Stress, the Stress System and the Role of Glucocorticoids

Abstract

All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases. © 2014 S. Karger AG, Basel.

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E-Mail karger@karger.com
Basic Research concerning Glucocorticoids
Neuroimmunomodulation 2015;22:6–19
DOI: 10.1159/000362736
Stress, the Stress System and the Role of
Glucocorticoids
NicolasC.Nicolaides  a,b ElliKyratzi  b AgaristiLamprokostopoulou  b
GeorgeP.Chrousos  a–c EvangeliaCharmandari  a,b 
a  Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens
Medical School, ‘Aghia Sophia’ Children’s Hospital, and
b  Division of Endocrinology and Metabolism,
Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens , Greece;
c  Saudi Diabetes Study Research Group, King Fahd Medical Research Center, King Abdulaziz University,
Jeddah, Saudi Arabia
adverse effects on many vital physiologic functions, such as
growth, development, metabolism, circulation, reproduc-
tion, immune response, cognition and behavior. A strong
and/or long-lasting stressor may precipitate and/or cause
many acute and chronic diseases. Moreover, stressors during
pre-natal, post-natal or pubertal life may have a critical im-
pact on our expressed genome. This review describes the
central and peripheral components of the stress system, pro-
vides a comprehensive overview of the stress response, and
discusses the role of glucocorticoids in a broad spectrum of
stress-related diseases. © 2014 S. Karger AG, Basel
Introduction
All living organisms must respond to many unfore-
seen extrinsic or intrinsic stressful stimuli, the stressors,
which constantly challenge our complex internal balance,
termed homeostasis
[1, 2] . The term stress is used to de-
fine a state of threatened or perceived as threatened ho-
meostasis
[3] . To respond to this threatened homeostasis,
organisms have developed a highly sophisticated system,
Key Words
Stress system · Stress response · Glucocorticoids ·
Glucocorticoid receptor · Hypothalamic-pituitary-adrenal axis
Abstract
All living organisms have developed a highly conserved and
regulatory system, the stress system, to cope with a broad
spectrum of stressful stimuli that threaten, or are perceived
as threatening, their dynamic equilibrium or homeostasis.
This neuroendocrine system consists of the hypothalamic-
pituitary-adrenal (HPA) axis and the locus caeruleus/norepi-
nephrine-autonomic nervous system. In parallel with the
evolution of the homeostasis and stress concepts from an-
cient Greek to modern medicine, significant advances in the
field of neuroendocrinology have identified the physiologic
biochemical effector molecules of the stress response. Glu-
cocorticoids, the end-products of the HPA axis, play a funda-
mental role in the maintenance of both resting and stress-
related homeostasis and, undoubtedly, influence the phys-
iologic adaptive reaction of the organism against stressors.
If the stress response is dysregulated in terms of magnitude
and/or duration, homeostasis is turned into cacostasis with
Published online: September 12, 2014
Nicolas C. Nicolaides, MD, PhD
Division of Endocrinology and Metabolism, Clinical Research Center
Biomedical Research Foundation of the Academy of Athens
4 Soranou tou Efessiou Street, GR–11527 Athens (Greece)
E-Mail nnicolaides  @  bioacademy.gr
© 2014 S. Karger AG, Basel
1021–7401/14/0222–0006$39.50/0
www.karger.com/nim
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7
the stress system, which provides the appropriate central
and peripheral neuroendocrine responses
[1–3] . If these
adaptive responses are inadequate, excessive or pro-
longed, they may have severe adverse effects on vital
physiologic functions, such as growth, metabolism, circu-
lation, reproduction and the inflammatory/immune re-
sponse
[3] .
The stress system functions through the co-ordinated
activation of the hypothalamic-pituitary-adrenal (HPA)
axis and the locus caeruleus (LC)/norepinephrine (NE)-
autonomic nervous system
[1–3] . Glucocorticoids, the
end-products of the HPA axis, are cholesterol-derived
molecules that exert their pleiotropic genomic and non-
genomic actions through the glucocorticoid receptor
(GR), a ubiquitously expressed transcription factor,
which influences the stress response substantially
[4] . In
this review, we describe the functional components of the
stress system, provide an overview of the physical and be-
havioral alterations observed during the stress response,
and discuss the role of glucocorticoids in the most com-
mon diseases associated with acute and chronic dysregu-
lation of the stress system. Finally, we discuss the emerg-
ing role of the epigenetic modifications of crucial mole-
cules involved in the adaptive response.
Historical Milestones of Stress Concepts
… he who knows things from their beginning
and origins understands them better …
Aristotle , 4th century BC
The term stress derives from the Indo-European root
‘str’. This root has been highly preserved throughout the
centuries. Indeed, the ancient Greek gerund ‘strangalizein’,
its English synonym ‘to strangle’ and the Latin ‘strigere’
have been etymologically associated with the root ‘str’ and
have the meaning of exerted pressure
[1] . Nowadays, we
consider stress as a ‘strangulated’ balance of life.
