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Physiology
Dr. Hanan Luay
Lec :6
Objectives:
1- List the main groups of hormones released from the adrenal
cortex?
2- Discuss the physiological action of glucocorticoids?
3- Explain the causes behind the effects of increased or decreased
cortisol secretion?
4- Discuss the physiological action of mineralocorticoids?
Suprarenal gland:
The two adrenal glands, lie at the superior poles of the two kidneys, each gland
is composed oftwo distinct parts, the adrenal medulla and theadrenal cortex.
The adrenal medulla, the central part of the gland, is functionally related to
thesympathetic nervous system; it secretes the hormonesepinephrine and
norepinephrine in responseto sympathetic stimulation. In turn, these hormones
cause almost the same effects as direct stimulation of the sympathetic nerves in
all parts of the body.
The adrenal cortex (the outer part) secretes an entirely different group of
hormones, calledcorticosteroids.These hormones are all synthesized from the
steroid cholesterol,and they all have similar chemical formulas. These hormones
are:
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1-Mineralocorticoids: they have gained this name because they especially
affect the electrolytes (the “minerals”) of the extracellular fluids-sodium and
potassium,in particular.
2-The Glucocorticoids have gained their name because they exhibit important
effects that increase blood glucose concentration.Approximately 90 to 95 per
cent of the cortisol in the plasma binds to plasma proteins, especially a globulin
called cortisol-binding globulin or transcortin and, to a lesser extent, to albumin.
About 2% is in the free form which is the active form.This high degree of
binding to plasma proteins slows the elimination of cortisol from the
plasma; therefore, cortisol has a relatively long half life (the bound cortisol
act as a reservoir for the hormone)
Two are of exceptional importance to the normal endocrine function of the
human body: aldosterone, which is the principal mineralocorticoid, and cortisol,
which is the principal glucocorticoid.
3-Sex hormones .
Functions of the Glucocorticoids:
At least 95 per cent of the glucocorticoid activity of the adrenocortical secretions
results from the secretion of cortisol,
Cortisol:
The physiological action of cortisol:
1-Effects of Cortisol on Carbohydrate Metabolism:
It increases blood glucose concentration(antihypoglycemic effect) .When
hypoglycemia →stimulation of CRH (corticotrophin releasing hormone)
secretion→ release of ACTH → cortisol release and increase in blood glucose
level.How?
a-
It stimulates gluconeogenesis
(formation of carbohydrate from proteins and
some other substances) by the liver, this effect is part of the effect on protein
,because it increases the enzymes required to convert amino acids into glucose
in the liver cells. And it causes mobilization of amino acids from the
extrahepatic tissues mainly from muscle. As aresult, more amino acids become
available in the plasma to enter into the gluconeogenesis process of the liver and
thereby to promote the formation of glucose.
The increase in glucose level will stimulate insulin secretion; also it reduces the
sensitivity of many tissues, especially skeletal muscle and adipose tissue, to
the stimulatory effects of insulin on glucose uptake and utilization. If this
persists for long time it will cause B cell exhaustion →diabetes mellitus.
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b-
Decreased Glucose Utilization by Cells
:
Cortisol causes a moderate decrease in the rate of glucose utilization by most
cells in the body (skeletal , muscles and adipose tissue) ,by inhibiting glucose
entry to the cells→ increase blood glucose concentration to be available for
normal brain function ,so it protect the brain from hypoglycemia.
2-Effect on protein metabolism:
It exerts
catabolic
effect on proteins. It will reduce the protein stores in
essentially all body cells except those of the liver. This is caused by both
decreased protein synthesis and increased catabolism of protein already in the
cells.
Also it depresses the formation of RNA and subsequent protein synthesis
in many extrahepatic tissues, especially in muscle and lymphoid tissue.
It diverts amino acids from the muscles and the liver for the process of
deamination and gluconeogenesis, so it facilitates the breakdown of proteins
.
3-Effects of Cortisol on Fat Metabolism:
It promotes mobilization of fatty acids from adipose tissue. This increases the
concentration of free fatty acids in the plasma, which also increases their
utilization for energy.
