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STRESS and the GENERAL ADAPTATION SYNDROME* by HANS SELYE, M.D., Ph.D., D.Sc., F.R.S.C

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STRESS and the GENERAL ADAPTATION SYNDROME* by HANS SELYE, M.D., Ph.D., D.Sc., F.R.S.C BRITISH MEDICAL JOURNAL LONDON SATURDAY JUNE 17 1950 I STRESS AND THE GENERAL ADAPTATION SYNDROME* BY HANS SELYE, M.D., Ph.D., D.Sc., F.R.S.C. Professor and Director of the Institute of Experimental Medicine and Surgery, Universite de Montreal, Montreal, Canada With the concept of the general adaptation syndrome we factorily elucidated. In fact, we shall never truly " under- have attempted to integrate a number of seemingly quite stand" this phenomenon, since the complete comprehen- unrelated observations into a single unified biologic system. sion of life is beyond the limits of the human mind. But I would draw attention briefly to the work of Claude there are many degrees of " elucidation." It seems that the Bernard, who showed how important it is to maintain the fog has now been just sufficiently dispersed to perceive the constancy of the "milieu interieur" ; Cannon's concept of general adaptation syndrome through that measure of " homoeostasis "; Frank Hartmann's " general tissue hor- "twilight " which permits us to discern the grandeur of mone" theory of the corticoids; Dustin's observations on its outlines but fills us with the insatiable desire to see the " caryoclastic poisons," the " post-operative disease," more. the curative action of fever, foreign proteins, and of other We realize that many lines in our sketch will have to be " non-specific therapeutic agents "; the " nephrotoxic sera " hesitant, some even incorrect, if we try to put on paper of Masugi; and to the " Goldblatt clamp" for the now what we still see only vaguely. But a preliminary production of experimental renal hypertension. map-albeit largely incomplete and partly inaccurate-is At first sight it would seem that all these observations needed now by those eager to exploit this field which holds have little in common and that there is no reason to so much promise for all who suffer from stress. I hope attempt their integration into a unified system of physio- that these pioneers in uncharted territories will accept my logical and pathological events. Yet most of my research partial and distorted map in the sp-rit in which it is offered, work has been devoted to the construction of bridges to complete and rectify it. between these and many additional facts, since they were It is in this sense that I should like the reader to consider thought to be interconnected in nature. Through the com- the following synopsis of what I think I see. prehension of their unity we hoped to learn how to use them better for the understanding of life and the treatment Principal Facts and Theories upon which the General of disease. Adaptation Syndrome Concept is Based tenet that all The keynote of this unification was the Apart from the many specific defence reactions (e.g., living organisms can respond to stress as such, and thiat formation of specific antibodies, adaptation to cold, habitua- in this respect the basic reaction pattern is always the muscle stress. tion to morphine, hypertrophy of much-used groups) same, irrespective of the agent used to produce there is an integrated syndrome of closely interrelated We called this response the general adaptation syndrome, adaptive reactions to non-specific stress itself; this has been and its derailments the diseases of adaptation. termed the "General Adaptation Syndromes" (G.A.S.). Anything that causes stress endangers life, unless it is It develops in three stages: the " Alarm Reaction " (A.R.), met by adequate adaptive responses; conversely, anything the Stage of Resistance, and the Stage of Exhaustion. that endangers life causes stress and adaptive responses. Most of the characteristic manifestations of the A.R. (tissue Adaptability and resistance to stress are fundamental pre- catabolism, hypoglycaemia, gastro-intestinal erosions, dis- requisites for life, and every vital organ and function par- charge of secretory granules from the adrenal cortex, ticipates in them. In order to present a well-proportioned haemoconcentration, etc.) disappear or are actually reversed outline of the general adaptation syndrome it was necessary, during the stage of resistance, but reappear in the stage of therefore, to peruse every branch of physiology, biochemis- exhaustion. This suggests that the ability of living organ- try, pathological anatomy, and clinical medicine in search isms to adapt themselves to changes in their surroundings, of the "stress factor" in all aspects of normal and their adaptability or " adaptation energy," is a finite quan- abnormal life. tity; its magnitude appears to depend largely upon genetic It will take many years, indeed many generations, before factors. the details of the general adaptation syndrome are satis- In the general adaptation syndrome the manifestations of passive non-specific damage are intricately intermixed *The first part of the Heberden Oration, given on June 2, 1950. those of active defence. This is an inherent charac- The second part, being principally a commentary on lantern