ESTRADIOL A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 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., 1960Estradiol: 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: 0-597-84415-1 1. Estradiol-Popular works. I. Title.
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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.
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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 estradiol. 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.
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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.
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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
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON ESTRADIOL ................................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Estradiol........................................................................................ 4 E-Journals: PubMed Central ....................................................................................................... 65 The National Library of Medicine: PubMed ................................................................................ 73 CHAPTER 2. NUTRITION AND ESTRADIOL .................................................................................... 111 Overview.................................................................................................................................... 111 Finding Nutrition Studies on Estradiol..................................................................................... 111 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 117 CHAPTER 3. ALTERNATIVE MEDICINE AND ESTRADIOL .............................................................. 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 128 General References ..................................................................................................................... 131 CHAPTER 4. DISSERTATIONS ON ESTRADIOL ................................................................................ 133 Overview.................................................................................................................................... 133 Dissertations on Estradiol.......................................................................................................... 133 Keeping Current ........................................................................................................................ 135 CHAPTER 5. CLINICAL TRIALS AND ESTRADIOL .......................................................................... 137 Overview.................................................................................................................................... 137 Recent Trials on Estradiol.......................................................................................................... 137 Keeping Current on Clinical Trials ........................................................................................... 138 CHAPTER 6. PATENTS ON ESTRADIOL........................................................................................... 141 Overview.................................................................................................................................... 141 Patents on Estradiol................................................................................................................... 141 Patent Applications on Estradiol ............................................................................................... 166 Keeping Current ........................................................................................................................ 195 CHAPTER 7. BOOKS ON ESTRADIOL .............................................................................................. 197 Overview.................................................................................................................................... 197 Book Summaries: Online Booksellers......................................................................................... 197 Chapters on Estradiol................................................................................................................. 198 CHAPTER 8. PERIODICALS AND NEWS ON ESTRADIOL ................................................................ 199 Overview.................................................................................................................................... 199 News Services and Press Releases.............................................................................................. 199 Academic Periodicals covering Estradiol ................................................................................... 201 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 203 Overview.................................................................................................................................... 203 U.S. Pharmacopeia..................................................................................................................... 203 Commercial Databases ............................................................................................................... 204 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 209 Overview.................................................................................................................................... 209 NIH Guidelines.......................................................................................................................... 209 NIH Databases........................................................................................................................... 211 Other Commercial Databases..................................................................................................... 213 APPENDIX B. PATIENT RESOURCES ............................................................................................... 215 Overview.................................................................................................................................... 215 Patient Guideline Sources.......................................................................................................... 215 Finding Associations.................................................................................................................. 217
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APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 219 Overview.................................................................................................................................... 219 Preparation................................................................................................................................. 219 Finding a Local Medical Library................................................................................................ 219 Medical Libraries in the U.S. and Canada ................................................................................. 219 ONLINE GLOSSARIES................................................................................................................ 225 Online Dictionary Directories ................................................................................................... 226 ESTRADIOL DICTIONARY ....................................................................................................... 227 INDEX .............................................................................................................................................. 315
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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 estradiol 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 estradiol, 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 estradiol, 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 estradiol. 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 estradiol, 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 estradiol. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON ESTRADIOL Overview In this chapter, we will show you how to locate peer-reviewed references and studies on estradiol.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and estradiol, 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 “estradiol” (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: •
Transdermal Estradiol in the Management of Aggressive Behaviors in Male Patients With Dementia Source: Clinical Gerontologist. 15(3): 54-58. 1995. Summary: This report describes five cases of aggressive male patients with dementia who were treated with transdermal estradiol to control their aggression. The low dose estradiol (0.05 mgm or 0.10 mgm per day) administered via a patch placed between the shoulder blades was at least partially effective in the treatment of these physically aggressive behaviors in about 50 percent of the patients. Estrogen, when effective, appeared to work quickly, within 1 to 3 days. Mood was secondarily improved, and there was no sedative effect. Not only was the medication well tolerated by the patient, it was also accepted by the families. Observations suggest that the drug, in terms of risk
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profile and positive benefits, is a benign and relatively safe medication for this particular population. 5 references.
Federally Funded Research on Estradiol The U.S. Government supports a variety of research studies relating to estradiol. 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 estradiol. 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 estradiol. The following is typical of the type of information found when searching the CRISP database for estradiol: •
Project Title: 17 BETA-ESTRADIOL INDUCED CASPASE INHIBITORY FACTOR Principal Investigator & Institution: Leblanc, Andrea C.; Associate Professor; Mc Gill University James Admin. Bldg., Room 429 Montreal, Pq H3a 2T5 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The primary goal of this application is to isolate a caspase inhibitory factor induced by 17-beta-estradiol in primary cultures of human neurons. A group of mammalian cysteinyl caspases is activated in a cell-, insult- and species-specific manner during apoptosis of various cell types. In human neurons, caspase-6 is active during serum deprivation-mediated neuronal apoptosis. We have previously shown that caspase-6 activity is lethal to human neurons in culture. Now, we find that 17 -beta-estradiol but not 17-alpha-estradiol, testosterone, or epitestosterone delay caspase-6 mediated neuronal cell death (Zhang et al. 2001). 17-beta-estradioltreated neuronal extracts directly inhibit recombinant active caspase-6 in an in vitro assay. In contrast, 17-beta-estradiol does not induce CIF nor prevent caspase-mediated cell death in astrocytes. We conclude that 17-beta-estradiol induces a caspase inhibitory factor (CIF) that is preventing neuronal apoptosis. CIF is induced through estrogen receptors via a non-genomic pathway. We show that CIP is a broad spectrum caspase inhibitor between 10 and 14 kDa in size that is fairly resistant to boiling and proteinase K in neuronal extracts. Our results indicate that 17-beta-estradiol induces a novel inhibitor of active caspases and provide an additional mechanism for the neuroprotective action of 17-beta-estradiol. In this proposal, the primary goal is to identify CIF and determine its role in neuronal survival and cell death. In aim #1, we will biochemically isolate and sequence CIF. In aim #2, we will clone CIF cDNA and obtain antibodies. We will then confirm the role of CIF in neuronal survival and against caspases (aim #3), and determine the mode of activation of CIF (aim #4) and
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).
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inactivation of caspase-6 (aim #5). Finally, we will study the regulation of CIF expression in normal and AD brains (aim #6). Given the strong epidemiological link of estrogen against Alzheimer's disease and its possible prophylactic role in neuroprotection, our results suggest a novel mechanism of action of 17-Beta-estradiol that could be exploited to promote neuroprotection in injury or neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A NOVEL GROWTH REGULATORY FACTOR IN BREAST CELLS Principal Investigator & Institution: Montano, Monica M.; Pharmacology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by the applicant) The vast majority of human breast cancers are initially hormone-dependent with estradiol playing a crucial role in their development and evolution (1). However there is relatively little known about how estrogen activation of the estrogen receptor (ER) results in the initiation or promotion of human breast cancer. We have identified a novel gene that is down regulated by estradiol, Estrogen-Down-regulated Gene 1 (EDG1), in breast epithelial cells. Subsequent studies indicate that EDG1 inhibits ERalpha transcriptional activity. A self-contained tetracycline-regulated retroviral vector system (2) has been used to both positively and negatively regulate the expression of EDG1 in breast cancer cells (MCF7 and MDA-MB231) and normal breast cells (MCF 10A). Compared to control cells, cells that over express EDG 1 (MCF7-EDG 1, MCF 10-EDG1 and MDA-MB-23 1-EDG1) exhibit decreased growth rate, while cells that have decreased EDG1 expression (MCF7EDG1AS and MCF10-EDG1AS) have enhanced growth rate. Moreover EDG1 overexpression inhibited anchorage independent growth and estrogen-induced MCF7 proliferation. While we see cross talk between estrogen and EDG1, we propose that EDG1 may also function as a tumor suppressor independent of ERa levels. A mechanistic basis for the growth effect of EDG1 is suggested by the interaction of EDG1 with Integrin beta4-interactor protein (p27/BBP) and the 67 kD laminin receptor (67LR). p27/BBP protein interacts with the cytodomain of beta4 integrin and has been proposed to link beta4 integrin with the cytoskeleton, while 67LR binds to laminins and interacts with the alpha6beta4 integrin multimeric complex. Based on our preliminary findings we hypothesize that the growth inhibitory effects of EDG1 in breast cells have ERalphadependent and ERalphs-independent components; and EDG1 helps maintain the balance of signaling events generated through the extracellular matrix that regulates normal breast epithelial cell function. To test our hypothesis we will: (1) characterize EdG1 inhibition of ERalpha transcriptional activity and its role in the growth inhibitory effects of EDG1 (2) examine the role of Integrin-beta4-interactor protein and the 67 kD laminin receptor in EDG1 cellular effects and (3) characterize other phenotypic effects of EDG1 and identification of other downstream effectors of EDG1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ACTIONS OF ESTROGEN & ENVIRONMENTAL ESTROGENS ON NEURONS Principal Investigator & Institution: Belcher, Scott M.; Pharmacology & Cell Biophysics; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005
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Summary: (provided by applicant): The broad long-term goal of the proposed research is to understand the functions of 17beta-estradiol (estrogen; E2) and estrogen receptors (ERs) in the developing nervous system and to determine to what extent environmental estrogens influence these functions. E2 influences the development and function of many regions of the brain in both males and females. Thus, it is possible that other estrogenic compounds can impact development of the brain. Environmental estrogens, also known as "endocrine disrupters," are a diverse group of compounds that can mimic or antagonize the normal actions of E2. The extent to which environmental estrogens impact the developing nervous system is unclear. Proposed experiments employing primary cultures of neonatal rat cerebellar neurons and the developing cerebellum as models will address the following Specific Aims-Specific Aim 1: Determine whether E2 modulates cellular signaling in developing cerebellar neurons through rapid, nongenomic actions on MAPK signal transduction; Specific Aim 2: Determine the networks of estrogen responsive genes whose expression is modulated by E2 in cerebellar neurons; Specific Aim 3: Determine to what degree representative environmental estrogens mimic or inhibit the effects of E2 in developing cerebellar neurons. Specific Aims 1 & 2 test the hypothesis that E2 normally functions in developing neurons by rapidly modulating the activity of MAPK signaling, and also through genomic ERmediated mechanisms which together, modify expression of discrete networks of gene products. Specific Aim 3 will test the hypothesis that environmental estrogens influence developing neurons by modifying both MAPK signaling and genomic ER-mediated mechanisms, which results in altered networks of expressed genes. All three Specific Aims will be addressed through experiments using activation-state specific antisera to determine E2-mediated signaling pathways and by cDNA array and RT -PCR analysis of E2-responsive gene expression. From these results a neuronal "E2-signature cDNA array" will be developed and used in Aim 3 to determine how environmental estrogens influence E2-responsive gene expression in these developing neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALTERED PHYSIOLOGY RESULTING IN LARGE FOLLICULAR CYSTS. Principal Investigator & Institution: Wiltbank, Milo C.; Associate Professor; Dairy Science; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 06-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The development of follicular cysts has been detected in numerous mammalian species, including humans, suggesting that this reproductive abnormality may be due to an underlying physiological pathway that is fairly ubiquitous in mammals. The research in this proposal focuses on the physiology that underlies the development of large follicular cysts. The cow has been chosen as the animal model for studies of this abnormality because follicular cysts are fairly common in this species and have been extensively described in previous research. In addition, the cow is a mono-ovulatory species and has been a useful animal model for understanding follicular development particularly because key follicular events (follicular selection, ovulation) occur at similar follicular diameters in humans and cows. The studies in this proposal test a working model based on previous scientific research, as well as our recent studies on the physiology that underlies the development of follicular cysts. This model predicts that during each estrous cycle, the normal estradiol surge induces a physiological condition that resembles the condition that results in follicular cysts. However, this "physiological lesion" is removed by the increase in circulating progesterone following ovulation. This model is very appealing because it provides a
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generalized physiological explanation for the development of large follicular cysts. It may also provide an explanation for the varied clinical, environmental, and experimental situations that result in the development of follicular cysts as well as provide a rationale basis for the treatment of this disorder. However, it is prudent to test whether this physiological model has experimental validity prior to extensive studies on the specific cellular and molecular mechanisms that underlie this disorder or extrapolation of this working model into species other than the cow. Therefore, we propose two specific objectives that will use the bovine animal model to test whether a normal endogenous estradiol surge will result in the postulated physiological condition. Specific Objective I. Determine whether follicular cysts will develop following an endogenous estradiol and GnRH surge if the LH surge is blocked with a GnRH antagonist. Specific Objective II. Determine whether follicular cysts will develop following an endogenous estradiol, GnRH, and LH surge if the freshly ovulated follicle (corpus hemmoragicum) is removed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANALYSIS OF SEX HORMONES AND LIPOPROTEINS IN YOUNG MALES Principal Investigator & Institution: Barton, Bruce A.; Senior Statistician and Vice President; Maryland Medical Research Institute, Inc 600 Wyndhurst Ave Baltimore, Md 21210 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Provided by Applicant) This application requests support for secondary analysis of the Sex Hormones and Lipoproteins in Adolescent Males Study (HD/HL18281), a 3-year (1984-1987) study of lipids, blood pressure, weight, fat patterning, and sex steroid hormones (SSH) in adolescent males. A total of 664 black and white males, ages 10-15, were enrolled into a study designed as a series of repeated data collections over 2 years within age cohorts. Cross-sectional analyses have been used to explain differences during adolescence in SSH and SSH-lipid relationships between black and white boys and between boys with and without a family history of CHD. When the data were originally collected for this study, theoretical models of flexible longitudinal analytic techniques had been developed, but were not available for computer use. These techniques, now supported by software, allow a more powerful and complete analysis of these data. The primary aim of these analyses is to explicate the contribution of changes in SSH and fat patterning to changes in plasma concentrations of high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, triglycerides (TG), and apolipoproteins (apo) Al, All, and B occurring during puberty in males. SSH assayed included estradiol (E2) and free testosterone (T). We will test the following hypotheses: (1) increasing free T predicts/leads to decreases in HDL-C and increases in LDL-C, apo B, and the LDL-C/HDL-C ratio in adolescent males; (2) increasing E2 predicts decreases in apo B, LDL-C and the LDL-C/HDL- C ratio, but the resultant effects will vary with adiposity and fat patterning; (3) rapid weight gain predicts increased central adiposity, defined as the ratio of truncal skinfolds to total skinfolds, and with greater decreases in HDL-C and increases in triglycerides, apo B, LDL-C and the LDL- C/HDL-C ratio. Rapid weight gain predicts increased E2, but the atherogenic effects of increased central adiposity on lipids are greater than the antiatherogenic effects of E2. These analyses will provide a better understanding of metabolic factors underlying obesity-hormone-lipoprotein relationships. Given the welldocumented increase in obesity in American youth, these analyses are especially pertinent and address important public health issues.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANGIOGENIC DETERMINANTS OF ENDOGENOUS ADULT NEUROGENESIS Principal Investigator & Institution: Goldman, Steven A.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-AUG-1992; Project End 31-MAR-2006 Summary: (provided by applicant): The vocal control nucleus HVC of adult songbirds generates new neurons throughout life from nearby ventricular zone progenitor cells. The recruitment and survival of these neurons is modulated by the gonadal steroids testosterone and estradiol. Yet endothelial cell division is the first cellular response noted in the adult HVC after testosterone administration, and precedes androgenassociated gliogenesis and neuronal recruitment by over a week. We have found that testosterone rapidly induces the production of both vascular endothelial growth factor (VEGF) and its receptor VEGF-R2/KDR in HVC. This leads to endothelial division, which anticipates the regionally-restricted expansion of the HVC microvasculature. The activated endothelial cells then produce the neurotrophin BDNF, which has been shown to support neuronal recruitment from the mammalian as well as the avian ventricular zone, and whose induction is associated with the recruitment of new neurons to HVC. Gonadal steroid-induced endothelial and matrix-released cytokines may thereby contribute importantly to neuronal recruitment in the adult brain. In this competitive renewal application, we postulate that gonadal steroid-induced angiogenesis may be critical to neuronal addition to the adult HVC, and that angiogenesis may provide necessary permissive conditions for neuronal recruitment into adult brain parenchyma. To better understand the permissive conditions for the integration of new neurons into adult brain, we propose to ask the following: 1) Is the gonadal steroid-associated induction of VEGF and its receptor necessary for testosterone-induced angiogenesis in the adult HVC? 2) Is steroid-induced angiogenesis necessary for testosterone-mediated neuronal recruitment? Does the suppression of angiogenesis abrogate neuronal addition to HVC? 3) Is local angiogenesis sufficient to direct neuronal recruitment from a neurogenic epithelium? Do new neurons migrate selectively to HVC because of its high BDNF levels after gonadal steroid activation? 4) Do steroid-activated matrix metalloproteinases contribute importantly to neuronal addition? Does MMP inhibition suppress recruitment? These experiments ask if neurogenesis in the adult HVC depends upon antecedent local angiogenesis. They seek to define those necessary and sufficient conditions for neuronal recruitment that may be provided by steroid-activated endothelial cells. By so doing, they extend our understanding of the permissive conditions for neurogenesis in the adult brain, and may inform us as to how to induce neuronal recruitment to, and acceptance by, otherwise non-neurogenic regions of the adult brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: AROMATASE HYPERPLASIA
INHIBITOR
IN
MALES
WITH
ADRENAL
Principal Investigator & Institution: Sarafoglou, Kyriakie; Pediatrics; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Our objective is to treat males who have congenital adrenal hyperplasia (CAH) and decreased spermatogenesis with an aromatase inhibitor
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in order to investigate its effects on hormonal parameters and spermatogenesis. CAH is a family of inherited disorders caused by reduced activity of the enzyme required for cortisol synthesis. Decreased cortisol production increases the secretion of ACTH from the pituitary and increases the production of adrenal androgens through negative feedback. In turn, the increased levels of adrenal androgens are aromatized/converted in glandular (i.e., testes) and extraglandular tissues by the aromatase enzyme and result in elevated estrogen levels. Ideally, the production of adrenal androgens is normalized in CAH patients by glucocorticoid replacement therapy. However, even well controlled CAH patients still manifest the adverse effects (compromised final height, polycystic ovarian disease, male infertility, etc.) of elevated androgens/estrogens. Glucocorticoid therapy does not continually normalize ACTH levels because it lacks the close temporal relationship to ACTH pulses and any adrenal activity will result in greater than normal androgen (and thus estrogen) production. We hypothesize that these elevated estrogen levels affect spermatogenesis in males with CAH through the following mechanisms: (1) Elevated estrogens suppress the hypothalamic-pituitary-gonadal axis through negative feedback. Normal LH/FSH gonadotropin secretion is essential for the initiation and maintenance of testicular function and normal spermatogenesis. Chronically elevated estrogen levels (estradiol) affect testicular morphology and testicular steroidogenesis (a) by suppressing pituitary-gonadal secretion, and (b) by a direct toxic effect of estradiol on testicular tissue resulting in a decrease in testicular testosterone production, decrease number of androgen receptors, and create a further negative imbalance in the testosterone-to-estradiol ratio at the gonadal level; (2) Elevated estrogens adversely affect testicular function including Leydig cell, Sertoli cell and germ cell development as shown in experiments with rodents that have been exposed to excess estrogens; (3) Elevated estrogens cause dysfunction of the efferent ductules and epididymis. Therefore, the overarching question of our study is the following: What degree of positive effect will controlling the conversion/aromatization of elevated adrenal androgens into estrogens by gonadal tissue have on spermatogenesis in CAH males? We propose that inhibiting aromatization of androgens to estrogens with an aromatase inhibitor, will improve testicular function and spermatogenesis by normalizing the estradiol to testosterone ratio at the gonadal level and reversing the negative effects of elevated estrogen on androgen receptors, testicular steroidogenesis and pituitary gonadotropins. Aromatase inhibitors have selective action, are well tolerated by patients, and do not interfere with the production of steroid hormones by other related cytochrome P450-dependent enzymes making it ideal for use in CAH patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASTROCYTE-NEURON INTERACTIONS AND GNRH NEURONAL FUNCTION Principal Investigator & Institution: Brann, Darrell W.; Associate Professor; Neurology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2006 Summary: (Scanned from the applicant's description): Estrogen is well known to play a critical role in reproduction and to have important beneficial effects on the brain. The mechanism(s) underlying these important effects of estrogen are unknown and represent the focus of this grant application. Our major hypothesis is that astrocytes function to mediate, at least in part, the reproductive and beneficial effects of estrogen on the brain. Thus, we propose that astrocytes are capable of regulating the neurosecretion, neuronal connectivity and survival of GnRH and non-GnRH neurons and that these effects are primarily due to the ability of astrocytes to release
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transforming growth factor-beta (TGFbeta). Central to this proposed mechanism, is the hypothesis that 17beta-estradiol exerts regulatory control over astrocytes to stimulate release of TGFbeta. This putative 17beta-estradiol-astrocyte-TGF-beta signaling pathway could have important implications not only to reproduction, but could also provide a conceptual framework to explain how estrogen may be beneficial in certain clinical situations such as stroke and Alzheimer's disease. Aim 1 would establish whether TGFbeta mediates the GnRH-releasing, neurite outgrowth and neuroprotective actions of hypothalamic astrocytes. This aim would characterize the different TGF-beta isoforms released by hypothalamic astrocytes, the degree of correlation between their levels and the functional effects of hypothalamic astrocyte-conditioned media (HA-CM), and perform causative studies to prove a role for TGFbeta. Aim 2 would characterize the recently discovered 17beta-estradiol-astrocyte-TGFbeta signaling pathway in the hypothalamus and establish the underlying mechanisms and functional implications of the pathway. This aim would determine the specific TGFbeta isoforms regulated by 17beta-estradiol, the functional importance of such regulation, whether it is ERalpha or ERbeta that mediates the 17beta-estradiol effects, and the applicability of the novel pathway to other clinically important estrogen target tissues, such as cortex and hippocampus, as well as to the human. Aim 3 will establish whether steroid hormones upregulate TGFbeta type I, II and/or III receptors in GnRH neurons during the time of the LH surge. Preliminary results showed a dramatic up-regulation of the TGFbeta type II receptor in the hypothalamus at the time of the LH surge induced by estrogen plus progesterone. This aim would confirm these preliminary observations and extend them by determining whether the up-regulation occurs in GnRH neurons, whether it is 17beta-estradiol or progesterone which is responsible for the effect, and determine if the steroid regulation extends to the type I and type III TGFbeta receptors as well. Aim 4 will establish the cell signaling mechanism utilized by HA-CM and TGFbeta to promote neurite outgrowth and exert neuroprotection on GnRH neurons. This study would examine the Ras-Raf-ERK pathway, with the hypothesis that this signaling pathway activates downstream mediators such as the neurite-outgrowth promoting factor, growth associated protein-43 (GAP-43), and the anti-apoptotic proteins bcl-2 and bcl-xl in order to promote neurite-outgrowth and survival of GnRH and non-GnRH neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BLOOD PRESSURE IN POSTMENOPAUSAL WOMEN: A GCRC STUDY Principal Investigator & Institution: Seely, Ellen W.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): This is a Mid-Career Investigator (K 24) proposal for Ellen Seely, MD. The goal of this proposal is threefold. First, it would increase the depth of Dr. Seely's research by enabling the investigator to receive further advanced training in human genetics. Second, it would give the investigator the supported time to formally train young investigators in patient-oriented research in the field of hormonal control of blood pressure. Third, it would allow the investigator to use her experience as Associate Program Director of the General Clinical Research Center (GCRC) to teach the next generation of patient-oriented researchers about the use of a GCRC for the study of human pathophysiology using varied GCRC-based investigative techniques. Dr. Seely's research topic "Blood Pressure in Postmenopausal Women: a GCRC Study" serves as fertile ground for a K24. Hypertension affects over 20 million women in the United States and the majority of these women are postmenopausal. Although there is clearly a
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genetic component to hypertension in both men and women, its incidence increases dramatically in women following menopause superceding that in men and suggests that the hormonal milieu of the premenopausal state may be protective against the manifestation of hypertension. The overall goal of Dr. Seely's research plan is to utilize the GCRC for detailed studies of the pathophysiology of hypertension in postmenopausal women. Dr. Seely plans to determine how polymorphisms of genes of the renin-angiotensin-aldosterone system (RAAS), a major regulator of blood pressure, are influenced by estradiol. An understanding of the interaction of estradiol with specific polymorphisms of the RAAS that lead to blood pressure lowering may enable the development of selective estrogen receptor modulators that have antihypertensive effects. Thus, funding of this proposal will allow Dr. Seely to expand her own research career and simultaneously provide time to expand her mentorship role. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BRAIN MECHANISMS OF REPRODUCTIVE BEHAVIOR Principal Investigator & Institution: Pfaff, Donald W.; Professor and Head; Lab/Neurobiology/Behavior; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2002; Project Start 01-MAY-1978; Project End 31-MAR-2003 Summary: The most advanced system for understanding neural and molecular mechanisms of mammalian behavior is the effect of estradiol (E) on lordosis behavior by the female rat upon mounting by the male. Now we must begin to understand signals from important environmental sources other than the male which are permissive for female reproductive behavior. Luckily, thyroid hormones (T3) and their receptors (TRalpha and TR-beta) are present in hypothalamus and offer exciting opportunities for study. At the molecular level, TR s can bind on DNA to estrogen response elements (EREs) and could influence E-stimulated synthetic events in neurons. At the biological level, changes in thyroid hormone in the blood can signal environmental temperature changes as well as stress. Thus, we will study the ability of thyroid hormones to alter the stimulation of lordosis behavior by estradiol, we will determine where in the nervous system these interactions occur, and we will analyze their molecular mechanisms in the brain of the female rat. Precise sites of T3-TR action will be determined both by blocking- maneuvers (antisense DNA, etc.) And by direct T3 microinjections. The behaviorally relevant genes, for progesterone receptor (PR) and for the enkephalin peptides (PPE) will elucidated in this connection. In doing these experiments we have the chance of illuminating how permissive environmental conditions are integrated with the main hormal and sensory determinants of a biologically crucial behavior. Medically, high thyroid hormone levels are well known in the clinic to cause irritability in women. More generally, discovering in neurobiological detail how hormonal or environmental alterations quite separate from ovarian changes influence a female s reproductive status will be important for fostering women s health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CELL GROWTH INHIBITION AND ESTROGEN ACTION Principal Investigator & Institution: Markaverich, Barry M.; Associate Professor; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-1983; Project End 31-JUL-2002 Summary: The long-term objective of the proposed research is to define the mechanism by which methyl p-hydrophenylactate (MeHPLA) controls mammalian cell
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proliferation. Our laboratory identified MeHPLA as an endogenous ligand for nuclear type II [3H] estradiol binding sites and this bioflavonoid or tyrosine metabolite appears to inhibit cell proliferation through this binding interaction. Type II sites appear closely coupled to DNA replication and cellular proliferation, however, the precise function of this nuclear matrix protein in normal and abnormal cells is unknown. The goal of this project is to define the function of MeHPLA and type II sites in normal and malignant cells and to study type II gene structure and expression as it relates to hormonal (MeHPLA, estrogen, anti-estrogen) modulation of cellular proliferation. To accomplish these goals we have solubilized type II sites from rat uterine nuclear matrix and have purified the [3H] estradiol binding activity to near homogeneity to near homogeneity by dye ligand affinity chromatography (Affigel Blue) and HPLC. SDS-PAGE analysis of this highly purified material revealed a single 37 kDa protein which co-puries with the type II site [3H] estradiol binding activity. Affinity labeling studies indicate [3H] estradiol to the 37 kDa protein is blocked by the bioflavonoid luteolin and this protein is induced in the uterus by estrogen. Based upon our initial sequencing studies which have identified 10 amino acids of internal sequence, it appears that the 37 kDA protein may be unique. A major goal of this revised application is to obtain more exclusive amino acid sequence analysis of the 37 kDa protein to be used for the generation of oligonucleotide and anti- peptide antibody probes to the type II site (Specific Aim 1). These oligonucleotide probes and antibodies will be used to screen a cDNA library prepared from estrogen-treated rat uterine tissue to identify type II site cDNA sequences and characterizes the gene(s) (Specific Aim 2). The cDNA and antibody probes will also be utilized to study estrogen, MeHPLA, and anti-estrogen (tamoxifen, ICI-164, 384 ICI182,780) modulation of type II gene expression and subsequent effects on cell proliferation in the rat uterus and in MCF-7 (ER+) and MDA-468 ( ER-) human breast cancer cells in vitro (Specific Aim 3). The availability of these molecular probes will facilitate future structure/function analyses which will define ligand binding and/or other functional domains of this nuclear regulatory protein(s). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELLULAR CALCIUM TRANSPORT IN URINARY EPITHELIA Principal Investigator & Institution: Friedman, Peter A.; Professor; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-MAR-2003 Summary: The long-term objective of our work is directed toward a complete understanding of the cellular mechanisms and regulation of calcium transport by renal tubular epithelial cells. Although most calcium absorption proceeds in proximal tubules, distal tubules are the site of the physiological regulation of calcium transport by parathyroid hormone (PTH), calcitonin and vitamin D3. The specific aims of the present proposal are to: 1) characterize the mechanism of calcium entry across apical plasma membranes of distal convoluted tubule (DCT) cells; 2) evaluate the participation and regulation of Na+/Ca2+ exchange in mediating calcium efflux; and, 3) define the signaling pathways activated by PTH and calcitonin in DCT cells, and to examine the coordinate regulation of PTH-dependent calcium transport by 1,25(OH)2 vitamin D3 and estradiol. We identified and partially characterized a novel calcium channel that mediates calcium entry. To acquire additional information about these channels we will: 1) characterize the properties of these channels with regard to their ion selectivity, pharmacologic sensitivity and voltage- dependence; 2) determine the regulation of these calcium channels by protein kinases; 3) define the participation of G-proteins in regulating calcium entry channels; and, 4) identify and clone calcium channel
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transcripts. Extrusion of calcium across basolateral plasma membranes of distal tubules is mediated by Na+/Ca2+ exchange and by /ca2+-ATPase. Pilot studies suggest that Na+/Ca2+ exchange is the dominant efflux mechanism in DCT cells. We will: 1) Test the hypothesis that thiazide diuretics can inhibit Na+/Ca2+ exchange; and 2) Characterize the stimulatory effects of PTH on Na+/Ca2+ exchange. Calcium transport in distal nephrons is regulated by PTH, calcitonin and 1,25(OH)2 vitamin D3. The following studies will evaluate the mechanism mediating the hormonal regulation of calcium transport in DCT cells. The goals of these experiments are to: 1) Characterize the signaling pathways with particular regard to the phospholipases responsible for activating PKA and PKC and characterize the temporal sequence in which PKA and PKC are activated. We will test the hypothesis that PTH and calcitonin activate PKC via phospholipase D. 2) Identify the mechanism by which PTH activates C1- channels, a primary event in membrane hyperpolarization and stimulation of calcium transport in DCT cells. We will test the hypothesis that these chloride channels are regulated by the PKA limb of the PTH-activated signaling pathway. 3) Examine the regulation of vitamin D3 and estradiol accelerate PTH dependent calcium transport by up-regulating PTH receptor expression. The specific aims will be achieved by applying single cell fluorescence, patch clamp, tracer flux measurements, biochemical and molecular techniques to a DCT cell line that we developed, which expresses an appropriate phenotype. In selected studies, primary cell cultures of proximal or distal tubule cells will be used to verify results in transformed cells or as controls. All procedures are established in our lab. Results from the proposed experiments will provide new information on the mechanism and regulation of calcium transport in the kidney under normal conditions, but also in calcium-wasting syndromes including hyperparathyroidism, renal failure, osteoporosis and malignancy- associated hypercalcemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CIRCUMVENTRICULAR ORGANS: GENDER AND HYPERTENSION Principal Investigator & Institution: Hay, Meredith; Director and Associate Professor; None; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 15-FEB-2000; Project End 31-JAN-2004 Summary: It has been proposed that estrogen delays and or prevents the onset of hypertension and may function to keep women "cardiovascularly younger" than men of the same age. Similar observations have been made in experimental hypertensive animals, however, the underlying mechanisms of estrogen's protective effects are incompletely understood. Given the importance of estrogen replacement therapy in women's health, it is clear that an understanding of the cellular mechanisms underlying estrogen's cardiovascular protective effects is critical for continuing development of clinical therapies for the treatment of hypertension in women. Angiotensin II (Ang II) is an important factor in some forms of both clinical and experimental hypertension. Chronic intravenous infusions of low levels of Ang II in experimental animals result in an increase in blood pressure that involves an increased neurogenic contribution to the maintenance of blood pressure which is prevented by prior lesioning of the area postrema (3,6,33,57,95). It is thought that circulating Ang II acts on area postrema neurons to maintain the hypertension. The proposed studies will test the general hypothesis that estrogen protects against the Ang II induced hypertension by inhibiting the actions of Ang II on area postrema neurons. To test this hypothesis and to characterize the effects of estrogen (17beta-estradiol) on area postrema neurons, Ang II induced increases in blood pressure and baroreflex modulation, this proposal will
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utilize whole-cell patch clamp recordings from isolated area postrema neurons, in vivo single unit recordings of area postrema neurons and hemodynamic measurements in conscious animals to address the following 4 major and distinct aims. 1) To evaluate area postrema membrane properties following exposure to 17beta-estradiol. 2) To determine the effects of acute and chronic 17beta-estradiol on area postrema calcium handling. 3) To determine the effect of 17beta-estradiol on activation of area postrema neurons. 4) To evaluate the effects of acute and chronic 17beta-estradiol on Ang II hypertension. Determination of the effects of estrogen on CNS mechanisms underlying Ang II dependent hypertension will have a significant impact on our understanding of the cardiovascular benefits of estrogen replacement therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COOPERATIVE MULTICENTER REPRODUCTIVE MEDICINE NETWORK Principal Investigator & Institution: Mc Govern, Peter G.; Ob/Gyn & Women's Health; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2002; Project Start 30-JUN-2000; Project End 31-MAR-2005 Summary: Infertility is a common problem in the United States. Technological advances have made therapy for infertility quite effective. However, all of the assisted reproductive techniques require the use of gonadotropins (whether recombinant or derived from menopausal urine) to induce ovulation. Serious complications of these therapies include multiple pregnancy, ovarian hyperstimulation syndrome (OHSS), and premature delivery (even in singletons). These complications exact a huge toll upon the physical, emotional and financial status of these couples, and place a major strain on the health care resources of our entire society. Our hypothesis is that the hypersecretion of luteal products (such as VEGF, renin and IL-6) caused by multiple corpora lutea is responsible for the development of OHSS. We also hypothesize that the hypersecretion of luteal products such as relaxin causes much of the prematurity associated with gonadotropin use. We have presented data that hyperrelaxinemia (in pregnancies conceived after the use of gonadotropins) correlates with prematurity. We have also demonstrated relaxin receptors in the human cervix, and that relaxin stimulates proMMP-1 and proMMP-3 expression as well as inhibiting TIMP-1 production, all effects which can contribute to increased collagen breakdown and cervical ripening. We plan to develop a method of superovulation which should result in luteal regression, which in turn should eliminate OHSS and decrease the risk of prematurity. This could have the secondary effect of making multiple pregnancies safer. hLH, with a much shorter half-life, will be substituted for hCG as the ovulatory stimulus. Pretreatment with a GnRH-agonist will eliminate endogenous LH secretion. The lack of continued luteotrophic stimulus will allow luteolysis. The endometrium will be maintained with exogenous estradiol and progesterone as is done in oocyte donation cycles. We will then test the hypothesis that this novel protocol, by preventing the hypersecretion of luteal products in gonadotropin-induced pregnancies, will result in safer infertility therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE-- NEUROCHEMISTRY Principal Investigator & Institution: Millard, William J.; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2003
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Summary: The major goal of this program project is to develop drugs that may prove beneficial to Alzheimer's disease (AD) patients. Paramount to the establishment of a drug or class of drugs that may have therapeutic applications in AD is the establishment of alterations (improvements or possibly further deterioration) in the neurochemical profile while undergoing drug therapy. It is the primary focus of this Neurochemistry Core to maintain a central laboratory facility which will support the various projects outlined in the program by providing assay service for a number of hormonal, cholinergic and peptidergic neurochemical markers. The services provided will be as follows; 1) radioimmunoassay (RIA) support for the various estrogens (17beta-estradiol, 17alpha-estradiol, estrone, estriol), anterior pituitary hormones (luteinizing hormone [LH] and thyroid stimulating hormone [TSH] and the thyroid hormones T3 and T4; 2) enzyme- linked immunoabsorbant assay (ELISA) service for the neurotrophic agent nerve growth factor (NGF); 3). radiometric analysis of various markers of cholinergic function (high affinity choline uptake [HACU], acetylcholine release and choline acetyltransferase [ChAT] activity) and protein kinase C (PKC) in both neural tissue and cells from neuron-enriched cultures; 4) semiquantitative measurement of high affinity NGF receptor protein (trkA) by immunoprecipitation and electrophoretic separation in both neural tissue and cells from neuron-enriched cultures; 5) radiometric monitoring of intracellular ionized (free) calcium [Ca++]i by using calcium dye Fura2/AM and photon counting spectrofluorometric procedures; 6) immunocytochemical analysis of ChAT, cyclic AMP response element binding protein (CREB), phosphorylated form of the cyclic AMP response element binding protein (P- CREB) and mitochondrial proto-oncogene protein bcl-2 levels in neural tissue and 7) in situ end-labeling of DNA oligonucleotides in brain tissue and cultured neurons to determine the extent of apoptosis in cultured neurons when exposed to cellular insults such as serum deprivation, exposure to NMDA or beta-amyloid protein,. Thus, the Neurochemistry Core will be integral to this program project by providing analytical service for the monitoring of neurochemical status while selected drugs undergo both preliminary screening and more detailed evaluation for potential therapeutic uses in the treatment of AD and related disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEPO-PROVERA AND BONE DENSITY IN PREMENOPAUSAL WOMEN Principal Investigator & Institution: Clark, M Kathleen.; Associate Professor; None; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: (Adapted from abstract): Registered nurses (RNs) and advanced practice nurses (APNs) play an important role in providing contraceptive services to women of reproductive age. Education and counseling regarding use, risks, and benefits of contraceptive choices are long-standing nursing interventions. With prescriptive authority, APNs are additionally responsible for providing safe, effective pharmacological interventions for preventing pregnancy. DMPA is a progestin only injectable contraception, approved for use in the US in 1992. Of concern is a potential adverse effect of DMPA on bone mineral density. Because DMPA disrupts the hypothalamic-pituitary-ovarian-axis (HPO), it theoretically will suppress estrogen production causing a relative estrogen deficiency, and corresponding loss of bone mineral density. The overall goals of this study are to determine the effect of DMPA on bone mineral density in women aged 18 to 30 years and to determine whether the effect can be modified by calcium intake or predicted by, baseline estradiol levels, irregular vaginal bleeding or weight gain. A two-year prospective longitudinal study of 275
