Ernst Schering Research Foundation Workshop Supplement 13 Biologie und Epidemiologie der Hormonersatztherapie – Biology and Epidemiology of Hormone Replacement Therapy Ernst Schering Research Foundation Workshop Supplement 13 Biologie und Epidemiologie der Hormonersatztherapie – Biology and Epidemiology of Hormone Replacement Therapy Diskussionen zur Postmenopausalen Gesundheit – Discussions on Post-Menopausal Health M.A. Lewis, M. Dietel, P.C. Scriba, W.K. Raff Editors With 16 Figures 123 Series Editors: G. Stock and M. Lessl Bibliografische Information der Deutschen Bibliothek Die Deutsche Bibliothek verzeichnet diese Publikation in der Deutschen Nationalbibliografie; detaillierte bibliografische Daten sind im Internet unter http://dnb.ddb.de abrufbar. Library of Congress Control Number: 2006923357 ISSN 0947-6075 ISBN-10 3-540-32341-4 Springer Berlin Heidelberg New York ISBN-13 978-3-540-32341-9 Springer Berlin Heidelberg New York Dieses Werk ist urheberrechtlich geschützt. Die dadurch begründeten Rechte, insbesondere die der Übersetzung, des Nachdrucks, des Vortrags, der Entnahme von Abbildungen und Tabellen, der Funksendung, der Mikroverfilmung oder der Vervielfältigung auf anderen Wegen und der Speicherung in Datenverarbeitungsanlagen, bleiben, auch bei nur auszugsweiser Verwertung, vorbehalten. Eine Vervielfältigung dieses Werkes oder von Teilen dieses Werkes ist auch im Einzelfall nur in den Grenzen der gesetzlichen Bestimmungen des Urheberrechtsgesetzes der Bundesrepublik Deutschland vom 9. September 1965 in der jeweils geltenden Fassung zulässig. Sie ist grundsätzlich vergütungspflichtig. Zuwiderhandlungen unterliegen den Strafbestimmun- gen des Urheberrechtsgesetzes. Springer ist ein Unternehmen von Springer Science+Business Media springer.com © Springer-Verlag Berlin Heidelberg 2006 Printed in Germany Die Wiedergabe von Gebrauchsnamen, Warenbezeichnungen usw. in diesem Werk berechtigt auch ohne besondere Kennzeichnung nicht zur Annahme, dass solche Namen im Sinne der Warenzeichen- und Markenschutzgesetzgebung als frei zu betrachten wären und daher von je- dermann benutzt werden dürften. Produkthaftung: Für Angabe über Dosierungsanweisungen und Applikationsformen kann vom Verlag keine Gewähr übernommen werden. Derartige An- gaben müssen vom jeweiligen Anwender im Einzelfall anhand anderer Literaturstellen auf ihre Richtigkeit überprüft werden. Editor: Dr. Ute Heilmann, Heidelberg Desk Editor: Wilma McHugh, Heidelberg Herstellung: Monika Riepl, Leipzig Umschlaggestaltung: design & production, Heidelberg Satz und Herstellung: LE-TEX Jelonek, Schmidt & Vöckler GbR, Leipzig Gedruckt auf säurefreiem Papier 21/3100/YL – 5 4 3 2 1 0 Foreword The Kloster Andechs Workshop The presentations and discussion points in this volume are the records of a workshop entitled “Women Between Biology and Culture”, held at Kloster Andechs (fittingly a Bavarian monastery) from 27 to 29 August 2003. This workshop was sponsored by Schering AG, who had expressed an interest in obtaining an objective view by experts on the situation re- garding the risks (and benefits) of hormone replacement therapy (HRT). The scientific co-ordination and moderation of discussions was under- taken by Prof. Peter Scriba and Prof. Werner Karl Raff, the former a renowned internist in Munich, Germany and the latter head of the business unit hormonal therapy and fertility control at Schering AG up to his retirement in 2002. Both workshop leaders adhered to the principle that this would be an independent workshop guided by the interest and opinion of independent experts. Schering AG was not to be involved in any aspects of the meeting. Accordingly, Schering AG had no influence on the objective, agenda, selection of participants, or on any other or- ganizational or scientific aspect of this meeting. The discussion points were documented and summarized by Dr. Michael Lewis. Because the discussion on hormone replacement therapy (HRT) has again reached a more objective tenor in the last few months, we have decided to pub- VI Foreword lish the proceedings of this workshop with the consent of all workshop participants. Like the workshop, the publication of these proceedings has received financial support by Schering AG. The presentations, as they were held at the workshop, were drafted by the workshop participants and consti- tute their opinion on selected aspects of HRT and its issues as they are currently presented. The summaries of the discussion points are a faith- ful representation of the discussion as it took place, and the overall conclusions of the workshop were drafted on site with the participation of all independent scientific experts. We, the editors, were pleased with the reception of the presentations and with the lively discussion at the workshop, and hope to convey some of the excitement of these sessions. Introduction to the Kloster Andechs Workshop Werner Karl Raff Hormonal therapy for complaints associated with menopause has been available for several decades. Its use is particularly widespread in the United States. This high prevalence is presumably due to the high fre- quency of partial and total hysterectomies in that country. The discussion of the risk of HRT is almost as old as the therapy itself, particularly as it concerns the risk of breast cancer, which may be associated with long-term treatment with HRT. However, the tone of the discussions on HRT has changed and be- come more terse after the discontinuation of the oestrogen/gestagen arm of the Women’s Health Initiative (WHI) study. The NIH workshop con- ducted in Washington, at which the preliminary results of this study were