Endocrine Abstracts

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. In adipose tissue, GCs are regulated at the prereceptor level by oxo-reductase activity of 11beta-hydroxysteroid dehydrogenases type 1 (11β-HSD1). The hexose-6-phosphate dehydrogenase null mouse (H6PDH/KO) has shown that H6PDH is required for generating NADPH within the endoplasmic reticulum which determines the direction of 11β-HSD1 enzyme. We have shown that mRNA f...

Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Despite the increasing use of GCs as therapeutic agents, the molecular mechanisms that underpin the GC mediated changes in insulin signalling are not clear. The majority of previous studies have used rodent models and have shown regulation at the level of the insulin receptor (IR), IRS-1 and PI3 kinase.Primary cultures of human skeletal myocytes ...

(This poster is based on OC19)...

P450 oxidoreductase (POR) has a pivotal role as electron donor to all cytochrome P450 enzymes that are microsomally located, i.e. CYP type II enzymes. Importantly, those include key enzymes involved in glucocorticoid and sex steroid biosynthesis such as CYP17 and CYP21. In addition, the activity of hepatic CYP enzymes involved in drug metabolism and detoxification also crucially depend on the transfer of electrons from NADPH via POR. Recently, mutations in P450 oxidoreductase ...

Glucocorticoid (GC) hormone action can be modulated at the pre-receptor level by the endoluminal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). 11βHSD1 is a bidirectional enzyme that primarily acts as an oxo-reductase in vivo, converting the pro-hormone cortisone to its active form cortisol, while its dehydrogenase activity results in inactivation of cortisol to cortisone. 11βHSD1 oxo-reductase activity allows GC reactivation in a tissue s...

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...

Ion and fluid transport mechanisms within the eye are important for several key physiological processes including the maintenance of corneal transparency and the regulation of intraocular pressure (IOP). The mechanism involved in epithelial sodium transport in the eye is regulated by corticosteroids and at a pre-receptor level, by 11β-hydroxysteroid dehydrogenase (11β-HSD) activity. Recent studies localised type 1 (11β-HSD1), an oxo-reductase that activates cort...

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...