Hormone Metabolism


Published on

Published in: Health & Medicine, Technology
1 Comment
  • Excellent presentation. Can you please kindly share at mfardad@rogers.com
    Are you sure you want to  Yes  No
    Your message goes here
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Hormone Metabolism

  1. 1. Hormone Metabolism BELLA MARILOU BAXA-DAGUPLO, MD Department of Biochemistry & Nutrition Fatima College of Medicine Our Lady of Fatima University (Review ’09)
  2. 2. Hormones <ul><li>from the Greek term ( ὁρμή ) &quot;impetus“ </li></ul><ul><ul><li> - “to arouse to activity” </li></ul></ul><ul><li>substance synthesized in one tissue & transported </li></ul><ul><li>by circulatory system to act on another organ </li></ul>Hormone Metabolism “ ON” “ OFF” Target cell Cell origin (Effects)
  3. 3. Hormone Metabolism <ul><li>Endocrine </li></ul><ul><li>Paracrine </li></ul><ul><li>Autocrine </li></ul>Functions of Hormones
  4. 4. Hormone and Neurotransmitters… Hormone Metabolism <ul><li> Norepinephrine/Serotonin -> depression </li></ul><ul><li>oversensitivity to serotonin -> OCD behaviors </li></ul><ul><li> Dopamine -> Parkinson’s disease </li></ul><ul><li>Too much dopamine in the limbic system and </li></ul><ul><li>not enough in the cortex -> personality given </li></ul><ul><li>to bouts of paranoia or (-) social interaction </li></ul><ul><li> norepinephrine (NE) -> aggression </li></ul>
  5. 5. Hormone and Neurotransmitters… Hormone Metabolism <ul><li>Phenylethylamine + dopamine -> mild anti- </li></ul><ul><li>depressant effect </li></ul><ul><li> Phenylethylamine in the limbic system -> </li></ul><ul><li>“ feelings of bliss” </li></ul><ul><li> oxytoxin -> impulse to “cuddle”; multiple orgasm </li></ul><ul><li> norepinephrine w/ dopamine & phenylethylamine </li></ul><ul><li>-> give us the feeling of infatuation </li></ul><ul><li>too much stress in children can create permanently </li></ul><ul><li> levels of serotonin and  levels of NE -> creating </li></ul><ul><li>a potential of violent behavior </li></ul>
  6. 6. Hormone Metabolism General Characteristics of Hormones <ul><li>Not secreted at a uniform rate </li></ul><ul><li>Exert their effects in biocatalytic amounts </li></ul><ul><li>Turnover is varied and usually rapid </li></ul><ul><li>Exert multiple actions </li></ul><ul><li>Exhibit high degree of specificity </li></ul><ul><li>Different tissues may respond </li></ul><ul><ul><li>differently to a given hormone </li></ul></ul>
  7. 7. Regulation of Hormone Secretion A. Feedback Control 1) Negative Feedback 2) Positive Feedback Hormone Metabolism B. Neural Control - visual/ olfactory/ gustatory C. Chronotropic Control - sleep-wake cycle/ physiologic cycle
  8. 8. Regulation of Hormone Secretion … Hormone Metabolism Feedback Control Negative Feedback <ul><li> T3 and T4 </li></ul><ul><li>inhibits secretion </li></ul><ul><li>of TRH and TSH </li></ul>HPT Axis Hypothalamus TRH TSH T 3 , T 4 + - + + - Anterior Pituitary Thyroid Increased metabolism
  9. 9. Regulation of Hormone Secretion … Hormone Metabolism Feedback Control Positive Feedback <ul><li> estrogen level </li></ul><ul><li>results to LH surge </li></ul><ul><li>during ovulation </li></ul>Female HPG Axis + + Hypothalamus + Anterior Pituitary Ovaries Estrogen Progesterone + + + - - FSH LH GnRH
  10. 10. Forms of Hormone in the Circulation Hormone Metabolism A. Free Molecules (unbound) - water-soluble hormones B. Bound Molecules - water insoluble hormones - bound with specific globulins or transport proteins such as albumin, “cortisol-binding globulin”, and “thyroid-binding globulin”
  11. 11. Fates of Hormone Hormone Metabolism <ul><li>A. Target cell uptake </li></ul><ul><li>B. Metabolic degradation </li></ul><ul><li>Urinary or biliary excretion </li></ul><ul><li>kidney and liver are the major sites of </li></ul><ul><li>hormone metabolism and degradation </li></ul>
