TBME-00306-2011 1 Abstract—Glucocorticoids are steroid hormones which, amongst other functions, exert an anti-inflammatory effect. Endogenous glucocorticoids are normally secreted by the adrenal gland in discrete bursts. It is becoming increasingly evident that this pulsatile secretion pattern, leading to ultradian rhythms of plasma glucocorticoid levels, may have important downstream regulatory effects on glucocorticoid-responsive genes. Mathematical modeling of this system can compliment recent experimental data and quantitatively evaluate hypothesized mechanistic underpinnings of differential pulsatile signal transduction. In this paper, we describe an integrated model of pulsatile secretion of glucocorticoids by the hypothalamic– pituitary–adrenal (HPA) axis and the pharmacodynamic effect of glucocorticoids. This model is used to investigate the difference in transcriptional responses to pulsatile and constant glucocorticoid exposure. Nonlinearity in ligand-receptor kinetics leads to the differential expression of glucocorticoid-responsive genes in response to different patterns of glucocorticoid secretion, even when the total amount of glucocorticoid exposure is held constant. Understanding the implications of ultradian rhythms in glucocorticoids is important in studying the dysregulation of HPA axis function leading to altered glucocorticoid secretion patterns in disease. Index Terms—systems biology, pharmacodynamics, ultradian rhythms, mathematical modeling, glucocorticoids I. INTRODUCTION Endogenous glucocorticoids (corticosterone (CS) in rats, cortisol in humans) are a component of the neuroendocrine stress response mechanism, exerting regulatory effects on immunologic and metabolic function in peripheral tissues. Manuscript received March 28, 2011. JDS and IPA acknowledge support from NIH GM082974. JDS, SEC and SFL are supported, in part, from NIH GM34695. AKK acknowledges support from the Aresty Research Center for Undergraduates. J. D. Scheff and A. K. Kosmides are with the Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854 USA (e-mail: jdscheff@gmail.com; akosmides@gmail.com). S. E. Calvano and S. F. Lowry are with the Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901 USA (e-mail: calvanst@umdnj.edu; lowrysf@umndj.edu). I. P. Androulakis is with the Department of Biomedical Engineering and the Department of Chemical & Biochemical Engineering, Rutgers University, Piscataway, NJ 08854 USA (e-mail: yannis@rci.rutgers.edu). Copyright (c) 2011 IEEE. Personal use of this material is permitted. However, permission to use this material for any other purposes must be obtained from the IEEE by sending an email to pubs-permissions@ieee.org. They are released into systemic circulation as the output of the hypothalamic–pituitary–adrenal (HPA) axis in discrete bursts with a period of approximately one hour. Clearance of glucocorticoids from circulation is sufficiently fast that the pulsatile hormone release produces a clear ultradian pattern in the plasma glucocorticoid profile. The observation of these robust ultradian rhythms, combined with the ability of the glucocorticoid receptor (GR) to rapidly exchange with regulatory sites [1], has in recent years motivated the study of physiological importance of glucocorticoid pulsatility [2]. Pulsatile glucocorticoid treatment in vitro has been shown to provoke a differential transcriptional response relative to constant glucocorticoid treatment [3], even when the total glucocorticoid exposure is the same in both cases [4]. This is due to the rapid transcriptional response to activated GR, leading to the phenomenon of gene pulsing in nascent mRNA on the same timescale as the ultradian rhythms. This type of gene pulsing has also been observed in adrenalectonized rats given a square wave of CS infusion intravenously [3]. It has been hypothesized that this type of pulsatile GR activation regulates the behavior of the GR signaling pathway without desensitizing the system, thus maintaining the acute responsiveness of the HPA axis [5]. If the pattern of ultradian glucocorticoid rhythms is lost in stress [6], this may have important implications on the regulation of glucocorticoid- responsive genes and on the ability to mount an acute stress response via activation of the HPA axis. Modeling the mechanisms that give rise to differences in responses caused by the pattern of glucocorticoid secretion is important in understanding the physiological relevance of ultradian rhythms in both homeostatic and stressed conditions. In this paper, we describe an integrated mathematical model encompassing the pulsatile release of CS and CS activity in peripheral tissues. Ultradian and constant hormone levels were used to investigate the importance of both pulsatility and concentration on glucocorticoid-responsive genes. Significant differences in transcriptional responses were present even in the case when the total area under the plasma glucocorticoid concentration versus time curve (AUC) is the same in pulsatile and continuous cases, due to the nonlinear relationship between plasma glucocorticoid concentration and GR activity, illustrating a mechanism by which pulsatility can modulate the regulatory effects of glucocorticoids in peripheral tissues. Because glucocorticoid therapy is widely used clinically Pulsatile glucocorticoid secretion: origins and downstream effects Jeremy D. Scheff, Alyssa K. Kosmides, Steven E. Calvano, Stephen F. Lowry, and Ioannis P. Androulakis