Hydrocortisone

What it is

Hydrocortisone is the pharmaceutical name for cortisol, the main glucocorticoid hormone the human adrenal cortex makes. Unlike most drugs it is therefore identical to a hormone already in the body, released in a daily rhythm under the control of the hypothalamic-pituitary-adrenal axis. It is sold as tablets and injections for systemic use and as creams, ointments, lotions, foams, suppositories and eye preparations for local use; the 0.5% and 1% skin creams are sold over the counter in the US while 2.5% strengths are prescription-only. Because it is both a glucocorticoid and a weak mineralocorticoid, it retains salt as well as suppressing inflammation.

What the research says

The uses split into two very different evidence bases. As hormone replacement in adrenal insufficiency it is life-sustaining, and the comparative literature is thin and low certainty: a systematic review of 34 studies found no clear difference in quality of life between higher and lower daily doses or between dosing frequencies, and adrenal crises still happen at about 8 per 100 patient-years even in educated patients. As an anti-inflammatory it suppresses inflammation wherever it is applied, and the Cochrane review of topical corticosteroid strategies in eczema shows potency matters up to a point. The harms are well characterised and dose- and duration-dependent: suppression of the body's own cortisol production after stopping, thinning of the skin where creams are used long-term on the face, a 40% relative increase in gastrointestinal bleeding, and raised blood sugar. In critical illness the trials disagree - one large trial found no mortality benefit in septic shock, another found a 6-percentage-point reduction with added fludrocortisone, and a third found a 5.6-percentage-point reduction in severe pneumonia.

Evidence grade: Well established.

How it works

Drug class: Glucocorticoid (adrenal corticosteroid) with additional mineralocorticoid activity; identical to endogenous cortisol

Cortisol is a steroid hormone made by the adrenal cortex in a daily rhythm, highest in the morning and lowest at night, under the control of CRH from the hypothalamus and ACTH from the pituitary, with negative feedback from cortisol itself. Once in the blood it enters cells, binds the glucocorticoid receptor and changes which genes are switched on - which is how it both damps down inflammation and immune responses and alters metabolism, blood sugar, bone, blood vessels and brain function. Giving hydrocortisone as a drug adds to this same system, which is why it both does the job of the missing hormone in adrenal insufficiency and shuts down the body's own production when given in excess. (Source 1)

What it is used for

• Hydrocortisone or cortisone is the first-choice replacement on the label, and the need for replacement is not in dispute - it is a hormone the body cannot do without. What the literature does NOT establish is the best regimen: a systematic review of 34 studies found no difference in quality of life between higher (>=30 mg/day) and lower daily doses or between once, twice and three-times daily dosing, and rated the evidence low quality. Evidence: established. (Source 2)
• Topical corticosteroids are labelled for the inflammatory and itchy manifestations of corticosteroid-responsive skin disease, and the Cochrane review of 104 trials found moderate-certainty evidence that moderate-potency steroids beat mild ones (52% versus 34% treatment success) and potent beat mild (70% versus 39%), with no clear advantage of very potent over potent. Hydrocortisone is at the mild end of that scale, so it is the weaker comparator in most of these trials. Evidence: established. (Source 3)
• The oral label lists a long catalogue of conditions, mostly as adjunctive therapy to tide someone over an acute episode. For most of these there is no modern placebo-controlled outcome trial of hydrocortisone specifically; the indications are largely historical, and the label itself is a regulatory position dated to its publication rather than evidence. Evidence: limited. (Source 2)
• Two large trials published within weeks of each other disagreed. ADRENAL (3,800 patients) found 90-day mortality of 27.9% on hydrocortisone versus 28.8% on placebo - no difference - though shock resolved faster. APROCCHSS (1,241 patients) gave hydrocortisone plus fludrocortisone and found 43.0% versus 49.1% mortality at 90 days. The two trials differed in severity of illness and in whether fludrocortisone was added. Evidence: disputed. (Source 4)
• The CAPE COD trial randomised 800 adults in intensive care with severe community-acquired pneumonia and found 28-day death in 6.2% on hydrocortisone versus 11.9% on placebo, an absolute difference of 5.6 percentage points. It is one trial, stopped early at a planned interim analysis, so the effect size should be treated with caution. Evidence: limited. (Source 5)
• In the WHO-sponsored prospective meta-analysis of seven corticosteroid trials, corticosteroids overall reduced 28-day mortality (OR 0.66), but the hydrocortisone subgroup alone - three trials, 374 patients, 94 deaths - did not reach statistical significance (OR 0.69, 95% CI 0.43 to 1.12). The class benefit was driven largely by dexamethasone. Evidence: limited. (Source 6)
• Two randomised placebo-controlled trials tested low-dose hydrocortisone on the theory that people with chronic fatigue syndrome have mildly low cortisol. One crossover trial of 32 patients found a small reduction in fatigue scores; the larger JAMA trial of 70 patients found improvement on one of several scales only, and documented suppression of adrenal responsiveness in 12 of 30 hydrocortisone recipients versus none on placebo, concluding that this precludes practical use. Evidence: not-supported. (Source 7)
• A systematic review of 58 studies found no substantiation that adrenal fatigue is a real condition, criticising in particular the unvalidated cortisol testing it rests on. There is therefore no recognised condition for which hydrocortisone could be the treatment here, and giving it would carry the documented risk of suppressing the body's own cortisol production. Evidence: not-supported. (Source 8)

