Oral Medicine

THE ALARM REACTION, THE GENERAL ADAPTATION

SYNDROME, AND THE ROLE OF STRESS AND OF THE
ADAPTIVE HORMONES IN DENTAL MEDICINE

Jlnss XELYE, ALI)., I’H.~).. I).Sc., F.R.S.( C’.), MOSTREAL, (las:\n~

T Fill‘( YtrrHS concept, ”

as formulated in my earlier writings.
itself to he applicable to many pr~~l~lems of dental medicine. and hence
it is with pleasure that 1 accepted the kind invitation
has shown

of The Arnerdcan Insti-

tute of I)ent,al Medicine to ordine ib hefore you.
Tinfortunately, as it happens with most new concepts in medicine, the
formulation of novel ideas necessitat,etl the intrvtluction of new ter*ms. which
should 1~ calearly defined at the outset. Ijet me, therefore, first place More
you a glossary of technical terms and abbreviations, which may act as a handy
~fcrencr in following my lectures. (Set> Glossit~~~ of Terhnicnl Tt’r~r~ ;I])-
pencled.)
It is always easiest to enter* into the spirit of a new concept l)y following
its development historically. JIcnce, I shall tlo so trow. basing my remarks
upon Ihc introduction to my “Second Annual Report 011 Stress. “I*
Precursors of the Stress Concept.---EveI. siucc man mxtl th(B war-tl
“iliseasc” he hild some, at least subconscious, inklin # Of the St WSS WIIWJ)t.
The very fad that a single term can he used to tlenotr ij gt*cat variety of
intliviclual maladies cle;lrly indicates that they have something in common.
They possess, as we would now say, some nonsl)c~cific features which ptlrmit lo
distinguish disease from the couditiou of health. Tot, 1)~e&rly JWC~UWthese
manifestations are not charxctrt?stic of any one tliscasr. they tlo Ilot help in
making a differential diagnosis.
These nonspecific featur*es of’ (lisease have t,eceivrtl little attention in vom-
paSson with the specific ones, because, unlike the latter*, they (lo tlot help to
I*ecognizr the “eliciting pathogen” or lent1 themselves to any effective typcJ
of specific therapy.

P’r‘oru ttw Institute of 1Sxpt~rirnent;d Medicine an11 Surgc~r~y. 17niversitt’ (1~ Montr’6al.
Presented before the tenth annual mwting of the ,2rnt~ricun Institute of Dental Merlic’int>,
The Desert Inn, Palm Springs, Calif., Oct. 26. 1953.
*Since this paper ras presented, the “Third Annual Report of Stress”” has appeawri:
in it new observations conrrrning stress. which WVSTC publish4 in 1953. hare rc~ceirc~l wrticular
attention.
of the ner\-ous system ;IrIte~l;I~t~s, I,,y far. th(b clc,\.c.lol,~r~(~~~i 111’~tt,~~lt,I.t~t~11~1~)
erinology, it is I~lltleI~staIltlill~l~~ lh;it. ill11011~ IlIe IL\,, M.l’t’ill, iIlt(‘gl’ill ill: S.\ hit’lllX

of the lady, the II~~voIIs :IIICI tl~r h,,~.lll(tllill S~SIC’III. IIIIL 1’()1*111cv L\‘;IS t llca firxt,

to he examined froni this l)~~iIit 01’ TirLr.. Hicker. Slwr~rr~sky. Reilly. l111It’.:lll(i
IIIRIIY others have gatheretl iI)Ipt)rtaIIt tlata ccllIcrI.nitIy 111r role 01 111t, tlt’r\-ltllx
system in such nonspeeitic rtn;IetiolIs :IS fc\~c~r,I)~)l?~IIIo~~~,lIoIIII(~lt~i~~~ I(lIIkoc*y1 ttsis.
inflamrIIatioii. and so fool II. I IL 1hr tloIiiaiII 01’ what trmp Iw callrtl * ’ physiolibpic*
I L ’ ’ IV. VanIIoIi’s
sl ress studies 11elpecl us to lmilcrstallcl the fbart play-(~1 1)~.fl~v
sympathetic nervous syst,em :I IItl its 1~u~r10~xl pff~~tor sulchnces.

