CONTRACEPTION A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
ii
ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Contraception: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83843-7 1. Contraception-Popular works. I. Title.
iii
Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail:
[email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.
iv
Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on contraception. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
v
About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
vi
About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
vii
Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CONTRACEPTION ...................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Contraception................................................................................ 6 E-Journals: PubMed Central ....................................................................................................... 63 The National Library of Medicine: PubMed ................................................................................ 64 CHAPTER 2. NUTRITION AND CONTRACEPTION .......................................................................... 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Contraception ............................................................................ 109 Federal Resources on Nutrition ................................................................................................. 114 Additional Web Resources ......................................................................................................... 114 CHAPTER 3. ALTERNATIVE MEDICINE AND CONTRACEPTION .................................................... 119 Overview.................................................................................................................................... 119 National Center for Complementary and Alternative Medicine................................................ 119 Additional Web Resources ......................................................................................................... 126 General References ..................................................................................................................... 130 CHAPTER 4. DISSERTATIONS ON CONTRACEPTION ...................................................................... 131 Overview.................................................................................................................................... 131 Dissertations on Contraception ................................................................................................. 131 Keeping Current ........................................................................................................................ 137 CHAPTER 5. CLINICAL TRIALS AND CONTRACEPTION ................................................................ 139 Overview.................................................................................................................................... 139 Recent Trials on Contraception ................................................................................................. 139 Keeping Current on Clinical Trials ........................................................................................... 142 CHAPTER 6. PATENTS ON CONTRACEPTION ................................................................................ 145 Overview.................................................................................................................................... 145 Patents on Contraception........................................................................................................... 145 Patent Applications on Contraception....................................................................................... 158 Keeping Current ........................................................................................................................ 185 CHAPTER 7. BOOKS ON CONTRACEPTION .................................................................................... 187 Overview.................................................................................................................................... 187 Book Summaries: Federal Agencies............................................................................................ 187 Book Summaries: Online Booksellers......................................................................................... 188 The National Library of Medicine Book Index ........................................................................... 195 Chapters on Contraception ........................................................................................................ 196 CHAPTER 8. MULTIMEDIA ON CONTRACEPTION ......................................................................... 199 Overview.................................................................................................................................... 199 Video Recordings ....................................................................................................................... 199 Audio Recordings....................................................................................................................... 200 Bibliography: Multimedia on Contraception ............................................................................. 200 CHAPTER 9. PERIODICALS AND NEWS ON CONTRACEPTION ...................................................... 203 Overview.................................................................................................................................... 203 News Services and Press Releases.............................................................................................. 203 Newsletters on Contraception.................................................................................................... 205 Newsletter Articles .................................................................................................................... 206 Academic Periodicals covering Contraception ........................................................................... 207 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 209 Overview.................................................................................................................................... 209 U.S. Pharmacopeia..................................................................................................................... 209 Commercial Databases ............................................................................................................... 211
viii Contents
APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 215 Overview.................................................................................................................................... 215 NIH Guidelines.......................................................................................................................... 215 NIH Databases........................................................................................................................... 217 Other Commercial Databases..................................................................................................... 221 APPENDIX B. PATIENT RESOURCES ............................................................................................... 223 Overview.................................................................................................................................... 223 Patient Guideline Sources.......................................................................................................... 223 Finding Associations.................................................................................................................. 235 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 237 Overview.................................................................................................................................... 237 Preparation................................................................................................................................. 237 Finding a Local Medical Library................................................................................................ 237 Medical Libraries in the U.S. and Canada ................................................................................. 237 ONLINE GLOSSARIES................................................................................................................ 243 Online Dictionary Directories ................................................................................................... 246 CONTRACEPTION DICTIONARY........................................................................................... 247 INDEX .............................................................................................................................................. 317
1
FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with contraception is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about contraception, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to contraception, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on contraception. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to contraception, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on contraception. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
3
CHAPTER 1. STUDIES ON CONTRACEPTION Overview In this chapter, we will show you how to locate peer-reviewed references and studies on contraception.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and contraception, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “contraception” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Contraception in Women With Diabetes Mellitus Source: Diabetes Spectrum. 6(2): 80-86. March-April 1993. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: In this article, the author brings readers up-to-date on the current contraceptive options for the women with diabetes, previously impaired glucose tolerance, or previous gestational diabetes mellitus. The author stresses that the concept of total reproductive care must be developed for women with diabetes and those with prior GDM. Topics covered include the metabolic effects of estrogen and progestin; oral contraceptives and gestational diabetes mellitus; oral contraceptives and insulindependent diabetes mellitus (IDDM); oral contraceptives and noninsulin-dependent
4
Contraception
diabetes mellitus (NIDDM; the long-acting progestins, Depoprovera and Norplant; intrauterine devices; and barrier methods and sterilization. The author concludes that effective family planning programs can manage and reduce both contraceptive and diabetes risks for these patients. 2 tables. 44 references. •
Oral Contraception and Adolescent Women With Insulin-Dependent Diabetes Mellitus: Risks, Benefits, and Implications for Practice Source: Diabetes Educator. 22(4): 374-378. July-August 1996. Contact: Available from American Association of Diabetes Educators. 100 West Monroe, 4th floor, Chicago, IL 60603. (800) 338-3633 or (312) 424-2426. Fax (312) 424-2427. Summary: In this article, the author reviews oral contraceptive issues for teens with diabetes. The author provides practice implications for health professionals who are in a favorable position to influence the quality of diabetes and general health care for these adolescents. Topics include adolescent sexuality in general and in adolescents with diabetes; the use of oral contraceptives (OC) and their impact on diabetes; and the risks and benefits of using oral contraception in adolescents with diabetes. The author notes that adolescents frequently have poor impulse control, and many adolescents with diabetes who feel bleak about their future anyway may have a live-for-today attitude that interferes with effectively using contraceptive planning and improving glycemic control. On the other hand, women who are able to maintain optimal metabolic control regarding their diabetes also may do well with other health-related issues, such as the use of birth control. The author encourages health care providers to become comfortable discussing sexual issues with teens as part of a holistic approach to diabetes care. 39 references. (AA-M).
•
Contraception: Part of Planning a Health Baby Source: Diabetes Self-Management. 18(1): 15-18, 20, 23, 26-27, 29. January-February 2001. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Website: www.diabetes-self-mgmt.com. Summary: This article addresses the issue of contraception among people who have diabetes. For women who have diabetes and their partners, using birth control while planning a pregnancy can allow a woman the time she needs to get her blood glucose in the best control possible. This reduces the risks of birth defects to the baby and preserves the health of a woman prior to conception. Despite these important reasons for using birth control, the unplanned pregnancy rate for women with diabetes is 76 percent. This high rate of unintended pregnancy has been influenced by myths and misconceptions about diabetes, pregnancy, and birth control. Common myths are that women who have diabetes cannot get pregnant or cannot use birth control. Both myths are untrue, and women and their partners have a range of birth control options. No birth control option is off limits to a woman with diabetes just because she has diabetes. These options include nonhormonal methods and hormonal methods. Nonhormonal methods include natural methods such as abstinence, coitus interruptus, and fertility awareness and barrier methods such as the diaphragm, the cervical cap, male and female condoms, and one type of intrauterine device. Hormonal methods include contraceptive implants, injections, and pills. Two new hormonal contraceptive methods are expected to be available soon. One is an estrogen/progestin injection that has a 1 month duration, and the other is a 7 day contraceptive patch. In addition, the article offers suggestions for planning a pregnancy, identifies sources of help in preparing for a healthy pregnancy, and lists resources on contraceptive choices. 3 tables.
