Introduction

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 by a complex interplay of nervous, endocrine, and immune mechanisms that involves activation of the sympathetic-adreno-medullar (SAM) axis, the hypothalamus-pituitary-adrenal (HPA) axis, and immune system.[1] The stress response is adaptive, to begin with, that prepares the body to handle the challenges presented by an internal or external environmental challenge (stressor) e.g., the body's physiologic responses to trauma and invasive surgery serve to attenuate further tissue damage. But if the exposure to a stressor is actually or perceived as intense, repetitive (repeated acute stress), or prolonged (chronic stress), the stress response becomes maladaptive and detrimental to physiology e.g., exposure to chronic stressors can cause maladaptive reactions including depression, anxiety, cognitive impairment, and heart disease.[2] 

Cellular Level

The physiology of stress response has two components; a slow response, mediated by the HPA axis,  and a fast response, mediated by the SAM axis. The fast response due to activation of SAM results in increased secretion of norepinephrine(NE) and epinephrine(E) from the adrenal medulla into the circulation and increased secretion of NE from the sympathetic nerves and thus result in elevated levels of NE in the brain. The released E and NE interact with α- adrenergic and β-adrenergic receptors, present in the central nervous system and on the cell membrane of smooth muscles, and other organs throughout the body. The norepinephrine(NE) and epinephrine(E), once released, bind to specific membrane-bound G-protein receptors to initiate an intracellular cAMP signaling pathway that rapidly activates cellular responses. Activation of these receptors results in, contraction of smooth and cardiac muscles cells leading to vasoconstriction, increased blood pressure, heart rate, cardiac output, skeletal muscle blood flow,  increased sodium retention,  increased glucose levels (due to glycogenolysis and gluconeogenesis), lipolysis, increased oxygen consumption, and thermogenesis. It also leads to reduced intestinal motility, cutaneous vasoconstriction, bronchiolar dilatation. In addition, SAM activation cases behavioral activation (enhanced arousal, alertness, vigilance, cognition, focused attention, and analgesia).

The slow response is due to activation of the HPA axis resulting in the release of Corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus into the circulation. The CRH released from the hypothalamus acts on two receptors; CRH-R1 and CRH-R2.CRH-R1 is widely expressed in the brain in mammals. It is the key receptor for the stress-induced ACTH release from the anterior pituitary. CRH-R2 is expressed primarily in peripheral tissues including skeletal muscles, gastrointestinal tract, and heart, as well as in subcortical structures of the brain. Cortisol releasing hormone binding protein CRH-BP binds with CRH with a higher affinity than CRH to its receptors. CRH-BP gets expressed in the liver, pituitary gland, brain, and placenta.[3] The role of CRH-BP as a controller of the bioavailability of CRH has support by studies finding 40 to 60% of CRH in the brain is bound by CRH-BP.[4] In exposure to stress, the expression of CRH-BP increases in a time-dependent fashion, which is thought to be 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 (CBG) and 10% is bound to albumin. Unbound cortisol is biologically active. 

The released CRH then stimulates the anterior pituitary gland to release adrenocorticotrophin hormone (ACTH) into the bloodstream. ACTH stimulates the adrenal cortex to secrete glucocorticoid hormones, such as cortisol, into the circulation. Cortisol's inactive form, cortisone, is catalyzed to its active form, cortisol, by 11 beta-hydroxysteroid dehydrogenases.

The HPA axis is regulated by pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP may play a role in the production of CRH and have a modulatory role in multiple levels of the HPA axis.[5] Evidence also points to PACAP's involvement in the autonomic response to stress through increased secretion of catecholamines.[5] The PACAP receptors are G-protein coupled and PACAP-R1 is the most abundant in both central and peripheral tissues. PACAP may also modulate estrogen's role in the potentiation of the acute stress response.[6] 

Once CRH is released, it binds with cortisol releasing hormone binding protein (CRH-BP) because CRH has a higher affinity for CRH-BP than for its receptors. CRH-BP gets expressed in the liver, pituitary gland, brain, and placenta.[5] The role of CRH-BP as a controller of the bioavailability of CRH has support by studies finding 40 to 60% of CRH in the brain is bound by CRH-BP.[6] 

In exposure to stress, the expression of CRH-BP increases in a time-dependent fashion, which is thought to be 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 (CBG) and 10% is bound to albumin. Unbound cortisol is biologically active. 

Organ Systems Involved

Stress generally affects all systems of the body including cardiovascular, respiratory, endocrine, gastrointestinal, nervous, muscular, and reproductive systems. With regards to the 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. The respiratory system works with the cardiovascular system to supply cells of the body with oxygen while removing carbon dioxide waste. Acute stress constricts the airway which leads to shortness of breath and rapid breathing. The endocrine system increases its production of steroid hormones, which include cortisol, to activate the stress response of the body. Stress can affect the gastrointestinal tract by affecting how quickly food moves through the bowels. It can also affect digestion and what nutrients the intestines absorb. With regards to the nervous system, stress will activate the sympathetic nervous system which in turn activates the adrenal glands. The parasympathetic nervous system facilitates the recovery of the body after the acute stress-induced crisis is over. Stress affects the musculoskeletal system by tensing up the muscles as a way of guarding against pain and injury. In the reproductive system, chronic stress can negatively impact sexual desire, sperm production/ maturation, pregnancy, and menstruation. 

