LECTURE 1 INTRODUCTION TO ENDOCRINE PHYSIOLOGY.pptx

describes the overview of the physiology of endocrine glands and how they influence body functions and cell activity

1. The Endocrine Physiology Introduction to Endocrinology Dr. Lubwama Conrad

2. Objectives Identify the chemical nature of the major hormones. Describe how the chemical nature influences hormone synthesis, storage, secretion, transport, clearance, mechanism of action, and appropriate route of exogenous hormone administration. Explain the significance of hormone binding to plasma proteins. Describe the major signal transduction pathways, and their mechanism for termination, for different classes of hormones and provide a specific example of each

3. Endocrine System: Overview Endocrinology : It is study of homeostatic functions of substances called HORMONES, that are released from glands called endocrine glands distributed throughout the body. Hormones: A re secretions of ductless glands that are directly released into the blood stream. They can act on cells in the vicinity or on distant target cells. Endocrine system – the body’s second great controlling system which influences metabolic activities of cells by means of hormones

4. Endocrine System: Overview Endocrine glands – pituitary, thyroid, parathyroid, adrenal, pineal, and thymus The pancreas and gonads produce both hormones and exocrine products The hypothalamus has both neural functions and releases hormones Other tissues and organs that produce hormones - adipose cells, pockets of cells in the walls of the small intestine, stomach, kidneys, and heart

5. The Endocrine System

6. Hormones and Their Sites of Production

7. Autocrines and Paracrines Autocrines – chemicals that exert their effects on the same cells that secrete them Paracrines – locally acting chemicals that affect cells other than those that secrete them These are not considered hormones since hormones are long-distance chemical signals

8. Chemical nature of Hormones Proteins/ peptides, – most hormones belong to this class, including: Amines (Tyrosine: Catecholamines and Thyroid hormones, Tryptophan: Melatonin) Polypeptide hormones protein hormones Steroids – Derived from Cholesterol, gonadal and adrenocortical hormones Fatty acid derived : Eicosanoids, derived from arachidonic leukotrienes and prostaglandins Catecholamines: A drenal medulla and neurons e.g., norepinephrine, epinephrine, and dopamine Thyroid hormones/ Iodothyronines

9. Chemical nature of a hormones The chemical nature of a hormone determines the following: How it is synthesized, stored, and released How it is carried in the blood Its biologic half-life (t1/2) and mode of clearance Its cellular mechanism of action

10. A Structural Classification of Hormones

11. Proteins/Peptides Synthesized as prehormones or preprohormones Stored in membrane-bound secretory vesicles (sometimes called secretory granules) Regulated at the level of secretion (regulated exocytosis) and synthesis Often circulate in blood unbound thus short t1/2 (except IGFs and GH ) Hydrophilic and signal through transmembrane receptors

12. Proteins/Peptides - Clinical Many protein hormones are small enough to appear in the urine in a physiologically active form FSH, LH and hCG Pregnancy tests using human urine are based on the presence of the placental LH-like hormone , human chorionic gonadotropin (hCG) They must be administered by injection or, in the case of small peptides, through a mucous membrane (sublingually or intranasally).

13. Prehormone and preprohormone processing

14. Catecholamines Derived from enzymatic modification of tyrosine Stored in membrane-bound secretory vesicles Regulated at the level of secretion (regulated exocytosis) and through the regulation of the enzymatic pathway required for their synthesis Transported in blood free or only loosely associated with proteins Often administered as an aerosol puff for opening bronchioles, and several specific analogs (agonists and antagonists) can be taken orally Hydrophilic and signal through transmembrane G-protein-coupled receptors called adrenergic receptors

15. Structure of the catecholamines

16. Steroid Hormones Derived from enzymatic modification of cholesterol Cannot be stored in secretory vesicles because of lipophilic nature Regulated at the level of the enzymatic pathway required for their synthesis Transported in the blood bound to transport proteins (binding globulins) Signal through intracellular receptors (nuclear hormone receptor family) Can be administered orally

17. Steroid hormones

18. Cholesterol and steroid hormone derivatives

19. Thyroid Hormones Derived from the iodination of thyronines Lipophilic, but stored in thyroid follicle by covalent attachment to thyroglobulin Regulated at the level of synthesis, iodination, and secretion Transported in blood tightly bound to proteins Signal through intracellular receptors (nuclear hormone receptor family) Can be administered orally

20. Structure of thyroid hormones, iodinated thyronines

21. Correlation of Plasma Half-Life & Metabolic Clearance of Hormones with Degree of Protein Binding Hormone Protein binding (%) Plasma half-life Metabolic clearance (ml/minute ) Thyroid Thyroxine Triiodothyronine Steroids Cortisol Testosterone Aldosterone Proteins Thyrotropin Insulin Antidiuretic hormone 99.97 99.7 94 89 15 little little little 6 days 1 day 100 min 85 min 25 min 50 min 8 min 8 min 0.7 18 140 860 1100 50 800 600 MCR = (mg/minute removed)/(mg/ml of plasma) = ml cleared/minute

