Endocrine Abstracts

Short Synacthen test (SST) is performed to exclude adrenal insufficiency; it’s frequently used for investigations of hyponatremia to rule out adrenal insufficiency as a possible cause. However the cost of Synacthen® (tetracosactide) 250 μg in 1 ml has increased from £14.63 to £228.55 for box of 5 A. (15-fold rise in price). This price hike needs to be taken into considerations when ordering SST. The objective of this retrospective audit was ...

Background: Heat acclimatisation (HA) describes phenotypic changes (decreased heart rate, HR; lower core body temperature, Tc) resulting from exposure to a hot environment. Heat tolerance with HA may reflect altered adrenocortical and autonomic nervous responses to heat stress, though evidence for sympathetic downregulation is lacking. Methodological limitations to further investigation (e.g. with direct catecholamine measurement) could be overcome by assaying the catecholamin...

Background: Understanding hypoadrenal patients’ perceptions of adrenal crisis is vital in the prevention of this endocrine emergency. This study explored the experiences, knowledge and attitudes of hypoadrenal patients to adrenal crises and their prevention.Method: A cross-sectional qualitative study using structured interviews with patients with primary and secondary adrenal insufficiency. Data were analysed using thematic content analysis.<p c...

Cellular reprogramming describes the process where a fully differentiated, specialized cell type is induced to transform into a different cell. Cell reprogramming techniques can become powerful tools for modelling diseases, drug testing and for personalized cellular therapy. The adrenal cortex is the primary site of steroid synthesis. Adrenal insufficiency, which can be life threatening, is caused by a number of adrenal disorders, and lifelong management of these patients with...

Introduction: Germline mutations in succinate dehydrogenase subunit B (SDHB) are one of the commonest findings in familial paraganglioma (PGL) syndromes and account for one quarter of PGLs associated with germline mutations. Although the penetrance is low, the malignancy conversion is high; up to 30%. With the increasing availability of genetic testing and the identification of ‘asymptomatic carriers’ of the SDHB gene mutation, it is therefore impor...

Introduction: Computed tomography (CT) scan is the first imaging method used to characterize adrenal lesions in order to select patients for surgical treatment. Our aim was to specify the performance of this tool in the work up of adrenal masses (AM) recruited in a department of Endocrinology.Material and methods: This retrospective study included 100 patients hospitalized in our department between 2008 and 2014 for adrenal tumors. After a systematic exc...

Nocturnal salivary cortisol (NSC), urinary free cortisol (UFC) and overnight dexamethasone suppression testing (ODS) are recommended screening tests for Cushing’s syndrome (CS). Individual centers differ in their screening approach; UFC being the test of choice in Northern Ireland with ODS in patients with adrenal incidentalomas. NSC, which measures free cortisol, is not routinely used. The aims of this study were to 1. Evaluate the utility of NSC in the diagnosis of CS; ...

Introduction: Pituitary and adrenal Cushing’s may be managed by pharmacological-inhibition of adrenal steroidogenesis, using metyrapone and/or ketoconazole. Assessment of biochemical control is challenging owing to cross-reactivity in immunoassays (e.g. cortisol and 11-deoxycortisol) leading to over/under-treatment. Off-target effects can also result, e.g. hyperandrogenism/mineralocorticoid hypertension (increased 11-deoxycorticosterone/DOC). LC-MS/MS analysis is free fro...

Aim: Short Synacthen test has been widely used screening test for assessment of hypothalamo-pituitary-adrenal axis (HPA). The most widely used is 30 min plasma cortisol Post synacthen. We have compared 30 min cortisol with 60 min for assessment of the HPA axis of patients with known endocrine disorders and on long term steroid, opiate use and obesity (non endocrine disorder).Method: Cortisol Response to 30 and 60 min post synacthen were measured in rando...

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), whilst effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bidirectional GC activating enzyme, potently up-regulated by inflammation within mesenchymal derived tissues. We assessed the regulation of this enzyme with inflammation in muscle and examined its functi...

