Glucocorticoids (GCs) have been widely used in clinical practice for more than 50 years for the non-specific treatment of acute and chronic inflammatory diseases; along with their excellent anti-inflammatory effects, numerous adverse reactions are common, some of which are serious and irreversible, often leading to the loss of anti-inflammatory therapy and greatly limiting their application. The molecular mechanism of action of GCs has progressed in the past decade or so, and it has been clarified that the two unused pathways of transcriptional activation (TA) and transcriptional repression (TR) mediated by the GCs receptor (GR) are the molecular mechanisms of GCs’ action on gene transcription. while their adverse effects are mediated by TA. The molecular pathways of action of existing GCs on cells determine their efficacy and various adverse effects, and with the recent research and development of these drugs, it is expected that a new generation of GCs without TA mechanism will be available for clinical application in the near future. The adverse effects of GCs are related to their type, dose, duration of treatment, mode of administration (systemic vs. local), as well as to various aspects of the patient’s condition, age, and other factors. In principle, GCs used for replacement therapy at doses close to the daily physiologically secreted amount of cortisol (25-37 mg) generally do not cause adverse reactions. The required dose beyond the physiological requirement is the pharmacological dose (i.e., amplification of the TR effect), and because the pharmacological dose-effect can vary significantly in clinical practice due to the reactivity of the body and the specificity of various disease states, attention must be paid to individualized dosing. Usually when critically ill patients require short-term life-saving GCs, despite the existence of counterindications to GCs therapy, GCs can still be effective on balance, and their adverse effects may be overcome or disappear with the improvement of the disease process. However, for chronic diseases requiring long-term high dose treatment with GCs, it is necessary to pay great attention to and closely follow up the various adverse effects and respond to them in a timely and positive manner. Adverse reactions of GCs are actually amplification of TA, unlike the side effects of general drugs; serious adverse reactions can cause death, with bacterial and fungal infections being the main causes, followed by cardiovascular complications, bleeding and perforation of gastrointestinal lesions, and perforation of gastrointestinal anastomoses. The following describes the main adverse reactions of GCs and their prevention and treatment respectively. (i) Infection and immunosuppression Since GCs have strong immunosuppressive effects, long-term application can significantly reduce the patient’s resistance to infection. They are prone to various infections such as bacteria, viruses, fungi and parasites, or aggravate the infection that was in latent state or spread the lesion. Tuberculosis, septic infections (mostly pulmonary, subdiaphragmatic, abdominal, urinary tract, perianal, etc.) and fungal infections are common. It is worth noting that the symptoms of infection may sometimes be masked by the anti-inflammatory effect of GCs, which can increase both total white blood cells and neutrophils, so the infection may be overlooked. Therefore, the presence of potential infectious lesions should be routinely sought before GCs treatment. In general, small doses of GCs (prednisone 10 mg/d or less) have little effect on the body’s immune function against infection, and the higher the dose and the longer the course of treatment, the higher the risk of causing infection. In case of infection during the treatment with GCs, the nature of the infection must first be clarified, sensitive anti-infective drugs must be selected, and adequate and effective treatment must be given in order to control the infection as soon as possible, and the dosage of GCs must be withdrawn and reduced at the same time. The use of GCs should be contraindicated in patients with existing infection that has not yet been controlled, except when the pathogenic organism has been identified and treated with effective anti-infective drugs and there is a strong indication for the use of GCs (e.g., infectious shock). In addition, GCs can contribute to the development of Kaposi’s sarcoma, which is not uncommon. (ii) Steroid ulcers, damage to the gastrointestinal mucosa and poor wound healing Long-term high-dose GC therapy may induce peptic ulcers, called “steroid ulcers”, and may also worsen the recurrence of existing ulcer disease, often leading to bleeding or perforation, by the same mechanism as stress ulcers, i.e., high-dose GCs may promote gastric acid and gastrin secretion and reduce the mucosal repair capacity. decreases the mucosal repair capacity. For this reason, patients on long-term high-dose GC therapy, especially those with a history of ulcers, should be given concomitant acid regulators and PPIs. Hemorrhagic perforation is also seen in inflammatory bowel disease (IBD), and budesonide (16-alpha hydroxyprednisolone), an agent with high intestinal local drug concentrations, is