Endocrine Abstracts

Background: Liver fibrosis in cirrhosis is characterized by accumulation of extracellular matrix from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) limit HSC activation in vitro. Local GC levels are regulated by 11β-hydroxysteroid dehydrogenase-1 (11βHSD1) which converts inactive GCs (11-dehydrocorticosterone) into active GCs (corticosterone). In this study we hypothesized that 11βHSD1 could potentially inhibit liver fibrosis.<p cla...

The CYP11B1 and CYP11B2 genes encode the enzymes responsible, respectively, for the terminal stages of cortisol and aldosterone biosynthesis, and have been implicated in the development of essential hypertension. Previously, we investigated the role of microRNAs in the regulation of these genes and showed in vitro that levels of the adrenally-expressed microRNA-24 (miR-24) inversely correlate with those of CYP11B1 and CYP11B2 mRNA, ...

Glucocorticoids (GCs) are highly effective anti-inflammatory drugs, however their use is limited by serious side effects. We have previously shown that 5αTHB binds GC receptor (GR) and suppresses inflammation in vitro and in vivo, without affecting metabolism. Here the underlying molecular mechanisms were explored in cell models of ligand-induced GR phosphorylation, nuclear localisation and gene transcription. Data are mean±S.E.M. (th...

Due to the rarity of autoimmune Addison’s disease (AAD), it has proved difficult to gather large case cohorts for genetic studies. Linkage analysis offers a powerful means of identifying genetic susceptibility loci but has never been applied to AAD because of the scarcity of families containing ≥2 affected individuals. We collected DNA from 23 such families to perform the first linkage study in AAD.We genotyped 117 samples (50 cases, 67 contro...

Zebrafish has emerged as an important vertebrate in vivo model to study human disease. Steroidogenesis in zebrafish is not well characterised. Human CYP11A1 (hCYP11A1) catalyses the first step of steroidogenesis, the conversion of cholesterol to pregnenolone. Zebrafish Cyp11a1 (zCyp11a1) is essential during embryogenesis. Published data suggest that zCyp11a1 facilitates steroidogenesis in the interrenal (equivalent to mammalian adrenal), gonad and brain. We identified...

Patients with glucocorticoids (GC) excess develop central obesity, insulin resistance and hepatic steatosis in up to 20% of cases. Current dogma suggests that GCs cause insulin resistance in all tissues. However, we have previously demonstrated that GCs induce insulin sensitisation in adipose tissue in vitro, whilst causing insulin resistance in skeletal muscle. In rodent hepatocytes, GCs enhance insulin stimulated lipogenesis but studies in human hepatocytes have not...

Mitochondrial steroidogenic cytochrome P450 (CYP) enzymes, such as P450 side-chain cleavage, rely on electron transfer from the redox partner ferredoxin (FDX1) for catalytic activity. Previous in vitro data suggest these cofactors are key regulators of CYP enzyme activity. This study aims to establish the role of redox regulation on steroidogenesis using zebrafish as a vertebrate in vivo model.In contrast to humans, zebrafish have two F...

Introduction: Steroid profiling using liquid chromatography with tandem mass spectroscopy (LC:MS) has a low cost per sample and has the potential for high through-put processing. However, although this technology is becoming more widely used, little is known of the normal ranges of many less well studied steroid compounds as well as their response to a variety of physiological stimulants.Methods: Volunteers were recruited to a randomised, double blind cr...

Estrogen receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor in response to the ligand estrogen. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances fro...

In order to understand the significance of circadian and ultradian hormonal rhythms in man, both in health and disease, it is essential to be able to obtain multiple samples over extended periods, especially during the hours of sleep. The human automated blood sampling (HABS) system reported by Henley and colleagues can achieve this but is recommended for use in the setting of a clinical investigation unit which is its major drawback. For many diagnostic and scientific questio...

Glucocorticoid receptor (GR) is a ligand-dependent nuclear receptor which regulates the transcription of a wide spectrum of genes that are responsible for vital immunological, metabolic, developmental, and anti-inflammatory functions. GR transcriptional regulatory effects are modulated by co-regulators including the tetratricopeptide 5 (TTC5) which has been shown to stabilize GR and alter its action in response to cellular stress. TTC5 is a stress-responsive activator of p300 ...

The final reaction for cortisol production in the adrenal gland is catalysed by the 11β-hydroxylase enzyme, encoded by the CYP11B1 gene. Variants in this gene have been associated with alterations in cortisol levels, which increase blood pressure. This gene is traditionally thought to consist of 9 exons. However, recent evidence has predicted the existence of at least one alternatively spliced form.The presence of novel CYP11B1 mRN...

Background: Immune responses to self-peptides should not generally occur. However, four of 12 autoimmune Addison’s disease (AAD) patients developed adverse reactions immediately after synacthen injections, following repeated subcutaneous synacthen injections during a clinical trial (RoSA study). We wondered if these adverse effects were due to the production of anti-synacthen (ACTH1–24) antibodies.Methods: We evaluated the presence o...

