Ernst Schering Research Foundation Workshop 52 New Mechanisms for Tissue-Selective Estrogen-Free Contraception

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Ernst Schering Research Foundation Workshop 52

New Mechanisms for Tissue-Selective

Estrogen-Free Contraception

H.B. Croxatto, R. SchuÈrmann, U. Fuhrmann, I. Schellschmidt

Editors

With 36 Figures

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Series Editors: G. Stock and M. Lessl

Library of Congress Control Number: 2004111707 ISSN 0947-6075

ISBN 3-540-23089-0 Springer Berlin Heidelberg New York

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Preface

Currently, combined oral contraceptives are the most convenient and accepted way of hormonal contraception. Nevertheless, there is a constant demand for innovation both from the medical community and from consumers. Despite the high safety profile of available products, consumers and physicians seek contraceptives with addi- tional benefits and lower hormonal load. One option for addressing this need is tissue-specific progestins.

With the development of new molecules such as progestins with a tissue-specific mode of action, opportunities arise for new concepts in contraception.

Estrogen-free contraception ± e.g., by progestin-only pills ± is an established concept but with significant disadvantages which could be overcome by introducing potent locally active, tissue-specific progestins.

A major success factor for the realization of this concept is a deeper understanding of local pharmacological response to progestins in general and to new progestins in particular. The target organs in focus are the cervix, endometrium, ovary, tube and potentially the gonadotropic axis. To characterize specific effects on these targets is one of the major challenges in the development of contraceptives in general and new progestins in particular. There is a major interest from both molecular biologists and clinicians working in reproductive medicine to gain further insight into these mechanisms of action responsible for the contraceptive effect.

The aim of this workshop was to bring together experts in the field of molecular and pharmacodynamic actions of progestins with

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clinicians and medical specialists to discuss potential clinical endpoints, physiological reactions and (bio)markers which would be useful to describe the tissue-selectivity and the contraceptive action of new progestins in different target organs.

The contributions of the experts in this field will lead to a better understanding of the mechanisms underlying the organ-specific action of progestins and will help to design future clinical studies addressing the tissue-specific action of those compounds using mean- ingful endpoints (preferably surrogate markers). These endpoints are needed for the proof of concept of new concepts for fertility control.

The editors gratefully acknowledge the contributions of the au- thors in this book and the assistance provided by the Ernst Schering Research Foundation, in particular Dr. M. Lessl and Mrs. K. Szivos.

U. Fuhrmann, I. Schellschmidt, R. Schçrmann

VI Preface

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Contents

1 Progesterone Receptors and Opportunities for Contraception

H. B. Croxatto . . . . 1 2 Reproductive Tissue-Selective Actions of Progesterone

Receptors

B. Mulac-Jericevic, O.M. Conneely . . . . 19 3 The Progesterone Receptor/Estradiol Receptor

Association and the Progestin-Triggered S-Phase Entry A. Migliaccio, G. Castoria, M. Di Domenico, C. Ballar, M. Beato, F. Auricchio . . . . 39 4 Endometrial Morphology and Progestogens

H. O.D. Critchley . . . . 55 5 Role of Progesterone in the Structural and Biochemical

Remodeling of the Primate Endometrium

O. D. Slayden, R. M. Brenner . . . . 89 6 Effects of Progestogens on Endometrial Maturation

in the Implantation Phase

K. Gemzell-Danielsson, M. Bygdeman . . . . 119

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7Gene Expression During the Implantation Window:

Microarray Analysis of Human Endometrial Samples A. Schmidt, P. Groth, B. Haendler, H. Hess-Stumpp,

J. Kråtzschmar, H. Seidel, M. Thaele, B. Weiss . . . . 139 8 Role of EBAF/Lefty in Implantation and Uterine

Bleeding

S. Tabibzadeh . . . . 159 9 Mechanisms Underlying Menstrual Bleeding

Disturbances with Progestogens

M. Hickey, C. d'Arcangues . . . . 191 10 Human Endocervical Mucins

I.K. Gipson . . . . 219 11 Fallopian Tube Physiology: Preliminaries to Mono-

spermic Fertilization and Cellular Events Postfertilization R.H.F. Hunter . . . . 245 Previous Volumes Published in This Series . . . . 263

VIII Contents

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List of Editors and Contributors

Editors Croxatto, H.B.

