Any physical or psychological stimuli that disrupt homeostasis result in a stress response.

The
stimuli are called stressors, and physiological and behavioral changes in response to exposure to
stressors constitute the stress response. A stress response is mediated through a complex interplay
of nervous, endocrine, and immune mechanisms, activating the sympathetic-adreno-medullar
(SAM) axis, the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system.[1] The
stress response is adaptive to prepare the body to handle the challenges presented by an internal
or external environmental challenge, such as stressors. For example, the body's physiological
responses to trauma and invasive surgery serve to attenuate further tissue damage. Suppose the
exposure to a stressor is actually or perceived as intense, repetitive (repeated acute stress), or
prolonged (chronic stress). In that case, the stress response is maladaptive and detrimental to
physiology. Exposure to chronic stressors can cause maladaptive reactions, including depression,
anxiety, cognitive impairment, and heart disease.[2]
Not all forms of stress are detrimental. Some stressors are enjoyable, stimulating, and inspiring.
Termed eustress, these positive stressors replenish our energy, enhance cardiovascular health,
boost endurance, and sharpen cognitive function. Eustress fosters mental acuity and motivation.
In contrast, distress is characterized by adverse effects on the body and mind.
Stress is categorized into various types based on duration, source, and response.
 Acute stress: The short-term stress that typically results from immediate stressors or
challenging situations. The body's fight-or-flight response leads to temporary
physiological changes such as increased heart rate and adrenaline release.
 Chronic stress: This occurs when the stressor persists over an extended period. Prolonged
exposure to chronic stress can lead to cumulative physiological and psychological effects,
increasing the risk of health problems such as cardiovascular disease, anxiety, and
depression.
 Episodic acute stress: The stress occurs when individuals experience frequent episodes of
acute stress. This pattern may be characteristic of individuals who lead chaotic or
disorganized lifestyles, constantly facing deadlines, commitments, or interpersonal
conflicts. The cycle of stress exacerbates health issues and impairs daily functioning.
 Traumatic stress: This type results from exposure to traumatic events, such as natural
disasters, accidents, or violent acts. The trauma overwhelms an individual's ability to cope
and may lead to symptoms of posttraumatic stress disorder (PTSD), including intrusive
memories, avoidance behaviors, and hyperarousal.
 Environmental stress: This type arises from adverse or challenging conditions in one's
surroundings, including noise, pollution, overcrowding, or unsafe living conditions. These
stressors can have detrimental effects on physical and mental health, contributing to a
sense of discomfort or unease.
 Psychological stress: The stress stems from cognitive or emotional factors, such as
perceived threats, worries, or negative thoughts. Typical stressors include work-related
pressures, academic expectations, social comparisons, or self-imposed demands.
Manifestations include anxiety, rumination, or perfectionism.
  Physiological stress: Physiological stress refers to the body's response to internal or
external stressors that disrupt homeostasis. Examples include illness, injury, sleep
deprivation, or nutritional deficiencies, which activate physiological stress pathways and
compromise health and well-being.[3][4][5][6]
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Cellular Level
The physiology of stress response has 2 components—a slow response mediated by the HPA axis
and a fast response mediated by the SAM axis.
Sympathetic-Adreno-Medullar System
The quick response triggered by SAM activation leads to increased secretion of norepinephrine
and epinephrine from the adrenal medulla into the circulation and increased secretion of
norepinephrine from the sympathetic nerves, resulting in elevated levels of norepinephrine in the
brain.[7] The released epinephrine and norepinephrine interact with α- and β-adrenergic receptors
in the central nervous system and on the cell membrane of smooth muscles and other organs
throughout the body. When released, norepinephrine and epinephrine bind to specific membrane-
bound G-protein receptors to initiate an intracellular cyclic adenosine monophosphate (cAMP)
signaling pathway that rapidly activates cellular responses. The activation of these receptors
results in the contraction of smooth and cardiac muscle cells, leading to vasoconstriction,
increased blood pressure, heart rate, cardiac output, skeletal muscle blood flow, increased sodium
retention, increased levels of glucose due to glycogenolysis and gluconeogenesis, lipolysis,
increased oxygen consumption, and thermogenesis. The physiological response also reduces
intestinal motility, cutaneous vasoconstriction, and bronchiolar dilatation. In addition, SAM
activation causes behavioral activation, such as enhanced arousal, alertness, vigilance, cognition,
focused attention, and analgesia.
