6. Homeostasis and the Stress Response | Handbook of Pathophysiology

Authors: Corwin, Elizabeth J.

Title: Handbook of Pathophysiology, 3rd Edition

> Table of Contents > Unit II - Effective and Ineffective Health Protection > Chapter 6 - Homeostasis and the Stress Response

Chapter 6

Homeostasis and the Stress Response

Laura Cousino Klein

Elizabeth J. Corwin

To experience stress is part of what it means to be human. Stress may cause or result from sorrow, or may accompany joy. Stress is a subjective experience that can have negative health consequences. The physiologic pathways and pathophysiologic effects of stress can be evaluated objectively and are described in this chapter.

Physiologic Concepts

Definition of Stress

Stress has been defined in many different ways for over 100 years. The modern concept of stress assumes that humans live in a world that has multiple threats (e.g., terrorism) and challenges (e.g., living in a 24-7 world) and that the ever-changing demands of daily life require constant psychological, behavioral, and physiological adjustment. Thus, stress is defined as a process in which stressors threaten an organism's safety and well-being.

Types of Stressors

Stressors include a wide scope of factors ranging from psychological (e.g., speech anxiety, worry, mental anguish) and environmental (e.g., natural disasters, socioeconomic status) to physical (e.g., exercise, trauma) and

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immunological (e.g., infection, physical disease). Stressors can be pleasant ( eustress ), as in the case of a wedding or graduation, or unpleasant ( distress ), such as losing a job. They also vary in duration (i.e., acute versus chronic) and frequency (e.g., daily versus monthly). A stressor does not always need to be physically present for a person to experience its negative consequences, as in the case of posttraumatic stress disorder (PTSD). Although they occurred in the past, remembered stressors, such as the events of September 11, 2001 or the death of a spouse, can be traumatic enough to provoke a stress response just from being recalled. While occasional stress exposure can provide stimulation and intellectual challenge, prolonged stress challenges the body's ability to maintain physical and emotional homeostasis and is associated with negative bodily responses.

Homeostasis

Homeostasis was defined by Walter B. Cannon, a noted American physiologist of the early 20th century, as the maintenance of the physiological internal environment. Stressors threaten the body's ability to maintain physiological homeostasis. The body responds to any change in internal conditions with reflexes designed to return itself to the previous state. Homeostasis is usually accomplished by activation of a negative feedback cycle. An initiating stimulus (i.e., the stressor) causes activation of a response, which then directly or indirectly leads to a lessening of the initiating stimulus. This feedback loop allows the body to remain in a dynamic steady state, whereby it continually adjusts to maintain its internal composition and function. Figure 6-1 shows a negative feedback cycle for a physical or mental stressor.

Cannon also noted the role that homeostasis plays in species survival. The fight-or-flight response, proposed in the early 1900s, is a prototypical mammalian stress response in which an organism (such as a human) either fights or flees when faced with a threat (such as a tiger) in order to survive. Thus, stressors trigger a coordinated cascade of biological and behavioral responses that are designed to ensure the safety and well-being

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of the organism. Under acute conditions, this biobehavioral cascade can be incredibly adaptive in preventing harm. In contrast, continued exposure to stressors and their consequent physiologic end products can result in damage to the body. These biobehavioral cascades are discussed in the following section.

Figure 6-1. A stressor causes a response that acts in a negative feedback manner to reduce the impact of the original stressor.

Nervous System and Hormonal Responses to Stress

The response to stress involves activation of the sympathetic nervous system and the release of various hormones and peptides, including those of the hypothalamic-pituitary-adrenal (HPA) axis, the endogenous opioid system, arginine vasopressin, and oxytocin. The stress response also affects the release of growth and reproductive hormones. These responses prepare the body to cope with or overcome the stressor and are important for the survival and well-being of the organism.

The Sympathetic Nervous System

The fight-or-flight response begins with activation of the sympathetic nervous system (SNS), a branch of the autonomic nervous system (ANS) (Fig. 6-2). Immediately following stressor exposure, the SNS responds with the release of the catecholamines epinephrine and norepinephrine from sympathetic neurons and the adrenal medulla, located in the center of the adrenal glands.

