Human studies on hypothalamo-pituitary-adrenal (HPA) axis

The daily rhythm of the hypothalamo-pituitary-adrenal (HPA) axis is regulated by the central clock in the suprachiasmatic nucleus. Cortisol, a glucocorticoid, acts as a secondary messenger between the central clock and the peripheral tissues. Changes in clock time, as seen in shift workers, alters the HPA axis and results in metabolic disturbances associated with ill health. Depression, anorexia nervosa and obstructive sleep apnoea, are associated with cortisol rhythm phase shifts and increased cortisol exposure. Higher nocturnal cortisol exposure is observed in patients with Cushing's syndrome and adrenal incidentalomas with autonomous cortisol secretion and is associated with insulin resistance, and increased cardiovascular risk and mortality. A decrease in cortisol rhythm amplitude is seen in adrenal insufficiency, and despite replacement, patients have an impaired quality of life and increased mortality. Research on cortisol replacement has focused on replacing the cortisol daily rhythm by subcutaneous hydrocortisone infusions and oral modified release hydrocortisone formulations with the aim of improving disease control and quality of life.