Endocrine Abstracts

Introduction: Humans with glucocorticoid receptor (GR) deficiency and global heterozygous GR knockout (GR+/−) show compensatory activation of the hypothalamic-pituitary-adrenal axis, resulting in salt-sensitive hypertension due to increased mineralocorticoid activity. Previous studies suggest renal mechanisms, including changes in cell proliferation, gene expression and electrolyte transport, may contribute to this phenotype but underlying adaptive adrenal responses have...

Steroid sulphatase (STS) is the primary enzyme for desulphating steroids from their inactive to their active forms. Principal substrates include steroid precursors oestrone-sulphate and dehydroepiandrosterone sulfate. Alterations in STS activity can directly affect local concentrations of oestradiol, testosterone and dihydrotestosterone; steroids that are frequently dysregulated in disease. Despite the importance of STS activity on steroid synthesis, little is known about its ...

Glucocorticoids act via the glucocorticoid receptor (GR). Upon ligand binding, GR translocates to the nucleus and binds directly to glucocorticoid responsive elements (GREs) to regulate transcriptional output. Glucocorticoid secretion increases in response to stress to affect transcriptional output within specific areas of the brain including the hippocampus (HC). Therefore, here we assess changes in genome-wide GR chromatin binding profiles in the rat HC in response to a gluc...

The uterus is an androgen-responsive organ; androgen receptors (AR) are expressed in human endometrial stromal fibroblasts and can regulate proliferation and survival of this cell type. Although chronic androgen exposure results in atrophy of human endometrium, previous studies have suggested that it may have trophic effects in the rodent uterus. We hypothesised that androgens may have different impacts on endometrial function in the presence or absence of oestrogens. In the c...

Background: Corticosteroid-binding globulin (CBG) plays a critical role in regulating glucocorticoid bioavailability. During inflammation, plasma CBG behaves as an acute phase “negative” protein due to the down-regulation of hepatic SerpinA6 (Cbg) expression and proteolytic cleavage of CBG. CBG contains a protease-cleavage domain (RCL) that promotes the release of CBG-bound steroids at sites of inflammation. Using an established adjuvant induced art...

Congenital adrenal hyperplasia (CAH) is one of the most common inherited disorders. The majority of CAH cases are due to 21-hydroxylase deficiency (21-OHD) caused by mutations in CYP21A2. Because of the profound impact of steroids on physiology and gene expression, the imbalances in steroid hormones resulting from 21-OHD are supposedly leading to a whole-organism response on transcriptome and metabolome level. The systemic consequences of severe 21-OHD during early development...

AT-rich interacting domain (ARID) subunits can interact with the glucocorticoid receptor (GR) and therefore may be essential for gene transcription dependent on receptor signalling. Glucocorticoids are steroid hormones important for regulating a variety of physiological processes through the binding and activation of GR. GR associates with numerous co-regulators, such as chromatin remodelling factors, to mediate gene induction or repression. One chromatin remodelling complex w...

A 51 year old woman presented with severe Cushing’s syndrome. In addition to a typically Cushingoid appearance she demonstrated increased cutaneous pigmentation in her face and upper chest. Biochemical investigation confirmed elevated serum cortisol levels with loss of circadian variation, and failure to suppress with low dose dexamethasone (0.5 mg 6 hourly for 48 hours). Serum ACTH levels were undetectable. Cross-sectional imaging revealed bilateral macronodular adrenal ...

ACTH signalling at the adrenal zona fasciculata induces rapid synthesis of glucocorticoids, accompanied by rapid transcription of genes encoding steroidogenic enzymes, including the labile, rate-limiting protein, StAR protein. ACTH induction of StAR transcription has been demonstrated to be predominantly CREB-dependent, and this mechanism is regulated by both CREB phosphorylation and its binding to the CREB co-activator TORC (transducer of regulated CREB activity, also known a...

Steroid hormones are important regulators of many physiological processes. The steroid precursor pregnenolone is converted through several enzymatic steps into all types of steroids, including the stress hormone cortisol. Mitochondrial steroidogenic cytochrome P450 (CYP) enzymes crucially relying on electron transfer from the redox partner ferredoxin (FDX1) are involved in key steps of the cortisol biosynthesis pathway.Cortisol is well-known regulator of...

