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

ZONA FASCICULATA

ZONA RETICULARIS

ZONA GLOMERULOSA

ZONA FASCICULATA

ZONA 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

+

Synthesis of aldosterone

absent in zona glomerullosa

MIT

SER

SER

MIT

Primary capilaryplexus

Neural lobe

AdenopituitaryAnterior lobe

OxytocinVasopresin

ACTH, GH,TSH, LH, FSH, Prolactin

Secretorycells

Chiasmaopticum

Nc. supraopticus

Nc. paraventricularis

Portal vein

***magnocellular

parvocellular

Hypothalamic neuronssecreting releasing, inhibitinghormones (nuclei:nARC, mPOA NPE)

HYPOTHALAMO - PITUITARY SYSTEM

REGULATION OF CORTISOL SYNTHESIS AND SECRETION OF

+

CORTISOL: extra-hypothalamic neurotransmitters CRH (AVP)

ACTH cortisol (corticosterone)

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 liverstimulates gluconeogenesis, glycogenesis (glycogen synthase).Inhibits glucose utilization in the periphery, contributes to insulin resistance by loweringaffinity of insulin receptors for insulinstimulates glucose-6-phosfphatase (hyperglycemic effect)

metabolism of protein proteolysis in fat tissue and skeletal muscle provide amino acids for gluconeogenesis

metabolism of lipidsreduces lipogenesis in the liver, stimulates lipolysis, (FFA) permissive effects on the action of adrenaline via Zn-α2-glycoprotein

Immune systemcortisol inhibits T1-helper cells and activates T2-helper cells, i.e. the action isantiinflammatory

CNSthrough 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 effectsarterioral 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 TOANY DEMAND

stressor - stimulusstress - 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 stress-induced 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 andapproach it.

Based on the findings of the existence of stressor-specific neuroendocrineresponses and mapping of stressor-specific central circuits participating inthese 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 organismare activated to sustain homeostasis. The adaptive responses reflect activation of specific central circuits and are genetically programmed andconstantly modulated by environmental factors

Pacak K.: Stressor-specific activation of the hypothalamic-pituitary-adrenocortical axis. Physiol Res 2000; 49: S11-S17

STRESS SITUATIONSA 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 longlasting exposition).Many of the stressors described above, act in concert, e.g. majority of somaticstressors 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

NA - 1500 pg/mL

A - 50 pg/mL tachycardia

75 pg/mL lipolysis and

enhanced cystolic blood pressure

General and Clin. Endocrinol.

Bratislava, 2004

CO

RT

GH

CO

RT

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

lact

ate

mm

ol L

-1

PLASMA LEVELS OF HORMONES IN HEALTHY MEN DURING HYPERTHERMIA IN SAUNA

General and Clin. Endocrinol.

Bratislava, 2004

GH

ng

ml-1

CO

RT

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

GH

ng

mL

-1

CO

TR

ng

ml-1

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

behavioralresposes

STRESS

hypothalamuslocus. coeruleusNucl tractus. sol.

amygdala

hippocampus

pituitary

adrenals

CRH, DANA, 5-HT

GABA

CRH / AVP

ACTH

CRH

cortisol sympathetic ganglion

NA A

cortisol

cardiovascular toneInsulin rezistance (hyperglycemia)adiposityimmunosuppression

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

DYSREGULATION OF IMMUNO-NURO-ENDOCRINE LOOP IN STRESS

STRESS