Step 2 CK · Internal Medicine · Endocrinology

Chronic Glucocorticoid Therapy: Complications, Stress Dosing & Tapering

Name: Chronic Glucocorticoid Therapy: Complications, Stress Dosing & Tapering
Creator: Veli Bakalov, MD

Taper wisely, cover the stress, and prevent the predictable harms

Endocrinology·Pituitary, Adrenal & Neuroendocrine·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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HPA suppression is likely with ≥20 mg/day prednisone for ≥3 weeks or cushingoid features, unlikely with <3 weeks of therapy or <5 mg/day in the morning.
Abrupt withdrawal causes secondary adrenal insufficiency: hypotension, hyponatremia, and hypoglycemia without hyperkalemia or hyperpigmentation.
Taper to a physiologic dose (prednisone about 5 mg), then check an 8 AM cortisol with the dose held 24 h; >10 μg/dL means recovery, indeterminate values need cosyntropin testing.
Minor procedures need only the usual dose; moderate–major surgery or serious illness needs IV hydrocortisone 50–100 mg, then a taper back to maintenance.
Sick-day rules: double or triple the dose with fever, IM hydrocortisone if vomiting, and a medical alert ID.
At ≥2.5 mg/day for ≥3 months, give calcium and vitamin D, get a DXA, and add a bisphosphonate if fracture risk is moderate or high.
Morning prednisone raises afternoon glucose: check pre-dinner values and use morning NPH insulin.
TMP-SMX prophylaxis when prednisone ≥20 mg/day for ≥4 weeks is combined with other immunosuppression.
Steroid myopathy has a normal CK; groin pain means MRI for avascular necrosis; fluticasone plus ritonavir causes iatrogenic Cushing syndrome.

HPA-axis suppression and withdrawal

Mechanism. Exogenous glucocorticoids feed back on the hypothalamus and pituitary, suppressing CRH and ACTH. Without ACTH the zona fasciculata atrophies, so cortisol cannot rise when the drug is stopped or stress hits. The zona glomerulosa is driven by renin–angiotensin, not ACTH, so aldosterone is preserved. Steroid withdrawal is the most common cause of adrenal insufficiency.

Who is suppressed. Assume suppression with ≥20 mg/day of prednisone (or equivalent) for ≥3 weeks, or with a cushingoid appearance at any dose. Suppression is unlikely with any dose for <3 weeks or with <5 mg/day taken in the morning; such courses can be stopped without a taper unless the disease itself needs one. Doses of 5–20 mg/day for ≥3 weeks are indeterminate: taper and test. Evening or divided dosing suppresses more than the same dose taken each morning, and high-dose inhaled, topical, or intra-articular steroids can also suppress the axis.

Approximate glucocorticoid equivalents

Drug	Equivalent dose	Mineralocorticoid effect	Duration
Hydrocortisone	20 mg	Significant	Short
Prednisone / prednisolone	5 mg	Modest	Intermediate
Methylprednisolone	4 mg	Minimal	Intermediate
Dexamethasone	0.75 mg	None	Long

Physiologic replacement ≈ prednisone 5 mg or hydrocortisone 15–20 mg daily.

Secondary adrenal insufficiency. Abrupt withdrawal produces fatigue, anorexia, nausea, orthostatic hypotension, hyponatremia, and hypoglycemia. Because ACTH is low there is no hyperpigmentation, and because aldosterone is intact there is no hyperkalemia or salt craving, the classic contrasts with primary adrenal failure.

Glucocorticoid withdrawal syndrome. Myalgias, arthralgias, fatigue, and low mood can occur during a taper even when the axis is adequate. Separate it from adrenal insufficiency and from a flare of the underlying disease; a temporary dose increase and a slower taper usually help.

