Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man

The hypothalamic-pituitary-adrenal axis is a critical neurohormonal network that regulates homeostasis and coordinates the stress response. Glucocorticoids (GCs) are critical for life and are key regulators of cognitive, metabolic and immunologic homeostasis (4). Clinical studies in healthy human subjects, using functional neuroimaging techniques, have clearly demonstrated the importance of GCs in the neural response to stress. During the basal physiological state, plasma cortisol concentrations display circadian rhythmicity, which is important for synaptic function and is made up from an underlying ultradian rhythm that can be modified by internal or external stressors (5). Current cortisol replacement therapy for patients with adrenal insufficiency cannot mimic physiologic cortisol secretion and results in significant morbidity, such as impaired health-related quality of life, adverse metabolic and cardiovascular risk profiles, increased concentrations of proinflammatory cytokines, as well as reduced activity, low motivation, and mental fatigue, with associated high levels of unemployment and disability benefits.