Endocrine Abstracts

Glucocorticoids (GCs) exert a wide variety of functions throughout the human body, including mediation of the stress response, regulation of lipid and glucose metabolism, immunosuppressive and anti-inflammatory actions, vascular effects, increase of bone resorption, as well as effects on the development and function of numerous organs. The immuno-suppressive effects of GCs are routinely used in the treatment of chronic inflammatory or immune diseases (e.g. inflammatory bowel disease, asthma). However, severe side effects (including diabetes and osteoporosis) are associated with GC-treatment, limiting its therapeutic usefulness.

Within the normal population, there exists a considerable inter-individual variation in GC sensitivity. Whereas some patients develop side effects on relatively low doses of topically administered GCs, others appear to be less sensitive to GCs, as they do not show an adequate improvement in response to treatment even on high doses. Some patients are even resistant to the anti-inflammatory effects of GCs while at the same time showing side effects known to reflect normal sensitivity to GCs, including suppression of the hypothalamic-pituitary-adrenal axis. Variability in GC sensitivity can be divided into GC resistance and GC hypersensitivity.

The signaling pathway of GCs is a complex process, in which distinct pathways are involved that can influence GC sensitivity. Also, other mechanisms such as the transport, local conversion and degradation of GCs play a role in the intracellular bioavailability of GCs.

Here we will discuss the possible consequences for the clinic of genetic variation in genes involved in the GC signalling pathway, and resulting in inter-individual differences in glucocorticoid sensitivity.