19th May 2025

Glucocorticoid therapy

Indications

Glucocorticoid therapy may take the form of systemic (intravenous or oral), topical, inhaled, or intraarticular therapy. This section will focus specifically on the adverse effects of systemic therapy. The indications for glucocorticoid therapy are numerous, but in general it is used for autoimmune, allergic, and inflammatory diseases; it may also be used to establish a diagnosis of Cushing’s syndrome, and to treat adrenal insufficiency. Examples of glucocorticoids include prednisolone, prednisone, methylprednisolone, dexamethasone, triamcinolone, and betamethasone. 

Mechanism of action

Glucocorticoids are hormones released as a physiological response to stress (primary stress hormones). Adrenal glucocorticoid release is under the control of the hypothalamic-pituitary-axis (HPA). Synthetic derivatives of glucocorticoid hormones are used to treat a wide range of inflammatory and immune disorders. Glucocorticoid molecules act via the intracellular glucocorticoid receptor (GR) found within a variety of tissues, with different tissues showing variability in responses to GR binding due to differences in GR variants. GRs are activated as a result of glucocorticoid molecule binding, and subsequently up- or downregulate the expression of many genes via direct DNA binding. GRs also function via non-genomic pathways, which are poorly understood. The effects of exogenous glucocorticoid administration result largely from either suppression of the HPA, or the development of iatrogenic Cushing’s syndrome.

Adverse effects

Cardiovascular 

At higher doses, glucocorticoids promote fluid retention. Patients with pre-existing cardiac and renal disease are at particular risk of this effect. Hypertension is also seen, again particularly in those on higher-dose therapy, and is present in 20% of patients diagnosed with iatrogenic Cushing’s syndrome. Patients receiving glucocorticoid therapy are at higher risk of myocardial infarction, angina, stroke, transient ischaemic attack, and heart failure. The risk of developing atrial fibrillation, atrial flutter, and sudden cardiac death is also reportedly higher in patients receiving glucocorticoids.

Endocrine /metabolic 

Hyperglycaemia is a notable metabolic effect of patients receiving glucocorticoid therapy. The effect is dose-related. In patients without pre-existing diabetes, the largest increase is seen in postprandial blood glucose levels; a less marked increase is also demonstrated in fasting glucose levels. The development of diabetes mellitus as a result of glucocorticoid therapy in patients with previously normal glucose tolerance is rare. In patients with pre-existing diabetes, an increase in blood glucose levels, and thus challenging diabetic control, may be seen. Patients with early previously undiagnosed diabetes or impaired glucose tolerance may develop diabetic ketoacidosis or hyperglycaemic hyperosmolar state. The mechanism by which glucocorticoids result in hyperglycaemia is believed to be attributable to a combination of factors, including receptor functions, increased hepatic gluconeogenesis, and reduced uptake of glucose in adipose tissue. 

A second endocrine effect of glucocorticoids is inhibition of the HPA, with abrupt withdrawal of exogenous glucocorticoid leading to acute adrenal insufficiency and associated hypotension and/or shock. Additional features such as weakness, nausea, vomiting, anorexia, fever and confusion are commonly seen in the event of adrenal crisis.  Thus, a tapering regimen is recommended in patients receiving glucocorticoids for greater than 2 weeks.

Bone

Glucocorticoid use is associated with reduction in bone mineral density leading to osteoporosis. The risk of osteoporotic fracture is also increased. This effect is a result of both increased bone resorption through stimulation of osteoclast proliferation and differentiation, and reduced bone formation as a result of inhibition of osteoblast development. Vertebral fractures are the most common. These phenomena of osteoporosis and fractures are most often seen in the first few months of treatment with glucocorticoids. Osteonecrosis is also seen with high-dose steroid use. The mechanism for this is unclear but one proposed theory is that glucocorticoids stimulate an increase in circulating lipids which result in microembolism within arterial supply to bones. 

Muscle

Occasionally, myopathy is seen as a result of glucocorticoid therapy. This manifests as painless proximal weakness in the upper and lower limbs. The pathogenesis of this relates to both catabolic and anti-anabolic effects of glucocorticoids, likely mediated through muscle glucocorticoid receptors. 

