ADRENAL GLANDSNajam-us-saharRiphah Internatiopnal University, Pakistan

ADRENAL GLANDS Two adrenal glands Each weighs 4 grams Lie at the superior poles of the two kidneys Two distinct parts, adrenal medulla and adrenal cortex

Adrenal medulla, central 20 % of the gland, is functionally related to the SNS

It secretes epinephrine and norepinephrine in response to sympathetic stimulation

Adrenal cortex secretes corticosteroids.

ADRENAL GLANDS

ADRENOCORTICAL HORMONES

CORTICOSTEROIDS Adrenocortical hormones: Mineralocorticoids Glucocorticoids Androgens (small amounts) Mineralocorticoids: affect electrolytes (“minerals”) of

extracellular fluids -sodium and potassium, in particular

Glucocorticoids : important effects that increase blood glucose concentration + additional effects on protein and fat metabolism

More than 30 steroids have been isolated from the adrenal cortex

Aldosterone principal mineralocorticoid Cortisol principal glucocorticoid.

ADRENAL CORTEX Three Distinct Layers1. Zona glomerulosa, 15% of the adrenal cortex A thin layer of cells that lies just underneath the

capsule Secrete aldosterone Secretion is controlled by ECF concentrations of

angiotensin II and potassium, which stimulate aldosterone secretion.

2. Zona fasciculata, 75% of the adrenal cortex Middle and widest layer Secretes glucocorticoids cortisol, corticosterone,

and small amounts of adrenal androgens and estrogens.

Secretion is controlled by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH).

Zona reticularis, deep layer of cortex Secretes adrenal androgens,

dehydroepiandrosterone (DHEA) and androstenedione, small amounts of estrogens and glucocorticoids.

ACTH regulates secretion of these cells Cortical androgen-stimulating hormone, released

from the pituitary, may also be involved.

Adrenal Gland

ADRENOCORTICAL HORMONES ARE STEROIDS Derived from Cholesterol Cholesterol is provided by LDL in the circulating

plasma. Transport of cholesterol is regulated by feedback

mechanisms For example, ACTH increases the number of

adrenocortical cell receptors for LDL, as well as the activity of enzymes that liberate cholesterol from LDL.

Cholesterol enters cell, delivered to mitochondria, cleaved by enzyme cholesterol desmolase to form pregnenolone

This initial step in steroid synthesis is stimulated by the different factors that control secretion of the major hormone

SYNTHESIS OF ADRENAL STEROIDS Synthesis occur in two of the organelles of the cell, mitochondria and endoplasmic reticulum

Each step is catalyzed by a specific enzyme system.

MINERALOCORTICOIDS

1. Aldosterone (very potent, accounts for about 90 per cent of all mineralocorticoid activity)

2. Desoxycorticosterone3. Corticosterone4. 9a-Fluorocortisol (synthetic)5. Cortisol (very slight mineralocorticoid activity)6. Cortisone (synthetic)

GLUCOCORTICOIDS

1. Cortisol (very potent, accounts for about 95 percent of all glucocorticoid activity)

2. Corticosterone3. Cortisone (synthetic)4. Prednisone (synthetic)5. Methylprednisone (synthetic)6. Dexamethasone (synthetic)

FUNCTIONS OF THEMINERALOCORTICOIDS-

ALDOSTERONE

MINERALOCORTICOID DEFICIENCY

Causes Severe Renal Sodium Chloride Wasting and Hyperkalemia.

Total loss of adrenocortical secretion death within 3 days to 2 weeks unless the person receives extensive salt therapy or injection of mineralocorticoids.

Without mineralocorticoids: Potassium ion concentration of ECF rises Sodium and chloride are rapidly lost from the body Total ECF volume and blood volume greatly reduced Develops diminished cardiac output Progresses to a shock like state Followed by death Mineralocorticoids are said to be the acute “lifesaving”

portion of the adrenocortical hormones.

RENAL AND CIRCULATORY EFFECTS

Increases Renal Tubular Reabsorption of Sodium and Secretion of Potassium

From renal tubular epithelial cells especially in the principal cells of the collecting tubules and, to a lesser extent, in the distal tubules and collecting ducts.

Aldosterone causes sodium to be conserved in the ECF while increasing potassium excretion in the urine.