The concepts of stress were first enunciated clearly by
the ancient Greek philosophers
[1, 2] . The pre-Socratic
philosophers Pythagoras and Alcmaeon were the first to
use the terms ‘harmony’ and ‘isonomia’, respectively, to
express the dynamic balance of the cosmos or life. Py-
thagoras used the term ‘harmony’ to describe the equilib-
rium or balance of the universe (The harmony of the cos-
mos). This ‘harmony’ is threatened by numerous disturb-
ing forces, while other counteracting forces tend to
re-establish it. Alcmaeon of Croton termed ‘isonomia’ the
balance of opposing forces. Empedocles of Agrigentum
proposed that the four basic elements (‘rhizomata’ or ‘ra-
cins’), earth, water, air and fire, being in dynamic opposi-
tion to one another, need to reach a balance for achieving
the harmony of the cosmos ( table1 )
[2, 6] .
Hippocrates of Cos termed health as a harmonious
balance of the four humors: blood, phlegm, black and yel-
low bile, which correspond to the heart, the brain, the
liver and the spleen, respectively. He was the first to use
the term ‘eucrasia’ to describe the balance of the humors
and subsequently proposed that their imbalance, ‘dyscra-
sia’, led to disease
[2] . Hippocrates also suggested that
‘eucrasia’ and ‘dyscrasia’ have their origins in nature, and
introduced the concept that ‘Nature is the healer of dis-
eases’
[2] . Many years later, Epicurus spoke of ‘eustatheia’
or ‘eustasis’, which refers to the serene emotional state of
a harmonious balance in a human being. The not uncom-
mon Greek first name ‘Eustathios’ is a remnant of that
era. Epicurus suggested that the mind could be one of
these healing forces and wrote that ‘ataraxia’ or ‘imper-
turbability of mind’ and ‘aponia’ (no pain) represent de-
sirable states in a human being
[2] .
During the years of Renaissance, Thomas Sydenham
proposed that an individual’s adaptive response to the
disturbing forces that lead to systematic disharmony
could result in pathologic changes. Two hundred years
later, Claude Bernard suggested that the ‘milieu intéri-
eur’, the internal medium that surrounds living cells, pro-
vides a steady state and ‘is the pre-condition of a free and
independent life’
[7] . At the beginning of the 20th cen-
tury, Walter Bradford Cannon coined the term ‘fight or
flight response’, and expanded on Claude Bernard’s con-
cept of the stability of the ‘milieu intérieur’ to ‘homeosta-
sis’ (from the Greek ‘homoios’, or similar, and ‘stasis’, or
position) in order to describe the physiologic processes
that maintain the steady state of the organism
[2, 7] . He
popularized his theories in The Wisdom of the Body,
published in 1932.
Finally, Hans Hugo Bruno Selye
[8] , a pioneering
Hungarian endocrinologist, conducted very important
scientific work on the response of an organism to stress-
ors, and described the general adaptation syndrome or
stress syndrome and the diseases of adaptation. He no-
ticed that patients with distinct disorders may present
with common ‘non-specific’ symptoms as a
common re-
sponse to stressors. He borrowed
the term stress from
physics and defined it as ‘the non-specific neuroendo-
crine response of the body’. Selye termed the ‘General Ad-
aptation or Stress Syndrome’ as the condition occurring
in severely ill patients who present with common clinical
manifestations due to severe prolonged adaptation re-
sponses.
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 /Charmandari 
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DOI: 10.1159/000362736
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In addition to the first definition of stress, Selye
coined the term ‘heterostasis’ (from the Greek ‘heteros’,
or other, and ‘stasis’, or position) and set it to mean ‘sta-
bility through change’
[2, 7] . Moreover, he clarified that
not all stressful conditions had adverse effects on human
health; thus, ‘eustress’ represented those states of stress
that could cause pleasant feelings and further enhance
human growth and development at the emotional and
intellectual level. On the other hand, he believed that
‘distress’ consisted of all the stressful conditions that
triggered severe pathologic conditions
[2] . More impor-
tantly, Selye suggested that not only the catecholamines,
which are secreted by the adrenal medulla and the sys-
temic sympathetic system, but also the adrenal cortex-
derived ‘corticoids’ participate in the stress response
[9] .
He was also the first to demonstrate that glucocorticoids
(which he named) exert strong anti-inflammatory ef-
fects
[9] . Further to these pioneering findings, the 1950
Nobel Prize in Physiology or Medicine was jointly
awarded to Edward Kendall, Philip Hench and
Tadeus
Reichstein for the isolation, synthesis and use of corti-
sone, a synthetic pre-glucocorticoid, in patients with
rheumatoid arthritis.
The Stress System
The stress system has both central and peripheral com-
ponents ( fig.1 ). The central components include: (i) the
parvocellular neurons, which secrete corticotropin-re-
leasing hormone (CRH); (ii) the neurons of the paraven-
tricular nuclei (PVN) of the hypothalamus that secrete ar-
ginine vasopressin (AVP); (iii) the CRH neurons, which
form the paragigantocellular and parabrachial nuclei of
the medulla and the LC, and (iv) other neural groups in
the medulla and pons (LC/NE system) mostly secreting
NE. The peripheral components include: (i) the neuroen-
docrine HPA axis; (ii) the efferent systemic sympathetic-
adrenomedullary systems, and (iii) components function-
ing under the control of the parasympathetic system
[10] .
The central and peripheral components of the stress sys-
tem have many sites of interaction with other systems at
multiple levels
[1, 2, 10, 11] ( fig.2 ). Indeed, activation of
CRH neurons activates the LC/NE system and vice versa.