Hypothalamic-Pituitary-Adrenal System
The slow response is due to the activation of the HPA axis, releasing corticotropin-releasing
hormone (CRH) from the paraventricular nucleus of the hypothalamus into the circulation. The
CRH released from the hypothalamus acts on 2 receptors—CRH-R1 and CRH-R2. CRH-R1,
widely distributed in the mammalian brain, is the key receptor for the stress-induced
adrenocorticotropic hormone (ACTH) release from the anterior pituitary. CRH-R2 is expressed
primarily in peripheral tissues, including skeletal muscles, gastrointestinal tract, and heart, and in
subcortical structures of the brain. CRH-binding protein (CRH-BP) has a greater binding affinity
with CRH compared to receptors. CRH-BP is expressed in the liver, pituitary gland, brain, and
placenta.[8] The role of CRH-BP as a controller of the bioavailability of CRH is supported by
studies finding that CRH-BP binds 40% to 60% of CRH in the brain.[9] In exposure to stress, the
expression of CRH-BP increases in a time-dependent manner, a negative feedback mechanism to
decrease the interaction of CRH with CRH-R1.[2] Serum cortisol level describes the body's total
cortisol level, of which 80% is bound to cortisol-binding globulin and 10% is bound to albumin.
Unbound cortisol is biologically active.
The released CRH then stimulates the anterior pituitary gland to release ACTH into the
bloodstream. ACTH stimulates the adrenal cortex to secrete glucocorticoid hormones, such as
cortisol, into the circulation. The inactive form of cortisol, cortisone, is catalyzed to the active
form, cortisol, by 11-β-hydroxysteroid dehydrogenases (see Image. The Hypothalamic-Pituitary-
Adrenal Axis).[10]
The HPA axis is regulated by pituitary adenylate cyclase-activating polypeptide. Pituitary
adenylate cyclase-activating polypeptide may play a role in the production of CRH and modulate
multiple levels of the HPA axis. Evidence also points to the involvement in the autonomic
response to stress through increased secretion of catecholamines.[11] The pituitary adenylate
cyclase-activating polypeptide receptors are G-protein coupled, and the R1 receptor is the most
abundant in both central and peripheral tissues. This polypeptide may also modulate estrogen's
role in potentiating the acute stress response.[12]
After CRH is released, the hormone binds with CRH-BP because CRH has a higher affinity with
CRH-BP compared to the receptors. CRH-BP is expressed in the liver, pituitary gland, brain, and
placenta.[5] The role of CRH-BP as a controller of the bioavailability of CRH is supported by
studies finding that CRH-BP binds 40% to 60% of CRH in the brain.[6] In exposure to stress, the
expression of CRH-BP increases in a time-dependent manner, which is believed to be a negative
feedback mechanism that decreases the interaction of CRH with CRH-R1.[2] Serum cortisol level
describes the body's total cortisol level, of which 80% is bound to cortisol-binding globulin and
10% is bound to albumin. Unbound cortisol is biologically active.
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Organ Systems Involved

Stress generally affects all body systems, including cardiovascular, respiratory, endocrine,
gastrointestinal, nervous, muscular, and reproductive systems. The endocrine system
increases the production of steroid hormones, including cortisol, to activate the body's stress
response. In the nervous system, stress triggers the sympathetic nervous system, prompting the
adrenal glands to release catecholamines. Once the acute stress-induced crisis subsides, the
parasympathetic nervous system aids in the body's recovery.
Cardiovascular System
Acute stress causes an increase in heart rate, stronger heart muscle contractions, dilation of the
heart, and redirection of blood to large muscles. In contrast, chronic stress induces sustained
activation of the sympathetic nervous system and HPA axis, leading to elevated levels of stress
hormones such as cortisol and epinephrine.[13] The presence of these stress hormones promotes
oxidative stress, endothelial dysfunction, and inflammation, thereby promoting the development
of atherosclerosis and compromising vascular function. Moreover, stress-related alterations in
lipid metabolism also contribute to dyslipidemia, exacerbating cardiovascular risk.[14]
Respiratory System
The respiratory and cardiovascular systems play crucial roles in supplying oxygen to the body's
cells and eliminating carbon dioxide waste. Acute or chronic stress triggers dysregulation of the
autonomic nervous system. This dysregulation can lead to a cascade of physiological effects,
inducing bronchial hyperresponsiveness and inflammation. More importantly, acute stress can
result in changes in breathing patterns due to airway constriction, leading to shortness of breath
and rapid shallow breathing, exacerbating respiratory symptoms. Chronic stress also
compromises immune function, increasing susceptibility to respiratory infections and
exacerbating conditions such as asthma and chronic obstructive pulmonary disease. Furthermore,
stress-induced alterations in inflammatory cytokines contribute to airway inflammation and
mucus production.