Interactions

• Liquorice (glycyrrhizin-containing confectionery, teas and supplements) (clinical trial): Liquorice blocks the kidney enzyme 11-beta-hydroxysteroid dehydrogenase that normally inactivates cortisol, so cortisol - whether the body's own or taken as hydrocortisone - lingers in the kidney and acts like a salt-retaining hormone, raising sodium retention and blood pressure. This is a documented human mechanistic finding, not theory. (Source 9)
• Liquorice, in relation to cortisol testing (clinical trial): Eating liquorice for a week raised late-night salivary cortisol by 49% at a medium dose and 97% at a high dose, returning to baseline four days after stopping - so liquorice can make a cortisol test look abnormal when nothing is wrong. (Source 10)
• Hydrocortisone cream on the fingers, in relation to cortisol testing (clinical trial): In a randomised study of 30 volunteers, topical hydrocortisone on the fingers holding the saliva collection swab raised measured salivary cortisol more than a thousandfold. Anyone using hydrocortisone cream who is having a cortisol test needs to keep it off their hands and the swab. (Source 10)
• Rifampin (rifampicin), phenobarbital and phenytoin (label): These drugs induce the liver enzymes that break hydrocortisone down, so blood levels fall and more may be needed. In someone dependent on hydrocortisone replacement this can tip them into an adrenal crisis, which has been reported in case reports. (Source 11)
• Ketoconazole and troleandomycin (and other strong CYP3A4 inhibitors) (label): These slow the breakdown of corticosteroids, so the same dose produces more effect and more risk of steroid toxicity. (Source 11)
• High-dose aspirin and salicylates (label): Corticosteroids speed up the clearance of chronic high-dose aspirin, so salicylate levels fall while the steroid is on board and can rise toward toxicity when the steroid is withdrawn. Aspirin should be used cautiously with corticosteroids in people with hypoprothrombinaemia. (Source 11)
• Warfarin and other oral anticoagulants (case reports): The direction of the interaction is unpredictable - both strengthened and weakened anticoagulation have been reported - so clotting tests need watching rather than a fixed dose adjustment. (Source 11)
• Alcohol and non-steroidal anti-inflammatory drugs (shared gastrointestinal bleeding risk) (clinical trial): No pharmacokinetic interaction with alcohol is documented for hydrocortisone. What is documented is that corticosteroids themselves raise gastrointestinal bleeding and perforation risk by about 40% in relative terms, and the meta-analysis showed the increase persisted even when trials involving NSAIDs were excluded - so the drug contributes its own bleeding risk independent of other irritants. (Source 12)
• Hypothyroidism and cirrhosis (physiological state rather than a drug) (label): The label records an enhanced effect of corticosteroids in people with an underactive thyroid and in people with cirrhosis, meaning the same dose does more. (Source 13)

Stopping it

• Stopping systemic hydrocortisone after a course is not a clean break. The label states that drug-induced secondary adrenal insufficiency can be reduced by tapering the dose gradually, and - the part that matters most - that this relative insufficiency can persist for months after treatment ends, so steroid cover may be needed again during any period of physical stress in that window. (Source 13)
• The meta-analysis of 74 studies found adrenal insufficiency after stopping glucocorticoids is common and not confined to high oral doses - it occurred in 4.2% after nasal use and 52.2% after intra-articular injection, rose with dose from 2.4% (low dose) to 21.5% (high dose), and rose with duration from 1.4% (95% CI, 0.3-7.4) at under 28 days of treatment to 27.4% (95% CI, 17.7-39.8) beyond one year. The authors concluded there is no form, dose or duration where it can be excluded with certainty. (Source 14)
• For hydrocortisone creams, the prescribing information treats withdrawal as a two-sided problem: if cortisol axis suppression is detected the drug should be withdrawn, the frequency reduced or a weaker steroid substituted, and recovery of the axis is usually prompt - but signs and symptoms of steroid withdrawal can occur and may need systemic steroid cover. (Source 3)
• Topical corticosteroid withdrawal - burning, stinging and redness after stopping prolonged potent steroid use, usually on the face - is described in the literature as a distinct adverse effect of misuse rather than of normal prescribed use. Both the 2015 systematic review and its 2026 update stress that the evidence is case reports and case series with inconsistent diagnostic criteria, so the frequency is unknown. (Source 15)
• Replacement hydrocortisone in adrenal insufficiency is the opposite case: it cannot be stopped at all, and the risk runs the other way. In a 2-year prospective study of 423 patients who had been given written stress-dosing instructions, adrenal crises still occurred at 8.3 per 100 patient-years and four of ten deaths were crisis-related. (Source 16)
• For oral hydrocortisone, the label's own dosing instruction is to come down in small steps rather than at once: the maintenance dose is found by decreasing the initial dose in small decrements at appropriate intervals to the lowest dose that keeps control, and after long-term therapy the drug should be withdrawn gradually rather than abruptly. (Source 13)

