Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability
© Gupta et al; licensee BioMed Central Ltd. 2007
Received: 27 August 2006
Accepted: 14 February 2007
Published: 14 February 2007
The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases.
We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS).
Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.
The hypothalamic pituitary adrenal (HPA) axis represents a self-regulated dynamic feedback neuroendocrine system that is essential for maintaining body homeostasis in response to various stresses. Stress can be physical (e.g. infection, thermal exposure, dehydration) and psychological (e.g. fear, anticipation). Both physical and psychological stressors activate the hypothalamus to release corticotropin releasing hormone (CRH). The CRH is released into the closed hypophyseal portal circulation, stimulating the pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH is released into the blood where it travels to the adrenals, inducing the synthesis and secretion of cortisol from the adrenal cortex. Cortisol has a negative feedback effect on the hypothalamus and pituitary that further dampens CRH and ACTH secretion .
Cortisol affects a number of cellular and physiological functions to maintain body homeostasis and health. Cortisol suppresses inflammation and certain immune reactions, inhibits the secretion of several hormones and neuropeptides and induces lymphocyte apoptosis [1, 2]. These widespread and potent effects of cortisol demand that the feed forward and feedback loops of the HPA axis are tightly regulated. Disruption of HPA axis regulation is known to contribute to a number of stress-related disorders. For example, increased cortisol (hypercortisolism) has been shown in patients with major depressive disorder (MDD) [3, 4], and decreased cortisol (hypocortisolism) has been observed in people with post-traumatic stress disorder (PTSD), Gulf War illness, post infection fatigue and chronic fatigue syndrome (CFS) [5–9]. While it is not clear if dysregulation of the HPA axis is a primary or secondary effect of these disorders, there is evidence that stress-related disorders are influenced by early life adverse experiences that affect the neural architecture and gene expression in the brain . Childhood events such as severe infection, malnutrition, physical, sexual and emotional abuse are associated with many chronic illnesses later in life .
Definitive research on HPA axis function in chronic diseases has been hampered by the complexity of the numerous systems affected by the HPA axis, such as the immune and neuroendocrine systems, the lack of known or accessible brain lesions and the correlative nature of much of the existing data. Since the organization of the HPA axis has been characterized to detail the feedback and feed forward signalling that regulates HPA axis function , it is a system that is amenable to modelling. Models of the HPA axis have been constructed using deterministic coupled ordinary differential equations [13–17]. These models were successful in capturing features such as negative feedback control and diurnal cycling of the HPA axis. Our goal was to understand the dynamic effects of CRH, ACTH and cortisol with a mathematically parsimonious model to gain insight into HPA axis regulation. This model is novel in that it incorporates expression of the glucocorticoid receptor (GR) in the pituitary and demonstrates that repeated stress and GR expression reveals the bistability inherent in the HPA axis given the enhanced model.
The HPA axis has three compartments representing the hypothalamus, pituitary and adrenals regulated by simple, linear mass action kinetics for the production and degradation of the primary chemical product of each compartment. In this model, stress to the HPA axis (F) stimulates the hypothalamus to secrete CRH (C). CRH (C) signals the induction of ACTH synthesis (A) in the pituitary. ACTH (A) signals to the adrenal gland and activates the synthesis and release of cortisol (O). Cortisol (O) regulates its own synthesis via inhibiting the synthesis of CRH (C) in the hypothalamus, and ACTH (A) in the pituitary. The equation for the hypothalamus can be written as:
In this equation, -K cd C models a constant degradation rate of CRH in the blood of the portal vein. The term (K c + F)* models a circadian production term K c and a stress term F, both reduced by a linear inhibition term represented by . For small , we may write (K c + F) * ≈ . The latter form, , corresponds to standard linear inhibition of (K c + F) with inhibition constant Ki 1. This form also guarantees positive ACTH concentrations. We write for the hypothalamus:
For the pituitary:
Equation 3 models a constant degradation rate of ACTH by the term -K ad A and an ACTH production term, , with a cortisol inhibition factor similar to (2).
For the adrenal:
Equation 4 models a constant degradation rate of cortisol -K od O and a cortisol production rate K o A linearly dependent on ACTH.
We have augmented this model by including synthesis and regulation of the glucocorticoid receptor (R) in the pituitary [18, 19]. In the pituitary, cortisol enters the cell and binds the glucocorticoid receptor in the cytoplasm, causing the receptor to dimerize. This dimerization causes the complex to translocate to the nucleus (dimerization, translocation, and transcription factor binding are not modelled, but assumed to be fast), where it up regulates glucocorticoid receptor (R) synthesis and down regulates production of ACTH (A).
