Stress and Homeostasis

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The Concepts of Stress and
Stress System Disorders
Overview of Physical and Behavioral Homeostasis
George P. Chrousos, MD, Philip W. Gold, MD
Objective.\p=m-\Thisarticle defines stress and related concepts and reviews their
historical development. The notion of a stress system as the effector of the stress
syndrome is suggested, and its physiologic and pathophysiologic manifestations
are described. A new perspective on human disease states associated with dys-
regulation of the stress system is provided.
Data Sources.\p=m-\Publishedoriginal articles from human and animal studies and
selected reviews. Literature was surveyed utilizing MEDLINE and the Index Med-
icus.
Study Selection.\p=m-\Originalarticles from the basic science and human literature
consisted entirely of controlled studies based on verified methodologies and, with
the exception of the most recent studies, replicated by more than one laboratory.
Many of the basic science and clinical studies had been conducted in our own lab-
oratories and clinical research units. Reviews cited were written by acknowledged
leaders in the fields of neurobiology, endocrinology, and behavior.
Data Extraction.\p=m-\Independent extraction and cross-referencing by the authors.
Data Synthesis.\p=m-\Stressand related concepts can be traced as far back as
written science and medicine. The stress system coordinates the generalized
stress response, which takes place when a stressor of any kind exceeds a thresh-
old. The main components of the stress system are the corticotropin-releasing
hormone and locus ceruleus-norepinephrine/autonomic systems and their periph-
eral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system.
Activation of the stress system leads to behavioral and peripheral changes that im-
prove the ability of the organism to adjust homeostasis and increase its chances
for survival. There has been an exponential increase in knowledge regarding the
interactions among the components of the stress system and between the stress
system and other brain elements involved in the regulation of emotion, cognitive
function, and behavior, as well as with the axes responsible for reproduction,
growth, and immunity. This new knowledge has allowed association of stress sys-
tem dysfunction, characterized by sustained hyperactivity and/or hypoactivity, to
various pathophysiologic states that cut across the traditional boundaries of med-
ical disciplines. These include a range of psychiatric, endocrine, and inflammatory
disorders and/or susceptibility to such disorders.
Conclusions.\p=m-\Wehope that knowledge from apparently disparate fields of
science and medicine integrated into a working theoretical framework will allow
generation and testing of new hypotheses on the pathophysiology and diagnosis
of, and therapy for, a variety of human illnesses reflecting systematic alterations in
the principal effectors of the generalized stress response. We predict that pharma-
cologic agents capable of altering the central apparatus that governs the stress re-
sponse will be useful in the treatment of many of these illnesses.(JAMA. 1992;267:1244-1252)
ALTHOUGH human societies have be¬
come more complex and in many ways
more demanding, our physiological
mechanisms for coping with adversity
have not evolved appreciably over the
past several thousand years. Hence, it
seems that our physiological responses
to social pressures, information over¬
load, and rapid change resemble those
set into motion during physical danger
and outright threats to survival. Recent
technological advances have allowed us
to elucidate some of the neurophysio-
logical and biochemical events that pro¬
mote successful adaptation during
stressful situations, and we have begun
to identify illnesses that occur as a re¬
sult of, or associated with, dysregula-
tion of the stress response. Whether
these illnesses have always been with
us in abundance or are a more promi¬
nent part of the landscape of modern
life—which may present us with a
greater variety of adverse situations—
is conjectural. In the present overview,
we shall attempt to provide a historical
perspective on the concept of stress, to
review current ideas regarding the neu-
rophysiological and biochemical events
that are set into motion during stressful
situations, and to suggest how vulner¬
ability to several major disease entities,
such as affective illnesses and chronic
inflammatory processes, reflects dysreg-
ulation of the stress response.
From the Developmental Endocrinology Branch,
National Institute of Child Health and Human Develop-
ment (Dr Chrousos), and the Clinical Neuroendocrinol-
ogy Branch, National Institute of Mental Health (Dr
Gold), National Institutes of Health, Bethesda, Md.
Reprint requests to National Institutes of Health, Bldg
10, Room 10N262, Bethesda, MD 20892 (Dr Chrou-
sos).
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DEFINITION OF STRESS AND ITS
HISTORICAL DEVELOPMENT
Living organisms survive by main¬
taining an immensely complex dynamic
and harmonious equilibrium, or homeo-
stasis, that is constantly challenged or
outright threatened by intrinsic or ex¬
trinsic disturbing forces or Stressors.1
The steady state required for successful
adaptation is maintained by counteract¬
ing/reestablishing forces, or adapta-
tional responses, consisting of an ex¬
traordinary repertoire of physical or
mental reactions that attempt to coun¬
teract the effects of the Stressors in or¬
der to reestablish homeostasis. In this
context, we define stress as a state of
disharmony, or threatened homeosta¬
sis. The adaptive responses can be
specific to the Stressor or can be gen¬
eralized and nonspecific. The latter
can be Stereotypie and generally oc¬
cur only if the magnitude of the
threat to homeostasis exceeds a cer¬
tain threshold.