Studies
•
5
Hormonal Choices After Gestational Diabetes: Subsequent Pregnancy, Contraception, and Hormone Replacement Source: Diabetes Care. 21(Supplement 2): B50-B55. August 1998. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article assesses the effects of subsequent states of excess hormone exposure, that is, subsequent pregnancy, hormonal contraception, and hormonal replacement therapy, on the development of diabetes in women with prior gestational diabetes mellitus (GDM). The article reviews current literature on the effect of parity, hormonal contraception, and hormonal replacement therapy in healthy women and women with previous gestational diabetes and current diabetes. Subsequent pregnancy in women with prior GDM appears to triple the risk of subsequent diabetes, while lowdose progestin and estrogen combination oral contraceptives do not appear to clinically increase risk. Hormonal replacement therapy appears to lead to the greatest reduction in coronary artery disease in women at greatest risk, that is, those who have developed diabetes. Careful followup and metabolic surveillance should be provided when prescribing hormonal contraception or replacement therapy. In women with prior GDM, exposure to repeat pregnancy poses a greater risk for subsequent diabetes than either an exposure to low-dose progestin and estrogen combination oral contraceptives or to postmenopausal hormonal therapy, both of which do not appear to increase the risk of diabetes. Women must be educated about their individual risk of developing diabetes based on their identifiable risk factors. In addition, their general health status, including any cardiovascular risk factors, should be evaluated. 27 references. (AA-M).
•
Contraception: Preventing Pregnancy and Disease Source: Diabetes Forecast. 54(8): 32-34. August 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article discusses contraceptive options available for women with diabetes who are sexually active. Oral contraceptives are made from synthetic forms of estrogen and progesterone, two hormones involved with regulating the menstrual cycle. Although very effective and convenient to use, some women who have diabetes find that oral contraceptives affect blood glucose control, so they may have to adjust their diabetes treatment. In addition, oral contraceptives have some other side effects, including rising cholesterol or triglycerides, causing problems with clotting and circulation, and failing to provide protection from infectious diseases. Another form of contraception is the barrier method. Two common barrier methods are the diaphragm and condom. These methods, which do not interfere with blood glucose control, must be used every time a woman has intercourse and must be used correctly to be effective. Implantable devices are also another form of contraception. The intrauterine device (IUD) and Norplant are two devices available. The IUD, which does not affect blood glucose control or cause cholesterol or triglycerides levels to rise, is an attractive option for women who are no longer having children or who have just one sex partner. Norplant is a medication that comes in six small capsules surgically implanted under the skin of the arm. Depo-Provera, another medication that prevents pregnancies, requires getting an injection from a doctor every 3 months. The article includes a list of questions women can use to help them choose a contraceptive that is right for them.
6
Contraception
•
Birth Control Choices Source: Diabetes Self-Management. 8(3): 6-8, 10-12, 14-16. May-June 1991. Contact: Available from R.A. Rapaport Publishing Company. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: This article provides information on the various methods of birth control available to women with diabetes. Topics include pregnancy planning; choosing a method of contraception; the process of human reproduction; barrier methods including diaphragms, condoms, contraceptive sponges, cervical caps, and vaginal spermicides; oral contraceptives; the intrauterine device; fertility-awareness methods; ineffective methods; sterilization; and contraceptive implants. Two final sections consider birth control methods currently in the research and trial phases and a comment on making the right choice. The contact addresses for three family planning organizations are included.
Federally Funded Research on Contraception The U.S. Government supports a variety of research studies relating to contraception. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to contraception. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore contraception. The following is typical of the type of information found when searching the CRISP database for contraception: •
Project Title: ACROSOMAL MATRIX, FERTILIZATION
EXOCYTOSIS AND
MAMMALIAN
Principal Investigator & Institution: Gerton, George L.; Research Professor; Obstetrics and Gynecology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 28-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): Sperm competent for fertilization can become capacitated, bind to the zona pellucida (ZP) of an egg in a specific manner, and complete acrosomal exocytosis. Failure to carry out these functions results in infertility. Although the interactions between the ZP and the plasma membrane overlying the sperm acrosome have been considered important for sperm-egg recognition and signaling, recent results have prompted a reassessment of current paradigms concerning these interactions. The broad, long-term objective of this proposal is to understand how the acrosome functions in fertilization. The general hypothesis is that acrosomal exocytosis 2
Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
Studies
7
leads to the exposure of acrosomal matrix proteins that become a de facto extracellular matrix (ECM) on the surface of the sperm head, and that the dynamic interactions of this newly-exposed sperm ECM with the egg ECM (the ZP) govern sperm-egg recognition and sperm penetration of the ZP. Specific Aim 1 is to investigate acrosomal exocytosis using novel, sensitive analytical approaches to monitor OAM and PM fusion events in live sperm. The possibility will be examined that spontaneous acrosomal exocytosis is initiated during capacitation, a poorly defined maturation process that normally takes place within the female reproductive tract but can be mimicked experimentally. The hypothesis is that acrosomal exocytosis is initiated during capacitation and, in the absence of stimulatory factors, is a slow, discontinuous and Ca- dependent process. However, in the presence of stimulatory factors (e.g., ZP), acrosomal exocytosis is completed at an accelerated rate. Specific Aim 2 is to characterize the interactions of the acrosomal matrix with the zonae pellucidae of mammalian eggs. Components of the AM will be studied to determine if they possess ligand-binding properties that enable them to bind to the ZP of unfertilized eggs. Specific Aim 3 is to determine how structural properties and exocytosis-associated processing of AM components, e.g., sp56, affect their function. Structural determinants of sp56 will be studied to learn which domains are essential for binding of sperm to ZP glycoproteins by examining the structurefunction relationships of mutated recombinant sp56 proteins. In addition, mutant mice null for the sp56 gene will be created to determine if sp56 is essential for fertilization. The proposed experiments will develop new technologies for the study of molecular mechanisms of acrosomal exocytosis. Results from these experiments may provide new ways to address the poor ZP binding of sperm from some human infertility patients and may offer new avenues for contraception through the disruption of purposeful spermZP binding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOLESCENT CONTRACEPTION
MISCONCEPTIONS
ABOUT
HORMONAL
Principal Investigator & Institution: Clark, Liana R.; Assistant Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 15-JUL-1999; Project End 30-JUN-2004 Summary: PROFESSIONAL GOAL: The overall goal of this patient-oriented research career development award proposal is to contribute to the professional, academic, and research development of Dr. Liana Clark. In addition to the proposed project exploring the concerns and misconceptions about hormonal contraception, Dr. Clark will also pursue research training at the University of Pennsylvania. She will take courses toward the Master's degree in Clinical Epidemiology and Biostatistics, as well as courses in bioethics and financial issues in medicine. Under the mentorship of Dr. Loretta Jemmott, Dr. Clark hopes to use this award to establish herself as an academic leader in the area of adolescent sexual risk behaviors. SPECIFIC AIMS OF CONTRACEPTION PROJECT: This project will use both cross sectional and longitudinal study design to: a) identify the attitudes, concerns and misconceptions of adolescents regarding hormonal methods of contraception (Norplant, Depo-Provera and the oral contraceptive pill); b) determine the gender, racial/ethnic, sexual history, and sociodemographic factors associated with attitudes, concerns and misconceptions about hormonal contraception; and c) determine how strongly these attitudes, concerns and misconceptions predict nonuse of, or noncompliance with hormonal contraception. This study will have two parts: (1) a baseline component that includes three stages designed to identify adolescent attitudes, concerns and misconceptions about hormonal contraception and the gender,
8
Contraception
