The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Over 60 years ago, Selye1 recognized the paradox that the physiologic systems activated by stress can not only protect and restore but also damage the body. What links these seemingly contradictory roles? How does stress influence the pathogenesis of disease, and what accounts for the variation in vulnerability to stress-related diseases among people with similar life experiences? How can stress-induced damage be quantified? These and many other questions still challenge investigators. This article reviews the long-term effect of the physiologic response to stress, which I refer to as allostatic load.2 Allostasis — the ability to achieve stability through change3 — . . .

/pdf/protective-and-damaging-effects-of-stress-mediators-34e0m747fy.pdf

Protective and Damaging Effects of Stress Mediators

This meta-analysis reviews 208 laboratory studies of acute psychological stressors and tests a theoretical model delineating conditions capable of eliciting cortisol responses. Psychological stressors increased cortisol levels; however, effects varied widely across tasks. Consistent with the theoretical model, motivated performance tasks elicited cortisol responses if they were uncontrollable or characterized by social-evaluative threat (task performance could be negatively judged by others), when methodological factors and other stressor characteristics were controlled for. Tasks containing both uncontrollable and social-evaluative elements were associated with the largest cortisol and adrenocorticotropin hormone changes and the longest times to recovery. These findings are consistent with the animal literature on the physiological effects of uncontrollable social threat and contradict the belief that cortisol is responsive to all types of stressors.

http://anthro.vancouver.wsu.edu/media/Course_files/anth-260-edward-h-hagen/acute-stressors-and-cortisol-responses-a-theoretical-integration-and-synthesis-of-laboratory-research-1.pdf

Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research.

Part I. From There to Here - Theoretical Background: 1. From visiousness to viciousness: theories of intergroup relations 2. Social dominance theory as a new synthesis Part II. Oppression and its Psycho-Ideological Elements: 3. The psychology of group dominance: social dominance orientation 4. Let's both agree that you're really stupid: the power of consensual ideology Part III. The Circle of Oppression - The Myriad Expressions of Institutional Discrimination: 5. You stay in your part of town and I'll stay in mine: discrimination in the housing and retail markets 6. They're just too lazy to work: discrimination in the labor market 7. They're just mentally and physically unfit: discrimination in education and health care 8. The more of 'them' in prison, the better: institutional terror, social control and the dynamics of the criminal justice system Part IV. Oppression as a Cooperative Game: 9. Social hierarchy and asymmetrical group behavior: social hierarchy and group difference in behavior 10. Sex and power: the intersecting political psychologies of patriarchy and empty-set hierarchy 11. Epilogue.

http://catdir.loc.gov/catdir/samples/cam032/98044356.pdf

Social Dominance: An Intergroup Theory of Social Hierarchy and Oppression

In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Stress and the brain: from adaptation to disease

Glucocorticoid receptors and physiology: a personal history.

Recent studies have brought additional clarity to the mechanisms by which glucocorticoid (GC) steroid hormones exert both suppressive and permissive effects on immune responses. Widely used for their immunosuppressive and anti-inflammatory actions, stress-elevated and therapeutic levels of GCs suppress defense mechanisms that would otherwise overshoot and damage the organism. Basal levels, on the other hand, are essential for permissive effects that prime defense mechanisms for more efficient action against a challenge. Both suppressive and permissive actions on immunity and inflammation have been documented in intact organisms. Suppressive actions are often due to inhibition by GCs of the production of cytokines and other mediators, whereas permissive effects include both induction of cytokine receptors and enhancement of activity of certain cytokines. GCs interact with both innate and adaptive immune responses. This is exemplified by immune–adrenal crosstalk wherein exposure to endotoxin stimulates the hypothalamic–pituitary–adrenal (HPA) axis and GC production, largely via endotoxin-induced cytokines. These stress-induced levels of GCs are, in turn, essential for survival in the face of endotoxic shock. GCs influence adaptive immunity in many ways. They inhibit antigen-specific T-lymphocyte activation, slow or redirect the maturation of macrophages and dendritic cells, favor Th2 over Th1 responses, and enhance the development as well as actions of specialized T-regulatory cells. GCs also induce T-cell apoptosis selectively on different T-cell populations, and can protect thymocytes from apoptosis induced by activation of the T-cell receptor. Moreover, experiments with rats that are highly susceptible to autoimmune disorders demonstrate the importance of a normal stress-induced increase in GC levels for the physiological control of autoimmunity. At the molecular level, at least three mechanisms contribute to GC effects on immunity and inflammation. Transactivation and transrepression are the “classical” mechanisms whereby ligand-activated glucocorticoid receptors (GRs) bind to DNA sequences called GC response elements and either activate or repress transcription of the targeted gene. Transactivation of genes encoding inhibitory proteins and transrepression of inflammatory genes have been described. However, the majority of anti-inflammatory effects are due to so-called cross-talk in which GC-liganded GRs interact with transcription factor proteins such as nuclear factor-κB (NF-κB) and activator protein-1(AP-1), interfering with their ability to activate transcription of target genes.

Glucocorticoid Effects on Immune Responses

Differential solubilization of nuclear glucocorticoid receptors by DNAase I and DNAase II.

Glucocorticoids are widely used for therapeutic purposes and have many toxic side effects. It seems likely that their physiological, therapeutic, and toxic effects are exerted through similar receptors and may be inherently inseparable. Lymphoid cells are targets for all these effects. With rat thymus cells in vitro, glucocorticoids immediately bind to cytoplasmic receptors, which are translocated to the nucleus, where they apparently induce messenger RNA for specific proteins that rapidly inhibit glucose transport. Protein and RNA metabolism are inhibited more slowly and eventually the cells die. The rate of formation of nuclear complexes and the timing of the hypothetical RNA-synthetic step are such as to suggest that the hormone-receptor complexes stimulate RNA synthesis in proportion to the rate at which they bind to nuclear sites rather than in proportion to the number of nuclear sites occupied. With normal peripheral human lymphocytes the rates of formation of hormone-receptor complexes are similar to those in rat thymocytes. The rate of onset of inhibition of glucose transport is lower, however, as is the rate of cytolysis. In human peripheral lymphocytes stimulated to undergo blast transformation with concanavalin A there is a dramatic increase in the number of glucocorticoid receptor sites per cell. This increase may be associated with a stage of the normal cell cycle, the mitogen stimulus inducing partial synchronization of the cell population. It has not been found, contrary to widespread belief, that mitogen stimulation renders cells insensitive to glucocorticoids.

Allan Munck

Papers

Glucocorticoid receptors and physiology: a personal history.

Glucocorticoid Effects on Immune Responses

Differential solubilization of nuclear glucocorticoid receptors by DNAase I and DNAase II.

Effects and receptors of glucocorticoids in rat thymus cells and human peripheral lymphocytes.

Nonactivated and activated glucocorticoid-receptor complexes in WEHI-7 and rat thymus cells