These contemporary concepts regard¬
ing stress have evolved over the past
2V2 millennia.16 In the beginning of the
classic era, Heracleitus was the first to
suggest that a static, unchanged state
was not the natural condition, but rather
that the capacity to undergo constant
change was intrinsic to all things. Shortly
afterward, Empedocles proposed the
corollary idea that all matter consisted
of elements and qualities in a dynamic
opposition or alliance to one another,
and that balance or harmony was a nec¬
essary condition for the survival of liv¬
ing organisms. One hundred years later,
Hippocrates equated health to a har¬
monious balance of the elements and
qualities of life and disease to a system¬
atic disharmony of these elements. The
terms "dyscrasia" and "idiosyncrasy" are
derived from the Hippocratic concept of
health and disease, meaning, respec¬
tively, a defective or peculiar mixing of
the elements. Hippocrates also sug¬
gested that the disturbing forces that
produced the disharmony of disease de¬
rived from natural rather than super¬
natural sources and that the counter¬
balancing or adaptive forces were of a
natural origin as well. Thus, he intro¬
duced the concept that "Nature is the
healer of disease," a notion later echoed
by the Romans when they referred to
the counterbalancing forces as Vis Med-
icatrix Naturae, or the "healing power
of nature." Epicurus had, in the mean¬
time, suggested that the mind could be
among or influence these healing forces,
and he wrote that ataraxia, or "imper¬
turbability of mind," represented a par¬
ticularly desirable state.
In the years of the Renaissance,
Thomas Sydenham extended the Hip-
pocratic concept of disease as a system¬
atic disharmony brought about by dis¬
turbing forces, when he suggested that
an individual's adaptive response to such
forces could itself be capable of produc¬
ing pathological changes. Claude Ber¬
nard extended our notion of harmony or
the steady state in the 19thcentury,
when he introduced the concept of the
milieu intérieur, or the principle of a
dynamic internal physiological equilib¬
rium. Walter Cannon later coined the
term "homeostasis" and extended the
homeostatic concept to emotional as well
as physical parameters. He also de¬
scribed the "fight or flight reaction" and
linked the adaptive response to stress
with catecholamine secretion and ac¬
tions. In the 1930s, Hans Selye borrowed
the term "stress" from physics and set
it to mean the mutual actions of forces
that take place across any section of the
body. He hypothesized that a constel¬
lation of Stereotypie psychological and
physiological events occurring in seri¬
ously ill patients represented the con¬
sequences of a severe, prolonged appli¬
cation of adaptational responses. He re¬
ferred to this state as the "General Ad¬
aptation or Stress Syndrome" and, in
effect, redefined Sydenham's concept of
diseases of adaptation.
Selye made it clear that not all states
of stress, or threatened homeostasis,
were noxious when he coined the terms
"eustress" and "distress." Hence, he be¬
lieved that mild, brief, and controllable
states of challenged homeostasis could
actually be perceived as pleasant or ex¬
citing and could be positive stimuli to
emotional and intellectual growth and
development. It was the more severe,
protracted, and uncontrollable situations
of psychological and physical distress
that Selye believed led to frank disease
states.
STRESS SYNDROME-
PHENOMENOLOGY
Both physical and emotional Stressors
set into motion central and peripheral
responses designed to preserve homeo¬
stasis (Table l).1·7·8 Centrally, there is a
facilitation of neural pathways mediat¬
ing, among other functions, arousal,
alertness, vigilance, cognition, and fo¬
cused attention, as well as appropriate
aggression, with concurrent inhibition
of pathways that subserve vegetative
functions, such as feeding and repro¬
duction. Peripheral changes occur prin¬
cipally to promote an adaptive redirec¬
tion of energy. Thus, oxygen and nu¬
trients are directed to the central ner¬
vous system and the stressed body
site(s). Moreover, increases in cardio¬
vascular tone lead to elevations in blood
pressure and heart rate, while increases
Table 1. — Behavioral and Physical Adaptation
During Stress
Behavioral Adaptation
Adaptive redirection of behavior
Acute facilitation of adaptive and inhibition of nonadap-
tive neural pathways
Increased arousal, alertness
Increased cognition, vigilance, and focused atten¬
tion
Suppression of feeding behavior
Suppression of reproductive behaviorContainment of the stress response_
Physical Adaptation
Adaptive redirection of energyOxygen and nutrients directed to the central nervous
system and stressed body site(s)
Altered cardiovascular tone, increased blood pres¬
sure and heart rate
Increased respiratory rate
Increased gluconeogenesis and lipolysis
Detoxification from toxic productsInhibition of growth and reproductive systems
Containment of the stress response
Containment of the inflammatory/immune response
in respiratory rate, gluconeogenesis, and
lipolysis all promote enhanced availabil¬
ity of vital substrates. As a corollary,
peripherally mediated restraint of
growth and reproduction preserves en¬
ergy that could be used more efficiently
to the adaptive advantage conferred by
a successful general adaptational re¬
sponse. The latter depends not only on
its capacity to respond quickly to ap¬
propriate stimuli, but also on its ability
to respond to counterregulatory ele¬
ments that prevent an overresponse.
