Stress and Disease in Modern Society (McCance Chapter)

C H AP T E R 11 Stress and Disease Lorey K. Takahashi, Kathryn L. McCance, Margaret F. Clayton CHAPTER OUTLINE Historical Background and General Concepts, 323 Concepts of Stress, Homeostasis, and Allostasis, 324 Psychoneuroimmunologic Mediators of Stress, 327 Stress Response, 327 Sympathetic Nervous System, 328 Neuroendocrine Regulation, 329 Stress, Illness, and Coping, 338 AGING and Stress: Stress-Age Syndrome, 340 To observe the obvious, modern society is full of stress. As a culture, Westerners are champions of the work ethic, a Protestant philosophy originating in the sixteenth century that views idleness as taboo. Stressful experiences include daily hassles, major life events (e.g., loss of loved one, life-threatening illness, loss of job), social isolation, early-life social deprivation, abuse, trauma, workrelated stress, work-life balance, low-socioeconomic status (SES), and many other events. For example, the pressure to remain in contact despite illness, travel, vacation, and other events that used to provide socially acceptable temporary absences is now customary in the American, and indeed global, culture. When added to other well-identiﬁed stressors, such as ﬁnancial problems, the individual may suﬀer and develop symptoms that reﬂect the socalled stress-related disorders. When thinking about stress, one must consider the factors producing a perception of stress, which begin when the brain perceives a stimulus as stressful and then, in turn, promote adaptational and survival-related physiologic responses. However, when the psychologic perception of environmental demand exceeds the adaptive capacity of the individual to cope, stress may lead to negative aﬀective and health-related disease states.1,2 Another way to think about stress involves the short- or long-term consequences of stress. Today, most researchers consider acute stress to be immunoenhancing (protective) whereas chronic, unremi ing stress is thought to be immunosuppressive (destructive).1,2 A variety of adverse life circumstances aﬀects the pool of circulating leukocytes, involves transcription with increased expression of genes that promote inﬂammation, and decreased expression of genes that promote antiviral responses.3 Chronic inﬂammation contributes to many diseases and drives contemporary morbidity and mortality. Historical Background and General Concepts Walter B. Cannon used the term stress to encompass both physiologic and psychologic ideas as early as 1914.4 He applied the engineering concept of stress and strain in a physiologic context and believed that emotional stimuli also were capable of causing stress. In 1946 Hans Selye popularized these same ﬁndings, viewing stress as a biologic phenomenon.5 Originally, Selye inadvertently discovered the biologic syndrome of stress while he was a empting to discover a new sex hormone by injecting crude ovarian extracts into rats.5 He repeatedly found that three structural changes occurred: (1) enlargement of the cortex of the adrenal gland, (2) atrophy of the thymus gland and other lymphoid structures, and (3) development of bleeding ulcers in the stomach and duodenal lining. Selye soon discovered that these manifestations were not speciﬁc to injected ovarian extracts but also occurred after he exposed the rats to other noxious stimuli, such as cold, surgical injury, and restraint. He called these stimuli stressors. Selye concluded that this triad or syndrome of manifestations represented a nonspeciﬁc response to noxious stimuli, naming it the general adaptation syndrome (GAS). He identiﬁed the three following successive stages of the GAS: (1) the alarm stage or reaction, in which the central nervous system (CNS) is aroused and the body's defenses are mobilized (e.g., “ﬁght or ﬂight”) (Fig. 11.1); (2) the stage of resistance or adaptation, during which mobilization contributes to “ﬁght or ﬂight”; and (3) the stage of exhaustion, where continuous stress causes the progressive breakdown of compensatory mechanisms (acquired adaptations) and homeostasis. Exhaustion marks the onset of certain diseases (diseases of adaptation). FIGURE 11.1 Neural Recognition and Response to Real or Predicted Stressors. CRH, Corticotrophin-releasing hormone. Initially one becomes alarmed by a stressor that activates the hypothalamus and sympathetic nervous system (see Figs. 11.1 and 11.2). The resistance or adaptation phase begins with the actions of the hormones cortisol, norepinephrine, and epinephrine. Exhaustion (also known as allostatic overload; discussed later) occurs if stress continues and adaptation is not successful, ultimately causing impairment of the immune response, heart failure, and kidney failure, leading to death. FIGURE 11.2 The Stress Response. From a physiologic perspective, what is emerging across the disciplines involved—molecular biology, immunology, neurology, endocrinology, and behavioral science—is a more holistic and complex model that involves biochemical relationships of the CNS, autonomic nervous system (ANS), the hypothalamic-pituitaryadrenal (HPA) axis (Fig. 11.3), and the immune system that causes the stress responses identiﬁed by Selye. FIGURE 11.3 Hypothalamic-Pituitary-Adrenal (HPA) Axis. The response to stress begins in the brain. The hypothalamus is the control center in the brain for many hormones including corticotropin-releasing hormone (CRH). ACTH, Adrenocorticotropic hormone. Concepts of Stress, Homeostasis, and Allostasis Selye believed that stressors cause a general or nonspeciﬁc response. However, research in the past 50 years has shown the remarkable sensitivity of the central nervous system and endocrine system to psychologic inﬂuences (emotion is included as a psychologic factor that modulates social stress). Thus, although Selye's identiﬁcation of the GAS is regarded as tremendously important and the cornerstone of stress research, the idea that stress is a purely physiologic response is vastly oversimpliﬁed. In the mid-1950s, studies showed that activation of the adrenal cortex occurred in humans in response to psychologic stressors,6 in monkeys with conditioned emotional responses,7 and in humans subjected to a stressful interview technique.8 In the early 1960s, researchers found that plasma cortisol levels increased in groups of subjects exposed to war movies and decreased while they viewed Disney nature ﬁlms.9,10 Mason later demonstrated that the initiation of the GAS depended on psychologic factors surrounding the stressors.11 He also showed that various factors, such as degrees of discomfort or unpleasantness or the suddenness of the stress, could account for the presence or absence of physiologic stress responses.11 Although the term stress was used by many disciplines and with numerous disagreements over its deﬁnition, in recent years, stress was deﬁned as a transactional or interactional concept. Transactionally, stress is viewed as the state of aﬀairs arising when a person relates to (i.e., interacts or transacts with) situations in certain ways. People are not disturbed by situations per se but by the ways they appraise and react to situations. In general, a person experiences stress when a demand exceeds a person's coping abilities, resulting in reactions such as disturbances of cognition, emotion, and behavior that can adversely aﬀect well-being. Moreover, psychologic stressors can elicit reactive or anticipatory stress responses. The reactive response is a physiologic response derived from psychologic stressors. For example, the stress of an examination may produce an increased heart rate and dry mouth in the unprepared student. The anticipatory response occurs when physiologic responses develop in anticipation of disruption of the optimal steady-state, also known as homeostasis. These anticipatory responses can be generated either by species-speciﬁc innate programs, such as reacting to the presence of predators and p g g p p unfamiliar situations, or by experience-dependent memory programs created by conditioning.12 Anticipatory responses are learned responses under ﬁne control by regions located in the brain regions most frequently associated with learning and memory and include the hippocampus, amygdala, and prefrontal cortex. In order for these regions to elicit a stress response, the paraventricular nucleus (PVN) of the hypothalamus must be stimulated. These brain structures interact with the PVN through intermediary neurons, some of which are primarily used for the reactive response. In a conditional response one learns that speciﬁc stimuli (i.e., objects or situational context) are associated with danger, and as such anticipation of subsequent encounters with the stimulus produces a physiologic stress response. For example, a child abused by a parent may experience a physiologic stress response in anticipation of further abuse when the parent enters the room. Under some circumstances these memory programs may become so strong that psychologic disorders, such as phobias, develop. In a similar fashion, some persons develop pos raumatic stress disorder (PTSD) in response to the memory, as opposed to the anticipation of traumatic events. PTSD is characterized by ﬂashback memories, sleep disturbances, depression, and other symptoms. These symptoms have the potential to greatly compromise normal activities, such as employment, personal relationships, and quality of life. Today, evidence implicates stress as a precipitating factor across a range of diseases and health conditions. The term allostasis, as opposed to homeostasis, is currently used in stress research as a be er way to understand how stress inﬂuences the development of disease. Unlike having a set point and physiologic equilibrium in Selye's homeostasis view of physiologic stress systems, the allostasis view proposes that physiologic systems are dynamic and capable of changing set-points after exposure to stress. This change in physiologic set point (e.g., chronic stress– induced elevation in cortisol secretion) may be the culprit underlying pathophysiologic conditions. Allostatic load (Fig. 11.4) is the individualized cumulative eﬀects of stressors that exist in people's lives and inﬂuence their physiologic responses. Allostatic load may result from a vulnerable physiologic/genetic makeup, lifestyle (including damaging health behaviors), daily stressful encounters, and extraordinary events (such as disasters).2,13 Over time this load exacts a toll on people's bodies (i.e., “wear and tear”). Because the brain is a key player in deciding what is stressful, it is inﬂuential in determining when they feel toxic allostatic overload. Under conditions of allostatic overload, the parasympathetic system may decrease its restraint of the sympathetic system, resulting in increased or prolonged inﬂammatory responses.2,14 Furthermore, in response to acute and chronic stress some regions of the brain (the hippocampus, amygdala, and prefrontal cortex) may respond by undergoing structural remodeling, which can alter behavioral and physiologic responses (such as cognitive impairment or depression).2 The adult brain and the developing brain possess structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover.15 Many intra- and intercellular mediators and processes are involved in changing the brain during stress and recovery from stress experiences. Examples of molecules that are necessary or permissive for brain remodeling include brain-derived neurotrophic factor (BDNF), tissue plasminogen activator (tPA), corticotropin releasing hormone (CRH), the secreted protein Lipocalin-2, and endocannabinoids (eCBs).16 Stress causes an imbalance of neural circuitry that serves cognition, decisionmaking, and anxiety and mood that can disrupt behavioral states.16 The imbalance can then aﬀect systemic physiology through neuroendocrine, autonomic, immune, and metabolic mediators.16 Key mediators and biomarkers of allostatic overload (exaggerated pathophysiologic responses to stress) include the glucocorticoid cortisol, catecholamines (released from sympathetic nervous system activation), and proinﬂammatory cytokines. A prevalent example is sleep deprivation resulting from excessive stress. Sleep deprivation has signiﬁcant damaging eﬀects, including elevated evening cortisol level; elevated insulin