Instituto Chileno de Medicina Reproductive (ICMER), Jos Ramon Gutierrez 295, Santiago de Chile, Chile

e-mail: [email protected] Fuhrmann, U.

Schering AG, CRBA, Gynecology and Andrology, Female Health Care, Mçllerstr. 178, 13342 Berlin, Germany

e-mail: [email protected] Schçrmann, R.

Schering AG, Strategic Business Unit, Gynecology and Andrology, Mçllerstr. 178, 13342 Berlin, Germany

e-mail: [email protected] Schellschmidt, I.

Schering AG, Strategic Business Unit, Gynecology and Andrology, Mçllerstr. 178, 13342 Berlin, Germany

e-mail: [email protected]

Contributors d'Arcangues, C.

Department of Reproductive Health and Research, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland

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Auricchio, F.

Dipartimento di Patologia Generale della II Universit di Napoli, Via L. de Crecchio 7, 80138 Napoli, Italy

e-mail: [email protected] Ballar, C.

Centre de RegulaciÕ Gen×mica (CRG), Passeig Maritim 37±49, 08003 Barcelona, Spain

Beato, M.

Centre de RegulaciÕ Gen×mica (CRG), Passeig Maritim 37±49, 08003 Barcelona, Spain

Brenner, R.M.

Oregon National Primate Research Center, Division of Reproductive Sciences, Oregon 97006-3448, Beaverton, USA

Bygdeman, M.

Department of Obstetrics and Gynecology, Karolinska University Hospital/Institute, S-17176 Stockholm, Sweden

Castoria, G.

Conneely, O.M.

Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, TX 77030 Houston, USA

e-mail: [email protected] Critchley, H.O. D.

The University of Edinburgh, Reproductive and Developmental Sciences, Obstetrics and Gynaecology, Chancellor's Building 49 Little, France Crescent, EH 16 4SB Edinburgh, UK e-mail: [email protected]

Di Domenico, M.

X List of Editors and Contributors

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Gemzell-Danielsson, K.

Department of Woman and Child Health, Division for Obstetrics and Gynecology, Karolinska Hospital/Institute,

S-17176 Stockholm, Sweden e-mail: [email protected] Gipson, I.K.

Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114 USA

e-mail: [email protected] Groth, Ph.

Genomics and Bioinformatics, Schering AG, Mçllerstr. 178, 13342 Berlin, Germany

e-mail: [email protected] Haendler, B.

Experimental Oncology, Schering AG, Mçllerstr. 178, 13342 Berlin, Germany

e-mail: [email protected] Hess-Stumpp, H.

Experimental Oncology, Schering AG, Mçllerstr. 178, 13342 Berlin, Germany

e-mail: [email protected] Hickey, M.

School of Women's and Infants' Health, University of Western Australia, King Edward Memorial Hospital, 374 Bagot Rd, Subiaco, WA 6008, Australia

e-mail: [email protected] Hunter, R.H.F.

Department of Clinical Studies ± Reproduction, Royal Veterinary and Agricultural University, Dyrlaegevej 68, 1870 Frederiksberg C, Copenhagen, Denmark

Kråtzschmar, J.

Genomics & Bioinformatics, Schering AG, Mçllerstr. 178, 13342 Berlin, Germany

List of Editors and Contributors XI

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Migliaccio, A.

Mulac-Jericevic, B.

Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, TX 77030 Houston, USA

Schmidt, A.

Schering AG, Female Health Care, S 10702 310, Mçllerst. 178, 13342 Berlin, Germany

e-mail: [email protected] Seidel, H.

e-mail: [email protected] Slayden, O.D.

Oregon National Primate Research Center, Division of Reproductive Sciences, Beaverton, Oregon 97006-3448, USA

e-mail: [email protected] Tabibzadeh, S.

Departments of Obstetrics and Gynecology and Fetomaternal Medicine, Stony Brook University, Stony Brook, NY 11794, USA e-mail: [email protected]

Thaele, M.

Institut fçr Fortpflanzungsmedizin, Kaiserstr. 5±7, 66111 Saarbrçcken, Germany

e-mail: [email protected] Weiss, B.

XII List of Editors and Contributors