dgain quite iIidepentleIiily. a gwi11 tleal of progress has I)ecsIi Iuadc in the
study of pituitary aud adrenoeort ical ho~‘~~~o~~es 1)~.t~hcmists, ph?-siologisis, n ntl
clinicians, too I~IIIC’I~OUS to ,IieIItion 1)~ naln(‘.
All the knowledge aeclIIiu~t1 as ii result of these early in\-cstigatiolls was
iIIdispensahle for the l’ormIIl;rtioII oI’ the stress c~oIIeel)t. whose Icatling motive
is one of unification. Numerons additional experiments had IO he 1)erformcd
to show that the many noIIspctif!c responses of iIIdi\.idIxIl target organs arc
closely integratetl and aciually I~~l~I~~sent part 01’ ;I sitlglc hiologie rcspoirse,
t,he general adaptation s,vtrtlroIrre. Thus it I)tei\I~It~ evident that this patiertl
of response plays :IIl itItegt*;I I I);lrt iIt I he IIIost v;I rictl physiologic,. I)athologicz.
and pharmacologic reactions.
The Concept of Stress.mm-l:?a series of esl~ei~inicnts on animals it was
tlemonst~rated in 19% t,hat the organism responds in a. stP).P&Jjr)icu1 manner lo
a variety of widely different factors. such ilS: infections, intosieatioiIs, tixriIIi;I.
nervous strain, heat, coltl, muscula 1’ fatigue. ot* s-iI*I’;Iili;ItioIl. The sl~ecifit
actions of all these agents art’ quite tlifYerent. Their only ~wrn~no~~ Fcntnrc~ is
that, they place the l)ody iIr iI state of geIIet*iIl (systemic’) stress. 17(11I(*e.lve
conclndetl that the stereotypical response’. which is superiInl~oset1 upotl illI
specific effects. represents the somatic nIanifesta?tioIIs of nonspecific ~‘stress”
itself.
ht, what, is annspecific, ‘*s~wss”? The term had long heen used in physics
to tienote the interaction I)etweeII iI force ant1 the resist:IIIee ol)l)osecl to it.
li’or instance, pressure anal tensioti cause stwss in illilflimiltf~ matteI*. The 1iol1-

specific response mentionetl was thought to represent the biologic e(lIIi\‘:IlelIt or

such physical stress. The tern1 has now been quite generally ncwpttyl iti this
sense riot only in English, hut, since attempts to t?2llSl;lte “strew” lctl 10 m11d1
confusion, also in most other 1aIIgIIages.
The Concept of the G-A-S.--The most outstanding manifestations t,f this
stress response \vcre : ntl?.cJ?Ii)~o/.fic~fr/cn7rr/-,qc))iuIt with histologic signs of hy-
peractivity, th!~?)licol:llrn2,~~~~~~, itr ~wl~~tim, with certain conromitanl c+ti;n~pes iii
the bloocl eomlt (eosinopcnia, I>-rIil~lIopeIria, l~ol~tiuc~leosis), atIt ~~nst~wi~t tPsfin/r/
ulcc~x, often arcom1~aIIietl 1)~.other IIIatiifeslatioIis of tln~ngc 0)’ “shoc~X.”
We were struck 1)~ the I’aet. that? while clIIritIg this reactioIl iI11 the t)I’giIIIs
of the body show involutioIIa1 or degetlerative chatrges, the atlt~enal cortex
actually seems to flourish on stress. Ye suspected this a(lreIIal respoosc to
 Ghcocorticoitls 01’ (i-C “A i suc~li 2s vortisoilt~ 1, 011 Ill<‘ c,tllPr 11;111~1. \V(‘l’(‘

highly potent in causing f/l!~~,tic,ol!l,)r~,/rrrfic. involLtt ioll anti in talic*iting t h(t (+l)ilr-
acaterist ic hloorl cofllrf clra Ilgc3 II I’ 1II(~ ;1lil1’111 I’(~ilc~liOll. ‘I’llt’y illSI it’ll(tC’tl trl