  12. 12. Classification of Hormones I. According to Structure A. Protein hormones 1) Simple or polypeptide [insulin, glucagon, somatostatin, growth h., ACTH, MSH, PRL, CS …] 2) Complex or glycoprotein [TSH, FSH, LH, hCG…] B. Steroid hormones [glucocorticoids, mineralocorticoids, sex androgens, retinoic a., calcitriol…] C. Biogenic amine hormones [ thyroxine,catecholamines] II. According to Mechanism of Action A. Group 1 B. Group 2 Hormone Metabolism
  13. 13. Hormone Metabolism Classification of Hormones … [Protein] A-Chain B-Chain Insulin and C-peptide Formation Ribosome ER Golgi A. Vesicles
  14. 14. Hormone Metabolism Classification of Hormones … [Protein] Pro-opiomelanocortin Peptide Family
  15. 15. Hormone Metabolism Classification of Hormones … [Steroids]
  16. 16. Classification of Hormones … [Amines] Hormone Metabolism Some Biogenic Amines Dopamine CH 2 - CH 2 – NH 2 HO HO CH - CH 2 – NHCH 3 OH HO HO Epinephrine Tetraiodothyronine Norepinephrine CH - CH 2 – NH 2 OH HO HO
  17. 17. Classification of Hormones Hormone Metabolism According to Mechanism of Action Group 1 Group 2 Type Steroids, thyroid h., Polypeptides and retinoic acid …. catecholamines… Solubility Lipophilic Hydrophilic Transport Protein Yes No Plasma T1/2 Longer Shorter Receptor Intracellular Plasma membrane Mediator HRC/HRE 2nd messengers
  18. 18. Hormone Metabolism Steps Involved in Eliciting Response of Target Cell <ul><li>Recognition and binding of the hormone </li></ul><ul><li>to specific receptor </li></ul><ul><li>2) Coupling to generate signal </li></ul><ul><li>Changes in intracellular processes </li></ul><ul><li>brought about by the generated signal </li></ul>
  19. 19. Hormone Metabolism Receptors <ul><li>specific proteins that must first bind a </li></ul><ul><li>hormone before cellular response can </li></ul><ul><li>be elicited </li></ul><ul><li>have at least 2 Functional domains: </li></ul><ul><li>1) Recognition domain - binding domain </li></ul><ul><li>2) Coupling domain - generates signal that </li></ul><ul><li>couples hormone recognition to some </li></ul><ul><li>intracellular function </li></ul>
  20. 20. Hormone Metabolism Classes: A. Cell surface receptors B. Intracellular receptors 1) Nuclear receptors 2) Cytoplasmic receptors Receptors
  21. 21. Cell Membrane Receptors Functional Domains: 1) Ligand-binding domain 2) Transmembrane domain 3) Cytoplasmic domain Hormone Metabolism Receptors N C Typical cell membrane receptor (seven membrane-spanning domain) Extracellular Intracellular
  22. 22. Intracellular Receptors Functional Domains: 1) A hormone binding region in the C-terminal 2) An adjacent DNA binding region 3) A specifier region (N-terminal) necessary for high-affinity binding to the proper region of DNA 4) One or more regions that activate or repress gene transcription Hormone Metabolism Receptors (1) (2) (3) N C
  23. 23. Hormone Metabolism Signal Transduction <ul><li>process which occurs after a hormone </li></ul><ul><li>binds to a receptor </li></ul><ul><li>an intracellular signal is generated </li></ul><ul><li>[second messenger] which delivers </li></ul><ul><li>the hormonal message </li></ul><ul><li>amplifies the original signal converting </li></ul><ul><li>substrate molecules to products </li></ul>
  24. 24. Hormone Metabolism Signal Transduction Peptides Catecholamines Neurotransmitters… Steroids Thyroid hormones Estrogen, RA… Insulin, EGF, IGF-1 Growth hormone Prolactin… Signal Transduction Pathways Enzyme Activation Nucleus
  25. 25. Hormone Metabolism Mechanism of Action… [Group 1]  Cytoplasm Nucleus Hormone Action with intracellular receptors +  “ Activation”  + Specific Protein Transcription mRNA Translation mRNA Metabolic response Hormone response element (HRE) Hormone receptor complex (HRC) Receptor Steroid/Thyroid h.  Thyroid h.