Introduction: Prolonged therapy (≥ 3 months) with high-dose corticosteroids (≥ 7.5 mg Prednisolone or 1–1.5 mg Dexamethasone daily) can result in adrenal atrophy and secondary adrenal failure. Abrupt withdrawal of corticosteroids after prolonged use can lead to adrenal insufficiency, corticosteroid withdrawal symptoms or a relapse of the initial disease. A safe flexible management plan is required for each patient. We illustrate with two cases.<p class="ab...

ATR-101 is a selective Acyl-CoA: cholesterol acyltransferase 1 (ACAT1) inhibitor in development for the treatment of diseases of the adrenal cortex including rare endocrine diseases, such as congenital adrenal hyperplasia (CAH) and Cushing’s syndrome (CS), and in adrenocortical carcinoma (ACC). ATR-101 has been shown to inhibit adrenal steroidogenesis at low doses and cause apoptosis at high doses. To better understand the adrenal-specific effects of ATR-101, in vivo<...

Cushing’s syndrome (CS) in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. ATR-101 is a novel small molecule therapeutic currently in clinical development for the treatment of congenital adrenal hyperplasia and adrenocortical carcinoma in humans. ATR-101 is an adrenal-selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1). ACAT1 catalyz...

Good clinical practice encourages patients to minimise long-term glucocorticoid overexposure to preserve bone density and prevent the development of glucose intolerance or hyperlipidaemia. However, the absence of a protective “cushion” of excess cortisol implies an increased risk of adrenal crisis. (White & Arlt 2010) This assumption has been challenged by a leading adrenal specialist, who suggested instead that chronic over-replacement may increase the susceptib...

Background: Primary aldosteronism is identified in approximately 10% of hypertensive all-comers. Adrenal vein sampling (AVS) allows localization of aldosterone production, identifying cases where unilateral adrenalectomy can be curative. Unfortunately, AVS is technically challenging.Methods: Data from AVS procedures performed in BC were extracted from the SunQuest laboratory information system in Vancouver Coastal Health. Cortisol and aldosterone levels ...

Introduction: Misdiagnosis of secondary hypocortisolaemia can have profound consequences on a patient’s life. Due to contraindications the gold standard dynamic diagnostic test of cortisol reserve – the insulin tolerance test (ITT) – may not always be suitable. Here we examine the diagnostic accuracy of the second line dynamic tests: the overnight metyrapone test (OMT), short synacthen test (SST) and glucagon stimulation test (GST).Patient...

Background: Despite the widespread use of the 250-μg Cosyntropin test (ACTH test) for the diagnosis of adrenal insufficiency (AI), the effect of timing of the test on 30- vs. 60-min serum cortisol values remains unclear. Also, there is limited evidence comparing the value of performing both 30- and 60-min cortisol levels.Methods: We conducted a retrospective cohort study of all ACTH tests conducted at the Halifax Neuropituitary Program, Nova Scotia,...

Aims: Recent Endocrine Society Guidelines (2016) suggest establishing the aetiology of primary adrenal insufficiency (PAI) and screening for other autoimmune conditions. The aim of our audit was to compare current practice against these recommendations.Methods: We identified patients seen in clinic over 18 months between January 2015 and May 2016. The data was collected by reviewing electronic and paper records.Results: Eighty-thre...

Aims: Adrenal crisis (AC) is a life- threatening condition with an incidence of 6–10 adrenal crises per 100 patient year in European populations. The aim of our study is to identify the prevalence of adrenal crisis in our clinic population and assess the preventative measures in use.Methods: Data was obtained from electronic records and paper records were reviewed in adrenal crisis patients.Results: There were 230 patients wit...

Current trust protocol for the Short Synacthen Test (SST) is to perform cortisol levels at 0, 30 min and 60 min; there is a variation in this policy in different trusts. This quality improvement project determined if the 60 min test was significant and, if so, in what proportion of patients. A further aspect of the audit was in regards to determining if the number of SSTs in the trust could be reduced. We investigated every adult having a SST run through the SWFT laboratory du...

Context: Recent guidelines recommend a diagnosis of adrenal insufficiency when stimulated peak cortisol level falls below 500 nmol/l. This may not be valid when using a highly specific cortisol immunoassay or cortisol measured by liquid chromatography-mass spectroscopy.Objective: Determine the diagnostic threshold for adrenal insufficiency using a highly specific cortisol assay.Design: For 4 months, all subjects having a dynamic te...

