Endocrine Abstracts

The role of endogenous glucocorticoid (GC) production and metabolism in the pathogenesis of obesity, insulin resistance and type 2 diabetes remains unclear. Patients with Cushing’s syndrome develop central obesity, insulin resistance and in some cases type 2 diabetes (T2DM), yet circulating cortisol levels are not elevated in simple obesity. Alterations in GC metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that generates active cortisol ...

The diagnosis of Cushing’s syndrome (CS) remains a major clinical challenge especially in a proportion of patients that have discordant results in the available tests. Although the measurement of 24-h urine free cortisol (UFC) is a useful test for the diagnosis of CS, 10–15% of patients have at least one measurement within the normal range and multiple measurements may be required in order to raise its sensitivity. In this study we sought to evaluate the value of the...

Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Despite the increasing use of GCs as therapeutic agents, the molecular mechanisms that underpin GC mediated changes in insulin signalling are not clear. Within skeletal muscle, the microsomal enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive GC, 11-dehydrocorticosterone (A) to active corticosterone (B) and thus regulates GC availabi...

Stress results in activation of the hypothalamic–pituitary–adrenal axis with increased circulating cortisol. It has been argued that a syndrome of ‘relative adrenal insufficiency’ is common in critically ill patients. Patients who fail to increase their cortisol by >250 nmol/30 min following the administration of 250 μg ACTH in the short synacthen test (SST) have been reported to have a higher mortality (JAMA 2000, 283 1038–1045)...

It is well established that the use of therapeutic glucocorticoids to treat inflammatory disease has detrimental effects on bone and we have proposed that these clinical effects are determined by intracellular glucocorticoid generation (inactive cortisone/prednisone to cortisol/prednisolone) by 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1). We have recently shown that glucocorticoids and cytokines are able to act cooperatively to upregulate the action of 11b-HSD1, a fi...

Congenital adrenal hyperplasia (CAH) caused by mutations in the electron donor enzyme P450 oxidoreductase (POR) is unique amongst all CAH variants in that it can be associated with ambiguous genitalia (disordered sex differentiation, DSD) both in 46,XX and 46,XY individuals. POR has a pivotal role in facilitating electron transfer from NADPH to microsomal P450 enzymes, including CYP17, which catalyses a key step in human androgen synthesis, the conversion of 17-hydroxypregneno...

Androgen excess is a key feature of polycystic ovarian syndrome (PCOS). Pre-receptor regulation contributes to this with increased activation of testosterone (T) to 5α-dihydrotesterone (DHT) by 5α-reductase type 1 (SRD5A1), as we have shown previously in PCOS (Lancet 1990,335:431; JCE&M 2003,88:2760). Peripheral blood mononuclear cells (PBMCs) are easily accessible and a useful model for studying pre-receptor regulation in the immune compartment. We have previous...

Therapeutic glucocorticoids are used in rheumatoid arthritis (RA) to reduce inflammation and bone destruction. We recently reported that primary synovial fibroblasts generate active glucocorticoids via expression of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme activates cortisol from inactive cortisone (and prednisolone from prednisone) and this activity is up-regulated by inflammation. We have now examined glucocorticoid metabolism in synovial tissu...

Previous studies investigating steroidogenic enzymes in the brain have often focused on only a few genes at a time, using animal models or pooled human RNA to investigate their expression. For this study, we obtained RNA from individual archived human brain tissue samples in order to analyse the transcription of twelve genes involved with steroid biosynthesis and metabolism within the cerebellum and hippocampus.We developed realtime RT-PCR assays for twe...

In vivo the 11β-HSD1 enzyme converts inactive cortisone to the active glucocorticoid cortisol. 11β-HSD1 is implicated in the metabolic syndrome through its expression in liver and adipose tissue by increasing local cortisol concentrations. However, little is known regarding the expression and function of 11β-HSD1 in muscle.Murine C2C12 muscle cells (myocytes) were differentiated from myoblasts to myotubules for 8 days, with and without the...