Rapid turnover of corticosterone in humans: the role of a second glucocorticoid hormone

BACKGROUNDAdrenal insufficiency is primarily treated with replacement of cortisol, which is the predominant circulating glucocorticoid. Human adrenals also secrete corticosterone and emerging evidence suggests this may be a safer glucocorticoid replacement therapy. However, little is known about corticosterone in humans, particularly related to its metabolism. METHODSTo investigate the secretion and metabolism of corticosterone in comparison with cortisol, we: 1) investigated the diurnal rhythm of circulating cortisol/ corticosterone in 7 healthy volunteers; 2) quantified A-ring reduction of both hormones in human hepatic cytosol and 3) measured glucocorticoid metabolites in vivo in 24 healthy men; 4) determined the pharmacokinetics of corticosterone via intravenous infusion of 2,2,4,6,6,17,21,21-[2H]8-corticosterone; 5) assessed the response of corticosterone and cortisol to 1mcg ACTH in 279 healthy volunteers. RESULTSThe natural diurnal rhythm of corticosterone closely mirrored that of cortisol, and accounted for [~]3% of total circulating glucocorticoid concentrations. Daily corticosterone production, as measured through urinary steroid profiling, was approximately 10-fold lower than cortisol, and corticosterone demonstrated substantially greater metabolism by both 5- and 5{beta}-reductase than cortisol. In keeping with greater metabolism, the half-life of corticosterone was 28.5 {+/-} 3.3 minutes. Finally, corticosterone demonstrated a greater relative rise in response to ACTH than cortisol, particularly in men, revealing sex-specific differences. CONCLUSIONSCorticosterone is a dynamic glucocorticoid with faster metabolism and greater response to stimulation than cortisol in humans. These data raise the possibility of distinct roles for these two glucocorticoids and highlight important pharmacokinetic differences with implications for the therapeutic potential of corticosterone replacement in humans.