What goes wrong

Adrenal insufficiency was found after every corticosteroid route studied - 4.2% after nasal use up to 52.2% after intra-articular injection - and rose steeply with exposure, from 1.4% (95% CI, 0.3-7.4) with less than 28 days of treatment to 27.4% (95% CI, 17.7-39.8) beyond one year of treatment in asthma patients. (Source 14)

• Systematic review, Moderate certainty.
• Size: 74 articles, 3,753 participants.
• Who: Adults who had taken corticosteroids for a range of conditions, tested for adrenal insufficiency.
• How long: Varied; the review stratified by treatment duration from under 28 days to over 1 year.
• Result: Stratified by administration form, percentages of patients with adrenal insufficiency ranged from 4.2% for nasal administration (95% confidence interval [CI], 0.5-28.9) to 52.2% for intra-articular administration (95% CI, 40.5-63.6). Stratified by disease, percentages ranged from 6.8% for asthma with inhalation corticosteroids only (95% CI, 3.8-12.0) to 60.0% for hematological malignancies (95% CI, 38.0-78.6). The risk also varied according to dose from 2.4% (95% CI, 0.6-9.3) (low dose) to 21.5% (95% CI, 12.0-35.5) (high dose), and according to treatment duration from 1.4% (95% CI, 0.3-7.4) (<28 d) to 27.4% (95% CI, 17.7-39.8) (>1 year) in asthma patients.
• Funding: Academic meta-analysis in the Journal of Clinical Endocrinology and Metabolism; no industry funding stated.

Stratified by administration form, percentages of patients with adrenal insufficiency ranged from 4.2% for nasal administration (95% confidence interval [CI], 0.5-28.9) to 52.2% for intra-articular administration (95% CI, 40.5-63.6). Stratified by disease, percentages ranged from 6.8% for asthma with inhalation corticosteroids only (95% CI, 3.8-12.0) to 60.0% for hematological malignancies (95% CI, 38.0-78.6). The risk also varied according to dose from 2.4% (95% CI, 0.6-9.3) (low dose) to 21.5% (95% CI, 12.0-35.5) (high dose), and according to treatment duration from 1.4% (95% CI, 0.3-7.4) (<28 d) to 27.4% (95% CI, 17.7-39.8) (>1 year) in asthma patients.

Corticosteroids raised the risk of gastrointestinal bleeding or perforation by about 40% in relative terms, from 2.0% to 2.9% in absolute terms, with the increase statistically significant only in hospitalised patients. (Source 12)

• Meta-analysis, Moderate certainty.
• Size: 159 randomised double-blind trials, 33,253 participants, 804 bleeding or perforation events.
• Who: Patients given a systemic corticosteroid versus placebo for any medical condition, or healthy volunteers; hospitalised and ambulatory.
• How long: Trials published 1983 to May 2013; varied durations.
• Result: In total, 804 (2.4%) patients had a gastrointestinal bleeding or perforation (2.9% and 2.0% for corticosteroids and placebo). Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66). For patients in ambulatory care, the increased risk was not statistically significant (OR 1.63, 95% CI 0.42 to 6.34).
• Funding: Academic systematic review in BMJ Open; no industry funding stated.

Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66).

Even in people formally educated about dose adjustment, adrenal crises occurred at 8.3 per 100 patient-years and about 6% of crises were fatal. (Source 16)

• Cohort study, Moderate certainty.
• Size: 423 patients with adrenal insufficiency at baseline (221 primary, 202 secondary); 364 completed; 767.5 patient-years.
• Who: Adults with chronic adrenal insufficiency on glucocorticoid replacement, given written stress-dosing instructions.
• How long: 2 years of prospective follow-up with 6-monthly questionnaires.
• Result: Sixy-four AC in 767.5 patient-years were documented (8.3 crises per 100 patient-years). Precipitating causes were mainly gastrointestinal infection, fever, and emotional stress (20%, respectively) but also other stressful events (eg, major pain, surgery, strenuous physical activity, heat, pregnancy) or unexplained sudden onset of AC (7%) were documented. Patients with a previous AC were at higher risk of crisis (odds ratio 2.85, 95% confidence interval 1.5-5.5, P < .01). However, no further risk factors could be identified. Ten patients died during follow-up; in four cases death was associated with AC (0.5 AC related deaths per 100 patient-years).
• Funding: Academic prospective study in the Journal of Clinical Endocrinology and Metabolism; no industry funding stated in the abstract.