  26. 26. Hormone Metabolism Mechanism of Action… [Group 1] Structural requirements for hormonal regulation of gene transcription 5’ 3’ Hormone response elements (HRE) Promoter element (PE) Gene Transcription Initiation site Termination Site 1 + Regulatory DNA region Structural DNA region
  27. 27. Hormone Metabolism Mechanism of Action… [Group 1] Hormones that bind to Intracellular receptors (Group 1) <ul><li>Mineralocorticoids </li></ul><ul><li>Glucocorticoids </li></ul><ul><li>Androgens </li></ul><ul><li>Progestins </li></ul><ul><li>Estrogens </li></ul><ul><li>Calcitriol (1,25[OH] 2 -D 3 ) </li></ul><ul><li>Retinoic acid </li></ul><ul><li>Thyroid hormones (T 3 and T 4 ) </li></ul>
  28. 28. Hormone Metabolism Mechanism of Action of Group 2 Hormones Effector Systems <ul><li>Effector systems that produce cytosolic </li></ul><ul><li>second messengers (couple w/ G-protein) </li></ul><ul><li>for signal transduction </li></ul><ul><li>Adenylyl cyclase - cAMP </li></ul><ul><li>Guanylyl cyclase - cGMP </li></ul><ul><li>Phospholipase C - phosphoinositides </li></ul><ul><li>(DAG & IP 3 ) </li></ul><ul><li>Calcium - calmodulin (Ca ++ ) </li></ul>
  29. 29. Hormone Metabolism Mechanism of Action… [Group 2] Effector Systems <ul><li>Effector system as an intrinsic part of the </li></ul><ul><li>receptor </li></ul>- does not require G-protein to transduce the physiologic action of the ligand - contains an enzymatic activity within the intracellular domain that phosphorylates tyrosine kinase residues
  30. 30. Mechanism of Action… [Group 2]
  31. 31. Mechanism of Action… [Coupling w/ G-protein]
  32. 32. Mechanism of Action… [Coupling w/ G-protein]
  33. 33. Mechanism of Action… [Coupling w/ G-protein]
  34. 34. Hormone Metabolism Mechanism of Action… [Group 2] Adenylate cyclase – cAMP ES Regulation through cAMP-dependent protein kinases Adenylate cyclase ATP  Mg 2+ cAMP ( • ) 5’-AMP Phosphodiesterase 4 cAMP C R R C Inactive protein kinase R R • • • • C Active protein kinase 2 + Protein Phosphoproteins Phosphatase Physiologic effects
  35. 35. Hormone Metabolism Mechanism of Action… [Group 2] Adenylate cyclase – cAMP ES 1. Activators of adenylyl cyclase <ul><li>Cholera toxin – inactivates GTPase; </li></ul><ul><li> s is frozen in active form </li></ul><ul><li>Pertussis toxin – prevents activation of </li></ul><ul><li> i subunit </li></ul>2. Inhibitor of adenylyl cyclase <ul><li>Phosphodiesterase – hydrolyzes cAMP </li></ul><ul><li>to 5’-AMP </li></ul>
  36. 36. Hormone Metabolism Mechanism of Action… [Group 2] Hormone Action using cAMP Second Messenger Glycogen synthase a Glycogen synthase b Protein kinase (Inactive) Protein kinase (Active) Phosphoprotein phosphatase Insulin (+) (+) (+) (+) Glycogen Phosphorylase b Glycogen Phosphorylase a Glycogen Glucose-1-PO4 (+) GLYCOGENOLYSIS Phosphorylase kinase (inactive) Phosphorylase kinase (active) Phospho- protein phosphatase Adenylate cyclase ATP cAMP (+) (-) (+) Muscles Liver