and blood glucose levels; increased blood pressure; reduced parasympathetic activity; p p y p y increased levels of proinﬂammatory cytokines; and increased concentrations of the gut hormone ghrelin, which stimulates appetite. Altogether, these physiologic alterations induced by the cumulative eﬀects of insomnia can lead to increased caloric intake, depressed mood, cognitive problems, and a host of other potential health issues.17 FIGURE 11.4 Physiologic and Behavioral Stress Responses. Stress processes arise from bidirectional communication patterns between the brain and other physiologic systems (autonomic, immune, neural, and endocrine). Importantly, these bidirectional mechanisms are protective, promoting short-term adaptation (allostasis). Chronic stress mechanisms, however, can lead to long-term dysregulation and promote behavioral responses and physiologic responses that lead to stress-induced disorders/diseases (allostatic load) that compromise health. (From McEwen BS: Eur J Pharmacol 583[2–3]:174–185, 2008.) As studies point increasingly to the important role that stress plays in certain disease processes, research has begun to focus on the mechanisms and interactions among social, psychologic, biologic, and behavioral risk factors responsible for these mindbody interactions. Molecular biologists, immunologists, neurologists, clinicians, and behavioral scientists are now exploring the role of the other half of the mind-body (dualistic) model—that is, the mind. What is emerging is a more holistic and complex model of health and disease states. This model involves the biochemical relationships of the central and autonomic nervous systems, the endocrine system, and their relationships to stresselicited coping behaviors that can modify the integrity of the immune system. Discoveries of these complex links have led to the creation of the ﬁeld of psychoneuroimmunology. Psychoneuroimmunologic Mediators of Stress Psychoneuroimmunology (PNI) is the study of how the consciousness (psycho), the brain and spinal cord (neuro), and the body's defenses against infection and abnormal cell division (immunology) interact. Psychoneuroimmunology assumes that all immune-mediated diseases result from interrelationships among psychosocial, emotional, genetic, and behavioral factors with the neurologic, endocrine, and immune systems.18-20 The immune system is integrated with other physiologic processes and is sensitive to changes in CNS and endocrine functioning that accompany psychologic states. Stressors (e.g., infection, noise, decreased oxygen supply, pain, malnutrition, heat, cold, trauma, prolonged exertion, radiation, responses to life events [including anxiety, depression, anger, fear, loss, and excitement], obesity, old age, drugs, disease, surgery, and medical treatment) can elicit the stress response through the action of the nervous and endocrine systems. The ﬁeld of PNI has generated a large body of research, some of which has led to strenuous scientiﬁc debate. For example, mouse models suggest a strong link between stress and breast cancer progression, yet this eﬀect is not consistently found in humans,21,22 especially with respect to the causal role of personality in cancer mortality and morbidity.21 Current understanding in the PNI ﬁeld is that hormones released by stress inﬂuence many metabolic systems and corresponding physiologic events. Furthermore, data now suggest that psychosocial stressors or interventions modulate the immune system to impact health outcomes.2,14,17,23-37 Studies support the link between psychosocial stressors and health outcomes for infectious disease and wound healing.38-43 A metaanalysis of 10 studies conducted among persons living in England found that any level of psychologic distress is associated with increased mortality and increased risk of death from cardiovascular disease, external causes, and cancer (albeit only at higher levels of distress); 68,000 persons were used in this study and personal factors, such as age, smoking, and alcohol use, were adjusted accordingly.44 Investigators studied workplace stressors and health outcomes.45 Using meta-analysis of 228 studies they found that job insecurity increases the odds of reporting poor health by about 50%, high job demands raise the odds of having a diagnosed illness by 35%, and long work hours increase mortality by almost 20%.45 Work-related stress can cause both behavioral and psychosocial problems. The World Health Organization (WHO) report focuses on the stress and health outcomes from work.46 Fig. 11.5 summarizes psychosocial hazards that may aﬀect both psychologic and physical health directly or indirectly through the experience of stress and risks for work-related stress. FIGURE 11.5 Psychosocial Work Environment and Work-Related Stress (Data from Leka S, Jain A: Health impact of psychosocial hazards at work: An overview, Geneva, 2010, Institute of W ork, Health & Organizations, University of Nottingham, W orld Health Organization.) Stress Response The perception of stress initiates a series of events in the central and peripheral nervous systems (see Fig. 11.1). In the brain, stress elicits an anticipatory response that activates the limbic system; the brain area responsible for motivation, emotions, and cognition. The limbic system also indirectly elicits both an endocrine stress response by stimulating neural pathways responsible for receiving sensory information and the release of norepinephrine from the locus ceruleus (LC). Norepinephrine release promotes arousal, increased vigilance, and anxiety, as well as other protective emotional responses. The fast-acting sympathetic adrenal medullary system in the periphery releases the catecholamines norepinephrine and epinephrine and the slower-acting HPA system culminates in the secretion of cortisol. The activation of these two stress systems redirects adaptive energy to the CNS and peripheral body sites to cope with stress (see What's New? Insights into How the Mind Aﬀects the Body). W h a t 's N e w ? Insights into How the Mind Aﬀects the Body Walter Cannon recognized nearly a century ago that stress or threat triggers the sympathetic nervous system to rapidly prepare the body for the ﬁght-or-ﬂight response. This adaptive activation of the sympathetic nervous system to eﬀectively ﬁght or ﬂee from a dangerous situation involves, to name a few, increased blood ﬂow to the heart and viscera, elevated metabolism, and pupil dilation. Catecholamine secretion from the adrenal medulla into the circulatory system plays a major role in facilitating this myriad of physiologic eﬀects. Although the adrenal medulla is well-known to be connected to sympathetic neurons that project from the thoracic spinal cord to stimulate release of epinephrine and norepinephrine, until recently how the brain inﬂuences this adrenal-medullary system has been a mystery. Using a technique to trace the pathways from the primate cerebral cortex that are linked to the adrenal medulla, Dunn and colleagues found cortical motor areas of the frontal lobe and somatosensory cortex also are involved in facilitating visceromotor and skeletomotor output. This cortical pathway coordinates the body's motor system required to cope with stress with increased metabolism through adrenal medulla catecholamine secretion. Another pathway from the medial prefrontal cortex plays a role in regulating cognitive and emotional processing. Cognitive control over a stressful situation determines the degree or intensity of adrenal medulla secretion of catecholamines. Failure to assess or cope with a stressful situation may then lead to uncontrolled emotional states, heightened activation of the sympathetic nervous system, and the onset disorders, such as pos raumatic stress disorder or chronic psychosomatic illness. In summary, this study identiﬁes key cortical brain regions involved in coordinating motor, cognitive, and emotional functions with adrenal medulla catecholamine secretion. This research oﬀers insights into the mind-body connection underlying health and psychosomatic illness. Data from Dunn RP et al: Proc Natl Acad Sci U S A 113(35):9922–9927, 2016. Sympathetic Nervous System Catecholamines Stress activates the sympathetic nervous system (SNS) to stimulate the release of catecholamines (epinephrine and norepinephrine) from the adrenal medulla into the bloodstream and nerve endings that innervate peripheral organs and tissues. The adrenal medulla is an extension of the SNS because preganglionic ﬁbers from the splanchnic nerve terminate in the medulla to innervate chromaﬃn cells that produce catecholamines. These adrenergic eﬀector molecules have multiple eﬀects on gene expression and cellular function in the nervous, endocrine, cardiovascular, gastrointestinal, respiratory, reproductive, and immune systems. Each adrenergic system regulates cellular functions through distinct receptors (α1, α2, β1, β2, β3) coupled to G-protein–mediated signal transduction pathways. For example, acute ﬁght-or-ﬂight responses increase heart rate by activating β1-adrenergic receptors in the heart muscle; blood from superﬁcial tissues is redistributed to long muscles by activating vascular α1- and β2-adrenergic receptors; respiratory rate is increased by activating bronchial α1- and β2-adrenergic receptors; energy is mobilized by activating β2- and β3-adrenergic receptors in adipose tissue and the liver; and immune cells, such as natural killer (NK) cells, are mobilized into circulation by activating β2adrenergic receptors on leukocytes.47 The physiologic eﬀects of the catecholamines on organs and tissues are summarized in Table 11.1 and Fig. 11.2. TABLE 11.1 Some of these responses require glucocorticoids (e.g., cortisol) for maximal activity (see text for explanation). * Data from Elenkov IJ, Chrousos GP: Ann N Y Acad Sci 966:290–303, 2002; Granner DK: Hormones of the adrenal medulla. In Murray RK et al, editors: Harper's biochemistry, ed 25, New York, 2000, McGraw Hill. Epinephrine is rapidly transported to and acts on several organs, but it is metabolized quickly, making it short-acting. Metabolically, epinephrine causes transient hyperglycemia (high blood glucose level), decreases glucose uptake in the muscles and other organs, and decreases insulin release from the pancreas. This is accomplished by activating enzymes whose actions promote glucose formation (gluconeogenesis) and glycogen breakdown (glycogenolysis) in the liver, while inhibiting glycogen formation. This prevents glucose from being taken up by peripheral tissue and preserves it for the CNS. Further, very li le adrenal norepinephrine reaches distal tissue; thus the eﬀects caused by norepinephrine during the stress response are primarily elicited from the SNS.48,49 Epinephrine has a greater inﬂuence on cardiac action and is the principal catecholamine involved in metabolic regulation. Epinephrine enhances myocardial contractility (inotropic eﬀect), increases heart rate (chronotropic eﬀect), and increases venous return to the heart, all of which increase cardiac output and blood pressure. Epinephrine dilates blood vessels of skeletal muscle, allowing for greater oxygenation. Epinephrine in the liver and skeletal muscles is rapidly metabolized and dilates blood vessels supplying skeletal muscles, allowing for more oxygenation. Epinephrine also mobilizes free fa y acids and cholesterol by stimulating lipolysis, freeing triglycerides and fa y acids from fat stores, and by inhibiting the degradation of circulating cholesterol to bile acids. The metabolic actions of epinephrine aid the metabolic actions of cortisol, which are similar. Table 11.2 summarizes the actions of the two subclasses of adrenergic receptors. Epinephrine binds to and activates both αand β-adrenergic receptors. Norepinephrine at physiologic concentrations binds primarily to α-adrenergic receptors.50 TABLE 11.2 PHYSIOLOGIC ACTIONS OF α- AND β-ADRENERGIC RECEPTORS RECEPTOR PHYSIOLOGIC ACTIONS α1 Increased glycogenolysis; smooth muscle contraction (blood vessels, genitourinary tract) α2 Smooth muscle relaxation (gastrointestinal tract); smooth muscle contraction (some vascular beds); inhibition of lipolysis, renin release, platelet aggregation, and insulin secretion β1 Stimulation of lipolysis; myocardial contraction (increased rate, increased force of