Diurnal variation of cerebrospinal fluid immunoreactive corticotropin-releasing hormone levels in healthy volunteers

CRH is not only secreted into hypophyseal protal blood where it is believed to regulate the circadian rhythm of pituitary-adrenal activity, but is also measurable in cerebrospinal fluid (CSF). Altered CSF immunoreactive CRH (IR-CRH) levels have been found in patients with a number of neuropsychiatric disorders and have been implicated in some of the symptoms of these disorders. To further study the potential functional relevance of CRH in human CSF, we examined whether a nonuniform temporal pattern of IR-CRH levels existed in CSF using hourly sampling over a 30-h period in six healthy volunteers. CSF was withdrawn continuously at 6 mL/h through a catheter placed in the lumbar subarachnoid space and connected to a miniroller pump and fraction collector. A significant diurnal variation in CSF IR-CRH levels was observed (P0.001), with highest levels between 1830-2330 h and lowest levels around 0730 h. This pattern was nearly opposite that of plasma cortisol levels, which showed the expected peak around 0800 h and nadir around 2000-2200 h. In addition, CSF IR-CRH levels in three of the six volunteers showed significant negative correlations with simultaneous plasma cortisol levels. These data suggest that CSF IR-CRH concentrations are negatively modulated by peripheral cortisol secretion, which may be one factor involved in the entrainment of this rhythm. Although the functional significance of this diurnal variation in CSF IR-CRH levels is unknown, the presence of a distinct temporal organization of CRH release into the CSF in humans is compatible with the idea that CSF may play a functional role in or otherwise reflect nonsynaptic information processing in the central nervous system. Diurnal factors should be taken into account in future studies of CRH concentrations in human CSF.