  37. 37. Hormone Metabolism Mechanism of Action… [Group 2] Hormone Action using cAMP Second Messenger Specific Protein  or  Transcription mRNA Translation mRNA Metabolic response cAMP response element (CRE) Adenylate cyclase ATP cAMP Protein kinase (Inactive) Protein kinase (Active) CREB CREB-P (+) (-) (+) Muscles Liver
  38. 38. Hormone Metabolism Mechanism of Action… [Group 2] Phosphatidylinositol Cycle and Calcium Receptor DAG IP 3 Ca ++ Protein kinase C Phosphoproteins Proteins Physiologic responses Ca ++ -Calmodulin Calmodulin kinases (+) (+) GDP GTP Phospholipase C GTP GDP (+) PIP 2 Hormone Action using DAG, IP 3 and Ca ++ as Second Messengers
  39. 39. Hormone Metabolism Mechanism of Action… [Group 2] Kinase Cascade System 1 [Autophoshorylation] (Autophosphorylation) Phosphorylation of protein substrates (Tyrosine) Cell growth DNA synthesis Early response genes Enzyme Activity Protein Translocation Gene Expression P P ES utilized by Insulin, EGF PDGF and IGF-1
  40. 40. Hormone Metabolism Mechanism of Action… [Group 2] Kinase Cascade System 2 ES utilized by Growth hormone, Prolactin, EPO, cytokines… Regulates transcription Nucleus Dimerization X = SHC GRB2 PLC  PI-3K GAP JAK P JAK P P P P P STATs X SH2 P P ) ( JAK P JAK P P P P P JAK JAK
  41. 41. Hormone Metabolism Mechanism of Action… [Group 2] Hormones that bind to CM receptors <ul><li>2a – second messenger is cAMP </li></ul><ul><li>2b – second messenger is cGMP </li></ul><ul><li>2c – second messenger is Ca ++ or </li></ul><ul><li>phosphoinositols or both </li></ul><ul><li>2d – second messenger is kinase/ </li></ul><ul><ul><li>phosphatase cascade </li></ul></ul>
  42. 42. Hormone Metabolism Hormone Metabolism Factors Affecting Response of Target Cells to Hormones <ul><li>concentration of the hormone </li></ul><ul><li>number of receptors </li></ul><ul><li>duration of exposure </li></ul><ul><li>intracellular conditions such as </li></ul><ul><li>conc. of rate-limiting enzymes, </li></ul><ul><li>substrates or cofactors </li></ul><ul><li>antagonistic or synergistic hormones </li></ul>
  43. 43. Hormones That Affect Fuel metabolism Hormone Metabolism <ul><li>Insulin </li></ul><ul><li>Glucagon </li></ul><ul><li>Somatostatin </li></ul><ul><li>Catecholamines </li></ul><ul><li>Steroid Hormones </li></ul><ul><li>Thyroid Hormones </li></ul><ul><li>Growth Hormones </li></ul>
  44. 44. Metabolic Effects of Hormones (+) Stimulated; (-) Inhibited (+) (+) (+) (+) (-) (-) (-) (-) (-) (-) (-) (+) (+) (+) “ central” “ peripheral” “ Liver” “ L & M” DM, Lepre- chaunism Glucagonoma Parkinson’s Pheochromo- cytoma Grave’s D. Myxedema Cretinism Goiter Cushing’s Conn’s Addison’s Dwarfism Gigantism Pathology Protein Synthesis Lipolysis Lipogenesis Gluconeogenesis Glycogenolysis Glycogenesis Glycolysis GH Cortisol T3, T4 Epi Glucagon Insulin Pathways (+) (-) (-) (-) (+) (+) (+) (+) (-) (-) (+) (+) (+) (+) (-) (+) (+) (+) (-) (+) (+) (-) (+) (-) (++) (+) (+) (+)
  45. 45. Hormone Metabolism Insulin … Mechanism of Action <ul><li>Transduction thru tyrosine kinase </li></ul>Autophosphorylation [  -subunit] (+)/(-) of cytoplasmic proteins Phosphorylation of proteins (+) of tyrosine kinase activity Biologic effects [long term effects]
