Stress and Disorders of the Stress System

George P. Chrousos

Concepts of Homeostasis and Stress

All living organisms maintain a complex dynamic equilibrium, or homeostasis, which is constantly challenged by internal or external adverse effects, termed stressors.^[4,5] Thus, stress is defined as a state in which homeostasis is actually threatened or perceived to be so; homeostasis is re-established by a complex repertoire of behavioral and physiological adaptive responses of the organism. The development of concepts of homeostasis and stress is summarized in Box 1.

Stressors comprise a long list of potentially adverse forces, which can be emotional or physical. Both the magnitude and chronicity of stressors are important. When any stressor exceeds a certain severity or temporal threshold, the adaptive homeostatic systems of the organism activate compensatory responses that functionally correspond to the stressor. The stress system has a major role in coordination of this process (Box 2).^[2,3] The stress syndrome is a relatively stereotypic, innate response that has evolved to co-ordinate homeostasis and protect the organism during acute stress. Changes take place in the central nervous system (CNS) and in various peripheral organs and tissues. In the CNS, the stress response includes facilitation of neural pathways that subserve acute, time-limited adaptive functions, such as arousal, vigilance and focused attention, and inhibition of neural pathways that subserve acutely nonadaptive functions, such as eating, growth and reproduction. In addition, stress-related changes lead to increased oxygenation and nutrition of the brain, heart and skeletal muscles, which are all organs crucial to the central coordination of the stress response and the 'fight or flight' reaction.

Homeostatic mechanisms, including the stress system, exert their effects in an inverted U-shaped dose–response curve (Figure 1). Basal, healthy homeostasis (or eustasis) is achieved in the central, optimal range of the curve. Suboptimal effects may occur on either side of the curve and can lead to insufficient adaptation, a state that has been called allostasis (different homeostasis) or, more correctly, cacostasis (defective homeostasis, dyshomeostasis, distress), which might be harmful for the organism in the short term and/or long term.^[2,3] Both hypofunction and hyperfunction of the homeostatic systems of the organism have multiple adverse effects. For instance, both defective and excessive reactions to fear entail a decreased ability to survive of the individual and the species. Thus, both fearless, uninhibited individuals and fearful, excessively inhibited individuals have increased risks of morbidity and mortality, the former as a result of underestimating danger, the latter as a result of decreased social integration.

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Figure 1.

Homeostatic systems exert their effects in an inverse, U-type dose response.^[2] Eustasis is in the middle, optimal range of the curve. Suboptimal effects may be on either side of the curve and can lead to suboptimal adaptation, termed allostasis or, more correctly, cacostasis, which may be harmful for the organism in the short term or long term.

The interaction between homeostasis-disturbing stressors and stressor-activated adaptive responses of the organism can have three potential outcomes. First, the match may be perfect and the organism returns to its basal homeostasis or eustasis; second, the adaptive response may be inappropriate (for example, inadequate, excessive and/or prolonged) and the organism falls into cacostasis; and, third, the match may be perfect and the organism gains from the experience and a new, improved homeostatic capacity is attained, for which I propose the term 'hyperstasis'.

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Cite this: Stress and Disorders of the Stress System - Medscape - Jul 01, 2009.

Table 1. Adaptive responses to evolutionary stressors and related diseases in modern human societies ^[68]
Response to survival threat	Selective advantage	Contemporary disease
Combat starvation	Energy conservation	Obesity
		Metabolic syndrome
Combat dehydration	Fluid and electrolyte conservation	Hypertension
Combat injurious agents	Potent immune reaction	Autoimmunity
		Allergy
Anticipate adversaries	Arousal and fear	Anxiety
		Insomnia
Minimize exposure to danger	Social withdrawal	Depression
Prevent tissue strain and damage	Retain tissue integrity	Pain syndromes
		Fatigue syndromes

Box 1. History of stress
The term stress originates from the indo–european root 'str', which has been historically associated with exertion of pressure. Thus, both the Greek 'strangalizein' and its english derivative and synonym 'to strangle', as well as the Latin 'strigere' (to tighten), have their origins in the very distant past. The concept of homeostasis as the general principle of balance or equilibrium of life was first enunciated clearly by the ancient Greek natural philosophers, who called it 'harmony' (Pythagoras) or 'isonomia' (Alkmaeon).^[4,75] The modern synonym 'homeostasis', which means steady state, was coined by the American physiologist walter Cannon in the beginning of the 20th century, whereas the word 'stress' was first used with its current meaning and popularized by the Hungarian Canadian experimentalist Hans selye a few decades later. Both Cannon and selye employed Hooke's law of elasticity to heuristically and creatively extrapolate physical concepts into biology.^[76–81]

Box 2. Central and peripheral functions of the stress response ^[2]
Functions of the central nervous system Facilitation of arousal, alertness, vigilance, cognition, attention and aggression Inhibition of vegetative functions (e.g. reproduction, feeding, growth) Activation of counter-regulatory feedback loops
Peripheral functions Increase of oxygenation Nutrition of brain, heart and skeletal muscles Increase of cardiovascular tone and respiration Increase of metabolism (catabolism, inhibition of reproduction and growth) Increase of detoxification of metabolic products and foreign substances Activation of counter-regulatory feedback loops (includes immunosuppression)

Box 3. Conditions with altered HPA axis activity ^[2]
Increased activity of the HPA axis Cushing syndrome Chronic stress Melancholic depression Anorexia nervosa Obsessive–compulsive disorder Panic disorder Excessive exercise (obligate athleticism) Chronic, active alcoholism Alcohol and narcotic withdrawal Diabetes mellitus Central obesity (metabolic syndrome) Post-traumatic stress disorder in children Hyperthyroidism Pregnancy
Decreased activity of HPA axis Adrenal insufficiency Atypical/seasonal depression Chronic fatigue syndrome Fibromyalgia Premenstrual tension syndrome Climacteric depression Nicotine withdrawal Following cessation of glucocorticoid therapy Following Cushing syndrome cure Following chronic stress Postpartum period Adult post-traumatic stress disorder Hypothyroidism Rheumatoid arthritis Asthma, eczema

Abbreviation: HPA, hypothalamic–pituitary–adrenal.

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