racial/ethnic, sexual history, sociodemographic features associated with holding such concerns; and (2) a follow-up component to determine whether hormonal contraceptive use and/or compliance is related to attitudes, concerns and misconceptions about these methods of contraception. HYPOTHESES: 1. The majority of adolescents studied will have concerns and misconceptions about hormonal contraception. 2. Minority adolescents (African-American and Hispanic) will have greater negative attitudes, concerns and misconceptions about hormonal contraception than will white nonHispanic adolescents. 3. Adolescents who have strongly negative attitudes, concerns and misconceptions about hormonal contraception will be less likely to choose to use these methods. 4. Adolescents who have negative attitudes, concerns and misconceptions about hormonal contraception will be less compliant with the use of these methods. CONCLUSIONS: By targeting the negative attitudes, concerns and misconceptions regarding hormonal contraception, we will be better able to encourage use of these highly effective methods by adolescents. Increased usage and improved compliance with Depo-Provera, Norplant and the oral contraceptive pill will result in an overall decrease in the rate of unintended adolescent pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APPLICATION OF TRANSGENIC TECHNOLOGIES TO BABOONS Principal Investigator & Institution: Mccarrey, John R.; Professor of Cell & Molecular Biology; Southwest Foundation for Biomedical Res San Antonio, Tx 782450549 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 30-APR-2004 Summary: (provided by applicant): The long-term goal of this project is to develop technology to produce transgenic baboons and to make this technology available at the Southwest Regional Primate Research Center and elsewhere to provide a powerful genetic, developmental and physiological nonhuman primate model system for biomedical research. Specific applications of this technology relevant to areas of reproductive biology and contraception and genetics of complex diseases are described herein. However, the availability and optimization of this technology will revolutionize experimental approaches in a wide variety of biomedical areas in nonhuman primate research. Standard methodology currently used to produce transgenics in smaller animals such as mice is prohibitively impractical in nonhuman primates. The approach used will be based on a recently developed technique of producing transgenesis by ICSI as first developed in the mouse by Yanagimachi and coworkers, and recently applied to rhesus monkeys by Schatten and coworkers. A method based on pronuclear injection of IVF embryos will be tested. Recent progress in optimizing superovulation ultrasound monitoring of ovarian stimulation, oocyte harvest, production of embryos by IVF and ICSI and introduction of transgenes into baboon embryos using ICSI is summarized. The goal of the research proposed in this R21 application is to further optimize these technologies for use in the baboon, and in so doing to enhance the efficiency of this approach in nonhuman primates in general. The specific aims of this application include optimization of the following methodologies in the baboon: 1) production of embryos in vitro by IVF and ICSI and subsequent culture to cleavage and blastocyst stages, 2) transfer of IVF embryos to female recipients to foster development to term, and 3) the production of transgenic embryos, including analyses of expression and integration of the transgene and demonstration of tissue-specific transgene expression in embryos. These aims are designed to demonstrate the feasibility and to optimize the efficiency of producing transgenic baboon embryos and the potential to carry these to term to yield transgenic offspring. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies
•
9
Project Title: AUTO/PARACRINE MECHANISMS IN HUMAN IMPLANTATION Principal Investigator & Institution: Giudice, Linda C.; Professor; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 02-MAY-2002; Project End 31-MAR-2007 Summary: For successful implantation in humans, the endometrium must be adequate prepared by steroid hormones to allow attachment of the embryo to the epithelium, passage through the epithelium, and invasion of the trophoblast into the maternal stroma. We have had a long-standing interest in the insulin-like growth factor (IGF) family and its role in the invasive phase of human implantation. IGF-II is exclusively expressed by the invading trophoblast, and it regulates restraints of invasion produced by the maternal decidua. Two inhibitors of IGF action, IGF binding protein (IGFBP)-1 and IGFBP-1, are made by the decidua. We have identified an enzyme that cleaves IGFBP-4 and decreases its affinity for IGF-II and identified it as a known protein with unknown function, pregnancy-associated plasma protein-A (PAPP-1). Its naturally occurring inhibitor is also a major product of the invading trophoblast in human pregnancy. In this grant we propose to investigate the hypothesis that IGFBP-4 proteolysis increases IGF-II bioavailability in the placental bed to enhance IGF-II action on the decidua, resulting in regulation of maternal restraints on invasion. In addition to the invasive phase, we have initiated studies relevant to paracrine dialogs between the endometrial epithelium and stroma important during the window of implantation. Our recent gene profiling of human endometrial biopsy specimens reveals marked upregulation of IGF and wnt family mRNAs during the implantation window. Wnts are important in epithelial- mesenchymal interactions, and we have identified selective expression of wnt family members in human endometrial epithelial and stroma. IGF-II and wnt signaling may interface through a common, pathway, suggesting a role for stromal-derived. IGF-II interacting with epithelium-derived wnt on effects on the stroma during the implantation window. Herein, we propose: (1) during the invasive phase of implantation to investigate the function(s) of IGF-II, IGFBP-4, PAPP-A, and its inhibitor at the decidual: trophoblast interface; (2) during the window of implantation, to investigate the role of wnt and IGF-II signaling in epithelial-stromal communication. We work with the human model because of uniqueness of implantation in humans. These studies have relevance to infertility, ectopic pregnancy, and contraception. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: AUTOIMMUNE OOPHORITIS: CONSEQUENCES OF GAMETE VACCINES Principal Investigator & Institution: Tung, Kenneth S.; Professor; Pathology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 28-FEB-2007 Summary: (provided by applicant): A major long-term goal of my laboratory is to develop a safe and effective human contraceptive vaccine. To this end, we have taken a two pronged approach: 1) To develop an effective method of reversible contraception, and 2) To assure safety of the vaccine by identifying and resolving potential problems associated with contraceptive vaccination. A chimeric peptide (CP2) that contained a native ZP3 B cell epitope (335-342) and a foreign T cell epitope has proved to be an efficacious vaccine that does not in duce ovarian autoimmune disease in adult animals. CP2 immunization led to 70% reduction in female fertility that was reversible, and their ovaries were free of pathology. However, we have now encountered a new problem associated with the CP2 vaccine. Although the ovaries of adult mice immunized with
10
Contraception
CP2 were free of pathology, the ovaries of their progeny developed AOD, and in some cases there was loss of oocytes. It is unclear is why progenic AOD [autoimmune ovary disease] should occur only in B6AF 1 neonates but not the neonate of five other inbred strains and one outbred strain. Nor do we understand why progenic AOD should occur only in mice with Ab to one ZP3 B cell epitope [ZP3 (335-342)] but not with Ab to anotherZP3 B epitope [ZP3 (l7I-l80)]. These findings have prompted the hypothesis that progenic AOD represents a unique occurrence confined to a unique mouse strain in response to a unique ZP3 B cell epitope. In the proposed research, we will determine the generalizability of progenic AOD, understand the mechanism of neonatal ovarian injury, elucidate the basis for its unique occurrence, and define its long-term effect. At the same time, our goal is to identify new oocyte antigen (Ag) and examine their potential as candidate Ag in a new, safe and effective ZP contraceptive vaccine. In Aim 1, we will determine the natural history and generalizability of progenic AOD, the fertility of postpubertal mice with a antecedent progenic AOD, the variations in the murine neonatal response to CP2 antibody, and the occurrence of progenic AOD in the primate. Aim 2 will identify new ZP B cell epitopes that confer contraception without progenic AOD. In Aim 3, we will further investigate the mechanism of progenic AOD, and identify the mechanism responsible for the unique occurrence of progenic AOD. Specifically, we will determine the immunogenetic regulation of the immune response to CP2, and the influence of the B cell epitope specificity of the ZP Ab on the induction of progenic AOD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOCHEMISTRY FERTILIZATION
OF
SPERM-EGG
INTERACTION
AND
Principal Investigator & Institution: Vacquier, Victor D.; Marine Biology Research Div; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JUN-1978; Project End 31-MAY-2002 Summary: The objective of this research is to gain fundamental knowledge of the cell biology and biochemistry of sperm-egg interaction. Sea urchins and abalone are used because they are nonmammalian, yet exhibit striking similarities to mammalian gamete interaction. The cell biology and biochemistry of sperm-egg interaction is one of the least understood fundamental biological processes. Basic knowledge gained by this research may be used in the future development of novel methods of contraception in mammals. In sea urchins this proposal focuses on the interaction of REJ (the sperm membrane receptor for egg jelly) with ARI (the acrosome reaction inducing glycoprotein purified from egg jelly). 50% of REJ is homologous to the human polycystic kidney disease protein PKD1. Study of how REJ regulates sperm ion channels may aid in the understanding of this significant human disease. In abalone, this project focuses on the egg vitelline envelope ligand for lysin, the sperm protein which dissolves the egg envelope by a nonenzymatic mechanism. This study may aid in understanding the biochemical mechanism mammalian sperm use to penetrate the egg zona pellucida. The specific aims for sea urchin sperm are: 1. To identify sperm membrane proteins associated with the 210kDa receptor for egg jelly (REJ). 2. To clone, sequence and characterize the proteins associated with REJ. 3. To determine the functions of the protein modules of REJ. 4. To characterize the acrosome reaction inducer (ARI) from sea urchin egg jelly which binds sperm REJ. 5. To isolate and characterize the oligosaccharide of ARI which binds to REJ. 6. To use syntaxin and synaptotagmin, which we have cloned from sperm, to identify proteins associated with exocytosis of the acrosomal vesicle. The specific aims for the abalone ligand for lysin are: 7. To study the
