Adrenocortical Hormones- Dr. Chintan

Adrenal GlandsThe two adrenal glands, each of which weighs about 4 grams, lie at the superior poles of the two kidneys.

each gland is composed of two distinct parts, the adrenal medulla and the adrenal cortex.

The adrenal medulla, the central 20 per cent of the gland, is functionally related to the sympathetic nervous system; it secretes the hormones epinephrine and norepinephrine in response to sympathetic stimulation.

The adrenal cortex secretes an entirely different group of hormones, called corticosteroids. These hormones are all synthesized from the steroid cholesterol.

Adrenal GlandsAdrenal cortex – mineralocorticoids, glucocorticoids and androgenic hormones

Mineralocorticoids - they affect the electrolytes (the “minerals”) of the ECF (Na & K)

Aldosterone - the principal mineralocorticoid

Glucocorticoids - increase blood glucose concentration

Cortisol - the principal glucocorticoid

Adrenal Cortex1. The zona glomerulosa - just underneath the capsule - 15 % - aldosterone - enzyme aldosterone synthase - controlled by the ECF concentrations of angiotensin II and potassium

2. The zona fasciculata – middle layer – 75 % - glucocorticoids cortisol and corticosterone - small amounts of adrenal androgens and estrogens - controlled by the hypothalamic-pituitary axis via ACTH

3. The zona reticularis - deep layer of the cortex - the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione - small amounts of estrogens and some glucocorticoids - ACTH

Mineralocorticoids• Aldosterone (very potent, accounts for about 90 per cent of all mineralocorticoid activity)• Desoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted)• Corticosterone (slight mineralocorticoid activity)• Cortisol (very slight mineralocorticoid activity, but large quantity secreted)

• Cortisone (synthetic, slight mineralocorticoid activity)• 9a-Fluorocortisol (synthetic, slightly more potent than aldosterone)

Glucocorticoids• Cortisol (very potent, accounts for about 95 per cent of all glucocorticoid activity)• Corticosterone (provides about 4 per cent of total glucocorticoid activity, but much less potent than cortisol)

• Cortisone (synthetic, almost as potent as cortisol)• Prednisone (synthetic, four times as potent as cortisol)• Methylprednisone (synthetic, five times as potent as cortisol)• Dexamethasone (synthetic, 30 times as potent as cortisol)

Adrenocortical HormonesCortisol: cortisol-binding globulin or transcortin and, to a lesser extent, to albuminlong half-life of 60 to 90 minutes

Aldosterone: 60 per cent of combines with the plasma proteins, about 40 per cent is in the free formshort half-life of about 20 minutes

conjugated especially to glucuronic acid and, to a lesser extent, sulfates – bile, feces, urine

AldosteroneAldosterone increases absorption of Na & simultaneously increases secretion of K by the renal tubular epithelial cells,

especially in the principal (P) cells of the collecting tubules and, to a lesser extent, in the distal tubules and collecting ducts.

Therefore, aldosterone causes Na to be conserved in the ECF while increasing K excretion in the urine

Excess Aldosterone Increases ECF Volume & BP but Has Only a Small Effect on Plasma Sodium Concentration

pressure natriuresis and pressure diuresis - aldosterone escape

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

NaCl lost - Total ECF volume and blood volume become greatly reduced – hyperkalemia

diminished cardiac output – shock like state – death

Aldosterone’s mineralocorticoid activity is about 3000 times greater than that of cortisol, but the plasma concentration of cortisol is nearly 2000 times that of aldosterone

AldosteroneExcess aldosterone causes loss of K ions from the ECF into the urine & also stimulates transport of K from the ECF into most cells of the body.