In addition to interactions between the two central compo-
nents of the stress system themselves, the stress system ac-
tivates the mesocortical and the mesolimbic dopaminergic
reward system, while it receives inhibitory input from the
Table 1. Historical overview of stress concepts
Historical figure Stress concept
Pythagoras (580 – 489 BC) The harmony of the cosmos
Alcmaeon (c. 500 BC) The intellect is based in the brain
Health is the equipoise of opposing forces: ‘Isonomia’
Empedocles (500 – 430 BC) Matter consists of essential elements and qualities in opposition or alliance to one another
Hippocrates (460 – 375 BC) A harmonious balance of the elements and qualities of life is health – disharmony is disease.
‘Νούσων φύσεις ιητροί = Vis medicatrix naturae’
Sceptics/Stoics Epicureans Ataraxia (imperturbability of mind, equanimity)
Epicurus (341 – 270 BC) Ataraxia (imperturbability of mind), aponia (no pain) and ‘hedone’ (tranquil, non-sensual
pleasure) as desirable states. ‘Ευστάθειος’ = good balance, Carpe diem = seize the day
Thomas Sydenham (1624 – 1689) Symptoms and signs of a disease also arise from the reaction of the patients’ system
Claude Bernard (1813 – 1878) The ‘milieu intérieur’
Walter Cannon (1871 – 1945) Homeostasis/stress
Bodily responses to emotions
Fight or flight (and freeze) reaction
Hans Selye (1907 – 1982) The general adaptation syndrome (the stress syndrome)
Diseases of adaptation, distress versus eustress
Adapted from Chrousos et al. [5].
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latter systems [2, 10, 11] . The stress system also activates the
central nucleus of the amygdala, which participates in the
generation of fear and/or anger; upon activation, the central
nucleus of the amygdala stimulates the stress system, form-
ing a positive regulatory feedback loop with it
[2, 10, 11] .
The PVN of hypothalamus communicates with the arcuate
nucleus through CRH neurons that induce the release of
α-melanocyte-stimulating hormone and β-endorphin from
the pro-opiomelanocortin-containing neurons in the arcu-
ate nucleus. These two molecules both inhibit the activity
of the CRH and LC/NE systems. Moreover, the two com-
ponents of the stress system appear to respond to many
neurochemical modulators, such as serotonin and acetyl-
choline, which are acutely stimulatory, and γ-aminobutyric
acid and benzodiazepines, which are inhibitory to CRH
neurons and the LC/NE system
[2, 10, 11] . Finally, the neu-
ropeptide Y, leptin and substance P have been recently
shown to play an important role in the regulation of stress
system activity
[11] .
Significant progress in the evolving field of neuroendo-
crinology uncovered the key molecules involved in the
complex molecular pathways of the above central and pe-
ripheral anatomical loci responsible for the generation
and regulation of the stress response. CRH, AVP and NE
play the role of bona fide neurotransmitters primarily –
but not exclusively – in the CNS, whereas NE, epinephrine
and the glucocorticoids, which will be discussed in a sepa-
rate section of this review article, are considered to be the
final effector molecules of the peripheral stress system.
The HPA Axis
The HPA axis consists of stimulatory signals and neg-
ative feedback loops that regulate its activity. This neuro-
endocrine axis is composed of three distinct anatomical
loci: the PVN of the hypothalamus, the pituitary gland
and the adrenal cortices ( fig. 1 ). A broad spectrum of
Pituitary
Locus
caeruleus
Cortex
Glucocorticoids
Epinephrine
Norepinephrine
CRH
ACTH
Norepinephrine
Hypothalamus
Medulla
Fig. 1. The stress system. Modified from
Chrousos
[12] .
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stressors trigger the synthesis and secretion of CRH and
AVP by a group of neurons located in the PVN of the hy-
pothalamus
[12, 13] . CRH, through the hypophysial por-
tal system, reaches the anterior lobe of the pituitary gland
and binds to its cognate G-protein-coupled receptor lead-
ing to the production and release of adrenocorticotropic
hormone (ACTH) into the systemic circulation
[14, 15] .
Upon binding to its transmembrane G-protein-coupled
receptor of the adrenocortical cells of the zona fasciculata,
ACTH induces the activity of proteins and the expression
of genes implicated in the biosynthetic pathway of gluco-
corticoids (cortisol in humans, corticosterone in rodents)
[16] . Moreover, ACTH regulates adrenal androgen secre-
tion by the zona reticularis, and participates in the control
of aldosterone secretion by the zona glomerulosa.
Glucocorticoids, the end-products of the HPA axis,
are steroid hormones with pleiotropic effects in almost all
tissues and organs. These molecules regulate the basal ac-
tivity of the HPA axis and terminate the stress response
by acting mainly at the hypothalamus and the pituitary
gland, thereby forming negative feedback loops on the
secretion of CRH and ACTH, respectively. These nega-
tive feedback mechanisms, especially in the case of ACTH,
appear to also be mediated by non-genomic rapid gluco-
corticoid actions
[17] .
