cells

Review
The Role of Cortisol in Chronic Stress, Neurodegenerative
Diseases, and Psychological Disorders
Emilija Knezevic 1,2,† , Katarina Nenic 1,3,† , Vladislav Milanovic 1,4 and Nebojsa Nick Knezevic 1,5,6, *

1 Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA;
[email protected] (E.K.); [email protected] (K.N.); [email protected] (V.M.)
2 College of Liberal Arts and Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
3 Department of Psychology, University of Central Florida, Orlando, FL 32826, USA
4 College of Medicine Rockford, University of Illinois, Rockford, IL 61107, USA
5 Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA
6 Department of Surgery, University of Illinois, Chicago, IL 60612, USA
* Correspondence: [email protected]
† These authors contributed equally to this work.

Abstract: Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal
role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic
nucleus, governing the circadian rhythm and activating the intricate hypothalamic–pituitary–adrenal
(HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining home-
ostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound
implications for multiple bodily systems. Animal models have been instrumental in elucidating
these complex cortisol dynamics during stress, shedding light on the interplay between physiological,
neuroendocrine, and immune factors in the stress response. These models have also revealed the
impact of various stressors, including social hierarchies, highlighting the role of social factors in
cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenera-
tive diseases, like Alzheimer’s and Parkinson’s, driven by excessive cortisol production and HPA
axis dysregulation, along with neuroinflammation in the central nervous system. The relationship
between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis
hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol
Citation: Knezevic, E.; Nenic, K.;
patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mecha-
Milanovic, V.; Knezevic, N.N. The
nisms and their effects is essential, as they offer insights into potential interventions to mitigate the
Role of Cortisol in Chronic Stress,
detrimental consequences of chronic stress and cortisol dysregulation in these conditions.
Neurodegenerative Diseases, and
Psychological Disorders. Cells 2023,
Keywords: cortisol; hypothalamic–pituitary–adrenal (HPA) axis; chronic stress; neuroinflammation;
12, 2726. https://doi.org/10.3390/
cells12232726
physiological processes

Academic Editor: Markus Fendt

Received: 31 October 2023

Revised: 22 November 2023 1. Introduction
Accepted: 26 November 2023 Chronic stress has long been examined as a crucial factor in the development and pro-
Published: 29 November 2023 gression of illness. This manuscript delves into the multifaceted interplay between cortisol
and various diseases by examining the immune, nervous, and endocrine systems, shed-
ding light on the profound implications of cortisol and hypothalamic–pituitary–adrenal
(HPA) axis dysregulation for the onset, progression, and potential prevention pathways of
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
conditions such as depression, Alzheimer’s disease, and Parkinson’s disease. By exploring
This article is an open access article
the molecular, neurobiological, and clinical dimensions of stress, we aim to contribute a
distributed under the terms and comprehensive review of the existing literature on the role cortisol plays in illness with the
conditions of the Creative Commons ultimate goal of informing more effective prevention and therapeutic strategies as well as
Attribution (CC BY) license (https:// the direction for future research in this area.
creativecommons.org/licenses/by/
4.0/).

Cells 2023, 12, 2726. https://doi.org/10.3390/cells12232726 https://www.mdpi.com/journal/cells

Cells 2023, 12, 2726 2 of 18

2. Mechanisms
Cortisol, a glucocorticoid hormone produced by the adrenal glands, plays a crucial role
in various physiological processes in the human body [1]. Cortisol release follows the circa-
dian rhythm that is regulated by the pacemaker within the suprachiasmatic nucleus [2,3].
The nucleus activates the hypothalamic–pituitary–adrenal (HPA) axis. Its mechanisms
are finely tuned to respond to stress and maintain homeostasis [4]. One key mechanism
involves the hypothalamic–pituitary–adrenal (HPA) axis, a complex neuroendocrine sys-
tem. When the body perceives stress, the hypothalamus releases a corticotropin-releasing
hormone (CRH), which stimulates the anterior pituitary gland to produce an adrenocorti-
cotropic hormone (ACTH). The ACTH, in turn, prompts the adrenal cortex to synthesize
and release cortisol [5]. Approximately 5% of all cortisol circulates in a free, soluble form.
The other 90–95% is bound to proteins, including 80% to corticosteroid-binding globulin
(CBG) with high affinity and up to 15% to albumin with low affinity [6]. Out of the two
forms, only free cortisol is a biologically active hormone that can enter cells and interact
with glucocorticoid receptors, thus providing feedback inhibition in the hypothalamus and
pituitary gland, which are ultimately responsible for crucial functions, such as controlling
inflammation and ensuring euglycemia [7].
Over the past decade, significant progress has been made in understanding the regula-
tion of the hypothalamic–pituitary–adrenal (HPA) axis. Homeostatic physiological circuits
integrate various internal and external signals to produce an appropriate response for target
tissues, and the HPA axis exemplifies a homeostatic system [8]. Recent research reveals that
the circadian rhythm of adrenal glucocorticoid hormones, corticosterone in rodents and
predominantly cortisol in humans, consists of pulses with varying amplitudes [9]. These
pulses are generated by a sub-hypothalamic pulse generator. The oscillating endogenous
glucocorticoid signals interact with regulatory systems within different parts of the HPA
axis, including the adrenal gland itself, where a regulatory network can modify the pulsatile
hormone release [10]. The HPA axis output is a dynamic, oscillating glucocorticoid signal
that requires decoding at the cellular level [11]. Eliminating the pulsatile signal through
long-acting synthetic glucocorticoid administration can disrupt physiological regulation
and negatively affect various glucocorticoid-dependent bodily systems [12]. Even slight
alterations in the system’s dynamics during chronic stress or specific disease states can
potentially impact the functional output of multiple cells and tissues throughout the body.
This can lead to changes in metabolic processes, behavior, mood, and cognitive function in
susceptible individuals [13].
Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are the two
types of receptors that glucocorticoids exert their effects through on the hypothalamic–
pituitary–adrenal axis (HPA axis) [14]. Whereas GRs are present throughout the CNS,
MRs are mostly concentrated in the limbic structures, specifically the hippocampus [15].
MRs have a much higher affinity to glucocorticoids than GRs (high only at the peak of the
circadian rhythm and immediately after exposure to stress), and studies on GC receptor
occupancy have provided a basis for the proposition that MRs (proactive feedback mode)
mediate the inhibitory action of the hippocampus on HPA activity, whereas GRs (reac-
tive feedback mode) mediate HPA activity under conditions of elevated glucocorticoid
levels [15,16]. The binding of cortisol to glucocorticoid receptors initiates a cascade of intra-
cellular events, leading to the regulation of gene transcription and ultimately influencing
various physiological processes. Cortisol helps regulate glucose metabolism by increas-
ing gluconeogenesis and insulin resistance, ensuring an adequate energy supply during
stress [17]. Cortisol also influences the cardiovascular system by regulating blood pressure
and vascular tone. It enhances vasoconstriction and increases cardiac output, contributing
to the body’s readiness for the “fight or flight” response during acute stress [18].
Cells 2023, 12, 2726 3 of 18

