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The introduction of adrenocortical extract in 1930, improved life expectancy to between two and five years with further increases seen with the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multi-dose regimens. Today there remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with detrimental risk of excess glucocorticoid at later times in the day. The way forwards involves replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both prednisolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2-4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.

Introduction Adrenal Insufficiency (AI), especially iatrogenic-AI, is a treatable cause of mortality. The difficulty in obtaining 9am cortisol levels means samples are taken at suboptimal times, including a substantial proportion in the afternoon. Low afternoon cortisol levels often provoke short Synacthen Tests (SSTs). It is important that this does not lead to patients misdiagnosed with AI, exposing them to the excess mortality and morbidity of inappropriate steroid replacement therapy. Methods This retrospective study collected 60,178 cortisol results. Medical records, including subsequent SSTs of initial cortisol results measured after midday were reviewed. Results ROC analysis (AUC- 0.89) on 6531 suitable cortisol values showed that a limit of <201.5nmol/L achieved a sensitivity and specificity of 95.6% and 72.6%, whilst a limit of <234nmol/L had a sensitivity of 100% and a specificity of 59.5%. Out of 670 SSTs, 628 patients passed. Of these, 140 would have otherwise failed if only their 30-minute cortisol was assessed without the 60-minute value. A 30-minute and 60-minute SST cortisol cut-off of 366.5nmol/L and 418.5nmol/L respectively, can achieve a sensitivity of >95% on the Abbott analyser platform. Conclusion An afternoon cortisol >234nmol/L excludes AI on Abbott analyser platforms. In patients who have an afternoon cortisol <234nmol/L, including both a 30-minute and a 60-minute SST cortisol values prevents unnecessary glucocorticoid replacement therapy in 22.3% of individuals in this study. The Abbott analyser SST cortisol cut-offs used to define AI should be 366.5nmol/L and 418.5nmol/L at 30- and 60-minutes respectively. All patients remained well subsequently with at least one year longitudinal follow up.