Q J Med 2003; 96: 481-490
© 2003 Association of Physicians
Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension
From the 1Academic Unit of Ophthalmology, Division of Immunity and Infection, and 2Department of Endocrinology, Division of Medical Sciences, University of Birmingham, Birmingham, UK, 3Regional Endocrine Unit, Southampton General Hospital, Southampton, UK, and 4Department of Ophthalmology and Visual Science, Yale University School of Medicine, Connecticut, USA
Received 4 November 2002 and in revised form 3 April 2003
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 11ß-hydroxysteroid dehydrogenase (11ß-HSD) isozymes (11ß-HSD1 activating cortisol from cortisone, 11ß-HSD2 inactivating cortisol to cortisone).
Aim: To analyse expression of 11ß-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 11ß-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11ß-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 11ß-HSD) on IOP.
Results: ISH defined expression of 11ß-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11ß-HSD1, with additional GR and MR, but not 11ß-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 11ß-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 11ß-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11ß-HSD1 could provide a novel treatment for patients with glaucoma.
Address correspondence to Professor Paul M. Stewart, Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH. e-mail: p.m.stewart{at}bham.ac.uk
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