Ketoconazole blocks cortisol secretion in man by inhibition of adrenal 11β-hydroxylase

Summary

We investigated basal and ACTH stimulated levels of cortisol, corticosterone, 17α-hydroxyprogesterone, 11-deoxycortisol and 11-deoxycorticosterone as well as plasma levels of ACTH before and during the oral administration of ketoconazole in five patients with Cushing's syndrome (3 with bilateral adrenal hyperplasia, 1 with adrenal adenoma and 1 with adrenal carcinoma) and in three controls. The influence of ketoconazole on the transformation of³H-17α-hydroxyprogesterone to³H-11-deoxycortisol and³H-cortisol and of³H-11-deoxycortisol to³H-cortisol as well as of³H-11-deoxycorticosterone to³H-corticosterone was also examined in slices or homogenates of normal and hyperplastic adrenal tissue from four patients. Ketoconazole induced a rise of 11-deoxycortisol and 11-deoxycorticosterone, but not of cortisol and inconsistantly of corticosterone which were increased by ACTH. Thus the ratio 11-deoxycortisol/cortisol rose more after ketoconazole than after ACTH and the ratio 11-deoxycorticosterone/corticosterone rose after ketoconazole but fell after ACTH. Plasma ACTH levels were stimulated 2–50 fold by ketoconazole. Incubation studies of adrenal tissue slices with³H-17α-hydroxyprogesterone showed that ketoconazole inhibited the transformation of³H-17α-hydroxyprogesterone to³H-cortisol but not to³H-11-deoxycortisol so that the ratio³H-11-deoxycortisol/³H-cortisol increased 15–80 fold. After incubation of adrenal slices with³H-11-deoxycortisol or³H-11-deoxycorticosterone and ketoconazole, a 2–260 fold increase of the ratios³H-11-deoxycortisol/³H-cortisol and³H-11-deoxycorticosterone/³H-corticosterone were also found.

In conclusion, the in vivo data indicate and the in vitro data confirm that ketoconazole inhibits cortisol and corticosterone secretion by blocking adrenal 11β-hydroxylase activity in normal subjects as well as in patients with Cushing's syndrome, an effect which is compensated in vivo by high ACTH levels.