The responses to catecholamines are similar whether they are released from nerves or from the adrenal medulla. However, catecholamines released from the adrenal gland are rapidly metabolized and thus show more limited effects. Effects of the catecholamines include the following:

Figure 6-2. A simplified representation of the components of the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis stress system. CRH = corticotropin-releasing hormone, ACTH = adrenocorticotropic hormone, EPI = epinephrine, NE = norepinephrine, AVP = arginine vasopressin. Solid lines represent direct or indirect stimulatory pathways. Dashed lines represent direct or indirect inhibitory pathways. (Adapted from

Klein & Corwin, 2002.

)

Circulating and neurally released norepinephrine binds to receptors called alpha-receptors, identified as alpha1 and alpha2 receptors. Binding to alpha1 receptors present on most vascular smooth muscle cells causes the muscles to contract, leading to a decrease in blood flow to organs supplied by those vascular beds. By this means, sympathetic activation causes a decrease in blood flow to the organs of the gastrointestinal (GI) tract, the skin, and the kidneys. Decreasing blood flow to these organs ensures maximum blood flow to the brain, heart, and skeletal muscles in times of stress. Norepinephrine also binds to receptors on the smooth muscle of the GI tract, causing relaxation of the muscle and thereby slowing digestion and GI motility.
Norepinephrine release causes an increase in plasma glucose levels by increasing the breakdown and release of glucose storage forms in the liver and skeletal muscles, thereby providing the body with a ready supply of energy.
Norepinephrine released by sympathetic nerves innervating the eye causes dilation of the pupil, preparing the body for any type of attack or surprise.

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Circulating and neurally released epinephrine acts by binding not only to alpha-receptors, but also to beta-receptors, identified as ₁ and ₂. By binding to ₁ receptors on the heart, epinephrine causes an increase in heart rate and an increase in cardiac contractility, both of which serve to increase the cardiac output during stress.
Epinephrine binding to ₂ receptors in the liver and skeletal muscle causes an increase in glucose release, resulting in increased glucose available for all cells to use if fight or flight is necessary.
Epinephrine binding to ₂ receptors present on bronchiolar smooth muscle increases airflow to the lungs by relaxing the muscle, thereby opening up the air passages and facilitating oxygenation of blood for tissues that may be called on during a stressful situation.

The Hypothalamic-Pituitary Hormones

The hypothalamus is the primary structure in the brain responsible for maintaining physiologic homeostasis. It is affected by both physical and psychological stressors. Considered the master endocrine (hormonal) gland of the body, the hypothalamus controls the secretion of several important hormones. The hypothalamus also is connected through a wide neural network to other structures throughout the cerebral cortex and the limbic system. The hypothalamus is the part of the brain that is important in controlling water balance, body temperature, body growth, and hunger (Chapter 9). It is involved in monitoring and responding to feelings of rage, passion, and fear. The hypothalamus also integrates the responses of the sympathetic and parasympathetic systems. Stress affects the hypothalamus and therefore the release of several important hormones and neurotransmitters.

Overview of HPA Axis Activation

SNS activation by stress stimulates the HPA axis (see Fig. 6-2). HPA axis activation begins with the secretion of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus into the hypothalamic-pituitary portal blood flow system, which in turn stimulates the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary, as well as arginine vasopressin (AVP) from the posterior pituitary gland. While AVP acts centrally to support the fight-or-flight response, ACTH circulates to the cortex of the adrenal glands to stimulate glucocorticoid release, including release of the corticosteroids (e.g., cortisol, corticosterone). Corticosteroids themselves regulate continued HPA axis function through a negative feedback loop by dampening further CRH release from the hypothalamus and ACTH release from the anterior pituitary gland. Ultimately, these stress hormones mobilize energy stores so that an organism can adapt to the stressor.

