Adrenocortical Hormones

Prof. dr. Zoran ValićDepartment of PhysiologyUniversity of Split School of Medicine

two adrenal glands, at the superior poles of the two kidneys (about 4g)

1) medulla – central 20% (functionally related to the sympathetics – epinephrine & norepinephrine)

2) cortex – 80% (corticosteroids – synthesized from the steroid cholesterol; similar chemical formulas)

Mineralocorticoids, Glucocorticoids, and Androgens

androgens of only slight importance, although extreme quantities can be secreted – masculinizing effects

MC – affect electrolytes (minerals) of the extracellular fluids (Na+ and K+)

GC – increase BGC, but protein and fat also

more than 30 steroids have been isolated two important: aldosterone and cortisol,

Synthesis and Secretion of Adrenocortical Hormones adrenal cortex has three distinct layers:

1) zona glomerulosa – thin layer underneath capsule, 15% of cortex, aldosterone synthase (angiotensin II and K+)

2) zona fasciculata – 75% of cortex, cortisol and corticosterone, small amounts of adrenal androgens and estrogens (ACTH)

3) zona reticularis – deep layer of cortex, DHEA and androstenedione (ACTH, cortical androgen-stimulating hormone, ?)

all human steroid hormones are synthesized from cholesterol

cells can synthesize de novo cholesterol (from acetate), 80% comes from LDL

cells coated pits – endocytosis ACTH receptors for LDL and activity

of enzymes LDL degradation cholesterol pregnenolone (desmolase,

rate-limiting step, in mitochondria)

90-95% of the cortisol in plasma binds to cortisol-binding globulin or transcortin, less to albumin – long half-life (60-90 min)

60% of circulating aldosterone combined with plasma proteins (half-life 20 min)

degraded in liver – conjugation especially to glucuronic acid and sulfates (25% excreted in the bile, remaining by kidneys)

Functions of Mineralocorticoids – Aldosterone

total loss of MC – rapid in NaCl and in K+ (death within 3 days without therapy), EC fluid volume and blood volume

acute "lifesaving" hormones aldosterone – 90% MC activity cortisol – 3000x less activity, but 2000x

concentration

aldosterone – reabsorption of Na+ and secretion of K+ (principal cells of the collecting tubules)

aldosterone – EC fluid volume & MAP, cNa + stays the same (osmotic absorption of water, stimulation of thirst)

transient Na+ retention occurs – pressure natriuresis and pressure diuresis (ECF 5-15% MAP 15 to 25 mmHg)

aldosterone escape in the meantime hypertension develops

when aldosterone secretion becomes zero – large amounts of salt are lost and ECF

severe extracellular fluid dehydration and low blood volume – circulatory shock – death

excess aldosterone causes hypokalemia (from 4,5 to 2 mmol/L; transport into cells) and muscle weakness (alteration of the electrical excitability); too little aldosterone causes hyperkalemia and cardiac toxicity (rise of 60-100%, arrhythmia – heart failure)

excess aldosterone – secretion of H+ (intercalated cells of the cortical collecting tubules, metabolic alkalosis)

aldosterone transport Na+ & K+ in sweat glands and salivary glands

important in hot environments greatly enhances Na+ absorption by the

intestines, especially in the colon; in the absence – diarrhea

Cellular Mechanism of Aldosterone Action

still not fully understood1) lipid soluble – diffuses readily to the interior of

the tubular epithelial cells2) in cytoplasm combines with a highly specific

cytoplasmic mineralocorticoid receptor protein3) aldosterone-receptor complex diffuses into the

nucleus DNA RNA4) mRNA diffuses back into the cytoplasm –

ribosomes – protein formation

one or more enzymes membrane transport proteins for Na+, K+, H+

especially increases Na+/K+ -ATPaze which serves as the principal part of the pump for Na+ & K+ exchange at the basolateral membranes of the renal tubular cells

increases epithelial sodium channel (ENaC) protein – inserted into the luminal membrane

sequence of events (30-45 minimal, maximal effect after several hours)

possible nongenomic actions – increase formation of cAMP (fast – less than 2 minutes), but also involves phosphatidylinositol second messenger system

