Hydrocortisone (Cortef): Uses, Dosing, Side Effects, and How It Compares to Prednisone, Dexamethasone, and Fludrocortisone

What hydrocortisone (Cortef) is, and what it is FDA-approved for

Hydrocortisone is the pharmaceutical form of cortisol, the primary glucocorticoid secreted by the zona fasciculata of the adrenal cortex. That single fact is what separates it from prednisone or dexamethasone, which are synthetic analogs used almost exclusively for pharmacologic anti-inflammatory suppression. Hydrocortisone is also used at low, physiologic doses to replace a hormone the body cannot make, which is a different clinical use case from suppressing inflammation.

Cortef is FDA-approved for primary and secondary adrenal insufficiency, congenital adrenal hyperplasia (CAH), and a broad list of inflammatory, allergic, rheumatic, and dermatologic conditions at higher doses. Higher-dose intravenous hydrocortisone (Solu-Cortef, typically 100 to 500 mg) is also used in hospitals for anaphylaxis, severe asthma exacerbations, thyroid storm, and perioperative stress coverage in patients already known to have adrenal insufficiency.

The core distinction that determines dosing: hydrocortisone used for replacement therapy (15 to 25 mg/day) is trying to restore a normal hormone level, while hydrocortisone or any other corticosteroid used at pharmacologic doses (well above that range) is trying to suppress the immune system or inflammation. Confusing these two goals is the most common source of both under-treatment (adrenal crisis) and over-treatment (cushingoid side effects).

Primary adrenal insufficiency (Addison's disease) is uncommon. Autoimmune primary adrenal insufficiency has been associated with increased overall mortality and an altered pattern of cancer incidence in Swedish registry data, which is one reason ongoing monitoring matters even once replacement therapy is stable [1]. Secondary adrenal insufficiency, caused most often by prolonged exogenous corticosteroid use that suppresses the hypothalamic-pituitary-adrenal (HPA) axis, is encountered far more often in general practice than primary adrenal insufficiency.

The 2016 Endocrine Society Clinical Practice Guideline on adrenal insufficiency recommends hydrocortisone as the first-choice glucocorticoid for replacement in adults, based on its pharmacokinetic similarity to endogenous cortisol [2]. A healthy adrenal gland secretes roughly 5 to 10 mg of cortisol per square meter of body surface area daily, which after accounting for first-pass hepatic metabolism corresponds to the 15 to 25 mg/day oral hydrocortisone range most adults are prescribed. Cortef's 5 mg, 10 mg, and 20 mg tablet strengths make fine titration to this range straightforward.

Hydrocortisone is chemically identical to endogenous cortisol and carries both glucocorticoid and mineralocorticoid activity, unlike prednisone, prednisolone, and dexamethasone, which have negligible-to-no mineralocorticoid effect. The Endocrine Society's 2016 guideline recommends hydrocortisone 15 to 25 mg daily in two to three divided doses as first-line replacement in adults with adrenal insufficiency [2]. Prednisone and dexamethasone are more often chosen for pharmacologic anti-inflammatory suppression rather than replacement, partly because their longer half-lives allow once-daily dosing and their potency lets a smaller absolute milligram amount do the work. Whether a patient needs replacement dosing or suppressive dosing, not which drug "sounds stronger," is what should drive the choice.

How hydrocortisone compares to prednisone, prednisolone, and dexamethasone

Corticosteroid selection is not interchangeable. Agents differ in potency, duration of action, mineralocorticoid activity, and how deeply and how long they suppress the HPA axis.

The equivalency figures below are the standard reference ranges used in clinical pharmacology and endocrinology teaching, drawn from pharmacokinetic review literature rather than a single trial [4]:

Prednisone is a prodrug converted in the liver to prednisolone, its active form. It has roughly four times the anti-inflammatory potency of hydrocortisone at equal milligram doses, according to standard pharmacology references [4]. That potency, combined with a longer half-life, makes prednisone efficient for conditions like rheumatoid arthritis or inflammatory bowel disease, where the goal is sustained suppression, but a poor tool for physiologic replacement, where the goal is matching a normal hormone level and rhythm.

Prednisolone is the active metabolite of prednisone and is preferred in patients with significant hepatic impairment who may not reliably convert prednisone, and is the standard oral glucocorticoid for children in the UK and Australia. Its bioavailability is more predictable than prednisone's, but anti-inflammatory equivalency at the same dose is essentially the same [4].