4-Effect on minerals:
It has a similar effect to aldosterone, although it is weaker than it (1/10 the
power of Aldosterone).
It promotes sodium retention and potassium elimination, excessive secretion will
lead to more sodium retention → water retention, but no edema because there
is increase in the glomerular filtration rate (GFR).
5-Effect on respiration:
It is important for the synthesis of surfactant during intrauterine life (to prevent
respiratory distress syndrome). In females who are about to deliver preterm
babies we usually give them cortisol to promote the formation of surfactant).
6-Effect on water balance:
It causes sodium retention which leads to water retention .It also causes increase
in GFR(glomerular filtration rate), which counteract the water retention and the
person does not develop edema.
7-Effect on cardiovascular system:
Cortisolrestores vascular reactivity. Ithelps in maintaining arterial response to
sympathetic tone. Deficiency of the hormone leads to hypotensive subject due to
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failure to maintain the peripheral resistance. While patients with hyperfunction
of the adrenal cortex are hypertensive(because of the increase in peripheral
resistance).
8-Effect on GIT:
Cortisol reduces the resistance of gastric mucosa to HCL so increase secretion of
it leads to ulcer (so before giving the patient steroid tablets ask him if he has
gastric pain or ulcer otherwise it may cause perforation to the stomach). Also it
has an anti vitamin D effect .It prevent the absorption of the vitamin from the
intestine.
9-Effect on lymphoid tissue and heamopoiesis:
Cortisol suppresses the production of antibodies (used in chronic inflammatory
diseases) in which inappropriate antibodies are produced in the subject against
his own tissues
(
The administration of large doses of cortisol causes decreases
the output of both T cells and antibodies from the lymphoid tissue. As a result,
the level of immunity for almost all foreign invaders of the body is
decreased.
Conversely, this ability of cortisol and other glucocorticoids to suppress
immunity makes them useful drugs in preventing immunological rejection of
transplanted hearts, kidneys, and other tissues.
10-Effect on bones:
Excessive secretion leads to osteoporosis due to destruction of the matrix of the
bone (catabolic effect of cortisol on protein found in the matrix).This effect of
cortisol in mobilizing proteins could make amino acids available to needs of the
cells to synthesize substances essential to life.
11-Anti- inflammatory effect of cortisol:
It has the following effects to prevent inflammation:
1-Cortisol stabilizes the lysosomal membranes, so decreases the proteolytic
enzymes that are released by the lysosomes.
2. Cortisol decreases the permeability of the capillaries. This prevents loss of
plasma into the tissues.
3. Cortisol decreases both migration of white blood cells into the inflamed area
and phagocytosis of the damaged cells.
4. Cortisol suppresses the immune system, causing lymphocyte reproduction to
decrease markedly(especially T lymphocytes).
5. Cortisol attenuates fever mainly because it reduces the release of interleukin-
1 from the white blood cells.
Inaddition to that Cortisol causes resolution of inflammation, the rate of healing
is enhanced.So it can be used in disease that are characterized by severe local
inflammation like rheumatoid arthritis, rheumatic fever, and acute
glomerulonephritis.
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12-Effect on allergy:
It blocks the inflammatory response to allergic reactions in the same way that it
blocks the other types of inflammatory response.
13-Effect on blood:
It decreases the number of eosinophils and lymphocytes in the blood. It also
increases the production of red blood cells (mechanisms unclear).When excess
cortisol is secreted by the adrenal glands, polycythemia often results, and
conversely, when the adrenal glands secrete no cortisol, anemia often results.
Mineralocorticoids:
They are secreted by the adrenal cortex ,the most important is Aldosterone
which increases the reabsorption of Na from the tubules of the kidney ,salivary
,sweat ,gastric and intestinal glands ,so it elevates the level of sodium in blood
while K level is eliminated in the opposite direction.
Control of aldosterone secretion:
The release of aldosterone is under the influence of:
1-The level of K and Na in plasma:
The increased level of K and the reduction in Na level will cause stimulation of
aldosterone secretion (direct effect on the adrenal gland).
