BIOLOGYOF THE

UTERUS Second Edition

BIOLOGY OF THE

UTERUS Second Edition

Edited by

RALPH M. WYNN, M.D. Professor, Departments of Obstetrics & Gynecology

and Anatomy & Cell Biology Wayne State University School of Medicine Detroit, Michigan

and

WILLIAM P. JOLLIE, Ph.D. Professor and Chairman, Department of Anatomy Medical College of Virginia Virginia Commonwealth University Richmond, Virginia

PLENUM MEDICAL BOOK COMPANY NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Biology of the uterus / edited by Ralph M. Wynn and William P.Jollie. -2nd ed. p. cm.

Includes bibliographies and index. ISBN-13: 978-1-4684-5591-5 e-ISBN-13: 978-1-4684-5589-2 DOl: 10.1007/978-1-4684-5589-2 1. Uterus. I. Wynn, RalphM. II. Jollie, WilliamP. [DNLM: 1. Uterus-anatomy & histology. 2. Uterus-physiology. WP 400 B615]

QP265.B543 1989 599'.016-dc19 DNLMIDLC for Library of Congress

The previous edition of this work was published by Plenum Press in 1977 under the title Biology oj the Uterus. That volume, in turn, was a revision of Cellular Biology oj the Uterus, published by Appleton-Century-Crofts in 1967.

© 1989, 1977, 1967 Plenum Publishing Corporation Softcover reprint of the hardcover 1st edition 1989

233 Spring Street, New York, N.Y. 10013

89-3540 CIP

Plenum Medical Book Company is an imprint of Plenum Publishing Corporation

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

Contributors

L. L. Anderson Department of Animal Science Iowa State University Ames, Iowa 50011

John D. Aplin Departments of Obstetrics and

Gynaecology, Biochemistry, and Molecular Biology

University of Manchester Manchester M13 OJK, England

Christine Bergeron Departments of Pathology and

Obstetrics and Gynecology McGiII University and The Sir Mortimer B. Davis Jewish

General Hospital Montreal, Quebec H3T lE2,

Canada

w. C. Cole Division of Cardiovascular Sciences St. Boniface Research Institute Department of Physiology University of Manitoba Winnipeg, Manitoba R2H 2AG,

Canada

Allen C. Enders Department of Human Anatomy University of California School of

Medicine Davis, California 95616

v

Alex F erenczy Departments of Pathology and

Obstetrics and Gynecology McGill University and The Sir Mortimer B. Davis Jewish

General Hospital Montreal, Quebec H3T lE2,

Canada

R. E. Garfield Departments of Neurosciences and

Obstetrics and Gynecology McMaster University, Health

Sciences Hamilton, Ontario L8N 3Z5,

Canada

Randall L. Given Department of Anatomy and

Neurosciences University of Texas Medical

Branch Galveston, Texas 77550

Frank C. Greiss, Jr. Department of Obstetrics and

Gynecology Bowman Gray School of Medicine

of Wake Forest University Winston-Salem, North Carolina

27103

VI

CONTRIBUTORS

Gabor Huszar Department of Obstetrics and

Gynecology Yale University School of Medicine New Haven, Connecticut 06510

c. Y. Kao Department of Pharmacology State University of New York

Downstate Medical Center Brooklyn, New York 11203

Wendell W. Leavitt Departments of Biochemistry and

Obstetrics and Gynecology Texas Tech University Health

Sciences Center Lubbock, Texas 79430

Harland W. Mossman Department of Anatomy University of Wisconsin-Madison Madison, Wisconsin 53706

A. I. Musah Department of Animal Science Iowa State University Ames, Iowa 50011

Ronan O'Rahilly Carnegie Laboratories of

Embryology California Primate Research Center Davis, California 95616

Helen A. Padykula Department of Cell Biology University of Massachusetts

Medical School Worcester, Massachusetts 01655

Earl L. Parr Department of Anatomy School of Medicine Southern Illinois University Carbondale, Illinois 62901

Margaret B. Parr Department of Anatomy School of Medicine Southern Illinois University Carbondale, Illinois 62901

Elizabeth M. Ramsey Department of Embryology Carnegie Institution of Washington Baltimore, Maryland 21210