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women, 160 who are receiving their first DMPA injection, and 115 control subjects who are not using any hormonal method of contraception, will be completed. All participants will receive a baseline evaluation, and follow-up evaluations every three months for two years. At baseline, participants will have their bone mineral density of the femoral neck, lumbar spine and total body measured using dual energy x-ray densitometry (DEXA). Blood will be drawn for estradiol levels and other physical measurements completed. Participants will complete nutritional and physical activity assessments, as well as a comprehensive interview detailing demographic, medical reproductive and lifestyle behaviors that may influence bone mineral density. All participants will be given one 90-day menstrual calendar for the daily recording of vaginal bleeding. At each followup evaluation bone mineral density and body composition will be measured, nutrition and physical activity reassessed and components of the interview updated. The menstrual calendar will be collected, reviewed and new calendars provided. Random coefficient regression (RCR) analysis will be the major analytic strategy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DETERMINANTS OF TISSUE ESTRADIOL SENSITIVITY Principal Investigator & Institution: Santen, Richard J.; Professor of Medicine; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 07-AUG-1994; Project End 31-JUL-2004 Summary: (Adapted from the applicant's abstract): The mechanisms allowing women with estrogen dependent breast cancer to respond to secondary hormonal therapies are incompletely understood. As a potential explanation, the applicant postulated that breast cancer cells adapt to estrogen deprivation by developing hypersensitivity and developed a model system demonstrating this phenomenon. Based on the results, the applicant suggested that hypersensitivity is not mediated primarily at the level of estrogen receptor transcription but rather involves up-regulation of growth factor signaling pathways. His working hypothesis is that growth factor and estrogen mediated events interact synergistically at the level of the cell cycle to mediate hypersensitivity. The proposed studies will further examine growth factor pathway upregulation and determine the specific mediators responsible. Based upon recent preliminary data, the applicant will also examine hypersensitivity and apoptosis. In his model, long term estrogen deprivation sensitizes cells to a paradoxic, stimulatory effect of estradiol on apoptosis. Accordingly, he plans to systematically examine this phenomenon and has envisioned a novel breast cancer treatment based upon his findings. The strategy rests upon the concept that cell proliferation and apoptosis are intrinsically linked and regulated by survival factors. Certain proteins such as c-Myc, activated Ras, MAP kinase, and E2F1 and that a PI-3-kinase inhibitor can induce apoptosis. The integration of these concepts provides a rationale to "Kill" tumor cells with estrogen as part of a combined treatment strategy for breast cancer. This utilizes alternate cycles of therapy first to block cell proliferation with anti-estrogens and growth factor inhibitors and then to stimulate apoptosis with estradiol and PI-3-kinase inhibitors. Specific Aim 1 will demonstrate which growth factor mediated pathways are up regulated during adaptation to long term estradiol deprivation. Specific Aim 2 will delineate the separate mechanistic roles of c-Myc and the MAP kinase pathway on cell proliferation and on cell death. Specific Aim 3 will optimize the conditions for enhancing apoptosis and inhibiting cell proliferation in vitro. Specific aim 4 will demonstrate in an in vivo model that the strategy of alternate blockade of proliferation followed by stimulation of apoptosis results in greater tumor regression than with each
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intervention alone. The applicant expects these studies to be the basis for future clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISRUPTION OF ESTROGENIC RESPONSES BY PCB-PAH MIXTURES Principal Investigator & Institution: Arcaro, Kathleen F.; Research Assistant Professor; Veterinary and Animal Sciences; University of Massachusetts Amherst 408 Goodell Building Amherst, Ma 01003 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: There is widespread concern that exposure to chemicals in the environment may be related to the observed increase in the incidence of breast cancer. Among the chemicals of concern are polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), which have the potential to disrupt estrogenic responses. It is difficult to predict the health effects of exposure to complex mixtures of these chemicals because individual congeners of PCBs and PAHs can be either estrogenic or antiestrogenic and act through a variety of mechanisms potentially leading to additive, antagonistic or synergistic effects. Furthermore, the microbial reductive dechlorination of PCBs and the metabolic transformation of both PCBs and PAHs within the body, may substantially alter the activity of these mixtures. It is hypothesized that reductive dechlorination of PCBs increases the estrogenic activity of the resulting mixture, and that metabolism of PCBs and PAHs further alters the estrogenic and anti-estrogenic activity of these mixtures. Thus, the objective of this proposal is to determine how mixtures of PCBs and PAHs may interact and modulate estrogenic activity in human cells. Specifically we will: 1) Determine the estrogenic and anti-estrogenic activity of relevant complex mixtures of PCBs and PAHs. Extracts from sediment samples and mixtures reflecting the composition of PCBs and PAHs detected in human tissue, food and water will be tested in human breast cancer cells for their estrogenic and antiestrogenic activity. 2) Determine how mixtures of PCBs and PAHs alter estrogenic activity and assess whether knowledge of the activity of the individual components is sufficient to predict the activity of the mixture. Mechanisms to be investigated include, estrogen receptor (ER) binding, regulation of ER level, metabolism of 17-estradiol metabolism of PCBs and PAHs in breast cancer cells. The nature of the interactions will be explored using full dose-response curves and probit analysis. 3) Determine the extent to which the estrogenic and anti-estrogenic activity of a mixture is altered by metabolism in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes will be tested for their estrogenic and anti-estrogenic activity in human breast cancer cells. Knowledge gained from these studies will provide insight into the relationship between exposure to environmental estrogens and health risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DNA SEQUENCES IMPACT ESTROGEN AND ANTIESTROGEN ACTIVITY Principal Investigator & Institution: Klinge, Carolyn M.; Associate Professor; Biochem and Molecular Biology; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2003
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Summary: Type I antiestrogens, e.g. tamoxifen (TAM), are used to prevent recurrence of estrogen-dependent disease in women with breast cancer and have beneficial agonist effects in other estrogen target tissues. TAM, and its metabolite 4-hydroxyTAM(4-OHT), compete with estradiol (E2) for binding to estrogen receptor (ER), activating the ER and enhancing its binding to specific DNA sites, estrogen response elements (ERE). The precise molecular mechanisms allowing ERE-containing genes to be selectively responsive to estrogens versus ligands for other nuclear receptors and bind EREs, e.g., COUP-TF and retinoic acid receptors, are not well understood. Preliminary evidence suggests that the nature of the ERE sequence acts as an allosteric effector, altering ER conformation and thus modulating liganded-ER interaction with coactivators and components of the transcription initiation complex to regulate gene expression. The proposed studies will test the following hypotheses: 1) ERE sequence and that of its immediate adjacent sequences impact ER binding and conformation and impact ligand binding. I propose that ligand binding stability is important for maintaining ER in a conformation necessary for transactivation of target gene expression. Results will correlate DNA sequence, ligand binding stability, and alterations in ER sensitivity to trypsin digestion with transcriptional activation in transiently transfected cells. 2) The distance between ERE half-sites and the nature of immediately adjacent flanking sequences regulate ER versus type II nuclear or orphan receptor binding. Preliminary studies show ER binds more avidly to ERE half-sites located on opposite faces of the DNA helix. Results will provide detailed analysis of how ERE half-site spacing contributes to estrogen and antiestrogen action. 3) ER synergizes with Sp1 to regulate the transcription of two natural estrogen target genes: creatinine kinase B and lactoferrin by direct interactions that increase ER-ERE binding affinity and stability. Results will reveal the basis for how ER ligand and the sequence of the ERE and its surrounding nucleotides, impact ER conformation, ERE binding affinity, ER interaction with Sp1, and ligand- dependent induction of gene expression in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DRUG ADOLESCENCE
ABUSE
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Principal Investigator & Institution: Martin, Catherine A.; Psychiatry; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Mentored Clinical Scientist Development Award: The nominee, Catherine A. Martin, M.D., proposes to develop as an independent clinical researcher in the University of Kentucky Department of Psychiatry and the Center on Drug and Alcohol Research. Her research focus and the purpose of this study is to determine if drug use risk in adolescents with impulse disorders; e.g. Attention Deficit Hyperactivity Disorder (ADHD) and co-morbid Conduct Disorder (CD), is altered by pubertal hormonal changes. Measures of impulsivity, drug use and testosterone in males and testosterone and estradiol in females, will be obtained from 120 subjects at pre-, early and mid-adolescence, (ages 11 l/2 -12 1/2; 13-14; and 14 l/2 -15 1/'2). The overall hypothesis is that testosterone and estradiol increase impulsivity in an already at risk population. This increased impulsivity escalates risk for drug use. Ultimately, the long range goal of this study is to add to the knowledge base and the understanding of how pubertal hormonal changes in impulsive adolescents are related to risk for drug use. The nominee is an established clinician and medical educator with an ongoing investment, but no formal training in research. This award will allow the nominee to acquire the knowledge and experience to develop research paradigms involving at risk
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psychiatric populotions, particularly those with impulse disorders, and drug use. The nominee will use these skills to develop a drug research program on the course of drug use in children and adolescents with impulse disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECT OF RALOXIFENE ON NEURONAL PHYSIOLOGY Principal Investigator & Institution: Audesirk, Teresa E.; Biology; University of Colorado at Denver P.O. Box 173364 Denver, Co 802173364 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Selective estrogen receptor modulators (SERMs) are synthetic compounds that bind to genomic estrogen receptors (ER), mimicking estrogen in some tissues, and antagonizing it in others. The SERM raloxifene antagonizes estrogen in both the breast and uterus, conferring a degree of protection against breast and uterine cancers, while it serves as an estrogen agonist in lipid and bone metabolism, providing some protection against both osteoporosis and heart disease. In 1997, the U.S. FDA approved the use of raloxifene for the prevention of osteoporosis. As a result, raloxifene will soon be used by millions of postmenopausal women. There is a large and rapidly growing literature concerning the effects of b-estradiol on the brain, both on brain function generally (maintenance of cognitive abilities and protection against Alzheimer's disease) and on individual neurons (promotion of neurite outgrowth and dendritic spine production, nitric oxide synthase activation, and neuroprotection). A major gap in the current understanding of raloxifene is how it influences the brain. We will use cultured rat hippocampal and cortical neurons to accomplish the following aims: 1. To test the hypothesis that raloxifene will either mimic or antagonize the neuroprotective effects of b-estradiol against oxidative stress in vitro. 2. To test the hypothesis that raloxifene will mimic or antagonize the effects of b-estradiol on calcium levels in neurons. 3. To test the hypothesis that raloxifene will either reduce or enhance calmodulin activation. The SERM tamoxifen reduces calmodulin activity, suggesting that raloxifene should also be tested for this property. 4. To test the hypothesis that raloxifene will mimic or antagonize the effects of b-estradiol on nitric oxide synthase. The production of NO, which has been implicated in several aspects of neuronal differentiation and learning, is enhanced by b-estradiol. This enhancement is blocked by the SERM tamoxifen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENDOCRINE DISRUPTION MEDIATED THROUGH NUCLEAR RECEPTOR Principal Investigator & Institution: Baldwin, William S.; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): The goal of this project is to investigate whether particular toxicants, including some putative endocrine disrupting chemicals, can increase intracellular estradiol concentrations by inhibiting estradiol metabolism and depuration, and thus increasing estradiol-responsive growth. Further, the role of the Pregnane X-receptor (PXR) and its ligands in regulating estradiol metabolism and elimination will be investigated. Steroid hormone metabolism and depuration is controlled by the same enzymes that metabolize and eliminate toxicants in phase I, II and III reactions. Perturbing these metabolic processes can result in toxicant interactions, as well as, perturb steroid hormone homeostasis. MCF-7 breast cancer cells will be
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stably transfected with the PXR receptor and putative PXR ligands, such as 4nonylphenol, DEHP (antagonists) and rifampicin (agonist) will be used to determine whether PXR ligands can significantly alter intracellular estradiol homeostasis and increase estrogen-responsive proliferation. The PXR regulates induction of CYP3A and MRP2 and may be involved in the induction of glucuronosyltransferases, as well. CYP3A is a major steroid hydroxylase, glucuronosyltransferases are important in conjugating steroids and MRP2 is a steroid hormone transporter. Hence, these enzymes are important in metabolizing and eliminating estradiol. Recent evidence in our lab and others suggests that some chemicals may bind the PXR and act as antagonists. Our hypothesis is that these chemicals, including the endocrine disrupters, DEHP and 4nonylphenol, can down-regulate estradiol metabolism and depuration in this manner, thus increase effective estrogen concentrations and induce proliferation. This alternate mechanism of endocrine disruption could cause developmental abnormalities and/or cause estrogen-responsive cancers, such as breast and ovarian cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENDOCRINE REGULATION OF MATERNAL BEHAVIOR Principal Investigator & Institution: Bridges, Robert S.; Professor of Biomedical Sciences; Veterinary Biomedical Sciences; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-SEP-1990; Project End 31-MAY-2005 Summary: The long-term goal of this project is to identify the neural and neurochemical mechanisms underlying the regulation of maternal behavior and to elucidate potentially novel mechanisms of neural plasticity associated with the expression of maternal behavior in the adult mammal. The specific hypothesis that will be tested is that the induction, maintenance, and retention of maternal care are under endocrine regulation by a neural lactogenic system, a system that displays significant plasticity as a function of reproductive experience. The first series of studies will examine the role of the neural prolactin (PRL) receptor in the initiation of maternal behavior. Using a rat model, we will determine whether placental lactogens, like PRL, act via the PRL receptor to stimulate the onset of behavior. A second study will use the novel PRL receptor antagonist, S 179D-PRL, which will be administered centrally to test the hypothesis that activation of the PRL receptor by lactogenic hormones around the time of birth is essential for the normal onset of maternal care. The third study using ISHH will measure how pregnancy concentrations of progesterone (P) and estradiol affect expression of mRNA for neural PRL receptors. Then, central sites of P action will be examined to see how P affects the onset of maternal care and to delineate a mechanism of P's action in the initiation of maternal behavior. A second series of experiments will determine the involvement of the endocrine system in ongoing maternal care. First, the effects of exposure to PRL-secreting ectopic pituitary grafts on pup-directed maternal care and maternal aggression will be measured. Then, the effects of central administration of the PRL receptor antagonist, S179D- PRL, will be examined in lactating rats. The third set of experiments will delineate the role of the endocrine system in the retention of maternal behavior: The involvement of PRL in the opioidmediated establishment of the retention of maternal behavior will be assessed. Finally, the effects of prior maternal experience on activation of the neural lactogenic system will be measured to see whether prior maternal experience up-regulates the brain PRL system and makes the female more sensitive to her own neural hormones. The results of these investigations will delineate common endocrine and neurochemical regulators of maternal care in mammals, present a new model for examining neuroplasticity in the
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adult female, and provide a basis for evaluating the effects of endocrine and neurochemical imbalances on mother-young interactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENDOMETRIOSIS IN BABOON--ESTABLISHMENT /FERTILITY Principal Investigator & Institution: Fazleabas, Asgerally T.; Professor; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 02-MAY-2002; Project End 31-MAR-2007 Summary: Endometriosis is defined as the presence of endometrium-like tissue outside of the uterine cavity. It is one of the most common causes of infertility and chronic pelvic pain and affects 1 in 10 women in the reproductive age group. It is inherited in a polygenic manner with a complex and multifactorial etiology. Although existence of this disease has been known for over 100 years, our current knowledge of its pathogenesis, the pathophysiology of related infertility and its spontaneous evolution is limited. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long term studies in women. Therefore, we have developed an appropriate non-human primate to study the etiology of this disease. We propose that endometriosis develops in two distinct phases. Phase I is invasive and dependent on ovarian steroids. Phase II, which is the active phase of the disease, is characterized by endogenous estrogen biosynthesis. Using the baboon model for endometriosis we will; 1) explore the role of paracrine factors produced by the endometrial tissue itself in endometriosis; 2) determine the role of endocrine factors on the ectopic establishment of endometrial tissue; and 3) investigate the physiological consequences of endometriosis on reproduction. Specifically, in Specific Aim 1, we will use the in vivo model system to characterize changes in estrogen receptor and aromatase gene expression during disease progression. These changes will establish the role for estrogen to directly or indirectly regulate metalloproteinases (MMP-3 and MMP-7) and vascular endothelial growth factor (VEGF) to enable menstrual tissues to implant in an ectopic site. In Specific Aim 2 we will determine the role of ovarian steroids, particularly estradiol, in the establishment of endometriotic lesions. We propose to use three treatment modalities following introduction of menstrual effluent into the peritoneal cavity: a) suppression of ovarian function following menses with GnRH agonists; b) addition of low doses of exogenous progesterone during the follicular phases; c) ovariectomy and steroid replacement following menstruation. In Specific Aim 3 we will determine the effects of endometriotic lesions on uterine receptivity. Using a simulated pregnant baboon model we will determine if the hCG-induced, functional changes in both epithelial and stromal cells are affected in baboons with endometriosis during the period of uterine receptivity. In addition, we will determine if treatment with an aromatase inhibitor suppresses the disease and reverses the deleterious effects on endometriosis on uterine receptivity. These studies will provide significant information on the establishment and progression of endometriosis and its potential effects on fertility. These studies have direct relevance for the diagnosis and treatment of this disease in women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EPIDEMIOLOGIC STUDY OF THE LATE REPRODUCTIVE YEARS Principal Investigator & Institution: Freeman, Ellen W.; Research Professor; Obstetrics and Gynecology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 10-FEB-1996; Project End 31-JAN-2006
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Summary: (Adapted from the Investigator's Abstract) This is a prospective study of ovarian aging in African American and Caucasian women in their late reproductive years, commencing at ages 35-47 and continuing to ages 45-52. The specific aims are to 1) compare hormone dynamics (FSFL estradiol, DHEAS) and the follicular product inhibin between African American and Caucasian women; 2) evaluate menopauserelated symptoms over the study period and compare their severity and changes between African American and Caucasian women; and correlate physical and psychological factors (body mass, hot flashes, depression, steep disturbance and others) with hormone levels, fluctuations and rates of change and compare the associations between the two racial groups. The study is conducted with a randomly-identified population-based sample of approximately 400 women. The second phase of the study has four annual follow-up periods, each with two assessments at 1-month intervals, for a total of eight visits to collect blood samples for hormone assays and questionnaire data. More than 8O percent of U.S. women experience physical or psychological symptoms in the transition to menopause with varying degrees of severity and disruption of normal functioning. Whether these symptoms commonly attributed to the menopause are associated with the hormonal changes of the waning reproductive years is not well understood. Symptoms that diminish quality of life are a significant problem for women who experience them, their relationships and their productivity. Poor understanding of the symptoms and their associations with biological and environmental factors is a problem for health care when distressed women seek medical relief. This study provides the first information on racial differences in the associations between symptoms and the changing hormonal milieu compared between African American and Caucasian women. The investigators state that the findings will also inform clinicians addressing fertility problems of women in the late reproductive years and will increase understanding of the role of reproductive aging in the increased morbidity and mortality of postmenopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPIDEMIOLOGY OF OVARIAN AGE Principal Investigator & Institution: Kline, Jennie K.; Research Scientist; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 31-MAR-2004 Summary: (provided by applicant): The goal of this study is to identify factors that influence ovarian age. We define "ovarian age" as the size of oocyte pool. Ovarian follicle (oocyte) counts are highest before birth and decrease as women age; similarly, the number of follicles that develop during each menstrual cycle decreases as women age. At any particular chronologic age, women vary in both the size of their oocyte pools and the number of antral (developing) follicles. These variations may reflect differences in the size of the pool at its formation or in rates of oocyte atresia. Increasing numbers of women are deferring childbearing to the later years. Since ovarian aging is accompanied by conception delay and an increased risk of infertility and trisomic conception, the identification of risk factors for accelerated ovarian aging would have significant implications for reproductive research and primary prevention. The proposed study draws on data from two already completed studies to identify risk factors for ovarian age. In the first study, ovarian age is measured by age at onset of the menopausal transition and at menopause in 494 women. In the second study. ovarian age is measured shortly after an index pregnancy by counts of ovarian antral follicles and three hormonal indicators of ovarian age-follicle stimulating hormone, inhibin B and estradiol-in 173 women. Both studies include extensive data on maternal characteristics
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and exposures that might influence ovarian aging. They thus provide an excellent and unique opportunity to (i) identify determinants of ovarian age in fertile women during natural cycles and (ii) examine whether determinants of ovarian age during the reproductive years differ from determinants during the menopausal transition. The specific aims are: 1. To examine whether maternal characteristics (e.g., body mass index) or exposures (e.g., smoking) are associated with ovarian age measured by (i) antral follicle counts, (ii) selected hormonal indicators, (iii) age at onset of the menopausal transition, and (iv) age at menopause. 2. To conduct exploratory studies, using data from the Oocyte study, to assess whether or not skewed X-inactivation is associated with advanced ovarian age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESTRADIOL FOR NEUROCOGNITIVE DYSFUNCTION AFTER CABG Principal Investigator & Institution: Hogue, Charles W.; Anesthesiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: Women undergoing coronary artery bypass graft (CABG) surgery have a higher operative mortality rate, longer hospitalizations, and higher hospital cost compared with men. A large proportion of this excess morbidity and mortality of surgery for women is due to perioperative neurologic injury. Estrogens have been consistently shown to reduce the extent of neurologic injury in a variety of in vitro and animal experimental stroke models. These data together strongly suggest that the higher risk for perioperative neurologic complications for elderly women may relate to their estrogen deficient state. In this randomized, placebo controlled study, we will test the hypothesis that perioperative estrogen replacement in postmenopausal women reduces the risk for neurologic injury after CABG surgery. Three hundred thirty four women undergoing CABG surgery will be prospectively randomized to receive either 17betaestradiol or placebo in a double-blind fashion beginning the day before surgery and continued for 5 days after surgery. Patients will be assessed for neurocognitive dysfunction, the most common manifestation of neurologic injury from cardiac surgery. Neurocognitive testing will be performed 1-2 days before surgery, 4 to 6 weeks postoperatively, and 6- months after surgery. The primary endpoint will be neurocognitive function 4 to 6 weeks after surgery for women who received 17betaestradiol compared with placebo perioperatively. We will also evaluate for the importance of postoperative cognitive decline on measures of cognitive function and quality of life 6 months after surgery and whether perioperative 17beta-estradiol treatment improves these latter outcomes. The results of this study will evaluate the efficacy and safety of an easily implemented therapy for improving neurologic outcome and quality of life after CABG surgery for postmenopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ESTROGEN EFFECTS ON CARDIOVASCULAR RESPONSE TO EXERCISE Principal Investigator & Institution: Kaufman, Marc P.; Professor of Internal Medicine & Human p; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2006
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Summary: (Applicant's abstract): Static and moderate dynamic exercise are known to increase heart rate, myocardial contractility, arterial blood pressure, breathing and muscle sympathetic nerve discharge. These effects, which are believed to increase the delivery of oxygen to metabolically active tissues (i.e., the exercising muscles), appear to be less in women than in men. This difference is often attributed to the effect of estrogen on neuronal function. Consequently, the aim of the experiments proposed in this application is to identify the effect of estrogen on "central command" and the muscle reflex, the two neural mechanisms responsible for evoking the autonomic responses to exercise. The proposed studies will be done in decerebrate unanesthetized female and male cats, which have been either ovariectomized or castrated, respectively two to four weeks prior to the experiment. In this preparation, the two neural mechanisms, central command and the muscle reflex, can be investigated separately without the influence of anesthesia. The effect of estrogen (i.e., 17-beta-estradiol) on the central command to exercise will be studied while the cats are paralyzed with vecuronium, and will be evoked by both electrical and chemical stimulation of the hypothalamic and mesencephalic locomotor regions. Motoneuron discharge to agonist and antagonist hindlimb muscles will be recorded. The criterion for elicitation of central command will be "fictive locomotion." Likewise, the effect of estrogen on the muscle reflex will be studied, but the cats will not be paralyzed. The muscle reflex will be evoked both while the hindlimb muscles are freely perfused and while they are ischemic. Dose response relationships for the effect of estrogen on both the cardiovascular and respiratory responses to central command and the muscle reflex will be determined. Moreover, studies will be extended to estrogen pretreatment with timed release pellets implanted into castrated male cats and ovariectomized females. In addition, the effect of microinjections of 17beta-estradiol into the hypothalamic and mesencephalic locomotor regions will be determined because preliminary data suggest that central command, but not the muscle reflex, is responsible for the estrogen-induced attenuation of the cardiovascular and ventilatory responses to exercise. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESTROGEN, CA2+ CHANNELS AND (CA2+) IN HIPPOCAMPAL AGING Principal Investigator & Institution: Porter, Nada M.; Pharmacology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant): Very little is known about cellular patterns of brain aging in female mammals or about how brain aging in male or female rodents depends on hormonal status. An increase in L-type voltage-gated Ca2+ channels (LIGCCs)/currents and expression of the L-VGCC alpha1 subunit in hippocampal CA1 neurons and altered recover of [Ca2+]i responses have been found to be among the most consistent cellular/molecular biomarkers of brain aging in male rats and female rabbits. These age changes in Ca2+ homeostasis also appear to contribute directly to impaired plasticity and learning. Estradiol (E2) has been found to be neuroprotective and to counteract a number of aging-related alterations in long-term potentiation/depression (LTP/LTD) and cognitive function, and may retard Alzheimer's disease (AD). However, the molecular/cellular mechanisms that mediate these actions are not understood. Recently, we found a potential link between this cellular aging biomarker (L-VGCCs) and E2 actions, in that E2 downregulated L-VGCCs in hippocampal "zipper" slices ,f ovariectomized (OVX), aged female rats and in hippocampal cultures. E2 decreases in an ageiependent manner and it has been suggested that this contributes to brain aging
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and declining function in Females and possibly males. This application proposes to test the hypothesis that declining E2 levels with age are a stimulus for altered Ca2+ homeostasis and increased L-VGCCs in hippocampal neurons, whereas chronic E2 retards development of these cellular and behavioral biomarkers of brain aging. In addition, we will identify cellular/genomic pathways through which E2 regulates LVGCCs and other aging markers. To carr out these studies we will combine two highly advantageous preparations, the hippocampal "zipper" slice, and an age-dependent hippocampal cell culture model, with single channel electrophysiology, Ca2 imaging in single cells, and gene expression analyses by real-time PCR and Affymetrix gene chip microarray technology. Recently, we adapted the hippocampal "zipper" slice for single cell gene expression/function studies, and therefore, will be able to test correlations between L-VGCC activity and expression of multiple genes in the same cells. Together, these studies will systematically determine whether the development of some biomarkers of brain aging is modulated by E2 in female and male rats, and will elucidate linkage of functional biomarkers to specific genomic pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESTROGEN-INDUCED NEUROPROTECTIVE MITOCHONDRIAL MECHANISM Principal Investigator & Institution: Brinton, Roberta Diaz.; Professor of Molecular Pharmacology And; Molecular Pharm & Toxicology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The long-term goal of our research program is to develop an estrogen replacement therapy that meets the unique requirements of the brain by activating estrogen-inducible mechanisms of memory and neuroprotection without activating mechanisms of proliferation within the uterus or breast. To achieve this long-term goal, multiple levels of mechanistic understanding of estrogen receptor function in brain must first be achieved. Towards elucidating mechanisms of estrogen promoted neuroprotection, we propose a model of estrogen-inducible proactive adaptation as a strategy whereby estrogen proactively protects neurons against insults of calcium dysregulation. The proposed model incorporates both novel mitochondria mechanisms of estrogen action and several existing estrogen-inducible pathways into a unified concept of proactive adaptation. Four specific aims are proposed. Specific Aim 1 will determine essential basics and generalizability of 17beta-estradiol (E2)-induced mitochondrial sequestration of calcium. Specific Aim 2 will investigate the impact of 17beta-estradiol on the threshold for mitochondrial Ca 2+ sequestration and the underlying mechanism for the shift in threshold. Specific Aim 3 will address the mechanism by which 17beta-estradiol protects against increased mitochondrial calcium load to prevent mitochondrial dysfunction. Specific Aim 4 will determine the mechanism underlying 17beta-estradiol regulation of Bcl-2 family of proteins. Throughout each of the specific aims, we will determine whether 17beta-estradiolinduced mitochondria mechanisms activated in vitro are present in vivo. Seven technological approaches will be extensively utilized: neuronal culture, fluorescent intracellular calcium imaging, biochemical analyses of enzyme activation, immunocytochemical protein labeling, Western blot, mitochondrial isolation and HPLC for polyamines. Mitochondrial function will be assessed within cultured hippocampal neurons and in mitochondria derived from adult rat hippocampal neurons. Results of the proposed studies will provide a unified mechanistic model of estrogen-induced neuroprotection that incorporates both novel mitochondria mechanisms of estrogen
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action and estrogen-inducible MAPK, AKT and antiapoptotic pathways. From a clinical perspective, elucidation of the sites and targets of estrogen action should have a clear impact on both the use of estrogen replacement therapy for the prevention of neurodegenerative disease and the future design of target specific estrogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FEMALE SEXUALITY: MODULATION BY ESTROGEN AND ANDROGEN Principal Investigator & Institution: Wallen, Kim; Dobbs Professor of Psychology and Behavi; Psychology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The hypothesis is investigated that female sexual interest is stimulated by the neural actions of ovarian estrogens and that androgens regulate the bioavailability of these estrogens through interactions with sex hormone binding globulin (SHBG). Three projects, using a rhesus monkey model of endocrine function and behavior, investigate the hormonal basis of female sexual initiation. Project I investigates sexual initiation in females across the menstrual cycle, comparing the occurrence of female sexual initiation in a social group context during normal cycles treated with an androgen receptor blocker (flutamide) or an estrogen receptor blocker (tamoxifen). This will clarify whether androgens or estrogens act neurally to modulate female sexual motivation. Project II tests the novel hypothesis that SHBG regulates bioavailable estrogens and androgens through these steroids' different affinities for SHBG. This project uses a monkey model of hormonal replacement therapy for reproductively prime females after surgical removal of their ovaries and tests the hypothesis that chronic estradiol (E2) ceases to effectively stimulate female sexual interest as estrogen is sequestered by SHBG. It further investigates whether an androgen, 5a-dihydrotestosterone (DHT), with a markedly higher affinity for SHBG than estradiol can acutely and rapidly reinstate female sexual interest by increasing free estradiol by displacing SHBG-bound estradiol. Ovariectomized females receiving chronic estradiol treatment mimicking mid-follicular estradiol levels will be observed for sexual initiation during chronic E2 treatment alone and following chronic E2 and an injection of DHT or E2. Concurrent administration of flutamide or tamoxifen with the estrogen or DHT will discriminate between behavioral changes resulting from the activation of neural androgen or estrogen receptors. The effects of these treatments on neuroendocrine function will also be investigated. Project III investigates whether common human hormonal replacement therapies of chronic estrogen, or chronic estrogen plus testosterone with or without concurrent progestin, can reinstate female sexual interest in reproductively prime ovariectomized female monkeys. The hypothesis will be tested that chronic progestin therapy reduces or eliminates the effectiveness of therapies that reinstate female sexual interest without progestin. These therapies will also be compared on their effects on neuroendocrine function. These studies will markedly increase our understanding of the role that ovarian steroids play in modulating women's sexuality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FSH, ESTRADIOL AND INHIBIN IN FEMALE REPRODUCTION Principal Investigator & Institution: Hall, Janet E.; Associate Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 10-JUL-2002; Project End 31-MAY-2007
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Summary: The broad goal of this project is to continue to investigate the neuroendocrine and gonadal regulation of reproduction in women, focusing on the complex interrelationships between FSH, estradiol and the inhibins. There is now evidence that both estradiol and the inhibins contribute to the negative feedback control of FSH in women. However, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. There are two unique circumstances in which we have shown that the coordinated secretion of estradiol and the inhibins is altered: in reproductive aging, estradiol levels are increased in the presence of low levels of inhibin while in African-American women, normal reproductive cycles are characterized by increased estradiol relative to Caucasian women in the face of identical levels of inhibin. Determining the mechanisms responsible for these changes will provide us with important insights into the interactions of inhibin, estradiol and gonadotropins in normal reproductive physiology. Aim 1 will determine the relative contributions of estradiol and the inhibins to the negative feedback regulation of FSH secretion during the follicular and luteal phases of the normal menstrual cycle using normal and GnRH-deficient women in whom estrogen secretion is altered by aromatase blockade. Aim 2 will seek to elucidate the mechanisms underlying the dichotomy between estradiol and inhibin secretion in reproductive aging by investigating inhibin and estradiol secretion in response to fixed FSH stimulation and by determining the number of granulosa cells and inhibin subunit expression and aromatase function and expression in antral and preovulatory follicles as a function of reproductive aging. Aim 3 will determine the feedback and feed-forward interactions between FSH, estradiol and the inhibins that result in an increase in estradiol levels across normal reproductive cycles in African- American women. Feedback will be examined using an estrogen infusion protocol while feed-forward will examine the control of estradiol and inhibin secretion in preovulatory follicles. Understanding the feedback and feed-forward dynamics of the hypothalamic-pituitary and ovarian components of the reproductive system is critical to an appreciation of the pathophysiology of reproductive disorders. This information is ultimately required for the design of therapeutic options for patients with reproductive disorders including infertility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC MECHANISMS OF ESTROGEN ATHEROPROTECTION Principal Investigator & Institution: Villablanca, Amparo C.; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: The candidate is a Hispanic female (U.S. citizen) from Santiago, Chile. I am clinically trained in cardiovascular medicine and have interest and expertise in heart disease in women. As a newly promoted Associate Professor at the University of California, Davis I have prior research experience in cellular and molecular biology investigating the actions of vasoactive peptides in endothelial cell growth and function in vitro. My clinical interest in estrogen as a modulator of cardiovascular risk and mortality in women, leads me to now seek to extend my prior research work in a new research direction to investigate mechanisms of hormonal regulation of vascular gene expression in atheroprotection. I am at a critical juncture in my career where clinical responsibilities threaten my future research progress. I need and seek protected research time and additional research training under the guidance of a mentor in three areas: [1] the use of murine models of disease, [2] molecular genetics, and [3] physiologic studies to investigate functional significance of genetic changes. To attain this goal I have
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enlisted the help of Dr. Stephen Barthold as mentor and Dr. Beverly Paigen as comentor. Dr. Barthold is an expert in mouse biology and directs the UCDavis Center for Comparative Medicine which oversees the Mouse Biology Program. Dr. Paigen has expertise in murine models of atherosclerosis and is a senior research scientist at the Jackson Laboratories. Together, we propose a research development plan with five components: [1] didactic course work at UCDavis, [2] didactic and hand-on laboratory work at the Jackson Laboratory, [3] participation in research seminars and lectures, [4] attendance at National and International scientific meetings, and p5[ a state-of-the-art hands-on research program. The research development plan provides seamless integration with the research plan. The overall goal of the research proposal is to understand the action of estradiol, the estrogen receptor, and estrogen/receptor interactions on atheroprotection, vascular function and gene expression in mice. Previous studies suggest the possibility of both receptor-dependent and independent mechanisms of atheroprotection by estrogen, yet surprisingly, genetic mechanisms of atheroprotection by estrogen have not been investigated and a suitable atherogenic mouse model has not been developed. In conjunction with physiological studies we wish to use established mouse genetic models, and create new genetically engineered models, in order to investigate the overall hypothesis that: [1] The atheroprotective action of estrogen is mediated by the estrogen receptor, and [2] The beneficial effects of estrogen are accompanied by expression of estrogen-sensitive genes that regulate atheroprotection in the vascular wall. To investigate this hypothesis we will pursue the following specific aims: [1] Develop an estrogen receptor alpha deficient and sufficient mouse model of atherosclerosis and characterize it by quantitative histology of atheroma and vasomotor tone using aortic tension assays in vitro. [2] Use the model developed in aim 1 to identify vascular genes that are up-regulated by estrogen by differential gene expression RNA fingerprinting by RT-PCR, and examine the role of selected other candidate genes that are likely to be influenced by estrogen (Ath 1, CASH, PAI-1, and aldose reductase) by Northern analysis. [3] Use molecular genetic methods for targeted deletion of mouse genes to determine the physiologic role of specific genes in newly created gene knock out mice, using the parameters optimized in Aim 1. The research and training environment available to the candidate for the conduct of these studies of vascular function and genetics is robust, the candidate's commitment is very strong, and the potential for success substantial. Advances in our basic understanding of mechanisms of hormone action could lead to more effective strategies for treatment of coronary artery disease in both men and women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GNRH GONADOTROPIN TRANSCRIPTION AND STEROID FEEDBACK Principal Investigator & Institution: Shupnik, Margaret A.; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2003; Project Start 23-APR-2003; Project End 31-MAR-2008 Summary: GnRH pulses and sex steroids act on the pituitary to regulate the synthesis and secretion of LH and FSH. In the past funding period, we cloned the rat alphasubunit promoter, identified GnRH-responsive DNA elements and transcription factors for rat LHbeta and alpha-subunit promoters, and characterized intracellular signaling pathways mediating GnRH responses. The LHbeta promoter requires pulsatile GnRH stimulation in vivo, and has two cooperating complex DNA elements, a distal element with overlapping Sp1 and CArG box sites, and a proximal element with two bipartite sites for SF-1 and Egr-1. Both elements bind Sp1 family zinc finger proteins that could
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differentially affect transcription. Relative roles of these transcription factors in GnRH stimulation will be assessed by DNA-protein binding, chromatin immunoprecipitation (CHIP) and real-time RT-PCR, and transfection ot deletion/mutation luciferase constructs in LbetaT2 ceils. Preliminary data show that steroids both enhance (17betaestradiol (E) or pM dihydrotestosterone, DHT) and suppress (nM DHT) the GnRH transcriptional response, without steroid receptor binding to DNA. Coactivator/integrator proteins SNURF and CBP will be tested in cotransfection and protein-protein binding studies for modulation of the GnRH response. Parallel biochemical and functional strategies will be used to investigate both stimulatory and suppressive effects of steroids in normal gonadotropes and LbetaT2 cells. These include tests of altered promoter occupancy by Sp1/Egr- 1 family members in ChIP assays, rescue of suppression by overexpression of transcription factors, and alteration of gene expression by focused microarray analysis and real-time RT-PCR. Promoter regions and transcription factors mediating steroid responses will be defined. Nuclear receptor requirements will be tested with steroid antagonists, and the Tfm androgen receptor mutant mouse. Non-genomic steroid effects on intracellular signaling pathways will be measured in the absence or presence of GnRH. These studies will further our understanding of GnRH regulation of the gonadotropins, and steroid modulation of this response. This research has important implications for understanding fertility disorders such as PCOS, in which elevated circulating androgens are accompanied by altered GnRH and LH secretion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GONOCOCCAL INFECTION AND GENE EXPRESSION IN FEMALE MICE Principal Investigator & Institution: Jerse, Ann E.; Associate Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, Md 20852 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: (Adapted from the applicant's abstract): Neisseria gonorrhoeae has a serious impact on women=s health due to the frequency with which this pathogen infects the upper reproductive tract, and the resultant serious complications (e.g., chronic pelvic pain, involuntary infertility and ectopic pregnancy). Current models for studying gonococcal pathogenesis are limited in their ability to sufficiently mimic the intricate balance of host factors in the female reproductive tract. Therefore, the long-term objectives of this proposal are to further develop a female mouse model of gonorrhea for studying the adaptation of N. gonorrhoeae to the host in terms of phase and antigenic variation of surface molecules and gene expression in vivo. The specific aims designed to achieve this objective are to: i. further characterize experimental infection of estradioltreated mice for use as a research tool for studying specific aspects of gonococcal genital tract infection; ii. identify the host factor(s) that play a role in the selection for gonococcal opacity (Opa) protein expression during experimental infection and to test the capacity of an Opa-specific immune response to drive antigenic variation of Opa phenotype in vivo; iii. identify gonococcal genes that are induced during experimental murine infection using reporter gene fusions. The proposed experiments designed to address these aims are: i.) the susceptibility of estradiol- treated outbred (SLC:ddY) and inbred (BALB/6) mice to N. gonorrhoeae will be characterized with regard to duration of infection and degree of inflammation. Upper reproductive tract infection will be assessed in terms of bacterial interactions with the murine endometrium; ii.) host factors that select for Opa-positive gonococci in vivo will be studied by monitoring Opa protein expression in neutrophil-depleted mice, complement-deficient mice and inbred mice
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that uniformly do not produce inflammation in response to infection. The PI will compare the Opa phenotype of vaginal isolates from unimmunized mice and from mice immunized with a single purified Opa protein antigenic variant to determine if an Opaspecific immune response decreases the number of gonococci expressing the homologous Opa protein in vivo; iii.) expression of a gonococcal catalase-reporter gene fusion will be measured during murine infection and in neutrophil adherence assays to study the regulation of gonococcal catalase in response to inflammation. A transcriptional gene fusion bank using the green fluorescent reporter gene will be constructed and screened for promoters that are expressed during experimental murine infection; genes identified under these conditions will be cloned for further study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HORMONAL AND INFLAMMATORY MARKERS IN ADULT-ONSET ASTHMA Principal Investigator & Institution: Camargo, Carlos A.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2004 Summary: (provided by applicant): The proposed study would examine the relationships between hormonal factors, inflammatory mediators, related gene variants and adult-onset asthma in the Nurses' Health Study (NHS). The NHS is an ongoing prospective cohort study involving 121,700 women age 30 to 55 in 1976. Since 1988, all participants have been asked about a new "physician diagnosis of asthma" and a new "physician diagnosis of chronic obstructive pulmonary disease (COPD)." The primary aim will be to examine the relationship of endogenous female reproductive hormones and risk of newly diagnosed asthma. The main hypotheses are listed here as questions: 1) Do elevated endogenous levels of free (bioavailable) estradiol and other estrogens prospectively increase risk of physician diagnosed asthma in postmenopausal women? 2) Do elevated estrogen-associated inflammatory markers, such as C-reactive protein and interleukin-6, prospectively predict adult-onset asthma? 3) Do estrogen receptor and metabolism gene variants, such as the low activity allele of catechol-O-methyl transferase (COMT), increase risk of adult-onset asthma among postmenopausal women? We propose to study the above hypotheses in nested case-control studies in the cohort of postmenopausal women in the NHS. In 1989, 23,099 blood samples were obtained from postmenopausal women. Follow-up of these participants through 2000 revealed approximately 300 reports of new physician diagnoses of diagnosed asthma that required use of an asthma medication. Use of this existing cohort with previously collected blood samples will provide relatively quick and very cost-effective answers to longstanding uncertainty about the effect of female reproductive hormones on asthma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HORMONE & PROSTAGLANDIN REGULATION OF STAR IN THE OVARY Principal Investigator & Institution: Mc Lean, Mark P.; Obstetrics-Gynecology; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2007 Summary: (provided by applicant) Steroidogenesis is acutely regulated in the ovary by gonadotropins. Production of steroid hormones requires synthesis of a cholesterolshuttling protein to translocate cholesterol from the outer to the inner mitochondrial membrane. The steroidogenic acute regulatory (StAR) protein was demonstrated to be