recommended for the treatment of Crohn’s disease (Crohn’s disease). GCs promote proteolytic metabolism and inhibit fibroblast proliferation and scar formation. This results in poor wound healing. To overcome this adverse effect, protein intake can be increased and anabolic hormones can be used if necessary. (iii) Medical cortisolism Long-term application of GC can cause medical cortisolism (Cushing-like syndrome), whose clinical manifestations are similar to those of endogenous cortisolism. However, hypertension, hirsutism, menstrual disorders, impotence and other symptoms are mostly seen in endogenous cortisolism, especially Cushing’s disease; while glaucoma, posterior subcapsular cataract, benign intracranial hypertension, aseptic necrosis of bone and pancreatitis are mostly seen in Cushing’s-like syndrome and rarely in endogenous cortisolism. In order to avoid or reduce the occurrence of Cushing’s syndrome, local medications can be used, such as aerosol preparations for patients with bronchial asthma and intra-articular injections for patients with rheumatoid arthritis, to reduce the effects on the whole body. (iv) Adverse effects on cardiovascular system Long-term GCs treatment can induce and aggravate hypertension, insulin resistance, dyslipidemia, hyperglycemia, blood hypercoagulability and metabolic syndrome, and accelerate the progression of atherosclerotic lesions and increase the incidence of coronary heart disease and cardiovascular events (including venous thrombosis). It is important to note that the above risk factors for cardiovascular disease persist after discontinuation of GCs. GCs are detrimental to water and sodium retention for heart failure. (E) steroidal diabetes GCs can inhibit glucose utilization and promote the allogenic effect of sugar, so long-term high-dose GCs treatment can cause impaired glucose tolerance or lead to steroidal diabetes, mostly in children and the elderly. GCs treatment can also worsen the condition of diabetic patients, so diabetic patients are listed as a contraindication to GCs treatment. However, if GCs treatment is necessary due to the condition, close monitoring of blood glucose and intensive treatment with insulin should be applied. (F) Adverse effects on water-electrolyte balance Hydrocortisone, cortisone, prednisone and other GCs have mild salt corticosteroid-like effects, and long-term high-dose application may cause water-sodium retention and hypokalemia, and patients may develop muscle weakness or even hypokalemic paralysis and cardiac arrhythmia. (vii) Adverse effects on the eye Long-term treatment with GCs may cause increased intraocular pressure, and even steroidal glaucoma may occur. It is reported in the literature that it generally occurs when oral prednisone is given for six months to one year, while topical 0.1% dexamethasone drops can be used in a few weeks to a few months that there is an increase in intraocular pressure, often seen in patients over 40 years of age or diabetes mellitus, etc. The increase in intraocular pressure caused by GCs is related to the type, dose, duration and mode of administration of GCs, and the response of topical ocular medication is greater than that of systemic medication, and dexamethasone, betamethasone, prednisone, and Prednisolone is more likely to cause an increase in intraocular pressure than hydrocortisone and cortisone. To prevent the development of steroidal glaucoma, IOP should be measured frequently during the use of GCs. increased IOP due to GCs is generally reversible, and GCs should be discontinued or reduced if necessary, and appropriate medications should be used to lower IOP. GCs should be contraindicated in patients with glaucoma who have not been effectively treated. GCs can also cause cataracts, mostly in children, and it has been reported that irreversible crystal clouding occurs in about 20% of children with nephrotic syndrome treated with hormones and can continue to develop after discontinuation of the drug. Therefore, long-term GCs users should have regular eye examinations. It has been reported that GCs aerosol inhalation therapy is generally less likely to cause cataracts. (viii) Effects on fetus and children The fetus may suffer from cleft rabbit and cleft palate if it receives a large amount of GCs in early pregnancy (before 14 weeks); it may cause miscarriage or premature birth in middle and late pregnancy. Therefore, GCs should be avoided in the early 14 weeks of pregnancy, and the dose should be minimized in the middle and late stages of pregnancy. Because of the effect of GCs on protein breakdown and inhibition of growth hormone secretion, long-term application of GCs in children may cause growth retardation and affect height and organ development, which is expected to recover gradually after discontinuation of the drug. In order to avoid affecting the growth and development of children, alternate day therapy or ACTH that does not inhibit growth hormone secretion should be planned as early as possible. (ix) Adverse effects on bones and muscles Long-term GCs treatment is a common cause of secondary osteoporosis. High doses of GCs can cause accelerated bone resorption, inhibition of osteoblast viability, and negative nitrogen and calcium