Endocrine Abstracts

Short synacthen tests (SST) are used to investigate patients with suspected HPA pathology and a rise of serum total cortisol > 550nmol/L is accepted as demonstrating sufficient cortisol reserve. However, cortisol is 80% bound to cortisol binding globulin (CBG) and therefore abnormal values of CBG can influence serum total cortisol used to interpret dynamic tests of the HPA axis. The free cortisol index (FCI) is a surrogate marker for serum free cortisol and is defined as s...

Sodium transport across the human ocular non-pigmented ciliary epithelium (NPE) is fundamental to the production aqueous humour and maintenance of intraocular pressure. In sodium transporting tissues, serum and glucocorticoid regulated kinase isoform 1 (SGK1) has been identified as an early corticosteroid target gene in the activation of pre-existing epithelial sodium channels (ENaC). We previously demonstrated the presence of both the mineralocorticoid (MR) and glucocorticoid...

Our recent studies have localised 11 beta hydroxysteroid dehydrogenase type 1 (11 beta HSD1), which activates cortisol from cortisone, to the human ocular non-pigmented ciliary epithelium, and in an open blinded study conducted on healthy male volunteers, systemic inhibition of this isozyme with oral carbenoxolone (CBX) resulted in a 17% reduction of intraocular pressure (IOP). The aim of this study was to evaluate whether CBX reduced IOP in patients with ocular hypertension (...

Male hypogonadism can occur either due to disorders at the hypothalamic or pituitary levels or as a result of primary testicular failure. Conventionally, testosterone is replaced by depot intramuscular injections of testoterone esters or as implants producing non-physiological levels of serum testosterone. Human chorionic gonadotrophin (hCG) given twice-weekly s.c., stimulates endogenous testosterone secretion through its LH like action resulting in physiological serum testost...

Background: The adverse effects of corticosteroid therapy are similar to those of endogenous glucocorticoid excess. Previous studies have established the usage patterns of oral corticosteroids in the primary healthcare setting, but these have concentrated on corticosteroid-induced osteoporosis. The aim of this study was to investigate the prevalence and morbidity of long-term oral corticosteroids in a General Practice setting.Methods: From a population ...

BACKGROUND: We have previously shown that men with coronary artery disease (CAD) have lower serum bioavailable testosterone levels than men with normal coronary arteries and this may have detrimental effects in coronary disease. It has been suggested that low androgen levels in men with CAD could be accounted for by the high prevalence of statin therapy and other factors such as smoking. We investigated the effects of statin therapy and smoking on testosterone in men with CAD....

BACKGROUND: Previous work has demonstrated a relationship between impaired carbohydrate metabolism and low serum levels of androgens in men. Men with diabetes have lower testosterone levels, and administration of physiological doses of testosterone improves glucose tolerance in these men. Men with coronary artery disease (CAD) have lower androgen levels than men with normal coronary arteries. We studied the relationship between testosterone, glucose, hypertension and DM in a p...

Objectives: Pro-inflammatory cytokine levels are elevated in heart failure and have been implicated in disease progression. Testosterone has been shown to have anti-inflammatory properties and plasma levels may be reduced in men with heart failure. We studied the relation of endogenous testosterone with plasma cytokines in men with chronic heart failure and the effects of testosterone administration.Methods: Baseline plasma levels of total and bio-avail...

Objectives: Testosterone deficiency has been associated with depressive symptoms, which may be improved by replacement therapy. Patients with chronic heart failure have a high prevalence of depression, which is associated with early mortality in these patients. Men with heart failure may also have low plasma levels of testosterone, which could contribute to depressed mood. In a clinical study investigating whether testosterone treatment benefits men with heart failure, patient...

Background: Testosterone has been shown to have anti-inflammatory properties and may suppress production of pro-inflammatory cytokines. In this study, we examined the effects of testosterone on the ex-vivo production of the anti-inflammatory cytokine interleukin- (Il-)10 in whole blood from hypogonadal men.Method: 16 men with new diagnosis of hypogondism were studied. Mean age was 61.7 (2.9) years, plasma total testosterone was 6.4 (0.4) nM. Blood was c...

Objectives: Patients with chronic heart failure (CHF) almost universally complain of exercise intolerance due, in part, to alterations of skeletal muscle. In men, testosterone is an important determinant of muscle bulk and strength. Relative androgen deficiency in men with CHF could contribute to exercise intolerance. We studied the relationship between plasma levels of testosterone and measures of skeletal muscle bulk and strength and exercise capacity in men with CHF.<p ...