Sixy-four AC in 767.5 patient-years were documented (8.3 crises per 100 patient-years). Precipitating causes were mainly gastrointestinal infection, fever, and emotional stress (20%, respectively) but also other stressful events (eg, major pain, surgery, strenuous physical activity, heat, pregnancy) or unexplained sudden onset of AC (7%) were documented.

Long-term topical corticosteroid use causes skin atrophy, striae, rosacea, perioral dermatitis, acne and purpura, and systemic effects including hyperglycaemia, glaucoma and adrenal insufficiency have followed skin application. (Source 17)

• Expert review, not systematic, Low certainty.
• Size: Not a pooled analysis; an expert review of the published adverse-effect literature.
• Who: People using topical corticosteroids, with children highlighted as higher risk because of their surface-area-to-weight ratio.
• How long: Effects described as occurring regularly with prolonged treatment.
• Result: No pooled rates given. The review states that reporting of adverse reactions to topical corticosteroids is 'poor and incomplete' and that contact sensitisation to corticosteroids is commoner than generally believed.
• Funding: Continuing-medical-education review in the Journal of the American Academy of Dermatology; funding not stated.

The most frequent adverse effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura. Those that occur with lower frequency include hypertrichosis, pigmentation alterations, delayed wound healing, and exacerbation of skin infections. Of particular interest is the rate of contact sensitization against corticosteroids, which is considerably higher than generally believed. Systemic reactions such as hyperglycemia, glaucoma, and adrenal insufficiency have also been reported to follow topical application.

Within the subset of trials that tested flare-up treatment strategies, abnormal skin thinning was identified in only 26 of 2,266 participants (1% across 22 trials) and was concentrated in the higher-potency steroids; this is the rate inside those short flare trials, not a general rate of skin thinning from topical corticosteroid use. (Source 18)

• Systematic review, Low certainty.
• Size: 26 cases among 2,266 participants across 22 trials.
• Who: Children and adults treated for an eczema flare in randomised trials of flare-up treatment strategies; not a general population of topical corticosteroid users.
• How long: Mostly one to five weeks.
• Result: we identified only 26 cases of abnormal skin thinning from 2266 participants (1% across 22 trials). Most cases were from the use of higher-potency topical corticosteroids (16 with very potent, 6 with potent, 2 with moderate and 2 with mild).
• Funding: Cochrane review; the authors rate this adverse-event evidence low or very low certainty and note the trials were short.

Limit of this finding: The 1% figure comes only from the trials of treating an eczema flare-up, which were mostly one to five weeks long, and the review authors rate this adverse-event evidence low or very low certainty. It should not be read as the chance of skin thinning from using a topical corticosteroid in general, and especially not from long-term or repeated use, which these trials were too short to measure.

we identified only 26 cases of abnormal skin thinning from 2266 participants (1% across 22 trials). Most cases were from the use of higher-potency topical corticosteroids (16 with very potent, 6 with potent, 2 with moderate and 2 with mild). We assessed this evidence as low certainty, except for very potent versus potent topical corticosteroids, which was very low-certainty evidence.

Topical corticosteroid withdrawal is a described adverse effect of prolonged misuse of potent steroids, mostly on the face and genitals of women, with burning and stinging the commonest symptoms. (Source 15)

• Systematic review, Very low certainty.
• Size: 34 studies meeting inclusion criteria from 294 search results.
• Who: Patients with atopic dermatitis and other dermatoses who had used topical corticosteroids long-term, mostly women.
• How long: Mostly long-term inappropriate use of potent preparations.
• Result: TCS withdrawal was reported mostly on the face and genital area (99.3%) of women (81.0%) primarily in the setting of long-term inappropriate use of potent TCS. Burning and stinging were the most frequently reported symptoms (65.5%) with erythema being the most common sign (92.3%). TCS withdrawal syndrome can be divided into papulopustular and erythematoedematous subtypes, with the latter presenting with more burning and edema.
• Funding: Systematic review commissioned in response to National Eczema Association patient enquiries; funding not stated.

Low quality of evidence, variability in the extent of data, and the lack of studies with rigorous steroid addiction methodology are limitations.

