Endocrine Abstracts

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF1 remain uncertain. The West Midlands Acromegaly database contains details of 419 patients (178 males). Serum IGF1 data from the Regional Endocrine Laboratory was available for 338 patients (81%). At diagnosis mean age was 47 years (range 12-84) and mean GH was 70plus/minus5.4 milliunits per litre. 61% were treated by surge...

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 ...

It is now evident that ghrelin is more than just a growth hormone (GH) secretagogue; it plays an important role in energy homeostasis, increasing food intake and fat deposition, has cardiovascular effects, and inhibits cell proliferation.Ghrelin mRNA expression is widespread in human tissues, but little is known about the molecular mechanisms and signals that regulate gene expression at the transcriptional level. To address this we cloned and sequenced a 4kb region upstrea...

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...

Patients with Cushing's syndrome develop florid, but reversible central obesity. However, circulating cortisol levels are not elevated in simple obesity. Within human adipose tissue, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is highly expressed and converts inactive glucocorticoid, cortisone to active cortisol. Rodents over-expressing 11beta-HSD1 in adipocytes develop central obesity exclusively as a result of increased adipocyte size. Whilst it has ...

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 central obese phenotype characteristic of Cushing's syndrome emphasises the role of glucocorticoids (GC) in regulating adipose tissue mass and distribution. We have shown that GCs stimulate adipocyte differentiation, but equally inhibit adipose stromal cell (ASC) proliferation. These effects are regulated at a pre-receptor level through 11beta-hydroxysteroid dehydrogenase type 1, but the 'post-receptor' signalling pathways remain unclear. To define novel GC targets in huma...

Ghrelin, the natural ligand for the GHS-R, modulates proliferation in cell lines derived from malignant breast tissue. It has been suggested that this action is independent of the GHS-R. We have previously demonstrated that MCF7 cells expressed ghrelin but not GHS-R mRNA and MDA-MB231 cells expressed GHS-R but not ghrelin mRNA. To determine whether ghrelin modulates proliferation in MCF7 and MDA-MB231 cells we performed proliferation assays treating with saline, 1 and 10nM ghr...

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...