  46. 46. Hormone Metabolism Insulin … Mechanism of Action <ul><li>Second Messengers </li></ul>Release of glycoinositol derivative (+)/(-) of cytoplasmic proteins Dephosphorylation of proteins (+) Phosphoprotein phosphatase Biologic effects [short term effects]
  47. 47. Hormone Metabolism Insulin … Mechanism of Action
  48. 48. Hormone Metabolism Insulin … Effects on Metabolism Enzyme Change in Activity Possible Mechanism cAMP metabolism Phosphodiesterase (low Km) Increase Phosphorylation Protein kinase (cAMP-dependent) Decrease Association of R and C subunits Glycogen metabolism Glycogen synthase Increase Dephosphorylation Phosphorylase kinase Decrease Dephosphorylation Phosphorylase Decrease Dephosphorylation Glycolysis & Gluconeogenesis Pyruvate dehydrogenase Increase Dephosphorylation Pyruvate kinase Increase Dephosphorylation Phosphofructokinase Increase Dephosphorylation Fructose-2,6-bisphosphatase Decrease Dephosphorylation
  49. 49. Hormone Metabolism Insulin … Effects on Metabolism Enzyme Change in Activity Possible Mechanism Lipid metabolism Acetyl-CoA carboxylase Increase Dephosphorylation HMG-CoA reductase Increase Dephosphorylation Triacylglycerol lipase Decrease Dephosphorylation Signaling molecules p42/44MAP kinase Increase Dephosphorylation p90RSK Increase Dephosphorylation GSK3 Decrease Dephosphorylation p70 S6 kinase Increase Dephosphorylation Phosphoprotein phosphatase Increase Dephosphorylation 1G
  50. 50. Hormone Metabolism Insulin … Pathophysiology <ul><li>Diabetes Mellitus </li></ul><ul><li>Type 1 – Insulin dependent DM (IDDM) </li></ul><ul><li>Type 2 – Non-insulin dependent DM </li></ul><ul><li>(NIDDM) </li></ul>
  51. 51. Insulin … <ul><li>Leprechaunism </li></ul><ul><li>[“Donohue’s Syndrome”] </li></ul>
  52. 52. <ul><li>Metabolic Syndrome / Insulin Resistance Syndrome </li></ul>Hormone Metabolism Insulin … <ul><ul><ul><ul><ul><li>Syndrome X, </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reaven Syndrome Dysmetabolic S. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>The “H” phenomenon </li></ul></ul></ul></ul></ul><ul><li>The “Deadly Quartet” </li></ul>
  53. 53. Hormone Metabolism Insulin … Pathophysiology <ul><li>Somogyi Effect [rebound hyperglycemia] </li></ul><ul><li>- rapid  in blood glucose that generates </li></ul><ul><li> the release of counterregulatory hormones </li></ul><ul><li> (Epi, glucagon, cortisol)  rapid  of glucose </li></ul><ul><li>- hypoglycemia results from: </li></ul><ul><li>1) autonomic neuropathy </li></ul><ul><li>2) inappropriate timing of insulin </li></ul><ul><li>3) exercise w/o adequate caloric intake </li></ul><ul><li>4) excessive insulin treatment </li></ul>
  54. 54. Hormone Metabolism Insulin … Pathophysiology <ul><li>Dawn Phenomenon </li></ul><ul><li>- early morning (5:00 to 6:00AM) increase </li></ul><ul><li> in blood glucose associated with the </li></ul><ul><li> release of nocturnal growth hormone </li></ul><ul><li>- 3:00 AM glucose is normal, while </li></ul><ul><li> 8:00 AM glucose is  </li></ul>