Hence, every element of the stress re¬
sponse, including that originating from
an inflammatory/immune reaction, must
briskly respond to restraining forces.
Otherwise, these responses lose their
adaptive quality and contribute to the pro¬
cess of pathological change (see below).
STRESS SYSTEM-PHYSIOLOGY
Because the general adaptational re¬
sponse is both essential for survival and
remarkably consistent in its presenta¬
tion, it has been suggested that a dis¬
crete, dedicated system has evolved spe¬
cifically for its coordination.17,8 The iden¬
tification of some of the biochemical ef¬
fectors of the stress response and the
central loci responsible for producing
and releasing these informational sub¬
stances has preliminarily substantiated
this hypothesis.
The two principal components of the
general adaptational response are the
corticotropin-releasing hormone (CRH)
and the locus ceruleus-norepinephrine(LC-NE)/autonomic (sympathetic) ner¬
vous systems.1,7,8 The CRH system is
widespread throughout the brain but is
best characterized in the paraventricu-
lar nucleus of the hypothalamus.9"13 The
intraventricular administration of mod¬
erate doses of CRH sets into motion a
coordinated series of physiological and
behavioral responses that are adaptive
during stressful situations.7,8,12"20 These
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include activation of the pituitary-adre¬
nal axis13·14 and the sympathetic ner¬
vous system,1346 leading to increases in
glucose, heart rate, and blood pressure.
In addition, centrally administered CRH
in moderate doses enhances arousal and
promotes cautious restraint, while in¬
hibiting vegetative functions such as
feeding and reproduction.13·17-20 In larger
doses, the central administration ofCRH
produces effects that can be construed
as frankly anxiogenic, including hyper-
responsiveness to sensory stimuli, as¬
sumption of the freeze posture and de¬
creased exploration in unfamiliar envi¬
ronments, and enhancement of condi¬
tioned fear responses during aversive
stimuli.13·21·22
The LC-NE/sympathetic systems are
located in the brain stem.23 Activation
of the LC-NE system leads to release of
NE from an extraordinarily dense net¬
work of neurons throughout the brain,
resulting in enhanced arousal and vig¬
ilance, as well as increased anxiety. Clas¬
sically, the sympathetic division of the
autonomie system is primarily associ¬
ated with conferring an adaptive advan¬
tage during stressful situations via its
effectors, the sympathetic nerves and
the adrenal medulla, located in the pe¬
riphery. The parasympathetic division
of the autonomie nervous system, on
the other hand, is closely linked func¬
tionally to the sympathetic system. Pri¬
marily, however, it produces effects an¬
tithetical to those of the sympathetic
nervous system, whereas its inhibition
can produce effects analogous to those
of sympathetic activation. Although, to
maintain simplicity, we refer herein to
the sympathetic system only, one should
keep in mind the concurrent stress-re¬
lated changes of its parasympathetic
counterpart.
There are many potential sites of in¬
teraction among the different compo¬
nents of the stress system, shown in Fig
1. Functionally, the CRH and LC-NE/
sympathetic systems seem to partici¬
pate in a positive, reverberatory feed¬
back loop so that activation of one sys¬
tem tends to activate the other as well.
As an example, the application of CRH
onto LC neurons markedly increases the
LC firing rate,13·2426 while NE is a po¬
tent stimulus to the release of CRH.2729
Similarly, the central administration of
a CRH antagonist diminishes the re¬
sponses of the LC to a variety ofstimuli,
while ß-adrenergic blockade attenuates
the arousal-producing effects ofcentrally
administered CRH.13·22 The neuroana-
tomical contexts for these interactions
are complex but include projections of
CRH-secreting neurons from the lat¬
eral paraventricular nuclei (PVN) to the
arousal and sympathetic systems in the
hindbrain23,30 and, conversely, projec¬
tions of catecholaminergic fibers from
the LC-NE system, via the ascending
noradrenergic bundle, to the PVN in
the hypothalamus.23,28,29,31 In addition to
the interactionsbetween CRH and NE
themselves, the PVN-CRH and LC-NE/
sympathetic systems seem to respond
similarly to many of the same neuro-
chemical modulators. Hence, both se¬
rotonin and acetylcholine appear exci¬
tatory to PVN/CRH neurons3237 and the
LC-NE/sympathetic systems,36,38"11
while both of these centers respond to
inhibition by gabaergic38,39,42,43 and opi-
oid peptidergic38,41,4448 neurotransmission
and by the glucocorticoids.46,49 Projec¬
tions of CRH neurons from the PVN to
proopiomelanocortin-containingneurons
in the arcuate nucleus also promote the
release ofcorticotropin and ß-endorphin
from the latter,50,61 and each of these
serves to inhibit the release of CRH
from the PVN.46"48,50,51 Finally, the PVN/
CRH and LC-NE/sympathetic systems
respond to autoregulation by CRH and
a2-adrenergic-mediated inhibition, re¬
spectively.38,39,46,62"54
A variety of other neuropeptides and
informational substances play an impor¬
tant role in the stress response, includ¬
ing arginine vasopressin and dynorphin-
related peptides. Arginine vasopressin
synergizes CRH's capacity to release
corticotropin and ß-endorphin from the
anterior pituitary and the hypothalamus,
stimulates the LC-NE/sympathetic sys¬
tem, and might synergistically enhance
some of the central behavioral effects of
CRH as well, w.22·51·65-68 The opioid dynor-