In the 1950s, when Hench, Kendall, and Reichstein demonstrated the powerful anti-
inflammatory effects and applications of cortisone in clinical use to treat inflammatory
diseases, such as rheumatoid arthritis, the impact of glucocorticoids on inflammation in
the body and their regulation of it is clear [19]. Glucocorticoids play a powerful role in
regulating inflammation, and their anti-inflammatory effect has been known and utilized in
clinical applications for decades. However, exposure to chronic stress promotes sustained,
non-resolving inflammation within the CNS through the gradual development of gluco-
corticoid resistance, which further drives inflammation. Social conflicts and stress activate
the sympathetic nervous system (SNS) and HPA axis. The two act together and release
norepinephrine (NE), which upregulates the transcription of proinflammatory immune
response genes IL-1, IL-6, and TNF [20,21]. In the case of GC resistance due to chronic
stress, immune cells demonstrate decreased sensitivity to glucocorticoids. Therefore, in this
case, cortisol release does not result in significant anti-inflammatory effects, as one would
otherwise expect. Once GC resistance develops, the “fight or flight” response to social
threats is altered and results in exaggerated inflammation, consequently perpetuating the
proinflammatory state [22].
As mentioned above, under normal conditions and short-term stress, the glucocorti-
coids released are implicated in a mechanism of inhibiting proinflammatory cytokines and
upregulating anti-inflammatory cytokines. Interleukin-1 beta (IL-1 beta) seems to be the
culprit of stress-induced adverse effects [23] that stimulate the release of norepinephrine,
which further causes a cascade of events involving the central nervous, endocrine, and
immune systems. This modulation of the immune response is crucial in preventing exces-
sive inflammation but can also make individuals more susceptible to infections and impair
wound healing under chronic stress conditions [24].
Chronic stress exerts its ill effects over time through a mechanism of prolonged cortisol
release; consequently, the HPA axis seems to become increasingly desensitized over a period
of time. One of the proposed mechanisms is that constant GC release will blunt HPA axis
response over time, leading to HPA axis dysregulation and cortisol resistance, which
are implicated in many different diseases like Alzheimer’s disease, Parkinson’s disease,
depression, etc., through a plethora of different factors, most notably an interplay between
the central nervous system, endocrine, and immune interactions.
It is proposed that in chronic stress, a resulting increase in the IL-1 beta proinflamma-
tory cytokine is transformed into a nervous signal—norepinephrine (NE). Consequently,
endocrine system hormones melatonin and cortisol are utilized to provide a counterbal-
ance against IL-1 beta. However, the counterbalancing is unsuccessful due to chronic
stress-induced cortisol resistance. Consequently, a loop effect is created that increments
all mediators, thus creating an imbalance between the immune, endocrine, and central
nervous systems (Figure 1). The elevated levels of IL-1 beta appear to occur when an
individual is unable to cope and succumbs to a stressful event, thus showing sickness
behavior symptoms [25].
Cells 2023, 12, x FOR PEER REVIEW 4 of 20

Cells 2023, 12, 2726 4 of 18

Figure 1. Proposed interplay between the CNS, endocrine, and immune systems.
Figure 1. Proposed interplay between the CNS, endocrine, and immune systems.
3. Animal Models and Mechanisms
3. Animal Models and Mechanisms
Animal models have played a crucial role in unraveling the intricate mechanisms un-
Animal the
derlying models have played
regulation a crucial
of cortisol role instress
levels during unraveling the intricate
[26]. These mechanisms
models allow researchers
underlying the regulation of cortisol levels during stress [26]. These
to stimulate and manipulate stressors, offering valuable insights into the physiological models allow re-and
searchers to stimulate
neuroendocrine and manipulate
responses associatedstressors, offering
with stress. Byvaluable
studyinginsights
animalsinto the controlled
under physi-
ological and neuroendocrine
conditions, scientists can betterresponses associated
understand with stress.
the pathways Byfeedback
and studyingsystems
animalsthatundergovern
controlled conditions,
cortisol secretion [27]. scientists can better understand the pathways and feedback sys-
tems thatOne govern
notablecortisol
study secretion [27].
by [28] employed a rodent model to examine the molecular mecha-
One notable
nisms of cortisolstudy by [28] employed
synthesis within theaadrenal
rodent model
glandstoduring
examine the molecular
stress. mech-
Their research high-
anisms of cortisol
lighted the rolesynthesis within the adrenal
of the adrenocorticotropic glands during
hormone (ACTH)stress. Theircortisol
in driving research high-
production.
lighted the role ofit the
Furthermore, adrenocorticotropic
revealed the feedback loops hormone (ACTH)
involved in driving
in regulating cortisol
cortisol produc-
levels, shedding
tion.light
Furthermore, it revealed
on the intricacies the axis
of HPA feedback loops involved in regulating cortisol levels,
functioning.
sheddingInlight on thetointricacies
addition of HPA
shedding light on axis functioning.
physiological mechanisms, animal models have also
In addition to shedding light on physiological mechanisms,
provided insights into how various stressors, from physicalanimal models haveinfluence
to psychosocial, also
cortisol
provided secretion.
insights For instance,
into how a study by
various stressors, from[29] employed
physical a non-human
to psychosocial, primatecor-
influence model
tisoltosecretion.
explore the Forimpact
instance,of social stress
a study by on[29]cortisol
employeddynamics. Their work
a non-human demonstrated
primate model to the
significant
explore the impactinfluence
of social of stress
socialon
hierarchies within primate
cortisol dynamics. groups
Their work on cortisol the
demonstrated regulation.
sig-
Dominant
nificant influenceindividuals exhibited distinct
of social hierarchies cortisol groups
within primate profiles,onemphasizing the roleDom-
cortisol regulation. of social
inantfactors in modulating
individuals exhibited cortisol secretion.
distinct cortisol profiles, emphasizing the role of social factors
in modulating cortisol secretion. for stress regulation in rodents is plasma corticosterone;
The main glucocorticoid
however,
The mainit glucocorticoid
is uncertain whether plasma
for stress cortisol in
regulation canrodents
serve asisan indicator
plasma of rodent stress
corticosterone;
activation.
however, A study by
it is uncertain [30] examined
whether plasma the effects
cortisol ofserve
can the estrous cycle stage,
as an indicator of circadian rhythm,
rodent stress
and various
activation. A study stressors
by [30]on serum
examinedcortisol
the and
effectscorticosterone
of the estrous in mice.
cycleThe research
stage, found a
circadian
strong
rhythm, correlation
and (r = 0.6–0.85)
various stressors between
on serum serum
cortisol cortisol
and and corticosterone
corticosterone in mice. Theacross both con-
research
ditions or predictable and unpredictable stress. Both hormones
found a strong correlation (r = 0.6–0.85) between serum cortisol and corticosterone acrosspeaked on day 1 of repeated
or unpredictable stress, but the dynamics differed afterward.
both conditions or predictable and unpredictable stress. Both hormones peaked on day 1 The corticosterone declined
during repeated restraints but remained high during unpredictable stress. During forced
swimming or heat stress, cortisol peaked within 3 min, while corticosterone peaked after
Cells 2023, 12, 2726 5 of 18

