CELL COMMUNICATION AND Endocrine System-KULIAH-2012.pptx

CELL COMMUNICATION AND Endocrine System

1. SUSILO WIBOWO 2012 CELL COMMUNICATION and ENDOCRINE SYSTEM The tiniest world organization: Inside story

2. No cell live in isolation, particularly Multicellular organism Inside cell and cell to cell comm.network will coordinate: Growth , Differentiation , and Metabolism Communication , over micrometres to metres & m s ec . to months Type of communication: Direct contact: gap junction & surface ligand receptor Electrical : nervous system communication Chemical : 1. Intracell  intracrine 2. Intercell  Autocrine , Ju n ctacrine , Paracrine , Endocrine , Ectocrine

3. Cell-to-Cell Interactions Cells within a tissue are connected to each other by cell junctions 1. tight junctions – create sheets of cells 2. anchoring junctions – connect the cytoskeletons of adjacent cells 3. communicating junctions – permit small molecules to pass between cells a. gap junctions – in animal cells b. plasmodesmata – in plant cells c. Sel surface signal - in Immune cells

4. Gap Junction Chanels grow from each cell joint up Permit movement of small molecules between adjucent cell Not permanently open-if neigbouring cells dies, healthy cell close chanels Permit close communication between cells within a tissue *coordinated activity Flow of Ca 2+ between hearth muscle cells to generate hearth beat Cell surface signals Cell surface glycoproteins in physical cell-to-cell association Promote adhesion and recognition Initiates action following receptor activation Important in Development and growth Communication between immune cells

5. Principles of cell signaling Signal transduction Message is converted from one form to another Electric signal Sound Electric signal Chemical

6. Principles of cell signaling Ligands or stimulus “Message” from extracellular Chemical (i.e. hormone) Electrical Receptors “Receivers” for cell Second messengers Intracellular relay, amplification or “translation” of message Secretion “out put” from the secretion or activation of a new molecule

7. Types of Ligands Chemical Structures Amines Steriods Peptides or proteins Eicsanoids

8. Nervous System communication/neurotransmitter Electrical signal (impuls)-extremely fast 1-100m/sec Can be over vast distances-many meters in a giraffe or whale High precision and specificity-cos signal transported along particular nerve pathway only to target cells Intra cellular communication Responses to external stimuly Cell membrane isolate cell from its environment, but transmits information about external stimuli Most common external stimuly: PHYSICAL: light, voltage change, strech/mechanical distortion CHEMICAL: hormons/ENDOCRINE , neurotransmitter, cell surface mulecul, taste, smell

9. ENDOCRINE SYSTEM Cells, organs, and functions in the human or animal body are regulated practically every day by the endocrine system. Structurally, the endocrine system is a collection of ductless glands that secrete chemical messages known as hormones. Main function of the endocrine network is to maintain homeostasis of and long-term control in the body by means of chemical signals. It works in parallel with the nervous system to control many body functions . The glands that make up the (human’s) endocrine system are hypothalamus, pituitary, thyroid, parathyroid, adrenals, pineal body, pancreas, ovaries, and testicles.

10. B y releasing chemical substances into the blood called hormones Hormone is c hemical messenger produced by a ductless gland or tissue & c arried in the blo od to a target organ where it effects a change in cellular activity Classic: H ormone is a chemical secreted by a cell or group of cells into the blood for a distant target, its effect at very low T he shape of each hormone molecule is specific and can bind to certain cellular receptors only.

11. Types of Glands (a) Exocrine glands

12. Types of endocrine actions Paracrine - released from effector cell (E) interact with a different target cell (T ) in adjuscent cell E T E 2) Autocrine - secreted by E interact with original E cell or similar cell types.

13. 3) Ju nc tacrine -expressed on surface of effector cell and interacts with target cell via direct cell-cell contact E T 4) Intracrine – Secretes own hormone within an intercellular to bind to a receptor. 5) Endocrine – Secreted in to blood sirculation and affect on distance target cell EffectorCell 1 Targe t Cell 2 Capillary

14. 6 ) Ectocrine (Pheromones ) are chemical signals that are released by an individual into the environment and which affect the physiology or behavior of other members of the same species Lee-Boot effect : Crowded female mice become anestrous when no mal es are present . Bruce effect : A newly mated female mouse will abort if placed with a strange male (not the previous mate) Dormitory effect : M enstrual synchrony in all-females living groups

15. Regulation by chemical messengers Axon Neurotransmitter Endocrine gland Receptor proteins Hormone carried by blood Target cell Neurotransmitters released by neurons Hormones release by endocrine glands

16. Signal-Transduction S ignals that are released from one cell and allowed to freely diffuse to a second (or more) recipient cell(s) These communications are deliberately initiated, received, and interpreted in order to increase the physiological coordination of the cells in multicellular organisms Three Stages of Signal Transduction Reception of extracellular signal by cell Transduction of signal from outside of cell to inside of cell - often multi- stepped Cellular Response Response is inititiated and/or occurs entirely within receiving cell

17. Three Stages of Signal Transduction

18. Various Responses Note that more than one response can result from the reception of a single ligand

19. Various Responses

20. Ligands e.g., steroid hormones e.g., nitric oxide

21. Intracellular Reception

22. Extracellular Reception e.g., insulin e.g., epinephrine

23. Receptor Types 3 subclasses of membrane receptors: 1. channel linked rec , ion channel that opens in response to a ligand 2. enzymatic rec , is an enzyme that is activated by the ligand 3. G protein-coupled receptor , G-protein (bound to GTP) assists in trans - mitting the signal

