Will Hydrocortisone Supplementation Affect Serum Cortisol?
Yes, hydrocortisone supplementation will dramatically increase serum cortisol levels and completely confound assessment of adrenal function—measured cortisol will reflect both endogenous production and exogenous hydrocortisone, making diagnostic testing invalid while on therapy. 1
Magnitude of Effect on Serum Cortisol
Hydrocortisone therapy increases total plasma cortisol levels by 4.2-fold and free cortisol by 8.5-fold within 24 hours of initiation, with median total cortisol reaching 3,587 nmol/L (considerably exceeding both basal and ACTH-stimulated endogenous levels). 2
During standard "low-dose" hydrocortisone regimens (100 mg bolus followed by 10 mg/hour), plasma cortisol concentrations initially far exceed physiologic levels, then decline to median levels of 1,310 nmol/L by day 7 despite continuous dosing. 2
Even standard replacement doses of hydrocortisone 15-25 mg daily produce measurable serum cortisol that represents the sum of therapeutic steroid plus any residual endogenous production. 1
Why Diagnostic Testing Cannot Be Performed on Hydrocortisone
Morning cortisol measurements in patients actively taking hydrocortisone are not diagnostic because cortisol assays measure both endogenous cortisol and therapeutic hydrocortisone, with cross-reactivity varying by assay. 1
Patients on hydrocortisone will have suppressed ACTH due to negative feedback, creating iatrogenic secondary adrenal insufficiency that makes interpretation of the hypothalamic-pituitary-adrenal axis impossible. 1
Laboratory confirmation of adrenal insufficiency should not be attempted until hydrocortisone treatment is discontinued and sufficient washout time has elapsed—typically requiring hydrocortisone to be held for at least 24 hours before testing. 1
Critical Timing Considerations
Hydrocortisone has a half-life ranging from 40-225 minutes (mean 76.5 minutes), with considerable inter-individual variation affecting how long elevated cortisol levels persist after dosing. 3
Time to reach plasma cortisol <100 nmol/L after oral hydrocortisone ranges from 140-540 minutes (mean 289 minutes), depending on both absorption rate and elimination half-life. 3
A minimum 24-hour washout is required before attempting diagnostic cortisol testing, though longer periods may be needed in patients with slower elimination kinetics. 1
Alternative Approach When Testing Is Needed
If you must treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—dexamethasone does not interfere with cortisol assays and allows subsequent ACTH stimulation testing. 1, 4
However, dexamethasone causes prolonged HPA axis suppression due to its longer plasma elimination half-life, so ACTH stimulation testing should ideally be performed after an adequate washout period when transitioning off dexamethasone. 4
Common Pitfall to Avoid
Never attempt ACTH stimulation testing or morning cortisol/ACTH measurements while a patient is on established hydrocortisone replacement therapy—if the diagnosis of adrenal insufficiency is already confirmed, there is no reason to check cortisol levels, as the measured values will simply reflect therapeutic dosing. 1
In cases where diagnostic confirmation is needed (such as questioning whether adrenal insufficiency truly exists), hydrocortisone must be completely discontinued with appropriate washout before valid testing can occur. 1