Endocrine System Module PDF

1) The Endocrine System Introduction Hormone synthesis: Peptide hormone synthesis controlled by modulating transcription Amine and steroid hormones controlled by regulating enzymes and substrate availability Precursors to hormones are typically inactive...

1) The Endocrine System Introduction Hormone synthesis: Peptide hormone synthesis controlled by modulating transcription Amine and steroid hormones controlled by regulating enzymes and substrate availability Precursors to hormones are typically inactive Most hormones created as a larger polypeptide, requires conversion to final hormone molecule by an enzyme  1) The Endocrine System Introduction Hormone secretion Some hormone secretion controlled by a process of exocytosis Triggered when the cell receives a specific signal Other hormones continuously secreted via diffusion Rate of diffusion changed by modification of enzymes or proteins involved in its production Some hormones secreted in a pulsatile manner Large concentration of hormones causes a different effect than constant low levels  1) The Endocrine System Introduction Hormone transport in the blood Much reach target site in free-form to exert effect Depends on: 1) Affinity of hormone for plasma protein carriers 2) Hormone degradation 3) Availability of receptors 4) Receptor binding 5) Hormone uptake  1) The Endocrine System Introduction Hormone transport in the blood 1) Affinity of hormone for plasma protein carriers Binding to a protein has a number of functions: Protects hormone from degradation or uptake Allows for fine control over circulating levels Prevents hormone from binding to unintended sites Allows transport of lipid soluble hormones Plasma protein carriers themselves are regulated  1) The Endocrine System Introduction Hormone transport in the blood 2) Hormone degradation All hormones have a half-life, and will eventually degrade 3) Availability of receptors – influenced by: Down-regulation Up-regulation 4) Receptor binding Hormone must be able to bind to the target cell’s receptor 5) Hormone uptake  1) The Endocrine System Introduction Hormone action Main goal of hormones is to maintain homeostasis Key hormones: thyroid, cortisol, parathyroid, vasopressin, mineralocorticoids, insulin Achieved by regulating: Extracellular fluid Metabolism Biological clock Contraction of cardiac and smooth muscle Glandular secretion Some immune function Growth and development Reproduction  1) The Endocrine System Introduction Hormone action When a hormone binds to cell surface or cell nuclei, the cell may: Synthesize new molecules Change permeability of the membrane Alter rate of reactions Examples: Insulin binding to liver cells causes … Thyroid hormone binding to cardiac cells causing …  1) The Endocrine System Introduction Hormone action A hormone’s action can be… Permissive Binding to a target cell allows a different hormone to have its full effect Synergistic Two hormones act together to achieve a greater effect Antagonistic Two hormones produce an opposite effect  1) The Endocrine System Introduction Hormone feedback control Feedback loops allow for fine control of hormone levels Controlled by the nervous system, chemical changes in blood, or other hormones Negative feedback High levels of hormone → signal to reduce secretion / production of itself Low levels of hormone → signal to increase secretion / production Positive feedback Action of the hormone causes more of the hormone to be released  1) The Endocrine System Anatomy Pineal gland Located in the epithalamus Produces melatonin Binds to melatonin receptors causing anti-excitatory effects Levels peak at 1-2 years of age, remain stable until puberty, then declines Regulates sleep patterns (circadian and seasonal) High levels during childhood inhibits puberty Release stimulated by darkness; inhibited by light Often used as a supplement to help with sleep; does it work?  1) The Endocrine System Anatomy Hypothalamus Major integrating link between nervous and endocrine system Receives input from the cortex, thalamus, limbic system and other organs Communicates with the pituitary gland to control homeostasis, using: Growth hormone-releasing (+) and inhibiting (-) hormone Somatostatin (-) Dopamine (-) Corticotropin-releasing hormone (+) Thyrotropin-releasing hormone (+) Gonadotropin-releasing hormone (+) Oxytocin (+) Vasopressin (+) Hypothalamic hormones mostly inhibited by production of target hormones Regulates almost all aspects of growth, development, metabolism and homeostasis  1) The Endocrine System Anatomy Pituitary gland (anterior) Controlling hormones sent from hypothalamus cause secretion of various hormones Growth hormone-releasing hormone → Human growth hormone Thyrotropin-releasing hormone → Thyroid stimulating hormone Gonadotropin-releasing hormone → Follicle stimulating and luteinizing hormone Corticotropin-releasing hormone → Adrenocorticotrophic hormone Dopamine → prolactin Somatostatin → human growth hormone and thyroid stimulating hormone Secretion inhibited by production of target hormones  1) The Endocrine System Anatomy Pituitary gland (anterior) Human growth hormone The most plentiful anterior pituitary hormone Promotes synthesis of a protein insulin-like growth factor (IGFs) Various stimuli promote and inhibit hGH production Binds mostly to liver, skeletal muscle, cartilage and bone Increases cell growth and ATP use Pulsatile secretion peaks during puberty, declines after What is the consequence of excess human growth hormone? How would this be treated? What about HGH deficiency?  