Endocrine Abstracts

5α-Reductase (5αR) inhibitors decrease prostatic dihydrotestosterone in benign prostatic hyperplasia (BPH) treatment; finasteride inhibits 5αR type 2, while dutasteride inhibits 5αR1 and 2. 5αRs, especially 5αR1, are also expressed in metabolic tissues regulating actions of androgens and other substrates, including glucocorticoids.Hypothesis: 5αR1 inhibition with dutasteride induces metabolic dyshomeostasis.<p class...

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...

11β-Hydroxysteroid dehydrogenase type one (11β-HSD1) converts inert glucocorticoids to active forms, amplifying intracellular glucocorticoid action. 11β-HSD1 also catalyses the reduction of seven-ketocholesterol (7KC) to 7β-hydroxycholesterol (7βHC). 7KC may inhibit cholesterol biosynthesis (Brown et al. 2002). Alteration of cholesterol homeostasis is a major atherosclerotic risk factor. 11β-HSD1 deficiency/inhibition is atheroprotective ...

Background and aims: Bile acids regulate cholesterol metabolism and the digestive system. They are conserved through enterohepatic circulation, a glucocorticoid-modulated process. We investigated whether the regeneration of active glucocorticoid by 11β-hydroxysteroid dehydrogenase type one (11β-HSD1) affects bile acid release and enterohepatic transport after re-feeding.Methods: Bile acid turnover was assessed in global (Hsd11b11<...

Tissue cortisol levels are amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In mice, transgenic overexpression of 11β-HSD1 causes the metabolic syndrome, consequently 11β-HSD1 inhibitors are a promising therapeutic target. However, determining the importance of 11β-HSD1 in humans has proved more complicated, in part due to difficulty quantifying in vivo activity. We hypothesized that cortisol regeneration by 11β-H...

Background & Aims: Observational studies implicate glucocorticoid excess, principally due to altered steroid metabolism in target tissues, in both the insulin resistance and liver fat accumulation that accompanies type 2 diabetes. To test the contribution of glucocorticoid signalling to metabolic dysfunction we blocked cortisol secretion (with metyrapone) and action (with the GR antagonist mifepristone) simultaneously in men with type 2 diabetes ± fatty liver.<p c...

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 ...

Circulating estrogens decrease after the menopause from 60–400 to 5–30 pg/ml in postmenopausal women and in men are below 30 pg/ml. These low physiological concentrations present an analytical challenge. Analysis of steroids by tandem mass spectrometry is attractive due to its high specificity compared with immunoassays. However, estrogens do not ionise efficiently and therefore chemical modifications are necessary to achieve the sensitivity required.<p class="ab...

The glucocorticoid hormone, cortisol, regulates fuel metabolism, inflammation and stress–responses. Its circulating concentrations are tightly controlled by the hypothalamic–pituitary–adrenal axis. However, 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) generates additional cortisol in tissues, by reduction of inert cortisone. Using a tracer (9,11,12,12[2H]4-cortisol; d4-cortisol), the velocity of 11βHSD1 can be determined as t...

Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are being developed to prevent cortisol regeneration from cortisone in liver and adipose tissue in type 2 diabetes (T2DM). However, the target patient group is uncertain. In obesity 11β-HSD1 activity is increased in adipose tissue but decreased in liver, as judged indirectly by plasma cortisol levels after oral cortisone administration. However, in T2DM, urinary steroid ratios suggest liver 11&#946...