James C. Rose Departments of Physiology and

Obstetrics and Gynecology Bowman Gray School of Medicine

of Wake Forest University Winston-Salem, North Carolina

27103

Melvyn S. Soloff Department of Biochemistry Medical College of Ohio Toledo, Ohio 43699

Michael P. Walsh Department of Medical

Biochemistry University of Calgary Calgary, Alberta T2N 4Nl, Canada

Ralph M. Wynn Departments of Obstetrics and

Gynecology and Anatomy and Cell Biology

Wayne State University School of Medicine

Detroit, Michigan 48201

Preface

Almost a quarter of a century has elapsed since Cellular Biology of the Uterus, the predecessor of the present volume, was planned. During that period, especially in the decade since the publication of the last edition of Biology of the Uterus, new information in the field has been so voluminous as to require major revisions of most of the chapters, the addition of several new chapters, and the collaboration of a second editor to facilitate the selection of appropriate experts as authors. As in prior editions, a balance has been struck between classical biology and modem biochemistry and biophysics. The inclusion of basic histological and embryo­logical information provides a necessary, though often lacking, background for the protein chemist and molecular biologist and a bridge between the cell biologist and clinician. Thus, major practical problems in human reproduction, such as the genesis of endometrial carcinoma and the cause of the initiation of labor, may be approached on a firm scientific footing.

The current edition deals primarily with the biology of the uterus itself (comparative and human) rather than placentation or pregnancy and thus is a synthesis of data derived from many techniques, both conventional and modem. As it is clearly beyond the competence of anyone scientist to prepare such a text on the basis of personal knowledge and experience, the aid of 22 distinguished scientists was enlisted. All of these authors, acknowledged experts in their respective fields, agreed to extensive revisions of their chapters in the previous edition or preparation of entirely new contributions.

A scholarly history of uterine biology has been retained to illustrate the evolution of studies from superstition to speculation to science. The chapters on comparative anatomy and embryology of the human genitourinary tract have been revised by their original authors. It is noteworthy that Dr. Mossman's chapter was prepared on the occasion of that distinguished scientist's 90th birthday. An extensively revised chapter on vascular anatomy and a new chapter on vascular physiology of the uterus, emphasizing the nonpregnant condition, precede the final 12 chapters, which stress cell biology. Comparative embryology of the miillerian derivatives provides the basis for predicting and analyzing the cellular response of the uterus to hormones. The chapters on vascular anatomy and physiology illustrate the dominant role of blood vessels in critical uterine functions such as menstruation and pregnancy, the effects on uterine blood flow of hormones, oxygenation, vasoactive amines, and prostaglandins, and the changes in uterine arteries as they relate to preeclampsia and retardation of intrauterine growth.

Two entirely new complementary chapters on biochemistry and cell biology of the endometrium bridge the gap between morphology and biochemistry and illustrate the crucial role of receptors in endocrine regulation of uterine activity. The cytoskeletal proteins, the biochemistry of the cellular surface, the extracellular matrix, and the secretory components of the endometrium are discussed as they relate to implantation and associated phenomena. The interrelations of the actions of steroid and peptide hormones, receptor status, synthesis of

VB

Vlll

PREFACE

nucleic acids and proteins, and regulation of gene expression are detailed in one of the new pivotal chapters of this edition. The chapter on delayed implantation has been revised and extended to include a discussion of the uterus during early implantation, with detailed data derived from studies of marsupials and several orders of eutherian mammals. Delayed implan­tation strikingly illustrates the mediation of the developmental rate of one organism (the unimplanted blastocyst) by the internal environment (the uterus) of another. A new chapter on the implantation reaction discusses experimental techniques and hormonal sensitization of the endometrium for implantation. Contributions of electron microscopy to the understanding of several fundamental problems in reproductive biology are well documented. In particular, the role of prostaglandins in the initiation of decidualization and the importance of apoptosis as the mode of cellular death in uterine epithelium are discussed. A short but stimulating chapter on the role of stem cells in the regeneration of the primate uterus presents work currently in progress in the author's laboratory.

