Searchable abstracts of presentations at key conferences in endocrinology

ea0019p243 | Pituitary | SFEBES2009

Growth hormone deficiency in adults: the NICE criteria do not discriminate an adverse cardiovascular phenotype

Aragon Alonso Aurora , Sherlock Mark , McGregor Elizabeth , Murray Robert , Stewart Paul M , Toogood Andrew A

Severe growth hormone (GH) deficiency in adults is associated with adverse changes in quality of life (QoL), body composition and cardiovascular risk profile. NICE guidance restricts GH replacement in the UK to those with impaired QoL, defined by a score of >11 in the QoL-AGHDA questionnaire.Aims: To assess whether the NICE guidance differentiates other clinical or biochemical features in GH deficient adults.Patients and...

ea0015oc30 | Pituitary, disease | SFEBES2008

Local cortisol generation by human macrophage subsets by 11β-hydroxysteroid dehydrogenase type 1 enzyme and its role in ocular immune privilege

Joganathan Varajini , Al-Hakami Ahmed , Rauz Saaeha , Stewart Paul M , Wallace Graham R , Bujalska Iwona J

The eye is an organ vulnerable to a variety of external and internal stimuli that can abolish its vital function to allow accurate vision of images for survival. Inflammation is the key mediator of immune protection but its consequence leads to the disruption of the visual axis integrity. Due to this precise reason, through adaptation and evolution, the eye has developed mechanisms of immune tolerance and privilege. Glucocorticoids have potent immunosuppressive and anti-inflam...

ea0015p150 | Diabetes, metabolism and cardiovascular | SFEBES2008

Activation of the unfolded protein response pathway in the skeletal muscle of hexose-6-phosphate dehydrogenase knockout mice induces a severe myopathy

Lavery Gareth , Bujalska Iwona , Turan Nil , Falciani Francesco , Walker Elizabeth , Stewart Paul

Hexose-6-phosphate dehydrogenase (H6PD) is a sarcoplasmic reticulum (SR) resident enzyme that metabolizes glucose-6-phosphate and generates NADPH that drives the activation of glucocorticoids by 11β-hydroxysteorid dehydrogenase type 1. H6PD KO mice exhibit improved skeletal muscle insulin sensitivity increased glucose uptake and glycogen storage. However, H6PD KO mice also develop a myopathy with switching from Type II to Type I fibers. Affected muscles have apparently no...

ea0015p158 | Diabetes, metabolism and cardiovascular | SFEBES2008

Glucocorticoid metabolism in human obesity; increased 5α-reductase activity is associated with insulin resistance in both men and women

Tomlinson Jeremy , Hughes Beverly , Hughes Susan , Vassiliadi Dimitra , Arlt Wiebke , Stewart Paul

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 ...

ea0015p274 | Pituitary | SFEBES2008

Use of the morning urinary cortisol to creatinine ratio in the diagnosis of mild Cushing’s disease in patients with discordant test results

Vassiliadi Dimitra A , Holder Geoff , Johnson Alan P , Arlt Wiebke , Stewart Paul M

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...

ea0015p322 | Steroids | SFEBES2008

Serine phosphorylation of IRS-1 as a mechanism of glucocorticoid induced insulin resistance in mouse C2C12 myotubes

Morgan Stuart A , Gathercole Laura L , Bujalska Iwona , Stewart Paul M , Smith David , Tomlinson Jeremy W

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...

ea0015p324 | Steroids | SFEBES2008

Adrenal function testing in 273 patients with severe sepsis reveals baseline cortisol as a reliable predictor of outcome

Mowatt Christopher J , Vassiliadi Dimitra A , Holder Geoff , Clark Penny , Bion Julian , Stewart Paul M , Arlt Wiebke

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)...

ea0013oc3 | Steroid synthesis and action | SFEBES2007

Transcriptional regulation of 11beta-hydroxysteroid dehydrogenase type 1 under the synergistic control of glucocorticoids and cytokines

Kaur Kirrenjit , Lavery Gareth , Walker Elizabeth , Stewart Paul , Hewison Martin , Cooper Mark , Rabbitt Elizabeth

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...

ea0013oc7 | Society for Endocrinology/Clinical Endocrinology Trust Young Investigator Basic Prize winner | SFEBES2007

Differential effects of P450 oxidoreductase mutants on CYP17 activity provides evidence for an alternative pathway in human androgen biosynthesis

Dhir Vivek , Ivison Hannah E , Krone Nils , Stewart Paul M , Shackleton Cedric HL , Arlt Wiebke

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...

ea0013oc11 | Clinical and translational endocrinology | SFEBES2007

Reduced 5α-reductase activity in peripheral blood mononuclear cells in polycystic ovarian syndrome – a compensatory mechanism for androgen excess?

Hammer Fabian , Bozhinova Nadya , Hughes Beverly A , Fassnacht Martin , Stewart Paul M , Allolio Bruno , Arlt Wiebke

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...