Steroid synthesis inhibition with ketoconazole and its effect upon the regulation of the hypothalamus–pituitary–adrenal system in healthy humans

Steroid synthesis inhibitors are commonly used in the treatment of patients with Cushing's disease, but may also improve psychopathology in hypercortisolemic depressed patients. Since glucocorticoids exert a negative feedback at pituitary and supra-pituitarylevels, the inhibition of steroid synthesis may lead to increased expression of corticotropin-releasing hormone (CRH) and argininevasopressin (AVP). We studied the effect of treatment with 800 mg ketoconazole (3 weeks) upon the concentrations of basalplasmacortisol in the evening, corticosteroid-binding globulin (CBG), dehydroepiandrosterone-sulfate (DHEA-S), and ACTH as wellas theconcentrations of cortisol, CRH, and AVP in cerebrospinal fluid (CSF) at 8.30 h in 10 healthy, male volunteers. While we found cortisolplasma concentrations to be unchanged, we noted a significant increase in ACTH (post: 45.1 ± 43.5; pre: 14.2 ± 5.2 pmol/l; F8= 9.78, p<0.02) and CBG concentrations (post: 38.8 + 4.3; pre: 31.9 + 4.2mg/l), but DHEA-S plasma concentrations declined (post:1.75 ± 1.83; pre: 2.75 ± 2.80 mg/l; F8= 7.9, p<0.03). CRH concentrations in CSF were unchanged after treatment (post: 62.5 ± 15.9;pre: 63.7 ± 13.9 pg/ml), while there was a trend for AVP concentrations to rise during treatment (post: 2.52 ± 1.18; pre: 1.92 ± 0.96 pg/ml; pairedt= — 1.9, p<0.1). CortisolCSF concentrations declined in the elderly (pre: 52.5 ± 23.2; post: 26.7 ± 4.6nmol/l), but not inthe young subgroup (pre: 15.6 ± 11.3; post: 27.7 ± 9.4nmol/l). We thus conclude that the treatment of healthy controls with steroidsynthesis inhibitors does not lead to a major increase in CRH secretion.