Cerebrospinal Fluid Corticosteroid Levels and Cortisol Metabolism in Patients with Idiopathic Intracranial Hypertension: A Link between 11 beta-HSD1 and Intracranial Pressure Regulation?

Context: The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) activity. Objective: The aim was to characterize 11 beta-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11 beta-HSD1 activity after therapeutic weight loss in IIH. Design and Setting: We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. Patients or Other Participants: Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. Intervention: Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. Main Outcome Measures: Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. Results: 11 beta-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2 +/- 7.8 kg; P <0.001), global 11 beta-HSD1 activity decreased (P = 0.001) and correlated with reduction in intracranial pressure (r = 0.504; P = 0.028). CSF and serum glucocorticoids remained stable, although the change in CSF cortisone levels correlated with weight loss (r = -0.512; P = 0.018). Conclusions: Therapeutic weight loss in IIH is associated with a reduction in global 11 beta-HSD1 activity. Elevated 11 beta-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11 beta-HSD1 in IIH is needed, our results suggest that 11 beta-HSD1 inhibition may have therapeutic potential in IIH. (J Clin Endocrinol Metab 95: 5348-5356, 2010)