Studies
11
biochemistry and ultrastructure of the vitelline envelope ligand (VE-L) for lysin. To determine the affinities of homospecific and heterospecific combinations of lysins and VE-Ls. 8. To clone, sequence and characterize the cDNA for the VE-L. 9. To determine if the binding of lysin to VE-L is based on protein or carbohydrate components of the VEL. 10. To cleave the VE-L into the smallest fragment retaining affinity for lysin. To isolate and characterize this fragment. To cocrystallize lysin complexed with this fragment for x-ray diffraction analysis. 11. To determine which residues of lysin are responsible for its species-specific dissolution of the egg vitellin envelope (VE). 12. To determine the mechanism by which lysin dissolves the VE. Is it based on the stereospecific severing of hydrogen bonds, or hydrophobic interaction? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BRAIN GENES GOVERNING REPRODUCTION Principal Investigator & Institution: Steiner, Robert A.; Professor; Obstetrics and Gynecology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-APR-1993; Project End 30-JUN-2003 Summary: In mammals, reproductive activity is initiated and maintained by physiological factors associated with nutrition, adiposity, and metabolism; however, little is understood about mechanisms that mediate the integration of metabolism and reproduction. Leptin is a newly discovered satiety hormone and metabolic activator, which has recently been shown to have stimulatory effects on the reproductive system and has been postulated to serve as an important conduit linking the body~s metabolic and reproductive control systems. The overall goal of this research is to understand the cellular and molecular mechanisms of leptin~s action on the neuroendocrine reproductive axis-focusing on 4 hypothalamic regions-the arcuate, dorsomedial, paraventricular, and medial preoptic nuclei. The specific aims are first, to elucidate the role of proopiomelanocortin neurons and the melanocortin type 4 receptor in mediating leptin's effect on reproductive function and to identify their anatomical substrate; second, to examine the functional significance of agouti- related protein (ARP) in mediating leptin~s action in the brain and to trace the cellular pathway of ARP~s action in the hypothalamus. These studies will be performed with laboratory rats and different lines of transgenic mice as the experimental animals. The methods used to accomplish these objectives will include various in vivo pharmacological and endocrine manipulations, hormone assays, single- an double-label in situ hybridization, antisense oligonucleotide blockade of neuropeptide synthesis, neuronal tract tracing, and the creation and analysis of several new lines of mutant/transgenic mice bearing alterations in one or more genes related to leptin's signaling mechanism. Learning more about the mechanisms of leptin's action on the brain may help us to understand the molecular basis of certain disorders of human reproduction (e.g., hypothalamic amenorrhea and infertility linked to metabolic wasting diseases such as diabetes mellitus) and may even provide a rationale for the development of better methods of contraception. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: BREAST TUMOR INHIBITION BY ANTIPROGESTINS Principal Investigator & Institution: Wiehle, Ronald D.; Zonagen, Inc. 2408 Timberloch Pl, B-4 the Woodlands, Tx 77380 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: (provided by applicant): The use of antiestrogens in women for the treatment of breast cancer, although far from ideal, is one of the few therapies currently available.
12
Contraception
The following revised proposal outlines experiments to be performed under a SBIR that would clarify the properties of certain new antiprogestins as adjuvant therapies analogous to current therapies utilizing tamoxifen and SERMs. In May 1999, a Licensing Agreement between Zonagen and the NICHD was finalized to develop new antiprogestins. We expect that the new generation of compounds will be used for a number of indications where the etiology is dominated by progesterone. The promise of the first antiprogestin, RU 486, has gone unfulfilled because of its extensive antiglucocorticoid effects and the political backlash to its use as an abortifacient. Indications for antiprogestin use could include oral contraception, labor induction, cervical ripening, hormone replacement therapy (HRT), and treatment of uterine fibroids, endometriosis, and especially breast cancer. It is the overall aim of this proposed SBIR to determine effects on the growth of previously established rodent breast cancers with the ultimate intention of introducing a new adjuvant treatment for human breast cancer. The rat model has been shown to respond to antiprogestins such as RU 486 with a decrease in the growth of lesions following treatment. There is a need to determine whether our lead compound. CDB-4124, has the same anticancer properties as RU 486 as a proof-of-principle. Moreover, we need to determine the doseresponse of that lead compound. Phase II would determine whether a secondary class of compounds have similar activity, whether the best compound(s) reduce the ultimate size and appearance of lesions if used prior to frank appearance, and their synergism with antiestrogens. Additionally, the possibility that antiprogestins can inhibit breast tumor growth and development would greatly enhance the potential of such compounds for chemoprevention and other long-term therapies (fibroids, endometriosis, HRT) and such a drug should find wide and unqualified acceptance among women. PROPOSED COMMERCIAL APPLICATION: Antiprogestational compounds from the Licensing Agreement could fill Zonagen's developmental pipeline with drugs for those diseases and, potentially, several other indications. New antiprogestins discovered by NICHD and realized as drugs through this proposed SBIR, satisfy the need to bring the results of government-sponsored science into the public domain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CAREER DEVELOPMENT AWARD IN INTERNATIONAL WOMEN'S HEALTH Principal Investigator & Institution: Stringer, Elizabeth M.; Obstetrics and Gynecology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant): The purpose of this International Research Scientist Development Award is to provide Dr. Elizabeth Stringer, Instructor in the Department of Obstetrics and Gynecology at the University of Alabama at Birmingham (UAB), with sufficient protected time to 1) develop a broad base of understanding in the theoretical aspects of clinical research; 2) gain practical experience in the conduct of methodologically-rigorous clinical research in the developing world, particularly in the area of contraception; and 3) develop expertise in decision analysis and outcomes research. These skills will be obtained in a systematic fashion, as outlined in this research career award application. Dr. Stringer will undertake Master's level coursework in the UAB School of Public Health, with a special emphasis on epidemiology, clinical trials design, and outcomes research. Under the direction of her mentors, Drs. Sten Vermund and Moses Sinkala, the candidate will conduct a randomized clinical trial of the intrauterine contraceptive device (IUD) versus "user-chosen" hormonal
Studies
13
contraception among HIV-infected women in Lusaka, Zambia. The trial will be linked to the ongoing collaborative research activities of her mentors. The candidate will be primarily responsible for all aspects of the randomized trial, including protocol development, training, implementation, daily management, and analysis. This experience will provide her with valuable field expertise in the conduct of clinical research in the developing world. In the latter part of the award, under the direction of UAB faculty member Dr. Dwight Rouse, the candidate will develop a decision analysis model to describe the health effects and costs of the IUD and other contraceptive strategies in the developing world. Data collected from the randomized trial will be used to inform the model. The cumulative effect of this award will be to enable Dr. Stringer to compete successfully for NIH individual investigator funding, with an ultimate goal of helping to advance the health and status of women and their infants in the developing world. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CDB-2914 /PROGESTERONE RECEPTOR MODULATOR /VAGINAL RING Principal Investigator & Institution: Tsong, Yun-Yen; Population Council 1 Dag Hammarskjold Plaza New York, Ny 10017 Timing: Fiscal Year 2002; Project Start 30-AUG-2002; Project End 28-FEB-2007 Summary: (provided by applicant): A new progesterone receptor modulator, CDB-29 14, with potent antiovulatory properties will be investigated for its potential as a contraceptive for women when delivered through a sustained-released system such as a contraceptive vaginal ring. The molecule has been synthesized and developed by the National Institute of Child Health and Human Development (NICHD) for emergency contraception. Toxicology studies conducted at the NICHD indicate that the compound is safe, and the Food and Drug Administration (FDA) has approved an Investigational New Drug for clinical study. CDB-2914 binds to the progesterone receptor (PR) with high affinity and is a potent progesterone antgonist (PA). It exhibits potent antiovulatory properties in animal models. These properties of CDB-2914 make it attractive as a potential contraceptive, and preliminary studies suggest the possibility of delivering CDB-2914 continuously at low doses via a silastic vaginal ring. The research project described in this proposal will include the following studies: 1) The mechanism of action at the ovarian level will be explored. 