Searchable abstracts of presentations at key conferences in endocrinology

ea0034p349 | Steroids | SFEBES2014

Hyperandrogenaemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione

O'Reilly Michael , Taylor Angela , Crabtree Nicola , Hughes Beverly , Capper Farfia , Crowley Rachel , Stewart Paul , Tomlinson Jeremy , Arlt Wiebke

Polycystic ovary syndrome (PCOS) is a clinical triad of anovulation, insulin resistance, and androgen excess. Hyperandrogenism may correlate with metabolic risk but PCOS consensus criteria currently define androgen excess on the basis of serum testosterone only. Here we studied the utility of the androgen precursor serum androstenedione in conjunction with serum testosterone as a predictor of metabolic dysfunction in PCOS.86 PCOS patients fulfilling Rott...

ea0034p368 | Steroids | SFEBES2014

Glucocorticoid activation in muscle by 11β-hydroxysteroid dehydrogenase type 1: contributions to inflammatory muscle wasting

Hardy Rowan , Lavery Gareth , Pierson Mark , Doug Craig , Filer Andrew , Buckley Christopher , Lord Janet , Stewart Paul , Cooper Mark , Raza Karim

Muscle wasting remains a significant complication in patients with inflammatory disease where it contributes to disability, risk of falls and early mortality. Interestingly, muscle wasting in patients with glucocorticoid excess mirrors that observed in patients with inflammatory disease. We have previously reported that the glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is potently up-regulated within mesenchymal derived cell popu...

ea0034p371 | Steroids | SFEBES2014

Enhanced expression of hepatic inflammatory markers in 11β-hydroxysteroid dehydrogenase type 1 knockout mice fed a steatogenic diet

Larner Dean , Morgan Stuart , Gathercole Laura , Nasiri Maryam , Guest Philip , Chapman Matthew , Tomlinson Jeremy , Stewart Paul , Lavery Gareth

Non-alcoholic fatty liver disease (NAFLD) is characterised by intra-hepatocyte lipid accumulation. Simple steatosis, which is a reversible condition, can progress to non-alcoholic steatohepatitis (NASH), cirrhosis and eventually hepatocellular carcinoma. The aetiology of NAFLD is not fully understood and it is suggested that glucocorticoid reactivation through the activity of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme may promote hepatic lipid accu...

ea0070aep130 | Bone and Calcium | ECE2020

Phase II study of the impact of AZD4017, a selective 11β-HSD1 inhibitor, on osteocalcin in post-menopausal osteopenia

Abbas Afroze , Eastell Richard , K Crowley Rachel , Ainsworth Gemma , Brown Sarah , Flanagan Louise M , Fairclough Rebecca J , Stewart Paul M

The causative link between circulating glucocorticoid excess and osteoporosis is established. Although circulating cortisol levels do not change significantly with age, local tissue metabolism may be implicated in age-related bone loss. The enzyme11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) increases local cortisol production, is expressed in human osteoblasts and its activity increases with age leading to a decrease in bone formation. We hypothesised that sele...

ea0031oc4.2 | Obesity, metabolism and bone | SFEBES2013

11β-HSD1 knockout mice are protected from the adverse metabolic effects of exogenous glucocorticoid excess

Morgan Stuart , Bujalska Iwona , Gathercole Laura , Hassan-Smith Zaki , Guest Phil , Abrahams Lianne , Stewart Paul , Lavery Gareth , Tomlinson Jeremy

Glucocorticoids (GC), such as prednisolone, are widely prescribed for their anti-inflammatory and immunosuppressive properties. However, they have significant side-effects including insulin resistance and hepatic steatosis. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts 11-dehydrocorticosterone (11DHC) to active corticosterone (CORT) and thus amplifies local GC action. We hypothesise that enhanced local GC regeneration of exogenously administered GCs by ...

ea0031p220 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2013

Hepatic 11β-hydroxysteroid dehydrogenase type 1 is elevated following weight loss secondary to bariatric surgery

