Endocrine System

1. Endocrine System Lecture 1 Characters and mechanisms of actions of hormones Pituitary hormones Asso. Professor Dr Than Kyaw 17 September 2012

2. What is endocrinology? Endocrinology Study of: - Intercellular Chemical Communication - about communication systems & information transfer.

3. Hormones Definition (classical) - Chemical substances produced by specialized ductless glands - Released into the blood - Carried to other parts of the body - Produce specific regulatory effects. Is that definition true? PGF2α - produced by most of the body cells, transmitted by diffusion in interstitial fluid rather than by circulation in the blood. Pheromones – transmission through olfaction (smell) -- outside the body

4. Modes of transmission Hormone transmission restricted only to blood – incorrect 1. Epicrine transmission - Hormones pass through gap junctions of adjacent cells without entering extracellular fluid. 2. Neurocrine transmission - Hormones diffuse through synaptic clefts between neurons. Neural – through neurons (neurotransmitters)

5. Gap junctions - Pores connecting adjacent cells. Small molecules and electrical signals in one cell can pass through the gap junctions to adjacent cells.

6. Synaptic cleft • Between a neuron and a muscle fiber or • Between 2 neurons • Acetylcholine

7. Mode of transmission 3.Paracrine transmission - Hormones diffuse through interstitial fluid - PGF2α 4. Endocrine transmission - Hormones are transported through blood circulation. - Typical of most hormones 5. Exocrine transmission - Hormones are secreted to the exterior of the body. E.g - Somatostatin secreted into the lumen of GI tract (and inhibit intestinal motility and absorption) - Pheromones

8. Endocrine Functions • Maintain Internal Homeostasis • Support Cell Growth • Coordinate Development • Coordinate Reproduction • Facilitate Responses to External Stimuli

9. Elements of an endocrine system • Sender = Sending Cell (where hormone is produced) • Signal = Hormone • Nondestructive Medium = Serum & Hormone Binders • Selective Receiver = Receptor Protein (Target cells) • Transducer = Transducer Proteins & 2º Messengers • Amplifier = Transducer/Effector Enzymes • Effector = Effector Proteins • Response = Cellular Response

10. What are transducers? Transducers - proteins that convert the information in hormonal signals into chemical signals understood by cellular machinery. - They change their shape & activity when they interact directly with protein-hormone complexes. - Usually enzymes or nucleotide binding proteins, they produce 2nd messengers, or change the activity of other proteins by covalently modifying them (adding or removing phosphate, lipid groups, acetate, or methyl groups), or they interact with other proteins that do these things. - They begin amplifying the energy content of the original hormone signals.

11. Classes of hormone 1. Amine hormones (can b lipophilic/ hydrophilic) - thyroid hormones, catecholamines (aromatic amines) - all derived from single amino acids - thyroid hormones - from tyrosine (lipophilic) - catecholamines - from tyrosine - melatonin - from tryptophan

12. Classes of hormone 2. Peptide hormones - Peptides, polypeptides and proteins - Hydrophilic/Lipophobic - short half life - hormones of hypothalmus (releasing and inhibiting) - pituitary hormones - Insulin, glucagon

13. Classes of hormone 3. Steroid hormones - adrenocortical and reproductive hormones - derived from cholesterol - Hydrophobic/lipophilic - long half life - travel with a protein carrier - bind to cytoplasmic/nuclear receptor

14. Classes of hormone 4. Eicosanoids (Lipid hormones) - produced from 20 carbon fatty acids (arachidonic acid) - produced in all cells except RBCs - prostaglandin, leukotrienes (smooth m/s contraction in trachea), thromboxanes, prostacyclin

15. Hormone Interactions Responsiveness of a target cell to a hormone depends on: - The hormone concentration - The abundance of the target cell’s hormone receptors - influences exerted by other hormones 1. Permissive effect: when the action of a hormone on target cells requires a simultaneous or recent exposure to a second hormone. (not directly involved in the action) - e.g: Epinephrine – alone, weakly stimulates lipolysis but presence of a small amounts of thyroid hormones - the same amount of epinephrine stimulates lipolysis much more powerfully.

16. Hormone Interactions Synergistic effects when the effect of two hormones acting together is greater or more extensive than the sum of each hormone acting alone Antagonistic effects when one hormone opposes the activation of another hormone. E.g, Insulin promotes glycogen synthesis by the liver cells and glucagon stimulates glycogen breakdown

17. Enzyme amplification • One hormone molecule does not trigger • - the synthesis of just one enzyme molecule • It activates thousands of enzyme molecules through cascade called enzyme amplification • This enables a very small stimulus to produce a very large effect • Hormones are therefore needed in very small quantities • circulating concentration very low compared to other blood substances: on order of nanograms per deciliter of blood • Because of amplification target cells do not need a great number of hormone receptors

18. Hormone clearance • - Hormone signals, like nervous signals, must be turned off when they have served their purpose • - Most hormones are taken up and degraded by the liver and kidneys and then excreted in bile or urine • - Some are degraded by the target cells • Rate of hormone removal (metabolic clearance rate – MCR) • Halflife – the length of time required to clear 50% of the hormone from the blood • - the faster the MCR – the shorter half life