  55. 55. Hormone Metabolism Insulin … Pathophysiology <ul><li>Maillard reaction </li></ul><ul><li>- non-enzymatic glycosylation of proteins </li></ul><ul><li>due to high blood glucose levels </li></ul><ul><li>- sugar aldehyde or ketone group condenses </li></ul><ul><li> with a free amino group  Schiff base  </li></ul><ul><li> Amadori products (stable ketoamines)  </li></ul><ul><li> degrade into reactive carbonyl-containing </li></ul><ul><li> products  react w/ amino groups  </li></ul><ul><li> cross-linkages and adducts  DAMAGE </li></ul>
  56. 56. Hormone Metabolism Catecholamines … Synthesis & Structures CH 2 - C – NH 2 HO H COOH Tyrosine Dopa HO HO CH 2 - C – NH 2 H COOH Dopamine HO HO CH 2 - CH 2 – NH 2 Norepinephrine HO HO CH - CH 2 – NH 2 OH Epinephrine HO HO CH - CH 2 – NH CH 3 OH Tyrosine hydroxylase Dopa decarboxylase Dopamine  -hydroxylase PNMT
  57. 57. Catecholamines … Biosynthesis Hormone Metabolism Chromaffin Cell Tyrosine (+)  - adrtenergic & cholinergic agents (-)  -adrenergic agents E E NE NE Tyrosine Dopa Dopamine Granule E NE NE DBH TH DD PNMT
  58. 58. Hormone Metabolism Catecholamines … Secretion of Stress Hormones Stress Hypothalamus ACTH Cortisol EP Blood glucose Blood Tyr, Phe Chromaffin Cell EP EP Tyrosine NEP PNMT
  59. 59. Catecholamines … Metabolism <ul><li>rapidly metabolized in the liver and </li></ul><ul><li>skeletal muscles </li></ul><ul><li>metabolized by: </li></ul><ul><li>catechol-O-methyl transferase (COMT) </li></ul><ul><li>monoamine oxidase (MAO) </li></ul><ul><li>free catecholamines may also be </li></ul><ul><li>inactivated by conjugated with sulfate or </li></ul><ul><li>glucoronide in the liver </li></ul>Hormone Metabolism
  60. 60. Hormone Metabolism Catecholamines … Mechanism of Action <ul><li>act through 2 major classes of receptors: </li></ul><ul><li> -Adrenergic (  1,  2) </li></ul><ul><li> -Adrenergic (  1,  2) </li></ul><ul><li>Epinephrine binds and (+) both  and  R: </li></ul><ul><li>- much greater affinity with  R </li></ul><ul><li>Norepinephrine primarily binds with  R </li></ul>
  61. 61. Hormone Metabolism Catecholamines … Mechanism of Action  1,  2  (+) adenylyl cyclase  2  (-) adenylyl cyclase  1  couples to processes that alter Ca ++ concentration or modify phosphatidylinositol metabolism or both <ul><li>Binding of catecholamines to: </li></ul>
  62. 62. Pathophysiology Hormone Metabolism Catecholamines … <ul><li>Parkinson’s disease </li></ul><ul><li>Pheochromocytoma </li></ul>
  63. 63. Thyroid Hormones … Hormone Metabolism Pathophysiology <ul><li>Hypothyroidism/Myxedema </li></ul><ul><li>-  T3 and T4;  BMR </li></ul><ul><li>Hyperthyroidism/Thyrotoxicosis </li></ul><ul><li>-  T3 and T4;  BMR </li></ul><ul><li>- Grave’s disease </li></ul><ul><li>Goiter </li></ul><ul><li>- enlarged thyroid gland ; elevated TSH </li></ul><ul><li>- due to iodine deficiency or excess </li></ul><ul><li>- defect in any steps in the synthesis </li></ul>
  64. 64. Steroids … Hormone Metabolism Synthesis Pregnenolone Progesterone Cortisol, Aldosterone , etc. Cholesterol (1) SCC (2) Oxidation & isomerization (3) Hydroxylation
