11β-Hydroxysteroid Dehydrogenase Type 1 and Its Role in the Hypothalamus-Pituitary-Adrenal Axis, Metabolic Syndrome, and Inflammation

Context: 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) enzymes are now appreciated to be important regulators of hormone action at a tissue level. 11 beta-HSD1 is widely expressed and increases glucocorticoid action through its unique ability to convert inactive glucocorticoids (cortisone in man, 11-dehydrocorticosterone in rodents) to their active forms (cortisol and corticosterone, respectively). The enzyme has roles in the normal hypothalamus-pituitary-adrenal (HPA) axis, has been implicated in metabolic syndrome, and may modulate various aspects of the immune response. Evidence Acquisition: A review of published, peer-reviewed medical literature (1990 to June 2009) on the physiology and pathophysiology of 11 beta-HSD1 was performed with an emphasis on HPA axis consequences, the metabolic syndrome, and the inflammatory response. Evidence Synthesis: Studies of patients with genetic defects in 11 beta-HSD1 action show abnormal HPA axis responses with hyperandrogenism being a major consequence. The mechanisms underlying these abnormalities have been explored in mouse models with targeted deletion of components of the 11 beta-HSD1 system. A range of experimental studies emphasize the role of 11 beta-HSD1 in the metabolic syndrome and the potential for treatment with chemical inhibitors. An emerging area is the role of 11 beta-HSD1 in the inflammatory response. Conclusions: 11 beta-HSD1 activity is an important component of the HPA axis and contributes to the metabolic syndrome and the normal immune response. Ongoing clinical observations and the development of selective inhibitors will further clarify the role of 11 beta-HSD1 in these areas. (J Clin Endocrinol Metab 94: 4645-4654, 2009)