title: Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jones
authors.affiliation: National Institutes of Health Clinical Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Mallappa
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, 80366 Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Reisch
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom.|Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, OX3 7LE, United Kingdom.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Nikolaou
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom.|Academic Unit of Endocrinology, Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors.forename: Nils
authors.initials: N
authors.lastname: Krone
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Hughes
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Donna M
authors.initials: DM
authors.lastname: O'Neil
authors.affiliation: Academic Unit of Endocrinology, Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom.|Diurnal Ltd., Cardiff, CF14 4UJ, United Kingdom.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Whitaker
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, OX3 7LE, United Kingdom.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.affiliation: Department of Biochemistry, University of Stellenbosch, Stellenbosch 7600, South Africa.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Storbeck
authors.affiliation: National Institutes of Health Clinical Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
authors.affiliation: Academic Unit of Endocrinology, Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom.|Diurnal Ltd., Cardiff, CF14 4UJ, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, United Kingdom.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000652:urine; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D000328:Adult; D000728:Androgens / Q000378:metabolism*; D000738:Androsterone / Q000031:analogs & derivatives / Q000652:urine; D002940:Circadian Rhythm; D003350:Cortodoxone / Q000031:analogs & derivatives / Q000652:urine; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use; D011279:Pregnanetriol / Q000031:analogs & derivatives / Q000652:urine; D055815:Young Adult
chemical_list: D000728:Androgens; D003692:Delayed-Action Preparations; D005938:Glucocorticoids; D011279:Pregnanetriol; D006907:17-alpha-Hydroxypregnenolone; C002528:11 beta-hydroxyandrosterone; C009030:pregnanetriolone; C009412:tetrahydro-11-deoxycortisol; D003907:Dexamethasone; D011239:Prednisolone; D000738:Androsterone; D003350:Cortodoxone; D006854:Hydrocortisone