Since the late s synthetic

Since the late 1940s, synthetic GC (e.g. prednisone, prednisolone, dexamethasone) have been used extensively in the treatment of chronic inflammatory conditions such as rheumatoid arthritis and asthma, and for their immunosuppressant action in preventing organ rejection post transplantation. Corticosteroids are also used to hasten maturation of the fetal lung, thus decreasing prematurity-associated mortality and morbidity from respiratory causes (Liggins and Howie, 1972) (Crowley, 1995, Kadmiel and Cidlowski, 2013, Bolt et al., 2001). Synthetic GC have been prescribed for many years in palliative care settings for a range of reasons, although such non-specific use has been questioned (Denton and Shaw, 2014). Finally, GC exhibit anti-proliferative, pro-apoptotic and anti-angiogenic properties (Almari and Melemedjian, 2002, Nauck et al., 1998). These drugs thus represent a powerful arsenal in the treatment of multiple conditions sharing an inflammatory, allergic, neoplastic or autoimmune basis. It is well recognized, however, that long-term administration of synthetic GC comes at a cost. Synthetic glucocorticoids, unlike natural Thonzonium Bromide may not be susceptible to inactivation by 11β-HSD (e.g. dexamethasone), nor be bound by CBG. Thus, potency and metabolic clearance of the synthetic steroid can differ from that of the endogenous ligand (Kadmiel and Cidlowski, 2013), perhaps contributing to the multiplicity of adverse effects associated with prolonged and excessive exposure to exogenous GC. Undesirable effects may manifest in many body systems and include osteoporosis, muscle wasting, skin atrophy, delayed wound healing, impaired reproductive function, glaucoma, Cushing's disease (presenting as central adiposity, hyperglycaemia, hyperlipidaemia and hepatic steatosis), insulin resistance, overt diabetes, cardiovascular disease and immunosuppression (Kadmiel and Cidlowski, 2013, van Raalte et al., 2009). Of relevance to this review are also the systemic effects of hypoadrenalism whereby insufficient adrenal glucocorticoid, mineralocorticoid and sex hormone secretion is manifested in symptoms of profound lethargy, ACTH-associated skin pigmentation, hypotension, hypoglycaemia, weight loss and the inability to respond physiologically to physical and psychological stressors (Kadmiel and Cidlowski, 2013). Thus, both side effects and the phenomenon of glucocorticoid resistance represent very real therapeutic challenges.
The Glucocorticoid Receptor family Both synthetic and natural GC produce their local and systemic effects by binding to GR. Additionally, endogenous GC can act by binding to mineralocorticoid receptor (MR), and mineralocorticoids can likewise bind GR (Farman and Rafestin-Oblin, 2001). GR is also triggered by a growing range of recently discovered non-steroidal agonists (De Bosscher, 2010). GR is an intracellular protein present in almost every human cell type. It belongs to sub-class 3C of the steroid/thyroid hormone nuclear receptor superfamily (NR3C1, GR) located on human chromosome 5q31–32. It acts primarily as a ligand-dependent transcription factor capable of regulating expression of GC-responsive genes in both a positive and a negative manner (Nicolaides et al., 2010) (Ratman et al., 2013). In the absence of ligand, GR is located in the cytosol (where it is predominately found) and is affiliated with a large chaperoning protein complex that includes heat shock proteins (HSPs) 90, 70 and 50 (Schaaf and Cidlowski, 2002, Grad and Pickard, 2007) (Nicolaides et al., 2010). Once bound by ligand, the chaperoning complex disassociates to expose nuclear localization sequences. These in turn facilitate nuclear translocation of the receptor whereupon GR binds as a homodimer to Gucocorticoid Response Elements (GREs) in the promoter regions of target genes to exert its gene trans-activating or trans-repressing effects, depending on the GRE sequence and the promoter context (Ratman et al., 2013) (Kadmiel and Cidlowski, 2013, Schaaf and Cidlowski, 2002, Bamberger et al., 1996).