Searchable abstracts of presentations at key conferences in endocrinology
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Society for Endocrinology BES 2009

ea0019p302 | Steroids | SFEBES2009

Differential transcription of 11β-hydroxylase and aldosterone synthase alleles in human adrenocortical tissue

MacKenzie S , Stewart P , Plouin P-F , Fraser R , Connell J , Davies E

Background: The CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes are found in close proximity on human chromosome 8 and are highly polymorphic, enabling the definition of two common haplotypes. Haplotype1 includes the -344T and the Intron2 conversion polymorphisms in CYP11B2 and also the -1889T, -1859G polymorphisms in the regulatory region of CYP11B1. We and others have shown that these associate with increased aldosterone pr...

ea0019p303 | Steroids | SFEBES2009

Report of the first missense mutation of MRAP within the MC2R interaction domain in a family causing FGD

Hughes C , Chung T , Storr H , Clark A , Metherell L

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by ACTH resistance resulting in isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Approximately 25% of cases result from mutations in the ACTH receptor (MC2R) and 20% result from mutations in the Melanocortin 2 receptor accessory protein (MRAP). MRAP is a small single transmembrane domain protein that is specifically required for trafficking MC2R to the ce...

ea0019p304 | Steroids | SFEBES2009

Modified-release hydrocortisone to provide circadian cortisol profiles

Debono M , Ghobadi C , Rostami-Hodjegan A , Huatan H , Campbell MJ , Newell-Price J , Darzy K , Merke DP , Arlt W , Ross RJ

Background: A basic tenet for hormone replacement is to replicate physiology but this is rarely if ever achieved. The adrenal glucocorticoid, cortisol, has a distinct circadian rhythm regulated by the brain’s central pacemaker. Loss of the cortisol circadian rhythm is associated with metabolic abnormalities, depression, fatigue and a poor health-related quality of life. Based on pharmacokinetic modelling we have developed a modified-release hydrocortisone (MR-HC) and test...

ea0019p305 | Steroids | SFEBES2009

Differences in aldosterone synthase and 11β-hydroxylase genes between Caucasian and Afro-Caribbean hypertensive families

Alvarez-Madrazo S , Padmanabhan S , Friel E , McKenzie C , Keavney B , Davies E , Connell J

Aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) genes are highly homologous in their coding regions (95%), lie in tandem approximately 40kb apart in human chromosome 8, and may have arisen from gene duplication. The pattern of linkage disequilibrium (LD) of this region in a population is determined not only by the distribution of recombination events but also by demographic factors determining the amount of random genetic drift. There is suggestiv...

ea0019p306 | Steroids | SFEBES2009

Prenatal dexamethasone programmes renal 11β-hydroxysteroid dehydrogenase type 2 expression

Tang JI , Seckl JR , Nyirenda MJ

Numerous epidemiological studies worldwide have shown a strong association between low birth weight and an increased risk of developing cardiometabolic disease, including hypertension. Excessive fetal exposure to glucocorticoids has been hypothesised to mediate this relationship. Here, we have used an established rodent model – in which dexamethasone, a synthetic glucocorticoid that readily crosses the placenta, is administered to pregnant Wistar rats during the last trim...

ea0019p307 | Steroids | SFEBES2009

Hyperglycaemia presenting as adrenal insufficiency in type 1 diabetes

Ullah A , Abouglila K , Ibrahim I , Zeb S

Introduction: It is known that certain endocrine disorders are related to each other and occur together due to their autoimmune aetiology. Patients with an autoimmune disease must be considered at risk for other autoimmune disease. Addison’s disease usually presents with recurrent hypoglycaemia in subjects with type 1 diabetes mellitus.We present a case Addison’s disease in type 1 diabetes presenting with severe hyperglycaemia.<p class="abs...

ea0019p308 | Steroids | SFEBES2009

Cushing’s syndrome presenting as weight loss

Ullah A , Abouglila K , Ibrahim I , Zeb S

Introduction: Cushing’s syndrome is characterised by glucocorticoid excess. This is more commonly caused by excess adrenocorticotropic hormone (ACTH) produced either by a pituitary tumour (Cushing’s disease) or ectopic secretion. An example of the latter is the production of ACTH by a lung carcinoma (typically small cell)1. Other causes of Cushing’s syndrome include long term steroids or adrenal carcinoma.Case history: A 62-year...

ea0019p309 | Steroids | SFEBES2009

Corticosteroid-binding globulin (CBG) deficiency caused by a novel mutation in exon 3

Perogamvros I , Henley D , Hadfield K , Underhill C , Newman W , Hammond G , Lightman S , Ray D , Trainer P