An updated systematic review found the topical corticosteroid withdrawal literature still consists almost entirely of case reports, with inconsistent diagnostic criteria. (Source 19)

• Systematic review, Very low certainty.
• Size: 7 studies added (five case reports, one case series, one qualitative cross-sectional survey)
• Who: People reporting symptoms after prolonged topical corticosteroid use, predominantly adult women using potent steroids on the face.
• How long: Literature October 2020 to June 2024.
• Result: TCSW appears to predominantly occur in adult women (90%) using TCS for atopic dermatitis (99.5%), mostly on the face (90%). Common symptoms include burning (89.8%), itching (85.6%), and skin hypersensitivity (82.3%), with erythema (89.6%) and desquamation (88.7%).
• Funding: Academic systematic review in Cureus; funding not stated.

Inconsistent diagnostic criteria, variable definitions, and the primarily descriptive nature of the currently available evidence complicate accurate diagnosis and treatment of TCSW.

Systemic absorption of corticosteroid applied to skin has produced reversible suppression of the body's own cortisol axis, Cushing's syndrome features, high blood sugar and sugar in the urine. (Source 3)

• Official position, Certainty not rated.
• Size: Cumulative label safety data; no numbers given.
• Who: People using topical corticosteroids, especially over large areas, for long periods, or under occlusive dressings.
• How long: Not stated.
• Result: No rates given in the label. Risk factors listed are more potent steroids, use over large surface areas, prolonged use and occlusive dressings.
• Funding: US FDA-approved prescribing information (a regulatory position with its publication date, not a trial)

Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.

In septic shock trials hydrocortisone did not increase serious adverse events overall, but hyperglycaemia and insulin requirement were consistently higher. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 1,241 patients in APROCCHSS; 795 analysed in CAPE COD.
• Who: Adults with septic shock, and adults in intensive care with severe community-acquired pneumonia.
• How long: 7 days of treatment (APROCCHSS); 8 to 14 days including taper (CAPE COD)
• Result: APROCCHSS: serious adverse event rates did not differ significantly, but hyperglycaemia was more common on hydrocortisone plus fludrocortisone. CAPE COD: hospital-acquired infection and gastrointestinal bleeding were similar, but the hydrocortisone group needed higher daily insulin doses in the first week.
• Funding: Both trials publicly funded (French Ministry of Health / Ministry of Social Affairs and Health)

The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.

Rifampicin accelerates cortisol metabolism enough to precipitate an adrenal crisis in someone whose adrenal reserve is already compromised. (Source 21)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: A 55-year-old man with tuberculous infiltration of the adrenal glands started on antituberculosis therapy including rifampicin.
• How long: Crisis one week after starting treatment.
• Result: Single case; he improved only after hydrocortisone was started and rifampicin stopped, and a short Synacthen test then confirmed primary adrenal insufficiency.
• Funding: Case report in BMJ Case Reports; no funding stated.

He was transferred to critical care and only improved after starting hydrocortisone and stopping rifampicin. His short synACTHen test subsequently confirmed primary adrenal insufficiency, and a CT of the abdomen showed bilateral adrenal enlargement. Rifampicin is known to accelerate cortisol metabolism.

What the evidence supports

Potency matters for topical corticosteroids in eczema up to a point: moderate beats mild and potent beats mild, but potent does not clearly beat moderate and very potent does not clearly beat potent. (Source 22)

• Systematic review, Moderate certainty.
• Size: 104 trials, 8,443 participants; the potency comparisons pooled 420, 392, 1,053 and 216 participants.
• Who: Children and adults with eczema, usually moderate or severe, mostly in high-income outpatient or hospital settings.
• How long: Usually one to five weeks for flare treatment; 16 to 20 weeks for relapse prevention.
• Result: Moderate-potency topical corticosteroids probably result in more participants achieving treatment success, defined as cleared or marked improvement on IGA (52% versus 34%; odds ratio (OR) 2.07, 95% confidence interval (CI) 1.41 to 3.04; moderate-certainty evidence).
• Funding: Cochrane review; only one of 104 trials was judged low risk of bias across all domains, and 55 had high risk of bias in at least one domain.

Potent topical corticosteroids probably result in a large increase in number achieving treatment success (70% versus 39%; OR 3.71, 95% CI 2.04 to 6.72; moderate-certainty evidence). We pooled 15 trials that compared potent versus moderate-potency topical corticosteroids (1053 participants). There was insufficient evidence of a benefit of potent topical corticosteroids compared to moderate topical corticosteroids (OR 1.33, 95% CI 0.93 to 1.89; moderate-certainty evidence).

