Physiology, Stress Reaction


Article Author:
Brianna Chu
Komal Marwaha


Article Editor:
Derek Ayers


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
7/22/2019 2:51:34 PM

Introduction

The body's response to stress is to promote cell homeostasis. A stress response causes physiologic and behavioral changes that include various systems such as nervous, endocrine, and immune. Physiologic responses to stress are carried out through several pathways such as activation of the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and the behavioral fight or flight response.[1] The body's physiologic responses to trauma and invasive surgery serve to attenuate further tissue damage. Exposure to chronic stress insults can cause maladaptive reactions including depression, anxiety, cognitive impairment, and heart disease.[2] 

Cellular

The essential component in the physiology of a stress response is cortisol. Cortisol is one of the glucocorticoid hormones, which are steroid hormones synthesized from cholesterol. The inactive form, cortisone, is catalyzed to its active form, cortisol, by 11 beta-hydroxysteroid dehydrogenase 1. The HPA axis controls the release of glucocorticoids into the bloodstream.  

The HPA axis is regulated upstream by pituitary adenylate cyclase activating polypeptide (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.[3] PACAP may play a role in the production of CRH and have a modulatory role in multiple levels of the HPA axis.[4] Evidence also points to PACAP's involvement in the autonomic response to stress through increased secretion of catecholamines.[4]

The first step in increasing cortisol activity is the interaction of CRH with its receptors CRH-R1 and CRH-R2. CRH-R1 is the key receptor for ACTH release in response to stress and gets widely expressed in the brain in mammals. CRH-R2 is expressed primarily in peripheral tissues.  Cortisol releasing hormone binding protein CRH-BP binds with CRH with higher affinity to CRH to 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 from 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]

Activation of the HPA axis causes the release of corticotropin-releasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus. CRH acts on the pituitary gland to cause the release of adrenocorticotrophic hormone (ACTH), which stimulates the adrenal cortex to secrete glucocorticoid hormones into the circulation. 

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. 

Function

Physical stress engages 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.[7] An effect of downregulation of the immune response is apoptosis of B-cells.[8][9] Wound healing is also delayed through effects on collagen synthesis.[10] 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.[11]

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 include threats to the body such as hypoglycemia, hemorrhagic shock, exercise beyond the anaerobic threshold, and asphyxiation.[12] Epinephrine is also associated with active escape, attack, and immobile fear.

Related Testing

Various testing techniques are used to measure stress response in humans. The cortisol immunoassay can be used to study serum cortisone level. Sympathetic responses are measurable through microneurography and norepinephrine level. 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 preservation of homeostasis and survival are positive outcomes of the stress response, chronic stress and dysfunctional responses to stress can lead to heart disease, stomach ulcers, sleep dysregulation, and psychiatric disorders. The HPA axis may become suppressed or dysregulated in 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 GI tract through decreases in blood circulation. Reduced cell turnover and reduced secretion of mucus and bicarbonate are some mechanisms that protect against stomach acid become damaged, leading to ulceration and bleeding. Additionally, stress response causes the release of inflammatory mediators such as cytokines and oxygen-free radicals. Patients experience occult blood loss due to stress ulcers, and occult stress ulcer bleeding is prevalent in long-term stays in intensive care units. 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.[13]  Lower HPA activity measured by hair shaft cortisol was a feature in women with a history of childhood trauma and greater perceived exposure to stress as measured by the Perceived Events Scale.[14] Psychiatric disorders are related to chronic activation of the HPA. Changes in brain regions associated with stress such as the hippocampus, amygdala, paraventricular nucleus, and bed nucleus of the stria terminalis are through to contribute to anxiety disorders, PTSD, and depression.[15][16][17][14] Chronic stress can impair antibody response to vaccines.[18][8]

Addison's disease, Cushing syndrome, and pheochromocytoma are pathophysiologic changes to the body's response to stress. Patients have a lack of glucocorticoid and or mineralocorticoid hormones in Addison's Disease. Patients may present with fatigue, darkened skin, hypoglycemia, and hypotension. Lifelong hormone replacement has been found to extend the life expectancy of these patients.[19] Hypercortisolism due to endogenous or exogenous causes is observed in Cushing syndrome and may manifest with moon facies, increased central adiposity, abdominal striae, and weakness. Pheochromocytomas are catecholamine-secreting tumors of the adrenal glands. Patients present with symptoms of sympathetic overactivity, including tachycardia, resistant hypertension, headache, perspiration, and pallor. 

