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Selye 1951
Selye 1951
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THE GENERAL-ADAPTATION-SYNDROME
By HANS SELYE
Institut de Medecine et de Chirurgie exp�rimentales, Universitlde
Montrtal, Montreal, Canada
frame of this brief synopsis. Since, on the other hand, it would be unadvisable
and misleading to select a few references at random for discussion here, the
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327
328 SELYE
anatomy, and clinical medicine in search of the "stress factor" in all aspects
of normal and abnormal life.
Unfortunately, during the past few years there existed a tendency to
apply to clinical medicine certain aspects of this problem in a rather hap
hazard manner without much effort to understand the underlying physiologic
mechanisms. Since some of the hormones produced during stress have
definitely toxic effects, this kind of procedure is not without danger. It ap
pears desirable at this time, therefore, to survey at least the main lines of the
G-A-S.
It will take many years, indeed many generations, before the details of
the G-A-S are satisfactorily elucidated. In fact, we shall never truly under
Annu. Rev. Med. 1951.2:327-342. Downloaded from www.annualreviews.org
seems that now the fog has been just sufficiently dispersed to p erceive the
G-A-S through that measure of "twilight" which permits us to discern the
grandeur of its outlines but fills us with the insatiable desire to See more.
We realize that many lines in our sketch will have to be hesitant, some
even incorrect, if we try to put on paper now what we still see only vaguely.
But a preliminary map-albeit largely incomplete and partly inaccurate
is needed now by those eager to exploit this field which holds so much promise
for all who suffer from stress! We hope that these pioneers in uncharted
territories will accept my partial and distorted map in the spirit in which it is
offered, to complete and rectify it. It is in this sense that I shOUld like the
reader to consider the following synopsis of what I think I see.
Apart from the many specific defense reactions (e.g., formation of specif
ic antibodies, adaptation to cold, habituation to morphine, hypertrophy of
much-used mu�cle groups), there is an integrated syndrome of closely inter
related adaptive reactions to nonspecific stress itself; this has been termed the
"General-Adaptation-Syndrome." It develops in three stages: the Alarm
Reaction, the Stage of Resistance, and the Stage of Exhaustion. Most of
the characteristic manifestations of the Alarm-Reaction (tissue catabolism,
hypoglycemia, gastrointestinal erosions, discharge of secretory granules from
the adrenal cortex, hemo-concentration, etc.) disappear or are actually re
versed during the Stage of Resistance, but reappear in the Sta ge of Exhaus
tion. This suggests that the ability of living organisms to adapt themselves
to changes in their surroundings, their adaptability or "adaptation energy,"
is a finite quantity; its magnitude appears to depend largely upon genetic
factors.
In the G-A-S, the manifestations of passive, nonspecific damage are in
tricately intermixed with those of active defense. This is an inherent charac
teristic of the stress, which elicits the G-A-S. In the biologic sense, stress is
the interaction between damage and defense, just as in physics, tension or
GENERAL-ADAPTATION-SYNDROME 329
pressure represent the interplay between a force and the resistance offered
to it.
In addition to damage and defense, every stressor also produces certain
specific actions, e.g., anesthetics act upon the nervous system, diuretics upon
water metabolism, insulin upon the blood-sugar, quite apart from their
stressor effects. Hence, the G-A-S never occurs in its pure form, but is al
ways complicated by superimposed specific actions of the eliciting stressors.
In contemplating any biologic response, e.g., a spontaneous disease, an in
toxication, a psychosomatic reaction, it is usually quite difficult to identify
individual manifestations as being due respectively to damage, defense, Of
specific actions of the provocative agent. Only nonspecific damage and de
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fense are integral parts of the G-A-S, but the specific actions of the eliciting
stressors modify the course of the resulting G-A-S, e.g., the glycemic curve
wiJI deviate from the characteristic pattern if insulin is used as the stressor
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DEFENSE
The systemic defense measures against both general and localized (topi
cal) injuries are coordinated through the hypothalamic vegetative centers
and the hypophysis. The intitial pathways through which stressors act upon
these centers are not yet known. Probably, either humoral or nervous im
pulses coming from the site of direct injury can induce the hypothalamus
hypophysis system to gear the body for defense. Subsequently both of the
two great integrating mechanisms, the nervous and the endocrine system,
are alerted.
