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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.
AuthorsDawn E W Livingstone, Emma M Di Rollo, Chenjing Yang, Lucy E Codrington, John A Mathews, Madina Kara, Katherine A Hughes, Christopher J Kenyon, Brian R Walker, Ruth Andrew
JournalThe Journal of endocrinology (J Endocrinol) Vol. 222 Issue 2 Pg. 257-66 (Aug 2014) ISSN: 1479-6805 [Electronic] England
PMID24872577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 The authors.
Chemical References
  • 5-alpha Reductase Inhibitors
  • Membrane Proteins
  • Dexamethasone
  • Adrenocorticotropic Hormone
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Srd5a1 protein, mouse
  • Corticosterone
Topics
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase (deficiency)
  • 5-alpha Reductase Inhibitors (adverse effects)
  • Adrenal Insufficiency (etiology)
  • Adrenocorticotropic Hormone (pharmacology)
  • Animals
  • Corticosterone (blood)
  • Dexamethasone (pharmacology)
  • Hypothalamo-Hypophyseal System (drug effects, physiology)
  • Male
  • Membrane Proteins (deficiency)
  • Mice
  • Mice, Knockout
  • Pituitary-Adrenal System (drug effects, physiology)
  • Stress, Psychological (physiopathology)

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