title: The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans.
abstract: Alprazolam (ALP), a benzodiazepine that activates gamma-aminobutyric acid-ergic receptors, inhibits the activity of hypothalamo-pituitary-adrenal (HPA) axis, probably via inhibition of hypothalamic CRH and/or arginine vasopressin release. To further clarify the effects of ALP on the HPA axis in humans, in six normal young women (26-34 yr old) we studied the effects of 0.02 mg/kg ALP (administered orally at 0700 h) or placebo on ACTH, cortisol (F), and 11-deoxycortisol (S) levels assayed after placebo or metyrapone (MET; 0.04 g/kg administered orally at 2300 h the night before). After placebo administration, ACTH, F, and S levels showed a progressive decrease from 0700-1200 h (P < 0.03). At 0700 h, ACTH, F, and S levels before ALP overlapped with those after placebo. At 1200 h, ACTH, F, and S levels after ALP were lower than those after placebo (P < 0.03). MET pretreatment strongly increased ACTH (P < 0.03) and S (P < 0.02) while clearly inhibiting F (P < 0.03) levels at 0700 h. After MET, ACTH levels did not show any decrease up to 1200 h; similarly, S levels persisted similar up to 1200 h, whereas F levels at 1200 h were significantly increased (P < 0.03). At 0700 h, MET-induced ACTH and F levels before ALP overlapped with those after MET alone. The MET-induced ACTH levels at 1200 h were markedly inhibited by ALP (P < 0.05). At 1200 h after MET and ALP, a clear reduction of S levels (P < 0.02) and an insignificant F reduction were also found. In conclusion, our present data show that ALP inhibits basal and, much more, metyrapone-induced corticotroph secretion. These findings indicate that the inhibitory effect of central gamma-aminobutyric acid-ergic activation by ALP overrides the stimulatory effect of the MET-induced lack of negative F feedback on corticotroph secretion. These results also point toward potential contraindication of ALP administration in patients with suspected hypoadrenalism.
authors.affiliation: Department of Internal Medicine, University of Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Arvat
authors.forename: B
authors.initials: B
authors.lastname: Maccagno
authors.forename: J
authors.initials: J
authors.lastname: Ramunni
authors.forename: L
authors.initials: L
authors.lastname: Di Vito
authors.forename: R
authors.initials: R
authors.lastname: Giordano
authors.forename: L
authors.initials: L
authors.lastname: Gianotti
authors.forename: F
authors.initials: F
authors.lastname: Broglio
authors.forename: F
authors.initials: F
authors.lastname: Camanni
authors.forename: E
authors.initials: E
authors.lastname: Ghigo
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D000525:Alprazolam / Q000494:pharmacology*; D003350:Cortodoxone / Q000378:metabolism*; D005246:Feedback; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008797:Metyrapone / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects
chemical_list: D018757:GABA Modulators; D000324:Adrenocorticotropic Hormone; D003350:Cortodoxone; D006854:Hydrocortisone; D000525:Alprazolam; D008797:Metyrapone