Introduction to Endocrinology PDF

Introduction to Endocrinology Lecture Outline I. Coordination of body functions by chemical messengers II. Chemical structure and synthesis of hormones III. Hormone secretion, transport, and clearance from the blood IV. Mechanisms of actions of hormones V. Eicosanoids 1 Introduction to Endocrinology...

Introduction to Endocrinology Lecture Outline I. Coordination of body functions by chemical messengers II. Chemical structure and synthesis of hormones III. Hormone secretion, transport, and clearance from the blood IV. Mechanisms of actions of hormones V. Eicosanoids 1 Introduction to Endocrinology Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Identify similarities between the nervous and endocrine system Identify major endocrine glands and their hormones Compare the modes of intercellular communication Define terminology related to hormone signaling Compare the chemical structure and the implications of the three main classes of hormones Identify the classifications of endocrine disorders Compare down-regulation and up-regulation of hormone receptors List and briefly explain four types of hormone receptors and their activation Give examples of second messengers Explain eicosanoid production and the four major groups of eicosanoids including major actions Describe the inhibition of biosynthesis of eicosanoids 2 References Assigned reading from your text: Hall Chapter 75 3 I. Coordination of Body Functions by Chemical Messengers 4 Introduction to Endocrinology ❑ Endocrine glands regulate various body metabolic functions through secretion of hormones Almost every organ secretes hormones Endocrine cells may be dispersed throughout the body Chemical messengers maintain homeostasis Hormone- derived from Greek horman- “to set in motion” Diseases often due to excess or deficiency of hormones Other diseases may have endocrine components (cancers, atherosclerosis) 5 Comparison to the Nervous System ❑ Differences Nervous system uses electrical impulses; endocrine system uses hormones Transmission in the endocrine system tends to be slower with longer lasting responses Targets can be far away ❑ Similarities in the organization of the endocrine and nervous system Relies on the release of chemicals that bind to specific receptors on target cells Hormones affect target cells by binding to receptors in PM or within cells Both are regulated primarily by negative feedback Share chemical messengers; epi and NE are hormones in the blood and NTs at synapses Both share the common goal of homeostasis by coordinating activities of cells, tissues, organs, and systems (all levels of organization) 6 The Endocrine System ❑ Major endocrine glands and tissues Hypothalamus- releasing and inhibiting hormones Pineal gland - melatonin Anterior pituitary- tropic hormones (target other glands) Posterior pituitary – oxytocin, ADH Thyroid gland- thyroxine, triiodothyronine, calcitonin Parathyroid glands - parathyroid hormone Thymus gland- thymosin Heart- atrial natriuretic peptide Digestive tract- gastrin, secretin, cholecystokinin Liver- insulin-like growth factors Adrenal glands- steroid hormones and catecholamines Pancreatic islets- insulin, glucagon, somatostatin Kidneys- erythropoietin, calcitriol, renin Adipose tissue- leptin Ovaries- estrogen, progestin, relaxin Testes- testosterone White cells and some connective tissue cells- various cytokines Placenta- human chorionic gonadotropin 7 Modes of Intercellular Communication Ganong FIGURE 2–20 Intercellular communication by chemical mediators. A, autocrine; P, paracrine. Netter’s Anatomy Coloring Book: Overview of hormone cell-to-cell communication 8 Definitions of Hormone Signaling ❑ Synaptic transmission- across synapses Neurotransmitters are released by axon terminals of neurons into synaptic junctions to control nerve cell function ❑ Endocrine transmission- through the bloodstream ❑ Endocrine hormones are released by glands/cells into blood to target cells elsewhere eg insulin Neuroendocrine hormones are secreted by a nerve axon into blood eg ADH, oxytocin, and hypothalamus releasing hormones, ECL cells of gut Local hormones Paracrine- Hormone diffuses locally (ISF) to act on a different cell type eg acetylcholine, gastrin Autocrine- Cell regulates itself eg cytokines interleukin and leptin ❑ Cytokines are peptides secreted by cells into ECF to function as autocrine/paracrine/endocrine eg interleukins and adipokines (leptin) 9 II. Chemical Structure and Synthesis of Hormones 10 Classification