Can Hydrocortisone Suppress ACTH?
Yes, hydrocortisone (cortisol) suppresses ACTH production through negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, acting on both the pituitary corticotrophs and hypothalamic CRH-secreting neurons. This is a fundamental physiological mechanism and a recognized adverse effect of therapeutic hydrocortisone use.
Mechanism of ACTH Suppression
Hydrocortisone exerts dose-dependent negative feedback that inhibits both continuous basal ACTH secretion and pulsatile ACTH bursts. 1 The suppression occurs through:
- Direct pituitary effects: Hydrocortisone binds to type II (glucocorticoid) receptors on corticotroph cells, directly inhibiting ACTH synthesis and release 2, 1
- Indirect hypothalamic effects: Cortisol suppresses CRH and vasopressin production in the paraventricular nucleus, reducing hypothalamic drive for ACTH secretion 2, 1
- Dual receptor mechanism: Type I (mineralocorticoid) receptors mediate basal HPA tone, while type II receptors provide additional inhibition during stress or elevated cortisol states—importantly, type II receptor occupation requires concurrent type I receptor occupation for full suppressive potency 2
Clinical Evidence of Suppression
Exogenous hydrocortisone causes iatrogenic secondary adrenal insufficiency by suppressing the HPA axis, resulting in low ACTH and low endogenous cortisol production. 3, 4 This is why:
- Morning cortisol measurements are unreliable in patients taking hydrocortisone, as the assay detects both endogenous and exogenous steroids 4
- ACTH levels become suppressed in patients on chronic glucocorticoid therapy 3, 4
- Hydrocortisone must be held for 24 hours before accurate HPA axis testing can be performed 4
Dose-Response Relationship
The degree of ACTH suppression depends on hydrocortisone dose, timing, and duration of exposure. 1, 5
- Physiologic replacement doses (15-25 mg daily in divided doses) provide sufficient negative feedback to maintain normal HPA regulation in patients with adrenal insufficiency 4
- Supraphysiologic doses (≥20 mg prednisone equivalent for ≥3 weeks) reliably suppress the HPA axis and increase risk of adrenal crisis upon discontinuation 4
- Acute administration: A single 200 mg IV dose of hydrocortisone significantly suppresses plasma ACTH levels within 60 minutes in adrenalectomized patients 5
Time Course of Suppression
ACTH suppression occurs rapidly (within 30-60 minutes) after hydrocortisone administration, but HPA axis recovery after chronic suppression takes months. 4, 6, 5
- Patients on long-term corticosteroids require 3 months of maintenance hydrocortisone therapy before testing for HPA axis recovery 3, 4
- The HPA axis should be tested for recovery after 3 months in patients with isolated central adrenal insufficiency from prior steroid use 3
Important Clinical Caveats
The FDA drug label explicitly lists "suppression of growth in children" and "secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress" as endocrine adverse effects of hydrocortisone. 7
In rare cases of pituitary pathology (microadenoma or hyperplasia), ACTH may remain elevated despite hydrocortisone replacement, though this represents autonomous ACTH secretion rather than failure of negative feedback. 8 One case report documented persistent hyper-ACTH in Addison's disease despite conventional hydrocortisone replacement, attributed to pituitary microadenoma with preserved but altered ACTH regulation 8.
The normal physiologic relationship shows plasma ACTH and cortisol changing in opposite directions—when cortisol is high, ACTH is low, and vice versa. 3 This inverse relationship is the hallmark of intact negative feedback and confirms that hydrocortisone suppresses ACTH under normal circumstances.