(533a) Modeling the Sexual Dimorphism in Feedback Regulation of the HPA Axis

Significant sex differences are observed in disease prevalence. In general, it is observed that there is a greater prevalence of autoimmune diseases in women, while men are more prone to developing infectious diseases and coronary heart disease (1). Furthermore, a number of studies show evidence for sex differences in the endocrine response to acute stress (2). The primary component of this stress response is the hypothalamic-pituitary adrenal (HPA) axis, which is composed of the important neuroendocrine mediators corticotrophin releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and cortisol (corticosterone in rodents). In response to stress (both physical and psychological) there is increased hypothalamic CRH release, which induces the secretion of ACTH from the pituitary, inducing the release of the adrenal cortisol, the primary effector molecule of the HPA axis, which promotes adaptation to stress through both receptor-mediated genomic as well as non-genomic mechanisms. Finally, cortisol binds to the glucocorticoid receptor to regulate its own synthesis by inhibiting the expression of CRH and ACTH, respectively, thus, completing the feedback loop.

Rodent studies consistently report sex differences in the HPA axis in response to variety of stressors such as immune challenges, foot shocks and forced running. In general, studies have demonstrated that administration of stressors results in a greater secretion of both ACTH and corticosterone (CST) in females than in males. Interestingly, basal levels of CST also exhibit sexual dimorphism (3). These differences are most apparent in the circadian rhythms of the CST. In general, female rats exhibit higher plasma CST than male rats throughout the circadian period, with differences being most prominent at the circadian peak. Moreover, the amplitude of the circadian rhythm in females is twice as high compared to that in males (4). Furthermore, studies have also shown that both the circadian characteristics and its response to stress vary with estrous cycle in rats (5). Given these observations, it is hypothesized that sexual dimorphism in the HPA axis might be due to differential feedback regulation in the HPA axis under the possible influence of gonadal steroids, primarily estrogen in females and testosterone in males.

In such circumstances mathematical modeling can be particularly insightful as it can be used to formulate and test hypotheses, when it is not as feasible to do so through experimental means. In the present work, we develop a mathematical model that can study the possible differential feedback regulation of the circadian dynamics of the HPA axis in female and males rodents both in a baseline homeostatic state. We focus our current modeling efforts on sexual dimorphism in rodents since; the literature on human studies is much less consistent in comparison due to differences in demographic composition of study subjects and methodological considerations. Furthermore, modeling with a focus on rodent data supports broader experimental efforts in studying sexual dimorphism in the pharmacological response to glucocorticoids.

Our model builds on earlier work by Sriram et al. and our group, and is comprised of three components (6-8); a central oscillatory compartment that simulates the circadian secretion of CST in the HPA axis, and a peripheral compartment that captures the downstream effects of secreted CST on the expression of proinflammatory cytokines, which we intend to use as a physiological mediator for an immune stressor. The oscillations in the central compartment are generated due to the negative feedback between CST and corticotropin-releasing hormone (CRH)/adrenocorticotropic hormone (ACTH) using a modified Goodwin oscillator model that incorporates Michaelis-Menten kinetics to express the degradation terms in the hypothalamus, pituitary, and adrenals. The HPA axis is positively modulated by the expression of cytokines in the peripheral compartment, which in turn is balanced by the negative feedback of CST. We estimated kinetic parameters to calibrate our model to the relatively high amplitude oscillations observed in female CST circadian data as obtained by Atkinson et al (5). As a first approximation, we consider the influence of the gonadal steroids on the HPA axis to be implicit in the kinetic parameters of the differential equations describing CRH, ACTH and CST dynamics.As proof of concept in evaluating the prevailing hypothesis regarding the differential regulation of the HPA axis in females and males, we have identified an initial set of physiologically important parameters that the amplitude of circadian oscillation is dependent on, including the strength of negative feedback of CST on CRH and ACTH, and additionally, the rate of production of CST. We hypothesize that these parameters are important in accounting for the observed sex differences in basal HPA axis activity and its response to stress. The parameter space is explored to determine possible transitions in model output and response to immune stressor.

This work provides a quantitative framework for improving our mechanistic understanding of the critical processes responsible for the observed differences in stress response in females and males and will have broad application to efforts in quantitative systems pharmacology, which seek to address issues relating to sexual dimorphism.

References: 

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2. Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005;69(1):113-32. doi: 10.1016/j.biopsycho.2004.11.009. PubMed PMID: 15740829.

3. Goel N, Workman JL, Lee TT, Innala L, Viau V. Sex differences in the HPA axis. Compr Physiol. 2014;4(3):1121-55. doi: 10.1002/cphy.c130054. PubMed PMID: 24944032.

4. Seale JV, Wood SA, Atkinson HC, Bate E, Lightman SL, Ingram CD, et al. Gonadectomy reverses the sexually diergic patterns of circadian and stress-induced hypothalamic-pituitary-adrenal axis activity in male and female rats. J Neuroendocrinol. 2004;16(6):516-24. doi: 10.1111/j.1365-2826.2004.01195.x. PubMed PMID: 15189326.

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6. Mavroudis PD, Corbett SA, Calvano SE, Androulakis IP. Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes. Physiological Genomics. 2014;46(20):766-78. doi: 10.1152/physiolgenomics.00026.2014.

7. Sriram K, Rodriguez-Fernandez M, Doyle FJ. Modeling Cortisol Dynamics in the Neuro-endocrine Axis Distinguishes Normal, Depression, and Post-traumatic Stress Disorder (PTSD) in Humans. PLoS Computational Biology. 2012;8(2). doi: 10.1371/journal.pcbi.1002379.

8. Ramakrishnan R, DuBois DC, Almon RR, Pyszczynski NA, Jusko WJ. Fifth-generation model for corticosteroid pharmacodynamics: application to steady-state receptor down-regulation and enzyme induction patterns during seven-day continuous infusion of methylprednisolone in rats. J Pharmacokinet Pharmacodyn. 2002;29(1):1-24.