Dynamic Pituitary-Adrenal Interactions in Response to Cardiac Surgery*

Abstract

Objectives-To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting (CABG) both on and off pump. Since our data pointed to a major change in adrenal responsiveness to ACTH we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. Measurements and Results-Clinical studies: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and ACTH were measured every 10 and 60 minutes respectively, and corticosteroid binding globulin (CBG) was measured at the beginning and end of the 24 hour period and at the end of operation. There was an initial rise in both levels of ACTH and cortisol to supra-normal values at around the end of surgery. ACTH levels then returned towards pre-operative values. Ultradian pulsatility of both ACTH and cortisol was maintained throughout the peri-operative period in all individuals. The sensitivity of the adrenal gland to ACTH increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of 'basal' levels of ACTH. This sensitivity began to return towards pre-operative values at the end of the 24-hour sampling period.Animal studies: Adult, male Sprague-Dawley rats were either given lipopolysaccharide (LPS) or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for ACTH and corticosterone measurement. Rats were sacrificed 6 hours after the injection and the adrenal glands were collected for measurement of StAR, SF-1 and DAX1 mRNA and protein using RTqPCR and Western immunoblotting, respectively. Adrenal levels of the ACTH receptor (MC2R) mRNA and its accessory protein (MRAP) were also measured by RTqPCR. In response to LPS, rats showed a pattern of ACTH and corticosterone that was similar to patients undergoing CABG. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in StAR, SF-1 and MRAP mRNAs and StAR protein, and a reduction in DAX1 and MC2R mRNAs, 6h after LPS injection.Conclusions-Severe inflammatory stimuli activate the HPA axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following CABG there is a massive increase in both ACTH and cortisol secretion. Despite a subsequent fall of ACTH to basal levels, cortisol remains elevated and co-ordinated ACTHcortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to ACTH, which we confirmed in our animal model of immune activation of the HPA axis. Using this model we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal HPA responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients.Gibbison et al.

Dynamic responses of the adrenal steroidogenic regulatory network

“…This could be a factor underlying the dissociated dynamics between ACTH and CORT observed in stress scenarios. Uncovering the origin of these dissociated dynamics is key to understanding a number of physiological and pathological conditions where sustained high levels of CORT have been observed even after ACTH has returned to normal (8). Consistent with this, our model predicts that cytokine effects on the DAX-1 regulatory "hub" of the SRN may explain the dynamic dissociation between ACTH and CORT during inflammation.…”

“…6), suggesting that the SRN has the ability to decode ACTH signals in a contextdependent manner. Motivated by this, we used our model to investigate how the SRN responds to a larger ACTH perturbation, comparable to that measured in response to an inflammatory stress (8), and tested our model predictions experimentally. We have previously developed an experimental methodology to apply a large ACTH stimulus to the rat adrenal glands (8).…”

“…Motivated by this, we used our model to investigate how the SRN responds to a larger ACTH perturbation, comparable to that measured in response to an inflammatory stress (8), and tested our model predictions experimentally. We have previously developed an experimental methodology to apply a large ACTH stimulus to the rat adrenal glands (8). This consists of four sequential s.c. injections of ACTH at 35-min intervals, which results in a large surge in ACTH plasma concentrations comparable to that observed during inflammatory stress (Fig.…”

“…For example, there is evidence that proinflammatory cytokines released during inflammation can potentiate adrenal responsiveness to ACTH and can activate the adrenal steroidogenic pathway directly (7). Recent examples of this are the hormonal stress responses observed during cardiac surgery in humans and in a rodent model of inflammation (8). It has been hypothesized that this dynamic dissociation is due to increased adrenal sensitivity to ACTH, presumably as a result of the effect of circulating proinflammatory cytokines.…”

Rhythms Within Rhythms: The Importance of Oscillations for Glucocorticoid Hormones

“…In a study of patients undergoing coronary artery bypass graft procedures (Fig. 2), we found an initial surge in both ACTH and CORT, followed by a fall in ACTH back to baseline levels but maintenance of the high levels of CORT, with continued but amplified ultradian responses of CORT to small changes in basal ACTH (Gibbison et al 2014). The initial rise in both hormones was delayed after the actual surgery itself, suggesting it was the result of inflammatory cytokine production (from the sternotomy), which is known to go up at this time (Lahat et al 1992;Roth-Isigkeit et al 1999;de Mendonca-Filho et al 2006).…”