Twice-weekly 'weekend' application of a topical corticosteroid cut the chance of an eczema relapse from 58% to 25%. (Source 23)

• Systematic review, Moderate certainty.
• Size: 1,149 participants in 7 trials (9 trials assessed this comparison)
• Who: Children and adults with a range of eczema severities, mainly moderate or severe.
• How long: Generally 16 to 20 weeks.
• Result: Relapse risk ratio 0.43 (95% CI 0.32 to 0.57); relapse fell from 58% to 25%; no cases of abnormal skin thinning were identified in the seven trials (1,050 participants) that assessed it, though that evidence was low certainty.
• Funding: Cochrane review; adverse events described by the authors as not well reported.

topical corticosteroids weekend (proactive) therapy is probably better than no topical corticosteroids/reactive use to prevent eczema relapse (flare-ups). Adverse events were not well reported and came largely from low- or very low-certainty, short-term trials.

Hydrocortisone plus fludrocortisone reduced 90-day mortality in septic shock from 49.1% to 43.0%. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 1,241 patients (614 hydrocortisone plus fludrocortisone, 627 placebo)
• Who: Adults with septic shock in French intensive care units.
• How long: Treatment for 7 days; follow-up to 180 days.
• Result: the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99).
• Funding: Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health (public funding)

Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06).

In severe community-acquired pneumonia treated in intensive care, hydrocortisone reduced death at 28 days from 11.9% to 6.2%, an absolute difference of 5.6 percentage points. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 795 patients analysed (400 hydrocortisone, 395 placebo) out of 800 randomised.
• Who: Adults admitted to intensive care with severe community-acquired pneumonia, on standard antibiotics and supportive care.
• How long: Hydrocortisone 200 mg daily for 4 or 7 days then tapered over a total of 8 or 14 days; outcome at 28 days.
• Result: By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006).
• Funding: French Ministry of Health (public funding)

By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006).

What the evidence does not support

In the largest septic shock trial, hydrocortisone did not reduce 90-day mortality compared with placebo. (Source 24)

• Randomized trial, High certainty.
• Size: 3,800 randomised; primary outcome ascertained in 3,658 (1,832 hydrocortisone, 1,826 placebo)
• Who: Adults with septic shock undergoing mechanical ventilation, in an international trial.
• How long: Hydrocortisone 200 mg per day for 7 days or until death or ICU discharge; follow-up 90 days.
• Result: At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50).
• Funding: National Health and Medical Research Council of Australia and others (public funding)

Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

In critically ill COVID-19 patients, the hydrocortisone subgroup of the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group's prospective meta-analysis did not show a statistically significant mortality benefit, unlike dexamethasone. (Source 6)

• Meta-analysis, Moderate certainty.
• Size: Hydrocortisone subgroup: 3 trials, 374 patients, 94 deaths (overall meta-analysis 1,703 patients in 7 trials)
• Who: Critically ill adults hospitalised with COVID-19 in 12 countries, February to June 2020.
• How long: 28-day mortality (one trial 21 days, one 30 days)
• Result: the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths).
• Funding: Prospective meta-analysis conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, the corporate author of the paper, pooling independently funded trials.

The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths)

In chronic fatigue syndrome, low-dose hydrocortisone missed its primary endpoint - 66.7% of hydrocortisone recipients versus 54.3% on placebo improved on the Wellness scale, which was not statistically significant (P=.31) - and it suppressed adrenal responsiveness in 12 of 30 recipients, which the authors judged to rule out practical use. (Source 25)

• Randomized trial, Moderate certainty.
• Size: 70 patients (56 women, 14 men); 30 received hydrocortisone, 35 placebo were analysed on the Wellness scale.
• Who: Adults aged 18 to 55 meeting the 1988 CDC criteria for chronic fatigue syndrome, withholding other medicines, at a single tertiary research centre.
• How long: Approximately 12 weeks.
• Result: The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P =.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales.
• Funding: Conducted at a US tertiary care research institution, 1992-1996; no industry funding stated in the abstract.

Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001). Conclusions: Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.

Across 34 studies of glucocorticoid replacement regimens in chronic adrenal insufficiency, neither daily dose nor dosing frequency made a measurable difference to quality of life, and the evidence was rated low quality. (Source 26)

• Systematic review, Low certainty.
• Size: 34 studies.
• Who: Adults and children with chronic adrenal insufficiency on glucocorticoid replacement.
• How long: Mostly short-term studies.
• Result: We found no difference in QoL scores between higher (≥30 mg/day of hydrocortisone [HC] equivalence) vs. lower daily doses (<30 mg/day of HC equivalence) (P = .15) or based on frequency of daily dosing (once, twice or thrice daily). Extended-release (1 study), dual-/modified-release (3 studies), and continuous subcutaneous (3 studies) forms of GCs were associated with higher QoL scores. There was no significant association between dose and type of GC and the incidence of adrenal crises. The effect on bone mineral density was heterogeneous.
• Funding: Academic systematic review (Endocrine Practice); no industry funding stated in the abstract.

The quality of evidence was low due to increased risk of bias, imprecision, and heterogeneity. Conclusion: Extended-/dual-release, and continuous subcutaneous forms of GC may be associated with higher QoL scores. However, this is derived from short-term and imprecise evidence, warranting low confidence.

