Endocrine Abstracts

5alpha-Reductase1 (5aR1) catalyses glucocorticoid metabolism, potentially modulating glucocorticoid clearance and therefore affecting the activity of the hypothalamic–pituitary–adrenal (HPA) axis. 5aR1 is up regulated in obesity associated with activation of the hypothalamic–pituitary–adrenal (HPA) axis. Here we investigated if inhibition of 5aR1 impairs glucocorticoid clearance and suppresses the HPA axis.

Age-matched male and female mice homozygous for transgenic disruption of 5aR1 (KO) and wild type littermates (WT) were studied under basal (0700 h) and stress stimulated (15 min restraint) conditions (n=8–12/group). Mice were culled (0800–1100 h), at least 1 week later. In further groups of male mice, corticosterone was chronically infused (50 μg/day, 4 weeks). Plasma corticosterone (radioimmunoassay) adrenal morphology (in tissue sections stained with haematoxylin and eosin), and mRNA for pro-opiomelanocortin and CYP11B1 in pituitary and adrenal respectively (real-time PCR) were assessed.

Indices of basal HPA activity (basal corticosterone concentrations, adrenal mass, adrenal CYP11A1 expression or pituitary POMC expression) did not differ between genotypes in either gender. Adrenal morphology (cell size or number) was also unaffected. However, the corticosterone rise in response to stress was blunted in KO compared to in WT male (peak: 202.2±18.0 vs 268.7±28.75 nM; P=0.04: AUC suppressed by 44%; P=0.02) and female (peak: 915±62 vs 1150±115 nM; P=0.08: AUC suppressed by 36%; P=0.009) mice. Circulating concentrations of corticosterone were not different following chronic infusion (176±48 vs 166±21 nM).

In summary, global 5aR1 KO is not associated with changes in glucocorticoid clearance or basal activity of the HPA axis, suggesting that mechanisms exist to compensate for lack of this enzyme. However, the central drive to the HPA axis in response to stress is attenuated in 5aR1 KO.