Inhibitors of cortisol biosynthesis
To reduce the effects of corticosteroids one can either inhibit their synthesis, or inhibit their receptors by antagonists
Biosynthesis inhibitors of cortisol are metopirone, aminoglutethimide and ketoconazole.
Aminoglutethimide inhibits the synthesis of corticosteroids by inhibiting several reactions of hydroxylation. It also inhibits aromatase responsible for the conversion of androgens into estrogens. Aminoglutethimide can be used in the treatment of hypercorticism and of metastatic breast cancer.
Metyrapone (Metopirone) reversibly inhibits the synthesis of cortisol, corticosterone and aldosterone by inhibition of 11-hydroxylation. It is used for diagnostic purpose in the exploration of the biosynthesis of adrenal cortex hormones and for the treatment of Cushing disease. Although metyrapone also inhibits aldosterone synthesis, its long-term use does not induce a mineralocorticoid deficiency because the synthesis of 11-desoxycorticosterone, which has a mineralocorticoid activity, is increased. The active metabolite of metyrapone is metyrapol.
Ketoconazole antifungal with an imidazole structure, inhibits, in large doses, the synthesis of adrenal and testicular steroids, which explains the possibility of adverse endocrine effects.
Mitotane or O, p'-DDD is a compound whose chemical structure is closely related to that of the insecticide DDT. When it is given in large doses (several grams daily) it blocks the synthesis of adrenal hormones. It can be used in the treatment of Cushing disease secondary to inoperable adrenocortical tumours.
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