Jones, C.M., Mallappa, A., Reisch, N. et al. (10 more authors) (2016) Modified release and conventional glucocorticoids and diurnal androgen excretion in congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism. jc20162855. ISSN 0021-972X
Abstract
CONTEXT: The classic androgen synthesis pathway proceeds via DHEA, androstenedione and testosterone to 5α-dihydrotestosterone (DHT). However, DHT synthesis can also be achieved by an alternative pathway originating from 17α-hydroxyprogesterone (17OHP), which accumulates in congenital adrenal hyperplasia (CAH). Similarly, recent work has highlighted androstenedione-derived 11-oxygenated 19-carbon steroids as active androgens and, in CAH, androstenedione is generated directly from 17OHP. The exact contribution of alternative pathway activity to androgen excess in CAH and its response to glucocorticoid therapy is unknown. OBJECTIVE: We sought to quantify classic and alternative pathway-mediated androgen synthesis in CAH, their diurnal variation and their response to conventional glucocorticoid (GC) therapy and modified release hydrocortisone. METHODS: We employed urinary steroid metabolome profiling by gas chromatography-mass spectrometry for 24-h steroid excretion analysis, studying the impact of conventional GCs (hydrocortisone, prednisolone, dexamethasone) in 55 adults with CAH and 60 controls. We studied diurnal variation in steroid excreton by comparing 8-hourly collections (23:00-7:00h, 7:00-15:00h, 15:00-23:00h) in 16 CAH patients on conventional glucocorticoids and during six months of treatment with modified release hydrocortisone, Chronocort. RESULTS: CAH patients on conventional GCs showed low excretion of classic pathway androgen metabolites but excess excretion of the alternative pathway signature metabolites 3α,5α-17-hydroxypregnanolone and 11β-hydroxyandrosterone. Chronocort reduced 17OHP and alternative pathway metabolite excretion to near normal levels more consistently than other GC preparations. CONCLUSIONS: Alternative pathway mediated androgen synthesis significantly contributes to androgen excess in CAH. Chronocort therapy appears superior to conventional GC therapy in controlling androgen synthesis via alternative pathways through attenuation of their major substrate, 17OHP.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 Endocrine Society. This is an author produced version of a paper subsequently published in Journal of Clinical Endocrinology and Metabolism. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number DIURNAL LTD NONE DIURNAL LTD UNSPECIFIED |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Nov 2016 15:28 |
Last Modified: | 24 Mar 2018 02:35 |
Published Version: | http://doi.org/10.1210/jc.2016-2855 |
Status: | Published |
Publisher: | Endocrine Society |
Refereed: | Yes |
Identification Number: | 10.1210/jc.2016-2855 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:108390 |