Glucocorticoids: Exemplars of multi-tasking

Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith W12 0NN.
British Journal of Pharmacology (Impact Factor: 4.84). 02/2006; 147 Suppl 1(S1):S258-68. DOI: 10.1038/sj.bjp.0706456
Source: PubMed


Well over 80 years ago Philip Smith described the beneficial clinical effects of adrenocortical extracts in animal models of adrenal insufficiency. In the ensuing years, scientists across the globe have sought to understand the mechanisms by which adrenal hormones and their synthetic analogues produce their complex and varied actions. Particular attention has focused on the glucocorticoids, partly because they have a vital place in the treatment of inflammatory and autoimmune disorders but also because dysregulation of the secretion and/or activity of endogenous glucocorticoids is increasingly implicated in a number of common disorders that pose a growing clinical burden, such as obesity, type II diabetes, the metabolic syndrome, hypertension and depression. This review considers some of the key advances that have been made in our understanding of the physiology, pathology and pharmacology of the glucocorticoids. Emphasis is placed on the molecular mechanisms of glucocorticoid signalling and the complex mechanisms that regulate the access of steroids in the systemic circulation to their receptors in their various target cells and tissues. In addition, consideration is given to the irreversible ‘organisational’ actions of glucocorticoids in perinatal life and to the potential role of the steroids in the aetiology of disease.
British Journal of Pharmacology (2006) 147, S258–S268. doi:10.1038/sj.bjp.0706456

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Available from: Julia Buckingham, Sep 22, 2014
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    • "Glucocorticoids are multitasking molecules (Julia, 2006) that influence almost all physiological functions including reproduction (Saplosky et al., 2000). Dex, a commercially available synthetic glucocorticoid, acts primarily as a potent anti-inflammatory (Barnes, 1998) and immunosuppressive (Franchimont, 2004) drug in clinical conditions namely chronic asthma (Barnes, 1998), rheumatoid arthritis (Kirwan , 1995; Laan et al., 1999), autoimmune diseases (Chatham & Kimberly, 2001) and prevention of graft rejection (Almawi et al., 1998). "
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    ABSTRACT: This study investigated the protective effect of melatonin on dexamethasone (Dex), an extensively used anti-inflammatory and immunosuppressive synthetic glucocorticoid, induced testicular oxidative stress and germ cell apoptosis in golden hamster. Hamsters were randomly divided into four groups (n = 7): group I – control; group II – melatonin treated (10 mg kg−1 day−1); group III – Dex treated (7 mg kg−1 day−1) and group IV – combination of Dex and melatonin. All the injections were administered intraperitoneally for seven consecutive days. The histopathological changes, specific biochemical markers, including antioxidative enzymes, plasma melatonin level and the markers for germ cell apoptosis were evaluated. Dex administration decreased antioxidant enzyme activities (SOD, CAT, GSH-PX), plasma melatonin level and melatonin receptor (MT1) expression with a concomitant increase in lipid peroxidation (TBARS) and altered testicular histopathology which might culminate into increased germ cell apoptosis as evident from increased Bax/Bcl-2 ratio and caspase-3 expression. However, melatonin pre-treatment enhanced enzyme activities for SOD, CAT, GSH-PX with a simultaneous decrease in Bax/Bcl-2 ratio and caspase-3 expression. Our findings clearly suggest that melatonin improved defence against Dex-induced testicular oxidative stress and prevented germ cell apoptosis, suggesting a novel combination therapeutic approach for management of male reproductive health.
    Andrologia 10/2014; 47(8). DOI:10.1111/and.12357 · 1.63 Impact Factor
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    • "The physiological stress response is typically thought of as an activation of the sympathetic nervous system in order to mount immediate effects on metabolic, cardiovascular and immune systems; this is closely followed by activation of the hypothalamo–pituitary– adrenal (HPA) axis to increase circulating levels of glucocorticoids (cortisol in humans; corticosterone in rodents) (Buckingham, 2006). These glucocorticoid hormones support and prolong physiological stress responses, which are protective, enabling the individual to survive the stressor. "
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    ABSTRACT: The knowledge that diverse populations of dopaminergic neurons within the ventral tegmental area (VTA) can be distinguished in terms of their molecular, electrophysiological and functional properties, as well as their differential projections to cortical and subcortical regions has significance for key brain functions, such as the regulation of motivation, working memory and sensorimotor control. Almost without exception, this understanding has evolved from landmark studies performed in the male sex. However, converging evidence from both clinical and pre-clinical studies illustrates that the structure and functioning of the VTA dopaminergic systems are intrinsically different in males and females. This may be driven by sex differences in the hormonal environment during adulthood ('activational' effects) and development (perinatal and/or pubertal 'organizational' effects), as well as genetic factors, especially the SRY gene on the Y chromosome in males, which is expressed in a sub-population of adult midbrain dopaminergic neurons. Stress and stress hormones, especially glucocorticoids, are important factors which interact with the VTA dopaminergic systems in order to achieve behavioral adaptation and enable the individual to cope with environmental change. Here, also, there is male/female diversity not only during adulthood, but also in early life when neurobiological programing by stress or glucocorticoid exposure differentially impacts dopaminergic developmental trajectories in male and female brains. This may have enduring consequences for individual resilience or susceptibility to pathophysiological change induced by stressors in later life, with potential translational significance for sex bias commonly found in disorders involving dysfunction of the mesocorticolimbic dopaminergic systems. These findings highlight the urgent need for a better understanding of the sexual dimorphism in the VTA if we are to improve strategies for the prevention and treatment of debilitating conditions which differentially affect men and women in their prevalence and nature, including schizophrenia, attention/deficit hyperactivity disorder, autism spectrum disorders, anxiety, depression and addiction.
    Neuroscience 06/2014; 282. DOI:10.1016/j.neuroscience.2014.05.033 · 3.36 Impact Factor
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    • "In the context of stress, the most important glucocorticoid in humans is cortisol (Groeneweg et al. 2011). Cortisol plays a critical role in regulating cardiovascular , metabolic, and immunologic changes during stress (Buckingham 2006; Dhabhar 2009), and homeostatic mechanisms exist to limit the extent and duration of cortisol's catabolic actions. The most obvious of these homeostatic mechanisms involves negative feedback regulation by glucocorticoids , via stimulating hippocampal, hypothalamic, and pituitary glucocorticoid receptors to inhibit further secretion of ACTH and CRH, thereby terminating the HPA axis response to stress (Myers et al. 2012). "
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    ABSTRACT: A robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness. The pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABAA receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans. Implications of this research to the development of human stress-related illness are discussed in the context of two human stress-related psychiatric disorders - major depressive disorder and premenstrual dysphoric disorder. Neurosteroid-mediated HPA axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified.
    Psychopharmacology 04/2014; 231(17). DOI:10.1007/s00213-014-3572-8 · 3.88 Impact Factor
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