24. Ion-Channel Receptors

25. G-Protein Coupled Receptors G-protein – protein bound to GTP G-protein-coupled rec (GPCRs) – receptors bound to G proteins -G-protein is a switch turned on by the receptor -G-protein then activates an effector protein (usually an enzyme) Once activated, the effector protein produces a second messenger . second messenger generates the cellular response to the original signal For example – one common effector protein is adenylyl cyclase which produces cAMP as a second messenger. Other second messengers: inositol phosphates, calcium ions (Ca 2+ )

26. G Protein-Linked Receptors

27. G Protein-Linked Receptors

28. G Protein-Linked Receptors

29. G Protein-Linked Receptors note how activation is reversible the more ligand binding, the greater the cellular response

30. G Protein-Linked Receptors

31. G Protein-Linked Receptors

32. G Protein-Linked Receptors

33. G Protein-Linked Receptors

34. G Protein-Linked Receptors note how activation is reversible

35. G Protein-Linked Receptors T he more ligand binding, the more K + in cytoplasm

36. Protein Kinase & Phosphatase A cell’s response to a signal often involves activating or inactivating proteins. Phosphorylation is a common way to change the activity of a protein. protein kinase – an enzyme that adds a phosphate to a protein phosphatase – an enzyme that removes a phosphate from a protein

37. Tyrosine Kinase Receptors Note steps involved: Ligand Reception Receptor Dimerization Catalysis ( Phosphorylization ) Subsequent Protein Activation Further Transduction Response K inase cascade a series of protein kinases that phosphorylate each other in succession A mplifies the signal because a few signal molecules can elicit a large cell response M itogen -activated protein (MAP) kinases A re activated by kinase cascades

38. Tyrosine Kinase Receptors

39. Signal Amplification (Cascade) Note how, via catalysis , one ligand molecule binding gives rise to many new intracellullar molecules

40. Phosphorylation Cascade This reversibility contributes to the dynamic nature of cells: A protein that is activated by a Protein Kinase in turn is inactivated by a Protein Phosphatase This means that the effect of signals can’t last forever For the cellular response to continue, more signal must be received

41. Phosphorylation Cascade

42. Epinephrine  Glycogen Breakdown 10 molecules 10 2 molecules 10 4 molecules 10 4 molecules 10 5 molecules 10 6 molecules 10 8 mol Glu-1-Phosphate

43. Second Messengers: cAMP 1st of 2 major pathways triggered by G-protein-coupled receptors Effector ( adenylyl cyclase ) generates cAMP as second messenger cAMP activates specific protein kinases Second Messengers: cAMP -Receptor-Response Pathw

44. Second Messengers

45. Cyclic AMP ( cAMP ) 2 nd Messenger

46. Second Messengers: IP 3 and DAG 2nd major pathway triggered by G-protein–coupled receptors Activated effector ( phospholipase C ), generates two second messengers, IP 3 and DAG IP 3 activates transport proteins in the ER Releasing stored Ca 2+ into the cytoplasm Released Ca 2+ (alone or with DAG ) activates specific protein kinases Adds phosphate groups to target proteins IP 3 / DAG Receptor-Response Pathway

47. Inositol Triphosphate 2 nd Messenger

48. Pathway Controls cAMP and IP 3 /DAG pathways are balanced by reactions that eliminate second messengers Stopped by protein phosphatases that continually remove phosphate groups from target proteins Stopped by endocytosis of receptors and their bound extracellular signals Mutations Mutated systems can turn on the pathways permanently, contributing to progression of some forms of cancer

49. Gene Regulation: Ras Some pathways in gene regulation link certain receptor tyrosine kinases to a specific G protein ( Ras ) When the receptor binds a signal molecule, it phosphorylates itself Adapter proteins then bind, bridging to and activating Ras Activated Ras Activated Ras turns on the MAP kinase cascade Last MAP kinase in cascade phosphorylates target proteins in the nucleus Activates them to turn on specific genes Many of these genes control cell division Gene Regulation

50. Specificity of Cell Signaling Note how same ligand gives rise to different responses Cells differ in terms of their proteins Different proteins respond differently to the same environental signals (note, though, same receptors, different relay) Different cells behave differently because some, but not all proteins can differ between cell types

51. Integration of Cell Communication Pathways - Cross Talk Cell signaling pathways communicate with one another to integrate responses to cellular signals May result in a complex network of interactions between cell communication pathways Modification of Cell Response Cross-talk often results in Modifications of cellular responses controlled by the pathways Fine-tuning effects of combinations of signal molecules binding to receptors of a cell Cell Communication Pathways In Animals I nputs from other cellular response systems also can become involved in the cross-talk network Cell adhesion molecules Molecules arriving through gap junctions

52. Chemical characteristics of hormones HORM0NE

53. Function of the hormon differ appropriatelly Different organ secreted different hormon and regulate different action

54. Location Classical location

55. “Classic ” g lands Hypothalamus: GHRH, CRH, TRH, GnRH Somatostatin ADH Pituitary: Growth hormone Prolactin ACTH , TSH FSH & LH Oxytocin ADH Pancreas: Insulin Glucagon Ovaries: Estrogens Progesterone Epiphysis /Pineal : Melatonin Thyroid gland: T3, T4 Calcitonin Parathyroid glands: Parathyroid h. Adrenal cortex: Cortisol Aldosterone Androgens DHEA Adrenal medulla: Catecholamines

56. Less traditional sources P lacenta : All hormones A dipocytes : L eptin C ardiocytes : ANP (Atrial Natriuretic Peptide) Kidney : E rythropoietin RAS renin-angio- tensin system GIT : Gastrin Cholecystokinin Secretin , E ndothelium: Endothelins NO Prostanoids,... Immune system: Cytokines Platelets, mesenchyme: Growth factors Gonads : Inhibins Activins