Dexamethasone (DEX) is a widely used synthetic glucocorticoid whose effects are mediated via glucocorticoid receptor (GRs). Synthetic glucocorticoids are widely used in the clinical setting, due to their potent anti-inflammatory actions. However they are associated with numerous systemic side-effects and may also promote cognitive dysfunction, including impaired memory and learning processes in both patients and animal models.Discrete pulses of endogenou...

Chronic treatment with the synthetic glucocorticoid (GC) prednisolone has been reported in association with many detrimental health effects. In addition to well-documented adverse metabolic effects, there is evidence for memory impairments in these patients. GCs are known to have effects on memory, either enhancing or impairing dependant upon timing of exposure. Cell experiments have shown that synthetic GCs such as methyl-prednisolone (MPL) cause an alteration in timing of gl...

Vitamin D metabolites such as 25-hydroxyvitamin D (25D) circulate bound primarily to vitamin D binding protein (DBP). However, for most extra-renal tissues 25D uptake is independent of DBP, even though the ‘free’ 25D fraction is very small. DBP has a lower binding affinity for 25D2 compared to 25D3. We hypothesized that this would increase serum free 25D2, with possible variations in vitamin D function. Mice were placed on diets containing equal amounts (1000 IU/kg) ...

Non-alcoholic fatty liver disease is the hepatic manifestation of the global epidemic of metabolic disease. It is tightly associated with obesity and type 2 diabetes, yet the precise mechanisms that drive its aetiology are not fully defined. Steroid hormones, including glucocorticoids and sex steroids, regulate metabolic phenotype, and in addition, bile acids have recently been identified as potent metabolic regulators. AKR1D1 (5β-reductase), is predominantly expressed in...

Primary aldosteronism (PA) accounts for the largest proportion of cases of secondary hypertension worldwide. The majority of PA cases are a result of a unilateral aldosterone-producing adenoma (APA). The pathogenesis of APAs, the most curable form of hypertension, has been the focus of worldwide clinical interest, and is associated with mutations in four genes: KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Investigation into these mutations may lead t...

Adrenocortical carcinoma (ACC) is a rare malignancy, but accounts for up to 11% of adrenal masses investigated in referral centres. Diagnosis remains a challenge. Up to two thirds are biochemically inactive, resulting from de facto enzyme deficiencies in the steroid hormone biosynthetic pathways, as shown by urine steroid profiling by gas chromatography-mass spectrometry. Increased metabolites of pathway intermediates in ACC discriminate it from benign adrenal lesions...

Background: Excess glucocorticoid (GC) exposure is associated with an adverse body composition and metabolic profile characterised by increasing fat mass, muscle atrophy, insulin resistance, fatty liver, and dyslipidaemia culminating in increased cardiovascular risk. GCs are widely prescribed with increasing age where their effects can have deleterious effects.Objectives: To investigate the impact of GC exposure on subcutaneous adipose lipid metabolism a...

Background: Using a deuterated tracer (D4-cortisol) to measure cortisol regeneration from cortisone in vivo we have quantified tissue-specific 11βHSD1 activity in health and disease, and acute regulation eg by insulin. These studies relied on tracer enrichment in the total plasma cortisol pool, assuming rapid equilibration between free and protein-bound pools. Slower equilibration would result in underestimation of enzyme activity, and has implications for the co...

Background: In men there is a strong relationship between androgens and erythropoiesis; however this has not been shown in women. Patients with congenital adrenal hyperplasia (CAH) if uncontrolled may have high androgen levels and if over treated with glucocorticoids low androgen levels. Therefore CAH provides a potential model to examine the relationship between androgens and erythropoiesis in women.Aim: To investigate the relationship between androgens...

Many cases of hypertension are associated with inappropriately high levels of aldosterone secretion and it has been proposed that microRNAs play a role in this dysregulation. Previously, we showed that microRNAs expressed within the adrenal cortex significantly repress aldosterone production. Furthermore, stimulation of aldosterone secretion by three different means in the H295R cell line – the most commonly-used in vitro model of the human adrenal cortex – ...