inhibit the hypertrnsi\~e ;rlltl rlielu~l;ltic (‘llilII~(‘S whic*h (‘iI I)tJ r~lirilecl irb illl-
itnals IQ rllifiel.Rloc~ol.ti(~oi~ls. ‘1’1~11s.iI1 IllilllJ. t.(,sJ)(s(*fs. thca l\~rb 1~~1~~ a1tY
c*orticoitl horllrorres ;Illt:rg(Jlliz(t cac*h othrara.‘. ”
The ternIs “glrrcocc,~~tic.oitIs” ai1(1 ” Iiiillel~illoc~~~r~tic~~itls” e~~lptiwsizc~ tlrc,
SitliP1It, rnetaholic actions of’ these slrl~starl~es ; f1’0111il c~linical Ijoint of view,
liow-e~er*, their effects upon inflaniiiiation arc> perhaps 01’ eren greater interest.
Since the plucocorticoitls inhibit infl;trlrmatiorl, while the ~ni~rer;rlo~o~~lic~oitJs
errh>rlt(ae it, the (i-(“s Irkay ;I/)J)t*o/)ri;rtely 1~ cirlle(l “cm tipklogistic~ f~r~r+icvitl.s ' *
oy '*A-(",s" and the XC' 's ” /,,.f~l~hlo!/i.stic, f~0rticvicl.s ” w “P4”s. *’ when the>

arc tliscussetl with rcfere~~ce to their dt’ects upon inflammation.

