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24th Joint Meeting of the British Endocrine Societies

Oral Communications

Oral Communication 4: Steroids

ea0009oc26 | Oral Communication 4: Steroids | BES2005

Identification of a defective gene in Familial Glucocorticoid Deficiency type 2 as a ACTH receptor accessory factor responsible for cell surface trafficking

Metherell L , Chapple J , Cooray S , Naville D , Begeot M , Huebner A , Cheetham M , Clark A

FGD is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex to stimulate glucocorticoid production. The disease is caused by mutations in ACTHR or MC2R in 25% of cases, termed FGD type 1, and has previously been linked to a locus on chromosome 8q12.2-21.2 in a single family with FGD type 2. We have recently described a novel gene (FGD2) that when defective is a second cause of FGD. Sequencing of this gene in 100 FGD2 patients ha...

ea0009oc27 | Oral Communication 4: Steroids | BES2005

Interaction of the ACTH receptor C-terminal tail with a nuclear envelope protein

Doufexis M , Clark A

Adrenocorticotrophic hormone (ACTH), a 39 amino acid peptide is the principal regulator of adrenal steroidogenesis and is thus essential for life. ACTH mediates its effects through a cell surface G-protein coupled receptor which elevates the intracellular production of cAMP through adenylate cyclase. There have been significant difficulties in developing a suitable heterologous expression system to study the ACTH receptor (or melanocortin 2 receptor - MC2R), and we have postul...

ea0009oc28 | Oral Communication 4: Steroids | BES2005

Impact of dietary chenodeoxycholic acid on the hypothalamic-pituitary-adrenal axis in rats

McNeilly A , Walker B , Andrew R

Alterations in the rate of glucocorticoid(GC) metabolism induce compensatory changes in GC secretion under the control of the hypothalamic-pituitary-adrenal (HPA) axis. The principal routes of metabolic clearance of GCs are by hepatic A-ring reduction however the regulation of these enzymes is poorly understood. Recently we and others have demonstrated that bile acids act as potent inhibitors of GC metabolism by 5beta-reductase and 11beta-hydroxysteroid dehydrogenases in vi...

ea0009oc29 | Oral Communication 4: Steroids | BES2005

Characterisation of a novel protein interacting with the glucocorticoid receptor

Rice L , Waters C , Garside H , White A , Ray D

Glucocorticoids (Gcs) exert their pleiotropic effects through activation of the ubiquitously expressed glucocorticoid receptor (GR). The mechanism of transcriptional activation by the GR involves interaction with co-modulator proteins. Glucocorticoid sensitivity is mediated by the expression level of these co-modulator proteins and GR concentration. Therefore, the aim of this study was to identify additional GR interacting proteins that may influence glucocorticoid sensitivity...

ea0009oc30 | Oral Communication 4: Steroids | BES2005

Cortisol, DHEA and DHEAS in severe sepsis - a paradigm revisited

Arlt W , Hammer F , Sanning P , Filko D , Allolio B , Stewart P , Annane D

In severe sepsis circulating DHEA sulfate (DHEAS) has been shown to decrease whilst serum cortisol increases. This has led to the suggestion of an intraadrenal shift from adrenal androgen towards glucocorticoid synthesis in severe stress. Patients with sepsis are therefore assumed to be DHEA deficient and have been suggested to benefit from DHEA replacement. However, only desulfated DHEA is biologically active and DHEAS and DHEA may not freely interconvert as previously though...

ea0009oc31 | Oral Communication 4: Steroids | BES2005

Functional effects of mutations in the 11beta-hydroxylase (CYP11B1) gene

Barr M , Wilkinson D , Holloway C , Miller S , MacKenzie S , Kazi S , Fraser R , Connell J , Davies E

Up to 15% of unselected patients with hypertension have evidence of inappropriate aldosterone production, identified by a raised ratio of plasma aldosterone to renin (ARR), suggesting that altered regulation of aldosterone synthesis is a key intermediate phenotype in essential hypertension. We previously described an association between the -344C/T 5'UTR polymorphism in the CYP11B2 (aldosterone synthase) gene and hypertension with raised ARR; the same genetic variation associa...

ea0009oc32 | Oral Communication 4: Steroids | BES2005

Differential induction of fibroblast 11beta-HSD1: a mechanism for tissue-specific regulation of inflammation

Hardy R , Cooper M , Filer A , Parsonage G , Buckley C , Stewart P , Hewison M

Acute inflammation plays an important role in the normal immune system by helping to coordinate host responses to danger signals such as infection. In most cases the inflammation is rapidly resolved but in chronic inflammatory diseases such as rheumatoid arthritis (RA) the inflammation persists leading to localized accumulation of potentially damaging immune cells. It remains unclear why inflammation persists in some tissues and not in others. Recent studies have shown that st...

ea0009oc33 | Oral Communication 4: Steroids | BES2005

Generation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase isozymes in the perfused mouse hindlimb

Dover A , Hadoke P , Miller E , Newby D , Walker B

Glucocorticoids (cortisol in man, corticosterone in rodents) can inhibit angiogenesis, alter contractile function and reduce the inflammatory response to injury in the vascular wall. These effects are regulated by the 11beta-hydroxysteroid dehydrogenases (11HSDs) which inter-convert active glucocorticoids and their inactive 11-keto metabolites (cortisone; 11-dehydrocorticosterone) within target tissues. 11HSD2 is a unidirectional, exclusive dehydrogenase which inactivates gluc...