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an essential component in the acute regulation of steroid hormone biosynthesis. Compelling evidence for StAR's role in steroidogenesis was established through studies on the disease congenital lipoid adrenal hyperplasia (CAh). CAH patients present with mutations in the StAR gene and lack the ability to synthesize steroids. Targeted disruptions of the StAR gene in mice cause all affected mice (male and female) to present with female external genitalia and exhibit premature death. The long-term objective of this research is to characterize the mechanisms involved in the regulation of StAR to ensure that sufficient amounts of steroid hormones are synthesized for proper ovarian function. The rat StAR promoter gene has been shown to contain regulatory elements through which positive and negative regulatory factors can directly affect StAR transcription. Our laboratory has reported that the transcription factors YY1 and DAX-1 repress StAR gene expression principally through disruption of StAR's interaction with positive regulatory factors. Preliminary data demonstrates that estradiol/estrogen receptors activate StAR transcription and this effect can be enhanced through interactions with SREBP-1a. We hypothesize that StAR gene expression in the ovary is regulated by at least three distinct mechanisms. These include: 1) an alteration in the ratio of YY1 proteins to other positive regulatory factors which leads to the repression of StAR, 2) activation of DAX-1 by PGF2alpha, which can directly or indirectly decrease StAR activation and 3) positive cis- and trans-activating regulation of StAR transcription via estrogen receptors. We propose to examine these mechanisms by the following abbreviated specific aims: Aim I: To 1) investigate the mechanisms involved in YY1 repression of StAR in the ovary through histone deacetylases/methylases, and through disruption of positive protein-protein interactions, 2) identify regions of YY1 necessary for repression and 3) determine whether methylation of the StAR promoter affects YY1 binding. Aim II: To determine whether DAX-1 repression of StAR transcription occurs through disruption of positive interactions or recruitment of co-repressors. Aim III: To define which co-activators or corepressors are involved in estrogen receptor regulation of StAR. Since studies on patients with CAH and targeted disruption of StAR in mice demonstrate the essential role of StAR in reproductive functions, our studies will provide vital information with respect to the molecular regulation of StAR and identify ovarian factors that are crucial to regulate StAR gene expression in order to maintain adequate amounts of steroidogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HORMONE CONTROL OF SPERMATOGONIAL ARREST IN MUTANT MICE Principal Investigator & Institution: Meistrich, Marvin L.; Professor; Expermtl Radiation Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Juvenile spermatogonial depletion (jsd) mice initiate a wave of spermatogenesis at puberty, but then sperm differentiation ceases despite the continued presence of A spermatogonia. Although the mechanism is not known, we showed that testosterone (T) inhibits spermatogonial differentiation, which can be restored with GnRH antagonist or estradiol (E2). We hypothesize that inhibition of spermatogonial differentiation in jsd mice is due to the action of T on gene expression in a specific somatic cell (Sertoli, Leydig, peritubular myoid, or arteriolar smooth muscle). We utilize the power of mouse genetics to elucidate the mechanism by which T mediates spermatogonial "arrest" in jsd mice and begin identifying the cell type and hormonally regulated gene(s) involved in the following Aims: (I) To establish the specific role of
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androgen and not FSH, we will complete studies using jsd mice also carrying mutations in the androgen receptor (AR) and FSHbeta genes. To determine the mode and the site of action of E2, the restoration of spermatogenesis with GnRH-antagonist and E2 treatment will be compared in jsd mice with that in jsd mice carrying mutations for estrogen receptor (ER)-alpha or for ERbeta. (II) To establish that the hormones affect spermatogonial differentiation by direct action on the testis and/or seminiferous tubules, we will examine their effects on spermatogonia in in vitro cultures of testicular tissue and tubules from jsd mice. (III) To identify the cell that is the target for hormonal inhibition of spermatogonial differentiation, we will transplant tubules between jsd mice and AR-deficient jsd mice and use cell-type specific elimination of an AR gene with loxP sites using Cre-recombinase driven by promoters specific for the different somatic cells. (IV) To identify the responsible gene, we will differentially screen for candidate hormone-regulated genes in the target cell of jsd mice using microarrays. A good candidate gene must have its level changed by GnRH antagonist in one direction and by T in the opposite direction. Elucidation of the mechanism of this spermatogonial "arrest" and its reversal in the jsd mouse could apply to cases of genetically determined male infertility. Because of its remarkable similarity to the failure of spermatogonial differentiation in toxicant-treated and aging rats, these results could also apply to azoospermia induced by reproductive toxicants and the decline in spermatogenesis with aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HORMONES ACTION IN ENDOMETRIOSIS Principal Investigator & Institution: Bulun, Serdar E.; Professor & Head; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 02-MAY-2002; Project End 31-MAR-2007 Summary: The long-term objective of this application is to characterize the common cellular and molecular mechanisms responsible for resistance to progesterone action and impaired estradiol metabolism in endometriotic tissue in contrast to the eutopic endometrium. Progesterone induces the expression of 17beta-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, estradiol to a less estrogenic steroid, estrone in endometrial epithelial cells. Our recent data are suggestive that stromal progesterone receptors (PR) mediate the stimulatory effect of progesterone on 17beta-HSD type 2 expression in epithelial cells. Our recent data are suggestive that stromal progesterone receptors (PR) mediate the stimulatory effect of progesterone on 17beta-hSD type 2 expression in epithelial cells. Interestingly, we also demonstrated in vivo the absence of 17beta-HSD type 2 expression in epithelial cells of endometriotic tissue in response to progesterone stimulation and interpreted this find as evidence for resistance to progesterone action. We further showed the that PR isoform B, which mediates the transactivating effects of progesterone in general is absent in endometriotic tissue, whereas only the transrepressor type isoform PR- A is present in this tissue. In contrast, both PR-B and PR-A are expressed and regulated by ovarian steroids in the eutopic endometrium. We hypothesize that the lack of PR-B causes resistance to progesterone action and disruption of the paracrine signaling, which mediates 17beta-HSD type 2 induction in epithelial cells. This results in elevated levels of estradiol, a mitogen for endometriotic tissue. Additionally, the absence of PR-B and the unopposed functions of PR- A may inhibit differentiation and apoptosis and enhance proliferation in endometriotic cells. We propose the following specific aims. (1) The cellular and molecular mechanisms responsible for the lack of PR-B expression in endometriotic tissue will be determined. We will determine, in particular, whether
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aberrations in steroid receptor expression in endometriotic tissue modulate the differential effects of estradiol on PR-A and PR-B expression. (2) Aberrations in epithelial- stromal interactions, which disrupt the progesterone induction of 17beta-HSD type 2 expression in endometriotic tissue will be characterized. (3) We will determine whether the lack of PR-B and the unopposed functions of PR-A in endometriotic tissue are responsible for altered differentiation, apoptosis and proliferation in endometriotic tissue. Identification of the molecular mechanisms responsible for progesterone resistance and their functional consequences in endometriotic tissue may lead to novel strategies for treatment of endometriosis such as the development and use of selective progesterone receptor modulators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HORMONES, NEURONAL PHOSPHOPROTEINS AND BEHAVIOR Principal Investigator & Institution: Mani, Shailaja K.; Instructor; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: (adapted from applicant's abstract): The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in the alterations in physiology and behavior. As in other reproductive tissues, the neural effects of estradiol and progesterone on sexual behavior are believed to require their interaction with cognate, intracellular receptors in the hormone sensitive neurons. Steroid receptors function as ligand-regulated transcription factors which undergo conformational change upon hormone binding, permitting tight association of the hormone-receptor complexes with hormone response elements on the target genes and affect neural networks involved in the control of sexual behavior. Numerous neurotransmitters are known to be involved in the neuronal processes by which steroid hormones influence sexual behavior in female mammals. The effects of neurotransmitter dopamine on sexual behavior in female rodents has been demonstrated to occur by means of cross-talk between membrane receptors for dopamine and intracellular progesterone receptors. While the cellular and molecular mechanisms involved in the interactions underlying this regulation are not well understood, it is assumed that this may occur via the phosphorylation of progesterone receptors. In the proposed research, the signal transduction pathways mediating the cross talk will be elucidated by identifying the neuronal phosphoproteins induced/phosphorylated by steroid hormones and dopamine. The interactions between these phosphoproteins and steroid hormones, estradiol and progesterone, will be examined. It will be determined whether the phosphoproteins phosphorylate the progesterone receptor per se or modulate the coregulator proteins, thereby activating the receptor and facilitating sexual behavior. These phosphoproteins will be delineated in the steroid receptor-rich regions surrounding the hypothalamus and the adjacent pre-optic area of the rat brain the areas known to be involved in the dopamine and progesterone-facilitated sexual behavior. Finally, the transcription activation functional domains of progesterone receptor involved in the dopamine activation of the receptor or its accessory proteins will be determined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IL-LB AND MEAL PATTERNS: OVARIAN HORMONES AND CCK Principal Investigator & Institution: Butera, Peter C.; Professor; Psychology; Niagara University Niagara University, Ny 14109
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Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Interleukin (IL-1) is a cytokine that is released by monocytes and macrophages activated during the acute phase response soon after infection or injury. IL-1 is responsible for many of the responses to inflammation and also induces a constellation of symptoms known as sickness behavior" (e.g., malaise, fatigue, decreased eating and drinking, lack of interest in usual activities; Hart, 1988). When administered to rats and mice, IL-1 causes profound alterations in behavior including a suppression of food and water intake (Kent et al., 1995). Previous research provides strong evidence for sex differences in immune function and its modulation by gonadal steroids, indicating that in both human and nonhuman animals females are immunologically stronger then males (Homo-Delarche et al., 1991). Consistent with these observations is the finding that the behavioral responsiveness of female rats to IL-1 is influenced by ovarian hormones (Butera et al., 2001). In this report, the anorectic effects of IL-1 were greater in estradiol-treated ovariectomized females than in untreated controls. Similar findings have also been reported for the febrile response following peripheral treatment with IL-1 (Mouihate et al., 1998). These data indicate that the effects of IL-1 in female rats are influenced by estradiol and suggest that interactions between gonadal steroids and cytokines may contribute to sex differences in the immune response. The general goals of this proposal are to further characterize this endocrine-immune interaction by examining the effects of IL-1 Beta on spontaneous meal patterns during the rat estrous cycle. Examining changes in the microstructure of feeding behavior will provide a better understanding of the ways in which ovarian hormones and IL-1 interact with direct controls of eating (Smith, 2000) to produce the changes in food intake previously observed. The research will evaluate a potential physiological mechanism for these effects on food intake by examining the role of endogenous CCK in estrogen/IL1 interactions. The role of IL-1 in the normal control of food intake will also be evaluated by determining whether changes in endogenous IL-1 contribute to the decrease in food intake that occurs during the proestrus phase of the rat estrous cycle. Information obtained from these experiments will not only contribute to our understanding of how cytokines and gonadal steroids influence ingestive behavior, but will also illustrate how interactions between the endocrine and immune systems may contribute to sex differences in the immune response and disease anorexia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOLOGICAL ASPECTS OF HEMORRHAGE Principal Investigator & Institution: Chaudry, Irshad H.; Professor, Professor, Vice Chairman & Di; Surgery; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2003 Summary: Our recent studies indicate that proestrus female mice [with cycle- increased levels of estrogen and prolactin (PRL)] have improved immune responses after traumahemorrhage as opposed to markedly depressed responses in males. Moreover, the survival rate of proestrus females following sepsis after trauma-hemorrhage was significantly higher than age-matched males. In contrast to young proestrus mice, aged females (defined by lowered estradiol levels) show marked immunosuppression after trauma. Our hypothesis, therefore, is that it is the high estradiol or a high estradiol: androgen ratio which directly (receptor- mediated) or indirectly (receptor-independent) enhance immune functions in proestrus females, and the loss of these estrogenic effects may contribute to the failure to maintain immune responses in aged females after trauma-hemorrhage. Studies are proposed to determine the mechanism of regulation of
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estradiol and estrone by hypothalamic/pituitary factors adrenals and aromatase activity and determine how differences in estradiol levels or the estradiol: androgen ratio due to the estrus cycle, ovariectomy (OVX, in middle aged mice to reduce estrogen), and age affect immune responses after trauma. Sex steroids (SS) receptor- mediated and receptor-independent gene activation mechanisms will be studied in T-cells and macrophages (Mphi). Since activation of AF-1 and AF-2 regions of estrogen receptor (ER) is critical for agonist and antagonist effects, activation of the ER agonist regions by estrogens in T-lymphocytes will be evaluated by transfection studies. Moreover, since SS non-ligand response also involve [Ca2+]i mobilization, T cells and Mphi will be examined for Ca2+ signal transduction and the expression and translocation of PKC isoforms. The release of TH1 and TH2 cytokines and IL-6 and the effects of PRL on their release in proestrus, OVX, aged, ER-, and PRL-knockout mice will also be evaluated. Additionally, the effect of SS on PRL and TH1 and TH2 cytokine-induced JAK-STAT expressions will be evaluated. Analysis of bone marrow for lymphoblastoid/myeloblastoid cell composition, and the effect of SS on the population of these cells will be determined. We will evaluate if administration of beta-estradiol, Raloxifene or PRL in vivo after trauma-hemorrhage improves the depressed immune responses in estrogen deficient mice. If a single dose is ineffective, multiple doses of these drugs with or without gonadotropin releasing hormone (GnRH) or flutamide (androgen receptor antagonist) will be administered to determine whether synergistic beneficial effects on immune responses are produced and whether the susceptibility to sepsis after trauma is decreased. Detailed mechanistic studies of T cell and Mphi functions using molecular biological techniques to determine why low estradiol fails to maintain immune functions in aged females after trauma and the use of estradiol, Raloxifene, PRL, GnRH or flutamide to restore immune functions should yield novel information and provide an innovative approach for improving the immune responses and reducing mortality from sepsis following trauma-hemorrhage in postmenopausal as well as in surgically OVX patients with low estrogen activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIGAND STRUCTURE AND ER MEDIATED TRANSACTIVATION Principal Investigator & Institution: Schwartz, Janice A.; Biochem and Molecular Biology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 15-FEB-1999; Project End 31-JAN-2005 Summary: The ability of the estrogen receptor (ER) to function as a ligand- mediated transcription factor requires the participation of residues from multiple regions throughout the ligand binding domain (LBD). These regions collaborate with the remainder of the receptor to mediate a wide spectrum of activities observed in response to physiologic and synthetic ligands which are varied in their structures. An understanding of the capacity of ER to accommodate such a wide variety of ligand structures and the gene selective control which results from the complexes formed, will be the focus of these investigations. Progress in this laboratory has shown that A-ring isomers of estradiol (E2) can induce dramatic changes in the activation profiles of certain ER-regulated genes. Mutant ERs with substitutions to residues in the AF2 activation function demonstrate tremendous sensitivity to alterations in the structure of the binding ligand. Point mutations to residues on the polar side of the AF2 helix produce ERs which become activated in response to stimulation with inert isomers of E2. Agonism can be induced in response to structurally diverse antagonists when bound to ER mutants bearing changes to residues on the non polar side of the AF2 helix. The goal of this proposal is to examine the mechanism used by the ER to distinguish
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between different elements of ligand structure and to discern the receptor residues involved in the transfer of this information to regulatory interaction surfaces on the ER which maybe required for coactivation. These investigations will use as probing ligands the A-ring isomers of E2, monohydroxyestrogens, and certain other estrogen analogs to trace the path of ligand-induced activation in the LBD of the ER protein. Specifically, the proposed experiments will employ the design and use of selected mutants of ER to examine the effects that structurally altered estrogens have on transactivation and coactivator-mediated enhancement. This will be accomplished using both the alpha and beta forms of ER and it will include an assessment of conformational change and phenotypic dominance. Results from these studies are expected to advance our understanding of the ligand-based transcriptional control mechanisms which are used by the ER and to produce information which can aid in the design of new ligands to control estrogen activity in hormone dependent breast cancer, osteoporosis, endometrial cancer, and fertility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF SEX-DETERMINED RESISTANCE TO L. MEXICANA Principal Investigator & Institution: Satoskar, Abhay R.; Assistant Professor; Microbiology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: Sex hormones have been shown to have a profound influence on modulation of immune responses and the outcome of various diseases in males and females. We have found that female mice are relatively more resistant visceral and cutaneous leishmaniasis than the male mice. In the L. mexicana model, we found that female DBA/2 mice mount an efficient Th1-like response and develop smaller lesions than the male mice that develop large, non-healing lesions. Moreover, we also found that ovactomized female DBA/2 mice treated with dihydrotestosterone (DHT); a derivative of testosterone that can not be converted to estradiol, become susceptible to L. mexicana whereas castrated male mice treated with 17-beta-estradiol become resistant. These findings suggest that while estrogen plays a critical role in induction of protective immunity against L. mexicana, testosterone may be detrimental. Despite these findings it is not clear how sex hormones (estrogen and testosterone) regulate immune responses during L. mexicana infection. Our long term goal is to understand the immunological mechanisms responsible for gender dimorphism in susceptibility of mice to different Leishmania species. In this project, we propose to determine how these sex hormones (estrogen and testosterone) regulate in vivo immune responses and influence the outcome of cutaneous leishmaniasis caused by L. mexicana. The first specific aim would determine how estrogen induces the development of protective immunity against L. mexicana. The studies proposed in the second specific aim would determine how testosterone prevents development of protective immune response and mediates susceptibility to L. mexicana. The third specific aim will focus on studies using bone marrow chimeras to determine whether endogenous sex hormones regulate functional development of T cells in vivo and affects their ability to differentiate into Th1 or Th2 subsets The experiments proposed in this project are designed to investigate several potential mechanisms of the protective effects of estrogen (17-beta-estradiol) and the susceptibility-inducing effects of testosterone. We hypothesize that each hormone will act through a subset of the proposed mechanisms. We hope to identify immune mechanisms that are specifically modulated by each. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS REGULATING UTERINE MORPHOGENESIS Principal Investigator & Institution: Spencer, Thomas E.; Assistant Professor; None; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2002; Project Start 06-APR-2001; Project End 31-MAR-2005 Summary: (Scanned from the applicant's abstract) Human infertility, pregnancy loss and intrauterine growth retardation represent major public health problems. A large number of reproductive age women experience these problems, which may be due to uterine dysgenesis, dysplasia and/or dysfunction. Long-term objectives are to understand the hormonal, cellular and molecular mechanisms regulating uterine morphogenesis. The proposed research specifically focuses on mechanisms regulating endometrial gland differentiation and development or adenogenesis. Adenogenesis is a critical period of uterine morphogenesis that occurs in the fetus in humans, but in the neonate after birth in ungulates and rodents. Studies in sheep and rodents indicate that uterine glands are unequivocally required for conceptus survival, growth and implantation. Thus, success of developmental mechanisms regulating uterine morphogenesis dictates the embryotrophic potential and functional capacity of the adult uterus. Our studies indicate that: neonatal ovine endometrial adenogenesis occurs during the first eight weeks after birth and is associated with increased levels of serum prolactin (PRL) and estradiol-17b (E2-17b); proliferating and morphogenetically active endometrial glands in the neonatal uterus express short and long prolactin receptors (PRL-R), insulin like growth factor one receptors (IGF1R), and high levels of estrogen receptor alpha (ER-a); and stromal cells surrounding the developing glands express IGF-I, IGF-II and ER-a. Both the IGF1R and the short and long PRL-Rs stimulate the mitogen activated protein kinase (MAPK) signaling cascade. In other systems, stimulation of the IGF1R can lead to activation of ER-a in a ligand independent manner by MAPK. Our central hypothesis is that PRL, E2-17b and IGFs regulate endometrial adenogenesis by activation of the MAPK signaling pathway and ER-a through ligand-dependent (E2-17b) and ligandindependent (PRL, IGFs) mechanisms. Using a multidisciplinary, collaborative approach, in vivo and organ culture systems will be used to test the central hypothesis using the neonatal ovine uterus as model system. Accomplishment of these research goals is expected to significantly advance our understanding of the developmental aspects of uterine biology, determinants of adult uterine function, and provide a foundation for the design of clinical therapies to prevent, identify and treat human reproductive problems, such is infertility and pregnancy loss due to endometrial gland dysgenesis, dysplasia or dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODELS OF ESTROGEN INTERACTIONS WITH ALZHEIMER DISEASE Principal Investigator & Institution: Finch, Caleb E.; Professor; Gerontology Research Institute; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-JUL-2007 Summary: (provided by applicant): This program project grant, entitled "Models of estrogen action in Alzheimer disease," addresses age changes in brain cell responses to sex steroids that are pertinent to Alzheimer disease, with a focus on estradiol (E2). The five projects investigate components of the general pathway of E2 effects on astrocytes and neurons, using mice that lack sex steroid receptors or src. Project 1: Astrocytes, estradiol, and aging in hippocampal plasticity; C Finch and I Rozovsky Project 2:
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Estrogenic steroids: neurotrophic action and mechanism; R Brinton and T Berger Project 3: Sex hormones, synaptic plasticity, aging and stress; R Thompson and M Foy Project 4: Estrogen and glutamate receptors in plasticity and AD; M Baudry Project 5: Androgens and neuroprotection in AD models; C Pike Core A ( Finch) includes a Biostatistics Module and Database (D Lavond) for data obtained on the same animals by separate projects Core B (Animals, Finch) provides aging rodents of defined hormonal status (Sprague-Dawley rats; C57BL/6J mice) and genotyped mutant and knockout mice (Eralpha-KO, Er-beta-KO, Tfm (mutant androgen receptor), and src-KO). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION OF KCA CHANNELS BY THE BETA1 SUBUNIT Principal Investigator & Institution: Perez, Guillermo J.; Masonic Medical Research Laboratory, Inc 2150 Bleeker St Utica, Ny 13501 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The candidate's long-term goal is to develop a career in cardiovascular research as an independent investigator. This project will be developed at the Masonic Medical Res. Lab., a well-established institution in cardiovascular research, under the direct mentorng of Dr. Antzelevitch, head of the institute. Dr. Antzelevitch, will guide this applicant in his career development plan as well as in his research project. An extramural consultation with Dr. Nelson, is also planned to better help this applicant's research potential. The career development plan includes course attending, weekly reports, oral presentations, scientific meeting attending, publication preparation and submission, and extramural collaborations with Dr. Escobar to learn "state of the art" biophysical techniques proposed in this application. The research project will investigate fundamental remaining questions about the actual mechanisms of the beta1 of the KCa channels in its native environment, as well as to explore potential roles for future therapeutic approaches. The disruption of the beta1 subunit leads to severe consequences such as increased arterial tone, elevated blood pressure and enlarged heart size. However, the very nature of the molecular mechanisms involved in this vasoregulation and the potential involvement of this protein in vasodilatory pathways has yet to be investigated. This proposal seeks to provide an integrated picture of how the beta1 subunit modifies KCa channel behavior based on quantitative measurements. The specific aims of this proposal will be addressed in a series of experimental objectives designed to dissect the molecular components of KCa channel function. These objectives are intended to define the role of the beta1 subunit in native arterial smooth muscle KCa channels, in terms of their voltage sensitivity, calcium sensitivity, activation kinetics, channel-toxin interaction and channel distribution. They will also try to identify the involvement of the beta1 subunit in the activation of KCa channels in vasodilatory pathways mediated by protein kinases (PKG and PKA) and in the direct action of estradiol on KCa channels as a possible non genomic vasodilatory effect of estradiol. This study should provide fundamental quantitative bases to understand the molecular tuning of a potassium channel highly relevant to vasoregulation and blood pressure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODULATION OF TMJ DEGRADATION BY RELAXIN AND ESTROGEN Principal Investigator & Institution: Kapila, Sunil D.; Associate Professor; Growth and Development; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747
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Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: This proposal delineates a structured 5-year career development plan that will help the applicant to effectively and efficiently achieve his research career goals. It defines a comprehensive and cohesive program incorporating novel areas of research, participation in formal basic biomedical science courses, and the development of a course in translational research methodologies. The research component Of this program aims to identify the role of the female reproductive hormones relaxin and estrogen in the etiopathogenesis of temporomandibular joint (TMJ) disease in women. Despite their debilitating nature and predilection for women of reproductive age, the etiology and pathogenesis of temporomandibular disorders remain unknown. The applicant's recent findings that relaxin increases the expression of the matrix metalloproteinases (MMPs) collagenase-1 and stromelysin-l in TMJ disc fibrocartilaginous cells, but not in synoviocytes, suggests a potential mechanism of action for this hormone in TMJ diseases. Furthermore, relaxin's induction of these MMPs is potentiated by prior exposure of the cells to beta-estradiol. These observations suggest that disc cells may be specific target sites for the matrixdegradative effects of relaxin. Therefore, the overriding hypothesis proposed studies is that relaxin and estrogen cause TMJ disease in women by increasing the expression of MMPs and decreasing that of their inhibitors and collagen in joint cells. On the basis of recent findings, the specific aims of the R29 grant have been expanded to include studies to (I) identify the promoter sites and transcription factors involved in the induction of collagenase-1 by relaxin, and (2) elucidate the mechanisms by which beta-estradiol potentiates this induction. These studies will provide insights into the molecular regulation of collagenase-l by relaxin and beta-estradiol. Together, the findings of the R29 and proposed studies may be critical in designing specific diagnostic methods and rational treatments for TMJ diseases in women. This research will be complemented by relevant cutting-edge courses in cell, developmental, connective tissue and reproductive biology and in bioinformatics. The short-term goals of this program are to (I) strengthen the applicant's understanding of contemporary molecular and cell biology techniques, (2) enhance the magnitude and depth of his ongoing studies, and (3) generate additional data for an ROl grant application. In the long-term, this period of intensive research-related activity will serve as a springboard for his goal of becoming a competent and successful translational researcher. The Independent Scientist Award will be critical in achieving these goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIONS
MOLECULAR
MECHANISMS
OF
ESTROGENS
VASCULAR
Principal Investigator & Institution: Clark, Kenneth E.; Professor; Obstetrics and Gynecology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: Although the uterine vascular effects of estrogen have been studied for over 70 years, the mechanism by which estrogen produces vasodilation remains unclear. Our laboratory was the first to show that a significant component of the uterine response to estrogen in the nonpregnant sheep is mediated by the release of nitric oxide (NO). We and others have shown that estradiol-17beta increases the expression and activity of endothelial nitric oxide synthase (eNOS) in the uterine circulation. However, it is not currently clear how this occurs or if, in addition to eNOS, neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) are also important in maintaining the sustained vasodilatory response seen after estrogen administration. Furthermore, it is not clear how estrogen modulates these NOS isoforms at the cellular and molecular
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level. Recently a new estrogen receptor, ERbeta has been isolated and emerging data suggest that this receptor may mediate a significant portion of the effects of estrogen in the vasculature. We hypothesize that uterine vasodilation produced by estradiol-17beta is mediated by specific interaction with both ERalpha and ERbeta, which subsequently activates eNOS (and potentially nNOS) via a nongenomic pathway, and iNOS via a genomic pathway, leading to increases in NO. The present application plans to evaluate the role of ER as a modulator of the NOS isoforms in the uterine circulation using a combination of physiologic and molecular endpoints. We will monitor the uterine hemodynamic responses to locally and systemically administered pharmacological antagonists that are selective for specific isoforms of NOS using a well-characterized ovine model. We intend to evaluate the expression of ERalpha and ERbeta in the ovine uterine vasculature and explore how estrogen alters eNOS, nNOS and NOS expression in endothelial cells and vascular smooth muscle. Finally we plan to determine if endogenous estrogen, acting through the uterine vascular NOS system, plays a critical role in increasing and maintaining uterine blood flow in late pregnancy. We believe that the information obtained in this revised application will provide new and important understanding into the mechanisms regulating vascular tone and hemodynamics in the uterine circulation in both the nonpregnant and pregnant animal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEGATIVE REGULATION OF ESTROGEN RECEPTORS Principal Investigator & Institution: Smith, Carolyn L.; Assistant Professor; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): Although great effort has been spent examining the mechanisms through which ligands activate estrogen receptor-alpha (ERalpha) transcriptional activity, relatively little is known about the molecular events through which Estrogen receptor action is negatively regulated. It is clear that estrogen treatment of many cell types leads to the down regulation of ERalpha expression through polyubiquitination and degradation of the receptor by the 26S proteasome. However, it is unknown how ligand binding to receptor targets it for degradation. Paradoxically, proteasome inhibitors block ERalpha-dependent gene expression, even though there is more receptor present within the cell, and this indicates an important link between the proteasome and gene expression. The overall goal of the experiments outlined in this application is to provide a more detailed understanding of the mechanisms utilized by ligands to induce ERalpha degradation by the proteasome, how cell-specific regulation of this is achieved, and how this contributes to the cell specificity of ERalpha transcriptional activity. Our planned studies are based on five key observations. First, the ligand binding domain of ERalpha is sufficient to mediate ligand-dependent down regulation. Second, induction of ERalpha degradation by estradiol and ICI 182,780 is blocked by proteasome inhibitors. Third, proteasome-mediated down regulation of ERalpha is cell-type specific. Fourth, estradiol and ICI 182,780 induce interactions between the ERalpha ligand binding domain and CBP/p300 in a cell-specific manner that correlates with ERalpha degradation. Lastly, inhibition of CBP/p300 function blocks ligand-dependent ERalpha down regulation. These findings support the hypothesis that the ability of CBP and/or p300 to be recruited to ERalpha by agonist or pure antagonist ligands is an important molecular event necessary for ERa degradation by the 26S proteasome, and that cell specific ERa interactions with CBP and/or p300 therefore contribute to cell-type dependent ERa down regulation as well as transcriptional activity. This will be tested in the following specific aims: 1) Examine the
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relationship of the 26S proteasome with ligand-dependent down regulation of ERalpha expression and ERalpha-dependent transcriptional activity; 2) Determine the role of AF2 interacting factors in ligand-induced down regulation of ERalpha and 3) Examine the relationship between cell-type specific receptor down regulation and transcriptional activity, particularly with respect to the relative transcriptional strength of ERalpha's AF-1 and AF-2 domains. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NO DIFFERENTIATION
AND
ESTRADIOL
SUSTAINED
NEURONAL
Principal Investigator & Institution: Farias-Eisner, Robin; Obstetrics and Gynecology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (provided by applicant) The long-term objective of this proposal is to study the molecular mechanism(s) of fetal neuronal development and neuronal differentiation under the effects of the female hormone, estradiol (E2). The investigators hypothesize that E2 induced nNOS is an important molecular mediator of E2 mediated sustenance of neuronal differentiation in NGF-withdrawal PCl2 cells. This hypothesis will be tested under the following specific aims: to determine the molecular mechanism by which E2 sustains neuronal differentiation and neurite outgrowth of PCl2 cells, derived originally from a rat pheochromocytoma, by determining whether E2-induced NO is required for the continued differentiation program; and to identify the cis-acting response elements in the nNOS promoter, the transcription factors that transactivate the nNOS gene, and the signaling transduction pathways required for estrogen-mediated induction of nNOS gene expression. These experiments will direct future studies critical to the understanding of E2- mediated fetal neuronal development and neuronal differentiation, that will lend insights into the approach to neurodegenerative diseases. In order to achieve these goals, the research design and methods will include the PC12 cell line, which is widely used as a model system to study NGF- mediated neuronal differentiation. The E2 mediated molecular mechanisms which participate in sustaining PCl2 cell differentiation following NGF-withdrawn are not known. Blocking production of Nitric Oxide (NO) with an inhibitor of NOS, N (omega)-nitro-L-arginine methyl ester (L-NAME), but not D-NAME, inhibits neurite extension, implicating nNOS in the differentiation process. E2, like NGF, markedly induces nNOS activity and mRNA levels in neuronal cells and anti-estrogen drugs act as strong inhibitors of purified nNOS, suggesting that E2 may sustain neuronal differentiation and neurite growth via an NOmediated process. Based on these observations, the investigators hypothesize that E2 induced nNOS is an important molecular mediator of E2 mediated sustenance of neuronal differentiation in NGFwithdrawal PCl2 cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPIOID EFFECTS ON HYPOTHALAMIC NEURONAL EXCITABILITY Principal Investigator & Institution: Kelly, Martin J.; Physiology and Pharmacology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-JUL-2004 Summary: (Applicant's Abstract) The overall goal of the present proposal is to understand the cellular mechanism(s) by which the gonadal steroid 17 beta-estradiol (E2) modulates opioidergic (beta-endorphin) tone and subsequently the neurosecretion
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Estradiol
of hypothalamic peptides and amines and activation of reward pathways in the female. We use the guinea pig as a model because the ovulatory cycle mimics the human. Physiological levels of E2 rapidly uncouple mu-opioid and GABAB receptors from K+ channels (IKir) in beta-endorphin (betaEND) neurons via a protein kinase pathway. In addition, chronic opiate uncouples and down-regulates mu-opioid receptors. In Experiments 1, we will test the hypothesis that chronic morphine activates a protein kinase A (PKA) pathway to specifically uncouple mu-opioid receptors in arcuate neurons. We will measure: (a) changes in mu-opioid agonist potency in females treated with morphine using membrane permeable protein kinase inhibitors; (b) the time course of morphine actions; and (c) the effects of morphine on the coupling of the orphanin FQ receptor to IKir. In Experiments 2, we will test the hypothesis that E2 activates a protein kinase C (PKC) pathway to uncouple mu-opioid and GABAB receptors from IKir at the site of the G protein coupling. We will measure: (a) the changes in the potency of muopioid and GABAB agonists in ovariectomized females treated acutely with E2 using protein kinase activators and inhibitors; (b) changes in agonist-stimulated 3HGTPgammaS binding in ARC membranes and autoradiography of 3H-GTPgammaS in ARC slices following E2 treatment; and (c) elucidate the pathway by which longer-term (24 h) E2 uncouples mu-opioid and GABAB receptors. In Experiments 3, we will determine to which effector systems mu-opioid, K-opioid and orphanin FQ receptors are coupled in supraoptic (SON) vasopressin and oxytocin neurons and the effects of chronic morphine. We will: (a) further characterize the inhibition Ih by mu-opioid agonists, the inhibition of a Ca2+ T-current by K-opioid agonists and the specific K+ conductance(s) activated by OFQ; (b) ascertain the effects of chronic morphine on the popioid, K-opioid and OFQ responses in SON neurons; (c) measure the changes in muopioid, K-opioid and orphanin FQ receptors mRNA expression and receptor binding in the SON with chronic morphine treatment; and (d) characterize the opioid-mediated presynaptic inhibition of excitatory input to SON neurons in morphine-tolerant animals. These results should not only elucidate the mechanisms by which E2 and opioids regulate hypothalamic neurons but also their interaction in altering opioid tone in the female CNS, which will help us understand the gender differences in reward and homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ORAL ADOLESCENT GIRLS
CONTRACEPTIVES
FOR
DYSMENORRHEA
IN
Principal Investigator & Institution: Davis, Anne R.; Obstetrics and Gynecology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (Adapted from applicant's description) This is an initial application submitted by a new investigator. Primary dysmenorrhea is defined as pain during the menses in the absence of a pathologic lesion and is probably caused by prostaglandin effects on the uterus. Primary dysmenorrhea is highly prevalent among adolescents. More than 50% of adolescent girls in various populations report dysmenorrhea which is severe in about 15%. Dysmenorrhea is a major cause of morbidity in adolescents leading to activity restriction and school absence. Combined oral contraceptives (COC) are a common treatment for primary dysmenorrhea. Some small laboratory studies show decreased prostaglandins associated with COC use compared to non-COC use. Larger observational studies show a lower prevalence of dysmenorrhea among COC users compared to non-COC users and improved dysmenorrhea after initiating open-label COC use. In the only randomized, double blind, placebo-controlled trial, Matthews
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showed modest improvement of dysmenorrhea among a small number of women using a high- dose COC compared to placebo (1968). None of the existing studies compare the efficacy of a low-dose COC with placebo in the treatment of primary dysmenorrhea. The proposed study is a double blind, randomized, placebo-controlled trial to determine the efficacy of a low-dose COC in the treatment of primary dysmenorrhea among urban, adolescent girls. Healthy girls aged 19 years or less with moderate to severe dysmenorrhea as determined by the Robinson modification of the Andersch scale will be eligible (Robinson, 1992). 150 girls will be randomized to receive either a COC containing 20 micrograms ethinyl estradiol and 0.1 milligrams levonorgestrel or a placebo. The main effect will be change in score on the pain sub-scale of the Moos Menstrual Distress Questionnaire (MDQ) after three months of treatment. This study will have 80% power to detect a 50% reduction in pain score with an alpha of.05 and a drop-out rate of 40%. Secondary outcome measures will be changes in school absence, activity restriction and medication use. Also, we plan to determine if psychological measures of depression, life-crisis events or self- concept ratings predict response to treatment. Given their efficacy in pregnancy prevention, safety, and non-contraceptive health benefits, COC may be an ideal therapy for primary dysmenorrhea in adolescent girls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OVARIAN HORMONE REGULATION OF LHRH BIOSYNTHESIS Principal Investigator & Institution: Petersen, Sandra L.; Associate Professor; Biology; University of Massachusetts Amherst 408 Goodell Building Amherst, Ma 01003 Timing: Fiscal Year 2002; Project Start 01-MAR-1992; Project End 31-JUL-2004 Summary: The long-term objective of this research is to determine the mechanism(s) by which estradiol (E2) and progesterone (P4) regulate LHRH biosynthesis and surge release. E2 and P4 differentially regulate two intracellular markers of changes in LHRH neuronal activity in a subpopulation of LHRH neurons--an E2-induced increase in LHRH gene transcription before the onset of LHRH surge release and a P4-dependent increase in Fos expression at the onset of the surge. Because few, if any, LHRH neurons contain estrogen receptors (ER) or progestin receptors (PR), these intracellular events must be mediated by afferent neuronal systems. Recent indirect evidence suggests that noradrenergic (NA) and GABAergic may be these afferent systems. Therefore, in the proposed studies we will test the novel hypothesis that sequential changes in NA and GABAergic signalling directly regulate steroid-specific changes in LHRH synthesis and release and alter intracellular markers of neuronal function. We will first determine whether E2 induces changes in NA release around the time of increased LHRH gene expression. To do this we will assess changes in the activity of brainstem neurons that supply LHRH neurons, and changes in NA turnover rates in the region containing LHRH neurons. We will use dual-label in situ hybridization to determine whether increases in LHRH gene transcription occur preferentially in neurons with ARs and whether specific AR antagonists can block transcription in these neurons. Finally, we will determine whether ligand-independent activation of PR decreases GABAergic signalling to LHRH neurons, and whether this signal is amplified by administration of P4 and marked by Fos expression. To accomplish this goal, we will test whether RU486 blocks the decline in GABA turnover rates and in levels of glutamic acid decarboxylase (GAD) mRNA previously observed before LHRH surge release, whether P4 furthers these declines, whether changes in GAD mRNA occur preferentially in neurons that also express PR, and whether GABA receptor agonists block the appearance of Fos expression in LHRH neurons. These studies will provide important new information on
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the identity of the afferent neuronal systems that transduce steroid signals to LHRH neurons. In addition, they win form the basis for future studies on the intracellular mechanisms regulating LHRH biosynthesis and release. This information will be critical for under- standing the neuroendocrine mechanisms controlling ovulation, as well as alterations in these control mechanism that result in precocious puberty, hypothalamic infertility and menopause. Thus, this information will be important for developing safer and more effective contraceptives and therapeutic modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLASTICITY
OVARIAN
STEROID
HORMONES
AND
HIPPOCAMPAL
Principal Investigator & Institution: Desmond, Nancy L.; Psychologist; Neurological Surgery; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-MAR-2005 Summary: adapted from applicant's abstract) Hippocampal function is modulated by changing levels of the ovarian steroids, estradiol and progesterone, in adult females. Of particular interest here are the observations that 1) estradiol modulates long-term potentiation (LTP) and long-term depression (LTD) of the CA3-CA1 synapses and 2) estradiol increases the excitability of CAl pyramidal neurons. We hypothesize that these two observations are not independent and that the increased neuronal excitability underlies the estradiol-dependent changes in synaptic plasticity. Thus the long-term goal of this new R01 application is to understand how changing levels of estradiol modulate the excitability of the hippocampal CA1 region and thereby the long-term synaptic modification that occurs at the CA3-CA1 synapses. Here the focus of study is the hypothesis that estradiol increases recurrent CA 1-CA 1 connectivity. Using electrophysiological and pharmacological methods in hippocampal CA1 mini-slices from adult, ovariectomized (OVX) rats pretreated with estradiol or vehicle, Aim 1 characterizes the magnitude of this changed excitability and tests hypotheses concerning the proximal causes of this enhanced excitability. Aim 2 addresses the physiological significance of this enhanced excitability using CAl mini-slices from normally cycling rats across the estrous cycle. We will also determine whether the time course of the increase in excitability across the estrous cycle correlates with the time course of the changes of synaptic plasticity (LTP and LTD) at the CA3-CA 1 synapses. Aim 3 uses morphological methods to explore the hypothesis that this estradiol-dependent increase in the excitability of CAl pyramidal neurons involves the formation of recurrent excitatory CAl-CAl synapses. We will determine if the local axonal arborizations of CAl pyramids increase with estradiol treatment of OVX rats. Aim 4 tests the hypothesis that this estradiol-dependent increase in hippocampal excitability requires the action of genomic estrogen receptors. These studies will help us to understand better how estrogens modulate the hippocampal function and thus its cognitive functions in females. Moreover, these are likely to provide important insights for understanding the biological basis of memory problems that can occur with menopause. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: POLYMORPHISMS OF INS/IGF SIGNAL PATHWAYS & FEMALE CANCER Principal Investigator & Institution: Ho, Gloria Y.; Associate Professor; Epidemiology & Population Health; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007
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Summary: (provided by applicant): Breast, colorectal, and endometrial cancers are among the top 4 leading cancer sites in women in the U.S. While environmental factors associated with these cancers have been well studied, the underlying genetic mechanisms are not well understood. The identification of susceptibility genes is important for understanding the biological basis of the causes of these cancers. This proposed study will be integrated in an ongoing NIH-funded case-cohort study conducted within the Women's Health Initiative (WHI), a large prospective study of postmenopausal women. The ongoing case-cohort study aims to measure serum levels of insulin, IGF-I, IGFBP-3, and estradiol in 900 breast, 500 colorectal, and 300 endometrial cancer cases and a sub-cohort of 900 subjects and to examine their effects on risk of the 3 cancers. The study proposed here will examine the insulin/IGF system at the genetic level in the same study subjects. There are several reasons to focus on the insulin/IGF system: (1) It has significant regulatory effects on cell proliferation and transformation. (2) Serum levels of insulin/IGF are associated with risk of several cancers. (3) It is particularly relevant to the hormone-related cancers, since insulin, IGF-I, and estradiol potentiate each other's signaling effects. On these bases, it is hypothesized that variations in the genes involved in insulin/IGF signaling may lead to altered biological effects and/or serum levels of these growth factors, and these genes could influence the susceptibility of cancer. The objectives of this study are: (1) To identify genetic variation in 9 genes that are involved in insulin/IGF signaling, namely the PI3K and MAPK pathways, and to examine their associations with risks of breast, colorectal, and endometrial cancer. (2) To examine in the subcohort if the genetic variation is associated with altered serum levels of insulin, IGF-I, and IGFBP-3. (3) To determine among the cancer cases if variation in these genes are associated with diagnostic characteristics. The secondary objective of this study is to explore the interactive effects between estradiol and variation of these genes on risk of the 3 cancers. Using existing DNA samples from the WHI, this study will apply the latest genetic analytical approach to evaluate candidate genes of 3 cancers. This genetic study, in conjunction with the ongoing serological study, will provide a comprehensive examination of the role of the insulin/IGF system in tumorigenes Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: POSTNATAL DEVELOPMENT OF IONOTROPIC GLUTAMATE RECEPTORS Principal Investigator & Institution: Urbanski, Henryk F.; Associate Professor; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-SEP-1993; Project End 31-MAR-2007 Summary: L-glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. It plays a major role in behavioral processes such as learning and memory, and is a key component of the neuroendocrine mechanism that controls sexual maturation. Although ionotropic glutamate receptors have been studied extensively in the rodent brain, both at the molecular and pharmacological levels, the postnatal ontogeny of these receptors in humans is poorly understood. To help resolve this issue, the proposed studies will use sexually immature male and female rhesus macaques (Macaca mulatta) to test various hypotheses regarding: 1) the temporal expression of genes encoding different glutamate receptor subunits, 2) the neurotransmitter identity of neurons that show developmental plasticity in glutamate receptor gene expression, and 3) the influence of the changing sex steroid environment on the induction of these developmental receptor changes. The studies will involve a series of molecular and immunohistochemical approaches to characterize and quantify