The chapter on the human endometrium, which encompasses histology and scanning and transmission electron microscopy, has been expanded to include a detailed discussion of the endometrial vascular changes in normal and hypertensive pregnancies. The information de­rived from transmission electron microscopy deals with basic problems, such as the origin and significance of the nucleolar channel system and the functions of the decidua, and clinical applications, such as the morphological effects of contraceptives and the cause of menstrua­tion. The morphological correlates of preeclampsia and other abnormal gestational states are illustrated. The chapter on pathology of the endometrium advances the thesis that hyperplasia and neoplasia may have fundamentally different causes in this tissue.

Two of the three chapters dealing with biochemistry, electrophysiology, and ultrastruc­ture of the myometrium are entirely new. The need for collaboration between the electron microscopist and the biochemist in elucidating the contractile mechanism of the myometrium is amply demonstrated. Although much more is known about skeletal muscle than about smooth muscle, the major data concerning the provision of energy and the proteins of the contractile mechanisms of mammalian myometrium are presented. The organelles of smooth muscle are discussed in detail, with particular emphasis placed on the role of gap junctions in myometrial contractility. The chapter on electrophysiology of the myometrium focuses on patterns of ionic distribution and resting potential and their modifications by hormonal and gestational influences. Current experiments dealing with single-cell myometrial preparations are discussed authoritatively in appropriate detail.

The last two chapters, the second of which is entirely new, discuss the uterine regulation of ovarian function and the endocrine control of parturition. Effects of hysterectomy on ovarian function and luteolytic action of the uterus are analyzed. The effects of ovarian and adrenal steroids, prostaglandins, and oxytocin on uterine activity in several species, including man, are discussed. Although the emphasis of the volume as a whole is not on pregnancy, the final chapter is obviously relevant to experimental biologists, endocrinologists, and obstetricians.

Even though each of the chapters is a self-contained unit, which provides a critical review and a comprehensive list of references for the graduate student, the intended interdisciplinary orientation is best achieved by reading the chapters in the order in which they appear. The volume is designed to serve as an introduction for the academic clinician to the scientific foundations of reproductive biology, as a suggestion to the basic scientist of significant applications of uterine biology, and as a bridge between morphologists and pathologists on the one hand and biochemists and physiologists on the other. If new or enhanced interdisciplinary collaboration is stimulated by this volume, the efforts of the authors and the editors will be rewarded.

Detroit, Michigan Richmond, Virginia

Ralph M. Wynn William P. Jollie

Contents

1 History 1

ELIZABETH M. RAMSEY

1. Greece. . . . . . . . . . . .. . . .. . . . . .. . . .. .. . .. .. . . . .. . . . . . . . . . . . . . . . 1 2. Alexandria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3. Rome....................................................... 4 4. The "Dark Ages" ............................................ 4 5. Renaissance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6. Seventeenth to Early Twentieth Centuries . . . . . . . . . . . . . . . . . . . . . . 8 7. Contemporary.. .. ............................ .......... ..... 13 8. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2 Comparative Anatomy 19

HARLAND W. MOSSMAN

1. Types of Uteri .............................................. 22 2. Distribution and Probable Evolution of Uterine Types .......... 23 3. Correlations of Uterine Types with Other Biological

Features .................................................... 27 4. Miscellaneous Aspects of the Comparative Morphology

of the Uterus. . . . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . 29 5. Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 6. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 7. Bibliography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

3 Prenatal Human Development 35

RONAN O'RAHILLY

1. Urinary Preliminaries 35

IX

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CONTENTS

2. The Para mesonephric Ducts............ ........ ... ..... ...... 37 3. The Vaginal Controversy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 4. The Fetal Uterus ............................................ 49 5. The Second Half of Prenatal Life ............................. 50 6. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4 Vascular Anatomy

ELIZABETH M. RAMSEY

57

1. Basic Aspects of Architecture and Physiology of Uterine Arteries 58 1.1. Nonpregnant.......................................... 58 1.2. Pregnant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

2. Interaction of Trophoblast and Decidua ....................... 62 3. Contemporary Studies ....................................... 65 4. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

5 Vascular Physiology of the Nonpregnant

1.

2.

3. 4.

5. 6.

