Mifepristone
Mifepristone is a potent antagonist of both the progesterone and glucocorticoid receptors. At high doses (Korlym) it blocks cortisol's action at the receptor and is approved to control hyperglycaemia in endogenous Cushing's syndrome. In a cortisol context it does not lower cortisol production — it blocks its effect — which can paradoxically raise circulating cortisol and cause potassium loss. Better known separately as an abortifacient (Mifeprex).
01 Overview
As a glucocorticoid receptor antagonist, mifepristone is used at high doses (300-1200 mg/day as Korlym) to counter the metabolic effects of excess cortisol in patients with Cushing's syndrome who cannot have surgery. Because it blocks the receptor rather than cortisol synthesis, cortisol and ACTH levels rise, so treatment is titrated to clinical and glucose response, not cortisol levels.
Its unopposed cortisol then acts on the mineralocorticoid receptor, causing hypokalaemia and hypertension in some patients. It is also a strong antiprogestin, hence its separate low-dose use in medical termination of pregnancy. It is not an anabolic or physique agent; interest in cortisol-blockade for recovery is theoretical and unsupported by athletic data.
02 Mechanism
Competitive antagonist at the glucocorticoid receptor (and progesterone receptor); blocks cortisol action peripherally without reducing cortisol synthesis.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Cushing's (Korlym) | 300–1200 mg/day | Oral | Titrated to glucose and clinical response; not to cortisol levels. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Blockade of cortisol actionReduces hyperglycaemia and metabolic effects of excess cortisol by receptor blockade. | improved glycaemia in Cushing's | Clinical | |
| Rise in circulating cortisol/ACTHBecause synthesis is not inhibited, cortisol and ACTH rise; levels cannot guide dosing. | receptor blockade effect | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| HypokalaemiaLow potassium as unblocked cortisol activates mineralocorticoid receptors. | Severe | Common | Clinical | |
| Adrenal insufficiency (functional)Symptoms of cortisol deficiency despite normal/high levels, because the receptor is blocked. | Severe | Uncommon | Clinical | |
| Endometrial thickening / bleedingAntiprogestin action causes endometrial changes and irregular bleeding. | Moderate | Common in women | Clinical |