ADRENAL GLANDS, STRESS
Jana Jurčovičová
In mammals, the adrenal glands (also known as suprarenal glands) are the
triangular-shaped endocrine glands that sit on top of the kidneys. They
synthesize and release hormones related to stress such as cortisol and
catecholamines.
ADRENAL GLANDS
Anatomically, the adrenal glands are located in the
retroperitoneum situated atop the kidneys, one on each
side. They are surrounded by an adipose capsule and
renal fascia. Each adrenal gland is separated into two
distinct structures:
the adrenal cortex and medulla, both of which produce
hormones. The cortex produces mainly aldosterone,
cortisol and androgens, while the medulla produces
epinephrine, norepinephrine and dopamine. The
combined weight of the adrenal glands in an adult
human ranges from 7 to 10 grams.
ADRENAL GLAND
ADRENAL CORTEX
EMBRYOLOGY:
4th WEEK THE CORTEX CELLS START TO DEVELOP .
6th WEEK NERVE FIBERS PENETRATE INTO THE DEVELOPING CORTEX
8th WEEK TWO ZONES DEVELOP, CENTRAL – FETAL AND OUTER,
DEFINITIVE ZONES
DURING FETAL DEVELOPMENT PRIMITVE ADRENOCORETICAL CELLS
CAN MIGRATE AROUND KIDNEY, UTERUS, LUNG - ACCESORY
ADRENOCIRTICAL RESIDUES
ADRENAL CORTEX
ZONA GLOMERULOSA
GLOMERULOSA
ZONA FASCICULATA
FASCICULATA
ZONA RETICULARIS
RETICULARIS
ADRENAL CORTEX
80 % of the whole adrenal gland. The adrenal cortex comprises
three zones, or layers.
zona glomerulosa (5% of the cortex) – ALDOSTERON
zona fasciculata (70% of the cortex) – GLUCOCORTICOIDS
zona reticularis (25% of the cortex) – GLUCOCORTICOIDS
– SEX HORMONES
men DHAE, testosterone 100 µg daily (testes 7000µg daily),
women androgens, plus some estrogens – biological
significance after the menopause
the precursor is CHOLESTEROL
BIOSYNTHESIS OF ADRENAL GLAND HORMONES
absent in zona
glomerullosa
MIT
+
SER
SER
MIT
Synthesis of aldosterone
HYPOTHALAMO - PITUITARY SYSTEM
Nc. paraventricularis
Nc. supraopticus
Hypothalamic neurons
secreting releasing, inhibiting
hormones (nuclei:nARC, mPOA NPE)
Primary capilary
plexus
Chiasma
opticum
Neural lobe
Portal vein
Adenopituitary
Anterior lobe
Secretory
cells
Oxytocin
Vasopresin
ACTH, GH,
TSH, LH, FSH, Prolactin
REGULATION OF CORTISOL SYNTHESIS AND
SECRETION OF
+
CORTISOL:
extra-hypothalamic neurotransmitters
ACTH
cortisol (corticosterone)
CRH (AVP)
TRANSPORT AND DISTRIBUTION OF CORTISOL
Corticosteroids circulate bound to transport protein:
CBG Cortisol Binding Globulin – 90 %;
ALBUMIN – 6 %
3 – 10 % is free, biologically active form
T/2 (half life time) is 60 - 90 minutes
CBG is synthesized in the liver, estrogen stimulate its production
Disorder of CBG hereditary decrease of CBG synthesis, obesity liver diseases
Steroids are metabolized in the liver after conjugation with glucuronic acid
EFFECTS OF CORTISOL
metabolism of glycides - HYPERGLYCEMIA
stimulates glucose uptake in the liver
stimulates gluconeogenesis, glycogenesis (glycogen synthase).
Inhibits glucose utilization in the periphery, contributes to insulin resistance by lowering
affinity of insulin receptors for insulin
stimulates glucose-6-phosfphatase (hyperglycemic effect)
metabolism of protein
proteolysis in fat tissue and skeletal muscle provide amino acids for gluconeogenesis
metabolism of lipids
reduces lipogenesis in the liver, stimulates lipolysis, (FFA)
permissive effects on the action of adrenaline via Zn-α2-glycoprotein
Immune system
cortisol inhibits T1-helper cells and activates T2-helper cells, i.e. the action is
antiinflammatory
CNS
through type I a II receptors in limbic system affect memory, mood, emotions
DEFECTS IN CORTISOL SECRETION
Congenital defects in synthesizing enzymes results in insufficient cortisol
production and secretion and leads to adrenal hyperplasia.
