Endocrine Abstracts

Acute inflammation plays an important role in the normal immune system by helping to coordinate host responses to danger signals such as infection. In most cases the inflammation is rapidly resolved but in chronic inflammatory diseases such as rheumatoid arthritis (RA) the inflammation persists leading to localized accumulation of potentially damaging immune cells. It remains unclear why inflammation persists in some tissues and not in others. Recent studies have shown that st...

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. GCs are regulated at the prereceptor level by 11beta-HSDs. 11beta-HSD1 predominately displays oxo-reductase activity (cortisone/11-dehydrocorticosterone to cortisol/ corticosterone), requiring the cofactor NADPH. Recently, studies in humans have shown that the enzyme H6PDH, by generating NAPDH in the endoplasmic reticulum (ER) is crucial for oxo-reductase activity. This study ...

Glucocorticoids (GCs) are important therapeutic agents for a wide-variety of inflammatory diseases but are known to have potentially detrimental side-effects such as osteoporotic bone-loss. These effects of GCs are mediated via the intracellular GC receptor (GR) and by local GC metabolism catalyzed by 11beta-hydroxysteroid dehydrogenase (11beta-HSD). We have postulated that autocrine activation of GCs via 11beta-HSD1 plays a key role in counteracting the effects of inflammator...

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been implicated in the pathogenesis of human obesity and insulin resistance through 11-oxoreductase activation of cortisol (F) from cortisone (E) stimulating adipocyte differentiation and hepatic glucose output. In its purified state however, 11beta-HSD1 is a dehydrogenase inactivating F to E. In patients with cortisone reductase deficiency we recently identified two inactivating mutations, delta29bp and R453Q, withi...

The role of oestrogens and androgens on bone metabolism has been studied extensively. However, less is known about the effects of progestins. The progesterone receptor (PR) is expressed in human osteoblasts. Progestins have been found to stimulate osteoblast proliferation, differentiation and growth factor expression (e.g. IGFBP-5) and to increase bone formation. In postmenopausal women progestins combined with oestrogen increased bone density to a greater extent than oestroge...

Generalised and periarticular osteoporosis are common features of inflammatory arthritides. These effects appear due to high levels of pro-inflammatory cytokines. 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an intracellular enzyme that generates active cortisol from inactive cortisone and is an important determinant of the effects of glucocorticoids on osteoblasts. In vitro, osteoblastic 11b-HSD1 expression is induced by pro-inflammatory cytokines. We thus ...

The role of 11beta-HSD2 is to provide selective access of aldosterone to the mineralocorticoid receptor (MR) by inactivating cortisol. Evidence suggests impaired 11beta-HSD2 activity in some patients with hypertension but also in patients with renal disease where it may contribute to sodium retention, oedema and hypertension. To date these studies have relied upon urinary cortisol metabolite analyses as markers of renal 11beta-HSD2 activity. We have directly analysed renal 11b...

Studies in rats suggest that androgens are involved in sex-specific differences in blood pressure. In human studies there is no difference in blood pressure between boys and girls, but following puberty, men present with a higher blood pressure than women. Modulation of sodium reabsorption through the ENaC is an important component in the control of sodium balance. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohy...

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...

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...