phin-related peptides coexist within pop¬
ulations ofhypothalamic neurons secret¬
ing CRH or arginine vasopressin or are
produced by hypothalamic arcuate nu¬
cleus neurons.5961 Dynorphin-related
peptides and CRH have reciprocal ac¬
tions on the release of each other, with
CRH stimulating dynorphin secretion50
and dynorphin inhibiting CRH re¬
lease.47,48 In addition, it appears that
dynorphin 17 significantly inhibits the
activating actions of CRH on the LC-
NE/sympathetic systems.62
The stress system that plays so pro¬
found a role in setting the level ofarousal
also interacts with other central ner¬
vous system elements that influence the
retrievability and analysis of informa¬
tion, the initiation of specific action, and
the setting of the emotional tone. Three
major brain systems are activated by
the stress system and, in turn, influence
its activity (Fig 1). First, the mesocor-
tical and mesolimbic dopamine systems
are activated by the LC-NE/sympathetic
systems during stress.23,63"67 The former
innervates the prefrontal cortex, a brain
region thought to be involved in antic-
ipatory phenomena and cognitive func¬
tion. The latter is closely linked to the
nucleus accumbens, thought to play a
principal role in motivational/reinforce¬
ment/reward phenomena. Second, the
amygdala/hippocampus complex is ac¬
tivated during stress, primarily by nor-
adrenergic neurons, whose origin is the
brain stem LC-NE/sympathetic sys¬
tems, or by an incoming "emotional"
Stressor, such as conditioned fear, gen¬
erated, perhaps, at memory-storing sub-
cortical and cortical fields.68"73 Activa¬
tion of the amygdala by the LC-NE/
sympathetic system is important for re¬
trieval and emotional analysis of
information pertinent to the Stressor
and, ifthe Stressor is emotional, for stim¬
ulation of the activity of the PVN-CRH
and LC-NE/sympathetic systems.73"76
The hippocampus appears to play a ma¬jor inhibitory influence on the activity
of the amygdala and the PNV/CRH sys¬
tem.76"78 Third, activation of the CRH
neuron in the PVN leads to activation of
arcuate proopiomelanocortin neurons
that send projections to the PVN brain
stem and other brain areas to counter-
regulate CRH neuron and LC-NE/sym¬
pathetic system activity, respectively;
to induce opioid receptor-mediated,
stress-related analgesia; and perhaps to
influence the emotional tone.46"48·79·80
The systems responsible for repro¬
duction, growth, and immunity are di¬
rectly linked to the stress system, and
each is profoundly influenced by the ef¬
fectors of the stress response (Fig 2).
As an example, the reproductive axis is
inhibited at all levels by various com¬
ponents of the hypothalamic-pituitary-
adrenal ( ) axis81"85 (Fig 2A). Either
directly or via ß-endorphin, CRH sup¬
presses the luteinizing hormone releas¬
ing hormone neuron of the arcuate nu¬
cleus of the hypothalamus. Glucocorti-
coids, on the other hand, exert inhibi¬
tory effects at the levels ofthe luteinizing
hormone releasing hormone neuron, the
pituitary gonadotroph, and the gonad
itself and render target tissues of sex
steroids resistant to these hormones.
The growth axis is also inhibited at
many levels during stress (Fig 2B).82·86"89
Although an acute elevation of growth
hormone concentration in plasma is usu¬
ally observed during the onset of the
stress response in man, prolonged ac¬
tivation of the stress system leads to
suppression of growth hormone secre¬
tion and inhibition of somatomedin C
and other growth factor effects on their
target tissues. Increases in somatosta-
tin secretion stimulated by CRH, with
resultant inhibition of growth hormone
secretion, as well as direct glucocorti-
coid effects—acutely stimulatory but
chronically inhibitory89·90—on growth
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Mesocortical/
Mesolimbic Systems
Amygdala-
Hippocampus
Complex
Serotonin
Acetylcholine
GABA/BZD
 Dynorphin
Epinephrine
Norepinephrine
Target
Tissues
Fig 1.—A simplified, heuristic representation of the central and peripheral components of the stress system,
their functional interrelations, and their relationships to other central nervous system systems involved in
the stress response. The hypothalamic oorticotropln-releasing hormone (CRH) neuron in the paraventric-
ular nucleus and the centers of the arousal and autonomie systems in the brain stem represent major cen¬
ters of this system connected anatomically and functionally to each other (see text). POMC indicates pro-
opiomelanocortin; LC/NE Symp Syst, locus ceruleus-norepinephrlne/sympathetic system; AVP, arginine
vasopressin; GABA, y-aminobutyric acid; BZD, benzodiazepine; and ACTH, corticotropin.
hormone secretion have been implicated
as potential mechanisms for the stress-
related suppression of growth hormone
secretion. A corollary phenomenon to
growth axis suppression is the stress-
related inhibition of thyroid axis func¬
tion. Stress is associated with decreased
production of thyroid-stimulating hor¬
mone and inhibition of conversion of the
relatively inactive thyroxine to the more
biologically active triiodothyronine in pe¬
ripheral tissues. Although the exact
mechanism(s) for these phenomena is
not known, both phenomena may be
caused by the increased levels of glu-
cocorticoids and may serve to conserve
energy during stress.91·92 Inhibition of
thyroid-stimulating hormone secretion
by CRH-stimulated increases in somato-
statin might also participate in the
central component of thyroid axis sup¬
pression during stress.