ACTH is a 39 amino acids polypeptide which stimulates adrenocortical steroid production. The N-terminal segment of ACTH(1–24) is biologically active and the C-terminal is considered to have greater antigenicity. In one previous (‘RoSA’) and one current (‘RADS2’) clinical trial synthetic ACTH (zinc tetracosactide; depot synacthen) was administered to autoimmune Addison’s disease (AAD) patients to stimulate adrenocortical regeneration. 4/13 RoSA pat...

Background: The human adrenal cortex is composed of different zones, namely the zona glomerulosa (ZG), zona fasciculata (ZF), zona reticularis, and the recently proposed undifferentiated zone (UZ). The adrenal cortex synthesises and secretes steroids, mainly aldosterone and cortisol, both responsible for essential physiological and metabolic functions. Adrenal cortex disorders can be life threatening and current treatment involves life-long steroid replacement, which is not id...

Glucocorticoids (GC) influence immune responses, and exogenous GC are widely used clinically for their potent anti-inflammatory effects. Endogenous GC action is modulated by pre-receptor GC metabolising enzyme 11β-hydroxysteroid dehydrogenase (11b-HSD). 11b-HSD1 predominantly reactivates GCs, amplifying their action. Recent work has shown that 11b-HSD1 modulates immune and inflammatory response. However how innate immune system affect GC metabolism within cells remains la...

Canrenone and mifepristone (RU486) are respectively mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) antagonists commonly used to block or displace steroid for clinical pharmacological or research purposes. The aim of this study was to develop and validate a sensitive, quantitative assay for the combined analysis of glucocorticoids (cortisol, cortisone, corticosterone, and 11-dehydrocorticosterone), mineralocorticoids (aldosterone), canrenoate, and mifepristone...

Background: Mitotane is a strong inducer of hepatic CYP3A4 activity (cortisol metabolism) and increases cortisol-binding globulin (CBG). High hydrocortisone dosages are necessary in patients with adrenocortical cancer (ACC) on mitotane treatment. The newly modified release hydrocortisone has not been used in mitotane-treated ACC patients yet.Aim: To compare cortisol (serum and saliva), calculated free serum cortisol and ACTH levels in ACC patients on mit...

The synthesis and metabolism of bile acids and steroid hormones are conflicted at several levels. We investigated potential interactions using a feeding paradigm to stimulate bile acid secretion and salivary steroid measurements to monitor post-prandial changes.The study followed a randomised cross over design; both cortisol and cortisone were measured by specific ELISAs to assess effects on 11 beta-hydroxysteroid dehydrogenase activity (11βHSD). At...

Background: One percent of the adult population are, at any one time, prescribed oral glucocorticoids (GC). GCs are known to be associated with hypothalamic–pituitary–adrenal axis suppression. However, there remains uncertainty regarding: i) the prevalence of GC-induced adrenal insufficiency (AI); ii) the effects of GC dose and duration; and iii) the time course of adrenal recovery and how GCs should be withdrawn. We undertook a systematic literature review to addres...

Introduction: Prednisolone is the standard treatment for most inflammatory conditions. However, it is also used in hormone replacement therapy in adrenal insufficiency (AI) due to historical reasons or due to its longer half-life and once daily application. Recent data showed that 5 mg daily prednisolone promotes loss in bone mineral density compared to 20 mg of hydrocortisone in patients with AI questioning the 4:1 conversion rate. Data is scarce on prednisolone treated AI pa...

Introduction: Patients with subclinical Cushing’s syndrome (SCS) present with increased cardiovascular morbidity and mortality, however, the beneficial effect of adrenalectomy on cardiovascular risk factors is uncertain.Objective: Systematic meta-analysis to determine the effect of adrenalectomy vs conservative follow-up on cardiovascular risk factors in patients with adrenal tumors and SCS.Methods: We searched 6 databases thr...

Introduction: DHEA and its sulfated form (DHEAS) are the most abundant steroid in humans, produced mainly by the adrenal cortex, converted to androgens and estrogens in peripheral tissues by tissue-specific steroidogenic enzymes. There are experimental evidences indicating DHEA anti-obesity, anti-inflammatory, and anti-oxidative effects in cell lines, animal models, and human.Aim: The aim of this study was analyse the protective effect of DHEA in the ske...

