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Schering Foundation Workshop
Editors: Gunter Stock Ursula-F. Habenicht
Vol. 1 Bioscience'" Society Workshop Report Editors: D. J. Roy, B. E. Wynne, R. W. Old
Vol. 2 Round Table Discussion on Bioscience'" Society Editor: J. J. Cherfas
Vol. 3 Excitatory Amino Acids and Second Messenger Systems Editors: V. I. Teichberg, L. Turski
Vol. 4 Spermatogenesis - Fertilization - Contraception Editors: E. Nieschlag, U.-F. Habenicht
Vol. 5 Sex Steroids and the Cardiovascular System Editors: P. Ramwell, G. Rubanyi, E. Schillinger
Schering Foundation Workshop 5
Sex Steroids and the Cardiovascular System P. Ramwell, G. Rubanyi, E. Schillinger, Editors
With 56 Figures
Springer-Verlag Berlin Heidelberg GmbH
ISBN 978-3-662-02766-0 ISBN 978-3-662-02764-6 (eBook) DOI 10.1007/978-3-662-02764-6
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting. reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1992 Originally published by Springer-Verlag Berlin Heidelberg New York in 1992 Softcover reprint ofthe hardcover 1st edition 1992 The use of general descriptive names, registered names, trademarks, etc. in this publicati on does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
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Preface
Evidence accumulated over the past decade show that gonadal steroid hormones participate in an important way in the physiological and pathophysiological regulation of the cardiovascular system. The hormonal profile appears to put males at a disadvantage biologically in terms of cardiovascular diseases. The incidence of hypertension is higher in men than in pre-monopausal women indicating an influence of gender on the hypertensive disease process. Males and females have equivalent cholesterol levels until puberty but males suffer an exponential increase in heart disease in their forties, while the female rise does not start until a decade later, after menopause. Animal and human studies provided ample evidence, that estrogens lower the levels of low density lipoproteins and keep high density lipoproteins elevated. These changes may be advantageous in the prevention of heart diesease. Coronary artery atherosclerosis has been shown to be more pronounced in ovarectomized female monkeys as in intact females. Androgen, conversely, lowers the high density lipoproteins and elevates low density lipoproteins. Regarding blood pressure, it is well established that hypertension is more severe or develops more rapidly in male than female rats in several genetic forms of hypertension, and that gonadal steroid hormones are probably playing an important role in explaining this observation. Risk factors of human hypertension and coronary heart dies ease include menopause and ovarectomy.
Despite these convincing evidences from epidemiological and animal studies, there are presently few data to link menopause to the increased rate of hypertension or coronary heart disease. For example, studies on cellular mechanisms of atherosclerosis have been conducted predomi-
VI Preface
nantly in male animals. The mechanisms by which steroids may influence the proliferation of smooth muscle cells and plaque formation is unclear. Although endothelial injury, activation and consequent dysfunction is an important feature in both hypertension and atherogenesis, data are not available on gender differences in vascular wall response to injury, endothelial integrity or the proliferative response.
The Schering Foundation Workshop on "Sex Steroids and the Cardiovascular System", which took place in Berlin on February 5-7, 1992, was organized to discuss the present knowledge and future research directions in this important, but still poorly understood field. Leading basic scientists, epidemiologists and clinicians reviewed and discussed three main themes: Firstly, sexual dimorphism and the role of sex steroids (estrogen, progesterone and testosterone) in the control of the cardiovascular system and physiological (e.g. pregnancy) and pathological (e.g. hypertension) conditions; secondly, sex steroids and vascular wall biology and pathology, and thirdly, oral contraceptive steroids and hemostasis.
This book contains the proceedings of the workshop. The excellent chapters by the leading experts give an overview of the methodologies (from transgenic techniques to classical physiology methods) and the multidisciplinary approaches utilized to analyze some of the scientific questions.
In addition to the comprehensive summary of the present state of the art in these three areas, this book also points out basic questions where future research is needed. The organizers of the workshop and editors of this volume consider the latter as one of the major achievements of the meeting and hope that this book will stimulate scientists and clinicians alike to continue or initiate research in these and related areas.
Peter Ramwell Gabor M. Rubanyi Ekkehard Schillinger
Contents
Cardiovascular Sexual Dimorphism Peter W. Ramwell and Estelle Ramey . ................. .
