Metyrapone
Metyrapone is a cortisol-synthesis inhibitor that blocks the adrenal enzyme 11-beta-hydroxylase, the final step in cortisol production. It is used both diagnostically (the metyrapone test of HPA axis integrity) and therapeutically to lower cortisol in Cushing's syndrome. Unlike receptor blockers it genuinely reduces cortisol output, but it diverts steroid synthesis toward androgens and mineralocorticoid precursors.
01 Overview
By inhibiting 11-beta-hydroxylase (CYP11B1), metyrapone blocks conversion of 11-deoxycortisol to cortisol, lowering circulating cortisol and, via loss of feedback, raising ACTH and the precursor 11-deoxycortisol. This is the basis of the metyrapone stimulation test. Therapeutically it is used to control cortisol excess in Cushing's syndrome, often rapidly.
The enzyme block shunts precursors into the androgen and mineralocorticoid pathways, so it can cause hirsutism/acne (from raised androgens) and hypertension with fluid retention and hypokalaemia (from raised 11-deoxycorticosterone). There is no legitimate physique use; the notion of using it to blunt cortisol for recovery is unsupported and risks adrenal insufficiency.
02 Mechanism
Inhibits adrenal 11-beta-hydroxylase (CYP11B1), blocking the final step of cortisol synthesis and lowering cortisol while raising ACTH and precursors.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Diagnostic test | 30 mg/kg | Oral | Single midnight dose (max ~3 g) for the overnight metyrapone test. |
| Cushing's treatment | 500–6000 mg/day | Oral | Divided doses titrated to cortisol; wide therapeutic range. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Reduced cortisol synthesisEffectively lowers circulating cortisol in cortisol-excess states. | dose-dependent | Clinical | |
| Diagnostic HPA testingRise in 11-deoxycortisol/ACTH after dosing assesses pituitary-adrenal integrity. | test tool | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Adrenal insufficiencyExcessive cortisol lowering causes nausea, hypotension and adrenal crisis. | Severe | Dose-dependent | Clinical | |
| Hypertension / hypokalaemiaFluid retention, raised blood pressure and low potassium from accumulated mineralocorticoid precursor. | Moderate | Common | Clinical | |
| Hirsutism / acneAndrogenic skin effects from precursor diversion to androgen synthesis. | Mild | Common in women | Clinical |