Biology of Stress & Disease
Copyrighted work available under Creative Commons by-nc-nd 2.0 UK
CH0576: The Biology of Disease - Dr Rosemary Bass
rosemary.bass@northumbria.ac.uk
Summary of Lecture
Evolution of ideas about stress:
-Physiological
-Psychological
Causes & consequences of stress
Definitions
Any condition: Physical or Emotional can be a
potential stressor
Stress (Biological) Interruption to Homeostasis
Psychological
(emotional) stress
Exacerbate many
disease states
Stress is a relatively modern concept
Disease States/Conditions Exacerbated by Stress
Coronary artery disease
Cancer
Hypertension
Stroke
Rheumatoid arthritis
Immunosuppression
Ulcers
Irritable bowel
Impotence
Type 2 diabetes
Chronic fatigue syndrome
Depression
Potential Stressors:
● Infection
● Noise
● Pain
● Malnutrition
● Exercise
● Heat
● Cold
● Trauma
● Obesity
● Age
● Drugs
● Surgery
● Doctors
● Anxiety
● Depression
● Anger
● Fear
Health outcomes
Mind
Healthy
Individual
Transient
Effect
Environmental
Elevated
stress
response
Return to
Steady
Expression of
state
Disease/illness
Coping strategy
Symptomatic individuals – ineffective coping
strategy to stressor – Exacerbate illness
How Stress Affects the Heart
Acute emotional
stress/trauma can cause:
•MI if have underlying CHD
•Left ventricle dysfunction
especially in older women –
sudden chest pain,
shortness of breath
•Ventricle Dysrhythmias
leading to cardiac death
Stress: General adaptation syndrome (GAS)
Stressors – Ovarian steroid injections
(cold, surgical injury, restraint,)
Same generalized pattern of hormonal and
physiological response
GAS or “stress response”
Hans-Selye-1974
1936 – experiments
on rats
(humans, monkeys
the same)
STRESS
•Can impact on general health as long term
stress changes way body functions.
•Evidence causes epigenetic changes – which
affects next generation if in germ cells
•Epigenetic alterations = chemical modification of
DNA associated histones which alters
transcription
GAS = Physiological Stress Response
3 phases:
1) Alarm stage (CNS arousal, fight or flight response, SNS)
2) Resistance (adaptation) stage (Period of stress longer
than a few hours) – Long term metabolic adjustments
3) Exhaustion Stage (Breakdown of homeostatic
regulation)
1)
2)
Normal
3) Resistance
Level
Selye defined 3 components of physiologic stress:
1)Exogenous/endogenous stressor initiating the
disturbance
2)Chemical/physical disturbance produced by the
stressor
3)Body’s adaptational response to the disturbance
Psychological Mediators of Stress
(Not just all physiologic)
1950’s - Activation of adrenal cortex
‘Psychological stressors’ e.g. stressful interview
techniques or exams
1960’s – Changes in plasma cortisol levels
Elevated – watching war films
Decreased – watching Disney nature films
1970’s – Presence or absence of Stress response –
psychologic factors influence GAS:
‘discomfort’, ‘unpleasantness’, ‘suddenness’
Biology of
Disease Exam
eg. of reactive response
Increased heart rate, dry
mouth (sympathetically
mediated)
Psychological Mediators of Stress: Anticipatory
response (conditioned fear)
Animal hears sound stimulus
Autonomic: Small increase in BP
Behavioural: Cessation Movement - Short
Sound plus short electric shock
Autonomic: Dramatic increase in BP
Behavioural: Cessation Movement - Long
Conditioned
Stimulus, No shock
Autonomic: Dramatic increase in BP
Behavioural: Cessation Movement - Long
Bilateral amygdalectomy abolishes conditioned response – Amygdala
(limbic system) – learning response to fearful stimulus
Limbic System
•First described by Broca in 1878
•Thought to be involved in emotions especially
relating to survival, primative behavioural responses
•Located on top of brain stem & is an extension of the
olfactory system
(Amygdala, parahippocampal gyrus, hippocampus,
fornix, mamillary body of the hypothalamus,
thalamus, cingulate gyrus, septal area, habenula)
Modern Concepts of the “Limbic system”
Purves et al Neuroscience
Evidence from lesion studies
in animals and humans as well
as pathology in humans
● Orbital and medial
prefrontal cortex
● Ventral parts of the
basal ganglia
● Mediodorsal nucleus
of the thalamus
● Amygdala
Hippocampus/Mammillary
body are now thought to have
little or no role in emotional
behaviour
Conditioned Fear : Clinical correlations:
Anxiety (stress) disorders – types
Panic Disorder - frequent panic attacks, discrete periods
with sudden onset of intense fearful feelings, fear of
dying etc.