Woods Conor , Taylor Angela , Hughes Beverly , Corrigan Michelle , Stewart Paul , Tomlinson Jeremy , Shea Donal O , Sherlock Mark

In the pathogenesis of obesity, dysregulated tissue cortisol metabolism (controlled by 11β-HSD1), is postulated to be involved. Fifteen patients (seven mens, mean BMI 50.8±7 kg/m2) awaiting Roux En Y gastric Bypass (RYGB) surgery underwent assessment of 11β-HSD1 activity using cortisol generation profile. Corticosteroids in serum and subcutaneous adipose tissue microdialysis fluid and urinary corticosteroid metabolites were analysed by liquid and gas ...

ea0028oc5.4 | Growth, tumours and pituitary | SFEBES2012

Steroid metabolomics in adrenocortical carcinoma reveals mitotane as an inducer of CYP3A4 and an inhibitor of 5alpha-reductase activity with major implications for drug metabolism and hydrocortisone replacement

Chortis Vasileios , Taylor Angela , Schneider Petra , Tomlinson Jeremy , Hughes Beverly , Smith David , Porfiri Emilio , Shackleton Cedric , Stewart Paul , Arlt Wiebke

Mitotane (o,p’DDD) is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the primary tumour. Mitotane is considered an adrenolytic substance, but no information is available regarding distinct steroidogenic effects. Here we carried out steroid metabolomics by gas chromatography/mass spectrometry in 24-hour urine samples from 106 patients with ACC and with samples coll...

ea0025p166 | Diabetes, metabolism and cardiovascular | SFEBES2011

Lack of beneficial metabolic profile in liver-specific 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) knockout mice

Lavery Gareth , Rabbitt Elizabeth , Zielinszka Agnieszka , Huges Beverley , Semjonous Nina , Saqib Khalid , Morgan Stuart , Gathercole Laura , Walker Elizabeth , Stewart Paul

In humans glucocorticoid (GC) excess can promote hepatic glucose and triglyceride production contributing to obesity, fatty liver and diabetes. 11β-HSD1 activates GCs (11-DHC to corticosterone in mice), thereby increasing tissue concentrations. The liver has the highest 11β-HSD1 activity, and its inhibition has emerged as a therapeutic option. To investigate this we generated 11β-HSD1 liver-specific knockouts (HSD1LKO) and examined GC metabolism and responses to...

ea0021oc3.3 | Young Endocrinologists prize session | SFEBES2009

Development of urinary steroid profiling as a high-throughput screening tool for the detection of malignancy in patients with adrenal tumours

Taylor Angela , Biehl Michael , Hughes Beverly , Stiekema Han , Schneider Petra , Smith David , Nightingale Peter , Shackleton Cedric , Stewart Paul , Arlt Wiebke

Adrenal tumors have an incidence of 2–3% in the general population and the work-up of incidentally discovered adrenal masses represents a major burden to the health system. Differentiating adrenocortical adenoma (ACA) from adrenocortical carcinoma (ACC) represents a continuous challenge, with unfavorable sensitivities and specificities provided by tumor size, imaging and even histology. Here, we aimed to develop a reliable screening tool for the detection of adrenal malig...

ea0021oc3.7 | Young Endocrinologists prize session | SFEBES2009

Effects of glucocorticoids on Wnt gene expression in synovial fibroblasts: potential role in inflammatory bone loss

Hardy Rowan , Patel Pushpa , Ahasan Mohammad , Rabbitt Elizabeth , Filer Andrew , Raza Karim , Buckley Chris , Stewart Paul , Cooper Mark

Synovial fibroblasts (SFs) form a substantial component of inflamed rheumatoid synovium and generate endogenous glucocorticoids (GCs) during inflammation. Recently, production of DKK-1 (a Wnt signalling inhibitor that reduces bone formation) by SFs in response to TNFα has been proposed to be the master regulator of inflammatory osteoporosis. We have identified that in addition to TNFα, GCs potently induce DKK-1 secretion. This may provide a novel mechanism whereby lo...