contraction) β2 Increased hepatic gluconeogenesis; increased hepatic glycogenolysis; increased muscle glycogenolysis; increased release of insulin, glucagon, and renin; smooth muscle relaxation (bronchi, blood vessels, genitourinary tract, gastrointestinal tract) Catecholamines can modify the numbers of cells of the immune system circulating in the blood.51 Injection of epinephrine into healthy human subjects is associated with a transient increase of the number of lymphocytes (e.g., T cells and natural killer [NK] cells) in the peripheral blood. Speciﬁcally, the levels of T cytotoxic and especially NK cells increase,51 whereas li le change occurs in the levels of B lymphocytes. Qualitatively, lymphocyte responsiveness of T and B lymphocytes is reduced. Similar quantitative and qualitative changes are found 5 to 6 minutes after exposure to a psychologic or physical stressor.52 However, the eﬀects of acute elevation of catecholamine levels on the alteration of lymphocyte function are short-lived, lasting only about 2 hours.53 Catecholamines also increase proinﬂammatory cytokine production, for example, causing increased heart rate and blood pressure. Glucocorticoids are known to inhibit this proinﬂammatory production; however, inhibition depends on dose and cell or tissue type.31 More simply, glucocorticoids can also promote inﬂammation depending on dose and cell type.14 The possibility that chronic and dysfunctional HPA axis stimulation (as may occur during chronic inﬂammation) increases inﬂammation in the brain and other tissue may contribute to other diseases, including osteoporosis, metabolic disease (diabetes, obesity), and cardiovascular disease.32 Additionally, these interactions are nonlinear and are very complex (Fig. 11.6). FIGURE 11.6 Stress Interactions Are Nonlinear and Complex. GOOD stress is shown on the left of the spectrum and involves a rapid biologic response to the stressor, followed by a rapid shutdown of the response upon cessation of the stressor. These responses support physiologic conditions that are likely to enhance protective immunity, cognitive and physical performance, and overall health. BAD stress, represented on the right of the spectrum, involves exposure to chronic or long-term biologic changes that are likely to result in dysregulation or suppression of immune function, a decrease in cognitive and physical performance, and an increased likelihood of disease. Short- and/or long-term stress is generally superimposed on a psychophysiologic RESTING ZONE of low/no stress that also represents a state of health maintenance/restoration. To maintain health, one needs to optimize GOOD stress, maximize the RESTING ZONE, and minimize BAD stress. Achieving psychologic and physiologic resilience involves a multipronged approach. Sleep of a quality and duration that helps one feel rested in the morning, a moderate and healthy diet, and consistent and moderate exercise or physical activity are three Lifestyle Factors that are likely to enable one to stay on the “good” side of the stress spectrum. Effective appraisal and coping mechanisms, genuine gratitude, social support, and compassion toward others and oneself are likely to provide Psychosocial Buffers against bad stress and enable one to stay on the “good” side of the stress spectrum. Additionally, depending on individual preferences, Activities, such as, meditation, yoga, being in nature, exercise/physical activity, music, art, craft, dance, fishing, painting, also may reduce BAD stress, extend The RESTING ZONE, and optimize GOOD stress. Such personal activities are likely to involve different strokes for different folks and need not always be meditative or reflective in nature. (Adapted from Dhabhar FS, McEwen BS: Bidirectional effects of stress on immune function: possible explanations for salubrious as well as harmful effects. In Ader R, editor: Psychoneuroimmunology IV, San Diego, 2007, Elsevier.) Parasympathetic System The parasympathetic system balances the sympathetic nervous system and, thus, it inﬂuences adaptation or maladaptation to stressful events. The parasympathetic system also has antiinﬂammatory eﬀects and opposes the sympathetic (catecholamine) responses, for example, by slowing the heart rate.14 Researchers evaluate the relative balance of the parasympathetic and sympathetic nervous systems using a technique known as heart rate variability (the measurement of R wave variability from heartbeat to heartbeat). Neuroendocrine Regulation Hypothalamic-Pituitary-Adrenal System In sequence, the PVN of the hypothalamus secretes corticotropinreleasing hormone (CRH), which binds to speciﬁc receptors on anterior pituitary cells that, in turn, produce adrenocorticotropic hormone (ACTH). ACTH is then transported through the blood to the adrenal glands located on the top of the kidneys. After binding to speciﬁc receptors on the adrenal glands, the glucocorticoid hormones (primarily cortisol; from the adrenal cortex) are released. Cortisol (hydrocortisone is a synthetically produced but chemically identical version of cortisol) initiates a series of metabolic changes (see the following section Glucocorticoids: Cortisol); however, these hormones overall are thought to enhance immunity during acute stress and suppress immunity during chronic stress because of prolonged exposure and increased concentration.1 Cortisol also sends a negative feedback signal to the pituitary and hypothalamus to terminate the HPA stress response.23 Cortisol reaches all tissues, including the brain; easily penetrates cell membranes; and reacts with numerous intracellular glucocorticoid receptors. Because they spare almost no tissue or organ and inﬂuence a large proportion of the human genome, they exert signiﬁcant diverse biologic actions.23 Glucocorticoids: Cortisol Cortisol circulates in the plasma, both protein-bound and free. The main plasma-binding protein is called transcortin or corticosteroidbinding globulin. The unbound, or free, fraction is approximately 8% of the total plasma cortisol and is biologically active.50 Cortisol mobilizes substances needed for cellular metabolism. One of the primary eﬀects of cortisol is the stimulation of gluconeogenesis, or the formation of glucose from noncarbohydrate sources, such as amino acids or free fa y acids in the liver. In addition, cortisol enhances the elevation of blood glucose level promoted by other hormones, such as epinephrine, glucagon, and growth hormone. This action by cortisol is said to be permissive for the actions of other hormones. Cortisol also inhibits the uptake and oxidation of glucose by many body cells. The overall action of cortisol increases blood glucose concentration, thereby enabling the body to combat the stressor. The physiologic eﬀects of cortisol are summarized in Table 11.3. TABLE 11.3 PHYSIOLOGIC AND ACUTE EFFECTS OF CORTISOL FUNCTIONS AFFECTED PHYSIOLOGIC EFFECTS Carbohydrate and lipid metabolism Diminishes peripheral uptake and utilization of glucose; promotes gluconeogenesis in liver metabolism cells; enhances gluconeogenic response to other hormones; promotes lipolysis in adipose tissue Protein metabolism Increases protein synthesis in liver and decreases protein synthesis (including immunoglobulin synthesis) in muscle, lymphoid tissue, adipose tissue, skin, and bone; increases plasma level of amino acids; stimulates deamination in liver Antiinﬂammatory eﬀects (systemic eﬀects) High levels of cortisol used in drug therapy suppress inﬂammatory response; inhibit proinﬂammatory activity of many growth factors and cytokines; however, over time some individuals may develop tolerance to glucocorticoids, causing an increased susceptibility to both inﬂammatory and autoimmune disease Proinﬂammatory eﬀects (possible local eﬀects) Cortisol levels released during stress response may increase proinﬂammatory eﬀects Lipid metabolism Lipolysis in extremities and lipogenesis in face and trunk Immune eﬀects Treatment levels of glucocorticoids are immunosuppressive; thus they are valuable agents used in numerous diseases; the T-cell or innate immunity system is particularly aﬀected by these larger doses of glucocorticoids with suppression of Th1 function or innate immunity; stress can cause a diﬀerent pa ern of immune response; these nontherapeutic levels can suppress innate (Th1) and increase adaptive (Th2) immunity —the so-called Th1 to Th2 shift; several factors inﬂuence this complex physiology and include long-term adaptations, reproductive hormones (i.e., overall, androgens suppress and estrogens stimulate immune responses), defects of hypothalamic-pituitary-adrenal axis, histamine-generated responses, and acute vs. chronic stress; thus stress seems to cause a Th2 shift systemically whereas locally, under certain conditions, it can induce proinﬂammatory activities and by these mechanisms may inﬂuence onset or course of infections and autoimmune/inﬂammatory, allergic, and neoplastic diseases FUNCTIONS AFFECTED PHYSIOLOGIC EFFECTS Digestive function Promotes gastric secretion Urinary function Enhances excretion of calcium Connective tissue function Decreases proliferation of ﬁbroblasts in connective tissue (thus delaying healing) Muscle function Maintains normal contractility and maximal work output for skeletal and cardiac muscle Bone function Decreases bone formation Vascular Maintains normal blood pressure; permits increased system/myocardial responsiveness of arterioles to constrictive action of adrenergic function stimulation; optimizes myocardial performance Central nervous system function Somehow modulates perceptual and emotional functioning; essential for normal arousal and initiation of daytime activity Possible synergism with estrogen in pregnancy? Suppresses maternal immune system to prevent rejection of fetus? Cortisol also aﬀects protein metabolism. It has an anabolic eﬀect; that is, it increases the rate of synthesis of proteins and ribonucleic acid (RNA) in the liver. The anabolic eﬀect of cortisol, however, is countered by its catabolic eﬀect on protein stores in other tissues. Protein catabolism acts to increase levels of circulating amino acids, and chronic exposure to excess cortisol can severely deplete protein stores in muscle, bone, connective tissue, and skin. Further, cortisol acts to reduce protein synthesis in nonhepatic tissues, a loss for which dietary protein cannot compensate. Some evidence suggests that cortisol depresses transport of amino acids into muscle cells while enhancing their uptake into the liver. Finally, cortisol promotes gastric secretion in the stomach and intestines, potentially causing gastric ulcers. This could account for the gastrointestinal ulceration observed by Selye. In contrast, norepinephrine reduces gastric secretion. Chronic Stress–Induced Effects of Glucocorticoids. Chronic secretion of glucocorticoids, along with catecholamines and the immune system, contributes to the development of the metabolic syndrome and the pathogenesis of obesity (Box 11.1). Elevated secretion of cortisol, norepinephrine (NE), epinephrine, and interleukin-6 (IL-6) promotes insulin release and decreases levels of growth and sex hormones. Over time, visceral fat increases accompanied by the loss of muscle mass (sarcopenia) and bone mass (osteoporosis).54 The increase in adipose tissue is accompanied by the secretion of IL-6 and other cytokines. As a result, a low-grade, systemic inﬂammatory state emerges that induces insulin resistance and the onset of type 2 diabetes mellitus, tumor growth, atherosclerosis, and neurodegeneration.55,56 Box 11.1 G lu co co rt ico id s, In su lin , In fla m m a t io n , a n d O b e sit y The signs and symptoms of Cushing syndrome (e.g., excess glucocorticoids [GCs]) include truncal obesity, relatively thin extremities, a “moon face,” and a “buﬀalo [neck] hump.” In such individuals the possibility of associated hypertension is high as well as increased risk of infection and metabolic syndrome or frank type 2 diabetes. In addition, the likelihood of an elevated ratio of intraabdominal subcutaneous fat mass to nonabdominal fat mass is high because the glucocorticoids mediate the redistribution of stored calories into the abdominal region. The speciﬁc increase in abdominal fat stores is a consequence of elevated levels of glucocorticoids combined with increased insulin