Agoraphobia - Anxiety about and/or avoidance of
unfamiliar places or situations
Obsessive compulsive disorder – Obsessions causing marked anxiety or
distress-repetitive behaviours (e.g. checking gas taps over and over).
Generalized anxiety disorder – 6 months or more of persistent
anxiety/worry
Phobia’s – Anxiety induced by objects/animals e.g. spiders or
social situations
Post-traumatic stress disorder – re-experiencing of a traumatic event,
increased arousal and avoidance of triggers
Neural recognition of real or predicted stressors and
physiological response:
•Stress response initiated by CNS & endocrine system
(CRH-corticotrophin releasing hormone
ACTH – adrenocorticotrophin releasing hormone)
•Initiation different if stressor is real or perceived
•Real stress starts a response in the limbic system or
specific sensory system
•Perceived stress starts a response in the limbic
system (as nothing real to start a response through a
sensory system)
Neural recognition of real or predicted stressors and
physiological response:
Limbic system
Sensory
Cortex
Stressor
Brainstem
(locus coeruleus)
Norepinephrine
secretion
Sympathetic
nervous
system
Adrenal medulla
(80% Epinephrine
20% NE)
Paraventricular
nucleus of
Hypothalamus
Adapted from Fig 10-1 (McCance and Huether)
Anterior
Pituitary
Adrenal
cortex
(Cortisol)
Stress
Hypothalamus
Anterior
Pituitary
CRH
Adrenal Gland
Catecholamines
Cortisol
Adrenaline (epinephrine)
Noradrenaline (norepinephrine)
ACTH
Physiological Stress response: Alarm phase
Stressor (exercise, thermal
changes, acute emotional stress)
Physiological Effect:
General
sympathetic
activation
Adr, NA
● Increased mental alertness
● Increased field of view
● Upregulation of energy use
by cells
● Mobilisation of glycogen
(skeletal muscle and liver)
● Redistribution of blood flow
(away from gut/skin)
● Reduced digestive activity
● Reduced urine production
● Increased sweating
● Increased heart rate
● Increased respiratory rate
Physiological Effects: Receptor Stimulation
Adr/NA
b 1, b 2, b 3
Adrenoceptors
(G-protein coupled
receptors)
Elevated
Sympathetic
Activity
(“fight or
flight”
NB. Other receptor subtypes e.g. a1 different downsteam signalling effects
Physiological Consequences of Adrenergic Receptor
Stimulation:
a1
– Increased glycogenolysis (breakdown); smooth muscle
contraction (blood vessels and urinary tract)
a2 – Smooth muscle relaxation (G.I. tract), Insulin secretion
– Primarily SNS mediated (NA)
b1 – Lipolysis, myocardial contraction (increased rate/force)
b2 – hepatic gluconeogenesis, glycogenolysis, increased glucagon
secretion, Smooth muscle relaxation (bronchi, skeletal muscle BV,
G.I. tract)
- Primarily hormonally mediated Adr from Adrenal medulla
Physiological Stress response: Resistance Phase
Hypothalamus
Releasing Factors
Anterior
pituitary
Long-term metabolic
adjustments
Growth
Hormone
SNS
ACTH
Adrenal
Cortex
Cortisol
Elevated blood
glucose
Glucagon
Renin
Angiotensin
● Mobilisation of energy reserves for
most tissues (lipolysis, skeletal
muscle proteins)
● Glucose conservation for brain
Mineralocorticoid
Conservation of salts and water
Sagittal Section Through Adrenal Gland
Mineralocorticoids
Aldosterone
Effects salt (mineral) balance
Influences how kidneys handle sodium, potassium & H+
Aldosterone is stimulated by angiotensin II
Na+ & H2O retention
K+ & H+ excretion in urine
Glucocorticoids
Cortisol (& corticosterone)
Regulation of metabolism
Rate protein catabolism
 conversion of amino acids→ glucose
lipolysis
Stress response – make nutrients available for ATP
production
Raises BP by vasoconstriction
Immune system
Anti-inflammatory effects reduced (skin cream)
reduce release of histamine from mast cells
decrease capillary permeability
depress phagocytosis
Pathological consequences of elevated cortisol:
Cushing Syndrome
Common symptoms:
•Increased & abnormal fat deposition: Moon
face/buffalo hump
•Hypertension
•Hirsutism
•May develop type 2 diabetes
•Commonly caused by tumours of the adrenal
gland or pituitary
•Excess ACTH (glucocorticoid hypersecretion)
•Muscle weakness
•Oedema
•Loss of muscle & bone mass
•Corticosteriod mediated elevation of
sympathetic nervous activity
http://www.csrf.net/
Prognosis Good: e.g.removal of tumours results in re-establishment
of normal homeostatic levels, patients loose weight etc.