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Estradiol
glutamate receptor gene expression at three key stages of postnatal development: 1) infantile, 2) juvenile, and 3) peripubertal, both with and without experimental manipulation of circulating estradiol and testosterone concentrations. Because macaques and humans show similar postnatal cognitive developments and similar developmental changes in their sex-steroid environment, the proposed studies are expected to yield new information about the ontogeny of ionotropic glutamate receptors in humans. Moreover, because the subunit composition of different glutamate receptors determines their affinity for different ligands (e.g., NMDA, AMPA and kainate) and influences their functional properties (e.g., permeability to Ca2+), elucidation of the mechanisms that regulate their developmental expression should help to lay a foundation for the development of pharmacological treatments for pediatric neurological disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PREGNANCY ESTROGENS, DIET, AND BREAST CANCER RISK Principal Investigator & Institution: Hilakivi-Clarke, Leena A.; Professor; V T Lombardi Cancer Res Center; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2006 Summary: Estrogen levels are elevated by 50-100 -fold during pregnancy, and interindividual variability in pregnancy estrogen levels is 4-6 -fold. Women exhibiting highest pregnancy estrogen levels are suggested to be at a significantly increased risk to develop breast cancer, perhaps due to an estrogen-induced promotion of existing transformed cells. Diet, particularly dietary fats, may affect pregnancy estrogen levels and later breast cancer risk. In our animal study, a high fat intake significantly increased pregnancy estrogen levels and increased pregnancy-promoted mammary tumor incidence. Polymorphism in genes that metabolize estrogens and have been linked to increased breast cancer risk, may also affect pregnancy estrogen levels. Our proposed study has two general aims: (1) to study whether dietary fat intake affects pregnancy estrogen levels in women, perhaps by interacting with polymorphism in CYP17 and COMT, and (2) to study whether highest pregnancy estrogen levels might increase breast cancer risk by increasing growth factor levels. These growth factors could originate from mutated or already transformed mammary cells, which during pregnancy are stimulated by high estrogen levels. Growth factor levels will be measured in nipple aspirate fluid (NAF) that can be obtained using a breast pump from nonlactating breast. Consequently, the following hypotheses will be tested: Hypothesis-1. We hypothesize that high dietary fat intake and weight gain increase pregnancy estrogen levels. We further hypothesize that polymorphism in CYP17 or COMT influences these interactions. Hypothesis-2. We hypothesize that higher circulating estradiol levels during pregnancy are associated with increased growth factor levels in nipple aspirate fluid, including EGF, TGFalpha and IGF-1/IGF binding protein 3. These aims will be studied in 200 pregnant women attending the Maternity Clinic at Solna in NAF will be obtained 12 months after giving birth. Our results may lead to modifications of pregnancy diet to reduce the risk to develop breast cancer. In particular, women who already are at high risk, for example, due to family history of breast cancer, age at first pregnancy (greater than 30 years), or other reproductive risk factors, may significantly benefit from pregnancy dietary modifications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RECEPTORS
PREGNANCY
HORMONES
AND
MEMBRANE
47
ESTROGEN
Principal Investigator & Institution: Htun, Han; Obstetrics and Gynecology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 09-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Uterotropic effects of pregnancy-related estrogens, such as 17beta-estradiol (E2) and estriol (E3), occur by two different mechanisms, involving intracellular and membrane estrogen receptors. Traditionally, steroid hormone activation of intracellular steroid receptors, ligand-dependent transcription factors, leads to changes in transcription occurring over hours to days, described as "genomic actions" of steroid hormones. In contrast, activation of plasma membranebound steroid receptors on the cell surface initiates changes in ioR fluxes, second messenger signals, and protein kinase activities in millisecond-to-minute time scale, collectively described as "rapid responses" or "nongenomic actions" of steroid hormones. Whether "rapid responses" ultimately lead to changes in transcription remains an open question. The underlying hypothesis of this proposal is that activation of plasma membrane-bound estrogen receptors by the two pregnancy-related hormones, 17betaestradiol (E2) and estriol (E3), leads to "rapid responses" which indirectly activate transcriptional regulation and cell proliferation. The research will use new chemically defined reagents constructed with E2 and E3 to isolate cells with membrane-bearing estrogen receptor. Preliminary studies have demonstrated that the reagent with E2 can bind to a subpopulation of MCF-7 cells. The following specific aims will be addressed: (1) Isolation can and characterization of plasma membrane estrogen receptor. Using the new chemically defined reagents of E2 and E3, as "bait," cells with membrane-bearing estrogen receptor will be isolated. Analysis of cell-surface-protein expression pattern of membrane estrogen receptor and non-receptor-bearing cells will identify candidate membrane estrogen-receptors. (2) Examination of biological effects of membrane estrogen receptor signaling. Using the same chemically defined reagents, the effect of membrane estrogen signaling on transcription will be determined, and genes regulated by membrane signaling will be identified using a genome-wide based approach. Finally, the effects of membrane estrogen signally on cell proliferation will be examined. The research will open a new avenue of investigation in which the genome integrates the actions of both membrane and intracellular estrogen receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PREVENTION ANTIOXIDANTS
OF
PROSTATIC
CARCINOGENESIS
BY
Principal Investigator & Institution: Bosland, Maarten C.; Professor; Environmental Medicine; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): The hypothesis addressed by this project is that selenium, vitamin E, and lycopene protect against prostate cancer development through their antioxidant activities. There are no definitive data about this from human studies. There are very few reports of experimental studies that tested this hypothesis, and those that did used models systems that do not involve oxidative stress mechanisms. Furthermore, there are no reports of studies that have investigated the probably critical synergisms that may exist between these antioxidants. Therefore, the purpose of this project is: (a) To address this hypothesis in an animal model of prostate carcinogenesis that does involve oxidative stress mechanisms; (b) To generate with this model data in
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Estradiol
support of the notion that antioxidant activity is a major mechanism by which selenium, vitamin E, and lycopene protect against prostate cancer; (d) To explore the efficacy and antioxidant activity of gamma-tocopherol. The project will use a unique animal model that is suitable to test chemopreventive activity of antioxidants and it will make a contribution to critically assessing the rationale for the SELECT trial; and (d) To determine the magnitude of the protective activity of these antioxidants individually and in combination to provide efficacy information in support of the design of prevention clinical trials. The Specific Aims of the project are: (1) To determine the efficacy of selenium, vitamin E (alpha-tocopherol), and lycopene to prevent prostate cancer in NBL rats treated with estradiol & testosterone. This model importantly involves oxidative stress mechanisms. The antioxidants will be given in the diet at nontoxic doses comparable to those used in previous studies with prostate cancer models that do not involve oxidative stress. (2) To determine whether treatments with these antioxidants reduce oxidative stress parameters related to oxidation of DNA bases, lipid peroxidation, and inactivation or alteration of antioxidant enzymes. These parameters will be measured in the areas of the prostate of NBL rats where treatment with estradiol & testosterone induces cancer and preneoplastic lesions, and the effects observed will be related to the outcome of the efficacy studies of Specific Aim 1. Prostatic antioxidant levels will also be measured. (3) To determine the efficacy and antioxidant activity of gamma-tocopherol There are epidemiological indications that gamma-tocopherol has stronger protective effects against prostate cancer than alpha-tocopherol and the effects of gamma-tocopherol will be compared with those of the alpha-tocopherol studies of Aims 1 and 2. (4) To determine the efficacy of combination treatment with the three antioxidants to prevent prostate cancer in NBL rats treated with estradiol & testosterone and to determine whether these treatments reduce oxidative stress parameters. The observed effects will be compared with the outcome of the single agent studies of Aims 1 and 2. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTECTIVE EFFECT OF PREGNANCY DOSES OF ESTROGENS IN EAE Principal Investigator & Institution: Voskuhl, Rhonda R.; Associate Professor; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Putative T helper (Th)l-mediated autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during late pregnancy when estrogen levels are high. In animal models of MS and RA, pregnancy doses of estrogens (estriol and estradiol) have been shown to ameliorate disease. In murine experimental autoimmune encephalomyelitis (EAE), estrogen treatment has been shown to cause a favorable shift in cytokine profile with an increase in production of the anti-inflammatory cytokine interleukin (IL)-10 during autoantigenspecific responses. The purpose of this application is to investigate further the mechanisms which underlie the protective effect of treatment of female EAE mice with pregnancy doses of estrogens (estriol and estradiol). In Specific Aim 1, it will be determined whether estrogens ameliorate disease by acting through estrogen receptor alpha or beta. This will be achieved by inducing EAE in ER beta knockout mice and assessing whether treatment with estrogens are still protective. The role of ER alpha will be determined by using a potent ER blocking agent (ICI 182,780) in ER beta knockout mice to ascertain whether the protective effects of estrogens are blocked when ER alpha
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is blocked. Treatment of EAE mice with selective ER alpha or beta agonists will confirm data above regarding whether estrogens act on ER alpha or beta when mediating disease protection. In Specific Aim 2, the immune cells that express each ER and the cells that are producing increased amounts of IL-10 during estrogen treatment will be identified. These studies will reveal whether estrogens increase IL-10 production by acting directly on a given immune cell versus acting indirectly via other immune cells. While an estrogen-mediated increase in IL-10 production by immune cells would be expected to be protective in EAE, this does not preclude additional protective mechanisms through which estrogens may act. Therefore, in Specific Aim 3, the possibility that estrogens may act through mechanisms other than increasing IL-10 production in immune cells will be examined. EAE will be induced in estrogen treated, IL-10 knockout mice to determine whether estrogen treatment is still protective in the absence of the IL-10 gene. Finally, the site of action of estrogens during EAE may be in the peripheral immune system and/or within the central nervous system (CNS). Systemic estrogen treatment used in combination with an ER blocking agent that acts only in the periphery will demonstrate whether estrogens act in the peripheral immune system or within the CNS. Administration of estrogens intra-ventricularly, within the CNS, will be used as a complementary approach. A detailed understanding of how each estrogen abrogates EAE pathogenesis may lead to treatment of MS and possibly other Th1-mediated autoimmune diseases with Selective Estrogen Receptor Modulators (SERMS) targeted to the pathogenic site of action. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEOMIC ANALYSES OF BREAST CANCER REFRACTORINESS Principal Investigator & Institution: Agnew, Brian J.; Proteomics Group Leader; Molecular Probes, Inc. 4849 Pitchford Ave Eugene, or 97402 Timing: Fiscal Year 2003; Project Start 18-FEB-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Molecular Probes, Inc., has developed a fluorescence-based, Multiplexed Proteomics (MP) platform that allows for the simultaneous identification and characterization of glycosylation, phosphorylation and total protein in a single 2-D gel. With subpicomolar sensitivity, the system provides for the rapid quantification of differentially regulated and/or post-translationally modified proteins, with subsequent mass spectrometry based identification. The central objective of this proposal is to utilize this technology to discover the important protein targets which confer pregnancy-induced protection against mammary carcinogenesis. Full-term pregnancy early in life is the most effective natural protection against breast cancer in women, and in experimental models, rats are similarly protected. It is proposed that these pregnancy-specific changes in susceptibility to mammary tumorigenesis are ultimately due to changes in the mammary epithelial proteome and include altered post-translational regulation and expression of key signaling proteins involved in maintaining cellular homeostasis and protection from cellular transformation. There have been no published comprehensive proteomic studies aimed at determining the molecular origin of pregnancy-induced mammary carcinogenesis protection. Our MP platform is uniquely capable of rapid detection and quantitation of changes in the posttranslational modification state of proteins, an event which we believe is crucially linked to the understanding of this effect. Phase I studies will characterize protein-based changes that take place in the virgin rat mammary epithelial cell proteome in response to full-term pregnancy or treatment with pregnancy levels of ovarian hormones. A fully integrated approach to sample preparation, 2-D gel/mass spectrometry techniques, and data analyses is demonstrated. A minimum of three protein targets linked to pregnancy-
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Estradiol
induced protection will be identified. Using a combination of laser-tissue microdissection and antibody-based blotting techniques, these initial protein targets will be independently validated. Building upon this validated proteomics-based discovery platform, Phase II of this program will expand its efforts to characterize and classify the important signaling cascades and protein targets linked to the pregnancy-induced cancer protection phenotype. These protein targets will be ideal candidates for the rational design of diagnostic indicators and/or therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RAPID EFFECTS OF ESTRADIOL IN THE BRAIN Principal Investigator & Institution: Becker, Jill B.; Professor; Psychology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): The classical receptor for estradiol, ERalpha in addition to its genome-activating properties, is also found within the extracellular membrane where it induces rapid responses to estradiol(E). These receptors are now referred to as membrane ERalpha (mERalpha). It has been demonstrated that E acting extracellularly on mERalpha can rapidly initiate a variety of signal transduction cascades. Brain regions known to be sensitive to the rapid effects of E include the striatum and nucleus accumbens (NAcc). Considerable research has demonstrated that ovarian hormones rapidly activate behavioral and neurochemical indices of dopamine activity in the striatum of female but not male rats. Electrophysiological experiments have shown that E rapidly inhibits the calcium current mediated by L-type calcium channels in medium spiny GABA neurons. Thus, we hypothesize that the enhancement of DA release after E treatment is due to decreased GABA release resulting in a release of inhibition at GABA (B) receptors on presynaptic DA terminals. The experiments proposed will investigate the mechanisms mediating the effects of E in the striatum and nucleus accumbens (NAcc). Specific Aim 1 will test the hypothesis that the enhanced DA release seen after estradiol treatment is due to estradiol, acting on neurons in the striatum to block current mediated by L-type calcium channels. This is hypothesized to produce decreased GABA release and thereby decrease activity at GABA (B) receptors on presynaptic DA terminals. Specific Aim 2 will test the hypothesis that mERa mediates the response to estradiol in the striatum and NAcc. Experiments will use an adeno-associated viral vector (AAV) that expresses the ERa transgene, a transgene that is a dominant negative for the mERalpha, or a control vector to determine whether the behavioral and neurochemical effects of estradiol in the striatum are mediated by mERalpha. The mechanisms through which E acts in the brain and body are important to understand in order to improve our treatment and decrease risks for hormone replacement therapy, breast cancer, and ovarian cancer. It may also be important for our understanding and treatment of a number of neurological disorders including stroke, Alzheimer's disease and Parkinson's disease where estradiol may be neuroprotective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF LEYDIG CELL MITOSIS AND DIFFERENTIATION Principal Investigator & Institution: Hardy, Matthew P.; Senior Scientist; Population Council 1 Dag Hammarskjold Plaza New York, Ny 10017 Timing: Fiscal Year 2002; Project Start 01-JAN-1995; Project End 31-MAR-2004 Summary: The capacity for testosterone production in the adult male results from increases in Leydig cell numbers during puberty. Leydig cells increase in number
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through a gradual sequence of events in which Leydig cell precursors initially proliferate, than lower their rate of mitosis as they begin to express proteins that are characteristic of adult Leydig cells, most notably, steroidogenic enzymes. Studies of purified Leydig cells conducted by the PI and others, have defined discrete stages within the continuum of progressive Leydig cell differentiation: spindle shaped, highly proliferative progenitor Leydig cells; immature Leydig cells, which, though less proliferative, remain in the cell cycle, contain steroidogenic organelles, synthesize steroids, but secrete 5alpha-reduced androgens rather than testosterone; adult Leydig cells, which do not divide and which secrete primarily testosterone. Luteinizing hormone (LH) controls Leydig cell function through LH receptors that are present in abundant numbers that the adult stage. However, Leydig cell progenitors have negligible numbers of LH receptors and are comparatively unresponsive to this hormone. These considerations led us to hypothesize that the beginning of Leydig cell development is regulated by other factors such as steroidogenic factor-1 (SF-1). LH is reported to increase Leydig cell numbers and is known to increase levels of testosterone production. This application focuses on two processes in which LH is unlikely to be the controlling stimulus: the decrease in mitotic rate during the transition from progenitor to immature Leydig cell; and stimulation of the androgen-metabolizing enzymes 5alpha- reductase and 3alpha-hydroxysteroid dehydrogenase, which lower testosterone secretion by progenitor and immature Leydig cells. Mullerian inhibiting substance (MIS) will be investigated because targeted deletion of the MIS gene causes Leydig cell hyperplasia, indicating that this factor is normally a growth inhibitor. In experiments planned for Specific Aim 1, we will determine if the reduction in progenitor Leydig cell mitosis, that is observed between days 14 and 21 postpartum in the rat, caused by MIS; establish whether testosterone-induced increases in mitosis of immature Leydig cells are required for terminal differentiation; investigate the involvement of estrogen in growth inhibition of the Leydig cells, because MIS is observed to regulate aromatase, the enzyme that catalyzes estradiol synthesis. The experiments planned for Specific Aim II will individually evaluate the regulation of testosterone biosynthetic and androgenmetabolizing enzyme activities by LH, testosterone, SF-1, and MIS; determine the extent of control of these enzymes by co-factor availability; and identify instances where steroidogenic enzyme activities are catalyzed by novel Leydig cell isoforms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF LUTEAL FUNCTION Principal Investigator & Institution: Gibori, Geula; Professor; Physiology and Biophysics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-MAY-2004 Summary: The establishment and maintenance of pregnancy requires the coordinate hormonal regulation of corpus luteum function. Extensive investigation from out laboratory has established a key role for estradiol and PRL in such regulation. Our research has led us to isolate a corpus luteum gene, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), whose expression is markedly inhibited by PRL. We have also discovered a novel protein, named PRAP, that associates with the intracellular domain of the short form of the PRL-receptor and whose expression is tightly regulated by estradiol. Most interestingly, the PRL inhibition of the 20alpha-HSD gene expression occurs through the short form of the PRL-receptor. In the first part of this investigation, we will determine the mechanism of PRL-signaling through the PRL-receptor short form using luteal derived cell lines generated in our laboratory. We will also define the role of PRAP in PRL signaling through this receptor type. Because stimulation of luteal
52
Estradiol
20alpha-HSD expression by LH/PGF/2a plays a key role in lowering progesterone production and allowing for parturition, we will investigate the molecular mechanism by which these hormones up regulate 20alpha-HSD gene expression. Our recent investigations have revealed that the synergism between PRL and estradiol action in luteal cells involves PRL stimulation of both estradiol receptor (alpha and beta) mRNAs and estradiol induction of PRAP expression. Estradiol and PRL also act together on elongation factor 2, a peptide involved in protein translation, to respective enhance its levels and state of phosphorylation. We will therefore investigate in the last specific aim the molecular mechanism by which estradiol and PRL attest in the luteal cell, the expression and state of phosphorylation of proteins involved in their respective signaling and in protein translation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF NITRIC OXIDE SYNTHASE IN DEVELOPING LUNG Principal Investigator & Institution: Shaul, Philip W.; Professor; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-MAR-2006 Summary: (Scanned from the applicant's description) Nitric oxide (NO), produced by endothelial NO synthase (eNOS), plays a key role in pulmonary vasodilation at birth and in the genesis of persistent pulmonary hypertension of the newborn (PPHN). Studies in fetal sheep have shown that the hormone estrogen, which rises markedly in the fetal blood during parturition, causes pulmonary vasodilation due to nongenomic effects on NO production. Estrogen also reverses the vascular abnormalities in a lamb model of PPHN. We have shown in ovine fetal pulmonary artery endothelial cells (PAEC) that estradiol (E2) cause eNOS activation through novel nongenomic actions of estrogen receptor (ER) a and calcium-mediated signaling. The OBJECTIVE of this proposal is to determine the molecular mechanisms by which E2 causes nongenomic eNOS activation in fetal PAEC. Four Aims will be addressed in primary and immortalized PAEC, and transfected COS-7 cells. We have new evidence that a subset of ERa is localized to PAEC plasma membrane (PM) where they modulate eNOS activity. AIM 1 is to determine the mechanisms underlying ERa PM function, testing the hypotheses that E2 causes internalization of PM ERa, that processes needed for genomic ERa function are not required, and that specific ERa domains are involved in PM function. We also have preliminary evidence that fetal PAEC express ERb, and that eNOS stimulation by E2 Is greater after ERb overexpression. AIM 2 is to determine the role of ERb in eNOS activation, testing the hypotheses that a subset of PM ERb is capable of nongenomic function, and that neither ERa nor dimerization are needed for PM ERb action. In further initial studies, E2 activation of eNOS was blocked by pertussis toxin. AIM 3 is to determine the role of G proteins in eNOS activation by E2, testing the hypotheses that G proteins are critically involved, that downstream signaling is mediated by Gai, and that E2 causes ERa-Gai interaction on PM. Finally, in recent studies we have detected ERa protein in PAEC caveolae, which compartmentalize signaling molecules on the PM including eNOS, and have found that E2 causes potent, ER-dependent eNOS activation in isolated caveolae membranes. AIM 4 is to characterize an E2-eNOS signaling module in PAEC caveolae, testing the hypotheses that known signaling proteins are coupled in caveolae, and that a caveolae-associated calcium pool is released by E2 to activate eNOS. Unknown components will be identified by ERa immunoprecipitation and microsequencing and yeast two-hybrid screening. These studies will fill major gaps in our understanding of NO production in the developing
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lung as well as our knowledge of nongenomic E2 actions in the coronary and uterine circulation and in nonvascular cells. Ultimately, we may be able to take greater therapeutic advantage of the effects of E2 on the pulmonary and also coronary and uterine circulations, thereby optimizing the vascular health of both the fetus and the mother. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REPRODUCTIVE ANDROGENIZATION
CONSEQUENCES
OF
PRENATAL
Principal Investigator & Institution: Padmanabhan, Vasantha; Professor of Pediatrics; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 08-AUG-2001; Project End 31-MAY-2006 Summary: Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy and it affects 10 percent of reproductive-aged women. The etiology of chronic hyperandrogenic anovulations, such as PCOS, may have genetic underpinnings. Although the underlying mechanisms are unknown, PCOS is now recognized as hyperandrogenism accompanied by anovulation. Polycystic ovarian morphology is highly correlated with conditions in which the fetus has been exposed to high amounts of sex steroids before birth. For example, women with classical 21-hydroxylase deficiency mimic PCOS, exhibit anovulation, ovarian hyperandrogenism, and LH hypersecretion. Perhaps excess sex steroids early in life may provide a hormonal "insult" that results in manifestation of PCOS later in adulthood. This proposal aims to use a new model, the prenatally-androgenized sheep (long gestation, mono-ovular species), to investigate causal mechanisms for the developmental origins of PCOS. Our preliminary studies indicate that these sheep develop ovulatory defects during adulthood similar to those of women with PCOS: anovulation, elevated LH levels, hyperandrogenemia, hyperinsulinemia, and multifollicular ovaries. In this proposal, we will test the following hypothesis: prenatal exposure to androgens disrupts adult reproductive function culminating in hyperandrogenic anovulation and that this disruption is mediated via reduced sensitivity to the positive feedback actions of estradiol, abnormal gonadotropic drive and/or altered ovarian sensitivity to FSH. The specific Aims of the proposed research are to determine 1) the extent to which fetal exposure to androgens disrupts reproductive cyclicity, ovarian function, ovulatory capacity and fertility in adulthood, (2) if reduced sensitivity to estradiol stimulatory feedback of gonadotropin secretion contributes to the disruptive effects of prenatal- androgenization on postnatal reproductive cyclicity, and (3) if abnormal gonadotropic drive and/or reduced ovarian sensitivity to FSH contributes to the disruptive effects of prenatal- androgenization on postnatal reproductive cyclicity. If our hyposthesis proves to be correct, this would form the basis for a distinct developmental origin of an important reproductive disease in adulthood. Specifically it will establish that discrete, experimentally induced androgen excess of fetal sheep provides the first clear etiology for hyperandrogenic anovulation in adulthood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REPRODUCTIVE PHYSIOLOGY OF OVARIAN FAILURE Principal Investigator & Institution: Santoro, Nanette F.; Professor and Director; Ob/Gyn & Women's Health; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 15-AUG-1994; Project End 31-MAR-2004
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Estradiol
Summary: Our group has previously reported striking increases in estrogen secretin and excretion in women in the early stage of the menopause transition. The causes of he shortened follicular phases, increased whole cycle estrogen, and decreased progesterone in perimenopause, as well as the consequences of this altered reproductive hormonal environment on the hypothalamic-pituitary and endometrial axes are the focus of this continuing renewal. We propose 3 Specific Aims: Aims 1 will determine the association of elevated FSH in the perimenopause with decreased inhibin A and B, and with increases in circulating activin A. In Aim 2, we will test the hypothesis that increased estrogen secretion in perimenopausal cycles will caused increased menstrual bleeding. We will also determine whether increased estradiol exposure causes increased endometrial angiogenesis and proliferation as assessed immunohistochemically. We will test the hypothesis that abundance and location of ER alpha and beta subtypes differ between perimenopausal and mid-productive aged women's endometrium. Aim 3 will test the hypothesis that perimenopausal anovulation is caused by LH surge failure secondary to supraphysiologic estradiol stimulation. We will administer physiologic and supraphysiologic estradiol by infusion and test the resulting LH surge. We will also test directly pituitary sensitivity to exogenous LH in estradiol primed perimenopausal women to determine if there id reduced positive feedback sensitivity in perimenopausal women to determine if there is reduced positive feedback sensitivity in perimenopausal women. In this manner, we hope to elucidate the critical mechanisms that may cause or be the consequence of the hormonal dynamics of the early stages of the menopausal transition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REWARD MOTIVATION
AND
REINFORCEMENT
IN
IMPLICIT
POWER
Principal Investigator & Institution: Schultheiss, Oliver C.; Psychology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (investigator's abstract): Although the implicit motive approach to human motivation has spawned a staggering amount of basic and applied research over the past 50 years, the processes at the core of implicit motives have received comparatively little attention in research. Specifically, there is a lack of empirical data elucidating why individuals high in a given motive seek to attain a motive-specific incentive in the first place and what consequences incentive consummation has for their behavior. For the case of the implicit power motive, the Principal Investigator has developed a model which posits that having impact - the incentive associated with the power motive - is rewarding for individuals high in implicit power motivation and reinforces behavior that was instrumental for having impact Importantly, because the power motive operates outside of a person's conscious awareness, individuals may be unaware of motive-based processes of reward and reinforcement These processes will therefore be assessed with objective behavioral and psychophysiological measures in the proposed research. Specifically, the gonadal steroid hormone testosterone is hypothesized to be an indicator of power motivation reward and to increase in high-power individuals in response to having impact. Enhanced implicit learning of behavior that was instrumental in having impact is hypothesized to reflect reinforcement in high-power individuals. Furthermore, the model states that power motivation reward, as indicated by surging testosterone, mediates power motivation reinforcement, as indicated by enhanced implicit learning. Three experimental studies on the role of personalized power motivation, a subtype of the implicit power motive, in winning or losing a
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dominance contest mark a first step towards validating this model. Study 1 will provide an initial test of the model in men, while Study 2 explores to which extent it also holds for women, in which estradiol may play a more important role than testosterone in power motivation reward. Study 3 will test whether the hypothesized rewarding effect of testosterone can be potentiated by a caffeine-induced increase of incentive motivation. In addition, the role of facial aflective expressions as indicators of power motivation reward and the time course of the hypothesized power motivation reward and reinforcement effects will be explored in these studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RISK FACTORS FOR AGE RELATED BONE LOSS Principal Investigator & Institution: Kiel, Douglas P.; Associate Professor; Hebrew Rehabilitation Center for Aged 1200 Centre St, Roslindale Boston, Ma 02131 Timing: Fiscal Year 2002; Project Start 30-SEP-1991; Project End 31-MAY-2007 Summary: (provided by applicant): The Framingham Osteoporosis Study (FOS) is a prospective study that is part of the Framingham Heart Study, one of the longest running cohort studies in the world. FOS involves participants from the Original Cohort (1948-present) and the Offspring Cohort (2nd generation and spouses). Both cohorts have comprehensive data about osteoporosis risk factors, as well as having stored DNA, relevant genotyping being performed by other groups, and large numbers of extended families in whom a genome wide scan has been carried out. We propose to continue the FOS. Our preliminary findings suggest that patterns of food consumption, dietary silicon and phosphoric acid intake have influences on bone mineral density (BMD). We will study these dietary factors as they relate to changes in BMD and fractures in both Cohorts. Findings from these studies may offer potential dietary approaches to preventing osteoporosis. We have recently completed a genome wide scan on some of the extended families in FOS who have completed BMD and quantitative calcaneal ultrasound (QUS), and found several loci with suggestive linkage. In some cases, loci differed between the BMD and QUS phenotypes. The results of this linkage analysis will be used to suggest potential gene candidates for association studies in addition to the ones that we will investigate in this project: interleukin-6 (IL-6), transforming growth factor beta (TGF-Beta), and estrogen receptors alpha and beta (ERa and ERBeta). We recently discovered that women with bone loss or low BMD have greater severity of vascular calcification, suggesting that the two processes may have a common etiology. We will test the hypothesis that this common etiology is related to estrogen and the estrogen receptors by using electron beam computed tomography to quantify vascular calcification, by measuring serum estradiol and sex-hormone binding globulin, and by genotyping women for ERa and ERBeta. This will advance our understanding of two of the most common chronic diseases affecting older persons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF 5-ALPHA REDUCTASE IN TESTOSTERONE ACTIONS Principal Investigator & Institution: Bhasin, Shalender; Professor and Chief; Internal Medicine; Charles R. Drew University of Med & Sci 1621 E 120Th St Los Angeles, Ca 90059 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Testosterone, the predominant circulating androgen in men, also serves as a prohormone that is converted in the body to two active metabolites, estradiol 17beta and 5-alpha dihydrotestosterone (DHT). Testosterone
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Estradiol
serves as the active hormone in some target tissues; however, androgen effects in other target organs require its conversion to estradiol or DHT. The role of 5-alpha reduction of testosterone in mediating its effects on the muscle and sexual function remains unclear. Therefore, the primary objective of this project is to determine whether 5-alpha reduction of testosterone to DHT is obligatory for mediating its effects on fat-free mass, muscle size, muscle strength, and leg power in men. The secondary objective is to determine whether 5-alpha reduction of testosterone is necessary for maintenance of androgen effects on sexual function (sexual desire, overall sexual activity, nocturnal penile tumescence (NPT), response to visual erotic stimulus, and penile rigidity) in men. In order to test these hypotheses about the role of 5-alpha reduction, we will compare testosterone dose response curves for each outcome measure in the absence and presence of a novel, potent 5-alpha reductase inhibitor (duasteride) that inhibits both type 1 and type 2 steroid 5-alpha -reductase isoenzymes. Healthy young men, 21-40 years of age, will be treated with a long acting GnRH agonist to suppress endogenous testosterone production, and concomitantly, randomly assigned to one of 8 groups: group 1, testosterone enanthate (TE) 50-mg weekly, plus placebo tablets daily; group 2, TE 125-mg weekly plus placebo daily; group 3, TE 300-mg weekly plus placebo daily; group 4, TE 600 mg TE weekly plus placebo; group 5, 50-mg weekly, plus duasteride 2.5-mg daily; group 6, TE 125-mg weekly, plus duasteride daily; group 7, TE 300 mg weekly, plus duasteride daily; group 8, 600-mg TE plus duasteride daily. Energy and protein intake, and exercise stimulus will be standardized. The following outcomes will be measured at baseline and after 20 weeks: body composition by DEXA scan, deuterium oxide and sodium bromide dilution; thigh muscle volume by MRI scan; muscle performance by measurements of 1-repetition maximum strength and leg power; sexual function by International Index of Erectile Function, Sexual Desire Inventory, and daily logs of sexual activity; and penile erections and rigidity during EEG-coupled, NPT recoding and in response to a visual erotic stimulus; total and free testosterone, DHT, estradiol, SHBG, and LH levels. For safety, we will follow hemoglobin/hematocrit, sleep apnea scores, AST and ALT, PSA, plasma lipids, apolipoproteins, and lipoprotein particles, and prostate examinations. A multidisciplinary team of investigators, the use of a previously validated "Leydig Cell Clamp" model, the use of a potent inhibitor of both subtypes of 5-alpha reductase enzyme, attention to potential confounding variables such as energy intake and exercise stimulus, and power and effect size should help elucidate the role of 5-alpha reduction in mediating androgen action. This study will enhance our understanding of the biologic role of the steroid 5-alpha-reductase system, and has immediate clinical relevance in establishing whether selective androgen receptor modulators that do not undergo 5-alpha reduction would be useful as anabolic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF GROWTH FACTORS IN BRAIN DEVELOPMENT Principal Investigator & Institution: Dreyfus, Cheryl F.; Professor; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 08854 Timing: Fiscal Year 2003; Project Start 23-MAY-2003; Project End 31-MAR-2008 Summary: We hypothesize that astrocytes, through their production of trophic molecules, play an active role in the development and perhaps maintenance of proximate neurons. Moreover, neuronal and hormonal signals of the local environment enhance this trophic capacity. We propose that this ability to support neurons is initiated during prenatam life, influencing neuronal survival and the development of mature function. Previous work in our tab supports this possibility. We focused on
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examination of astrocytes cultured from the basal forebrain and cortex, regions with well-characterized neuronal responses to neurotrophins, NGF, BDNF and NT-3. Astrocytes of these regions were found to express NGF, BDNF and NT-3; expression was regulated developmentally. Neurotrophins were highly expressed by cultured astrocytes derived from the fetus, but declined dramatically in astrocytes derived from the adult. Moreover, this expression was differentially regulated by the local neural signals, glutamate and acetylchotine, and, perhaps surprisingly, by estradiol. Estradiol binding sites as well as estrogen receptors a and b were detected on the cultured cells. Therefore, our culture studies suggest that astrocytes produce factors that support neurons and, further, that they are influenced by neurotransmitters and estrogen to do so optimally. To extend these studies we now propose to 1) evaluate neurotrophin expression in astroytes developing in vivo, 2) determine the biological actions of astrocyte-dedved neurotrophins on function and/or survival of nearby neurons, and 3) identify signaling cascades that underlie neuronal and hormonal signaling to astrocyles. These studies that evaluate the roles of astrocytes will provide insights with which to optimize the maintenance of the critical BF, HI and cortical regions that degenerate in such diseases as Alzheimer's dementia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SEX HORMONE REGULATION OF INNATE IMMUNITY Principal Investigator & Institution: Wira, Charles R.; Professor; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Description (provided by applicant): The overall objective of Project 1 is to define the role of sex hormones in regulating the innate immune system of the FRT. Epithelial cells within the fallopian tube, uterus, cervix and vagina are the first line of defense against potentially pathogenic microbes and are individually responsive to estradiol and progesterone. In studies proposed in this application, we will test the hypothesis that epithelial cells represent the front line of the innate immune system throughout the human FRT and that innate immune protection by these cells is precisely regulated by female sex hormones. These studies will define the mechanisms whereby sex hormones influence phenotype, innate function, and communication between the innate and adaptive immune systems. We postulate that the innate immune responses of epithelial cells are under hormone control and that, in addition to conferring protection, these cells are capable of initiating an adaptive immune response. More specifically, we will: 1) Define the processes by which sex hormones modulate anti-bacterial activity, defensins and Secretory Leukocyte Protease Inhibitor (SLPI) produced by epithelial cells throughout the FRT; 2) Determine if exposure to specific PAMP (antigens) enhances or limits continued expression/production of anti-bacterial activity, defensins and SLPI in a way which is mediated through TLRs, and is precisely controlled by sex hormones; 3) Examine the role of sex hormones in regulating cytokine expression by reproductive tract epithelial cells in the presence and/or absence of PAMP; and 4) Define the role of sex hormone environment in modulating the interactions between reproductive tract epithelial cells and immune cells and determine if sex hormones directly influence links between the innate and adaptive immune systems. Understanding how the immune system in the reproductive tract can respond to bacterial and viral challenges requires that we understand the unique characteristics of the immune system in the female reproductive tract and the ways in which the innate and adaptive immune system are either enhanced and/or suppressed at particular times in a woman?s life. These studies should provide the basis of knowledge essential for understanding the role of hormones
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Estradiol
in autoimmune diseases such as Multiple Sclerosis, the prevention of local infection in the genital mucosa, and the management of sexually transmitted diseases as well as the treatment of gynecological cancers and endometriosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SEX IN VIRAL MYOCARDITIS Principal Investigator & Institution: Huber, Sally A.; Professor; Pathology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAY-2005 Summary: (provided by applicant): Myocarditis is an inflammatory disease of the myocardium. Approximately 65% of cases follow recent enterovirus infections and occur in males. As in humans, CVB3 infections cause severe myocarditis in male, but not virgin female mice. Androgens (progesterone and testosterone) increase virus receptor expression on cardiac myocytes while 17- beta-estradiol treatment does not. Since lymphocytes also express CVB3 receptors, we hypothesize that hormones might modulate lymphocyte expression of these molecules as well. Furthermore, enterovirus receptors often belong to immunoglobulin and integrin superfamilies, which have important signal transduction functions. Direct virus binding to normal lymphocytes causes rapid calcium flux and cytokine release within four hours of virus exposure. Cytokine release differs between male and female lymphocytes with male cells producing interferon (IFN)gamma and female cells producing interleukin (IL)- 10. We hypothesize that viruses, which have repetitive symmetry of the virus capsid, cross-link important cell surface molecules on lymphocytes and cause rapid non-antigen-specific lymphocyte activation. This initial activation with associated cytokine release determines subsequent innate and adaptive immune responses to the virus, such as CD4+ T helper (Th) cell response and development/survival of autoimmune CD8+ T cells in vivo. The Specific Aims of this application are to: 1) Determine virus receptor expression, binding avidity, activation potential and cytokine production on male and female lymphoid cells exposed to non-infectious virus; 2) Determine the effects of direct virus interaction and hormone signaling on CD8+alpha,beta T cell receptor (TCR)+ and gamma,delta TCR+ effector cell function and survival in vivo; and 3) Determine the effects of direct virus interaction and hormone signaling on virus-specific CD4+alpha,beta TCR+ response and survival in vivo. These studies may provide new insights as to how viruses affect developing host defense responses and how hormones can modulate this initial response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTION
SEXUAL
DIFFERENTIATION
OF
MOUSE
VOMERONASAL
Principal Investigator & Institution: Cherry, James A.; Psychology; Boston University Charles River Campus 881 Commonwealth Avenue Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 31-MAR-2005 Summary: (provided by applicant): The vomeronasal organ (VNO) projection pathway mediates many of the effects of pheromones on essential psychosexual and neuroendocrine functions in a variety of vertebrate species. We have shown that different populations of neurons in the VNO of male and female mice respond to pheromones derived from male and female conspecifics and that estradiol and testosterone amplify these effects. Experiments are proposed to extend these findings by determining whether sex differences exist in the expression within the basal zone of the
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VNO of any three different V2R receptors previously cloned in mice, and whether any such differences in mRNA levels for these receptors are modulated by estradiol or testosterone. We will see whether the ability of male pheromones to augment Fos-IR in mitral cells that project to medial amygdaloid nuclei from the rostral as opposed to the caudal AOB differs in gonadectomized, estrogen-treated male and female mice and will use cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH) for the immediate-early-gene (IEG), c-fos, to determine whether mitral cells in the rostral versus caudal zones of the AOB are differentially activated by pheromones from male versus estrous female mice. Finally, we will determine whether the inhibition of male pheromone-induced IEG activation previously seen in the VNO of females two days after mating also occurs in male mice and in response to pheromones from both sexes, and we will assess the possible role of noradrenergic afferents from the superior cervical ganglia on the mating-induced 'silencing' of subsequent odor-induced IEG activation in the VNO. The results obtained in these studies should improve our understanding of the neurobiological mechanisms that underlie the effects of gender, steroid hormones, and previous coital experience on the processing of olfactory signals by the accessory olfactory system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELLS AND PERINATAL FACTORS FOR BREAST CANCER RISK Principal Investigator & Institution: Hsieh, Chung-Cheng; Professor of Medicine; Cancer Center; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-JAN-2006 Summary: (provided by applicant): This study proposes to examine whether hormone levels in human umbilical cord blood are associated with measurements of stem cell potential and expression of Bcl-2 family proteins indicating levels of apoptotic activity. Measurements of stem cells and Bcl-2 apoptosis will be further examined to see if they correlate with birth weight as an indicator of fetal growth. The study is based on the hypothesis that cancer risk can be influenced in part by the hormonal environment in utero and that cancer risk is proportional to the number of primitive proliferating stem cells. Umbilical cord blood from 300 donors will be obtained from singleton birth, fullterm, and low-risk deliveries at hospitals affiliated with the American Red Cross Cord Blood Program. Hormones and other growth factors including estradiol, estriol, progesterone, prolactin, sex-hormone binding globulin (SHIBG), testosterone, insulinlike growth factor-1 (IGF-1), and IGF binding protein-3 (IGFBP-3) will be assayed in cord blood samples. We will measure the total number of nucleated cells, number of cells per volume expressing CD34 protein on the cell surface as well as CD34+/CD38, CD34+/c-kit, and CD45/GlyA sub-population cells, and the number of colony-formingunit granulocytes and macrophages (CFU-GM) as laboratory parameters for primitive proliferating stem cells. Among Bcl-2 family proteins we will measure the expression of Bcl-2, Bcl-xL, Bax, and Bad to construct an overall apoptotic index. We will apply regression analysis treating as outcome variables each measurement of stem cell potential and Bcl-2 apoptotic index and as predictor variables hormone levels, controlling for maternal and neonatal characteristics. Stem cell measurements and index of Bcl-2 apoptotic expressions will be further examined as predictors of birth weight. The study seeks to obtain information on parameters of perinatal cell proliferation relevant to intervening steps between intrauterine hormone exposure and subsequent cancer risk.