2) CDB-2914 will be formulated into vaginal gel and rings and will involve assessment of in vitro release and stability studies. The extensive experience of The Population Council in laboratory scale manufacture of contraceptive rings (CRs) and in evaluation of their clinical performance provides a firm base for completing the development of the CDB-2914 device. 3) A radioimmunoassay will be set up for CDB-2914 and validated for kinetic studies to be conducted in animals and in women. 4) The potential proliferative action of CDB-2914 on human breast cells will be investigated as well for safety purposes, in anticipation of eventual long-term contraceptive efficacy studies in women. Parallel studies in women and monkeys, which relate to the above studies but for which funding has been obtained or will be requested from other sources, will be described separately. Ultimately, this new estrogen-free method should be associated with fewer side effects than estrogen-containing contraceptives and will likely induce endometrial changes resulting in amenorrhea, a condition highly acceptable to women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
14
Contraception
•
Project Title: CELLULOSE ACETATE PHTHALATE SPERMICIDE ACTION Principal Investigator & Institution: Mahony, Mary C.; New York Blood Center 310 E 67Th St New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 26-SEP-2001; Project End 31-JUL-2005 Description (provided by applicant): Spermicidal agents exert an anti-fertility effect upon spermatozoa as they pass through the female reproductive tract. They must act either to kill or immobilize sperm or render them incapable fertilization. These agents may act on a number of sperm functions; therefore, it is important to examine potential spermicidal actions with a battery of physiological, cellular and biochemical assays to secure a clear understanding of contraceptive efficacy. The spermicidal agent, nonoxynol-9, acts on the sperm plasma membrane to result in solubilization and cell death. Cellulose acetate phthalate (CAP) offers promise as a safe and effective broadspectrum microbicidal agent. While nonoxynol-9 disrupts sperm cellular integrity by its detergent nature, the phthalic acid residues of CAP, essential for its antiviral activity, are expected to exert spermicidal activity by providing low pH buffering and hydrophobicity. The objective of this proposal is to examine its potential spermicidal actions. From the aforementioned observations, the hypothesis is: CAP possesses spermicidal activity and will act to disrupt sperm functions by a number of different physical and biochemical actions. The specific aims are: (1) determine the effects of soluble CAP at neutral pH on sperm functional capacity; (2) determine the binding potential of soluble CAP at neutral pH to human sperm; (3) characterize the effects of a topical cream containing micronized CAP and a CAP sponge on sperm functional capacity and cervical mucus receptivity; and, test the in vivo contraceptive activity of CAP formulations in a rabbit model. Information gleaned for these studies will provide essential information on the spermicidal activity of CAP formulations. With a clear understanding of the spermicidal actions of CAP, the applicant will have identified a broad-spectrum microbicide with spermicidal activity that acts without detergent-like toxicity which will provide a woman-managed method of contraception and prevention of STD, including HIV-1 transmission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: CHANGING SOCIAL CONTEXTS AND FAMILY FORMATION Principal Investigator & Institution: Axinn, William G.; Professor; Population Studies Center; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-SEP-1994; Project End 31-AUG-2004 Summary: This is a continuation proposal to use new detailed dynamic measures of change over time in neighborhoods to dramatically advance our understanding of the impact of social context on behavior in several new directions. Our plan is to take advantage of a unique social setting in Nepal to investigate the social and economic factors which alter family formation processes and cause fertility decline. The aim of this research is to find empirical answers to five specific questions regarding the beginning of a transition from high fertility and no use of birth control to low fertility and the widespread use of birth control. These questions are: 1) To what extent do changes in the social and economic context influence family formation processes, particularly marriage, the timing of the first birth and contraception to terminate childbearing? 2) How do qualitative dimensions of these contextual changes, such as the quality of new schools or health services, shape family formation processes? 3) Do changes in the family organization of individual life courses transmit these contextual effects? 4) Does
Studies
15
the family organization of neighbors life courses transmit these contextual effects? and 5) Do variations in attitudes and beliefs, or neighbors attitudes and beliefs, explain these consequences of community-level changes? Although our preliminary research demonstrates significant effects of community-level social and economic change on the adoption of birth control, we still know little about the extent to which these same changes influence other dimensions of family formation or the mechanisms through which these influences are transmitted. The large number of unanswered theoretical questions regarding the causes of fertility decline, along with the high priority policy makers place on reducing fertility in South Asia, make this research particularly timely. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION OF FLAGELLAR PROTEINS INVOLVED IN SPER* Principal Investigator & Institution: Sapiro, Rossana; University of the Republic 1824 Av 18 De Julio Montevideo, Timing: Fiscal Year 2002; Project Start 18-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant) Sperm must have purposeful forward motion following deposition in the female reproductive tract in order to fertilize ovulated eggs. The factors that control the sperm flagellar power stroke and waveform are poorly understood. Spag6, a protein containing eight armadillo repeats, a protein interaction motife, is the murine orthologue of Chlamydomonas PF16, a central apparatus protein required for algae flagellar function. Mice lacking Spag6 are infertile due to a severe sperm motility defect, resulting in part from disruption of the flagellar axoneme architecture. This model will be used to identify proteins that interact with Spag6 and thus expand the catalogue of the mammalian axonemal proteins that are essential for flagellar structure and function. Using two dimensional gel electrophoresis and surfaceenhanced laser desorption/ionization mass spectrometry, the proteome of Spag6deficient sperm will be characterized and compared with wild-type mouse sperm to identify missing proteins. The missing proteins will be characterized and their cDNAs cloned for further documentation of interaction with Spag6 using yeast two-hybrid and pull-down assays and immunocytochemical co-localization. The domains of Spag6 that mediate protein-protein interactions will be defined using yeast two-hybrid and other assays. The proteome of human sperm with motility and ultrastructural defects that mirror those of the Spag6-deficient mouse will be examined to screen for humans with SPAG6 deficiency. The knowledge gained from this research will provide a molecular framework for understanding sperm motility defects that cause male infertility and possibly offer new avenues for contraception through the disruption of purposeful sperm motion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: COLLABORATIVE STUDY OF GENETICS OF DIZYGOTIC TWINNING Principal Investigator & Institution: Montgomery, Grant W.; Queensland Institute of Medical Research Bramston Terr, Herston Brisbane, Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Infertility is a major public health problem that affects 10-15% of couples (2.5 million) in the US. The goal of this program is to locate genes that make substantial contributions to variation in natural dizygotic (DZ) twinning to understand critical pathways controlling female fertility. This will have
16
Contraception
practical application in treatment of infertility and may provide new approaches to contraception. The proposed study extends our previous studies of the endocrinology, epidemiology, and molecular genetics of twinning in humans and in large animal models. We have ascertained 342 families with sister pairs who have both given birth to spontaneous DZ twins and a further 386 families with case-two parent triads and have collected DNA samples from the sisters' parents and other siblings. We shall use information from our twin studies and the Australian and Netherlands Twin Registries to collect an additional 240 affected sister pair families from Australia and New Zealand and 418 families from the Netherlands. DNA samples from these families will be used to complete a 10cM genome scan in 1000 families. We will use sib pair linkage analysis to locate QTLs for twinning. Our candidate positional cloning in animal models recently identified mutations in two genes (BMP15 and BMPRIB) from intra-ovarian signaling pathways that increase twinning frequency, and cause infertility in homozygous carriers of the BMP15 mutations. One important question is whether natural variation in human twinning is controlled by these emerging mechanisms or through other pathways. We will use available samples to immediately begin candidate gene studies by mutational screening and typing SNP markers in genes from this pathway (BMP15, GDF9, BMPR1B) using a matched case-control design with cases from our existing families and matched control samples. Significant associations will be tested in additional cases and their parents using the transmission disequilibrium test. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMPUTER-AIDED PREGNANCY/STDS