Function

The heightened autonomic response causes an increase in heart rate and blood pressure. During critical illness, catecholamine release decreases GI tract blood circulation. Plasma levels of norepinephrine and epinephrine during times of stress redistribute blood volume to conserve the brain's supply of blood. 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.[7] Epinephrine is also associated with active escape, attack, and immobile fear.

A stressful situation, whether environmental or psychological, can activate a cascade of stress hormones that produce physiological changes. Activation of the sympathetic nervous system in this manner triggers an acute stress response called the "fight or flight" response. This enables a person to either fight the threat or flee the situation. The rush of adrenaline and noradrenaline secreted from the adrenal medulla causes almost all portions of the sympathetic system to discharge simultaneously as a widespread mass discharge effect throughout the entire body. Physiologic changes of this mass discharge effect include increased arterial pressure, more blood flow to active muscles and 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/muscle. The net effect of all these effects allows a person to perform more strenuous activity than normal. After the perceived threat disappears, the body returns to pre-arousal levels. 

Mechanism

Physical stress stimulates the HPA and sympathetic nervous system. Cortisol has various physiologic effects, including catecholamine release, suppression of insulin, mobilization of energy stores through gluconeogenesis and glycogenolysis, suppression of the immune-inflammatory response, and delayed wound healing.[8] An effect of the downregulation of the immune response is the apoptosis of B-cells.[9][10] Wound healing is also delayed through effects on collagen synthesis.[11] 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 reduction of inflammation, restriction of growth, production of energy, removal of unnecessary or malfunctioning cellular components.[12]

Related Testing

Various testing techniques are used to measure stress response in humans. The cortisol immunoassay can be used to study serum cortisone levels. Sympathetic responses are measurable through microneurography and norepinephrine levels. The microneurography technique involves the insertion of an electrode to a peripheral nerve to measure sympathetic activity in the skin and muscle of the upper or lower limbs. 

Pathophysiology

Although restoration of homeostasis is the goal of the stress response, chronic stress leads to dysfunctional responses causing 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, and chronic activation of this response is a major cause of cardiovascular disease. Coronary artery disease, stroke, and hypertension occur at a greater incidence in those with stress-related psychological disorders. The release of catecholamines in the stress response can have maladaptive effects in the gastrointestinal tract through decreased local blood flow. Chronic stress, weakens the immune system, increasing the probability of H pylori gastric ulcers and bleeding. [13]  Sleep quality and quantity affect cortisol response to acute stress. Self-reported high sleep quality showed strong cortisol stress response, and fairly good sleep quality showed significantly weaker cortisol response in men but not in women. Independent of gender, a blunted cortisol response to stress was observed in people who reported trouble staying awake and difficulty maintaining enthusiasm.[14] 

Addison's disease, Cushing syndrome, and pheochromocytoma are diseases in the adrenal system, the latter of which play a role in the body's stress mechanisms via the release of cortisol and epinephrine. Patients have a lack of glucocorticoid and or mineralocorticoid hormones in Addison's disease. [15] Hypercortisolism due to endogenous or exogenous causes is observed in Cushing syndrome. [16]  Pheochromocytomas are catecholamine-secreting tumors of the adrenal glands. [17] 

General adaptation syndrome also describes the different stress-induced physiological changes through three different stages, with the last two stages showing the pathological changes of extended stress.[18] 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 responses (i.e. blood pressure and heart rate). During this recovery phase, the body remains on alert until the stressful event is no longer an issue. However, if the stressful event persists for extended periods of time, the body will adapt to cope with the higher level of stress. The body will continue to secrete stress hormones which keep the body's physical response to stress elevated. This induces the resistance stage and includes symptoms of poor concentration, irritability, and frustration. If the stressful event continues to persist, the body will enter 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 will continue to weaken. This is due to the suppressive effects of stress hormones on cells of the immune system.

Clinical Significance

The body's physiologic responses to stress have significance in the clinical setting in many applications, including the management of healthy and hypo adrenal surgical patients and understanding how patients' lifestyle modifications may be related to the body's stress response. 

The physiologic 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 1-5.[8] Postoperative pain severity was not found to correlate with cortisol levels after cardiac surgery.[7] Postoperative opiate analgesia was not found to affect stress cortisol response to surgery in a study of cortisol levels during minor, moderate, and major surgeries.[8] The varied level of cortisol secretion correlated to the stress of specific surgical operations has implications for hypo adrenal patients that require the replacement of cortisol when undergoing surgery.

Hydrocortisone injections for hypo adrenal patients undergoing surgery are given to replicate levels in patients undergoing surgery with normal adrenal function; this is thought to help hypo adrenal patients withstand the physiologic stress of surgery. Dose recommendations vary as well as a method of supplementation.[8] 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 that has as its basis the severity of the surgery. Testing cortisol level in surgeries of varying severity shows that peak cortisol correlates with surgical severity, but peak cortisol levels were demonstrated to be lower than previously suggested.[8]

ICU patients are subject to physical and environmental stress, and efforts have been made to investigate the link between cortisol levels and illness recovery, as well as to ameliorate stressors during the ICU stay that make it a problematic healing environment. Subjective patient perception of relaxation is heightened with the use of sleep adjuncts such as earplugs, eye masks, and relaxing music. However, these interventions did not influence nocturnal melatonin or cortisol level.[19]

Long-term exercise aids in the prevention of cardiovascular disease and adaption of baseline cardiac performance is thought to be one of the factors. Long-term moderate exercise is useful for relieving stress-induced cardiovascular response through changing baroreflex set points in the nucleus of the tractus solitarius for blood pressure control and blood volume homeostasis regulated by the paraventricular nucleus.