40 min. The results conclude that corticosterone is a more adaptation-related biomarker

during chronic stress, while cortisol responds more quickly during severe acute stress.
These animal models not only aid in uncovering the fundamental mechanisms govern-
ing cortisol levels during stress but also provide insights that have implications for human
health [31]. By understanding the intricacies of cortisol regulation in response to stress,
researchers can develop targeted interventions and treatments for stress-related disorders
in both animals and humans [32].

4. Measurements
Guidelines for measuring salivary diurnal cortisol in interventional studies are cur-
rently lacking, posing challenges for incorporating salivary cortisol as a biomarker in
randomized controlled trials (RCTs) for behavioral and health therapies. The inherent
complexity of salivary diurnal cortisol as a biomarker introduces unique difficulties in
RCTs, as different interventions may exert varying effects on the composite diurnal profile,
consisting of the cortisol awakening response, diurnal slope, and area under the curve—
each reflecting a distinct aspect of the HPA axis function. This complexity influences
decisions regarding the main measurement parameter, theories about potential paths for
change, and assessments of effectiveness, target engagement, and action mechanisms.
Moreover, concerns have been raised about the biomarker’s long-term stability over spans
exceeding one month and its short-term reliability in the context of day-to-day state effects,
non-compliance, and other factors [33–36].
In the realm of stress research, monitoring quantified long-term stress markers is vital
for preventing and intervening early in stress-related chronic diseases. While physiological
parameters such as heart rate, blood pressure, and metabolic hormones quantify acute and
chronic stress, determining cortisol levels’ specific temporal characteristics remains chal-
lenging. Serum and salivary cortisol levels indicate acute changes at a single time point, but
their utility in assessing long-term cortisol exposure is hindered by circadian fluctuations
and protein binding. Hair cortisol concentration (HCC), measured from hair samples, offers
a promising method for retrospectively assessing chronic stress over extended periods. The
predictable growth rate of scalp hair, approximately 1 cm per month, makes the 1 cm hair
segment a reflection of the prior month’s cortisol production. Combining chronic HCC
measurements with acute cortisol assessments provides a comprehensive understanding of
the stress response and its relevance to psychiatric and stress-related disorders [37,38].
In some studies, diurnal cortisol serves as a comprehensive measure, capturing cortisol
levels from morning to night and examining the diurnal cortisol slope, describing the
behavior of cortisol levels over the course of the day. Additionally, studies may focus
on the cortisol awakening response (CAR), measuring cortisol within the first hour after
awakening, a period when cortisol typically rises before gradually declining throughout
the day, with a nighttime increase. Integrating diverse cortisol measurement approaches
contributes to a nuanced understanding of stress dynamics in various contexts.

5. Overall Illness and Stress-Related Disorders

Numerous studies emphasize the substantial impact of chronic stress on the develop-
ment and exacerbation of chronic pain disorders, such as fibromyalgia and migraines [39].
Migraines, characterized by recurrent throbbing headaches often accompanied by nausea,
light, and sound sensitivity, are notably influenced by chronic stress, affecting both the onset
and duration of these episodes [40]. Sensitized meningeal afferents innervating the dural
vasculature are implicated in migraine pathophysiology, with these afferents projecting
to the nucleus caudalis in the trigeminal ganglion [41]. Trigeminal meningeal nociceptors
become sensitive to sterile inflammation in the intracranial meninges and are triggered by
various factors including nutrition, hormonal swings, chronic stress, or events, like cortical
spreading depression [42]. Stress, considered a major factor exacerbating migraine pain,
has been shown in preclinical rodent studies to cause the degranulation of intracranial mast
cells, an effect mediated by neuropeptides [43].
Cells 2023, 12, 2726 6 of 18