6

Uterus 69

FRANK C. GREISS, JR., AND JAMES C. ROSE

Fundamental Characteristics of the Uterine Vasculature ........ . 1.1. The Pressure-Flow Relationship ....................... . 1.2. Autonomic Influences ................................. . 1.3. Effects of Myometrial Contractions ..................... . 1.4. Endocrine Regulation ................................. . Uterine Blood Flow during the Ovarian Cycle ................. . 2.1. Temporal Changes .................................... . 2.2. Hormonal and Other Correlates ........................ . Mediators of Estrogen-Induced Vasodilatation ................. . Responses of the Nonplacental Uterine Vasculature during Pregnancy ................................................. . Conclusion ................................................. . References

Cellular Biochemistry of the Endometrium

JOHN D. APLIN

70 70 70 73 74 77 77 78 79

81 84 84

89

1. Methodological Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2. Intracellular Constituents ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

2.1. Cytoskeletal Proteins ................................... 91 2.2. Oncogene Products .................................... 95 2.3. The 24k Protein ....................................... 96

3. Cell Surface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.1. Cell Polarity ........................................... 97

3.2. Cell Location .......................................... 97 3.3. Hormone-Dependent Alterations........................ 98 3.4. Preparation for Implantation ........................... 100

4. Extracellular Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 4.1. Interstitial Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 4.2. Basal Laminal Components ............................. 106 4.3. Functional Significance of Matrix Reorganization ......... 108

5. Secretory Components ....................................... 109 5.1. Uteroglobin. .. . ... .. .. ..... .. . .. .. .. . . . . .. .... . ... . . .. 109 5.2. Iron-Binding Secretory Products ........................ 110 5.3. Prolactin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 111 5.4. Diamine Oxidase. .. . . . . . . .. .. . . . . .. . . ... . .. . . . . . . . . . . .. 111 5.5. <x2-PEG. . . . . . . . ... . .. ... .. . .. . . . . . . .. . . . .. . . .. . . . .. . .. 112 5.6. <XcPEG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 113 5.7. High-Molecular-Weight Components .................... 114 5.8. Other Glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 117

6. Concluding Remarks ......................................... 118 7. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 119

7 Cell Biology of the Endometrium

WENDELL W. LEAVITT

131

1. Mechanism of Hormone Action ............................... 134 1.1. General Mechanism of Hormone Action ................. 134 1.2. Polypeptide Hormones ................................. 134 1.3. Steroid Hormones ..................... ,............... 135 1.4. Estrogen Marker Proteins .............. ;. . . . . . .. . . . . . . .. 137 1.5. Progesterone Marker Proteins. . . . . . .. . . .. . . .. . . . . . . . . . .. 137

2. Steroid Receptors ............................................ 146 2.1. Receptor Distribution .................................. 146 2.2. Receptor Assays ....................................... 147 2.3. Nuclear Acceptor Sites ................................. 149 2.4. Estrogen-Progestin Interactions............ .... .... ..... 150 2.5. Hamster Estrous Cycle .................... ;............ 152 2.6. Pregnancy.. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. 154 2.7. Density-Shift Studies ................................... 154 2.8. A Unifying Concept. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 159

3. References. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 162

8 The Endometrium of Delayed and Early Implantation 175

RANDALL L. GIVEN AND ALLEN C. ENDERS

1. Marsupials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 176 2. Roe Deer ................................................... 179

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3. Armadillos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 182 4. Insectivores and Chiroptera .................................. 186 5. Carnivores. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 186

5.1. Seals... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187 5.2. Bears....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 188 5.3. Mustelids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 188

6. Rodents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 203 7. Nonhuman Primates. . . .... . . .. . . ... .. . .. .. .. . .. . .. . . .. .. . ... 212 8. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 219 9. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 223

9 The Implantation Reaction

MARGARET B. PARR AND EARL L. PARR

233

1. Adhesion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 233 l.l. Morphological Changes in the Uterine Epithelial Cell

Surface ............................................... 234 l.2. Surface Charge on Blastocysts . . . . . . . . . . . . . . . . . . . . . . . . . .. 234 l.3. Surface Charge on the Uterine Epithelium ............... 236 1.4. Cell Adhesion Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 237 l.5. Surface Glycoproteins on Blastocysts ..................... 237 1.6. Surface Glycoproteins on Uterine Epithelial Cells ......... 239

2. Vascular Permeability ........................................ 241 2.l. Blood Vessels Responsible for Increased Vascular

Permeability ........................................... 241 2.2. Role of Prostaglandins in Increased Vascular