The nervous defense m ech anis m .- N ervous impulses descend from the
hypothalamic vegetative centers, through the autonomic nerves, to the
peripheral organs. The splanchnics induce the adrenal medulla to discharge
adrenergic hormones (epinephrine and norepinephrine) into the blood. Other
adrenergic nerves influence their target organs directly through fibers which,
in the final analysis, again act through the liberation of adrenergic com
pounds, in this case at their endings in the effector organs themselves (blood
vessels, glands, etc.). Presumably, the discharge of adrenergic hormones
into the circulation is most effective when they are needed throughout the
body, while the sympathetic nerves are better suited to impart similar im
pulses selectively to certain circumscribed territories. The most conspicuous
results of such neuro-humoral discharges are changes in the contractility of
330 SELYE
DEFENSE DAMAGE
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Annu. Rev. Med. 1951.2:327-342. Downloaded from www.annualreviews.org
E.S.R.
and hypotensive actions; hence, the predominant response during the G-A-S
is a defensive (prophylactic) vasoconstriction and hypertension.
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onize each other, but since, at least at certain dose levels, their actions upon
the kidney are synergistic, it depends upon the conditioning circumstances
whether the administration of glucocorticoids to animals overdosed with
mineralocorticoids increases or decreases the blood pressure (d. also condi·
tioning effect of sodium and renotrophic substances, below).
There is no definite evidence to prove that either type of corticoid has any
direct vasopressor effect. Addition of corticoids to perfused vessel preparations
does not cause them to contract. Nevertheless, mineralocorticoids can aug·
ment the blood pressure even in the absence of the kidney, presumably by
raising the blood volume through their effect on mineral and water metabo·
.
lism.
Both types of corticoids act back upon the anterior lobe and inhibit its
ACTH production through the so·called phenomenon of "compensatory.
atrophy." I t is not yet known whether corticoids also impede the endogenous
production of that "X factor" which renders ACTH mineralocorticotrophic.
However, this is very probable, since otherwise ACTH therapy would only
aggravate conditions characteri�ed by symptoms of mineralocorticoid over·
dosage. If the production of the "X factor" is inhibited in the same manner
as that of ordinary ACTH, then the therapeutic action of ACTH is readily
explicable. In both instances, the pituitary is exposed to an excess of gluco·
corticoids. The latter are even more potent in eliciting the compensatory
atrophy phenomenon than the mineralocorticoids. Consequently, endogenous
corticotrophic stimuli (including "X factor") are virtually eliminated and the
exogenously administered, predominantly glucocorticotrophic ACTH acts
uninfluenced upon the adrenal cortex.
There is much to suggest that at least certain types of stress, e.g., emo·
tional stimuli, can increase the production of antidiuretic hormone, which is
probably identical with vasopressin. This effect is undoubtedly mediated by
nerve tracts descending from the hypothalamus to the posterior lobe since,
unlike the discharge of ACTH, it is abolished by transection of the hypophys
eal stalk. Vasopressin exerts important effects upon the blood pressure
and diuresis; these may be superimposed upon the typical reaction pattern
during the G-A-S. However, the role of vasopressin secretion during systemic
stress has not yet been adequately investigated.
334 SELYE
•
•
•
•
•
•
•
•
•
V �
Obviously, the end results of exposure to the three agents represented here
could not be the same.
This type of conditioning may also be illustrated by an example taken
from chemistry. All acids have many properties in common,yet the reactions
of each member in this group are essentially different. The characteristics
which they share are due to their acidity; the properties which distinguish
them are the specific reactions of the carriers of this acid function. In
pharmacology, the stressor effect is what the drugs have in common; their
other properties endow them with specific pharmacologic actions, Both in
chemistry and in pharmacology, the specific proper.ties condition that non
specific feature (acidity, stress) which the entire group shares. Hence, no two
acids-and no two stressors-act exactly alike. This may help to illustrate
conditioning by specific properties of the stressor.
We have seen, however, that even exposure to the same stressor agent
may result in qualitatively different responses. Here, polymorphism of the
G-A-S manifestations is due to selective conditioning by factors extraneous
to the stressor. This peripheral conditioning may occur at the various inter
mediate stations of the G-A-S or in the target organs themselves. We have
compared this to the manifold effects one can obtain with the same electric
current. During an emergency, it may be necessary to supply more electricity
for a community. This current will always be of the same quality and it will
always travel along the same, pre-existent, main channels. Yet, depending
336 SELYE
upon the kind of emergency and the special needs of each district, both its
quality and quantity has to be regulated locally in the periphery. Thus, the
same current can be used to produce mechanical work, sound, light of any
color, heat, or cold, and indeed, it may be shut out completely from a locality
where it would represent a fire hazard. Of course, the more we approach the
periphery of such an electric circuit, the more subject it will be to condition
ing, first, because the thin terminal wires can more easily be handled than
the thick principal cables, and second, because interventions anywhere along
the line, above such a peripheral point, would affect the latter.