Genomic and Non-Genomic Glucocorticoid Actions
Glucocorticoids are cholesterol-derived hormones,
which play a fundamental role in the maintenance of rest-
ing and stress-related homeostasis. These molecules are
involved in the maintenance of proper cardiovascular
tone, regulate the intermediary metabolism primarily
through catabolic actions in the liver, muscle and adipose
tissue, and influence substantially the quantity and qual-
ity of the inflammatory and immune response. Further-
more, vital functions, such as reproduction, growth, be-
Glucocorticoids Catecholamines
CRH
ACTH
LC/NC
Mesocortical/
mesolimbic systems
Amygdala/
hippocampus complex
Serotonin Acetyl-
choline
Arcuate nucleus
POMC
GABA BZD
AVP
NPY
Leptin
Inflammatory
cytokines
SP
Blood
pressure
Fig. 2. Schematic representation of the cen-
tral and peripheral components of the
stress system, their functional interrela-
tions and their interactions with other
homeostatic systems and molecules in-
volved in the stress response. Activation is
represented by solid lines and inhibition
by dashed lines. POMC = Pro-opiomela-
nocortin; GABA = γ-aminobutyric acid;
BZD = benzodiazepine; NPY = neuropep-
tide Y; SP = substance P. Modified from
Chrousos and Gold
[2] .
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havior, cognition, cell proliferation and survival are under
the control of genomic and non-genomic glucocorticoid
actions
[3, 4, 18] . Glucocorticoids also contribute to water
and electrolyte homeostasis. All these are essential life
functions of glucocorticoids and are mediated by an intra-
cellular, ubiquitously expressed protein, the human GR
(hGR), which belongs to the steroid receptor family of the
nuclear receptor superfamily of transcription factors
[19] .
In humans, the hGR gene is located on the short arm of
chromosome 5 and consists of 10 exons
[19] . Exon 1 forms
the 5 ′ -untranslated region, whereas the rest of the exons
encode the protein. The alternative use of two distinct ex-
ons, 9α and 9β, gives rise to two main protein isoforms, the
hGRα and the hGRβ
[18, 19] . Lu and Cidlowski [20]
showed that the translation of hGRα mRNA could start
from eight alternative sites through ribosomal leaky scan-
ning or ribosomal shunting producing eight functionally
distinct hGRα protein isoforms. Since hGRβ mRNA trans-
lation is initiated by the same 5 ′ termini, it is possible that
the same translation mechanisms could also generate eight
different hGRβ proteins
[18] . The total of sixteen hGRα
and hGRβ isoforms may potentially form 256 homo- or
hetero-dimers to transduce the glucocorticoid signal with-
in the target cells, turning the simplified glucocorticoid sig-
naling pathway into a highly stochastic system.
Within the target cell, the unliganded hGRα is primar-
ily localized in the cytoplasm of cells forming a large
multi-protein complex with the chaperon heat shock
proteins 90 and 70, as well as other proteins, such as the
immunophilins ( fig.3 ). Upon ligand-binding, hGRα dis-
sociates from the multi-protein complex, translocates
into the nucleus and interacts, as a homo- or hetero-di-
mer, with specific DNA sequences, the glucocorticoid re-
sponse elements (GREs) in the promoter regions of tar-
RNA
polymerase II
Transcription initiation
complex
Translated RNA
p160
SWI/SNF
FKBP
DRIP/
TRAP
HSPs
HSPsGR
GR
GR
GR GR
GR
GR GR
Proteasomal degradation
GR
GR
PI3K
MAPK
eNOS
cPLA2įL-Arginine NO
Adrenal
Fig. 3. Molecular pathways of genomic and non-genomic gluco-
corticoid actions. HSP = Heat shock proteins; FKBP = immuno-
philins; p160 = nuclear receptor co-activators p160; SWI/SNF =
switching/sucrose non-fermenting complex; DRIP/TRAP = vita-
min D receptor-interacting protein/thyroid hormone receptor-as-
sociated protein complex; MAPK = mitogen-activated protein
kinases; cPLA2α = cytosolic phospholipase A2 alpha; PI
3 K =
phosphatidylinositol 3-kinase; eNOS = endothelial nitric oxide
synthetase; NO = nitric oxide.
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 /Charmandari 
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get genes, influencing their transcription rate in a posi-
tive or negative way. Following binding to GREs, the
receptor undergoes further conformational changes that
lead to serial and co-ordinated recruitment of nuclear
receptor co-activators [p160, p300/CREB-binding pro-
tein (CBP) and p300/CBP-associated factor] and chro-
matin-remodeling complexes (switching/sucrose non-
fermenting complex and vitamin D receptor-interacting
protein/thyroid hormone receptor-associated protein
complex). This molecular complex influences the activ-
ity of the RNA polymerase II and its ancillary factors,
thereby facilitating initiation of the transcriptional pro-
cess of numerous glucocorticoid-responsive genes
[19]
( fig.3 ).
Alternatively, gene expression can be modulated by
the ligand-activated hGRα in a GRE-independent fash-
ion. Several studies have shown that hGRα physically in-
teracted, possibly as a monomer, with other core tran-
scription factors, such as the NF-κB, activator protein-1
(c-Fos/c-Jun, AP-1), p53 and signal transducers and acti-
vators of transcription (STATs), thus increasing or inhib-
iting their transcriptional activity
[18, 19] . Importantly,
the major anti-inflammatory and immunosuppressive ef-
fects of glucocorticoids appear to be mediated mostly by
the interaction of the activated hGRα with the pro-in-
flammatory transcription factors NF-κB and AP-1.
