Endocrine Abstracts

Glucocorticoids (Gc) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to treatment between individuals and over time. Generating a reversible model of Gc resistance in vitro that will mimic the cellular microenvironment in vivo is critical in (i) defining biomarkers that predict patient steroid responsiveness; (ii) provide a model to screen new GR modulators capable of potentiating GR ...

The potent effects of glucocorticoids (GCs) upon carbohydrate metabolism are well described. However, their actions upon lipid metabolism are poorly characterized. Patients with GC excess (Cushing’s syndrome) develop central obesity, insulin resistance and hepatic steatosis in up to 20% of cases. The A-ring reductases (5α-reductase type 1 [5αR1] and type 2 [5αR2]), inactivate cortisol as well as generate dihydrotestosterone (DHT) from testosterone (T) and a...

Glucocorticoids (GCs) are used extensively in the treatment of inflammatory disease. Unfortunately, as GC act on virtually every organ system they also carry a broad range of serious side-effects which limits their clinical use.The structure of the bound GC strongly impacts the final conformation of the glucocorticoid receptor (GR) and thereby dictates downstream events. Designing drugs with different GR binding properties therefore offers a plausible ro...

Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease. Several new therapies exist for RA but long-term patient management remains problematic.We have discovered that hypoxia, a characteristic of inflamed tissues, potently inhibits glucocorticoid (Gc) sensitivity. This effect is mediated, in part by HIF1α, whose activity is induced in hypoxia. HIF1α gene expression is also induced in primary peripheral blood mononuclear ce...

Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Although there is a strong inverse correlation between intramuscular triglyceride (IMTG) levels and insulin sensitivity, the impact of glucocorticoids upon the processes that regulate skeletal muscle lipid metabolism has not been explored.Mouse C2C12 skeletal myocytes were grown to confluence and differentiated into myotubes in chemically defined medi...

Pregnancy complications such as fetal growth restriction are associated with abnormal placental cell (cytotrophoblast) proliferation and apoptosis. Regulation of these events is unclear but recently we have used a placental explant model to demonstrate that IGFs influence cytotrophoblast kinetics and demonstrated that the protein tyrosine phosphatase (PTP) SHP-2 is required for IGF actions in the placenta. However, SHP-2 accounts for only 20% of total PTP activity, suggesting ...

Clinical guidance recommends titrating the dose of metyrapone against serum cortisol concentrations. These serum samples are usually measured by immunoassays; however it has been well documented that there are interferences in these assays in patients with altered steroid metabolism due to a pathological process or drug treatment. The increasing availability of mass spectrometry (MS) assays for steroid hormones may circumvent this issue and assays that measure multiple steroid...

Testosterone, androstenedione and DHEAS are commonly measured by immunoassays. Variations in antibody specificity and calibration of assays results in non-commutability of measurements. Even more specific mass spectrometry (LC–MS/MS) assays still exhibit differences in calibration. As the use of mass spectrometry for measuring steroids is becoming more common in the clinical laboratory, the development of LC–MS/MS reference ranges for these analytes is essential to h...

Cofactors of the nuclear hormone receptors are crucial in regulating their transcriptional activity. The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily, involved in the regulation of metabolism, inflammation and stress–responses and many GR cofactors are known, including p300. Here, we identify a new cofactor for GR: TTC5/Strap, tetratricopeptide repeat domain 5/ stress–responsive activator of p300. Strap is a TPR motif containin...

Although glucocorticoids (Gc) are used to treat a range of pathologies, an individuals response to therapy varies considerably. There is a distinct correlation between certain cell types and steroid sensitivity. Aberrant glucocorticoid receptor (GR) function is well-characterised in lymphoid malignant cells but not small cell lung cancer (SCLC) (DMS79) or osteosarcoma (U2OS) cell lines, which are both Gc resistant.Previously we have shown reduced GR cont...