Endocrine Abstracts

End stage renal disease (ESRD) is characterised by decreased renal synthesis of 1,25-dihydroxyvitamin D (1,25D). Therapeutic use of 1,25D analogues for the management of renal bone disease is routine. However ESRD patients are also deficient in 25D (the immediate precursor of 1,25D). Since 2014 UK guidelines recommend diagnosis and treatment of 25D deficiency/insufficiency in people with chronic kidney disease, but make no recommendations for dosage or monitoring. This, togeth...

Tissue inflammation is usually transient but in diseases such as rheumatoid arthritis (RA) inflammation persists. It remains unclear why inflammation persists in some tissues and not in others. Recent studies have shown that stromal cells such as fibroblasts play a pivotal role in determining this persisitance. We have hypothesized that glucocorticoid (GC) activation via the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within fibroblasts plays a key role in ...

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3) is a potent antiproliferative agent with putative applications in the treatment of common cancers. However, doses of 1,25D3 required to achieve tangible anticancer responses also stimulate unwanted calciotropic effects. Data suggest that this is due, in part, to acquired resistance to 1,25D3 in cancer cells, particularly in more aggressive tumours. To investigate this fu...

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3) is a potent antiproliferative/immunomodulatory steroid hormone with many applications outside calcium homeostasis. This is particularly true in the placenta which can generate 1,25D3 locally via the enzyme 1alpha-hydroxylase (CYP27b) in both trophoblast and decidua. We have investigated the potential function of 1,25D3 across gestation using human tissue obtained after l...

Hypercalcaemia is a prevalent complication in malignancies as a consequence of tumor secretion of parathyroid hormone related peptide (PTHrP). This complication is also associated with ovarian dysgerminomas but is much less common than for other tumours. To investigate this further we have studied 10 cases of dysgerminoma, assessing biochemical parameters and analysing mRNA and protein expression in tissue biopsies. Pathological reports show raised serum calcium and 1,25(OH)<s...

To dissect mechanisms which result in 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) insensitivity we have compared the antiproliferative actions of 1,25(OH)2D3 in a range of malignant breast cell lines (ZR-75-1, T-47D, MCF-7, MCF-7Res and MDA-MB-231) and the non-malignant breast epithelial cells MCF-12A cells. All the malignant cell lines displayed greater resistance than MCF-12A cells to 1,25(OH)2D3. For ex...

Glucocorticoids (GCs) mediate many of their physiological effects through inhibition of cell proliferation. More contentious is the antiproliferative action of GCs and their possible tumour-modifying effects in neoplastic tissues. However, in recent studies we have shown that 'prereceptor' metabolism of GCs by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is a pivotal determinant of cell proliferation and tumour formation. Two isozymes of 11beta-HSD interconvert ...

In humans the most abundant source of 11 beta-hydroxysteroid dehydrogenase type 2 is the placenta, notably placental trophoblast. This enzyme catalyses the conversion of cortisol (F) to cortisone (E) and is thought to protect the fetus from maternal hypercortisolaemia, thereby impacting on fetal growth and development. During gestation placental trophoblast is exposed to dramatic changes in oxygen tensions ranging from ~2% - 12%, changes thought to be pivotal in stimulating an...

11beta-hydroxysteroid dehydrogenase type 1 (11B-HSD1) catalyses the inter-conversion of cortisone and cortisol, and has been implicated in the pathogenesis of a number of disorders including insulin resistance and obesity. The enzyme is a glycosylated membrane-bound protein, located in the lumen of the endoplasmic reticulum (ER) and has proved difficult to purify in an active state. Previously, we reported the successful expression and purification of human 11B-HSD1 from E. co...

The risk of bone fracture at most skeletal sites rises rapidly with age. Changes in bone mass account for only a small part of this increased risk - an additional factor is the progressive reduction in the ability to form new bone. This decrease in bone formation and increased fracture risk is reminiscent of changes seen with glucocorticoid excess, however, circulating corticosteroid levels do not change with age. We have proposed that local rather than circulating levels of c...