Inflammntory pvn~ilom~~s, especially those prodric*etl in the vicdrrity of
joints by the local ;rpplicatiolr of irritants (e.g.. foriualirr. mustartl powderi.
as well iiS certain allergic IYilCtiOXlS, are likewise aggravated by P-C’s and
inhibited by A-Cl’s, dpparr~rtly, the t.rsponse of the atlrrnd cortex is most
impor~tarit not only in tlefrnse against systerrlicd stress (affecting the whole
organism), hut also in the ma Iiifoltl toJ~i(~;ll tlefensc reactions which occur*
up011 exposure to loctrl stwss (e.g., l)il(~tPYi:ll or chemical irritants, responxcs
of il “shock ora~rr” to arr ilJle~*~err).!‘~ “I
(‘crtain crude clntPri(~r-l)itllit(l1.~ ~.rtr~f.P ‘I cluplicate the previousl>~ men-
tioned act,ions of P-C’s upon tlic cardiovascular system, the blood pressure, the
connective tissue (inflammation ) ( and 1he kidneys. The hypophyseal prepara-
tions which we used were tlcfinitcl~ c~o~ticotroJ,hic. in that they enlarged the
adrenal cortex, hut the\- were particularly ricxli in the so-called “growth Jior-
111011e’” 01’ so??tntofrY$k’ homf,nr (Sl‘l I ). AS 50011 ilS We WC!lY iillle t0 ol.Aairt
Jnrrifirtl AC‘TH, it l~ecamc cl\-itlcnt thilt the J)re\:iously merrtiourd J)at,hogerrie
:Ietiorrs of the crude ;lntrl.ior.-pitnitn~.)- pr~eparatiorls wultl not l)e tluc to their
ACTH content. since even the highest tolerable tloses ol' the latter hormone
failed to duplicate their J)~‘e’tl()~~li~r:rrrt1’4 effects. OII the other hand, over-
tlosngc with pnre Sl’li causetl <‘iIrdio\~ascular anti r*etlirl lesions, identical with
those previously observed in ir~lir~rds treated with I’-( “s. It was c~orrclutled
t,hat t,he J)reyiously mentiollrcl ;l(*tiorrs of ow crude nntet,ior.-pitrdtar.?; pr*epar;l-
tions were mainly clue to thAr Sl’Il conterkt. It rcrllwirls to 1~ SC’CII to what es-
tent STIJ acts itrtlirectly 1)s stin~ulatitlg tire 1’4 production of the aclreual
(+ortex, or directly by sensitiziilg the J)eripheral tissues to NJ-(“s. J’reliminary
OlJSI?rTiltiOIlS suggest that J)oth these ~~l~~ll:Il~iSlns Itlily l)r irnJ~licaletJ.l~ Ijut
I his point is not yet settled.
l+om the internist’s J)oint of’ view, perhaps the most interesting role of
STIL iri the Adaptation SF-ntlrorrre is ihut it can effectively cornhat cntabolisnz
tr7d ,s,l,sceljtibilit?J to ilzfrctio~~s. Animals he;ldy ovrrd~sed with AC’TII or
A-(1’s terrtl to lose ir gtAe;rt tleal of weight. 15vetrtually they die. almost al-
ways as ;I result of gencr:~lizetl septicerniij, ea~~etl 1)~ tlortnnlly s;rJ)roJjhyt,ic
ttlic,root.K;tttis~lts. I II txts the lnttg tissue apJw;li+ to 1~ Singnlat~ly preclisposc(l
IO st~ch ittfwtiolts. I:tttlrr these contlitiotts, atlcquotc~ tlosrs of STII p~*eveul
1l-1(1loss oi’ I~~tly weight as bccll 2s tltv cscrssive ntic~t~ol~inl pt31if’eratiotl.73 It
tY~ltt;liIts to I,(, S(‘(‘ll IO \vh;lt (~stt~llt tttwc~ ;l(~tiotls ()(’ S’J’ll \ViII J,l’(‘“e t() I,ti ot
V;tIll(~ itr llt(t lt~itlt;1~~~ttt(~ttt of ittl’(~~lic~tls it1 tlliltl, I)rtl (~spel~it~tc~trts 011 rat:, Ita\-tb
;lit’(‘;I(I>- tl(~ttl~~ltStt~ilt~~t1
Iht’ gl’ritt ittfluettw oj’ tllwc~ ltclt~tltoll~~s IlJ)oIl wsisfattc~(~
t0 lSl)C’ Of tUl~~~t’~~ttlWiis. Sotvttiflly lltv txt is vif~ln;tll~- twisfitttf t,o
t 11(x IlUllIittl
tttlwt*c~ttlosis I)itc*iIli; it tttity lw t~ctttlvlxvl wttsili\.e 1)). A\( “1‘11 01’ ~14”s iitlct this
settsitivit!- vatt ill turtt lw ;tl)olishtvl lty STIR.
Conditioning of Hormone Actions.--,& wo~~k :I lotlg these Iittes J~r~og~msetl.
it l)e(.ittttt’ itlctwtsitlgly IIIOIY~ olwions that the ;teti\.ity of ~hc howtones pro-
tlnwcl tlut.ittg sttws clepetttls latygcly ulwti it variety of “c(~~ttlitio~ting faetotx”
Ih)th the ~~twlu(~iiotr ot’ the ” ntlaptirci hot~ttiottc~s” illI< their et’fect lr]x~n itt-
tli\3tlu;tl til t’g(‘t ot’gn 11s pt’cl\Yrtl to he r(~t’(hitfi\~ . illflllPltCe(J I))- JlelWlityz ilfi(‘, J)t’C-
viorw CSpoSUlT lo sttws, t hc ltltt?‘iti011itl state, etc.. Tht~s, t’or ittstanee, the J)ro-
tlrtctiott oi’ ~ot,tic~ott,ol)hi~ ho1*111o11e 1)~ the l)ituita ty is etthancetl lty ;I high
plot&r (lit+, while the action ni JI-Cl’s upon rttost tittaget or*g;tns is angmentrtl
ly excws sotlinm.
Stwss itself is ]wt*h:il)s the tttost el‘i’entive :itt(l ttrost, common i’actot.
capal~le of c~oiitlitioitittg the itctiotts oi’ adapti\-e hotwtotres. Thus systemic
st I’tJSS aoptc~fits the lytnpholytic, c;ttnl)olic, a11t1 hypet*glycetrtic actions of
(:-(“s, while the salient effect of the adaptive hot’tttoltty that of ntotlifyittg the
~Olll’St’ Of itltlit1tllll;ltiotl. tI;ttll~:tlly l?iltltlOt tttatiifcst itself 1Itdess SOme topical
st t~cssot~ti t.st elicitrtl iI I)hlogistic twpnse.
I II thtx fittitl attalgsis strcdlt fitct0t.s c*o~ltl ;tctrrally tl~$etmittc whether es-
JtoslltY to sttY~sso1~ agetlts would 1x1 tttet l)y il physiologic (‘~-d-R or Ciliise dis-
1’:tSCS 01’ ittl;tI~tiltiOll. Ittdcetl, itt the litttet’ irrst;tttet>, these conditioning factors
itl)lteitt’ to l)ta wspoltsihle i’o~* the selecti\-(5 l)r,e;tktlo\vtt o(: orte ot’ the othet* ot*gnlt.
\\‘e felt tltitt difYwcttces in p~edispositiott tltrvugh sltr*li factors might explain
why the sztttte kitttl oi’ stwss eatt ealrse tlivclt*se tyljes ol’ *‘diseases 01’ :ttl;tltfit-
tion ‘* it1 (liffcrettt itttlividuills.
The Concept of the Diseases of Adaptation.--E’mn OUI espet*itnents IIICII-
tionctl. we cwnvlittletl t ttat tlte pathogctticity of tiian~- spsteinic arid local stressor
;tgetttS tl(~p~~td~ lit t’g(>l>. \tl)otr the frrtrciiott of the h~l~o~~hysi~-i~d~ett~co~ticnl
s;%cttl. The latter ttia>~ cil ltw ctthartcc or irthihit the l~)d;\-‘s defense reactions
against st twsor agents. I\‘e thittk that tlct3iltttctils of tttis adaptive tne~hanisiit
;~ty tltc pt.itt(‘ipitl faciws itt the ptwludiort oi’ wrtaitt maladies which WCeottsiiicr.
tlt~~t~c~foly~. 10 1tC rss~~tltiitll~ Di.SC’C/SCJ.S
Of altlt/]JfUfiOH.
,2tt1011g the tlct.:rittncvtts ol’ tlto (:-,2-S which ttt:r>. (‘attse tlisease, the fotlow-
iitx it I’(’ JM t’ti(*tllilt’ly itllJ~(~l4illlt :

