Endocrine Abstracts

Glucocorticoid (GC) excess adversely affects many aspects of skin homeostasis, characteristics of which are also seen during ageing (e.g. poor wound healing). The mechanisms underlying this remain unclear. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates cortisol, independently of circulating concentrations, and we have previously demonstrated increased 11β-HSD1 expression in human dermal fibroblasts (HDF) from aged donors. We have now e...

The pathophysiological effects of glucocorticoid (GC) excess (Cushing’s syndrome) are similar to the aging phenotype. As such, we hypothesise that age-related changed in body composition (central obesity, reduced bone density, reduced muscle mass and skin thinning), and resultant chronic disease (type 2 diabetes, osteoporosis, sarcopenia and heart disease) may be caused by increased GC exposure with age. However, circulating GC’s show little change with advancing age...

In the endo/sarcoplasmic reticulum (ER/SR), hexose-6-phosphate dehydrogenase (H6PDH) generates an NADPH/ NADP ratio sufficient to drive 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-mediated glucocorticoid (GC) activation (11-DHC to corticosterone). In H6PDH knockout (H6PDKO) mice a reduced NADPH/NADP ratio leads to reversed 11β-HSD1 activity (corticosterone to 11-DHC), and GC insensitivity. They also display skeletal myopathy driven by activation of the un...

Steroid 17α-hydroxylase (CYP17A1) exerts two distinct activities that catalyze conversion reactions at key branch points in steroidogenesis. CYP17A1 17α-hydroxylase activity is the key step in cortisol synthesis whereas CYP17A1 17,20 lyase activity generates sex steroid precursors. Inactivating CYP17A1 mutations result in CYP17A1 deficiency (17OHD), a rare form of congenital adrenal hyperplasia that classically presents with combined glucocorticoid and sex steroid de...

Fetal Leydig cell (LC) dysfunction leads to human male reproductive disorders (‘testicular dysgenesis syndrome’; TDS) that manifest at birth (cryptorchidism, hypospadias) or in young adulthood (low sperm count, testicular germ cell cancer). The factors regulating fetal LC function in early gestation are unknown, but can be disrupted in rats by environmental chemicals (e.g. dibutyl phthalate (DBP)). We identify a novel repressor mechanism that explains this vulnerabil...

Mice with congenital adrenal hyperplasia due to a null mutation of cyp11b1, the gene encoding the steroidogenic enzyme 11β-hydroxylase, have low glucocorticoid levels, reduced adiposity and increased liver weight. It is notable that null mice are also glucose intolerant. Here, we have investigated these phenotypes in more detail. Plasma corticosterone levels were less responsive to restraint stress and cholesterol and triglyceride levels were not significantly different i...

Glucocorticoid (GC) excess, Cushing’s syndrome, is characterized by central obesity, proximal myopathy, insulin resistance and potentially type 2 diabetes mellitus. Current dogma dictates that GCs cause insulin resistance across all tissues. We have previously demonstrated that GCs cause insulin sensitization of human adipose tissue in vitro, whilst inducing insulin resistance in human skeletal muscle. No prior study has evaluated whether these observations transla...

Glucocorticoid receptor (GR) is a hormone-dependent nuclear transcription factor that modulates the expression of genes involved in development, inflammation, and metabolism. In addition, as GR is a key factor in several steroid dependent cancers steroid hormones are extensively used in the treatment of cancers such as leukemia. The transcriptional activity of GR is cell type specific and its magnitude and target selectivity depend on multiple factors including posttranslation...