action. However, the increased levels of glucocorticoids need not be present in the circulation, but can be generated locally in fat by conversion of inactive cortisone to active cortisol through the action of the isoenzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type-1. This conversion is referred to as “pre-receptor” metabolism of cortisol. The active steroid is secreted directly to the liver through the portal vein. In vitro insulin synthesis and secretion from the pancreas are inhibited by the glucocorticoids. However, increasing levels of glucocorticoids in vivo are associated with increasing insulin secretion possibly because of an antiinsulin eﬀect on the liver, which appears to be vulnerable to the negative eﬀects of glucocorticoids on insulin action. Hepatic insulin resistance is strongly associated with abdominal obesity. Recent data reveal that the plasma concentration of inﬂammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), is increased in the insulinresistant states of obesity and type 2 diabetes. Two mechanisms might be involved in the pathogenesis of inﬂammation: (1) glucose and macronutrient intake (i.e., which can be mediated through chronic stress) causes oxidative stress; and (2) the increased concentrations of TNF-α and IL-6 associated with obesity and type 2 diabetes might interfere with insulin signal transduction. This interference might promote inﬂammation. Chronic overnutrition (obesity) might thus be a proinﬂammatory state with oxidative stress. FIGURE Stress, Inflammation, Obesity, and Type 2 Diabetes. The induction of reactive oxygen species (ROS) generation and inflammation through the proinflammatory transcription factor, NF-κβ, activate most proinflammatory genes. Macronutrient intake, obesity, free fatty acids, infection, smoking, psychologic stress, and genetic factors increase the production of ROS. Interference with insulin signaling (insulin resistance) leads to hyperglycemia and proinflammatory changes. Proinflammatory changes increase the levels of TNF-α and IL-6, and also lead to the inhibition of insulin signaling and insulin resistance. Inflammation in pancreatic beta cells leads to beta-cell dysfunction, which in combination with insulin resistance leads to type 2 diabetes. CRP, C-reactive protein. Epidemiologic evidence suggests that prenatal stress or elevations in levels of glucocorticoids may increase the subsequent risk of disease in oﬀspring.57 One study reported that high maternal cortisol concentration during pregnancy was associated with low birth weight.58 This cortisol-induced low birth weight increases the oﬀspring's risk of disease in later life, for example, obesity; cardiovascular conditions, such as hypertension; and behavioral disorders a ributed to altered brain structure.35,58,59 Thus abnormal glucocorticoid elevation in utero dramatically aﬀects human pathophysiology and, consequently, longevity.2,23,60 The inhibitory eﬀects of chronic glucocorticoid secretion on the growth axis are caused, in part, by elevated CRH secretion, which increases somatostatin, the inhibitor of growth hormone (GH) from the pituitary. Evidence linking the role of the HPA system to growth is found in studies showing that children who experienced abuse may have decreased levels of GH and short stature, which is reversed when removed from the abusive, stressful environment and in children with Cushing syndrome where chronic exposure to glucocorticoids leads to arrested growth.61 The brain is a target of glucocorticoids and neurotransmi ers that alters physiologic, behavioral, cognitive, and immune functions. When exposed to chronic stress, speciﬁc brain regions that have glucocorticoid (GC), catecholamine, and excitatory amino acid receptors may undergo dendritic retraction or expansion, cell death, or inhibition of neurogenesis to alter the brain functions. GCs are involved in stress and circadian regulation and produce actions through the GC receptor (GR). GR can function as a nuclear transcription factor.62 Just like the nuclear genome, the mitochondria contain a small genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has found that in the brain and other systems, GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct inﬂuence on mtDNA transcription and mitochondrial physiology.62 Investigators also found that both acute and chronic stress and GC were linked with changes in the function of brain mitochondria.62 The hippocampus has GRs that support the HPA negative feedback systems. Activation of hippocampal GRs by moderate stress also may lead to temporary hippocampal dendritic shrinkage and loss of spines. However, chronic stress may lead to cell death and inhibit neurogenesis. The loss of hippocampal neurons compromises the HPA negative feedback system and promotes the chronic increase in glucocorticoid secretion. This elevated, prolonged stress-induced increase in glucocorticoids is linked to cognitive deﬁcits and major depression.16 Furthermore, chronic stress-induced elevations to glucocorticoids may be a risk factor for Alzheimer disease.63 Middle-aged women exposed to heightened stress are at increased risk of developing Alzheimer disease.64 An animal study showed that stress and glucocorticoid secretion impaired memory and increased Tau kinases and hyperphosphorylated Tau in the hippocampus and prefrontal cortex.65 This study provides insight into how the cumulative eﬀects yp g of stress and glucocorticoid exposure over time may progress to Alzheimer disease through the onset of Tau, which mediates the pathogenic actions of amyloid β. Another brain region inﬂuenced by stress is the amygdala, a major site linked to fear and anxiety. Here, chronic stress expands the dendritic ﬁeld and the synthesis of CRH neurons. The increase in amygdala CRH neurons is associated with increased fear and autonomic and HPA functioning found in anxiety disorders, such as pos raumatic stress disorder.16 The prefrontal cortex modulates higher order cognitive functions, such as abstract thinking, executive decision-making processing, and goal-directed behavior. Exposure to chronic stress causes dendritic shrinkage in the medial prefrontal cortex, which may lead to cognitive rigidity or inﬂexible thinking. However, another region, the orbitofrontal cortex, shows neurons with an expanded dendritic ﬁeld that may lead to increased fear vigilance. These alterations in the prefrontal cortex disrupt the balance between the feargenerating amygdala and cognitive control or coping with stress.16,66 People exposed to high levels of stress have high levels of HPA hormones and catecholamines, impairments in working memory, and the ability to switch to ﬂexible goal-directed behavior. Of relevance to mental disorders, stress may exacerbate the onset of schizophrenia. In addition, stress may facilitate the conversion from euthymia to bipolar disorder. In summary, the stress-induced alterations in the brain associated with emotional and cognitive disorders may develop because of an inability of the brain to readily induce synaptic changes that promote recovery and resilience. Eﬀective clinical treatments may be unlocking these inﬂexible neuronal functions and brain circuits and returning the brain to a functional state capable of generating adaptive cognitive and behavioral programs. Glucocorticoids, Stress, and the Immune System. Glucocorticoids or cortisol secretion during stress exerts beneﬁcial eﬀects by inhibiting initial inﬂammatory eﬀects, for example, vasodilation and increased capillary permeability.32 Cortisol also promotes resolution and repair. These actions are mainly accomplished by facilitating the eﬀects of GR, namely, the transcription of genetic material (through DNA binding) within leukocytes.32 Because GR is so widely expressed, glucocorticoids inﬂuence virtually all immune cells. However, whether cortisolinduced eﬀects are adaptive or destructive may depend on the intensity, type, and duration of the stressor; the tissue involved; and the subsequent concentration and length of cortisol exposure. Finally, glucocorticoids are shown to induce T-cell apoptosis.32 Cortisol acts to suppress the activity of Th1 cells, which leads to a decrease in innate immunity and the proinﬂammatory response. Cortisol also stimulates the activity of Th2 cells, which increases adaptive immunity and the antiinﬂammatory response. Epinephrine and norepinephrine have a similar eﬀect: a decrease in Th1 activity and an increase in Th2 activity. Initially, immune responses are regulated by cells of innate immunity called antigen-presenting cells (APCs), such as monocytes/macrophages, dendritic cells, and other phagocytic cells, and by Th1 and Th2 lymphocytes (cells involved in adaptive immunity). These cells secrete chemical messengers, called cytokines, that regulate innate and adaptive immune responses. Cytokines, such as interferons, interleukins, and tumor necrosis factors, can stimulate or inhibit various components of the immune system. Antigen-presenting cells also release cytokines that induce T cells to diﬀerentiate into Th1 cells. Th1 cells and APC cytokines work together to stimulate the activity of cytotoxic T cells, natural killer cells, and activated macrophages—the major components of innate immunity. These cytokines also stimulate the synthesis of nitric oxide and other inﬂammatory mediators that increase chronic delayed-type inﬂammatory responses. Because of this eﬀect, these cytokines are sometimes referred to as proinﬂammatory cytokines. The cytokines secreted by the Th2 cells act to inhibit Th1 cells and can promote adaptive immunity by stimulating the growth and activation of mast cells and eosinophils, as well as the diﬀerentiation of B-cell immunoglobulins. Thus these cytokines are g y 67 sometimes referred to as antiinﬂammatory cytokines (Fig. 11.7). Moreover, cytokines can act synergistically, antagonistically, or reciprocally. However, the roles of cytokines are highly complex and much remains unknown. Regardless, the decrease in Th1 activity and the increase in Th2 activity are sometimes called a Th1 to Th2 shift. Individuals experiencing a Th1 to Th2 shift are more likely to experience allergic responses, infections, and temporary worsening of autoimmune conditions such as arthritis. FIGURE 11.7 Effect of Corticotropin-Releasing Hormone (CRH)—Mast Cell— Histamine Axis, Cortisol, and Catecholamines on the Th1/Th2 Balance—Innate and Adaptive Immunity. Adaptive immunity provides protection against multicellular parasites, extracellular bacteria, some viruses, soluble toxins, and allergens. Innate immunity provides protection against intracellular bacteria, fungi, protozoa, and several viruses. Type 1 cytokines or proinflammatory cytokines include IL-12, interferon-gamma (IFN-γ), and tumor necrosis factoralpha (TNF-α). Type 2 cytokines or antiinflammatory cytokines include IL-10 and IL-4. Solid lines (black) represent stimulation, whereas dashed lines (blue) represent inhibition (i.e., Th1 and Th2 are mutually inhibitory, IL-12 and IFN-γ inhibit Th2, and vice versa; IL-4 and IL-10 inhibit Th1 responses). Stress and CRH modulate inflammatory/immune and allergic responses by stimulating cortisol (glucocorticoid), catecholamines, and peripheral (immune) CRH secretion and by changing the production of regulatory cytokines and histamines. CRH (peripheral, immune), CRH, Corticotropin-releasing hormone; IL, interleukin; NE, norepinephrine; NK, natural killer cell; Tc, cytotoxic T cell; Th, helper T cell. Dashed lines, decreased (inhibited); solid lines, increased (stimulation). (Redrawn from Elenkov IJ, Chrousos GP: Trends Endocrinol Metab 10:359–368, 1999.) The preceding description of the eﬀect of stress hormones on the Th1-Th2 balance may not be accurate for certain local responses.67,68 That is, the release of catecholamines (epinephrine and norepinephrine) can cause certain epithelial cells of the lung to release cytokines that promote recruitment of leukocytes, potentially enhancing inﬂammation and worsening lung function. This paradoxical stress-induced potentiation of inﬂammation in the lungs may explain why “acute respiratory distress syndrome” often develops in individuals with major infections associated with profound activity of the stress response.69 For years, stress hormones, especially glucocorticoids (cortisol), have been used therapeutically as powerful antiinﬂammatory/immunosuppressive agents. The synthetic forms of glucocorticoid hormones (exogenous types of antiinﬂammatory glucocorticoids administered for a pharmaceutical reaction) are poorly metabolized when compared to endogenous glucocorticoids, leading to a longer half-life and no circadian rhythm for these compounds. Moreover, these synthetic compounds bind to diﬀerent targets, so each has a unique eﬀect.14 Therapeutic levels of glucocorticoids inhibit the accumulation of leukocytes at the site of inﬂammation and inhibit the release of substances involved in the inﬂammatory response (i.e., kinins, plasminogen-activating factor, prostaglandins, and histamine) from the leukocytes. Glucocorticoids inhibit ﬁbroblast proliferation and function at the site of an inﬂammatory response. This inhibition accounts for the poor wound healing, increased susceptibility to infection, and decreased inﬂammatory response that often are noted in individuals with chronic glucocorticoid excess. Paradoxically, elevated levels of glucocorticoids and catecholamines (epinephrine and norepinephrine)—both endogenous and exogenously administered—may decrease innate immunity and increase autoimmune responses. These eﬀects, which can accentuate inﬂammation in general and potentially increase neuronal death (e.g., in stroke victims),14 may explain the seemingly contradictory stress response of immunosuppression and the increased risk of infection (decreased innate immunity) with a heightened antibody response and autoimmune disease (increased adaptive immunity). p y A perioperative risk factor for cancer recurrence is psychologic distress, beginning with the cancer diagnosis and following surgical and adjuvant treatment, when individuals experience stress, anxiety, and depression.70,71 Psychologic stress was reported to down-regulate cellular immune factors, including natural killer (NK) and cytotoxic T lymphocyte (CTL) activity, macrophage motility, and phagocytosis.72-75 Stress hormones, catecholamines, opioids, and glucocorticoids were relatedly shown in animal experiments to causally promote metastatic progression.76,77 Importantly, from animal experiments a single exposure to stress or stress hormones during a critical period of tumor progression could increase cancer mortality.76 Surgery, itself, profoundly suppresses cell-mediated immunity.78 Surgery, and associated neuroendocrine and paracrine responses, increased secretion of cortisol, leading to immune suppression and decreases in the number and function of NK, Th1, and CTL cells.79,80 These responses begin before surgery, are increased following surgery, and dissipate during the ﬁrst few postoperative days or weeks.80,81 Immunosuppression during the perioperative period can increase long-term cancer recurrence rates (Fig. 11.8).77,82 FIGURE 11.8 The Perioperative Period and the Excision of the Primary Tumor Can Promote the Development of Metastases. The perioperative timeframe is critical in determining long-term cancer outcomes. Various aspects of surgery, with the consequent paracrine and neuroendocrine responses and immunologic changes, can directly and indirectly affect malignant tissue. The cancer outcome is affected by surgery-related anxiety and stress, nutritional status, anesthetics and analgesics, hypothermia, blood transfusion, tissue damage, and levels of sex hormones. IL, Interleukin; M P, mononuclear phagocyte cells; NK, natural killer cells; TGF, transforming growth factor; V EGF, vascular endothelial growth factor. (Data from Horowitz M et al: Nat Rev Clin Oncol 12:213–226, 2015.) Corticotropin-Releasing Hormone (CRH) CRH inﬂuences the immune system indirectly by the activation of cortisol (glucocorticoids) and catecholamines. CRH is secreted by the hypothalamus and also peripherally at inﬂammatory sites (called peripheral [immune] CRH).26,67 Peripheral (immune) CRH is proinﬂammatory, causing an increase in vasodilation and vascular permeability.83 Therefore it appears that mast cells are the target of peripheral CRH. Mast cells release histamine, a well-known mediator of acute inﬂammation and allergic reactions (see Fig. 11.7). Recent evidence suggests that immune cells have histamine receptors and that histamine may have an eﬀect similar to that of catecholamines. This ﬁnding suggests that histamine induces acute inﬂammation and allergic reactions while suppressing Th1 activity (decreasing innate immunity) and promoting Th2 activity (increasing adaptive immunity).69,83,84 A number of stress factors initiate CRH production, including high levels of interleukin-1 (IL1) and IL-6. Increased CRH secretion facilitates cortisol secretion, which in turn inhibits further cytokine release by macrophages and monocytes. The observation that IL-1 can elicit changes in the nervous and endocrine systems by stimulating CRH production in the hypothalamus is part of a growing body of evidence demonstrating immune-induced regulation of the CNS. The release of the immune inﬂammatory mediators IL-6, tumor necrosis factoralpha (TNF-α), and interferon is triggered by bacterial or viral infections, cancer, and tissue injury that in turn initiate a stress response through the HPA pathway. Enhanced systemic production of these cytokines also induces other CNS and behavior changes during the acute phase of an infectious episode, acting either directly in a distant, systemic “endocrine” way or indirectly through the mediation of neuropeptides. These eﬀects include pyrogenesis (fever), induction of slow-wave sleep, and anorexia, which together are adaptive responses to infection and possibly cancer. Slow-wave sleep is associated with enhanced release of growth hormone (GH) and a reduction in levels of cortisol, which is beneﬁcial for tissue repair and enhanced immune response. In summary, stress can activate an excessive immune response and, through cortisol and catecholamines, suppress the Th1 response, causing a Th1 to Th2 shift. Locally, stress can exert proinﬂammatory or antiinﬂammatory eﬀects depending on the chemicals that are released in the local environment and the way that cells of the local environment respond to those chemicals. Moreover, diﬀerent types of stressors may have variable eﬀects on the immune response. Thus systemic responses to stress may cause a decrease in innate immunity and an enhancement in adaptive immunity, whereas local responses to stress, under certain conditions, may induce proinﬂammatory activities that inﬂuence the onset and cause of infectious, autoimmune/inﬂammatory, allergic, and neoplastic diseases. Other Hormones The immune system is integrated with other physiologic processes and is sensitive to changes in CNS and endocrine functioning, such as those that accompany psychologic states. For example, neuropeptide Y (NPY), a sympathetic neurotransmi er and growth factor for many cells, is a stress-mediator implicated in atherosclerosis and tissue remodeling.51 Other hormones that inﬂuence the stress response are listed in Table 11.4. Neuropeptides and hormones have a signiﬁcant eﬀect on the immune response. This eﬀect on immune function depends on the type of factor secreted, with some factors enhancing activity, some suppressing activity, and some both enhancing and suppressing activity, depending on the concentration and length of exposure, the target cell, and the speciﬁc immune function studied. TABLE 11.4 Hormones of the Female Reproductive System. The HPA axis exerts powerful, multilevel eﬀects on the female reproductive system. Stress generally inhibits the female reproductive system (Fig. 11.9), primarily through the HPA axis by (1) CRH suppression of hypothalamic gonadotropin-releasing hormone (GnRH) secretion and CRH stimulation of β-endorphin release; (2) cortisol-inhibited secretion of luteinizing hormone (LH), estradiol, progesterone, and possibly testosterone;85,86 and (3) cortisol-induced target tissue resistance by estradiol.87,88 The locus ceruleus–norepinephrine (LC/NE) system provides positive input to the reproductive system, which is frequently altered by the stress-activated HPA axis. Sexual stimulation and GnRH neuron activation, however, may cause the gonadal axis to be resistant to suppression by the HPA axis. Table 11.5 presents potential pathologic eﬀects of central and peripheral CRH in women. FIGURE 11.9 Stress and the Female Reproductive System. Interactions of the reproductive system with the hypothalamic-pituitary-adrenal (HPA) axis and locus ceruleus–norepinephrine system (LC/NE). Corticotropic cells of the pituitary gland express proopiomelanocortin (POMC) peptides. Stress generally inhibits the female reproductive system primarily through the HPA by (1) suppressing hypothalamic gonadotropin-releasing hormone (GnRH) secretion by corticotropinreleasing hormone (CRH) and CRH-induced β-endorphins; (2) inhibiting GnRH, pituitary luteinizing hormone (LH), and ovarian estradiol (E2) secretion by cortisol; and (3) enhancing cortisol-induced target tissue resistance to estradiol. The LC/NE system provides positive input to the reproductive system, which can be overridden by the stress-activated HPA. Estradiol can cause the reproductive system to stimulate the stress system by stimulating CRH secretion and inhibiting reuptake and catabolism of catecholamines. ACTH, Adrenocorticotropic hormone; FSH, follicle-stimulating hormone. Dashed lines refer to inhibitory pathways. Solid lines refer to direct stimulatory pathways. (Adapted from Chrousos GP et al: Ann Intern Med 129:229–240, 1998.) TABLE 11.5 New line of investigation: Filipcik P et al: Cell Mol Neurobiol 32(5):837–845, 2012. * Data from Chrousos GP et al: Ann Intern Med 129(3):229–240; Kalantaridou SN et al: J Reprod Immunol 62(1–2):61–68, 2004. Estrogen stimulates the HPA axis, and HPA responsiveness is greater in women than in men.88 Estrogen directly stimulates the CRH gene promoter and the central NE system, which may explain the eﬀects of estradiol ﬂuctuations on adult women's slight hypercortisolism, increases in aﬀective anxiety and eating disorders, mood cycles, and vulnerability to autoimmune and inﬂammatory disease. Estradiol down-regulates glucocorticoid receptor binding in the anterior pituitary, hypothalamus, and hippocampus, which tends to increase HPA activity by interfering with glucocorticoid-negative feedback, whereas progesterone opposes these eﬀects.89 Thus alterations in estradiol levels during normal menses, perimenopause (including increases as well as decreases), and menopause modify the regulatory feedback loop, and adaptations over time develop as a new equilibrium is established in the relationship (see Fig. 11.9). Over time, these changes increase the incidence of mood alterations, eating disorders, anxiety, depression, weight alterations, and inﬂammatory and immune disorders. Endorphins and Enkephalins. Endorphins and enkephalins (endogenous opiates) are released into the blood as part of the response to stressful stimuli. These proteins found in the brain have pain-relieving capabilities. Stressful stimuli include traumatic injury and an acute, intense stress situation, such as ﬁrst-time parachute jumping. In inﬂamed tissue, immune cell–derived endorphins activate endorphin receptors on peripheral sensory nerves, leading to pain relief or analgesia.90 Hemorrhage increases β-endorphin levels, which inhibits blood pressure increases or delays compensatory changes that increase blood pressure.91 Thus endogenous opiates modulate blood pressure instability and neuroendocrine and cytokine responses to blood losses.92,93 In conditions or activities when endogenous opiate activity increases, people not only experience insensitivity to pain but also report increased feelings of excitement, positive well-being, or euphoria. In addition, cells of the immune system synthesize and release opioids when lymphoid cells are activated.94 T and B lymphocytes and mononuclear phagocytic cells have receptors for opioids. Endorphins may play a role in the excitement and exhilaration produced by dancing, contact sports, and combat. Li le direct evidence, however, links the endorphin system to most of these activities. Prolactin. Prolactin is released from the anterior pituitary gland as well as numerous extrapituitary tissue sites. It is necessary for