Hypokalemia - normal value of 4.5 mEq/L to as low as 2 mEq/L - muscle weakness - alteration of the electrical excitability of the nerve and muscle fiber membranes, which prevents transmission of normal action potentials.

aldosterone is deficient – Hyperkalemia - serious cardiac toxicity, including weakness of heart contraction and development of arrhythmia – diastolic heart failure

Aldosteronecauses secretion of H ions in exchange for Na in the intercalated cells of the cortical collecting tubules. This decreases the H ion concentration in the ECF, causing a mild degree of alkalosis.

Aldosterone Stimulates Na & K Transport in Sweat Glands, Salivary Glands - The effect on the sweat glands is important to conserve body salt in hot environments, and the effect on the salivary glands is necessary to conserve salt when excessive quantities of saliva are lost

Aldosterone also greatly enhances Na absorption by the intestines, especially in the colon, which prevents loss of sodium in the stools - absence of aldosterone, The unabsorbed NaCl and water then lead to diarrhea

Quick Nongenomic Actions of Aldosterone via CAMP

Mechanism of Aldosterone Actionlipid solubility in the cellular membranes, aldosterone diffuses readily to the interior of the tubular epithelial cells - in the cytoplasm of the tubular cells, aldosterone combines with a highly specific cytoplasmic receptor protein

aldosterone-receptor complex diffuses into the nucleus – DNA, mRNA, proteins (enzymes, transport proteins)

One of the enzymes especially increased is Na – K ATPase, which serves as the principal part of the pump for Na & K exchange at the basolateral membranes of the renal tubular cells.

Epithelial Na channel proteins inserted into the luminal membrane of the same tubular cells that allows rapid diffusion of Na ions from the tubular lumen into the cell → basolateral membrane Na – K ATPase → 45 minutes to several hours

Regulation of AldosteroneThe regulation of aldosterone secretion by the zona glomerulosa cells is almost entirely independent of the regulation of cortisol and androgens by the zona fasciculata and zona reticularis

1. Increased K ion concentration in the ECF greatly increases

2. Increased activity of the RAS (increased levels of angiotensin II) also greatly increases

3. Increased Na ion concentration in the ECF very slightly decreases

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

• Stimuli that increase aldosterone secretion

• Glucocorticoid secretion also increased • Surgery • Anxiety • Physical trauma • Hemorrhage

• Glucocorticoid secretion unaffected • High potassium intake • Low sodium intake • Constriction of inferior vena cava in thorax • Standing • Secondary hyperaldosteronism (in some cases of congestive heart

failure, cirrhosis, and nephrosis)

GlucocorticoidsStimulation of Gluconeogenesis - formation of carbohydrate from proteins and some other substances by liver

1. Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells

2. Cortisol causes mobilization of amino acids from the extra hepatic tissues mainly from muscle

marked increase in glycogen storage in the liver cells. This effect of cortisol allows other glycolytic hormones, such as epinephrine and glucagon, to mobilize glucose in times of need, such as between meals

Carbohydrate MetabolismDecreased Glucose Utilization by Cells – glucocorticoids depress the oxidation of NADH to form NAD+. Because NADH must be oxidized to allow glycolysis.

The rise in blood glucose in turn stimulates secretion of insulin.

high levels of glucocorticoid reduce the sensitivity of many tissues, especially skeletal muscle and adipose tissue, to the stimulatory effects of insulin on glucose uptake and utilization - adrenal diabetes

Protein Metabolismreduction of the protein stores in essentially all body cells except those of the liver – muscle weakness

This is caused by both decreased protein synthesis and increased catabolism of protein - decreased amino acid transport into extrahepatic tissues - cortisol mobilizes amino acids from the nonhepatic tissues

enhance amino acid transport into liver cells and enhance the liver enzymes required for protein synthesis - Cortisol Increases Liver and Plasma Proteins

Protein Metabolism(1) increased rate of deamination of amino acids

by the liver,

(2) increased protein synthesis in the liver,

(3) increased formation of plasma proteins by the liver,

(4) increased conversion of amino acids to glucose

Fat MetabolismMobilization of Fatty Acids - increases the concentration of free fatty acids in the plasma, which also increases their utilization for energy. Cortisol also seems to have a direct effect to enhance the oxidation of fatty acids in the cells

diminished transport of glucose into the fat cells: alpha - glycerophosphate, which is derived from glucose, is required for both deposition and maintenance of triglycerides in these cells, and in its absence the fat cells begin to release fatty acids.

