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. 2020 Jul;16(7):e9510.
doi: 10.15252/msb.20209510.

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks

Omer Karin  1 , Moriya Raz  1 , Avichai Tendler  1 , Alon Bar  1 , Yael Korem Kohanim  1 , Tomer Milo  1 , Uri Alon  1
Affiliations

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks

Omer Karin et al. Mol Syst Biol. 2020 Jul.

Abstract

Stress activates a complex network of hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders.

Keywords: dynamical compensation; endocrine circuits; exact adaptation; mathematical models of disease; systems medicine.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. After prolonged stress, ACTH response is blunted for weeks after cortisol response normalizes

  1. Schema of the classic HPA axis. CRH causes the secretion of ACTH and cortisol.

  2. In the CRH test, the secretion of these hormones is measured after CRH administration.

  3. Patients suffering from major depressive disorder (MDD) show a blunted ACTH response to CRH (black line, N = 10), compared with controls (gray line, N = 10)—data from (von Bardeleben et al, 1988), shown are mean ± SEM.

  4. Patients suffering from anorexia and admitted to treatment show a blunted ACTH response and hypercortisolemia, which resolves within 6–24 months after weight normalization—data from Gold et al (1986a). However, 3–4 weeks after weight normalization, cortisol dynamics are normal whereas ACTH dynamics are blunted. Pregnancy is associated with elevated cortisol levels due to CRH secretion by the placenta. 3 weeks after delivery, cortisol levels and dynamics return to normal, whereas ACTH dynamics are blunted—data from Magiakou et al (1996). After 12 weeks, ACTH dynamics normalize as well. Individuals recovering from alcohol abuse show hypercortisolemia and blunted ACTH response after admission—data from von Bardeleben et al (1989). After 2–6 weeks, these individuals show normal cortisol dynamics, but blunted ACTH responses persist. In all panels, control patient data are denoted by thin gray line (Anorexia: N = 13. Pregnancy: N was unspecified. Alcohol abuse disorder: N = 11), and case data by a thicker black line (Anorexia: left panel, N = 9, center panel, N = 5, right panel, N = 6. Pregnancy: N = 17. Alcohol abuse disorder: N = 20). Shown are mean ± SEM for all panels.

Figure 2
Figure 2. Model with functional mass dynamics shows ACTH blunting for weeks even after cortisol normalizes

  1. The classic model of HPA axis dynamics without gland‐mass dynamics produces elevated levels of stress hormones during prolonged stress. However, it does not produce blunted ACTH responses in the CRH test, and, after cessation of the stressor, all hormones return to baseline within hours.

  2. To account for the control of pituitary corticotroph growth by CRH and adrenal cortex growth by ACTH, we added to classic HPA model two equations that represent the dynamics of the functional mass of corticotrophs (C) and the adrenal cortex (A). (Inset) Such dynamics explain, for example, the enlarged adrenals of stressed rats (inset, right) compared with control (inset, left), adapted from Selye (1952). The model shows the three distinct phases of HPA axis dysregulation observed in experiments. At the end of a prolonged stress period, the adrenal mass is enlarged and the corticotroph mass is slightly enlarged, which results in hypercortisolemia and blunted ACTH responses in the CRH test. After a few weeks, corticotroph mass drops below baseline, while adrenal mass is slightly enlarged, causing normal cortisol dynamics with blunted ACTH responses to the CRH test. Finally, after a few months both tissue masses return to normal, leading to normalization of both cortisol and ACTH dynamics.

Data information: In all panels, simulations are of a CRH test (Materials and Methods), where “case” (black) is after stress and “control” (gray) is after basal HPA axis activation, as described in Fig 3.
Figure 3
Figure 3. Model dynamics of HPA axis after prolonged stress
  1. A–C

    Numerical solution of the HPA model after a prolonged pulse of input (u = 4) lasting 3 months, followed by return to baseline input u = 1 (A). During the pulse, gland masses (B) increase over weeks, leading to exact adaptation of ACTH and CRH levels after a few weeks (C) despite the increased input level. After stress ends, gland masses adjust back over weeks. During this adjustment period, the HPA axis is dysregulated.

  2. D

    To model a CRH test, we add exogenous CRH to the simulation and follow the hormones over several hours. The response is defined as the maximum response to a CRH test (case) relative to the maximum response to a CRH test in steady state with basal input conditions (control).

  3. E

    The response to a CRH test given at time t is shown as a function of t. Thus, this is the predicted response to CRH tests done at different days during and after the stressor. The model (black lines) shows blunted (reduced) responses to CRH tests after the stress similar to those observed in Fig 1, as well as a mismatch between cortisol and ACTH dynamics that develops a few weeks after cessation of stress. EW is early withdrawal, IW is intermediate withdrawal and LW is late withdrawal.

Figure 4
Figure 4. GR provides resilience to the HPA axis against prolonged stressors
  1. A, B

    Here, we show the dynamics of the HPA axis during and after a prolonged pulse of stress, described in Fig 3, for K GR = 2 (strong feedback), K GR = 4 (moderate feedback), and K GR = 8 (weak feedback). Stronger feedback from the GR attenuates the dysregulation of all HPA axis hormones.

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References

    1. Adinoff B, Junghanns K, Kiefer F, Krishnan‐Sarin S (2005) Suppression of the HPA axis stress‐response: implications for relapse. Alcohol Clin Exp Res 29: 1351–1355 - PMC - PubMed
    1. Aguilera G, Rabadan‐Diehl C (2000) Vasopressinergic regulation of the hypothalamic–pituitary–adrenal axis: implications for stress adaptation. Regul Pept 96: 23–29 - PubMed
    1. Alon U (2019) An introduction to systems biology: design principles of biological circuits. Boca Raton: CRC Press;
    1. Amsterdam JD, Marinelli DL, Arger P, Winokur A (1987) Assessment of adrenal gland volume by computed tomography in depressed patients and healthy volunteers: a pilot study. Psychiatry Res 21: 189–197 - PubMed
    1. Anacker C, Zunszain PA, Carvalho LA, Pariante CM (2011) The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36: 415–425 - PMC - PubMed

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