Although a complex metabolic pathway for vitamin D exists, serum measurement of inactive 25-hydroxyvitamin D3 (25OHD3) continues to be the most common determinant of vitamin D ‘status’. However, several other metabolites contribute to the physiological role of vitamin D, notably the active form 1α,25-dihydroxyvitamin D (1α,25(OH)2D3), inactive 3-epi-25OHD3 and chiral 23R and 24R,25(OH)2D3 metabolites. Quantification of these additional metabolites could pro...

Background: Short Synacthen tests (SST) are inconvenient and expensive, especially since the cost of tetracosactide recently increased to over £45/ampule. Historic literature on the minimum 9 am cortisol required to avoid a SST ranges from 243 to 500 nmol/l and individual endocrinologist practice varies greatly.Methods: In an audit of all 182 SST’s from 1 year at our institution, either a previous 0900 h cortisol was recorded or the basal corti...

The adrenal cortex is the primary site of steroid synthesis, producing glucocorticoids under the control of the hypothalamic–pituitary axis and mineralocorticoids under the control of the renin–angiotensin system.Adrenal insufficiency, which can be life threatening, is cause by a number of adrenal disorders, and lifelong management of these patients with exogenous steroids can be challenging. No drug suitably mimics the diurnal pattern of corti...

Steroid-dependent patients have a lifelong dependency on replacement therapy and a lifelong vulnerability to sudden death from under treated adrenal crisis. Yet evidence about the adequacy of medical response to adrenal crisis within the UK is largely anecdotal.We invited members of the main UK support groups representing steroid-dependent patients to complete an online questionnaire identifying the frequency, causes and location of their adrenal crises ...

Steroid-dependence is a life-long condition with a risk of premature mortality from undertreated adrenal crisis, hospital omission of steroids, or running out of maintenance drugs at home. We invited members of the main UK support groups representing steroid-dependent patients to complete an online questionnaire about their experiences of adrenal crisis. Respondents (n=1042) were asked to provide demographic information that explored predisposing factors, including co...

Introduction: Hypogonadism is prevalent in older men and associated with various comorbidities. Despite this, it is underdiagnosed and undertreated.Aim: To identify factors associated with underdiagnosis and undertreatment of male hypogonadism.Methods: Quantitative, questionnaire-based, online survey conducted in the UK among men aged ≧40 years with hypogonadism confirmed by blood test (n=101, from N=3 871 ...

Introduction: Glucocorticoid (GC) replacement therapy is administered to patients with adrenal insufficiency (AI) in multiple daily doses; however, there are no consensus guidelines on the optimal regimen.Methods: The European Adrenal Insufficiency Registry (EU-AIR) is a multinational, multicentre, observational study sponsored by Shire, initiated to monitor the long-term safety of GC replacement in patients with chronic AI. We analysed baseline data to ...

Stress related cardiomyopathy or Takotsubo LV dysfunction has been described in phaeochromocytoma related cardiomyopathy.16 y female, admitted in A&E on 23 June 2013 with severe epigastric pain, vomiting and dyspnoea. History of episodes of palpitations and exertional syncopal attacks for 2 years, for which she had been investigated. Her symptoms were attributed to panic attacks. There was no known family history of Endocrinopathy. On admission, BP w...

Introduction: Congenital Adrenal Hyperplasia (CAH) is a rare genetic disorder characterised by deficiency of cortisol and/or mineralocorticoid hormones with over production of sex steroids. 21-hydroxylase deficiency is the commonest cause of CAH accounting for 95% of cases. Severe form of classic CAH occurs in 1 in 15 000 live births.Case report: A 30 year old women with CAH diagnosed at birth was on replacement with hydrocortisone and fludrocortisone. S...

A 38 year old woman was admitted with three day history of right sided chest pain, right upper abdominal pain and vomiting. She has anti-phospholipid syndrome (APS) treated with long term lower molecular weight heparin (Dalteparin) for inferior vena cava thrombosis. On presentation, she was hemodynamically stable with haemoglobin of 154 g/l, CRP 170 mg/l, white cell count 15×109/l, platelet of 90×109/l and sodium of 136 mmol/l. CXR showed consol...

