General adaptation syndrome
(GAS)
Definition of stress and GAS
Phases of stress reaction
Consequences of GAS
Definition of stress and GAS
 GAS is a term describing body's short-and long-term
reactions and adaptations to stress in order to restore
homeostasis, which, regardless on the nature of the
stress, have quite uniform pattern
 stress
– a sum of biological reactions to stimul or events that we
perceive as challenging or threatening (= stressors) that
tends to disturb the homeostasis
 “positive” stress (eustress) – limited duration, helps to
overcome daily challenges and accomplish demanding tasks 
stimulates performance and leads to reward afterwards
lack of ability to react to stress due to diseases affecting the
relevant pathways (e.g. Addison disease) is life-threatening
 “negative” stress (disstress) - should the compensating
reactions be inadequate or inappropriate or stressor acts far
too long, the situation can lead to disorders
 stressor
– any factor disturbing body homeostasis
 type: physical, mental, emotional
 source: external or internal
GAS was introduced by Hans Selye
 Austrian-born physician (1907-1982) who emigrated to Canada in 1939
– born in Hungary, studied in Prague
– he searched for a new hormone (by injecting rats with ovary extracts, which produced enlargement of adrenal
cortex, involution of immune tissue and hemorrhagic gastric ulcers; however, he found out that numerous
substances produce the same effect  he described a stereotypical reaction to all sorts of substances as a
stress response or GAS
 therefore, old-fashioned, non-scientific methods such as bloodletting could have exercised some effects in fact, because it
relieved the body from common final consequences of various initiating stressors
– wrote > 30 books and > 1,500 articles on stress and related problems, incl. Stress without Distress (1974) and
The Stress of Life (1956)
 Nature 138, 32, 1936: GAS represents a three-stage reaction or ways of coping with stress
– (1) general - because it is produced only by agents which have a general effect upon large portions of the
body
– (2) adaptive - because it stimulates defense
– (3) a syndrome - because its individual manifestations are coordinated and largely dependent upon each other
 GAS involves 2 major regulatory systems of the body
– autonomic nervous system (ANS), mainly sympathetic
– endocrine system – hypothalamo-pituitary-adrenal axis
 3 distinctive stages in the syndrome's evolution
– alarm reaction (already described by Walter B. Cannon in 1914 and 1935)
– stage of resistance
– stage of exhaustion
 the novelty of his work was recognition of GAS as uniform predetermined reaction to deviation from
homeostasis
– Claude Bernard (specific regulatory mechanisms to maintain individual homeostatic components stable) vs.
Hans Selye (powerful stereotypic unspecific reaction to maintain crucial homeostatic parameters within the
range compatible with life)
Stages of stress & their purpose
 (1) alarm reaction (AR)
– fright  fight or flight (F&F or Cannon´s emergent reaction)
– the body's resistance to physical damage drops for a short-time so that organism can rearrange its priorities to cope with
the stressor
 use of available body sources for energy (glycogen), redistribution of blood to maintain higher blood pressure by increase of the peripheral
resistance, increased oxygenation by bronchodilation, increased muscle, coronary and brain perfusion in order to act
– if the stressor no longer exists the body returns to its normal level of resistance
 (2) stage of resistance (SR)
– if the stressor persists (“we can't fight or flee from it or, rather, we are unable to apply counteracting psychosocial
resources”), level of resistance increases beyond normal, relaxed levels  quite energy-consuming state
 increased energy demands covered by adipo- and proteo-catabolism, blood pressure maintained by Na retention, …
– this stage is an example of allostasis (= achieving stability through change, active process)
 (3) stage of exhaustion (SE)
– if the exposure to stressor continues (allostatic overload) for a long time (weeks – years) body resistance collapses due
