Clinical observations on patients with Cushing's syndrome highlight the importance of cortisol in regulating blood pressure and body fat mass. However, most patients with hypertension and obesity 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 active cortisol (F) to inactive cortisone (E). 11b-HSD1 is an oxoreductase expressed in human liver and adipose tissue, responsible for E to F conversion. Within adipose tissue, expression is higher in omental compared to subcutaneous fat; 11b-HSD1 generates F to stimulate 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. 'Cushing's disease of the omentum' may be a novel mechanism underpinning central obesity.
11b-HSD2 is a high affinity dehydrogenase expressed in adult mineralocorticoid target tissues (kidney, colon). By inactivating F to E it protects the mineralocorticoid receptor from cortisol excess. Mutations in the human 11b-HSD2 gene explain a severe form of hypertension, the syndrome of Apparent Mineralocorticoid Excess, in which cortisol acts as a potent mineralocorticoid. Liquorice inhibits 11b-HSD2 and results in an identical form of cortisol-induced hypertension. 'Milder' mutations in the human 11b-HSD2 gene have been reported in patients with 'essential' hypertension, but at present the prevalence of defects in cortisol metabolism in hypertensive patients is unknown.
11b-HSD's by activating or inactivating cortisol in peripheral tissues, can amplify or inhibit corticosteroid hormone action at an autocrine level. The manipulation of 11b-HSD expression in peripheral tissues may offer a novel therapeutic option for diseases such as obesity and hypertension without the deleterious systemic effects of cortisol excess or deficiency.
03 - 04 Dec 2001
Society for Endocrinology