Gastrointestinal System
Catecholamines, such as epinephrine and norepinephrine, released during stress profoundly affect
the gastrointestinal system. These hormones bind to adrenergic receptors distributed throughout
the gastrointestinal tract, influencing various physiological processes. By activating α-adrenergic
receptors in the smooth muscle of the intestines, they cause delayed gastric emptying and reduced
intestinal transit (motility).[15] Vasoconstriction in the gastrointestinal vasculature through α-
adrenergic receptor activation reduces blood flow to the gut, thus inhibiting gastrointestinal
secretions and nutrient absorption.[16]
Stress-induced changes in gut motility can manifest as diarrhea or constipation, whereas
increased visceral sensitivity may contribute to symptoms such as irritable bowel syndrome. In
addition, stress impairs the integrity of the gastrointestinal mucosal barrier, leading to increased
permeability and susceptibility to inflammation and infection. Dysregulation of the gut-brain
axis, mediated by stress, exacerbates gastrointestinal disorders and can worsen symptoms through
bidirectional communication between the central nervous system and the gut microbiota.
[17] Furthermore, stress-related alterations in gut microbiota composition and diversity can
further contribute to gastrointestinal dysfunction, highlighting the intricate interplay between
stress and gastrointestinal health.
Musculoskeletal System
Chronic stress elicits a cascade of physiological responses, including increased secretion of stress
hormones such as cortisol and catecholamines, which impact the musculoskeletal system.
Prolonged exposure to elevated levels of cortisol can lead to muscle wasting and decreased bone
density by inhibiting osteoblast activity and promoting osteoclast function. In addition, activation
of the stress-induced sympathetic nervous system can exacerbate musculoskeletal tension and
contribute to conditions such as tension headaches, temporomandibular joint disorders, prolonged
recovery from musculoskeletal injuries, and risk of developing conditions, including
fibromyalgia and low back pain.
Immune System
When exposure to stress is chronic, the sympathetic nervous system, including the HPA axis, is
activated, which can suppress innate and adaptive immune responses.[18] Prolonged elevation of
cortisol levels suppresses immune function by inhibiting the production of pro-inflammatory
cytokines and reducing the activity of immune cells, particularly lymphocytes. This
immunosuppressive effect can increase infection susceptibility, delay wound healing, and
exacerbate inflammatory conditions. In addition, chronic stress promotes systemic inflammation
through the upregulation of inflammatory mediators, contributing to the pathogenesis of
autoimmune diseases and chronic inflammatory disorders.[19]
Reproductive System
Chronic stress can disrupt the delicate balance of the reproductive axis by suppressing the
secretion of gonadotropin-releasing hormone from the hypothalamus, which subsequently
reduces the release of luteinizing hormone and follicle-stimulating hormone from the pituitary
gland. Consequently, this disruption impairs ovarian function in women and reduces testosterone
production in men. Chronic stress can also lead to menstrual irregularities, anovulation, and
infertility in women, and impaired sexual desire, erectile dysfunction, and decreased sperm
quality in men. In addition, stress-induced alterations in sex hormone levels and impaired
reproductive function may contribute to conditions such as polycystic ovary syndrome and male
hypogonadism.[20]
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Function
The heightened autonomic response causes an increase in heart rate and blood pressure. During
critical illness, the release of catecholamine decreases blood circulation to the gastrointestinal
tract. During stress, plasma levels of norepinephrine and epinephrine redistribute blood volume to
conserve the brain's blood supply. Stimulation of the sympathetic nervous system is varied but
includes threats to the body such as hypoglycemia, hemorrhagic shock, exercise beyond the
anaerobic threshold, and asphyxiation.[21] Epinephrine is also associated with active escape,
attack, and fear.
A stressful situation, whether environmental or psychological, can activate a cascade of stress
hormones that produce physiological changes. Activating the sympathetic nervous system in this
manner triggers an acute stress response called the fight-or-flight response. This response enables
an individual to either fight the threat or flee the situation. The rush of adrenaline and
noradrenaline secreted from the adrenal medulla leads to a widespread discharge of almost all
portions of the sympathetic system throughout the body. Physiological changes of this mass
discharge effect include increased arterial pressure, more blood flow to active muscles, less blood
flow to organs not needed for rapid motor activity, increased rate of blood coagulation, increased
rates of cellular metabolism through the body, increased muscle strength, increased mental
activity, increased blood glucose concentration, and increased glycolysis in the liver and muscle.
