Anabolic androgenic steroids effects on the immune system: a reviewAs an untoward do anabolic steroids cause immunosuppression of chronic anabolic steroid use, immunologic alterations may be induced. To evaluate this possibility five commercially available steroids with various types of structural differences were studied in male Sprague-Dawley rats. Animals were divided into five groups and treated with testosterone Group 1testosterone propionate Group stegoidstestolactone Group 3oxandrolone Group 4and stanozolol Group 5. Androgenic anabolic steroids were administered daily, subcutaneously dissolved in oil, at a dose of 1. Immune alterations were assessed by skin-test responses to phytohemagglutinin.
Glucocorticoid - Wikipedia
Glucocorticoids GCs are a class of corticosteroids , which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor GR ,  that is present in almost every vertebrate animal cell. A less common synonym is glucocorticosteroid. GCs are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as inflammation.
They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases , and sepsis.
GCs have many diverse pleiotropic effects, including potentially harmful side effects, and as a result are rarely sold over the counter. This includes inhibitory effects on lymphocyte proliferation, as in the treatment of lymphomas and leukemias, and the mitigation of side effects of anticancer drugs.
GCs affect cells by binding to the glucocorticoid receptor GR. The activated GR complex, in turn, up-regulates the expression of anti-inflammatory proteins in the nucleus a process known as transactivation and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus transrepression. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects.
In technical terms, " corticosteroid " refers to both glucocorticoids and mineralocorticoids as both are mimics of hormones produced by the adrenal cortex , but is often used as a synonym for "glucocorticoid. Cortisol or hydrocortisone is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular , metabolic , immunologic , and homeostatic functions. Various synthetic glucocorticoids are available; these are widely utilized in general medical practice and numerous specialties either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.
Glucocorticoid effects may be broadly classified into two major categories: In addition, glucocorticoids play important roles in fetal development and body fluid homeostasis. As discussed in more detail below, glucocorticoids function through interaction with the glucocorticoid receptor:. Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes. This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids.
The name "glucocorticoid" derives from early observations that these hormones were involved in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood. Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption both of which can lead to osteoporosis , delayed wound healing, muscle weakness, and increased risk of infection.
These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids. Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function.
Mice with homozygous disruptions in the corticotropin -releasing hormone gene see below die at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell survival  and may also play a role in hippocampal development.
Glucocorticoids act on the hippocampus , amygdala , and frontal lobes. Along with adrenaline , these enhance the formation of flashbulb memories of events associated with strong emotions, both positive and negative. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory this effect was more important in men. The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation.
In multiple animal studies, prolonged stress causing prolonged increases in glucocorticoid levels have shown destruction of the neurons in this area of the brain, which has been connected to lower memory performance. Glucocorticoids have also been shown to have a significant impact on vigilance attention deficit disorder and cognition memory. This appears to follow the Yerkes-Dodson curve , as studies have shown circulating levels of glucocorticoids vs.
For example, long-term potentiation LTP; the process of forming long-term memories is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy low-GC state or after exogenous glucocorticoid administration high-GC state. Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body's action to atrial natriuretic peptide ANP.
Centrally, glucocorticoids could inhibit dehydration induced water intake;  peripherally, glucocorticoids could induce a potent diuresis. Glucocorticoids bind to the cytosolic glucocorticoid receptor GR , a type of nuclear receptor that is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly formed complex translocates itself into the cell nucleus , where it binds to glucocorticoid response elements GRE in the promoter region of the target genes resulting in the regulation of gene expression.
This process is commonly referred to as transcriptional activation, or transactivation. The proteins encoded by these up-regulated genes have a wide range of effects, including, for example: The opposite mechanism is called transcriptional repression, or transrepression.
The classical understanding of this mechanism is that activated GR binds to DNA in the same site where another transcription factor would bind, which prevents the transcription of genes that are transcribed via the activity of that factor. New mechanisms are being discovered where transcription is repressed, but the activated GR is not interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with other proteins that interfere with the function of other transcription factors.