Non-invasive methods to measure enzyme activity in vivo can provide a useful tool for the development of selective inhibitors. Tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a reductase enzyme that amplifies active intracellular glucocorticoid levels, has been shown in obese patients using invasive tools (biopsy, microdialysis and arteriovenous sampling with stable isotope tracers). 11β-HSD1 inhibitors are efficacious in...

Background: Addison’s disease (AD) in both humans and dogs is characterised by corticosteroid deficiency requiring lifelong hormone therapy. In humans autoimmune pathogenesis is established; at diagnosis ~90% of patients are 21-hydroxylase (21-OH) autoantibody positive, with antibodies to other adrenal antigens also detected. The pathogenesis of canine AD is less well characterised; autoimmune mechanisms are suspected, with anti-adrenal autoantibodies demonstrated by indi...

Canrenone is a mineralocorticoid receptor antagonist used as a diuretic agent to treat hypertension. It is the major active metabolite of spironolactone and may be quantified in clinical studies either to ensure compliance or to gain information about pharmacokinetic-pharmacodynamic interactions.The aim of this study was to develop and validate a sensitive, quantitative assay for the analysis of canrenone in plasma.HPLC mass spectr...

Background: Quality of life (QoL) has been variously reported as normal or impaired in congenital adrenal hyperplasia (CAH) adults. We found impaired QoL in UK CAH adults and now report the relationship between QoL, glucocorticoid treatment and health outcomes in these patients.Methods: Cross-sectional analysis of 151 CAH adults with 21-hydroxylase deficiency aged 18–69 years in whom QoL (SF-36), glucocorticoid regimen, anthropometric, and metabolic...

Polycystic ovary syndrome (PCOS) is a clinical triad of anovulation, hyperandrogenism and insulin resistance. Patterns of fat distribution in PCOS may be associated with androgen activation, glucocorticoid metabolism and insulin resistance. Here we analysed the relationship between fat distribution, steroid metabolism and insulin resistance in women with PCOS.We compared results from 100 PCOS patients (Rotterdam criteria) with 80 sex- and BMI-matched con...

Despite lifelong glucocorticoid and mineralocorticoid replacement, there is excess morbidity and mortality associated with autoimmune Addison’s disease (AAD). Adrenal cortical cells undergo continuous self-renewal from a population of subcapsular progenitor or stem cells, under the influence of ACTH. We aimed to determine if synthetic ACTH analogue could revive adrenal steroidogenic function and ameliorate AAD.We performed an open-label trial of syn...

Background: Calculation of a urinary steroid metabolite ratio (uSMR) may be a useful method of improving diagnostic yield when investigating disorders of steroid hormone synthesis.Objective & HypothesisTo investigate the range of uSMR in children with suspected disorders of steroid hormone synthesis.Population / MethodsTen ratios were calculated on steroid metabolite data analysed b...

Background: Military training has been associated with changes in the hypothalamic–pituitary–testicular axis that are consistent with central hypogonadism (fall in testosterone, LH and FSH concentrations). The effects on the hypothalamic–pituitary–testicular axis of deployment to a combat zone are not known. The aim of this study was to clarify this situation.Methods: Military personnel were investigated pre-deployment (Pre-) and foll...

Cushing’s syndrome (CS) associated with dilated cardiomyopathy without LVH is rare but important to recognise as treatment of CS can lead to total recovery of heart function.A 30-year-old previously fit and well Turkish man presented with chest pain and was diagnosed with NSTEMI and CCF. An MRI of the heart and CT coronary angiogram showed normal coronary arteries but a large right adrenal tumour of 11.5 cm with extension into IVC. The transthoracic...

Background: Oral corticosteroids are a known risk factor for developing osteoporosis and subsequent fracture at higher bone mineral density than post menopausal osteoporosis. Bone loss is thought to be most pronounced in the first 12 weeks of steroid use, and existing guidelines recommend a fracture risk assessment and appropriate osteoporosis prophylaxis with calcium and vitamin D supplements and bisphosphonates. There is also a recognized role for FRAX scoring to help strati...

Introduction: Iatrogenic Cushing’s syndrome from potent topical steroid use, resulting in suppression of the hypothalamic-pituitary-adrenal axis is well recognised. However, this may not be well acknowledged in amongst a general medical take. We report a case of Cushing’s syndrome from long term use of skin whitening cream and topical steroids, highlighting the importance of detailed history taking.Case history: A 49-year-old Nigerian female wa...

Introduction: Cushing’s syndrome(CS) is associated with high morbidity and mortality which warrants a good screening test that is less laborious. We explored the possibility of using urine spot cortisol:creatinine ratio (UCCR) as a new screening test for Cushing’s syndrome.Aims and objectives: To study the efficacy of UCCR as a screening test for patients with Cushing’s syndrome.To compare UCCR in patients with CS, o...

