Glucocorticoids

Mechanisms of Action

The dosage of GCs used often increases based on clinical activity and severity of the RA.^3,4 The rationale for this (mostly successful) clinical decision is: higher dosages increase GC receptor saturation in a dose-dependent manner, which intensifies the therapeutically relevant genomic GC actions; and it is assumed that with increasing dosages additional and qualitatively different nonspecific nongenomic actions of GCs increasingly come into play.

Anti-inflammatory and immunosuppressive effects

Suppression of inflammatory and immune reactions and treatment of cancers of the lymphoid system are among the major applications of glucocorticoids. As noted above, despite early assumptions that such ‘pharmacological’ effects had no physiological basis, it is now clear that they are as physiological as are the effects on glucose metabolism. For example, induction of adrenal insufficiency in experimental animals (by adrenalectomy or administration of the glucocorticoid antagonist RU486) enhances inflammatory and immune reactions, showing that these reactions are physiologically regulated by endogenous glucocorticoids. Studies by Sternberg and coworkers also strongly suggest that dysregulation of the HPA axis can result in autoimmunity.

Anti-inflammatory and immunosuppressive actions of glucocorticoids are now known to be closely related, affecting nearly all cells that participate in immunity and inflammation and sharing fundamental cellular and molecular mechanisms that are under glucocorticoid influence. Glucocorticoids dramatically alter the distribution of leukocytes, markedly decreasing blood counts of lymphocytes, monocytes, eosinophils and basophils within 1–3 h of glucocorticoid administration. Recent work has shown that changes in blood leukocyte distribution result from glucocorticoid interaction with the type II adrenal steroid receptor. While neutrophil counts rise in the blood, glucocorticoids decrease the accumulation of leukocytes at inflammatory sites. Glucocorticoids also kill lymphocytes, largely by the initiation of apoptosis, a striking effect that is applied in the treatment of lymphocytic leukemias and lymphomas.

The complexity of the interplay between glucocorticoids and inflammatory mediators is evidenced by the increased expression of certain cytokine receptors in response to glucocorticoids, and probably by altered expression of glucocorticoid receptors induced by some cytokines. How might such effects fit with the models presented in Figures 3 and 4? Basal levels of glucocorticoid, and possibly the surge which occurs early in an immune response, may initially enhance the actions of cytokines by increasing expression of cytokine receptors. As cytokine concentrations rise, they act on the HPA to stimulate even higher levels of glucocorticoids which restrain further cytokine production unless very strong inflammatory signals persist. Normally, elimination of the antigen and resolution of the inflammation allows cytokine production to cease so that both cytokines and glucocorticoids return to basal levels. However, sustained inflammation with continued high levels of cytokines can persist in spite of high levels of glucocorticoid. This outcome might result in part from cytokine-induced reduction in glucocorticoid receptor expression, a mechanism postulated by some to contribute to steroid-resistant asthma.

Inhibition of the HPA Axis by GC

GC elevations inhibit activity in PVN CRF cells and pituitary corticotropes, first by membrane GR-mediated effects, then by GC-associated GR protein–protein interactions altering gene expression. Feedback ensures controlled neuroendocrine responses. Longer term feedback effects exist in both brain and pituitary (e.g., through GC–GR complexes interacting with a negative GRE on POMC in corticotropes). Chronic GCs diminish HPA axis outflow in proportion to exposure, provided no concurrent stress exists, making the axis unresponsive to new stressors and thus explaining the requirement for extra GC coverage during major surgery in patients on chronic GC therapy.

There is rapid inhibitory GC feedback on both CRF and ACTH secretion. In hypothalamic slices in vitro, GC alters neuronal activity, including CRF-synthesizing cells, within 3 min. GC stimulates endocannabinoid secretion, presynaptically inhibiting glutamate-stimulated miniature excitatory postsynaptic currents (mEPSCs) via endocannabinoid EC-1 receptors. GCs infused directly into neurons does not have this effect, and rapid GCs actions on pituitary ACTH secretion in vitro are not inhibited by exposure to protein or by RNA synthesis inhibitors, suggesting membrane-mediated feedback.

Abstract

Glucocorticoids (GCs) are a class of steroid hormones that have been known to be widely used clinically as antiinflammatory, immunosuppressive, antishock drugs. Unfortunately, they can also produce numerous and potentially serious adverse effects that limit their usage. Thus, it is necessary to search for novel GCs with a better benefit-risk ratio compared to conventional GCs. GCs are believed traditionally to take effects mainly via the so-called genomic mechanisms, which are also largely responsible for GCs’ side effects. However, an ever-growing body of evidence indicates that some effects of GCs can be mediated by the nongenomic mechanism. Theoretically, the discovery of nongenomic mechanisms of GCs provides novel approaches for the development of GCs to treat various diseases safely. The new GC drugs will take clinical effects mainly through the nongenomic mechanisms instead of classical genomic mechanisms to reduce side effects.

Abstract

Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.