For the hypothalamus:
For the pituitary:
For the adrenal:
Equation (7) describes the production of GR in the pituitary. The term in equation 7 is in Michaelis-Menten form since we assume the bound glucocorticoid receptor (OR) dimerizes with fast kinetics, so that the amount of dimer is in constant quasi-equilibrium, depending on the abundance of OR and the equilibrium binding affinity (K). The model further assumes that cortisol (O) and the glucocorticoid receptor (R) bind to each other with very fast kinetics compared to the rate of change of the 4 state variables (A, C, O, and R), so that OR stays in quasi-equilibrium as well. These are reasonable assumptions, given that high affinity receptor-ligand kinetics are often much faster than enzyme kinetics (as is assumed in the standard Michaelis-Menten equation) or than steps requiring transcription and/or translation for protein synthesis. Equation (7) also models a linear production term K cr and a degradation term -K rd R for pituitary GR production. Equation (6) reflects the inhibition dependence of glucocorticoid receptor (R) and cortisol (O) with an inhibition constant Ki 2.
Scaling of the equations (5) – (8) has been done to reduce the parameters used in simulations. The scaled variables are defined as;
The scaled equations thereby obtained are;
These scaled equations were used in the simulations. The advantage of scaling is that it obviates the need for knowledge of unknown parameter values such as the synthesis rate of CRH in the hypothalamus and ACTH and GR in the pituitary. The parameter values that can be measured are the degradation rates of CRH, ACTH, and cortisol. The scaled parameter values used in simulation were, k cd = 1, k ad = 10, k rd = 0.9, k cr = 0.05, k = 0.001, ki 1= 0.1, and ki 2= 0.1. Further, these simulated results for CRH, ACTH and cortisol are converted back to their commonly used dimensions and values obtained in experiments. The simulated time course plots ignore the circadian input to the hypothalamus.
Models were programmed in Matlab (The Mathworks, Natick, MA). The meta-modeling of bi-stability used the CONTENT freeware package. All Matlab code will be provided upon request. Dr. Leslie Crofford provided the human subject serum cortisol data .
Normal stress response
Adaptation of HPA axis
Chronic stress response
HPA axis challenge
Previous models of the HPA axis have not demonstrated bistability in steady state cortisol or ACTH. We believe this is because none of the previous models have explicitly accounted for nonlinear kinetics, such as the homodimerization of GR after cortisol activation [18, 19]. This is essential for the negative feedback control of the HPA axis. This homodimerization engenders the existence of two stable steady states and one unstable steady state in GR expression in the pituitary. While increased cortisol following a short period of stress produces a small perturbation in GR concentration, long and repeated periods of stress resulting in elevated cortisol levels produce a large perturbation in GR concentration that force the HPA axis into an alternate steady state. Because of the existence of two stable steady states in this model, a small increase GR concentration can be regulated, but a large perturbation in GR concentration is sustained even after the removal of the long duration stress. A higher concentration of GR increases the concentration of cortisol-GR complexes that in turn enhance the inhibition of ACTH synthesis in the pituitary. Since ACTH stimulates the production of cortisol, less ACTH results in lower cortisol secretion and a decrease HPA axis activity.
GR is found in cells throughout the human brain and body. However, GR synthesis and regulation is tissue and organ specific. For example, while corticosterone injection in rats inhibits the synthesis of GR-mRNA in lymphocyte, hypothalamic and hippocampal cells [20, 21], it induces the synthesis of GR-mRNA and increases the sensitivity in the anterior pituitary [22, 23]. Our model incorporates the increased synthesis of GR in the anterior pituitary. Increased GR makes anterior pituitary cells more sensitive to cortisol and enhances the negative feedback effect of cortisol on ACTH production. Enhanced negative feedback control of ACTH production in the anterior pituitary may produce a hypocortisol state.
We were also able to demonstrate that these simulation results are qualitatively similar to cortisol levels measured in a human subject (Figure 2). A large number of studies have investigated alterations of the HPA axis in CFS, including both studies of basal HPA axis activity as well as studies of HPA axis responsiveness to challenge (for review see ). A hypocortisol steady state, such as was demonstrated in this modelling and simulation study, is in keeping with many of these studies
There may be other physiologically plausible mechanisms that produce bi-stability other than the anterior pituitary GR homodimerization mechanism investigated here. The point of this investigation is not to conclusively prove that pituitary GR dimerization is the cause of hypocortisolism, but rather to demonstrate that there are physiologically plausible mechanisms for producing bistability in the HPA-axis that are stress modulated. Further mining of the experimental literature together with mathematical modelling will reveal additional plausible mechanisms.
Moderate, short-lived stress responses that result in transient increases in cortisol are important and necessary for maintaining body homeostasis and health. Strong and prolonged stress can force the HPA axis into an altered steady state. We demonstrate bistability in the HPA axis due to pituitary GR synthesis. This altered steady state, characterized by hypocortisolism, is observed in a number of stress-related illnesses. The elucidation of bistability in this model of the HPA axis through the action of pituitary GR effects may lead to targeted treatments of stress-related illness where hypocortisolism is the primary clinical manifestation.
The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the funding agency.
The funding for this project was made possible by funding from DARPA MIPR number 05-U357. We would also like to acknowledge the Dr. Leslie Crofford and the University of Michigan (GCRC M01-RR00042 and R01-AR43148) for providing experimental data.
