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The following points highlight the four main endocrine functions of adrenal cortex. The functions are: 1. Adrenal Cortex 2. Adrenal Androgens 3. Aldosterone 4. Endocrine Function of Adrenal Medulla.
Function # 1. Adrenal Cortex:
It is divisible into three different layers, from outwards within will be:
i. Zona glomerulosa
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ii. Zona fasciculata
iii. Zona reticularis.
All three layers secrete the hormones.
Zona glomerulosa secretes mineralocorticoids of which the most important is aldosterone.
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Zona fasciculata and reticularis together secrete glucocorticoids of which the most important are Cortisol and corticosterone. The layers also secrete sex steroids, of which adrenal androgen is most important. Both the glucocorticoids and mineralocorticoids can exert the action of the other group as well especially when the concentration of the hormone is very high.
Principal hormones of renal cortex have been enumerated in Table 6.1, and the relative efficacy of glucocorticoid and mineralocorticoid and certain other substance actions have been compared in Table 6.2.
Biosynthesis of Hormones (Figs 6.19 and 6.20):
Genetic defects in Cortisol biosynthesis have important consequences. A defect in 21 or 11-hydroxylase enzyme gene leads to overproduction of androgenic steroids from the precursors. Hence there will be production of excess of androgens and this causes masculinization of female fetuses’ in utero and early secondary sexual changes in male infants and young boys.
Cortisol is transported in circulation. A major part of it is in the protein bound form along with globulin (Cortisol binding globulin—CBG). The level of this protein increases in pregnancy because of which in the initial stages, the free form of hormonal level in circulation decrease.
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This in turn stimulates more of secretion of the hormone by increased secretion of ACTH from the anterior pituitary gland. Levels of CBG decrease in cirrhosis of liver and in nephrosis.
Actions:
Permissive Action:
Cortisol should be present in the target organs for the action of certain other hormones, e.g. the catecholamine can exert the vasoconstrictor effect on vascular smooth muscle only in the presence of Cortisol. The vasoconstrictor effect is necessary to maintain peripheral resistance and hence blood pressure. Permissive action of Cortisol is also required for certain actions of growth hormone and glucagon.
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Metabolic Actions (Fig. 6.21):
a. Carbohydrate metabolism:
It is a hyperglycemic agent and increases blood glucose level.
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i. By decreasing peripheral utilization of glucose in almost all parts of body except heart and brain.
ii. By increasing the gluconeogenesis and glycogenesis in liver.
iii. Excessive use of Cortisol as therapeutic agent may lead to exhaustion of beta cells of pancreas and cause metasteroid diabetes.
b. Protein metabolism:
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In large doses, it enhances the protein breakdown especially in the lymphoid tissue, muscles, and bones.
i. Leading to decreased immunity
ii. Muscular weakness
iii. Weight loss
iv. Susceptibility of the bones for fracture.
v. The amino acids released due to protein breakdown are used for gluconeogenesis in the liver.
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c. Fat metabolism:
The hormone generally increases the lipolysis in adipose tissue. So brings about the breakdown of neutral fats and triglycerides. This will result in increase in free fatty acids and glycerol in circulation.
i. The free fatty acids are used both for energy supply to the tissues and gluconeogenesis in the liver.
ii. There will be redistribution of fats in the body.
iii. Fats are removed from the peripheral parts and deposited in the more central parts of body resulting in moon face, buffalo hump and pendulous abdomen.
d. Mineral metabolism:
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Excess of Cortisol can also exert some amount of action like aldosterone. Hence it increases the sodium reabsorption in the distal convoluted tubule and in exchange for this, potassium excretion in the urine increases. Reabsorption of sodium increases water retention, so blood volume and blood pressure are increased.
e. Water metabolism:
Person with low levels of Cortisol has defective water regulation in the body. This could be because of the increase in the plasma antidiuretic hormone level (ADH degradation rate is slowed) and decreased glomerular filtration rate. Both of these contribute for delayed water excretion. The retention of water by the body can lead to water intoxication.