to the inability to meet energy demands and due to side effects of extreme or exaggerated stress reactions  diseases of
adaptation
 extreme catabolism, immunodeficiency, cardiovascular consequences of metabolic derangements, …
(1) Alarm reaction (AR)
 adaptive, enabling surveillance by alteration of metabolism,
cardiovascular & respiratory functions, decreasing pain
perception (analgesia) and, at the same time, inhibition of
processes decreasing surveillance chance such as reproductive
functions and food intake and processing
– metabolic alterations  increase of glycemia using catecholamines
(CAT) and glucocorticoids (GC)
  insulin-stimulated glucose uptake
  protein, fatty acid and glycogen synthesis
  lipolysis and proteolysis (incl. part of the immune systems which is
“sacrificed” in order to gain AA)
  glycogenolysis by CAT (short-term effects on glycemia)
  gluconeogenesis by GC (long-term effects on glycemia)
– cardiovascular and respiratory alterations  glucose and
oxygen traffic to muscles, heart and brain using CAT, GC and ADH
 apart from CAT effects on cardiovascular and respiratory functions and
effect of GC on Na retention in the kidney there is also release of ADH to
help  circ. volume
– stress-induced analgesia (SIA)  decrease of pain perception by
2 ways
 opiates-dependent SIA: enkephalins and -endorphines
 opiates independent SIA: glutamate
– cognitive and emotional alterations
  motivation, arousal, vigilance, anxiety by  delivery of NE to CNS
structures
Analysis of the situation by CNS
 (1) analysis of the potentially threatening situation
– higher cognitive areas – prefrontal cortex
 major connections to amygdala and LC, however, gives us a voluntarily option to
modify automatic responses (conscious control over anxiety)!
 process of extinction = stimulus that triggers a conditioned fear gradually loses this effect
 involved in the final phase of confronting a danger, = after the initial automatic, emotional
reaction, the action that is best for us is chosen (people whose frontal cortex is damaged “frontal
syndrome“ can’t plan the simplest task)
 (2) respective autonomic and neuroendocrine reactions
– limbic system
 hippocampus
 memory (storage and retrieving), connections to amygdala  origin of strong emotions
triggered by particular memories
 processing of the context of a situation
 connections to hypothalamus
 amygdala
 essential for decoding emotions, and in particular stimuli that are threatening to the
organism
 many inputs converge in the amygdala directly from the sensory thalamus or from various
sensory cortexes
– thalamus
 sensory information to amygdala
– hypothalamus
 activated by the structures of the limbic system
 controls activity of pituitary and ANS (LC)
– brain stem
 pons
 locus coeruleus (LC) – afferentation from hypothalamus, controls activity of the SNS
and other CNS parts by NE release  increase of cognitive functions (prefrontal cortex),
motivation, HPA activity ( CRH), SNS activation
 medulla oblongata – n. tractus solitarii
Limbic system
Various nature of the stressors vs.
uniform reaction
 stress response can be elicited by
various stressors:
– real
 external (sensed)
from sensory cortex via prefrontal cortex
 internal (detected/quantified)
from various hypothalamic centers, somatic
and autonomous afferent nerves perceived
 emotional (amygdala)
 memory (hippocampus)
 no matter what was the initial
stressor, reaction is carried by
uniform pathways involving limbic
system 
– LC - SNS – adrenal medulla – CAT
– hypothalamus – HPA – cortisol
– higher CNS functions (motoric,
cognitive, behavioral reactions)
(1a) AR – nervous response - ANS
SNS  adrenal medulla  CAT
 adrenal medulla = stress-responsive CAT reservoir whose activity is modulated by
limbic system, LC and hypothalamus (CRH), pituitary (ACTH) and cortisol
 produces
– 80% of E (thus majority of response during F&F reaction is carried predominantly by E from
adrenal medulla)
– 20 % of NE
 CAT circulate bound to albumin, rapid degradation in liver  quite short-acting and
thus flexible regulators
 CAT synthesis and metabolism (see Fig.)