Essentially, the same is true of the G-A-S. The more we approach the
periphery, the more often do we note deviations from the standard G-A-S
Annu. Rev. Med. 1951.2:327-342. Downloaded from www.annualreviews.org
pattern. AU stressors cause an ACTH discharge, but this may or may not be
accompanied by the production of the "X factor," which is necessary for
mineralocorticotrophic actions. Interference at a lower level may cause even
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more selective deviations from the typical stress response. Thus, transection
of the splanchnics may impede epinephrine discharge during the Alarm Reac
tion without interfering with any G-A-S manifestations except those resulting
directly from hyperadrenalinemia. Possibilities for conditioning become ever
more selective as we approach the peripheral target organs, each of which can
be individually protected or sensitized to the typical actions of the G-A-S.
I t is an inherent characteristic of most ramifying systems that side
branches are more readily influenced than main lines. The following sche
matic drawing will help to illustrate this.
c
2 3 5 6 7 8 9 10 11 12
Illustration of selective conditioning in a ramifying system. Here, 12 target organs
received impulses through branches of a single main line. Conditioning at A would
affect targets 7 to 12 without affecting targets 1 to 6. Conditioning at B permits us to
single out targets 10 to 12 specifically. Conditioning at C influences only the one
target organ marked 12.
GENERAL-ADAPTATION-SYNDROME 337
The general outlines of the G-A-S concept have not been challenged, but
some of its aspects became the subject of much debate and criticism; these
deserve special consideration here.
Why are the "diseases of adaptation" so polymorph in their manifestations
if they are all due to stress?�We mention this question only for the sake of
completeness, since it has already been answered in the preceding section.
We believe that the principal reasons for this polymorphism are the so-called
conditioning factors, namely, the specific effects of the evocative stressors
and other exogenous or endogenous factors (heredity, pre-existent disease of
certain organs, diet, previous exposure to stress, etc.) which can affect, selec
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excreted in the urine of men who had received DOCA in doses conducive
to hypertension, increased blood volume, edema, and renal damage do not
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meningococcus carrier who lives in perfect harmony with the deadly germs
present in his body.
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As regards clinical medicine, we feel that the principal value of the G-A-S
concept is that, by helping to understand the rtlle of the stress factor in
disease, it enables us to adjust our therapeutic measures accordingly.
Nonspecific therapy.-It becomes increasingly more evident that many of
the time-honored, though not spectacularly effective, nonspecific therapeutic
measures, such as fever therapy, shock therapy, parenteral administration of
foreign proteins, blood-letting, or mere starvation, are beneficial, largely,
through the G-A-S. Often their principal value appears to be that they stimu
late ACTH and glucocorticoid production. Wherever this is so, it may be
preferable in the future to inject ACTH or cortisone. In certain instances,
however, nonspecific therapy proved efficacious where ACTH failed. For
instance, in mental patients, who did not respond to ACTH, it could be
shown by subsequent shock therapy that they are benefited by nonspecific
stress. Here, presumably, certain specific changes incident to the shock act
together as conditioning factors of the hypophysis-adrenal discharge or
separately through other channels of the G-A-S, e.g., the nervous system or
the catabolic response of the Alarm-Reaction.
There is a striking parallelism between the diseases empirically shown to
respond to nonspecific therapy and those which show dramatic remissions
under the influence of ACTH and cortisone, e.g., rheumatoid arthritis, vari
ous inflammatory conditions of the eye, allergies. Through the use of the
corticotrophic and corticoid hormones, we are on the threshold of developing
340 SELYE
more readily tolerated than meat and especially whether, in the face of
heavy urinary protein losses in renal disease, it is better to prescribe low
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protein diets to protect the kidney against overwork or rations rich in pro
tein to substitute for the constant urinary losses.
A study of the mechanism through which stress causes cardiovascular
and renal disease has established certain definite facts concerning the role
·
played by protein and minerals in the pathogenesis of the experimental
replicas of such maladies. If these data can be applied to the corresponding
clinical diseases, and there is much reason to think that they can, then we
shall soon be able to prescribe diets on a much more rational basis. Now that
we know how to reproduce these diseases in animals, it is comparatively
simple to establish the pathogenic rale of each dietary constituent under
rigorously controlled experimental conditions.
Corticotrophin and corticoid therapy.
- Undoubtedly, the most important
pertinent data are those derived from the clinical use of ACTH and cortisone.