Inherited CBG deficiencies are rarely reported and only 3 causative mutations in 4 families have been described. The objective of this study was to investigate a family with potential CBG deficiency.The index case, a 29-year-old female of Pakistani origin with consanguineous parents, presented with hirsutism and a slightly elevated 17-OHP. In a subsequent Short Synacthen Test (SST) 17-OHP was normal but serum cortisol (SerC) values were abnormal (case 1 ...

ea0019p310 | Steroids | SFEBES2009

Simultaneous measurement of cortisol and cortisone in saliva by LC-MS/MS: application in basal and stimulated conditions

Perogamvros I , Owen L , Ray D , Trainer P , Keevil B

Salivary cortisol is an increasingly popular tool in endocrine, psychological and sports studies. Immunoassays used for its measurement are limited by cross-reactivity from related steroids, mainly cortisone, which is abundant in saliva.A method was developed for the simultaneous measurement of cortisol and cortisone (SalF and SalE respectively) in saliva using LC-MS/MS. 40 μl of extract was injected onto a C8 4×2 mm guard cartridge attached to...

ea0019p311 | Steroids | SFEBES2009

Effects of endogenous and exogenous hypercortisolemia on low-dose ACTH outcome in humans

Kerlik Jana , Penesova Adela , Vlcek Miroslav , Imrich Richard , Starka Luboslav , Radikova Zofia

Context: The interpretation of low-dose ACTH test during endogenous and exogenous hypercortisolemia induced by stress and glucocorticoid therapy in critically ill patients with possible relative adrenal insufficiency.Objective: The hypothesized inhibitory effects of hypercortisolemia on adrenal responsiveness in humans were tested using two model situations in low-dose ACTH testing.Subjects and methods: Nine young healthy women und...

ea0019p312 | Steroids | SFEBES2009

A biphasic rhythm of testosterone secretion: evidence for regulation by glucocorticoids

Waite Eleanor , Kershaw Yvonne , Spiga Francesca , Lightman Stafford

Two-way interactions between the hypothalamo–pituitary–adrenal (HPA) axis and the hypothalamo–pituitary–testicular (HPT) axis are well recognised. For example, in rats disruption of the HPT axis alters the circadian secretion of corticosterone. Conversely, stress conditions have varying effects on the level of testosterone secretion in both rats and humans. In contrast to humans, where several pulses of testosterone secretion can be detected across the 24 h...

ea0019p313 | Steroids | SFEBES2009

Dehydroepiandrosterone steroids are regulators of immune function via leukocyte annexin 1

Renshaw D , Flower R

There is evidence from human studies that dehydroepiandrosterone (DHEA) may regulate acquired immunity by promoting a shift towards a T helper type 1 (Th1) phenotype and in innate immunity by suppression of inflammation. Interestingly, circulating levels of DHEA/DHEA-S are significantly reduced in patients with rheumatoid arthritis and systemic lupus erythematosis and are also negatively correlated with age.Annexin 1 (ANXA1) is a glucocorticoid-induced p...

ea0019p314 | Steroids | SFEBES2009

The adipokine, Pre-B cell colony enhancing factor (PBEF)/visfatin, activates steroidogenic acute regulatory protein (StAR) protein expression and steroid production in human adrenocortical-H295R-cells via MAPK and PI3/AkT signalling pathways

Kaur Jaspreet , Ramanjaneya Manjunath , Chen Jing , Randeva Harpal

PBEF/Visfatin is an adipokine highly enriched in adipose tissue which is increased in obesity and has been shown to be involved in numerous physiological processes. The adrenal gland plays a pivotal role in the integration of metabolic activity and energy balance, through production of steroids, mainly glucocorticoids. Steroidogenesis is a tightly controlled and essential process, which is mediated by steroidogenic acute regulatory protein (StAR), a protein that transports cho...

ea0019p315 | Steroids | SFEBES2009

Orexin-stimulated MAP Kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells: differential regulation by orexin A and orexin B

Chen Jing , Ramanjaneya Manjunath , Conner Alex , Kumar Prashanth , Brown James , Johren Olaf , Lehnert Hendrik , Stanfield Peter , Randeva Harpal

Orexin-A and orexin-B orchestrate their diverse central and peripheral effects via two G-protein coupled receptors, OX1R and OX2R, which activate multiple G-proteins. They are involved in a host of physiological processes including, steroidogenesis, appetite control and energy regulation. Whilst some signalling mechanisms have been proposed for individual recombinant orexin receptors in generic mammalian cell types, it is clear that the peripheral effects of orexin are spatial...