The stress system also has profound
inhibitory effects on the inflammatory/
immune response (Fig2C). Alterations
of leukocyte traffic and function, de¬
creases in production of cytokines and
mediators of inflammation, and inhibi¬
tion of the latter's effects on target tis¬
sues are among the main immunosup-
pressive effects of glucocorticoids.93·94
Conversely, however, several products
of the immune system exert stimula¬
tory effects on the axis, hence clos¬
ing a negative feedback loop. Most stim¬
ulatory effects from the immune system
are exerted by the inflammatory cyto¬
kines interleukin 1 (IL-1), IL-6, and tu¬
mor necrosis factor, or by mediators of
inflammation—such as several ei-
cosanoids and platelet-activating factor—
on hypothalamic CRH secretion.96"99
It is not clear which of the above ef¬
fects are endocrine and which para-
crine. Presence of cytokinergic neural
pathways and local involvement of
eicosanoidsand platelet-activating
factor in CRH secretion are certain.
Direct effects of cytokines and media¬
tors of inflammation on pituitary cor¬
ticotropin secretion, on the other
hand, have also been shown or sug¬
gested for IL-1, IL-6, tumor necrosis
factor, serotonin, several eicosanoids,
and platelet-activating factor, and di¬
rect effects on adrenal glucocorticoid
secretion might also be present.
STRESS SYSTEM-
PATHOPHYSIOLOGY
Generally, the stress response is
meant to be acute or at least of a limited
duration. The time-limited nature of this
process renders its accompanying anti-
anabolic, catabolic, and immunosuppres-
sive effects temporarily beneficial and
of no adverse consequences. Chronicity
and excessiveness of stress system ac¬
tivation, on the other hand, would lead
to the syndromal state that Selye de¬
scribed in 1936.56 He suggested then
that severe chronic disease of any eti¬
ology could present with anorexia, loss
of weight, depression, hypogonadism,
peptic ulcers, and immunosuppression.
Increased and protracted production of
CRH in these patients could explain the
pathogenesis ofthe syndrome, since this
peptide would be expected to cause ev¬
ery one of the above symptoms and
signs.
The syndrome of melancholic depres¬
sion also seems to represent dysregu-
lation ofthe generalized stress response,
which in this state seems to escape the
usual counterregulatory elements that
serve to make it a self-limiting process.7,s
Hence, the cardinal manifestations of
melancholic depression are the hyper-
arousal and redirection of energy that
are extremes of the classic manifesta¬
tions of the generalized stress response(Table 1). Because of the failure of ad¬
equate counterregulation, however,
what is adaptive and temporally limited
in the generalized stress response ap¬
pears to quantitatively and qualitatively
change and be, thus, prolonged and mal-
adaptive in melancholic depression.
Thus, arousal becomes dysphoric hyper-
arousal and anxiety, and vigilance is
turned into hypervigilance and insom¬
nia. The dysphoria observed in melan¬
cholic depression may represent tachy-
phylaxis of the mesocorticolimbic sys¬
tem to chronic activation of the stress
system. On the other hand, cognition,
memory, and attention are focused ob-
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Reproduction
ß-endorphin
• \
LHRH -4-CRH
LH, FSH \ ACTH
Testosterone, ^- - Glucocorticoids
Estradiol
B
Growth and Thyroid Function
GHRH STS <*- CRH - STS TRH
SmC
Target Tissues Target Tissues
ACTH
Glucocorticoids
TSH
 4
Target Tissues
Immune Function
*CRH^
Cytokines(IL-1, IL-6, TNF) > ACTH ;
I
Mediators at \
Inflammation
-^--Glucocorticoids(Eicosanoids,
PAF, Serotonin) „
s4t
Target Tissues
Fig 2.—A simplified, heuristic representation of the interactions between the hypothalamic-pituitary-adrenal axis and other neuroendocrine systems, including the
reproductive axis (A), the growth and thyroid axis (B), and the immune system (C) (see text). LHRH indicates luteinizing hormone releasing hormone; CRH,
corticotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; ACTH, corticotropin; GHRH, growth hormone releasing hormone; STS,
somatostatin; TRH, thyrotropin-releasing hormone; GH, growth hormone; TSH, thyroid-stimulating hormone; T„, thyroxine; SmC, somatomedin C; T3, triiodothy¬
ronine; IL-1, interleukin 1; IL-6, interleukin 6; TNF, tumor necrosis factor; and PAF, platelet-activating factor.
sessively on depressive ideas, adversely
influencing the ability of the individual
to remember and focus on learning and
solving practical, everyday, or pertinent
problems. In this disease, assertiveness
is often transformed into excessive cau¬
tiousness and anxiety. Moreover, de¬
creased emphasis on feeding and repro¬
duction, which is adaptive in the con¬
text of the generalized stress response,
becomes maladaptive in the sustained
anorexia, hypothalamic hypogonadism,
and decreased libido that are the hall¬
marks of melancholic depression. Both
the axis and the sympathetic sys¬
tem appear chronically activated in this
illness.7·8·100"103 Could increased and
chronic CRH secretion explain the
pathophysiological picture ofdepression?
