH. However, the other endogenous glucocorticoid in humans, corticosterone, is actively transported out of metabolic tissues such as adipose tissue and muscle, so we hypothesized that corticosterone could control adrenal androgens while causing fewer metabolic adverse effects than hydrocortisone. Methods: Thirteen patients (8 female, 5 male) with CAH due to 21-hydroxylase deficiency completed a randomized placebo-controlled crossover study comparing 5 h intravenous infusions of either hydrocortisone, corticosterone or placebo. 6-6[2H]2-glucose and 1,1,2,3,3-[2H]5-glycerol were infused to measure glucose and glycerol kinetics, and blood samples were collected throughout. Subcutaneous abdominal adipose tissue biopsies were obtained at the end of each infusion. Results: During the infusion, corticosterone and hydrocortisone similarly reduced ACTH, 17α-hydroxyprogesterone, androstenedione, and testosterone (in females only) compared with placebo. Despite achieving circulating corticosterone concentrations ∼2.5-fold higher than hydrocortisone, by T + 300 min hydrocortisone but not corticosterone increased glucose and insulin concentrations and reduced 6-6-[2H]2-glucose clearance compared with placebo. Hydrocortisone increased mRNA levels of the glucocorticoid regulated transcript PER1 in adipose to a greater extent than corticosterone. Conclusions: Corticosterone acutely controls biochemical markers of androgen excess similarly to hydrocortisone but without inducing markers of glucocorticoid "toxicity" in CAH. These data demonstrate proof of concept that corticosterone may be a safer glucocorticoid replacement than current medications, although further research is required to assess the longer-term effects of corticosterone replacement. Competing Interests: Conflict of interest: None of the authors have any conflicts to disclose. (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)
Databáze:	MEDLINE
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