COUNSELING
TO
PREVENT
Principal Investigator & Institution: Gold, Melanie A.; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213
TEEN Hosp
Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 30-MAR-2007 Summary: (provided by investigator): Adolescent unintended pregnancy and STDs remain at epidemic levels in the United States. Healthy People 2010 Objectives set a goal to increase to 90 percent the proportion of sexually active adolescents who use contraception that both effectively prevents pregnancy and provides barrier protection against disease. How to effectively counsel adolescents to reach this goal is unclear. Counseling and feedback based on the Transtheoretical Model (TTM) have demonstrated greater success than standard, action-oriented advice in several domains of behavior change. The effectiveness of this type of counseling to alter female adolescents' sexual and contraceptive behaviors has not been rigorously evaluated. We propose recruiting 660 female adolescents, ages 13 to 21 years, from an inner-city, hospital-based clinic and randomizing them to either an innovative Computer-Assisted Motivational Intervention (CAMI) or a Didactic Educational Control (DEC). The CAM! group will receive three, 30-minute sessions of one-on-one counseling with a counselor that is guided by computer-generated personalized feedback. The CAMI is based on the principles of the TTM and on Motivational Interviewing. The DEC provides three 30minute sessions of one-on-one didactic information on contraception, STD prevention, and abstinence. The two interventions are identical in length and timing but vary in educational content, counseling style, and the provision of personalized feedback. We will track the two groups of female adolescents in this study through a 6-month intervention phase and a 12-month follow-up phase to assess differences in sexual and contraceptive behaviors by group. The primary specific aim for the study is to evaluate the efficacy of the CAMI as compared to the DEC in reducing sexual behaviors that increase the risks of both unintended pregnancy and STDs. We will examine protective
Studies
17
sexual behaviors in three ways: 1) behaviors that protect against pregnancy; 2) behaviors that protect against STDs; and 3) behaviors that protect against both pregnancy and STDs. Our primary hypothesis is that the CAMI will decrease the proportion of subjects who engage in any intercourse that is poorly protected against pregnancy and against STDs. We also predict that among sexually active subjects, the CAMI will increase the percentage of episodes of intercourse that are well protected by the use of both condoms plus another contraceptive. Finally, we also predict that the CAMI will increase the prevalence of abstinence among the entire sample. If proven effective, computer-assisted personalized motivational counseling could be broadly implemented as a method to decrease the incidence of unintended pregnancy and STDs among female adolescents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTRACEPTION BY AFFECTING TESTIS CELL JUNCTION DYNAMICS Principal Investigator & Institution: Cheng, C Y.; Population Council 1 Dag Hammarskjold Plaza New York, Ny 10017 Timing: Fiscal Year 2002; Project Start 30-AUG-2002; Project End 28-FEB-2007 Summary: (provided by applicant): Throughout spermatogenesis, developing germ cells must remain attached to the seminiferous epithelium via testis-specific adherens junctions (AJ) between Sertoli and germ cells, such as ectoplasmic specializations and tubulobulbar complexes. The long-term objective of the PL's laboratory is to prepare male contraceptives that would perturb the functionality of these AJs thereby inducing the loss of cell adhesiveness, which in turn causes germ cells to deplete prematurely from the epithelium making them incapable of fertilizing the egg. Studies from this laboratory in the past decade have permitted the synthesis and identification of two potential male contraceptives: l-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF2364) and 1 -(2,4,- dichlorobenzyl)-indazole-3-acrylic acid (AF-2785), having the effects of disrupting the adhesion of spermatids and spermatocytes onto the epithelium. Both AF-2364 and AF-2785 are effective to induce reversible male fertility in rats. They are neither nephrotoxic, hepatotoxic, nor affecting the hypothalamus-pituitary-testicular axis. Furthermore, recently completed acute toxicity studies and standard mutagenicity studies, which were performed by licensed toxicologists according to the FDA guidelines, have shown that both compounds are safe for further development. However, the mechanism(s) of action of these compounds at the cellular and molecular level is not known. We hereby propose two hypotheses to be tested by performing two series of mechanistic studies. First, AF-2364 exerts its effects exclusively on testis-specific AJs without affecting the blood-testis barrier (BTB) in the testis and AJs in other epithelia (Specific Aim 1). Second, AF-2364 and AF-2785 exert their effects by compromising the functionality of AJ-proteins (Specific Aim 2). Aim 1 will largely be in vivo studies investigating the effects of AF-2364 on the kinetics of spermatogenesis and AJ functionality using the techniques of histology, immunohistochemistry, micropuncture, and assays to assess the status and/or function of tight junctions (TJs) and AJs. Aim 2 will largely be in vitro studies to examine if these compounds exert their effects via the RhoB GTPase pathway, integrins, and other AJ-signaling molecules. These studies not only will unfold the site of action of either compound in the testis at the cellular and molecular levels; they will provide a framework to understand the biology and regulation of AJ dynamics in the testis. As such, additional targets, such as a specific signal transduction pathway pertinent to maintain the AJ functionality in the testis, will be identified to perturb germ cell attachment onto the epithelium. We also
18
Contraception
seek support to expand ongoing toxicity studies by performing 2 longterm toxicity studies in rats & dogs in anticipation of Phase I clinical Trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTRACEPTION WITH MINI DOSE ANTIPROGESTIN IN MACAQUES Principal Investigator & Institution: Zelinski-Wooten, Mary B.; Affiliate Assistant Scientist; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001; Project Start 01-JUN-1995; Project End 30-JUN-2002 Summary: Continual administration of low doses of the antiprogestin, ZK 137 316, to female rhesus monkeys permits ovarian/menstrual cyclicity, but sufficiently alters the function(s) of the reproductive tract to inhibit fertility. Studies with pair-housed male and female monkeys demonstrated the contraceptive efficacy of minidose antiprogestin over six consecutive cycles of treatment. A pilot experiment suggests that normal pregnancies and live offspring can occur after cessation of the six-month regimen, but restoration of fertility following withdrawal of antiprogestin after longer treatment intervals needs rigorous testing. Studies are proposed to test the hypothesis that chronic, low dose ZK 137 316 during sustained ovarian/menstrual cyclicity acts at multiple sites in the reproductive tract to provide protection from pregnancy. Using the female rhesus monkey, the specific aims of this proposal are to determine whether this novel antiprogestin regimen: 1) is reversible with respect to restoration of fertility after one year of treatment; 2) impairs oocyte nuclear maturation, fertilization or early embryonic development; 3) disrupts gamete/embryo transport through the oviduct; and 4) prevents uterine receptivity/implantation. Females will receive vehicle or minidose antiprogestin for one year, followed by pairing with males to assess pregnancy as an endpoint of the reversibility of antiprogestin treatment. Resumption of oocyte meiosis, fertilization after insemination in vitro and development of resultant embryos of blastocysts during in vitro coculture with somatic cells will be evaluated after follicular stimulation of macaques in vivo with human gonadotropins alone or in combination with antiprogestin treatment. Pregnancy rates and histological analyses of the reproductive tract after oviductal and intrauterine transfer of untreated embryos to antiprogestin-treated recipients will delineate the oviductal and endometrial capacity for timely embryo transport and to support implantation, respectively. The ability of embryos exposed to antiprogestin in vivo to be transported and implant will be tested following oviductal and intrauterine transfer to untreated recipients. Oviductal fluid collected via indwelling catheter will be examined for sperm following artificial insemination and for changes in oviductal secretory protein. Restoration of fertility and identification of potential sites of contraceptive action within the reproductive tract following continual, minidose treatment with ZK 137 316 will support further investigation of biochemical mechanisms that prevent pregnancy, and support development of this regimen as a new mode of contraception for women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: CONTRACEPTIVE PHARMACIES
PRACTICE
/DELIVERY
--
COMMUNITY
Principal Investigator & Institution: Gardner, Jacqueline S.; Associate Professor of Pharmacy; Pharmacy; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2006
Studies
19