The net effect of all these effects allows a person to perform more strenuous activity than usual.
After the perceived threat disappears, the body returns to basal levels.
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Mechanism
Physical stress stimulates the HPA and sympathetic nervous systems. Cortisol has various
physiological effects, including catecholamine release, insulin suppression, mobilization of
energy stores through gluconeogenesis and glycogenolysis, suppression of the immune-
inflammatory response, and delayed wound healing.[22] B-cell apoptosis is an effect of the
downregulation of the immune response.[23][24] Wound healing is also delayed due to the
effects of collagen synthesis.[25] Aldosterone is a mineralocorticoid hormone that preserves
blood pressure through sodium and water retention.
Glucocorticoid-binding receptors exist in the brain as mineralocorticoid and glucocorticoid
receptors. The brain's first response to glucocorticoids is to preserve function. Glucocorticoid
hormones such as cortisol, corticosterone, and dexamethasone have various effects of conserving
energy and maintaining energy supply, such as reducing inflammation, restricting growth,
producing power, and removing unnecessary or malfunctioning cellular components.[26]
Stress response is a nuanced interplay among diverse brain centers, particularly the neural
mechanisms responsible for triggering stress reactions, which include the locus coeruleus, limbic
system, and hypothalamic efferent activation complex.[7] These components are interconnected
through various pathways, including ventral and dorsal adrenergic and serotonergic projections.
The complex includes the locus coeruleus, hippocampus, septal-hippocampal-amygdaloid
complexes, and anterior and posterior hypothalamic nuclei, serving as pivotal anatomical hubs
for visceral and somatic efferent responses to emotional stimuli.[27] Essentially, the amygdala,
particularly the central nucleus, plays a crucial role in processing emotional aspects of stress and
initiating fear responses. The hippocampus, critical for memory formation, regulates the stress
response by providing negative feedback to the hypothalamus, thus modulating cortisol release.
The prefrontal cortex, involved in executive functions, including decision-making and impulse
control, regulates stress responses through top-down inhibition of the amygdala and
hypothalamus.[28] The dysregulation of these brain centers is implicated in stress-related
disorders such as anxiety, depression, and PTSD.
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Related Testing
Various testing techniques are used to measure stress response in humans.
 Biological markers: Assessing stress hormones such as cortisol, epinephrine, and
norepinephrine levels in the blood, saliva, and urine provides objective indicators of the
physiological stress response. These markers reflect the activity of the HPA axis and the
SAM system. Sympathetic responses are also measurable through microneurography. The
microneurography technique involves the insertion of an electrode into a peripheral nerve
to measure sympathetic activity in the skin and muscles of the upper or lower limbs.
 Heart rate variability: Heart rate variability analysis assesses the variation in the time
interval between consecutive heartbeats, reflecting the balance between the sympathetic
(fight-or-flight) and parasympathetic (relaxation) nervous systems. Decreased heart rate
variability is associated with sympathetic dominance and increased stress levels, whereas
higher heart rate variability is associated with stress resilience and improved
cardiovascular health.
 Electroencephalography: This method measures brainwave activity and can accurately
gauge stress response. The findings of a study conducted in 2020 suggest that alpha
asymmetry, an imbalance in alpha brainwave activity between brain hemispheres, is a
potential stress biomarker. Mental health clinicians use neurofeedback to measure
brainwaves and provide positive feedback during treatment.
 Electrodermal activity: This is measured by skin conductance or galvanic skin response
and reflects changes in sweat gland activity in response to sympathetic arousal. Increased
electrodermal activity indicates heightened physiological arousal and stress.
  Blood pressure and heart rate: Monitoring changes in blood pressure and heart rate
provides insights into cardiovascular responses to stress, including increased sympathetic
activation and vasoconstriction.[29][30][31][32]
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Pathophysiology
General Adaptation Syndrome
General adaptation syndrome provides a framework for understanding the physiological
responses to stress and the potential consequences of chronic stress on health and well-being. The
syndrome describes the different stress-induced physiological changes through 3 different stages,
with the last 2 stages showing the pathological changes of extended stress.[33] This syndrome is
divided into the alarm reaction stage, resistance stage, and exhaustion stage.