Similarly, a robust correlation has been established between chronic stress and fi-
bromyalgia, a complex condition characterized by widespread musculoskeletal pain, fa-
tigue, and localized soreness. The intricate neurobiological interplay between stress and
these chronic pain syndromes involves alterations in pain processing pathways, the modu-
lation of the immune system, and the dysregulation of hormones. Recognizing the role of
chronic stress in migraines and fibromyalgia advances our understanding of the etiological
factors contributing to these conditions, underscoring the importance of comprehensive,
holistic management approaches that consider both physiological and psychosocial aspects.
Fibromyalgia is characterized by chronic widespread pain (CWP), which significantly
impacts the lives of those affected [44–47]. The management of FM is challenging, with
limited effectiveness shown by pharmacological therapies [48–51]. Promising outcomes in
terms of prevention are observed when regional and broad pain is diagnosed early and
treated appropriately, with prominent risk factors including somatic symptoms, sick behav-
ior, regional or non-widespread pain, and sleep disturbance [52–54]. Steroidal hormone
cortisol, a marker of HPA axis dysfunction, reflects changes in FM and CWP.
Stress is widely acknowledged for its pivotal role in the development of mental ill-
nesses and stress-related disorders, yet the intricate biological mechanisms governing
pathological stress regulation continue to challenge our comprehension [55]. Recent re-
search has made significant strides in shedding light on these mechanisms [56], notably
through the innovative use of hair cortisol concentration (HCC) measurements. A notewor-
thy study, “Hair cortisol concentration and common mental disorder: A population-based
multi-cohort study” [57], underscores the relevance of this approach. The study unveils a
compelling association between elevated HCC and exposure to stressful life events [58],
providing tangible evidence of the link between chronic stress and physiological markers.
By quantifying cortisol levels in hair samples, this research not only highlights the pro-
found impact of stress on the body but also emphasizes the potential of HCC as a robust
biomarker for assessing stress-related psychiatric conditions [59]. This innovative method
holds promise in advancing our understanding of the intricate interplay between stress,
cortisol regulation, and the development of mental health disorders, potentially paving
the way for more precise diagnostic and therapeutic strategies in the realm of mental
health [60].
Stress management techniques, including relaxation exercises, mindfulness, and cog-
nitive behavioral therapy (CBT), have emerged as valuable interventions for individuals
seeking to regain control over their stress response and alleviate pain [61]. Several studies
have underscored their efficacy in mitigating the physiological and psychological impact
of stress [62]. For instance, mindfulness-based stress reduction (MBSR) has been shown
to reduce cortisol levels, enhance emotional regulation, and improve pain perception [63].
Similarly, CBT, with its focus on modifying maladaptive thought patterns and behaviors,
has been associated with reductions in stress-related symptoms and pain intensity [64].
Relaxation exercises, such as progressive muscle relaxation and deep breathing, contribute
to decreased muscle tension and heightened relaxation responses, which can alleviate
stress-related physical discomfort [65]. These stress management techniques provide valu-
able tools for individuals seeking to address stress, highlighting their potential to improve
both physical and mental health outcomes [62].

6. Alzheimer’s and Parkinson’s Diseases

Stress and aging are prerequisites for neurodegenerative disease [66]. Although
glucocorticoids are essential to homeostasis and a normal response to stress, excessive
glucocorticoid production under conditions of chronic stress is implicated in many disease
models [67]. The overproduction of GCs and a dysfunctional HPA axis keep appearing
in the literature addressing possible contributions to the processes that are involved in
the development of Alzheimer’s disease [68–70]. There seems to be a cyclical relationship
between key brain areas, such as the hippocampus, its atrophy, and the feedback on the
HPA axis contributing to its dysfunction [71] (Figure 2). Normally, the hippocampus
 and PD, respectively), and leads to an increase in oxidative stress, mitochondrial dysfunc-
tion, and metabolic changes [73].
In recent years, researchers have used the term “type 3 diabetes”, first proposed over
a decade ago, [74] to refer to Alzheimer’s disease due to the plethora of shared mecha-
Cells 2023, 12, 2726 nisms implicated both in AD and type 1 and type 2 diabetes mellitus (T1DM and T2DM) 7 of 18
[75]. In T2DM, one of the markers also involved in AD is inflammation that is caused due
to insulin resistance in diabetes, which in turn causes a surge in proinflammatory cyto-
kines (IL-6, IL-1 beta) and tumor necrosis factor-alpha (TNF-α) [76–78]. This is the same
exerts an inhibitory effect on the HPA axis. One of the proposed mechanisms is that
mechanism that is triggered by chronic stress in AD and which we delve into below in the
since the hippocampus is one of the primary areas compromised in AD and contains the
section on AD and PD. Increased oxidative stress and mitochondrial dysfunction, which
highest number of GC receptors in the brain, it is especially susceptible to the detriment of
are mentioned above and occur in critical brain areas to cause neurodegeneration impli-
chronically excessive GC production [72]. Neurodegeneration occurs in critical brain areas,
cated in diseases, such as AD and PD [73], occur due to insulin resistance in T2DM [75]. It
such as the hippocampus and substantia nigra (two of the crucial brain areas implicated
might be important to acknowledge the similar inflammatory mechanisms implicated in
in AD and PD, respectively), and leads to an increase in oxidative stress, mitochondrial
T2DM for future work examining chronic stress and their role in diabetes in more depth.
dysfunction, and metabolic changes [73].

Figure 2. Feedback loop of hippocampal atrophy, overactive HPA axis, and GC hypersecretion.
Figure 2. Feedback loop of hippocampal atrophy, overactive HPA axis, and GC hypersecretion.
In recent years, researchers have used the term “type 3 diabetes”, first proposed over a
decadeItago, [74]to
is hard toconclude
refer to Alzheimer’s
which comes disease duehypersecretion
first, the to the plethoraof ofGCs
shared
andmechanisms
the deleteri-
implicated both in AD and type 1 and type 2 diabetes mellitus (T1DM
ous effect on neurons leading to atrophy of the hippocampus and subsequent dysregula-and T2DM) [75]. In
T2DM, one of the markers also involved in AD is inflammation that is
tion of the HPA axis given the negative feedback of the hippocampus being disruptedcaused due to insulinor
resistance in diabetes, which in turn causes a surge in proinflammatory
the compromised hippocampus in AD, which leads to HPA axis dysfunction, causing cytokines (IL-6, IL-1
GC
beta) and tumor necrosis factor-alpha (TNF-α) [76–78]. This is the same
hypersecretion to further contribute to neurodegenerative processes. One study found mechanism that is
triggered by chronic stress in AD and which we delve into below in the section on AD and
that in mice models of AD, heightened stress and glucocorticoid production aided in the
PD. Increased oxidative stress and mitochondrial dysfunction, which are mentioned above
production of beta-amyloid, a key feature of AD, and worsening cognitive and memory
and occur in critical brain areas to cause neurodegeneration implicated in diseases, such
deficits [79]. In mice research, the administration of glucocorticoid receptor antagonists
as AD and PD [73], occur due to insulin resistance in T2DM [75]. It might be important to
acknowledge the similar inflammatory mechanisms implicated in T2DM for future work
examining chronic stress and their role in diabetes in more depth.
It is hard to conclude which comes first, the hypersecretion of GCs and the deleterious
effect on neurons leading to atrophy of the hippocampus and subsequent dysregulation
of the HPA axis given the negative feedback of the hippocampus being disrupted or the
compromised hippocampus in AD, which leads to HPA axis dysfunction, causing GC
hypersecretion to further contribute to neurodegenerative processes. One study found
that in mice models of AD, heightened stress and glucocorticoid production aided in the
production of beta-amyloid, a key feature of AD, and worsening cognitive and memory
deficits [79]. In mice research, the administration of glucocorticoid receptor antagonists
resulted in improved cognition and reduced AD pathologies, supporting findings that
glucocorticoid signaling influences and likely plays a contributing role in the development
and progression of AD pathologies. Further research in mice showed that glucocorticoids
reduce tau degradation, resulting in tau accumulation [80].
Another insightful study with rats was conducted in order to study the effects and
mediation of chronic stress in the pathology of the hippocampal cytoskeleton [81]. The
findings support the notion that chronic stress may in fact play a crucial role in either
buffering against or making more susceptible to neurological injury and subsequent neuron
Cells 2023, 12, 2726 8 of 18

