Adrenocortical Hormones

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

2. two adrenal glands, at the superior poles of the two kidneys (about4g) • medulla– central20% (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: • zonaglomerulosa – thin layer underneath capsule, 15% of cortex, aldosteronesynthase (angiotensin II and K+) • zonafasciculata – 75% of cortex, cortisol and corticosterone, small amounts of adrenal androgens and estrogens (ACTH) • zonareticularis – 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  inNaCl and  in K+ (death within 3 days withouttherapy),  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 60-100%, arrhythmia – heart failure) • excess aldosterone –  secretion of H+ (intercalated cells of the cortical collecting tubules, metabolic alkalosis)

16. aldosterone transportNa+ & 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 cytoplasmicmineralocorticoid 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 forNa+, K+, H+ • especially increases Na+/K+ -ATPazewhich 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 ofECF, blood volume and MAP • almost entirely independent of the regulation of cortisol and androgens •  K+inECF •  angiotensin II concentration in ECF •  Na+inECF 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 ofNa+&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 GCreduce the sensitivity of many tissues to insulin • unknown, high levels of fatty acids •  BGCgreater of50% – 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.  AAin 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 nonhepatictissues • 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 andtheir 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 • GCcause rapid mobilization of amino acids and fats from cellular stores– release of energy and glucose synthesis • use ofamino acidsin damaged tissues • synthesis ofpurines, 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 lysosomalmembranes–  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 glucocorticoidresponse elements at DNA – transcription • rapid nongenomic effects

42. Regulation of Cortisol Secretion • ACTH (corticotropin or adrenocorticotropin) enhancessecretion of cortisol • ACTH is a large polypeptideof39 amino acids(24 has all effects of total molecule) • corticotropin-releasing factor (CRF, 41amino acids, paraventricular nucleus)

43. ACTH activate adenylylcyclase– cAMP(in3 min), activation of the protein kinaseA – initial conversion of cholesterol to pregnenolone (rate-limiting step) • ACTH – hypertrophy and proliferation of the adrenocorticalcells in the zonafasciculata and zonareticularis • physical or mental stress  ACTH

45. cortisolhas direct negative feedback effects: • hypothalamus  CRH • anterior pituitary gland  ACTH • stress stimuli are the prepotent • circadian rhythm of glucocorticoid secretion–measurements of blood cortisollevels

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 intermediain 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