of Hormones According to Chemical Structure ❑ Hormones are chemically diverse- Three main classifications Peptides and polypeptides- largest group of hormones Peptides contain (8-10 amino acids) in their molecular structure (ADH and oxytocin) Polypeptides (11-99 amino acids) Proteins (insulin) and glycoproteins (GH, FSH)- typically > 100 AAs Amino Acid derivatives- a small group of hormones Thyroid hormones- produced by thyroid AA with 3 or 4 iodine atoms - T3 (triiodothyronine) or T4 (thyroxine or tetraiodothyronine) Catecholamines- Epi, NE, and dopamine Trytophan- melatonin is a derivative of trytophan Lipid derivative- carbon rings with side chains of cholesterol (steroids) or FA (eicosanoids) Steroid hormones are synthesized from cholesterol Released by reproductive organs, adrenal cortex, and kidneys Eicosanoids are paracrine factors that regulate ECF activities - synthesized from fatty acids Leukotrienes are eicosanoids that have secondary roles as hormones Prostaglandins are eicosanoids involved in coordinating local cellular activities 11 Synthesis of Hormones ❑ Synthesis of three main classifications: Peptides & Polypeptides Synthesized in the rough ER Usually synthesized as prohormones- inactive Stored in intracellular vesicles until stimulation → active secretion by exocytosis Generally water soluble Amines – catecholamines- epinephrine and norepinephrine derived from tyrosine Usual stimulus for exocytosis is calcium Formed by actions of enzymes in cytoplasmic compartment of glandular cells Thyroid hormones are synthesized and stored in thyroid gland until secretion Poorly water soluble and are bound to different proteins in thyroid gland and blood Catecholamines are formed in secretory granules and released by exocytosis Water-soluble hormones that do not require carrier proteins Steroids: Mineralcorticoids (aldosterone), glucocorticoids (cortisol), and sex hormones (testosterone) are: Not stored in vesicles; once synthesized diffuse out of the cell due to lipid solubility. Generally require carrier proteins in blood due to low water solubility eg corticosteroid binding hormone and albumin Mechanism of action is predominantly altered gene expression Slow onset with sustained response 12 III. Hormone Secretion, Transport, and Clearance from the Blood 13 General Mechanisms of Action- Secretion ❑ Secretion varies by: Stimulus Duration of action- Seconds for catecholamines; months for thyroxine or GH Concentrations required to produce a response- usually small ❑ Hormone secretion is controlled by feedback mechanisms Simple negative feedback- A hormone or response inhibits further secretion of that hormone Complex negative feedback→ Hormone secretion from a primary target gland is controlled by hormones that are controlled by other factors Positive feedback causes surges of hormones ❑ eg anterior pituitary hormones are controlled by hypothalamic factors Occurs when biological action of the hormone causes additional secretion of the hormone Rhythmic patterns of secretion- cyclic (circadian) & pulsatile A single blood sample less useful than stimulation tests 14 Negative Feedback Control ❑ Prevents overactivity of hormone systems Simple negative feedback The hormone- or response to the hormoneinhibits further secretion of that hormone Complex negative feedback (hierarchical) Hormone secretion from a primary target gland is controlled by the anterior pituitary hormones which are controlled by hypothalamic factors Negative feedback operates at the level of the primary gland, anterior pituitary, or hypothalamus Medical Physiology FIGURE 8-2 Negative feedback control secretion. A. Simple negative feedback in which a hormone, or a response to ahormone, inhibits further hormone secretion. Complex (hierarchical) negative feedback in which a hormone secreted from a primary taret gland exerts negative feedback on the hypothalamus and pituitary gland. Endocrine Disorders Classifications ❑ Endocrine disorders classified as: Primary if the disorder is at the target gland Secondary if the disorder is by the pituitary gland Tertiary if the disorder is by the hypothalamus FIGURE 16–3 Summary of feedback loops regulating endocrine axes. CNS, central nervous system. (Reproduced with permission from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010.) 