: A 61-year-old gentleman was referred to the Endocrine team with acute bilateral adrenal haemorrhage. He had undergone a successful left popliteal embolectomy for critical limb ischaemia a week ago following which he was commenced on anticoagulation therapy. He presented to the Emergency Department with acute severe abdominal pain and low grade pyrexia of 37.6 C. He was haemodynamically stable. His International Normalised Ratio was noted to be elevated at 4.7. An urgent abdo...

Objective: X-linked adrenoleukodystrophy (X-ALD) is a rare, sometimes devastating disorder caused by-mainly inherited- mutations in the ABCD1 gene. Cerebral X-ALD can be prevented or modified if diagnosed presymptomatically. Mutation can lead to very long chain fatty acid (VLCFA) accumulation in adrenocortical cells, which can cause antibody negative primary Addison’s disease (ANPAD). There are recommendations that all males affected by ANPAD should have VLCFA analysis. W...

Introduction: Primary testicular lymphoma is very rare and constitutes about 2% of all extra nodal lymphomas, mostly in men above the age of 60. Bilateral adrenal masses could be due to metastatic disease, congenital adrenal hyperplasia, bilateral macro-nodular hyperplasia, adrenal adenomas, lymphomas, infiltrative diseases, amyloidosis and infections like tuberculosis. Metastasis occurs most commonly from lung, bowel, breast and pancreatic cancer. Metastasis from lymphomas is...

Introduction: We present a case which highlights the non-specific nature of the presenting symptoms of adrenal failure due to bilateral adrenal haemorrhage.Case report: A 75-year-old gentleman had an uncomplicated right total hip replacement for osteoarthritis and his warfarin for atrial fibrillation was restarted on the third post-operative day before discharge. A week later, he was admitted with watery diarrhoea and vomiting. On examination, he was cli...

Sixty seven years old lady was admitted with profound weakness and weight loss for 3–4 months. She has background of Primary hyperparathyroidism, HTN and Osteoporosis.Examination revealed BP of 175/90 mmHg, slightly plethoric with proximal myopathy and bruising. CTTAP bilateral axillary and para aortic lymphadenopathy and right adrenal adenoma 32×26 mm. CT guided biopsy which showed CLL. She was worked up f...

Case: A 32 year old with known classical 21 hydroxylase deficiency was planning her first pregnancy. She had a history of clitoral reduction and vaginal reconstructive surgery as a baby. Pre-conception control on prednisone and fludrocortisone was good: 17(OH) progesterone 8.3 nmol/l, androstenedione 9.8 nmol/l (0.7–10.8), testosterone 3.0 nmol/l (0.2–3). EUA showed a small vaginal opening and she was given vaginal dilators. She conceived successfully and was counsel...

Background: Excessive ingestion of Liquorice produces a state of apparent mineralocorticoid excess may result in sodium and water retention, hypertension, hypokalemia and suppression of the renin-aldosterone system. Yorkshire is famous for Liquorice confectionaries. In this paper we discuss about a patient with persistent hypokalemia secondary to excessive liquorice.Case report: Fifty years old lady referred by GP with one year history of hypertension on...

Autoimmune Polyendocrine Syndromes (APS) are heterogenous organ-specific autoimmune disorders affecting multiple endocrine glands, although non-endocrine organs can also be affected. We describe a 58 year old gentleman with a background of type 1 diabetes mellitus (T1DM), Addison’s disease and primary autoimmune hypothyroidism, who presented with a two day history of vomiting. He had no associated diarrhoea, abdominal pain, or fever and there was no history of recent trav...

: We present a case of 79 year old lady who presented to hospital with symptoms of polyuria and polydipsia requiring admission for level 3 care. She reported no bowel symptoms or alcohol usage. Her past medical history showed that she suffered from T2DM, Epilepsy, Asthma, Hypertension and Chronic Kidney disease. Her biochemistry revealed a combination of Hyperglycaemia, Hypokalaemia, Hypomagnesemia, Hypophosphatemia, Hyponatremia and Hypocalcaemia. Her medications revealed no ...