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 mechanismis 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 malemice with targeted disruption of 5α-reductase type 1, clearance of corticosteronewas lower after acute or chronic (eightfold, P<0.05) administration, compared with WT controlmice. In intact 5α-reductase-deficientmale mice, although resting plasma corticosterone level swere 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^lt;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. © 2014 The authors Published by Bioscientifica Ltd Printed in Great Britain.