2-Heamorhage and hypovolemia:
This result in decrease in venous return decrease in cardiac output systolic
blood pressure is reduced→ pressure in afferent arterioles in the kidney is
reduced →stimulation of juxtaglomerular apparatus in the kidney →release of
renin which acts on angiotensinogen (alpha 2 globulin synthesized by the liver),
and convert it to angiotensin I .During its passage to the capillaries of the lung
converted to angiotensin II by converting enzyme secreted by the endothelial
lining of the blood vessel of the lung.
Angiotensin II 1-increases the peripheral resistance and 2- it has direct
stimulation to the adrenal cortex to release aldosteron→Na retention and K
elimination as a result we have increase in the blood pressure
So suprarenal gland is essential for life removal of it will lead to
hypotension and death within short period of time.
Clinical conditions related to the adrenal gland disturbances:
1-Hyperadrenalism-
Cushing’s Syndrome
Hypersecretion by the adrenal cortex (or prolonged exposure to high level of
steroids) causes a complex cascade of hormone effects called Cushing’s
syndrome.
The cause for this abnormality is either:
1-ACTH dependent causes: Increase of ACTH →↑ cortisol level. As in case:
a- Tumor (like adenoma) of the anterior pituitary.
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b- Abnormal function of the hypothalamus that causes high levels of
corticotropin-releasing hormone (CRH),
c- “ectopic secretion” of ACTH by a tumor elsewhere in the body,such as an
abdominal carcinoma;
When Cushing’s syndrome is secondary to excess secretion of ACTH by the
anterior pituitary, this is referred to as Cushing’s disease.
2-Non- ACTH dependentcauses:
a-Adrenocortical hyperplasia.
b-Adenoma or tumor of the adrenal cortex.( Primary overproduction of cortisol
by the adrenal glands is usually associated with reduced ACTH levels due to
cortisol feedback inhibition of ACTH secretion by the anterior pituitary gland).
c-Iatrogenic : administration of large amounts of synthetic glucocorticoid ,as in
case of asthma, skin diseases and renal disorder
(so if we are giving a patient cortisol for long time we are inhibiting the
secretion of ACTH from the pituitary gland, so when we stop giving the drug
we must do it gradually to give chance to the pituitary to regain producing
the ACTH in order to prevent hypofunction of the adrenal gland because
ACTH is low in the blood as a result of the drug use).
Symptoms of Cushing’s disease:
1-Effects on carbohydrate metabolism:
Increased blood glucose concentration. This results mainly from enhanced
gluconeogenesisand decreased glucose utilization by the tissues and may cause
diabetes mellitus.
2-The effects on protein:
Protein catabolism is often profound in Cushing’s syndrome, causing greatly
decreased tissue proteins almost everywhere in the body. Severe muscles
weakness and wasted thin limbs. Skin atrophy (bruises) and osteoporosis of
the bones (back pain).The loss of protein synthesis in the lymphoid tissues
leads to a suppressed immune system, so that many of these patients die of
infections. Also because of loss of protein in the subcutaneous tissues, they
tear easily, resulting in development of large purplish striaein the skin
.
3-The most striking feature of the disease:
Buffalohamp:mobilization of fat from the lower part of the body andabnormal
deposition of fat in the lower part of the neck, the thoracic and upper abdominal
regions.
a- Moon face
b- Increase of Na and water retention.
c- Excessive secretion of sex hormone acne, hirsutism(excess growth of hair
on the face).
d- About 80 per cent of patients have hypertension, presumably because of
the slight mineralocorticoid effects of cortisol.
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Hypofunction of the adrenal cortex:
Hypoadrenalism-Addison’s Disease:
1-Primary →tumor in the adrenal glandAddisson's disease.
2-Secondary→ reduction of the ACTH secretion due to pituitary or
hypothalamic disorder.
The causes of Addisson's disease:
a-Autoimmune disease: antigene –antibody reaction.
b-Tuberculosisor invasion of the adrenal cortices by cancer →destruction of the
gland. The symptoms partly due to aldosteron deficiency but mainly due to
glucocorticoid deficiency.