57. 1) Amines (from tyrosine ) Amine hormones are (all) derived from the amino acid tyrosine secreted by the glands hydroxylation – catecholamines iodination - thyroid hormones Epinephrine and Norepinephrine converted from Tyrosine Involved in sympathetic responses and stress S ecreted from the adrenal medulla

58. Steroids (from cholesterol) Nearly all responsible for development of many sex characteristics : Adrenocortikoids sex hormones active metabolites of vit D

59. Steroid Metabolism

60. 3) Proteins and Peptides Most hormones are peptides, thus each with only a short chain of amino acids; they are synthesized largely as proteins first. Peptide - Few - Several amino acids Gonadotropin Releasing Hormone ( GnRH ) - 10 amino acids Oxytocin - 8 amino acids Glycoprotein - Protein hormone with carbohydrate molecules Some have large amount of sialic acid - FSH Protein - Long chains of amino acids Prolactin - 198 amino acids Adrenalcorticotropic Hormone (ACTH) – 39 AA

61. 4). Prostaglandins Produced by all tissues from fatty acids or phospholipids Can have a local effect on tissues (same tissue which produced it) Rapidly degraded in lungs Arachidonic Acid Precursor to Prostaglandins Aspirin inhibits PGF2a vasoconstriction of Blood vessels PGE2 vasodilatation of blood vessels

62. Prostaglandins (a group of related compounds). Named from discovery in semen (fluids from prostate): stimulate contraction of uterine smooth muscle pump sperm up to the ejaculatory duct Note: this particular function is a chemical signal to another individual or paracrine Potentiates pain by sensitizing nearby ‘ pain receptor’ neurons ( nociceptors ): more responsive to slightest pressure. Prostaglandins are one of the Chemical Signals (cytokines ) that recruit phagocytes to wounds and potentiate pain - to get your attention , so you’ll protect wound while it heals.

63. Cyclooxygenases COX1 & COX2 catalyze prostaglandin synthesis.  NonSteroidal Anti- Inflamatory Drugs (NSID) act by inhibiting cyclooxygenases generally – both COX1 & COX2 . Prostaglandins from COX 1 act to suppress acid secretion in the stomach & promote protective mucus coating on the stomach wall, general cyclooxygenase inhibitors, such as aspirin, cause pitting and bleeding of the stomach wall.

64. Transport of hormones Freely in blood: Catecholamines Most peptides Specific transport ( globulins /albumin & other protein) : Steroids Thyroid hormones Plasma halftime (days) % bound hormone Thyroxin T3 Testosterone Cortisol Transporter binding lengthens hormone halftime

65. Lipid solubility of hormone Steroid Hormones: Lipid soluble Diffuse through cell membranes Endocrine organs Adrenal cortex Ovaries Testes placenta Nonsteroid Hormones: Not lipid soluble Received by receptors external cell membrane Endocrine organs Thyroid gland Parathyroid gland Adrenal medulla Pituitary gland pancreas

66. Receptors Cells of target organ have specific receptors for hormones. Hormone binds to receptor and stimulates a specific cellular response - protein & peptide, receptor is in plasma membrane. - steroids receptor is in nucleus - prostaglandins- receptor is in plasma membrane. Number of receptors on or in cell regulate degree of cell stimulation and cellular response to the hormone Hormones can also regulate whether there is a increase or decrease in the number of receptors Most common in mammals is the “7-transmembrane G-coupled receptor”

67. Number of Receptors Down-regulation : is the decrease of hormone receptors which decreases the sensitivity to that hormone Up-regulation : is the increase in the number of receptors which causes the cell to be more sensitive to a particular hormone Lack of androgen receptor in male – Testicular Feminization syndrome Number of receptors on or in cell determined the degree of response agains stimulation

68. Hormone action depends on lipid solubility Peptide/Proteins Catecholamines Steroid & Thyroid hormones Receptor in cell membrane Receptor in cytosol or nucleus Second messengers ---> Protein activity Gene expression Fast Slower cAMP cGMP IP 3 Ca/ calmodulin tyr kinases Smad MAP kinases One hormone can use several systems (in various cells or for different functions)

69. STIMULATION Regulation of hormone release Feedback Negative Gland Target tissue hormone product INHIBITION  Positive (only narrow dose range)  Gland Target tissue hormone product Nerve regulation pain, emotions, sex, injury, stress, etc e.g.  oxytocin with nipple stimulation

70. Hormones & Homeostasis Negative feedback stimulus triggers control mechanism that inhibits further change body temperature sugar metabolism Positive feedback stimulus triggers control mechanism that amplifies effect lactation labor contractions Anterior pituitary Inhibition – Inhibition Target glands Hypothalamus Releasing hormones (TRH, CRH, GnRH ) Tropic hormones (TSH, ACTH, FSH, LH) – (thyroid, adrenal cortex, gonads) Hormones

71. triggers uptake of glucose by body cells triggers storage in liver - depresses appetite pancreas pancreas beta islet cells alpha islet cells Regulating blood sugar levels - triggers release of glucose by liver - stimulates appetite

72. ADH Dehydration Lowers blood volume & pressure Increased water retention Increased vasoconstriction leading to higher blood pressure Reduced urine volume Osmotic concentration of blood increases ADH synthesized in hypothalamus ADH released from posterior pituitary into blood Osmoreceptors Negative feedback Negative feedback Regulating blood osmolarity If amount of dissolved material in blood too high, need to dilute blood

