Endocrine Abstracts

The rate limiting steps of hepatic glucocorticoid clearance are via A-ring reduction by 5α- and 5β-reductases. Our recent in vitro studies suggested that products of 5α-reduction (eg 5α-tetrahydrocorticosterone) can activate glucocorticoid receptors and hence may contribute to glucocorticoid action in liver. Here we compared the effects of administering 5α-tetrahydrocorticosterone (5αTHB) in vivo with those of corticosterone (B).

B, 5αTHB (50 μg/d, 14 d) or vehicle (DMSO: propylene glycol; 1:1) were infused subcutaneously into male C57BL/6 mice (8–10 weeks old, n=12). Body weight, blood pressure and glucose tolerance (GTT) were assessed. B, insulin and ACTH were quantified by immunoassay, glucose and hepatic enzyme activity spectrophotometrically, mRNAs by Q-PCR. Data are mean±SEM; B v 5αTHB v vehicle; *P≤0.05, **P≤0.001 v vehicle.

Infusions of B but not 5αTHB caused an increase in plasma B (223±32** v 59±9 v 45±13 nM), smaller adrenal glands (1.1±0.1** v 2.0±0.1 v 2.0±0.1 mg) and thymus (11.7±0.7** v 27.5±1.6 v 30.5±1.7 mg), redistribution of fat to subcutaneous depots (0.19±0.01* v 0.18±0.01 v 0.16±0.01 g), impaired glucose tolerance and enhanced insulin release (15 min glucose, 19.4±1.2 v 19.1±1.6 v 21.0±1.4 mM; 15 min insulin 1.48±0.38* v 0.83±0.17 v 0.76±0.16 ng/mL). However, both B and 5α-THB reduced ACTH (1.2±0.5** v 21.2±11.4** v 96.3±24.9 pg/mL). There were not changes in body weight, blood pressure, liver phosphoenolpyruvate carboxykinase, tyrosine aminotransferase (TAT) and angiotensinogen mRNA or TAT activity. In subcutaneous and retroperitoneal adipose tissue, expression of the glucocorticoid responsive gene, 11β-hydroxysteroid dehydrogenase 1, was induced approximately 2-fold by B but not 5αTHB.

We conclude that 5αTHB does not induce the chronic metabolic effects observed with B but does induce hypothalamic-pituitary negative feedback responses. 5αTHB may therefore mediate endocrine communication between the liver and the HPA axis.