– rate-limiting enzyme: tyrosin hydroxylase
– inherited defects of synthesis (enzyme defects)
– overproduction in pheochromocytoma cells
 effects
–  GIT secretion, motility, digestion
–  salivation
–  heart rate, conduction & contractility
–  respiration & bronchodilation
– blood redistribution from splanchnic circulation and skin to muscles, brain and heart
–  activity and vigilance
– metabolic effects ( Glc and FFA)
 effects mediated by post-synaptic adrenergic receptors and respective signaling
cascades
– G-protein coupled receptor superfamily
 α (1 and 2) – PLC/IP3/DAG pathway
  (1 to 3) - cAMP/PKA pathway
Metabolic effects of E - glycemia
(1b) AR – humoral response – HPA
 CRH produced in n.
paraventricularis (PVN) 
reaches pituitary via
hypothalamo-hypophyseal portal
system  stimulates release of
ACTH
– from the precursor
proopiomelanocrtin (POMC)
– ACTH binds to G-prot. receptor 
cAMP
 effects of CRH
– HPA-mediated
 metabolic action of cortisol
– non-HPA mediated
– in immune system
 cortisol half-life in circulation
~90min
– majority bound to cortisolbinding
globulin (CBG, ~75%)
and albumin (~15%)
 peripheral tissue-specific
modulation of cortisol availability
by enzymes
– 11β hydroxysteroid
dehydrogenase type 1
(11βHSD1)
– 11β hydroxysteroid
dehydrogenase type 2
(11βHSD2)
 pathological stress response
– hypocorticalism (Addison
disease)
– panhypopituitarism (Sheehan sy)
Regulation of cortisol production
 several factors influence cortisol production
– (1) diurnal rhythm
– (2) negative feedback
 cortisol  ACTH and CRH
 substrates (Glc)  insulin  HPA
– (3) stress
 GC participate in all 3 stages of GAS
– alarm reaction is associated with short-term activation of HPA
– sustained activation represents the stage of resistance
– upon further prolongation of stress GC overproduction induces stage of
exhaustion
ACTH action
Major steroid biosynthetic pathways
 p450 enzymes are in mitochondria, each catalyses several reaction steps
 3βHSD (hydroxysteroid dehydrogenase) is in cytoplasm, bound to endoplasmic
reticulum
 17βHSD and p450aro are found mainly in gonads
GC action – genomic effects
 GCs have receptor (GR) existing in two isoforms
– cytoplasmic (cGR)
– membrane bound (mGR)
 therefore, GCs have several modes of action
– genomic – mediated by cytosolic receptors (cGR) upon binding to GC responsive elements (GREs)
– non-genomic – mediated by cGR, mGR and non-specific effects by interaction with other proteins and
cell membranes
 (A) genomic effects – via cGR – majority of metabolic effects are achieved by
genomic effects
– GC responsive genes represent ~ 20% of all coding genes, indispensable for life
 GR knock-out animals are not viable!!
– cGR has 3 domains: N-terminal transactivation domain / DNA-binding domain / ligand-binding domain
– following synthesis GRs are located in the cytoplasm in the complexes with molecular chaperons
 Hsp-70 – newly synthesized, helps further folding of the nascent GR
 Hsp-90 – helps to full maturation and achieving hormone-activavable state
– GR/Hsp (+ other proteins) complexes
 protect GRs from degradation by proteasome
 increase affinity of GRs for GCs (~100)
 blocking action of other proteins (e.g. MAPK) bound to complex
– receptor activation
 upon binding of GC in cytoplasm  conformational changes and release from inhibitory complexes with
Hsp  translocation to nucleus and homodimerisation
– effects:
 (1) transactivation = binding to GREs
 short specific sequences of DNA located in promoters  gene transcription [I]
 (2) transrepression = binding to negative GRE (nGRE) [II] or interaction with other TF [III] or their
coactivators [IV]
 repression of transcription or blocking action of other TF on gene transcription (such as AP-1, NFkB, ...)
