Glucocorticoid therapy, withdrawal and adverse effects

• Systemic glucocorticoids are among the most widely used anti-inflammatory and immunosuppressive drugs; at least 1 in 100 people in the United Kingdom and the United States is on chronic glucocorticoid therapy at any time. ^[1]
• As a guide, the same anti-inflammatory effect is provided by about 20 mg hydrocortisone, 5 mg prednisone or prednisolone, 4 mg methylprednisolone or triamcinolone, and 0.5 mg dexamethasone or betamethasone. ^[1]
• Any daily dose above the physiologic daily dose equivalent can suppress the hypothalamic-pituitary-adrenal axis, but courses shorter than 3 to 4 weeks usually do not produce clinically important suppression. ^[1]
• Tapering is more rapid in the supraphysiologic range and slower near the physiologic range; morning serum cortisol guides when stopping is safe. ^[1]
• Systemic adverse effects are common: they occur in nearly 50% of long-term users, and doses as low as prednisone 2.5 to 7.5 mg per day are linked to bone, cardiovascular and infection risk. ^[1][2]

By the end of this page you should be able to:

1. Explain how exogenous glucocorticoids suppress the hypothalamic-pituitary-adrenal axis and why recovery varies.
2. Convert between systemic glucocorticoids using the equivalent-dose table and explain its limits.
3. Distinguish short-term from long-term courses and know when testing is needed.
4. Taper a glucocorticoid safely, separating the therapeutic taper from the endocrine taper.
5. Recognise and manage glucocorticoid withdrawal syndrome.
6. Prescribe stress-dose cover for illness, procedures and surgery.
7. List the serious and common adverse effects of systemic therapy and the monitoring they require.
8. Apply sick-day rules, emergency cards and patient education in practice.

Glucocorticoids are steroid drugs that mimic cortisol, the hormone made by the adrenal cortex. They are prescribed because they reduce inflammation and suppress immune responses, and they remain central to the treatment of autoimmune, inflammatory, allergic, haematological and transplant-related disease. ^[1] This page covers the safe use of systemic glucocorticoid therapy in adults: how doses are compared, why and how the stress system is suppressed, how to withdraw treatment without adrenal crisis, how to give extra doses during stress, and what monitoring limits harm. ^[1][2]

This page does not deal with replacement therapy for adrenal failure or with individual disease protocols. It sets out the principles that apply to every patient who takes a systemic glucocorticoid for a non-endocrine condition. ^[1]

Systemic glucocorticoids are used when inflammation or immune activity itself is harming the patient, for example severe asthma, inflammatory bowel disease, connective tissue disease, nephrotic syndrome, autoimmune cytopenias, multiple sclerosis relapse, selected malignancies and severe skin disease. They are also given in large doses for short periods in anaphylaxis and severe allergic reactions and are used as lifelong replacement when the adrenal cortex fails. ^[1] The decision to prescribe is clinical and disease-specific; this page addresses what follows from that decision. ^[1]

No benefit is absolute, and caution is needed where a glucocorticoid is likely to worsen the disease course. Conditions needing caution include active infection, uncontrolled hypertension, poorly controlled diabetes mellitus, osteoporosis or recent fragility fracture, peptic ulcer disease, recent live vaccination, severe psychiatric disease and a history of steroid-induced psychosis. ^[2] In such situations the lowest effective dose and shortest duration should be used, with the patient and pharmacist involved in the plan. ^[2] Pregnancy, childhood and older age are not absolute barriers but need specific measures described later. ^[3]

Cortisol is produced by the zona fasciculata of the adrenal cortex under the control of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH in turn is driven by corticotropin-releasing hormone (CRH) from the hypothalamus. Cortisol completes the loop by negative feedback, suppressing both CRH and ACTH. ^[1] This is the hypothalamic-pituitary-adrenal (HPA) axis, and it is this axis that exogenous glucocorticoids suppress. ^[1]