Regulation of Aldosterone Secretion deeply intertwined with the regulation of

ECF electrolyte concentrations, volume of ECF, blood volume and MAP

almost entirely independent of the regulation of cortisol and androgens

1) K+ in ECF2) angiotensin II concentration in ECF3) Na+ in ECF very slightly decreases4) ACTH necessary for secretion, not for control

in turn, the aldosterone acts on the kidneys:1) help them excrete the excess K+

2) increase the blood volume and MAP

effects of Na+ & ACTH usually minor (total absence of ACTH can significantly reduce aldosterone secretion – "permissive" role)

Functions of Glucocorticoids

MC can save the life of an acutely adrenalectomized animal, metabolic systems remain considerably deranged

animal cannot resist physical or even mental stress (infection = death)

on a long run GC equally important as MC 95% of activity – cortisol (hydrocortisone) smaller effect – corticosterone

Effects of Cortisol on Carbohydrate Metabolism stimulation of gluconeogenesis ( 6-10x)

enzymes required to convert amino acids into glucose

mobilization of amino acids from the extrahepatic tissues mainly from muscle

increase in glycogen storage in the liver cells glucose utilization by cells

cause of this decrease is unknown depress the oxidation of NADH to form NAD+

BGC & “adrenal diabetes” rate of gluconeogenesis & rate of glucose

utilization high levels of GC reduce the sensitivity of

many tissues to insulin unknown, high levels of fatty acids BGC greater of 50% – adrenal diabetes

(tissues are resistant to the effects of insulin)

Effects of Cortisol on Protein Metabolism

of the protein stores in all body cells except those of the liver

synthesis & catabolism – decreased amino acid transport into extrahepatic tissues; formation of RNA and subsequent protein synthesis (muscle and lymphoid tissue)

liver and plasma proteins (from liver) enhancement of amino acid transport into liver

cells the liver enzymes for protein synthesis

AA in blood, transport into extrahepatic cells, transport into hepatic cells

transport into muscle cells (isolated tissues) synthesis of protein in those cells catabolism continues normally – mobilization

of AA from the nonhepatic tissues increasing the liver enzymes required for the

hepatic effects

Effects of Cortisol on Fat Metabolism

mobilization of fatty acids from adipose tissue – free fatty acids in the

plasma and their utilization for energy enhance the oxidation of fatty acids in the cells mechanism unknown, diminished transport of

glucose ( α-glycerophosphate) in times of starvation or other stresses – shift to

utilization of fatty acids for energy (requires several hours to develop)

obesity caused by excess cortisol peculiar type of obesity (despite fatty acid

mobilization) deposition of fat in the chest (buffalo-like

torso) and head regions (moon face) obesity results from excess stimulation of food

intake – fat being generated more rapidly than mobilized and oxidized

Cortisol Is Important in Resisting Stress and Inflammation

physical or neurogenic stress – marked in ACTH secretion by anterior pituitary gland

within minutes – secretion of cortisol

1) trauma of almost any type2) infection3) intense heat or cold4) injection of norepinephrine5) surgery6) injection of necrotizing substances beneath skin7) restraining an animal so that it cannot move8) almost any debilitating disease

unknown why cortisol secretion is of significant benefit

GC cause rapid mobilization of amino acids and fats from cellular stores – release of energy and glucose synthesis

use of amino acids in damaged tissues synthesis of purines, pyrimidines, and

creatine phosphate from amino acids preferential mobilization of labile proteins

Anti-Inflammatory Effects of High Levels of Cortisol

trauma or infection – inflammation inflammation can be more damaging than

trauma or disease itself (rheumatoid arth.) cortisol:

1) block the early stages of the inflammation process before inflammation even begins

2) rapid resolution of the inflammation and increased rapidity of healing

1) stabilization of lysosomal membranes – proteolytic enzymes

2) decreased permeability of the capillaries – secondary

3) decreased migration of white blood cells into the inflamed area and phagocytosis of the damaged cells – prostaglandins and leukotrienes