Symptoms of Addisson's disease:
1-Mineralocorticoid Deficiency:
Sodium ions, chloride ions, and water are lost into urine in great amounts while
K is preserved. The net result is a greatly decreased extracellular fluid volume
which leads to hypotension. Cardiac output decreases, and the patient dies in
shock if not treated.
2-Glucocorticoid Deficiency:
Hypoglycemia due to reduction of gluconeogenesis. It reduces the mobilization
of bothproteins and fats from the tissues, thereby depressingmany other
metabolic functions of the body.
2-Melanin Pigmentation: pigmentation of the mucous membranes and skin.
Especially of the area that is already pigmented exposed to light e.g. face, neck,
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back of the neck, hand, elbow ,knee.Also mucus membrane like lips, eyelids
and vagina.
The cause of pigmentation is as follows:
When cortisol secretion is depressed, thenormal negative feedback to the
hypothalamus andanterior pituitary gland is also depressed, thereforeallowing
tremendous rates of ACTH secretion as well as simultaneous secretion of
increased amounts ofMSH. Probably the tremendous amounts of ACTHcause
most of the pigmenting effect because they canstimulate formation of melanin
by the melanocytes in the same way that MSH does.
13 24 39
↓
↓
This is like MSHAll the activity of the ACTH is due to this limit
Addisonian Crisis.Great quantities of glucocorticoids are occasionally
secretedin response to different types of physical or mentalstress. In a person
with Addison’s disease, at rest the patient is normal but the output
ofglucocorticoids does not increase during stress. Yetwhenever different types of
trauma, disease, or otherstresses, such as surgical operations, a personis likely to
have an acute need for excessive amounts ofglucocorticoids and often must be
given morethan the normal quantities of glucocorticoids toprevent death.
This critical need for extra glucocorticoids and theassociated severe debility in
times of stress is called anaddisoniancrisis, in which GIT symptoms happen and
acute abdominal pain,and hypotension. We have to correct it rapidly by
dexamethazol injection.
The crises happens sometimes in cases like asthma we give the patients high
doses of cortisol, so we have suppression of the activity of the adrenal gland,
when stop giving the drug we have to stop it gradually not suddenly to avoid
Addissonian crises.
Adrenal medulla:
This gland secretes adrenalin and noradrenalin (catecholamine), it is not under
the control of pituitary gland or hypothalamus, but it is controlled by the
autonomic nervous system so the hormones are called the hormones of
emergency.
The quantity of adrenalin is about 4-5 times as much as that of noradrenalin
Themetabolic effect of catecholamine is mainly due to the effect of adrenalin
rather than noradrenalin these effects include:
a- Increase the glucose level in the blood by:
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1- Stimulation of gluconeogenesis.
2-Inhibiting the release of insulin.
b- Increase the level of free fatty acids in blood so it is concerned as a
ketogenic factor.
These effects of the hormones in various tissues are grouped according to the
receptors with which they interact .we have 2 groups:
1- Alpha receptors serve excitatory function as vasoconstriction.
2- Beta receptors: serve predominantly inhibitory function as vasodilatation
and bronchodiltation.
Except the effect on the heart → increase the force of concentration→ increase
cardiac output→ increase systolic blood pressure→ increase pulse pressure.
Adrenalin causes tachycardia with an increase in cardiac output and a fall in the
peripheral resistance, so we have increase in systolic blood pressure and a drop
in the diastolic pressure, increase in pulse pressure.
Noradrenaline increase the total peripheral resistance while adrenalin causes
vasoconstriction in splanchnic areas and dilatation of skeletal muscle blood
vessels→ decrease in peripheral resistance→ decrease in blood pressure.
The clinical conditions result from disturbances of the release of
catecholamins:
Pheochromocytoma a tumor of the adrenal medulla → increase secretion of
catecholamins continuously or periodically (in young age mainly 20-25 years
old).Increase in blood pressure →decrease diastolic pressure→ increase in
pulse pressure.
This case is associated with flushing, sweating (perspiration), palpitation or
tachycardia, tremor of the hand and the patient may have headache.
Estimation of adrenalin and noradrenalin is done through the estimation of their
metabolites in urine which is called venylmandillic acid (VMA).