Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age.

Abstract

The relation between blood and cerebrospinal fluid (CSF) concentrations of cortisol, dehydroepiandrosterone (DHEA), and its sulfate (DHEAS) was measured in 62 subjects aged 3-85 yr old, fitted with ventriculo-peritoneal or lumbar-peritoneal shunts for a variety of diagnoses. There were 36 males and 36 females. Forty-eight subjects were not taking exogenous corticosteroids; the other 14 were receiving either systemic or local steroids. A single sample of blood and CSF was taken from each subject within 10 min for measurement of cortisol, DHEA, and DHEAS. The proportional levels of cortisol (5.8%) and DHEA (5.4%) in the CSF compared with those in the blood were similar in subjects not taking steroids. However, CSF DHEAS levels were only 0.15% of those in the blood. Because DHEAS blood levels were so much greater than DHEA, DHEAS in the CSF was still higher than DHEA despite the reduced penetration of the sulfated steroid. The blood/CSF ratios were similar in subjects taking steroids. There were significant correlations in steroid-free subjects between blood and CSF levels for DHEA (r = 0.65) and DHEAS (r = 0.88) but not for cortisol (r = 0.26). Steroid treatment significantly lowered blood cortisol, DHEA and DHEAS, and CSF DHEA, but not CSF cortisol or DHEAS compared with an age- and sex-matched sample of steroid-free subjects. In steroid-free adults (18 yr and over; n = 37), blood cortisol showed no age-related change. However, CSF cortisol was markedly raised in a proportion of steroid-free subjects over the age of 60 yr. Levels of corticoid-binding globulin in plasma did not alter with age. As expected, there were significant age-related decrements in both blood DHEA and DHEAS. CSF DHEA (r = 0.42) and CSF DHEAS (r = 0.39) were significantly negatively correlated with age. In steroid-free juveniles (n = 11) there were no age-related changes in either blood or CSF cortisol, but significant increases with age in DHEA and DHEAS in both blood and CSF. Calculation of the cortisol/DHEA and cortisol/ DHEAS molar ratios in the CSF showed both to be raised in the very young (3-8 yr) and the elderly (60 yr and over) by a factor of 4-5 compared with young adults aged 18-39. There were no sex differences in any of the parameters measured. These findings show that the relation between levels in the blood and CSF differ for each of these three neuroactive steroids. The brain is exposed to relatively high levels of DHEA and DHEAS during later childhood and early adulthood but to relatively or absolutely high levels of cortisol during infancy and older age. In view of the known antiglucocorticoid action of DHEA and DHEAS, and the direct action of these steroids on membrane-bound transmitter events (such as gamma-aminobutyric acidA receptors), these changes may have important implications for age-related alterations in brain function.

Brain-immune interactions and disease susceptibility

“…46 Animals studies in rodents have generally found memory-enhancing effects, 47 antidepressant-like effects, 48 antianxiety effect, 49 and neurotrophic effects. 50,51 In humans, levels in circulation decline with age, 52 with chronic stress and medical illness. 53 DHEA and DHEA-S may physiologically buffer the effects of excessive glucocorticoid exposure.…”

Cortisol Levels and Hippocampus Volumes in Healthy Preadolescent Children

“…The few studies on serum cortisol in healthy children between the ages of 2 and 18 years reported similar large interindividual variability and also failed to find correlations with age (Guazzo et al 1996;Knutsson et al 1997). In contrast, studies that measured cortisol in saliva samples in children have found agerelated increases (Lupien et al 2001), with the most prominent age associations occurring between years 10 and 12 (Lupien et al 2001) and during adolescence (Netherton et al 2004;Walker et al 2001).…”

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity

“…Parallel experiments showed that, although DHEAS also protected neurons in vitro against NMDA, it seemed less potent because significant protection only was observed at Ϸ10 times the lowest effective dose of DHEA (10 nM) used in these experiments. It is therefore interesting to note that, although levels of DHEAS in the blood of adult humans are more than 100 times those of DHEA, in the CSF, the ratio is only about three times (17). This suggests that DHEA may play a predominant role in the combined neuroprotective effects of these steroids in the brain.…”

“…This suggests that DHEA may play a predominant role in the combined neuroprotective effects of these steroids in the brain. However, radioimmunoassays showed that the neuroprotective action of DHEAS is not due to conversion to DHEA, so DHEAS may contribute directly to the overall protective actions in species, such as humans, that have appreciable amounts of both steroids in their CSF (17). The protective actions of DHEA(S) stand in contrast to those of glucocortoids, which induce hippocampal pyramidal neuron degeneration (10).…”