Factors Regulating Levels of Cortisol in Cerebrospinal Fluid of Monkeys during Acute and Chronic Hypercortisolemia

Abstract

Cortisol levels in the serum and cerebrospinal fluid (CSF) were studied in ovariectomized, estrogen-treated monkeys during either prolonged hypercortisolemia or the more transient effects of a bolus injection of cortisol. Control (saline-treated) animals showed the expected diurnal rhythm in serum cortisol, but proportionately more cortisol was present in the CSF when serum levels were high (i.e. in the morning). Prolonged hypercortisolemia for up to 37 days was produced by either thrice daily injections of cortisol itself or single daily injections of ACTH_1-24 in the morning. Both treatments produced disproportionately larger amounts of cortisol in the CSF than in the serum, and the CSF/serum cortisol ratio was increased. Furthermore, prolonged ACTH treatment caused a marked elevation in CSF cortisol in afternoon samples taken at 16.30 h compared with those at 10.00 h, in the absence of a similar change in serum cortisol levels. The relative importance of entry and clearance of cortisol in the CSF in these conditions was studied in several ways. ‘Free’ cortisol levels in serum (determined by equilibrium dialysis) were equal to CSF cortisol levels in control monkeys, but were less than those in the CSF of hypercortisolemic animals. Entry of cortisol into CSF after a bolus injection was rapid, but, unlike serum, CSF cortisol levels did not decline significantly over a 70-min sampling period and the delayed clearance from the CSF could account for some of the effects seen during hypercortisolemia. Neither high levels of prolactin (which is elevated together with cortisol in ‘stress’), induced by giving sulpiride, nor treatment with progesterone (which is also bound by corticosteroid binding globulin) altered the distribution of cortisol between blood and CSF. The concentrations of cortisol in the CSF therefore are regulated by factors influencing both its entry and clearance from the cerebral compartment. Neural tissues sensitive to cortisol are thus exposed to levels of this hormone that are both qualitatively and quantitatively different from those expected by direct extrapolation from serum levels.

Modulation by Social Status of the Relationship between Cerebrospinal Fluid and Serum Cortisol Levels in Male Talapoin Monkeys

“…However, it was striking that in each case there was apparently excess cortisol in the CSF of dominant ani mals from the levels expected. Cortisol seems to be cleared slowly from CSF compared with plasma [9], and a further selective delay in the clearance from the CSF of dominant males might explain this finding. We have also shown, in rhesus monkeys, that the shape of the circadian rhythm in the vascular and the cerebral compartments is different [11].…”

“…Cortisol was measured by radioimmunoassay without chroma tography as described previously [9]. inter-and intra-assay coeffi cients of variation were: for serum 8.1 and 3.5%: for CSF 8.1 and 7.9%.…”

“…Although corti sol, being lipid soluble, enters the brain readily [12], levels in the CSF cannot be inferred directly from the total amount in the blood, because several factors modulate in tracerebral concentrations. The proportion of cortisol bound to plasma proteins is one such factor, since only the 'free' fraction crosses the blood-brain barrier [12], Another is the finding that cortisol is cleared more slowly from CSF than from blood; thus the shape of the circadian rhythm is different in the two compartments [II], and steroid may ac cumulate in the CSF if blood levels are very high [9], Under physiological conditions, cortisol is a highly la bile hormone. Levels in the blood fluctuate hourly during the day [10], and, perhaps most importantly, in response to a variety o f 'stressors' both acute and chronic, of which so cial subordination is of particular interest [7], An individual monkey's position in the hierarchy of his group has marked effects upon his endocrine function.…”

Naturally occurring scrapie is associated with a lower CBG binding capacity in ewes

“…It is generally thought that only the CBG-free fraction of cortisol can cross the blood-brain barrier (Rosner 1990, Hammond 1990) and that CBG-free serum cortisol is of the same order of magnitude as the cerebrospinal fluid (CSF) cortisol levels (Martensz et al 1983, Schwarz & Pohl 1992). In addition, previous studies in monkeys showed a disproportionate elevation in CSF cortisol when blood levels of the hormone were persistently elevated by repeated injections of either cortisol or adrenocorticotropin (ACTH), due probably to an accumulation of cortisol within CSF (Martensz et al 1983).…”

“…It is generally thought that only the CBG-free fraction of cortisol can cross the blood-brain barrier (Rosner 1990, Hammond 1990) and that CBG-free serum cortisol is of the same order of magnitude as the cerebrospinal fluid (CSF) cortisol levels (Martensz et al 1983, Schwarz & Pohl 1992). In addition, previous studies in monkeys showed a disproportionate elevation in CSF cortisol when blood levels of the hormone were persistently elevated by repeated injections of either cortisol or adrenocorticotropin (ACTH), due probably to an accumulation of cortisol within CSF (Martensz et al 1983). These observations raise the question of the effect, in scrapie-affected sheep, of a putative chronic overexposure to a high level of free cortisol in the central nervous system, prolonged elevated corticosteroid exposure leading to neurodegenerative loss of neurons in the rodent brain regions possessing high concentrations of glucocorticoid receptors and particularly in the hippocampus (Sapolsky et al 1985).…”