19. Hormone Half-life Amines 2-3 min Thyroid hormones: T4 T3 6.7 days 0.75 days Polypeptides 4-40 min Proteins 15-170 min Steroids 4-120 min Metabolic Clearance Rate or Half-life of some hormones

20. Modulation of target cell sensitivity • - Hormones affect only target cells • - cells that carry specific receptors that bind the recognized hormone • - Down regulation: when receptor quantity decrease • when hormone is in excess • - Decreases responsiveness to hormone • for example, in response to obesity when cells become less sensitive to insulin. • Up regulation: when receptor quantity increases when hormone is deficient • - Make target cell more sensitive to hormone • for example, in response to regular exercise when cells become more sensitive to insulin.

21. Hormone receptors(Cell surface receptor,membrane receptors, transmembrane receptors) • Cellular proteins that bind with high affinity to hormones & are altered in shape & function by binding. • exist in limited numbers. • - Binding to hormone is noncovalent & reversible. • - Hormone binding will alter binding to other cellular proteins & may activate any receptor protein enzyme actions.

22. Hormone & Receptor in General

23. Hormone receptors • - Specialized integral membrane proteins • Communication between the cell and the outside world. • Extracellular signalling molecules (usually hormones, neurotransmitters, cytokines, growth factors or cell recognition molecules) • Attach to the receptor, trigger changes in the function of the cell. • This process is called signal transduction: The binding initiates a chemical change on the intracellular side of the membrane. In this way the receptors play a unique and important role in cellular communications and signal transduction.

24. G Protein Any of a class of cell membrane proteins that function as intermediaries between hormone receptors and effector enzymes and enable the cell to regulate its metabolism in response to hormonal changes. 2 Types -- Stimulatory (GS) -- Inhibitory (GI)

25. Surface Hormone Receptors 4 types or 4 domains of Surface hormone receptors 1. Seven-transmembrane domain receptors - β adrenergic - Parathyroid hormones (PTH) - Luteinizing hormone (LH) - Thyroid-stimulating hormone (TSH) - Growth hormone-releasing hormone (GHRH) - Thyrotropin releasing hormone (TRH) - Adrenocorticotropic hormone (ACTH) - MSH (melanocyte-stimulating hormone)

26. Surface Hormone Receptors 2. Single transmembrane receptors - Insulin - Insulin like growth factor I (IGF I) - Epidermal growth factor (EGF) - Platelet derived growth factor (PDGF) 3. Cytokine receptor super family - GH, Prolactin, - Erythropoietin - Interleukin - Leptin Guanylcyclase –linked receptor - Natriuretic peptide

27. 1. A seven-transmembrane domain receptor 2. A single-ransmembrane domain receptor with kinase activity typical of many growth factors

28. 3. Receptors with no intrinsic tyrosine kinase activity but activation by soluble transducer molecules. 4. Receptors dependent on guanylylcyclase or adenylylcyclase and synthesis of cGMP and cAMP.

29. G protein-linked hormone mechanism Activation of receptor induced by binding of the hormone (1st messenger). Cytoplasmic tail of receptor activates G protein The activated G protein complex links to 2nd messenger which is responsible for the effect associated with hormone action

30. Second messenger systemscyclic AMP - Hormone travels in blood plasma - Hormone binds to its receptor in the plasma membrane GPCR (G-protein coupled receptor) - Hormone-receptor binding activates a G protein (in plasma membrane) - Activated G protein in turn activates the enzyme adenylcyclase - Adenylcyclase causes ATP to lose two P, becoming cAMP (cyclic AMP [adenosine monophosphate]) - cAMP activates protein kinases (enzymes that activate other proteins/enzymes), producing the hormonal effect

31. Hormone Class of hormone Location Amine (epinephrine) Water-soluble Cell surface Amine (thyroid hormone) Lipid soluble Intracellular Peptide/protein Water soluble Cell surface Steroids and Vitamin D Lipid Soluble Intracellular Hormones and their receptors by classifying water soluble and lipid soluble

33. Endocrine glands of animals

34. Hypothalamus and Pituitary gland (hypophysiscerebri)

36. Hypothalamic releasing hormone Effect on pituitary Corticotropin releasing hormone (CRH) Stimulates ACTH secretion Thyrotropin releasing hormone (TRH) Stimulates TSH and Prolactin secretion Growth hormone releasing hormone (GHRH) Stimulates GH secretion Somatostatin Inhibits GH (and other hormone) secretion Gonadotropin releasing hormone (GnRH) a.k.a LHRH Stimulates LH and FSH secretion Prolactin releasing hormone (PRH) Stimulates PRL secretion Prolactin inhibiting hormone (dopamine) Inhibits PRL secretion Hypothalamic releasing hormones

38. Putuitary gland = Master gland • Because pituitary gland produces many hormones –k/s master gland • Pituitary extracts – obtained from pituitary glands from slaughter houses • Laborious and low yields • - 340 g/100 cattle; 30 g/100 pigs • - Pituitary extracts are used for research or commercial purposes

