Cerebrospinal fluid corticosteroid levels and cortisol metabolism in patients with idiopathic intracranial hypertension: a link between 11beta-HSD1 and intracranial pressure regulation?

Abstract

CONTEXT:

The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity.

OBJECTIVE:

The aim was to characterize 11β-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11β-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:

11β-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 11β-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 11β-HSD1 activity. Elevated 11β-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 11β-HSD1 in IIH is needed, our results suggest that 11β-HSD1 inhibition may have therapeutic potential in IIH.

• Authors: Alexandra J Sinclair, Elizabeth A Walker, Michael A Burdon, Andre P van Beek, Ido P Kema, Beverly A Hughes, Philip I Murray, Peter G Nightingale, Paul M Stewart, Saaeha Rauz, Jeremy W Tomlinson
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 95 Issue 12 Pg. 5348-56 (Dec 2010) ISSN: 1945-7197 [Electronic] United States
• PMID: 20826586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenal Cortex Hormones
• Biomarkers
• RNA, Messenger
• Steroids
• RNA
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Hydrocortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, metabolism)
• Adrenal Cortex Hormones (blood, cerebrospinal fluid, urine)
• Adult
• Biomarkers (cerebrospinal fluid, metabolism)
• Choroid Plexus (pathology, physiopathology)
• Chromatography, Liquid
• Epithelial Cells (pathology)
• Female
• Gas Chromatography-Mass Spectrometry
• Humans
• Hydrocortisone (blood, cerebrospinal fluid, metabolism)
• Intracranial Hypertension (complications, metabolism, physiopathology)
• Intracranial Pressure (physiology)
• Mass Spectrometry
• Obesity (blood, cerebrospinal fluid, complications, urine)
• Polymerase Chain Reaction
• RNA (genetics, isolation & purification)
• RNA, Messenger (genetics)
• Steroids (urine)
• Weight Loss