Cortisol is not secreted evenly across the day: it peaks in the early morning, is lowest late at night and surges during illness, trauma, surgery and severe stress. A healthy adult produces roughly 9 to 10 mg of cortisol a day on average in the ESE/ES 2024 guideline (about 5.7 to 7.4 mg per m2 of body surface area per day, or 5 to 22 mg per day, in Priya et al. 2024), which is the physiologic benchmark used to judge replacement and tapering doses. ^[1][4] The adrenal cortex also makes mineralocorticoids (aldosterone) and weak androgens, controlled mainly by the renin-angiotensin system and potassium rather than ACTH. This is why these hormones are usually spared when tablets suppress the axis. ^[1]

Before a prolonged or high-dose course is begun, record a baseline. Weight, blood pressure and, where relevant, blood glucose should be measured, fracture risk assessed, and eye and mood history noted. ^[2] Complications such as hypertension, diabetes, bone loss and infection often develop silently, so baseline data matter. ^[1][2] Education at the outset is also essential: patients should receive written information about the endocrine effects of treatment. ^[1]

The 2024 European Society of Endocrinology and Endocrine Society guideline divides courses by both duration and dose. ^[1]

• Short-term glucocorticoid therapy is any glucocorticoid therapy of less than 3 to 4 weeks duration. ^[1]
• Long-term glucocorticoid therapy is glucocorticoid therapy for greater than 3 to 4 weeks at a dose above the physiologic daily dose equivalent. ^[1]
• Physiologic daily dose equivalent is the daily dose equal to average daily cortisol production: 15 to 25 mg hydrocortisone, 4 to 6 mg prednisone or prednisolone, 3 to 5 mg methylprednisolone, or 0.25 to 0.5 mg dexamethasone. ^[1]
• Supraphysiologic glucocorticoid therapy is any dose above that physiologic daily dose equivalent. ^[1]

A course is considered to put the HPA axis at risk only if both thresholds are crossed: at least 3 to 4 weeks, at a dose above 15 to 25 mg hydrocortisone equivalent per day (4 to 6 mg prednisone or prednisolone, 3 to 5 mg methylprednisolone, 0.25 to 0.5 mg dexamethasone). ^[1] However, any dose above the physiologic daily dose equivalent can potentially suppress the axis, and individual susceptibility varies. ^[1]

Short courses of less than 3 to 4 weeks, whatever the dose, need not be tapered. They may be stopped without testing because concern for HPA axis suppression is low. ^[1]

For long-term therapy, tapering should be attempted only when the disease being treated is controlled and the drug is no longer required. ^[1] The taper then passes through two phases. ^[1] The therapeutic taper reduces the dose according to the underlying disease; the endocrine taper reduces it according to the needs of the HPA axis. As a clinical rule, tapering can be more rapid while the dose remains supraphysiologic, followed by a slower taper once the physiologic daily dose equivalent is reached (around 4 to 6 mg prednisone). ^[1] This is also the point at which glucocorticoid withdrawal most often appears. ^[1]

Patients taking long-acting glucocorticoids such as dexamethasone or betamethasone should be switched to shorter-acting agents such as hydrocortisone or prednisone when the long-acting drug is no longer needed. ^[1] Shorter-acting drugs are easier to taper and allow recovery of the axis to be assessed. ^[1]

Routine testing for adrenal insufficiency in a patient still on a supraphysiologic dose, or still needing glucocorticoid treatment for the underlying disease, is not recommended. ^[1] Testing belongs only to the final phase, when the aim is to stop therapy altogether. ^[1]

A patient on a physiologic daily dose equivalent who aims to discontinue therapy has two acceptable routes. ^[1]

1. Continue a gradual taper of the glucocorticoid dose while being monitored clinically for signs and symptoms of adrenal insufficiency. ^[1]
2. Stop tapering and test with a morning serum cortisol. ^[1]

When confirmation of HPA axis recovery is desired, morning serum cortisol is the first test; its value is a continuum, with higher values indicating more complete recovery. ^[1]