Activated GR has effects that have been experimentally shown to be independent of any effects on transcription and can only be due to direct binding of activated GR with other proteins or with mRNA. For example, Src kinase which binds to inactive GR, is released when a glucocorticoid binds to GR, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation, epidermal growth factor EGF , reducing its activity, which in turn results in reduced creation of arachidonic acid - a key proinflammatory molecule.
This is one mechanism by which glucocorticoids have an anti-inflammatory effect. A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use.
They differ in both pharmacokinetics absorption factor, half-life, volume of distribution, clearance and pharmacodynamics for example the capacity of mineralocorticoid activity: Because they permeate the intestines easily, they are administered primarily per os by mouth , but also by other methods, such as topically on skin. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin also called corticosteroid-binding globulin , whereas all of them bind albumin.
In the liver, they quickly metabolize by conjugation with a sulfate or glucuronic acid , and are secreted in the urine. Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency vary.
Cortisol is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol. The data below refer to oral administration. Fludrocortisone acetate and deoxycorticosterone acetate are, by definition, mineralocorticoids rather than glucocorticoids, but they do have minor glucocorticoid potency and are included in this table to provide perspective on mineralocorticoid potency. Glucocorticoids may be used in low doses in adrenal insufficiency.
In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic , inflammatory , and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for asthma. They are also administered as post-transplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease.
Nevertheless, they do not prevent an infection and also inhibit later reparative processes. Newly emerging evidence showed that glucocorticoids could be used in the treatment of heart failure to increase the renal responsiveness to diuretics and natriuretic peptides. Glucocorticoids are historically used for pain relief in inflammatory conditions. Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing.
Glucocorticoids cause immunosuppression , and the therapeutic component of this effect is mainly the decreases in the function and numbers of lymphocytes , including both B cells and T cells. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response. Smaller cytokine production reduces the T cell proliferation.
Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect - glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid sensitivity lies in the Bcl-2 gene. Glucocorticoids also suppress the humoral immunity , thereby causing a humoral immune deficiency.
This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated. The effect of glucocorticoids on Fc receptor expression in immune cells is complicated. Dexamethasone decreases IFN-gamma simulated Fc gamma RI expression in neutrophils while conversely causing an increase in monocytes.
This is because Fc receptors bind antibodies attached to cells targeted for destruction by macrophages. Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary anti-inflammatory mechanism is lipocortin-1 annexin-1 synthesis.
Lipocortin-1 both suppresses phospholipase A2 , thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events epithelial adhesion , emigration , chemotaxis , phagocytosis , respiratory burst , etc. In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. In addition, glucocorticoids also suppress cyclooxygenase expression.
Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for rhinitis or inhalers for asthma. These preparations have the advantage of only affecting the targeted area, thereby reducing side effects or potential interactions. In this case, the main compounds used are beclometasone , budesonide , fluticasone , mometasone and ciclesonide. In rhinitis, sprays are used.
For asthma, glucocorticoids are administered as inhalants with a metered-dose or dry powder inhaler. Glucocorticoids can be used in the management of familial hyperaldosteronism type 1.
They are not effective, however, for use in the type 2 condition. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation such as allergens , immunological phenomena that bypass glucocorticoids, and pharmacokinetic disturbances incomplete absorption or accelerated excretion or metabolism. Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics.
Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Mineralocorticoid effects can include salt and water retention, extracellular fluid volume expansion, hypertension , potassium depletion, and metabolic alkalosis.
In addition to the effects listed above, use of high-dose steroids for more than a week begins to produce suppression of the patient's adrenal glands because the exogenous glucocorticoids suppress hypothalamic corticotropin-releasing hormone and pituitary adrenocorticotropic hormone.
With prolonged suppression, the adrenal glands atrophy physically shrink , and can take months to recover full function after discontinuation of the exogenous glucocorticoid. During this recovery time, the patient is vulnerable to adrenal insufficiency during times of stress, such as illness.
While suppressive dose and time for adrenal recovery vary widely, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The following is one example:.