Addison’s disease:hypoglycemia, insifficient protein and fat mobilization,
increased ACTH secretion, pigmentation, propensity to autoimmune
diseases
Overproduction of cortisol – Cushing syndrome:
hyperglycemia, insulin resistance, redistribution of fat, retention of Na+,
and water, hypertension
MECHANISM OF ALDOSTERONE SYTHESIS AND
SECRETION – ACTH route
ALDOSTERONE:
its production and secretion is 100-1000 times less than that of cortisol.
Stimulation: ACTH, angiotensin II and K+ (depolarization of plasma membrane, Ca ++
entry into the cell, activation of aldosterone synthase)
MECHANISM OF ALDOSTERONE SYNTHESIS AND
SECRETION - RAS route
FEEDBACK MECHANISMS OF
ALDOSTERONE REGULATION
TRANSPORT AND DISTRIBUTION OF
ALDOSTERONE
Aldosterone has no specific binding protein
CBG - 17 %
ALBUMIN - 47%
T/2 half life time is 15 to 20 minutes
EFFECTS OF ALDOSTERONE
The main effect of aldosterone is to retain intravascular volume by reabsorption of
Na+ from urine sweat saliva into epithelial cells. In the kidney aldosterone acts in
the distal tubules and collecting ducts of the nephron.
It causes also elimination of K+. Via specific receptors aldosterone activates the
transcription of mRNA for Na+ K+- ATPase.
Receptor for aldosterone binds also cortisol with comparable affinity. But, tissues
sensitive to aldosterone express
11-beta- hydroxysteroid-dehydrogenase
which destroys cortisol, while leaving aldosterone intact.
OVERPRODUCTION OF ALDOSTERONE (Conn syndrome) – depletion of K+ ,
body fluid volume expansion, hypertension. When body fluid volume exceed
certain limits the excretion of Na + occurs.
„Escape phenomenon “ The effect is most probably mediated by enhanced
secretion of atrial natriuretic peptide
ADRENAL MEDULLA
The chromaffin cells of the medulla,
(named for their characteristic brown staining with chromic acid salts) they are
modified postganglionic cells of the autonomic nervous system that have lost their
axons and dentrites, and receive innervation from cholinergic preganglionic fibers.
These cells are the body's main source of the circulating adrenaline (epinephrine) –
85%, they produce noradrenaline (norepinephrine), and dopamine, plus some
peptides, neurotensin, neuropeptid-Y, vasopresin, oxytocin, somatostatin,
met-enkefalin.
The source of plasma noradrenaline is predominantly sympathetic ganglion, 50 % of
dopamine in plasma originate in adrenal medulla, 50 % sympathetic ganglion
adrenaline in plasma comes from adrenal medulla.
T/2 of catecholamines is about 2 minutes.
receptors – signals are received via cholionergic – nicotine type receptors, (a few
opioid receptors)
SCHEME OF THE SNS
EFFECTS OF CATECHOLAMINES
receptors: adrenergic α1, α2; β1, β2; are localized in all parts of cardiovascular system
and play a role in blood pressure regulation
hemodynamic effects
arterioral contraction - α1, α2 (IP3 mechanism)
arterioral dilation - β2 (cAMP mechanism)
heart rate, cardiac contractility, blood pressure - β1(cAMP mechanism)
Others
bronchiole dilation - β2, lowering of GIT motility - β1
bronchiole constriction (α) and relaxation (β) of myometrium
Notable all the effects are characteristic of the fight-or-flight response
during stress.
Dopaminergic D1, D2 ; localized in smooth muscle of blood vessels, increase
dilation in renal, and coronar vessels and increase cardiac contractility
(overall less pronounced effects than that of adrenergic receptors)
EFFECTS OF CATECHOLAMINES
metabolic effects
stimulation of output of glucose from the liver
adrenaline and noradrenaline stimulate phosphorylase in the liver (cleavage of
1 – 4 binding in glycogen) via cAMP activation ( β2 receptors)
stimulation of output of lactate from the muscle
stimulation of phosphorylase, glucose –6-phosphate is metabolized to pyruvate
due to absence of glucose-6-phosphatase. Pyruvate is subsequently converted
to lactate. Lactate from blood enters liver and by the oxidation process gives
rise to glycogen.
stimulation of lipolysis (β1 , β2 ) release of FFA,
stimulation of ketogenesis in liver
release of amino acids from muscle
EFFECTS OF ADRENALINE ON TISSUE GLYCOGEN,
PLASMA LACTATE AND A GLUCOSE
INTERACTION OF ADRENAL CORTEX AND MEDULLA
What is the ganglion doing inside the gland?
1.
Adrenocortical steroids influence the differentiation of
adrenomedullary cells from norepinephrine producing
neuronal precursors cells towards epinephrine producing
adrenomedullary chromaffin cells. They also direct the
phenotypic development of adrenal chromaffin cells.
