Endocrine Abstracts

Patients with Cushing's syndrome emphasize the importance of cortisol in regulating body fat mass and distribution, bone mineral density and intraocular pressure. However, patients with the prevalent diseases, obesity, osteoporosis and glaucoma, invariably have normal circulating cortisol concentrations. We have focussed on the concept of 'pre-receptor' metabolism as a mechanism of modulating the action of cortisol in a tissue-specific fashion. Two isozymes of 11b-hydroxysteroid dehydrogenase (11b-HSD) catalyse the interconversion of hormonally active cortisol (F) to inactive cortisone (E). 11b-HSD2 is a high affinity dehydrogenase expressed in adult kidney that inactivates F to E protecting the mineralocorticoid receptor from cortisol excess. Mutations in the human 11b-HSD2 gene explain an inherited form of hypertension, the syndrome of 'Apparent Mineralocorticoid Excess' and milder mutations in the human 11b-HSD2 gene have been reported in patients with 'essential' hypertension.

11b-HSD1 is an oxoreductase expressed in human liver, adipose, bone and ciliary epithelium where it facilitates glucocorticoid action through E to F conversion. Specifically within human adipose tissue, expression is higher in omental compared to subcutaneous fat. Here the generation of F via 11b-HSD1 stimulates adipocyte differentiation and this may explain the predilection of glucocorticoids for visceral obesity. 11b-HSD1 within adipose tissue is inhibited by IGF-1 and enhanced expression in hypopituitary, GH-deficient, subjects may explain the visceral obesity of this condition. In the eye, 11b-HSD1 may regulate intraocular pressure. 'Cushing's disease of the omentum or eye' may be a novel mechanism underpinning central obesity and glaucoma respectively; data indicate that inhibition of the 11b-HSD1 results in a fall in intraocular pressure in patients with intraocular hypertension.

11b-HSD1 by activating cortisol in peripheral tissues, amplifies corticosteroid hormone action at an autocrine level. The manipulation of 11b-HSD1 expression in peripheral tissues may offer a novel therapeutic option for diseases such as obesity and glaucoma without the deleterious systemic effects of cortisol excess or deficiency.