The role of corticosterone in human hypothalamic-pituitary-adrenal axis feedback.
OBJECTIVE
In humans, the glucocorticoid corticosterone circulates in blood at 10-20-fold lower levels than cortisol, but is found in higher relative amounts in postmortem brain samples. Access of cortisol and corticosterone to the central nervous system may not be equal. Additionally, the relative affinities for the glucocorticoid and mineralocorticoid receptors differ, such that corticosterone may play a significant role in human brain function.


METHODS
We measured cortisol and corticosterone levels in paired plasma and cerebrospinal fluid (CSF) samples. To test the relative potency of cortisol vs. corticosterone on hypothalamic-pituitary-adrenal (HPA) feedback, subjects underwent a three-phase, single-blind, randomized study assessing the postmetyrapone ACTH response over 3 h to an intravenous bolus of vehicle, cortisol or corticosterone (0.15 mg/kg and 0.04 mg/kg).


METHODS
Outpatients undergoing diagnostic lumbar puncture who were subsequently deemed to be free of disease. Feedback was tested in healthy male volunteers.


METHODS
Plasma and CSF corticosterone to cortisol ratio was calculated and the ACTH response over time after the bolus glucocorticoid measured.


RESULTS
Plasma corticosterone : cortisol was 0.069 +/- 0.007; CSF corticosterone : cortisol was 0.387 +/- 0.050 (P < 0.001). Cortisol and corticosterone (0.15 mg/kg) suppressed ACTH vs. vehicle (P = 0.002); there was no difference between corticosterone and cortisol. The 0.04 mg/kg dose had no effect on ACTH despite supraphysiological plasma corticosterone levels.


CONCLUSIONS
Corticosterone contributes almost 40% of total active glucocorticoids (cortisol and corticosterone) in the CSF. Significant effects on HPA axis suppression were only seen with supraphysiological levels of corticosterone, suggesting that corticosterone is not important in this model of nonstress-induced ACTH hypersecretion, in which the effect of cortisol predominates.
Raubenheimer
Peter J
PJ
Department of Endocrinology, University of Edinburgh, Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh, UK. praubenh@uctgsh1.uct.ac.za
Young
Elizabeth A
EA
Andrew
Ruth
R
Seckl
Jonathan R
JR
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D002493:Central Nervous System Diseases / Q000134:cerebrospinal fluid; D003345:Corticosterone / Q000097:blood / Q000134:cerebrospinal fluid / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000134:cerebrospinal fluid; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D008797:Metyrapone; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000502:physiology*; D016037:Single-Blind Method
D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D006854:Hydrocortisone; D008797:Metyrapone