Endocrine Abstracts

Corticosteroid therapy is associated with potentially serious side effects, but there is no information available regarding glucocorticoid requirements in adult hypopituitary patients with partial adreno-corticotrophin hormone (ACTH) deficiency.10 male adult hypopituitary patients with partial ACTH deficiency, baseline plasma cortisol > 200 nanomole/ litre but a peak stimulated cortisol < 550 nanomole/ litre, were randomised to a cross-over protoco...

There is considerable evidence to indicate that the hypothalamic-pituitary-adrenal axis is activated in obesity and that glucocorticoids may have a stimulatory effect on adipocyte leptin production. However, the precise interactions between glucocorticoids and leptin are complex and remain poorly understood. To investigate whether the glucocorticoid/leptin interaction is affected by genetic factors, we investigated the heritability of BMI, leptin and glucocorticoid metabolite ...

The objectives of this study were to assess patients' knowledge on the management of steroid replacement therapy (SRT) and explore patient satisfaction with the management and education given on SRT.The study used a quantitative before and after one group design. Self-administered questionnaires were utilised for data collection (baseline and one month after the intervention of the Patient Information Leaflet (PIS) on Managing SRT) to assess knowledge an...

18-hydroxycortisol (18-OHF) and 18-oxocortisol (18oxo-F) are derivatives of cortisol whose origin and regulation are uncertain. 18-OHF is synthesised by zona fasciculata 11-beta hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase. Levels of both steroids are increased in patients with Primary Aldosteronism. However, the origin of these steroids in normal subjects is not known.8 normal subjects and 6 subjects with primary adrenal failure performed...

Analysis of sweat is well-established for the diagnosis of cystic fibrosis and for testing for drug abuse. Cortisol, cortisone and aldosterone were identified in sweat in 1948, and the presence of 11 beta hydoxysteroid dehydrogenase type 2 in the epidermis was reported in 1990. At present there are no studies of the diagnostic value of sweat cortisol measurement. We have evaluated the use of a sweat patch comprising a small 47 by 32 mm rectangle of filter paper secured by a wa...

Dehydroepiandrosterone sulphate is a steroid product of the adrenal gland, which circulates in micromolar concentrations, but whose function is unclear. Epidemiological studies have suggested that high circulating DHEAS levels may be protective against cardiovascular disease. The present study was designed to determine whether DHEAS altered vascular cell growth using the human microvascular endothelial cell line HMEC.HMECs were grown in MCDB131 medium co...

Hepatic A-ring reduction of glucocorticoids is enhanced in obesity, perhaps contributing to compensatory activation of the hypothalamic-pituitary-adrenal axis and adrenal androgen excess. One pathway activated is the formation of tetrahydro metabolites by two sequential steps catalysed by 5beta-reductase (5bR) followed by 3alpha-hydroxysteroid dehydrogenases (3HSD). However, regulation of these enzymes is understood poorly. 5bR and 3HSD are also involved in the conversion of c...

Background: Giving patients information about steroid replacement is an inherent part of endocrinologists' and endocrine nurse roles. This information can be life saving and it is imperative that patients have not only understood the information correctly when it is given to them, but that they retain it and are able to act appropriately in times of stress and illness.Method: Following a pilot study, a questionnaire was sent to 102 patients attending the...

11Beta-Hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) catalyse the synthesis of corticosterone and aldosterone respectively in the rat adrenal cortex. Recent studies have shown that CYP11B1 and CYP11B2 are also expressed in the central nervous system (CNS) but little is known about their regulation. In this study, we have quantified CYP11B1 and CYP11B2 gene expression in the CNS following treatment with ACTH and dexamethasone.Three groups of ma...

The crucial role of vitamin D in mineral homeostasis is well known. However recent evidence has documented its importance for immunomodulation and inflammation. The kidney is the main source for the endocrine synthesis of the active metabolite 1,25-dihdroxyvitamin D3 (1,25D3), with expression of the key enzyme, 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-OHase). Our aim was to investigate the alteration of the vitamin D hormonal system in renal failure and assess the impact...

Testicular feminised (Tfm) mice bear an X-linked, single base pair deletion in the gene encoding the classical androgen receptor(1) consequently these animals express a truncated, non-functional form of the receptor protein. Affected animals (XTfmY) are rendered insensitive to actions mediated via this receptor. The Tfm mouse is therefore an excellent model for studying non-genomic testosterone signalling mechanisms. Unfortunately, Tfm mice are also deficient in the...

11Beta-Hydroxylase and aldosterone synthase catalyse the synthesis of corticosterone and aldosterone in the rat adrenal cortex and are encoded by the CYP11B1 and CYP11B2 genes respectively. These genes are also expressed in distinct regions of the CNS and cardiovascular system where they may play a key role in behavioural response and blood pressure homeostasis. However, it is unclear whether this extra-adrenal expression is regulated by, or contributes to, circulating levels ...

Radioimmunoassay of steroid hormones is widely used but in application to clinical samples the technique can give erroneous results. In the diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency raised plasma levels of 17-hydroxyprogesterone (17-OHP) are supportive evidence for the disorder. In the immunoassay of 17-OHP there are particular difficulties with the assay of plasma from neonates due to interference from steroids such as 17-hydroxypregne...

Spironolactone (Sp) is an aldosterone-antagonist diuretic, that is traditionally used in the treatment of hirsutism due to its antiandrogenic effects. Sp can inhibit ovarian and adrenal biosynthesis of androgens, compete for the androgen receptor in the hair follicle, and directly inhibit 5alpha-reductase activity. The steroid suppressive effects are so variable that the receptor-blocking action is considered the most important mechanism. It is probable for this reason that co...

