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

Steroid synthesis inhibitors are used in the treatment of Cushing’s disease, but also improve psychopathology in hypercortisolemic depressed patients. Since glucocorticoids exert a negative feedback, the inhibition of steroid synthesis may lead to increased corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). We studied the effect of 800mg ketoconazole (3 weeks) upon the concentrations of evening cortisol, corticosteroid-binding globulin (CBG), dehydroepiandrosterone-sulfate (DHEA-S), and ACTH as well as the concentrations of cortisol, CRH, and AVP in cerebrospinal fluid (CSF) at 8.30h in 10 healthy, male volunteers. While we found cortisol plasma concentrations to be unchanged, we noted a significant increase in ACTH and CBG, but DHEA-S concentrations declined. CRH concentrations in CSF were unchanged after treatment, while there was a trend for AVP concentrations to rise during treatment. Cortisol CSF concentrations declined in the elderly, but not in the young subgroup. We thus conclude that the treatment of healthy controls with steroid-synthesis inhibitors does not lead to a major increase in CRH secretion.

Deuschle, M. et al. Neuropsychopharmacology 28 (2003) 379–383