loss. In this study, one of the markers of neurodegeneration worsened by stress was tau
antigenicity, a major hallmark of AD. In rats exposed to stress, stress acted as a potentiator
of excitotoxin-induced tau immunoreactivity accumulation contributing to neuron loss in
the hippocampus [81].
Research in animals showed that chronic stress and cortisol release increase vulnera-
bility to Alzheimer’s disease via the accumulation of tau and beta-amyloid, maladaptive
immune responses, brain atrophy, and synaptic dysregulation [80]. Glucocorticoid recep-
tor DNA binding sites exist in two genes associated with the formation of beta-amyloid
(amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1).
Therefore, it is thought that glucocorticoids can bind to these sites and influence beta-
amyloid production [82]. In rat research, the administration of a glucocorticoid receptor
antagonist resulted in improved cognition and reduced AD pathologies [83]. This evi-
dence indicates that glucocorticoid signaling influences the likelihood and the extent of
AD pathologies. Further research showed that glucocorticoids reduce tau degradation,
resulting in tau accumulation [84].
Research demonstrated that microglia are important in forming memories and sup-
porting neurogenesis within the brain [85,86]. Early in the AD process, microglia can
phagocytose and clear accumulating beta-amyloids. However, with chronic stress, mi-
croglial response becomes ineffective with compromised phagocytosis. This results in a
chronic proinflammatory state, resulting in an increasingly neurotoxic environment through
the production of proinflammatory cytokines, altered synaptic pruning, and the reduced
production of protective factors [87]. The research found apolipoprotein E transcripts
to be significantly upregulated in AD-associated microglia [88,89]. Additionally, it was
discovered that chronically activated microglia induce cognitive decline indirectly via the
accumulation of neurofibrillary tangles [90].
Human research indicates that microglia promote beta-amyloids and subsequent tau
accumulation, thus having a key role in cognitive decline [90,91]. The nucleotide-binding
oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3), within mi-
croglia recruits the adaptor protein apoptosis-associated speck-like protein containing a
C-terminal caspase recruitment domain (ASC) to form an inflammasome complex. This
inflammasome complex is responsible for the production of IL-1 beta, which is a proinflam-
matory cytokine. Both beta-amyloids and tau can activate the NLRP3-ASC inflammasome
within microglia [92,93]. Rat research has identified the NLRP3-ASC inflammasome as a
major mechanism through which microglia may drive pathological features of AD [92–94].
Furthermore, it was discovered that beta-amyloid oligomers have the ability to facilitate
NLRP3 inflammasome activation in microglia cells, indicating that inflammation in the
CNS may precede the accumulation of beta-amyloid plaques [95]. The inflammasome
could have an independent role in promoting tau aggregation. The disruption of the
NLRP3-ASC inflammasome in mice resulted in significantly decreased forming of tau
aggregates [93]. The NLRP3-ASC inflammasome mechanisms contributing to increased
beta-amyloids and tau are thought to be a combination of kinases and phosphatases in-
volved in tau phosphorylation [96] through the production of IL-1 beta. IL-1 beta was
shown to exacerbate tau pathologies [97] and reduce microglial phagocytic activity [92–94].
Ultimately, chronic stress is associated with AD progression by priming microglia to enter
an increased proinflammatory response and drive the accumulation of phosphorylated tau
following exposure to a secondary stimulus, such as an accumulating beta-amyloid [80].
Parkinson’s disease is a progressive neurodegeneration of the dopaminergic neurons
in the substantia nigra. Chronic stress and elevated cortisol are implicated in many of
the mechanisms that are implicated in the progression and, potentially, development of
the disease including metabolic changes, mitochondrial dysfunction, and neuroinflamma-
tion [78] (see Figure 3 for a possible disease progression/development flowchart). Normal
cortisol secretion acts inhibitory toward cells that produce peripheral cytokines, mitigating
inflammation. On the other hand, excessive cortisol secretion promotes neuroinflammation
through the mechanism in which glucocorticoid receptors or GR (anti-inflammatory actions)
 disease including metabolic changes, mitochondrial dysfunction, and neuroinflammation
[78] (see Figure 3 for a possible disease progression/development flowchart). Normal cor-
tisol secretion acts inhibitory toward cells that produce peripheral cytokines, mitigating
inflammation. On the other hand, excessive cortisol secretion promotes neuroinflamma-
Cells 2023, 12, 2726
tion through the mechanism in which glucocorticoid receptors or GR (anti-inflammatory 9 of 18
actions) are downregulated as a compensatory response to excess cortisol production and
GC resistance, which further promote the release of GCs. Under normal conditions, cate-
cholamines and glucocorticoids regulate inflammation through the inhibition of proin-
are downregulated as a compensatory response to excess cortisol production and GC resis-
flammatory cytokines, such as IL-6, IL-1β, and TNF-α, and the stimulation of anti-inflam-
tance, which further promote the release of GCs. Under normal conditions, catecholamines
matory cytokines, such as IL-4, IL-10, and IL-13 [38], by exerting action in the cytoplasm
and glucocorticoids regulate inflammation through the inhibition of proinflammatory cy-
of immune cells. Through an interplay of inflammation due to immune response and sub-
tokines, such as IL-6, IL-1β, and TNF-α, and the stimulation of anti-inflammatory cytokines,
sequent cytokine release and a lack of downregulation normally executed by GCs, neu-
such as IL-4, IL-10, and IL-13 [38], by exerting action in the cytoplasm of immune cells.
roinflammation persists, leading to the atrophy of neurons in critical brain areas, such as
Through an interplay of inflammation due to immune response and subsequent cytokine re-
the hippocampus [79,98]. Neuroinflammation is prominent in diseases, such as Parkin-
lease and a lack of downregulation normally executed by GCs, neuroinflammation persists,
son’s disease and Alzheimer’s disease, and may be the driving factor in both the progres-
leading to the atrophy of neurons in critical brain areas, such as the hippocampus [79,98].
sion of and contribution to disease development. When examining the proinflammatory
Neuroinflammation is prominent in diseases, such as Parkinson’s disease and Alzheimer’s
cytokines in PD, such as IL-6 and IL-1 beta, researchers have observed an increase in these
disease, and may be the driving factor in both the progression of and contribution to disease
inflammation-promoting
development. When examiningcytokines in the diseased brains
the proinflammatory of both
cytokines AD
in PD, andasPD
such IL-6sufferers
and IL-1
[99,100], which could suggest the crucial role of inflammation exacerbated by chronic
beta, researchers have observed an increase in these inflammation-promoting cytokines in
stress in neurodegenerative
the diseased disease.
brains of both AD and PD sufferers [99,100], which could suggest the crucial
role of inflammation exacerbated by chronic stress in neurodegenerative disease.