Clinical Significance

The body's physiologic responses to stress have significance in the clinical setting in many applications, including management of healthy and hypoadrenal 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 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.[7] Postoperative pain severity was not found to correlate with cortisol levels after cardiac surgery.[12] 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.[7] The varied level of cortisol secretion correlated to the stress of specific surgical operations has implications for hypoadrenal patients that require replacement of cortisol when undergoing surgery.

Hydrocortisone injections for hypoadrenal patients undergoing surgery are given to replicate levels in patients undergoing surgery with normal adrenal function; this is thought to help hypoadrenal patients withstand the physiologic stress of surgery. Dose recommendations vary as well as a method of supplementation.[7] 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.[7]

ICU patients are subject to physical and environmental stress, and efforts have been made to investigate the link of 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 mask, and relaxing music. However, these interventions did not influence nocturnal melatonin or cortisol level.[20]

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.


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Physiology, Stress Reaction - Questions

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A 63-year-old male presents to the emergency department with left-sided, constant, aching chest pain and pressure. EKG shows ST elevations in leads V1-V4. Heart catheterization shows a left anterior descending artery and left coronary artery occlusion. The patient undergoes open coronary artery bypass graft surgery using the left internal mammary artery. The patient receives general anesthesia, and the surgery lasts five hours. Which of the following substances is expected to decrease?



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A patient presents with a chief complaint of weight gain. She says that despite changing her diet and exercising 5 days a week, she cannot reduce the fat around her midsection. She also complains that she has gained weight in her face. An abdominal CT shows an enlargement of the adrenal gland suspicious for a mass. Which of the following most accurately describes the patient’s labs that led to her diagnosis?



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A firefighter arrives at the scene of a major forest fire. Peripheral vessels constrict, shunting blood towards the heart. Digestive activity slows. His heart rate increases to 20 beats per minute and blood pressure rise to 145/85. What substance is upregulated first?



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A 60-year-old male presents to the emergency department with right lower quadrant pain. His past medical history is significant for hypertension, hyperlipidemia, ulcerative colitis, and gastroesophageal reflux. The patient says the pain was first located in the center of his abdomen and became sharp and moved to the right as the day went on. Tenderness is elicited upon palpation of McBurney's point. Psoas sign is positive. The patient is admitted for nonoperative treatment of appendicitis with antibiotics and bowel rest. However, the next day the patient's white count increases, and he develops a new-onset fever of 101.4 F. The patient now requires an appendectomy. Which of the following statements best summarizes glucocorticoid supplementation in this patient?



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Physiology, Stress Reaction - References

References

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Ketchesin KD,Stinnett GS,Seasholtz AF, Corticotropin-releasing hormone-binding protein and stress: from invertebrates to humans. Stress (Amsterdam, Netherlands). 2017 Sep;     [PubMed]
Westphal NJ,Seasholtz AF, Gonadotropin-releasing hormone (GnRH) positively regulates corticotropin-releasing hormone-binding protein expression via multiple intracellular signaling pathways and a multipartite GnRH response element in alphaT3-1 cells. Molecular endocrinology (Baltimore, Md.). 2005 Nov;     [PubMed]
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van Gulik L,Ahlers S,van Dijk M,Bruins P,Meima ME,de Rijke YB,Biemond-Moeniralam HS,Tibboel D,Knibbe CA, Procedural pain does not raise plasma levels of cortisol or catecholamines in adult intensive care patients after cardiac surgery. Anaesthesia and intensive care. 2016 Jan;     [PubMed]
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