Gastrointestinal 

The main gastrointestinal (GI) side effects of glucocorticoids are gastritis, ulcer formation, and gastrointestinal bleeding. This risk is significantly increased when glucocorticoids are used concurrently with non-steroidal anti-inflammatory drugs (NSAIDs). Further possible GI effects include gastrointestinal tract perforation, hepatic steatosis and even cirrhosis. There is mixed evidence as to whether they may cause acute pancreatitis; some studies suggest that the underlying disease for which glucocorticoids are indicated, for example systemic lupus erythematosus (SLE), is in fact the causative factor making this more likely in patients taking glucocorticoids.

Neuropsychiatric 

Psychiatric and cognitive effects seen include emotional lability, mania, hypomania, depression, psychosis confusion, delirium, and memory impairment. These tend to be dependent on glucocorticoid dose and duration of therapy. Older patients are particularly at increased risk of particular mood and memory disturbances, including depression, mania and hypomania, confusion, delirium and memory impairment. ‘Steroid dementia’ is a term given to a phenomenon whereby severe memory impairment develops in smaller group of patients (approximately 1%), which may persist for up to 11 months following cessation of treatment. Often reported are also disturbances in sleep, which results particularly from evening doses which disrupts the normal diurnal pattern of endogenous cortisol release. 

Mood disorders in glucocorticoid use typically take the form of a sense of euphoria, hypomania, mania, or anxiety within the first few days. Symptoms are more severe in higher-dose therapy. In longer-term therapy, depression is more commonly seen. Psychosis may be seen, but this is almost exclusively seen in patients on long term therapy and high doses (at least 20mg prednisolone per day). These patients tend to respond well to antipsychotic medication. An increased risk of suicide is reported in patients taking glucocorticoids, in particular in younger patient groups (however absolute risk is low). 

Rarer reported neuropsychiatric effects include pseudotumour cerebri, panic disorder and akathisia.

Ophthalmic

The main ophthalmic effects of glucocorticoids are cataract and glaucoma. Cataracts occur in patients on long-term therapy and this is a dose-related effect. Most commonly they are posterior subcapsular cataracts and are usually seen bilaterally. 

Raised intraocular pressure occurs more commonly in patients using topical steroid therapy (i.e. eye drops, and dermatological use on the eyelids and in the periorbital region) but it can also be seen with systemic therapy, particularly in long term use. While the pathogenesis is not certain, it is believed to be a result of reduced drainage through the trabecular meshwork. 

More rarely, lid swelling and exophthalmos can be seen in association with glucocorticoid use. 

Dermatologic 

Skin thinning and bruising are commonly seen and can occur even with low daily doses of glucocorticoid use. The prevalence of these features has been shown to increase with higher doses. 

Cushingoid features of central obesity, moon facies and buffalo hump can be seen within the first two months of glucocorticoid use, but the prevalence again increases with increasing dose and duration of therapy. While the prevalence of Cushingoid features shows a linear effect with relation to dose, weight gain shows a threshold effect, with no significant change in weight seen below 5mg per day or above 7.5mg per day of prednisolone. 

Acne, facial erythema, striae, and hirsutism are additional dermatologic effects seen in association with glucocorticoid use.

Immune 

There is a dose-related increase in the risk of infection with glucocorticoid use. Infectious pathogens are typically common bacteria, viruses and fungi. This is mediated via effects on both innate and acquired immunity. The main mechanisms of glucocorticoid effects on the immune system are via its direct effects on DNA, which result in:

• increased production of anti-inflammatory gene products (e.g. I-kappa-B-alpha, interleukin-1 receptor II)
• blocking the effects of pro-inflammatory genes (e.g. interleukin-1 alpha and beta) 
• inhibition of cytokine synthesis. 

Clinical features of infection may be masked by glucocorticoid use, making it more difficult to detect, as a result of inhibition of cytokine release and dampened inflammatory response.

Haematologic 

Glucocorticoid therapy induces a leukocytosis, which is largely a neutrophilia. This results from a reduction in the adherence of neutrophils to the vascular endothelium, and increased mobilisation of granulocytes from the bone marrow.