Introduction: Acute adrenal insufficiency (adrenal crisis) is a life-threatening condition caused by glucocorticoid deficiency. Patient and carer education is key in the prevention, early identification and prompt management of this condition. We assessed the knowledge of adrenal insufficiency/crisis in patients with adrenal and pituitary disease to evaluate the strengths and weaknesses of local ‘sick day’ education processes.Methods: We utilis...

Background: Prednisolone is used for glucocorticoid replacement therapy in Adrenal Insufficiency. Package inserts indicate that prednisolone should be administered with or after food as there is a belief that prednisolone causes stomach ulcers. We have investigated the impact of various fasted and non-fasted states on its pharmacokinetic profile.Method: A healthy volunteer provided three 4 mg prednisolone profiles. The first was a fasted reference curve....

Intracellular cortisol is regulated by 11βHSD1. Although the field has focused on regeneration of cortisol from inert cortisone by 11β-reductase activity of 11βHSD1, we have used stable isotope tracers and arteriovenous sampling to quantify simultaneous dehydrogenase (cortisone generation) and reductase (cortisol regeneration) in human adipose and skeletal muscle. In vitro studies suggest insulin regulates this balance of reductase vs dehydrogenase acti...

Introduction: Phaeochromocytomas and paragangliomas (PPGLs) are rare tumours with high morbidity. The majority are benign and surgically curable, but genetic testing suggests that many are associated with germline mutations, and careful long-term follow-up of patients and their family members is important. Regular biochemical screening with plasma or urinary metanephrines (uMetanephrines) is essential, but currently 24-h collections of uMetanephrines is cumbersome and inconven...

Background: The cortisol circadian rhythm has an early morning peak with an increase before awakening, and a second lunchtime peak. Using a UPLC-MS/MS technique to measure prednisolone, the active metabolite of prednisone, we investigated the suitability of modified release (MR) prednisone (Lodotra) as a replacement therapy.Method: Blood samples were taken at fixed time points after the administration of MR-prednisone. Concentrations of the active metabo...

Nicotinamide nucleotide transhydrogenase (NNT) is an integral protein of the inner mitochondrial membrane and plays a major role in maintaining the redox balance by catalysing the trans-hydrogenation between NADH and NADP+ and proton translocation across the mitochondrial membrane.Genetic variants in NNT have recently been reported in patients with familial glucocorticoid deficiency (FGD), combined mineralocorticoid and glucocorticoid deficiency...

Objective: To examine the monitoring, management and outcomes of adrenal tumours in pregnancy.Design: A national, prospective observational, cohort study over 4 years using the UK Obstetric Surveillance System (UKOSS).Setting: Consultant led obstetric units.Patients: Women with hormone-secreting adrenal tumours (pheochromocytoma, primary aldosteronism or Cushing’s syndrome) diagnosed before or during pre...

Disturbed oestrogen homeostasis is associated with an increased risk of cardiovascular disease. However, the impact of dysregulated oestrogen signalling on vascular development, maintenance and disease is not fully understood. Zebrafish is a well-established model in translational vascular research. In addition, oestrogen receptor expression and oestrogen-responsiveness in endothelial cells (EC) is conserved in zebrafish. Therefore, the aim of this study was to characterise th...

Delayed wound healing (WH), characterized by ischemia, is exacerbated by glucocorticoid (GC) excess. Local GC availability is regulated by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which generates the GC cortisol from inactive cortisone. We previously reported improved WH in 11β-HSD1-null mice but regulation of 11β-HSD1 by hypoxia in human skin remains unknown. Primary human dermal fibroblasts (HDF, biological n=3), were treated...

Introduction: The adrenal gland dominates in human fetal steroid endocrinology and produces large amounts of Δ5 androgens. Adrenal development in the human is poorly understood, and species differences make animal models only partially relevant. In this study we measured the steroid content of the human adrenal during fetal development and determined whether maternal smoking affects adrenal steroid concentrations or associated steroidogenic enzymes....