4) suppression of immune system – lymphocyte reproduction

5) attenuation of fever – release of interleukin-1

reducing all aspects of inflammatory process

block most of the factors that promote the inflammation

rate of healing is enhanced (mobilization of amino acids, increased glucogenesis, increased amounts of fatty acids)

useful in: rheumatoid arthritis, rheumatic fever, and acute glomerulonephritis

blocks the inflammatory response to allergic reactions – anaphylaxis

decreases the number of eosinophils and lymphocytes in the blood; decreases the output of both T cells and antibodies (fulminating tuberculosis / preventing immunological rejection)

increases the production of red blood cells

cortisol binds with its protein receptor in the cytoplasm

easily diffuse through the cell membrane hormone-receptor complex interacts with

glucocorticoid response elements at DNA – transcription

rapid nongenomic effects

Regulation of Cortisol Secretion

ACTH (corticotropin or adrenocorticotropin) enhances secretion of cortisol

ACTH is a large polypeptide of 39 amino acids (24 has all effects of total molecule)

corticotropin-releasing factor (CRF, 41 amino acids, paraventricular nucleus)

ACTH activate adenylyl cyclase – cAMP (in 3 min), activation of the protein kinase A – initial conversion of cholesterol to pregnenolone (rate-limiting step)

ACTH – hypertrophy and proliferation of the adrenocortical cells in the zona fasciculata and zona reticularis

physical or mental stress ACTH

cortisol has direct negative feedback effects: hypothalamus CRH anterior pituitary gland ACTH

stress stimuli are the prepotent circadian rhythm of glucocorticoid secretion

– measurements of blood cortisol levels

when ACTH is secreted several other hormones are secreted simultaneously (preprohormone – POMC)

melanocyte-stimulating hormone (MSH), β-lipotropin and β-endorphin

under normal conditions small secretion MSH – stimulates formation of the black

pigment melanin (pars intermedia in some lower animals, ACTH is normally more important than MSH in determining the amount of melanin in the skin in humans)

Adrenal Androgens

especially during fetal life most important – dehydroepiandrosterone in female: growth of pubic and axillary hair some of the adrenal androgens are

converted to testosterone in extra-adrenal tissues

Abnormalities of Adrenocortical Secretion

hypoadrenalism (adrenal insufficiency) – Addison's disease

hyperadrenalism – Cushing's syndrome primary aldosteronism – Conn's syndrome adrenogenital syndrome

Hypoadrenalism – Addison's disease

adrenal cortices do not produce hormones most frequently caused by primary atrophy or

injury of the adrenal cortices – in 80% autoimmunity, tuberculosis, or cancer

lack of MC – ECF volume, hyponatremia, hyperkalemia & mild acidosis plasma volume, Ht, CO – death (shock, 4 days)

lack of GC – disturbances in BGC, fats and proteins – sluggishness of energy mobilization; deteriorating effects of different types of stress

melanin pigmentation of the mucous membranes and skin

melanin is not always deposited evenly but occasionally is deposited in blotches (thin skin areas –lips and the thin skin of the nipples)

tremendous rates of ACTH & MSH secretion due to normal negative feedback

treatment – daily administration of small quantities of MC & GC

Hyperadrenalism – Cushing's Syndrome

hypersecretion by adrenal cortex (adenomas of anterior pituitary, abnormal function of hypothalamus, "ectopic secretion" of ACTH by a tumor, adenomas of adrenal cortex)

adenomas of anterior pituitary – Cushing's disease dexamethasone test (incorrect diagnosis) iatrogenic Cushing's syndrome fat deposition – buffalo torso, "moon face", acne

and hirsutism, 80% – hypertension

increase in BGC after meals to 11 mmol/L (enhanced gluconeogenesis and decreased glucose utilization)

greatly decreased tissue proteins everywhere in the body with the exception of liver and plasma – severe weakness, suppressed immune system, large purplish striae (collagen), osteoporosis

treatment – removal of a tumor (before – drugs that block steroidogenesis)

Primary Aldosteronism – Conn's Syndrome

small tumor of the zona glomerulosa cells – secretes large amounts of aldosterone

hypokalemia, mild metabolic alkalosis, ECF volume & blood volume, hypertension

occasional periods of muscle paralysis caused by the hypokalemia (depressant effect of hypokalemia on action potential transmission)

diagnostic criteria – decreased plasma renin treatment – surgical removal of the tumor

Adrenogenital Syndrome

tumor secretes excessive quantities of androgens – intense masculinizing effects

in a 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

in prepubertal male: early masculinization in adult male: difficult to make a diagnosis excretion of 17-ketosteroids in the urine increase

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