1) The Endocrine System Anatomy Thyroid gland Butterfly-shaped endocrine gland in the front of the neck LINK Responsible for synthesis, storage and release of the two thyroid hormones, T3 and T4 Hormones produce many physiological effects  1) The Endocrine System Anatomy Thyroid gland 1. Colloid 2. Follicular cells 3. Parafollicular cells LINK  1) The Endocrine System Anatomy Thyroid gland Synthesis and secretion of T3 and T4 controlled by thyroid stimulating hormone (TSH), which is controlled by thyrotropin-releasing hormone Creation of T3 and T4 requires iodide, thyroglobulin and tyrosine 1) Iodide binds with tyrosine attached to thyroglobulin = mono or di-iodotyrosine (MIT or DIT) 2) MIT + DIT = T3 or DIT + DIT = T4 3) Then secreted into circulation Why would the thyroid produce two different thyroid hormones?  Involves: 1) Thyroglobulin synthesis 2) Iodide trapping 3) Oxidation of iodide 4) Iodination of tyrosine 5) Coupling of MIT and DIT 6) Secretion of hormones  1) The Endocrine System Anatomy Thyroid gland Actions of T3 and T4 Heart – chronotropic and inotropic Adipose tissue – catabolic Muscle – catabolic Bone – developmental Nervous system – developmental Gut – metabolic Other tissues - calorigenic 1) The Endocrine System Anatomy Thyroid gland Control of T3 and T4 secretion A negative feedback loop Low blood levels stimulate hypothalamus which then stimulates the pituitary gland Lithium and iodide levels also influence Most T3 and T4 exists in protein-bound form  1) The Endocrine System Anatomy Parathyroid gland Located on the posterior surfaces of the lateral lobes of the thyroid LINK Produces parathyroid hormone (PTH) to regulate calcium and phosphate Increases blood calcium by: Stimulating number and activity of osteoclasts Increasing calcium and magnesium reabsorption from urine Increasing synthesis of calcitriol, which increases calcium and magnesium absorption from GI Decreases blood phosphate by: Increasing excretion from kidneys  1) The Endocrine System Anatomy Parathyroid gland Action of parathyroid hormone opposed by calcitonin Secreted by follicular cells in thyroid Inhibits activity of osteoclasts Decreases reabsorption of calcium from urine Regulation of PTH and calcitonin secretion: Circulating calcium levels act on parathyroid gland to reduce PTH secretion What are potential consequences of removing the parathyroid gland? Potential consequences of losing calcitonin?  1) The Endocrine System Anatomy Thymus Located in front of the heart and behind the sternum Critical part of immune system – T-cell development Releases various thymus hormones to stimulate T-cell development Thymosin alpha 1 Thymulin Thymopoietin Prolactin, T3 and T4, and luteinizing hormone may also stimulate production  1) The Endocrine System Anatomy Adrenal glands Two supra-renal glands The adrenal cortex releases: Mineralocorticoids → aldosterone Inhibits level of sodium excreted into urine → maintains blood volume and blood pressure LINK Glucocorticoids → cortisol Widespread effects on the metabolism of carbohydrates and proteins Augments properties of epi- and nor-epinephrine Anti-inflammatory Androgens → dehydro-epi-androsterone (DHEA) Promotes protein anabolism and growth Main source of androgens in females 20% as potent as testosterone  1) The Endocrine System Anatomy Adrenal glands The adrenal medulla releases: Epinephrine Chronotropic and inotropic Increases blood flow to muscles and brain Increases conversion of glycogen to glucose Stimulation of metabolic rate Norepinephrine Similar, but less potent effect as epinephrine Main action: vasoconstriction to increase blood pressure  1) The Endocrine System Anatomy Pancreas (islet cells) Produces three hormones Insulin Anabolic activity increases storage of glucose (glycogenesis), fatty acids and amino acids Glucagon Catabolic activity mobilizes glucose (glycogenolysis), fatty acids and amino acids (gluconeogenesis) Somatostatin Suppresses release of insulin and glucagon  2) Thyroid Disorders and Their Treatment Learning Outcomes Understand the causes, clinical presentation and complications of hypo- and hyper-thyroidism Understand the detailed mechanisms of action for methimazole, propylthiouracil and levothyroxine Know the common and serious side effects of methimazole, propylthiouracil and levothyroxine Understand dosing options for levothyroxine  2) Thyroid Disorders and Their Treatment Hyperthyroidism Disease caused by excess synthesis and secretion of thyroid hormone Severity ranges from mild symptoms to life-threatening No curative pharmacotherapy available Definitive treatment is radioactive iodine or surgery  2) Thyroid Disorders and Their Treatment Hyperthyroidism - Common Causes I. Toxic diffuse