Cortisol

The primary corticosteroid associated with stress is cortisol. Cortisol can be measured in blood, urine, feces, and saliva, and has multiple effects on

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the body, many of which allow an individual to cope with and survive a stressor. The effects of cortisol include the following:

Stimulates new formation of glucose (gluconeogenesis), which increases the availability of glucose as an energy source in times of immediate need.
Stimulates the breakdown of stored energy molecules such as fat, protein, and carbohydrate to allow mobilization of energy if immediate fight or flight is required.
Primes the body to respond to all stressors by promoting sympathetic responses, including those geared toward enhancing cardiac output and maintaining blood pressure.
Appears to affect the central nervous system. When confronted by a stressor, arousal is initiated and maintained, and the individual becomes cognitively and emotionally equipped to respond.
Regulates further HPA axis activation through a negative feedback loop by returning CRH release from the hypothalamus and ACTH release from the anterior pituitary gland toward baseline levels (see Fig. 6-2).
Stimulates gastric acid secretion, which may lead to a breakdown of the gastric mucosa.
Affects the release of other hypothalamic-releasing factors and hormones. It inhibits the gonadotropin-releasing factors that control ovulation in women and sperm production and testosterone synthesis in men.
Appears also to stimulate the release of the hypothalamic hormone somatostatin, an inhibitor of growth hormone release. It is possible that these effects of cortisol contribute to the reproductive dysfunction and growth deficiencies seen in some individuals with long-term stress.
A high level of cortisol has many effects on the immune and inflammatory reactions, all of which are geared toward reducing inflammation and immune function. For instance, cortisol inhibits the production and release of all white blood cells, blocks B cell and T cell functions, and blocks the production of interleukins, which allow for communication among white blood cells. Cortisol reduces white blood cell accumulation at sites of injury or infection, causing a reduction in the usual inflammatory reactions. As a result of its effects on the immune system, elevated levels of cortisol can cause an increased susceptibility to infection and may delay or block healing. Because of these negative effects, it is often wondered why cortisol release is stimulated during states of infection or tissue injury. It may be that a short-term release of cortisol helps to limit damage to tissues caused by inflammation, and it is only with chronic stress that harmful effects of prolonged immunosuppression become obvious.
Chronic elevations in cortisol levels are associated with destruction of hippocampal neurons, thereby leading to problems in learning, memory, and attention, as well as the development of psychiatric disorders such as episodes of repeated and severe depression.

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The Endogenous Opioid Peptides

Endogenous opioid peptides (EOPs; also called -endorphins) are derived from proopiomelanocortin (POMC), which is also the precursor for ACTH. Both ACTH and EOPs are released from the anterior pituitary. EOPs may be released directly in response to stress or following stimulation by CRH from the hypothalamus.

EOPs have several physiological functions, including effects on pain, appetite regulation, and modulation of the stress response through the HPA axis. The functions of EOPs are believed to include the following:

Reduce the perception and experience of pain (EOPs often have been called the body's natural morphine ). Prolonged exposure to pain or other stressors, however, can deplete the store of EOPs, leading to increased pain perception and despair.
Improve mood and increase feelings of well-being.
May play a role in the rewarding aspects of some drugs of abuse. For example, the U.S. Food and Drug Administration (FDA) has approved the use of naltrexone, a long-acting opioid antagonist (i.e., it blocks the effects of EOPs on the brain), in the treatment of alcoholism to curb alcohol cravings and decrease alcohol intake.
May play a role in regulating social interactions such that elevations in EOPs seem to be associated with increased social affiliation, at least for women. EOPs also may be involved in psychopathologies of social functioning such as autism.

Arginine Vasopressin (Antidiuretic Hormone)

Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is a hormone synthesized in separate magnocellular neurons of the supraoptic nuclei, paraventricular nuclei, and accessory nuclei of the hypothalamus. AVP is released from the posterior pituitary gland in response to stress and acts to support the fight-or-flight response by stimulating ACTH release (see Fig. 6-2). AVP also is an important hormone that controls salt and water handling by the kidney, stimulates the sensation of thirst, and is involved in the control of arterial blood pressure (see Chapters 13 and 18). AVP may also play a role in enhancing cognitive functioning, increasing affiliative behavior and motor behavior, and mood disorders such as depression.