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Estradiol
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEROID HORMONES AND NEURONAL REGENERATION Principal Investigator & Institution: Jones, Kathryn J.; Professor; Cell Bio & Neurobio & Anatomy; Loyola University Medical Center Lewis Towers, 13Th Fl Chicago, Il 60611 Timing: Fiscal Year 2001; Project Start 01-JAN-1990; Project End 31-JUL-2004 Summary: The investigator has identified a role for testosterone propionate (TP) in enhancing neuronal regeneration of the crushed facial nerve in adult hamsters. It is thought that testosterone mediates its actions through androgen receptors (AR) that are more prevalent in males than in females and are present at the surface of this particular neuronal subtype. Previously, a working model of the mechanism by which steroids augment peripheral nerve regeneration has been developed. The main objective of this project is to test specific aspects of this model, with particular focus on the initial injury phases of the regenerative response and on the role of the androgen receptor in these early phenomena. The aims are to test the following 4 hypotheses. First, it was shown that TP administration coincident with facial nerve injury alters early stress responses of injured FMN. Two series of experiments, utilizing northern blot and immunoblot procedures in conjunction with heat shock protein 70 cDNA probes and antibodies will be used to determine the effect of TP on the stress response of injured FMN. Second, the effects of TP on facial nerve regeneration occur during the initial stages of the FMN injury response although all previous studies have used TP administration for lengthy time periods. To learn if TP can work early on, TP exposure will be limited to time periods of 6-2 hours after facial nerve injury and 2 series of analyses will be done. Radioisotopic labeling procedures will be used to determine the effects of limited Tp exposure on the rate of facial nerve regeneration, and in situ hybridization studies with cytoskeletal probes will be done to determine the effects of limited TP exposure on cytoskeletal response patterns throughout the recovery period. Third, the gender differences in the augmentation of facial nerve regeneration by TP are AR mediated. In 3 series of experiments, females will receive TP prior to facial nerve injury, in order to upregulate levels of AR mRNA to those of males, and the effects of TP on facial nerve regeneration, and rRNA/cytoskeletal gene expression will be determined. Fourth, estradiol (E) acts via AR to augment racial nerve regeneration. It has been shown that E given from the time of facial nerve injury, results in an androgen- like acceleration of regeneration rates. Two series of experiments will be done. The effects of high doses of E in the presence of the anti-androgen, flutamide, and high versus low doses of E on the rate of regeneration will be determined. AR binding assays will also be done to determine if E binds to AR in the facial nucleus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PRODUCTION
STEROIDS
/VASCULAR
REACTIVITY
/NITRIC
Principal Investigator & Institution: Keller-Wood, Maureen Pharmacodynamics; University of Florida Gainesville, Fl 32611
E.;
OXIDE Professor;
Timing: Fiscal Year 2002; Project Start 06-APR-2001; Project End 31-MAR-2004 Summary: (Adapted from applicant's description): The overall goal of these studies is to test the hypothesis that there is an interaction between increased secretion of adrenal corticosteroids and increased secretion of estrogen during pregnancy which is necessary for normal blood pressure control in the peripartal period. Studies in pregnant, hypocorticoid ewes and clinical experience in pregnant women with
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hypoadrenocorticism suggest that normal blood pressure control in late pregnancy requires increased adrenal secretion. Insufficient supply of cortisol results in rapid and profound hypotension, with increased morbidity and mortality in both mother and fetus. The experiments in this proposal will directly test the hypothesis that a decrease in cortisol at a time of increased estrogen results in a greater decrease in vascular reactivity to phenylephrine and that this correlates with increased production of nitric oxide production in one or more sites in the body. Four groups of ewes will be studied: adrenalectomized, ovariectomized ewes, adrenalectomized ovariectomized ewes treated with estradiol, adrenal- intact ovariectomized ewes, and adrenal-intact ovariectomized ewes treated with estradiol. All adrenalectomized ewes will be treated with aldosterone and cortisol for one week following surgery, and then the adrenal steroid infusions will be stopped to produce the hypoadrenal state. Animals will be studied at a time point (8 hours) in which the adrenalectomized estrogen treated animals are hypotensive, but the adrenalectomized ewes without estradiol treatment are not overtly hypotensive. Experiments will test vascular reactivity in response to phenylephrine in all 4 groups of ewes to test the hypothesis that estrogen administration decreases vascular reactivity in adrenalectomized ewes. Experiments will also determine plasma levels of nitrates and nitrites and the ability of infusion of L-NAME, an inhibitor of nitric oxide synthase (NOS), to increase vascular reactivity in adrenalectomized ewes with estradiol treatment. Experiments will also test the concentrations of cGMP, and levels of iNOS, eNOS, and nNOS protein measured by Western analysis and mRNA by RT-PCR in aorta, uterine artery, mesenteric artery, renal artery, renal interlobular artery, renal medulla and cortex, and skeletal muscle, taken from animals in the same 4 experimental groups. These experiments will determine if absence of cortisol results in increased NOS in one or more of these sites. Samples of tissue will also be examined by immunohistochemistry to more precisely identify the cell populations containing iNOS, eNOS or nNOS in these ewes. These experiments will therefore describe which isoform(s), and in which cells, NOS is altered by cortisol withdrawal, either alone or in combination with increased estrogen. This information will form the basis of future experiments to determine the mechanism of the interaction of estrogen and cortisol in control of NO and regulation of blood pressure during pregnancy. These studies will therefore add to our understanding of normal blood pressure control during pregnancy, and of the pathophysiology of hypoadrenocorticism at term. These studies will also to our understanding of the counterbalancing effects of increased cortisol and increased estrogens in control of normal blood pressure in normal pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESTROGENS
SYNAPTIC
PLASTICITY
OF
HYPOTHALAMIC
NEURONS--
Principal Investigator & Institution: Ronnekleiv, Oline K.; Professor; Physiology and Pharmacology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2000; Project Start 01-JUN-1997; Project End 31-MAR-2004 Summary: The long-term objectives of these experiments are to explore the biphasic effects of 15beta-estradiol (E2) on synaptic transmission that results in both inhibition and excitation of gonadotropin releasing hormone (GnRH) neurons. Our hypothesis is that prolonged exposure to preovulatory levels of E2 enhances excitatory synaptic input and attenuates inhibitory synaptic input onto GnRH neurons, which ultimately facilitates bursting activity and peptide release. The first experiments will test the hypothesis that E2 will decrease the inhibitory input and increase the excitatory input to GnRH neurons after a period of at least 24 h. Tissues will be prepared from
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Estradiol
ovariectomized, estrogen- and oil-treated females at 1, 24, 36, and 40 h after treatment. Inhibitory neurotransmitter agonists (and antagonists) selective for mu-opioid and GABAB receptors will be tested on POA neurons and the underlying conductances which they activate characterized using sharp electrode recording. Excitatory neurotransmitter agonists (and antagonists) selective for alpha1-noradrenergic and glutamate receptors will be tested and the underlying conductances which they activate characterized in POA (GnRH) neurons. Focal electrical stimulation of afferent pathways into the POA will be done to identify inhibitory and excitatory synaptic currents using whole-cell patch recording. The second experiments will test the hypothesis that preovulatory levels of E2 will increase the intrinsic conductances underlying phasic bursting activity in GnRH neurons. Tissues will be prepared from ovariectomized, estrogen- and oil-treated females at 42 h after treatment. The expression of calcium Tcurrent and the small conductance, calcium-dependent K+ (SK) current will be measured using single-electrode voltage clamp and in situ hybridization. In addition, the expression of the hyperpolarization-activated, non-selective cation current (Ih) will be measured using single-electrode voltage clamp. Lastly, the biocytin-injected neurons will be analyzed using histochemical techniques combined with confocal microscopy to elucidate the transmitter phenotype of the biocytin-injected neurons and their anatomical interaction with other neurons. The results from these studies will provide important new information about the mechanism by which estrogen alters the responsiveness of hypothalamic (GnRH) neurons, and how estrogens in general modify synaptic plasticity in the mammalian brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TDM & DRUG INTERACTIONS IN HIVINFECTED SUBSTANCE ABUSERS Principal Investigator & Institution: Morse, Gene D.; Chairman; Pharmacy Practice; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): This application describes an innovative approach to the rapid assessment of complex drug interactions between protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), and commonly prescribed medications including methadone, ethinyl estradiol, fluconazole, pravastatin, and fluoxetine in HIV-infected, substance abusers The proposed methodology employs a Therapeutic Drug Monitoring (TDM) program that will facilitate rapid determination of ART in subjects receiving multiple interacting medications Specific aims 1) Implement a TDM program that will establish a mechanism to investigate protease inhibitor (PI) and NNRTI pharmacokinetics in HIV-infected, substance abusers receiving ART, determine drug exposure parameters (Cmin, AUC) and inhibitory quotients (IQs), 2) Determine the pharmacokinetics of selected interacting medications (methadone, ethinyl estradiol, fluconazole, pravastatin, fluoxetine) in HIV-infected, substance abusers receiving ART, 3) Determine in vitro and ex vivo total and unbound plasma concentrations of protease inhibitors and NNRTIs in HIV-infected, substance abusers utilizing novel analytical approaches including HPLC, LC-MS-MS and capillary electrophoresis, 4) Develop and validate a capillary electrophoresis assay capable of enantiomeric separation to enhance the pharmacokinetic analysis of interacting medications, 5) Examine pharmacogenetic factors that may identify individuals at greater risk for insufficient or excessive systemic drug exposure while receiving complex regimens with multiple drug-drug interactions The proposed TDM-drug-drug interaction program integrates a comprehensive antiretroviral clinical pharmacology research group, an HPLC/LC-MS analytical facility,
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a pharmacometrics laboratory, a web-based TDM enrollment infrastructure, and four HIV clinical centers caring for substance abusers Innovative pharmacokinetic and pharmacodynamic modeling approaches to assess complex drug-drug interaction analyses of PI and NNRTIs from HIV-infected substance abusers and non-substance abusers will be conducted. Clinical sites will enroll subjects while drug measurement and data analysis will be conducted at the central pharmacology laboratory. These studies will provide insight into clinical interactions that face clinicians and patients today, and identify priority drug interactions that require more traditional pharmacokinetic trials to identify specific mechanisms of interaction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE INVOLVEMENT OF THE VMH IN MATERNAL BEHAVIOR IN RATS Principal Investigator & Institution: Mann, Phyllis E.; Veterinary Biomedical Sciences; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2005 Summary: (provided by applicant): Based on new evidence from our laboratory, which has discovered an important inhibitory role of the ventromedial nucleus of the hypothalamus (VMH) in maternal behavior, the objective of this grant proposal is to elucidate the involvement of the VMH in the onset of maternal behavior. The experiments described in the present grant proposal will use behavioral, molecular, and anatomical approaches to identify the possible mechanisms of action of the VMH on the inhibition of maternal behavior. The hypothesis underlying the present proposal is that under normal physiological conditions the VMH inhibits the display of maternal behavior in virgin and late-pregnant rats by inhibiting the actions of the medial preoptic area (MPOA, an area considered to be crucially involved in the display of maternal behavior). The specific aim of the first three experiments will be to examine the role of the VMH in the regulation of maternal behavior in estradiol-primed, virgin rats. Experiment 1 will analyze the timing of neurotoxin administration into the VMH and subsequent maternal behavior stimulation. Experiment 2 will determine if infusions of the sodium channel blocker, tetrodotoxin, will stimulate short-latency maternal behavior, while experiment 3 will examine the role of GABA infusions into the VMH and subsequent maternal behavior. The second specific aim is to determine the changes in receptor gene expression of the key pregnancy hormones, estrogen, progesterone, and prolactin, in estradiol-primed, virgin rats. Experiments 4,5 and 6 will use in situ hybridization histochemistiy (ISHH) to determine the changes in estrogen, progesterone, and prolactin receptor gene expression, respectively, in the VMH and MPOA following estradiol stimulation in virgin rats. These 3 experiments will also investigate the changes in receptor gene expression in the MPOA following neurotoxic lesions to the VMH. The third specific aim is to determine, using anatomical, tracktracing methods, whether neurons in the VMH that are activated in the presence of pups project to the MPOA (experiment 7). Experiment 8 will determine the neurotransmitter involved in the regulation of the MPOA by the VMH. Together, these studies will help elucidate the role of the VMH in maternal behavior in virgin rats and identify the neural basis of parental care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE ROLE OF PLACENTAL LACTOGEN IN FETAL DEVELOPMENT Principal Investigator & Institution: Freemark, Michael S.; Pediatrics; Duke University Durham, Nc 27706
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Timing: Fiscal Year 2003; Project Start 01-MAY-1988; Project End 31-MAY-2008 Summary: (provided by applicant): Prolactin (PRL) and placental lactogen (PL) stimulate fat deposition, weight gain, and leptin production in rodents and humans, suggesting that lactogens play roles in maternofetal lipid metabolism and obesity. The mechanisms by which lactogens promote fat storage and weight gain are unknown. We hypothesize: (a) that lactogens promote fat deposition through induction of adipogenesis, the process of differentiation of adipocytes from stromal precursors; (b) that adipogenic effects of lactogens are mediated through induction of transcription factors including PPARkhi-2; (c) that PPARkhi-2 induction is mediated through activation of Stat5; and (d) that adipogenic effects of lactogens are modulated by insulin, IGF-1, glucocorticoids, and sex steroids. To test these hypotheses we will examine effects of exogenous PRL and PL on adipogenesis in 3T3-L1 preadipocytes, primary mouse preadipocytes and embryonic fibroblasts and the effects of constitutive expression of PL in a novel 3T3-L1 cell line. To determine if lactogenic signaling is required for preadipocyte differentiation, we will compare rates of adipogenesis in preadipocytes of PRL receptor (PRLR)-deficient mice with rates of adipogenesis in cells of wild-type littermates. To characterize effects of lactogens on PPARkhi expression we will examine effects of PRL and PL on PPARkhi1 and 2 mRNA and protein levels in 3T3-L1 cells, primary preadipoyctes, mouse embryonic fibroblasts and will compare PPARkhi expression in tissues of PRLR deficient mice with that in wild-type littermates, We will examine effects of lactogens on transcriptional activation of the human and mouse PPARkhi-2 promoters expressed in 3T3-L1 cells and will compare the time course of expression of PPARkhi1I and 2 mRNAs in PRL-treated cells with that of ADD1 and c/EBPs beta, delta, and alpha. To test the hypothesis that induction of PPARkhi-2 is mediated through activation of Stat5, we will determine if lactogens induce binding of STAT 5 to consensus binding sites in the human and mPPAR c-2 promoters. We will examine the effect of mutating PPARkhi-2 Stat5 consensus sequences on lactogendependent activation of PPAR gamma2 transcription, and the effect of a dominantnegative STAT5 construct on the induction of PPARkhi mRNA and protein levels in 3T3-L1 cells. Finally, to test the hypothesis that the adipogenic effects of the lactogens are modulated by sex steroids, we will examine the effects of progesterone and estradiol on the adipogenic effects of PRL in 3T3-L 1 cells and the effects of progesterone supplementation on fat deposition and leptin production in PRLR-deficient mice. The results of our studies should provide new insist into the roles of pituitary and placental hormones in adipose development and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: WHI SEX HORMONE & GENETIC RISK FACTORS FOR HIP FRACTURE Principal Investigator & Institution: Cummings, Steven R.; California Pacific Med CtrPacific Camp 2200 Webster Street, Suite 514 San Francisco, Ca 94115 Timing: Fiscal Year 2003; Project Start 24-SEP-2003; Project End 31-MAR-2006 Summary: (provided by applicant): In the United States, many hip fractures occur each year, causing significant disability and premature deaths. Cases of hip fractures cost an estimated $7 billion annually. Several etiologic factors are implicated in fracture risk including hormonal, metabolic, and genetic contributions. We propose to examine promising hormonal and genetic markers for hip fracture risk; this is a major objective of the Women's Health Initiative Observation Study (WHI-OS), a prospective study of over 93,000 postmenopausal women. Among WHI-OS participants, we will investigate whether low levels (especially very low levels) of estradiol, high levels of steroid
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hormone binding globulin, and low levels of insulin like growth factor 1 increase the risk of hip fracture. Recent studies also have identified promising polymorphisms in several candidate genes related to bone metabolism that may substantially affect hip fracture risk. We will test whether candidate polymorphisms in the following genes contribute to hip fracture risk: APOE, estrogen receptor alpha-l, transforming growth factor-beta and collagen type 1 alpha 1, and LDL receptor-related protein 5. Recent data support the functional role of these polymorphisms in the maintenance of bone mass and metabolism, suggesting that they may contribute to osteoporotic fracture risk. Identifying such hormonal and genetic markers for increased fracture risk ultimately may provide insight into treatment methods, at risk populations that could benefit from preventive measures, and new hypotheses about the pathophysiologic mechanisms for increased fracture risk. Among eligible WHI-OS participants aged 55-79 years at baseline, we will use a nested case-control study design to identify 400 cases of first hip fracture and 400 age-, ethnicity-, and center-matched controls for this study. This study will use previously collected baseline data and stored specimens in WHI-OS, including existing baseline serum and buffy coat samples and documentation/adjudication of hip fracture events. WHl data include comprehensive measurements of potential confounders and effect modifiers that will be considered in the analyses. The proposed study is a very efficient approach to understanding the etiologies of hip fracture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “estradiol” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for estradiol in the PubMed Central database: •
17 beta-estradiol acts directly on the clonal osteoblastic cell line UMR106. by Gray TK, Flynn TC, Gray KM, Nabell LM.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299052
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17[beta]-Estradiol Hydroxylation Catalyzed by Human Cytochrome P450 1B1. by Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR.; 1996 Sep 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38505
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17[beta]-Estradiol Inhibits Apoptosis in MCF-7 Cells, Inducing bcl-2 Expression via Two Estrogen-Responsive Elements Present in the Coding Sequence. by Perillo B, Sasso A, Abbondanza C, Palumbo G.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85519
3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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17[beta]-Estradiol Mimics Ligand Activity of the c-erbB2 Protooncogene Product. by Matsuda S, Kadowaki Y, Ichino M, Akiyama T, Toyoshima K, Yamamoto T.; 1993 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47866
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17[beta]-Estradiol responsiveness of MCF-7 laboratory strains is dependent on an autocrine signal activating the IGF type I receptor. by Hamelers IH, van Schaik RF, Sussenbach JS, Steenbergh PH.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=169177
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2,3,7,8-Tetrachlorodibenzo-P-Dioxin Causes an Extensive Alternation of 17 [beta]Estradiol Metabolism in MCF-7 Breast Tumor Cells. by Spink DC, Lincoln DW II, Dickerman HW, Gierthy JF.; 1990 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54649
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2-Methoxyestradiol, an Endogenous Mammalian Metabolite, Inhibits Tubulin Polymerization by Interacting at the Colchicine Site. by D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E.; 1994 Apr 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43703
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36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. by Laborda J.; 1991 Jul 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=328497
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4-Hydroxylation of Estradiol by Human Uterine Myometrium and Myoma Microsomes: Implications for the Mechanism of Uterine Tumorigenesis. by Liehr JG, Ricci MJ, Jefcoate CR, Hannigan EV, Hokanson JA.; 1995 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40956
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A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor --deficient mice. by Sims NA, Clement-Lacroix P, Minet D, Fraslon-Vanhulle C, Gaillard-Kelly M, Resche-Rigon M, Baron R.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154447
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Activation of [kappa]B-Specific Proteins by Estradiol. by Shyamala G, Guiot M.; 1992 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50394
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Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17 beta-estradiol or v-Ha-ras oncogene. by Dickson RB, Kasid A, Huff KK, Bates SE, Knabbe C, Bronzert D, Gelmann EP, Lippman ME.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304311
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Adherence of Escherichia coli in pathogenesis of endometritis and effects of estradiol examined by scanning electron microscopy. by Nishikawa Y.; 1985 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261515
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Alterations in osteoclast morphology following long-term 17beta-estradiol administration in the mouse. by Gruber HE, Puzanov IJ, Bennett M, Kumar V, Gordon B.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29068
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Biphasic Estradiol-induced AKT Phosphorylation Is Modulated by PTEN via MAP Kinase in HepG2 Cells. by Marino M, Acconcia F, Trentalance A.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194905
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Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons. by Murphy DD, Cole NB, Segal M.; 1998 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21656
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Candida albicans Estrogen-Binding Protein Gene Encodes an Oxidoreductase that is Inhibited by Estradiol. by Madani ND, Malloy PJ, Rodriguez-Pombo P, Krishnan AV, Feldman D.; 1994 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43065
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Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. by Swaneck GE, Fishman J.; 1988 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282290
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Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway. by Bi R, Foy MR, Vouimba RM, Thompson RF, Baudry M.; 2001 Nov 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60881
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Degradation of 17[beta]-Estradiol by a Gram-Negative Bacterium Isolated from Activated Sludge in a Sewage Treatment Plant in Tokyo, Japan. by Fujii K, Kikuchi S, Satomi M, Ushio-Sata N, Morita N.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123865
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Direct effects of 17 beta-estradiol on trabecular bone in ovariectomized rats. by Takano-Yamamoto T, Rodan GA.; 1990 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53648
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Distinct Nongenomic Signal Transduction Pathways Controlled by 17[beta]-Estradiol Regulate DNA Synthesis and Cyclin D1 Gene Transcription in HepG2 Cells. by Marino M, Acconcia F, Bresciani F, Weisz A, Trentalance A.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129978
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Distribution of estradiol receptor and vitellogenin gene in chick liver chromatin fractions. by Alberga A, Tran A, Baulieu EE.; 1979 Dec 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=342364
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Effect of beta-estradiol on production of the cell-detaching factor of Trichomonas vaginalis. by Garber GE, Lemchuk-Favel LT, Rousseau G.; 1991 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270222
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Effect of estradiol and progesterone on lymphocyte and neutrophil functions in steers. by Roth JA, Kaeberle ML, Hsu WH.; 1982 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351146
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Effect of estradiol on chlamydial genital infection of female guinea pigs. by Rank RG, White HJ, Hough AJ Jr, Pasley JN, Barron AL.; 1982 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=347795
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Effect of estrogen (17 beta-estradiol) on the susceptibility of mice to disseminated gonococcal infection. by Kita E, Takahashi S, Yasui K, Kashiba S.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262084
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Effect of estrogen upon cyclic ADP ribose metabolism: [beta]-Estradiol stimulates ADP ribosyl cyclase in rat uterus. by Chini EN, de Toledo FG, Thompson MA, Dousa TP.; 1997 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20873
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Effects of 17beta-estradiol on the replication of rubella virus in an estrogenresponsive, continuous cell line. by Roehrig JT, Brawner TA, Riggs HG Jr.; 1979 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=353148
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Effects of estradiol and progesterone on Bacteroides melaninogenicus and Bacteroides gingivalis. by Kornman KS, Loesche WJ.; 1982 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351023
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Effects of Estradiol and Progesterone on Susceptibility and Early Immune Responses to Chlamydia trachomatis Infection in the Female Reproductive Tract. by Kaushic C, Zhou F, Murdin AD, Wira CR.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101727
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Enhanced osteoblast proliferation and collagen gene expression by estradiol. by Ernst M, Schmid C, Froesch ER.; 1988 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279980
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Enzymatic bromination of 16-dehydroestradiol 3-methyl ether 17-acetate to 16-alphabromoestrone 3-methyl ether. by Neidleman SL, Oberc MA.; 1968 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=315184
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Estradiol and the Inhibition of Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator Activity in the Rhesus Monkey. by Ordog T, Knobil E.; 1995 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41591
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Estradiol Causes the Rapid Accumulation of cAMP in Human Prostate. by Nakhla AM, Khan MS, Romas NP, Rosner W.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44003
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Estradiol differentially regulates lipocalin-type prostaglandin D synthase transcript levels in the rodent brain: Evidence from high-density oligonucleotide arrays and in situ hybridization. by Mong JA, Devidze N, Frail DE, O'Connor LT, Samuel M, Choleris E, Ogawa S, Pfaff DW.; 2003 Jan 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140964
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Estradiol down regulates the binding activity of an avian vitellogenin gene repressor (MDBP-2) and triggers a gradual demethylation of the mCpG pair of its DNA binding site. by Jost JP, Saluz HP, Pawlak A.; 1991 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=328989
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Estradiol induces the calcium-dependent translocation of endothelial nitric oxide synthase. by Goetz RM, Thatte HS, Prabhakar P, Cho MR, Michel T, Golan DE.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15847
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Estradiol rapidly inhibits soluble guanylyl cyclase expression in rat uterus. by Krumenacker JS, Hyder SM, Murad F.; 2001 Jan 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14654
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Estradiol repression of tumor necrosis factor-[alpha] transcription requires estrogen receptor activation function-2 and is enhanced by coactivators. by An J, Ribeiro RC, Webb P, Gustafsson JA, Kushner PJ, Baxter JD, Leitman DC.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24790
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Estradiol Stimulates Tyrosine Phosphorylation of the Insulin-Like Growth Factor-1 Receptor and Insulin Receptor Substrate-1 in the Uterus. by Richards RG, DiAugustine RP, Petrusz P, Clark GC, Sebastian J.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38173
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Estradiol-binding proteins from mycelial and yeast-form cultures of Paracoccidioides brasiliensis. by Stover EP, Schar G, Clemons KV, Stevens DA, Feldman D.; 1986 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261086
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Estradiol-induced Wasting Syndrome in Conventionally Reared and Germ-free Mice. by Hatch GG, Reed ND.; 1969 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=250114
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Estrogen receptor [alpha], not [beta], is a critical link in estradiol-mediated protection against brain injury. by Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM.; 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29363
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Estrogen receptor-[alpha] mediates the brain antiinflammatory activity of estradiol. by Vegeto E, Belcredito S, Etteri S, Ghisletti S, Brusadelli A, Meda C, Krust A, Dupont S, Ciana P, Chambon P, Maggi A.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170966
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Experimental Gonococcal Genital Tract Infection and Opacity Protein Expression in Estradiol-Treated Mice. by Jerse AE.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96944
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Expression and localization of estrogen receptor-[beta] in annulus cells of the human intervertebral disc and the mitogenic effect of 17-[beta]-estradiol in vitro. by Gruber HE, Yamaguchi D, Ingram J, Leslie K, Huang W, Miller TA, Hanley EN Jr.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65546
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Expression and localization of estrogen receptor-alpha protein in normal and abnormal term placentae and stimulation of trophoblast differentiation by estradiol.