39. Pituitary gland (hypophysiscerebri) • Anterior lobe (adenohypophysis) • Posterior lobe (neurohypophysis)

40. Location of the pituitary gland • Just below the hypothalmus • Provide direct delivery of releasing and inhibiting hormones from the hypothalmus to the anterior lobe • direct entry of secretory neurons from the hypothalmus to posterior lobe • Hypophyseal portal circulation • The venous blood drained from the hypothalmus is redistributed by another capillary system within the anterior lobe. Shortages of hormones in arterial blood are directed by specific cells within the hypothalmus, which are stimulated to secrete releasing hormones. The hormones produced are distributed by the second capillary bed to their appropriate cells in the anterior lobe.

41. Anterior Pituitary

42. Hormone Acronym Hypophysial Cell Type Hypothalamic Regulator(s) Hormonal Function(s) Corticotropin, Adrenocorticotropin ACTH Corticotrope +Corticotropin Releasing Hormone, Corticoliberin (CRH); + Interleukin 1 ; - Glucocortical Steroids (via CRH); + Vasopressin Stimulates glucocorticoid production by adrenal fasiculata & reticularis Thyrotropin, Thyroid Stimulating Hormone TSH Thyrotrope -Thyroxine (T4); +Thyroid Releasing Hormone, Thyroliberin (TRH); -Somatostatin (SS)  Stimulates thyroxine production by thyroid Prolactin, Mammotropin, Luteotropin PRL Lactotrope; Mammotrope -Dopamine; + TRH; - SS; + Estrogens; + Oxytocin Stimulates milk synthesis by secretory epithelium of breast; supports corpus luteum function Somatotropin, Growth Hormone GH Somatotrope + Growth Hormone Releasing Hormone, Somatoliberin (GHRH); - SS Stimulates somatic growth, supports intermediary metabolism Follitropin, Follicle Stimulating Hormone FSH Gonadotrope + Gonadotropin Releasing Hormone, Luteinizing Hormone Releasing Hormone, Gonadoliberin (GnRH, LHRH); - Inhibin; - Sex steroids (via LHRH)  Supports growth of ovarian follicles & estradiol production; Supports Sertoli cell function & spermatogenesis Lutropin, Luteinizing Hormone LH Gonadotrope + GnRH (LHRH); - Sex steroids (via LHRH); + Estradiol in near midcycle Supports late follicular development, ovulation, & corpus luteum function (especially progesterone synthesis); Supports testosterone synthesis, Leydig cell  Melanotropin, Melanocyte Stimulating Hormone MSH Melanotrope + CRH Supports dispersal & synthesis of pigment in melanocytes; may alter adrenal response to ACTH

43. STIMULUS Hypothalamus Releasing Hormone (Release-Inhibiting Hormone) Pituitary Stimulating Hormone Gland Hormone Target

45. Anterior Putuitary Hormones Regulated by: Releasing Hormones and Inhibiting hormones of hypothalmus

46. Cells of anterior pituitary and hormones 5 cell type; 7 hormones 1. Somatotrope cells (Growth hormone) 2. Corticotrope cells (adrenocorticotropic hormone and beta-lipotropin hormone) 3. Mammotrope cells (prolactin) 4. Thyrotrope cells (thyroid stimulating hormone) 5. Gonadotrope cells (Follicle stimulating hormone and luteinizing hormone) • Nature of anterior pituitary hormones • Polypeptides to large proteins • Different structures among species • - Replacement therapy from one spp to another not uniformly successful

47. Growth hormone (GH) • Somatotropic hormone (STH) • Stimulatory effect of increase in body size • Growth of all tissues of the body • Both cell numbers and cell size • Epiphyseal bone plates are more sensitive to GH • Increases mitotic activity • Stimulate the liver to form several small proteins, somatomedins (Insulin-like growth factors 1 and 2, IGF 1 and IGF2) • Somatomedins act on cartilage and bone growth. Therefore bone and cartilage are not stimulated directly by GH but indirectly by this intermediate compound.

48. GH • Several specific metabolic effects • because of this, GH is necessary throughout life • Metabolic effects • Increases • - rate of protein synthesis in all body cells • - mobilization of fatty acids from fat • - use of fatty acids for energy • Decreased rate of glucose uptake throughout the body • Use of fats for energy conserves glucose and promotes glycogen storage – the heart can endure emergency contraction more effectively whereby glycogen stored in the heart is converted to glucose.

49. GH • Milk production • Increasing milk yield in lactating cows by growth hormone is not stimulation on mammary gland but by partitioning of available nutrients from body tissues towards milk synthesis

50. Abnormal GH production Excessive production of GH Before puberty: – increase growth of long bones (prolonged proliferation of growth plate chondrocytes) After puberty – closure of epiphyseal plates - acromegaly - enlargement of extremities and facial bones Gigantism – frequently seen in human Failure to produce sufficient GH – stunted growth - dwarfism