Permeability ........................................... 244

2.3. Endometrial Prostaglandins. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 245 2.4. Blastocyst Prostaglandins ............................... 246

3. The Decidual Cell Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 247 3.l. The Primary Decidual Zone. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 248 3.2. Antimesometrial Decidua.. .. .. . .. .. . . .. . . .. .. . .. . .... .. 251 3.3. Mesometrial Decidua ................................... 255 3.4. The Role of Prostaglandins in Initiating Decidualization ... 256 3.5. Mechanisms of Prostaglandin Effects on Vascular

Permeability and Decidualization ........................ 257 3.6. Decidual Cell Metabolism ............................... 258 3.7. Functions of Decidual Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . .. 260

4. Epithelial Cell Loss .......................................... 260 4.l. The Uterine Epithelium Adjacent to the

Trophoblast ........................................... 260 4.2. Apoptosis as the Mode of Cell Death in Uterine

Epithelium ............................................ 261 4.3. Effects of Trophoblast on Uterine Epithelium ............ 263 4.4. Effects of Decidual Tissue on Uterine Epithelium. . . . . . . .. 266

5. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 267

10 Regeneration in the Primate Uterus: The Role of Stem Cells

HELEN A. PADYKULA

1. Endometriectomy and the Location of the Endometrial

279

Stem Cells .................................................. 280 2. Compartmentalization of the Primate Endometrium ............ 282 3. Zonation of the Primate Endometrium......................... 283 4. Cyclic Changes in Endometrial Zonal Uptake of [3H]Thymidine . 285

4.l. Epithelial Mitotic Activity in the Transient Compartment during Estrogen Dominance ............................ 285

4.2. Germinal Mechanisms in the Endometrial Basalis ......... 285 5. Hypothesis: Cyclic Endometrial Renewal in Menstruating

Primates .................................................... 287 6. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 287

11 The Human Endometrium: Cyclic and Gestational Changes 289

RALPH M. WYNN

1. Histology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 289 2. Ultrastructure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 294

2.l. The Normal Menstrual Cycle ........................... 294 2.2. The Nucleolar Channel System.......................... 302 2.3. The Decidua .......................................... 304 2.4. The Arias-Stella Reaction .............................. 310 2.5. Scanning Electron Microscopy. . . . . . . . . . . . . . . . . . . . . . . . . .. 311 2.6. Ultrastructural Localization of Enzymes .................. 314

3. Clinical Correlations ......................................... 317 3.1. Effects of Contraceptive Agents ......................... 317 3.2. Menstruation .. '" . .. . . .. . .. . . . .. . .... . . . . . .. . . . . . . .. .. 319

4. Structural Vascular Changes in Normal and Hypertensive Pregnancies ................................................. 320

5. References. . . . . . .. . . ... . .. .. .. ...... .. .. .... . . . .... . . . ..... .. 329

12 Endometrial Hyperplasia and Neoplasia 333

ALEX FERENCZY AND CHRISTINE BERGERON

l. Laboratory Evidence ......................................... 334 l.l. Histology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 334 l.2. Electron Microscopy. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. .. 335 l.3. Morphometry, DNA-Feulgen Microspectrophotometry,

and Flow Cytometry .................................... 337

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1.4. In Vitro DNA Histoautoradiography ..................... 338 1.5. Immunohistochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 339

2. Clinical Evidence ............................................ 342 3. Coexistent Association. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 349 4. Clinical Implications of the Two-Disease Concept ............... 350 5. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 351

13 Biochemistry of the Myometrium and Cervix

GABOR HUSZAR AND MICHAEL P. WALSH

355

1. The Structure of the Myometrium ............................ 356 1.1. Cellular Organization .................................. 356 1.2. Filament Structure and Function ........................ 356

2. Calcium and Contractile Regulation ........................... 358 2.1. The Importance of Ca2 + Ions .......................... 358 2.2. The Source of Activating Calcium ....................... 360 2.3. Measurements of Cellular Ca2 + Transients. . . . . . . . . . . . . .. 360

3. Regulation of Transmembrane Ca2 + Fluxes.. . . . . . . . . . . . . . . . . .. 361 3.1. Mechanisms of Ca2 + Efflux. . . . . . .. . .. . . . . .. .. . . .. . . . . .. 361 3.2. The Ca2 + Transport System of the Sarcoplasmic

