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The glucocorticoid hormone cortisol is released in pulses resulting in a complex and dynamic ultradian rhythm of plasma cortisol that underlies the classical circadian rhythm. These oscillating levels are also seen at the level of tissues such as the brain and trigger pulses of gene activation and downstream signalling. Different patterns of glucocorticoid presentation (constant versus pulsatile) result not only in different patterns of gene regulation but also different neuroendocrine and behavioural responses. Current "optimal" glucocorticoid replacement therapy results in smooth hormone blood levels and does not replicate physiological pulsatile cortisol secretion. We have now validated a novel portable pulsatile continuous subcutaneous hydrocortisone delivery system in healthy volunteers that more closely replicates the physiological circadian and ultradian rhythmicity. This article is protected by copyright. All rights reserved.