Readjusting the glucocorticoid balance: an opportunity for modulators of 11beta-hydroxysteroid dehydrogenase type 1 activity?

Glucocorticoids play a pivotal role in the regulation of most essential physiological processes, including energy metabolism, maintenance of electrolyte balance and blood pressure, immune-modulation and stress responses, cell proliferation and differentiation, as well as regulation of memory and cognitive functions. There are several levels at which glucocorticoid action can be modulated. On a tissue-specific level, glucocorticoid action is tightly controlled by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes. The conversion of inactive 11-ketoglucocorticoids (cortisone and 11-dehydrocorticosterone) into active 11beta-hydroxyglucocorticoids (cortisol and corticosterone) is catalyzed by 11beta-HSD1, which is expressed in many tissues and plays an important role in metabolically relevant tissues such as the liver, adipose tissue and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity rather than elevated systemic glucocorticoid levels has been associated with metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that compounds inhibiting 11beta-HSD1 activity ameliorate the adverse effects of excessive glucocorticoid concentrations on metabolic processes, providing promising opportunities for the development of therapeutic interventions. This review addresses recent findings relevant for the development and application of therapeutically useful compounds that modulate 11beta-HSD1 function.

Disruption of glucocorticoid action by environmental chemicals: potential mechanisms and relevance

Glucocorticoids play an essential role in the regulation of key physiological processes, including immunomodulation, brain function, energy metabolism, electrolyte balance and blood pressure. Exposure to naturally occurring compounds or industrial chemicals that impair glucocorticoid action may contribute to the increasing incidence of cognitive deficits, immune disorders and metabolic diseases. Potentially, "glucocorticoid disruptors" can interfere with various steps of hormone action, e.g. hormone synthesis, binding to plasma proteins, delivery to target cells, pre-receptor regulation of the ratio of active versus inactive hormones, glucocorticoid receptor (GR) function, or export and degradation of glucocorticoids. Several recent studies indicate that such chemicals exist and that some of them can cause multiple toxic effects by interfering with different steps of hormone action. For example, increasing evidence suggests that organotins disturb glucocorticoid action by altering the function of factors that regulate the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) pre-receptor enzymes, by direct inhibition of 11beta-HSD2-dependent inactivation of glucocorticoids, and by blocking GR activation. These observations emphasize on the complexity of the toxic effects caused by such compounds and on the need of suitable test systems to assess their effects on each relevant step.

Randomized, Double-Blind Trial of the Effect of Fluid Composition on Electrolyte, Acid-Base, and Fluid Homeostasis in Patients Early After Subarachnoid Hemorrhage.

Hyper- and hyponatremia are frequently observed in patients after subarachnoidal hemorrhage, and are potentially related to worse outcome. We hypothesized that the fluid regimen in these patients is associated with distinct changes in serum electrolytes, acid-base disturbances, and fluid balance.