Adrenocortical Hormones - PowerPoint Presentation

1. Adrenocortical HormonesProf. dr. Zoran ValićDepartment of PhysiologyUniversity 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)

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4. Mineralocorticoids, Glucocorticoids, and Androgensandrogens of only slight importance, although extreme quantities can be secreted – masculinizing effectsMC – affect electrolytes (minerals) of the extracellular fluids (Na+ and K+)GC – increase BGC, but protein and fat alsomore than 30 steroids have been isolated two important: aldosterone and cortisol,

5. Synthesis and Secretion of Adrenocortical Hormonesadrenal 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, ?)

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8. all human steroid hormones are synthesized from cholesterolcells can synthesize de novo cholesterol (from acetate), 80% comes from LDLcells  coated pits – endocytosisACTH   receptors for LDL and  activity of enzymes LDL degradationcholesterol  pregnenolone (desmolase, rate-limiting step, in mitochondria)

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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 – Aldosteronetotal loss of MC – rapid  in NaCl and  in K+ (death within 3 days without therapy),  EC fluid volume and blood volumeacute "lifesaving" hormones aldosterone – 90% MC activitycortisol – 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)

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14. aldosterone escapein the meantime hypertension developswhen aldosterone secretion becomes zero – large amounts of salt are lost and ECFsevere 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 60-100%, 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 glandsimportant in hot environmentsgreatly enhances Na+ absorption by the intestines, especially in the colon; in the absence – diarrhea

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18. Cellular Mechanism of Aldosterone Actionstill not fully understoodlipid soluble – diffuses readily to the interior of the tubular epithelial cellsin cytoplasm combines with a highly specific cytoplasmic mineralocorticoid receptor proteinaldosterone-receptor complex diffuses into the nucleus  DNA  RNAmRNA diffuses back into the cytoplasm – ribosomes – protein formation

19. one or more enzymesmembrane 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 cellsincreases 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

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22. Regulation of Aldosterone Secretiondeeply intertwined with the regulation of ECF electrolyte concentrations, volume of ECF, blood volume and MAPalmost entirely independent of the regulation of cortisol and androgens K+ in ECF angiotensin II concentration in ECF Na+ in ECF very slightly decreasesACTH 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 MAPeffects of Na+ & ACTH usually minor (total absence of ACTH can significantly reduce aldosterone secretion – "permissive" role)

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25. Functions of GlucocorticoidsMC can save the life of an acutely adrenalectomized animal, metabolic systems remain considerably derangedanimal 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 Metabolismstimulation of gluconeogenesis ( 6-10x) enzymes required to convert amino acids into glucosemobilization of amino acids from the extrahepatic tissues mainly from muscleincrease in glycogen storage in the liver cells glucose utilization by cellscause of this decrease is unknowndepress the oxidation of NADH to form NAD+

27.  BGC & “adrenal diabetes” rate of gluconeogenesis &  rate of glucose utilizationhigh levels of GC reduce the sensitivity of many tissues to insulinunknown, 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 cellscatabolism continues normally – mobilization of AA from the nonhepatic tissuesincreasing the liver enzymes required for the hepatic effects

30. Effects of Cortisol on Fat Metabolismmobilization of fatty acidsfrom adipose tissue –  free fatty acids in the plasma and their utilization for energyenhance the oxidation of fatty acids in the cellsmechanism 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 cortisolpeculiar 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 Inflammationphysical or neurogenic stress – marked  in ACTH secretion by anterior pituitary glandwithin minutes –  secretion of cortisol

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34. trauma of almost any typeinfectionintense heat or coldinjection of norepinephrinesurgeryinjection of necrotizing substances beneath skinrestraining an animal so that it cannot movealmost any debilitating disease

35. unknown why cortisol secretion is of significant benefitGC cause rapid mobilization of amino acids and fats from cellular stores – release of energy and glucose synthesisuse of amino acids in damaged tissuessynthesis of purines, pyrimidines, and creatine phosphate from amino acidspreferential mobilization of labile proteins

36. Anti-Inflammatory Effects of High Levels of Cortisoltrauma or infection – inflammationinflammation can be more damaging than trauma or disease itself (rheumatoid arth.)cortisol:block the early stages of the inflammation process before inflammation even beginsrapid resolution of the inflammation and increased rapidity of healing

37. stabilization of lysosomal membranes –  proteolytic enzymesdecreased permeability of the capillaries – secondarydecreased migration of white blood cells into the inflamed area and phagocytosis of the damaged cells –  prostaglandins and leukotrienessuppression of immune system –  lymphocyte reproductionattenuation of fever –  release of interleukin-1

38. reducing all aspects of inflammatory processblock most of the factors that promote the inflammationrate 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 – anaphylaxisdecreases 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 cytoplasmeasily diffuse through the cell membranehormone-receptor complex interacts with glucocorticoid response elements at DNA – transcriptionrapid nongenomic effects

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42. Regulation of Cortisol SecretionACTH (corticotropin or adrenocorticotropin) enhances secretion of cortisolACTH 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 reticularisphysical or mental stress   ACTH

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45. cortisol has direct negative feedback effects:hypothalamus   CRHanterior pituitary gland   ACTHstress stimuli are the prepotentcircadian rhythm of glucocorticoid secretion – measurements of blood cortisol levels

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47. when ACTH is secreted several other hormones are secreted simultaneously (preprohormone – POMC)melanocyte-stimulating hormone (MSH), β-lipotropin and β-endorphinunder normal conditions small secretionMSH – 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)

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49. Adrenal Androgensespecially during fetal lifemost important – dehydroepiandrosteronein female: growth of pubic and axillary hairsome of the adrenal androgens are converted to testosterone in extra-adrenal tissues

50. Abnormalities of Adrenocortical Secretionhypoadrenalism (adrenal insufficiency) – Addison's diseasehyperadrenalism – Cushing's syndromeprimary aldosteronism – Conn's syndromeadrenogenital syndrome

51. Hypoadrenalism – Addison's diseaseadrenal cortices do not produce hormonesmost frequently caused by primary atrophy or injury of the adrenal cortices – in 80% autoimmunity, tuberculosis, or cancerlack 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 skinmelanin 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 feedbacktreatment – daily administration of small quantities of MC & GC

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55. Hyperadrenalism – Cushing's Syndromehypersecretion 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 diseasedexamethasone test (incorrect diagnosis)iatrogenic Cushing's syndromefat 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), osteoporosistreatment – removal of a tumor (before – drugs that block steroidogenesis)

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59. Primary Aldosteronism – Conn's Syndromesmall tumor of the zona glomerulosa cells – secretes large amounts of aldosteronehypokalemia, mild metabolic alkalosis,  ECF volume & blood volume, hypertensionoccasional periods of muscle paralysis caused by the hypokalemia (depressant effect of hypokalemia on action potential transmission)diagnostic criteria – decreased plasma renintreatment – surgical removal of the tumor

60. Adrenogenital Syndrometumor secretes excessive quantities of androgens – intense masculinizing effectsin 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 clitorisin prepubertal male: early masculinizationin adult male: difficult to make a diagnosisexcretion of 17-ketosteroids in the urine increase

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