goiter (Graves disease) II. Toxic multi-nodular goiter (Plummers disease) III. Acute phase of thyroiditis IV. Toxic adenoma  2) Thyroid Disorders and Their Treatment Hyperthyroidism - Common Causes I. Toxic diffuse goiter (AKA Graves disease) More common in younger, female patients (ages 20-50) Most common cause of hyperthyroidism Autoimmune disorder Immune system creates antibodies against the TSH receptor Can result in hyperplasia of thyroid gland, leading to a goiter  2) Thyroid Disorders and Their Treatment Hyperthyroidism - Common Causes II. Toxic multi-nodular goiter (AKA Plummers disease) Most common in older, female patients (>50) Second most common cause of hyperthyroidism Iodine deficiency most common trigger for nodules to grow, but can be many others Develops slowly over several years Iodine deficiency → less T4 production → thyroid cells grow larger (multi-nodular goiter) → TSH receptors mutate → continually active  2) Thyroid Disorders and Their Treatment Hyperthyroidism - Common Causes III. Toxic adenoma Benign tumours growing on thyroid gland Become active and act just like thyroid cells, secreting T3/T4 but not responding to negative feedback IV. Acute phase of thyroiditis Causes inflammation and damage to the thyroid gland Damage causes excess hormone to be released Eventually leads to hypothyroidism once T3/T4 stores exhausted  2) Thyroid Disorders and Their Treatment Hyperthyroidism - Clinical Presentation and Symptoms non-specific hyperthyroidism symptoms Tremor in hands Anxiety Soft nails Diarrhea Hyperreflexia Emotional lability Heat intolerance Atrial fibrillation Insomnia Unintentional Increased perspiration Hair loss weight loss Weakness Hyperactivity Apathy Tachycardia Palpitations Amenorrhea Hypertension  2) Thyroid Disorders and Their Treatment Clinical Presentation and Symptoms Toxic Diffuse Goiter specific: Exophthalmos (or proptosis) Peri-orbital edema Diplopia Diffuse Goiter Pre-tibial myxedema Aside from the clinical presentation and symptoms, what are potential long-term complications with hyperthyroidism?  2) Thyroid Disorders and Their Treatment Hyperthyroidism – Treatment 1) Pharmacotherapy Thioamides Beta-blockers 2) Radioactive Iodine 3) Surgery  2) Thyroid Disorders and Their Treatment Hyperthyroidism Treatment - Thioamides Includes propylthiouracil (PTU) and methimazole (MMI) Not typically used life-long Main use is to reduce severity of hyperthyroidism to prepare a patient for curative therapy  2) Thyroid Disorders and Their Treatment Hyperthyroidism Treatment - Thioamides Mechanism of action Inhibits production of thyroid hormones (T3 and T4) by preventing iodine from incorporating with tyrosine residue on thyroglobulin Inhibits coupling reaction of MIT and DIT All of this achieved through inhibition of thyroid peroxidase oxidization Iodide ion (I-) --------------------------> Iodine atom (I0)----------------> attaches to tyrosine residue thyroid peroxidase Propylthiouracil additionally inhibits peripheral conversion of T4 → T3 Does this by inhibiting 5’-deiodinase  2) Thyroid Disorders and Their Treatment Hyperthyroidism Treatment - Thioamides Dosing and Administration Begins with a high initial dose, followed by lower maintenance doses Titrate every 4-6 weeks based on lab data Decrease dose gradually once target reached methimazole propylthiouracil Initial: 10-15mg OD Initial: 300mg divided BID - TID Mild hyperthyroidism Maint: 5-15mg OD Maint: 100-150mg div. BID – TID Initial: 20-30mg OD Moderate hyperthyroidism Same as above Maint: 5-15mg OD Initial: 30-40mg OD Severe hyperthyroidism Same as above Maint: 5-15mg OD  2) Thyroid Disorders and Their Treatment Hyperthyroidism Treatment - Thioamides Common side effects GI upset Rash Arthralgia  2) Thyroid Disorders and Their Treatment Hyperthyroidism Treatment - Thioamides Serious side effects Agranulocytosis 0.3 – 0.4% of patients (higher with PTU) Usually occurs within the first 90 days WBC falls to 50 years old Severe, long-standing hypothyroidism Start low (12.5-50mcg) and titrate up by 12.5 – 25mcg q4-6 weeks Administer on empty stomach, 30 min before meals or 1 hour after, QAM best  2) Thyroid Disorders and Their Treatment Hypothyroidism – Treatment 3) Levothyroxine – Side effects Should be minimal side effects if dosed properly Hyperthyroidism symptoms Cardiac risk increase Aggravate existing CVD BMD reduction  2) Thyroid Disorders and Their Treatment Hypothyroidism – Treatment 3) Levothyroxine – Drug Interactions Antacids / H2 blockers / PPIs Iron Calcium / mineral supplements Cholestyramine Raloxifene Manage by taking levothyroxine 2 hours before, or 4 hours after these meds  2) Thyroid Disorders and Their Treatment Hypothyroidism – Treatment 3) Levothyroxine – Monitoring Thyroid-stimulating hormone (TSH) levels most important Inverse relationship to T3/T4 levels due to negative feedback loop High TSH indicates low levels of T3/T4 Low TSH indicates higher levels of T3/T4 Also check free T3 and free T4 levels “Free” levels are checked since this is the physiological active hormone (NOT protein bound) If TSH is high, do you increase or decrease the dose of Levothyroxine?