Reticulum ............................................. 363 3.3. Mechanisms of Ca2 + Influx....................... . . .. .. 363

4. Contractile Proteins of the Myometrium ....................... 366 4.1. Myosin................................................ 366 4.2. Thin Filament Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 368

5. Regulation of Myometrial Contractility. . . . . . . . . . . . . . . . . . . . . . . .. 369 5.1. Calmodulin.......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 369 5.2. Calmodulin-Dependent Myosin Light Chain Kinase ....... 369 5.3. The Mechanism of MLCK Action ....................... 372 5.4. Modulation of Smooth Muscle Contractility

by MLCK ............................................. 373 5.5. Myosin Light Chain Phosphatase ........................ 374 5.6. Phosphorylation of Myosin Light Chain and Heavy Chains

by Other Kinases ...................................... 374 5.7. Second-Site Phosphorylation of Myosin .................. 375

6. Mechanisms of Smooth Muscle Regulation Other Than MLCK .. 375 6.1. Thin Filament Regulation: Caldesmon ................... 376 6.2. Regulation of Smooth Muscle Contraction by Cyclic

Nucleotides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 376 6.3. Endocrine Regulation of Myometrial Contractility. . . . . . . .. 377

7. Integrated Model for Regulation of Smooth Muscle Contractility. 380 8. Preterm Birth and Tocolytic Therapy ......................... 382

8.1. Calcium Channel-Blocking Agents. . . . . . . . . . . . . . . . . . . . . .. 382 8.2. Prostaglandin Synthesis Inhibitors ....................... 383 8.3. Calmodulin-Inhibiting Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . .. 383 8.4. Functional Peptides .................................... 384 8.5. The Efficacy of I3-Adrenergic Agents .................... 385

9. Cervix...................................................... 385 9.1. Biochemistry of Cervical Maturation............ ...... ... 385 9.2. Hormonal Control of Cervical Maturation . . . . . . . . . . . . . . .. 387 9.3. Relationship between Myometrial Contractility and

Cervical Maturation .................................... 388 10. References........................................... ........ 390

14 Electrophysiological Properties of Uterine Smooth Muscle 403

C.Y.KAO

1. Review of Methodology, ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 404 1.1. Comparison of Uterine, Cardiac, and Skeletal

Muscles ............................................... 404 1.2. A Brief Statement of the Ionic Theory

of Excitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 405 1.3. Methods of Studying Electrical Activities of Smooth

Muscles................................................ 409 2. Ionic Distribution as the Basis of Electrophysiological

Phenomena ................................................. 418 2.1. Studies in Ionic Contents and Distribution ............... 418 2.2. Ionic Contents and Intracellular Concentrations .......... 419 2.3. Hormonal and Gestational Influences on Ionic

Distribution ........................................... 423 3. Electrical Activity of the Myometrium and Other Mammalian

Smooth Muscles ............................................. 424 3.1. Descriptive Phenomena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 424 3.2. Ionic Basis of Electrical Activity ......................... 428 3.3. Tissue Phenomena ..................................... 442 3.4. Actions of Some Drugs on the Myometrium .............. 445

4. Summary and Concluding Remarks ........................... 449 5. References.. ... . . ... ..... . .. .. .. ... . . . .. .. . . . . . . . . .. . . . . .. .. 450

15 Ultrastructure of the Myometrium 455

w. C. COLE AND R. E. GARFIELD

1. Cellular Organization of the Myometrium.. . ... .. . . .. . . . .. . . . .. 455 2. Ultrastructure of Myometrial Smooth Muscle Cells . . . . . . . . . . . . .. 458

2.1. Size and Shape ........................................ 458 2.2. Organelles ............................................ 459 2.3. The Plasma Membrane ................................. 464 2.4. Effects of Hormones and Pregnancy............. ...... .. 468

3. Gap Junctions and Cell-to-Cell Communication in the Myometrium ................................................ 469 3.1. Gap Junction Structure ................................. 469 3.2. Gap Junctions in the Myometrium. . .. . . . . . . . . .. . . . . . . . .. 471