Congenital adrenal hyperplasia (CAH) is a group a rare autosomal recessive disorders characterised by a deficiency on one of the enzymes necessary for cortisol biosynthesis. More than 90% of CAH is caused by mutations or deletions in cytochrome P450 21-hydroxylase gene. Impaired glucocorticoid synthesis results in chronic elevation of ACTH causing adrenal hyperplasia and accumulation of steroid precursors such as 17-hydroxyprogesterone (17-HOP). The main goal in CAH managemeng...

Introduction: Adrenal venous sampling (AVS) is the reference standard test to differentiate between unilateral and bilateral adrenal diseases in patients with primary hyperaldosteronism. Current Endocrine society guidelines recommend AVS in all cases of primary hyperaldosteronism where surgery is desirable and practical. However, this procedure is technically challenging and failure rate is high.Aims: The aim of this audit was to evaluate success rate of...

Introduction: Lifelong corticosteroid replacement is the treatment for patients with Addison’s disease. Steroid therapy need to be altered in the event of illness such as infection, accident or any other major stress. Patients need to be advised on sick day rules and this information should be reiterated at every time of patient contact.We conducted an online survey among doctors across all specialties in the Countess of Chester hospital to assess t...

Antiphospholipid antibody (APLA) syndrome is a rare autoimmune systemic disorder which can occur as primary condition or secondary to connective tissue diseases, most frequently systemic lupus erythematosis. We are presenting a rare case of a lady who developed adrenal insufficiency secondary to adrenal vein thrombosis, as a late sequel to APLA Syndrome.A 50-year-old lady admitted to the medical ICU with one day’s history of severe abdominal pain an...

Introduction: A 77-year-old man with glipizide treated type 2 diabetes presented acutely unwell, with weakness, intermittent breathlessness, and poor glycaemic control (previously well control with HBA1c of 42 mmol/mol). Initial assessment showed body weight of 74.5 kg, mild leg oedema, blood pressure of 190/100 mmHg, expiratory wheeze, oxygen saturation 91% and PO2 7.8 mmHg on air. Chest XR showed chronic right lower lobe shadowing and a bulky hilum. His plasma glu...

Cushing’s syndrome in pregnancy is rare and is associated with increased fetal and maternal morbidity. It has previously been described in the presence of ectopic LH receptor expression, and has been associated with gestational diabetes and preeclampsia but to our knowledge has never been associated with any other endocrine pathology.We here report a 34-year-old woman, who presented with hypertension, weight gain, fluid retention and easy bruising a...

Background: Hypercortisol states present a diagnostic conundrum. Other conditions such as cyclical and subclinical Cushings pose additional challenges. We report a complex clinical presentation of thymoma with coexisting subclinical Cushing’s.Case report: A 65-year-old man presented to chest clinic with breathlessness and anterior mediastinal mass on CXR. CT scan demonstrated a 7.5 cm probable thymoma and bilateral adrenal masses of varying sizes up...

A 70-year-old female presented with general lethargy and a two day history of painful muscle twitching and paraesthesia in her right hand. No other symptoms were reported. Past medical history included hypertension, hypothyroidism and she had recently been diagnosed with Type 2 diabetes. Examination was unremarkable.The overall biochemical picture was that of a hypokalaemic alkalosis with hypocalcaemia and hyperglycaemia: Na+140 mmol/l, K...

Case history: A 60-year-old male underwent left sided orchidectomy for a Seminoma in November 2005. As a part of work up for the Seminoma, he was noted to have bilateral adrenal masses which raised the possibility of metastasis.Investigations: CT scan of the abdomen showed 22 mm mass on the right with a Hounsfield units of −31 and a 12 mm mass on the left with Hounsfield units of −1. The radiological phenotype of these masses along with densi...

A 55-year-old lady was referred by her GP to the acute medical unit with a 4-week history of fatigue, generalised swelling and weight gain of a stone, together with a potassium 2.8 mmol/l and sodium 146 mmol/l. Her blood pressure was 211/85 mmHg and she was suspected of having Conn’s syndrome. Treatment was started with Amlodipine 5 mg daily and Spironolactone 25 mg daily which was increased to 100 mg daily on subsequent follow-up in the acute medical unit. She remained u...

Introduction: We describe a case of young girl, who initially presented with androgen producing adrenal adenoma, and post-operatively, the other adrenal gland profoundly cortisol suppressed, raising suspicion, if it was originally co-producing both androgen and cortisol.Case report: A 29-year-old girl initially presented, with 8 months history of hirsutism and cranial hair loss.She had a normal menarche and menstrual cycles and con...

Introduction: We describe a case of young girl, who initially presented with androgen producing adrenal adenoma, and post-operatively, the other adrenal gland profoundly cortisol suppressed, raising suspicion, if it was originally co-producing both androgen and cortisol.Case report: A 29-year-old girl initially presented, with 8 months history of hirsutism and cranial hair loss.She had a normal menarche and menstrual cycles and con...