Interestingly, it was recently shown that the transcrip-
tion factor ‘circadian locomotor output cycle kaput’
(CLOCK), which forms a heterodimer with its partner
brain-muscle Arnt-like protein 1 (BMAL1), is a novel
partner of GR and catalyzes the acetylation of lysine resi-
dues within the hinge region of the receptor, thus leading
to decreased sensitivity to glucocorticoids. These in vitro
studies have also demonstrated that the heterodimer
CLOCK/BMAL1 behaves as a negative regulator of hGRα
in peripheral target tissues, and antagonizes the physio-
logic actions of fluctuating cortisol
[21–24] . Further in
vivo and ex vivo studies demonstrated that CLOCK-me-
diated acetylation of hGRα was higher in the morning
(when circulating cortisol concentrations are elevated),
leading to decreased tissue sensitivity to glucocorticoids.
In contrast, hGRα was less acetylated by CLOCK at night
(when cortisol concentrations reach their nadir), which
resulted in increased sensitivity of tissues to glucocorti-
coids
[25] . The CLOCK system and the HPA axis com-
municate with one another at multiple signaling levels;
therefore, any conditions that disrupt their molecular
communication may lead to the development of the met-
abolic syndrome
[22–24] . Indeed, night-shift workers
and people frequently exposed to jet lag are at an in-
creased risk for developing symptoms and signs of chron-
ic hypercortisolemia, such as central obesity, insulin re-
sistance, dyslipidemia and hypertension, which represent
the cardinal clinical manifestations of metabolic syn-
drome
[22–24] .
In addition to the above-described genomic actions,
accumulating evidence suggests that glucocorticoids can
induce some of their pleiotropic actions within seconds
or minutes. Apart from their short time frame, these glu-
cocorticoid actions do not require hGRα-mediated tran-
scription/translation, and thus are referred to as ‘non-ge-
nomic’, and can occur in various systems, including the
neuroendocrine, cardiovascular and immune systems
[26–29] . Representative examples of non-genomic gluco-
corticoid actions are: (i) the immediate suppression of
ACTH secretion from the anterior pituitary by glucocor-
ticoids
[30] ; (ii) the glucocorticoid-induced rapid in-
crease in the frequency of excitatory post-synaptic poten-
tials in the hippocampus
[31] ; (iii) the rapid and transient
decrease in blood pressure associated with a concomitant
increase in coronary and cerebral blood flow in patients
with myocardial infarction or stroke
[32] , and (iv) the
rapid inhibition of T cell receptor signaling through dis-
ruption of the T cell receptor complex
[33] . These actions
are thought to be mediated by membrane-localized GRs,
which, upon ligand binding, trigger the activation of ki-
nase signaling cascades, such as the mitogen-activated
protein kinase or the phosphatidylinositol 3-kinase path-
ways
[26–29] . Although the downstream events of non-
genomic glucocorticoid signal transduction have been
partially elucidated, the origin and membrane localiza-
tion mechanism(s) of the membrane GR still remain an
enigma.
The LC/NE, Systemic Sympathetic, Adrenomedullary
and Parasympathetic Nervous Systems
The sympathetic and parasympathetic systems repre-
sent the two functional components of the autonomic
nervous system and influence the activity of many vital
physiologic systems, such as respiratory, cardiovascular,
renal, gastrointestinal, neuroendocrine and others. The
sympathetic system plays an important role through the
adrenal medulla in the ‘fight or flight reaction’ by secret-
ing all circulating epinephrine and some of the NE
[11] .
On the other hand, the parasympathetic system antago-
nizes or assists sympathetic functions by increasing or
withdrawing its activity, respectively
[10, 11] .
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To transmit the neural signal, the sympathetic and
parasympathetic systems employ the well-known neu-
rotransmitters acetylcholine and NE, numerous neuro-
peptides, as well as lipid mediators of inflammation,
adenosine triphosphate or nitric oxide
[11] .
The Adaptive Response to Stress
When homeostasis is threatened or perceived as
threatened by a stressor, the stress system is activated
through two waves of serial hormonal secretion provid-
ing the adaptive response. The first wave begins within
seconds and involves: (i) increased release of epinephrine
and NE from the sympathetic nervous system; (ii) secre-
tion of hypothalamic CRH into the hypophysial portal
system and subsequent enhanced release of ACTH; (iii)
decreased release of hypothalamic gonadotropin-releas-
ing hormone (GnRH) followed by decreased secretion of
follicle-stimulating hormone (FSH) and luteinizing hor-
mone (LH) from the anterior pituitary, and (iv) enhanced
secretion of pituitary-derived prolactin and growth hor-
mone (GH), and increased release of glycogen from the
pancreas
[34] .
A second wave of hormonal secretion occurs more
slowly and involves the glucocorticoids. All these stress-
mediated hormonal changes during both waves are trans-
lated in cellular end-effects. The hormones involved in
the first wave signal through GPCRs and rapid second
messenger pathways. By contrast, glucocorticoids acti-
vate the GR, a transcription factor that needs more time
from at least 20 min to hours and even days to complete
the appropriate molecular scenario.
However, mounting evidence suggests that many of
the non-genomic glucocorticoid actions are undoubtedly
involved in the acute phase of the stress response
[35, 36] .
Not only do glucocorticoids bind to membrane GRs, but
they also trigger the mineralocorticoid receptor (MR),
another member of the steroid hormone receptor family
of transcription factors, which is evolutionarily related to
the GR. It seems that glucocorticoids, even at lower con-
centrations than those activating the GR, bind to mem-
brane or cytoplasmic MRs and increase the activity of
multiple kinases involved in distinct signal transduction
cascades. Both the GR and MR play important roles in
glutamatergic neurotransmission ( fig.4 ).
