stress continuum disease development
Stress and Immunity

The Stress Continuum of Chronic Disease Development

and ·

Stress continuum – chronic disease

Abstract

Stress is defined as the state of a threatened homeodynamic balance termed homeostasis by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli, defined as stressors. Neuroendocrine responses to stress depend on developmental timing, duration, time of day and nature of stressors. Repeated, ephemeral and motivating stress states lead to adaptive responses and response habituation, being potentially beneficial, while inadequate, aversive, excessive or prolonged stress may surpass the regulatory capacity of the organism and produce maladaptive responses and vulnerable phenotypes with disrupted stress reactivity. Such a chronically altered homeodynamic state (i.e., hyper- or hypoactivation of the stress system) is associated with a cumulatively elevated long-term risk of mental and physical morbidity. We discuss a conceptual model of acute and chronic stress pathophysiology as a continuum in chronic disease development.

Stress definition and concepts

Stress is defined as the state of a threatened homeodynamic balance or homeostasis (1, 2) by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli, defined as stressors (3, 4). To preserve this optimal homeodynamic state, organisms have developed a highly sophisticated system, the stress system, which serves self-regulation and adaptability of the organism by energy redirection according to the current needs (1, 2, 5).

When stressors exceed a certain severity or temporal threshold, the so-called “stress or adaptive reaction” is initiated (i.e., the  fight, flight or freeze reaction), comprised by acute, remarkably consistent, normally adaptive and time-limited micro-, meso- and macrophysiologic compensatory responses (2, 4, 5) through different levels of effector tissues, orchestrating a well-organized overall response (6). This process, leading to a different homeodynamic adaptation, has been defined as allostasis (7, 8).

fig 1Figure 1. The interaction between homeostasis-disturbing stressors and stressor-activated adaptive responses of the organism is dynamic and can have three potential outcomes. First, the organism can return to its basal and functional homeodynamic balance (i.e., eustasis; gr.: “good state”); second, the adaptive response may be inappropriate (for example, inadequate, excessive and/or prolonged) and the organism falls (i.e., catabasis; gr.: “descent”) into a negatively altered, defective homeodynamic state (i.e., cacostasis; gr.: “bad state”), associated with cacostatic load and, third, the match may be perfect and the organism gains from the experience (i.e., anabasis; gr.: “ascent”) and a new, improved homeodynamic capacity is attained (i.e., hyperstasis; gr.: “higher/better state”).

The differentiation between “eustress” and “distress”, suggests that not all stress states are unpleasant or harmful, and that chronicity, quality, magnitude, subjective appraisal and context of stressors are all important moderators of the stress response. Thereby, protection and damage are the two sides of the same physiological coin. Repeated, ephemeral and motivating stress states lead to adaptive responses and response habituation, usually being beneficial and leading to an improved homedynamic capacity (i.e., hyperstatis, gr.: “higher/better state”), while inadequate, aversive, excessive (i.e., traumatic) or prolonged stress may surpass the natural regulatory capacity and adjustive resources of the organism and result to a state of disharmony defined as cacostasis (gr.: “bad state”; i.e., a negatively altered, defective homeodynamic state, dyshomeostasis) and accumulated allostatic or – more correctly – cacostatic load (i.e., cumulative pathophysiological burden of the organism) associated with maladaptive neuroendocrine responses to stress (1, 2, 9, 10), (Figure 1).

The latter stage can lead to a vulnerable phenotype characterized by distinct psychophysiological alterations, such as disrupted hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-andrenal-medullary (SAM) system reactivity and impaired glucocorticoid signaling during stress, with potentially profound debilitating effects on neurodevelopment, and mental and somatic health of an individual (stress continuum), (3, 11).

Hyper- vs. hypo-activation of the stress system

Normally, under chronic stress, prolonged (hyper)activation of the stress system results in the “stress syndrome” with extended periods of elevated cortisol levels (i.e., hypercortisolemic phase) and decreased negative feedback regulation by glucocorticoids (i.e., cortisol resistance at the level of the central nervous system) (12), (Figure 2). Hypercortisolemia is observed in melancholic depression, but also in other conditions, such as generalized anxiety and panic disorder, alcohol withdrawal, excessive exercising, poorly controlled diabetes mellitus and hyperthyroidism (2, 13).

fig2Figure 2. Hypothetical graphical models of the effects of adaptive and chronic stress system activation on cortisol levels over time. Proposed hypothetical models of cortisol responses to stress: Cortisol adaptive response to acute stressors: normally it is time-limited and self-limiting; after an initial peak, cortisol soon returns to normal levels. Under chronic stress: A prolonged response leads to ongoing increased HPA axis activation resulting to a “hypercortisolemic” state. Chronic continuation of HPA axis activation may lead to a secondary, compensatory and self-preserving HPA axis down-regulation (“adrenal fatigue/exhaustion”), accompanied by a “hypocortisolemic” state.

