Endocrine Abstracts

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...

The most robust biochemical marker for the diagnosis of PCOS is hyperandrogenism (androstenedione, testosterone), thought to originate from the ovaries and/or adrenals. However the change in circulating androgen/LH ratios with increasing body mass in women with PCOS suggests the autocrine generation of androgens within adipose tissue itself. The enzyme 17beta hydroxysteroid dehydrogenase (17betaHSD) which has seven human isoforms is an important regulator of sex steroid metabo...

11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is responsible for the conversion of hormonally active cortisol (F) to inactive cortisone (E), and is expressed in mineralocorticoid target tissues (kidney, colon). However, the most abundant source of this enzyme is human placenta, notably placental trophoblast where it is thought to protect the fetus from maternal hypercortisolaemia and play a role in fetal growth and development. During gestation placental trophobla...

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)...

When used to treat inflammatory disease therapeutic glucocorticoids (GCs) cause rapid bone loss. However clinical studies suggest that in patients without inflammation GCs have little impact on the skeleton. The mechanism by which inflammation magnifies the effects of GCs is unknown. We have proposed that intracellular GC generation (inactive cortisone/prednisone to active cortisol/prednisolone conversion) via the 11 beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) enzyme d...

Glucocorticoids (GCs) play a fundamental role in the endocrinology of pregnancy but excess GC in utero may lead to IUGR. Protection against fetal exposure to GCs is provided by the enzyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) located in the placental trophoblast. By contrast, relatively little is known concerning the function of GC-activating 11beta-HSD1 which is expressed within maternal decidua. We have used human deciduas (n=32 first, n=10 second and n=...

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...