• Recovery is suggested when morning cortisol is greater than 300 nmol/L (greater than 10 microg/dL); glucocorticoids can be stopped safely. ^[1][5]
• When the value is between 150 and 300 nmol/L (between 5 and 10 microg/dL), the physiologic dose should be continued and morning cortisol repeated after weeks to months. ^[1][5]
• When the value is below 150 nmol/L (below 5 microg/dL), the physiologic dose should be continued and morning cortisol repeated after a few months. ^[1][5]

Morning cortisol cut-offs are a continuum and vary between references: the ESE/ES 2024 guideline (Ref 1) and the Endocrine Society (Ref 5) use the 300 and 150 nmol/L cut-offs above, whereas Priya et al. 2024 (Ref 4) describes morning cortisol below 100 nmol/L (below 3 microg/dL) as diagnostic of adrenal insufficiency and above 450 nmol/L (above 15 microg/dL) as excluding it, with 100 to 450 nmol/L inconclusive. ^[1][4]

Routine dynamic testing, such as the 250 microg ACTH stimulation test, is not recommended in this setting. ^[1]

The degree and persistence of axis suppression depend on overall exposure: the potency and dose of the drug, the duration of therapy, the route of administration and individual susceptibility. ^[1] Recovery of the adrenal cortex is highly variable and may take months to years. In one meta-analysis, pooled adrenal insufficiency fell from 38.7% to 14.9% four weeks after stopping short-term high-dose courses, and from 56.4% to 25.3% six months after long-term medium-dose courses. ^[1] Other series report recovery anywhere from a few months to up to 4 years in some patients. ^[1] All biochemical suppression is not the same as clinical disease: in one meta-analysis of 521 patients, only 10 of 98 with biochemical suppression reported symptoms. ^[1]

A patient who has been on a physiologic daily dose equivalent for about a year without recovery of the axis should be evaluated by an endocrinologist, and so should any patient with a history of adrenal crisis. ^[1]

Glucocorticoid withdrawal syndrome is the set of symptoms that can occur while tapering within the supraphysiologic dose range. ^[1] It is defined as symptoms that are neither due to the underlying disease being treated nor the result of untreated adrenal insufficiency, since the total daily dose is still supraphysiologic. ^[1] In practice, the symptoms of withdrawal overlap with those of adrenal insufficiency, which is what makes tapering challenging. ^[1]

When withdrawal is severe, the dose can be increased temporarily to the most recent dose tolerated, and the duration of the taper extended. ^[1] Patients should be monitored clinically throughout. ^[1]

Equivalent dose is a rough conversion between preparations, used when switching drugs. It is an estimate based on historically accepted factors, not a precise calculation, and the relationships change with route of administration, individual metabolism and individual susceptibility. ^[1] Equivalent potencies apply to oral or intravenous administration and do not capture mineralocorticoid effects: hydrocortisone and cortisone have appreciable mineralocorticoid activity, whereas synthetic glucocorticoids have much less. ^[1]

Equivalent doses are estimates and differ between sources. The ESE/ES 2024 guideline (Ref 1) gives dexamethasone 0.5 mg, betamethasone 0.5 mg and deflazacort 7.5 mg, whereas other common tables give dexamethasone 0.75 mg and betamethasone 0.6 mg (Liu et al. 2013, Ref 5; Priya et al. 2024, Ref 4) or dexamethasone 0.75 mg and betamethasone 0.75 mg (BNF/NICE table, Ref 6), and deflazacort 6 mg (BNF/NICE table, Ref 6; Calcort product label). Follow the table named by your guideline or local formulary. ^[1][4][5][6]

A few practical points follow. ^[1][3]