Figure 3. Model for the potential mechanism of cortisol dysregulation implication in PD.
Figure 3. Model for the potential mechanism of cortisol dysregulation implication in PD.
Aging, as the crucial risk factor for PD development coupled with chronic stress
Aging,to
contribute asthe
theincreased
crucial risk factorlevels,
cortisol for PDand
development
vice versa,coupled with chronic
which together drivestress con-
the mecha-
tribute to the increased
nisms (oxidative stress, cortisol levels, and vice
neuro-inflammation, versa, whichdysfunction,
mitochondrial together drive theROS,
more mecha-
and
nisms (oxidative
metabolic stress,
changes) thatneuro-inflammation, mitochondrial
triggers the development dysfunction,
and the progression more ROS, and
of PD.
metabolic changes) that triggers the development and the progression of PD.
7. Depression
7. Depression
Experiencing acute stress induces the temporary release of cortisol in increments that
eventually decrease.
Experiencing This
acute temporary
stress induces incremental
the temporary release is of
release notcortisol
dangerous for long-term
in increments that
health outcomes. However, research has shown that during chronic stress,
eventually decrease. This temporary incremental release is not dangerous for long-term cortisol loses its
circadian
health rhythmHowever,
outcomes. [23]. This research
results inhas
GCshown
resistance
thatdue to the
during desensitization
chronic of GRloses
stress, cortisol and
the absence of a proper response to cortisol. Consequently, it is hypothesized
its circadian rhythm [23]. This results in GC resistance due to the desensitization of GR that HPA
axis the
and hyperactivity
absence ofand resulting
a proper GC resistance
response may Consequently,
to cortisol. represent a connection between chronic
it is hypothesized that
stress and a major depressive disorder [101,102].
HPA axis hyperactivity and resulting GC resistance may represent a connection between
chronicExposure to chronic
stress and a majorstress promotes
depressive sustained,
disorder non-resolving inflammation within the
[101,102].
CNS that could result in symptoms of depression [103]. Animal models of depression-like
behavior demonstrated elevated proinflammatory cytokine levels, most commonly IL-1
beta and tumor necrosis factor-alpha (TNF-alpha) [104,105] (see Table 1). IL-1 beta promotes
proinflammatory genes and proteins in the brain [106–108], as well as IL-1 beta-induced
sickness behavior in rodents, resulting in social withdrawal, loss of appetite, decreased
motor activity, and a decrease in cognitive function [109] (see Table 1). As supporting
evidence, research demonstrated that the inhibition of the IL-1 beta receptor was able to
rescue anhedonia in rats exposed to chronic stress [110] (see Table 1), thus demonstrating
the importance of IL-1 beta in studying chronic stress-related depression. Furthermore,
IL-1 beta exhibited the ability to activate the HPA axis and suppress the hypothalamic–
pituitary–gonadal (HPG) axis [111–113]. IL-1 beta also stimulates NE release through its
influence on the HPA axis [23]. In healthy subjects, cortisol decreases IL-1 beta, generating
an anti-inflammatory response. However, with adaptations to chronic stress, cortisol’s
Cells 2023, 12, 2726 10 of 18

