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

Abstract

We investigated basal and ACTH stimulated levels of cortisol, corticosterone, 17 alpha-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 of 3H-17 alpha-hydroxyprogesterone to 3H-11-deoxycortisol and 3H-cortisol and of 3H-11-deoxycortisol to 3H-cortisol as well as of 3H-11-deoxycorticosterone to 3H-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 inconsistently 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 with 3H-17 alpha-hydroxyprogesterone showed that ketoconazole inhibited the transformation of 3H-17 alpha-hydroxyprogesterone to 3H-cortisol but not to 3H-11-deoxycortisol so that the ratio 3H-11-deoxycortisol/3H-cortisol increased 15-80 fold. After incubation of adrenal slices with 3H-11-deoxycortisol or 3H-11-deoxycorticosterone and ketoconazole, a 2-260 fold increase of the ratios 3H-11-deoxycortisol/3H-cortisol and 3H-11-deoxycorticosterone/3H-corticosterone were also found.

• Authors: D Engelhardt, G Dörr, C Jaspers, D Knorr
• Journal: Klinische Wochenschrift (Klin Wochenschr) Vol. 63 Issue 13 Pg. 607-12 (Jul 01 1985) ISSN: 0023-2173 [Print] Germany
• PMID: 2993735 (Publication Type: Journal Article)

Chemical References

• Hydroxyprogesterones
• Desoxycorticosterone
• 17-alpha-Hydroxyprogesterone
• Adrenocorticotropic Hormone
• Steroid Hydroxylases
• Steroid 11-beta-Hydroxylase
• Ketoconazole
• Corticosterone
• Cortodoxone
• Hydrocortisone

Topics

• 17-alpha-Hydroxyprogesterone
• Adrenal Glands (enzymology)
• Adrenocorticotropic Hormone (blood)
• Corticosterone (blood)
• Cortodoxone (blood)
• Cushing Syndrome (drug therapy, enzymology)
• Desoxycorticosterone (blood)
• Humans
• Hydrocortisone (blood)
• Hydroxyprogesterones (blood)
• Ketoconazole (therapeutic use)
• Steroid 11-beta-Hydroxylase (antagonists & inhibitors)
• Steroid Hydroxylases (antagonists & inhibitors)