An Overview of the Role of Glucocorticoids in the Pathophysiology of Endocrine Disorders
GR-induced transrepression occurs principally via a mechanism independent of DNA binding,18
with GR monomers
specifically binding to and interfering with the actions of transcription factors such as nuclear factor kappa B (NF-κB) or activating protein- 1 (AP-1).19
For example, the ability of the NF-κB p65 subunit to induce expression of pro-inflammatory mediators is suppressed by binding of GR.20
These differences are highly cell-specific and can determine GC responses, with specific genes demonstrating activation or repression depending on circumstances.
In addition to influencing gene transcription directly, GCs may also act via non-genomic mechanisms.21,22
For example, GCs promote
the cellular exportation of the anti-inflammatory protein annexin 1 from pituitary folliculostellate cells,23,24 non-genomic mechanism.24
predominantly through a Croxtall and colleagues demonstrated
that this action involves the rapid release of Src kinase from cytoplasmic GR heterocomplexes and subsequent inhibition of arachidonic acid release.25
It is also possible that some non-genomic
actions are associated with activation of a membrane-bound GR. These receptors are present in small numbers per cell, but are actively upregulated after immunostimulation. It has been suggested that overstimulation of the immune system would lead to upregulation of membrane-bound GR, which would act in a feedback manner to reduce the excessive immune reaction.26
The non-
genomic mechanisms of GC action remain poorly understood; therefore, further studies are warranted, particularly since manipulation of these events may prove therapeutically useful.
Glucocorticoids and Human Disease The clinical features associated with conditions of severe GC excess (Cushing’s syndrome) and deficiency (Addison’s disease) are well established, but these conditions are relatively rare. However, considerable evidence points to a role for GCs in the pathophysiology of numerous other endocrine-related disorders such as type 2 diabetes, dyslipidaemia and metabolic bone disease. Prolonged increases in physiological GC production are most likely to be the result of exposure to chronic stress. Alternatively, alterations in the local intracellular mechanisms that regulate the access of GCs to their receptors may cause local disturbances in GC homeostasis that influence disease processes.
Acute stress is an allostatic process that aims to restore homeostasis via adaptation, using mediators from numerous systems including the HPA axis. Chronic stress is likely to be associated with allostatic overload, where adaptive processes are used in a sustained manner. It is this prolonged inappropriate use of adaptive physiological processes that can result in dysfunction or disease. For example, increased food intake and fat deposition can be seen as an allostatic response to ensure there is sufficient metabolic resource to maintain homestatic processes, whereas in allostatic overload, this might result in abdominal obesity. Prolonged increases in cortisol due to exposure to chronic stress are likely to exact an allostatic load, with increased wear and tear apparent in certain GC-senstitive tissues, whereas decreased function will be apparent in other tissues owing to prolonged inhibitory effects of GCs or redistribution of metabolic resource to physiological systems involved in restoring homeostasis. However, it should be noted that tissue-specific alterations in GC concentrations without corresponding increases in circulating GC
EUROPEAN ENDOCRINOLOGY
recognition sites for GR can subtly alter GR transcriptional activity, suggesting that there may be gene-specific GR effects within tissues.17
levels can also influence disease processes. It is interesting to note that the high circulating levels of GCs caused by Cushing’s syndrome are associated with a number of negative metabolic outcomes,10,27 whereas near normal serum GC levels are usually found in patients with the more prevalent metabolic syndrome.28
It has been suggested
that an alteration in tissue sensitivity to GCs underlines the metabolic syndrome, specifically an alteration in the expression of 11β-HSD1. Numerous animal studies have demonstrated that 11β-HSD1 expression within metabolic tissues (e.g. adipose tissue, liver) is correlated with an adverse metabolic outcome,29–31
and metabolic
disease within humans is commonly associated with elevated 11β- HSD1 expression/activity.32,33
Therefore, tissue-specific alterations in
11β-HSD1 expression coupled with increased intracellular GC concentrations and subsequent GR activation may be a common feature of metabolic disease. It has also been demonstrated that there are a number of polymorphisms within the GC receptor gene itself that influence GC sensitivity.34–36
variants are associated with hypersensitivity to GCs37–39
Several of these GC receptor and therefore
might predispose an individual to negative health outcomes associated with GC overexposure.
The developing organism is particularly sensitive to GCs, and unwanted increases in foetal GR activation due to maternal stress or synthetic GC administration (often used in peri-natal medicine to mature the lung in conditions of pre-term birth) have the potential to induce programming effects on multiple body systems. Studies performed on laboratory animals have shown that exposure of the developing foetus or neonate to supraphysiological GC levels or synthetic GCs results in irreversible morphological and physiological changes in the organism, which predispose it in adulthood to diseases that are endemic in the developed world, such as type 2 diabetes, cardiovascular disease, depression and other mental health disorders. More limited data from clinical studies support these conclusions. The maternal–foetal unit is designed to prevent excessive foetal exposure to GCs, with placental 11β-HSD-2 acting as a barrier to the passage of maternal GCs.40–42
However, this
mechanism may become saturated if endogenous GC levels rise excessively, or can be ineffective, as is the case with synthetic GCs. A key feature of GC programming in early life is prolonged, tissue- specific change in the expression of GR. Reduced GR expression within the HPA axis leads to impairment of GC negative feedback in adulthood, leading to raised GC levels and exaggerated HPA responses to stress. Conversely, GR expression in the liver is increased, thus predisposing the individual to hyperglycaemia.
Glucocorticoids and Endocrine-related Disorders This section deals with a number of endocrine-related disorders that are associated with aberrant GC levels and in terms of pathophysiology may be linked with chronic tissue-specific alterations in GC actions.
Glucocorticoids and Hyperglycaemia/Type 2 Diabetes Patients with Cushing’s syndrome or on long-term GC therapy classically present with hyperglycaemia43,44 diabetes43
and symptoms of type 2
– in this case termed steroid diabetes. It is important to note that the development of type 2 diabetes is usually multifactorial, but this article will discuss steroid diabtetes induced by increased GC levels. GCs act within the liver to upregulate the rate-limiting enzyme for gluconeogensis, phosphoenol-pyruvate carboxykinase (PEPCK), providing a mechanism to explain GC-induced hyperglycaemia. Insulin
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