Approximately 10% of essential hypertension cases is attributed to primary aldosteronism (PA), where inappropriately high levels of aldosterone are secreted. Almost half of these PA cases result from aldosterone-producing adenoma. microRNAs are single-stranded, short non-coding RNAs that negatively regulate gene expression post-transcriptionally. In a previous study, we showed that microRNAs directly modulate CYP11B2 (aldosterone synthase) gene expression and aldoster...

Introduction: Primary aldosteronism (PA) is the most common endocrine cause of hypertension affecting up-to 10% of hypertensives. Saline suppression, a confirmatory test for PA helps avoiding patients undergoing invasive lateralisation procedures due to a false positive aldosterone-to-renin ratio (ARR). The proposed cut-off to exclude PA is post-saline aldosterone suppression to <140 pmol/l. We reviewed our biochemical work-up in order to optimise laboratory assessment.</p...

Introduction: The human fetal adrenal has unique structure/function and produces hormones (DHEA, corticoids, catecholamines) that control fetal development, organ maturation and parturition. Maternal smoking during pregnancy has immediate (pre-term delivery, low birth weight) and long-term effects on the offspring (metabolic syndrome, disrupted adrenal function). We performed shotgun proteomics to characterise human fetal adrenal development and to explore adverse effects of m...

Glucocorticoids (GC) drive multiple adverse effects in skin e.g. epidermal thinning, dermal atrophy and impaired wound healing (WH). Our previous findings indicate increased expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in primary human dermal fibroblasts (HDF), full-thickness skin from older donors and during the inflammatory phase of mouse skin WH. We also reported protection from age-induced dermal atrophy and improved W...

Aim: To define a basal Cortisol threshold that could potentially predict the outcome of short synacthen test (SST) and thus reduce the need for performing SST in patients with low clinical probability for adrenal insufficiency.Methods: We analysed SSTs done at our hospital in non-critically ill general medical and endocrine patients, who had abnormal 0900 h Cortisol levels (n=110, male-45, female-65) between January 2016 to March 2016. The SST w...

Background: Self-management is essential for patients with adrenal insufficiency (AI) to achieve optimal outcomes of glucocorticoid (GC) replacement therapy by minimising adverse effects from over- or under-replacement and appropriately adjusting the dose in intercurrent illness to prevent adrenal crisis. Evidence suggests that many patients report deficits in self-management especially concerning ‘sick day rules’, prevention and management of adrenal crisis and have...

Background/aims/method: Evaluation/management of adrenal incidentalomas (AI) is an increasingly prevalent challenge. CT/MRI characteristics may be useful in determining whether a lesion is a benign adenoma and forthcoming ESE-ENSAT guidance suggests a role for 18F-FDG-PET/CT in distinguishing benign vs malignant lesions. We have previously demonstrated the utility of 11C-metomidate (MTO), which binds CYP11B1/B2, in localising aldosterone-producing adenoma...

Introduction: Hydrocortisone therapy in adrenal insufficiency and medical management of Cushing’s syndrome requires accurate monitoring of glucocorticoid status. Currently, this necessitates admitting patients to hospital for serial measurements of serum cortisol. From previous studies in Cushing’s, the goal of medical therapy is a mean (based on five samples) serum cortisol of 150–300 nmol/l, which is known to equate to a normal cortisol production rate. Saliva...

Background: The urinary steroid metabolome is considered the fingerprint of adrenal gland function. Novel methods using mass spectrometry profiling have seen the advent of a new era for metabolomics with powerful implications for both diagnostics and discovery. Its interpretation is difficult and performed by few specialists with the expertise to do so. This makes it a relatively inaccessible tool for the majority of Clinical Endocrinologists.Objective: ...

Background: The pathogenesis of autoimmune Addison’s disease (AAD) remains incompletely understood, but it is thought to be due to interplay between genetic, immune and environmental factors. A month of birth effect, with increased risk amongst those born in autumn and winter months, have been described in autoimmune conditions such as type 1 diabetes and autoimmune thyroid disease.Aim: To investigate month of birth effect in two independent cohorts...