Excess Aldosterone Increases ECF Volume and Arterial Pressure but Has Only a Small Effect on Plasma Sodium Concentration

Concentration of sodium in the ECF rises only a few milliequivalents, when sodium is reabsorbed by the tubules, there is simultaneous osmotic absorption of almost equivalent amounts of water.

ECF volume increases almost as much as the retained sodium, but without much change in sodium concentration.

Aldosterone-mediated increase in ECF volume lasting more than 1 to 2 days also leads to an increase in arterial pressure

The rise in arterial pressure then increases kidney excretion of both salt and water, called pressure natriuresis and pressure diuresis

This return to normal of salt and water excretion by the kidneys is called aldosterone escape

When aldosterone secretion becomes zero, large amounts of salt are lost in the urine, not only diminishing the amount of sodium chloride in the extracellular fluid but also decreasing the ECF volume.

The result is severe ECF dehydration and low blood volume, leading to circulatory shock.

Without therapy, this usually causes death within a few days after the adrenal glands suddenly stop secreting aldosterone.

EXCESS ALDOSTERONE CAUSES HYPOKALEMIA AND MUSCLE WEAKNESS

Excess aldosterone causes loss of potassium ions from the ECF into the urine and also stimulates transport of potassium from ECF into most cells of the body.

Excessive secretion of aldosterone, may cause a serious decrease in the plasma potassium concentration, This condition is called hypokalemia.

When the potassium ion concentration falls below about one-half normal, severe muscle weakness often develops.

TOO LITTLE ALDOSTERONE CAUSES HYPERKALEMIA AND CARDIAC TOXICITY

When aldosterone is deficient, ECF potassium ion concentration can rise far above normal.

When it rises to 60 to 100 per cent above normal, serious cardiac toxicity, including weakness of heart contraction and development of arrhythmia becomes evident

Progressively higher concentrations of potassium lead inevitably to heart failure.

EXCESS ALDOSTERONE INCREASES TUBULAR HYDROGEN ION SECRETION, CAUSES MILD ALKALOSIS

Also causes secretion of hydrogen ions in exchange for sodium in the intercalated cells of the cortical collecting tubules.

This decreases the hydrogen ion concentration in the extracellular fluid, causing a mild degree of alkalosis.

SWEAT GLANDS, SALIVARY GLANDS, AND INTESTINAL EPITHELIAL CELLS

Aldosterone Stimulates Sodium and Potassium Transport

These glands form a primary secretion that contains large quantities of sodium chloride, but most of it is reabsorbed, whereas potassium and bicarbonate ions are secreted.

Aldosterone greatly increases the reabsorption of sodium chloride and the secretion of potassium by the ducts.

This effect is used to conserve body salt in hot environments

The effect on the salivary glands is necessary to conserve salt when excessive quantities of saliva are lost.

Aldosterone also greatly enhances sodium absorption by the intestines, especially in the colon, which prevents loss of sodium in the stools.

REGULATION OF ALDOSTERONE SECRETION

1. Increased potassium ion concentration in the extracellular fluid greatly increases aldosterone secretion.

2. Increased activity of the renin-angiotensin system (increased levels of angiotensin II) also greatly increases aldosterone secretion.

3. Increased sodium ion concentration in the extracellular fluid very slightly decreases aldosterone secretion.

4. ACTH from the anterior pituitary gland is necessary for aldosterone secretion but has little effect in controlling the rate of secretion.

FUNCTIONS OF THE GLUCOCORTICOIDS

Cortisol Is the Primary Glucocorticoid Secreted by the Adrenal Cortex

More than 95% of glucocorticoid activity exerted by the adrenocortical hormones can be attributed to cortisol known also as hydrocortisone

Most of the remaining glucocorticoid activity is due to corticosterone.

Cortisol mediates most of its effects by binding with intracellular receptors in target tissues and inducing or repressing gene transcription

This results in alterations in the synthesis of enzymes that alter cell function.

EFFECTS OF CORTISOL ON CARBOHYDRATE METABOLISM

Stimulation of Gluconeogenesis. Formation of carbohydrate from proteins and some

other substances by the liver Decreased Glucose Utilization by Cells Elevated Blood Glucose Concentration and

“Adrenal Diabetes.” The rise in blood glucose in turn stimulates

secretion of insulin. High levels of glucocorticoid reduce the sensitivity

of many tissues to the stimulatory effects of insulin on glucose uptake and utilization.