1. .\II trl~dtltc
CJYPSS(II* tlefic%‘~~*,t/ in the anro~utt oi’ cot?icoids and STH
prorlflcctl tluiillg stress.
.) l\~~ al)solttte rs~css ot’ tlrficiclttvy itt the ;ttttorrtIt o-l’ cwt*ticoids ;ttt(l STIR
wftriiul (I)). ‘ ‘fi.m/“) 1l.l. it tcir pc~t~ipltrl~ilt tatag’ct Org:lttS cltit~itt~ stt’ess.
2
 It1 ljhC C’OUtw of tbllr (~\lwriittottls vc,ric*rrttitr:! lilt‘ c~‘~‘(Y,I o~’ II~~I~I~~~~II~.s ~I~~oI~
the ttevrl0ptllrtJt 0I’ “tol~ic~;il it.riI;tIicrtt ;lt~lirt~itis“ iti tlrci t'ill." il s(~Iiir~tttttc~s

happened that, the anitttals Iw~:.;IJI to ~II;IL\. tllcdt~ ,joittts \rhc’~t I/ICW~ IHY~;IIIIC

swollet~ and pa~ittt’rtl. Ttt c)t*tlei* 10 I)t’v\.c~tll this. \ve cdliplwcl off tlrv iif’s rjl Iltttir,
lower incisor tC,Pttl. This is il Sl~ltlctil txl lit.Oc(~cl1tt.c’ iti 0111’ Iill,Ol’iltc~t’i(~:~~ L\.ll(‘ti-

PTel' it is Il~~WSilt'~ to ])r~c~v(~ttl t~o(lcttts t’twttj ;tll;i~~kitig l~f~~l;t~~~ 01’ ILI)(‘I!

