[Antiglucocorticoid action of RU 486]

RU 486 is a synthetic steroid molecule with high affinity to the glucocorticoid receptor and which exerts an antiglucocorticoid activity. In animals RU 486 constantly inhibits the various effects induced by dexamethasone in classical experimental models. Its mechanism of action is not totally elucidated: RU 486 seems to inhibit both the glucocorticoid receptor activation and the gene transcription phenomenon. The antiglucocorticoid action of RU 486 in man was first demonstrated by studying the corticotropic response: a single dose of 400 mg of RU 486, given at 0200 h, triggers a corticotropic retort as if the pituitary felt it was deprived of cortisol. RU 486 inhibits, in a dose-dependent manner, various biological responses acutely induced by dexamethasone in man: corticotropic suppression, skin blanching, circulating oesinophils drop. RU 486 suppresses the peripheral features of chronic hypercortisolism in non-pituitary dependent Cushing's syndromes. In Cushing's disease administration of RU 486 immediately induces a strong and long lasting corticotropic (and cortisol) rise, especially since the drug has a long plasma half-life. This inescapable pituitary retort is a major drawback which suggests that chronic RU 486 administration will always and inevitably induce the secretion of its own antidote...cortisol!