Endocrine Abstracts

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...

Intracellular cortisol is regulated by 11βHSD1. Although the field has focused on regeneration of cortisol from inert cortisone by 11β-reductase activity of 11βHSD1, we have used stable isotope tracers and arteriovenous sampling to quantify simultaneous dehydrogenase (cortisone generation) and reductase (cortisol regeneration) in human adipose and skeletal muscle. In vitro studies suggest insulin regulates this balance of reductase vs dehydrogenase acti...

Congenital adrenal hyperplasia (CAH) is associated with poor health outcomes. This is, in part, because doses of glucocorticoid sufficient to suppress excess adrenal androgens are also associated with adverse metabolic effects such as insulin resistance. This toxicity occurs with efficacious doses of all commonly prescribed glucocorticoids (hydrocortisone, prednisolone and dexamethasone). However, the glucocorticoid corticosterone may have an improved therapeutic index because...

Background: Both excess and insufficient glucocorticoid exposure in utero is associated with adverse fetal outcomes. Characterising the maternal hypothalamic-pituitary-adrenal (HPA) axis is challenging with large intra-individual variations in plasma and saliva. We hypothesised that 24-hour total urinary glucocorticoid (TUG) is a marker of maternal HPA axis during pregnancy. We tested associations of TUG with maternal BMI and birthweight.Methods: TUG was...

Pulmonary arterial hypertension (PAH) is a devastating disease characterised by increased pulmonary arterial pressures due to clustered proliferation of cells within the vessel. Untreated this leads to right heart failure and premature death. PAH predominates in females implicating sex hormones, in particular estrogenic metabolites, as being key in the progression of PAH phenotypes. We hypothesised that hydroxy and methoxy estrogens, with known proliferative and anti-prolifera...

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...

Human plasma contains both cortisol (F) and corticosterone (B). B has been largely neglected in humans as it is 10–20 times less abundant however previous studies suggest B and F have differential tissue-specific actions. Compared with F, B has an enhanced response to ACTH, relatively higher concentrations in brain and CSF and differential transmembrane trafficking by ATP-binding cassette (ABC) transporters. Plasma F is bound to corticosteroid-binding globulin (CBG) and a...

Background: Using a deuterated tracer (D4-cortisol) to measure cortisol regeneration from cortisone in vivo we have quantified tissue-specific 11βHSD1 activity in health and disease, and acute regulation eg by insulin. These studies relied on tracer enrichment in the total plasma cortisol pool, assuming rapid equilibration between free and protein-bound pools. Slower equilibration would result in underestimation of enzyme activity, and has implications for the co...

Background and aims: Bile acids are conserved through enterohepatic circulation, a glucocorticoid-modulated process. 11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts cortisone/11-dehydrocortisone to cortisol/corticosterone, thus increasing intracellular glucocorticoid levels. 11β-HSD1 also metabolises 7-oxo-lithocholic acid, a bile acid. 11β-HSD1 is highly expressed in the liver and may alter bile acid transport through regeneration of active glu...