Obesity - excess deposition of fat in the chest and head regions of the body, giving a buffalo-like torso and a rounded “moon face” - excess stimulation of food intake, with fat being generated in some tissues of the body more rapidly than it is mobilized and oxidized

Stress and Inflammation1. Trauma of almost any type2. Infection3. Intense heat or cold4. Injection of norepinephrine and other sympathomimetic drugs5. Surgery6. Injection of necrotizing substances beneath the skin7. Almost any devastating disease

Energy, Glucose, Proteins

Anti-inflammatory Effects1. Cortisol stabilizes the lysosomal membranes - proteolytic enzymes that are released by damagedcells to cause inflammation, which are mainly stored in the lysosomes, are released in greatly decreased quantity

2. Cortisol decreases the permeability of the Capillaries - prevents loss of plasma into the tissues.

3. Cortisol decreases both migration of WBC into the inflamed area and phagocytosis of the damaged cells - cortisol diminishes the formation of PGs and LTs that increase vasodilation, capillary permeability, and mobility of WBC

Anti-inflammatory Effects4. Cortisol suppresses the immune system, causing T lymphocyte reproduction to decrease markedly - reduced amounts of T cells and antibodies in the inflamed area decrease the tissue reactions

5. Cortisol reduces fever mainly because it reduces the release of IL-1 from WBC, which is one of the principal excitants to the hypothalamic temperature control system - decreased temperature reduces vasodilation

Rate of healing is greater - mobilization of amino acids and use of these to repair the damaged tissues – extra glucose – fatty acids - Resolution of Inflammation

Rheumatoid arthritis, rheumatic fever and acute glomerulonephritis

Anti-inflammatory EffectsCortisol Blocks the Inflammatory Response to Allergic Reactions - cortisol effectively prevents shock or death in anaphylaxis

Cortisol decreases the number of eosinophils and lymphocytes in the blood - atrophy of all the lymphoid tissue throughout the body - fulminating infection and death

Prevents immunological rejection of transplanted hearts, kidneys, and other tissues

Increase RBC – polycythemia, MOA - Intracytoplasmic

Permissive Action Small amounts of glucocorticoids must be present for a number of metabolic reactions to occur, although the glucocorticoids do not produce the reactions by themselves. This effect is called their permissive action.

1. For glucagon and catecholamines to exert their calorigenic effects,2. For catecholamines to exert their lipolytic effects, 3. For catecholamines to produce pressor responses and bronchodilation

During fetal life, glucocorticoids accelerate the maturation of surfactant in the lungs

Regulation of Cortisol SecretionCRF are located mainly in the paraventricular nucleus of the hypothalamus

ACTH (Polypeptide) Stimulates Cortisol Secretion – cAMP - protein kinase A - initial conversion of cholesterol to pregnenolone

Physical stress - Pain stimuli caused by physical stress or tissue damage are transmitted first upward through the brain stem and eventually to the median eminence of the hypothalamus

Mental stress - increased activity in the limbic system, especially in the region of the amygdala and hippocampus, both of which then transmit signals to the hypothalamus

Circadian Rhythm

POMC: ACTH + MSH, Beta - lipotropin, Beta – endorphin

N – no significanceAddison's disease: MSH – melanocytes - melanin – hyperpigmentation

pars intermedia – arctic animals - darkened fur in the summer and have entirely white fur in the winter

Adrenal Androgens

Hypoadrenalism - Addison’s Disease

primary atrophy of the adrenal cortices – autoimmunity (80%)

tuberculous destruction of the adrenal glands or invasion of the adrenal cortices by cancer