73. Regulating blood calcium levels Increased blood Ca ++ Thyroid Parathyroids Low blood Ca ++ Parathyroid hormone (PTH) Increased absorption of Ca ++ from intestine due to PTH activation of Vitamin D Reabsorption of Ca ++ & excretion of PO 4 Osteoclasts dissolve CaPO 4 crystals in bone, releasing Ca ++ – Negative feedback

74. Regulating blood sugar levels

75. THEREFORE : hormone levels are only one part of endocrine systems CHANGES CAN OCCUR AT ANY LEVEL!!

76. Rhythms circadian light/dark fine/tune endogenous rhythm of cells & suprachiasmatic nucleus of hypothalamus melatonin, cortisol monthly seasonal (day length; atavistic) developmental (puberty, menopause) Pulsations/oscillations gonadotropins

77. Rhythms circadian Cortisol ( nM ) Time of day 09 09 21

78. Pulsatility in GnRH & LH rele ase 12:00 16:00 14:00 Time of day

79. CLASSIC HORMON IN THIS LECTURE

80. Major vertebrate hormones (1)

81. Major vertebrate hormones (2)

82. 1. MELATONIN Produced by Pineal gland (seat of the soul) and retina Often named as “mother of Hormone” Function as Zeitgeber or “time giver” Produce melanin

83. Melatonin is N-acetyl-5-methoxytryptamine in animals, & microbes. Many biological effects of melatonin are produced through activation of melatonin receptors . O thers are due to its role as a pervasive and powerful antioxidant, with protect nuclear and mitochondrial DNA. R egulates s leep -wake cycle by causing drowsiness & lowering body temperature, central y (specifically, the suprachiasmatic nuclei, SCN) that controls the daily cycle in most components of the paracrine & endocrine systems rather than the melatonin signal . Melatonin have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts. What is Melatonin? Soporofic (make sleepy)

84. Produced when is dark enough Produced when sleeping deep enough

85. Almost equal circadian between men and women

86. Increase after delivery Start decrease aproxima- tely at age 5-9 years Decrease concentration by age Decrease peak of daily circadian by age and cause insomnia

87. In humans, sleep becomes shorter with increasing age

88. Melatonin easily cross cell membranes & blood-brain barrier. Melatonin is a direct scavenger of OH, O2-, and NO. D oes not undergo redox cycling that regain their antioxidant properties. O nce oxidized forms several stable end-products . More powerful than both glutathioneand mannitolin neutralizing hydroxyl radicals and may protect cell membranes more effectively than vitamin E. P revent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer. Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease M ay play a role in preventing cardiac arrhythmia M ay increase longevity; it has been shown to increase the average life span of mice by 20% in some studies. Powerfull Antioxidant

89. I nteracts with the immune system, with unclear mechanism . E nhance cytokine production & counteract acquired immunodeficiency. Es eful for infectious disease incl . viral, such HIV & bacterial i nfections , P otentially for the treatment of cancer , BUT still inconclusive. Enhance Immune System A utism spectrum disorders (ASD) have lower levels of melatonin. In 2008 found , unaffected parents of ASD also have lower melatonin & were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis. Attention-deficit hyperactivity disorder (ADHD) . Research found melatonin administered to ADHD patients on methylphenidate, significantly reduces the time needed to fall asleep THAT remain undiminished 3 months efficacy, as one week into the treatment. Play role in Autism treatment

90. Insomnia Stress Delayed Sleep Phase Syndrome PMS Seasonal Affective Disorder Menstrual Irregularities Depression Infertility Immune Disorders Abnormal Sexual Development Cardiovascular Disease Cancer Other positive effects Affect physical & psychological disorders in relation with DHEA & GH Now, Melatonin Spray place melatonin in tiny nano already available

91. 2. DHEA DHEA/DHEAS IS PRECUSOR OF T ESTOSTERON & ESTROGEN Produced by ZONA RETICULARIS ADRENAL gland Determine: ♫ Brain Development icluding : ♥ formal thinking ; ♥ higher math ematic; ♥ Syntax ; and ♥ hypotheses formulation

92. Up Regulation of DHEA Receptor in c ub -cortical & cortex cerebri The receptor ▼ in line with puberty & DHEA converted to T or E The most abundantly produced steroids High when still fetus mximal in 40 weeks gestation and birth Decrease after delivery and increase through puberty

93. Abnormal cortisol levelshave been observed in chronic fatigue, depression, panic disorders, male impotence, infertility, PMS, menopause, anorexia nervosa, and sleep disturbances. Low DHEA has been associated with immunedysregulation, osteo- porosis, insomnia, depression, fatigue, and decreased libido. Long-term effectsof elevated cortisolor of a low DHEA: cortisol ratio include fatigue, irritability, dysglycemia, central obesity, impaired immunity, and osteoporosis. Relation of DHEA with several disorders depicted in right diagram

94. DHEA and DHEAS levels were decline with advancing age of men and women. Peak Levels at age 20-25

95. Low DHEA has been associated with arthritis DHEA also related with concentration and production of melatonin. When someone could not sleep, the body use DHEA and when they wake up, they feel tired The Melatonin and DHEA peak production seems correlate with the stage of Development

96. By inhibiting tryptophan hydroxylase enzyme activity, DHEA provided protection in rats subjected to acute sound stress. U se of DHEA-S as a biological indicator of stress, aging, age- related diseases : neurosis, depression, psychosomatic disorders, peptic ulcer, irritable bowel syndrome, and others. E xhibits pronounced anti- cortisol activity, normal DHEA levels may be key indicators of a patient’s ability to cope with stress. DHEA and Stress DHEA demonstrated a “consistent, independent, inverse, dose- response relationship” with coronary atherosclerosis in men. Suggested that DHEA-S could serve as an important, modifiable factor in the development & progression of coronary atherosclerosis. DHEA and Heart Attack

