60 YEARS OF NEUROENDOCRINOLOGY: Glucocorticoid dynamics: insights from mathematical, experimental and clinical studies

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   Figure 1

   The HPA axis and glucocorticoid ultradian rhythm. (a) Stress and circadian inputs activate the hypothalamic PVN to release CRH and AVP into the hypothalamic–pituitary portal circulation. CRH and AVP activate corticotroph cells in the anterior pituitary, which respond with the rapid release of ACTH into the general blood circulation. In turn, ACTH reaches the adrenal gland where it activates the synthesis of glucocorticoid hormones (CORT). Glucocorticoids regulate the activity of the HPA axis, and thus their own production, through feedback mechanisms acting at the level of the pituitary gland where they inhibit ACTH release, and at the level of the PVN where they inhibit the release of CRH and AVP. (b) Under basal (i.e., unstressed) conditions, CORT levels are characterized by both a circadian and an ultradian rhythm. The data represent an example 24-h profile of plasma CORT from an adult male rat. Shaded region indicates the dark phase. Adapted from Walker JJ, Spiga F, Waite E, Zhao Z, Kershaw Y, Terry JR & Lightman SL (2012) The origin of glucocorticoid hormone oscillations. PLoS Biology 10 e1001341. Published under the terms of the Creative Commons Attribution (CC BY) license.
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   Figure 2

   CORT responses (black) to different patterns of CRH drive (grey). Model predictions of CORT pulsatility for constant CRH (a), pulsatile CRH (b) and circadian CRH (c). Response demonstrates a frequency in CORT governed by the pituitary–adrenal system and not by the frequency of the CRH forcing. Data adapted from Walker et al. (2010). Adapted from Walker JJ, Terry JR & Lightman SL (2010) Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis. Proceedings of the Royal Society B: Biological Sciences 277 1627–1633. Published under the terms of the Creative Commons Attribution (CC BY) license.
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   Figure 3

   Dynamics of human ACTH and cortisol in health and disease. Changes in cortisol and adrenocorticotropic hormone (ACTH) levels throughout the 24-h perioperative period of cardiac surgery (A–C), and in a healthy volunteer (D). (A) mean±s.e.m. 24-h cortisol and ACTH profile from patients undergoing coronary artery bypass grafting (CABG). (B) specific mean±s.e.m. 24-h cortisol profile from patients undergoing CABG using the off-pump or the on-pump technique. In (A) and (B) the light grey area represents the period during which some patients were undergoing surgery. The dark grey area represents the period during which all patients were undergoing surgery. (C) individual 24-h ACTH and cortisol profile of a patient undergoing off-pump CABG; the light grey area represents the period during which the patient was undergoing surgery (09:19–13:49 h). After the initial surge of ACTH and cortisol, both ACTH and cortisol continue to pulse. However, while both the absolute values of ACTH and the pulse amplitude are reduced, the cortisol levels remain elevated. The grey area represents the period of surgery. (D) individual 24-h ACTH and cortisol profile from a healthy volunteer. ACTH and cortisol both display a tightly correlated ultradian rhythm. Reproduced, with permission, from Gibbison B, Spiga F, Walker JJ, Russell GM, Stevenson K, Kershaw Y, Zhao Z, Henley D, Angelini GD & Lightman SL (2015) Dynamic pituitary-adrenal interactions in response to cardiac surgery. Critical Care Medicine 43 791–800. Copyright 2015 Society of Critical Care Medicine and Wolters Kluwer Health, Inc. The original source of (D) is Henley DE, Leendertz JA, Russell GM, Wood SA, Taheri S, Woltersdorf WW & Lightman SL, Journal of Medical Engineering & Technology, 2009; 33: 199–208, copyright 2009 Informa Healthcare. Reproduced with permission of Informa Healthcare.
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   Figure 4

   Schematic model of dynamic expression of steroidogenic genes. Pulsatile ACTH induces dynamic transcription of StAR (hnRNA); circadian variation in ACTH pulse amplitude, as well as circadian variation in adrenal responsiveness to ACTH, determine changes in the amplitude of StAR hnRNA pulses leading to circadian expression of StAR protein. Model based on data from Carnes et al. (1988a), Spiga et al. (2011b) and Park et al. (2013).
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   Figure 5

   Model hypothesis of glucocorticoid-mediated regulation of the adrenal steroidogenic network. ACTH binding to it specific receptor MC2R induces rapid glucocorticoid secretion by PKA-mediated non-genomic regulation of steroidogenic proteins involved in cholesterol metabolism. This includes phosphorylation of hormone-sensitive lipase (HSL), a protein that increases the levels of intracellular cholesterol (the precursor of steroid hormones), and phosphorylation of steroidogenic acute regulatory protein (StAR), which promotes the transport of cholesterol into the mitochondria, where cholesterol is converted into pregnenolone by the enzyme side-chain cleavage cytochrome P450. PKA also mediates adrenal genomic activity by inducing the transcription of genes encoding for steroidogenic proteins, including StAR. Our mathematical modeling work suggests that CORT regulates an intra-adrenal inhibition mechanism of CORT synthesis, and that this is an important factor regulating CORT synthesis over the timescales of both the ultradian rhythm and the rapid response to stress. It is therefore our hypothesis that CORT may regulate the steroidogenic response by acting both at a genomic level (e.g., by regulating steroidogenic gene transcription) as well as at a non-genomic level by regulating the phosphorylation of steroidogenic proteins such as StAR and HSL.

• © 2015 Society for Endocrinology