Mechanism of Prednisolone-Induced ACTH Suppression
Prednisolone reduces ACTH through negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, acting primarily at the pituitary corticotrope cells and hypothalamus to suppress ACTH synthesis and secretion. 1, 2
Primary Mechanism: Negative Feedback on the HPA Axis
Prednisolone, as a synthetic glucocorticoid, mimics the physiological actions of endogenous cortisol and exerts powerful suppressive effects on the HPA axis through multiple mechanisms 1:
Direct pituitary suppression: Prednisolone acts on corticotrope cells in the anterior pituitary to inhibit ACTH production and release, with synthetic glucocorticoids like prednisolone having particularly potent effects at the pituitary level because they do not bind to transcortin (cortisol-binding globulin), allowing greater tissue penetration 2
Hypothalamic suppression: Prednisolone inhibits corticotropin-releasing hormone (CRF) synthesis and secretion from the hypothalamus, which is the primary driver of ACTH release 2
Genomic mechanism: Through the classical steroid receptor mechanism, prednisolone reduces pituitary ACTH content by decreasing levels of mRNA encoding for pro-opiomelanocortin (POMC), the ACTH precursor molecule—this "slow feedback" mechanism inhibits both basal and stimulus-induced ACTH secretion 2
Time Course of ACTH Suppression
The suppression occurs through three distinct temporal mechanisms 2:
Fast feedback (minutes): Occurs within minutes and inhibits stimulated ACTH release through non-genomic mechanisms, likely at the cell membrane level, affecting stimulus-secretion coupling 2
Intermediate feedback (hours): Develops over 2-4 hours and requires synthesis of a corticosteroid-dependent protein, affecting both ACTH and CRF release in response to stimulation 2
Slow feedback (days to weeks): Involves genomic mechanisms that reduce POMC mRNA levels and total pituitary ACTH stores, leading to sustained suppression of both basal and stimulated ACTH secretion 2
Clinical Consequences of HPA Axis Suppression
Daily doses of prednisolone ≥5 mg for ≥1 month can cause clinically significant HPA axis suppression, creating a state of iatrogenic secondary (or tertiary) adrenal insufficiency 3:
High prevalence of suppression: In patients receiving ongoing low-dose prednisolone 5 mg daily for rheumatoid arthritis, 39-48% demonstrated adrenal insufficiency on Synacthen testing, with generally low ACTH concentrations confirming secondary adrenal insufficiency 4
Duration of suppression after discontinuation: Even brief courses of high-dose prednisone (25 mg twice daily for 5 days) can limit the adrenal response to stress for up to 5 days after stopping treatment, with the adrenal component of the HPA axis remaining suppressed even after hypothalamic-pituitary recovery 5
Mechanism of adrenal atrophy: Prolonged ACTH suppression leads to adrenal cortex atrophy from lack of trophic stimulation, creating a state where the adrenal glands cannot respond adequately even when ACTH levels eventually recover 3, 6
Critical Clinical Pitfall
The suppressed ACTH and resulting adrenal insufficiency means patients cannot mount an appropriate cortisol response to physiological stress (infection, surgery, trauma), placing them at risk for life-threatening adrenal crisis 3, 7:
All routes of glucocorticoid administration (oral, inhaled, topical, intranasal, intra-articular) can cause HPA axis suppression and are the most common cause of adrenal insufficiency that clinicians encounter 3
Patients require stress-dose glucocorticoid coverage during illness, surgery, or other physiological stressors, as psychological stress alone does not require dose adjustment 7
Treatment of suspected adrenal crisis should never be delayed for diagnostic procedures—immediate IV hydrocortisone 100 mg plus saline infusion is required 3, 6