Schering Foundation Workshop 5

Sex Steroids and the Cardiovascular System

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

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© 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