lactation and breast development. Prolactin receptors are present in many diﬀerent tissues, including the liver, kidney, intestine, and adrenals. Prolactin is also produced by lymphoid cells.95 Prolactin is necessary for lactation and breast development. Plasma prolactin levels also increase after exposure to a variety of stressful stimuli, including gastroscopy, proctoscopy, pelvic examination, and surgery; after taking examinations; and after receiving various sexual stimuli, for example, stimulation of the nipple or areola in women. Unlike GH, prolactin levels show li le change after exercise. However, similar to GH, prolactin secretion appears to require more intense stimuli than those leading to increases in catecholamine or cortisol levels. Immune cells also are inﬂuenced by prolactin. Prolactin acts as a second messenger for IL-2 and has a positive inﬂuence on B-cell activation and diﬀerentiation. Several classes of lymphocytes have receptors for prolactin, suggesting a direct eﬀect of prolactin on immune function. Oxytocin. Oxytocin, a peptide hormone and neurotransmi er produced in the hypothalamus, is well-known to be secreted by the posterior pituitary in females to induce parturition and lactation. In the brain, oxytocin acts on brain circuits, including the amygdala, HPA, and sympathetic nervous systems, to modulate or buﬀer fear and anxiety and a enuate the HPA stress response.96 Animal studies further indicate that oxytocin stimulates prosocial behavior, such as maternal or parental care and mother-infant bonding. In humans, oxytocin facilitates interpersonal gaze; social support; maternal care;97,98 and, when secreted during orgasm in both sexes, the prosocial hormone may promote bonding and social a achment. Some but not all studies further suggest oxytocin may have a role in promoting trust.98 In summary, oxytocin is increasingly recognized as a prosocial hormone that strengthens social relationships, social support, and protection and also a enuates psychosocial stressful events. Testosterone. Testosterone, a hormone secreted by Leydig cells, regulates male secondary sex characteristics and libido. Testosterone levels decrease after stressful stimuli. This decrease in testosterone level occurs after stimuli such as ether or anesthetic administration, surgery, marathon running, and mountain climbing. The mechanism causing decreased levels of testosterone is thought to be exerted by cortisol and β-endorphin. Psychologic stimuli also lead to a decrease in testosterone levels. Men engaged in rigorous combat training and those engaged in the ﬁrst several weeks of oﬃcer candidate school experience signiﬁcant drops in testosterone levels.99,100 However, other data have shown that the psychologic stress associated with some types of competition (e.g., pistol shooting) increases both testosterone and cortisol levels, especially in athletes older than 45 years.101 Moreover, individuals with acute illness, such as respiratory failure, burns, and congestive heart failure, show a marked reduction in plasma testosterone level.102 The direct immunologic eﬀects of sex hormones contribute to the sexual dimorphism seen in the incidence of autoimmune disease103 and the greater susceptibility to sepsis and mortality in males following injury.104 Estrogens generally are associated with a depression of T-cell–dependent immune function and an enhancement of B-cell functions, and androgens suppress both Tand B-cell responses.102 In injury, however, males produce greater amounts of proinﬂammatory cytokines, a proﬁle that is associated with poor outcome.105 Additionally, androgens appear to induce a greater degree of immune cell apoptosis following injury, a mechanism that may elicit a greater immunosuppression in injured males vs. females.106 (A list of other hormones, including melatonin, substance P, neuropeptide Y, calcitonin gene–related peptide, somatostatin, and vasoactive intestinal peptide, is contained in Table 11.4.) Stress, Illness, and Coping Cortisol secretion during stress may be beneﬁcial for several reasons. Gluconeogenesis prompted by cortisol ensures an adequate source of glucose (energy) for body tissues, and nerve cells in particular. The pooling of amino acids from catabolized proteins may ensure amino acid availability for protein synthesis in certain cells. The redistribution of protein to sites where replacement is critical, such as muscle or cells of damaged tissue, would be beneﬁcial. Short-term, cortisol-induced alterations in immune cell distribution (e.g., traﬃc) pa erns may be adaptive, with a decrease in peripheral blood cell numbers as eﬀector cells locate to sites of injury or inﬂammation. In addition, decreased immune cell activity by cortisol is beneﬁcial in some situations because it prevents immune-mediated tissue damage by prolonged cell exposure to high levels of certain cytokines. Whether cortisolinduced eﬀects are adaptive or destructive may depend on the intensity, type, and duration of the stressor, and the subsequent concentration and length of cortisol exposure that target cells of the individual experience. Extreme physiologic stressors, such as severe burn injury, represent a predictable stimulus for the stress responses described previously. A less severe and deﬁned event or situation, however, can be a stressor for one person and not for another. Many stressors, such as fasting or temperature changes, do not necessarily cause a physiologic stress response if psychologic factors are minimized. Stress itself is not an independent entity but a system of interdependent processes that are moderated by the nature, intensity, and duration of the stressor and the perception, appraisal, and coping eﬃcacy of the aﬀected individual, all of which in turn mediate the psychologic and physiologic response to stress. Further, adjustment to repetitive stressors is based on a person's appraisal of a situation.107 Illustrating the inﬂuence of an individualized stress appraisal on physiologic processes, a metaanalysis of the relationships between stressors and immunity found that a higher perception of stress was associated with reduced Tcytotoxic (Tc) cell cytotoxicity although not with levels of circulating Th or Tc lymphocytes.108 Appraisals of highly threatening stressors also are coupled to intense cognition rumination and greater inﬂammatory stress responses.109,110 Of relevance to the importance of mental well-being in the context of overall health, a recent study reported that after adjusting for age, sex, follow-up year, all psychiatric and physical conditions, and socioeconomic factors, individuals who perceived higher levels of stress were at increased risk of requiring hospitalization or rehospitalization.111 Psychosocial distress may be predictive of psychologic and physical health outcomes. In psychologic distress, the individual feels a general state of unpleasant arousal after exposure to life events that manifest as physiologic, emotional, cognitive, and behavioral changes. Periods of depression and emotional upheaval often are associated with adverse life events and place the aﬀected individual at risk for immunologic deﬁcits, increasing the risk of ill health.112 An older meta-analysis of studies demonstrates the longstanding relationship between depression and reduction in lymphocyte proliferation and NK cell activity.113 Multiple moderating factors may be important in immune modulation in depressed individuals, including comorbidities such as alcoholism. Adverse life events having the most negative eﬀect on immunity are characterized as uncontrollable, undesirable, and overtaxing the individual's ability to cope. Low socioeconomic status (SES), as indicated in terms of income, education, or occupation, is found to be associated with higher rates of mortality and morbidity. People of lower SES may be confronted with situations characterized by uncontrollable exposure to psychosocial stress or allostatic overload that increase the risk for disease by continuously activating the sympathetic and y y g y p HPA systems. Indeed, low SES individuals exhibit higher basal levels of cortisol and catecholamines than those with higher income and education.115 This association between SES and physiologic measures was independent of race, age, gender, and body mass. Evidence also points to the emerging connection between early stressful life events and a range of chronic illnesses in later life. Childhood adversity (e.g., abuse, neglect, a dysfunctional family lifestyle, low SES) increases the risk of developing cardiovascular disease, type 2 diabetes, cancer, and a number of somatic disorders. Exposure to stress-induced dysregulation of the immune system in vulnerable children may be a major factor responsible for the subsequent onset of chronic diseases and premature death116 (see What's New? How Childhood Poverty Compromises Adaptive Body and Brain Functions located on the Evolve site). It should be further noted that the developing HPA axis is hypothesized to be inﬂuenced by parental rearing styles. Inconsistent parental discipline and monitoring are related to a ﬂa er diurnal cortisol slope (e.g., lower morning and elevated evening cortisol secretion), problem behavior of children characterized by aggression and deﬁance,117 and decreased physical and mental health.1 This altered diurnal cortisol secretion pa ern is reported to be a reﬂection of chronic exposure to stress occurring in young children.118 Animal studies reported that stress contributes to the initiation, growth, and metastasis of certain tumors.119 In humans, stress aﬀects important processes in cancer including antiviral responses, deoxyribonucleic acid (DNA) repair, and aspects of cellular aging.119 The role of epigenetics and stress is an emerging ﬁeld with strong implications for the intersection between stress and disease. A very recent study suggests that breast cancer bone metastases may be inﬂuenced by chronic stress by increasing the levels of Receptor Activator of Nuclear Factor κB Ligand (RANKL) that are expressed by osteoblasts, a known chemoa ractant for RANK-expressing breast cancer cells.120 However, the overall evidence is mixed from prospective studies linking stress with cancer incidence and progression. Although stress may inﬂuence the progression and 114 p g g y p g recurrence of cancer, critical prospective studies have not always been supportive.121 Studies examining impairments in antiviral immunity and chronic activation of hormonal responses (e.g., HIVrelated tumors, hepatocellular carcinoma, and cervical cancer) may be more successful for deﬁning the stress-related mechanisms.119 Previous and current evidence show a relationship between immune stimulation and heart disease.122 The relationship between stress and cardiovascular health may be mediated by stress-induced changes in immune function, which may potentiate proinﬂammatory processes and permit alterations leading to heart disease.123 A new study of heart disease and inﬂammation demonstrates that monocytes and splenic macrophages invade atherosclerotic plaques after an initial myocardial infarction (heart a ack), rendering them unstable and as such contribute to secondary heart a acks.124 In the past decade, evidence has accumulated linking severe psychosocial stress resulting from negative life events to a chronic syndrome with mental and physical consequences. Pos raumatic stress disorder (PTSD) has been described in many populations.125127 A cascade model has been proposed to describe the pathogenesis and clinical course illustrating the clinical, epidemiologic, neurobiologic, and psychosocial components of PTSD.128 The study of PTSD has contributed to the knowledge concerning mechanisms involved in the chronic stress and disease relationship. Recently an appreciation of the association of chronic stress with high levels of cortisol production and paradoxical biounavailability (i.e., bound to plasma protein and therefore not bioavailable) of cortisol has been gained.129 Another well-documented ﬁnding is that exposure to major stressful life events, such as interpersonal loss (e.g., death of spouse, job termination) or the advent of serious healththreatening issues (e.g., cancer diagnosis, cardiovascular disease), increases the risk of major depressive disorder.130 Furthermore, studies