ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Proc Natl Acad Sci U S A. 2017; 114(31): E6466-E6474

Cortisol production is tightly regulated in a dynamic way within the hypothalamic-pituitary adrenal system, which seems further embedded in a wider steroidogenic regulatory network (SRN). Normally, the connection from ACTH to cortisol production is in line with the HPA axis, but there are stressful events, in which the connection is lost, and the sensitivity of the adrenal cortex to ACTH seems “decoded in a context-dependent manner”, as described by the authors. While the components of this network have been described in numerous studies, the exact dynamic interplay between the players has not been investigated in great details so far.

To this end, here, Spiga et al. devised a mathematical model to simulate the effect of physiologic as well as an inflammatory stress-like, robust ACTH stimulation on the dynamic cascade of few essential components of the SRN, ultimately leading to cortisol production. Predictions obtained by the model were then verified by in vitro experiments in rats. Interestingly, the prediction for both physiologic and large scale ACTH stimulation was pretty good. However, this prediction failed to simulate cortisol production directly induced by stimulation of the immune system; e.g. through endotoxin LPS, which is known to act via the HPA axis and on adrenocortical cells directly. But when including immune pathways in the SRN, the resulting model was also able to simulate the cytokines’ effects on cortisol production as assessed in the rat experiments. Overall, this study reveals further evidence for an intra-adrenal feedback loop for the regulation of cortisol production involving SF-1, DAX-1, STAR, the GR as well as cytokines, as previously suggested (6-8). It enhances our understanding of dissociated conditions as seen during inflammation, in which cortisol concentrations remain high after ACTH is normalized.

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7. Bamberger AM, Schulte HM, Wullbrand A, Jung R, Beil FU, Bamberger CM. Expression of leukemia inhibitory factor (LIF) and LIF receptor (LIF-R) in the human adrenal cortex: implications for steroidogenesis. Mol Cell Endocrinol. 2000; 162(1-2): 145-9.

8. Bornstein SR, Zacharowski P, Schumann RR, Barthel A, Tran N, Papewalis C, Rettori V, McCann SM, Schulze-Osthoff K, Scherbaum WA, Tarnow J, Zacharowski K. Impaired adrenal stress response in Toll-like receptor 2-deficient mice. Proc Natl Acad Sci U S A. 2004; 101(47): 16695-700.