slides, with 10. teristic of the stress which elicits the general adaptation was summarized in the British Medical Journal of June 4667 BRMTISH 1384 JUNE 17, 1950 $TRESS AND THE GENERAL ADAPTATION SYNDROME MEDICAL JOURNAL syndrome. In the biological sense stress is the interaction hypothalamic vegetative centres and the hypophysis. The between damage and defence, just as in physics tension or initial pathways through which stressors act upon these pressure represents the interplay between a force and the centres are not yet known. Probably either humoral or resistance offered to it. nervous impulses, coming from the site of direct injury, In addition to damage and defence, every stressor also can induce the hypothalamus-hypophysis system to gear produces certain specific actions (e.g., anaesthetics act upon the body for defence. Subsequently both of the two great the nervous system, diuretics upon water metabolism, integrating mechanisms, the nervous and the endocrine insulin upon the blood sugar) quite apart from their system, are alerted. stressor effects. Hence the general adaptation syndrome The Nervous Defence Mechanism.-Nervous impulses never occurs in its pure form, but is always complicated descend from the hypothalamic vegetative centres, through by superimposed specific actions of the eliciting stressors. the autonomic nerves, to the peripheral organs. The In contemplating splanchnics induce S tRESSOR any biologic re- S RESSOR the adrenal medulla sponse (e.g.,a spon- to discharge adren- taneous disease, an ergic hormones intoxication, a psy- DEFENSE NaCcrobios (adrenaline and nor- chosomatic reac- adrenaline) into the tion), it is usually blood. Other adren- quite difficult to -ON~AoOTROP.w4s j~ ~:ergic nerves influ- identify individual SH.LH.PR0LACY- - -'.;.- T ence their target manifestations as VA,11t organs directly being due respec- kt4 BIsLOSOD l ' through fibres tively to damage, *-i.PS£ | t which in the final -] defence, or specific * *E55R analysis again act actions of the pro- ----------------; TISSUE- through the libera- vocative a g e n t \iECO~ tion of adrenergic Only non-specific compounds, in this damage and de- case at their end- fence are integral OD>- - ] ' ings in the effector parts of the general organs themselves PHATC T , adaptation syn- RESISTANCE ,HAT_-TISSU (blood vessels, drome, but the N ",a CONEOGENESIS]* , glands, etc.). Pre- specific actions of sumably the dis- the elicitingt i n g -j...4 charge of adren- stressors modify ~~w j {. soav"A ergic hormones the course of the _ into the circulation resulting general o ag0 ', /EcSV is most effective a d a p t a t i o n when they are syndrome (e.g., the -c CO ° ' needed throughout glycaemic curve W o _ -| the body, while the will deviate from a sympathetic nerves the characteristic _| , ~~~~~~arebetter suited to pattern if insulin is BLOOD- 1 | ' impart similar im- used as the stressor PRES209 ./ pulses selectively to agent; the neuro- VCLUME 1 certain circum- logical manifesta- SUBSTAKEtS| | scribed territories. tions will be atypi- 'Oe The most conspicu- cal if the general PRESSURE ous results of such adaptation syn- neuro-humoral dis- drome is provoked charges are changes by ether). In this AOOO in the contractility sense they act as LRITATIPICAL of smooth muscle. "conditioning fac- Owing to an adren- tors." Certain cir- ESR ergic vasoconstric- cumstances, not tion, peripheral directly related to the stress situation, are also prone resistance increases and the blood pressure rises. This hyper- to alter the course of the general adaptation syn- tensive response may be further accentuated by an increased drome. Among these heredity, pre-existent disease of cardiac volume and the opening, of the " renal shunt," certain organ systems, and the diet are especially important. which deviates blood from the cortical glomeruli to the The accompanying schematic drawing disregards the juxtamedullary region of the kidney. This neurogenic specific actions of stressors, since they are not part of activation of the " shunt" is quite comparable to that the general adaptation syndrome. It attempts to depict only induced by mechanical interference with the arterial inflow the main stress pathways through which non-specific itself (Goldblatt clamp, " endocrine kidney " operation) into the affects the organism and the manner in which such reactions kidney; hence it augments the production of renal pressor are conditioned. substances (R.P.S.). The latter also cause peripheral vaso- Defence constriction; thus they further augment peripheral resis- The systemic defence measures, against both general and tance in the cardiovascular system and hence the blood localized (topical) injuries, are co-ordinated through the pressure rises (cf. below). JUNE 17, 1950 STRESS AND THE GENERAL ADAPTATION SYNDROME BRIrISH 1385 MDICAL JOURNAL There is some evidence of a simultaneous cholinergic In this respect gluco-corticoids and mineralo-corticoids discharge during systemic stress. Concurrent activation of may mutually synergize each other. both agonists and antagonists occurs in many effector The gluco-corticoids inhibit the production of arterio- systems during the general adaptation syndrome.
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