This initial adaptive hypercortisolemic phase may possibly transit over time to a secondary, compensatory and self-preserving HPA axis down-regulation (enhanced negative feedback regulation) with reduced cortisol production (i.e., a hypocortisolemic phase), and increased mild systemic inflammation, called the “sickness syndrome” (13-15). Such a hypocortisolemic state has been correlated to both traumatic and chronic stress exposure and is often accompanied by a “hypocortisolemic symptom triad”, including high-stress sensitivity, and chronic fatigue, and/or pain (9, 14). Patients with atypical depression, chronic fatigue syndrome, fibromyalgia, hypothyroidism, early life stress or childhood trauma experiences (ELS/CT) and posttraumatic stress disorder frequently fall into this category (13, 16).

This stress continuum, together with several orther clinical parameters (i.e., sex, ELS/CT history, comorbidities, recurrence, etc.) have regularly led to many seemingly contradictory research results with respect to the short- and long-term cortisol output in prior literature (13, 17). Interestingly, mounting evidence supports the fact that exaggerated as well as blunted stress reactivity of the HPA axis are both related to altered GC signaling and distinct physical morbidity over time (15, 18).

However, less in known about the transitional phase, in which acute stress becomes chronic and gets “under the skin” to influence disease development (19). Hereby, the most important factors affecting this probably chronic transition from hypercortisolemic states into hypocortisolemia are developmental timing, duration, frequency, nature, circadian timing, controllability, genetic/epigenetic idiosyncrasy, and subjective appraisal of the stressor (2, 12).

Clinical repercussions of stress system dysregulation

Acute and chronic dysregulation of the stress system at different levels has been implicated as a major downstream pathway and link to a broad range of complex behavioural (e.g., anxiety, depression, eating disorders, post-traumatic stress disorder, sleep disorders, etc.) and somatic disorders (e.g., chronic pain and fatigue syndromes, obesity, metabolic syndrome, chronic inflammation, diabetes type II, hypertension, atherosclerosis, cardiovascular diseases, body composition disorders, such as sarcopenia, splachnic obesity, osteopenia/osteoporosis, “medically unexplainable symptoms” or MUS, cancer, etc.), impairing life quality and curtailing life expectancy (15, 20-22). In fact, chronic stress is suggested as a common major risk factor of 75-90% of chronic, non-communicable diseases (23).

Figure 3 newFigure 3. Physiological components of the acute stress and sickness syndromes.

The immune system, for example, is vitally affected by HPA axis dysregulation, with altered GC levels influencing all aspects of cellular, humoral, innate and adaptive immunity, thus contributing to increased susceptibility to infections, immune and  inflammatory disorders, allergies, and cancer (24). For example, a hypercortisolemic state may result in immunosuppression, along with a switch from T helper-1 (cellular) to T helper-2 (humoral) immunity, while a hypocortisolemic state may result in immune system over activity and increased inflammatory responses due to a decrease in the suppressive effects of cortisol (9, 14). The mild systemic inflammation observed in chronic stress with devastating rather than salutary effects has been called “para-inflammation”.

 Conclusions

An optimal neuroendocrine coordination of the stress system and its reactivity is essential for survival, proper development, health and well-being. Acute and mostly chronic stress exposure can disrupt optimal neuroendocrine reactivity, resulting in enhanced vulnerability of the organism to stressors, thus, mediating a repeatedly well-documented higher risk for mental and physical (co-)morbidity.

Surprisingly, there is still little recognition of the importance of the stress system neuroendocrinology within most medical disciplines, and only few stress-system-related implications flow into broad clinical practice.

Novel approaches are needed for the proper neuroendocrine assessment and efficacious management of stress system dysregulation in both mental and physical stress-related disorders, especially in view of the challenges of the rapidly evolving lifestyle of modern societies.

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Acknowledgments

The contents of this article were adapted from: Agorastos & Chrousos. The Neuroendocrinology of Stress: The Stress-related Continuum of Chronic Disease Development. Molecular Psychiatry, 2022;27(1) :502-513. doi: 10.1038/s41380-021-01224-9.

Author Affiliations:

Agorastos Agorastos, MD, PhD, Department of Psychiatry, Division of Neurosciences, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.

George P. Chrousos, MD, PhD, University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, Medical School, Aghia Sophia Children’s Hospital, Athens, Greece.

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