16 General Mechanisms of Action- Clearance ❑ Magnitude of a response to a hormone depends on: How many receptors are occupied at target cell Which depends on free hormone concentration in the ECF ❑ Plasma free hormone concentration is is increased or decreased by: Rate of hormone secretion into the blood Rate of removal of hormone from the blood Rate of hormone binding to plasma proteins ❑ AKA- the metabolic clearance rate (eg spider nevus w/ alcoholic liver failure) Most peptide hormones and catecholamines are water soluble and are degraded by enzymes in the blood and quickly excreted by liver and kidneys Protein bound are cleared at slower rates Hormones are removed from plasma in multiple ways: Metabolic/enzymatic destruction by tissues Binding with tissues Excretion by the liver into the bile Excretion by the kidneys into the urine Ganong FIGURE 16–2 Summary of factors that determine the level of free hormones circulating in the bloodstream. Factors that increase (green upward arrow) or decrease (red downward arrow) hormone levels are shown. Free hormones also equilibrate with the forms bound to either receptors or plasma carrier proteins. 17 IV. Mechanisms of Actions of Hormones 18 Hormone Receptors ❑ A response to a particular hormone is seen only in cells with specific receptors for that hormone ❑ Hormones affect target cells after binding to receptors on or in the cell: 1. In the plasma membrane Receptors for catecholamines, peptide hormones, and eicosanoids are in the PM of their target cells Binding does not produce a direct effect on its intracellular activities Hormone binding gives rise to a 2nd messenger which acts as an enzyme activator, inhibitor, or cofactor to change the rate of metabolic reactions Two most important 2nd messengers are cAMP and Ca++ The hormone, the first messenger, uses an intracellular 2nd messenger to exert the hormone’s effects in the cells 2. In the cell cytoplasm or nucleus Steroid hormones diffuse across the PM and bind to receptors in the cytoplasm or nucleus The hormone-receptor complex then alters the activity of specific genes Steroid hormones alter the rate of DNA transcription in the nucleus – changing pattern of protein synthesis Directly affects target cells metabolic activity or structure 3. In the cell nucleus Thyroid hormones are transported across the PM where they bind to receptors on mitochondria and within the nucleus Bound hormones increase the rate of ATP synthesis in the mitochondria 19 Number and Sensitivity of Hormone Receptors ❑ Hormone receptors are regulated and the number of receptors of target cell varies Number of receptors determines the sensitivity of a target cell to a hormone ❑ Down-regulation decreases the number of receptors Increased hormone concentration and increased binding with its target cell receptors causes the number of active receptors to decrease Down-regulation decreases target tissue’s responsiveness to the hormone Down-regulation of receptors occurs as a result of: Inactivation of some receptor molecules Inactivation of some of the intracellular protein signaling molecules Temporary sequestration of receptor away from sites of interaction Destruction of receptors by lysosomes after internalized Decreased production of the receptors ❑ Up-regulation increases the number of receptors Makes the target tissue progressively more sensitive to the stimulating effect of the hormone Stimulating hormone induces greater than normal formation of receptor or intracellular signaling molecules by the target cell or greater availability of the receptor for interaction Intracellular Signaling after Hormone Receptor Activation ❑ Hormones affect cellular reactions by combining with the following receptors types: Ion channel-linked receptors Only a few hormones Most NTs (including Ach and NE) combine with receptors in the postsynaptic membrane Usually causes opening or closing of a channel for K+, Ca++, etc G Protein-linked hormone receptors Many hormones activate receptors using 2nd messengers The link between the first and 2nd messenger involves a G protein The G-protein is an enzyme complex coupled to a membrane receptor Enzyme-linked hormone receptors Binding of hormone on the extracellular portion of receptor produces an immediate intracellular response Intracellular hormone receptors Lipid soluble, readily cross PM and interact with receptors in cytoplasm or nucleus Hormone-receptor complex binds a promoter sequence of DNA and activates or represses transcription mRNA 21 Receptor Types- G Protein-Linked Hormone Receptor ❑ Most hormones that open or close channels do so by coupling with G-proteins Heterotrimeric guanosine triphosphate (GTP) binding proteins or “G-proteins” The