Oxytocin

Structurally similar to AVP, oxytocin also is synthesized in the supraoptic nuclei, paraventricular nuclei, and accessory nuclei of the hypothalamus and is released from the posterior pituitary gland in response to stress (Fig. 6-3). Here is where the similarities between AVP and oxytocin appear to end, however. Whereas AVP plays a stimulatory role in the HPA axis response to stress, oxytocin appears to dampen the HPA axis response to stress by inhibiting ACTH and, perhaps, CRH release. This stress-dampening effect of

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oxytocin on the HPA axis has been termed the tend-and-befriend response to stress, because elevated oxytocin levels are associated with increased affiliative (friendship-oriented) behavior, which can be particularly adaptive for females in fighting stress. More specifically, the tend-and-befriend response to stress suggests that for females, a more adaptive response to some stressors may not be either fight or flight, but rather the use of social interactions to provide physical and perhaps psychological protection against a stressor. Designed to increase the likelihood of survival when faced with a threat, the tend-and-befriend response promotes safety and diminishes distress through nurturing activities that protect the female and her offspring (i.e., tending ) and creating and maintaining social networks (i.e., befriending ). Because oxytocin levels are higher in females than in males and the biobehavioral effects of oxytocin are enhanced in the presence of estrogen, oxytocin's stress-reducing effects appear to be more prominent in females. These stress-reducing effects include lowering of blood pressure, perceived stress levels, anxiety, aggression, and depression, and perhaps improved attention and memory.

Figure 6-3. The role that oxytocin plays in the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis stress system. CRH = corticotropin-releasing hormone, ACTH = adrenocorticotropic hormone, EPI = epinephrine, NE = norepinephrine.

Growth and Reproductive Hormones

Growth Hormone

Growth hormone (GH) is released from the anterior pituitary in response to a balance of stimulatory and inhibitory hormones from the hypothalamus. GH release is initially stimulated by stress and results in metabolic responses aimed at conserving energy. With prolonged stressor exposure, the release of GH is inhibited. Inhibition of GH with prolonged stress supports the clinical finding of failure to thrive in children exposed to physical or psychological abuse or neglect.

Reproductive Hormones

The reproductive hormones estrogen, progesterone, and testosterone are released primarily from the ovaries or testes in response to stimulation by gonadotropic hormones from the anterior pituitary. The gonadotropic hormones, in turn, are controlled by hormones from the hypothalamus. With prolonged stress, circulating levels of reproductive hormones may decrease, leading to reductions in fertility and libido. Similarly, the pituitary hormones prolactin and oxytocin, which are essential for breastfeeding, may be reduced during prolonged stress.

Pathophysiologic Concepts

The body's response to stress is adaptive in that it helps the organism meet the changing demands of the environment. A stress response that persists beyond the scope and timing of the challenge, however, can become maladaptive and lead to a multitude of negative health consequences.

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General Adaptation Syndrome

Endocrinologist Hans Selye's stress research, spanning a 40-year period, did much to popularize the notion of stress and to bring it to the attention of scientists in many disciplines. In doing so, he stimulated an extensive amount of research on the negative health consequences of stress. In the 1940s, Selye developed the concept of the general adaptation syndrome(GAS), a triad of stress responses that were nonspecific, he argued, because they appeared to result from any noxious or aversive event. In other words, Selye believed that all stressors, regardless of type, produced essentially the same pattern of pathophysological responding. Whereas Cannon's stress theory of fight or flight emphasized catecholamine secretion, Selye's theory emphasized adrenocortical responses to stress. The three stages of the GAS are alarm, resistance, and exhaustion.