Dexamethasone has no clinically meaningful mineralocorticoid activity and the longest half-life of the group (36 to 54 hours), making it the most potent and longest-acting agent in routine use. The RECOVERY trial (N=6,425) found that dexamethasone 6 mg daily for up to 10 days reduced 28-day mortality in hospitalized COVID-19 patients who required respiratory support (rate ratio 0.83, 95% CI 0.75 to 0.93, P<0.001) [5]. That result applies specifically to hospitalized patients on supplemental oxygen or ventilation, not to COVID-19 broadly, and it is a trial finding about an inflammatory-suppression use, not evidence about adrenal replacement. Dexamethasone is also standard for cerebral edema, adjunctive bacterial meningitis therapy, and fetal lung maturation in preterm labor, in part because it crosses the placenta efficiently.

Fludrocortisone (Florinef) is a separate case. It has roughly ten times the glucocorticoid potency of hydrocortisone but 125 to 150 times the mineralocorticoid potency, which is why it is the standard mineralocorticoid-replacement agent in primary adrenal insufficiency and in salt-wasting CAH, rather than a glucocorticoid substitute. The Endocrine Society guideline recommends 0.05 to 0.2 mg once daily as adjunctive therapy alongside hydrocortisone in primary adrenal insufficiency, with the guideline authors describing a typical starting dose around 50 mcg/day, adjusted by clinical assessment and biochemical monitoring [2]. Fludrocortisone is not appropriate as a standalone glucocorticoid replacement, because the glucocorticoid effect at a mineralocorticoid-effective dose would be excessive and would suppress the HPA axis.

What is the standard hydrocortisone dose for adrenal insufficiency?

Physiologic replacement targets both the total daily cortisol output and its circadian rhythm. Cortisol peaks 30 to 60 minutes after waking and falls to its lowest point around midnight.

The 2016 Endocrine Society guideline recommends 15 to 25 mg of hydrocortisone daily, in two or three divided doses [2]. A common split is 10 mg on waking, 5 mg at noon, and 5 mg in the early afternoon, given no later than about 4:00 PM to avoid disrupting sleep. The largest dose is taken on waking to approximate the natural cortisol surge. Chronic overreplacement carries the same downstream risks as long-term pharmacologic steroid use: weight gain, dysglycemia, hypertension, and bone loss.

A prospective cohort study of patients with adrenal insufficiency examined whether bone mineral density correlated with glucocorticoid replacement dose and found that it did not correlate significantly across the dose range studied. That null finding complicates any simple assumption that "a slightly higher dose obviously causes more bone loss," but it does not overturn the broader, better-established principle from long-term pharmacologic steroid use that higher cumulative glucocorticoid exposure raises fracture risk over time [10]. The practical takeaway guideline authors and clinicians draw from this mixed evidence base is still to use the lowest dose that controls symptoms, rather than to assume any specific milligram threshold is safe.

Modified-release hydrocortisone (marketed as Plenadren in parts of Europe; not widely available in the United States as of 2025) is dosed once daily with a delayed-release profile designed to better approximate the diurnal cortisol curve. A randomized crossover trial of 64 patients showed improved metabolic markers and reduced weight with the dual-release formulation compared with conventional immediate-release hydrocortisone at 12 months [7]. This is trial evidence in a specific formulation not routinely prescribed in the US market at this writing, so it should not be read as a claim about standard Cortef tablets.

When should the dose be increased for illness or surgery? (stress dosing)

Patients with adrenal insufficiency cannot mount the normal cortisol surge that a healthy adrenal gland produces automatically during illness, surgery, or trauma. Without extra hydrocortisone, they are at risk of adrenal crisis. A prospective German registry study following 883 patients through 1,675 crisis events reported crisis-associated mortality in the range of several percent per episode, underscoring that this is a genuine emergency rather than a routine inconvenience [8].

The general sick-day framework used by the Endocrine Society and patient education materials from endocrine professional societies is:

• Minor physiologic stress (common cold, mild fever): double the daily dose for the duration of the illness.
• Moderate stress (vomiting, fever above about 38.5°C, moderate dental procedure, colonoscopy): triple the daily dose; switch to injectable hydrocortisone if oral intake is unreliable.
• Major stress (surgery under general anesthesia, severe infection, significant trauma): 50 to 100 mg IV hydrocortisone at the time of the procedure, then up to roughly 200 mg over 24 hours by continuous infusion or divided doses until the patient is stable and tolerating oral intake.

These are general sick-day rules published by endocrine societies, not individualized dosing instructions. The exact adjustment for any one patient should come from that patient's own endocrinologist, especially for patients with kidney or liver disease, pregnancy, or unusual illness severity.

Patients with adrenal insufficiency should carry a medical alert bracelet and an emergency hydrocortisone injection kit (such as a Solu-Cortef Act-O-Vial) for self-administration or bystander administration if they lose consciousness [2].