function is diminished, which results in increased levels of IL-1 beta. Research showed that
IL-1 beta can be produced by glial cells, neurons, and the immune system and that it can
pass through the blood–brain barrier, resulting in sickness behavior symptoms [25]. These
mechanisms and implications, which are mediated by chronic stress, could shed light on
the possible etiology of depression through a complex interplay of the immune, endocrine,
and nervous systems.
One large cohort study examined the implications of the hypothalamic–pituitary–
adrenal axis in MDD. Researchers looked at individuals with both remitted and current
MDD, as well as healthy controls. Their findings showed that both currently depressed and
those with remitted MDD had a significantly higher cortisol awakening response (CAR)
than their non-depressed counterparts [114]. Although the findings were modest, they
were significant for both groups. Another study found similar associations: women suffer-
ing currently from depression had significantly higher average cortisol levels throughout
the day, as well as a significantly higher CAR, than the non-depressed group [115]. A
third study showed similarly intriguing findings when examining basal cortisol in various
DSM-IV dimensions and categories of depression and anxiety [116]. The findings showed
that CAR had a nonlinear relationship with anhedonic depression and general distress
dimensions of the MASQ (specifically an inverted U-shape association). The indication
here is that depressive symptoms are associated with both a hyper- and hypoactive HPA
axis. The findings might suggest that disorders, like anxiety and depression, may initially,
given high cortisol in the morning, cause the HPA axis to be hyperactive and with pro-
gression lead to a blunting of that response, yielding lower cortisol in the morning [58].
They also observed that diurnal cortisol decline had a linear relationship with general
distress and anhedonic depression, pointing to an increased concentration of cortisol as
the severity of symptoms increased. Patients with DSM-IV depressive disorder had higher
concentrations of cortisol and a steeper slope than the controls [25]. The findings for studies
measuring diurnal cortisol and CAR in MDD have been inconsistent. There are those that
have demonstrated significant differences, demonstrating those with MDD to have higher
measures than their non-depressed counterparts, like the ones mentioned above. On the
other hand, there are also those that have not found a significantly hyperactive HPA axis
in depression [25]. It is important to note that the methods of measuring cortisol vary
extensively in their sensitivity to HPA axis function, and there seem to be differences that
depend on the dimension and category of depression being examined [116].
Research suggests that the severity of depression is associated with the level of circulat-
ing cytokines and chemokines, which compromise the blood–brain barrier and activate the
central immune response [117] (see Table 1). When the overactivated immune response ex-
ceeds the resolving capacity of resident immune cells within the brain, psychiatric disorders
tend to develop. Peripheral CD4+ T cells appear to be major contributors to the occurrence
of mental disorders [118,119] (see Table 1). Chronic stress induces the release of cytokines
and promotes the differentiation of peripheral CD4+ cells into different phenotypes [120].
Th17 cells are particularly interesting because of their high pathogenic potential in CNS
diseases [121,122]. Research showed an increase in Th17 cells in mice exhibiting learned
helplessness. Additionally, mice receiving Th17 cells displayed significant depressive-like
behaviors [119,123]. Multiple studies support the idea that the severity of depression is
associated with both increased levels of proinflammatory cytokines and with structural as
well as functional alterations in the dorsal part of the striatum [124–126]. Aberrant activity
in the dorsal striatum is implicated in the core symptoms of depression, such as anhedonia
and psychomotor retardation. Stressed rats exhibited significant symptoms of depres-
sion, blood–brain barrier disruption, and neuroinflammation in the dorsal striatum [117].
Research in rats conducted by Peng et al. showed a time-dependent increase in thymus-
derived and spleen-derived naïve CD4+ T cells, along with aggregation of inflammatory
Th17 cells in the dorsal striatum during exposure to stress. It was demonstrated that an
increase in Th17-derived cytokines within the brain can impair the blood–brain barrier
integrity. This facilitates CNS access for other immune cells and cytokines. Inflammatory
Cells 2023, 12, 2726 11 of 18

cytokines, IL-1 beta and IL-6, were significantly elevated in the serum and dorsolateral
striatum of rats exposed to chronic stress. In addition, IL-1 beta, IL-6, and TNF-alpha levels
were elevated within the dorsomedial striatum. Furthermore, reactive astrogliosis was
noted in the dorsolateral and dorsomedial striatum of rats exposed to chronic stress [117].
Notably, IL-17 and IL-22 are major Th17-produced cytokines that generate tissue
inflammation [121]. IL-17 impairs blood–brain barrier integrity, allowing for more immune
cells to cross into the CNS [127,128]. Astrocytes can respond to IL-17 and release mediators
that promote tissue damage [129]. Recruitment of activated Th17 cells into the CNS and the
increased production of IL-17 and IL-22 may be crucial for the development of symptoms
of depression [117]. Importantly, Peng et al. showed that preventing the transformation
of CD4+ T cells into inflammatory Th17 cells in the early phases of stress decreases stress-
induced symptoms of depression. This prevention resulted in lower levels of expressed
proinflammatory cytokines IL-6, IL-17, and IL-22.

Table 1. Animal studies.

Study Subjects Mechanism of Stress Measure of the Outcome Results and Findings
Anhedonia, defined as a
Exposure to
Grippo et al. reduction in sucrose intake Humoral assays showed increased levels of
Male Sprague–Dawley rats anhedonia-inducing CMS
(2005) [104] without concomitant effect on TNF-alpha and IL-1 beta
(Chronic Mild Stress)
water intake
Exposure to the social stress
model: repeated social defeat Elevated IL-6 levels in the serum of the
stress due to exposure to a stress-susceptible mice along with increased
Hodes et al.
C57BL/6J mice larger, aggressive CD-1 Social avoidance and IL-6 levels social avoidance behavior; IL-6 levels were
(2014) [105]
mouse, resulting in the strongly negatively correlated with social
development of interaction behavior
depressive-like symptoms
Sickness behavior and depressive
symptoms; rodents showed no interest in
Dantzer et al. Administration of IL-1 beta or their physical and social environment, had
Rats and mice Behavior
(2008) [109] TNF-alpha decreased motor activity, exhibited social
withdrawal, decreased food and water
intake, and impaired cognition
Control group: wild type rats The control group exhibited anhedonia; in
Experimental group: rats the experimental group, blockade of the
Koo et al. Exposure to CUS (Chronic Anhedonia, measured through
with a blockade of an IL-1 IL-1 beta receptor blocked the
(2008) [110] Unpredictable Stress) sucrose preference testing
beta receptor (IL-1RI) by an anti-neurogenic effect of stress and
inhibitor or IL-RI null rats prevented anhedonic behavior
Rats exhibited depressive-like symptoms,
BBB disruption, and neuroinflammation in
the dorsal striatum. There was also a
Behavior, BBB changes, time-dependent increase in thymus- and
Peng et al. 6 h of daily CRS (Chronic
Rats neuroinflammation, and CD4+ spleen-derived CD4+ T cells. Inhibition of
(2022) [117] Restraint Stress)
T cell level measurements CD4+ cell differentiation with SR1001 in the
early stages of CRS exposure ameliorated
stress-induced depressive-like behavior and
the inflammatory response
Administration of Th17, but not Th1 or Treg
Beurel et al. Administration of Th17, Th1,
Male Rag2 knockout mice Behavior cells, increased susceptibility to learned
(2018) [119] and Treg cells
helplessness depressive-like behavior

8. Pain
Chronic pain is a debilitating condition that affects millions of individuals worldwide,
and it has been associated with alterations in cortisol levels [1]. It is often associated
with a cascade of physiological and psychological responses, one of which is altered
cortisol levels [130]. Several studies have explored the dysregulation of the hypothalamic–
pituitary–adrenal (HPA) axis in individuals with chronic pain, as well as the crucial role
of the glucocorticoid receptor (GCC) [130] (see Figure 4). The HPA axis is a key regulator
of cortisol production, and abnormalities in the axis can lead to alterations in cortisol
levels [24].
 Cells 2023, 12, x FOR PEER REVIEW 13

Cells 2023, 12, 2726 of cortisol production, and abnormalities in the axis can lead to alterations in cortisol
12 of 18
els [24].