J. Q. presented initially at age 2 years with hypoglycaemia following a six-hour fast prior to an elective surgical procedure. Investigations demonstrated a low plasma glucose (1.6mmol/l), elevated beta Hydroxybutyrate (5.2 mmol/l), normal lactate (1.09nmol/l) and a detectable serum insulin level (2.5 mU/L). A plasma amino-acid profile was normal. The dorsum of his hands and the extensor region of his arms were noted to be pigmented, however a synacthen test at that time, ind...

A 61 year old woman presented with a six months history of nausea, vomiting and lethargy. She is a non-smoker and drinks little alcohol. She was on 100mcg of Thyroxine following partial thyroidectomy. Physical examination was unremarkable apart from postural hypotension (BP 140/80mmHg laying, 105/75mmHg standing). Blood tests showed plasma sodium of 121mmol/L with normal potassium, urea, creatinine, FBC, random glucose and TFTs. A short synacthen test (1mcg) was normal with a ...

Central obesity is associated with increased morbidity and mortality. Pre-adipocyte proliferation and differentiation contribute to increases in adipose tissue mass, yet the mechanisms that underpin these processes remain unclear. Patients with glucocorticoid excess develop central obesity, but circulating cortisol levels in idiopathic obesity are normal. The enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive cortisone (E) to active cortisol (F)...

Obesity is associated with hypothalamic-pituitary-adrenal (HPA) axis activation. In obese humans and leptin-resistant obese Zucker rats, we have reported increased excretion of A-ring reduced glucocorticoid metabolites. We have now investigated regulation of hepatic A-ring reductases in the obese Zucker rat.Lean and obese Zucker rats (9wks) were studied either: 3-weeks after adrenalectomy (ADX) or sham surgery; or after 3-weeks treatment with metformin ...

The key enzymes in the terminal stages of human adrenal gland corticosteroid biosynthesis are aldosterone synthase (AS) and 11beta-hydroxylase (11beta-OHase). Their amino acid sequences differ by only 7% but they exhibit markedly different enzymatic activities. AS is expressed solely in the zona glomerulosa and converts 11-deoxycorticosterone (DOC) to aldosterone whereas 11beta-OHase is expressed mainly in the zona fasciculata and produces cortisol from 11-deoxycortisol. The 3...

Glucocorticoids are potentially important in obesity; recent data suggest both circulating levels and tissue-specific changes in glucocorticoid responsiveness and metabolism may influence their effect. In obese Zucker rats, the phenotype is ameliorated by adrenalectomy, and shows the same pattern of altered glucocorticoid metabolism as in human obesity. However, previous reports suggest hepatic glucocorticoid receptor (GR) binding is impaired. We have now explored expression o...

Corticosteroids are major contributors to normal blood pressure control and to hypertension. The diagnosis of 'primary aldosteronism' based on raised aldosterone: renin ratios is now common although demonstration of an adrenocortical tumour remains rare. Moreover, the relationship between aldosterone and renin or angiotensin II in essential hypertension is often disturbed, suggestive of altered control of aldosterone biosynthesis. Aldosterone is synthesised from 11-deoxycortic...

The adrenal cortex produces aldosterone, cortisol and adrenal androgens. ACTH regulates the production of both cortisol and adrenal androgens. However there are physiological and pathophysiological conditions where the production of these steroids is divergent. We examined the effect angiotension II (A-II) and insulin on the relative production of cortisol and adrenal androgens in the human adrenal H-295 cell line. We determined the ability of these secretogogues to regulate t...

The adrenal cortex produces aldosterone, cortisol and adrenal androgens in response to secretogogues including ACTH, angiotensin II(A-II) and insulin. Differential regulation of adrenal steroids is through the modulation of specific key steroidogenic enzymes. The capacity of the adrenal to produce cortisol is controlled in part by the transcription of 3beta-hydroxysteroiddehydrogenase (3beta HSD) and production of adrenal androgens by 17 hydroxylase/17-20 lyase (CYP17). Protei...

Patients with obesity are relatively Growth Hormone (GH) deficient. GH has potent effects on adipocyte biology, stimulating lipolysis but also promoting pre-adipocyte proliferation. Conversely, we have shown that cortisol inhibits pre-adipocyte proliferation and enhances differentiation. Furthermore, GH, acting through IGF-1, inhibits 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which converts the inactive glucocorticoid, cortisone (E) to active cortisol (F) in ad...

A South Asian woman aged 44 years presented with longstanding hirsutism. Her periods had always been regular and she had two children. She had been treated with spironolactone and Dianette without clinical benefit and the hirsutism was managed cosmetically. Investigations showed a high serum testosterone of 6.1 nmol/l ( 1-3nmol/l) and androstenedione 25nmol/l (2-10nmol/l). Serum sex hormone binding globulin was elevated at 96 nmol/l (23-85nmol/l), with normal DHEA sulphate, 4....