ea0019p316 | Steroids | SFEBES2009

Regulation of 11β-hydroxysteroid dehydrogenase type 1 activity in myocytes by differentiation stage, GH/IGF1 and glucocorticoids

Jones CM , Sherlock M , Hardy R , Patel P , Stewart PM , Cooper MS

GH/IGF1 stimulate muscle function whereas excess glucocorticoids induce myopathy. Myocytes express 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme which converts inactive cortisone to active cortisol. GH/IGF-I inhibit 11β-HSD1 expression in some tissues and thus reduce cellular glucocorticoid exposure. This suggests that anabolic actions of GH/IGF1 could be mediated indirectly through effects on 11β-HSD1. The regulation of 11β-HSD1 has be...

ea0019p317 | Steroids | SFEBES2009

Cofactors and modify Cofactors and modifications of the glucocorticoid receptor

Davies L , Gkourtza A , Symeou C , Lynch J , Taylor S , Demonacos C , Krstic-Demonacos M

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily that acts as a hormone responsive transcription factor. GR function is controlled by hormone binding, post-translational modifications and through interaction with cofactors. Here, we report that JNK dependent phosphorylation of GR affects its sumoylation. JNK activation by UV radiation that targets GR for phosphorylation at serine 246 (S246) facilitated subsequent GR sumoylation at lysine...

ea0019p318 | Steroids | SFEBES2009

Associated health conditions and occupational status are risk factors for adrenal crisis in treated Addison’s disease

White K , Arlt W , Wass J , Elliott A

Patients with chronic adrenal insufficiency (Addison’s) have mildly but significantly increased mortality from cardiovascular, malignant, and infectious diseases, predominantly pneumonia (Bergthorsdottir et al. 2006). Death from adrenal crisis is rare and largely preventable, but life-threatening adrenal crisis is a regular event in treated Addison’s with a previously reported annual incidence of 8% in the UK.We analysed the frequency of...

ea0019p319 | Steroids | SFEBES2009

Testosterone increases 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression in the rat heart

Michaelis M , Hofmann P , Goetz F , Kienitz T , Quinkler M

Introduction: 11β-HSD1 is the key enzyme of intracellular glucocorticoid regulation by converting inactive cortisone to active cortisol. The latter binds to the glucocorticoid and mineralocorticoid receptor (MR) in the heart. Cortisol excess in Cushing’s syndrome leads to left ventricular hypertrophy. Also androgens cause myocardial remodelling. However, the impact of testosterone on the cardiovascular system is strongly disputed showing beneficial and deleterious ef...

ea0019p320 | Steroids | SFEBES2009

Sexual dichotomy in long term growth trajectories of children with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH)

Chandrasekhar Sudha , Patel Leena , Gemmell Islay , Amin Rakesh , Banerjee Indi , Hall Catherine , Jones Julie , O'Shea Elaine , Clayton Peter

Objective: To evaluate longitudinal growth in 21-hydroxylase deficiency CAH, factors contributing to this and outcome for BMI, weight (Wt) and height (Ht) in adolescence.Methods: Multi-level longitudinal models were used to evaluate growth patterns of 28 males and 29 females with CAH. Age at adiposity rebound was derived from the roots of the fitted curves and compared to UK 1990 references. The influence of hydrocortisone (HC) and fludrocortisone (FC) d...

ea0019p321 | Steroids | SFEBES2009

MicroRNA: a novel post transcriptional regulator of 11β-hydroxlase (CYP11B1) and aldosterone synthase (CYP11B2)

Wood S , Forbes G , MacKenzie S , Stewart P , Connell J , Davies E

The corticosteroids aldosterone and cortisol are implicated in the aetiology of hypertension. The CYP11B1 and CYP11B2 genes encode 11β-hydroxlylase and aldosterone synthase; polymorphisms across the CYP11B1/B2 locus are associated with increased aldosterone production, inefficient 11β-hydroxlation and hypertension. While polymorphisms located in the promoter region of both genes may alter transcription factor binding, other variants located in th...

ea0019p322 | Steroids | SFEBES2009

Group education for emergency hydrocortisone injection

Cavan M , Fayers K , Everett J , Cavan D , Armitage M

Patients on hydrocortisone (HC) replacement for pituitary failure, Addisons disease or congenital adrenal hyperplasia are at risk of developing an Addisonian crisis if they become unwell with a severe infection or injury. This can be averted by prompt administration of intramuscular HC, traditionally by a medial professional. From 2004 we offered training to patients and a carer/partner in self-administration of HC. This was time consuming and the take up was slow. We therefor...