EFFECTS ON PROTEIN METABOLISM

Reduction in Cellular Protein. Reduction of the protein stores in essentially all

body cells except those of the liver. protein synthesis catabolism of protein in the

cells. amino acid transport into extra hepatic tissues Enhance amino acid in plasma and increased

transport into liver cells Cortisol Increases Liver and Plasma Proteins. Increased conversion of amino acids to glucose-that

is, enhanced gluconeogenesis

EFFECTS ON FAT METABOLISM Mobilization of Fatty Acids from adipose

tissue Increases concentration of free fatty acids in the

plasma, increases their utilization for energy. Cortisol also enhance the oxidation of fatty acids in

cells. Obesity Caused by Excess Cortisol A peculiar type of obesity, with excess deposition

of fat in the chest and head regions of the body, giving a buffalo-like torso and a rounded “moon face.”

Results from excess stimulation of food intake, with fat being generated in some tissues of the body more rapidly than it is mobilized and oxidized.

Any type of physical or mental stress causes an immediate and marked increase in ACTH secretion by the pituitary gland, followed by greatly increased adrenocortical secretion of cortisol

CORTISOL IN RESISTING STRESS AND INFLAMMATIO

ANTI-INFLAMMATORY EFFECTS OF CORTISO

Large amounts of cortisol have two basic antiinflammatory effects:

1. It can block early stages of inflammation process before it even begins

2. If inflammation has already begun, it causes rapid resolution of the inflammation and increased rapidity of healing

OTHER EFFECTS OF CORTISOL Blocks Inflammatory Response to Allergic

Reactions Cortisol effectively prevents shock or death in

anaphylaxis, which otherwise kills many people Effect on Blood Cells and on Immunity in

Infectious Diseases Large amount of Cortisol decreases the number of

eosinophils and lymphocytes in the blood Large doses also causes atrophy of lymphoid tissue,

which decreases the output of T cells and antibodies The level of immunity for foreign invaders is

decreased Leads to increased infection and death from

diseases Useful drugs in preventing immunological rejection

of transplanted hearts, kidneys, and other tissues. Cortisol increases the production of red blood cells

REGULATION OF CORTISOL SECRETION

GLUCOCORTICOID ACTION

ADRENAL ANDROGENS The adrenal androgens DHEA and androstenedione

are secreted in appreciable amounts, but they have only weak androgenic effects.

Consequently, the normal plasma concentrations of these hormones exert little effect on secondary sex characteristics

In females, adrenal androgens are responsible for pubic and axillary hair.

In males Most of the androgenic activity of adrenal hormones may be due to the conversion of adrenal androgens to testosterone in peripheral tissues

The secretion of adrenal androgens is stimulated by ACTH.

ABNORMALITIES OF ADRENOCORTICAL SECRETION

HYPOADRENALISM-ADDISON’S DISEASE

Failure of the adrenal cortices to produce adrenocortical hormones

Most frequently caused by primary atrophy of the adrenal cortices, caused by autoimmunity against the cortices.

Also caused by tuberculous destruction of the adrenal glands or invasion of the adrenal cortices by cancer.

These processes usually are gradual, leading to a progressive reduction in glucocorticoid and mineralocorticoid function.

As a result of the decreased cortisol secretion, there is a compensatory increase in ACTH secretion, which produces hyperpigmentation.

Mineralocorticoid Deficiency Excessive loss of sodium, hypovolemia,

hypotension, and increased plasma renin activity Excessive potassium retention and hyperkalemia Mild acidosis Glucocorticoid Deficiency Abnormal carbohydrate, fat, and protein

metabolism resulting in muscle weakness, fasting hypoglycemia, and impaired utilization of fats for energy

Loss of appetite and weight loss Poor tolerance to stress. The inability to secrete increased amounts of

cortisol during stress leads to an Addisonian crisis that may culminate in death if supplemental doses of adrenocortical hormones are not administered.

Treatment

An untreated person with total adrenal destruction dies within a few days to a few weeks because of weakness and usually circulatory shock.

Such a person can live for years if small quantities of mineralocorticoids and glucocorticoids are administered daily.

