Endocrine Abstracts

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been implicated in the pathogenesis of human obesity and insulin resistance through 11-oxoreductase activation of cortisone (E) to cortisol (F) within the endoplasmic reticulum (ER) of adipocytes and hepatocytes. In its purified state 11beta-HSD1 is principally a dehydrogenase, converting F to E. Oxo-reductase activity can be regained by the addition of an NADPH regeneration system. In vivo hexose-6-phosphate ...

Triple A syndrome is is a rare autosomal recessive disorder characterised by achalasia, alacrima, adrenocorticotropin-resistant adrenal insufficiency and a variable and progressive neurological phenotype. The AAAS gene encodes a 60kD WD-repeat nuclear pore protein named ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder); its function and tissue distribution are unknown. In this study we performed in situ hybridization with 35S end-labelled AAAS mRNA oligon...

Recently, evidence has emerged that active 1,25dihydroxyvitamin D3 (1,25D3) is involved in modulating the immune response. Additionally, vitamin D3 insufficiency has been proposed as a predisposing factor for autoimmune diseases, which correlate with circulating inactive 25-hydroxyvitamin D3 (25D3). Substrate 25D3 is converted to 1,25D3 by the activating enzyme 1alpha-hydroxylase. We and others have p...

Glucocorticoid sensitivity is dependent on the intracellular concentration of the glucocorticoid receptor (GR). GR expression is regulated in a complex, cell-type specific manner, but in most cell types the GR is subject to negative autoregulation by glucocorticoid exposure. Many human diseases are associated with reduced tissue sensitivity to glucocorticoids, including inflammatory arthritis, asthma, and chronic obstructive pulmonary disease. Therefore there is interest in ap...

We have shown that linked polymorphisms in the aldosterone synthase gene (CYP11B2) are associated with hypertension and altered aldosterone production. However, the most consistent intermediate phenotype associated with this genetic variation is increased plasma 11-deoxycortisol (S) and urinary excretion of its metabolite, tetrahydrodeoxycortisol (THS); this is paradoxical as S is a substrate for the enzyme 11beta-hydroxylase, encoded by the neighbouring gene, CYP11B1. However...

The human adrenal H295R cell line expresses ACTH receptors (MC2R). However, it is generally accepted that ACTH treatment of these cells has little effect on steroid secretion and so forskolin is routinely used to mimic the actions of ACTH. It is unclear whether the ACTH receptors on these cells are functional. The present study was designed to investigate signalling pathways in H295R cells and their activation by ACTH.Adrenal H295R cells were cultured in...

Objective: The aim of this study was to determine dosing regimen to replace testosterone to physiological levels in the testicular feminised (Tfm) mouse, and also to produce similar supraphysiological testosterone concentrations in Tfm and XY littermates.Methods: Eight-week-old Tfm (n=66) and XY littermate controls (n=24) received a single 10 microlitre intramuscular injection of testosterone (Sustanon 100 - 100 milligrams testosterone per litre, or Sust...

Background: The action of a steroid in any physiological process is dependent on the bioavailable (free) fraction. Direct measurements of free cortisol are expensive, labour intensive and require a significant volume of plasma and as a consequence are not feasible in the neonate. One alternative is to calculate free cortisol from the Cortisol Binding Capacity (CBC) and the total plasma cortisol. The aim of the present study was to develop an assay for the measurement of CBC in...

WNK1 and WNK4 are serine/threonine kinases, With-No-K (lysine) residue at a key catalytic position within the active site. Mutations in either cause Pseudohypoaldosteronism type II (Gordon syndrome), an autosomal dominant, hypertensive, hyperkalaemic disorder, especially responsive to thiazide diuretics (first line treatment for essential hypertension). This novel WNK pathway is implicated in normal regulation of blood pressure (BP) and distal nephron Na+/K+</s...

The kidney plays a dominant role in long-term blood pressure (BP) control and electrolyte homeostasis but aldosterone (aldo) responsive molecular pathways in the kidney involved in regulating BP remain poorly understood despite identification of several participant genes. Many human single gene disorders affecting BP have been faithfully reproduced in mice by targeting the corresponding genes. Thus mouse is an excellent model to study molecular pathways underlying hypertension...

The N-terminal fragment of human POMC consists of a 76 residue peptide (also known as pro-gamma-MSH) that contains the sequence of gamma-MSH in its C-terminus. Previous studies have demonstrated that the N-terminal portion not containing the gamma-MSH sequence is a potent adrenal mitogen while gamma-MSH itself can act synergistically with ACTH to increase steroid output.Since previous studies [1] have suggested that N-POMC 1-28 can stimulate the ERK path...

Case reports in humans implicate glucocorticoid (GC) excess, through exogenous administration or endogenous overproduction, as a cause of non-alcoholic fatty liver disease. In rodents, massive doses of GCs have induced fatty liver when liver fat was measured in the fasting state. The mechanisms through which GCs might induce fatty liver are unknown, but are thought to be secondary to insulin resistance/hyperinsulinaemia. In this study, we examined the effect of dexamethasone (...

Primary adrenal insufficiency is a relatively rare endocrine condition requiring life-long glucocorticoid and mineralcorticoid replacement therapy. Unlike other endocrine conditions - such as diabetes - complications associated with early mortality are unusual and well-medicated patients can expect to have a normal life span. Nevertheless, patients typically report a variety of symptoms which reduce their quality of life.Data from an international survey...

Biochemical assessment of control of CAH includes measurement of adrenal-derived androgens in blood. Some androgens like 17-hydroxyprogesterone (17OHP) have a diurnal rhythm and show a widespread of values in well controlled children. Testosterone in children (except pubertal boys) may be useful in monitoring control as it may reflect the potential for androgen action better than weaker androgens. Our salivary testosterone (SalT) assay measures free testosterone and is sensiti...

During the luteal phase of the menstrual cycle aldosterone increases mainly due to the antagonistic properties of progesterone at the MR and due to estrogen-mediated stimulation of angiotensinogen. Little is known about other steroid-metabolizing enzymes that may influence steroid receptor binding, eg 11beta-HSDs, A-ring reductases. Therefore a group of ten normotensive female volunteers with regular menstrual cycles were studied on day 7 (follicular phase) and day 21 (luteal ...

Background: An elevated plasma aldosterone to renin ratio (ARR) is widely accepted as being important for the detection of primary hyperaldosteronism. The ability to measure renin at extremely low concentrations is the most critical factor in determining the diagnostic reliability of the ARR. We carried out this study to establish a reference interval for the ARR as part of an evaluation of a new automated platform for the simultaneous measurement of aldosterone (PAC) and dire...

Overt primary adrenocortical failure is preceded by several stages of subclinical hypoadrenocorticolism. Individuals with type 1 diabetes (T1D) or who have other autoimmune conditions are at risk for the development of Autoimmune Addison's disease (AAD). These at risk individuals can be identified by the detection of adrenal autoantibodies (AAb).The aim of this study was two fold: firstly, to evaluate the sensitivity of early morning cortisol: ACTH ratio...