22. Circulating Transport Proteins Specific Corticosteroid binding globulin (CBG, transcortin ) Thyroxine binding globulin (TBG) Sex hormone-binding globulin (SHBG) Nonspecific Albumin Transthyretin (prealbumin) Principle Hormone Transported Cortisol, aldosterone Thyroxine, triiodothyronine Testosterone, estrogen Most steroids, thyroxine, triiodothyronine Thyroxine, some steroids Transport Protein

23. Determinants of Free Hormone Receptor Binding Carrier-bound hormone Endocrine cell Free Hormone Hormone receptor Hormone degradation Biological effects

24. Hormone Action Hormones alter target cell activity by one of the following mechanisms: Ion Channel–Linked Receptors. G Protein–Linked Hormone Receptors. Enzyme-Linked Hormone Receptors. Intracellular Hormone Receptors and Activation of Genes (steroid and thyroid hormones)

25. Hormones circulate to all tissues but only activate cells referred to as target cells Target cells must have specific receptors to which the hormone binds Hormone Action

26. Location of receptors: 1. In or on the surface of the cell membrane. The membrane receptors are specific mostly for the protein, peptide, and catecholamine hormones. 2. In the cell cytoplasm. The primary receptors for the different steroid hormones are found mainly in the cytoplasm. 3. In the cell nucleus. The receptors for the thyroid hormones are found in the nucleus and are believed to be located in direct association with one or more of the chromosomes.

27. Hormone (first messenger) binds to its receptor, which then binds to a G protein The G protein is then activated as it binds GTP, displacing GDP Activated G protein activates the effector enzyme adenylate cyclase Adenylate cyclase generates cAMP (second messenger) from ATP cAMP activates protein kinases, which then cause cellular effects Cyclic Adenosine Monophosphate (cAMP) Second Messenger Mechanism

28. Cyclic Adenosine Monophosphate (cAMP) Second Messenger Mechanism

29. Hormone binds to the receptor and activates G protein G protein binds and activates a phospholipase enzyme Phospholipase splits the phospholipid PIP 2 into diacylglycerol (DAG) and IP 3 (both act as second messengers) DAG activates protein kinases; IP 3 triggers release of Ca 2+ stores Ca 2+ (third messenger) alters cellular responses Cell Membrane Phospholipid: Second Messenger System

30. Cell Membrane Phospholipid: Second Messenger System

31. Cytokine Receptors & Tyrosine Kinase Receptors

32. The Insulin Receptor & Mechanisms of Insulin Action

33. Protein Hormones - Mechanisms of Action Adenylyl Cyclase Mechanism Guanylate Cyclase Mechanism Tyrosine Kinase/Cytokine Receptor Mechanism Phospholipid Mechanism ACTH LH FSH TSH GHRH Somatostatin ADH (V 2 receptor) HCG MSH CRH Calcitonin PTH Glucagon GnRH TRH PTH Angiotensin II ADH (V 1 receptor) Oxytocin ANP Insulin IGF-1 GH Prolactin

34. Steroid hormones and thyroid hormone diffuse easily into their target cells Once inside, they bind and activate a specific intracellular receptor The hormone-receptor complex travels to the nucleus and binds a DNA-associated receptor protein This interaction prompts DNA transcription to produce mRNA The mRNA is translated into proteins, which bring about a cellular effect Steroid and Thyroid Hormones

35. Steroid & Thyroid Hormones - Mechanism of Action

36. Target cell activation depends on three factors Blood levels of the hormone Relative number of receptors on the target cell The affinity of those receptors for the hormone Up-regulation – target cells form more receptors in response to the hormone Down-regulation – target cells lose receptors in response to the hormone Target Cell Activation

37. Hormones circulate in the blood in two forms – free or bound Steroids and thyroid hormone are attached to plasma proteins Hormone Concentrations in the Blood

38. Concentrations of circulating hormone reflect: Rate of release Speed of inactivation and removal from the body Hormones are removed from the blood by: Degrading enzymes The kidneys Liver enzyme systems Hormone Concentrations in the Blood

39. Three types of hormone interaction Permissiveness – one hormone cannot exert its effects without another hormone being present Synergism – the total effect of two hormones together is greater than the sum of their individual effects Antagonism – one or more hormones opposes the action of another hormone Interaction of Hormones at Target Cells

40. PLASMA GH ( m G/L) CLOCK TIME PLASMA CORTISOL (nmol/L) Hormonal Rhythms 4 8 12 8 12 16 20 4 8 100 200 300 400 500 8 12 16 20 4 8

41. Blood levels of hormones: Are controlled by negative and positive feedback systems Vary only within a narrow desirable range Hormones are synthesized and released in response to humoral, neural, and hormonal stimuli Control of Hormone Release

42. Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion Positive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation Feedback Control

43. Feedback Mechanisms Endocrine cell Target cell _ + Biological effects Endocrine cell Target cell + + Biological effects Negative Feedback Positive Feedback

44. Negative feedback

45. Measurement of Hormone Concentrations Radioimmunoassay (RIA) Enzyme-Linked Immunosorbentm Assay (ELISA)