WOUrttlS. IIS IOtlg ilS tll(, illlitllillS ry~c~c~ivp gt*;rt~~~l;~tt~tl I’ootl. it is ~vI~II l~~l~~r~atc~cl
attct has nerct* ItJtl to ;rtty c’otttl)li(‘;ttic,tts itt tlr(b I,itst. I ti OIIC’ rwc~tit cbslwt’i
tttrnt, however. itt which rats so I twtt (>(I \VC’IY civctt snl)c~ttl;ttic~otts itl.jtvtic~trs 01’
oot*t~isotie. art estetisivt> ;tttcl I)rogtwsi\~t~ ~ilJt~l'C'llOllS slotii;ttitis tlt~v1~lo/tc’cl.
This cvcntuatl~ Icd to pcrl’otxtiott of the float. ot’ tltca tt1oltt It ili'i('t' I~t3ctwsivc~l~.
clestt~oyittg the gittgivac ;it~otltitt ttl(a shot~t~~ltcvl ittvisors. 111thIi/b. iltlCl I ilo t11115-
VIPS~~ttit(~h~tt to th(> ttti~tt(lil)ttl;tt* lt~tt(‘.
I tl thtl (!()tlt*st’ OF t lt(, I)itsi tw(, J’~‘;II’s. this v0trtiitiott has lwstt cbl~c~t~\~c~(l
scv(lr;rl tittles, I)llt illWll~S t~trl), itr t,;rts wlic1Se Io\v(.t. ittcGot*s li;l(l 1)4~vtl ttittittrc~tl
:ttttl \vho at the sitttt(’ titttt, tywsivtvl (~c,t*tisottt~. Svitlwt~ 01’ tllt%c~ t \\‘0 i'ilC+tOt'S
iIlOltC CVet' l,?‘O(lllC?tl SI1Cll (all;1 tIgt’S.
Qnitc iiidcl)r~tttlct~tl~~ 01’ ilit~sc~ ol~srt~\~iltiOtls, it tliltl ills0 ltc(‘ll tlotetl it1 0111’
lttstitute thilt tttost of t Iit, clil’c‘cdts ol’ c~ot~tisotlc~ itt*(l itthildecl 1,. tlrcb so-~~;~II~~~l
“growth honttottr ” Ot' Sc~lllill0l t’O])lliC~ 1101~111011f? (STIL). This Illl~t~MI ~Itllil~-
oriistn WilS rx-ictritt with t’tns1)t’c.tlo gt~o\vth. Il~~trti~~ol~~rtr~~h;tIic~ tissnt) ttrvc~lo~~-
tllrttt, iltttl SO fotth ; it bvits l)itt*ti(*ltli\ 1’14’strikittg wg;trclittg tltc tlf’f(~*t~ nl)ott
itJfliltJrtllittiOtl ;ltttl WOtlttfl ll~:illitlg of th(h t\Vo l10I~tItotl~S .jJlst irtc~titiotic~cl.‘~!’ ‘,’
111 \-irw of these fil<‘tS. 11’0clrc~ttic’tl it (II’ itttc‘twt to clwiglt il spt~vial cLspc,t’i-
Jll~‘tlt it1 OtYtcT~ to OStill)tiSh t/1(& t311’CCat o(’ ~~OI~tiSoll(~ ;ltltl S’I’If. ;11Otl(~ illltl ill (‘otll-
l)itliltiotl. lll)Otl tllP lY3iSlilIl~~(~ 01’ tllc, t)ll(‘(‘;tl sttitliw 01
tll11("OSiI. l~~~~~~‘l~itll~‘lltill
this type itnlrcssrtl IIS 21s ~III tltch tttot’c itttl)ot*titttt sittw \\‘itIlttt~t~S ‘I’hotttlwott.
att(t l,ichtrnstcitt’” 11;1(1tyc*(~tttly ~hc~\\tt th:~I ;\(“I‘lI i~\ltic’h ;tc.ts its :ttt itttti-
l)hlogistic: hotmotte. liktx vortisc~ttc) ;t~~t~;lVittc~S tulwt~~ttlous rsulcc~r;ttiotl (II’ ttl(s
lliJr(t j,aliJt(' iti lllilll.

Stl??t7?Lt!l’?/,
Ill itt c~spt~rittic~tits 011 I'iltS. tIlC> t)ll('('ill tIll1('OSil WilS (~Xl)USC3tl 10

excessi\-e rtt(~ch;tlti~:ll i1t.jttt.y t)y rlil)pitt g Of ItIt IOb\.t’t.itt&otx, iltl(l thlls I’owittg
the attittlitls to che\v Tvitlt their gitlgivit. l’ttcl(~i* thws cwttclitiotls. llica tx~giott
Of the gitlpivilc Jlwtt f’01, tii;lstic~illiOtl is s11l)jOc~tto t~slJl~~rl~;rliott. Sot~tria I Iy Ihi,
l’t~~(lisl~ositiott to tissur ~tillllil~t~ tlO?S IlOt ilC'tllCll1~ ('IIIISC ;ltl~ serioits lOPill cliltll-
;I~c. If, hoM’C\.(‘t*. the ttttittt:tt is l)t’(‘t t~t~ttt~(t \vitlt c*ot*tisottck. it ttcltt!;tliktb I)tx--
gt~essiw iltttl cltlsttYldi\c~ sl0llliltitis tic~vt~lO[)s. This c;lll ~'\.t'tllllilll~ df?stt7)~~

thtl lowet. lip aJ1c1 tllc floor of the l,JJ~<~i\I ca;tx-it)-.

l’he increase itt tisslw susw~~til~ilit~- to lrtwh:~nic~al insults. lltus (.ittts(‘cl
hp mrtisonr. (x:111 lw ill~Olisht~tt 1)~ sitttultattcous ttwtltii(~ttl \zith STI r.

