ESPE Abstracts (2018) 89 PL5

Dynamic Control of Tissue Glucocorticoids - Lessons for Optimising Replacement Therapy

Brian Walker

Newcastle University, Newcastle upon Tyne, UK

Although Endocrinologists have focused for decades on circulating concentrations of cortisol, arguably the important concentrations are those within tissues which are available at corticosteroid receptors. Tissue concentrations are influenced by plasma proteins binding cortisol, by physicochemical characteristics of the steroid, by active transport across cell membranes, and by steroid metabolism within target tissues. Many of these factors vary between individuals, and within individuals according to nutritional and inflammatory status. For example, common variants at the locus encoding corticosteroid binding globulin (CBG) make a genetic contribution to variations in plasma cortisol, affecting CBG stability and affinity for cortisol and thereby potentially altering the tissue delivery of cortisol. Moreover, cortisol metabolism within tissues varies substantially after feeding and during acute illness; indeed, tissue regeneration of cortisol by 11ß-HSD1 has provided a target for therapeutic manipulation of tissue cortisol levels independently of circulating levels. These variations reinforce the unmet need for monitoring of glucocorticoid effects which extends beyond measurement of blood steroid concentrations. Recently, we discovered differences between tissue-specific control of cortisol and corticosterone, the other endogenous glucocorticoid in humans. Using stable isotope tracers we found rapid exchange between free and bound cortisol pools in plasma, and between plasma and brain or liver cortisol pools, but very slow exchange between plasma and adipose tissue, consistent with substantial buffering of ultradian and circadian cortisol rhythms within adipose. We attributed this to tissue-specific expression of ABCB1, an ATP-binding cassette transporter, which exports cortisol from brain but not adipose tissue. However, in adipose we showed that an alternative transporter, ABCC1, exports corticosterone and not cortisol. Consistent with these findings, in Addison’s disease we showed that ACTH suppression is relatively resistant to cortisol while adipose tissue transcript induction is relatively resistant to corticosterone. Development of corticosterone as a novel replacement therapy may therefore allow adequate suppression of ACTH, for example in congenital adrenal hyperplasia, without adverse effects that are mediated in adipose tissue such as obesity and metabolic dysfunction.

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