Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension.

BACKGROUND

Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes (11beta-HSD1 activating cortisol from cortisone, 11beta-HSD2 inactivating cortisol to cortisone).

AIM

To analyse expression of 11beta-HSD in the human eye and investigate its putative role in AH formation.

DESIGN

Multipart prospective study, including a randomized controlled clinical trial.

METHODS

The expression of 11beta-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11beta-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11beta-HSD) on IOP.

RESULTS

ISH defined expression of 11beta-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11beta-HSD1, with additional GR and MR, but not 11beta-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11beta-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p<0.0001).

DISCUSSION

CBX lowers IOP in patients with ocular hypertension. Our data suggest that this is mediated through inhibition of 11beta-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11beta-HSD1 could provide a novel treatment for patients with glaucoma.