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Background: Transient generalized glucocorticoid hypersensitivity is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypo-activation of the hypothalamic-pituitary-adrenal axis. The condition itself and the underlying molecular mechanisms have not been elucidated., Objective: To present the clinical manifestations, endocrinologic evaluation and transcriptomic profile in a patient with transient generalized glucocorticoid hypersensitivity., Design and Results: A 9-year-old girl presented with an 8-month history of clinical manifestations suggestive of Cushing syndrome. Endocrinologic evaluation revealed undetectable 08:00 h ACTH (<1 pg/mL) and cortisol (0·025 μg/dL) concentrations, which remained decreased throughout the 24-h period and did not respond to stimulation with ovine CRH. The disease gradually resolved spontaneously over the ensuing 3 months. Sequencing of the human glucocorticoid receptor gene revealed no mutations or polymorphisms. Western blot analysis in peripheral blood mononuclear cells revealed equal protein expression of hGRα of the patient in the disease and postresolution phases compared with a control subject. Transcriptomic analysis in peripheral blood mononuclear cells in the disease and postresolution phases identified 903 differentially expressed genes. Of these, 106 genes were up-regulated and 797 were down-regulated in the disease compared with the resolution phase. Bioinformatics analysis on the differentially expressed gene networks revealed Nuclear Factor-κB as the predominant transcription factor influencing the expression of the majority of differentially expressed genes., Conclusions: Our findings indicate that a transient postreceptor defect, or a virus- or bacterium-encoded molecule, may have enhanced glucocorticoid signal transduction, leading to transient generalized glucocorticoid hypersensitivity and hypo-activation of the HPA axis., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

The hypothalamic-pituitary-adrenal (HPA) axis is an important regulator of the stress response. In healthy individuals, the HPA axis maintains an equilibrium, ensuring that endogenous glucocorticoid (GC) levels remain within the normal range. However, hypofunction of the HPA axis may have a role in the development of inflammatory diseases, such as rheumatoid arthritis (RA). Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein, the expression of which is upregulated by GC. Although GILZ mediates the anti-inflammatory effects of GC, it may not be associated with the adverse effects that are frequently caused by exogenous GC administration. This has raised interest in GILZ potentiation as a therapeutic approach in diseases such as RA, which may mimic the anti-inflammatory effects of GC without causing harmful side effects. This review will outline the involvement of the HPA axis in RA, as a prelude to highlighting emerging evidence regarding the role of GILZ in inflammation control and RA.

Studies using glucocorticoid receptor exon 2-disrupted knockout (GR2KO) mice provided strong evidence against an obligatory role for glucocorticoid receptor (GR) signalling in T-cell selection. These mice express a truncated form of the GR that is incapable of transmitting a range of glucocorticoid (GC)-induced signals, including GC-induced thymocyte death. However, one study that suggested that truncated GR function is preserved in the context of GR-mediated repression of T-cell activation-induced genes, challenged earlier conclusions derived from the use of these mice. Because GR versus T-cell receptor (TCR) signalling cross-talk is the means by which GCs are hypothesized to have a role in T-cell selection, we reassessed the utility of GR2KO mice to study the role of the GR in this process. Here, we show that GR-mediated repression of TCR signalling is impaired in GR2KO T cells in terms of TCR-induced activation, proliferation and cytokine production. GC-induced apoptosis was largely abolished in peripheral T cells, and induction of the GC-responsive molecule, interleukin-7 receptor, was also severely reduced in GR2KO thymocytes. Together, these data strongly re-affirm conclusions derived from earlier studies of these mice that the GR is not obligatory for normal T-cell selection.

Drug, hormonal, and nutritional exposures in pregnancy can cause birth defects, or have more subtle influences that may affect adult health through epigenetic developmental programming. Characterizing these epigenetic changes may provide valuable insight into the mechanism by which our health is influenced by the environment and provide biomarkers of exposure; however, currently there are few data from human studies directly addressing this. We review data on three types of exposures-nutritional, glucocorticoid, and endocrine-disrupting chemicals-and discuss how these may be associated with epigenetic changes in the fetus and the placenta, a key mediator of in utero environment. In addition, we outline some considerations for investigation of epigenetic effects in the fetus and placenta that are important to consider in the design of studies for the future.

Background: Glucocorticoids regulate a broad spectrum of physiologic functions and play important roles in resting and stress homeostasis. Their actions are mediated by the nuclear glucocorticoid receptor (GR)., Design: Using a patient as a stimulus, we reviewed briefly the area of Primary Generalized Glucocorticoid Resistance in man and nonhuman primates., Results: In man, Primary Generalized Glucocorticoid Resistance is a rare sporadic or familial syndrome characterized by target-tissue insensitivity to glucocorticoids and compensatory elevations in adrenocorticotropic hormone (ACTH), leading to increased secretion of cortisol and adrenal steroids with mineralocorticoid and/or androgenic activity, and causing hypermineralocorticoidism and hyperandrogenism without Cushing stigmata. The presentation, diagnosis and therapy of this condition are summarized. Many or, most likely, all New World primates have markedly elevated cortisol and ACTH, and resistance to dexamethasone suppression, without any pathology. These primates in fact have 'pan-steroid/sterol' resistance, including all five steroid hormones and 1,25-dihydroxy-vitamin D. In humans, the molecular basis of Primary Generalized Glucocorticoid Resistance has been mainly ascribed to recent mutations in the GR gene, which impair glucocorticoid signal transduction. In contrast, in the primates, steroid/sterol signalling systems have adapted under yet unknown selective pressures or genetic drift over many million years. Of course, other molecules of the signaling pathways may also be involved in both states. There are now a host of human states associated with tissue-specific pathologic glucocorticoid target tissue changes. These include allergic, autoimmune, inflammatory and lymphoproliferative disorders., Conclusions: In recognition of Professor George P. Chrousos' extensive ground-breaking research in this field, and for the sake of brevity, we propose that 'Chrousos syndrome' is used instead of 'Primary Generalized Familial or Sporadic Glucocorticoid Resistance'., (© 2010 No claim to original US government works. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

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.