title: Steroid synthesis inhibition with ketoconazole and its effect upon the regulation of the hypothalamus-pituitary-adrenal system in healthy humans.
abstract: 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-pituitary levels, the inhibition of steroid synthesis may lead to increased expression of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). We studied the effect of treatment with 800 mg ketoconazole (3 weeks) upon the concentrations of basal plasma cortisol in the evening, 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 8.30 h in 10 healthy, male volunteers. While we found cortisol plasma concentrations to be unchanged, we noted a significant increase in ACTH (post: 45.1+/-43.5; pre: 14.2+/-5.2 pmol/l; F(1,8)=9.78, p<0.02) and CBG concentrations (post: 38.8+/-4.3; pre: 31.9+/-4.2 microg/l), but DHEA-S plasma concentrations declined (post: 1.75+/-1.83; pre: 2.75+/-2.80 mg/l; F(1,8)=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; paired t=-1.9, p<0.1). Cortisol CSF concentrations declined in the elderly (pre: 52.5+/-23.2; post: 26.7+/-4.6 nmol/l), but not in the young subgroup (pre: 15.6+/-11.3; post: 27.7+/-9.4 nmol/l). We thus conclude that the treatment of healthy controls with steroid-synthesis inhibitors does not lead to a major increase in CRH secretion.
authors.affiliation: Central Institute of Mental Health, Mannheim, Germany. deuschle@as200.zi-mannheim.de
authors.forename: Michael
authors.initials: M
authors.lastname: Deuschle
authors.forename: Olivera
authors.initials: O
authors.lastname: Lecei
authors.forename: Günther K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.forename: Bettina
authors.initials: B
authors.lastname: Hamann
authors.forename: Florian
authors.initials: F
authors.lastname: Lederbogen
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Peter
authors.initials: P
authors.lastname: Luppa
authors.forename: Athanasios
authors.initials: A
authors.lastname: Maras
authors.forename: Michael
authors.initials: M
authors.lastname: Colla
authors.forename: Isabella
authors.initials: I
authors.lastname: Heuser
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D013256:Steroids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood
chemical_list: D013256:Steroids; D007654:Ketoconazole