Glucocorticoid Hormones

Glucocorticoid hormones have strong effects on memory and learning in most animals (Lupien and Lepage, 2001). Glucocorticoids are steroid hormones produced by the adrenal glands, and elevation in glucocorticoids is usually associated with stressful events. The most common glucocorticoid hormone in some mammals including humans is cortisol. Corticosterone, on the other hand, is the main glucocorticoid hormone in reptiles, birds, and other mammals (e.g., some rodents). Glucocorticoids (hereafter CORT) are essential hormones necessary for multiple physiological functions including regulation of metabolism and gluconeogenesis (e.g., Mizoguchi et al., 2004).

Glucocorticoid Receptor

Glucocorticoids are often referred to as stress hormones because they are synthesized and secreted in response to pain and emotional trauma, caloric restriction, agonistic social encounters, and general anxiety. Mice homozygous for a null mutation in the GR (i.e., GR knockouts) die around the time of birth, indicating that the GR and glucocorticoids are essential for life.⁵⁶ In humans, there are at least nine GR isoforms produced from a single gene. Whereas GRα and GRβ are produced by alternative splicing at the 3´ end of GR mRNA, GR-A, GR-B, GR-C1-3, and GR-D1-3 are produced by alternative translation initiation at the 5´ end of GR mRNA.⁵⁷ Glucocorticoids alter the physiology of numerous tissues throughout the body during periods of acute stress. For example, the inhibitory effects of stress on reproduction are mediated by glucocorticoids at all levels of the hypothalamic–pituitary–gonadal axis. These hormones also influence brain function and behavior. Glucocorticoids mobilize energy stores by inducing the degradation of proteins to free amino acids in muscle, lipolysis in adipose tissue, and gluconeogenesis in the liver. Glucocorticoids play a role in the immune and vascular systems, where they induce programmed cell death in lymphocytes and block inflammatory responses. Although these changes are adaptive in the short term, chronic stress accompanied by prolonged glucocorticoid secretion is pathological.

In addition to mediating stress responses, glucocorticoids play an essential part in normal physiology. For example, glucocorticoids regulate the expression of numerous genes involved in energy homeostasis. The expression of phosphoenolpyruvate carboxykinase (PEPCK), is induced by glucocorticoids and is enhanced by the glucocorticoid-dependent increase in the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) in the liver.^58,59 It has been reported that glucocorticoids also increase pyruvate dehydrogenase kinase 4 levels,⁶⁰ which phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC). In turn, PDC inactivation promotes gluconeogenesis by conserving three-carbon substrates. Glucocorticoids regulate the expression of genes related to other physiological processes as well. For example, the well-known anti-inflammatory effects of glucocorticoids are mediated in part by induction of the gene for inhibitor of nuclear factor kappa B alpha (IκBα), which keeps the proinflammatory transcription factor nuclear factor kappa B (NF-κB) in an inactive state in the cytoplasm.

Abstract

Glucocorticoids are primary stress hormones produced by the adrenal cortex. The concentration of serum glucocorticoids in the fetus is low throughout most of gestation but surge in the weeks prior to birth. While their most well-known function is to stimulate differentiation and functional development of the lungs, glucocorticoids also play crucial roles in the development of several other organ systems. Mothers at risk of preterm delivery are administered glucocorticoids to accelerate fetal lung development and prevent respiratory distress. Conversely, excessive glucocorticoid signaling is detrimental for fetal development; slowing fetal and placental growth and programming the individual for disease later in adult life. This review explores the mechanisms that control glucocorticoid signaling during pregnancy and provides an overview of the impact of glucocorticoid signaling on fetal development.

Abstract

Glucocorticoids, with cortisol being the foremost player, comprehend a class of steroid hormones responsible for a wide range of actions. An important regulator in the glucocorticoid cascade is the glucocorticoid receptor. After binding of the glucocorticoid, this receptor can both up- and downregulate certain target genes but can also directly influence processes outside the nucleus. Since glucocorticoids possess the ability to effect nearly all bodily systems, genetic variations of the glucocorticoid receptor have been linked to alterations in body composition, cardiometabolic features, mental health, and response to treatment with exogenous glucocorticoids.

Glucocorticoids

Glucocorticoids have both stimulatory and inhibitory effects on GH secretion, with the absolute effect depending on the timing and the glucocorticoid concentration. Glucocorticoid deficiency, as in Addision disease, leads to a decrease in GH secretion due to decreased expression of GHRH and GH secretagogue receptors.³⁰¹ Acute exposure to supraphysiologic levels of glucocorticoids decreases GH secretion within 1 hour followed by a subsequent transient increase in GH secretion.^301,302 Ongoing glucocorticoid excess then causes ongoing suppression of GH secretion. This decrease in GH secretion is due to an increase in somatostatin tone.³⁰¹ Glucocorticoids can also impair growth through direct actions at the growth plate, by inhibiting local IGF-1 production through suppression of chondrocyte GHR expression, impairment of chondrocyte IGF-1 receptor expression,^301,303 alterations in IGFBP levels, and impairment of intracellular signaling.³⁰⁴ Finally, glucocorticoids may stimulate apoptosis of growth plate chondrocytes.²⁹⁴

Additional indirect effects of excess glucocorticoids on growth can result from glucocorticoid inhibition of calcium absorption and reabsorption, with the development of secondary hyperparathyroidism.²⁹⁹ In pubertal children, glucocorticoid excess can induce sex hormone deficiency, causing a loss of the normal growth stimulatory effect of these hormones.²⁹⁹