On the site of action of the anti-adrenal steroidogenic effect of cyproterone acetate

Abstract

Cyproterone acetate (CA) inhibited 1–24 ACTH (50 ng/l)-stimulated cortisol production by dispersed guinea-pig adrenal cells in a dose-related manner. Inhibition occurred over the range 10 −6 to 5 × 10 −5 moles/l. The concentration of drug which induced 50% inhibition was 4.6 × 10 −6 moles/l. The sites of action of this anti-steroidogenic effect have been established. Dispersed adrenal cells were challenged with the cortisol precursor steroids (all at 10 −5 moles/l) pregnenolone (Pe), 17 α hydroxy- pregnenolone (17-OH Pe), 17 α-hydroxyprogesterone (17-Po), and 11 deoxycortisol or 1–24 ACTH (100 ng/l) in the absence and presence of increasing concentrations of CA (10 −5 to 10 −4 moles/l). In the absence of drug, the steroid precursors or ACTH provoked cortisol secretion greater than 10-fold that secreted by cells incubated in their absence. ACTH-stimulated cortisol secretion was inhibited >68% at concentrations of CA >10 −5 moles/l. CA (10 −5 moles/l) had no significant effect on steroidstimulated cortisol production when the Δ 4, 3 ketosteroids 17-OH Po and 11-deoxycortisol were used, but depressed secretion by >61% (P < 0.001) when the Δ 5 3 β hydroxysteroids (Pe, 17-OH Pe) were employed. Increasing CA concentrations to 10 −4 moles/l had little effect on cortisol secretion provoked by 11-deoxycortisol, but significantly (P < 0.05) depressed cortisol secretion stimulated by 17-OH Po. These results suggest that the major site of action of CA is Δ 5, 3β hydroxysteroid dehydrogenase (3β- HSD) with a secondary effect on 21-hydroxylase activity. To confirm these findings cortisol secretion provoked by 17, 21, dihydroxypregnenolone (17, 21 diOH Pe) and 21 deoxycortisol (21-DOC) was measured in the absence and presence of increasing concentrations of CA. At the lowest concentration of CA (5 × 10 −6 moles/l), cortisol secretion provoked by 17, 21 diOH Pe was inhibited by 28% (P < 0.01) whereas secretion provoked by 21-DOC was not significantly affected. At the highest concentration of CA (10 −4 moles/l), the relative inhibition was 80% for 17, 21 diOH Pe and 38% for 21-DOC. We conclude that cyproterone acetate inhibits adrenal steroidogenesis at both 3β-HSD and 21- hydroxylase, the degree of inhibition being more pronounced at 3β-HSD.