title: Relative adrenal insufficiency in mice deficient in 5α-reductase 1.
abstract: Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as 'relative adrenal insufficiency'. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and type 2 and 5β-reductase, resulting in compensatory downregulation of the hypothalamic-pituitary-adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency, we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1, clearance of corticosterone was lower after acute or chronic (eightfold, P<0.05) administration, compared with WT control mice. In intact 5α-reductase-deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, P<0.05), handling stress (2.5-fold lower, P<0.05) and restraint stress (43% lower, P<0.05) compared with WT mice. mRNA levels of Nr3c1 (glucocorticoid receptor), Crh and Avp in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause 'relative adrenal insufficiency' in mice, an observation with important implications for patients with critical illness or hepatic failure, and for patients receiving 5α-reductase inhibitors for prostatic disease.
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK Dawn.Livingstone@ed.ac.uk.
authors.forename: Dawn E W
authors.initials: DE
authors.lastname: Livingstone
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Di Rollo
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Chenjing
authors.initials: C
authors.lastname: Yang
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Codrington
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Mathews
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Madina
authors.initials: M
authors.lastname: Kara
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hughes
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: EndocrinologyQueen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency*; D058891:5-alpha Reductase Inhibitors / Q000009:adverse effects; D000309:Adrenal Insufficiency / Q000209:etiology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology
chemical_list: D058891:5-alpha Reductase Inhibitors; D008565:Membrane Proteins; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C518406:Srd5a1 protein, mouse; D003345:Corticosterone
keywords: 5α-reductases; HPA axis; adrenal insufficiency; glucocorticoids