There is no evidence base for "adrenal fatigue" as a condition, and the cortisol tests used to diagnose it are not validated. (Source 8)

• Systematic review, Moderate certainty.
• Size: 58 studies from 3,470 screened (33 in healthy individuals, 25 in symptomatic patients)
• Who: Healthy and symptomatic adults assessed for fatigue or burnout alongside cortisol measurement.
• How long: Literature to April 2016.
• Result: We found an almost systematic finding of conflicting results derived from most of the studies methods utilized, regardless of the validation and the quality of performed tests. Some limitations of the review include: (1) heterogeneity of the study design; (2) the descriptive nature of most studies; (3) the poor quality assessment of fatigue; (4) the use of an unsubstantiated methodology in terms of cortisol assessment (not endorsed by endocrinologists)
• Funding: Academic systematic review in BMC Endocrine Disorders; no industry funding stated.

This systematic review proves that there is no substantiation that "adrenal fatigue" is an actual medical condition. Therefore, adrenal fatigue is still a myth.

Where the research disagrees

Whether hydrocortisone reduces death in septic shock

• The ADRENAL investigators (Venkatesh and colleagues, 3,800 patients), Randomised, blinded, placebo-controlled trial of 3,800 mechanically ventilated patients, the largest in the field: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Source 24)
• The APROCCHSS investigators (Annane and colleagues, 1,241 patients), Randomised, double-blind, placebo-controlled trial with a 2-by-2 factorial design in which hydrocortisone was given together with fludrocortisone: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .). (Source 27)

Whether topical corticosteroid withdrawal is a real distinct syndrome or an artefact of poor-quality case reporting

• Hajar and colleagues (2015 systematic review for the National Eczema Association), Systematic review of 34 studies, the authors themselves rating the quality of evidence as low: TCS withdrawal is likely a distinct clinical adverse effect of TCS misuse. Patients and providers should be aware of its clinical presentation and risk factors. (Source 15)
• The 2026 updated systematic review, Systematic review of seven further studies, all descriptive, with the authors noting inconsistent diagnostic criteria and variable definitions: Seven studies were included in the analysis, including five case reports, one case series, and one qualitative cross-sectional survey, reflecting the limited and descriptive nature of the currently available evidence on TCSW. (Source 19)

How much

• Reference intake: There is no reference intake for a drug, and dosing is set by the prescriber. As a position, the US prescribing information states that the initial oral dose may vary from 20 mg to 240 mg per day depending on the condition, and emphasises in capital letters that requirements are variable and must be individualised. Physiological replacement in adrenal insufficiency is at the low end of that range, but this write-up does not give a dose for any reader. (Source 28)
• Upper limit: No upper limit in the nutrient sense exists. As a position, the label's stated initial oral range tops out at 240 mg per day for severe disease, with the maintenance dose then reduced in small decrements to the lowest effective amount; there is no fixed maximum because the ceiling is set by the condition being treated. (Source 28)
• Studied: ADRENAL gave hydrocortisone 200 mg per day as a continuous infusion for 7 days or until death or ICU discharge to 1,832 adults with septic shock. (Source 24)
• Studied: CAPE COD gave intravenous hydrocortisone 200 mg daily for either 4 or 7 days depending on clinical improvement, followed by tapering, for a total of 8 or 14 days. (Source 5)
• Studied: The JAMA chronic fatigue syndrome trial gave oral hydrocortisone 13 mg per square metre of body surface area each morning and 3 mg per square metre each afternoon for about 12 weeks. (Source 25)
• Studied: The Lancet crossover trial in chronic fatigue syndrome gave 5 mg or 10 mg of hydrocortisone daily for one month against one month of placebo. (Source 7)
• Studied: The systematic review of replacement regimens compared daily doses at or above 30 mg of hydrocortisone equivalent with doses below 30 mg, and once, twice and three-times daily schedules. (Source 26)

A common belief, and what the research shows

The belief: Hydrocortisone cream is the mild, harmless steroid, and only the strong prescription ones carry risks; and if you feel tired and stressed your adrenals are 'fatigued' and could use some hydrocortisone.

What the research shows: Two separate misconceptions. On the cream: hydrocortisone is indeed at the mild end, and in the Cochrane review abnormal skin thinning was found in only about 1% of participants in the trials of treating a flare - a figure from those short trials, not a general rate and was concentrated in the stronger steroids ('16 with very potent, 6 with potent, 2 with moderate and 2 with mild') - so two of those 26 cases were with mild steroids, and the label records that skin application has produced 'reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients'. Mild is not the same as inert, especially on the face or over large areas for long periods. On 'adrenal fatigue': a systematic review of 58 studies concluded that 'there is no substantiation that "adrenal fatigue" is an actual medical condition', and the trials that did give low-dose hydrocortisone for unexplained fatigue found adrenal suppression in 12 of 30 recipients versus none on placebo.

