ECE2015 Oral Communications Adrenal 2 (5 abstracts)
Alternative pathway synthesis dominates androgen production in patients with congenital adrenal hyperplasia and is decreased by Chronocort® more than by conventional glucocorticoid therapy
Christopher Jones 1 , Ashwini Mallappa 2 , Nicole Reisch 3 , Beverley Hughes 1 , Donna O’Neil 1 , Nils Krone 1 , Martin Whitaker 4 , David Eckland 4 , Deborah Merke 2 , Richard Ross 4, & Wiebke Arlt 1
1Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; 2National Institute of Health Clinical Center, Bethesda, Maryland, USA; 3Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany; 4Academic Unit of Endocrinology, Department of Human Metabolism, University of Sheffield, Sheffield, UK; 5Diurnal Ltd, Cardiff, UK.
Suppression of excess androgen production poses a considerable clinical challenge in the management of patients with congenital adrenal hyperplasia (CAH). Whilst the major route of androgen synthesis in humans is the classic pathway via androstenedione and testosterone, the relative contribution of the alternative pathway originating from 17-hydroxyprogesterone to androgen excess in CAH has not been defined. Androgen effects of both pathways are elicited in androgen target tissues by the action of the most potent androgen receptor agonist, 5alpha-dihydrotestosterone (DHT). Here we carried out urinary steroid metabolome profiling by gas chromatography/mass spectrometry in conjunction with serum steroid analysis and clinical phenotyping in patients with CAH due to 21-hydroxylase deficiency. Our aim was to determine the extent to which the alternative androgen synthesis pathway contributes to DHT production in CAH and to examine the potentially differential impact of conventional and modified delayed glucocorticoid therapy.
In a cross-sectional study we analysed 24 h-urinary steroid excretion in 40 patients with CAH on conventional glucocorticoid replacement with hydrocortisone (n=12), prednisolone (n=23) and dexamethasone (n=5) in comparison to 80 sex- and age-matched healthy controls. CAH patients had significantly higher excretion of 5alpha-17HP, the signature metabolite of the alternative pathway, representing 0.97% of the 5alpha-reduced androgen pool in healthy controls, but 15.12% in patients with CAH. In an interventional study we treated 16 adults with classic CAH (eight females; age 29±13 years; 12 salt-wasting, four simple virilising) with Chronocort, a modified and delayed release hydrocortisone preparation that mimics the physiological diurnal secretion profile of cortisol. Twenty-four hour urinary steroid excretion was analysed at baseline on conventional glucocorticoid therapy and after six months of Chronocort. Results revealed that Chronocort significantly reduced both the absolute amount and the relative percentage of 5a17HP (conventional HC 21.5% vs Chronocort 12.3%), concurrently exerting improved biochemical control with regard to overall and 5alpha-reduced androgen output.
Disclosure: This research was supported in part by the Intramural Research Program of the NIH and in part by Diurnal Ltd UK.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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