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Transcript
Introduction to the Endocrine Module October 20, 2015 Neil Gesundheit, M.D., M.P.H. [email protected] 724-5454 Conflicts of Interest I am a consultant to or have been a consultant to: Pfizer, Inc., on the topic of smoking cessation Vivus, Inc., on the topics of weight management and sexual dysfunction (I am also a shareholder) HealthEquityLabs.com on the topic of mobile health and disease prevention HIPAA: Patient photos shown in this presentation are either from the public domain or are being used with patient permission Module Logistics Endocrine physiology (60%), histology/pathology (25%), pharmacology (15%) One endocrine tutorial: Tuesday, November 3 (Bone Physiology and Disorders) – 10:30-12:00pm tutorial; 12:00-12:30pm Q&A and “Meet the Professor” session ◦ Attendance is highly encouraged One required integrated pathology/physiology lab on Thursday, November 5, 10:30am-12:30pm “Endocrine riddles” review sessions – NEW and fun – Fridays, October 23 and 30, 5:15-6:15 pm in LKSC 308 Two PBL case studies in POM Module exam (Thursday, November 6) Book resources: for endocrine physiology from lectures, syllabus, and Molina, Costanzo, or Greenspan; for pathology, from lectures, syllabus, and Robbins; for pharmacology, from lectures, syllabus, and Katzung Faculty/TAs (Katie Ransohoff for physiology: [email protected]) Syllabus Katie, your TA [email protected] Specific Objectives of the Module Master the vocabulary of endocrinology ◦ the names of the hormones, where hormones are made, what organ or tissues they affect Learn the principles of endocrinology ◦ sensing mechanisms, feedback loops, regulation ◦ molecular and whole organ mechanisms of action Learn to identify endocrine structures microscopically and how tissues change in endocrine disease states Learn the pharmacology of drugs used to treat endocrine conditions Learn “endocrine think” – how to analyze and solve problems based on logical pathophysiological thinking Objectives of this Lecture To discuss the functional organization of hormones ◦ their molecular structure and families To provide an introduction to the properties of hormones ◦ how hormones act; hormones as endogenous drugs Appreciate that endocrine disorders are visible to a discerning clinical eye: case examples To appreciate the potential of endocrine therapeutics ◦ let’s cure Robert Wadlow, using a group-participatory format What Are Hormones? The word “hormone” is derived from the Greek word meaning “arouse the activity” Endocrine hormones are endogenous chemical mediators that are made at one site, enter the bloodstream, and affect the function of distant organ or of an entire organism ◦ the “wi-fi internet of the human body” Paracrine hormones may act on nearby cells Autocrine hormones act on the cells where they are made Hormones at the Extremes: GH Deficiency and Excess Mr. and Mrs. Tom Thumb, (Charles and Lavinia Stratton) circa 1863 Hormones at the Extremes: GH Deficiency and Excess Mr. and Mrs. Tom Thumb, (Charles and Lavinia Stratton) circa 1863 The Alton Giant (Robert Wadlow), circa 1936 What Functions Do Hormones Regulate? GH, IGF-I, T/DHT/E2, insulin, cortisol, T3/T4 Insulin, glucagon, leptin, cortisol, T3/T4, Ghrelin, GLP-1 Insulin, cortisol, T3/T4, catecholamines T/DHT, E2, progesterone, cortisol, T3/T4 Vitamin D, PTH Aldosterone, ADH, catecholamines, cortisol, T3/T4 T3/T4, cortisol Growth and development Appetite and nutrition; lipids; overall well-being Regulation of intermediary metabolism Libido, reproduction, lactation, gender identity [Ca++], integrity of bone Blood pressure, volume regulation, electrolyte balance CNS development, mood Org Chart for the Hormones Steroid Hormones Peptides Glucocorticoids (cortisol) Mineralocorticoids (aldosterone) Estrogens (estradiol) Progestins (progesterone) Androgens (dihydrotestosterone) Vitamin D [1,25(OH)2D3] Insulin, IGF-I Growth Hormone (GH) Prolactin (PRL) Hypothalamic Releasing Hormones Somatostatin Adrenocorticotropic Hormone (ACTH) Thyroid-stimulating Hormone (TSH) Thyrotropin-releasing Hormone (TRH) Luteinizing Hormone (LH) Follicle-stimulating Hormone (FSH) Human Chorionic Gonadotropin (HCG) Glucagon Parathyroid Hormone Others Thyroid Hormones T3 and T4 Amines Epinephrine Norepinephrine Dopamine Five Motifs for Receptor-Ligand Signal Transduction (modified from Katzung 2004, Fig. 2-5) Outside Inside Type Intranuclear Tyrosine Kinase Cytokine Ion channel Example(s) Thyroid Hormone Insulin Growth Hormone Acetylcholine (at nicotinic R) G-protein coupled TSH/TRH Five Motifs for Receptor-Ligand Signal Transduction (modified from Katzung 2004, Fig. 2-5) Outside Inside Type Intranuclear Tyrosine Kinase Cytokine Ion channel G-coupled Example(s) Thyroid Hormone Insulin Growth Hormone Acetylcholine (at nicotinic R) TSH/TRH Tyrosine Kinase Receptor-Ligand Signal Transduction (modified from Katzung 2004, Fig. 2-7) Insulin +Insulin -Insulin Substrate Substrate-P Hypoglycemia After IV Insulin Infusion Insulin 0.15 u/kg Five Motifs for Receptor-Ligand Signal Transduction (modified from Katzung 2004, Fig. 2-5) Outside Inside Type Intranuclear Example(s) Thyroid Hormone Tyrosine Kinase Cytokine Ion channel G-coupled Insulin Growth Hormone Acetylcholine (at nicotinic R) TSH/TRH Cytokine Receptor-Ligand Signal Transduction (modified from Katzung 2004, Fig. 2-8) GH molecule dimerizes receptor Growth Hormone JAK = Janus kinase (tyrosine kinase) STAT = Signal transducers and activators of transcription Five Motifs for Receptor-Ligand Signal Transduction (modified from Katzung 2004, Fig. 2-5) Outside Inside Type Intranuclear Example(s) Thyroid Hormone Tyrosine Kinase Cytokine Ion channel Insulin Growth Hormone Acetylcholine (at nicotinic R) G-protein coupled TSH/TRH Signal Transduction in Receptors Coupled to G Proteins (modified from Katzung 2004, Fig. 2-11) Activates: adenylyl cyclase (cAMP) PK-A or phospholipase C (DAG) PK-C and (IP3) GTP free Ca++ Crystal structure of the beta(2) adrenergic receptor–Gs protein complex Rasmussen, S.G., Devree, B.T., Zou, Y., Kruse, A.C., Chung, K.Y., Kobilka, T.S., Thian, F.S., Chae, P.S., Pardon, E., Calinski, D., Mathiesen, J.M., Shah, S.T., Lyons, J.A., Caffrey, M., Gellman, S.H., Steyaert, J., Skiniotis, G., Weis, W.I., Sunahara, R.K., and Kobilka, B.K., Crystal structure of the beta(2) adrenergic receptor-Gs protein complex. Nature 477, 549-555 (2011) Org Chart for the Hormones Steroid Hormones Peptides Glucocorticoids (cortisol) Mineralocorticoids (aldosterone) Estrogens (estradiol) Progestins (progesterone) Androgens (dihydrotestosterone) Vitamin D [1,25(OH)2D3] Insulin, IGF-I Growth Hormone (GH) Prolactin (PRL) Erythropoietin (EPO) Hypothalamic Releasing Hormones Somatostatin Adrenocorticotropic Hormone (ACTH) Thyroid-stimulating Hormone (TSH) Thyrotropin-releasing Hormone (TRH) Luteinizing Hormone (LH) Follicle-stimulating Hormone (FSH) Human Chorionic Gonadotropin (HCG) Glucagon Parathyroid Hormone Others Thyroid Hormones T3 and T4 Amines Epinephrine Norepinephrine Dopamine Summary: Hormones and Their Actions Hormones are named after activities they subserve Hormones bind to receptors and mediate actions much in the way as drugs do with their receptors ◦ One step, two step, three step Hormones are Powerful Amplifiers Hormone Production is Regulated The hypothalamus synthesizes several thousand molecules of corticotropin-releasing hormone (CRH) each day The pituitary synthesizes several million molecules of adrenocortico-trophic hormone (ACTH) each day The adrenal glands make 4 mmoles (1017 molecules) of cortisol each day Cortisol is important to maintaining blood pressure, blood glucose, appetite, growth ◦ its absence can be fatal The Hypothalamic-PituitaryAdrenal (HPA) Axis in Cushing’s Disease Profile view of a patient with Cushing’s syndrome Endocrine Diseases Present a Good Test of Your Visual Recognition Skills What is the finding? What is the finding? What is the finding? What is the finding? What is the finding? What is the finding? What is the finding? Properties of Hormones Potent intercellular communicators ◦ Transmit signals at cell surface (amines, peptides, proteins) through protein phosphorylation(s) or activation of second messengers; or in the nucleus (steroids, T3) by binding to intracellular receptors and regulating transcription ◦ Hormone deficiency and excess can be devastating Amplifiers Regulate and are regulated Let’s Cure Robert Wadlow The facts ◦ Born 1918, Alton, IL: wt 8.7 lbs ◦ 1923 (age 5): 5’6” tall ◦ 1928 (age 10): 6’5” tall ◦ 1931 (age 13): 7’4” tall ◦ 1936 (h.s. graduation): >8’ tall Robert Wadlow, The Alton Giant Robert Wadlow at Summer Camp 1931 (age 13) Robert Wadlow’s H.S. Graduation Photo (age 18) Wilt Chamberlain in 4th Grade Robert Wadlow Standing Next to his Brother, circa 1936 Let’s Cure Robert Wadlow The Growth Axis Hypothalamus Somatostatin GHRH hypothalamus (-) hypothalamus GH Pituitar y pituitary Liver IGF-I (+) Group 2 Group 3 liver T3/T4 cortisol Growth Plate Bone Group 4 bone E2/T Group 1 nutrition