2.
Adrenomedullary chromaffin cells produce neurotransmitters
which stimulate adrenocortical functions.
STRESS – BASIC TERMS
Hans Selye
graduate from German Medical Faculty Charles University in Prague
term STRESS -1936
STRESS IS THE NONSPECIFIC RESPONSE OF THE BODY TO
ANY DEMAND
stressor - stimulus
stress - complex response of the organism to a stressor
STRESS CONCEPT
Selye introduced stress into medical and scientific literature. The starting point
for the elaboration of his stress theory was his report, published
letter to Nature in 1936
describing a pathological triad (adrenal enlargement, gastrointestinal ulceration,
and thymico-lymphatic involution) elicited by any stressors. From this
pathological triad he defined stress as
THE NONSPECIFIC RESPONSE OF THE BODY TO ANY DEMAND
emphasizing that the same pathological state — "stress syndrome"— would
result from exposure to any stressor.
Hans Selye used the term stress (load) from mechanics and transmitted this
term into the medical vocabulary.
HOMEOSTASIS
Cannon was the first to introduce the term "homeostasis" to describe the
coordinated physiological processes which maintain most of the steady
states in the organism. He turned his attention to the sympathetic nervous
system as an essential homeostatic system that serves to restore stressinduced disturbed homeostasis and to promote survival of the organism.
Cannon was the first to touch the issue of specificity of stress responses
since he showed, for example, that the homeostatic reaction to lack of
oxygen is quite different from that with which the body responds to exposure
to cold. However, Cannon never used the term "stress."
Cannon (1929)
- streotypical response to any demand does not provide the possibility of
the adaptation reactions, therefore it could not have developed during the
evolution
STRESS DEFINITION
Many current views exist concerning what stress means and how to define and
approach it.
Based on the findings of the existence of stressor-specific neuroendocrine
responses and mapping of stressor-specific central circuits participating in
these responses, there is generally accepted definition postulated by Pacak:
STATE OF THREATENED HOMEOSTASIS (PHYSICAL OR PERCEIVED
TREAT TO HOMEOSTASIS)
During stress, adaptive compensatory specific responses of the organism
are activated to sustain homeostasis. The adaptive responses reflect
activation of specific central circuits and are genetically programmed and
constantly modulated by environmental factors
Pacak K.: Stressor-specific activation of the hypothalamic-pituitary-adrenocortical axis. Physiol Res 2000; 49: S11-S17
STRESS SITUATIONS
A stressor is to be viewed as a stimulus that disrupts homeostasis.
Stressors can be divided into following categories:
1) physical stressors - physical load pain, heat, cold, noise restraint of
movement etc.
2) psychological stressors - fear, negative emotional experience, loss of job,
divorce, death in the family, that reflect a learned response to previously
experienced adverse conditions;
3) social stressors - reflecting disturbed interactions among individuals;
psychological and social stressors are often combined into psych-social
stressors
4) stressors that challenge cardiovascular and metabolic homeostasis hemorrhage, hypoglycemia, surgery in anesthesia, inflammation, infection
According to the duration of the exposition to stressor: acute (single,
intermittent) and chronic (continuous long lasting exposition, intermittent long
lasting exposition).
Many of the stressors described above, act in concert, e.g. majority of somatic
stressors include some psychological component.
PATOPHYSIOLOGY OF STRESS REACTION
Stimuli from the external environment acts via senses, stimuli from the
internal environment act via interoceptors
Stimuli are transmitted into the CNS by nerve or humoral route (toxins).
The signal is further directed to:
cortex (alertness, exploration),
autonomous nerve system (noradrenergic neurons in locus coeruleus,
nerve endings in various organs, activation of adrenal medulla),
somatomotor system (flight , fight)
neuroendocrine system (activation of ACTH, cortisol, growth hormone
via hypothalamus, in posterior pituitary vasopressin)
The main role of the endocrine system during stress is mobilization of
nutrients for brain, heart, and preservation of water in the organism.
TYPICAL ENDOCRINE RESPONSES TO SELECTED
ACUTE STRESSORS IN HUMANS
PHYSICAL LOAD (physical stressor)
HYPERTHERMIA OF THE ORGANISM (physical stressor)
INSULIN INDUCED HYPOGLYCEMIA (metabolic stressor)
PLASMA LEVELS OF HORMONES DURING
GRADED LOAD ON BICYCLE ERGOMETRY IN
HEALTHY MEN
THRESHOLD FOR CARDIOVASCULAR
AND METABOLIC EFFECTS
CORT
CORT
A - 50 pg/mL tachycardia
75 pg/mL lipolysis and
enhanced cystolic blood pressure
GH
NA - 1500 pg/mL
General and Clin. Endocrinol.