• Dexamethasone and betamethasone are long-acting and highly potent, so they are usually reserved for short-term use in severe acute conditions; they are not suitable for chronic replacement or easy tapering. ^[1]
• Dexamethasone is avoided for routine adrenal replacement because of difficulty in dose titration and Cushingoid side effects. ^[3]
• Prednisolone 3 to 5 mg per day is the typical physiologic adult replacement dose in some endocrine guidance (Bornstein et al. 2016, Ref 3), and hydrocortisone 15 to 25 mg per day is an equivalent physiologic adult replacement dose (Ref 3); the ESE/ES 2024 guideline quotes a slightly higher physiologic daily dose equivalent of 4 to 6 mg prednisone or prednisolone and 15 to 25 mg hydrocortisone (Ref 1). Higher daily doses are supraphysiologic. ^[1][3]
• Cortisone and hydrocortisone are the agents that behave physiologically; they are preferred for replacement. ^[3]

A patient who is on or has recently stopped a systemic glucocorticoid may not mount enough cortisol during illness, surgery, trauma or severe stress. That is why current or recent users who have not been biochemically tested require stress-dose cover whenever they are exposed to stress. ^[1]

Patients with current or recent glucocorticoid use who have not been biochemically tested to exclude glucocorticoid-induced adrenal insufficiency should receive stress-dose coverage whenever they are exposed to stress. ^[1]

• Oral glucocorticoids should be used in minor stress, and when there are no signs of haemodynamic instability or prolonged vomiting or diarrhoea. ^[1]
• Parenteral glucocorticoids should be used in moderate to major stress, procedures under general or regional anaesthesia, procedures requiring prolonged avoidance of oral intake, or when there are signs of haemodynamic instability or prolonged vomiting or diarrhoea. ^[1]

The diagnosis of adrenal crisis should be considered, regardless of glucocorticoid type, route or dose, in any patient with current or recent glucocorticoid use who presents with haemodynamic instability, vomiting or diarrhoea, and these patients should be treated with parenteral glucocorticoids and fluid resuscitation. ^[1]

The Endocrine Society's primary adrenal insufficiency guideline provides widely used stress-dose numbers, and the same principles are applied to glucocorticoid-induced insufficiency. ^[3]

• During intercurrent illness with fever, hydrocortisone replacement doses are doubled above 38 degrees C and tripled above 39 degrees C, until recovery, usually 2 to 3 days, with extra electrolyte-containing fluids as tolerated. ^[3]
• If the patient cannot take tablets because of gastroenteritis or trauma, give 100 mg hydrocortisone by intramuscular or subcutaneous injection in adults (50 mg per m2 in children), and seek help. ^[3]
• For minor to moderate surgical stress, give 25 to 75 mg hydrocortisone per 24 hours for 1 to 2 days. ^[3]
• For major surgery, trauma, delivery, or any condition needing intensive care: hydrocortisone 100 mg intravenously followed by a continuous intravenous infusion of 200 mg per 24 hours, alternatively 50 mg every 6 hours, with weight-appropriate intravenous fluids and rapid tapering back to an oral regimen as the clinical state allows. ^[3]
• For an acute adrenal crisis: 100 mg hydrocortisone intravenously immediately, followed by 200 mg per 24 hours, together with 1 L of isotonic saline rapidly, then continued fluid resuscitation. ^[3]

Hydrocortisone is preferred in crisis; if it is unavailable, prednisolone is the alternative, and dexamethasone is least preferred and reserved for when nothing else is available. ^[3] For minor illness, a patient on long-term sub-physiologic or physiologic therapy should increase their oral glucocorticoid as described and seek review if they cannot keep tablets down. ^[1][3]

Every patient who is on a systemic glucocorticoid should be educated about stress dosing. ^[1][3] Patient education should be individualised and should cover sick-day management, recognition of the symptoms of adrenal insufficiency, and when to seek urgent medical attention. ^[2]

• A steroid emergency card informs any healthcare worker who sees the patient that they are on, or have recently been on, a glucocorticoid and may need extra doses in an emergency. ^[2][3]
• Medical identification and a pre-filled glucocorticoid injection kit for emergency use should be provided, with training for the patient and, where possible, a family member or carer. ^[3]
• In glucocorticoid-induced adrenal insufficiency, fludrocortisone is not used, because the mineralocorticoid (renin-angiotensin-aldosterone) axis is intact. ^[1]