– the whole sequence of events following binding of GCs to cGRs takes at least 20-30min – late effects
compared to the action of peptide hormones or non-genomic action of GCs
– affinity of steroid receptors (for GC, aldosteron, estradiol) is not specific!!
 e.g. GCs bind avidly to MR in brain, not in kidney though (degraded)
 (B) non-genomic effects – many of anti-inflammatory and immunosuppressive
effects
Steroid hormone receptor signalling
 GR act as hormone dependent nuclear
transcription factor
– upon entering the cell by passive diffusion, the
hormone (H) binds the receptor[1], which is
subsequently released from heat shock proteins
[2], and translocates to the nucleus [3]
– there, the receptor dimerizes [4], binds specific
sequences in the DNA [5], called Hormone
Responsive Elements or HREs, and recruits a
number of co-regulators [7] that facilitate gene
transcription
– this latter step can be modulated by certain
cellular signalling pathways [10] or receptor
antagonists (like tamoxifen [11])
– subsequent gene transcription [8] represents a
genomic effect of GC
– action is terminated by proteasomal degradation
[9],
– other, non-genomic effects are mediated through
putative membrane-bound receptors [6]
Metabolic effects of GC – increased turnover of
free and stored substrates
Tissue/organ Physiologic effects Effects of overproduction
Liver hepatic gluconeogenesis ( Glc)
(stimulation of key enzymes – pyruvate carboxylase, PEPCK,
G6Pase)
impaired glucose tolerabce/diabetes
mellitus
hepatic lipogenesis ( FA and VLDL)
(stimulation of key enzymes acetyl-CoA-carboxylase and FA
synthase)
steatosis/steatohepatitis
Adipose tissue lipolysis in subscutaneous fat ( FFA)
(activation of HSL and inhibition of LPL)
insulin resistance in the muscle
(competition of FFA with Glc for oxidation)
Glc uptake
(down-regulation of IRS, inhibition of PI3K, Glut4 translocation)
insulin resistance by interference with
insulin post-receptor signalling
adipocyte differentiation in visceral fat
(expression of GR and 11βHSD1 different in adipose and
visceral fat)
truncal (abdominal) obesity, metabolic
syndrome
Skeletal muscle  Glc uptake
(down-regulation of IRS, inhibition of PI3K, Glut4 translocation)
insulin resistance by interference with
insulin post-receptor signalling
proteolysis,  proteosynthesis ( AA)
(counteracting effect of IGFs, activation of ubiquitin-mediated
degradation, induction of myostatin and glutamine synthetase)
muscle atrophy, weakness, steroid
myopathy
Pancreas
(β cells)
 insulin secretion
(supression of GLUT2 and K+ channel, apoptosis)
impaired glucose tolerabce/diabetes
mellitus
Peripheral modulation of GC availability
 peripheral tissue-specific modulation of cortisol availability by enzymes
catalysing interconversions of active and inactive forms of GCs
 (a) 11β hydroxysteroid dehydrogenase type 1 (11βHSD1)
– act as a reductase regenerating cortisol from cortisone   intracellular cortisol
concentration
 mainly in liver and adipose tissue
 expression of 11βHSD1 is higher in visceral than subcutaneous fat!  visceral fat is therefore more
flexible pool of energy substrate
– often co-localises with GR (e.g. in liver and adipose tissue) and thus locally amplifies
the GC action
 11βHSD1 overexpressing mice develop obesity, while 11βHSD1 knock-out mice are
protected from overeating-induced obesity
 liver and fat-tissue specific inhibitors of 11βHSD1 could be used for treatment of
metabolic syndrome and obesity
– pathology associated with 11βHSD1
 Cushing syndrome – higher expression of 11βHSD1 in visceral fat – normally first source
of substrate, but higher suppression with GC, while enhanced GC action leads to lipolysis
in adipose tissue, the fat cumulates in visceral
 congenital deficiency of 11βHSD1 (apparent cortison reductase deficiency) 
compensatory over-activation of HPA axis  adrenal androgen excess, oligomenorhea,
hirsutism in women
 overexpression of 11βHSD1 in subcutaneous tissue (congenital or acquired) leads to