During stress, increased concentrations of glucocorti-
coids activate post-synaptic membrane-localized GRs,
which, through the c-AMP-protein kinase A (PKA) path-
way, induce the production and release of the retrograde
molecules anandamide and 2-arachidonoylglycerol. The
latter activate the cannabinoid receptors type 1, located at
the membrane of pre-synaptic neurons, which finally in-
hibit the secretion of glutamate-containing vesicles
[35–
37] . On the other hand, pre- and post-synaptic mem-
brane MRs appear to facilitate glutamatergic transmis-
sion. Presynaptically, glucocorticoids bind to membrane
MRs, which, in turn, induce the activation of the extracel-
lular signal-regulated kinase cascade, leading to gluta-
mate release in the synaptic space. Simultaneously, the
post-synaptic activation of membrane MRs by glucocor-
ticoids results in the inhibition of potassium I
A -currents,
and facilitates the membrane diffusion of AMPA recep-
tors
[35, 36] . The above-discussed examples show con-
vincingly that glucocorticoids, acting through the classic
transcription factor GR, also participate in even the early
non-genomic molecular events underlying the adaptive
response.
Activation of the stress system through the above neu-
roendocrine mechanisms leads to a series of behavioral
and physical adaptation changes that increase acutely the
chances for survival
[1–4, 10, 11] . Therefore, organisms
may present with alertness, increased arousal, vigilance,
improved cognition, focused attention, as well as eupho-
ria, enhanced analgesia, suppression of feeding and inhi-
bition of reproductive function. In addition to behavioral
alterations, physical adaptation changes occur under
stressful conditions. Thus, oxygen and nutrients are redi-
rected to the CNS and the stressed body site(s) through a
high respiratory rate, increased cardiovascular tone and a
shift of intermediary metabolism towards catabolism.
Moreover, organisms activate detoxification processes
for any unnecessary metabolic products from the stress-
related reactions
[10] . Concurrently, organisms ‘switch
on’ restraining mechanisms during stress, which prevent
an over-response from the stress system. If they fail to
control stress-related adaptive changes, the stress re-
sponse may become excessive, prolonged and maladap-
tive and may, thus, contribute to the development of
acute or chronic pathologic conditions.
Stress System Disorders
Everything in moderation
Inscription at the Oracle of Delphi
Homeostasis is effectively achieved through normal
basal activity of the stress system and the appropriate
quantity and quality of the stress response to stressors
[1,
2] . These parameters are sine qua non for human health.
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By contrast, if the stress system has low or high basal ac-
tivity and/or excessive or prolonged responsiveness to
stressful stimuli, homeostasis is turned into cacostasis
with many adverse consequences on physiologic biologic
functions, leading to the development of acute or chron-
ic pathologic conditions.
Acute and Chronic Stress System Disorders
Stress may precipitate acute or chronic disorders in
humans with susceptible genetic loci and/or epigenetic
modifications in several genes
[1–4, 10–12, 38] . Under
acute stress, individuals may present with allergic condi-
tions (asthma, eczema or urticaria), or complaint for mi-
graines and/or gastrointestinal symptoms, such as ab-
dominal pain, indigestion, diarrhea and constipation. Of
note, the frequency of panic attacks and psychotic epi-
sodes is higher during acute stress. The molecular basis of
these stress-mediated conditions can be attributed to
acutely increased secretion of CRH, which exerts its ef-
fects through signaling in vulnerable end organs
[39–43] .
On the other hand, a long-lasting stress response may
cause excessive release and prolonged effects of the major
effector molecules of the stress system, including CRH,
cortisol and NE, on vital neuroendocrine and metabolic
axes leading to the development of a broad spectrum of
metabolic and/or neuropsychiatric disorders
[1, 4, 18,
39–43] .
Chronic stress exerts inhibitory effects on the growth
axis. Chronically increased circulating glucocorticoids
suppress the secretion of GH from the pituitary and in-
hibit insulin-like growth factor I actions at its target tis-
sues, possibly through interaction of the c-jun/c-fos het-
erodimer with the ligand-activated hGR
[44–46] . Fur-
thermore, CRH increases the levels of hypothalamic
somatostatin, a known inhibitor of GH secretion. These
mechanisms may explain the delayed or arrested growth
in children with Cushing syndrome
[45, 47] . Another ex-
ample of stress-mediated inhibition of growth is the ‘psy-
cAMP
PKA
MR
MR
GR
ERK
2-AG/AEA
CB1
AMPA
K+
Inhibition of
glutamatergic neurotransmission
Facilitation of
glutamatergic neurotransmission
Fig. 4. Inhibition and facilitation of glutamatergic neurotransmis-
sion through membrane GRs and MRs, respectively. cAMP = Cy-
clic-AMP; 2-AG = 2-arachidonoylglycerol; AEA = anandamide;
CB1 = cannabinoid receptor type 1; K
+ = potassium; AMPA =
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-
tor; ERK = extracellular signal-regulated kinase. Modified from
Groeneweg et al.
[35] .
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chosocial short stature’ in children or adolescents who
experienced physical or psychological maltreatment.
These children have typically decreased levels of GH,
which return to within a normal range a few days after
they are separated from the stressful environment
[48,
49] .
