ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Proc Natl Acad Sci U S A. 2018; 115(17): E4091-E4100

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.

Here, Kalafatakis et al. demonstrate that an oscillating pattern of plasma cortisol is important for maintenance of healthy brain responses as measured by functional neuroimaging and behavioral testing. These data highlight the crucial role of GC rhythmicity in (i) modulating sleep behavior and working memory performance, and in (ii) regulating the human brain’s responses under emotional stimulation. Current optimal cortisol replacement therapies for patients with primary or secondary adrenal insufficiently are associated with poor psychological status, and these results suggest that closer attention to aspects of chronotherapy will benefit these patients and may also have major implications for improved glucocorticoid dynamics in stress and psychiatric disease.

4. Kalafatakis K, Russell G-M, Zarros A, Lightman S-L. Temporal control of glu- cocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics. Neurosci Biobehav Rev 2016; 61: 12–25.

5. Liston C1, Cichon JM, Jeanneteau F, Jia Z, Chao MV, Gan WB. Circadian glucocorticoid oscillations promote learning- dependent synapse formation and maintenance. Nat Neurosci 2013; 16:698–705.