Endocrine Abstracts

The hypothalamic-pituitary adrenal (HPA) axis plays a key role in the metabolic response to stress, so it is to be anticipated that cortisol signalling might in turn be regulated by nutritional status. This regulation might operate either centrally, controlling ACTH and hence plasma cortisol, or peripherally, controlling metabolism of cortisol in target tissues.Plasma cortisol levels are elevated during starvation in animals and a recent meta-analysis co...

Similarities between the metabolic syndrome and Cushing’s syndrome, and reversibility of the features of Cushing’s syndrome, suggest that cortisol may contribute to pathophysiology in both conditions and that reducing cortisol action may provide a novel therapeutic approach in metabolic syndrome. There is substantial evidence that circulating cortisol concentrations are higher in people with hypertension and glucose intolerance. The basis for t...

Background: Glucocorticoids (GCs) modulate glucose homeostasis by acting on metabolic tissues including liver, adipose and skeletal muscle. GC access to corticosteroid receptors in these tissues is regulated e.g. by pre-receptor metabolism. We recently identified a role for ABCC1, a transmembrane ‘drug-resistance’ transporter, as a GC exporter which limits intracellular GC concentrations and action in adipose tissue. Here, we tested the hypothesis that ABCC1, which i...

A genome wide meta-analysis by the CORtisol NETwork (CORNET) consortium1 has identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with changes in morning plasma cortisol and predictive of cardiovascular disease (Crawford et al, Unpublished). SERPINA6 encodes Corticosteroid Binding Globin (CBG) which binds most cortisol in blood and influences delivery of cortisol to target tissues. We hypothesised th...

Background: Adipose tissue dysfunction could partially explain the well-demonstrated association between obesity and survival in breast cancer (BC). Oestrogen and glucocorticoid concentrations and their respective activation enzymes, oestrogenic 17β-hydroxysteroid dehydrogenases (17βHSDs) and aromatase, and 11βHSD1 are increased in adipocyte hyperplasia and hypertrophy, supporting the hypothesis of a potential role for locally generated steroids in obesity-assoc...

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...

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...

Background: Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol and controls the circulating free cortisol pool. Proteolytic cleavage by neutrophil elastase is proposed to reduce CBG binding affinity and increase free cortisol availability to inflamed tissues. The CORtisol NETwork (CORNET) consortium found that genetic variation at a locus spanning SERPINA1 (encoding alpha-1 antitrypsin, A1AT, the endogenous inhibitor of neutrophil elastase) and SE...