Samenvatting

Hypothalamic-pituitary-adrenal (HPA) axis function is regulated via negative feedback actions of glucocorticoids at the level of the pituitary, the hypothalamus as well as limbic structures such as the hippocampus and amygdala. Glucocorticoids exert their effects by binding to the glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) and subsequent up- or downregulation of GR and MR target genes. The bioactivity of glucocorticoids is tissue-specific and depends both on local GR expression and 11β-hydroxysteroid dehydrogenase activity (11β-HSD). 11β-HSD interconverts glucocorticoids between biologically active cortisol and inactive cortisone. Inhibition of 11β-HSD activity decreases corticotrophin-releasing-hormone (CRH) release from the hypothalamus into the hypophysial portal blood, suggesting that hypothalamic 11β-HSD is involved in the regulation of the HPA axis. Two types of 11β-HSD have been characterized. 11β-HSD1 has predominantly reductase activitity in vivo, whereas 11β-HSD2 has dehydrogenase activity. Thus, 11β-HSD1 increases local bioavailability of cortisol whereas 11β-HSD2 inactivates cortisol into cortisone. The reductase activity of 11β-HSD1 is NADPH-dependent.The expression and distribution of 11β-HSD1 and 11β-HSD2 in the human hypothalamus has not been reported to date.
In this study we characterized the neuroanatomical distribution of 11β-HSD in paraffin-embedded hypothalamic and pituitary tissue of 12 control patients (7 male, 5 female) using immunocytochemistry. The brain tissue was obtained from the Netherlands Brain Bank. The antibodies were tested on specificity in both tissues. In addition, we studied co-localisation of 11β-HSD with vasopressin (AVP), CRH, thyrotrophin-releasing hormone (TRH) and oxytocin (OXT) expressing neurons in the paraventricular nucleus of the hypothalamus. In the pituitary we confirmed co-localization found by Korbonits et al . This study suggest that 11β-HSD1 found in the hypothalamus can be of major importance in regulating glucocorticoid function; in particular, it would act to increase cortisol levels in the region of the glucocorticoid receptor (GR), thus increasing the functional feedback of the HPA-axis.