Glucocorticoids and depression

Depression has been associated with impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis, raised cortisol level and increased corticotropin-releasing factor activity, which may act in concert to induce the signs and symptoms of the disorder. Pre-clinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA axis abnormalities in depressed patients. Support for this view derives from models using genetically modified animals and/or chronic stress exposure at different developmental stages, although all of the current approaches have to be viewed within their limitations to model the disease. However, both animal and human studies challenging the HPA system show at least some neuroendocrine and behavioural changes comparable to those seen in depression, suggesting that some of the depressive symptoms can be attributed to HPA axis hyperactivity. Moreover, normalization of the neuroendocrine function following chronic antidepressant drug treatment seems to be a prerequisite for stable remission of depressive psychopathology, i.e. that normalization of HPA function is critical for relief of the clinical symptomatology of this disorder.     

糖皮质激素与骨

糖皮质激素在临床上应用广泛,但所致的骨质流失、代谢失调等不良反应也限制了其使用.本文对糖皮质激素对骨及其细胞的生理和病理生理作用进行综述,并对其不良反应发生的分子机制进行讨论.     

Glucocorticoids and cardiovascular disease

Chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic-pituitary-adrenal axis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11beta-hydroxysteroid dehydrogenase enzymes. These effects influence vascular function, atherogenesis and vascular remodelling following intra-vascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury. The conclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease.     

Glucocorticoids and diabetes mellitus

Diabetogenic effect of glucocorticoids is determined by dose volume, duration of administration and structure and type of particular preparation. The effect is influenced also by the state of glucocorticoid receptors (increased sensitivity of some gene mutations, resistance syndromes) and times of year and day when glucocorticoids are administered. Development of impaired glucose tolerance or diabetes mellitus depends on the ability of islets of Langerhans to control insulin resistance induced by glucocorticoids. The compensatory function of islets of Langerhans decreases with age and that is why steroid diabetes mellitus affects mostly seniors. Besides treatment regimes and application of sulfonylurea and insulin, there are some new therapeutic methods available: thiazolidindiones, metformin, short-acting secretagogue, alpha-glucosidase, and theoretically also antiglucocorticoids. Application of insulin in type 2 diabetics is justified by the effort to prevent nonketotic hyperosmolar coma. In type 1 diabetes, it is usually necessary to increase the overall insulin dose and change its dosage during the day.     

Glucocorticoids and immune responses

We describe a series of investigations on mechanisms of antiinflammatory and immunosuppressive actions of glucocorticoids. Glucocorticoid receptors and primary mechanisms of action have been studied with isolated rat thymus cells. When added to these cells glucocorticoids immediately form cytoplasmic hormone-receptor complexes which after activation bind to the nuclei where they apparently induce mRNA for specific proteins that rapidly inhibit glucose transport and acetate incorporation into lipids. Protein and RNA metabolism are inhibited more slowly and eventually the cells die. With normal peripheral human lymphocytes, similar but slower effects are produced. A dramatic increase in receptor sites per cell is seen in lymphocytes stimulated with concanavalin A or antigen. This increase is probably associated with preparation for mitosis. We do not find, contrary to widespread belief, that these stimulated cells are insensitive to glucocorticoids. Such insensitivity has been invoked to explain the insensitivity to glucocorticoid suppression of secondary compared to primary immune responses. An alternative explanation emerges from our experiments with T-cell growth factor. T-cell growth factor, produced by mitogen or antigen stimulated spleen cells, is necessary for the proliferation of T-lymphocytes in culture and may be responsible for clonal expansion of antigen-responsive T-cells. Treatment of Con A-stimulated rat spleen cells or human peripheral mononuclear cells with 100 nM dexamethasone inhibits the production of the growth factor by 95%. This effect is specific for glucocorticoids. Addition of T-cell growth factor completely reverses the inhibition by glucocorticoid of mitogen-induced blastogenesis. We propose that the inhibitory actions of glucocorticoids on antigen- or mitogen-induced T-cell blastogenesis are related to inhibition of production of T-cell growth factor and that the reason the primary immune response is more sensitive to glucocorticoids is that by inhibiting production of T-cell growth factor, glucocorticoids block the clonal expansion necessary to amplify the primary response. We have also studied effects of glucocorticoids on Fc receptors, which play important roles in phagocytosis and other aspects of immune responses. Treatment of the human progranulocytic cell line HL-60 with dexamethasone for 72 hours reduces by 35-50% the Fc receptors per cell with no effect on cell viability or proliferation and slight increase in leucine incorporation. The effect is specific for glucocorticoids. These findings indicate that an important component in glucocorticoid-induced immunosuppression may be a reduction in Fc receptors, and with the results on T-cell growth factor, suggest that glucocorticoids regulate immune processes via effects on lymphokines and other immunologically important proteins.     

