title: The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic--pituitary--adrenal (HPA) axis in humans.
abstract: Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic-pituitary-adrenal (HPA)-axis, mediating the "proactive"-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15', from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 μg/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p < 0.05 for the doses of 0.3, 0.1 and 0.075 mg). Conversely, 0.05 mg FC did not modify the CRH-stimulatory effect on both ACTH and cortisol secretion. Aldosterone levels were not modified by FC administration. Fludrocortisone inhibits corticotrope and adrenal response to hCRH in humans, in a dose-dependent manner. The 0.075 mg FC seems the lowest active while 0.05 mg the first neutral dose on HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency.
authors.affiliation: Division of Endocrinology, Diabetology and Metabolism, Department of Internal Medicine, Ospedale San Giovanni Battista-Molinette, C.so Dogliotti 14, 10126, Turin, Italy. karamouzisgiannis@yahoo.gr
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karamouzis
authors.forename: Rita
authors.initials: R
authors.lastname: Berardelli
authors.forename: Elisa
authors.initials: E
authors.lastname: Marinazzo
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Angelo
authors.forename: Domenico
authors.initials: D
authors.lastname: Zinnà
authors.forename: Marco Alessandro
authors.initials: MA
authors.lastname: Minetto
authors.forename: Clizia
authors.initials: C
authors.lastname: Zichi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Fussotto
authors.forename: Roberta
authors.initials: R
authors.lastname: Giordano
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Arvat
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D005260:Female; D005438:Fludrocortisone / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000324:Adrenocorticotropic Hormone; D005438:Fludrocortisone; D006854:Hydrocortisone