2 Sexual Dimorphism of Cardiovascular Function: The Role of Androgens Jurgen Bachmann. Ursula Ganten. Gunter Stock. and Detlev Ganten . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3 Sexual Dimorphism in the Cardiovascular Actions of Vasopressin Leonard Share and Joan T. Crofton . . . . . . . . . . . . . . . . . . .. 31
4 Cardiovascular Adaptation to Pregnancy Mark J. Morton .................................... 53
5 Oral Contraceptives and Thrombotic Risk: A Critical Overview Eberhard F. Mammen.. . . . . . . . . . . . . .. . . . . . . .. . . . . . .. 65
6 Studies on the Mechanisms of Action of Steroids on Coagulation and Fibrinolysis Cees Kluft, Jan A. Gevers Leuven, and Frans M. Helmerhorst . . . . . . . . . . . . . . . . . . . . . . . . . .. 95
VIII Contents
7 Can Animal Models Be Used to Predict the Hemostasiologic Effect of Steroid Hormones in Man? Andreas Siij3milch, Rupprecht Zierz, Karsten Parczyk, KrzystoJ Chwalisz, Karl-Heinrich Fritzemeier, and Berthold Baldus ................................ 111
8 Estradiol and Myointimal Proliferation Marie L. Foegh .................................... 129
9 Modulation of the Extracellular Matrix by Sex Steroids Hermann GraJ ..................................... 139
10 Vascular Non-genomic Effects of Estrogen Michel Farhat, Sylvie Abi-Younes, Roberto Vargas, Raymond M. Wolfe, Robert Clarke, and Peter W. Ramwell ............................... 145
11 Effects of Estrogens and Progestins on Atherosclerosis in Primates Michael R. Adams, Janice D. Wagner, and Thomas B. Clarkson ............................. 161
12 A Review of the Epidemiology of Postmenopausal Estrogens and the Risk of Coronary Heart Disease Meir J. StampJer ................................... 177
Subject Index ......................................... 199
List of Contributors
Abi- Younes, Sylvie Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC 20007, USA
Adams, Michael R. Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157
Bachmann, liirgen Gennan Institute for High Blood Pressure Research, 1m Neuenheimer Feld 366, 6900 Heidelberg, FRG
Baldus, Berthold Research Center of Schering AG, Miillerstr., 1000 Berlin 65, FRG
Chwalisz, Krzystof Research Center of Schering AG, Miillerstr., 1000 Berlin 65, FRG
Clarkson, Thomas B. Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157
x List of Contributors
Crofton, Joan T,
Department of Physiology and Biophysics, University of Tennessee, 894 Union Avenue, Memphis, TN 38163, USA
Farhat, Michel Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC 20007, USA
Foegh, Marie L. Department of Surgery, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC 20007, USA
Fritzemeier, Karl-Heinrich Research Center of Schering AG, Miillerstr., 1000 Berlin 65, FRG
Ganten, Detlef Max Delbriick Center for Molecular Medicine (MDC), Robert-RossleStr. 10, 1115 Berlin Buch, FRG
Ganten, Ursula Max Delbriick Center for Molecular Medicine (MDC), Robert-RossleStr. 10, 1115 Berlin Buch, FRG
Gevers Leuven, Jan A. IVVO-TNO, Gaubius Laboratory, P.O. Box 430, 2300 AK Leiden, The Netherlands
Graf, Hermann Institute of Pharmacology, Schering AG, Muellerstrasse 170-178, 1000 Berlin 65, FRG
Helmerhorst, Frans M. University Hospital, 2300 AK Leiden, The Netherlands
List of Contributors XI
Kluft, Cees IVVO-TNO, Gaubius Laboratory, P.O. Box 430, 2300 AK Leiden, The Netherlands
Mammen, Eberlwrd F. Departments of Obstetrics and Gynecology, Pathology and Physiology, Wayne State University School of Medicine, 275 East Hancock Avenue, Detroit, MI 48201, USA
Morton, Mark 1. Division of Cardiology, L464, Department of Medicine, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 9720l, USA
Parczyk, Karsten Research Center of Schering AG, Mtillerstr., 1000 Berlin 65, FRG
Ramey, Estelle Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington D.C. 20007, USA
Ram well, Peter W. Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC 20007, USA
Share, Leonard Department of Physiology and Biophysics, University of Tennessee, 894 Union Avenue, Memphis, TN 38163, USA
Stamp!er, Meir 1. Channing Laboratory, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, 180 Longwood Avenue, Boston, MA 02115, USA
Stock, Gunter Schering AG, Mtillerstr., 1000 Berlin 65, FRG
XII List of Contributors
Siij3milch, Andreas Research Center of Schering AG, Miillerstr., 1000 Berlin 65, FRG
Vargas, Roberto Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC 20007, USA
Wagner, Janice D. Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157
Wolfe, Raymond M. Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC 20007, USA
Zierz, Rupprecht Research Center of Schering AG, Miillerstr., 1000 Berlin 65, FRG