Outlook
IkJt4tlg IllC l)ilSt y('at', IWt’lla])s t Ills lllosl ittr~~ol~latrt ~~ofltril,tttiott 1,) ()ttt’
tuttlcrstanding of strc>SS a tt(I of the atlal)tive hot.ttlolles \\‘itS the J gtwwitlg t~cJalix;i-
tion of the limitatiotts of ;2(‘7‘?-1 iIltt1 A2-(’ tltct~;tp?-. Whcti l\(“l‘tT :i11(1 c~ot?isoJlv
c
 were first introduve(I into (~litlic.81 mc7lic4llc>. 1 tll’l‘~ \\‘ilh Ill~ll’lL lll~f’l’ ! tlill I l’(‘iI!

mrnt with t,hese hor~o11es tnight (qtt’(’ ;I. I;irp~ IIUII~~WI. 01’ hitherto incurillbt(k
diseases: indeed, it was t’ell that these tlrugs i ;11rt1 lh(ly bvert’ (~t)rrsi(lerc~cl ;IS
lnerely pha~rmaec)logic N~(‘~IIs, which lneillls cl~*llgs ) woultl hil\~ts s~lt*lr ;, \\-irlt*
spectrum Of prac+ical apl)li(~;ltioll that they woultl “l,c~\.l)li~tioirizt, inctlicdlit~.”
These hopes (lid uot nr:tIc~ri;lIize. 7’11C practical Villtlt’ of ;~ntil)hlc)gisiic titrl,-
moue treatment, as it is 110w practic~ctl, is limitctl IIF its unclrsir:ll)le sitIt
effects, and mauy cspcriclic~ctl clinic*jatis i~c~cO1ntr1c~l1clt~tl that. il. 1101. 1)~. i~se(l
routinely even in the treatnrcnl of rhrunii~toid ai*thritis whcr~ this t I~c~~;I~~,T~
\VilS
supposerl to he most useful. I :- I” Of wUrsr, it will ~011t ilium to l)e 11 v;llu;rl)l~~ ittltli-

tion to Our therapeutic ~l~~~~lii~ll~~~lt~~~illl~~. This is triic) ~~nrliculal~l~~ itr tl10 t real-
merit Of certain inflammator>~ diseases Of Ihc eye, \vhiclr do not teiltl to ~*(~IJIII’ so011
after t~iS~~~~ltiiiU~ltit~Il Of ti~W~~ll~~llt. 01’ (a:lJl’l~~l NllltlW~~t~tl tly the I’lllYly ltlls;ll ;I]‘-

plication Of A-C’s, wit,hout i~ltroduciug thcl tlanger 01’ systcGc< c~l,llll)lic~;ltiotrh.

liut, with such drastic limitation? the clinicill IISCJof ihc~st~I~OIYIIOII~SLVO\~!I~I,() iI
poor return for the ulltirill g efY0rts 0I’ all lliosc itl\cMigators who stutlietl t JIG
mechanism of respoltse to stwss wit,h the hope 01’ fincliilg a norm :IVCIIIIC to t tit’
rflective treatment ol tlisr;rsc* in gt’iit~r;11.
Although WC have not J-PI learuc~d how to IISC aclaptive hor~11011cscficientl~-
in the treatment, Of systemic2 tliseusrs. without l)rotluGug overclosagr efftds,
the body itself knows this secret. To take hut One striking exrmplc ill the
(‘OUl’W Of exposure to Sev(‘l’t’ stwss, illc llllrn:~U olyanistn Call al)pilrC>nt I$ pm-

dnce effective amounts of antiphlogistic hormoltcls (e.g.> during 1)regnancy.