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by Bukovsky A, Cekanova M, Caudle MR, Wimalasena J, Foster JS, Henley DC, Elder RF.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151787 •
Expression Profiling of the Maize Flavonoid Pathway Genes Controlled by EstradiolInducible Transcription Factors CRC and P. by Bruce W, Folkerts O, Garnaat C, Crasta O, Roth B, Bowen B.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140215
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EXTINCTION OF EXPERIMENTAL MAMMARY CANCER, I. ESTRADIOL-17[beta] AND PROGESTERONE. by Huggins C, Moon RC, Morii S.; 1962 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=220788
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HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI --dependent manner. by Gong M, Wilson M, Kelly T, Su W, Dressman J, Kincer J, Matveev SV, Guo L, Guerin T, Li XA, Zhu W, Uittenbogaard A, Smart EJ.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155043
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Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. by Russell KS, Haynes MP, Sinha D, Clerisme E, Bender JR.; 2000 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18536
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Identification of a high-affinity binder for estradiol and a low-affinity binder for testosterone in Coccidioides immitis. by Powell BL, Drutz DJ.; 1984 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263368
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Identification of a large precursor of vitellogenin mRNA in the liver of estradioltreated chicks. by Jost JP, Pehling G, Ohno T, Cozens P.; 1978 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=342788
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In vitro adherence of Escherichia coli to endometrial epithelial cells of rats and influence of estradiol. by Nishikawa Y, Baba T.; 1985 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261983
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In vivo Estradiol-Dependent Dephosphorylation of the Repressor MDBP-2-H1 Correlates with the Loss of in vitro Preferential Binding to Methylated DNA. by Bruhat A, Jost J.; 1995 Apr 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42024
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Inhibitory effect of estradiol-17 beta and progesterone on bactericidal activity in uteri of rabbits infected with Escherichia coli. by Matsuda H, Okuda K, Fukui K, Kamata Y.; 1985 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261220
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Insulin-like growth factor 1 is required for G2 progression in the estradiol-induced mitotic cycle. by Adesanya OO, Zhou J, Samathanam C, Powell-Braxton L, Bondy CA.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15934
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Interaction of two nonhistone proteins with the estradiol response element of the avian vitellogenin gene modulates the binding of estradiol-receptor complex. by Feavers IM, Jiricny J, Moncharmont B, Saluz HP, Jost JP.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299314
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Isolation and characterization of three endosomal fractions from the liver of estradioltreated rats. by Belcher JD, Hamilton RL, Brady SE, Hornick CA, Jaeckle S, Schneider WJ, Havel RJ.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299169
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Isolation of a chromatin fraction from calf endometrium highly enriched in estradiol binding sites. by Sala-Trepat JM, Hibner U, Vallet-Strouve C.; 1977 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=342469
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Methylation of the chicken vitellogenin gene: influence of estradiol administration. by Meijlink FC, Philipsen JN, Gruber M, Ab G.; 1983 Mar 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325802
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O dealkylation and aliphatic and aromatic hydroxylation of 3-methoxy-17 betaestradiol by Aspergillus alliaceus. by Williamson JS, Van Orden DE, Rosazza JP.; 1989 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=203211
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Oestradiol-receptor complexes in subnuclear fractions of rat uterine tissue. by de Boer W, de Vries J, Mulder E, van der Molen HJ.; 1978 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=341963
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Opposite regulation of XIAP and Smac/DIABLO in the rat endometrium in response to 17[beta]-estradiol at estrus. by Leblanc V, Dery MC, Shooner C, Asselin E.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194660
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Pentagastrin-induced release of free fatty acids in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol. by Morrow JD, McManus K, Tait GR, Bellavance F, Chrapko W, Lara N, Le Melledo JM.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161733
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PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. by Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125704
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Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. by Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, Welshons WV.; 1997 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20042
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Rat strain-specific actions of 17[beta]-estradiol in the mammary gland: Correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogeninduced mammary cancers. by Harvell DM, Strecker TE, Tochacek M, Xie B, Pennington KL, McComb RD, Roy SK, Shull JD.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16006
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Reduction of post injury neointima formation due to 17[beta]-estradiol and phytoestrogen treatment is not influenced by the pure synthetic estrogen receptor antagonist ICI 182,780 in vitro. by Finking G, Lenz C, Schochat T, Hanke H.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119852
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Regulation of Akt expression and phosphorylation by 17[beta]-estradiol in the rat uterus during estrous cycle. by Dery MC, Leblanc V, Shooner C, Asselin E.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161822
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Regulation of ribonuclease expression by estradiol in Rana catesbeiana (Bullfrog). by Tang PC, Huang HC, Wang SC, Jeng JC, Liao YD.; 2002 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135762
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Specific effect of estradiol on the genital mucosal antibody response in chlamydial ocular and genital infections. by Rank RG, Barron AL.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260701
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Stimulation of oligonucleotide binding of estradiol receptor complexes by accessory proteins. by Thanki KH, Beach TA, Bass AI, Dickerman HW.; 1979 Aug 24; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=327983
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Stimulation of RNA polymerase I and II activities by 17 beta -estradiol receptor on chick liver chromatin. by Dierks-Ventling C, Bieri-Bonniot F.; 1977 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=342439
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Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. by Cooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Korach KS, Taylor J, Lubahn DB, Cunha GR.; 1997 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21085
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Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women. by Licinio J, Negrao AB, Mantzoros C, Kaklamani V, Wong ML, Bongiorno PB, Mulla A, Cearnal L, Veldhuis JD, Flier JS, McCann SM, Gold PW.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19406
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Synergistic action of glucocorticoid and estradiol responsive elements. by Ankenbauer W, Strahle U, Schutz G.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282224
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Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis. by Mukherjee TK, Dinh H, Chaudhuri G, Nathan L.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122647
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Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase. by Nathan L, Shi W, Dinh H, Mukherjee TK, Wang X, Lusis AJ, Chaudhuri G.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30697
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The AF-1 activation-function of ER[alpha] may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. by Pendaries C, Darblade B, Rochaix P, Krust A, Chambon P, Korach KS, Bayard F, Arnal JF.; 2002 Feb 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122343
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Transient administration of estradiol-17 beta establishes an autoregulatory loop permanently inducing estrogen receptor mRNA. by Barton MC, Shapiro DJ.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282135
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Unexpected responses of the hypothalamic gonadotropin-releasing hormone "pulse generator" to physiological estradiol inputs in the absence of the ovary. by Kesner JS, Wilson RC, Kaufman JM, Hotchkiss J, Chen Y, Yamamoto H, Pardo RR, Knobil E.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299623
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with estradiol, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “estradiol” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for estradiol (hyperlinks lead to article summaries): •
17 beta-estradiol- and 4-hydroxytamoxifen-induced transactivation in breast, endometrial and liver cancer cells is dependent on ER-subtype, cell and promoter context. Author(s): Castro-Rivera E, Safe S. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 January; 84(1): 23-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648521&dopt=Abstract
6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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17 beta-Oestradiol attenuates nucleotide excision repair. Author(s): Evans MD, Butler JM, Nicoll K, Cooke MS, Lunec J. Source: Febs Letters. 2003 January 30; 535(1-3): 153-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560095&dopt=Abstract
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17Beta-eEstradiol stimulates arachidonate release from human amnion-like WISH cells through a rapid mechanism involving a membrane receptor. Author(s): Fiorini S, Ferretti ME, Biondi C, Pavan B, Lunghi L, Paganetto G, Abelli L. Source: Endocrinology. 2003 August; 144(8): 3359-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865314&dopt=Abstract
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17beta-estradiol activates ICI 182,780-sensitive estrogen receptors and cyclic GMPdependent thioredoxin expression for neuroprotection. Author(s): Lee SY, Andoh T, Murphy DL, Chiueh CC. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 May; 17(8): 947-8. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12626428&dopt=Abstract
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17Beta-estradiol and anti-estrogen ICI:compound 182,780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdominal adipocytes. Author(s): Palin SL, McTernan PG, Anderson LA, Sturdee DW, Barnett AH, Kumar S. Source: Metabolism: Clinical and Experimental. 2003 April; 52(4): 383-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701046&dopt=Abstract
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17beta-estradiol and tamoxifen regulate a maxi-chloride channel from human placenta. Author(s): Henriquez M, Riquelme G. Source: The Journal of Membrane Biology. 2003 January 1; 191(1): 59-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532277&dopt=Abstract
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17beta-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphatedependent protein kinase pathway. Author(s): Babiker FA, De Windt LJ, van Eickels M, Thijssen V, Bronsaer RJ, Grohe C, van Bilsen M, Doevendans PA. Source: Circulation. 2004 January 20; 109(2): 269-76. Epub 2004 Jan 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718400&dopt=Abstract
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17beta-estradiol downregulates beta3-integrin expression in differentiating and mature human osteoclasts. Author(s): Saintier D, Burde MA, Rey JM, Maudelonde T, de Vernejoul MC, Cohen-Solal ME. Source: Journal of Cellular Physiology. 2004 February; 198(2): 269-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14603529&dopt=Abstract
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17Beta-estradiol enhances the production of nerve growth factor in THP-1-derived macrophages or peripheral blood monocyte-derived macrophages. Author(s): Kanda N, Watanabe S. Source: The Journal of Investigative Dermatology. 2003 October; 121(4): 771-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14632195&dopt=Abstract
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17Beta-estradiol epoxidation as the molecular basis for breast cancer initiation and prevention. Author(s): Yu FL. Source: Asia Pacific Journal of Clinical Nutrition. 2002; 11 Suppl 7: S460-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492635&dopt=Abstract
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17Beta-estradiol inhibits MCP-1 production in human keratinocytes. Author(s): Kanda N, Watanabe S. Source: The Journal of Investigative Dermatology. 2003 June; 120(6): 1058-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12787135&dopt=Abstract
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17beta-estradiol inhibits NADPH oxidase activity through the regulation of p47phox mRNA and protein expression in THP-1 cells. Author(s): Sumi D, Hayashi T, Matsui-Hirai H, Jacobs AT, Ignarro LJ, Iguchi A. Source: Biochimica Et Biophysica Acta. 2003 May 12; 1640(2-3): 113-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729920&dopt=Abstract
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17beta-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. Author(s): Kanda N, Watanabe S. Source: The Journal of Investigative Dermatology. 2003 December; 121(6): 1500-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14675202&dopt=Abstract
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17beta-estradiol inhibits the production of interferon-induced protein of 10 kDa by human keratinocytes. Author(s): Kanda N, Watanabe S. Source: The Journal of Investigative Dermatology. 2003 March; 120(3): 411-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603854&dopt=Abstract
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17beta-estradiol inhibits the production of RANTES in human keratinocytes. Author(s): Kanda N, Watanabe S. Source: The Journal of Investigative Dermatology. 2003 March; 120(3): 420-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603855&dopt=Abstract
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17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality. Author(s): Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, Eckhoff DE. Source: Transplantation. 2002 November 15; 74(9): 1252-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12451262&dopt=Abstract
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17beta-estradiol reduces plasma Abeta40 for HRT-naive postmenopausal women with Alzheimer disease: a preliminary study. Author(s): Baker LD, Sambamurti K, Craft S, Cherrier M, Raskind MA, Stanczyk FZ, Plymate SR, Asthana S. Source: The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry. 2003 March-April; 11(2): 239-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12611754&dopt=Abstract
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17-epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting vascular cell adhesion molecule 1 (VCAM-1) mRNA expression. Author(s): Mukherjee TK, Nathan L, Dinh H, Reddy ST, Chaudhuri G. Source: The Journal of Biological Chemistry. 2003 April 4; 278(14): 11746-52. Epub 2003 January 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547825&dopt=Abstract
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2-methoxyestradiol alters cell motility, migration, and adhesion. Author(s): Sattler M, Quinnan LR, Pride YB, Gramlich JL, Chu SC, Even GC, Kraeft SK, Chen LB, Salgia R. Source: Blood. 2003 July 1; 102(1): 289-96. Epub 2003 March 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637335&dopt=Abstract
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2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production. Author(s): Djavaheri-Mergny M, Wietzerbin J, Besancon F. Source: Oncogene. 2003 May 1; 22(17): 2558-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730670&dopt=Abstract
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2-Methoxyestradiol interferes with NF kappa B transcriptional activity in primitive neuroectodermal brain tumors: implications for management. Author(s): Kumar AP, Garcia GE, Orsborn J, Levin VA, Slaga TJ. Source: Carcinogenesis. 2003 February; 24(2): 209-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584169&dopt=Abstract
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2-methoxyestradiol strongly inhibits human uterine sarcomatous cell growth. Author(s): Amant F, Lottering ML, Joubert A, Thaver V, Vergote I, Lindeque BG. Source: Gynecologic Oncology. 2003 November; 91(2): 299-308. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599859&dopt=Abstract
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2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. Author(s): LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS. Source: Cancer Research. 2003 January 15; 63(2): 468-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543804&dopt=Abstract
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2-Methoxyestradiol, a promising anticancer agent. Author(s): Lakhani NJ, Sarkar MA, Venitz J, Figg WD. Source: Pharmacotherapy. 2003 February; 23(2): 165-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587805&dopt=Abstract
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A 13-month multicenter clinical experience of a low-dose monophasic oral contraceptive containing 20 microg ethinylestradiol and 75 microg gestodene in Latin American women. Author(s): Bassol S, Alvarado G, Arreola RG, Celis-Gonzalez C, Pena EP, Flores JG, Ahued JR, Ricalde RL, Lopez CR, Prieto G, Gurucharri C, Heredia MG, Ortiz OC, Percossi G, Figueroa Casas PR, Botto E, Tozzini RI, Botti G, Nunez de Pierro A, Fernandez M, Lastreto E, Nanez M, Carneiro de Oliveira H, Diogenes Holanda Yazlle ME, Silva J, Salazar G, Gomez J, Penagos G, Cifuentes R, Torres LA, Reyes-Marquez R, Albrecht G. Source: Contraception. 2003 May; 67(5): 367-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742559&dopt=Abstract
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A comparative study of the effects of gestodene 60 microg/ethinylestradiol 15 microg and desogestrel 150 microg/ethinylestradiol 20 microg on hemostatic balance, blood lipid levels and carbohydrate metabolism. Author(s): van der Mooren MJ, Klipping C, van Aken B, Helmerhorst E, Spielmann D, Kluft C. Source: The European Journal of Contraception & Reproductive Health Care : the Official Journal of the European Society of Contraception. 1999 November; 4 Suppl 2: 2735. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14677622&dopt=Abstract
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A double-blind placebo-controlled trial on the effects of 25 mg estradiol implants on the urge syndrome in postmenopausal women. Author(s): Rufford J, Hextall A, Cardozo L, Khullar V. Source: International Urogynecology Journal and Pelvic Floor Dysfunction. 2003 June; 14(2): 78-83. Epub 2003 April 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851747&dopt=Abstract
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A facile synthesis of C(2)-symmetric 17 beta-estradiol dimers. Author(s): Rabouin D, Perron V, N'Zemba B, C-Gaudreault R, Berube G. Source: Bioorganic & Medicinal Chemistry Letters. 2003 February 10; 13(3): 557-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12565971&dopt=Abstract
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A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate. Author(s): Neven P, Lunde T, Benedetti-Panici P, Tiitinen A, Marinescu B, de Villiers T, Hillard T, Cano A, Peer E, Quail D, Nickelsen T; Eurolox 1 Study Group. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2003 February; 110(2): 157-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618160&dopt=Abstract
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A prospective, randomized, placebo-controlled study of the dose effect of oral estradiol on bone mineral density in postmenopausal Chinese women. Author(s): Haines CJ, Yim SF, Chung TK, Lam CW, Lau EW, Ng MH, Chin R, Lee DT. Source: Maturitas. 2003 July 25; 45(3): 169-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818461&dopt=Abstract
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A prospective, randomized, placebo-controlled study of the dose effect of oral oestradiol on menopausal symptoms, psychological well being, and quality of life in postmenopausal Chinese women. Author(s): Haines CJ, Yim SF, Chung TK, Lam CW, Lau EW, Ng MH, Chin R, Lee DT. Source: Maturitas. 2003 March 28; 44(3): 207-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648884&dopt=Abstract
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A randomized placebo-controlled study of the effect of transdermal vs. oral estradiol with or without gestodene on homocysteine levels. Author(s): Smolders RG, van der Mooren MJ, Teerlink T, Merkus JM, Kroeks MV, Franke HR, Stehouwer CD, Kenemans P. Source: Fertility and Sterility. 2003 February; 79(2): 261-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568832&dopt=Abstract
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A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism. Author(s): Gaspard U, Scheen A, Endrikat J, Buicu C, Lefebvre P, Gerlinger C, Heithecker R. Source: Contraception. 2003 June; 67(6): 423-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814810&dopt=Abstract
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A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone. Author(s): Portman DJ, Symons JP, Wilborn W, Kempfert NJ. Source: American Journal of Obstetrics and Gynecology. 2003 February; 188(2): 334-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12592236&dopt=Abstract
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Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation. Author(s): Tengstrand B, Carlstrom K, Fellander-Tsai L, Hafstrom I. Source: The Journal of Rheumatology. 2003 November; 30(11): 2338-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14677174&dopt=Abstract
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Absolute and attributable risk of venous thromboembolism in women on combined cyproterone acetate and ethinylestradiol. Author(s): Lidegaard O. Source: J Obstet Gynaecol Can. 2003 July; 25(7): 575-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851669&dopt=Abstract
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Adolescents' attitudes and experiences regarding levonorgestrel 100 mcg/ethinyl estradiol 20 mcg. Author(s): Rosenthal SL, Cotton S, Ready JN, Potter LS, Succop PA. Source: Journal of Pediatric and Adolescent Gynecology. 2002 December; 15(5): 301-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547661&dopt=Abstract
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An open-label study of the effects of a 24-day regimen of gestodene 60 microg/ethinylestradiol 15 microg on endometrial histological findings in healthy women. Author(s): Oosterbaan HP. Source: The European Journal of Contraception & Reproductive Health Care : the Official Journal of the European Society of Contraception. 1999 November; 4 Suppl 2: 38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14677619&dopt=Abstract
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Apoptotic action of 17beta-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo. Author(s): Liu H, Lee ES, Gajdos C, Pearce ST, Chen B, Osipo C, Loweth J, McKian K, De Los Reyes A, Wing L, Jordan VC. Source: Journal of the National Cancer Institute. 2003 November 5; 95(21): 1586-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14600091&dopt=Abstract
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Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females. Author(s): Kristiansen OP, Nolsoe RL, Larsen L, Gjesing AM, Johannesen J, Larsen ZM, Lykkesfeldt AE, Karlsen AE, Pociot F, Mandrup-Poulsen T; DIEGG; DSGD. Source: Human Molecular Genetics. 2003 May 15; 12(10): 1101-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719374&dopt=Abstract
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Association of CYP17 genetic polymorphism with intra-tumoral estradiol concentrations but not with CYP17 messenger RNA levels in breast cancer tissue. Author(s): Miyoshi Y, Ando A, Ooka M, Shiba E, Taguchi T, Tamaki Y, Noguchi S. Source: Cancer Letters. 2003 May 30; 195(1): 81-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767515&dopt=Abstract
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Association of DHEA-S and estradiol serum levels to symptoms of aging men. Author(s): Ponholzer A, Plas E, Schatzl G, Jungwirth A, Madersbacher S; Austrian Society of Urology. Source: The Aging Male : the Official Journal of the International Society for the Study of the Aging Male. 2002 December; 5(4): 233-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630070&dopt=Abstract
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Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. Author(s): Van Pottelbergh I, Goemaere S, Kaufman JM. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3075-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843146&dopt=Abstract
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Biosynthesis of MUC1 mucin in human endometrial adenocarcinoma is modulated by estradiol and tamoxifen. Author(s): Paszkiewicz-Gadek A, Porowska H, Anchim T, Wolczynski S, Gindzienski A. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 February; 17(1): 37-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724017&dopt=Abstract
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Biphasic effects of 17-beta-estradiol on expression of occludin and transendothelial resistance and paracellular permeability in human vascular endothelial cells. Author(s): Ye L, Martin TA, Parr C, Harrison GM, Mansel RE, Jiang WG. Source: Journal of Cellular Physiology. 2003 August; 196(2): 362-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811830&dopt=Abstract
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Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone. Author(s): von Holst T, Lang E, Winkler U, Keil D. Source: Maturitas. 2002 December 10; 43(4): 265-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468135&dopt=Abstract
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Bone mineral density in systemic lupus erythematosus and its relation to age at disease onset, plasmatic estradiol and immunosuppressive therapy. Author(s): Coimbra IB, Costallat LT. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2003 February; 70(1): 40-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639616&dopt=Abstract
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Catecholamines block the antimitogenic effect of estradiol on human glomerular mesangial cells. Author(s): Dubey RK, Zacharia LC, Gillespie DG, Imthurn B, Jackson EK. Source: Hypertension. 2003 September; 42(3): 349-55. Epub 2003 August 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12913061&dopt=Abstract
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Cell context-dependent differences in the induction of E2F-1 gene expression by 17 beta-estradiol in MCF-7 and ZR-75 cells. Author(s): Ngwenya S, Safe S. Source: Endocrinology. 2003 May; 144(5): 1675-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697671&dopt=Abstract
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Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? Author(s): Ghosh R, Ott AM, Seetharam D, Slaga TJ, Kumar AP. Source: Melanoma Research. 2003 April; 13(2): 119-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690294&dopt=Abstract
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Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Author(s): Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Source: Endocrinology. 2003 August; 144(8): 3382-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865317&dopt=Abstract
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Clinical comparative study of oral contraceptives containing 30 microg ethinylestradiol/150 microg levonorgestrel, and 35 microg ethinylestradiol/250 microg norgestimate in Thai women. Author(s): Tantbirojn P, Taneepanichskul S. Source: Contraception. 2002 December; 66(6): 401-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499031&dopt=Abstract
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Clinical efficacy and safety of combined estradiol valerate and dienogest: a new nobleed treatment. Author(s): von Schoultz B. Source: Climacteric : the Journal of the International Menopause Society. 2003 August; 6 Suppl 2: 24-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14669841&dopt=Abstract
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Clinical evidence of the endocrinological influence of a triphasic oral contraceptive containing norgestimate and ethinyl estradiol in treating women with acne vulgaris. A pilot study. Author(s): Sator PG, Schmidt JB, Honigsmann H. Source: Dermatology (Basel, Switzerland). 2003; 206(3): 241-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12673082&dopt=Abstract
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Clinical findings with the oral contraceptive combination ethinylestradiol/dienogest in Poland. Author(s): Golbs S, Domhardt R, Radowicky S, Kaluzny Z, Wisser KH, Zimmermann T. Source: Methods Find Exp Clin Pharmacol. 2002 November; 24(9): 585-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616705&dopt=Abstract
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Clinical significance of nuclear matrix-estradiol receptor complex in human sperm. Author(s): Gonzalez-Unzaga M, Tellez J, Calzada L. Source: Archives of Andrology. 2003 January-February; 49(1): 77-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12647781&dopt=Abstract
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Combination therapy of ethinylestradiol and somatostatin analogue reintroduces objective clinical responses and decreases chromogranin a in patients with androgen ablation refractory prostate cancer. Author(s): Di Silverio F, Sciarra A. Source: The Journal of Urology. 2003 November; 170(5): 1812-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532782&dopt=Abstract
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Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms. Author(s): Al-Azzawi F, Buckler HM; United Kingdom Vaginal Ring Investigator Group. Source: Climacteric : the Journal of the International Menopause Society. 2003 June; 6(2): 118-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841882&dopt=Abstract
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Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens. Author(s): Fanchin R, Cunha-Filho JS, Schonauer LM, Kadoch IJ, Cohen-Bacri P, Frydman R. Source: Fertility and Sterility. 2003 February; 79(2): 316-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568840&dopt=Abstract
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Cycle control, tolerability, and satisfaction among women switching from 30-35 microg ethinyl estradiol-containing oral contraceptives to the triphasic norgestimate/25 microg ethinyl estradiol-containing oral contraceptive Ortho TriCyclen LO. Author(s): Poindexter AN, Burkman R, Fisher AC, LaGuardia KD. Source: Int J Fertil Womens Med. 2003 July-August; 48(4): 163-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13677549&dopt=Abstract
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CYP450- and COMT-derived estradiol metabolites inhibit activity of human coronary artery SMCs. Author(s): Dubey RK, Gillespie DG, Zacharia LC, Barchiesi F, Imthurn B, Jackson EK. Source: Hypertension. 2003 March; 41(3 Pt 2): 807-13. Epub 2002 December 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624000&dopt=Abstract
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Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation. Author(s): Spitzer WO. Source: J Obstet Gynaecol Can. 2003 December; 25(12): 1011-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14663535&dopt=Abstract
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Differential contribution of testosterone and estradiol in the determination of cholesterol and lipoprotein profile in healthy middle-aged men. Author(s): Van Pottelbergh I, Braeckman L, De Bacquer D, De Backer G, Kaufman JM. Source: Atherosclerosis. 2003 January; 166(1): 95-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482555&dopt=Abstract
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Differential effects of oral and transdermal estradiol treatment on circulating estradiol fatty acid ester concentrations in postmenopausal women. Author(s): Vihma V, Vehkavaara S, Yki-Jarvinen H, Hohtari H, Tikkanen MJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 February; 88(2): 588-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574185&dopt=Abstract
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Differential p53 protein expression level in human cancer-derived cell lines after estradiol treatment. Author(s): Correa I, Cerbon MA, Salazar AM, Solano JD, Garcia-Carranca A, Quintero A. Source: Archives of Medical Research. 2002 September-October; 33(5): 455-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12459315&dopt=Abstract
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Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptorestrogen response element by beta-estradiol and 4-hydroxytamoxifen in human breast cancer. Author(s): Fleming FJ, Hill AD, McDermott EW, O'Higgins NJ, Young LS. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 37583. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715875&dopt=Abstract
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Diurnal rhythm of free estradiol during the menstrual cycle. Author(s): Bao AM, Liu RY, van Someren EJ, Hofman MA, Cao YX, Zhou JN. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 February; 148(2): 227-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12590642&dopt=Abstract
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Do basal oestradiol and oestradiol:androgens and oestradiol:FSH ratios reflect pregnancy potential of women receiving intrauterine insemination during natural cycles? Author(s): Fukuda M, Fukuda K, Yding Andersen C, Byskov AG. Source: Reproductive Biomedicine Online. 2003 June; 6(4): 452-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831593&dopt=Abstract
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Dose-dependent inhibition of mitochondrial ATP synthase by 17 beta-estradiol. Author(s): Massart F, Paolini S, Piscitelli E, Brandi ML, Solaini G. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2002 October; 16(5): 373-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587531&dopt=Abstract
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Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis. Author(s): Zegura B, Keber I, Sebestjen M, Koenig W. Source: Atherosclerosis. 2003 May; 168(1): 123-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732395&dopt=Abstract
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Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. Author(s): Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M, Clyne CD, Davis S, Simpson ER, Carani C. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 6170. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715828&dopt=Abstract
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Economic evaluation of norethisterone acetate/ethinylestradiol (FemHRT) for women with menopausal symptoms. Author(s): Coyle D, Cranney A, Tugwell P. Source: Pharmacoeconomics. 2003; 21(9): 661-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807367&dopt=Abstract
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Effect of 17 beta-estradiol on soluble P-selectin in coronary artery bypass grafting. Author(s): Wei M, Laurikka J, Kuukasjarvi P, Pehkonen E, Laine S, Tarkka M. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2003 January; 17(1): 93-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916519&dopt=Abstract
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Effect of an oral contraceptive containing ethinyl estradiol and drospirenone on premenstrual symptomatology and health-related quality of life. Author(s): Borenstein J, Yu HT, Wade S, Chiou CF, Rapkin A. Source: J Reprod Med. 2003 February; 48(2): 79-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621790&dopt=Abstract
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Effect of estradiol administration on splanchnic perfusion after trauma-hemorrhage and sepsis. Author(s): Yokoyama Y, Schwacha MG, Bland KI, Chaudry IH. Source: Current Opinion in Critical Care. 2003 April; 9(2): 137-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657977&dopt=Abstract
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Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Author(s): Stoica GE, Franke TF, Moroni M, Mueller S, Morgan E, Iann MC, Winder AD, Reiter R, Wellstein A, Martin MB, Stoica A. Source: Oncogene. 2003 September 11; 22(39): 7998-8011. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970748&dopt=Abstract
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Effect of frying-meat emission particulate on 17beta-estradiol 2- and 4-hydroxylation in human lung adenocarcinoma CL5 cells. Author(s): Wang HW, Ueng TH, Chen TL, Yang PC. Source: Journal of Toxicology and Environmental Health. Part A. 2003 June 27; 66(12): 1175-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791542&dopt=Abstract
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Effect of long-term continuous combined hormone replacement therapy with estradiol valerate and either dienogest or norethisterone acetate on mammographic density in postmenopausal women. Author(s): Georgiev DB, Manassiev NA. Source: Medscape Women's Health [electronic Resource]. 2002 July-August; 7(4): 1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466733&dopt=Abstract
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Effect of menstrual cycle phase on the concentration of bioavailable 17-beta oestradiol and testosterone and muscle strength. Author(s): Elliott KJ, Cable NT, Reilly T, Diver MJ. Source: Clinical Science (London, England : 1979). 2003 December; 105(6): 663-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848619&dopt=Abstract
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Effect of raloxifene, 17beta-estradiol, and progesterone on mRNA for vascular endothelial growth factor isoforms 121 and 165 and thrombospondin-1 in Ishikawa cells. Author(s): Navarro FJ, Mirkin S, Archer DF. Source: Fertility and Sterility. 2003 June; 79(6): 1409-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798890&dopt=Abstract
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Effect of statins combined with estradiol on the proliferation of human receptorpositive and receptor-negative breast cancer cells. Author(s): Mueck AO, Seeger H, Wallwiener D. Source: Menopause (New York, N.Y.). 2003 July-August; 10(4): 332-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851516&dopt=Abstract
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Effect of tamoxifen and 2-methoxyestradiol alone and in combination on human breast cancer cell proliferation. Author(s): Seeger H, Diesing D, Guckel B, Wallwiener D, Mueck AO, Huober J. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 255-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711011&dopt=Abstract
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Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Author(s): Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M. Source: Epilepsia. 2003 April; 44(4): 540-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12681003&dopt=Abstract
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Effect of transdermal estradiol and oral conjugated equine estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Author(s): Wakatsuki A, Okatani Y, Fukaya T. Source: Circulation. 2003 May 13; 107(18): E127-8; Author Reply E127-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742976&dopt=Abstract
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Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea. Author(s): Grinspoon SK, Friedman AJ, Miller KK, Lippman J, Olson WH, Warren MP. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3651-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915650&dopt=Abstract
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Effects of bilateral ovariectomy and postoperative hormonal replacement therapy with 17beta-estradiol or raloxifene on serum leptin levels. Author(s): Tommaselli GA, Di Carlo C, Nasti A, Giordano E, Pisano G, Pellicano M, Bifulco G, Nappi C. Source: Menopause (New York, N.Y.). 2003 March-April; 10(2): 160-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627042&dopt=Abstract
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Effects of estradiol and tamoxifen on proliferation of human breast cancer cells and human endometrial cells. Author(s): Zhang B, Chen D, Wang G, Wu Y. Source: J Huazhong Univ Sci Technolog Med Sci. 2003; 23(3): 283-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526435&dopt=Abstract
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Effects of low-dose 17-beta-estradiol plus norethisterone acetate and tibolone on fasting plasma homocysteine levels in postmenopausal women. Author(s): Kaleli B, Yildirim B, Demir S, Alatas E. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 December; 82(12): 1107-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616255&dopt=Abstract
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Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women. Author(s): Gambacciani M, Ciaponi M, Cappagli B, Monteleone P, Benussi C, Bevilacqua G, Genazzani AR. Source: Maturitas. 2003 February 25; 44(2): 157-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12590012&dopt=Abstract
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Effects of oral androstenedione administration on serum testosterone and estradiol levels in postmenopausal women. Author(s): Leder BZ, Leblanc KM, Longcope C, Lee H, Catlin DH, Finkelstein JS. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 December; 87(12): 5449-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466335&dopt=Abstract
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Effects of vaginally administered high estradiol doses on hormonal pharmacokinetics and hemostasis in postmenopausal women. Author(s): Hall G, Blomback M, Landgren BM, Bremme K. Source: Fertility and Sterility. 2002 December; 78(6): 1172-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477507&dopt=Abstract
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Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Author(s): Speroff L. Source: Obstetrics and Gynecology. 2003 October; 102(4): 823-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551014&dopt=Abstract
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Efficacy, safety and acceptability of a seven-day, transdermal estradiol patch for estrogen replacement therapy. Author(s): Jarupanich T, Lamlertkittikul S, Chandeying V. Source: J Med Assoc Thai. 2003 September; 86(9): 836-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14649968&dopt=Abstract
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Efficacy, safety and cycle control of five oral contraceptive regimens containing norgestimate and ethinyl estradiol. Author(s): LaGuardia KD, Shangold G, Fisher A, Friedman A, Kafrissen M. Source: Contraception. 2003 June; 67(6): 431-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814811&dopt=Abstract
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Elevated progesterone: estradiol ratio--another test of ovarian reserve? Author(s): Younis JS. Source: Fertility and Sterility. 2003 September; 80(3): 679; Author Reply 679-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12969737&dopt=Abstract
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Elevated serum estradiol suggesting recurrence of Leydig cell tumor nine years after radical orchiectomy. Author(s): Maeda T, Itoh N, Kobayashi K, Takahashi A, Masumori N, Tsukamoto T. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. 2002 November; 9(11): 659-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534915&dopt=Abstract
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Endogenous estradiol and risk of dementia in women and men: the Rotterdam Study. Author(s): Geerlings MI, Launer LJ, de Jong FH, Ruitenberg A, Stijnen T, van Swieten JC, Hofman A, Witteman JC, Pols HA, Breteler MM; Rotterdam Study. Source: Annals of Neurology. 2003 May; 53(5): 607-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730994&dopt=Abstract
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Endogenous estradiol metabolites stimulate the in vitro proliferation of human osteoblastic cells. Author(s): Seeger H, Hadji P, Mueck AO. Source: Int J Clin Pharmacol Ther. 2003 April; 41(4): 148-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708603&dopt=Abstract
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Endothelin-1 and nitric oxide levels are related to cardiovascular risk factors but are not modified by estradiol replacement in healthy postmenopausal women. A crosssectional and a randomized cross-over study. Author(s): Cagnacci A, Tarquini R, Perfetto F, Arangino S, Zanni AL, Cagnacci P, Facchinetti F, Volpe A. Source: Maturitas. 2003 February 25; 44(2): 117-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12590007&dopt=Abstract
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Enhancing effect of temperature on the transmucosal penetration kinetics of 17 betaestradiol. Author(s): van der Bijl P, van Eyk AD, van der Bijl P, Kriel J. Source: Sadj. 2003 April; 58(3): 95-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856400&dopt=Abstract
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Estradiol and interleukin-1beta exert a synergistic stimulatory effect on the expression of the chemokine regulated upon activation, normal T cell expressed, and secreted in endometriotic cells. Author(s): Akoum A, Lemay A, Maheux R. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 December; 87(12): 5785-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466387&dopt=Abstract
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Estradiol binding to maxi-K channels induces their down-regulation via proteasomal degradation. Author(s): Korovkina VP, Brainard AM, Ismail P, Schmidt TJ, England SK. Source: The Journal of Biological Chemistry. 2004 January 9; 279(2): 1217-23. Epub 2003 October 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555652&dopt=Abstract
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Estradiol effects on the growth hormone/insulin-like growth factor-1 axis in amenorrheic athletes. Author(s): Waters DL, Dorin RI, Qualls CR, Ruby BC, Baumgartner RN, Robergs RA. Source: Canadian Journal of Applied Physiology = Revue Canadienne De Physiologie Appliquee. 2003 February; 28(1): 64-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671196&dopt=Abstract
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Estradiol enhances osteolytic lesions in mice inoculated with human estrogen receptor-negative MDA-231 breast cancer cells in vivo. Author(s): Winding B, Misander H, Hoegh-Andersen P, Brunner N, Foged NT. Source: Breast Cancer Research and Treatment. 2003 March; 78(2): 205-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725420&dopt=Abstract
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Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury. Author(s): Nunez JL, McCarthy MM. Source: Endocrinology. 2003 June; 144(6): 2350-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746295&dopt=Abstract
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Estradiol exerts neuroprotective actions against ischemic brain injury: insights derived from animal models. Author(s): Wise P. Source: Endocrine. 2003 June; 21(1): 11-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777698&dopt=Abstract
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Estradiol in premenstrual asthma: a double-blind, randomized, placebo-controlled, crossover study. Author(s): Ensom MH, Chong G, Zhou D, Beaudin B, Shalansky S, Bai TR. Source: Pharmacotherapy. 2003 May; 23(5): 561-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12741429&dopt=Abstract
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Estradiol in severe asthma with premenstrual worsening. Author(s): Ensom MH, Chong G, Beaudin B, Bai TR. Source: The Annals of Pharmacotherapy. 2003 November; 37(11): 1610-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14565797&dopt=Abstract
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Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer. Author(s): Dabrosin C, Margetts PJ, Gauldie J. Source: International Journal of Cancer. Journal International Du Cancer. 2003 November 20; 107(4): 535-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520689&dopt=Abstract
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Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay. Author(s): Wilson CA, Heinrichs C, Larmore KA, Craen M, Brown-Dawson J, Shaywitz S, Ross J, Klein KO. Source: J Pediatr Endocrinol Metab. 2003 January; 16(1): 91-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12585345&dopt=Abstract
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Estradiol selectively affects processing of conspecifics' faces in female rhesus monkeys. Author(s): Lacreuse A, Herndon JG. Source: Psychoneuroendocrinology. 2003 October; 28(7): 885-905. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892656&dopt=Abstract
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Estradiol stabilizes p53 protein in breast cancer cell line, MCF-7. Author(s): Okumura N, Saji S, Eguchi H, Hayashi S, Saji S, Nakashima S. Source: Japanese Journal of Cancer Research : Gann. 2002 August; 93(8): 867-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716463&dopt=Abstract
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Estradiol stimulates expression of two human prolactin receptor isoforms with alternative exons-1 in T47D breast cancer cells. Author(s): Leondires MP, Hu ZZ, Dong J, Tsai-Morris CH, Dufau ML. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 October; 82(23): 263-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477494&dopt=Abstract
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Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu. Author(s): Veldhuis JD, Evans WS, Bowers CY. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5484-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602794&dopt=Abstract
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Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. Author(s): Veldhuis JD, Anderson SM, Patrie JT, Bowers CY. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 1217. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715838&dopt=Abstract
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Estradiol treatment redirects the isotype of the autoantibody response and prevents the development of autoimmune arthritis. Author(s): Latham KA, Zamora A, Drought H, Subramanian S, Matejuk A, Offner H, Rosloniec EF. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 December 1; 171(11): 58207. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14634091&dopt=Abstract
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Estradiol/progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal women. Author(s): Hamada AL, Maruo T, Samoto T, Yoshida S, Nash H, Spitz IM, Johansson E. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 June; 17(3): 247-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857433&dopt=Abstract
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Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway. Author(s): Sengupta K, Banerjee S, Saxena N, Banerjee SK. Source: International Journal of Oncology. 2003 March; 22(3): 609-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12579315&dopt=Abstract
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Estrogen receptor/Sp1 complexes are required for induction of cad gene expression by 17beta-estradiol in breast cancer cells. Author(s): Khan S, Abdelrahim M, Samudio I, Safe S. Source: Endocrinology. 2003 June; 144(6): 2325-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746293&dopt=Abstract
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Estrogen receptor-alpha mediates the brain antiinflammatory activity of estradiol. Author(s): Vegeto E, Belcredito S, Etteri S, Ghisletti S, Brusadelli A, Meda C, Krust A, Dupont S, Ciana P, Chambon P, Maggi A. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 August 5; 100(16): 9614-9. Epub 2003 July 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878732&dopt=Abstract
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Exogenous steroid substrate modifies the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estradiol production of human luteinized granulosa cells in vitro. Author(s): Moran FM, Lohstroh P, VandeVoort CA, Chen J, Overstreet JW, Conley AJ, Lasley BL. Source: Biology of Reproduction. 2003 January; 68(1): 244-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493720&dopt=Abstract
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Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy. Author(s): Kolibianakis EM, Albano C, Kahn J, Camus M, Tournaye H, Van Steirteghem AC, Devroey P. Source: Fertility and Sterility. 2003 April; 79(4): 873-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749423&dopt=Abstract
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Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta-estradiol in MCF-7 cells. Author(s): Katoh M. Source: International Journal of Oncology. 2003 January; 22(1): 209-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12469206&dopt=Abstract