lipodystrophy
 11βHSD1 plays a role in the pathogenesis of polycystic ovary syndrome
– regulation: starvation, cortisol, other hormones
 (b) 11β hydroxysteroid dehydrogenase type 2 (11βHSD2)
– act as a dehydrogenase degrading cortisol to cortisone   intracellular cortisol
concentration
 mainly in kidney
– by degrading cortisol 11βHSD2 enables tissue-specific preferential action of
aldosterone on MR even though concentration of plasma cortisol >>> aldosterone
– pathology associated with 11βHSD2
 congenital deficiency of 11βHSD2 (apparent mineralocorticoid excess)  monogenic form
of hypertension
 11βHSD2 is expressed in placenta (maintains lower cortisol in foetal circulation than in
maternal) – deficient action contributes to pregnancy pathologies (preeclampsia, IUGR,
...) and possibly to foetal metabolic programming
Summary – availability of GCs
(2) Stage of resistance
 if the stress does not cease shortly (after completing F&F
reaction) increased energetic demands must be met by
metabolism increasing availability of Glc and FFA
– mainly via regulation of hepatic gluconeogenesis and adipose
tissue lipolysis
 also, optimalisation of the survival following trauma or
infection is achieved by alterations of immune function
– suppression of adaptive immunity
– activation of certain parts of innate immunity, while suppressing
the others
 there are many non-metabolic, non-immune effects of
GC (see Tab.) which are desirable in short-term prospect but
become adverse in long-term
Tissue/organ Physiologic effects Effects of
overproduction
Bone and
connective
tissue
 osteoblast action and bone
formation vs.  osteoclast action
and bone resorption
osteoporosis
 collagen synthesis and
proteolysis
osteoporosis, poor
wound healing, easy
bruising, thin skin
GIT  calcium absorption osteoporosis
 gastric juice secretion,  mucus
secretion
stress-induced peptic
ulcers
Kidney  Na retention
(glucocorticoid-activated kinase,
increased Na channel and
angiotensinogen expression (liver))
hypertension,
hypokalemia
Bone marrow  erythrocyte and PMN maturation polyglobulia,
granulocytosis
Reproductive
system
supression of production of
estradiol and testosterone
oligomenorhea,
infertility
Behaviour Expression of GR in hippocampus
 genomic and non-genomic action
( glutamate, Ca, serotonin,
opiates, …), NE from LC
post-traumatic stress
disorder, “burn-out”,
depression, anxiety
Fetal and
neonatal
development
surfactant and fetal lung maturity;
fetal hepatic and gastrointestinal
enzyme systems
fetal lung immaturity
GC action on immunity
 suggested to be mediated via:
– genomic effects [I]
 transactivation and transrepression of
many immunoproteins
– non-genomic effects
 cGR by sequestering proteins [II]
e.g. kinases (MAPK)  blockade of action
 mGR [III] - multi-protein complexes with
other membrane receptors  blockade of
action
e.g. growth factors
alternatively, induction of apoptosis
 direct interactions of GC with cellular
membranes [IV]  intercalation into
membrane  stabilisation
inhibition of Na/Ca exchange
increase of proton leak in mitochondria 
less ATP
» ATP-dependent processes in immune
system (cytokinesis, migration,
phagocytosis, antigen processing and
presentation, Ig synthesis, cytotoxicity,
…)
GCs and immune system
Glucocorticoid effects on primary and secondary immune cells
Monocytes /
macrophages
↓ Number of circulating cells (↓ myelopoiesis, ↓ release)
↓ Expression of MHC class II molecules and Fc receptors
↓ Synthesis of pro-inflammatory cytokines (e.g. IL-1, -2, -6, TNFα) and
prostaglandins
T cells ↓ Number of circulating cells (redistribution effects)
↓ Production and action of IL-2 (most important)
Granulocytes ↑ Number of circulating neutrophils
↓ Number of eosinophile and basophile granulocytes
Endothelial cells ↓ Vessel permeability
↓ Expression of adhesion molecules
↓ Production of IL-1 and prostaglandins
Fibroblasts ↓ Proliferation
↓ Production of fibronectin and prostaglandins