HYPERADRENALISM-CUSHING’S SYNDROME

Hypersecretion by the adrenal cortex causes a complex cascade of hormone effects called Cushing’s syndrome.

Hypercortisolism can occur from multiple causes:1) adenomas of the anterior pituitary ACTH

adrenal hyperplasia cortisol secretion2) abnormal function of the hypothalamus CRH ACTH release3) “ectopic secretion” of ACTH by a tumor in the body4) adenomas of the adrenal cortex5) by administration of large amounts of exogenous

glucocorticoids. When Cushing’s syndrome is secondary to excess

secretion of ACTH by the anterior pituitary, this is referred to as Cushing’s disease.

Symptoms: Mobilization of fat from the extremities to the

abdomen, face, and supraclavicular areas Protein depletion resulting in muscle weakness, loss

of connective tissue and thinning of the skin (leading to purple striae), and impaired growth in children

Osteoporosis and vertebral fractures Impaired response to infections resulting from a

suppressed immune system Impaired carbohydrate metabolism, hyperglycemia,

and even insulin-resistant diabetes mellitus Masculinizing effects when adrenal androgens are

secreted in excess

Treatment Remove an adrenal tumor Hypertrophied pituitary glands can be surgically

removed or destroyed by radiation. Drugs that block steroidogenesis, such as

metyrapone, ketoconazole, and aminoglutethimide, or that inhibit ACTH secretion can also be used.

If ACTH secretion cannot easily be decreased, the only satisfactory treatment is usually bilateral partial (or even total) adrenalectomy, followed by administration of adrenal steroids to make up for any insufficiency that develops.

ADRENAL MEDULLA - HORMONES

FUNCTION OF THE ADRENAL MEDULLAE

Stimulation of the sympathetic nerves to the adrenal medulla causes large quantities of epinephrine and norepinephrine to be released into the circulating blood.

About 80% of the secretion from the adrenal medulla is epinephrine, and about 20% is norepinephrine.

The effect of the epinephrine and norepinephrine released from the adrenal medulla lasts 5 to 10 times longer than when they are released by sympathetic neurons because these hormones are slowly removed from the blood.

ADRENERGIC RECEPTORS

Alpha and Beta Receptors Norepinephrine excites mainly alpha

receptors but excites the beta receptors to a lesser extent as well.

Conversely, epinephrine excites both types of receptors approximately equally.

Therefore, the relative effects of norepinephrine and epinephrine on different effector organs are determined by the types of receptors in the organs.

ALPHA AND BETA RECEPTORS

The stimulation of α-receptors results in vasoconstriction, dilation of the iris, contraction of the intestinal and bladder sphincters, and contraction of the pilomotor muscles.

The β-receptor is subdivided into β1-, β2-, and β3 receptor subtypes.

Stimulation of β1-receptors causes an increase in heart rate and strength of contraction.

Stimulation of β2-receptors causes skeletal muscle vasodilation, bronchodilation, uterine relaxation, calorigenesis, and glycogenolysis.

Stimulation of β3-receptors induces lipolysis in adipose tissue and the conversion of energy in lipids into heat (thermogenesis).

NOREPINEPHRINE

The circulating Norepinephrine causes:

Vasoconstriction

Increased heart rate and contractility

Inhibition of the gastrointestinal tract

Dilated pupils.

EPINEPHRINE Epinephrine causes almost the same effects as

those caused by norepinephrine, except

The circulating epinephrine has a greater effect on cardiac performance

Epinephrine causes only weak constriction of the blood vessels in muscles

Slight increase in arterial pressure A dramatic increase in cardiac output. The metabolic rate of every cell of the body is

increased by these hormones, especially by epinephrine, as much as 100 per cent above normal

Epinephrine and norepinephrine are almost always released by the adrenal medullae at the same time that the different organs are stimulated directly by generalized sympathetic activation.

Therefore, the organs are actually stimulated in two ways: directly by the sympathetic nerves and indirectly by the adrenal medullary hormones.

The two means of stimulation support each other, and either can, in most instances, substitute for the other.

Tyrosine

L-Dopa

Dopamine

hydroxylation

Norepinephrine

decarboxylation

hydroxylation

EpinephrineAdrenal Glands

Synthesis