AIMS: Postmenopausal oestrogen replacement therapy (ERT) has been shown to lower serum insulin-like growth factor 1 (IGF-1) levels, requiring the use of higher doses of growth hormone (GH) replacement. Soy derived phytoestrogens (PE) are in widespread usage as a natural alternative to ERT. No data exists on the effects of PE on serum IGF-1 levels. The aim of this pilot study was to determine the effects of Phytoestrogen dietary supplementation on the serum IGF-1 level in postm...

Background: Testosterone acts as a coronary vasodilator, and improves myocardial ischaemia in men with coronary artery disease. The dilatory mechanism of testosterone is independent of the classical androgen receptor and also of the release of endothelial-derived vasodilators. The aim of the present study was to determine whether testosterone has any demonstrable calcium antagonistic action, and if so to determine whether this is via inhibition of voltage-operated calcium chan...

Background: Testosterone is a coronary vasodilator, and improves myocardial ischaemia in men with coronary artery disease. The dilatory mechanism of testosterone is independent of the classical androgen receptor and endothelial-derived vasodilators. The aim of this study was to determine whether testosterone increases cAMP production in vascular smooth muscle cells (VSMCs) derived from the primary culture of rat thoracic aortae or in a VSMC cell line (A7r5).<p class="abste...

Background: The testicular feminised (Tfm) mouse exhibits an X-linked single base-pair deletion in the gene encoding the androgen receptor. Gene transcription produces a truncated form of the receptor protein, which has a conformational change in the androgen binding site, preventing androgen binding. Affected male animals (XTfmY) are rendered androgen insensitive and 17-alpha hydroxylase deficient, a key enzyme in the steroidogenesis pathway. XTfmY males have reduced circulat...

Objective. Recent studies suggest that in utero programming of the hypothalamo-pituitary-adrenal axis is important in explaining the link between small size at birth and adult cardiovascular disease. We therefore examined the relationship between adult cortisol concentration and measurements at birth.Subjects. 420 men and women (mean age 69.5, range 65.0-75.8 yrs) born and living in Helsinki, Finland, with detailed birth records.<p class="ab...

Epidemiological studies of postmenopausal women on oral oestrogen replacement therapy (ERT) show a reduction in the risk of developing colon carcinoma. Our previous study demonstrated that 17beta-oestradiol (E2) induced apoptosis in COLO205, a colonic cancer cell line. The aim of this study is to identify the genes important in the E2-induced apoptosis. cDNA array analysis 24h post E2 treatment showed a decrease in mRNA of erbB3 of 92%, K-RAS of 83% and p68TRK-T3 of 98% wherea...

Towards the end of pregnancy, when maternal steroidogenesis is stimulated, the fetal adrenal gland undergoes significant developmental changes. To test responsiveness to external stimuli at this stage, we fed pregnant rats with diets containing 0.03% (low), 0.3% (normal) or 3% (high) sodium to manipulate aldosterone synthesis. Dietary sodium variations had no deleterious effects on numbers or weights of foetuses at embryo day 20. Maternal adrenal weights were unaffected by die...

Objectives: Aldosterone synthase catalyses the synthesis of aldosterone in the adrenal zona glomerulosa and is encoded by the CYP11B2 gene. Recent studies have shown that the CYP11B2 gene is also expressed in the rat central nervous system (CNS), particularly the cerebellum and hippocampus, suggesting local corticosteroid production. The renin-angiotensin system regulates the expression of the CYP11B2 gene in the adrenal cortex. However, little is k...

There have been few reports of long term remission rates after transsphenoidal surgery for Cushing's disease which incorporate both initial failure rates and later relapse rates. We have studied this in patients diagnosed and treated between 1979 and 2000. An early post-operative 0800h serum cortisol was measured 24h after the last dose of hydrocortisone, in addition to a low dose dexamethasone suppression test. Of the initial 63 patients, 18 did not achieve remission after su...

Metyrapone is a potent inhibitor of the conversion of 11-deoxycortisol (11-DOC) to cortisol and is used in the treatment of Cushing's syndrome. This study has assessed the clinical significance of 11-DOC cross-reaction in five serum cortisol assays provided on automated immunoassay analysers. Cross-reaction was determined from the linear regression of increase in measured cortisol against increasing levels of 11-DOC (0, 1590, 4310, 6490, 7040 nmol/L) added to a serum pool. In ...