Chorionic Gonadotropin

Chorionic Gonadotropin

Chorionic Gonadotropin Edited by Sheldon J. Segal The Rockefeller Foundation New York, New York PLENUM PRESS NEW YORK AND LONDON

Main entry under title: Chorionic gonadotropin. Library of Congress Cataloging in Publication Data Proceedings of the Conference on Human Chorionic Gonadotropin, held at the Rockefeller Foundation Conference and Study Center, Bellagio, Italy, November 14-16, 1979. Includes index. 1. Chorionic gonadotropin-congresses. I. Segal, Sheldon Jerome, 1926- II. Rockefeller Foundation. [DNLM: 1. Gonadotropin, Chorionic-Congresses. WK920C5511979j QP572.C53C48 ISBN-13: 978-1-4684-1064-8 001: 10.1007/978-1-4684-1062-4 599.01'6 e-isbn-13: 978-1-4684-1062-4 80-20274 Proceedings of the Conference on Human Chorionic Gonadotropin, held at the Rockefeller Foundation Conference and Study Center, Bellagio, Italy, November 14-16, 1979. 1980 Plenum Press, New York Sof'tcover reprint of the hardcover 1st edition 1980 A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

FOREWORD This volume is devoted to the chemistry, immunology, molecular biology, and physiology of the human chorionic gonadotropin, heg. For this glycoprotein molecule the course from discovery to chemical deciphering covered about fifty years. It was in 1928 that Ascheim and Zondek reported that urine from pregnant women contains something that stimulates the ovaries of mice or rats. This provided the basis for the famous A-Z test for pregnancy and for the "rabbit test" modification introduced by Friedman. As researchers sought to find more sensitive responses to heg, they used a wide variety of species including the South African aquatic toad, Xenopus Zaevis, the terrestrial toad of South America, Bufo arinarus, and the African weaver finch, EupZeetes afra. The weaver finch feather reaction was particularly noteworthy, for it disclosed a non-gonadal response to heg/lh. In retrospect, this may have been an important evolutionary clue to the realization that the designation of the hormone as a "gonadotropin" may have been only partially descriptive of the molecule's physiological function--a concept that is gaining attention, as the papers in this 1980 volume divulge. With crude extracts to work with and only bioassays to measure actjvity, the early workers sought to understand the physiology and chemistry of the placental gonadotropin. Within the first ten years it was established that the human placental gonadotropin appears early in pregnancy, reaches its peak during the second month, and falls off rapidly thereafter. With the development of each more sensitive bioassay the date of hormone appearance in the urine moved closer and closer to the day of the first missed period. A similar hormone in the rhesus monkey was found only between the 18th and 25th day. In the blood of the pregnant mare a gonadotropic hormone was identified which also has a stimulating effect on the ovaries of test animals. Since this material was not found in the urine in significant amounts, it was concluded that it must be different chemically from the human hormone with similar action. By analyzing the difference in animal responses, researchers concluded that there must be dissimilarities between the gonadotropic hormone produced by the pituitary and the one produced by the placenta. Just 14 years after the Ascheim-Zondek discovery, the distinguished anatomist, George W. v

FOREWORD Corner, could write a summary of the biology of hcg not very different from what can be said today. He also wrote, "The ovaries of the rat and the rabbit can distinguish [gonadotropins] better than the chemist. For the present we must content ourselves with being grateful for the pregnancy test and await the day when these troublesome substances yield themselves to chemical isolation." As revealed by the papers in this volume, that day has now come. Modern chemistry has made it possible not only to isolate the hormone, but to describe fully the chemical structure of its molecule. Nevertheless, many questions about hcg remain as troublesome today as they were then. We can confirm that the human pituitary and placental gonadotropins are chemically different; and different still is the one produced by the pregnant mare. As yet, we cannot define the structural basis for similarities or differences in action. We can quantify with precision the time course of hcg production during pregnancy. By using highly sensitive radioligand assays the day of onset of production has been moved across the day-of-expected-menses milestone, delimited by the sensitivity of previous bioassays, to a point in the luteal phase of the fertile cycle when the hcg can rescue the failing corpus luteum. But, as in the past, the role played by the hormone later in pregnancy remains completely unsolved. What was not evident before the emergence of the highly sensitive tests based on the antigenicity of hcg, is the surprising omnipresence of substances immunologically similar to hcg. In blood and urine samples of non-pregnant women, extracts of presumably normal tissue samples, or a number of non-trophoblastic tumors, scientists have found such substances. These observations, taken together with work establishing that some bacteria also can produce a factor with antigenic and biological properties similar to heg, open a new phase in the course of hcg research. The scope of interest is now broadened beyond the endocrinology of pregnancy to include immunology, infectious disease, and oncology. The rapid pace of these developments prompted the preparation of this comprehensive volume, the published proceedings of a conference held at the Rockefeller Foundation's Conference and Study Center, Bellagio, Italy, November 14-16, 1979. Many of the advances reported here depended for their achievement upon methodological improvements in the fields of protein chemistry, immunology, and radiochemistry. They would not, however, have been possible without the substantial knowledge base provided by those pioneering scientists who (using mice, rabbits, frogs, toads, and birds) learned so much about hcg. Sheldon J. Segal New York May, 1980

CONTENTS COMPARATIVE PHYSIOLOGY Early Studies of Chorionic Gonadotropin and Antihormones.... Roy Hertz Primary and Secondary Biologic Activities Intrinsic to the Human Chorionic Gonadotropin Molecule....... Bruce C. Nisula, George S. Ta1iadouros, and Pierre Carayon Chorionic Gonadotropin in Rodents Leif Wide, Bruce Hobson, and Mariam Wide Patterns of Secretion and Antigenic Similarities Among Primate Chorionic Gonadotropins: Significance in Fertility Research... Gary D. Hodgen 1 17 37 53 CHEMISTRY, METABOLISM, AND IMMUNOLOGY Chemistry and Immunochemistry of Human Chorionic Gonadotropin............... Steven Birken and Robert E. Canfield Chorionic Gonadotropins: Comparative Studies and Comments on Relationships to Other Glycoprotein Hormones..... William T. Moore, Jr., Bruce D. Burleigh, and Darrell N. Ward 65 89 vii

viii Structures of the Asparag ine Linked Sugar Chains of Human Chorionic Gonadotropin Yoshinori Endo, Yoshihiko Ashitaka, Akira Kobata, and Shimpei Tojo Production and Secretion of HCG and HeG Subunits by Trophoblastic Tissue.... Yoshihiko Ashitaka, Ryuichiro Nishimura, Masayuki Takemori, and Shimpei Toj 0 Large Molecular Species of Human Chorionic Gonadotropin........... Takeshi Maruo, Sheldon J. Segal, and S.S. Koide Distribution, Metabolism, and Excretion of Human Chorionic Goandotropin and its Subunits in Man. Bruce C. Nisula and Robert E. Wehmann Immuno-Biological Studies with Beta-Subunit of Human Chorionic Gonadotropin and its Subfragments.... S. Ramakrishnan and G.P. Talwar Limitations and Problems of HCG-Specific Antisera....... Hao-Chia Chen, Shuji Matsuura, and Masanobu Ohashi CONTENTS 127 147 177 199 213 231 MOLECULAR BIOLOGY AND REGULATORY GENETICS Human Chorionic Gonadotropin a and 8 Subunit mrnas: Translatable Levels During Pregnancy and Molecular Cloning of DNA Sequences Complementary to HCG. Mark Boothby, Susan Daniels-Mcqueen, Diana McWilliams, Maria Zernik, and Irving Boime Human Chorionic Gonadotropin: Studies on the Mechanism of Secretion... R. Folman, J. Ilan, N. de Groot, and A.A. Hochberg Synthesis, Processing, and Secretion of Human Chorionic Gonadotropin Subunits by Cultured Human Cells..... Raymond W. Ruddon, Charlotte A. Hanson, Albert H. Bryn, and Carmen Anderson 253 277 295

CONTENTS Regulation of Human Chorionic Gonadotropin Synthesis in Placenta, Choriocarcinoma, and Non-Placental Tumors........ Janice Yang Chou The Interaction of the LH/HCG Receptor with Adenylate Cyclase in the Rat Ovary. Yoram Salomon, Elhanan Ezra, Abraham Nimrod, Yehudith Arnir-Zaltsman, and Hans R. Lindner Testis-Determining H-Y Antigen and the Induction of the HCG Receptor Ulrich Muller 317 345 371 EVOLUTION AND ONCOLOGY Presence of an HCG-like Substance in Non- Pregnant Humans...... Glann D. Braunstein, Joan Rasor, and Maclyn E. Wade Apparent Chorionic Gonadotropin Immunoreactivity in Human Non-Placental Tissues... Christopher A. Adejuwon, Samuel S. Koide, S.M. Mitsudo, and Sheldon J. Segal Gonadotropin Produced by a Microorganism S.S. Koide, T. Maruo, H. Cohen, and S.J. Segal Immunodetection of Choriogonadotropin-like Antigen in Bacteria Isolated from Cancer Patients............. Hernan F. Acevedo, Elizabeth A. Campbell-Acevedo, and Malcolm Slifkin A Bacterial Factor Cross-Reacting with Anti-CG..... S.S. Koide, T. Maruo, H.F. Acevedo, E.A. Campbell-Acevedo, and M. Slifkin HCG Production by Non-Placental Tissue and Its Significance.... Brij B. Saxena Index 383 411 421 435 461 465 491