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Throughout history, scientists have hypothesized that disease can be affected by disposition or behavior. Some observations extend back many centuries when the Roman physician and philosopher Galen stated that "melancholy" women were more likely to develop cancer than women with a "sanguine" disposition.1 Other historical observations include the doctor who treated the author Alexandre Dumas for stomach cancer. This doctor believed that the principal causes for cancer were "deep sedentary study" and the "anxious agitation of public life."2 The Buddhist teacher Dogen observed in his Shobogenzo that people are less likely to be sick when life is removed of its complications. Although these ideas were primitive in their nature, modern research has started to show that these observations were not far from the truth.

Selye3 is considered a founder of contemporary concepts of how stress influences the body's ability to cope with disease. In 1936, he defined stress as a state of coactivation of the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis.3 More modern definitions describe stress as a complex process involving activation of several systems in both the peripheral and central nervous systems (CNS) that, in turn, affect many other body systems and processes.

The overall stress response involves activation of several body systems. The CNS activates the ANS, which in turn activates the sympathetic nervous system (SNS), causing release of catecholamines (Fig. 2-1).4 The major catecholamines include norepinephrine, epinephrine, and dopamine. Epinephrine and norepinephrine are responsible for controlling physiological responses and actions including increases in blood pressure and heart rate and causing the release of glucose from energy stores. Dopamine acts primarily as a neurotransmitter and controls the body's ability to feel pleasure or pain.5


Limbic system activation resulting in catecholamine and glucocorticoid secretion. Detection of a stressor activates the hypothalamus, which secretes corticotrophin-releasing factor (CRF) and arginine vasopressin. These, in turn, stimulate release of adrenocorticotrophic hormone from the pituitary, which signals release of glucocorticoids from the adrenal cortex. Activation of the noradrenergic system signals through sympathetic ganglia for release of catecholamines from sympathetic nerve endings. Reprinted with permission from Macmillan Publishers Ltd: Nat Rev Cancer. 6:240–248, copyright 2006.

The CNS also activates the hypothalamic responses that include the release of vasopressin and corticotropin-releasing hormone from the hypothalamus.6 These, in turn, cause release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary, which results in downstream release of glucocorticoids from the adrenal cortex, and constitute the HPA axis. Virtually all cell types in the body have receptors for glucocorticoids, which control many normal physiological activities such as circadian rhythms, and stress responses such as immune function and restoration of homeostasis.7

Although stress can be broken down into many categories such as physical, mental, emotional, social, or biological, ...

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