Such hypersécrétion of CRH was shown
in depression and was originally thought
to be an epiphenomenon.101·104·105 Admin¬
istration of CRH to experimental ani¬
mals, however, with its profound effect
on reproducing the stress response, sug¬
gests that CRH may participate in the
initiation and/or propagation of a vicious
cycle.
In addition to melancholic depression,
a host of other conditions may be asso¬
ciated with increased and prolonged
CRH secretion or activity (Table 2).
These include anorexia nervosa,106107
panic anxiety,108·109 obsessive-compulsive
disorder,110 chronic active alcoholism,111
alcohol and narcotic withdrawal,112"116 ex¬
cessive exercising,117 malnutrition,118
and, perhaps, hyperthyroidism119andthe
premenstrual tension syndrome.120 Al¬
though hypersécrétion ofCRH may con¬
tribute to many of the common mani¬
festations of these illnesses, however,
many other idiosyncratic alterations in
peptidergic or nonpeptidergic neuro-
transmitter function may confer patho-
physiological specificity to these disor¬
ders. For instance, although patients
withanorexianervosaoften show strongfamily histories ofmajor depression and
are often depressed themselves,121,122
they also show evidence ofneural mech¬
anisms influencing hunger and satiety
that could impel them in the direction of
pathological eating behaviors. Such pa¬
tients show hypersécrétion of centrally
directed arginine vasopressin, a peptide
that in experimental animals delays the
extinction ofbehaviors acquired during
aversive conditioning.123,124 This defect
could thus, theoretically, contribute to
anorexics' perseverative preoccupation
with the adverse consequences of eat¬
ing and weight gain.
Different manifestations are shown
by the other states associated with pro¬
longed hyperactivity of the stress sys¬
tem. Panic disorder is characterized by
panic attacks, which resemble acute dis-
charges of the sympathetic system or
withdrawals ofthe parasympathetic sys¬
tem, leading to acute episodes of dys-phoric hyperarousal and anxiety. Ob¬
sessive-compulsive disorder is charac¬
terized by obsessive thoughts, compul¬
sive actions, and anxiety, and chronic
active alcoholism and alcohol and nar¬
cotic withdrawal with extreme anxiety
and obsessive seeking ofalcohol or nar¬
cotics. Chronic excessive exercise is
characterized by obligate exercising125
and associated hypogonadism,126 fre¬
quently expressed as hypothalamic
amenorrhea in women.127 Characteris¬
tically, obligate athletes go through
withdrawal symptoms and signs if, for
any reason, they have to discontinue
their exercise. This syndrome has been
proposed to possibly result from with¬
drawal from the daily exercise-induced
elevations of ß-endorphin and/or other
opioid peptides that may be involved in
the pleasurable aspects of the stress re¬
sponse. Alternatively and/or concur¬
rently, stress-induced activation of the
mesocorticolimbic dopamine systems
may be involved in these phenomena.
Excessive exercising and malnutrition,
two states associated with increased
CRH secretion, are also primal compo¬
nents of anorexia nervosa. Although
studies ofhumans with hyperthyroidism
have not been conclusive, hyperactivity
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Table 2.—Disorders Associated With Dysregulatlon
of the Stress System
Increased Stress
System Activity
Decreased Stress
System Activity
Severe chronic disease
Anorexia nervosa
Melancholic depression
Panic disorder
Obsessive-compulsive
disorderChronic active
alcoholism
Alcohol and narcotic
withdrawal
Chronic excessive
exercise
Malnutrition
Hyperthyroidism
Premenstrual tension
syndrome
Vulnerability to addiction(rats)
Atypical depression
Cushlng's syndrome
Seasonal depression
Chronic fatigue
syndrome
Hypothyroidism
Obesity(hyposerotonergic
forms)
Posttraumatic stress
disorder
Nicotine withdrawal
Vulnerability to
inflammatory disease(Lewis rat)
of the CRH neuron would be expected
in this condition. The latter clearly oc¬
curs in experimental animals,119 and in¬
tense anxiety is a typical complaint of
hyperthyroid patients. In addition, hy-
perthyroidism is known to exacerbate
endogenous depression. Recently, the
premenstrual tension syndrome was as¬
sociated with what appears to be a trait¬
like transient activation ofthe axis;
clearly, however, this activation does
not result in hypercortisolism.120
A very interesting body of experi¬
mental studies was recently published
that provides a potential linkage be¬
tween a hyperactive axis response
to a mild Stressor and individual vul¬
nerability to narcotic self-administra¬
tion.128 In these studies, a predisposi¬
tion to develop amphetamine addiction
could be predicted by the behavioral re¬
activity of the individual animal to ex¬
posure to a novel environment. The au¬
thors implicated glucocorticoids in the
pathogenesis ofthis condition, since they
found that corticosterone facilitated the
acquisition of amphetamine self-admin¬
istration, perhaps by increasing the re¬
inforcing value of the drug.