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3.3. Function of Gap Junctions. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 473 3.4. Control of Myometrial Junctional Communication ........ 480 3.5. Significance of Gap Junctions and Their Modulation

to Pregnancy and Parturition ........................... 487 4. Contractile Mechanism of Myometrial Smooth

Muscle Cells. . . . . . . . . . . . . . . . .. .. . . . . . . . . . . .. . . .. . . . . . . . . . . . .. 488 4.1. Thin Filaments ........................................ 488 4.2. Thick Filaments ....................................... 491 4.3. Cytoplasmic and Membrane-Associated Dense

Bodies ................................................ 493 4.4. Intermediate Filaments ................................. 494 4.5. Structural Organization of the Contractile Apparatus and

Its Possible Association with the Cytoskeleton . . . . . . . . . . . .. 495 4.6. Mechanical Transmission in a Multicellular Tissue ........ 497

5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 497 6. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 498

16 Uterine Control of Ovarian Function 505

L. L. ANDERSON AND A. I. MUSAH

1. Ovarian Function ............................................ 505 1.1. Corpus Luteum in Rodentia and Lagomorpha ............ 506 1.2. Corpus Luteum in Artiodactyla ......................... 508 1.3. Corpus Luteum in Primates. . . . . . . . . . .. . . . . . . . . . . . . . . . .. 512

2. Uterine Function ............................................ 512 2.1. Development and Regression of Endometrium and

Myometrium .......................................... 512 2.2. Role of the Uterus in Cyclic Periodicity .................. 514

3. Uterine-Ovarian and Conceptus Interaction in Regulation of Ovarian Function ............................................ 517 3.1. Uterine-Ovarian Function during Pregnancy. . . . . . . . . . . .. 517 3.2. The Role of Uterine-Conceptus Interactions on Ovarian

Function .............................................. 522 3.3. Uterine-Ovarian Microcirculation and Ovarian Function .. 524

4. Luteolytic Actions of the Uterus: Effects of Hysterectomy on Ovarian Function ............................................ 526 4.1. The Uterus and Luteal Function in Rodentia and

Lagomorpha .......................................... 527 4.2. The Uterus and Luteal Function in Artiodactyla .......... 528 4.3. The Uterus and Luteal Function in Primates ............. 530

5. Uterine-Ovarian Hormones and Ovarian Function ............. 532 5.1. Prostanoids and Leukotrienes ........................... 532 5.2. Relaxin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 534 5.3. Oxytocin... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 536 5.4. Other Hormones Affecting Uterine Function:

ACTH ................................................ 538 6. Mechanisms of Uterine-Ovarian Interactions in Regulating

Ovarian Function ............................................ 538

6.1. Morphology and Function of Placental and Luteal Cells.................................................. 538

6.2. Cellular and Biochemical Basis of Uterine-Ovarian Interactions ........................................... 540

7. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 542

17 Endocrine Control of Parturition 559

MELVYN S. SOLOFF

1. Problems in Understanding Basic Mechanisms of Parturition ............................................... 559

2. Preparation of the Uterus for Labor: Estrogen ................. 560 2.1. Possible Regulation of Estrogen Action at the Receptor

Level ................................................. 562 2.2. The Role of Estrogens in Humans.................. .. ... 562 2.3. Identification of Active Estrogens in Humans. .. . . .. . . . . .. 562 2.4. Control of Estrogen Levels. . . . . . . . . . .. . . . . . . . . . . . . . . . . .. 563

3. Uterine Quiescence .......................................... 564 3.1. Progesterone.... ............... . ........ .... . ..... .. .. 564 3.2. Relaxin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 566 3.3. Adrenergic Agents ..................................... 568

4. Activators of Uterine Activity ................................. 569 4.1. Prostaglandins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 569 4.2. Oxytocin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 580 4.3. Relaxin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 590

5. Cervical Distensibility ........................................ 590 5.1. Hormonal Control of Cervical Maturation . . . . . . . . . . . . . . .. 591 5.2. Relationship between Cervical Maturation and Myometrial

Contractions .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 592 6. A General Model for Parturition .............................. 593 7. Unification of Mechanisms Proposed for Spontaneous Labor

Induction ................................................... 593 7.1. Prostaglandins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 593 7.2. Estrogen/Progesterone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 594 7.3. Fetal ACTH ........................................... 594

8. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 594

Index 609

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