The alarm stage begins with activation of the reticular activating system, a part of the brain spread diffusely throughout the cerebral hemispheres that controls arousal. During this stage, the body becomes alerted to the presence of the stressor, and the body's defenses are mobilized to fight or flee the stressor (the fight-or-flight response; Fig. 6-2). The fight-or-flight response depends on the release of hormones and the activation of the sympathetic nervous system.

The resistance stage includes physical and psychological defenses focused on overcoming the stressor. From the hormonal and neural defenses mobilized during the alarm stage, certain responses are selected that can best cope with that particular stressor.

The exhaustion stage is the final stage of the GAS. This stage develops only if the stressor was not adequately defeated or avoided during the resistance stage. In stage 3, the body's defenses fail and homeostasis cannot be maintained. It is during stage 3 that an individual may show the onset of certain disease states.

Seyle's GAS model has received much criticism for several reasons, including the fact that it does not take into account that one's psychological appraisal of events is an important moderator of stress reactivity (e.g., that the event is challenging rather than threatening) and that individual differences exist in one's ability to cope with stress, including personality, perceptions, and biological constitutions. Despite these criticisms, Selye's model is a key theory in the stress field.

Conditions of Disease

Stress-Related Illnesses

Stress may influence the function of several systems and processes of the body, including the immune, cardiovascular, and reproductive systems, and the digestion and metabolism of foodstuffs. The skin may also exhibit signs of stress, and the central nervous system is an integral link in recognizing and responding to all stressors.

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Because all parts of the body are affected by exposure to stressors, it is apparent why prolonged or intense physical or psychological stress can lead to changes in every organ or system. Examples of diseases or conditions that have been suggested to be stress related are shown in Box 6-1. How and if any one individual is affected by a particular stressor depends on a unique combination of genetics, personality, coping skills, current state of health and nutrition, family and social support systems, and previous experiences. Those in clinical practice see patients whose stress presents in a variety of ways, including GI upsets, headaches, skin outbreaks, hypertension, anxiety, and depression.

Clinical Manifestations

Specific clinical manifestations of the conditions mentioned in Box 6-1 are presented in chapters pertinent to the organ systems involved. Only the general clinical manifestations seen in response to a stressful situation are presented here. Clinical manifestations present during acute stress are different from the clinical manifestations present in response to chronic stress.

Acute stress is associated with:

Increased heart rate and respiratory rate
Sweating
Dilated pupils
Dry mouth
A heightened state of awareness

Chronic stress may not be associated with any changes in cardiovascular or respiratory patterns, if local reflexes compensate adequately, although at other times changes may occur, including:

Blood pressure may increase due to sympathetic stimulation of the cardiovascular system and increased arteriolar resistance.
With chronic stress, the person often appears distracted and distressed, is unable to sleep, and shows difficulty coping with the intense demands of the stressor.
Family and professional relationships may suffer.

Complications

All the conditions described in Box 6-1 can be complications of stress. In regard to the immune system, high levels of acute stress, and even moderately intense chronic stress, have been associated with an increased susceptibility to viral infections and other illnesses. Besides the direct effects of cortisol on the immune system, studies have found sympathetic nervous system innervation of immune cells in the skin, the Langerhans' cells. This finding offers a mechanism by which neural excitation may alter immune function.

Box 6-1. Examples of Stress-Related Disorders

Heart Disease/Coronary Artery Disease

Irregular heart rate and palpitations

Angina pectoris

Myocardial infarct

Elevated blood markers of coronary artery disease (e.g., elevated LDL and C-reactive protein)

Peripheral or Central Vascular Disorders

Hypertension

Stroke

Respiratory Disorders

Asthma

Hyperventilation

Gastrointestinal Disorders

Anorexia or obesity

Constipation or diarrhea

Gastric ulcer

Inflammatory bowel disease

Musculoskeletal Disorders

Headache

Backache

Reduced growth/failure to thrive

Skin Disorders

Psoriasis

Acne

Immune System Disorders

Frequent infections

Thyroid dysfunction

Autoimmune disease exacerbation

Cancer

Reproductive Disorders

Amenorrhea

Impotence

Sterility

Miscarriage

Behavioral Disorders

Dysregulated eating

Drug use (e.g., tobacco smoking, alcohol)