Prolonged activation of the stress system leads to de-
creased synthesis of thyroid-stimulating hormone due to
increased concentrations of CRH-induced somatostatin,
which in turn suppresses both thyroid-releasing hor-
mone (TRH) and thyroid-stimulating hormone (TSH).
Furthermore, elevated circulating concentrations of glu-
cocorticoids inhibit the activity of the enzyme 5-deiodin-
ase that converts inactive thyroxine to the biologically ac-
tive triiodothyronine in peripheral target tissues (the ‘eu-
thyroid sick’ syndrome)
[50] .
The hypothalamic-pituitary-gonadal axis is strongly
influenced at multiple levels by both CRH and glucocor-
ticoids
[51] . CRH inhibits the secretion of GnRH from
the hypothalamus
[52, 53] , while glucocorticoids sup-
press the activity of the reproductive axis by decreasing
secretion of GnRH, follicle-stimulating hormone/lutein-
izing hormone and gonadal steroids
[52–55] . Representa-
tive examples of stress-mediated suppression of the go-
nadal axis are highly trained runners and ballet dancers,
who may present with suppression of gonadal function
due to chronic activation of the HPA axis
[56, 57] .
Individuals under chronic stress are more susceptible
to specific infections and autoimmune disorders caused
by the glucocorticoid- and catecholamine-induced switch
from Th1 to Th2
[11, 12, 38, 40, 41] . Indeed, chronically
stressed individuals may have persistent infections with
Helicobacter pylori , Mycobacterium tuberculosis and the
common cold viruses. Moreover, the stress-induced Th1
to Th2 switch increases the risk for certain autoimmune
disorders, such as systemic lupus erythematosus, Graves
disease, and some allergic conditions
[1] .
Stress System and Non-Communicable Diseases
At present, our society is plagued by complex multi-
factorial non-communicable diseases, including obesity/
metabolic syndrome and its detrimental cardiovascular
complications, as well as depression, anxiety and insom-
nia. All these pathologic conditions are associated with an
excessive or long-lasting stress response to a variety of
external or internal stressors.
The pathogenesis of metabolic syndrome is closely as-
sociated with chronic hypersecretion of stress system me-
diators, such as cortisol, NE, epinephrine, immune CRH
and IL-6, which increase the secretion of insulin and de-
crease the release of GH and sex steroids, ultimately lead-
ing to visceral fat accumulation, and loss of muscle mass
(sarcopenia) and bone mass (osteoporosis)
[58, 59] . The
resultant visceral obesity and sarcopenia are closely asso-
ciated with other cardinal clinical manifestations of the
metabolic syndrome, such as dyslipidemia, hypertension
and type 2 diabetes mellitus. Moreover, elevated concen-
trations of IL-6, among other cytokines secreted by in-
flamed adipose tissue, and chronic hypercortisolism con-
tribute to stimulation of acute-phase reaction and blood
hypercoagulation. All these adverse factors may lead to
endothelial dysfunction and atherosclerotic cardiovascu-
lar disease
[1, 58, 59] .
In addition to the metabolic syndrome, stress par-
ticipates in the pathogenesis of major depression
[60–
62] . Major depression is a heterogeneous disorder with
two main subtypes: melancholic and atypical depres-
sion. Patients with melancholic depression have a hy-
peractive stress system and may present with anxiety,
guilt, fear, low self-esteem, insomnia and loss of appe-
tite. They also have hypersecretion of hypothalamic
CRH, as evidenced by elevated 24-hour urinary cortisol
excretion, decreased ACTH responses to exogenous
CRH administration, and elevated concentrations of
CRH in their cerebrospinal fluid throughout the 24-
hour period. Furthermore, the concentrations of NE in
cerebrospinal fluid are continuously elevated, even dur-
ing sleep. In contradistinction to melancholic depres-
sion, atypical depression is characterized by lethargy,
fatigue, hypersomnia and hyperphagia, which are asso-
ciated with downregulation of the HPA axis of central
origin.
All the above-discussed chronic non-communicable
disorders of modern societies are associated with mal-
adaptive stress responses and their origins lie deep in the
evolutionary process of human beings
[1, 4, 63] . Indeed,
our ancestors faced numerous environmental stressors,
including starvation, dehydration, infectious diseases,
threatening adversaries, dangers and injuries, which ap-
plied selective pressures upon genes implicated in the
adaptive stress response. This genomic selection obvious-
ly favored those individuals who were efficient in coping
with the above stressful stimuli.
Today, the same selected gene networks, subserving
functions important for human survival and species pres-
ervation, must encode effector molecules involved in the
‘contemporary’ adaptive stress response to address the
same types of stressors, but in different quantities and
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DOI: 10.1159/000362736
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contexts. For example, an excess of calories leads to obe-
sity, since the adaptive stress response has been pro-
grammed to cope with food deficiency, not excess. Thus,
the gene networks presented in table2 are now accepted
to be responsible for most of the contemporary diseases
of Western societies.