balance, resulting in osteoporosis. Osteoporosis may be detected by imaging or laboratory examination after 6 months of GCs treatment, and significant osteoporosis may occur if treatment with prednisone >20 mg/d continues for more than 1 year. Therefore, long-term users of GCs, regardless of the dose, should be examined, and calcium salts and vitamin D preparations should be routinely supplemented, with the addition of bisphosphonate preparations if necessary. Aseptic osteonecrosis associated with GCs treatment is common in the femoral head and can occur unilaterally or bilaterally, as well as in the humeral head and the long bone end of the knee joint. It is associated with prolonged high dose GCs causing vascular fat embolism with vasculitis and is also thought to be associated with inhibition of angiogenesis. This process often lasts for months to years, so it is easy to miss the diagnosis, and it is advisable to enhance vigilance for early diagnosis and treatment. Myasthenia gravis and muscle weakness caused by GCs treatment often involve the upper arm flexors and scapular muscles, and the histological changes are muscle fiber atrophy, which is called “steroid myopathy” in the literature. It is often seen with long-term use of GCs, especially long-acting agents such as dexamethasone or fluoxyprednisolone. If the dosage is reduced or topical administration is used, the muscle weakness symptoms can be improved. (J) Mental disorders The blood cortisol level can be increased when the human body is under various stressful conditions, such as exercise, hunger, alcoholism, anxiety, depression and so on. Although the exact function of the increased need for GCs during stress is not yet clear, it can indicate that the human mental and behavioral state is closely related to GCs. GCs can increase the excitability of the brain, the pharmacological dose of GCs can induce epilepsy, and people with a history of psychosis are prone to relapse if using GCs. The early stage of euphoria is the most common, manifesting as excitement, polyphonic, insomnia, light mania, but also depression, anxiety, and even suicidal tendencies. Some patients show alternating euphoria and depression; in addition, delusions, hallucinations, and malaise can also occur. The occurrence of these symptoms is often dose related, and the dose of dialnisone is often above 80mg/d. The symptoms can be gradually restored after the dose of GCs is reduced or stopped. Patients with the above-mentioned conditions who need long-term treatment with GCs can add immunosuppressive drugs to reduce the dose of GCs. (xi) Adrenocortical insufficiency and adrenal crisis Long-term application of GCs can inhibit the secretion of pituitary adrenocorticotropic hormone (ACTH) and reduce the secretion of endogenous adrenocorticotropic hormone. Generally, the application of prednisone 20-30mg/d for 2 weeks can cause the hypothalamic-pituitary-adrenal axis to be unresponsive, and the hypothalamic-pituitary-adrenal axis can be completely suppressed if the long-term application is overdosed. If the drug is suddenly stopped or withdrawn too quickly, the clinical manifestations of adrenocortical insufficiency may appear, or even cause adrenal crisis, which may be life-threatening. This kind of crisis can occur during the use of GCs until 9-12 months after the discontinuation of the drug in case of various stresses such as infection and surgery. In order to reduce the inhibitory effect of GCs on hypothalamic-pituitary-adrenal axis, short-acting and medium-acting hormones should be used according to the indications of GCs treatment, and long-acting hormones should not be used as much as possible. In the course of treatment, the dosage should be reduced or discontinued as appropriate, and maintenance therapy should not be used if unnecessary; if long-term application is needed, the maintenance dosage should be reduced to the minimum dosage that can control the disease. If local medication is effective, local medication should be considered first, and the dose of systemic medication should be reduced as much as possible. However, it must be noted that the local application of GCs also requires attention to their adverse effects and must not be abused. In order to prevent the occurrence of adrenal crisis due to the suppression of hypothalamic-pituitary-adrenal axis after the discontinuation of GCs, it should be noted that after the long-term use of GCs, the drug should never be suddenly discontinued, and should be gradually reduced and then carefully withdrawn. At the same time, patients should be repeatedly warned of the serious consequences if they reduce the dose or stop using GCs on their own. Clinical manifestations and treatment are the same as those of common acute hyperaldosteronism. （GCs themselves are semi-antigens that can cause the body to produce antibodies. It has been reported that atopic allergic patients may occasionally have rapid onset of allergic reactions, or even anaphylaxis, when dexamethasone is injected for the first time or again. Therefore, it is necessary to clarify the history of allergy and administer the drug carefully, and sometimes it is necessary to observe closely after the drug is administered for emergency purposes.