Glucocorticoids are highly effective, but they cause adverse reactions, especially at high doses and with prolonged use. Even relatively low doses, in the range of the physiologic daily dose equivalent, are linked to harm when used long term. ^[1] In a British cohort study of 9387 patients with rheumatoid arthritis followed for a median of 8 years (average prednisone 5.8 mg per day for about 9.5 months), treated patients had higher rates of diabetes, osteoporosis, fracture, hypertension, thrombotic events, gastrointestinal complications and increased mortality than those not treated with glucocorticoids. ^[1] Confounding by underlying disease severity cannot be excluded. ^[1] Additional studies link even low doses, prednisone 2.5 to 7.5 mg per day, to increased risks of cardiovascular disease, severe infection, hypertension, diabetes, osteoporosis and fracture, and increased overall mortality in people with type 2 diabetes mellitus. ^[1] Nearly half of long-term corticosteroid users worldwide experience adverse effects, with long-term meaning more than three months of continuous systemic use. ^[2] Adverse effects occur in nearly 50% of patients on long-term therapy. ^[2]

The main harms of systemic therapy are listed below. Each should be explained to the patient and considered in the monitoring plan. ^[1][2]

• Endocrine and metabolic. Weight gain and central obesity, hyperglycaemia and new-onset diabetes, fluid retention and signs of Cushing syndrome. ^[1][2]
• Bone and muscle. Loss of bone density, osteoporosis and fragility fracture, and proximal myopathy. ^[1]
• Cardiovascular. Hypertension, atherosclerotic disease and thromboembolic events. ^[1]
• Infection. General immunosuppression, with increased risk of bacterial, viral and fungal infection; this is the most dangerous risk of prolonged therapy. ^[2] A short 3-day burst of 10 mg per day can significantly raise the risk of gastrointestinal haemorrhage, sepsis and heart failure, particularly in the first month. ^[2]
• Eye. Posterior subcapsular cataract and glucocorticoid-induced raised intraocular pressure with glaucoma; risk rises with duration. ^[2]
• Gastrointestinal. Dyspepsia and peptic ulceration or bleeding, especially with concurrent NSAIDs. ^[1][2]
• Skin, connective tissue and wound healing. Skin atrophy, striae, bruising and impaired wound healing. ^[2]
• Neuropsychiatric. Insomnia, mood change, anxiety and, less often, psychosis or hypomania. ^[2]
• Growth. In children, prolonged therapy causes growth suppression in about 25 to 30% of patients and excessive weight gain in up to 50%. ^[2]
• HPA axis suppression. This is itself an adverse effect of treatment and is the cause of glucocorticoid-induced adrenal insufficiency. ^[1]

Systemic exposure is not the only source of harm, and every route can suppress the HPA axis. ^[1]

• Intra-articular injection can produce local flare and HPA axis suppression, particularly with frequent injections (more than 3 per year), high-potency agents such as triamcinolone above 40 mg, or concurrent systemic steroid. ^[2]
• Topical ophthalmic preparations can raise intraocular pressure and cause glaucoma, visual impairment and cataract; powerful formulations (dexamethasone, betamethasone) used for long periods are the main offenders, particularly in the young and in males. ^[2]
• Inhaled corticosteroids at high dose (501 to 1000 microg fluticasone equivalent) for more than a year are associated with posterior subcapsular cataract and glaucoma, particularly in older patients. ^[2]
• High-potency topical dermatological steroids used for more than 6 weeks can produce skin atrophy, hypopigmentation, striae and telangiectasia and can mask fungal or scabies infection (tinea incognito, scabies incognito); large-area or occluded application of potent topical preparations, alone or with systemic steroids, can produce systemic effects such as Cushingoid appearance, new-onset hypertension and diabetes. ^[2]