- Munck A, Guyre PM, Holbrook NJ: Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984, 5: 25-44.View ArticlePubMed
- Tuckermann JP, Kleiman A, McPherson KG, Reichardt HM: Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis. Crit Rev Clin Lab Sci. 2005, 42: 71-104. 10.1080/10408360590888983.View ArticlePubMed
- Juruena MF, Cleare AJ, Pariante CM: The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr. 2004, 26: 189-201. 10.1590/S1516-44462004000300009.View ArticlePubMed
- Gold PW, Chrousos GP: Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002, 7: 254-75. 10.1038/sj.mp.4001032.View ArticlePubMed
- Rohleder N, Joksimovic L, Wolf JM, Kirschbaum C: Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biol Psychiatry. 2004, 55: 745-751. 10.1016/j.biopsych.2003.11.018.View ArticlePubMed
- Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991, 73: 1224-1234.View ArticlePubMed
- Di GA, Hudson M, Jerjes W, Cleare AJ: 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosom Med. 2005, 67: 433-440. 10.1097/01.psy.0000161206.55324.8a.View Article
- Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ: Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006, 60: 145-153. 10.1016/j.jpsychores.2005.07.008.View ArticlePubMed
- Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA: Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004, 18: 314-25. 10.1016/j.bbi.2003.12.011.View ArticlePubMed
- National Scientific Council on the Developing Child, Early Exposure to Toxic Substances Damages Brain Architecture. Working Paper No. 4. 2006, Retrieved July 14, 006,http://www.developingchild.net/reports.shtml
- Turner-Cobb JM: Psychological and stress hormone correlates in early life: a key to HPA-axis dysregulation and normalisation. Stress. 2005, 8: 47-57.View ArticlePubMed
- Jacobson L: Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am. 2005, 34: 271-92. 10.1016/j.ecl.2005.01.003.View ArticlePubMed
- Gonzalez-Heydrich J, Steingard RJ, Kohane I: A computer simulation of the hypothalamic-pituitary-adrenal axis. Proc Annu Symp Comput Appl Med Care. 1994, 1010-
- Dempsher DP, Gann DS, Phair RD: A mechanistic model of ACTH-stimulated cortisol secretion. Am J Physiol. 1984, 246: R587-R596.PubMed
- Sharma DC, Gabrilove JL: A study of the adrenocortical disorders related to the biosynthesis and regulation of steroid hormones and their computer simulation. Mt Sinai J Med. 1975, 42: S2-S39.PubMed
- Savic D: A mathematical model of the hypothalamo-pituitary-adrenocortical system and its stability analysis. Chaos, solitons, and fractals. 2005, 26: 427-436. 10.1016/j.chaos.2005.01.013.View Article
- Lenbury Y, Pornsawad P: A delay-differential equation model of the feedback-controlled hypothalamus-pituitary-adrenal axis in humans. Math Med Biol. 2005, 22: 15-33. 10.1093/imammb/dqh020.View ArticlePubMed
- Drouin J, Sun YL, Tremblay S, Lavender P, Schmidt TJ, de LA: Homodimer formation is rate-limiting for high affinity DNA binding by glucocorticoid receptor. Mol Endocrinol. 1992, 6: 1299-1309. 10.1210/me.6.8.1299.PubMed
- Tsai SY, Carlstedt-Duke J, Weigel NL, Dahlman K, Gustafsson JA, Tsai MJ: Molecular interactions of steroid hormone receptor with its enhancer element: evidence for receptor dimer formation. Cell. 1988, 55: 361-369. 10.1016/0092-8674(88)90059-1.View ArticlePubMed
- Makino S, Smith MA, Gold PW: Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology. 1995, 136: 3299-3309. 10.1210/en.136.8.3299.PubMed
- Nishimura K, Makino S, Tanaka Y, Kaneda T, Hashimoto K: Altered expression of p53 mRNA in the brain and pituitary during repeated immobilization stress: negative correlation with glucocorticoid receptor mRNA levels. J Neuroendocrinol. 2004, 16: 84-91. 10.1111/j.1365-2826.2004.01131.x.View ArticlePubMed
- Hugin-Flores ME, Steimer T, Aubert ML, Schulz P: Mineralo- and glucocorticoid receptor mRNAs are differently regulated by corticosterone in the rat hippocampus and anterior pituitary. Neuroendocrinology. 2004, 79: 174-184. 10.1159/000078099.View ArticlePubMed
- Dayanithi G, Antoni FA: Rapid as well as delayed inhibitory effects of glucocorticoid hormones on pituitary adrenocorticotropic hormone release are mediated by type II glucocorticoid receptors and require newly synthesized messenger ribonucleic acid as well as protein. Endocrinology. 1989, 125: 308-31.View ArticlePubMed
- Cleare AJ: The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004, 15: 55-9. 10.1016/j.tem.2003.12.002.View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.