ea0019p323 | Steroids | SFEBES2009

Long-term consequences of auto-immune primary adrenal failure

Breen L , Thomas S , Doherty E , Powrie J , Brackenridge A , Carroll P

Background: Auto-immune Addison’s disease (AAD) is the most prevalent cause of primary adrenal insufficiency in the UK. Co-morbidities are commonly associated with AAD and can manifest years after the initial diagnosis. There is no clear consensus on the optimal surveillance and management of this condition.Objectives: To establish the prevalence of co-morbidities, assess bone health and review clinical surveillance practice of patients attending an...

ea0019p324 | Steroids | SFEBES2009

Expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes in mouse oocytes

Michael A , Tinworth L , Webb R

Introduction: The production of an oocyte competent of fertilisation and normal embryonic development is controlled by a series of highly organised signals and intracellular events which are known to be affected by physiological glucocorticoids. The actions of these adrenal steroids are modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes and we have recently reported that 11β-HSD activity in porcine oocytes increases 20-fold during meiotic maturation...

ea0019p325 | Steroids | SFEBES2009

The effects of glucocorticoids on first trimester trophoblast

Mukherjee S , Cartwright J , Whitley G , Michael A , Thilaganathan B

Introduction: Glucocorticoids may exert important actions in early pregnancy on the invading trophoblast. The local actions of glucocorticoids can be modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes which catalyse inter-conversion of cortisol with its inert metabolite, cortisone. Although two cloned 11β-HSD isoenzymes are known to be expressed in the term placenta, their expression and activity have not been well characterised in the first trimest...

ea0019p326 | Steroids | SFEBES2009

Adrenal insufficiency due to heparine induced thrombocytopenia

Wong YL , Ashawesh K , Padinjakara RN Kulambil , Murthy NPN , Sankar S

Introduction: Heparin induced thrombocytopenia (HIT), a complication of heparin therapy, is a reaction that is triggered by the immune system in response to heparin and causes thrombocytopenia. In this report, we describe an unusual case of HIT induced bilateral adrenal haemorrhage with resultant hypoadrenalism.Case: A 60-year-old Caucasian man was admitted with ascending cholangitis secondary to gallstone and underwent an emergency laparoscopic cholecys...

ea0019p327 | Steroids | SFEBES2009

Measuring cortisone production in man using a new stable isotope tracer

Hughes K A , Reynolds R M , Andrew R , Walker B R

Background: 11β-hydroxysteroid dehydrogenases (11β-HSD1&2) interconvert cortisol (F) and cortisone (E). Although 11β-HSD1 reductase activity has been measured in vivo, E production (dehydrogenase activity) has not been quantified using a Gold Standard technique, steady state tracer infusion.Aim: To develop a method to measure E production in vivo using the stable isotope tracer d2-cortisone (d2E).Me...

ea0019p328 | Steroids | SFEBES2009

Homeopathic medication and hyperthalamic–pituitary–adrenal (HPA) axis

Hawkins A , Boochandran T , Nikookam K

The aim of these two case reports (husband and wife) is to highlight the importance of homeopathic medication on HPA axis.The first case is a 60-year-old Indian lady known to have diabetes mellitus, hypertension and hypercholesterolaemia, who presented with difficulty in losing weight and generalised aches and pains. As part of the investigations by her General Practitioner her serum cortisol was found to be low at 32 mmol/l. Short synacthen test showed ...

ea0019p329 | Steroids | SFEBES2009

Testosterone deficiency in the testicular feminised mouse model is significantly associated with the development of liver steatosis: a mechanism that is independent of the androgen receptor

Dugdale C , Nettleship J , Jones TH

To determine the role of testosterone on liver fat deposition using the testicular feminised mouse (Tfm) model. The Tfm does not have a functional androgen receptor (AR) and low circulating levels of testosterone due to associated 17αhydroxylase deficiency.Liver tissue was obtained after 24 weeks of feeding with a cholesterol enriched diet from the following groups: (1) XY placebo-treated (littermate control), (2) Tfm placebo, (3) XY castrate placeb...

ea0019p330 | Steroids | SFEBES2009

Glucocorticoid regulation of 11β-hydroxysteroid dehydrogenase type 1 in dermal fibroblasts

Tiganescu A , Dekker P , Mayes A E , Stewart P , Walker E A

Topical glucocorticoid therapy causes adverse effects in human skin including a reduction in dermal fibroblast proliferation and extracellular matrix protein secretion (e.g. collagen 1) and epidermal thinning – effects paralleled in photoexposed and elderly skin. These cause reduced wound healing rates and a loss of elasticity with increased fragility and transepidermal water loss – signs also typical of Cushing’s syndrome characterised by raised circulating cor...