Supraphysiologic doses, defined as a prednisone equivalent dose greater than 5 mg daily, have been associated with a higher risk of all-cause mortality in rheumatoid arthritis patients, with an adjusted hazard ratio of 1.97 (95% CI 1.81 to 2.15), and the risk increases with higher current daily and cumulative doses. ^[1] This association was not observed with daily doses below 5 mg prednisone equivalent. ^[1] Confounding by disease activity cannot be excluded. ^{[1] [2]}

Monitoring should be guided by dose, duration, route, underlying condition and individual risk factors. ^[2]

• Clinical: weight, blood pressure, glucose, signs of Cushing syndrome, general well-being, mood and sleep. ^[1][2]
• Metabolic: blood glucose during prolonged courses; documented new-onset hyperglycaemia is a priority for pharmacovigilance. ^[2]
• Bone health should be assessed in patients on prolonged therapy or with risk factors, because bone density may be reduced. ^[1][2]
• Eye examination for raised intraocular pressure and cataract during prolonged or potent systemic, inhaled or topical use. ^[2]
• Infection vigilance throughout therapy and after stopping, because immunosuppression lingers; a short prednisone burst raises sepsis risk particularly in the first month. ^[2]
• Long-term patients need a documented taper plan; the presence of a taper plan is a measurable stewardship indicator. ^[2]
• Patients need an up-to-date steroid emergency card and education on sick-day dosing. ^[1][2][3]
• Documentation of indication, dose, duration, monitoring plan and, where applicable, taper strategy, supports continuity of care and planned follow-up. ^[2]

Therapy in children should use the lowest effective dose for the shortest duration. Children are particularly vulnerable to growth suppression (about 25 to 30%) and excessive weight gain (up to 50%). ^[2] Replacement for primary adrenal insufficiency uses hydrocortisone at about 8 mg per m2 body surface area per day divided into doses rather than long-acting synthetic glucocorticoids, and the same principle of preferring short-acting agents applies to systemic therapy given for other disease. ^[3]

Therapy in pregnancy is individualised and directed by the treating specialist team. The choice of agent matters: dexamethasone crosses the placenta and is not inactivated, so it is avoided in pregnancy when fetal exposure is undesirable; hydrocortisone, prednisone and prednisolone are preferred in replacement regimens. ^[3] Doses often need to rise during the third trimester, and stress dosing is required in labour and delivery. ^[3]

Older patients are more often prescribed systemic glucocorticoids and appear more often in population data. ^[1] They carry higher risks of bone loss, hyperglycaemia, hypertension and infection, so monitoring should be tighter. ^[2]

People with diabetes, hypertension, osteoporosis or glaucoma warrant closer monitoring, and steroid-sparing therapy should be considered early so that glucocorticoid exposure can be reduced once the disease is controlled. ^[2]

Glucocorticoid therapy can be given safely without advanced technology if a few principles are observed.

• Use the lowest effective dose for the shortest duration and use oral rather than parenteral administration whenever possible. ^[2]
• Taper when the disease is controlled and keep the final reduction slow near the physiologic dose equivalent. ^[1]
• Provide a steroid emergency card and teach sick-day dosing using ordinary hydrocortisone tablets where possible. ^[1][2][3]
• Ensure that at-risk patients can obtain an emergency hydrocortisone injection and that a relative or carer is trained to give it. ^[2][3]
• Monitor blood pressure, weight and glucose opportunistically; bone and eye screening may need referral. ^[2]
• Dexamethasone is widely available and inexpensive, but its long action makes it unsuitable for chronic use or easy tapering; switch to a shorter-acting agent for the endocrine phase. ^[1][2]
• Over-the-counter access to potent preparations should be regulated, because unsupervised dispensing drives misuse, dermatological harm and masking of infection. ^[2]

Adrenal insufficiency and adrenal crisis. Cushing syndrome. Osteoporosis and fragility fracture prevention. Diabetes mellitus. Systemic hypertension. Glaucoma and cataract. Peptic ulcer disease. Polymyalgia rheumatica.