Tapering and confirming recovery

Taper the supraphysiologic doseas quickly as the underlying disease allows; flares, not only the adrenals, set the pace
Slow down near physiologic rangeabout prednisone 5 mg; small (~1 mg) steps every few weeks
Test the axishold the dose ~24 h, then draw an 8 AM serum cortisol
Interpret>10 μg/dL: recovered, stop; <5 μg/dL: still suppressed, continue and retest
Resolve indeterminate valuescosyntropin stimulation test or repeat testing in weeks to months

Testing details. Prednisolone cross-reacts in cortisol immunoassays, so the dose must be held before blood is drawn; dexamethasone does not cross-react. In the cosyntropin test, a peak cortisol of about 18 μg/dL or higher (lower cutoffs with newer assays) indicates adequate adrenal reserve. Recovery can take 6–12 months or longer after prolonged high-dose therapy, and stress coverage is still needed until recovery is documented.

Stress dosing and sick-day rules

Glucocorticoid cover for a suppressed patient

Situation	Plan
Minor procedure under local anesthesia (dental work, skin biopsy)	Usual daily dose only; do not skip it
Moderate surgery (e.g., joint replacement)	Hydrocortisone about 50 mg IV at induction, then taper to the usual dose over 1–2 days
Major surgery, labor, or critical illness	Hydrocortisone 100 mg IV, then 50 mg every 6 h or 200 mg/24 h by continuous infusion; return to the usual dose as recovery allows
Febrile illness at home	Double or triple the oral dose for 2–3 days
Vomiting, cannot take pills	Emergency hydrocortisone 100 mg IM, then seek care

Education. Every patient with a possibly suppressed axis needs written sick-day rules, an emergency injection kit when appropriate, and a medical alert ID or steroid card.

A chronic steroid user in shock needs hydrocortisone 100 mg IV immediately with isotonic saline (plus dextrose if hypoglycemic). Draw a cortisol if convenient, but never delay treatment for results.

Preventing and detecting toxicity

Bone. Glucocorticoids suppress osteoblast function and survival and reduce gut calcium absorption. Bone loss is fastest in the first 3–6 months, and vertebral fractures occur at higher BMD than in postmenopausal osteoporosis. For anyone taking ≥2.5 mg/day for ≥3 months, give calcium and vitamin D, assess fracture risk with DXA, and add a bisphosphonate (alendronate, risedronate) when risk is moderate or high; denosumab and teriparatide are alternatives.

Glucose. Increased hepatic gluconeogenesis and insulin resistance give once-daily morning prednisone an afternoon–evening hyperglycemic peak with a normal fasting glucose. Check post-lunch or pre-dinner glucose and treat with morning NPH insulin timed to the steroid peak.

Infection. Give trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis when prednisone ≥20 mg/day is expected for ≥4 weeks alongside another immunosuppressant or immunocompromising condition. Screen for latent TB (IGRA) and hepatitis B before prolonged high-dose therapy, avoid live vaccines at ≥20 mg/day for ≥2 weeks, and screen for or empirically treat Strongyloides (ivermectin) in patients from endemic areas to prevent hyperinfection.

Other classic toxicities

Complication	Clue	Action
Myopathy	Painless proximal (hip-flexor) weakness; normal CK and aldolase; more with dexamethasone	Lower the dose, exercise; a high CK suggests polymyositis or statin myopathy
Avascular necrosis	Groin or hip pain with weight bearing; femoral head	MRI (plain films normal early)
Eye	Posterior subcapsular cataract; raised intraocular pressure	Periodic eye examinations
Peptic ulcer	Risk rises mainly with concurrent NSAIDs; steroids blunt peritoneal signs	Add a proton-pump inhibitor
Psychiatric	Insomnia, euphoria, mania, psychosis (more above ~40 mg/day, early); depression on withdrawal	Lower the dose; antipsychotic if severe; a prior steroid-induced episode raises the risk of another
Other	Hypertension, fluid retention, weight gain, skin thinning, bruising, poor wound healing, neutrophilic leukocytosis, growth suppression in children	Lowest effective dose for the shortest time

Fluticasone and boosters. Ritonavir and cobicistat strongly inhibit CYP3A4, so inhaled or intranasal fluticasone, budesonide, or intra-articular triamcinolone accumulates. The result is iatrogenic Cushing syndrome with a low serum cortisol and ACTH and a suppressed axis. Switch to beclomethasone or change the antiretroviral, and do not stop the steroid abruptly.