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Follicular growth, endometrial thickness, and serum estradiol levels in spontaneous and clomiphene citrate-induced cycles. Author(s): Haritha S, Rajagopalan G. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2003 June; 81(3): 287-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767571&dopt=Abstract
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Formation of estrone and estradiol from estrone sulfate by normal breast parenchymal tissue. Author(s): Chatterton RT Jr, Geiger AS, Gann PH, Khan SA. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 August; 86(2): 159-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568567&dopt=Abstract
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Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. Author(s): Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 477-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623547&dopt=Abstract
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Growth effects of raloxifene, estradiol, medroxy-progesterone acetate, and progesterone on human endometrial adenocarcinoma cells. Author(s): Boostanfar R, Amezcua CA, Tourgeman DE, Roy S, Felix JC, Stanczyk FZ. Source: Fertility and Sterility. 2003 January; 79(1): 223-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524096&dopt=Abstract
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Growth hormone, IGF-1, insulin, SHBG, and estradiol levels in girls before menarche. Author(s): Blogowska A, Rzepka-Gorska I, Krzyzanowska-Swiniarska B. Source: Archives of Gynecology and Obstetrics. 2003 October; 268(4): 293-6. Epub 2002 October 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504872&dopt=Abstract
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Growth inhibition of multi-drug-resistant breast cancer cells by 2-methoxyoestradiolbis-sulphamate and 2-ethyloestradiol-bis-sulphamate. Author(s): Suzuki RN, Newman SP, Purohit A, Leese MP, Potter BV, Reed MJ. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 269-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711013&dopt=Abstract
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HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. Author(s): Gong M, Wilson M, Kelly T, Su W, Dressman J, Kincer J, Matveev SV, Guo L, Guerin T, Li XA, Zhu W, Uittenbogaard A, Smart EJ. Source: The Journal of Clinical Investigation. 2003 May; 111(10): 1579-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750408&dopt=Abstract
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Human catechol-O-methyltransferase down-regulation by estradiol. Author(s): Jiang H, Xie T, Ramsden DB, Ho SL. Source: Neuropharmacology. 2003 December; 45(7): 1011-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14573393&dopt=Abstract
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Human chorionic gonadotropin and 17-beta estradiol regulation of human oviductin/oviduct specific glycoprotein mRNA expression in vitro. Author(s): Briton-Jones C, Lok IH, Chiu TT, Cheung LP, Haines C. Source: Fertility and Sterility. 2003 September; 80 Suppl 2: 720-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14505745&dopt=Abstract
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Human chorionic gonadotropin combined with progesterone for luteal support improves pregnancy rate in patients with low late-midluteal estradiol levels in IVF cycles. Author(s): Fujimoto A, Osuga Y, Fujiwara T, Yano T, Tsutsumi O, Momoeda M, Kugu K, Koga K, Morita Y, Wada O, Taketani Y. Source: Journal of Assisted Reproduction and Genetics. 2002 December; 19(12): 550-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503886&dopt=Abstract
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Human cytochrome P450 3A7 has a distinct high catalytic activity for the 16alphahydroxylation of estrone but not 17beta-estradiol. Author(s): Lee AJ, Conney AH, Zhu BT. Source: Cancer Research. 2003 October 1; 63(19): 6532-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14559847&dopt=Abstract
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Hypoxia and estrogen receptor profile influence the responsiveness of human breast cancer cells to estradiol and antiestrogens. Author(s): Coradini D, Pellizzaro C, Speranza A, Daidone MG. Source: Cellular and Molecular Life Sciences : Cmls. 2004 January; 61(1): 76-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14704855&dopt=Abstract
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Identification by MALDI-TOF mass spectrometry of 17 alphabromoacetamidopropylestradiol covalent attachment sites on estrogen receptor alpha. Author(s): Mattras H, Aliau S, Richard E, Bonnafous JC, Jouin P, Borgna JL. Source: Biochemistry. 2002 December 31; 41(52): 15713-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501200&dopt=Abstract
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Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis. Author(s): Basu A, Haldar S. Source: Febs Letters. 2003 March 13; 538(1-3): 41-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633850&dopt=Abstract
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Immunoassay of estradiol: unanticipated suppression by unconjugated estriol. Author(s): Cao Z, Swift TA, West CA, Rosano TG, Rej R. Source: Clinical Chemistry. 2004 January; 50(1): 160-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14709643&dopt=Abstract
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In vitro effects of estradiol, dydrogesterone, tamoxifen and cyclophosphamide on proliferation vs. death in human breast cancer cells. Author(s): Franke HR, Kole S, Ciftci Z, Haanen C, Vermes I. Source: Cancer Letters. 2003 February 10; 190(1): 113-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536084&dopt=Abstract
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Increased cell proliferation is associated with genomic instability: elevated micronuclei frequencies in estradiol-treated human ovarian cancer cells. Author(s): Stopper H, Schmitt E, Gregor C, Mueller SO, Fischer WH. Source: Mutagenesis. 2003 May; 18(3): 243-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714689&dopt=Abstract
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Influence of ethinyloestradiol propanolsulphonate on serum bile acids in healthy volunteers. Author(s): Barth A, Klinger G, Rost M. Source: Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Fur Toxikologische Pathologie. 2003 June; 54(5-6): 381-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877349&dopt=Abstract
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Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. Author(s): Pinkerton JV, Shifren JL, La Valleur J, Rosen A, Roesinger M, Siddhanti S. Source: Menopause (New York, N.Y.). 2003 January-February; 10(1): 45-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544676&dopt=Abstract
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Inhibin A, inhibin B, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls. Author(s): Chellakooty M, Schmidt IM, Haavisto AM, Boisen KA, Damgaard IN, Mau C, Petersen JH, Juul A, Skakkebaek NE, Main KM. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3515-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915629&dopt=Abstract
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Inhibition of MCF-7 breast cancer cell proliferation and in vivo steroid sulphatase activity by 2-methoxyoestradiol-bis-sulphamate. Author(s): Raobaikady B, Purohit A, Chander SK, Woo LW, Leese MP, Potter BV, Reed MJ. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 351-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711022&dopt=Abstract
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Inhibition of progesterone secretion by oestradiol administered in the luteal phase of assisted conception cycles. Author(s): Tay PY, Lenton EA. Source: Med J Malaysia. 2003 June; 58(2): 187-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14569738&dopt=Abstract
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Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. Author(s): Cheung J, Mak YT, Papaioannou S, Evans BA, Fogelman I, Hampson G. Source: The Journal of Endocrinology. 2003 June; 177(3): 423-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773123&dopt=Abstract
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Isoform-selective interactions between estrogen receptors and steroid receptor coactivators promoted by estradiol and ErbB-2 signaling in living cells. Author(s): Bai Y, Giguere V. Source: Molecular Endocrinology (Baltimore, Md.). 2003 April; 17(4): 589-99. Epub 2003 January 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554772&dopt=Abstract
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Isolation and characterization of androgen receptor mutant, AR(M749L), with hypersensitivity to 17-beta estradiol treatment. Author(s): Thin TH, Wang L, Kim E, Collins LL, Basavappa R, Chang C. Source: The Journal of Biological Chemistry. 2003 February 28; 278(9): 7699-708. Epub 2002 December 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499384&dopt=Abstract
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Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Author(s): Morrison MF, Kallan MJ, Ten Have T, Katz I, Tweedy K, Battistini M. Source: Biological Psychiatry. 2004 February 15; 55(4): 406-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14960294&dopt=Abstract
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Leptin, neuropeptide Y, beta-endorphin, gonadotropin, and estradiol levels in girls before menarche. Author(s): Blogowska A, Rzepka-Gorska I, Krzyzanowska-Swiniarska B, Zoltowski S, Kosmowska B. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 February; 17(1): 7-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724013&dopt=Abstract
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Liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of estradiol and estrone in human plasma. Author(s): Nelson RE, Grebe SK, OKane DJ, Singh RJ. Source: Clinical Chemistry. 2004 February; 50(2): 373-84. Epub 2003 December 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14656902&dopt=Abstract
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Longitudinal evaluation of serum estradiol and estrone in male patients infected with the human immunodeficiency virus. Author(s): Teichmann J, Schmidt A, Lange U, Stracke H, Discher T, Friese G, Lohmeyer J, Bretzel RG. Source: European Journal of Medical Research. 2003 February 21; 8(2): 77-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12626285&dopt=Abstract
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Luteal estradiol administration strengthens the relationship between day 3 folliclestimulating hormone and inhibin B levels and ovarian follicular status. Author(s): Fanchin R, Cunha-Filho JS, Schonauer LM, Righini C, de Ziegler D, Frydman R. Source: Fertility and Sterility. 2003 March; 79(3): 585-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620444&dopt=Abstract
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Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method. Author(s): Hogervorst E, Williams J, Combrinck M, David Smith A. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 January; 148(1): 67-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534359&dopt=Abstract
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Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. Author(s): Morin-Papunen L, Vauhkonen I, Koivunen R, Ruokonen A, Martikainen H, Tapanainen JS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 January; 88(1): 14856. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519844&dopt=Abstract
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Microemulsions for topical delivery of estradiol. Author(s): Peltola S, Saarinen-Savolainen P, Kiesvaara J, Suhonen TM, Urtti A. Source: International Journal of Pharmaceutics. 2003 March 26; 254(2): 99-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623186&dopt=Abstract
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Modulation of androgen metabolism by phenytoin, oestradiol and tamoxifen in human gingival fibroblasts. Author(s): Soory M, Tilakaratne A. Source: Journal of Clinical Periodontology. 2003 June; 30(6): 556-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795795&dopt=Abstract
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Molecular target of endocrine disruption in human luteinizing granulosa cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin: inhibition of estradiol secretion due to decreased 17alpha-hydroxylase/17,20-lyase cytochrome P450 expression. Author(s): Moran FM, VandeVoort CA, Overstreet JW, Lasley BL, Conley AJ. Source: Endocrinology. 2003 February; 144(2): 467-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538606&dopt=Abstract
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mRNA expression of the type I growth factor receptors in the human breast cancer cells MCF-7: regulation by estradiol and tamoxifen. Author(s): Revillion F, Pawlowski V, Lhotellier V, Louchez MM, Peyrat JP. Source: Anticancer Res. 2003 March-April; 23(2B): 1455-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820409&dopt=Abstract
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Neuroprotective effects of estradiol-17beta: implications for psychiatric disorders. Author(s): Kolsch H, Rao ML. Source: Archives of Women's Mental Health. 2002 November; 5(3): 105-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12510213&dopt=Abstract
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Novel 2-methoxyestradiol analogues with antitumor activity. Author(s): Tinley TL, Leal RM, Randall-Hlubek DA, Cessac JW, Wilkens LR, Rao PN, Mooberry SL. Source: Cancer Research. 2003 April 1; 63(7): 1538-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670902&dopt=Abstract
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Oestradiol enhances tumour regression induced by B7-1/IL-2 adenoviral gene transfer in a murine model of breast cancer. Author(s): Dabrosin C, Palmer K, Gauldie J. Source: British Journal of Cancer. 2003 July 21; 89(2): 385-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865933&dopt=Abstract
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Orally and transdermally replaced estradiol improves endothelial function equally in middle-aged women after surgical menopause. Author(s): Zegura B, Keber I, Sebestjen M, Borko E. Source: American Journal of Obstetrics and Gynecology. 2003 May; 188(5): 1291-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12748500&dopt=Abstract
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P53 expression in spontaneous and estradiol-induced endometrial hyperplasia during menopause. Author(s): Maia H Jr, Maltez A, Athayde C, Coelho G, Coutinho EM. Source: Maturitas. 2003 March 28; 44(3): 175-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648880&dopt=Abstract
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Paracrine oxytocin and estradiol demonstrate a spatial increase in human intrauterine tissues with labor. Author(s): Blanks AM, Vatish M, Allen MJ, Ladds G, de Wit NC, Slater DM, Thornton S. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3392400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843193&dopt=Abstract
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Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifenstimulated breast cancer. Author(s): Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Source: Journal of the National Cancer Institute. 2003 November 5; 95(21): 1597-608. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14600092&dopt=Abstract
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Pentagastrin-induced release of free fatty acids in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol. Author(s): Morrow JD, McManus K, Tait GR, Bellavance F, Chrapko W, Lara N, Le Melledo JM. Source: Journal of Psychiatry & Neuroscience : Jpn. 2003 March; 28(2): 127-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670129&dopt=Abstract
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Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Author(s): Wren BG, Day RO, McLachlan AJ, Williams KM. Source: Climacteric : the Journal of the International Menopause Society. 2003 June; 6(2): 104-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841880&dopt=Abstract
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Pharmacology of estradiol valerate/dienogest. Author(s): Teichmann A. Source: Climacteric : the Journal of the International Menopause Society. 2003 August; 6 Suppl 2: 17-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14669840&dopt=Abstract
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Photodegradation of 17alpha-ethynylestradiol in aqueous solution exposed to a highpressure mercury lamp (250 W). Author(s): Liu XL, Wu F, Deng NS. Source: Environmental Pollution (Barking, Essex : 1987). 2003; 126(3): 393-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963302&dopt=Abstract
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Phytoestrogens and 17beta-estradiol influence vitamin D metabolism and receptor expression-relevance for colon cancer prevention. Author(s): Lechner D, Cross HS. Source: Recent Results Cancer Res. 2003; 164: 379-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899537&dopt=Abstract
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Placement of the vaginal 17beta-estradiol tablets in the inner or outer one third of the vagina affects the preferential delivery of 17beta-estradiol toward the uterus or periurethral areas, thereby modifying efficacy and endometrial safety. Author(s): Cicinelli E, Di Naro E, De Ziegler D, Matteo M, Morgese S, Galantino P, Brioschi PA, Schonauer A. Source: American Journal of Obstetrics and Gynecology. 2003 July; 189(1): 55-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861138&dopt=Abstract
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Prediction of ovarian hyperstimulation syndrome (OHSS). Estradiol level has an important role in the prediction of OHSS. Author(s): Aboulghar M. Source: Human Reproduction (Oxford, England). 2003 June; 18(6): 1140-1. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773437&dopt=Abstract
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Prediction of ovarian hyperstimulation syndrome. Challenging the estradiol mythos. Author(s): Orvieto R. Source: Human Reproduction (Oxford, England). 2003 April; 18(4): 665-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660254&dopt=Abstract
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Pregnancy estriol, estradiol, progesterone and prolactin in relation to birth weight and other birth size variables (United States). Author(s): Mucci LA, Lagiou P, Tamimi RM, Hsieh CC, Adami HO, Trichopoulos D. Source: Cancer Causes & Control : Ccc. 2003 May; 14(4): 311-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846361&dopt=Abstract
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Prescribing pitfalls: cyproterone acetate with ethinyloestradiol. Author(s): Nicholls J. Source: Community Nurse. 2000 July; 6(6): 45. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778650&dopt=Abstract
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Promising preclinical activity of 2-methoxyestradiol in multiple myeloma. Author(s): Dingli D, Timm M, Russell SJ, Witzig TE, Rajkumar SV. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2002 December; 8(12): 3948-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473611&dopt=Abstract
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Quality of life issues. Potential role for an oral contraceptive containing ethinyl estradiol and drospirenone. Author(s): Dickerson V. Source: J Reprod Med. 2002 November; 47(11 Suppl): 985-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12497673&dopt=Abstract
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Quantitative determination of estradiol fatty acid esters in lipoprotein fractions in human blood. Author(s): Vihma V, Tiitinen A, Ylikorkala O, Tikkanen MJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2552-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788853&dopt=Abstract
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Raloxifene is a better antioxidant of low-density lipoprotein than estradiol or tamoxifen in postmenopausal women in vitro. Author(s): Arteaga E, Villaseca P, Bianchi M, Rojas A, Marshall G. Source: Menopause (New York, N.Y.). 2003 March-April; 10(2): 142-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627039&dopt=Abstract
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Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Author(s): Teyssier C, Belguise K, Galtier F, Cavailles V, Chalbos D. Source: Molecular Endocrinology (Baltimore, Md.). 2003 February; 17(2): 287-99. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554755&dopt=Abstract
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Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy. Author(s): Simon JA, Liu JH, Speroff L, Shumel BS, Symons JP. Source: American Journal of Obstetrics and Gynecology. 2003 January; 188(1): 92-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548201&dopt=Abstract
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Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults. Author(s): Elmlinger MW, Kuhnel W, Ranke MB. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 November; 40(11): 1151-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521235&dopt=Abstract
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Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. Author(s): Beagley KW, Gockel CM. Source: Fems Immunology and Medical Microbiology. 2003 August 18; 38(1): 13-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900050&dopt=Abstract
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Regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression by estradiol and progesterone in human endometrium. Author(s): Guzeloglu-Kayisli O, Kayisli UA, Al-Rejjal R, Zheng W, Luleci G, Arici A. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 5017-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557489&dopt=Abstract
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Relation of aromatase gene polymorphism and hormone replacement therapy to serum estradiol levels, bone mineral density, and fracture risk in early postmenopausal women. Author(s): Salmen T, Heikkinen AM, Mahonen A, Kroger H, Komulainen M, Pallonen H, Saarikoski S, Honkanen R, Maenpaa PH. Source: Annals of Medicine. 2003; 35(4): 282-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846271&dopt=Abstract
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Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles after embryo transfer on day 3 or day 5. Author(s): Chen CH, Zhang X, Barnes R, Confino E, Milad M, Puscheck E, Kazer RR. Source: Fertility and Sterility. 2003 July; 80(1): 75-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849804&dopt=Abstract
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Role of estradiol-17beta on nuclear and cytoplasmic maturation of pig oocytes. Author(s): Dode MA, Graves CN. Source: Animal Reproduction Science. 2003 September 15; 78(1-2): 99-110. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753786&dopt=Abstract
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Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2methoxyestradiol-induced p53 induction and apoptosis. Author(s): Shimada K, Nakamura M, Ishida E, Kishi M, Konishi N. Source: Carcinogenesis. 2003 June; 24(6): 1067-75. Epub 2003 April 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807754&dopt=Abstract
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Selective modulation of ER-beta by estradiol and xenoestrogens in human breast cancer cell lines. Author(s): Cappelletti V, Saturno G, Miodini P, Korner W, Daidone MG. Source: Cellular and Molecular Life Sciences : Cmls. 2003 March; 60(3): 567-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12737316&dopt=Abstract
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Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Author(s): Fanchin R, Schonauer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Source: Human Reproduction (Oxford, England). 2003 February; 18(2): 323-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571168&dopt=Abstract
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Serum estradiol levels after 4 days of ovarian hyperstimulation in oocyte donors are predictive of embryo quality and clinical outcomes. Author(s): Pena JE, Chang PL, Thornton MH 2nd, Sauer MV. Source: Gynecologic and Obstetric Investigation. 2002; 54(4): 207-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12592063&dopt=Abstract
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Serum folate and Vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 microg ethinyl estradiol. Author(s): Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003 March 26; 107(1): 57-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593896&dopt=Abstract
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Serum lipid and lipoprotein changes induced by preparations containing low-dose ethinylestradiol plus levonorgestrel. Author(s): Kiran G, Kiran H, Ekerbicer HC. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2003 April; 43(2): 145-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14712971&dopt=Abstract
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Sex differences in episodic memory: minimal influence of estradiol. Author(s): Yonker JE, Eriksson E, Nilsson LG, Herlitz A. Source: Brain and Cognition. 2003 July; 52(2): 231-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821106&dopt=Abstract
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Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone. Author(s): Molloy EJ, O'Neill AJ, Grantham JJ, Sheridan-Pereira M, Fitzpatrick JM, Webb DW, Watson RW. Source: Blood. 2003 October 1; 102(7): 2653-9. Epub 2003 June 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791649&dopt=Abstract
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Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Author(s): Cohen LS, Soares CN, Poitras JR, Prouty J, Alexander AB, Shifren JL. Source: The American Journal of Psychiatry. 2003 August; 160(8): 1519-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900318&dopt=Abstract
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Sleep, vigilance and cognition in postmenopausal women: placebo-controlled studies with 2 mg estradiol valerate, with and without 3 mg dienogest. Author(s): Saletu B. Source: Climacteric : the Journal of the International Menopause Society. 2003 August; 6 Suppl 2: 37-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14669843&dopt=Abstract
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Smoking, estradiol metabolism and hormone replacement therapy. Author(s): Mueck AO, Seeger H. Source: Arzneimittel-Forschung. 2003; 53(1): 1-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12608008&dopt=Abstract
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Solid-phase parallel synthesis of 17alpha-substituted estradiol sulfamate and phenol libraries using the multidetachable sulfamate linker. Author(s): Ciobanu LC, Poirier D. Source: Journal of Combinatorial Chemistry. 2003 July-August; 5(4): 429-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857111&dopt=Abstract
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Soy protein isolate with isoflavones does not prevent estradiol-induced endometrial hyperplasia in postmenopausal women: a pilot trial. Author(s): Murray MJ, Meyer WR, Lessey BA, Oi RH, DeWire RE, Fritz MA. Source: Menopause (New York, N.Y.). 2003 September-October; 10(5): 456-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501608&dopt=Abstract
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Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction. Author(s): Eckhoff DE, Smyth CA, Eckstein C, Bilbao G, Young CJ, Thompson JA, Contreras JL. Source: Surgery. 2003 August; 134(2): 169-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12947315&dopt=Abstract
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Synthesis and biological activities of phthalocyanine-estradiol conjugates. Author(s): Khan EH, Ali H, Tian H, Rousseau J, Tessier G, Shafiullah, van Lier JE. Source: Bioorganic & Medicinal Chemistry Letters. 2003 April 7; 13(7): 1287-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657265&dopt=Abstract
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Synthesis and evaluation of B-, C-, and D-ring-substituted estradiol carboxylic acid esters as locally active estrogens. Author(s): Labaree DC, Zhang JX, Harris HA, O'Connor C, Reynolds TY, Hochberg RB. Source: Journal of Medicinal Chemistry. 2003 May 8; 46(10): 1886-904. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723952&dopt=Abstract
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Synthesis, characterization and biological evaluation of 7 alphaperfluoroalkylestradiol derivatives. Author(s): Blazejewski JC, Wilmshurst MP, Popkin MD, Wakselman C, Laurent G, Nonclercq D, Cleeren A, Ma Y, Seo HS, Leclercq G. Source: Bioorganic & Medicinal Chemistry. 2003 February 6; 11(3): 335-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517429&dopt=Abstract
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Tamoxifen-resistant cells sensitive to oestradiol. Author(s): Bosch X. Source: The Lancet Oncology. 2003 December; 4(12): 711. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14682343&dopt=Abstract
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Testosterone metabolism in human skin cells in vitro and its interaction with estradiol and dutasteride. Author(s): Munster U, Hammer S, Blume-Peytavi U, Schafer-Korting M. Source: Skin Pharmacology and Applied Skin Physiology. 2003 November-December; 16(6): 356-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14528059&dopt=Abstract
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The activation of an extracellular signal-regulated kinase by oestradiol interferes with the effects of trastuzumab on HER2 signalling in endometrial adenocarcinoma cell lines. Author(s): Treeck O, Diedrich K, Ortmann O. Source: European Journal of Cancer (Oxford, England : 1990). 2003 June; 39(9): 1302-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763221&dopt=Abstract
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The correlations between estradiol, estrone, estriol, progesterone, and sex hormonebinding globulin and anterior cruciate ligament stiffness in healthy, active females. Author(s): Romani W, Patrie J, Curl LA, Flaws JA. Source: Journal of Women's Health (2002). 2003 April; 12(3): 287-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804359&dopt=Abstract
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The effect of 17 beta-oestradiol on variables of coagulation and fibrinolysis in postmenopausal women with type 2 diabetes mellitus. Author(s): Brussaard HE, Leuven JA, Krans HM, Kluft C. Source: Vascular Pharmacology. 2002 August; 39(3): 141-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616982&dopt=Abstract
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The effect of a novel vaginal ring delivering oestradiol acetate on climacteric symptoms in postmenopausal women. Author(s): Buckler H, Al-Azzawi F; UK VR Multicentre Trial Group. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2003 August; 110(8): 753-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892687&dopt=Abstract
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The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells. Author(s): Lippert C, Seeger H, Mueck AO. Source: Life Sciences. 2003 January 10; 72(8): 877-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493568&dopt=Abstract
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The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy. Author(s): Boyd RA, Zegarac EA, Eldon MA. Source: Journal of Clinical Pharmacology. 2003 January; 43(1): 52-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520628&dopt=Abstract
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The effect of ketoconazole and diltiazem on oestrogen metabolism in postmenopausal women after single dose oestradiol treatment. Author(s): Annas A, Carlstrom K, Alvan G, AL-Shurbaji A. Source: British Journal of Clinical Pharmacology. 2003 September; 56(3): 334-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919184&dopt=Abstract
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The effect of progesterone and synthetic progestins on serum- and estradiolstimulated proliferation of human breast cancer cells. Author(s): Seeger H, Wallwiener D, Mueck AO. Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2003 February; 35(2): 76-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734785&dopt=Abstract
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The effects of estradiol and selective estrogen receptor modulators on gene expression and messenger RNA stability in immortalized sheep endometrial stromal cells and human endometrial adenocarcinoma cells. Author(s): Farnell YZ, Ing NH. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 March; 84(4): 453-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732290&dopt=Abstract
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The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study. Author(s): Stojanovic ND, Kwong P, Byrne DJ, Arnold A, Jagroop IA, Nair D, Press M, Hurel S, Mikhailidis DP, Prelevic GM. Source: Angiology. 2003 July-August; 54(4): 391-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934758&dopt=Abstract
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The lipid and clinical effects of sequential transdermal estradiol and estradiol/norethisterone acetate in 674 women. Author(s): Cano A, Calaf J, Molina J. Source: Archives of Gynecology and Obstetrics. 2003 October; 268(4): 317-22. Epub 2002 November 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504877&dopt=Abstract
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The molecular mechanism of sensitization to Fas-mediated apoptosis by 2methoxyestradiol in PC3 prostate cancer cells. Author(s): Shimada K, Nakamura M, Ishida E, Kishi M, Matsuyoshi S, Konishi N. Source: Molecular Carcinogenesis. 2004 January; 39(1): 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14694442&dopt=Abstract
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The pharmacokinetics of sumatriptan when administered with norethindrone 1 mg/ethinyl estradiol 0.035 mg in healthy volunteers. Author(s): Moore KH, McNeal S, Britto MR, Bye C, Sale M, Richardson MS. Source: Clinical Therapeutics. 2002 November; 24(11): 1887-901. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501881&dopt=Abstract
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The phosphatidylinositol 3-kinase inhibitor LY294002 binds the estrogen receptor and inhibits 17beta-estradiol-induced transcriptional activity of an estrogen sensitive reporter gene. Author(s): Pasapera Limon AM, Herrera-Munoz J, Gutierrez-Sagal R, Ulloa-Aguirre A. Source: Molecular and Cellular Endocrinology. 2003 February 28; 200(1-2): 199-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644312&dopt=Abstract
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The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study. Author(s): Seaman HE, de Vries CS, Farmer RD. Source: Human Reproduction (Oxford, England). 2003 March; 18(3): 522-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615818&dopt=Abstract
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The serum concentration of estradiol after embryo transfer and the decline from preovulatory levels may influence the success of IVF treatment. Author(s): Vanderlelie J, Bell K, Perkins AV. Source: Hormone Research. 2003; 59(2): 95-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589114&dopt=Abstract
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Tibolone is not converted by human aromatase to 7alpha-methyl-17alphaethynylestradiol (7alpha-MEE): analyses with sensitive bioassays for estrogens and androgens and with LC-MSMS. Author(s): de Gooyer ME, Oppers-Tiemissen HM, Leysen D, Verheul HA, Kloosterboer HJ. Source: Steroids. 2003 March; 68(3): 235-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628686&dopt=Abstract
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Tibolone was associated with an increase in 7 alpha-methyl-ethinylestradiol. Author(s): Davis SR, Simpson ER, Kuhl H, Wiegratz I. Source: Menopause (New York, N.Y.). 2003 January-February; 10(1): 105-6; Author Reply 106-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544685&dopt=Abstract
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Tibolone was associated with an increase in 7 alpha-methyl-ethinylestradiol. Author(s): Egarter C, Kuhl H, Wiegratz I. Source: Menopause (New York, N.Y.). 2003 January-February; 10(1): 102-3; Author Reply 103-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544684&dopt=Abstract
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Transdermal contraceptive patch delivering norelgestromin and ethinyl estradiol. Effects on the lipid profile. Author(s): Creasy GW, Fisher AC, Hall N, Shangold GA. Source: J Reprod Med. 2003 March; 48(3): 179-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12698776&dopt=Abstract
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Transdermal estradiol therapy for advanced prostate cancer--forward to the past? Author(s): Ockrim JL, Lalani EN, Laniado ME, Carter SS, Abel PD. Source: The Journal of Urology. 2003 May; 169(5): 1735-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686820&dopt=Abstract
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Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Author(s): Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD. Source: Cancer Research. 2003 July 15; 63(14): 4048-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874005&dopt=Abstract
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Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. Author(s): Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Source: Jama : the Journal of the American Medical Association. 2003 August 27; 290(8): 1042-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941676&dopt=Abstract
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Upregulation of estrogen and androgen receptors modulate expression of FGF-2 and FGF-7 in human, cultured, prostatic stromal cells exposed to high concentrations of estradiol. Author(s): Smith P, Rhodes NP, Ke Y, Foster CS. Source: Prostate Cancer and Prostatic Diseases. 2002; 5(2): 105-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12496997&dopt=Abstract
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Up-regulation of LRP16 mRNA by 17beta-estradiol through activation of estrogen receptor alpha (ERalpha), but not ERbeta, and promotion of human breast cancer MCF-7 cell proliferation: a preliminary report. Author(s): Han WD, Mu YM, Lu XC, Xu ZM, Li XJ, Yu L, Song HJ, Li M, Lu JM, Zhao YL, Pan CY. Source: Endocrine-Related Cancer. 2003 June; 10(2): 217-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790785&dopt=Abstract
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Use of the Architect-i2000 estradiol immunoassay during in vitro fertilization. Author(s): Taieb J, Benattar C, Diop R, Birr AS, Lindenbaum A. Source: Clinical Chemistry. 2003 January; 49(1): 183-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507980&dopt=Abstract
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Variation in levels of serum inhibin B, testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin in monthly samples from healthy men during a 17-month period: possible effects of seasons. Author(s): Andersson AM, Carlsen E, Petersen JH, Skakkebaek NE. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 February; 88(2): 932-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574235&dopt=Abstract
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CHAPTER 2. NUTRITION AND ESTRADIOL Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and estradiol.
Finding Nutrition Studies on Estradiol The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “estradiol” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following is a typical result when searching for recently indexed consumer information on estradiol: •
By the way, doctor. I'm 53 and have been taking HRT with Estradiol and Prometrium daily for about a year. Should I also take a soy vitamin supplement? I took one before starting HRT because I thought it was supposed to prevent breast cancer. But I want to be on as little estrogen as possible. Will soy along with estrogen increase my risk of breast tumors? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 2000 February; 7(6): 8 1070910X
The following information is typical of that found when using the “Full IBIDS Database” to search for “estradiol” (or a synonym): •
17beta-estradiol benzoate decreases the AHP amplitude in CA1 pyramidal neurons. Author(s): Department of Molecular and Biomedical Pharmacology, University of Kentucky, College of Medicine, Lexington 40536, USA. Source: KuMarch, A Foster, T C J-Neurophysiol. 2002 August; 88(2): 621-6 0022-3077
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17beta-estradiol increases rat cerebrovascular prostacyclin synthesis by elevating cyclooxygenase-1 and prostacyclin synthase. Author(s): Department of Pharmacology, College of Medicine, University of California at Irvine, 92697-4625, USA. Source: Ospina, J A Krause, D N Duckles, S P Stroke. 2002 February; 33(2): 600-5 15244628
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17beta-estradiol, progesterone and testosterone concentrations in cystic fluids and response to GnRH treatment after emptying of ovarian cysts in dairy cows. Author(s): Institute of Obstetrics and Veterinary Gynaecology, University of Milan, Italy. Source: Cairoli, F Vigo, D Battocchio, M Faustini, M Veronesi, M C Maffeo, G ReprodDomest-Anim. 2002 October; 37(5): 294-8 0936-6768
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4-tert-octylphenol and 17beta-estradiol applied by feeding to flounder Platichthys flesus: induction of vitellogenin and accumulation in tissues. Author(s): Institute of Biology, University of Southern Denmark, Odense.
[email protected] Source: Madsen, L L Korsgaard, B Bjerregaard, P Mar-Environ-Res. 2002 Sep-December; 54(3-5): 729-33 0141-1136
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A comparison of the estrogenic potencies of estradiol, ethynylestradiol, diethylstilbestrol, nonylphenol and methoxychlor in vivo and in vitro. Author(s): US Environmental Protection Agency, 1 Sabine Island Drive, Gulf Breeze, FL 32561, USA.
[email protected] Source: FolMarch, L C Hemmer, M J Denslow, N D Kroll, K Chen, J Cheek, A Richman, H Meredith, H Grau, E G Aquat-Toxicol. 2002 October 2; 60(1-2): 101-10 0166-445X
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A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2. Author(s): Program in Neuroscience, University of Maryland at Baltimore, School of Medicine, Baltimore, Maryland 21201, USA.
[email protected] Source: Amateau, S K McCarthy, M M J-Neurosci. 2002 October 1; 22(19): 8586-96 15292401
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Assessment of quantitative dual-parameter flow cytometric analysis for the evaluation of testicular toxicity using cyclophosphamide- and ethinylestradiol-treated rats. Author(s): Department of Preclinical Science, Nippon Roche K. K., Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. Source: Katoh, C Kitajima, S Saga, Y Kanno, J Horii, I Inoue, T J-Toxicol-Sci. 2002 May; 27(2): 87-96 0388-1350
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Blood pressure stability in a normotensive population during intake of a monophasic oral contraceptive containing 20 microg ethinylestradiol and 75 g gestodene. Author(s): Schering AG, Berlin, Germany. Source: Endrikat, J Gerlinger, C Cronin, M Ruebig, A Schmidt, W Dusterberg, B Eur-JContracept-Reprod-Health-Care. 2001 September; 6(3): 159-66 1362-5187
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Clinical study of a monophasic pill containing 20 microg ethinylestradiol and 150 microg desogestrel in Thai women. Author(s): Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Source: Jaisamrarn, U Reinprayoon, D Virutamasen, P J-Med-Assoc-Thai. 2001 June; 84 Suppl 1: S377-83 0125-2208
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Cyproterone acetate could counteract the benefits of estradiol valerate in oophorectomized cholesterol-fed rabbits. Author(s): Menopause Clinic, Department of Gynecology & Obstetrics, University of Barcelona, Barcelona, Spain. Source: Sanjuan, A Castelo Branco, C Vicente, J J Ascaso, C Ordi, J Casals, E Mercade, I Escaramis, G Vanrell, J A Menopause. 2002 Jul-August; 9(4): 282-7 1072-3714
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Effect of 17-alpha-ethynylestradiol on activities of cytochrome P450 2B (P450 2B) enzymes: characterization of inactivation of P450s 2B1 and 2B6 and identification of metabolites. Author(s): Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA. Source: Kent, U M Mills, D E Rajnarayanan, R V Alworth, W L Hollenberg, P F JPharmacol-Exp-Ther. 2002 February; 300(2): 549-58 0022-3565
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Effects of 17beta-estradiol on blood-brain barrier disruption during focal ischemia in rats. Author(s): Department of Anesthesia, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901-1977, USA.
[email protected] Source: Chi, O Z Liu, X Weiss, H R Horm-Metab-Res. 2002 September; 34(9): 530-4 00185043
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Effects of a monophasic pill containing 20 microg ethinylestradiol and 150 microg desogestrel on lipid metabolism in Thai women. Author(s): Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Source: Jaisamrarn, U Taneepanichskul, S Wongwathanavikromn, R Reinprayoon, D JMed-Assoc-Thai. 2002 June; 85 Suppl 1: S429-34 0125-2208
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Effects of an environmental estrogen, 17alpha-ethinyl-estradiol, on the maternal-fetal trophic relationship in the eelpout Zoarces viviparus (L). Author(s): Institute of Biology, SDU, Odense University, Denmark.
[email protected] Source: Korsgaard, B Andreassen, T K Rasmussen, T H Mar-Environ-Res. 2002 SepDecember; 54(3-5): 735-9 0141-1136
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Effects of osthole on postmenopausal osteoporosis using ovariectomized rats; comparison to the effects of estradiol. Author(s): Department of Pharmacology, Intractable Diseases Research Center, Tokyo Medical University, Japan.
[email protected] Source: Li, X X Hara, I Matsumiya, T Biol-Pharm-Bull. 2002 June; 25(6): 738-42 0918-6158
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Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Author(s): Department of Experimental Endocrinology and Hormone Diagnostics, Institute of Endocrinology, Medical University of Lodz, 91-425 Lodz, Sterling Str.3, Poland.
[email protected] Source: Pawlikowski, M Kolomecka, M Wojtczak, A Karasek, M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 17-9 0172-780X
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Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17 betaestradiol combined with sequential 5-20 mg dydrogesterone. Author(s): Departments of Pathology and Obstetrics and Gynecology, McGill University, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, Quebec, Canada H3T IE2. Source: Ferenczy, A Gelfand, M M van de Weijer, P H Rioux, J E Climacteric. 2002 March; 5(1): 26-35 1369-7137
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Endometrial safety of a transdermal sequential estradiol-levonorgestrel combination. Author(s): Department of Obstetrics and Gynaecology, Birmingham Heartlands and Solihull NHS Trust, Solihull Hospital, Lode Lane, Solihull, West Midlands B91 2JL, UK. Source: Sturdee, D W van de Weijer, P von Holst, T Climacteric. 2002 June; 5(2): 170-7 1369-7137
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Estradiol and levonorgestrel: effects on bleeding pattern when administered in a sequential combined regimen with a new transdermal patch. Author(s): Department of Obstetrics and Gynecology, Gelre Hospital, 7300 DS Apeldoom, The Netherlands. Source: van de Weijer, P H Sturdee, D W von Holst, T Climacteric. 2002 March; 5(1): 3644 1369-7137
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Estradiol enhances the neurotoxicity of glutamate in GT1-7 cells through an estrogen receptor-dependent mechanism. Author(s): Department of Physiology, Kaohsiung Medical University, No. 100, ShihChuan 1st Road, Kaohsiung 807, Taiwan, ROC. Source: Yang, R C Shih, H C Hsu, H K Chang, H C Hsu, C Neurotoxicology. 2003 January; 24(1): 65-73 0161-813X
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Exposure to exogenous 17beta-oestradiol disrupts p450aromB mRNA expression in the brain and gonad of adult fathead minnows (Pimephales promelas). Author(s): Department of Biological Sciences, Brunel University, Uxbridge, UB8 3PH, Middlesex, UK. Source: Halm, S Pounds, N Maddix, S Rand Weaver, M Sumpter, J P Hutchinson, T H Tyler, C R Aquat-Toxicol. 2002 October 30; 60(3-4): 285-99 0166-445X
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Expression and regulation of WNT10B in human cancer: up-regulation of WNT10B in MCF-7 cells by beta-estradiol and down-regulation of WNT10B in NT2 cells by retinoic acid. Author(s): Genetics and Cell Biology Section, Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan. Source: Kirikoshi, H Katoh, M Int-J-Mol-Med. 2002 October; 10(4): 507-11 1107-3756
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Growth hormone-releasing hormone and gonadotropin-releasing hormone stimulate nitric oxide production in 17beta-estradiol-primed rat anterior pituitary cells. Author(s): Department of Medicine, Shimane Medical University, Izumo, Japan. Source: Tsumori, M Murakami, Y Koshimura, K Kato, Y Endocrine. 2002 April; 17(3): 215-8 0969-711X
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Influence of estrous cycle and estradiol on behavioral sensitization to cocaine in female rats. Author(s): Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-1031, USA. Source: Sell, S L Thomas, M L Cunningham, K A Drug-Alcohol-Depend. 2002 August 1; 67(3): 281-90 0376-8716
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Insulin action and insulin secretion in polycystic ovary syndrome treated with ethinyl oestradiol/cyproterone acetate. Author(s): Metabolic Unit, Royal Victoria Hospital, Royal Maternity Hospital and Regional Endocrinology Laboratory, Royal Hospital Trust, Belfast, UK. Source: Armstrong, V L Wiggam, M I Ennis, C N Sheridan, B Traub, A I Atkinson, A B Bell, P M QJM. 2001 January; 94(1): 31-7 1460-2725
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Lack of effect of testosterone and dihydrotestosterone compared to 17beta-oestradiol in 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine-mice. Author(s): Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL and Faculty of Pharmacy, Laval University, Quebec, Canada. Source: Ekue, A Boulanger, J F Morissette, M Di Paolo, T J-Neuroendocrinol. 2002 September; 14(9): 731-6 0953-8194
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Lipids and antioxidative effects of estradiol and sequential norethisterone acetate treatment in a 3-month randomized controlled trial. Author(s): Department of Public Health and Caring Sciences/Geriatrics, University of Uppsala, Uppsala, Sweden. Source: Falkeborn, M Lithell, H Persson, I Vessby, B Naessen, T Climacteric. 2002 September; 5(3): 240-8 1369-7137
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Low dose 25 mg oestradiol implants and 1 mg norethisterone as continuous combined hormone therapy: a prospective study. Author(s): Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK. Source: Panay, N Zamblera, D Sands, R Jones, J Alaghband Zadeh, J Studd, J W BJOG. 2002 August; 109(8): 958-60 1470-0328
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Mechanism-based inactivation of cytochrome P450 3A4 by 17 alpha-ethynylestradiol: evidence for heme destruction and covalent binding to protein. Author(s): Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, USA. Source: Lin, H L Kent, U M Hollenberg, P F J-Pharmacol-Exp-Ther. 2002 April; 301(1): 160-7 0022-3565
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Myometrial maxi-K channel beta1 subunit modulation during pregnancy and after 17beta-estradiol stimulation. Author(s): Department of Physiology and Biophysics, 5-660 Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA. Source: Benkusky, N A Korovkina, V P Brainard, A M England, S K FEBS-Lett. 2002 July 31; 524(1-3): 97-102 0014-5793
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Sensitive detection of the endocrine effects of the estrogen analogue ethinylestradiol using a modified enhanced subacute rat study protocol (OECD Test Guideline no. 407). Author(s): Bayer AG, PH PD Toxicology, 42096 Wuppertal, Germany.
[email protected] Source: Andrews, P Freyberger, A Hartmann, E Eiben, R Loof, I Schmidt, U Temerowski, M Folkerts, A Stahl, B Kayser, M Arch-Toxicol. 2002 May; 76(4): 194-202 0340-5761
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Successful pregnancy in a 42-year-old woman with imminent ovarian failure following ovulation induction with ethinyl estradiol without gonadotropins and in vitro fertilization. Author(s): The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, USA. Source: Check, M L Check, J H Choe, J K Berger, G S Clin-Exp-Obstet-Gynecol. 2002; 29(1): 11-4 0390-6663
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Synchronisation of oestrus and reproductive performance of dairy cows following administration of oestradiol benzoate or gonadotrophin releasing hormone during a synchronised pro-oestrus. Author(s): Department of Veterinary Science, The University of Melbourne, Werribee, Victoria. Source: Cavalieri, J Macmillan, K L Aust-Vet-J. 2002 August; 80(8): 486-93 0005-0423
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The effects of 17beta-estradiol and protein supplement on the response to purified and recombinant follicle stimulating hormone in bovine oocytes. Author(s): Centre de Recherche en Biologie de la Reproduction (CRBR), Department of Animal Science, Laval University, Quebec, Canada. Source: Ali, A Sirard, M A Zygote. 2002 February; 10(1): 65-71 0967-1994
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The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion. Author(s): Neurobiology Laboratory, Psychiatric University Hospital, CH-4025 Basel, Switzerland.