  65. 65. Steroids … Hormone Metabolism Subcellular comparmentalization of Glucocorticoid biosynthesis R ACTH G AC Cortisol Cholesterol Ester Cholesterol Lipase Pregnenolone ATP cAMP Protein kinase A Cholesterol Cortisol Progesterone 11-Deoxycortisol ER LDL
  66. 66. Steroids … Mechanism of Action
  67. 67. Steroids … Hormone Metabolism Pathophysiology <ul><li>Cushing’s syndrome </li></ul><ul><li>- glucocorticoid excess </li></ul><ul><li>- due to pharmacologic use of steroids </li></ul><ul><li>- ACTH-secreting pituitary adenoma or ca. </li></ul><ul><li>- hyperglycemia or glucose intolerance; </li></ul><ul><li> truncal obesity; severe CHON metabolism </li></ul><ul><li>Conn’s syndrome </li></ul><ul><li>- primary aldosteronism </li></ul><ul><li>- hypertension, hypokalemia, hypernatremia </li></ul><ul><li> and alkalosis </li></ul>
  68. 68. Steroids … Hormone Metabolism Pathophysiology <ul><li>Addison’s disease </li></ul><ul><li>- primary adrenal insufficiency </li></ul><ul><li>- severe hypoglycemia </li></ul><ul><li>- decrease BP, decrease GFR, decrease </li></ul><ul><li> ability to excrete a water load </li></ul><ul><li>- skin pigmentation </li></ul><ul><li>2 ° Adrenal Insufficiency </li></ul><ul><li>- deficiency of ACTH from tumors, infarct, </li></ul><ul><li> or infection </li></ul><ul><li>- metabolic syndrome w/o hyperpigmentation </li></ul>
  69. 69. Steroids … Hormone Metabolism “ High level of serum cortisol may be responsible for stress-induced memory loss.” “ Physiologic response to stress does not impair the learning aspect of memory but only the free recall of information.” “ Elevated glucocorticoid level may induce impairment in such stressful conditions as job interviews, combat, courtroom testimony and examinations.” [Nature Neuro-science 2000; 3:313-4 (April)]
  70. 70. Growth H. … Secretion
  71. 71. Growth H. … Mechanism of Action
  72. 72. Growth H. … Hormone Metabolism Pathophysiology <ul><li>GH deficiency dwarfism </li></ul><ul><li>Laron type dwarfism </li></ul><ul><li>Pygmies </li></ul>
  73. 73. Growth H. … Pathophysiology <ul><li>Pygmies </li></ul>
  74. 74. Pygmies
  75. 76. Growth H. … Pathophysiology <ul><li>Gigantism </li></ul>
  76. 77. Growth H. … Pathophysiology <ul><li>Acromegaly </li></ul>
  77. 78. Hormone Metabolism <ul><li>neuromuscular excitability </li></ul><ul><li>blood coagulation </li></ul><ul><li>secretory processes </li></ul><ul><li>membrane integrity/plasma </li></ul><ul><li>membrane transport </li></ul><ul><li>enzyme regulation </li></ul><ul><li>release of hormones and </li></ul><ul><li>neurotransmitters </li></ul>Calcium
  78. 79. Calcium <ul><li>Ca and phosphate are necessary </li></ul><ul><li>for bone mineralization </li></ul><ul><li>1 kg Ca [human body] </li></ul><ul><li>99%  bone (hydroxyapatite) </li></ul><ul><li>miscible pool (1% of the skeletal </li></ul><ul><li>muscle Ca and 1% periosteal space) </li></ul><ul><li>7.5-10.5 mg/dl or 1.1-1.3 mmol/L </li></ul>Hormone Metabolism
