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)

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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

Early clinical studies in which glucocorticoids were used alone in the treatment of acute nonlymphocytic leukemia (ANLL) reported a wide range of responses from remission in some patients to dramatic aggravation of the disease in others. In the hopes of identifying those patients likely to derive therapeutic benefit from glucocorticoids, we have studied glucocorticoid receptors and in vitro responses to glucocorticoids in 36 previously untreated adults with ANLL. The leukemic blasts of all patients contained glucocorticoid receptors (range, 4,300 to 28,400 total receptor sites per cell; median, 8,800). These receptors were similar in all respects studied to those from a variety of other normal and malignant tissues. There was little difference between receptor levels among the various French-American-British categories. In vitro responses to glucocorticoid were observed in leukemic blasts of 26 of 28 cases studied. These responses varied from near complete cell killing to stimulation of proliferation. Since the cells of patients with ANLL have about the same number of receptors as do cells from patients with acute lymphoblastic leukemia and these receptors are capable of mediating physiological responses in vitro, it is unlikely that qualitative or quantitative receptor defects underlie the relative resistance to glucocorticoid therapy of ALL compared to acute lymphoblastic leukemia. However, the broad range of in vitro responses and receptor levels suggests that these studies might be useful in identifying those patients with ANLL likely to derive benefit from steroid therapy.

https://cancerres.aacrjournals.org/content/canres/41/11_Part_2/4853.full.pdf

Glucocorticoid receptors and in vitro responses to glucocorticoid in acute nonlymphocytic leukemia.

Glucocorticoid-receptor complexes in cytoplasm from normal lymphoid cells incubated with [3H]dexamethasone can be resolved into three different components. Two of these correspond to the well-established activated and nonactivated forms, while the third appears similar to the mero-receptor complex first described by Sherman et al. (Fed. Proc., 37: 167–173, 1978). Based on their differential affinities for DNA- and DEAE-cellulose in buffers of low ionic strength (the activated complex binds to DNA- and DEAE-cellulose; the nonactivated complex binds to only DEAE-cellulose; the mero-receptor-like complex binds to neither), we have developed a rapid minicolumn chromatographic procedure for separating these forms, and have applied it to examine the relative proportion of different complexes in cytosols from cells of leukemia patients. All samples from nine patients with chronic lymphocytic leukemia contained these three complexes in proportions similar to those seen with normal lymphoid tissue. Cytosols from six of eight specimens from patients with acute nonlymphocytic leukemia contained a lower proportion of activated complexes and a higher proportion of mero-receptor-like complexes than cytosols from normal or chronic lymphocytic leukemia cells. Whether such differences in the properties of cytosolic complexes are due to degradation taking place after the cells are broken, and whether they can be correlated to in vivo therapeutic response, is not known, but studies are in progress to answer these questions. The minicolumn procedure described here offers a simple and reliable method for these purposes.

Analysis of activated and nonactivated cytoplasmic glucocorticoid-receptor complexes from human leukemia cells by rapid DNA-diethylaminoethyl minicolumn chromatography.

Concanavalin A-induced glucocorticoid resistance in rat thymus cells: decreased cytoplasmic and nuclear receptor binding of dexamethasone.

Glucocorticoid actions on the immune system: Inhibition of production of an Fc-receptor augmenting factor

A system has been developed for longterm incubation of rat thymus cells in suspension in a chemically defined medium consisting of Medium 199 and methylcellulose. With this system it is possible to study quantitatively the full time-course of glucocorticoid actions, from the early inhibitory effects on glucose uptake to the slow cytolytic effects. Cells incubated under these conditions preserve their sensitivity to the inhibitory effects of cortisol on glucose uptake for at least 12 h. Glucocorticoids at physiological concentrations lead to cytolysis (measured by reduction in viable cell counts determined by a modification of the pronase-cetrimide method) by 12 h incubation time. The cytolytic effect exhibits well-defined dose-response relationships and specificity for glucocorticoids. By 24 h, cortisol at 10-6M consistently reduces the total cell count by about 15‰, and the viable cell count by about 40‰. Cortisol is active down to 10-7M. Dexamethasone is roughly 10 times as active as cortisol, and corti...

Allan Munck

Papers

Glucocorticoid receptors and in vitro responses to glucocorticoid in acute nonlymphocytic leukemia.

Analysis of activated and nonactivated cytoplasmic glucocorticoid-receptor complexes from human leukemia cells by rapid DNA-diethylaminoethyl minicolumn chromatography.

Concanavalin A-induced glucocorticoid resistance in rat thymus cells: decreased cytoplasmic and nuclear receptor binding of dexamethasone.

Glucocorticoid actions on the immune system: Inhibition of production of an Fc-receptor augmenting factor

Long-term incubation of rat thymus cells: Cytolytic actions of glucocorticoids in vitro.