C - Central obesity, Cervical fat pads, Collagen fibre weakness
U - Urinary free cortisol &  glucose
S – Stretch marks, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycaemia, Hirsutism
I - Increased administration of corticosteroids
N – Neoplasia
G - Glucose intolerance, Growth retardation
Adrenalin and Cortisol are part of the body’s
stress response and are under negative
feedback
Neural Inputs
Hypothalamus
 CRH secretion
-ve
 Plasma CRH
Anterior pituitary
 ACTH secretion
-ve
 Plasma ACTH
Adrenal cortex
 Cortisol secretion
 Plasma cortisol
Target cells for cortisol
Respond to  cortisol
Long Loop
Feedback
Pathological consequences of elevated Cortisol:
Stress, inflammation, obesity and diabetes.
Emotional
stress
Increased Cortisol
Obesity
Food Intake
(stress
influenced?)
Plasma:
Increased
Glucose/FFA
NF-kB
activation
ROS
Smoking
Infection
Proinflammatory
cytokines
TNFa, IL6, CRP
Genetic
factors
Interference
Insulin Signalling
Pancreatic B-Cell Destruction
Type 2 Diabetes
Genetic factors
Refer to pg 319: McCance and Huether: Directed reading and Padgett DA, Glaser,
R: Trends Immunol 24 (8):444-8, 2003
Stress and the immune system: Role of Cortisol
Cortisol - suppress activity of Th1 cells (lymphocytes –
secrete cytokines)
- decrease in cellular immunity and pro-inflammatory response
Action on Th2 cells Stimulation
- increase in humoral immunity (secreted antibodies) and antiinflammatory response
Overall response is a balance between effects on both cell classes
Noradrenaline and adrenaline mediate similar effects
Activity switch from TH1 to TH2 is called TH2 shift
Glucocorticoids (Cortisol) used therapeutically as Antiinflammatory and immunosuppressive agents
Exhaustion Phase: Collapse of Vital Systems
Possible causes:
● Exhaustion of fuel reserves – lipids
● Failure of electrolyte balance
● Collapse of Glucocorticoid production
● Cumulate structural/functional damage to organs –
cardiac failure
E.g. Aldosterone (resistance phase)
- Conservation of Na+ but K+ excretion
K+ declines lead to malfunction of neurons and
muscle fibres (important for AP generation and
contraction)
Final Phase of GAS
Outcome if
corrective
actions not in
place
Effects of Stress on other hormones: Female Sex hormones
Cortisol
Stress Inhibition of
female reproductive
system
Suppresses LH, estradiol and progesterone
production
- Suppression of GnRH (elevated levels
of CRH)
- Suppressed GnRH, LH and E2 via
cortisol
-Target tissue resistance to E2 induced
by cortisol
Consequences:
● Amenorrhea or dysmenorrhea
● Dyspareunia
● If in long term: Atrophy of vaginal cells, vaginal
prolapse, osteoporosis
Effects of Testosterone in the Male
Required for initiation & maintenance of spermatogensis
Decreases GnRH secretion via hypothalamus
Induces differentiation of male accessory reproductive organs
Inhibits LH secretion via anterior pituitary
Induces male secondary sex characteristics
Stimulates protein anabolism, bone growth and ultimate cessation of
bone growth
Required for sex drive
Stimulates erythropoeitin secretion
Effects of Stress on other hormones:
Testosterone
Produced by leydig cells
Libido, sperm production, male secondary sexual
characteristics, anabolic
Stressors: marathon running, mountain climbing, work
stress, ageing.