97. Excretion of DHEA is reduced in individuals with essential hyper- tension, compared to controls. This deficiency also causes increased conversion of deoxycorti- costerone to corticosterone, leading to the overproduction of mineralocorticoid ( viz.aldosterone) syndrome characterized by hypertension. DHEA and Hypertension Decrease in serum DHEA levels was recorded in hypothyroidism. DHEA and Thyroid Function PREVALENCE of Adrenal androgen deficiency Syndrom = AADS ( dehydroepiandrosterone sulfate DHEAS deficiency) is a common cause of asthenia (42 %)

98. Epidemiology shows that DHEA are related to etiology of certain Ca . Decreasing DHEA & DHEA-S positively correlated with development of bladder cancer & gastric cancer in some patients. Patients with prostate Ca & lung Ca also shown have lower DHEA. In certain clinical situations, reduced DHEA may serve as a marker of adrenocortical tumor. When administered to laboratory animals, DHEA prevents growth of spontaneous & chemically-induced tumors, although in large doses it may exert a hepatocarcinogenic effect. DHEA and Cancer DHEA seems likely also act as a key factor in preventing age-related dementia and neuronal damage.

99. Frequency in Asthenic Patients (Total=354) DHEA-S deficient (AADS) pat i ents Total =150) Age > 60 Years* 118 (33.33%) 79 (52.67%) Sensory neuropathy* 186 (52.54%) 142 (94.66%) Motor neuropathy* 79(22.31%) 63 (42.00%) Albuminuria * 79 (22.31%) 47 (31.33%) Chronic renal failure* ( creat >1.5) 35 (10.1%) 24 (16.00%) Hypothyroidism* 75 (21.18%) 71 (47.33%) Poor glycemic control * (HB A1c >8.0%) 158 (44.64%) 95 (63.33%) CLINICAL CORRELATES OF DIABETES PATIENTS (p<0.05) Hypertension 288 (81.35%) 134 (89.33%) Coronary Heart disease 5 (1.41%) (0%) Stroke 27 (7.62%) 15 (10. 00%) Foot Ulcer 9 (2.54%) (0%) Anemia 130 (36.72%) 71 (47.33%) Hypoproteinemia 18 (5.08%) 8 (5.33%) Hepatic Dysfunction 28 (7.91%) (0%)

100. Male(n=8) Female(n=15) Total(n=23) Sensory neuropathy* 8(100%) 11(73.33%) 19(82.60%) Erectile dysfunction 8(100%) Chronic renal failure ( Creat >1.5)* 1(12.5%) 1(12.5%) 2(8.69%) Hypertension 3(37.5%) 6(40%) 9(39.13%) Hyperlipidemia 3(37.5%) 6(40%) 9(39.13%) Clinical correlates of AADS with hypothyroid patients Anaemia * 2(25%) 7(46.6%) 9(39.13%) Loss of Libido(male) 8(100%) ---- ----- Hypoproteinemia* 2(25%) 4(26.66%) 6(26.08%) Hepatic dysfunction* (SGPT > 80IU/ml) 1(12.5%) 2(13.33%) 3(13.04%) Diabetes mellitus* 3(37.5%) 8(53.33%) 11(47.82%) Insulin treatment 3(37.5%) 2(13.33%) 5(21.17%) LONGTERM EFFECT OF AADS Cognitive decline (both genders) Breast cancer (premenopausal women) Alzheimer’s disease Osteoporosis (women 45-69 y) Type 2 diabetes /insulin resistance (men) Depressed mood (women) Cardiovascular disease (elderly men )

101. Therefore, at the time moment DHEA’s Claims have several positive effect i.e.: • Energizes • Enhances libido • Restores Memory • Rejuvenates the immune system • Tames stress • Fights cancer • Prevents heart disease • Reduces body fat • Therapy for menopause For Premenopause and Menopause therapy, the new finding involving INTRACRINE was really world wide accepted. DHEA use for women also in the form for intravaginal suppository

102. LH LHRH Ovary E 2 - Progesterone E 2 Peripheral tissue TRADITIONAL CONCEPT WOMAN’S DHEA CRH ACTH Adrenal Cortisol - Aldosterone Intracrinology DHT DHEA PREMENOPAUSE New findings: intracrinology

103. LH LHRH Ovary E 2 - Progesterone E 2 Peripheral tissue CRH ACTH Adrenal Cortisol - Aldosterone Intracrinology DHT DHEA New findings: intracrinology PREMENOPAUSE Testo ? POSTMENOPAUSE MENOPAUSE

104. DHEA is tested anytime in the day to determine Adrenal stage of exhaustion The Physiological effect of DHEA was determine through ratio with other hormon, namely Cortisol

105. During stress pathwys from Pregnenolone-DHEA-Testosteron- Estrogen were reduce appropriately. Stolen or driven to other side pathways to make progesteron and cortisol

106. It seems that external factors may affecting the adrenal secretion and cause dedtrioration of the human health

107. Largest Endocrine organ in the body Involved in production, storage, & release of thyroid hormone Function influenced by Central axis (TRH) Pituitary function (TSH) Comorbid diseases (Cirrhosis, Graves , etc.) Environmental factors (iodine intake) 3) Thyroid Regulates basal metabolic rate Improves cardiac contractility Increases the gain of catecholamines Increases bowel motility Increases speed of muscle contraction Decreases cholesterol (LDL) Required for proper fetal neural growth

