Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol

Synthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this moment is to develop insights into the cause of the differences in the response between individuals to therapeutically applied GCs. Some patients respond to low doses, with or without side effects, while others do not respond at all. This thesis discusses a number of possible explanations for these differences in GC sensitivity and is focused on genetic, but also on transcriptional and translational aspects of the GR gene. Furthermore, it is also described how glucocorticoid sensitivity disorders can be characterized clinically and biochemically. An important tool in these studies has been a newly developed bioassay, measuring cellular GC sensitivity ex vivo, based on GR action at the transcriptional level by studying GC-regulated mRNA expression (chapter 2). Various polymorphism in the GR gene (N363S, ER22/23EK, and 9beta) are shown to affect GC sensitivity in vivo and in/ex vitro and result in a wide variety of phenotypic signs (chapters 3, 4, and 5). Furthermore, studies described in chapter 4, 5, 6, and 7 have demonstrated that also transcriptional and translational variants of the GR and the use of different promoters could modulate GC sensitivity. These factors modulating inter- individual sensitivity to GCs may have consequences for the use of GCs in a clinical setting. When treating patients with GCs, they need an individually determined optimal dose to obtain a balance between beneficial and adverse effects.