On Organs:
1. CNS:
It increases the activity of the neurons in central nervous system and hence the patient may have euphoria. It will also increase the irritation of neurons because of which, administration of this as drug to any patient susceptible to/suffering from epilepsy should be borne in mind. Administration of this drug may worsen the condition.
2. GIT:
In large dose, increase the gastric acid secretion and damages the mucus barrier. So the people are more prone to develop peptic ulcer.
3. Skeletal muscle:
Excess of Cortisol leads to muscular weakness promoting protein catabolism and insufficiency also causes muscular weakness.
4. Blood:
Cortisol insufficiency leads eosinophilia, lymphocytosis, etc. whereas excess of Cortisol brings about eosinopenia, lymphocytopenia. Eosinophil count is decreased because of sequestration of the cells in liver. Increased protein breakdown in the lymphoid tissue may lead to decreased antibodies in circulation and the person is more susceptible for infections.
5. Bone:
Excess of Cortisol impedes development of cartilage and causes thinning of epiphyseal plates. There will also be defective synthesis protein matrix and deposition of calcium salts. Because of these things, osteoporosis occurs in Cushing’s syndrome.
Pharmacological actions occur only when the levels are far in excess.
Anti-inflammatory Action:
In some people, acute inflammation can cause more damage to the tissues.
Inflammation is due to increased:
a. Blood flow due to increased metabolic rate of the bacteria at the site of infections
b. Permeability of the capillaries
c. Emigration of leukocytes to the site of infection from the blood vessels
d. Lysozyme release from the cells leading to proteolysis.
Cortisol counters the aforesaid effects by decreasing:
a. Metabolic rate of bacteria
b. Capillary permeability
c. Emigration of leukocytes and stabilizing the lysozymes.
Cortisol should never be administered alone in bacterial infection as anti-inflammatory agent. It should always be combined with antibiotics to take care of the bacteria otherwise it can lead to spread of the bacteria, without the overt reaction of the body due to infection. This can lead to severe problems.
Antiallergic Activity:
Especially in organ or tissue transplantation sometimes the recipient’s body resists or rejects the new organ/tissue. Cortisol can be used to decrease the immunosuppression reactions. This helps to prevent rejection of the transplanted tissues.
Suppresses immune responses by:
i. Decreasing the eosinophil, and lymphocyte count.
ii. Decreasing the eosinophil count by sequestration of the cells in liver and spleen.
iii. Decreasing the lymphocyte percentage by catabolism of proteins in lymphoid tissue. Hence it will decrease the concentration of circulating antibodies in course of time.
Regulation of Secretion:
By the negative feedback mechanism and there is involvement of hypothalamo-pituitary-adrenal axis. Increase free form of hormone in circulation acts on hypothalamus and anterior pituitary gland. From the hypothalamus, secretion of corticotrophin releasing factor (CRF) decreases, so it leads to decreased secretion of ACTH.
Cortisol also acts directly on the anterior pituitary gland and inhibits secretion of ACTH. Decreased ACTH leads to less of Cortisol secretion from the adrenal gland. Apart from this, stress and circadian rhythm directly act on hypothalamus to alter the secretions (Figs 6.22 and 6.23).
Cortisol as a drug when used one has to be careful at the time of discontinuation of the drug. Unlike many drugs, which can be stopped all of a sudden, this cannot be done with Cortisol. When exogenous Cortisol is administered, the increased level of free form of Cortisol in circulation constantly inhibits the hypothalamus.
This brings about the depression of the hypothalamopituitary-adrenal axis function. If Cortisol is withdrawn suddenly, the axis cannot get revived immediately and patient may develop a crisis.
If Cortisol is withdrawn slowly and steadily (tapering dose), more time is provided for the regaining of the activity of the hypothalamopituitary-adrenal axis and the restoration of the endogenous secretion of Cortisol can start once again (Fig. 6.24).