suggest that stressors dramatically disrupt the person's life plans and goals and not only promote major depression but also increase the likelihood of developing diverse health problems that p g p may be mediated and exacerbated at least, in part, by inﬂammation, such as asthma, rheumatoid arthritis, chronic pain, certain cancers,1,131-133 and cardiovascular disease, the leading cause of death in major depression.134 This complex interplay connecting stress, depression, and inﬂammation may be understood in the context that stress is known to up-regulate proinﬂammatory cytokines.133,135 One mechanism involving proinﬂammatory cytokines on major depression is the eﬀects of TNF-α, IL-2, and IL-6 in breaking down tryptophan, the essential amino acid of serotonin synthesis.136-138 IL6 and TNF-α also may deplete serotonin levels by metabolizing to 5-hydroxyindoleacetic acid. Over time, stress-induced proinﬂammatory cytokines reduce serotonin synthesis or increase serotonin degradation that together contribute to alterations in mood, emotion, and motivational states and the eventual onset of major depression. Another contributing factor that increases the risk of stressinduced inﬂammation and depression is oxidative stress, which potentially damages or shortens the telomeres and accelerates cellular aging.139,140 Telomeres are DNA-protein complexes that cap the chromosomal DNA ends to protect the chromosome from damage. Although telomere shortening is part of the normal aging process, chronic stress accelerates telomere shortening and over time increases the risk of a number of age-related diseases, including cancer, cardiovascular disease, diabetes, obesity, Alzheimer disease, and early death.141,142 Toxic exposure to glucocorticoids and catecholamines that promote oxidation, inﬂammation, and telomere shortening also is linked to depression, bipolar, and possibly anxiety disorders, especially when exposed to childhood maltreatment or trauma.143-145 The inﬂuence of repetitive but episodic stress on cancer survivors demonstrates a connection between events such as mammography and activation of the HPA axis. Early research with breast cancer survivors by Cordova and colleagues146 demonstrated a link between sympathetic activity and HPA axis activation, noting that some women reported symptoms of PTSD (heart palpitations, p y p p p panic, shakiness, nausea) during thoughts of recurrence triggered by events such as ﬁnding themselves near the hospital where they received initial treatment.146 HPA axis activation also inﬂuences organs and tissues that enable bidirectional communication processes (feedback loops) between neuroendocrine and immune processes.147 For example, among breast cancer survivors 3 to 5 years post diagnosis, elevated baseline cortisol levels and blunted cortisol reactivity were reported in response to the anticipation of a real, regularly scheduled mammogram, and alterations in cortisol level and heart rate variability were reported in women simulating the threat of cancer with a controlled laboratory stressor.148,149 Further, Ma and colleagues148 reported that the threat of cancer recurrence (using a simulated mammography event as a stressor to elicit thoughts of cancer recurrence) elicited greater alterations in heart rate variability when compared with another simulated controlled stressor. These studies suggest activation of the autonomic nervous system to events, such as mammography, that occur repeatedly throughout breast cancer survivorship, although the timing of onset of these autonomic activation responses to a stressor is unclear. Similar ANS activation may occur in association with events particular to the management of many other types of chronic illnesses as well as interactions with the healthcare system (see What's New? A enuating the Eﬀects of Stress on Cancer). W h a t 's N e w ? A enuating the Eﬀects of Stress on Cancer Chronic exposure to psychosocial stress can compromise health by increasing inﬂammation and promoting the development of diseases including cancer. Preclinical research demonstrates that prolonged stress-induced activation of the sympathetic nervous system (SNS) increases the progression of tumors by recruiting inﬂammatory cells to tumors and forming blood vessels that provide routes for tumor cell transport. In addition, the lymphatic system, which is innervated by the SNS and involved in immune function, also may inﬂuence cancer progression by providing a means for tumor cells to disperse through the lymphatic vasculature and a source of chemokines that promote the invasion of tumor cells. Of interest, a preclinical study by Le and colleagues recently showed the eﬀects of stress on tumor lymphatic vasculature and tumor breast cancer cell progression. In this study, investigators using an animal model of chronic stress reported an increase in intratumoral lymphatic vessel density (LVD), as well as increased dilation of lymphatic vessels that drain metastatic tumor cells into the lymphatic circulation. The investigators then examined whether blocking the stress-induced eﬀects of norepinephrine on β-adrenoceptors, which are present on both tumor and inﬂammatory cells, will a enuate the increase in intratumoral LVD. Mice treated with the beta-blocker propranolol, a drug used clinically to treat hypertension, reduced stress-induced intratumoral LVD and tumor cell dissemination. The potential beneﬁts of using propranolol treatment to limit LVD were then investigated in 956 people who had breast cancer. Analysis revealed that beta-blocker treatment signiﬁcantly reduced the risk of lymph node metastasis. Thus inhibition of SNS signaling through the norepinephrine β-adrenoceptor a enuates in animal models the eﬀects of chronic stress on intratumoral LVD and metastasis in people with breast cancer. The researchers conclude the results oﬀer a promising treatment strategy to reduce the adverse eﬀects of stress-induced SNS signaling on lymphatic vascular remodeling and the progression of cancer. Data from Cole SW et al: Nat Rev Cancer 15:563–572, 2015; Le CP et al: Nat Comm 7:10634, 2016. These additional stresses may aﬀect the course of illness as well as interfere with the eﬃcacy of the medical intervention. Identifying and reducing stress in the clinical se ing have particular applicability in both disease prevention and illness management. In addition to medical procedures, patient-provider communication also provides an important area for future research. Recent studies of cancer communication and patient-provider interaction have demonstrated a link between communication events and emotional outcomes, such as uncertainty and mood state in breast cancer survivors.150,151 Although a logical extension, it remains to be seen if these emotional outcomes aﬀect physiologically based health outcomes caused by activation of the HPA axis and subsequent immune processes. As indicated previously, coping can be considered as adaptive or maladaptive. Adaptive coping strategies, especially those that are problem focused and those that encourage seeking social support, are beneﬁcial during stressful experiences. The extent to which an individual responds to distress, using eﬀective positive coping strategies, determines the degree of successful moderation of the stress challenge. Conversely, ineﬀective negative coping a empts may exacerbate the eﬀects of distress on health, thus augmenting the potential for illness. Mediating factors that may inﬂuence stress susceptibility or resilience include age, socioeconomic status, gender, social support status, personality and lifestyle, self-esteem, genetics, life events, past experiences, and current health status.152 Evidence suggests that eﬀective intervention may result in greater stress resilience and improved psychologic and physiologic outcomes. In a study of nursing home residents randomly assigned to control or social support intervention groups, improved psychologic measures and immune function (NK cell activity) were observed in the experimental group at 6 weeks.153 In another study, women with recurrent metastatic breast cancer were given either routine follow-up (routine care) or weekly support group sessions. Survival in the support treatment group was an average of 19 months longer than in the routine care group, suggesting a mediating inﬂuence of additional support for these women.26,154 The importance of social support for seriously ill individuals has focused a ention on the health and well-being of family members who function as caregivers. Signiﬁcant stress manifested as depression, anxiety, and fatigue has been noted in family caregivers p y g y g of those with cancer, Alzheimer disease, and burn trauma.155 A recent study reported that a substantial percentage of spousal or common law caregivers may be at risk of clinical depression or suﬀer from psychologic health, especially in caregivers without a sense of control, social support, and low socioeconomic income.156 Individuals and caretakers exhibited suppression of various measures of immune function, with improved function associated with be er perceived social support.157-159 Gender-based coping diﬀerences may be a ributed, in part, to the hormonal milieu of the individual, with females more likely to oﬀer social support, a behavior with an oxytocin/estrogen association.94 Interventions to prevent or manage stress-related psychologic or physical problems include both short- and long-term coping strategies. Stress management consists of educational components speciﬁc to the individual's problems and relaxation techniques, which may include meditation, imagery, massage, and biofeedback. These approaches may be used on an individual or a support group basis. Incorporation of these approaches into clinical training facilitates their use in the clinical arena. Research should focus on the eﬃcacy of such approaches with various populations (What's New? Stress and Resilience). W h a t 's N e w ? Stress and Resilience People encounter many stressful experiences in modern society. In some people, stress may induce maladaptive coping behavior accompanied by pathophysiologic disorders, whereas other people are able to overcome adversity and keep in check adaptive psychologic and physiologic functioning. This la er group of individuals is considered to be resilient to the negative, toxic eﬀects of stress and recent studies are investigating the basis of resilience. A hypothesized neuroprotective factor underlying resilience is neuropeptide Y (NPY), a neurotransmi er that modulates stress. Higher plasma NPY levels were found in Special Forces soldiers than in non–Special Forces people and predicted be er psychologic performance under stressful training situations. Another factor contributing to resilience may be testosterone. Secretion of testosterone is elevated in dominant male animals and in men who won an athletic competition. The hormone is associated with feelings of success and positive mood. In contrast, low blood levels of testosterone are found in men with pos raumatic stress disorder (PTSD) and major depressive disorder. Of further interest, testosterone may have resilient eﬀects in men compared to women who are more likely to develop PTSD and depression. Other protective hormones may include dehydroepiandrosterone (DHEA) and DHEA sulfate ester (DHEAS). These hormones, secreted by the adrenal cortex, are some of the most abundant steroid hormones and suggested to modulate fat, mineral metabolism, and sexual functioning along with antiglucocorticoid, antiinﬂammatory, and antioxidant eﬀects. Studies show that soldiers undergoing underwater navigation stress tests performed physically and cognitively be er when DHEA levels are elevated or when the DHEA-tocortisol ratio in blood is high. DHEA and DHEAS may serve to buﬀer the potential deleterious eﬀects of stress and lead to superior performance eﬀects. Another example of the potential basis of resilience is the serotonin transporter promoter polymorphism (5HTTLPR). Carriers of the “short” (S) variant, which is less transcriptionally eﬃcient than the “long” (L) variant, are vulnerable to major depression and anxiety. In contrast, people with the L allele are be er able to cope and recover from stress. An L genetic variation in 5HTTLPR appears to promote emotional