A decision framework for choosing and adjusting corticosteroid dosing

The following table is not a replacement for personalized medical advice from your healthcare provider. Rather, it outlines the diagnostic thinking process that clinicians use when evaluating cortisol and adrenal function, helping you understand which clinical scenario applies to your case and what follow-up questions might be relevant.

Side effects: replacement doses versus pharmacologic doses

Side effects depend heavily on whether hydrocortisone is used at physiologic replacement doses or at higher pharmacologic doses for inflammatory conditions.

At physiologic replacement doses (roughly 15 to 25 mg/day): most patients tolerate this well. The main risks are overreplacement (cushingoid features, weight gain, hypertension, dysglycemia, bone loss over time) and underreplacement (fatigue, hypotension, hyponatremia, hypoglycemia). Insomnia is a common complaint when an afternoon dose is taken too late in the day.

At pharmacologic doses (roughly above 30 to 40 mg/day sustained for more than a few weeks), reported effects include:

• HPA axis suppression, with risk of adrenal insufficiency on tapering or abrupt discontinuation
• Weight gain and fat redistribution to the trunk, face, and posterior neck
• New-onset or worsened hyperglycemia; glucocorticoids increase insulin resistance, an effect studied specifically in critically ill patients [document verification needed for population-specific incidence figures] [9]
• Bone loss with prolonged use; the American College of Rheumatology recommends calcium (roughly 1,000 to 1,200 mg/day), vitamin D (roughly 600 to 800 IU/day), and consideration of bisphosphonate therapy for anyone expected to take the equivalent of 7.5 mg or more of prednisone daily for 3 or more months [10]
• Gastrointestinal irritation, particularly when combined with NSAIDs
• Mood changes, insomnia, and at higher doses, steroid-induced psychiatric symptoms
• Increased susceptibility to bacterial, viral, fungal, and opportunistic infections
• Posterior subcapsular cataracts and elevated intraocular pressure with prolonged use
• Sodium retention and potassium loss at higher doses, driven by hydrocortisone's residual mineralocorticoid activity

Note on the hyperglycemia figure above: an earlier version of this material cited a specific percentage for how many hospitalized patients develop steroid-induced hyperglycemia. That precise figure needs direct verification against its source population (dose, illness severity, and prior diabetes status all change the number substantially), so this draft states the direction of the effect rather than repeating an unverified number. Glucocorticoids do measurably worsen insulin resistance in critically ill patients, which is the mechanism behind steroid-induced hyperglycemia [9].

Prednisone at an anti-inflammatory-equivalent dose has a broadly similar side-effect profile to hydrocortisone, but because it is more potent per milligram, a lower absolute dose achieves the same effect, which may modestly reduce mineralocorticoid-driven effects like fluid retention compared with an equivalent hydrocortisone dose.

How is long-term corticosteroid use tapered safely?

Anyone who has taken more than roughly 20 mg/day of hydrocortisone (or about 5 mg/day of prednisone) for more than three weeks should be tapered rather than stopped abruptly. Prolonged exogenous corticosteroid exposure suppresses hypothalamic CRH and pituitary ACTH secretion, and the adrenal cortex can atrophy from disuse; stopping abruptly risks acute adrenal insufficiency.

A commonly used tapering approach for moderate-duration courses:

1. Reduce the total daily hydrocortisone-equivalent dose by 10 to 20% every 1 to 2 weeks until reaching about 20 mg/day.
2. At 20 mg/day, slow the taper to 2.5 to 5 mg decrements every 2 to 4 weeks.
3. At around 10 mg/day, an early-morning (8:00 AM) serum cortisol can help assess axis recovery; a level above roughly 18 mcg/dL is often taken as reassuring, though institutional cutoffs vary and this single number should not be used to self-diagnose readiness to stop.

The pace has to be individualized. Longer prior exposure, higher prior doses, and comorbid autoimmune disease often call for a slower taper. Steroid withdrawal symptoms (fatigue, muscle and joint aches, mood changes, nausea) can look like an adrenal insufficiency flare and complicate the clinical picture, which is why this decision belongs with the prescribing clinician.

Hydrocortisone in congenital adrenal hyperplasia

Hydrocortisone is generally preferred over dexamethasone or prednisone for children with CAH because its shorter half-life is thought to carry a lower risk of growth suppression [2]. CAH most often results from 21-hydroxylase deficiency, which blocks cortisol synthesis and drives a compensatory ACTH surge that overproduces adrenal androgens.

Typical pediatric dosing is 10 to 15 mg/m² per day in three divided doses, aiming to suppress excess androgen production while limiting growth-suppressive effects. A cited pediatric CAH study reportedly associated hydrocortisone doses above roughly 17 mg/m²/day with reduced adult height standard-deviation scores; the underlying citation for that specific figure was incomplete in this draft's source material and needs direct verification before it is presented as an established number. The broader, better-supported point is that dose matters for growth in CAH, and pediatric endocrinologists titrate carefully for that reason. Salt-wasting CAH additionally requires fludrocortisone, typically 0.05 to 0.2 mg/day, alongside hydrocortisone.

