Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone.
The hippocampal mineralocorticoid receptor (MR) is critical for the regulation of the basal activity of the hypothalamus-pituitary-adrenocortical (HPA) system. It has been hypothesized that reduced capacity of the hippocampal MR is involved in the HPA-system dysregulation found in depression and aging. We applied the combined dexamethasone suppression/corticotropin releasing hormone stimulation (DEX/CRH) test to six healthy young females both before and after 12 days of treatment with the MR antagonist spironolactone to assess HPA regulation. Treatment with spironolactone caused a significant increase in post-dexamethasone cortisol concentrations (75.1+/-56.7 vs. 36.6+/-24.6 nmol/l, p<0.05). Furthermore, we observed a significant rise in peak cortisol concentration after additional human CRH (hCRH) application (223. 6+/-139.1 vs. 126.7+/-73.3 nmol/l, p<0.02). There was no change in ACTH plasma concentrations. We thus conclude that (1) the MR antagonist spironolactone affects HPA system regulation as reflected in the DEX/CRH test and (2) these findings are in accordance with the assumption that MR dysfunction may underlie HPA-system dysfunction in depression and/or aging.
Heuser
I
I
Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstr. 10, 80804, Munich, Germany. isabella@as200.zi-mannheim.de
Deuschle
M
M
Weber
B
B
Stalla
G K
GK
Holsboer
F
F
D000311:Adrenal Glands / Q000187:drug effects / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D003346:Corticotropin-Releasing Hormone; D003907:Dexamethasone; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D000451:Mineralocorticoid Receptor Antagonists; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology*; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D013148:Spironolactone
D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone