Monographs on Endocrinology Volume 18 Edited by F. Gross, Heidelberg M. M. Grumbach, San Francisco A. Labhart, Zurich M. B. Lipsett, Bethesda T. Mann, Cambridge L. T. Samuels ("I), Salt Lake City 1. Zander, Mlinchen
Inder J. Chopra Triiodothyronines in Health and Disease With a Contribution by V. Cody With 76 Figures and 18 Tables Springer-Verlag Berlin Heidelberg New York 1981
Inder J. Chopra, M.D. Professor of Medicine, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90024, U.S.A. Vivian Cody, Ph.D. Associate Research Scientist, Medical Foundation of Buffalo, Inc., Research Laboratories, Buffalo, NY 14203, U.S.A. ISBN-13: 978-3-642-81550-8 e-isbn-13: 978-3-642-81548-5 DOl: 1O.1007! 978-3-642-81548-5 Library of Congress Catalogmg in Publication Data. Chopra, hider J 1939-. TriiOdothyronincs in health and disease. (Monographs on endocrinology; v. 18) Bibliography; p. Includes mdex. 1. Triiodothyronine. 2. Thyroid hormones. l. Title. [DNLM I Irllodothyronmc. WI M057 v. 18jWK 202 C 549 tj QP572.T5C47 612'.4480-27063 This work is sub]t!ct to copyright. All rights are reserved. whether the whole or part of the material IS concerned, specifically those of translation, reprmting. fe-use of illustrations, hroa.. -::asting, reproductlon by photocopying mach me or similar means, and storage lfi data banks. Under S 54 of the German Copynght Law Voihere COpIes are made for other than private usc, a fcc is payable to 'Verwertungsgesellschaft \Vort" Mumch. (0 Springer-Verlag Berlin, HeIdelberg 1981 Softcover reprint of the hardcover 1 st edition 1981 The use of registered names, trademarks, etc. in this publication docs not Imply, even in the absence of a specific statement, that such names are exempt from the relevant proleclive laws and regulations and therefore free for general use. Typesetting: Oscar Brandstetter Druckerel KG, Wiesbaden 2125/3020-543210
Preface The physiology and metabolism of thyroid hormones were areas of intense research investigation during the 1970s. Radioimmunoassays were applied to study the concentration of iodothyronines in biologic fluids. These techniques proved to be highly sensitive, specific, and reproducible as well as rapid. The availability of specific radioimmunoassays led to the detection of several iodothyronines in human biologic fluids, e. g., reverse triiodothyronine (rt 3), diiodothyronines, monoiodothyronines, and acetic acid derivatives of thyroxine (T 4) and T 3, which were previously either unknown or briefly considered but forgotten in the 1950s. This monograph is intended for readers who desire an overview of thyroid hormone physiology as it was understood in 1979. It should be especially useful to trainees in endocrinology and individuals interested in potential research projects. The main focus has been on the studies conducted between 1969 and 1978, alt~lough other information has been reviewed to provide an overall working knowledge of the field. A list of over 500 references, although probably still incomplete, should lead a reader to at least a few important articles in each area relevant to thyroid hormone physiology. The knowledge of several deiodinated derivatives as well as the production rates of thyroid hormones (T 4 and T 3) has raised several questions concerning the routes of metabolism of thyroid hormones along with the physiologic controls involved. In writing this book, 1 have examined the available information on various physiologic aspects of T 3 in health and their alteration in disease. In addition, key questions concerned with the understanding of thyroid hormone physiology have been reviewed; these include the following: (l) Is T 4 merely a prohormone for T 3 or is it also a hormone? (2) Is rt 3 merely a metabolic waste oft 4 or is it capable of biologic effects? (3) What is the nature of the processes of monodeiodination of T 4 to T 3 and to rt 3 and what are the factors that control these processes? (4) Why is serum T 310w and rt 3 high in the fetus, in starvation, in systemic illness, and after the administration of some drugs? (5) Can the measurement of rt 3 in amniotic fluid serve as a prenatal index of thyroid function in man? (6) What are the routes of metabolism of T 3S, and are these routes altered in a characteristic fashion in some situations? (7) What is the relativc potency ofvm ious circulating iodothyronines in the suppression of TSH? The information covered in cach chapter of the volume is as follows: Chapter 1 deals with the nomenclature, structure, and a history of the discovery of the triiodothyronines (T 3 and rt 3). Chapter 2 reviews serum binding of T 3S (T 3 and rt 3). Chapter 3, by Dr. Vivian Cody, reviews the molecular structure oft 3 and T 4, as determined by crystallographic studies. Dr. Cody analyzes the structure-activity relationship of thyroid hormones as it applies to serum binding as well as hormonal
VI Preface effects. Radioimmunoassay methodology for measurement of T 3S and the data on their concentration in biologic fluids during various clinical states is reviewed in Chap. 4. Chapter 5 discusses the data on metabolic clearance and production rates of T 3S, while information on the sources of T 3S is reviewed in Chap. 6. Chapters 7 and 8 discuss the metabolism oft 4 and T 3S in extrathyroidal tissues, and Chap. 9 is a brief overview of the biologic effects of iodothyronines. Much of the data on the serum concentrations ofiodothyronines is derived from the author's laboratory. The sections discussing the routes of iodothyronine metabolism, as reviewed here, should be considered gross estimates based on the available information. Sophisticated readers will no doubt appreciate the uncertainties and limitations of the analytic methods on which these estimates have been based. Although emphasis has been placed on data from my research, I have reviewed studies from various other laboratories, especially in controversial situations. I believe these reviews to be fair. However, I beg understanding and kind consideration from those who may feel that an insufficient or misplaced emphasis has been associated with their contributions. If this has occurred, it reflects naivety and/or other limitations in the ability of the author. Over the last 10 years, I have been extremely fortunate in my research to have benefited from the help and guidance of Dr. David H. Solomon, Professor and Chairman of the University of California, Los Angeles, Department of Medicine. He has been my mentor as well as a highly valued collaborator and colleague, and I am sorry that he was unable to join me in writing this monograph. Collaborative studies with Dr. Delbert Fisher of the Department of Pediatrics, University of California, Los Angeles, have also contributed invaluably to my work. I am grateful to Dr. Vivian Cody for contributing an excellent chapter on the molecular structure of thyroid hormones, which clearly enhances the scope of this monograph. I am grateful to Ms. Guadalupe N. Chua Teco and Ms. Aimee Nguyen, as well as the other research associates and many fellows who have contributed so significantly to this study and to the overall knowledge of thyroid hormone physiology. I also thank Ms. Kim Harrell, Ms. Teresa Aguilar, and Ms. Kate Kavanaugh for their cooperation and excellent secretatial assistance. I am very appreciative of the skillful editorial assistance of Ms. Linda 011. The research of the author cited in this monograph was supported in part by USPHS grants AM16155 and AMl7251 and the Research Career Development Award (K04 AM 70, 225) from the National Institutes of Health. Los Angeles, December 1980 Inder J. Chopra
Contents Chapter 1. Description, History, and Calorigenic Activity of Iodothyronines. 1 Chapter 2. Transport of Iodothyronines. 8 A. Thyroxine-Binding Globulin. 10 B. Thyroxine-Binding Prealbumin 12 C. Free Thyroid Hormones... 13 Chapter 3. Triiodothyronine: Molecular Structure and Biologic Function (V. Cody)... 15 A. Introduction............... 15 B. Stereochemistry and Molecular Conformation 16 C. Conformational Analysis.......... 24 I. Diphenyl Ring Conformation..... 24 II. 3' -Substituent Orientation - Distal or Proximal. 28 III. Side Chain Orientation........ 32 IV. Intermolecular Interactions...... 36 D. Role of Iodine in Conformation and Activity. 41 I. Conformational Constraints 42 II. Electronic Effects. 42 III. Iodine Interactions.... 44 IV. Acidity 4'-OH...... 45 E. Protein Binding and Biologic Activity. 46 I. Nuclear Binding Proteins.... 49 II. Binding and Potency of TBG.. 50 III. Thyroxine-Binding Prealbumin Interactions 53 F. Summary.................. 56 Chapter 4. Concentration of Triiodothyronines (T 3 and Reverse T 3) in Serum and Other Body Fluids.... 58 A. Methods of Measurements. 58 I. T 3 (3, 5, 3'-T 3).... 58
VIII Contents 1. T 3 Radioimmunoassay a) Reagents..... b) Procedure..... II. Reverse T 3 (3, 3', 5'-T 3, rt 3) 1. Reverse T 3 Radioimmunoassay a) Reagents......... b) Procedure......... B. Serum T 3 Concentration in Health and Disease. 69 69 69 73 74 I. Age-Related Changes...... 1. Fetal and Neonatal Life.... 2. Childhood (1-15 Years of Age). 3. Adult Life...... II. Effect of Sex...... III. Effect of Thyroid Disease 1. Hyperthyroidism.. 2. Hypothyroidism.. 3. Chronic Thyroiditis. 4. Endemic Goiter.. IV. Effect of Nonthyroidal Illnesses. V. Effect of Diet on Serum Concentration of T 3S 86 VI. Effect of Drugs.............. 88 1. Drugs Influencing Extrathyroidal Metabolism of Iodothyronines 88 2. Serum Levels oft 3S During Treatment with Thyroid Preparations 90 3. Effect of Administration of TSH and TRH 92 C. Urinary Excretion of T 3S................... " 94 62 62 65 67 68 68 68 74 74 74 77 78 78 80 Chapter 5. Kinetics of Peripheral Metabolism and Production Rates of T3S 95 A. Methods of Measurement and Normal Values 95 B. Alterations in Thyroid Diseases....... 99 C. Alterations in Nonthyroid Diseases and Low-T 3 Syndrome 99 Chapter 6. Sources of T3S: Thyroidal Secretion Versus Extrathyroidal Metabolism of T 4................ 102 Chapter 7. Nature of the Processes of and Factors Influencing Production of T3S from T 4............... 105 A. Outer-Ring Monodeiodination of T 4 to T 3'... 105 B. Inner-Ring Monodeiodination of T 4 to Reverse T 3 112 Chapter 8. Routes of T3S Metabolism. 114 A. In Vivo Studies. 114 B. In Vitro Studies. 116
Contents Chapter 9. Biologic Effects of Iodothyronines A. Mechanism of Action......... B. Some Other Interesting Effects of Thyroid Hormones. I. Erythropoiesis............ II. Cyclic (3', 5'-)Adenosine Monophosphate III. Self Degradation...... C. Relative Potency in Various Effects References.. IX 118 119 125 Subject Index 143