108. Thyroid Hormone Majority of circulating hormone is T 4 98.5 % T 4 (3,5,3’,5’-Tetraiodothyronine (L-thyroxine) 1.5 % T 3 (3,5,3’-Triiodothyronine) Total Hormone is influenced by binding proteins (TBP, Albumin , ??) Thyroid Binding Globulin 70% Albumin 15% Transthyretin 10 % Regulation and control production done by: TRH that Produced by Hypothalamus  Release is pulsatile , circadian  Downregulated by T 4 , T 3  Travels through portal venous syst to adenohypophysis  Stimulates TSH formation TSH that Produced by Adenohypophysis Thyrotrophs  Upregulated by TRH  Downregulated by T 4 , T 3  Travels to cavernous sinus, body.  Stimulates several processes  Iodine uptake  Colloid endocytosis  Growth of thyroid gland Thyroid Hormone Control

109. Hypothyroid Symptoms – fatigability, cold, weight gain, constipation, low voice Signs – Cool dry skin, swelling of face/hands/legs, slow reflexes, myxedema Newborn – Retardation, short stature, swelling of face/hands, possible deafness Types of Hypothyroidism Primary – Thyroid gland failure Secondary – Pituitary failure Tertiary – Hypothalamic failure Peripheral resistance Cause is determined by geography Diagnosis Low FT 4 , High TSH (Primary, check for antibodies) Low FT 4 , Low TSH (Secondary or Tertiary, TRH stimulation test, MRI)

110. Hashimoto’s ( Chronic, Lymphocytic) Most common cause of hypothyroidism Result of antibodies to TPO, TBG Commonly presents in females 30-50 yrs. Usually non-tender and asymptomatic Lab values High TSH Low T 4 Anti-TPO Ab Anti-TBG Ab Treat with Levothyroxine Biopsi of thyroid gland

111. Goiter Endemic goiter Caused by dietary deficiency of Iodide Increased TSH stimulates gland growth Also results in cretinism Goiter in developed countries Hashimoto’s thryoiditis Subacute thyroiditis Other causes Excess Iodide ( Amiodarone , Kelp, Lithium) Adenoma, Malignancy Genetic / Familial hormone synthesis defects

112. Hyperthyroid Jungle Hyperthyroid Symptoms – Palpitations, nervousness, fatigue, diarrhea, sweating, heat intolerance , Signs – Thyroid enlargement (?), tremor , Exoptalmus Lab work - up  TSH  FT4 Other Labs  Anti-TSH-R Ab , Anti-TPO Ab , Anti-TBG Ab  FT3  FNA  MRI Common Causes  *Graves  Adenoma  Multinodular Goiter  * Subacute Thyroiditis  *Hashimoto’s Thyroiditis Rare Causes Thyrotoxicosis factitia , struma ovarii , thyroid metastasis, TSH-secreting tumor, hamburger

113. 4) Insulin Produced by Pancreas gland that attach to duodenum

114. Pancreas a key gland located in the folds of the duodenum has both endocrine and exocrine functions secretes several key digestive enzymes Islets of Langerhans specialized tissues in which the endocrine functions of the pancreas occurs include 3 types of cells: alpha (  ) beta ( ) delta ( ) each secretes an important hormone . Alpha ( ) cells release glu - cagon , essential for control - ling blood glucose levels. When blood glucose levels fall,  cells  the amount of glucagon in the blood . The surge of glucagon stimulates the liver to release glucose stores (from glycogen and additional storage sites). Also, glucagon stimulates the liver to manufacture glucose gluconeogenesis .

115. Beta Cells ( ) release insulin (antagonistic to glucagon). Insulin  the rate at which various body cells take up glucose. Thus, insulin lowers the blood glucose level. Insulin is rapidly broken down by the liver and must be secreted constantly. Delta Cells ( ) produce somatostatin , which inhibits both glucagon and insulin. Target tissue of Pancreatic hormons Gland & Major Hormones Target Tissue Major Hormones Effects Pancreas Glucagon All cells, particularly in liver, muscle, and fat Stimulate hepatic glycogenolysis & gluconeogenesis, increasing blood glucose level Insulin All cells, particularly in liver, muscle, and fat Stimulate cellular uptake of glucose, increase rate of synthesisi of glycogen, proteins, and fats, decreasing blood glucose level Somatostatin Alpha & Beta cells in tne pancreas Suppresses secretion of glucagon and insulin within islets of Langerhans

116. 5) Hormons produced by Pituitary Gland

117. In endocrine system, it was well known that endocrine also divided into two categories i.e: Central Axis HPA (Hypophyseal - Pituitary Axis): Hypophysis Third Ventricle GRH, TRH, CRH, GnRH , Dopamine, Somatostatin Neurohypophysis Derived from Hypophysis ADH, Oxytocin Adenohypophysis Derived from Rathke’s pouch ACTH, LH, FSH, TSH, GH, PRL P eripheral Axis Thyroid Parathyroid Adrenal Gonadal Gastrointestinal 5a) GH One of several hormon that produced by Hypophyseal gland

118. HPA produce hormons depicted below.

119. Regulation of GH secretion R eleased in a pulsatile fashion in response to GHRH release from the hypothalamus, inhibited by GHIH R elease also stimulated by: hypoglycemia and fasting increased amino acids in plasma stress exercise The secretion of GH from the pytuitary occurs throughout life Maximal secretion occurs during puberty After puberty, levels gradually but progressively decline Levels throughout life

120. Effect on Growth G rowth hormone is only one necessary factor for normal development GH stimulates long bone growth GH effect through IGFs that stimulate bone & cartilage growth increases length prior to epiphyseal closure increases width after epiphyseal closure Increased rate of protein synthesis in all body cells Increased mobilization and use of fatty acids from adipose tissue for energy Decreased rate of glucose utilization (i.e. enhances body protein, uses up fat stores and conserves CHO)