cytoplasmic tail is intracellular- coupled to ⍺,β, and 𝛄 G-protein subunits Can bind guanosine nucleotides – GDP (inactive state) and GTP (active state) G protein alters activity of channels or enzymes such as adenylyl cyclase or phospholipase C A hormone can increase (Gs) or decrease (Gi) intracellular enzyme activity Receptor activation has three effects: Open or close ion channels in the cell membrane Change the activity of an enzyme in the cytoplasm of the cell Activate gene transcription 22 Receptor Types- Enzyme-Linked Hormone Receptor ❑ Enzyme-linked receptors act as or with enzymes when activated Single pass protein Hormone receptor binding site on outside; catalytic binding site on inside Directly initiate cascades of phosphorylation reactions within the cell when occupied by their hormone ❑ Many hormones use receptor tyrosine kinase signaling – Insulin (top image) – Leptin (bottom image) – Growth hormone 23 Receptor Types- Intracellular Hormone Receptor ❑ Several lipid soluble hormones bind with protein receptors inside the cell Includes steroid hormones, thyroid hormones, Vitamin D Hormone-receptor complex alters the activity of specific genes Alters rate of DN transcription and pattern of protein synthesis 24 Proteins Kinases ❑ Second messengers commonly use kinases to change cellular activity Kinases (enzymes) phosphorylate target proteins Are highly variable; action is dependent on cell type where found Examples of actions: Cause structural alterations of cellular components Cytoskeleton and cell junctions Affect cellular permeability by stimulating the creation and/or opening of ion channels (Na+, K+, Ca++) and aquaporins 25 Examples of 2nd Messengers Examples of 2nd messengers: cAMP- Cyclic adenosine monophosphate DAG and IP3 Produced by membrane-bound enzyme phospholipase C Phospholipase C activated via the G protein Gaq- cleaves membrane lipid PIP2 to generate DAG and IP3 In the presence of Ca++, DAG activates protein kinase C to change cellular behavior IP3 causes Ca++ release from ER Ca++ stores and the intracellular Ca++ alters cellular protein activity Receptor tyrosine kinases Formed from ATP by membrane-bound adenylyl cyclase When cAMP is produced inside a cell it activates protein kinase A (which affects cellular activity) cAMP signal is terminated when cAMP is broken down by PDE3 enzyme Initiates cascades of phosphorylation reactions within the cell when occupied by their hormone Cytoplasmic tyrosine kinases (JAK) are activated when a hormone binds to tyrosine kinase associated receptors cGMP is generate from GTP via the enzyme guanylyl cyclase Soluble guanylyl cyclase exists in cytoplasm and can be activated by NO PDE type V breaks down cGMP in pulmonary vascular smooth and erectile tissue PDE V inhibitor prolongs action of cGMP- pulmonary vasodilation and erection 26 2nd Messenger Mechanisms – Adenylyl Cyclase-cAMP ❑ cAMP is used by many hormones to produce their intracellular effects Inactive trimeric subunit binds GDP on the ⍺ subunit Changing the concentration of cAMP- a 2nd messenger- exerts intracellular effects Signaling terminated when the hormone is removed and a subunit inactivates itself by converting bound GTP to GDP 27 Phospholipase C System ❑ G protein (Gq) activated by a receptor that has bound a first messenger (hormone) activates a plasma membrane effector enzyme- Phospholipase C Phospholipase C catalyzes the breakdown of plasma membrane phospholipid PIP2 to DAG and IP3 – 2nd messengers are DAG and IP3 Stimulus: hormonal(usually), chemical, or physical ❑ Diacylglycerol (DAG) DAG activates protein kinase C when then phosphorylate a large number of other proteins to produce a cellular response Lipid portion of DAG is arachidonic acid Arachidonic acid – fatty acid of PM – Produces eicosanoids ❑ Inositol triphosphate (IP3) Does not activate a protein kinase- instead binds to Ca++ channels of ER and opens them Calcium has many 2nd messenger effects- including activating forms of protein kinase C (for Calcium) 28 V. Eicosanoids 29 Eicosanoids ❑ Eicosanoids are a group of lipid 2nd messengers derived from arachidonic acid – Group includes prostaglandins, prostacyclins, thromboxanes, and leukotrienes – Differ from other 2nd messengers since eicosanoids are hormones – Arachidonic acid is produced from membrane lipids (DAG) when the enzyme phospholipase A2 is activated via Gaq or Ga11. – Different eicosanoids produced with different enzymes in target cell Cyclooxygenase Lipoxygenase 30 Local hormones: Eicosanoids are