Examples of multiple action of GCs on immunity
Balance of Th1/Th2 immune responses Th2
shift as a consequence of stress
Summary – effects of GC on immunity
(3) Stage of exhaustion (wear and tear)
 examples of clinically significant
consequences:
– one of the non-heritable components of
metabolic syndrome ( cardiovascular
events)
– high incidence of death in the first years of
retirement for those not prepared for it
(sudden end of years in a stressful,
demanding job without much relaxation)
– weekend headache
– high incidence of illness during holidays
– anxiety or depressive disorders
Subjective stress responsibility
 flourish or perish
 there are enormous interindividual differences in the response to
stress due to
– prenatal stress
 fetal programming
– early-life experiences
 postnatal handling and mother care, mother separation, …
e.g. animal (rodent) models – maternal care (licking and grooming) produces
exploratory, open-to-novelty and less emotionally active animals = neophilic ( HPA
activity) with  longevity and less mortality later in the life, while poor maternal care or
separation produces less explorative, emotional, anxious animals scared of novelty =
neophobic with shortened life-span
» interestingly, apart of stressoric effect, abuse of the young (rough handling by the
mother) leads to attachment rather than avoidance  increases the chance of
survival by continuing to obtain food until weaning (much longer and complex in
humans though!)
– adult-life experiences
 school, work, family, relationships, sleep deprivation, …
e.g. someone who has been treated badly in the job and/or has been fired will approach
a new job quite differently than someone with altogether positive employment history
– sex differences
– genetics - sensitivity to stress/reward mediators
 many genes/common alleles !! e.g. serotonin transporter, brain-derived
neurotrophic factor, glucocorticoid receptor, …
Common indications for therapeutic use of
GCs and major adverse effects
 respiratory diseases
– allergies, asthma, sarcoidosis , prevention/treatment of
ARDS
 renal diseases
– some types of nephrotic syndromes and
glomerulonephritides
 gastrointestinal disease
– ulcerative colitis, Crohn's disease, autoimmune hepatitis
 rheumatological diseases
– systemic lupus erythematosus, polymyalgia rheumatica,
temporal arteritis, juvenile idiopathic arthritis, vasculitides,
rheumatoid arthritis
 emergency situations
– cerebral oedema
 skin diseases
– allergies, pemphigus, eczema
 tumours
– Hodgkin's lymphoma, other lymphomas
 transplantation immunosuppression
 side-effects
– physiological
 adrenal and/or pituitary suppression
– pathological
 increased blood pressure, peptic
ulceration (or exacerbation),
pancreatitis, polyuria, nocturia,
depression/uuphoria, psychosis,
insomnia, weight gain, impaired
glucose tolerance/diabetes, impaired
growth, qmenorrhoea, osteoporosis,
proximal myopathy and wasting,
aseptic necrosis of the hip,
pathological fractures, skin thinning,
easy bruising, cataracts (including
inhaled drug), increased susceptibility
to infection, septicaemia, reactivation
of TB, fungal infections
Phylogenetic differences in stress response
 stress response plays different roles in different
species according to the characteristic patterns of
social behaviors, environment etc.
– example: dominant and subdominant primates
(males)
 in stable conditions (no territorial emergency), dominant
males have lower GC levels than subdominant ones
 in unstable conditions, however, GC levels in dominant
males increase and they are the same or higher than in
subdominant males
– i.e. “personal power” of dominant male correlates
with low GCs levels during rest conditions
 human beings compared to other species are
used and ready to adapt to the long-term stress
situations by elevated activity of certain systems
(survival advantage)
– nowadays the outcome of such selection contributes
to the common pathologic conditions such as
metabolic syndrome