121. Increased abdominal fat mass Decreased glucose tolerance Decreased lean muscle mass Decreased protein synthesis Decreased bone mass Decreased skeletal muscle strength Decreased aerobic capacity Decreased immune function Decreased wound healing Decreased skin thickness Decreased quality of life (sleep, mood, body image, sense of well being) The elderly have mild GH deficiency. Ageing related changes that resemble GH deficiency i.e:

122. Young Old Hormones – a primary role in homeostasis , chenge with advantage age

123. 5b) Prolactin Instead of secreted by Pituitary Anterior (approximately 25% of hormon secreted by gland Pituitary galnd) Prolactin also secreted by variety of other cells in the body: A variety of immune cells Brain Decidua of pregnant uterus PRL “Small” (MW sp 22.000, aktivitas tinggi , monomeric PRL “Big” (MW sp 50.000, dimeric & trimeric PRL “Big-Big” (MW sp 100.000) PRL Glycosylate (MW sp 25.000), Abundant but activity < PRL”Small ” In Blood circulation, PRL have 4 differnt forms i.e.:

124. Macroprolactin ( Big-Big, Big, and Glycosylate PRL) is a prolactin - immunoglobulin complex which causes false positive results in many prolactin immunoassays. Laboratories require methods to identify this prolactin type major function of prolactin is milk pro - duction – oxytocin stimulates ejection of milk

125. Lactogenesis is triggered following the expulsion of the placenta by a fall in progesterone and estrogen levels and continued presence of prolactin . As progesterone and estrogen levels abruptly drop, the anterior pituitary gland, no longer inhibited by these two hormones, releases very large amounts of prolactin . Prolactin levels rise and fall in proportion to the frequency, intensity , and duration of nipple stimulation and the suckling stimulus . During the first week postpartum, prolactin levels in breastfeeding women drop about 50 percent. If a mother does not breastfeed, prolactin levels usually reach nonpregnant levels by seven days postpartum.

126. P rolactin levels during breastfeeding • Prolactin levels decline slowly over the course of lactation, but remain elevated for as long as the mother continues to breastfeed. • The level of prolactin is related with the frequency of suckling: the more feedings, the higher the prolactin level. More than eight breastfeedings per 24 hours prevent decline of the concentration of prolactin before the next feeding. Prolactin levels are higher in amenorrheic than in cycling women during the first year postpartum. Prolactin delays fertility. It delays the return of ovulation by inhibiting the ovarian response to follicle-stimulating hormone (FSH). Prolactin may be affected by smoking and beer. Smoking may reduce prolactin levels; drinking a beer may increase prolactin levels.

127. Lactation Hypothalamus releases PRH. Anterior pituitary releases prolactin: Stimulates milk production. Prolactin secretion primarily controlled by PIH. Oxytocin needed for “milk letdown.”

128. Development of Breast ( with GGH , cortisol , estrogen, progesteron ) O smotik Regulation in Amniotic fluid (Natrium and Kalium salt) Decrease SHBG Increase insulin Resistant in periphery & liver Other Physiological Roles of Prolactin In female Breast Milk Differentiation Mammogenesis (the growth of the mammary glands) Lactogenesis: the initiation of milk production Galactopoisis: the maintenance of the milk supply). Mc Donald Burger After delivery Hyperprolactin -----> Amenorrhoea

129. In Male Involve in Spermatogenesis Increase sensitivity FSH-LH receptor Androgen Spermatogenesis and Spermiogenesis Hyperprolactinemia could cause: G alactorrhea A menorrhea Gynecomastia (in Male) M ale impotence A ssociated with autoimmune diseases such as multiple sclerosis, lupus

130. 6) Hormon Produced by Gonads Female gonad: Ovaries Male gonad : Testes Ovaries Estrogen Most cells, particularly those of female reproductive tract Stimulates development of secondary sexual characteristics, play role in maturation of egg prior to ovulation. Progesteron Uterus Stimulate uterine change necessary for sucessful pregnancy Testis Testosteron Most cells, particularly those of male reproductive tract Stimulates development of secondary sexual characteristics, play role in development of sperm cells

131. Under the control of LH and FSH from the anterior pituitary 6a) ESTROGEN & PROGESTERON Produced by Ovaries

132. External factor as well as other hormons influence the production. This effect should be taken into account in the fertility work-up

133. Hormonal Control of the Ovarian & Uterine Cycles When ovulation Basal body temperatur increase. Used as indicator of ovulation

134. Estrogen and Progesteron decrease with advancing age In Premenopause and Menopause, estrogen is relative high compare to progesteron since woman less or not ovulation & no corpus luteum Some women experience hot flus. However some scientist believe that hot flush produce by peak of LH surge

135. Effects of Hormone s Estrogens Produced by follicle cells Cause secondary sex characteristics Enlargement of accessory organs Development of breasts Appearance of pubic hair Increase in fat beneath the skin Widening and lightening of the pelvis Onset of menses Progesterone Produced by the corpus luteum Production continues until LH diminishes in the blood Helps maintain pregnancy Healthy skin with sufficient Estrogen Old skin with less Estrogen

136. Estrogen and Progesterone have several functions, including sexual development and preparation of the uterus for implantation of the egg. Ovarian hormone (Estrogen & Progesteron) also have major role in Platelet – Derived factor as response to injury