The theory that the depressive dis¬
orders are associated with CRH hyper-
secretion or hyperactivity could not at
first be reconciled with two other de¬
pressive syndromes, "atypical" depres¬
sion and Cushing's syndrome, in which
the clinical picture of polyphagia and
weight gain, as well as fatigue, anergia,
and excessive sleep, was, in fact, con¬
verse to that expected from CRH hy¬
persécrétion. 7·8· 10° Direct measurements
of CRH in the cerebrospinal fluid of pa¬
tients with Cushing's syndrome, and in¬
ference from a variety of studies ex¬
ploring the functional integrity of each
component of the axis, suggested
that in these individuals CRH secretion
was indeed decreased.100·105 Further
studies in patients with seasonal depres¬
sion and the chronic fatigue syndrome
Fig 3.—Left, Theoretical sigmoidei dose-response curves between the potency of a Stressor and the activity
of the stress system in normally reactive individuals (1) vs hypersensitive (hyperreactive) (2) or hyposen¬
sitive (hyporeactive) (3) ones. Right, Theoretical inverse U-shaped dose-response curves between sense
of well-being and/or performance and the activity of the stress system in normally reactive individuals (1)
vs hyperreactive (2) or hyporeactive (3) ones. The numbers of the curves correspond in the two panels. In
both hyperreactive and hyporeactive individuals, the range of optimum is significantly curtailed.
also suggested that in the depressive(winter) state of the former and in the
period of fatigue in the latter, there was
chronically decreased CRH secre¬
tion. 129,130 Similarly, hypothyroid patients
and hypothyroid experimental animals
have clear evidence of CRH hyposecre-
tion.119,131 Interestingly, one of the ma¬jor manifestations of human hypothy¬
roidism is depression of the "atypical"
type. The overall impression from the
above data is that, perhaps, there is
another form of stress system dysreg-
ulation characterized by hypoactivation,
rather than sustained activation, in
which chronically reduced secretion of
CRH may result in pathological hypo-
arousal (Table 2). Such hypoarousal may
or may not be accompanied by dyspho-
ria, perhaps owing to inadequate stim¬
ulation of the mesocorticolimbic system
by the stress system. This category of
chronic CRH hyposecretion may also
include some forms of obesity that are
characterized by a hypoactive, hypose¬
rotonergic axis132134; subgroups of
adult patients with the posttraumatic
stress disorder, which was recently as¬
sociated with decreased urinary free Cor¬
tisol excretion135,136 and increased sym¬
pathetic system discharges in response
to specific memories or Stressors137,138;
and withdrawal from smoking, which
was associated with decreased adrena¬
line or noradrenaline excretion and de¬
creased plasma concentrations of epi-
nephrine and cortisol.139141 Decreased
CRH secretion in the early period of
nicotine abstinence could explain the hy-
perphagia and weight gain frequently
observed in these patients.142
An animal model of autoimmune in¬
flammatory disease, the Lewis rat, has
a hypofunctional CRH neuron, which
allows development of a rheumatoid ar¬
thritis-like syndrome and other autoim¬
mune inflammatory phenomena. This is,
to a great extent, because of an inter¬
ruption in the inflammatory mediator-
CRH negative feedback loop, which nor¬
mally counterregulates the inflamma¬
tory response via glucocorticoids148·144(Fig 2C). The defect of the CRH neuron
in this animal is generalized, so that the
CRH gene is hyporesponsive not only to
any of the physiological inflammatory
stimuli, but to neurochemical and envi¬
ronmental stimuli as well.145 Hence,
Lewis rats show not only evidence of
defective immune counterregulation, as
a consequence of their deficient CRH
neuron responsiveness, but also evi¬
dence of behavioral alterations compat¬
ible with decreased CRH synthesis and
release in the central nervous system.
Whether these experimental findings are
of any relevance to the pathogenesis of
human autoimmune disease is unknown,
but worthwhile to pursue.
STRESS SYNDROME
DYSREGULATION-POTENTIAL
MECHANISMS
We speculate that dysregulation of
the stress system, expressed either as
hyperfunction or as hypofunction, in¬
volves a number of human health prob¬
lems of enormous impact to society (Ta¬
ble 2). It would frequently be difficult to
distinguish between cause and effect in
such dysregulation, since this system
is, to a large extent, "nonspecific" and
meant to interact with internal or ex¬
ternal perturbations in a quite similar
manner. Thus, inappropriate adapta-
tional responses could be maladaptive
and act as Stressors themselves, feed¬
ing into a sustained vicious cycle.