Aminoglutethimide is a potent inhibitor of desmolase reaction and thereby decreases all adrenal steroid synthesis. This drug has been used to treat women with breast cancer. Ketoconazole an antifungal agent also inhibit several steps in biosynthesis of the hormones and thus effective in treating patients having excess of Cortisol secretion.
Function # 2. Adrenal Androgens:
Dehydroepiandrostenedione (DHEA) and androstenedione are weak androgens. In the peripheral tissues, they get converted to potent androgen, testosterone.
In female, the action of adrenal androgens will be:
i. Sustaining of normal pubic and axillary hair.
ii. In menopausal stage, estradiol of adrenal origin is important source of estrogen activity.
In normal male, the amount of testosterone secreted by the testis far exceeds the adrenal androgens and not much role to play by the adrenal androgens. If the adrenal androgen secretion becomes abnormally high especially in children, it can lead to precocious puberty.
Function # 3. Aldosterone:
As stated already, the most important mineralocorticoid is aldosterone, which is secreted by the zona glomerulosa.
Actions:
On the Kidney:
It acts on the distal convoluted tubule and increases the sodium reabsorption. In exchange for this, there will be increased secretion of either potassium or hydrogen ion. Sodium reabsorption will be coupled with chloride and water reabsorption as well. This will increase the extracellular fluid volume and hence blood volume.
On the epithelial cells of the kidney when aldosterone acts, it facilitates the Na+-K+ pumps activity at the basolateral surface and increases sodium movement from the cells into the interstititum and finally into the blood vessels.
Regulation of Secretion (Fig. 6.25):
a. Concentration of K+ and Na+ in circulation can act directly on the gland to alter the secretion. Of the two, the most potent is increase in the concentration of potassium. The normal plasma K+ level is low (5 mEq/L water) when compared to Na+ (150 mEq/L water). So, small alteration in K+ level will have a profound effect on the rate of secretion.
b. Angiotensin II: This is formed due to activity of renin-angiotensin system can directly act on the adrenals and enhance the secretion of the hormone.
c. Some of the other factors which can increase the secretion of aldosterone are anxiety, physical trauma and hemorrhage.
Cushing’s syndrome (Fig. 6.26) is due to hypersecretion of Cortisol. Hypersecretion could be because of problem in adrenal cortex (primary), anterior pituitary (secondary) or in hypothalamus (tertiary).
Addison’s disease is hyposecretion of all hormones of adrenal cortex.
Adrenogenital syndrome is due to hypersecretion of dehydroepiandrosterone. The features of a female suffering from adrenogenital syndrome have been shown in Fig. 6.27.
Virilism is due to deficiency of 21β hydroxylase enzyme which leads to lot of secretion of sex hormones from adrenal cortex. In boys, it leads to precocious sexual development and in female leads to pseudohermophroditism. In adult female, it leads to the development of adrenogenital syndrome.
Conn’s syndrome:
Conn’s syndrome is due to primary hyperaldosteronism. Secondary hyperaldosteronism can be due to liver disease, stenosis of renal artery, etc. Whether it primary or secondary cause, there will be abnormal increase in the secretion of aldosterone.
Cushing’s syndrome (Increased Cortisol secretion):
i. Redistribution of fat—moon face, bufello hump, pendulous abdomen
ii. Thin extremities—protein catabolism
iii. Poor wound healing
iv. Muscular weakness
v. Personality changes
vi. Hyperglycemic
vii. Hypertension
Features of Conn’s syndrome/hyperaldosteronism are:
1. Hypertension.
2. Increased total body sodium.
3. Decreased plasma potassium.
4. Urine acidic
5. The person will suffer from alkalosis.
6. Muscle weakness, fatigue and paralysis.
7. At times person may develop tetany.
8. Polyuria
9. No edema because of sodium escape phenomenon.
Disorders of adrenocortical functions:
1. Hypofunction—Addison’s disease signs and symptoms due to decreased aldosterone and decreased Cortisol
2. Excersive pigmentation (due to increased ACTH)
3. Anorexia, nausea, diarrhea and vomiting
4. Mental confusion
5. Decreased ability to withstand stress
6. Dehydration, hypotension, loss of weight
Adrenogenital syndrome (Fig. 6.27):
i. Excessive secretion of DHEA
ii. Women develop male sec. sex characters (adrenal virilism)
iii. Deepening of voice
iv. Amenorrhea
v. Enlarged clitoris
vi. Hair growth—masculine distribution
vii. Increased muscle mass
Congenital adrenal hyperplasia (virilism) due to enzyme deficiency (congenital) mostly due to lack of 21 p hydroxylase. Hyperplasia is due to increased secretion of ACTH. Signs and symptoms—due to increased secretion of DHEA
a. In boys—Precocious sexual development testes remains infantile (infant hercule)
b. Women—Genetically female external genitalia looks like a male child. Pseudohermophroditism
c. Adult women—Adrenogenital syndrome
Disorder of Adrenal Cortical Functions— Addison’s Disease:
a. Hypofunction of adrenal cortex (primary adrenal insufficiency)
i. Decreased secretion of Cortisol and aldosterone
ii. Hyperpigmentation of skin and buccal mucosa
iii. Anorexia, nausea, diarrhea and vomiting
iv. Confusion
v. Unable to withstand stress
vi. Dehydration, hypotension and loss of weight
vii. Hyperkalemia, salt wasting, metabolic acidosis
b. Secondary and tertiary adrenal insufficiency:
i. No hyperkalemia
ii. No metabolic acidosis
iii. No volume contraction
iv. No hyperpigmentation
v. Congenital adrenal hyperplasia
Enzyme deficiency and consequent hormonal abnormality and symptoms (Table 6.3).
21 beta hydroxylase—most common form of congenital adrenal insufficiency:
a. Decreased Cortisol and aldosterone
b. Increased ACTH
c. Hyperplasia of zona fasciculata and reticularis
d. Increased adrenal androgens
e. Virilization in women
f. Hypotension
g. Hyperkalemia
h. Hyponatremia
17 alpha hydroxylase deficiency:
a. Decreased glucocorticoid and androgens
b. Increased ACTH
c. Increased aldosterone
d. Hypoglycemia
e. Metabolic alkalosis, hypokalemia, hypertension
f. Lack of axillary and pubic hair
Function # 4. Endocrine Function of Adrenal Medulla:
It secretes the hormones of emergency. The secretion is stimulated in conditions, like fight, flight or fright. For the synthesis of the hormone, the amino acid required is phenylalanine. Catecholamine group includes the hormones adrenaline, noradrenaline and dopamine. In human beings, about 80% of the hormone secreted from this region is adrenaline.
Biosynthesis of Hormones (Fig. 6.28):
The precursor of tyrosine is phenylalanine amino acid (essential amino acid). Phenylalanine on hydroxylation by the enzyme phenylalanine hydroxylase is converted to tyrosine.
Degradation of Hormones (Fig. 6.29):
Metanephrine, normetanephrine and VMA are excreted from the body along with urine.
Most of the hormone will be degraded in the target organs and the end products of the metabolites are excreted along with the urine in the form of vanillylmandelic acid and as conjugates.
The receptors through which the hormone acts are termed as adrenergic receptors. The types of receptors are alpha and beta. They are further divided into alpha 1 and alpha 2 and beta 1 and beta 2. The action of the hormone on the target organ depends on the type of receptor through which the action is mediated.
Actions:
On Vascular Smooth Muscle:
In the presence of Cortisol, catecholamine is able to act on the smooth muscle of blood vessels especially in the arteriolar regions. Due to this, some amount of vasoconstriction is maintained all the time and hence peripheral resistance. Peripheral resistance is the factor that is responsible for the diastolic blood pressure. Noradrenaline is a powerful vasoconstrictor.