137. Estrogen have wider target and effect on the body, including skin Growth of Epithelium rate of bone blood skin structure Liver synthesis of follilcle Growth of endometrium Lowers plasma cholesterol Behavioral effects ESTROGENS Reproductive Tissues Vaginal Mammary Gland Decreases resorption Increases coagulability Maintains normal Reduces bowel motility Sperm transport Transport Proteins Ovarian Non-reproductive Tissues

138. Estrogen on the Breast (Mammogenesis) Causes: Development of stromal tissue Growth of an extensive ductal system Deposition of fat in the breasts Inhibits the actual secretion of milk Promotes development of lobules and alveoli Causes alveolar proliferat ion , enlarge & become secretory in nature Does not cause alveoli to secrete milk (actually inhibits the secretion of milk), milk is secreted only after the prepared breast is further stimulated by prolactin . Development of alveoli and lobules brought about by estrogens is slight. Progesterone and prolactin causes the determinative growth and function of these structures. Therefore, estrogens initiate growth and is responsible for the characteristic external appearance of the mature female breast, but they do n’ t complete converting the breasts into milk producing organs.

139. Mammogenesis or mammary gland development begins during the 7-8 week of gestation when primary and secondary ducts develop. Mammary gland development during childhood is limited to general growth. At puberty, estrogen becomes the major influence on breast growth in a girl, when primary and secondary ducts grow and divide along with an increase in the number of and development of lobuloalveolar units. Breast changes continue to occur during each menstrual cycle in response to the changes in hormones. Complete development of mammary function occurs only in pregnancy.

140. With the beginning of female puberty, however, the release of estrogen, at first alone, and then in combination with progesterone when the ovaries functionally mature, cause the breasts to undergo dramatic changes which culminate in the fully mature form. This process on average takes 3 to 4 years and is usually complet by age 16 years .

141. However Estrogen could be metabolized and have Cancerogenic or Tumorogenic effect

142. Testes: Seminiferous tubules: Contain receptor proteins for FSH in Sertoli cells. FSH stimulates spermatogenesis to occur. Leydig cells: LH stimulates secretion of testosterone. Contain receptor proteins for LH. 6b) TESTOSTERON

143. Control of LH and FSH Secretion Negative feedback: Testosterone inhibits LH and GnRH production. Maintain relatively constant secretion of LH and FSH. Declines gradually in men over 50 years of age. Testosterone converted to DHT, which inhibits LH. Inhibin inhibits FSH secretion. Aromatization reaction producing estradiol in the brain, is required for the negative feedback effects.

144. Endocrine Function of the Testes T estosterone and its derivatives are responsible for initiation and mainte - nance of body changes in puberty. Stimulate growth of muscles, larynx, and bone growth until sealing of the piphyseal discs. Promote hemoglobin synthesis. As paracrine for spermatogenesis . Estrogen Secretion Sertoli and Leydig cells secrete small amounts of estradiol . Receptors found in Sertoli and Leydig cells and accessory organs. May be responsible for: Negative feedback in brain. Sealing of epiphyseal plates. Regulatory function in fertility.

145. The overall function of Testosteron Testosteron Target Organ

146. The hormone decrease with advancing age, but E2 increase Age-related alterations of hormonal profiles in males with age. Note that the progressive rise in FSH and LH begins prior to a drop in testosteron levels. This believe to be due to the progressive loss of hypothalamic sensitivity to feedback inhibition by testosteron

147. *F ree -hormone" means And & Est not bound to SHBG is biologically active because : SHBG has high binding affinities SHBG has MW ± 90 kDa ( not penetrate) However other found that MEGALIN , an endocytic rec eptor in rep roductive tis sue , may mediate cell uptake for A nd rogen & E st rogen bound SHBG T bound to glob (SHBG), loosely to alb . & unbound (free T/FT ) T albumin-bound + FT are bioavailable T (bio-T) F T accounts ± 2 –3% of Total T (TT) in men & even less in women *Several T forms are: Androgens are hormone that incl . T , DHEA, androstenedione , etc It is a misnomer to classify them as "male hormones" since they are present in both ♂ & ♀ Form of Testosteron in the body

148. Therefore Serum Testosteron (T) certainly low in Older Men. However laboratory examination inconclusisve . Total T may be low or normal Serum Sex hormone binding globulin (SHBG) usually elevated Free serum T and Bioavailable T are low Serum LH and FSH may be elevated, low, or inappropriately normal Even researcher already make cut of value from more than tousand patients each laboratory

149. FAI= 100 x Total T(Te)/SHBG Calc FT= 21.7 { (23  SHBG  T T ) 2  92 x Te } Bio T assay by ammonium sulfate prec >reliabl e . Calc B io T=Fte + (Te x albumin)=23 x Fte pmol/l (x 0.001 nmol/l) There is an ongoing controversy which T assay is most appropriate ( Thijssen JHH. In:Textbook of Men’s Health 2002) Typical decreasing Andogen is easy to cry for other

150. Estrogen is a sex hormone Estrogen is responsible for the development of female sex characteristics 17 beta estradiol is the biologically active form There are many metabolites of estrogen Estrone is the biologically inactive form of estrogen 2-hydroxy-17-beta estradiol and 4-hydroxy-17-beta estradiol induce oxidative damage and are carcinogenic; their purpose in the cell is not understood Estrogen can stimulate cellular changes (i.e. the upregulation of specific proteins) by initiating a signal cascade or by acting as a transcription factor Estrogen and the Immune Response Estrogen may increase / exaggerate the immune response by ... increasing mitochondrial activity, thus promoting cell growth to replace damaged / dying cells upregulating proteins involved in the inflammatory response by stimulating the NF- kB pathway ♥ This is only <1 ‰ of Endrocrine system on the human body ♥ Keep study and keep searching, and ♥ Knowing that we know almost nothing