Mineralocorticoid Deficiency - greatly decreased ECF volume - hyponatremia, hyperkalemia and mild acidosis - CO decreases, and the patient dies in shock

Glucocorticoid Deficiency – cant maintain normal blood glucose concentration between meals - reduces the mobilization of both proteins and fats from the tissues - highly susceptible to stress and infection

Melanin Pigmentation - mucous membranes and thin skin (lips, nipples)

Treatmentsmall quantities of mineralocorticoids and glucocorticoids are administered daily

Addisonian CrisisIn a person with Addison’s disease, the output of glucocorticoids does not increase during stress.

whenever different types of trauma, disease, or other stresses, such as surgical operations, appear, a person is likely to have an acute need for excessive amounts of glucocorticoids and often must be given 10 or more times the normal quantities of glucocorticoids to prevent death.

This critical need for extra glucocorticoids and the associated severe debility in times of stress is called an addisonian crisis

Adrenal crisis – tapering dose always

Hyperadrenalism - Cushing’s Syndromeabnormal excess secretion of cortisol & androgens

(1) adenomas of the anterior pituitary that secrete large amounts of ACTH, which then causes adrenal hyperplasia and excess cortisol secretion;

(2) abnormal function of the hypothalamus that causes high levels of CRH, which stimulates excess ACTH release;

(3) “ectopic secretion” of ACTH by a tumor elsewhere in the body, such as an abdominal carcinoma;

(4) adenomas of the adrenal cortex – Reduced ACTH

When Cushing’s syndrome is secondary to excess secretion of ACTH by the anterior pituitary, this is referred to as Cushing’s disease

Dexamethasone TestIn patients who have overproduction of ACTH due to an ACTH-secreting pituitary adenoma or to hypothalamic-pituitary dysfunction, even large doses of dexamethasone usually do not suppress ACTH secretion.

In patients with primary adrenal overproduction of cortisol usually have low or undetectable levels of ACTH.

Cushing’s syndrome can also occur when large amounts of glucocorticoids are administered over prolonged periods for therapeutic purposes – Rheumatoid Arthritis

Cushing’s syndromemobilization of fat from the lower part of the

body, with concomitant extra deposition of fat in the thoracic and upper abdominal regions, giving rise to a buffalo torso – Buffalo hump

Edematous appearance of the face (Moon Face) – acne & hirsutism – Hypertension

Hyperglycemia - ↓ protein except liver (Plasma proteins) – muscle weakness - suppressed immune system - large purplish striae - severe osteoporosis

TreatmentRemoval an adrenal tumor – Adrenalectomy

Hypertrophied pituitary glands or tumors – Surgical removal or irradiation

When surgery is not possible; Drugs that block steroidogenesis - metyrapone, ketoconazole and aminoglutethimideDrugs that inhibit ACTH secretion - serotonin antagonists and GABA-transaminase inhibitors

Bilateral partial (or even total) adrenalectomy, followed by administration of adrenal steroids to make up for any insufficiency

Primary Aldosteronism (Conn’s Syndrome)

small tumor of the zona glomerulosa

Hypokalemia – Muscle Paralysis, slight increase in ECF volume and blood volume, Very slight Hypernatremia,almost always, hypertension

Decreased plasma renin concentration

Rx - surgical removal of the tumor or of most of the adrenal tissue

Adrenogenital SyndromeExcessive quantities of androgens that cause intense masculinizing effects throughout the body

Female - growth of a beard, a much deeper voice, occasionally baldness, masculine distribution of hair on the body and the pubis, growth of the clitoris to resemble a penis, and deposition of proteins in the skin and especially in the muscles

Prepubertal male - rapid development of the male sexual organs

It is often difficult to make a diagnosis of adrenogenital syndrome in the adult male – excretion of 17-ketosteroids (which are derived from androgens) in the urine may be 10 to 15 times normal