ea0019p331 | Steroids | SFEBES2009

A case of triple A syndrome: more than just glucocorticoid deficiency

Wallace I , Hunter S , Koehler K , Huebner A , Carson D

Triple A syndrome (also known as Allgrove’s syndrome, MIM #231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, alacrima and achalasia. Neurological features may also be present. Various combinations of these features may be present which evolve over time. Triple A syndrome is caused by mutations in the AAAS gene which encodes for the protein ALADIN, a member of the nuclear pore complex, whose function is incompletely under...

ea0019p332 | Steroids | SFEBES2009

Mitosis regulates GR trafficking and impacts GR function

Matthews L , Spiller D , Rivers C , Norman M , White M , Ray D

Glucocorticoids (Gcs) act via the intracellular glucocorticoid receptor (GR) to regulate cellular homeostasis. GR is a ligand-activated transcription factor that mediates effects within the nucleus or cytoplasm to regulate genomic and non-genomic events. Localisation of the GR to a specific cellular compartment is therefore an important determinant of the cellular response to Gcs.Live cell imaging of GR trafficking using fluorophore-tagged GR shows drama...

ea0019p333 | Steroids | SFEBES2009

Altered subcellular trafficking and gene regulation suggest a distinct role for GR gamma

Berry A , Matthews L , Rivers C , Spiller D , White M , Norman M , Ray D

The actions of glucocorticoids (Gc) are mediated by the glucocorticoid receptor (GR). Several isoforms of the GR exist. Whilst GR alpha is the most abundant isoform, constitutive alternative splicing at the exon 3/exon 4 boundary results in an additional arginine within the DNA binding domain to produce the gamma isoform. Although GR gamma comprises 4–8% of total GR transcripts and is highly conserved through mammalian evolution, its biological function remains unknown.</...

ea0019p334 | Steroids | SFEBES2009

GR is hyperphosphorylated during mitosis and associates with the mitotic spindle

Matthews L , Spiller D , Rivers C , Norman M , White M , Ray D

Glucocorticoids (Gcs) act via the intracellular glucocorticoid receptor (GR) to regulate cellular homeostasis. Previous studies have demonstrated altered Gc sensitivity during mitosis. This reduced sensitivity can be explained only in part through the selective export of GR in mitotic cell populations. In this study ligand-independent, cell cycle-dependent effects on GR have been explored.Mitotic cells show a marked increase in ligand-independent ser211 ...

ea0019p335 | Steroids | SFEBES2009

Epigenetic silencing of the GR and defining the pro-apoptotic actions of GR expression in human cancer cell lines

Kay Paul , Matthews Laura , Sommer Paula , White Anne , Ray David

Although glucocorticoids (Gc) are used to treat a range of pathologies, an individuals response to therapy varies considerably. There is a distinct correlation between certain cell types and steroid sensitivity. Aberrant glucocorticoid receptor (GR) function is well-characterised in lymphoid malignant cells but not small cell lung cancer (SCLC) (DMS79) or osteosarcoma (U2OS) cell lines, which are both Gc resistant.Previously we have shown reduced GR cont...

ea0019p336 | Steroids | SFEBES2009

1,25-dihydroxyvitamin D3 increases the expression of intercellular adhesion molecule-1 (ICAM-1) and interleukin 8 (IL-8) in a human proximal tubule cell line

Markovic D , Bland R

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is a potent regulator of the immune system and activation of the vitamin D receptor alters expression and secretion of cytokines, chemokines and cell adhesion factors. Initial studies suggested that 1,25D3 synthesis and metabolism are increased in renal epithelial cells by TNFα and IL-1β. Therefore, the aim of this study was to examine whether vitamin D alters the expression of immune activated molecule...

ea0019p337 | Steroids | SFEBES2009

The role of serum and urinary steroids in the monitoring of adults with congenital adrenal hyperplasia

Reisch N , Krone N , Hughes B A , Vassiliadi D A , Flade L , Bidlingmaier M , Shackleton C H L , Stewart P M , Arlt W

Glucocorticoid treatment in congenital adrenal hyperplasia (CAH) is a continuous challenge, with even the experienced clinician struggling to strike the right balance between glucocorticoid over- and undertreatment. There is no consensus on monitoring of glucocorticoid therapy in adults with CAH. Some recommend a serum 17-hydroxyprogesterone (17OHP) target range of 12–36 nmol/l prior to glucocorticoid morning dose. Here we investigated the value of serum and urinary stero...