Aggression

Sleeplessness

Psychological Disorders

Fatigue

Anxiety

Depression

Difficulty concentrating/memory problems

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Treatment

Treatment is aimed at reducing the various symptoms of each disease or condition mentioned in Box 6-1. These types of treatments are provided in each pertinent chapter. Perhaps better therapy is to help the individual with a stress-related condition avoid or remove the stressor or to develop more adaptive coping skills. If the stressor cannot be eliminated, the individual may be advised on how to deal more effectively with it. Therapies to reduce the impact of stressors include:

If the stressor has a psychological component, the individual is encouraged to talk about his or her concern with family, friends, or a therapist. Studies have shown that having even one person to count on and talk to can reduce the health effects of acute or prolonged stress.
If the stressor is physical, interventions to reduce pain and prevent infection are essential. Pain and infection are themselves stressors; without interruption or relief, they compound the effects of the original stimulus. For physical or psychological stressors, relaxation techniques, biofeedback, and visualization therapy may help the individual reduce the impact the stressor is having on his or her life. Regular exercise is known to increase endorphin release, which may relieve the impact of stressors.

Selected Bibliography

Baum, A., Gatchel, R.J., & Krantz, D.S. (1997). Stress. In An introduction to health psychology (3^rd ed., pp. 60 107). New York: McGraw-Hill.

Baum, A., & Grunberg, N.E. (1997). Measurement of stress hormones. In S. Cohen, R.C. Kessler, & L.U. Gordon (eds.), Measuring stress: A guide for health and social scientists (pp. 175 192). New York: Oxford University Press.

Cannon, W.B. (1914). The interrelations of emotions as suggested by recent physiologic researchers. American Journal of Psychology 25, 256 282.

Cannon, W.B. (1932). The wisdom of the body. New York: Norton.

Cannon, W.B., Britton, S.W., Lewis, J.T., & Groeneveld, A. (1927). The influence of motion and emotion in medulloadrenal secretion. American Journal of Physiology 79, 433 465.

Goleman, D., & Gurin, J. (1996). Mind/body medicine: How to use your mind for better health. New York: Consumer Reports Books.

Guyton, A.C., & Hall, J.A. (2006). Textbook of medical physiology (11th ed.). Philadelphia: W.B. Saunders.

Klein, L.C., & Corwin, E.J. (2002). Seeing the unexpected: How sex differences in stress responses may provide a new perspective on the manifestation of psychiatric disorders. Current Psychiatry Reports 4, 441 448.

Mason, J.W. (1975). Emotion as reflected in patterns of endocrine integration. In L. Levi (Ed.), Emotions: Their parameters and measurement (pp.143 181). New York: Raven Press.

Porth, C.M. (2005). Pathophysiology: Concepts of altered health states (7th ed.). Philadelphia: Lippincott Williams & Wilkins.

Sapolsky, R.M. (2004). Why zebras don't get ulcers: A guide to stress, stress-related disease, and coping (3^rd ed.). New York: Freeman and Company.

Selye, H. (1946). The general adaptation syndrome and the diseases of adaptation. Journal of Clinical Endocrinology 6, 117 230.

Selye, H. (1955). Stress and disease. Science 122, 625 631.

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Selye, H. (1976). The stress of life. New York: McGraw-Hill.

Shattock, P., & Whitely, P. (2002). Biochemical aspects in autism spectrum disorders: Updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opinion on Therapeutic Targets 6, 175 183.

Taylor, S.E. (2005). Health psychology (6^th ed.). New York: McGraw-Hill.

Taylor, S.E., Klein, L.C., Lewis, B.P., Gruenewald, T.L., Gurung, R.A.R., & Updegraff, J.A. (2000). Female responses to stress: Tend-and-befriend, not fight-or-flight. Psychological Review 107, 411 429.

Tsigos, C., & Chrousos, G.P. (2002). Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of Psychosomatic Research 53, 865 871.