Glucocorticoids suppress corticotropin-releasing hormone and vasopressin expression in human hypothalamic neurons

Abstract

Glucocorticoids are widely used in clinical practice in a variety of immune-mediated and neoplastic diseases, mostly for their immunosuppressive, leukopenic, antiedematous, or malignancy-suppressive actions. However, their usage is limited because of serious and sometimes life-threatening side-effects. Endogenous glucocorticoids are secreted by the adrenal cortex under the control of the hypothalamus and the pituitary gland. This hypothalamo-pituitary-adrenal axis, in turn, is under the negative feedback control of glucocorticoids. Although the suppression of adrenocortical and pituitary gland functions by glucocorticoids has been shown in humans, a feedback effect at the level of the hypothalamus, as shown in rat, has not been reported to date. The present study shows for the first time that glucocorticoids suppress both CRH and vasopressin (AVP) in the human hypothalamus. We studied immunocytochemically the postmortem hypothalami of nine corticosteroid-exposed subjects and eight controls. The number of CRH-expressing cells in the hypothalamic paraventricular nucleus of glucocorticoid-exposed patients was only 3.3% of that in the controls, and the total immunoreactivities for AVP were 31% and 33% of that in the controls in the supraoptic nucleus and the paraventricular nucleus, respectively, whereas the immunoreactivity for oxytocin did not differ between the two groups. Suppression of hypothalamic CRH and AVP neurons by glucocorticoids may have important consequences for neuroendocrinological mechanisms such as the disturbance of water balance during the treatment as well as the immunological processes in the brain and the pathogenesis of the withdrawal syndrome after discontinuation of corticosteroid treatment. In addition, as both AVP and CRH neurons also project to other brain structures and influence memory, mood, and behavior, their suppression by glucocorticoids may be responsible for at least part of the central nervous system side-effects of glucocorticoids.