The alarm reaction stage refers to the initial symptoms of the body under acute stress and the
fight-or-flight response. After the initial shock of the stressful event, the body begins to repair
itself by lowering cortisol levels and normalizing the physiologic reactions such as blood pressure
and heart rate. During this recovery phase, the body remains alert until the stressful event is no
longer triggering. However, if the stressful event persists for extended periods, the body adapts to
cope with higher stress levels.[34] The body continues to secrete stress hormones, which
maintain the body's elevated physical response to stress. This mechanism induces the resistance
stage and includes symptoms such as poor concentration, irritability, and frustration. If the
stressful event persists, the body enters the exhaustion stage. Symptoms of this stage include
burnout, fatigue, depression, anxiety, and reduced stress tolerance. As the stressful event persists,
the body's immune system weakens due to the suppressive effects of stress hormones on immune
system cells.
Systemic Effects of Stress
Although the restoration of homeostasis is the goal of the stress response, chronic stress leads
to dysfunctional responses, resulting in heart disease, stomach ulcers, sleep dysregulation, and
psychiatric disorders. The HPA axis may become suppressed or dysregulated in these
maladaptive responses to stress. Stress causes the cardiovascular system to respond with elevated
blood pressure and heart rate; chronic activation of this response is a significant cause of
cardiovascular disease. Coronary artery disease, stroke, and hypertension occur at a greater
incidence in individuals with stress-related psychological disorders. The release of
catecholamines in the stress response can have maladaptive effects on the gastrointestinal tract
through decreased local blood flow. Chronic stress weakens the immune system, increasing the
probability of developing Helicobacter pylori gastric ulcers and bleeding.[35] Sleep quality and
quantity affect cortisol response to acute stress. Self-reported high sleep quality showed a strong
cortisol stress response, whereas relatively good sleep quality showed a significantly weaker
cortisol response in men. Regardless of gender, a blunted cortisol response to stress was observed
in individuals experiencing difficulty staying awake and maintaining enthusiasm.[36]
Furthermore, diseases affecting the adrenal system, such as Addison's disease, Cushing's
syndrome, and pheochromocytoma, influence the body's stress mechanisms by releasing cortisol
and epinephrine. Addison's disease is characterized by a lack of glucocorticoid and/or
mineralocorticoid hormones.[37] Conversely, Cushing's syndrome is marked by hypercortisolism
due to endogenous or exogenous causes.[38] Pheochromocytomas are catecholamine-secreting
tumors of the adrenal glands.[39]
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Clinical Significance
The physiological responses of the body to stress have significant implications in various clinical
applications, such as managing healthy patients, patients with hypoadrenalism undergoing
surgery, and understanding the relationship between lifestyle changes and the stress response.
The physiological stress of surgery causes cortisol levels to rise in a positive correlation to the
severity of the surgery. In patients undergoing major surgeries as defined by the POSSUM scale,
cortisol levels return to baseline on postoperative days 1 to 5. Postoperative pain severity does
not correlate with cortisol levels after cardiac surgery.[21] A study examining cortisol levels
during minor, moderate, and major surgeries found that postoperative opiate analgesia does not
influence the stress cortisol response. For patients with hypoadrenalism who require cortisol
replacement during surgery, the varied level of cortisol secretion correlated to the stress of
surgical operations has implications.
For patients with hypoadrenalism undergoing surgery, hydrocortisone injections are administered
to mimic cortisol levels observed in individuals with normal adrenal function during surgery; this
is believed to help patients with hypoadrenalism withstand the physiological stress of surgery.
Recommendations for dosage and supplementation methods vary. European guidelines suggest
100 mg of hydrocortisone intramuscularly before anesthesia, regardless of surgery type.
Endocrine Society recommendations suggest 100 mg of hydrocortisone intravenously followed
by infusion, which is the basis of the severity of the surgery. Testing cortisol levels in surgeries of
varying severity shows that peak cortisol correlates with surgical severity, but peak cortisol
levels are lower than previously suggested.[22]
Patients in the intensive care unit are subject to physical and environmental stress, and efforts are
made to investigate the link between cortisol levels and illness recovery and to facilitate stressors
during the stay to study outcomes. Subjective patient perception of relaxation is heightened with
sleep adjuncts such as earplugs, eye masks, and relaxing music. However, these interventions did
not influence nocturnal melatonin or cortisol levels.[40]
Long-term exercise can help prevent cardiovascular disease by adapting baseline cardiac
performance. Long-term moderate exercise helps relieve stress-induced cardiovascular response
by changing baroreflex set points in the nucleus of the tractus solitarius, thereby regulating blood
pressure control and blood volume homeostasis regulated by the paraventricular nucleus.