THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE INHIBITOR GLYCYRRHETINIC ACID AFFECTS CORTICOSTEROID FEEDBACK-REGULATION OF HYPOTHALAMIC CORTICOTROPIN-RELEASING PEPTIDES IN RATS

Steroid-metabolizing enzymes modulate the effects of androgens on brain differentiation and function, but no similar enzymatic system has been demonstrated for adrenocorticosteroids which exert feedback control on the hypothalamus. 11beta-Hydroxysteroid dehydrogenase (11beta-OHSD) rapidly metabolizes physiological glucocorticoids (corticosterone, cortisol) to inactive products, thereby regulating glucocorticoid access to peripheral mineralocorticoid and glucocorticoid receptors in a site-specific manner. Using in-situ hybridization, we found expression of 11beta-OHSD mRNA in neurones of the hypothalamic paraventricular nucleus (PVN) where corticotrophin-releasing factor-41 (CRF-41) is synthesized and from where it is released into hypophysial portal blood. Administration of glycyrrhetinic acid (GE), a potent 11beta-OHSD inhibitor, decreased CRF-41 release into hypophysial portal blood in the presence of unchanged circulating glucocorticoid levels, suggesting that 11beta-OHSD regulates the effective corticosterone feedback signal to CRF-41 neurones. These effects of GE were not observed in adrenalectomized animals, demonstrating dependence on adrenal products. In contrast, GE led to two- to threefold increases in arginine vasopressin and oxytocin release into portal blood, effects also dependent upon intact adrenal glands. These results suggest that 11beta-OHSD in the PVN, and possibly other sites, may represent a novel and important control point of corticosteroid feedback on CRF-41 release in vivo.