Since only very limited amounts of these hormones have been available up to
date, it is not yet possible to assess their scope accurately. However, it is
precisely now that some general orientation in this field is most urgently
needed. By way of a summary, let us say, therefore, that apart from their
obvious utility in hyp ocorticoidism and ante rio r p ituitary deficiency, ACTH
-
and/or cortisone have been shown to excite an effect in the following con
ditions: agranulocytosis, alcoholism, allergies (various, in addition to those
specifically mentioned here), allergic rhinitis, asthma, atopic dermatitis,
blepharitis, choroideremia, choroiditis, conjunctivitis vernalis, dermatomyo
sitis, drug sensitization, eczema, exfoliative dermatitis, erythema multi
forme, fevers (apparently irrespective of etiology, though probably normal
ization of the temperature is not always an advantage), gouty arthritis,
hay fever, hemolytic anemias of various kinds, herpes zoster, Hodgkin's
disease, idiopathic hypoglycemia, iritis, iridocyclitis, keratitis, leukemias
(various), Loeffler's syndrome, lupus erythematosus disseminatus, lympho
sarcoma, nasal polyps, nephrosis, neurodermatitis, ophthalmologic conditions
(especially those characterized by allergic and inflammatory manifesta
tions), periarteritis nodosa, pneumonia (pneumococcus, primary atypical),
psoriasis, retinitis (centralis, pigmentos�), retrobulbar neuritis, rheumatic
fever, rheumatoid arthritis and spondylitis, serum sickness, tuberculosis of
GENERAL-ADAPTATION-SYNDROME 341
And now, in the last few paragraphs of this review, I should like to sum
marize concisely what appears to me its most important outcome. All agents
can act as stressors producing both stress and specific actions. No agent can
produce one without the other. The specific actions affect the target organs in
a variety of ways. Stress acts only through the G-A-S. It causes defense and
damage.
EXTRANEOUS
TARGET CONDITIONING
(Heredily. dieI ,previQus
ORGAN exposures Ie stress)
The defense mobilizes agonists and antagonists which, through their in
teraction ort the target organ, stabilize the latter and adjust its response to
injury. But stress also invariably causes some degree of damage through the
G-A-S. This likewise affects the target organ, though not through the hu
moral and nervous mediators of nonspecific defense.
Factors extraneous to the G-A-S, e.g., heredity, diet, previous exposure
to stress, ean condition these responses. Thus, in the final analysis, the reae-
342 SELYE
tion of the target organ will depend upon the specific actions of the stressor,
the effects of the resulting G-A-S (agonists, antagonists, nonspecific damage),
and extraneous conditioning factors. This explains how the' essentially
stereotypical G-A-S response can lead to a variety of polymorph syndromes
and why so many apparently unrelated diseases are amenable to therapy by
"stress hormones."
Disease consists of two components, damage and defense. Up to now
medicine has attempted almost always to attack only the damaging pathogen
(to kill the germs, to excise tumors, to neutralize poisons). As regards defense,
hitherto medicine limited itself to such vague advice as the usefulness of rest,
wholesome food, etc. A study of the G-A-S suggests that henceforth we will
Annu. Rev. Med. 1951.2:327-342. Downloaded from www.annualreviews.org
be able to rely upon much more effective means of aiding adaptation to non
specific local or systemic injury by supplementing the natural defensive
measures of the G-A-S, whenever these are sub-optimal.
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ADDENDUM
While t his article was being composed, we have been able to show that
electrophoretically pure growth hormone causes hypertension, myocarditis,
and nephrosclerosis in the rat under suitable experimental conditions. This
suggests that the hitherto unidentified /IX factor" in our crude anterior
pituitary preparations is identical with, or produced under the influence of,
growth hormone.
SELECTED REFERENCES
1. Selye, H., The Physiology and Pathology of Exposure to Stress (Acta, Inc. Pub-
lishers, Montreal, 1025 pp., 1950)
2. Selye, F. L., J. CUn. Invest., 26,1197 (1947)
3. Selye, H., Can. Med. A ssoc. J., 34, 706 (1936)
4. Selye, H., A m. J. Physiol., 119,400 (1937)
5. Selye, H., Endocrinology, 21,169 (1937 )
6. Selye, H., Science, 85, 247 (1937)
7. Selye, H., Am. J. Physiol., 123,758 (1938)
8. Selye, H., J. Am. Med. A ssoc., 115,2246 (1940)
9. Selye, H., Endocrinology, 30, 437 (1942)
10. Selye, H., Can. Med. A ssoc. J., SO, 426 (1944)
11. SeIye, H., J. A llergy, 17,231,289,358 (1946)
12. Selye, H., J. Clin. Endocrinol., 6, 117 (1946)
13. Selye, H., Lancet, I,942 (1946)
14. Selye, H., Ann. Internal Med., 29, 403 (1948)
15. Selye, H., J. Clin. Endocrinology, 8, 588 (1948)
16. Selye, H., Brit. Med. J., II, 1129 (1949)
17. Selye, H., Practitioner, 163, 393 (1949)
18. Selye, H., Brit. Med. J., I, 203 (1950)
19. Selye, H., and MacLean, A., Am. J. Digestive Diseases, 11,319 (1944)
20. Selye, H., and Pentz, E. I., Can. Med. A ssoc. J., 49, 264 (1943)
21. Selye, H., and Stone, H., Endocrinology, 43, 21 (1948)
22.. Selye, H., Sylvester, 0., Hall, C. E., and Leblond, C. P., J. Am. Med. A ssoc., 124,
201 (1944)