Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies

Cole, Michael; Kim, Paul J.; Kalman, Brian A.; Spencer, Robert L.

doi:10.1016/s0306-4530(99)00045-1

Cited by 197 publications

(125 citation statements)

References 47 publications

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“…Dexamethasone initiates a negative feedback response by binding to glucocorticoid receptors in the pituitary, thus suppressing the release of ACTH and ultimately the secretion of cortisol. Empirical findings support the notion that the dexamethasone suppression test indexes the direct effects of increased glucocorticoid receptor activation in the pituitary on HPA axis-initiated cortisol secretion and subsequent blood concentrations (for example, see Cole et al, 2000). Essentially, during this test, a normally regulated HPA axis would attenuate the production of cortisol, as the dexamethasone would render the body's natural endogenous cortisol production unnecessary.…”

Section: Glucocorticoid Feedback Sensitivity -Dexamethasone Suppressisupporting

confidence: 54%

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review

Rodriguez

Epel

White

et al. 2015

Psychoneuroendocrinology

324

195

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a b s t r a c tBackground: Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. Objectives: To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. Data sources: Included papers used Pubmed, Google Scholar, and the University of California Library search engines with search terms body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, sagittal diameter, abdominal versus peripheral body fat distribution, body fat percentage, DEXA, abdominal obesity, and cortisol with terms awakening response, slope, total daily output, reactivity, feedback sensitivity, long-term output, and 11␤-HSD expression. Study eligibility criteria: Empirical research papers were eligible provided that they included at least one type of obesity (general or abdominal), measured at least one relevant cortisol parameter, and a priori tested for a relationship between obesity and cortisol. Results: A general pattern of findings emerged where greater abdominal fat is associated with greater responsivity of the HPA axis, reflected in morning awakening and acute stress reactivity, but some studies did show underresponsiveness. When examined in adipocytes, there is a clear upregulation of cortisol output (due to greater expression of 11␤-HSD1), but in hepatic tissue this cortisol is downregulated. Overall obesity (BMI) appears to also be related to a hyperresponsive HPA axis in many but not all studies, such as when acute reactivity is examined. Limitations: The reviewed literature contains numerous inconsistencies and contradictions in research methodologies, sample characteristics, and results, which partially precluded the development of clear and reliable patterns of dysregulation in each investigated cortisol parameter. Conclusions and implications:The literature to date is inconclusive, which may well arise from differential effects of generalized obesity vs. abdominal obesity or from modulators such as sex, sex hormones, and chronic stress. While the relationship between obesity and adipocyte cortisol seems to be clear, further research is warranted to understand how adipocyte cortisol metabolism influences circulating cortisol levels and to establish consistent patterns of perturbations in adrenal cortisol activity in both generalized and abdominal obesity.

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Section: Glucocorticoid Feedback Sensitivity -Dexamethasone Suppressisupporting

confidence: 54%

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review

Rodriguez

Epel

White

et al. 2015

Psychoneuroendocrinology

324

195

View full text Add to dashboard Cite

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“…Given the opposite findings of the low-and high-dose dexamethasone treatment in the current study, an involvement of the blood-brain barrier or the P-glycoprotein seems likely. A potential explanation of our findings may be that the low dose of dexamethasone used in the study (20 μg/kg) is sufficient to fully occupy GRs at the periphery, including the pituitary, thereby effectively shutting down the HPA axis (re)activity and depleting the brain from endogenous GR agonists (native or synthetic) (Cole et al, 2000). This consequently results in decreased expression of Fkbp5.…”

Section: Discussionmentioning

confidence: 89%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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“…To assess whether there is an altered GR-mediated negative feedback we assessed the effects of the synthetic glucocorticoid dexamethasone which at low doses, such as that used here, acts as a GR agonist (Meijer et al, 1998;Cole et al, 2000;Groenink et al, 2002). Mice lacking mGluR7 show a clear hypersensitivity to dexamethasone at the lower dose tested (0.03 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

Mitsukawa

Mombereau

Lötscher

et al. 2005

Neuropsychopharmacol

125

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Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7 À/À ) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala-and hippocampus-dependent conditioned fear and aversion responses. Since the hypothalamic-pituitary-adrenal (HPA) axis regulates the stress response we investigate whether parameters of the HPA axis at the levels of selected mRNA transcripts and endocrine hormones are altered in mGluR7-deficient mice. Over all, mGluR7 À/À mice showed only moderately lower serum levels of corticosterone and ACTH compared with mGluR7 + / + mice. More strikingly however, we found strong evidence for upregulated glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly upregulated in the hippocampus of mGluR7 À/À animals, (ii) similar increases were seen with 5-HT 1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7 À/À mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7 + / + animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7 À/À mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7 À/À mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.

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Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies

Cited by 197 publications

References 47 publications

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

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