Questions and answers

What is it?

Hydrocortisone is cortisol - the steroid hormone your own adrenal glands make - supplied as a medicine. That makes it unusual: most drugs are foreign to the body, but this one is identical to a hormone already circulating in you. The adrenal cortex releases it in a daily rhythm in response to physiological cues and stress, controlled by signals from the hypothalamus and pituitary. As a medicine it comes as tablets, injections, skin creams and ointments, suppositories and eye preparations. (Source 1)

What does it do in the body?

Once released it reaches target tissues and regulates a long list of processes - metabolism, immune function, skeletal growth, cardiovascular function, reproduction and cognition. It is also the central stress hormone: the HPA axis it sits in is the system that adapts the body to stress and tries to restore equilibrium. Cortisol feeds back on the pituitary and hypothalamus to switch its own production off, which is exactly why taking hydrocortisone as a drug suppresses the body's own supply. (Source 1)

Is it good or bad for you?

Both, and the amount decides which. Without it you cannot live: hydrocortisone or cortisone is the first-choice replacement in adrenocortical insufficiency. In the right amount for a flare of inflamed skin it works, and in severe pneumonia in intensive care it cut 28-day death from 11.9% to 6.2%. Too much, for too long, and you get the harms: adrenal suppression after stopping, gastrointestinal bleeding up from 2.0% to 2.9%, raised blood sugar, thinned skin where creams are used on the face. The same molecule is essential at physiological levels and damaging in excess. (Source 2)

How do you get more of it?

Your own cortisol rises on its own when ACTH is released - it cannot be stored in the adrenal gland, so it has to be made on demand, which is why cortisol climbs within minutes of a stressor. There is no food or supplement that meaningfully raises it. Extra hydrocortisone comes only as a medicine: over the counter as 0.5% and 1% skin cream in the US, and otherwise on prescription as tablets, injections or stronger topical strengths. For people who depend on replacement, the dose is increased temporarily during illness or stress on medical instruction, not as a general measure. (Source 1)

If it is harmful, what reduces it?

When the problem is too much, the answer is reduction rather than removal, because an abrupt stop leaves you with neither the drug nor your own suppressed supply. The label's instruction is to taper gradually and to recognise that the resulting relative insufficiency can last for months, so steroid cover may be needed again during illness in that period. For creams, options are withdrawing the drug, applying it less often, or substituting a weaker steroid. Separately, the body clears cortisol itself through the 11-beta-hydroxysteroid dehydrogenase enzymes that convert it to inactive cortisone - the enzyme liquorice blocks. (Source 29)

Why might someone be low in it or missing it?

Genuine cortisol deficiency has two main routes. Primary adrenal insufficiency is damage to the adrenal glands themselves - autoimmune destruction in Addison's disease, or infection such as tuberculosis. Secondary is failure of the pituitary ACTH signal, including the commonest cause of all: having taken corticosteroids and then stopped. That drug-induced form is frequent and is not limited to high oral doses - it was found in 4.2% after nasal steroids and 52.2% after joint injections, and it rose with both dose (2.4% low dose to 21.5% high dose) and duration (1.4% under 28 days to 27.4% beyond a year). (Source 14)

Which whole foods contain it or feed it?

No whole food contains cortisol in a usable amount or reliably raises it, and this question has no real food answer. One food does act on the system: liquorice blocks the enzyme that inactivates cortisol in the kidney, so cortisol behaves more like a salt-retaining hormone and sodium is retained. That is the documented food-cortisol interaction in the human literature - a hazard to know about rather than a way to get more of a hormone you need. (Source 9)

What happens if you do not have it?

Without cortisol the body cannot mount a stress response, and an adrenal crisis - collapse with low blood pressure and dehydration - can follow an infection, injury or even emotional stress. In a 2-year prospective study of 423 people with chronic adrenal insufficiency who had already been taught how to increase their dose under stress, crises still happened at 8.3 per 100 patient-years, most often triggered by gastrointestinal infection, fever or emotional stress, and four deaths were crisis-related. (Source 16)

How can you test for it?

Cortisol can be measured in blood, saliva and urine, and adrenal reserve is tested with an ACTH (Synacthen) stimulation test. The meta-analysis of 30 studies found both the standard 250 microgram and the low-dose 1 microgram tests have low sensitivity and high specificity - good enough to confirm secondary adrenal insufficiency but not to rule it out - with confidence in the estimates rated only low to moderate. Two practical traps: liquorice in the previous few days inflates salivary cortisol, and hydrocortisone cream on the fingers holding the swab inflates it more than a thousandfold. (Source 30)

References

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