Existing treatments for pituitary-dependent Cushing's Syndrome include pituitary or adrenal surgery, pituitary irradiation and medical therapy. Pituitary microsurgery is the usual therapy of first choice but is not always successful in achieving early apparent remission and is associated with significant late relapses. An effective drug therapy for humans would be a major advance as there is significant morbidity and mortality in Cushing's Syndrome. Recent elegant in vitro and...

Angiogenesis, which is tightly regulated in health and disturbed in many diseases, is inhibited by glucocorticoids. Local glucocorticoid availability within the vessel wall is determined by the pair of enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11HSD-1 and 2) that catalyse the interconversion of active glucocorticoid (corticosterone in mice, cortisol in humans) with inactive 11-dehydrocorticosterone or cortisone. We hypothesized that regeneration of active gluco...

Previous data from this laboratory has shown that lipopolysaccharide (LPS) is a direct stimulant of adrenal cortisol secretion. The present study was designed to determine the mechanism of this effect.The human adrenocortical H295R cell line was used in these studies. Cells were incubated in the presence of varying concentrations of LPS (10 to 1000ng/ml) for periods up to 24 hours. PGE2 and cortisol were measured by RIA. Indomethacin and the specific COX...

Expression of the ACTH receptor, MC2-R, is highly restricted, being detectable in the mouse only in the adrenal cortex and adipose tissue. The promoter of the murine MC2-R contains binding sites for SF-1, a transcription factor that has been shown to be essential for the transcriptional activity of a number of steroidogenic genes. However, SF-1 is not expressed in adipocytes and therefore is not essential for MC2-R expression in these cells. We have investigated the requiremen...

A number of tissues have been identified as non-classical targets of oestrogen action. Oestrogen can significantly influence the hair cycle and the human hair follicle provides an accessible tissue to investigate mesenchymal:epithelial interactions in vitro. Recently, oestrogen receptor alpha (ERalpha) and beta (ERbeta) have been identified in human hair follicle cells. Although human hair follicles vary significantly with body site, non-balding scalp follicles have not been r...

A form of congenital adrenal hyperplasia (CAH) is associated with accumulation of steroid metabolites indicating impaired 17alpha-hydroxylase and 21-hydroxylase activities. However, sequencing of CYP17 and CYP21 genes does not reveal mutations, suggesting the involvement of a co-factor interacting with both enzymes. Affected females present with ambiguous genitalia at delivery, but circulating androgens are low and virilisation does not progress, a paradox yet to be explained....

A role for local corticosteroid metabolism by 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) has been proposed in bone and adipose tissue physiology. In vivo, 11b-HSD1 predominantly converts inactive cortisone to active cortisol and enzyme activity is critically dependent on substrate concentration. To examine 11b-HSD1 activity in vivo we have analysed the relationship between serum cortisone and markers of bone turnover, BMD and adipose tissue mass in a c...

Glucocorticoids are an important adipogenic factor. In man, circulating cortisol excess causes visceral obesity, but in simple obesity glucocorticoid levels are usually normal. However, in adipose tissue cortisol availability to bind to the glucocorticoid receptor (GR) is modulated by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). Human preadipocytes display both dehydrogenase (cortisol to cortisone) and oxo-reductase (cortisone to cortisol) activity. Recent genet...

The capacity of the adrenal to produce steroids is controlled in part through the transcriptional regulation of steroid enzymes. Steroidogenic factor 1 (SF-1), an orphan nuclear receptor is thought to be central to the transcriptional regulation of all steroid hydroxylase enzymes. Recently co-regulatory proteins have been implicated in the modulation of nuclear receptor transcriptional activity. We hypothesised that classic and novel secretogogues, including forskolin, angiote...

Replacement mineralocorticoid(MC)therapy in patients with primary hypoadrenalism is titrated according to clinical and /or biochemical criteria. No single objective assessment is adequate for monitoring,though targets for plasma renin and serum electrolyte concentrations and blood pressure(BP)have been proposed.Plasma renin concentrations within the middle to upper normal range would suggest adequate MC replacement. We reviewed the case notes of 18 patients in order to identif...

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisol (F) from cortisone (E). Our recent human studies identified 11beta-HSD1 to the non-pigmented layer (NPE) of the ocular ciliary epithelium, confirming that this enzyme is integral to the physiology of aqueous humour (AH) production vital for the maintenance of intraocular pressure (IOP). 11beta-HSD1 has also been implicated in the pathogenesis of obesity, and our previous data have defined this enzyme i...

The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain, which then drains principally into the dural sinuses. The balance between production and drainage, in part, facilitates a normal intracranial pressure. The secretion of sodium and anions by the CP, creates an osmotic gradient driving the movement of water into the ventricles. This mechanism is analogous to that found in the ocular ciliary ep...

The risks of over and under-replacement with glucocorticoid replacement therapy are well-known. In an attempt to minimise these risks cortisol day curves (CDC) are performed in many centres, however there is a dearth of data on the reproducibility of this assessment and the relationship between symptoms and serum cortisol levels. To address these issues, we have performed 2 cortisol day curves within 7 days in 20 patients (9 male, mean age 54 years, range 25-79, 6 primary and ...

Renal sodium handling and responses to aldosterone (aldo) are conserved across species and intrinsic to the dominant role of the kidney in long-term blood pressure (BP) control. Molecular pathways involved in hypertensive responses to aldo and escape from these remain largely unclear despite identification of several participant genes. We have characterized renal gene expression changes in mice, receiving aldo and/or dietary salt excess, using microarray analysis and concurren...