Stress and Disorders of the Stress System

George P. Chrousos

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In This Article

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.

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.

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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