Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH,
a phenomenon known as 'relative adrenal insufficiency'. Acutativemechanismis that elevated
bile acids inhibit inactivation of cortisol in liver by 5a-reductases type 1 and type 2 and
5b-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
5a-reductase type 1 deficiency in mice. In adrenalectomisedmalemicewith targeted disruption
of 5a-reductase type 1, clearance of corticosteronewas lower after acute or chronic (eightfold,
P! 0.05) administration, compared withWTcontrolmice. In intact 5a-reductase-deficientmale
mice, resting although plasma corticosterone levelsweremaintained, corticosterone responses
were impaired after ACTH administration (26% lower, P! 0.05), handling stress (2.5-fold lower,
P! 0.05) andrestraint stress (43% lower, P! 0.05) comparedwithWTmice.mRNAlevelsof 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 5a-reductase inhibitors for prostatic disease.
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