Modified release and conventional glucocorticoids and diurnal androgen excretion in congenital adrenal hyperplasia

Research output: Contribution to journalArticlepeer-review

Authors

  • Christopher Jones
  • Ashwini Mallappa
  • Nicole Reisch
  • Nikolaos Nikolaou
  • Beverly Hughes
  • Martin J Whitaker
  • Jeremy Tomlinson
  • Karl-Heinz Storbeck
  • Deborah P Merke
  • Richard Ross

Colleges, School and Institutes

External organisations

  • National Institute of Health Clinical Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MA, USA
  • Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universitat Munchen, Munich, Germany
  • Academic Unit of Endocrinology, Department of Human Metabolism, University of Sheffield, Sheffield
  • Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

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.

Details

Original languageEnglish
Pages (from-to)1797-1806
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number6
Early online date15 Nov 2016
Publication statusPublished - 15 Nov 2016