Glucocorticoids and neuroendocrine function

Recent experimental evidence supports the role of glucocorticoids in the neuroendocrine control of food intake and energy expenditure. In particular, glucocorticoids promote food consumption directly through stimulation of NPY and inhibition of CRH and melanocortin release. CRH and NPY are also functionally linked by a mutual regulation. CRH is anorexigenic when secreted acutely while it exerts the opposite effect when, upon sustained secretion, it stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The orexigenic effects of glucocorticoids are counteracted by a steroid-induced rise in leptin levels that closes a regulatory loop regarding food consumption. Furthermore, glucocorticoids may alter body fat distribution, increasing truncal adiposity both directly and by inhibition of growth hormone secretion. No clearcut alterations of the HPA function are apparent in obesity as a whole. However, subtle and specific abnormalities may be noted in subsets of obese patients. Indeed, obesity, mostly visceral type, is associated with an increased cortisol clearance and 11-beta hydroxysteroid dehydrogenase activity in the omental fat. In the same vein, an increased cortisol rise following a mixed meal has been observed in obese subjects. Finally, it has been proposed that adrenal incidentalomas, often characterized by enhanced cortisol secretion, might be a clinical expression of the X syndrome.     

Glucocorticoids and immune function

The prevailing notion has been that cytokines such as interleukin-1 released from sites of inflammation cross the blood-brain barrier and drive the hypothalamo-pituitary-adrenal (HPA) axis so that cortisol is released into the circulation to exert indiscriminate systemic anti-inflammatory effects. It is now clear that feedback from the HPA axis is subject to more subtle and localized regulation. The signal that activates cortisol release travels to the hypothalamus via vagal sensory afferents (so the brain 'knows' where the inflammation is), and the effects of the released cortisol are regulated within individual tissues via numerous mechanisms, including changes in the affinity of the cortisol receptors, and changes in the equilibrium point of the cortisol/cortisone shuttle (11 beta hydroxysteroid dehydrogenases 1 and 2). This equilibrium is locally regulated by cytokines. These mechanisms are central to the regulation of the balance of Th1 to Th2 cytokines within sites of inflammation, and to the appropriate or inappropriate termination of the inflammatory response in infections or autoimmunity.     

Glucocorticoids and the circadian clock

Glucocorticoids, hormones produced by the adrenal gland cortex, perform numerous functions in body homeostasis and the response of the organism to external stressors. One striking feature of their regulation is a diurnal release pattern, with peak levels linked to the start of the activity phase. This release is under control of the circadian clock, an endogenous biological timekeeper that acts to prepare the organism for daily changes in its environment. Circadian control of glucocorticoid production and secretion involves a central pacemaker in the hypothalamus, the suprachiasmatic nucleus, as well as a circadian clock in the adrenal gland itself. Central circadian regulation is mediated via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, while the adrenal gland clock appears to control sensitivity of the gland to the adrenocorticopic hormone (ACTH). The rhythmically released glucocorticoids in turn might contribute to synchronisation of the cell-autonomous clocks in the body and interact with them to time physiological dynamics in their target tissues around the day.     

Glucocorticoids and Hypertension in Man

Abnormalities of cortisol production or metabolism are involved in the genesis of hypertension in Cushing's syndrome, apparent mineralocorticoid excess and liquorice abuse and possibly in chronic renal failure and essential hypertension. We have studied the physiological mechanisms by which cortisol raises blood pressure in short term studies of cortisol administration in normal men. Cortisol induced hypertension cannot be explained by increases in vasopressor or decreases in vasodepressor hormone concentrations, or by any increase in sympathetic nervous activity. The hypertension is accompanied by substantial sodium retention but a significant component of the blood pressure rise is sodium independent. The hypertension is characterized by an increase in cardiac output but a rise in output is not essential for the rise in blood pressure. Our working hypothesis is that cortisol induced hypertension is a consequence of increases in renal vascular resistance.     

Glucocorticoids and invasive fungal infections

Since the 1990s, opportunistic fungal infections have emerged as a substantial cause of morbidity and mortality in profoundly immunocompromised patients. Hypercortisolaemic patients, both those with endogenous Cushing's syndrome and, much more frequently, those receiving exogenous glucocorticoid therapy, are especially at risk of such infections. This vulnerability is attributed to the complex dysregulation of immunity caused by glucocorticoids. We critically review the spectrum and presentation of invasive fungal infections that arise in the setting of hypercortisolism, and the ways in which glucocorticoids contribute to their pathogenesis. A better knowledge of the interplay between glucocorticoid-induced immunosuppression and invasive fungal infections should assist in earlier recognition and treatment of such infections. Efforts to decrease the intensity of glucocorticoid therapy should help to improve outcomes of opportunistic fungal infections.     

糖皮质激素与胃黏膜损伤

Hent于1950年发现糖皮质激素(glucocorticoids,GCs),明确了GCs在风湿性疾病治疗上的确切效果,并因此获得诺贝尔奖.此后数十年GCs被广泛应用于临床,但也带来一些胃肠道不良反应.不过,GCs究竟是否为消化性溃疡(pepticulcer disease,PUD)及上消化道出血的危险因素一直有争议,...     

Glucocorticoids in rheumatology

Glucocorticoids (GC) are effective drugs which are often used in rheumatology. However, they have a considerable potential for frequent and sometimes serious side effects that restrict their use. Their mechanisms of action are either receptor dependent (specific) or independent (unspecific) on the genomic as well as the non-genomic level. Many adverse effects are predominantly caused by transactivation while the desired effects are mostly mediated by transrepression. Treatment strategies are sub-classified into low, medium, high, very high dose and pulse therapy based on criteria such as dose, indication, duration of treatment and potential risk of adverse events. The musculoskeletal, gastrointestinal, neuro-endocrino-immunological, opthalmological and neuropsychiatric systems are examples where adverse effects may occur.