Modified-release and conventional glucocorticoids and diurnal androgen excretion in congenital adrenal hyperplasia
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Context:
The classic androgen synthesis pathway proceeds via dehydroepiandrosterone, androstenedione, and testosterone to 5α-dihydrotestosterone. However, 5α-dihydrotestosterone 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 (GC) 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 GC therapy and modified-release hydrocortisone.
Methods:
We used urinary steroid metabolome profiling by gas chromatography–mass spectrometry for 24-hour steroid excretion analysis, studying the impact of conventional GCs (hydrocortisone, prednisolone, and dexamethasone) in 55 adults with CAH and 60 controls. We studied diurnal variation in steroid excretion by comparing 8-hourly collections (23:00–7:00, 7:00–15:00, and 15:00–23:00) in 16 patients with CAH taking conventional GCs and during 6 months of treatment with modified-release hydrocortisone, Chronocort.
Results:
Patients with CAH taking 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.
The classic androgen synthesis pathway proceeds via dehydroepiandrosterone, androstenedione, and testosterone to 5α-dihydrotestosterone. However, 5α-dihydrotestosterone 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 (GC) 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 GC therapy and modified-release hydrocortisone.
Methods:
We used urinary steroid metabolome profiling by gas chromatography–mass spectrometry for 24-hour steroid excretion analysis, studying the impact of conventional GCs (hydrocortisone, prednisolone, and dexamethasone) in 55 adults with CAH and 60 controls. We studied diurnal variation in steroid excretion by comparing 8-hourly collections (23:00–7:00, 7:00–15:00, and 15:00–23:00) in 16 patients with CAH taking conventional GCs and during 6 months of treatment with modified-release hydrocortisone, Chronocort.
Results:
Patients with CAH taking 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.
Date Issued
2017-06-01
Date Acceptance
2016-11-11
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2017, 102 (6), pp.1797-1806
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
1797
End Page
1806
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
102
Issue
6
Copyright Statement
This article has been published under the terms of the Creative Commons Attribution License (CCBY;https://creativecommons.org/licenses/by/4.0/), whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/27845856
Subjects
19-CARBON STEROIDS
21-HYDROXYLASE DEFICIENCY
ADULTS
BACKDOOR PATHWAY
DIHYDROTESTOSTERONE
Endocrinology & Metabolism
HYDROCORTISONE
INSUFFICIENCY
Life Sciences & Biomedicine
OXIDOREDUCTASE
Science & Technology
TAMMAR WALLABY
TESTES
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2016-11-15