resilience. Studies also demonstrate that people with high cognitive control that is associated with increased prefrontal cortex activity exhibit more appropriate emotional responses compared to people diagnosed with PTSD. Volunteers with high trait resilience show insula and amygdala activation only to aversive pictures compared to low-trait resilience participants. Resilient p p p p people appear be er able to appropriately appraise and adjust the level of emotional resources required to meet the demands of stressful situations. Programs are currently oﬀered to train and prepare people (e.g., ﬁreﬁghters, soldiers) who are likely to encounter dangerous situations by developing stress management skills, such as relaxation training. This type of training involves developing skills to manage the thoughts and perception that one will recover from stressful life events. Mindfulness-based stress reduction (MBSR) is another resilience program associated with higher levels of physical and mental health and is used as a potential treatment for PTSD, anxiety and depression disorders, and chronic pain. MBSR focuses awareness on present mental processes, such as sensations, thoughts, and feelings, in order to reduce negative emotions and improve health and coping. Overall, cognitive-based training programs play a proactive role in promoting the development of skills to become resilient to the long-term negative eﬀects of stress disorders. Data from Horn SR et al: Exp Neurol 284(Pt B):119–132, 2016; Osorio C et al: Behav Med 2016 Apr 21 [Epub ahead of print]; Russo SJ et al: Nat Neurosci 15:1475–1484, 2012. Aging and Stress: Stress-Age Syndrome A set of neurohormonal and immune alterations, as well as tissue and cellular changes, sometimes develops with aging. These changes, which recently have been deﬁned as stress-age syndrome, include the following:152,160 Alterations in the excitability of structures of the limbic system and hypothalamus Increase of the blood concentrations of catecholamines, antidiuretic hormone (ADH), ACTH, and cortisol Decrease of the concentrations of testosterone, thyroxine, and others Alterations of opioid peptide concentration Alterations in immunodepression and pa erns of chronic inﬂammation Alterations in levels of lipoproteins Hypercoagulation of the blood Free radical damage of cells Some of the alterations are adaptational, whereas others are potentially damaging. These stress-related alterations of aging can inﬂuence the course of developing stress reactions and lower adaptive reserve and coping.152 In summary, it is clear that the mind and body are connected through a multitude of complex physical and emotional interactions. Understanding the complexity of these interactions is a challenge for many researchers. Areas of promise include investigating relationships between the potential for illness with respect to stressors, as well as developing eﬀective stress management techniques and approaches that can be easily and cost-eﬀectively employed. Summary Review Historical Background and General Concepts 1. Modern society is full of stress. 2. In general, a person experiences stress when a demand exceeds a person's coping abilities. 3. Hans Selye identiﬁed three structural changes in rats subjected repeatedly to noxious stimuli (stressors): enlargement of the cortex of the adrenal gland, atrophy of the thymus gland and other lymphoid tissues, and ulceration of the gastrointestinal tract. 4. Selye believed that the three changes were caused by a nonspeciﬁc physiologic response to any long-term stressor. He called this response the general adaptation syndrome (GAS). 5. The GAS occurs in three stages: the alarm stage, the stage of resistance or adaptation, and the stage of exhaustion. Diseases of adaptation develop if the stage of resistance or adaptation does not restore homeostasis. 6. Selye identiﬁed three components of physiologic stress: the stressor, the physiologic or chemical disturbance produced by the stressor, and the body's adaptational response to the stressor. 7. It is now known that, while important, the physiologic view of stress as outlined in the GAS is an oversimpliﬁed model of stress responses. 8. The stress response is currently viewed as the product of the interaction of the mind and body and how the cumulative eﬀects of stress or allostatic overload may lead to disease and mental disorders. Allostatic overload refers to how long-term functional changes in the stress-related hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) may compromise the immune system and health of the individual. Concepts of Stress, Homeostasis, and Allostasis 1. Psychologic stress may cause or exacerbate (worsen) several disease states. Stress is related to the severity of symptoms and the outcomes of diseases and conditions. Research is focused on the mechanisms responsible for these mindbody interactions. 2. Stress has been deﬁned as the state of aﬀairs arising when a person relates to (i.e., interacts or transacts with) situations in a certain way. The way a person appraises and reacts to situations has a profound impact on stress. 3. The nonspeciﬁc physiologic response consists of interaction among the sympathetic branch of the autonomic nervous system (ANS) and other neural signals that activate the endocrine system, known as the hypothalamic-pituitaryadrenal (HPA) axis. 4. The nonspeciﬁc physiologic response is a common residual response and can be elicited with diverse agents such as cold, heat, x-rays, adrenaline, insulin, tubercle bacilli, and muscular exercise. Although the reactions of these stages are nonspeciﬁc, evidence supports the coexistence of highly speciﬁc, adaptive reactions to any of these agents. 5. As with a physically mediated stress response, psychologic stressors can elicit a reactive stress response; that is, a physiologic response can be derived from psychologic stressors. 6. Another type of psychologic-mediated stress response is the anticipatory response. 7. In a conditioned response, the organism learns that speciﬁc stimuli are associated with danger and anticipation of subsequent encounters with that particular stimulus produces a physiologic stress response (e.g., PTSD). 8. Psychoneuroimmunology (PNI) is the study of the interaction of consciousness (psycho), the brain and spinal cord (neuro), and the body's defense against external infection and abnormal cell division (immunology). 9. Psychoneuroimmunology assumes that all immune-related disease is multifactorial. The immune system is integrated with other physiologic processes and is sensitive to changes in CNS and endocrine functioning, such as those that accompany psychologic states. 10. CRH is released centrally from the brain and peripherally at inﬂammatory sites. y Stress Response 1. The stress response is initiated by the CNS and endocrine system. Where the stress response begins depends on whether the stressor is perceived or real. 2. Perceived stressors elicit an anticipatory response that usually begins in the limbic system of the brain. The limbic system elicits an endocrine stress response indirectly by stimulating neural pathways responsible for receiving sensory information and elicits a central response directly by stimulating the LC to release LC/NE. 3. Real stressors elicit a reactive response that can begin either in the limbic system or in the brain in response to speciﬁc sensory information. This information is then relayed to the paraventricular nucleus (PVN). The PVN stimulates the LC and both central and endocrine stress responses. 4. The neuroendocrine response to stress consists of sympathetic stimulation of the adrenal medulla to secrete catecholamines (norepinephrine and epinephrine) and stressor-induced stimulation of the hypothalamus to secrete CRH, which in turn stimulates the pituitary to secrete ACTH, which then stimulates the adrenal cortex to secrete steroid hormones, particularly cortisol. 5. In general, the catecholamines prepare the body to act, and cortisol mobilizes energy stores (e.g., glucose) and other substances needed to fuel the action. 6. Epinephrine exerts its chief eﬀects on the cardiovascular system. Epinephrine increases cardiac output and increases blood ﬂow to the heart, brain, and skeletal muscles by dilating vessels that supply these organs. It also dilates the airways, thereby increasing delivery of oxygen to the bloodstream. 7. Norepinephrine's chief eﬀects complement those of epinephrine. Norepinephrine constricts blood vessels of the viscera and skin; this has the eﬀect of shifting blood ﬂow to the vessels dilated by epinephrine. Norepinephrine also increases mental alertness. 8. CRH inﬂuences the immune system indirectly by the activation of glucocorticoids (cortisol) and catecholamines. Peripheral CRH is proinﬂammatory, causing vasodilation and vascular permeability. It appears that the mast cells are the target of peripheral CRH. 9. Cortisol's chief eﬀects involve metabolic processes. By inhibiting the use of metabolic substances while promoting their formation, cortisol mobilizes glucose, amino acids, lipids, and fa y acids and delivers them to the bloodstream. 10. Glucocorticoids or cortisol secretion during stress exerts beneﬁcial eﬀects by inhibiting inﬂammation and promoting resolution and repair. Paradoxically, elevated levels of glucocorticoids and catecholamines (epinephrine and norepinephrine), administered both endogenously and exogenously, can decrease innate immunity and increase autoimmune (adaptive) responses. These immunosuppressive eﬀects can accentuate inﬂammation in general and potentially increase neuronal death (e.g., in stroke victims). In addition, chronic exposure to stress alters adaptive functions throughout the body and brain to increase the risk of developing a host of diseases including obesity, the metabolic syndrome, cardiovascular disease, and cognitive impairments, such as Alzheimer disease, and mental disorders, such as major depression, schizophrenia, and pos raumatic stress disorder. 11. The nervous, endocrine, and immune systems communicate through the common use of signal molecules and their receptors, which in turn regulate the behavior of cells in each system during stress challenge. 12. There are direct and indirect pathways of inﬂuence among the nervous, endocrine, and immune systems. Neuropeptides have direct eﬀects on immune cells, as well as indirect inﬂuences through neuromediated endocrine modulation of immune function. Endocrine products p (cortisol) also inﬂuence nerve cell behavior. Immune cell products aﬀect both nerve and endocrine cell function, reﬂecting an adaptive role for the immune system as a “signal” organ to alert other systems of threatening stimuli. 13. Other hormones are aﬀected by the stress response and include increased circulating levels of β-endorphins, growth hormone, prolactin, and oxytocin and a decrease in antidiuretic hormone level with extreme stress. Concentrations of luteinizing hormone, estradiol, progesterone, and possibly testosterone decrease during the stress response. Stress, Illness, and Coping 1. Stress is a system of interdependent processes that are moderated by the nature, intensity, and duration of the stressor and the coping eﬃcacy of the aﬀected individual, all of which in turn mediate the psychologic and physiologic response to stress. 2. Many studies have linked psychologic distress with altered immune function, and evidence strengthens the association of stress with potential for illness in humans, especially in vulnerable young children who are unable to control the adverse eﬀects of stress, such as poor housing and negative parental rearing conditions. 3. Adaptive coping strategies, especially those that are problem focused and those that encourage seeking social support, are beneﬁcial during stressful experiences. Aging and Stress: Stress-Age Syndrome 1. With aging, sometimes a set of neurohormonal and immune alterations develop; these changes have been deﬁned as stress-age syndrome. 2. These stress-related alterations of aging can inﬂuence the course of developing stress reactions and lower adaptive reserve and coping. Key Terms Adrenocorticotropic hormone (ACTH), 329 Allostasis, 324 Al

Stress and Disease in Modern Society (McCance Chapter)

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