Figure 4. Chronic stress mechanism and implications.

Figure 4. Chronic stress mechanism and implications.
This dysregulation can manifest as elevated baseline cortisol levels and blunted diurnal
cortisol patterns in This dysregulation
individuals can manifest
with chronic as elevated such
pain conditions, baseline cortisol levels
as fibromyalgia and blunte
[131]
urnal cortisol patterns in individuals with chronic pain
and chronic low back pain [132]. Additionally, there is evidence to suggest that cortisol conditions, such as fibromy
dysregulation[131]
mayand chronic low
exacerbate back pain [132].
the experience Additionally,
of chronic pain [133]. there is evidence
Chronic stress,tooften
suggest that
tisol
associated with HPAdysregulation may exacerbate
axis dysregulation, the experience
can contribute to increasedofpain chronic pain [133].
sensitivity and theChronic st
development often associated with
of hyperalgesia, makingHPA axis dysregulation,
individuals can contribute
more susceptible to increased
to pain [67]. Moreover, pain sensit
and the
elevated cortisol development
levels in response ofto hyperalgesia,
chronic pain making individualsthe
may perpetuate morepain susceptible
cycle by to pain
contributing to muscle tension
Moreover, elevatedand inflammation
cortisol levels in[134].
response to chronic pain may perpetuate the
The glucocorticoid receptor (GCC),
cycle by contributing to muscle a crucial
tensioncomponent
and inflammationof the HPA [134].axis, plays a
significant role in the
Theregulation of chronic
glucocorticoid pain(GCC),
receptor [130]. The GCCcomponent
a crucial is essential forof themodulating
HPA axis, plays a
the anti-inflammatory
nificant role and inimmunosuppressive
the regulation of chronic actionspain of[130].
cortisolThe[135].
GCCDysfunctional
is essential for modula
GCC signaling is implicated
the in chronicand
anti-inflammatory painimmunosuppressive
disorders, such as fibromyalgia
actions of and neuropathic
cortisol [135]. Dysfuncti
pain, where alterations
GCC signaling in GCC is expression
implicated or in sensitivity
chronic pain maydisorders,
influence such the body’s ability to and ne
as fibromyalgia
control inflammation
pathic pain,andwhere
modulate the nociceptive
alterations response [135].
in GCC expression or sensitivity may influence the bo
Stress adaptation encompasses the hypothalamic–pituitary–adrenocortical
ability to control inflammation and modulate the nociceptive response (HPA)[135].
axis,
where glucocorticoids are released upon activation to reallocate energy
Stress adaptation encompasses the hypothalamic–pituitary–adrenocortical (H resources [136].
Corticotropin-releasing
axis, wherehormone (CRH) production
glucocorticoids are released in upon
the hypothalamic
activation toparaventricular
reallocate energy resou
nucleus (PVN) constitutes
[136]. a key neuronal mechanism
Corticotropin-releasing hormoneunderlying HPA stress in
(CRH) production response [136].
the hypothalamic p
Chronic stress can activate the HPA axis through heightened stress responses,
ventricular nucleus (PVN) constitutes a key neuronal mechanism underlying HPA s persistent
basal hypersecretion,
responseand adrenal
[136]. depletion,
Chronic stress with the manifestation
can activate the HPA axis of this reactionheightened
through depen- stres
dent on various factors. Distinct brain mechanisms may govern chronic stress
sponses, persistent basal hypersecretion, and adrenal depletion, with the manifestatio responses
compared to this
acute ones, involving
reaction dependent theonactivation of newDistinct
various factors. limbic, brain
hypothalamic,
mechanisms andmaybrain-
govern chr
stem circuits stress
[137]. responses
Whether an individual’s acute or chronic stress reactions
compared to acute ones, involving the activation of new limbic, hypoare maladap-
tive or adaptive depends
lamic, on factors such
and brainstem as age,
circuits [137].sex, early lifeanexperiences,
Whether individual’s environment,
acute or chronic s
and heredity.
Understanding the intricate interplay between the HPA axis, glucocorticoid signaling,
and stress responses underscores the need for a comprehensive approach to chronic pain
management that considers the multifaceted nature of stress-induced alterations in the
Cells 2023, 12, 2726 13 of 18

body’s regulatory systems [130]. Investigating the intricate interactions among chronic
stress, the GCC/HPA axis, and chronic pain holds promise for identifying novel targets in
pain treatment. The intricate relationship between cortisol and chronic pain is crucial for
developing effective pain management strategies [130].

9. Conclusions
In conclusion, cortisol, a pivotal glucocorticoid hormone produced by the adrenal
glands, is integral to numerous physiological processes. Its release is intricately regulated
by the suprachiasmatic nucleus, governing the circadian rhythm and activating the complex
hypothalamic–pituitary–adrenal (HPA) axis, a vital neuroendocrine system responsible
for stress response and maintaining homeostasis. Disruptions in cortisol regulation due
to chronic stress, disease, and aging have profound implications for multiple bodily sys-
tems. Animal models have been essential in unraveling these complex cortisol dynamics
during stress, shedding light on the interplay between physiological, neuroendocrine, and
immune factors in the stress response. These models have also revealed the impact of
various stressors, including social hierarchies, highlighting the role of social factors in
cortisol regulation. There is a big spectrum of psychosomatic diseases that are a result of
chronic stress; however, in this review, we focused only on the most frequent diseases that
affect the central nervous system. Chronic stress is closely linked to the progression of
diseases, like Alzheimer’s and Parkinson’s, driven by excessive cortisol production and
HPA axis dysregulation, along with neuroinflammation in the central nervous system. The
relationship between cortisol dysregulation and major depressive disorder is complex,
characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is
associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility
and are closely related to depression. Understanding these multifaceted mechanisms and
their effects is essential, as they offer insights into potential interventions to mitigate the
detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

Author Contributions: Conceptualization, N.N.K.; writing—original draft preparation, E.K., K.N.

and V.M.; writing—review and editing, E.K., K.N. and N.N.K.; visualization, E.K. and K.N.; super-
vision, N.N.K.; project administration, N.N.K. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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