Derivatives of Arachidonic Acid ❑ Eicosanoids produce the 4 signs of inflammation Warmth, pain, swelling, and redness Function is to promote inflammation, immune response, control platelet aggregation, etc 4 major groups of eicosanoids involved in signaling are: Prostaglandins (PGs) Prostacyclins (PGIs) Thromboxanes (TXs) And leukotrienes (LTs)- biologically active compounds from leukocytes Have short half-lives 39 Prostaglandins (Autocrine and Paracrine Hormones) ❑ PGs are eicosanoids whose major functions include: Regulation of inflammation Smooth muscle contraction (blood vessels, GI, bronchial, uterine) Neurological pain Platelet function Hormone activity and cell growth ❑ PGH2 is the precursor for other PGs, thromboxanes and prostacyclin PGIs decrease platelet function (clot formation) and dilate blood vessels TXs act as vasoconstrictors to promote platelet aggregation and blood clot formation Oppose PGIs LTs (other pathway) seen in inflammation of lung- asthma and bronchitis 15 Biosynthesis and Classification of Prostaglandins ❑ Arachidonic acid proceeds through various steps to produce PGH2 Synthesis to PGH2 is tissue non-specific because most cells the body possess a cyclooxygenase system PGH2 has a short half-life PGH2 is metabolized by different enzyme pathways into three major groups (PGD, PGE and PGF) These synthetic pathways are tissue-specific thus different cell-types can synthesize different prostaglandins PGE group is the most common of the prostaglandins PGE is also is the group with the most physiological effects Eicosanoid Synthesis 34 Biosynthesis Inhibitors ❑ Adrenal corticosteroids (cortisol) are anti-inflammatory agents They inhibit phospholipase A2 - Inhibit the formation of arachidonic acid and eicosanoids ❑ Aspirin and other NSAIDS inhibits formation of PGH2 and its derivatives eg Ibuprofen, indomethacin inhibit COX-1 and COX- 2 These anti-inflammatory agents (aspirin et. Al) are used to Treat fever, pain and inflammation Inhibitory to blood clotting ❑ Active COX-1 is essential for the maintenance of gastrointestinal epithelium integrity Specific COX-2 inhibitors are NSAIDS that prevent formation of ulcers (Celebrex) 22 Pathological Conditions That Cause Changes In Release Of Prostaglandins ❑ Fever Cells of the immune system react to infectious agents Immune system cells produce cytokines that cross the blood-brain barrier Cytokines target endothelial cells of capillaries located in the organum vasculosum laminae terminalis (OVLT); located in the wall of the 3rd ventricle close to the hypothalamus Region is referred to as the “human thermostat” Endothelial cells in the OVLT synthesize and release PGE2 That migrates to the hypothalamus and resets the temperature Control center to a higher set point ❑ Damaged tissues cause pain Produce and release PGE2 that directly stimulates nociceptors ❑ Asthma: PGD2 and PGF2 cause bronchoconstriction 30 Leukotrienes Are Mediators Of Allergic Responses And Inflammation ❑ Their release is provoked when specific allergens combine with IgE antibodies on mast cells They produce bronchoconstriction, vasoconstriction of arterioles, increase vascular permeability, and attract neutrophils and eosinophils to inflammatory sites They are involved in psoriasis, asthma, acute respiratory distress syndrome, allergic rhinitis, rheumatoid arthritis, Crohn disease, and ulcerative colitis LTB4 is the most potent chemotactic agent known Many others are known as slow-reacting substances of anaphylaxis (LTC4, LTD4, LTE4 and LTF4) During anaphylaxis these lts are released in abundance Application of glucocorticoids inhibit phospholipase a2 activity preventing their production 42 1. Analogues of guanosine triphosphate (GTP) can activate G proteins in isolated cells. Which of the following signaling molecules would NOT be produced in response to GTP (which of the following do not couple to G proteins)? A. Arachidonic acid B. cAMP C. DAG D. IP3 E. Tyrosine kinase 2. Some cells secrete chemicals into the ECF that act on cells in the same tissue. Which of the following refers to this type of regulation? A. Neural B. Endocrine C. Neuroendocrine D. Paracrine E. Autocrine 3. Hormones maintain: A. Fluid balance B. Inflammation C. Cells D. Homeostasis 4. Which of the following will not bind to cell surface receptors based on their composition? A. Amines B. Peptides C. Proteins D. Steroids 5. Corticosteroids inhibit the formation of which inflammatory mediator? A. Cyclooxygenase B. Lipoxygenase C. PGH2 D. Arachidonic acid 38