Summary: We wish to assess the feasibility of community pharmacists directly initiating and managing hormonal contraceptive methods for women through use of collaborative drug therapy agreements (CDTA) in a pilot study, and then to expand the demonstration to measure its effectiveness with a larger number of women in more pharmacies on the basis of the pilot data. Despite the fact that 93% of women at risk of pregnancy in the United States use some form of contraception, unintended pregnancies nonetheless represented nearly half of all pregnancies occurring to American women in 1995. Recommendations of the Committee on Unintended Pregnancy writing for the Institute of Medicine urged increasing access to contraception through broadening the range of health professionals that provide birth control. Emergency contraceptive pills (ECP) are efficiently provided by community pharmacists and women report satisfaction with the direct access. However, ongoing effective contraception currently requires a clinic visit and many women purchasing less effective over-the-counter (OTC) methods could benefit from increased choices, such as hormonal methods. If women will accept and effectively use hormonal contraceptives obtained from a community pharmacist, and if pharmacists can provide appropriate hormonal contraceptive screening and monitoring as sustainable, reimbursable activities within their practices, women could gain a new choice or venue to prevent unintended pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTRACEPTIVE USE PATTERNS AMONG TEENS AND YOUNG ADULTS Principal Investigator & Institution: Manlove, Jennifer S.; Child Trends, Inc. 4301 Connecticut Ave, Ste 100 Washington, Dc 20008 Timing: Fiscal Year 2001; Project Start 08-AUG-2001; Project End 31-JUL-2005 Summary: The specific aim of the proposed project is to enhance our understanding of how to sustain recent improvements in contraceptive use at first sex so that teens and young adults can become more consistent contraceptive users. The proposed project will examine patterns of contraceptive use and consistency across sexual relationships, within current cohorts of teens and young adults. Our premise is that contraceptive use must be negotiated and sustained within each new sexual relationship. Understanding why teens and young adults use contraception consistently, as well as understanding patterns of inconsistent use, will help inform strategies to prevent unintended pregnancy and STIs. Analyses by race/ethnicity will help address disparities in reproductive health among racial and ethnic minorities. Additional sub-population analyses will include comparisons of teens and young adults, and males and females. The proposed project will incorporate an ecological framework, which posits that behaviors among teens and young adults will be influenced by factors from multiple domains of their lives. We will incorporate multi-level and multi-process models to examine how contraceptive use patterns are shaped by individual knowledge and motivations, characteristics of each sexual relationship (including partner characteristics and sexual activity), peer environments and family background, including parent-child communication. We will also examine the influence of school, community, and policy variables, such as sex education programs and the presence of economic opportunities. The project will analyze month-by-month histories of contraceptive use and sexual relationships within two cycles of the National Survey of Family Growth (1995, 2001) and information on sexual relationships and contraceptive use patterns within three waves of the National Longitudinal Study of Adolescent Health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
20
Contraception
•
Project Title: CO-OCCURING HIV RISK BEHAVIORS IN COMMUNITY CONTEXT Principal Investigator & Institution: Browning, Christopher R.; Sociology; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2003 Summary: (adapted from applicant's abstract): While researchers have acknowledged the spatial concentration of HIV risk behaviors, few systematic investigations of the relationship between community characteristics and these behaviors have been undertaken. Rooted in social disorganization theory, the proposed analyses assess the hypothesis that urban poverty and residential instability inhibit the development of socially organized and cohesive communities capable of collectively managing individual level behavior relevant to HIV/STD transmission. Using the 1992 National Health and Social Life Survey and two data sets describing the city of Chicago-the 1994 Project on Human Development in Chicago Neighborhoods Community Survey and the 1995-97 Chicago Health and Social Life Survey-this research will address the following questions: 1. What is the joint distribution of key HIV risk behaviors-specifically, anal sex, ineffective contraception, and alcohol use during sex, and illicit drug use during sex-in the U.S. adult population and the population of a large urban center? Do these activities cluster within the same individuals, partnerships, and sexual events? 2. Are structural features of urban communities-including concentrated disadvantage and residential stability-associated with the individual level likelihood of co-occurring HIV risk behaviors? To what extent does dimensions of community social organization including the capacity of local residents to intervene collectively to achieve shared goals (informal social control) - mediate the relationship between structural disadvantage and the prevalence of HIV risk behaviors at the individual level? 3. To what extent are neighborhood levels and egocentric social network characteristics relevant to participation in HIV risk behavior? Are neighborhood level social networks differentially consequential for the prevalence of HTV risk behaviors at the individual level depending on the degree of informal social control characterizing the neighborhood? Is neighborhood level social network density differentially consequential for the manifestation of HIV risk behavior depending on the social characteristics of network members or their relationships? For instance, are dense networks among kin differentially consequential for HIV risk behavior when compared with friendship density? The proposed analyses will employ sophisticated statistical techniques and high quality data sources to investigate the distribution and etiology of co-occurring HIV risk behaviors. The combination of data sources on Chicago will offer a rare opportunity to investigate the individual level organization of risk behaviors in neighborhood context. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: COOPERATIVE CONTRACEPTIVE RESEARCH CENTER Principal Investigator & Institution: Sitruk-Ware, Regine L.; Executive Director Contraceptive Develop; Population Council 1 Dag Hammarskjold Plaza New York, Ny 10017 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 28-FEB-2007 Summary: (provided by applicant): The U54 Cooperative Contraceptive Development Research Center Grant described in this proposal is comprised of four research and development projects and one Core facility. The goals are to identify new leads that can be developed into safe and effective contraceptive methods: (I) A new progesterone receptor modulator CDB-2914, with potent anti-ovulatory effect, will be investigated in
Studies
21
four aims: a) The molecular mechanism of action and the gene pathways involved at the ovarian level will be explored; b) CDB-2914 will be tested and formulated into vaginal gel and rings for contraceptive use in women; c) A radioimmunoassay will be established and validated for measuring serum levels of CDB-2914 for pharmacokinetic studies in women; d) The effects of CDB-2914 on human breast cells will be evaluated. Parallel studies investigating the effects of CDB-2914 on the primate endometrium and on ovarian function in women, for which funding will be requested from other sources, are also described in this document. (II) A vaginal gel containing both the microbicide Carraguard and the contraceptive steroid levonorgestrel (CARRA/LNG) will be tested for dual-protection against sexually transmitted infections and conception. Two mechanisms will be targeted for contraception in women having regular sex who will use this progestin microbicide daily: ovulation inhibition and thickening of the cervical mucus, which inhibits sperm penetration. Given the proven efficacy of LNG in emergency contraception, another goal is to test the product for use "on demand" before intercourse in women having occasional sex. (III) New compounds have been identified that are able to induce reversible germ cell depletion from the testis. The prime target of these compounds is the adherence junction (AJ) between Sertoli and germ cells in the testis. This project will focus on disruption in the AJs to induce germ cell loss without affecting hormonal pituitary-gonadal function. (IV) In a final project, sperm-supplied protein will be isolated from mammalian testes by recombinant DNA technology and will be investigated for its functional role in the development of early embryos from fertilized eggs. Antisense manipulation will be used to suppress the production of this novel sperm protein as a new method of fertility control. The Cell Culture Core facility will ensure the highest quality control standards, as well as priority access and services for Projects I, III, and IV. The Cell Culture Core Director will advise Core users concerning the latest technologies for facilitating their culture-based protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COOPERATIVE MULTICENTER REPRODUCTIVE MEDICINE NETWORK Principal Investigator & Institution: Carr, Bruce R.; Dir, Div of Reproductive Endocrinology; Obstetrics and Gynecology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 30-JUN-2000; Project End 31-MAR-2005 Summary: This research proposal describes the qualifications and experience of the Division of Reproductive Endocrinology faculty and research team at the University of Texas Southwestern Medical Center at Dallas, the facilities, and patient population available to them for carrying out clinical protocols to be designed by the NICHD Reproductive Medicine Unit (RMU) Network. The UT Southwestern Division of Reproductive Endocrinology includes 6 clinicians, 4 of whom are board certified in Reproductive Endocrinology. Within the division is the Women's Research Center which includes 3 research nurses led by a research nurse coordinator with 20 years experience in protocol development and implementation are available for participation in RMU network protocols. This research team has successfully completed an extensive number of randomized trials, some of which were supported by NIH grant support as well as multi-center randomized trials supported by pharmaceutical companies. These investigations included infertility, andrology, endometriosis, uterine leiomyomata, androgen excess, contraception, and menopause. In order to develop an interdisciplinary approach to the study of reproductive disorders we have brought to the RMU network support of UT Southwestern's NIH General Clinical Research Center,