Elevated Cortisol may inhibit production
Stress cause a marked fall in testosterone levels
Effects of Stress on other hormones: Endorphins
•Stressful stimuli cause endorphin release
•Injury, extreme exercise, haemorrhage etc.
•Haemorrhage – release of beta endorphins
inhibit BP increases
•Modulate BP instability
•Dancing, combat and sport.
•Increased endorphin production – feeling
of excitement, insensitivity to pain
•Endorphins released from anterior pituitary
in response to CRH (from hypothalamus)
Prolactin
Unique anterior pituitary hormone
Major function to stimulate mammary gland development & milk
production
Does this by direct effects
Not by stimulating the release of another hormone
Effects of Stress on other hormones: Prolactin
Anterior pituitary
Widespread receptor distribution
Liver, kidney, intestine etc.
Stressful stimuli:
Gastroscopy, pelvic examination, surgery,
exams, parachute jumping.
Stronger stimulus required than for
cortisol.
Lactation and
breast
development
May also be involved in immune function
prl receptors on lymphocytes
Stress leads to increased synthesis and release of prolactin
-ve
Hypothalamus
Short-loop feedback
Dopamine
Anterior pituitary
Prolactin Plasma Levels
X
Prolactin
Effects of Stress on other hormones: Oxytocin
Oxytocin: Childbirth, lactation
Animal experiments
● Elevated Oxytocin
● Decreased HPA (hypothalamuspituitary-adrenal ) activity & reduced
anxiety
Oxytocin may work in concert with
oestrogens to mediate calming
response in stressful situations
Promotion of ‘tend’ and
‘befriend’ response
Gender difference: Evidence for lower physiological stress response in women?
Vasopressin, with testosterone has opposite response – enhances fight or flight –
increased stress
Implicated in stress reduction
Oxytocin
Primarily a neurotransmitter in the brain, but can
act as a hormone when secreted into blood stream
by the posterior pituitary
Levels of oxytocin  during pregnancy
Used to induce labour
“Love hormone”
Oxytocin Receptor
G-protein coupled receptor – intracellular signals
Expressed by myoepithelium of mammary gland
Expressed by endometrium & myometrium of uterus – levels
increase during pregnancy
Oxytocin is part of a positive feedback
mechanism
Example:
HYPOTALAMUS
SENSOR
CONTROL
CENTER
OXYTOXIN
DELIVERY!
Uterine
contractions
EFFECTOR
PITUITARY
GLAND
Ageing and Stress:
● Neuronal Loss: Alterations in excitability of
Limbic system and HPA
● Rise in ‘Stress’ hormones
- Catecholamine
- ACTH
- Cortisol
● Decreased sex hormone levels
● Increased Free radical damage (ROS)
Lower adaptive reserve
and coping
● Depression of immune function
● Protein loss, muscle wasting, decrease in available fuel reserves
Stress – Age syndrome
Summary of Lecture
•Links between disease & stress (including stress
disorders )
•Different forms of stress
•GAS – General Adaptation Syndrome & how ideas
have subsequently changed
•Limbic system
•CNS & Endocrine system in stress
•How stress affects hormones
References – Stress or Endocrine chapters in:
Hadley, M.C. & Levine J.E. (2007). Endocrinology. 6th Edit, Pearson
International.
McCance, K. L. & Huether, S. E. (2006). Pathophysiology. (The
Biologic Basis for Disease in Adults and Children). 5th Edit. Elsevier
Mosby.
Marieb, E. N. (2009) Essentials of Human Anatomy & Physiology. 9th
Edit, Pearson International
Purves, D et al (2008). Neuroscience. 4th Edit. Sinauer.
Tortora G. J. & Derrickson B.(2006). Principles of Anatomy and
Physiology. 11th Edit, Wiley.
Unglaub Silverthorn D. (2007) Human Physiology (An integrated
approach), 4th Edit, Pearson International.