  79. 80. Hormones That Affect Calcium metabolism Hormone Metabolism <ul><li>PTH </li></ul><ul><li>Calcitriol </li></ul><ul><li>Calcitonin </li></ul>
  80. 81. Hormone Metabolism Parathyroid Hormone [PTH] <ul><li>84 amino acid peptide </li></ul><ul><li>regulates plasma Ca++ level </li></ul><ul><li>synthesized in the parathyroid gland </li></ul><ul><li>t½ = 20 min after proPTH is synthesized </li></ul><ul><li>metabolized in the parathyroid tissue </li></ul><ul><li>and liver </li></ul>
  81. 82. Hormone Metabolism PTH … preproPTH  proPTH  PTH (115 a.a) (84 a. a.) ER Ribosome GA <ul><li>PTH 1-34 (full biologic activity) </li></ul><ul><li>PTH 25-34 (receptor binding) </li></ul>
  82. 83. Hormone Metabolism Fates of PTH <ul><li>Transport to a storage pool </li></ul><ul><li>Degradation </li></ul><ul><li>Immediate secretion </li></ul>
  83. 84. Hormone Metabolism PTH Secretion <ul><li>Regulated by plasma Ca++: </li></ul><ul><ul><li>acute  Ca++   PTH mRNA </li></ul></ul><ul><ul><li>  PTH synthesis </li></ul></ul><ul><ul><li>1,25(OH)2-D3  VDRC/VDHRE </li></ul></ul><ul><ul><li>   PTH mRNA transcription </li></ul></ul><ul><li>(+) G-protein  (+) phospholipase C </li></ul><ul><li>  IP3   Ca++  secretion </li></ul>
  84. 85. Hormone Metabolism PTH Metabolism <ul><li>metabolized in the parathyroid tissue </li></ul><ul><ul><li>Cathepsins B and D </li></ul></ul><ul><ul><li>Cathepsins B cleaves: </li></ul></ul><ul><ul><li>PTH  [1-36 and 37-84] </li></ul></ul><ul><li>principal site of peripheral proteolysis </li></ul><ul><li>occurs in the liver (Kuppfer cells) </li></ul><ul><li>excretion of metabolites (kidneys) </li></ul>
  85. 86. Hormone Metabolism PTH Actions PTH  (+) G-protein  cAMP BONES KIDNEYS INTESTINES
  86. 87. Hormone Metabolism PTH Actions BONES KIDNEYS INTESTINES Direct Effects Indirect Effect <ul><li>Increase bone </li></ul><ul><li>resorption </li></ul><ul><li>Decrease renal </li></ul><ul><li>Ca++ excretion </li></ul><ul><li>Increase Ca++ </li></ul><ul><li>absorption </li></ul><ul><li>(CALCITRIOL) </li></ul>
  87. 88. CALCITRIOL <ul><li>derivative of vitamin D </li></ul><ul><li>regulates plasma Ca++ level </li></ul><ul><li>synthesized in the kidney </li></ul><ul><li>ensures Ca and phosphate for </li></ul><ul><li>bone mineralization </li></ul>Hormone Metabolism
  88. 89. Synthesis of Calcitriol Hormone Metabolism 7-dehydrocholesterol 25-OH-D3 SKIN Vit D3 1, 25-(OH) 2 -D3 LIVER KIDNEY [placenta] (Photolysis) (25-hydroxylase) (1-hydroxylase)
  89. 90. Mechanism of Action Hormone Metabolism <ul><li>Nuclear action </li></ul><ul><li>(+) VDRE </li></ul><ul><ul><li>Induces Ca binding protein (CBP) </li></ul></ul><ul><ul><li>Increases transfer of Ca & PO4 across </li></ul></ul><ul><ul><li>the intestinal mucosa </li></ul></ul>
  90. 91. When you do not succeed in taking giant steps on the road to your goal, be satisfied with little steps, and wait patiently till the time that you are able to run, or better still, to fly. Be satisfied to be a little bee in the hive who will soon become a big bee capable of making honey… Thank you … (Padre Pio)