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Adrenocortical Hormones

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Presentation on theme: "Adrenocortical Hormones"— Presentation transcript:

1 Adrenocortical Hormones
Prof. dr. Zoran Valić Department of Physiology University of Split School of Medicine

2 two adrenal glands, at the superior poles of the two kidneys (about 4g)
medulla – central 20% (functionally related to the sympathetics – epinephrine & norepinephrine) cortex – 80% (corticosteroids – synthesized from the steroid cholesterol; similar chemical formulas)


4 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,

5 Synthesis and Secretion of Adrenocortical Hormones
adrenal cortex has three distinct layers: zona glomerulosa – thin layer underneath capsule, 15% of cortex, aldosterone synthase (angiotensin II and K+) zona fasciculata – 75% of cortex, cortisol and corticosterone, small amounts of adrenal androgens and estrogens (ACTH) zona reticularis – deep layer of cortex, DHEA and androstenedione (ACTH, cortical androgen-stimulating hormone, ?)



8 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)


10 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)

11 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

12 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)


14 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

15 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 %, arrhythmia – heart failure) excess aldosterone –  secretion of H+ (intercalated cells of the cortical collecting tubules, metabolic alkalosis)

16 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


18 Cellular Mechanism of Aldosterone Action
still not fully understood lipid soluble – diffuses readily to the interior of the tubular epithelial cells in cytoplasm combines with a highly specific cytoplasmic mineralocorticoid receptor protein aldosterone-receptor complex diffuses into the nucleus  DNA  RNA mRNA diffuses back into the cytoplasm – ribosomes – protein formation

19 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

20 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


22 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  K+ in ECF  angiotensin II concentration in ECF  Na+ in ECF very slightly decreases ACTH necessary for secretion, not for control

23 in turn, the aldosterone acts on the kidneys:
help them excrete the excess K+ increase the blood volume and MAP effects of Na+ & ACTH usually minor (total absence of ACTH can significantly reduce aldosterone secretion – "permissive" role)


25 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

26 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+

27  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)

28 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

29  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

30 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)

31 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

32 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


34 trauma of almost any type
infection intense heat or cold injection of norepinephrine surgery injection of necrotizing substances beneath skin restraining an animal so that it cannot move almost any debilitating disease

35 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

36 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: block the early stages of the inflammation process before inflammation even begins rapid resolution of the inflammation and increased rapidity of healing

37 stabilization of lysosomal membranes –  proteolytic enzymes
decreased permeability of the capillaries – secondary decreased migration of white blood cells into the inflamed area and phagocytosis of the damaged cells –  prostaglandins and leukotrienes suppression of immune system –  lymphocyte reproduction attenuation of fever –  release of interleukin-1

38 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

39 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

40 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


42 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)

43 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


45 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


47 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)


49 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

50 Abnormalities of Adrenocortical Secretion
hypoadrenalism (adrenal insufficiency) – Addison's disease hyperadrenalism – Cushing's syndrome primary aldosteronism – Conn's syndrome adrenogenital syndrome

51 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

52 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



55 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

56 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)



59 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

60 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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