Endocrine Abstracts

Glucocorticoid excess is associated with increased anxiety and accelerated cognitive decline. Concentrations of glucocorticoids within tissues, including the brain, are influenced by local metabolism. 5α-Reductase 1 (5αR1), expressed in brain, converts corticosterone to its A-ring reduced metabolites, which have a different spectrum of activities. Here, we investigated if mice homozygous for disrupted 5αR1 alleles (5αR1-KO) experience heightened anxiety and...

Anti-inflammatory salicylates improve insulin sensitivity, however the mechanism remains unclear. We have observed down-regulation of the glucocorticoid regenerating enzyme 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) by salicylates in cultured adipocytes and in human adipose tissue after oral salsalate therapy, consistent with known transcriptional regulation of 11βHSD1 by pro-inflammatory cytokines. Since inhibition of 11βHSD1 improves insulin sensitivity...

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)....

Background: The 5α-reduced glucocorticoid, 5α-tetrahydrocorticosterone (5α-THB), displays a dissociated steroid profile exhibiting anti-inflammatory effects in a murine model of thioglycollate-induced peritonitis but failing to induce adverse metabolic effects caused by corticosterone. We assessed the topical anti-inflammatory properties of 5α-THB in a model of irritant dermatitis. Given the adverse effects of steroids on cutaneous wound healing, we also in...

Background: 5α-reductase 1 (5αR1) metabolises steroids such as glucocorticoids and androgens, and is highly expressed in murine liver. Genetic disruption of 5αR1 leads to adverse metabolic changes in mice. We hypothesised that dutasteride, a 5αR inhibitor, induces insulin resistance in mice, as in humans, and this effect is underpinned by increased hepatic glucocorticoid action; an experimental paradigm was set up using A-348441, a liver-selective glucocort...

5α-Reductase 1 (5aR1) catalyses A-ring reduction of glucocorticoids and androgens, predominantly in liver and modulates steroid hormone action. We previously demonstrated transgenic disruption of 5aR1 predisposes mice to developing fatty liver. Here we tested whether 5aR1 disruption increases susceptibility to the development of liver injury, using the carbon tetrachloride induced liver fibrosis model.Male 5aR1−/− (KO) mice and wild-type...

Inhibiting cortisol regeneration by 11β-HSD1 is a promising therapy for type two diabetes. In obesity, 11β-HSD1 activity is increased in adipose tissue but decreased in the liver, the latter putatively mediated by hyperinsulinaemia. We tested whether insulin sensitisation with metformin regulates 11β-HSD1 activity in whole body and in liver in obesity.Five obese men (age 48±5 years, BMI 39.8±3.6 kg/m2) participated in ...

Glucocorticoids (GC) have potent anti-inflammatory effects, acting mainly through the glucocorticoid receptor (GR). However GCs have debilitating side effects and a safer alternative is required. 5α-tetrahydrocorticosterone (5αTHB, a metabolite of the natural rodent glucocorticoid corticosterone) may provide a solution: 5αTHB is anti-inflammatory in vivo, effective topically to suppress irritant dermatitis, but with fewer syst...

Glucocorticoids (GC) have potent anti-inflammatory effects, acting mainly through the glucocorticoid receptor (GR). However GCs have debilitating side effects and a safer alternative is required. 5α-tetrahydrocorticosterone (5αTHB, a metabolite of the natural rodent glucocorticoid corticosterone) may provide a solution: 5αTHB is anti-inflammatory in vivo, effective topically to suppress irritant dermatitis, but with fewer syst...

Excess action of glucocorticoid hormones is implicated in metabolic disease and cognitive decline, 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) catalysing generation of active glucocorticoid hormones in tissues. The penetration rates and tissue-specific contribution of 11βHSD1 to glucocorticoid turnover were assessed using tracer kinetics. 9,11,12,12-d4-Cortisol (d4F) was infused (1.75 mg/day, 7 days) into C57Bl6/J male mice and mice lacking 11βHSD1 (n<...