On Heart and Blood Vessels:
It is able to increase both the heart rate and force of contraction. This action is mediated through the beta receptors present in cardiac muscle. It exerts both chronotropic and inotropic actions. Hence it increases cardiac output and systolic blood pressure in general.
On the Blood Vessels (Fig. 6.30 and Table 6.4):
Noradrenaline:
Alpha receptors are present on the smooth muscle of arterioles and when it exerts its influence there will be vasoconstriction. Noradrenaline predominantly acts through this group of receptors and hence there is an increase of total peripheral resistance in the body.
This is going to increase the diastolic blood pressure and hence there will be a secondary increase of systolic pressure as well. Increase in diastolic BP increases mean arterial pressure. The increase will stimulate the baroreceptors and hence there will be a reflex bradycardia and fall of cardiac output after sometime.
Adrenaline:
It acts through both alpha and beta receptors present on the smooth muscle of blood vessels.
When it acts through the alpha receptors, it brings about vasoconstriction and through beta receptors it brings about vasodilatation. Since the beta receptors present in the blood vessels of skeletal compartment, there will be an enormous amount of vasodilatation when compared to vasoconstriction. The net effect will be vasodilatation in the body.
Due to this, there will be a fall of peripheral resistance and hence the diastolic BP decreases. So the mean arterial pressure would remain almost normal, because of which there would not be any change in the activity of the baroreceptors.
Since Adrenalin also exerts its influence on heart not be any change in the activity of the baroreceptors through the beta receptors, there will be an increase of cardiac output and hence even the systolic BP is increased.
On Brain:
Increases the activity of the neurons of central nervous system and person becomes more alert. But if the amount acting on the brain is very much, it brings about the inhibition of spinal reflexes.
On Bronchial Smooth Muscle:
Brings about the bronchodilation and relieves a person suffering from bronchial asthma.
On Skeletal Muscle:
It increases the blood flow and help to sustain the increase in the muscular activity.
On Iris:
It acts on the dilator pupillae muscle and hence there will be dilation of pupil.
Metabolic Effects:
It acts as hyperglycemic agent and increases blood glucose level by stimulating the glycogenolysis in liver and muscle and gluconeogenesis in liver.
It also increases the lipolysis and increases the free fatty acid release and also the metabolic rate of the tissue. Since it enhances the rate of metabolism, it is termed as a calorigenic agent. This increases the metabolic rate in the body and hence there will be increased heat production.
Because of this, they have an important role to play when person needs immediate heat production when exposed to colder situations. There will also be more amount of blood flow to the cutaneous region to facilitate increase in heat loss.
GIT:
It stimulates the activity of the sphincters and relaxes the smooth muscle due to which there will be decreased motility of the GIT.
Regulation of Secretion:
Adrenal medulla has efferent nerve supply from the sympathetic nervous system only.
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The activity of the autonomic nervous system (parasympathetic and sympathetic) is under the influence of the activity of the neurons present in hypothalamus.
When the neurons present in the hypothalamus which control the activity of the sympathetic nerves get stimulated, impulses from hypothalamus reach the neurons present in the lateral horn cells of spinal cord. From the neurons of the lateral horn cells, the efferent sympathetic fibers taken origin and hence these neurons when get stimulated, will lead to increase in the sympathetic activity.
This increases the secretion of adrenal medulla.
Adrenal medullary secretion specially gets increased when a person is in fight/flight/fright situation, because of enormous increase in sympathetic activity.
Pheochromocytoma:
i. It is because of tumor in adrenal medulla.
ii. There will be an abnormally high amount of secretion of hormones from this region.
Some of the features of this condition are:
a. Sustained severe hypertension.
b. Palpitation.
c. Headache.
d. Sweating.
e. Hyperpnea.
f. Nausea and vomiting.
g. Anxiety and muscular weakness.