The Stress System in the Epigenetic Era
Interactions between genetic and environmental fac-
tors have been confirmed by many epidemiological stud-
ies
[64] . However, the molecular mechanisms through
which the environment acts to switch genes ‘on’ and ‘off’
Table 2. Gene networks subserving functions important for human survival and species preservation, which may
produce pathology in contemporary Western societies
Response to survival threat Selective advantage Contemporary diseases
Combat starvation Energy conservation Obesity
Combat dehydration Fluid and electrolyte conservation Hypertension
Combat infectious diseases Potent immune reaction Autoimmunity/allergy
Anticipate adversaries Arousal/fear Anxiety/insomnia
Minimize exposure to danger Withdrawal from danger Depression
Prevent tissue strain and injury Retain tissue integrity and reserve Pain and fatigue syndromes
Adapted from Chrousos and Kino [4].
cAMP
PKA
CBP
cAMP
PKA
CBP
NGF1A
CBP
17Nr3c1
NGF1A
CBP
High maternal licking/grooming Low maternal licking/grooming
Thyroid
hormones
5-HT 5-HT
NGF
GF
1A
1A
CBP
Nr3
c1
CH3
17
Fig. 5. Molecular mechanisms linking maternal licking/grooming with hippocampal GR expression. cAMP =
Cyclic-AMP; NGFIA = nerve growth factor-inducible A; Nr3c1 = nuclear receptor subfamily 3, group C, member
1 (GR) gene. Modified from Champagne
[68] .
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remain incompletely elucidated and are currently under
intense investigation.
Almost 30 years ago, a brief report published by
Meaney et al. [65] provided the first evidence of an asso-
ciation between post-natal pup handling and GR levels
within the hippocampus. In their pioneering work, they
compared rats exposed to maternal handling with non-
handled ones. They demonstrated that handled rats had
significantly increased protein levels of GR expressed in
the hippocampus compared with the non-handled rats
[65] . At that time, two possible mechanisms were pro-
posed to explain these effects: (i) elevated protein levels of
GR per cell, and (ii) increased post-natal neurogenesis in
the hippocampus in the handled rats. These results set the
stage for further molecular and cellular studies. Thus, it
was later shown that handling could increase the concen-
trations of plasma thyroid hormones (thyroxine and tri-
iodothyronine)
[66] , and that both handling and thyroid
hormones might boost serotonin (5-HT) turnover in hip-
pocampal neurons
[67] .
Further studies determined the molecules involved in
the serotonin-mediated GR expression
[68] ( fig. 5 ).
Upon binding to the 5-HT receptor, handling-induced
serotonin molecules trigger the production of c-AMP
and the subsequent activation of PKA. The latter facili-
tates – directly or indirectly through CBP – the binding
of the transcription factor nerve growth factor-inducible
factor A (NGFI-A) to a specific region of exon 1
7 of the
Nr3c1 gene inducing the expression of GR within the
hippocampus. The procedure of handling has been
shown to correspond to increased maternal licking/
grooming
[69] .
Subsequent studies demonstrated that high maternal
licking/grooming resulted in elevated thyroid hormone
levels, enhanced serotonin signaling and increased bind-
ing of NGFI-A to the Nr3c1 1 7 promoter [70] . By con-
trast, low maternal licking/grooming led to low GR ex-
pression that was attributed to increased hippocampal
cytosine methylation of the Nr3c1 1 7 promoter, an epi-
genetic modification that obviously altered gene expres-
sion without any changes in the underlying DNA se-
quence
[71] . The application of epigenetics research in
humans showed a clear association of childhood abuse
with increased Nr3c1 1 7 methylation at the NGFI-A
binding sites
[72] .
In addition to GR, other studies have investigated
stress-induced epigenetic modifications of genes involved
in the stress response. Among them, the Crh , glial-de-
rived neurotrophic factor (Gdnf) , brain-derived neuro-
trophic factor (Bdnf) and AVP (Avp) genes were studied
exclusively in animal models
[73] . Although all these epi-
genetic modifications are persistent and can be present in
the next generation, recent evidence suggests that drugs
altering DNA methylation/histone modifications can re-
verse the effects of early life experience in adulthood
[74] .
Thus, the emerging field of behavioral epigenetics will be
at the epicenter of stress research and will undoubtedly
provide a significant contribution to our conceptualiza-
tion of the impact of early-life events on the quality of
adult life
[75] .
Conclusions
We now know the central and peripheral compo-
nents of the stress system, the physiologic biochemical
effectors that mediate the behavioral and physical
changes during the stress response, and the molecular
mechanisms through which stress-induced neuroendo-
crine changes are translated to target tissue effects. Dis-
tress is a major factor in the pathogenetic mechanisms
of almost all disorders. Moreover, our lifestyles and en-
vironment in modern societies seem to be particularly
permissive for allostasis. The picture became more com-
plicated when we realized that early stressful life experi-
ences leave deep traces in our expressed genome. It is
imperative to develop effective strategies of stress man-
agement to decrease the incidence and alleviate the
symptoms and consequences of stress system disorders.
Although there remains much to learn about stress-me-
diated pathogenetic mechanisms, it is certain that less
distress improves the quality and increases the length of
our lives.
Acknowledgments
This work was supported by: (i) the European Union (Euro-
pean Social Fund – ESF) and Greek national funds through the
Operational Program ‘Education and Lifelong Learning’ of the Na-
tional Strategic Reference Framework (NSRF) – Research Funding
Program: THALIS – University of Athens, Athens, Greece; and (ii)
the intramural program of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, National In-
stitutes of Health, Bethesda, Md., USA.
All figures were prepared using image vectors from Servier
Medical Art (www.servier.com), licensed under the Creative Com-
mons Attribution 3.0 Unported License (http://creativecommons.
org/license/by/3.0/).
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DOI: 10.1159/000362736
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