Endocrine Abstracts

Background: The CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes are found in close proximity on human chromosome 8 and are highly polymorphic, enabling the definition of two common haplotypes. Haplotype1 includes the -344T and the Intron2 conversion polymorphisms in CYP11B2 and also the -1889T, -1859G polymorphisms in the regulatory region of CYP11B1. We and others have shown that these associate with increased aldosterone pr...

GH/IGF1 stimulate muscle function whereas excess glucocorticoids induce myopathy. Myocytes express 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme which converts inactive cortisone to active cortisol. GH/IGF-I inhibit 11β-HSD1 expression in some tissues and thus reduce cellular glucocorticoid exposure. This suggests that anabolic actions of GH/IGF1 could be mediated indirectly through effects on 11β-HSD1. The regulation of 11β-HSD1 has be...

The corticosteroids aldosterone and cortisol are implicated in the aetiology of hypertension. The CYP11B1 and CYP11B2 genes encode 11β-hydroxlylase and aldosterone synthase; polymorphisms across the CYP11B1/B2 locus are associated with increased aldosterone production, inefficient 11β-hydroxlation and hypertension. While polymorphisms located in the promoter region of both genes may alter transcription factor binding, other variants located in th...

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=...

Dehydroepiandrosterone (DHEA) is the crucial androgen precursor and hyperandrogenaemia is a major feature in Polycystic Ovary Syndrome (PCOS). DHEA sulfate (DHEAS) is generated from DHEA by DHEA sulfotransferase (SULT2A1) activity. The conversion of DHEAS to DHEA by steroid sulfatase has been reported to be of minor significance in human adults and only desulfated DHEA can be converted toward androgens. Therefore, SULT2A1 activity represents the rate-limiting step regulating t...

In severe sepsis circulating DHEA sulfate (DHEAS) has been shown to decrease whilst serum cortisol increases. This has led to the suggestion of an intraadrenal shift from adrenal androgen towards glucocorticoid synthesis in severe stress. Patients with sepsis are therefore assumed to be DHEA deficient and have been suggested to benefit from DHEA replacement. However, only desulfated DHEA is biologically active and DHEAS and DHEA may not freely interconvert as previously though...

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...