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.

5α-Reductase Type 1 Deficiency or Inhibition Predisposes to Insulin Resistance, Hepatic Steatosis, and Liver Fibrosis in Rodents

“…Others have reported recently that the 5aR1-KO mice are more susceptible to hepatocellular carcinoma after prolonged feeding (12 months) on the American lifestyle-induced obesity syndrome (ALIOS) diet (19), and that liver transcript changes in 5aR1-KO mice overlap with those induced by the administration of glucocorticoids rather than androgens (19). Given that we have demonstrated impaired hepatic metabolic clearance of corticosterone in 5aR1-KO mice (11) and persistence of the effect of finasteride in GDX rats, we conclude that local glucocorticoid excess is the most likely mechanism underpinning hepatic steatosis in 5aR1 deficiency or inhibition; combined alterations in androgen and/or glucocorticoid signaling may contribute to other aspects of the adverse metabolic phenotype.…”

“…Finasteride is a nonselective inhibitor in rats, inhibiting both 5aRs (21,25), and many of the adverse features observed in mice were recapitulated even after only 3 weeks of finasteride treatment, with steatosis being a highly robust finding. Insulin resistance, which is associated with steatosis, was observed after finasteride treatment in unmanipulated rats, but not after sham surgery; this may relate to the short duration of finasteride treatment in rats, at just 3 weeks, and the altered stress responses after 5aR1 inhibition in the postoperative period (11). The converse was true for drug-induced weight gain, which was revealed in the sham-operated animals receiving finasteride.…”

“…5a-Reduction contributes substantially to the clearance of glucocorticoids: corticosterone in rodents, and cortisol in humans. Mice deficient in 5aR1 have an eightfold slower clearance of corticosterone (11), and in humans, 5a-reduced glucocorticoids comprise approximately onethird to one-half of urinary cortisol metabolites (12).…”

“…The associated changes in cortisol clearance rate are thought to influence the hypothalamic-pituitary-adrenal axis in these conditions. We have previously demonstrated that mice deficient in 5aR1 accumulate excess glucocorticoid in liver and adipose (11), which may have direct consequences for glucocorticoid receptor activation. A recent report (19) shows that mice lacking 5aR1 are more prone to hepatic steatosis, but with no apparent differences in body fat distribution or insulin sensitivity and with protection from hepatocellular carcinoma; the mechanisms remain unclear, in particular the independent roles of glucocorticoid and androgen metabolism.…”

The modulation of corticosteroid metabolism by hydrocortisone therapy in patients with hypopituitarism increases tissue glucocorticoid exposure

“…Livingstone et al (46) have recently published studies assessing the effects of 5a-reductase type 1 deficiency in mice and have shown clearance of corticosterone was lower in mice with targeted disruption of 5a-reductase type 1 compared with WT control mice. They also showed that 5a-reductase-deficient male mice had impaired corticosterone responses to ACTH administration and stress compared with WT mice.…”