Fludrocortisone (Florinef): the mineralocorticoid half of replacement

Fludrocortisone acts on the mineralocorticoid receptor in the distal nephron, increasing sodium reabsorption and potassium excretion, which maintains extracellular fluid volume and blood pressure in patients who lack aldosterone.

Standard adult dosing in primary adrenal insufficiency is 0.05 to 0.2 mg once daily by mouth [2]. Monitoring typically includes blood pressure, serum potassium, plasma renin activity, and watching for signs of over-replacement (edema, hypertension) or under-replacement (salt craving, postural hypotension, hyperkalemia).

Fludrocortisone is not used in secondary adrenal insufficiency, because aldosterone secretion is controlled by the renin-angiotensin system rather than ACTH; patients with secondary adrenal insufficiency typically retain intact mineralocorticoid function.

Drug interactions to know about

• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St. John's Wort) accelerate hepatic metabolism of hydrocortisone, prednisolone, and prednisone, and can precipitate adrenal crisis in replacement-dependent patients; dose increases may be needed under medical supervision.
• CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin) reduce corticosteroid clearance and raise toxicity risk.
• NSAIDs add to gastrointestinal ulceration risk; proton pump inhibitor prophylaxis is often considered for combined use beyond about two weeks.
• Oral hypoglycemic agents and insulin may need dose adjustment, since corticosteroids antagonize insulin action.
• Loop diuretics add to hypokalemia risk, particularly with high-dose hydrocortisone or with fludrocortisone.
• Antihypertensives may be blunted by corticosteroid-driven sodium retention.

Anyone switching between corticosteroids, for example moving from pharmacologic prednisone down to physiologic hydrocortisone, should have the starting dose calculated from the equivalency ratios above and be monitored for signs of both over- and under-replacement for the first several weeks.

What monitoring is recommended for long-term use?

• Bone density (DEXA scan): at baseline for anyone expected to need the equivalent of 7.5 mg/day of prednisone for three months or more, then periodically thereafter [10].
• Fasting glucose or HbA1c: at baseline and roughly every 6 to 12 months on pharmacologic-dose therapy.
• Blood pressure: at every visit.
• Ophthalmic exam: periodically for patients on long-term therapy, to screen for cataracts and glaucoma.
• Weight and body composition: at each visit.
• Serum potassium: particularly for patients also on fludrocortisone or diuretics.
• Early-morning serum cortisol: specifically when tapering toward discontinuation, to assess HPA recovery, not as a routine check on stable replacement therapy.

The Endocrine Society's 2016 guideline advises against routinely measuring serum or urinary cortisol to judge whether glucocorticoid replacement is adequate in most patients with adrenal insufficiency, because those measurements do not reliably reflect how much cortisol reaches tissue [2]. In practice, clinicians instead rely on symptoms, energy level, blood pressure (lying and standing), weight trends, and electrolytes, along with the absence of crisis episodes, to judge whether a replacement dose is right.

What is established, what is plausible, and what is not established

Established: hydrocortisone is the guideline-preferred glucocorticoid for adrenal insufficiency replacement because of its pharmacokinetic match to endogenous cortisol [2]. Corticosteroids differ meaningfully in potency, half-life, and mineralocorticoid activity, and those differences drive drug choice [3][4]. Dexamethasone reduces mortality in a specific hospitalized, oxygen-requiring COVID-19 population [5]. Untreated adrenal crisis is a life-threatening emergency [8].

Plausible but not settled by strong direct evidence in this material: that a specific dose threshold in CAH predicts adult height loss with precision (the underlying study citation needs verification); that a specific percentage of hospitalized patients develop steroid-induced hyperglycemia (population-dependent, needs a matched source before quoting a number); that modified-release hydrocortisone's metabolic advantage generalizes broadly outside the trial population that studied it [7].

Not established from the sources reviewed here: a simple dose-response relationship between hydrocortisone replacement dose and bone mineral density; the cited cohort study found no significant correlation [6], which should not be read as proof that dose is irrelevant to bone health over the long run, only that this particular study did not detect that relationship.

This article does not provide individualized dosing advice. Anyone adjusting a corticosteroid dose, especially around illness, surgery, or a taper, should do so with their prescribing clinician, and anyone with symptoms of possible adrenal crisis (severe weakness, vomiting, confusion, fainting, very low blood pressure) needs emergency evaluation rather than a home dose adjustment alone.