Bratislava, 2004
lactate mmol L-1
GH ng mL-1
PLASMA GROWTH HORMONE, GLUCOSE AND
LACTATE DURING THE LOAD ON BICYCLE
ERGOMETER IN HEALTHY MEN
General and Clin. Endocrinol.
Bratislava, 2004
GH ng ml-1
PLASMA LEVELS OF HORMONES IN HEALTHY MEN
DURING HYPERTHERMIA IN SAUNA
General and Clin. Endocrinol.
Bratislava, 2004
GH ng mL-1
COTR ng ml-1
PLASMA LEVELS OF HORMONES AFTER INSULIN
INDUCED HYPOGLYCEMIA (i.v. 0,1U/kg) IN
HEALTHY MEN
General and Clin. Endocrinol.
Bratislava, 2004
CHRONIC STRESS AND ADAPTATION
During stress adaptive, compensatory specific responses of the organism
are are activated to maintaining homeostasis.
Adaptive responses represent the activation of specific central pathways,
the responses are genetically programmed and at the same time modulated
by environmental factors.
In relation to chronic stress the term “allostasis” has been introduced. (Its
meaning is to achieve stability by change). Allostasis represents an active
process of adaptation by production various mediators such as adrenal
steroids, cytokines, catecholamines, tissue mediators ect. It is a possibility
to maintain stability by change. When allostatic mechanisms are effective,
the organism undergoes process of adaptation and is protected from damage
Typical example of adaptation to hard physical load is lowering of
cardiovascular and neuroendocrine responses in long distance runners.
The adaptation is influenced by genetic factors, and personality trait. If the
stress exposure exceeds the ability of the organism to adapt, it results in
harmful consequences called allostatic overload .
CHRONIC STRESS AND LIMBIC SYSTEM
FRONTAL SECTION OF THE BRAIN
STRESS
behavioral
resposes
hippocampus
NA, 5-HT
GABA
CRH, DA
amygdala
hypothalamus
CRH
locus. coeruleus
Nucl tractus. sol.
CRH / AVP
sympathetic
ganglion
cortisol
pituitary
ACTH
NA
A
adrenals
cortisol
cardiovascular tone
Insulin rezistance
(hyperglycemia)
adiposity
immunosuppression
METABOLIC DISORDERS AS CONCEQUENCE OF
CHRONIC STRESS (metabolic syndrome)
Pervanidou P,and Chrousos GP:Metabolism, 2012
POSTTRAUMATIC STRESS DISORDER
In 1871 Da Costa, described symptoms in a group of soldiers such as tachycardia,
anxiety, breathlessness, and hyper-arousal. These symptoms were named
“Da Costa syndrome.” Some of the soldiers presented symptoms like staring eyes
unexplained deafness or blindness, and paralysis. Similar symptoms were reported in
World War II veterans. Nowadays these symptoms are termed “post-traumatic stress
disorder” (PTSD).
It is classified as a neurotic stress-related and somatoform disorder.
PTSD can be categorized into two types: acute PTSD, if symptoms persist for less than
three months, and chronic if symptoms persist for a longer time.
Exposure to unexpected extreme traumatic stressor may cause PTSD. Terrorist
attack, or severe car accidents, sexual abuse, earthquake, or unexpected death in
family. PTSD can appear at any age.
Work-related PTSD are common in health and social services, in specific
occupations, journalists, police, fire, and emergency service workers.
About 61.7 % women and 51.2% men experienced in life traumatic situation.
POSTTRAUMATIC STRESS DISORDER
PTSD can be considered as a maladaptation to a traumatic stressor, where
personality trait plays a role: hypersensitivity, neurosis).
Neuroimaging studies reported abnormalities in the prefrontal cortex (PFC),
hippocampus and amygdala in PTSD. These neural circuits are implicated in
impaired extinction of fear-related memories.
In the pathology of these cirquits are involved neurotransmitter pathways:
hyperreactivity of noradrenergic connections between amygdala and
hippocampus were described to which contribute also enhanced cortisol
levels .
Javidi H. Yadollahie M, 2011
Steckler T. a Riswbrough, 2012
IMMUNO-ENDOCRINE INTERACTIONS UNDER
PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL
SITUATIONS
CORTISOL –
PHYSIOLOGICAL SUPPRESSOR OF IMMUNE FUNCTIONS
ADRENALINE, NORADRENALINE PHYSIOLOGICAL SUPPRESSOR OF IMMUNE FUNCTIONS
GROWTH HORMONE, PROLACTIN –
PHYSIOLOGICAL ACTIVATOR OF IMMUNE FUNCTIONS
DYSREGULATION OF IMMUNO-NURO-ENDOCRINE
LOOP IN STRESS
STRESS