22
Contraception
Department of Urology, Psychiatry, Radiology, and Internal Medicine. A concept protocol is included which proposes to investigate pain relief in women suffering from endometriosis. This trial compares the effect of the medical treatment standard with gonadotropin releasing-hormone agonist versus continuous low-dose combined oral contraceptive pills. It is proposed that if continuous oral contraceptive pills are close in efficacy of relieving pain in women with endometriosis as are gonadotropin releasing hormone agonists, this mode of treatment would benefit a significant number of women wishing to save their reproductive organs for later reproduction. In summary, the reproductive endocrinology research team is experienced in multi- center clinical trials and is committed to collaborative participation consistent with the goals of the RMU network. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COUPLE DECISIONS ABOUT CONTRACEPTION Principal Investigator & Institution: Grady, William R.; Battelle Centers/Pub Hlth Res & Evaluatn Health Research & Evaluation Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Most of what we know about the nature of the contraceptive decision-making process in which couples engage was obtained by analyzing reports from women about their fertility-related beliefs, attitudes, preferences and experiences. However, the growth of the AIDS epidemic has increased awareness that men have an important role in influencing the reproductive health of heterosexual couples. Despite this awareness, there is very little research on the contraceptive choices of couples that is based on data from both partners. In the proposed study, we will address this large research gap. We will accomplish this goal by conducting an inperson survey of approximately 1,200 married and cohabiting couples where the female partner is aged 20-35, where neither partner is sterile and where the couple is not currently pregnant or attempting to conceive. This survey, in which we will obtain separate, parallel reports from both partners, will provide unique and detailed data on the power relations, birth desires, and method-related expectancies, values, perceptions, preferences, and behaviors of men and women making contraceptive choices within the context of an intimate heterosexual relationship. Most importantly, the proposed analysis of these data, together with the data obtained in a one-year telephone follow-up survey, will allow us to gain new insights into the nature of the contraceptive decisionmaking process in which couples engage. In particular, it will inform us about how men are involved in that process and how their involvement is related to both the types of methods that couples choose and the effectiveness with which they use them. Such information will help family planning service providers determine when and how to include male partners in the method selection process as a way of helping couples achieve their separate and joint reproductive goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: CSHL CONFERENCE ON GERM CELLS Principal Investigator & Institution: Grodzicker, Terri I.; Assistant Director for Academic Affairs; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: (provided by applicant): Germ cells are set aside from other lineages early in development, later differentiating into functioning gametes. To understand the nature
Studies
23
and differentiation of germ cells would be a major achievement in biology, providing important insights into infertility, contraception, human congenital diseases, germ cell tumors, and preservation of endangered species. The molecular basis of germ cell differentiation is beginning to be understood, due to major intellectual and technical advances. General mechanisms of germ cell fate and behavior are emerging from studies in both vertebrates and invertebrates. This meeting, to be held October 10 -13, 2002, 2004 and 2006, will provide a public forum for discussion of all aspects of germ cell research, from the primordial germ cell to the functioning gamete, in diverse model organisms. We expect to attract about 250 participants from all over the world. There are no competing meetings that are so wide in scope. Seven topics have been chosen for platform presentations: Germ Cell Origins, The Embryonic Germ Line, Germ Line Stem Cells, Germ Line/Soma Interactions and Sex Determination, Spermatogenesis, Oogenesis, and Gamete Success and Evolution. Each session will be organized and cochaired by two experts in the topic, who will invite half the speakers and select the other half from submitted abstracts. We will encourage platform presentations from young scientists. The meeting will facilitate interactions between scientists who study different model systems and different aspects of germ cell biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYCLODEXTRIN AS NOVEL SPERMICIDE AND MICROBICIDE Principal Investigator & Institution: Hildreth, James Ek.; Professor; Pharmacol & Molecular Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 27-APR-2001; Project End 31-MAR-2004 Summary: (provided by applicant): Locally applied biomedical barriers and microbicides have proven ineffectual in preventing sexual transmission of HIV. We have recently found that HIV requires intact lipid rafts, highly specialized subregions in cell membranes, for entry into cells and for budding of fully infectious particles. Betacyclodextrin (beta-CD), a cyclic heptasaccharide that removes cholesterol from cell membranes and disperses lipid rafts, has been shown to block HIV infection and drastically reduce the infectivity of budding HIV particles. Cholesterol is also required by other pathogens some of which are associated with STDs. Beta-cyclodextrin is nontoxic and currently in human use as a carrier for polar drugs. Thus properly formulated, this molecule may be an effective microbicide with activity against HIV and other pathogens. Cholesterol has been shown to play a role in regulating sperm cell acrosomal reaction and depletion of sperm cell cholesterol by beta-CD induces capacitation and premature acrosomal reaction. The latter has been associated with low rates of fertilization. Thus beta-CD, by depleting sperm cell cholesterol, may prevent fertilization in vivo by inducing premature acrosomal reactions and reducing fusion efficiency. The central hypothesis of this proposal is that because it rapidly and efficiently depletes cholesterol from lipid membranes beta-CD has great potential as a combination microbicide-spermicide with low host cell toxicity. The goal of this project is to use in vitro and in vivo animal models to test the potential of beta-CD as a microbicide, particularly against HIV, and spermicide and to determine the mechanisms by which beta-CD inactivates H1V. The specific aims are: 1. To characterize and optimize the inhibitory effect of Beta-cyclodextrin on HIV-1 infection. 2. To determine the mechanisms by which Beta-cyclodextrin inactivates cell-free HIV-1 particles. 3. To determine the mechanisms by which Beta-cyclodextrin inactivates cell-associated HIV-1. 4. To determine the effects of Beta-cyclodextrin on sperm function in a rabbit contraception model. 5. To determine the effect of Beta-cyclodextrin in vitro on bacterial pathogens and vaginal flora. 6. To determine the anti-HIV microbicide potential of Beta-
24
Contraception
cyclodextrin in a Hu-PBL-SCID mouse vaginal challenge model. 7. To determine the microbicide potential of Beta-cyclodextrin against HSV, papillomavirus, and chlamydia trachomatis in animal models. This project takes advantage of the shared importance of cholesterol in the biology of sperm and HIV and other pathogens to develop a novel microbicide/contraceptive approach. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEPO ADOLESCENTS
PROVERA
AND
BONE
MINERAL
DENSITY
IN
Principal Investigator & Institution: Cromer, Barbara A.; Frederick C. Robbins Professor of Child; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from Investigator's Abstract) The United States has one of the highest adolescent pregnancy rates among industrialized nations. One of the major contributing factors is inadequate contraception. A very effective contraceptive method is depot-medroxyprogesterone acetate (DMPA) which has become increasingly popular in this age group. Recent research in adults has suggested a negative effect of DMPA on bone mineral density (BMD). With decreased BMD, one's risk increases later for osteoporosis, a major public health problem affecting millions of postmenopausal women every year. Compromised BMD would appear to be a particular concern in adolescents, as they normally accrue up to 40% of their total bone mineral content during this period. In preliminary work, the investigators demonstrated a 3.0% decrease in BMD in adolescent DMPA users over 2 years, compared with a 9.0% increase in untreated controls (p