announced, seems to have polarized the scientific community’s thinking on HRT, with one implication being that questioning the WHI study’s results was scientifically unsound, or at least in bad taste. My impression at the Washington meeting was that no critique of study quality and validity would be condoned. The study was conducted on older postmenopausal American women, many of whom had consid- erable risk factors. The treatment allocated was a preparation with the highest market share in the United States (a combination of conjugated oestrogen and medroxyprogesterone-acetate). Although the investiga- VIII Werner Karl Raff tors asserted that the study was a randomized clinical trial, this assertion could hardly be maintained after due consideration of all elements. The overwhelming majority of experts who were either not involved in the study or who are independent of NIH funding classify this study as an observational study. In early May of 2003, a European Consensus Meeting was conducted in Athens, Greece. The results of the WHI study were discussed in the plenary sessions by epidemiologists and clinicians, and a set of state- ments was released. This meeting has undoubtedly contributed to a more objective discussion of matters concerning HRT. However, nonclinical experts, such as pathologists, were absent from this meeting, so that the majority of opinion was voiced by clinicians and gynaecologists. The focus of the risk–benefit evaluation therefore was on the observation of menopausal complaints and osteoporosis. Cultural changes, general life risk and altered disease risks due to an increase in the length of life and the consequences of not applying HRT did not receive particular consideration. In this context, it appears appropriate to cite the definition of health as stated by the World Health Organization (WHO). “Health is a state of complete physical, mental, and social well- being and not solely the absence of disease or infirmity.” We therefore consciously chose the comprehensive title of “Women Between Biology and Culture” for our workshop, and have not restricted our focus to risk–benefit evaluations as was done by WHI. In order to do justice to the ambitious workshop title, we invited gynaecologists, endocrinologists, internists, pathologists, epidemiologists, a philosopher and a risk expert to convene in Kloster Andechs. We planned 11 presentations with topic-oriented discussions and a full day of general discussion. Two presentations were designed to establish the framework for our human actions, one on the significance of the responsibility of our actions and inactions, another on the per- ception of risks and how risks are dealt with. Two presentations were intended to throw light on the circumstances of today’s woman after menopause. They deal with the epidemiology of the major medical con- ditions of advanced age and the lifestyle of today’s woman both in terms of biology and culture. Introduction to the Kloster Andechs Workshop IX This is followed by three lectures on the pathology of sex-specific female tumours, two epidemiological presentations, and one paper each on cardiovascular diseases in women and postmenopausal complaints, including osteoporosis. Hormone replacement therapy is addressed in all presentations. From the general discussions we are hoping to obtain an evaluation of the current knowledge on the risks and benefits of HRT and its relevance in medical practice. Finally, we are hoping for suggestions on how to address the questions left open by these studies and investigations. Contents I The Presentations 1 Introduction to the Presentations M.A. Lewis . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2 Zwischen Biologie und Kultur – Das HRT-Dilemma Women Between Biology and Civilization A. Teichmann . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 Probleme des Verantwortungsbegriffs im Spannungsfeld von Pharmaforschung und ärztlichem Handeln – Issues with the Term “Responsibility” H. Poser . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4 Epidemiology of Selected Diseases in Women L. Heinemann . . . . . . . . . . . . . . . . . . . . . . . . 47 5 Pathogenesis of Histological Types of Endometrial Cancer L.-C. Horn . . . . . . . . . . . . . . . . . . . . . . . . . . 55 6 HRT und Karzinome des Ovars und Kolon – Pathology of the Colon and Ovary M. Dietel . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 7 The Progenitor Cell Concept of Proliferative Breast Disease W. Böcker . . . . . . . . . . . . . . . . . . . . . . . . . . 71 XII Contents 8 Indication for HRT: Climacteric Complaints and Osteoporosis H.P.G. Schneider . . . . . . . . . . . . . . . . . . . . . . . 81 9 Hormonersatztherapie und kardiovaskuläre Erkrankungen – HRT and Cardiovascular Disease in Women E. Windler . . . . . . . . . . . . . . . . . . . . . . . . . . 103 10 The Million Women Study O. Lidegaard . . . . . . . . . . . . . . . . . . . . . . . . . 121 11 Paradigm Shift in Causal Thinking in Epidemiology S. Shapiro . . . . . . . . . . . . . . . . . . . . . . . . . . 127 12 Rezeption und Kommunikation von Risiken – Perception and Communication of Risk K. Heilmann . . . . . . . . . . . . . . . . . . . . . . . . . 135 13 Some Thoughts After the Kloster Andechs Workshop, August 2003 U. Karck . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 II The General Discussion 14 Menopause and the HRT Risk – Benefit Equation: Status and Outlook . . . . . . . . . . . . 151 III Conclusions of the Kloster Andechs Workshop 15 Workshop Consensus: The State of the Evidence . . . . . . 167 Previous Volumes Published in This Series . . . . . . . . . . . . 175