The Pathogenetic Role of Cortisol in the Metabolic Syndrome: A Hypothesis

Context: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities that increase the risk for type 2 diabetes mellitus and vascular disease. The common characteristics of MetS and hypercortisolemic conditions such as Cushing's syndrome (CS) suggest that the pathogenesis of MetS and central obesity might involve prolonged and excessive exposure to glucocorticoids. The present review summarizes the evidence on the potential role of cortisol in the pathogenesis of MetS and discusses new therapeutic approaches for these patients. Evidence Acquisition: Using PubMed, we searched for publications during the last 20 yr regarding the possible pathogenetic role of cortisol in the development of MetS. Evidence Synthesis: Emerging data suggest that patients with MetS show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to a state of "functional hypercortisolism." The cause for this activation of the HPA axis remains uncertain but may be partly associated with chronic stress and/or low birth weight, which are both associated with increased circulating cortisol levels and greater responsiveness of the HPA axis. Increased exposure to cortisol contributes to increased fat accumulation in visceral depots. However, cortisol metabolism is not only centrally regulated. The action of 11 beta-hydroxysteroid dehydrogenase-1 at the tissue level also modulates cortisol metabolism. Increased 11 beta-hydroxysteroid dehydrogenase-1 activity in adipose tissue and liver might contribute to the development of several features of the MetS. Conclusions: MetS shares many characteristics of CS, and cortisol might play a role in the development of MetS at both a central and a peripheral level. (J Clin Endocrinol Metab 94: 2692-2701, 2009)