darvation, am1 other types 01’ st~ss) without, elicitil1g il”s serious ~nani,frst;~-
tions Of hormonc~ overclosagc. Ii :rcc~omplishes this p1~sun1~1hly by ap1)ropr-
ate compensatory reactious wliich condition the response to theso horrnc~~~es.
We believe, therefore. that the real future OC this fieltl lies not irr 111e rllet.cl>,
empiric gathering ui’ data (*ollcerning the \~~lur ol’ iItl:ll)tive ~~~IwI~~I~~s in this
Or t,hat disease, ullguidrtl 1)~ iIll>- thi3or.y. l)nt iI1 the systenmtic* invc~stig;lfic~tl ot
t,he total integrated resp~nsc~ to stress.
Pasteur ant1 his colltcllll)oI,;lr.ic~s illtrotlucd the colleel)t of spcAficity into
medicine, a. concept whicah l~ro\-etl i o 1~ oi’ the greatest, hcllr*istic* V;IIW up to
the present time. Each i~ltlivitlual well-defined tlisease, they hrlcl. has its
owtt specific CiLUSC. Ii has t)CcJ~l (*lililtlt~cl 1):; lttilli)' ihilt l’:ISt(~ur f;iil(vI to ?.cJcOg-
nizci the importancc~ 011 Ihc “t(~r*rilill.” IGng too f)t*eoc*c*ul)ietl with I I](, ])a1 hogxlll
(microorganism) itself. This is illcorrrc.t. IIis IYOI*~ 011 illtlucetl itnlllunit>
shows how cleilrly he re;~lizt~tl the importance Of thcl “terrain.” The 1ll~WI~~
which dire&et1 the most Fruit Eul in\-estigations ot’ I’ilstt~lll. ;1n(1 his t’ollonc~rs
was that. the orgauism (aan dc\clop specific :~dapti\~c reactions ;lg:Lil1st iltfli-
\-dual pat,hogens and that I)y illliti1,tillg ;rncl c.orlil)lritiriitiIlp thcsr, wheilc~\~rr
they are short of optimal. wta (~a111 t~(ailt marry or thth tliseases whic.11 art’ clue IO
specific pathogens.
‘PO our mind, the G-A-S represeuts. in n sense, the negative counterfztrt,
OF mirror image, of this concept. It holds that, many tlisrnses h;lv(l no single
 4. Selve. H.: Bt.udies on Adaptation. E:ndocrinolo~rv 21: 169. 1937.
5. Rel$e: H., and Pentz, ,E. J.’ Patltogenetic: (lor%lations lktween I’eriarteritis Nodosa,
Renal Hvnertension and Rheumatic I,esions. Canatl. 12. A. .J. 49: 264. 194.7.
li. Sel,~e, H., Avi<ester, O., Hall, C’. E., and l,~l~lond. (‘. I’.: Horn~onal Product,ion of
Arthrit,is. .J. A. 11. A. 124: L’Ol. 194-t.
T. Siclye, I~.: On the Production et: hlaliynant Hvprrtension 1)~ (‘hronir F:xposure to
Various Iknaging Agents. Rev. canatl. de l,ioi. 2: 501. l!Wi.
S. Selycl, H.: The General .x;itlaptatiou Syntlrorur~ antI the IJiseases of Atlaptation, .I. Clin.
E~ndocrinol. 6: lli, 19-E.
!I. Relye, H.: Stress. The Physiology and Pathology of I~~slwsur~~ to Systemic Stress,
Montreal, 1950, Acta Inc.
10. Selye, Tf.: Further Studies (‘oncerning the Participation of the ilclrenal (‘ortex in
the pathogen&s of Arthritis, Hrit. If. .I. 2: I ll’!lj 1!1-19.
I I. Selye, H.: Koltr of the Hypophysis in the Pathogenesis of thca I)iseases of .\tlapt:c-
tion, (>anad. M. A. .I. 50: 426, 1944.

13. Selve. H.: The Influence of RTH, AC’I’H and (‘ortisone lpon Resistance to Tnfection,
(Ianad. hl. A. ,I. 64: 49 1951.
14. Selye, H.: Efiect of Cortisone and Somatotrophic Hormone 1Tpon the Development
of a Noma-lilie Condition in the Rat, ORAT, S17tw., ORhI. XTIL, ASI) ORAL PATH. 6:
.5.57 19:Ti:l
15. Selye, H.: First Annual Rtbport on Stress, Rlonlreal, 11151, Acta Inc.
16. Wallner, I,., Thompson, .J. R., ant1 T,icahttnstein, M. I<.: Clinical and Histopathologie
Study of the Effect of Corti,wne and (‘orticotropin on Tul)erculosis, Am. Rev.
Tuberc. 66: 161, 1952.
Ii’. Anonvmous: Cortisone and Caution. Lancet. Rlav 3. n. !lll. 1952.
18. Martin, G. M., Polleq-, H. F., and Anderson: T. P.: ‘I’hJ-sical Medicine Plus Cortisone
for Rheumatoid Arthritis, .I. 9. M. A. 148: 525, 1952.
19. Schmidt, I,.: Cortisone and Caution, Lancet, May 17, p. 1018, 1952.
20. Selw, H.: ‘Ilrc Story of the Adaptation Hyn~lronw, hlontwal, 1952, Acta Inc.
21. Se]:;-r*. H., ant1 Horava, A.: Third .\nnnal Report on Stress, 1fontrcal. 1!153. Arta
Inc.