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The individual variability in respon¬
siveness to Stressors may reflect ex¬
tremes of high or low sensitivity of the
stress system, resulting in persons with
altered vulnerability to stress. Thus,
there could be a family ofsigmoidal dose-
response curves between the potency of
a stressor and the activity of the stress
system, with some curves shifted to the
left, reflecting hyperresponsiveness, and
some to the right, reflecting hypore-
sponsiveness (Fig 3, left). We speculate
that there is also a corresponding family
of inverse {/-shaped dose-response
curves that relate a sense of well-being
or performance with the activity of the
stress system (Fig 3, right). For nor¬
mally active individuals, there is an op¬
timal level ofarousal, and potential shifts
in the activity of the stress system in
either direction could produce subjec¬
tive discomfort or decreasing perfor¬
mance. Those whose inverse [/-shaped
dose-response curves are shifted to the
left may be more prone to pathological
hypoactivity and may be liable to atyp¬
ical depression or inflammatory disease,
while those whose curves are shifted to
the right may be more vulnerable to
hyperactivity illnesses, such as melan¬
cholic depression. In both hyperactive
and hypoactive individuals, the range of
the optimum for sense ofwell-being and
performance would be significantly cur¬
tailed. The dysphoric component ofboth
extreme states may be explained, re¬
spectively, by hyperstimulation and ta-
chyphylaxisor by inadequate stimula¬
tion of the dopaminergic reward sys¬
tem, whose activity is influenced accord¬
ingly by the stress system.23,68"67
The categorization of disease states
in Table 2 and their correspondence to
the curves in Fig 3 are tenuous and are
based mostly on the state of the indi¬
vidual at the time of the study rather
than on his or her state-independent sen¬
sitivity to Stressors. Thus, patients with
severe chronic disease should have a
normal dose-response curve between a
stressor and the activity of the stress
system in their nondisease state. Pa¬
tients with melancholic depression, on
the other hand, who would be expected
to express an enhanced response of the
stress system to Stressors when not de¬
pressed and while eucortisolemic, might
be quite unresponsive to stimuli from
the external world during a depressive
episode. At that time, the heightened
awareness of internal cues and painful
memories, and concurrent activation of
the stress system, could make the sys¬
tem refractory to Stressors that would
otherwise influence its activity. Con¬
versely, a patient with panic disorder
will frequently express panic at times of
the day that the stress system is at the
nadir of its function. Another example
is patients with the posttraumatic stress
disorder. These patients are typically in
a basal state of stress system hypoac-
tivity that, however, is associated with
heightened responses of the stress sys¬
tem to certain stressors. More detailed
studies will be needed before one knows
exactly whether a disease state repre¬
sents hypersensitivity or hyposensitiv-
ity of the stress system to stressors and
whether situations exist in which, de¬
pending on the state, shifts could take
place from one side of the dose-response
curve to the other. Such a shift of the
dose-response curve from the left ex¬
treme to the right extreme appears to
occur during the early period of cocaine
withdrawal.146
Shifts in the dose-response curves of
Stressor vs stress system activity could
reflect a hereditary trait resulting from
a genetic defect in metabolism, such as
a change in the quantity or quality of
expression of a particular gene for a
hormone, a receptor, or an enzyme. A
trait defect, alternatively, might be ac¬
quired as a result of a critical change at
one point in life. Animal infants that are
separated from their mothers, for in¬
stance, develop a syndrome character¬
ized by hyperreactivity ofthe stress sys¬
tem to stressors and altered, "anxiety¬
like" behaviors throughout the rest of
their lives.147 The magnitude or dura¬
tion of the Stressor, the critical timing of
the event, the actual genetic vulnera¬
bility and makeup of the individual, and
the influences of her or his social envi¬
ronment (modifiers of coping and social
support) might, thus, ultimately deter¬
mine the pathogenesis of a syndrome
related to dysregulation of the stress
system.148"151
Based on the information presented
on the physiological regulation of the
stress system, one could postulate a
number ofpotential biochemical defects
that could, in theory, lead to basal or
stressor-induced hyperactivity or hypo-
activity of this system (Fig 1). Thus,
increased CRH peptidergic, serotoner-
gic, cholinergic, catecholaminergic, or
thyroid hormone-mediated stimulatory
activity, or decreased inhibitory activ¬
ity ofthe CRH-peptidergic, - -aminobu-
tyric acid/benzodiazepine, glucocorti-
coid-mediated, and opioid—or corti-
cotropin—peptidergic influences on the
stress system could result in diseases
characterized by increased stress sys¬
tem activity. The converse biochemical
changes, on the other hand, would be
expected in diseases characterized by
hypoactivity of the stress system. We
may be quite far from definitively elu¬
cidating the molecular defects respon¬
sible for a disease potentially attribut-
able to a dysregulated stress system,
such as depression, anorexia nervosa,
or autoimmune disease. Moreover, it is
likely that a combination of molecular
defects and/or environmental events
may be required for the expression of
each of these illnesses. However, the
theoretical framework for testing the
hypothesis that a dysregulation in the
stress system can lead to human disease
has been set in place, with the potential
for improved understanding, diagnosis,
and treatment of these disorders.
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