Endocrine Abstracts

Cushing’s disease presents with multiple symptoms of systemic glucocorticoid (GC) excess including increased skin thinning and poor wound healing (WH). Local GC concentrations are regulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes converting inactive cortisone/11-dehydrocorticosterone to cortisol/corticosterone (11β-HSD1) or vice versa (11β-HSD2). We previously demonstrated elevated 11β-HSD1 activity during early WH, hypothesized to antagonize wound repair.

We examined the effects of systemic GC excess (or vehicle) in female SKH1-hr mice which developed Cushingoid features and suppressed endogenous serum corticosterone vs vehicle (CORT, 5.5 vs 18.5 ng/ml, P<0.01) over 5 weeks CORT therapy (100 μg/ml in drinking water). Mice were treated bi-daily with 30 mM (200 μg) topical carbenoxolone (CBX, 11β-HSD inhibitor) or vehicle, 1 week prior to and post-wounding (by double 5 mm dorsal biopsy).

11β-HSD1 activity was 42% higher in unwounded CORT skin (3.1 vs 2.2 pmol/h, P<0.05) and inhibited >60% by CBX. CORT-induced epidermal thinning was 35% lower with CBX (10.1 vs 15.5 μm, P<0.01) and whilst CORT-treated skin required more desquamation (7.6 vs 4.9 tapes, P<0.001) to induce barrier disruption (trans-epidermal water loss >30 g/h per m²) this was 67% normalized by CBX (P<0.05). Supporting studies in primary human keratinocyte revealed 11β-HSD1 activity increased seven fold during differentiation (P<0.001). Moreover, cortisol treatment induced differentiation (loricrin) and suppressed proliferation (keratin-10) marker expression (normalized to β-actin by Western Blot); effects reversed by GC receptor (RU486) co-treatment. During WH, 11β-HSD1 activity increased to 5 pmol/h in vehicle and CORT-treated mice (P<0.001). However, whilst the former declined 25% by day 9 (P<0.05), the latter remained elevated. Furthermore, although day 6 wounds were 50–80% larger in all CORT mice (vs vehicle, P<0.01), subsequent healing was observed only with CBX co-treatment (34% by day 9, P<0.01).

Although CBX treatment did not affect any of the above parameters in young, healthy mice, topical 11β-HSD1 inhibitors may improve adverse dermatological consequences of systemic GC excess.