[email protected] Source: Olivieri, G Novakovic, M Savaskan, E Meier, F Baysang, G Brockhaus, M Muller Spahn, F Neuroscience. 2002; 113(4): 849-55 0306-4522
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The interaction of serum folate and estradiol levels in Alzheimer's disease. Author(s): Oxford Project To Investigate Memory and Ageing, University Department of Pharmacology, Radcliffe Infirmary, Oxford, United Kingdom.
[email protected] Source: Hogervorst, E Smith, A D Neuroendocrinol-Lett. 2002 April; 23(2): 155-60 0172780X
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Therapeutic effect of in vivo sustained estradiol release from poly (lactide-coglycolide) microspheres on bone mineral density of osteoporosis rats. Author(s): Department of Pharmaceutical Technology, Kobe Pharmaceutical University, Motoyama-Kitamachi 4-19-1, Higashi-Nada, Kobe 658-8558, Japan.
[email protected] Source: Otsuka, M Uenodan, H Matsuda, Y Mogi, T Ohshima, H Makino, K BiomedMater-Eng. 2002; 12(2): 157-67 0959-2989
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Vitellogenin mRNA regulation and plasma clearance in male sheepshead minnows, (Cyprinodon variegatus) after cessation of exposure to 17 beta-estradiol and pnonylphenol. Author(s): US Environmental Protection Agency, Gulf Ecology Division, 1 Sabine Island Drive, Gulf Breeze, FL 32561, USA.
[email protected] Source: Hemmer, M J Bowman, C J Hemmer, B L Friedman, S D Marcovich, D Kroll, K J Denslow, N D Aquat-Toxicol. 2002 July; 58(1-2): 99-112 0166-445X
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMD®Health: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to estradiol; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Vitamins Ascorbic Acid Alternative names: Vitamin C (Ascorbic Acid) Source: Integrative Medicine Communications; www.drkoop.com Vitamin C (Ascorbic Acid) Alternative names: Ascorbic Acid Source: Integrative Medicine Communications; www.drkoop.com Vitamin D Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Alternative names: Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com
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Minerals Alpha-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Beta-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com D-alpha-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Delta-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Gamma-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Quercetin Source: Healthnotes, Inc.; www.healthnotes.com
Nutrition
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Food and Diet Low-Fat Diet Source: Healthnotes, Inc.; www.healthnotes.com Soy Source: Prima Communications, Inc.www.personalhealthzone.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND ESTRADIOL Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to estradiol. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to estradiol and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “estradiol” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to estradiol: •
17beta-estradiol affords protection against 4-vinylcyclohexene diepoxide-induced ovarian follicle loss in Fischer-344 rats. Author(s): Thompson KE, Sipes IG, Greenstein BD, Hoyer PB. Source: Endocrinology. 2002 March; 143(3): 1058-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11861533&dopt=Abstract
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17beta-Estradiol and environmental estrogens significantly affect mammalian sperm function. Author(s): Adeoya-Osiguwa SA, Markoulaki S, Pocock V, Milligan SR, Fraser LR. Source: Human Reproduction (Oxford, England). 2003 January; 18(1): 100-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525448&dopt=Abstract
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17beta-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin. Author(s): Linford NJ, Dorsa DM.
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Source: Steroids. 2002 December; 67(13-14): 1029-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441188&dopt=Abstract •
17-epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting vascular cell adhesion molecule 1 (VCAM-1) mRNA expression. Author(s): Mukherjee TK, Nathan L, Dinh H, Reddy ST, Chaudhuri G. Source: The Journal of Biological Chemistry. 2003 April 4; 278(14): 11746-52. Epub 2003 January 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547825&dopt=Abstract
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2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta. Author(s): LaVallee TM, Zhan XH, Herbstritt CJ, Kough EC, Green SJ, Pribluda VS. Source: Cancer Research. 2002 July 1; 62(13): 3691-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12097276&dopt=Abstract
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A comparison of the anti-inflammatory activities of conjugated estrogens and 17-beta estradiol. Author(s): Thomas TN, Rhodin JA, Clark L, Garces A, Bryant M. Source: Inflammation Research : Official Journal of the European Histamine Research Society. [et Al.]. 2003 November; 52(11): 452-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14652679&dopt=Abstract
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Angiogenesis inhibition with TNP-470, 2-methoxyestradiol, and paclitaxel in experimental pancreatic carcinoma. Author(s): Ryschich E, Werner J, Gebhard MM, Klar E, Schmidt J. Source: Pancreas. 2003 March; 26(2): 166-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604915&dopt=Abstract
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Chronic treatment of male rats with daidzein and 17beta-oestradiol induces the contribution of EDHF to endothelium-dependent relaxation. Author(s): Woodman OL, Boujaoude M. Source: British Journal of Pharmacology. 2004 January; 141(2): 322-8. Epub 2003 December 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14691049&dopt=Abstract
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Comparison of the oestrogenic effects of infant milk formulae, oestradiol and the phytoestrogen coumestrol delivered continuously in the drinking water to ovariectomised mice. Author(s): Pocock VJ, Sales GD, Milligan SR.
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Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2002 May; 40(5): 643-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11955670&dopt=Abstract •
Dietary ethinyl estradiol exposure during development causes increased voluntary sodium intake and mild maternal and offspring toxicity in rats. Author(s): Ferguson SA, Delclos KB, Newbold RR, Flynn KM. Source: Neurotoxicology and Teratology. 2003 July-August; 25(4): 491-501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798966&dopt=Abstract
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Differential modulation by estradiol of P-glycoprotein drug resistance protein expression in cultured MCF7 and T47D breast cancer cells. Author(s): Zampieri L, Bianchi P, Ruff P, Arbuthnot P. Source: Anticancer Res. 2002 July-August; 22(4): 2253-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174911&dopt=Abstract
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Effect of dietary administration of genistein, nonylphenol or ethinyl estradiol on hepatic testosterone metabolism, cytochrome P-450 enzymes, and estrogen receptor alpha expression. Author(s): Laurenzana EM, Weis CC, Bryant CW, Newbold R, Delclos KB. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2002 January; 40(1): 53-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731036&dopt=Abstract
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Effect of estradiol, diethylstilbestrol, and resveratrol on F0F1-ATPase activity from mitochondrial preparations of rat heart, liver, and brain. Author(s): Kipp JL, Ramirez VD. Source: Endocrine. 2001 July; 15(2): 165-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11720242&dopt=Abstract
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Effects of 17beta-estradiol and the Japanese herbal medicine Keishi-bukuryo-gan on the release and synthesis of calcitonin gene-related peptide in ovariectomized rats. Author(s): Noguchi M, Ikarashi Y, Yuzurihara M, Kase Y, Takeda S, Aburada M. Source: Journal of Pharmacological Sciences. 2003 September; 93(1): 80-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501156&dopt=Abstract
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Effects of aging and estradiol supplementation on GH axis dynamics in women. Author(s): Lieman HJ, Adel TE, Forst C, von Hagen S, Santoro N. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 August; 86(8): 3918-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11502833&dopt=Abstract
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Effects of estradiol, phytoestrogens, and Ginkgo biloba extracts against 1-methyl-4phenyl-pyridine-induced oxidative stress. Author(s): Gagne B, Gelinas S, Bureau G, Lagace B, Ramassamy C, Chiasson K, Valastro B, Martinoli MG. Source: Endocrine. 2003 June; 21(1): 89-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777708&dopt=Abstract
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Effects of Lepidium meyenii Walp and Jatropha macrantha on blood levels of estradiol-17 beta, progesterone, testosterone and the rate of embryo implantation in mice. Author(s): Oshima M, Gu Y, Tsukada S. Source: The Journal of Veterinary Medical Science / the Japanese Society of Veterinary Science. 2003 October; 65(10): 1145-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14600359&dopt=Abstract
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Effects of ovariectomy and estradiol on acoustic startle responses in rats. Author(s): Vaillancourt C, Cyr M, Rochford J, Boksa P, Di Paolo T. Source: Pharmacology, Biochemistry, and Behavior. 2002 December; 74(1): 103-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12376157&dopt=Abstract
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Effects of PC-SPES on proliferation and expression of AR/PSA in androgenresponsive LNCaP cells are independent of estradiol. Author(s): Hsieh TC, Xiong W, Traganos F, Darzynkiewicz Z, Wu JM. Source: Anticancer Res. 2002 July-August; 22(4): 2051-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174883&dopt=Abstract
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Effects of the Japanese herbal medicine Keishi-bukuryo-gan and 17beta-estradiol on calcitonin gene-related peptide-induced elevation of skin temperature in ovariectomized rats. Author(s): Noguchi M, Ikarashi Y, Yuzurihara M, Kase Y, Chen JT, Takeda S, Aburada M, Ishige A. Source: The Journal of Endocrinology. 2003 March; 176(3): 359-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630921&dopt=Abstract
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Effects of Unkei-to on FSH, LH and estradiol in anovulatory young women with hyper- or hypo-functioning conditions. Author(s): Ushiroyama T, Hosotani T, Yamashita Y, Yamashita H, Ueki M. Source: The American Journal of Chinese Medicine. 2003; 31(5): 763-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14696679&dopt=Abstract
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Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Author(s): Stoica GE, Franke TF, Wellstein A, Czubayko F, List HJ, Reiter R, Morgan E, Martin MB, Stoica A.
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Source: Molecular Endocrinology (Baltimore, Md.). 2003 May; 17(5): 818-30. Epub 2003 January 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554767&dopt=Abstract •
Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu. Author(s): Veldhuis JD, Evans WS, Bowers CY. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5484-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602794&dopt=Abstract
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Estrone and 17beta-estradiol reverse breast cancer resistance protein-mediated multidrug resistance. Author(s): Imai Y, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y. Source: Japanese Journal of Cancer Research : Gann. 2002 March; 93(3): 231-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11927002&dopt=Abstract
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Evaluation of 7-hydroxy-flavones as inhibitors of oestrone and oestradiol biosynthesis. Author(s): Vinh TK, Nicholls PJ, Kirby AJ, Simons C. Source: J Enzyme Inhib. 2001 November; 16(5): 417-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11916147&dopt=Abstract
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Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta. Author(s): Seidlova-Wuttke D, Hesse O, Jarry H, Christoffel V, Spengler B, Becker T, Wuttke W. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 October; 149(4): 351-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514351&dopt=Abstract
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Evidence that estrogen receptor alpha, but not beta, mediates seasonal changes in the response of the ovine retrochiasmatic area to estradiol. Author(s): Hardy SL, Anderson GM, Valent M, Connors JM, Goodman RL. Source: Biology of Reproduction. 2003 March; 68(3): 846-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604634&dopt=Abstract
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Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Author(s): Naciff JM, Jump ML, Torontali SM, Carr GJ, Tiesman JP, Overmann GJ, Daston GP.
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Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2002 July; 68(1): 184-99. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075121&dopt=Abstract •
Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis. Author(s): Basu A, Haldar S. Source: Febs Letters. 2003 March 13; 538(1-3): 41-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633850&dopt=Abstract
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Interactions of ATP, oestradiol, genistein and the anti-oestrogens, faslodex (ICI 182780) and tamoxifen, with the human erythrocyte glucose transporter, GLUT1. Author(s): Afzal I, Cunningham P, Naftalin RJ. Source: The Biochemical Journal. 2002 August 1; 365(Pt 3): 707-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12133004&dopt=Abstract
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Interactive effects of soy protein and estradiol on coronary artery reactivity in atherosclerotic, ovariectomized monkeys. Author(s): Williams JK, Anthony MS, Herrington DM. Source: Menopause (New York, N.Y.). 2001 September-October; 8(5): 307-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11528355&dopt=Abstract
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Long-term estradiol treatment improves VIP-mediated vasodilation in atherosclerotic proximal coronary arteries. Author(s): Dalsgaard T, Mortensen A, Larsen CR, Larsen JJ, Ottesen B. Source: Regulatory Peptides. 2003 November 15; 116(1-3): 155-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599727&dopt=Abstract
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Neuroprotective effect of estradiol and phytoestrogens on MPP+-induced cytotoxicity in neuronal PC12 cells. Author(s): Gelinas S, Martinoli MG. Source: Journal of Neuroscience Research. 2002 October 1; 70(1): 90-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12237867&dopt=Abstract
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Phytoestrogens and 17beta-estradiol influence vitamin D metabolism and receptor expression-relevance for colon cancer prevention. Author(s): Lechner D, Cross HS. Source: Recent Results Cancer Res. 2003; 164: 379-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899537&dopt=Abstract
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Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis.
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Author(s): Cabanes A, Wang M, Olivo S, DeAssis S, Gustafsson JA, Khan G, HilakiviClarke L. Source: Carcinogenesis. 2004 January 16 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14729590&dopt=Abstract •
Reduction of post injury neointima formation due to 17beta-estradiol and phytoestrogen treatment is not influenced by the pure synthetic estrogen receptor antagonist ICI 182,780 in vitro. Author(s): Finking G, Lenz C, Schochat T, Hanke H. Source: Bmc Cardiovascular Disorders [electronic Resource]. 2002 August 6; 2(1): 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162794&dopt=Abstract
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Serum folate and Vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 microg ethinyl estradiol. Author(s): Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003 March 26; 107(1): 57-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593896&dopt=Abstract
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Soy product intake and serum isoflavonoid and estradiol concentrations in relation to bone mineral density in postmenopausal Japanese women. Author(s): Nagata C, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 2002 March; 13(3): 200-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11991438&dopt=Abstract
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Soy protein isolate with isoflavones does not prevent estradiol-induced endometrial hyperplasia in postmenopausal women: a pilot trial. Author(s): Murray MJ, Meyer WR, Lessey BA, Oi RH, DeWire RE, Fritz MA. Source: Menopause (New York, N.Y.). 2003 September-October; 10(5): 456-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501608&dopt=Abstract
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The effect of herbal medicine on nerve growth factor in estradiol valerate-induced polycystic ovaries in rats. Author(s): Lee JC, Pak SC, Lee SH, Lim SC, Bai YH, Jin CS, Kim JS, Na CS, Bae CS, Oh KS, Choi BC. Source: The American Journal of Chinese Medicine. 2003; 31(6): 885-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14992541&dopt=Abstract
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The molecular mechanism of sensitization to Fas-mediated apoptosis by 2methoxyestradiol in PC3 prostate cancer cells. Author(s): Shimada K, Nakamura M, Ishida E, Kishi M, Matsuyoshi S, Konishi N.
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Source: Molecular Carcinogenesis. 2004 January; 39(1): 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14694442&dopt=Abstract •
Upregulation of Steroidogenic Enzymes and Ovarian 17{beta}-Estradiol in Human Granulosa-Lutein Cells by Cordyceps sinensis Mycelium. Author(s): Huang BM, Hsiao KY, Chuang PC, Wu MH, Pan HA, Tsai SJ. Source: Biology of Reproduction. 2004 January 7 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14711788&dopt=Abstract
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Vitellogenin induction in painted turtle, Chrysemys picta, as a biomarker of exposure to environmental levels of estradiol. Author(s): Irwin LK, Gray S, Oberdorster E. Source: Aquatic Toxicology (Amsterdam, Netherlands). 2001 November 1; 55(1-2): 49-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11551621&dopt=Abstract
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMD®Health: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
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The following is a specific Web list relating to estradiol; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Menopause Source: Healthnotes, Inc.; www.healthnotes.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Prostate Cancer Source: Integrative Medicine Communications; www.drkoop.com Vaginitis Source: Healthnotes, Inc.; www.healthnotes.com
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Herbs and Supplements Alfalfa Alternative names: Medicago sativa Source: Healthnotes, Inc.; www.healthnotes.com Camellia Sinensis Source: Integrative Medicine Communications; www.drkoop.com Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Dioscorea Villosa Alternative names: Wild yam Source: Integrative Medicine Communications; www.drkoop.com Estradiol Source: Healthnotes, Inc.; www.healthnotes.com Estrogens Source: Healthnotes, Inc.; www.healthnotes.com Estrogens (Combined) Source: Healthnotes, Inc.; www.healthnotes.com
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Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Green Tea Alternative names: Camellia sinensis Source: Integrative Medicine Communications; www.drkoop.com Hibiscus Alternative names: Hibiscus, Roselle; Hibiscus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Isoflavones Source: Prima Communications, Inc.www.personalhealthzone.com Lepidium Meyenii Alternative names: Maca; Lepidium meyenii Walp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Luffa Alternative names: Luffa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Oral Contraceptives Source: Healthnotes, Inc.; www.healthnotes.com Oral Contraceptives Source: Prima Communications, Inc.www.personalhealthzone.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Passiflora Alternative names: Passion Flower; Passiflora alata L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Plantago Psyllium Alternative names: Psyllium, Ispaghula; Plantago psyllium/ovata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pregnenolone Source: Healthnotes, Inc.; www.healthnotes.com Progesterone Source: Healthnotes, Inc.; www.healthnotes.com Rosmarinus Alternative names: Rosemary; Rosmarinus officinalis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Tribulus Puncture Alternative names: Puncture Vine, Goathead; Tribulus terrestris L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Vitex Alternative names: Chaste; Vitex agnus-castus Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Wild Yam Alternative names: Dioscorea villosa Source: Integrative Medicine Communications; www.drkoop.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON ESTRADIOL Overview In this chapter, we will give you a bibliography on recent dissertations relating to estradiol. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “estradiol” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on estradiol, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Estradiol ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to estradiol. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
17-beta Estradiol Attenuation of Hypoxia-Induced Erythropoietin Expression by Mukundan, Harshini; PhD from The University of New Mexico, 2003, 142 pages http://wwwlib.umi.com/dissertations/fullcit/3085030
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Collagen Metabolism in the Estradiol-Stimulated Uterus by Mandell, Susan; PhD from University of Toronto (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK58277
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Effects of Estradiol-17b on Hormone Levels and Luteal Function in Cycling Gilts by Connor, Laurie; PhD from The University of Manitoba (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK50921
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Effects of Pregnancy, Estradiol Benzoate and Mer-25 on Voluntary Ethanol Consumption in the Rat by Sandberg, David E; PhD from Concordia University (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK58460
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Effects of the Menstrual Cycle on Protein Metabolism during Exercise (Ovarian Hormones, Urea Nitrogen Excretion, Progesterone, Sweat, Estradiol) by LaMont, Linda S., PhD from Kent State University, 1984, 161 pages http://wwwlib.umi.com/dissertations/fullcit/8508387
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Estradiol-induced Masculinization of the Developing Preoptic Area: Evidence from Form to Function by Amateau, Stuart Kevin; PhD from University of Maryland, Baltimore, 2003, 187 pages http://wwwlib.umi.com/dissertations/fullcit/3098830
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Factors Affecting the Activity of Estradiol Hydroxylase in Rat Liver Microsomal Subfractions by Brown, Bette Jo; PhD from Queen's University at Kingston (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK11694
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Hepatic Drug Metabolism Studies in Streptozotocin and Spontaneously Diabetic Rats the Possible Influence of [3h]-Estradiol Binding Proteins by Warren, Betty Lynne; PhD from The University of British Columbia (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK62880
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Mechanisms of Estradiol-Mediated Protection against Stroke-Like Injury by Rau, Shane Wyatt; PhD from University of Kentucky, 2003, 115 pages http://wwwlib.umi.com/dissertations/fullcit/3102029
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Metabolism of Estradiol by Estrogen-Induced Rat Uterine Enzymes by Lyttle, Cecil Richard Edmund; PhD from Queen's University at Kingston (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK12721
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Moderating Effects of Treadmill Running, Immobilization, and Estradiol on Plasma Concentrations of Hypothalamic-Pituitary-Adrenal Cortical Hormones after Acute Stress in Ovariectomized Rats (Cortical Hormones) by White-Welkley, Jill Elizabeth, PhD from University of Georgia, 1993, 83 pages http://wwwlib.umi.com/dissertations/fullcit/9329858
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Molecular Mechanisms Regulating Estradiol Production in the Rat Corpus Luteum by Risk, Michael Christopher; PhD from University of Illinois at Chicago, Health Sciences Center, 2003, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3083953
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On the Occurrence and Significance of Estradiol-17alpha As a Urinary Conversion Product of Injected Estrone or Estradiol-17beta in the Domestic Fowl by Mulay, Shree; AdvDeg from McGill University (Canada), 1969 http://wwwlib.umi.com/dissertations/fullcit/NK03972
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Pathologic Effects of Estradiol on the Hypothalamic Arcuate Nucleus by Schipper, Hyman M; PhD from McGill University (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK58057
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Regulation of Ovarian Follicular Development with Estradiol in Cattle by Burke, Christopher Richard; PhD from The Ohio State University, 2003, 181 pages http://wwwlib.umi.com/dissertations/fullcit/3093629
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Salivary Hormonal Levels, Anxiety and Self-Confidence Indices in Collegiate Football and Basketball Players over a Season of Play (College Athletes, Testosterone, Estradiol, Cortisol) by Bartolino, Amelie, PhD from The University of Texas at Austin, 1996, 244 pages http://wwwlib.umi.com/dissertations/fullcit/9633081
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Studies Relating Hepatic Cytosolic (3h)-Estradiol Binding Proteins to Hormonal and Drug Modulation of Hepatic Microsomal Aryl Hydrocarbon Hydroxylase in the Rat by Finlayson, Malcolm John Paul; PhD from The University of British Columbia (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK66863
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The Effect of Acute Exercise on Serum Estradiol Levels in Endurance Trained and Untrained Men by Alejandro-De Leon, Daniel, EDD from Columbia University Teachers College, 1989, 122 pages http://wwwlib.umi.com/dissertations/fullcit/9013529
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The Effects of 17beta-estradiol Injection on in Vitro Thyroid Hormone Deiodination in Liver, Brain, Gill, Heart, and Kidney of Female and Male Rainbow Trout (Oncorhynchus Mykiss) at Different States of Sexual Maturity by Wiens, Susanna C.; MSC from The University of Manitoba (Canada), 2003, 108 pages http://wwwlib.umi.com/dissertations/fullcit/MQ80087
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The Effects of Progesterone and Estradiol on the Spontaneous and GNRH-Induced Secretion of LH and FSH in the Anestrous and Cyclic Ewe by Rieger, Donald; PhD from The University of Saskatchewan (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK56009
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The Metabolism of Estrone, Estradiol and Their 3-sulfates by Guinea Pig Liver Preparations by Harvey, Percy Robert Craig; PhD from The University of Western Ontario (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK36273
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The Relationship between Resting Estradiol Levels and Lipid Metabolism in Physically Active Females (Menstrual Cycle) by Ashley, Candi Dawn, PhD from The University of Alabama, 1995, 88 pages http://wwwlib.umi.com/dissertations/fullcit/9604744
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. CLINICAL TRIALS AND ESTRADIOL Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning estradiol.
Recent Trials on Estradiol The following is a list of recent trials dedicated to estradiol.8 Further information on a trial is available at the Web site indicated. •
Zoledronate and Estradiol in Preventing Bone Loss in Patients With Prostate Cancer Condition(s): Osteoporosis; stage III prostate cancer; stage IV prostate cancer Study Status: This study is currently recruiting patients. Sponsor(s): Herbert Irving Comprehensive Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Zoledronate and estradiol may be effective in preventing bone loss. It is not yet known whether zoledronate and estradiol are more effective alone or in combination in preventing bone loss in patients who are receiving hormone therapy for prostate cancer. PURPOSE: Randomizedphase III trial to compare the effectiveness of zoledronate and estradiol alone to that of zoledronate combined with estradiol in preventing bone loss in patients who are receiving hormone therapy for prostate cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049491
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These are listed at www.ClinicalTrials.gov.
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Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “estradiol” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •
For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/
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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/
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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm
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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm
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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm
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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp
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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm
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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/
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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm
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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm
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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm
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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm
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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm
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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials
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CHAPTER 6. PATENTS ON ESTRADIOL Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “estradiol” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on estradiol, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Estradiol By performing a patent search focusing on estradiol, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We
9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on estradiol: •
Compositions and treatments for reducing potential unwanted side effects associated with long-term administration of androgenic testosterone precursors Inventor(s): Bucci; Luke R. (West Valley City, UT) Assignee(s): Weider Nutrition International, Inc (salt Lake City, Ut) Patent Number: 6,117,429 Date filed: August 11, 1998 Abstract: A method for reducing potential adverse effects of androgenic testosterone precursors by interfering with production or action of testosterone and estrogen metabolites by nutrient combinations is described. Although androgenic testosterone precursors themselves have little or no toxicity, there is the potential for their metabolites, estradiol and dihydrotestosterone, to enhance or cause hormoneresponsive illnesses such as breast or prostatic cancer, benign prostatic hyperplasia, or hirsutism or acne in women. The use of the invented nutrient combinations reduces the formation or action of estradiol and dihydrotestosterone, thereby reducing potential adverse effects from increased production of these hormones following androgenic testosterone precursor administration. This may be accomplished without negating the effects of testosterone on muscle anabolism. The nutrient combinations include androstenedione, DHEA, pregnenolone, androstenediols, norandrostenedione and norandrostenediols, and natural products which reduce estrogen effects in the estrogenresponsive tissues, and substances to reduce formation of dihydrotestosterone from testosterone in prostate tissue. Excerpt(s): The invention relates to the use of nutrient combinations to prevent or reduce potential adverse effects from administration of androgenic testosterone precursors to humans and other mammals Specifically, the invention relates to coadministration of androgenic testosterone precursors such as pregnenolone, androstenediols, norandrostenediols, norandrostenedione, androstenedione or dehydroepiandrosterone in combination with natural products which inhibit estrogen effects in liver, adipose, prostate, ovarian, uterine, breast and other estrogen-responsive tissues, and substances which inhibit the production of dihydrotestosterone in prostate tissue. Androstenedione (.DELTA.sup.4 -androstene-3,17-dione) is an adrenal steroid hormone. Pregnenolone is a precursor for dehydroepiandrosterone. Dehydroepiandrosterone (DHEA) is a precursor of androstenedione. Androstenedione is a direct precursor of estrone and testosterone in target tissues that possess the appropriate receptors and enzymes. Androstenediols are direct precursors for testosterone after oral administration in adult humans (unpublished data). 19Norandrostenedione is a precursor for 19-nortestosterone, which has anabolic actions similar to testosterone, with less androgenic actions. 19-Norandrostenedione is a potential precursor for estrone. Testosterone is important for the development and maintenance of male sexual organs and characteristics, behavioral effects, anabolic (growth-promoting) actions, and metabolic effects for all tissues, especially muscles, liver and kidney. (Kutsky, R. J., Handbook of Vitamins, Minerals and Hormones, 2.sup.nd ed., Van Nostrand Reinhold Company, New York, 1981). Estrogens are essential for the development and maintenance of female reproductive organs and characteristics, pregnancy, and metabolic effects for all tissues (Kutsky, 1981). Androstenedione levels in tissues, including skeletal muscle, of men and women decrease significantly with age. (Deslypere, J. P. and Vermeulen, A., Influence of age on
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steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men, J. Clin. Endocrinol. Metab. 61:648-653 (1985)). Since muscle wasting is associated with aging, these findings suggest that the loss of androstenedione is involved in muscle wasting. The corollary that androstenedione administration would maintain muscle mass is enticing, but has not been studied yet. Nevertheless, the data support an anabolic effect of androstenedione on muscle tissue in both men and women, with more effectiveness in men. Web site: http://www.delphion.com/details?pn=US06117429__ •
Compositions for inhibiting airway wall inflammation Inventor(s): Stewart; Alastair George (Melbourne, AU) Assignee(s): Amrad Operations Pty. Ltd. (richmond, Au) Patent Number: 6,200,966 Date filed: June 11, 1999 Abstract: The invention relates to compositions which modulate airway remodelling comprisiing the sterioid 2-methyoxy-estradiol or analogues thereof, for administration by inhalation. Excerpt(s): This invention relates to a method of treating chronic and acute inflammation of the airways, including asthmatic conditions. The invention also relates to steroid or steroid analogues used in the treatment, and to pharmaceutical compositions comprising these compounds as the active agent. In a preferred embodiment, the active component inhibits inflammation and smooth muscle cell proliferation in the airway wall. It may also have at least one other activity selected from anti-angiogenesis, anti-oxidation and the ability to disrupt microtubule formation. Two distinct classes of agents are currently used in the treatment of asthma. Symptomatic relief is provided by using bronchodilators which include the.beta.sub.2 -adrenoceptor agonists such as salbutamol and salmeterol. Other agents with bronchodilatory properties include the muscarinic-receptor antagonist, ipratroipium bromide, and phosphodiesterase inhibitors such as theophylline. The second class of agents is prophylactic, and includes glucocorticoids such as beclomethasone dipropionate. Disodium cromoglycate and nedocromil sodium are also used, even though these are less effective than the glucocorticoids. Web site: http://www.delphion.com/details?pn=US06200966__
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Determination of steroids by competitive immunoassay Inventor(s): Agdeppa; Dalmacio A. (Morton Grove, IL), Baker; Harold N. (Libertyville, IL), Groskopf; William R. (Libertyville, IL), Williams; Gregg T. (Villa Park, IL) Assignee(s): Abbott Laboratories (abbott Park, Il) Patent Number: 6,201,141 Date filed: June 18, 1999 Abstract: A method and kit for measurement of a steroid by means of a competitive immunoassay, preferably a competitive enzyme immunoassay. The method and kit involve the use of a steroid analogue conjugated to a label. The steroids that are amenable to detection by the method and kit of the present invention include estradiol
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and progesterone.The method comprises the steps of:a. incubating a mixture of a test sample suspected of containing a given steroid, a solid phase coupled to an antibody specific for that steroid, and a conjugate of an analogue of that steroid to form steroid/antibody complexes and conjugate/antibody complexes on said solid phase;b. separating said solid phase from said mixture;c. measuring the amount of label present in said mixture or in said solid phase; andd. determining the amount of steroid in said sample from the amount of label.The kit comprises a solid phase coupled to an antibody specific for a steroid and a conjugate of an analogue of that steroid. Excerpt(s): This invention relates to detection and measurement of steroids in biological fluids, and, more particularly, detection and measurement of steroids by means of competitive immunoassay. Detection and measurement of steroids in biological fluids is important for a variety of reasons. For example, the amount of a particular steroid in a biological fluid can be used to assist in diagnosing the occurrence of an endocrinological disorder, to monitor the amount of hormone required in hormonal replacement therapy, or to assess fertility. Determination of the presence and amount of steroids in a biological fluid can be determined by competitive diagnostic assay. Small molecule, competitive diagnostic assays require a labeled component that can compete with the analyte for available antibody sites. Examples of the labeled component include radioactive tracers, fluorophore/hapten conjugates, and enzyme/hapten conjugates. Typically, the labeled component consists of the analyte or an analogue of the analyte coupled to a label. The labeled component is typically referred to as a conjugate. Estradiol (1,3,5(10)-estratrien-3,17.alpha.-diol) is an analyte, the detection and measurement of which is of great importance in the area of fertility testing. Estradiol is secreted by the ovary and placenta. It is synthesized by the aromatization of androgens in the thecal and granulosa cells of the ovary and placenta. The aromatization is stimulated by follitropin (FSH). Estradiol synthesis in turn stimulates production of lutropin (LH) receptors necessary for the synthesis of androgen precursors. Web site: http://www.delphion.com/details?pn=US06201141__ •
Drugs for topical application of sex steroids in the treatment of dry eye syndrome, and methods of preparation and application Inventor(s): Lubkin; Virginia (One Blackstone Pl., Bronx, NY 10471) Assignee(s): Lubkin; Virginia (brnx, Ny) Patent Number: 6,096,733 Date filed: December 10, 1998 Abstract: A topical drug application for the alleviation of kerato-conjunctivitis sicca (dry eye syndrome) is comprised of a solution of 17-.beta.-estradiol suspended or dissolved in a vehicle, and the method of preparation and application of the same. In the preferred embodiments, 17-.beta.-estradiol is in a lipid vehicle or 17-.beta.-estradiol 3-phosphate disodium dissolved in an aqueous vehicle having a pH of between about 6 to about 8. This invention may also be useful in treating other conditions where KCS may occur, such as post-operative corneal transplant patients and patients who cannot receive replacement estrogen therapy. Excerpt(s): This invention relates to the topical application of sex steroids in the treatment of human dry eye syndrome (also known as keratoconjunctivitis sicca (KCS)) and, more specifically, to the preparation and application of 17-.beta.-estradiol and its derivatives in lipid, liposomes, polymers, or aqueous or non-aqueous vehicles for the
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topical treatment of the ocular surface tissues. This invention may also be useful in treating other conditions where KCS may occur, such as post-operative corneal transplant patients. The high incidence of keratoconjunctivitis sicca in the population of postmenopausal women is attended by symptoms ranging from mild foreign body sensation to frank pain and visual loss due to ocular surface abnormalities. The standard treatment with artificial lubricants, which provides temporary symptomatic relief in most cases does not, however, address the cause of the dry eyes. While there has been described treatment of post menopausal females with dry eye syndrome using oral Premarin therapy, the oral or parenteral administration of estrogen can frequently produce side effects such as vaginal bleeding, breast tenderness and other undesired effects and the therapeutic effects derived from oral therapy are minimal. This result is now understood as a result of studies showing that there are very few estrogen receptors in the conjunctiva relative to other tissues of the body (Gans, L. A., et al., Am. J. Ophthalmol. 109(4):474-477 (1990)). Further, such oral or parenteral administration implicates the entire body structure in an indeterminate effort to secure an effect in a localized area (the eye), in the absence of any data relating the level of estrogen introduced into the blood stream to the level, if any, resulting in the tear fluid (it is known generally, that estrogen concentrations in the eye to be in the range of about 10% of serum levels). Conservative medicine would indicate the desirability of limiting the specific effect of the hormone to the recipient site if possible. One possible method of accomplishing this is through the use of topically applied steroids, in drop form. One early reference (Bohigian, G. Handbook of External Diseases of the Eye (Alcon, Inc.) 1980, p. 79) did refer to the use of "special drops" for treating KCS which in fact, contained conjugated estrogens, however, in a declaration during prosecution of U.S. Pat. No. 5,041,434 issued to Lubkin (reissued as U.S. Pat. No. Re. 34,578) and hereby incorporated by reference, Dr. Bohigian stated that the concentration of estrone in the drops was 0.0066% by weight and that it was not effective in alleviating any symptoms. In contrast, the U.S. Pat. No. Re. 34,578 patent of Lubkin showed that treatment of dry eye syndrome or KCS was shown to be effective using a form of estrogen in solution at concentrations of at least 0.1 mg/mL or 0.1% (w/v). Web site: http://www.delphion.com/details?pn=US06096733__ •
Estradiol and progesterone-based medicament Inventor(s): Salin-Drouin; Dominique (Verrieres-les-Buissons, FR) Assignee(s): Laboratoires Besins Iscovesco (paris, Fr) Patent Number: 6,077,531 Date filed: September 28, 1998 Abstract: A medicament consisting of a biological medium-soluble capsule containing a micronised progesterone suspended in oil is disclosed, characterised in that the capsule also contains estradiol enclosed in microspheres, also suspended in oil, and which consist of one or more polymers that do not dissolve in oil but that dissolve in a biological medium. Excerpt(s): The present invention relates to a medicament based on estradiol and progesterone intended for the treatment of menopausal pathology. In effect, it is known that the estrogenic deficiency which manifests itself during the period of the menopause is sometimes difficult for the feminine organism to tolerate, due in particular to the fact that it is felt not only at the level of the central nervous system, where it is responsible for outward signs of neurovegetative order, such as hot flushes, but also at the level of
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the osseous cartilage. In the past, various methods of administration of estradiol have been proposed, and in particular a method of administration by the percutaneous route. As for the medicament forming the subject matter of the present invention, it can be administered by the oral route. Web site: http://www.delphion.com/details?pn=US06077531__ •
Estradiol penetration enhancers Inventor(s): Meconi; Reinhold (Neuwied, DE), Seibertz; Frank (Bad Honningen/Ariendorf, DE) Assignee(s): Lts Lohmann Therapie-systeme Gmbh (neuwied, De) Patent Number: 6,090,404 Date filed: October 11, 1996 Abstract: An active substance-containing patch for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or in combination with gestagens from a backing layer, an active substance-containing reservoir connected thereto and produced by using pressure sensitive adhesives and at least one penetration enhancer, and a removable protective layer is characterized by the fact that the penetration enhancer is selected from substances based on carboxylic acids. Excerpt(s): This application is a 371 of PCT/EP95/00032 filed Jan. 5, 1995. The present invention relates to an active substance-containing patch for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or in combination with gestagens to the human or animal skin by using pressure sensitive adhesives and at least one penetration enhancer. The present invention further relates to its use and to a process for its production. Estrogen-containing patches have been known for some time. However, they have the disadvantages that they either contain ethanol, or that there is the potential risk that the active substance recrystallizes in the course of time, or that they do not release estradiol in an amount sufficient for therapy. Web site: http://www.delphion.com/details?pn=US06090404__
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Estrogen or estradiol need determination by vaginal acidity determination Inventor(s): Caillouette; James C. (685 Oak Knoll Cir., Pasadena, CA 91106) Assignee(s): None Reported Patent Number: 6,083,178 Date filed: May 1, 1997 Abstract: In the method of determining need for human estrogen or estradiol level change, the steps include determining local acidity proximate a moist wall surface of the vagina, as differing from desired threshold level, and administering sufficient estrogen or estradiol to result in change in acidity toward such level. Excerpt(s): This invention relates generally to factors involved in determining estrogen or estradiol administration to human females, and more particularly to a simple and effective method and means to effect such determination such as need for changes in dosage of estrogen or estradiol. There is need for improvements in methods to determine whether or not a human female should be administered higher or lower
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levels of estrogen or estradiol. The present invention addresses that need. b) and administering sufficient estrogen or estradiol to result in change in acidity toward such level. Web site: http://www.delphion.com/details?pn=US06083178__ •
Estrogen receptor ligands Inventor(s): Bonn; Tomas (Huddinge, SE), Brzozowski; Andrzeji (York, GB), Carlquist; Mats (Spanga, SE), Engstrom; Owe (Nacka, SE), Hubbard; Roderick (York, GB), Ljunggren; Jan (Solna, SE), Pike; Ashley (York, GB), Thorsell; Ann-Gerd (Stockholm, SE) Assignee(s): Kara Bio AB (huddinge, Se) Patent Number: 6,476,196 Date filed: April 27, 2001 Abstract: The present invention is directed to crystals of ER.beta. ligand binding domain complexed with (1) N-(n-butyl)-11-[3,17.beta.-dihydroxyestra-1,3,5(10)-trien-7.alpha.yl]N-me thylundecanamide; estradiol and a peptide comprising the amino acid sequence LXXLL; or 17-epiestriol and a peptide comprising the amino acid sequence LXXLL. Excerpt(s): This invention relates to estrogen receptors and ligands for them, and in particular to crystalline estrogen.beta. receptor (ER.beta.) and to methods of identifying ligands utilizing crystalline ER.beta. The thyroid hormone receptor (TR) is known and its three-dimensional structure, and hence its ligand binding domain, has been determined. Knowledge of the three-dimensional structure has enabled a better understanding of the modes of ligand binding and the determination of the optimum conformation of ligand to bind to the receptor. It is generally believed in the art that the TR structure also provides a guide to the design of ER ligands. It has been proposed that the receptor possesses a multifunctional modular structure potentially having discrete domains for DNA binding, ligand binding, and transactivation. The ligand binding domain (LBD) has been designated domain E and is the largest domain of the estrogen receptor. The ligand binding domain includes a ligand recognition site and regions for receptor dimerization interation with heat shock proteins, nuclear localization and ligand dependent transactivation. Web site: http://www.delphion.com/details?pn=US06476196__
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Formulations for peptide release Inventor(s): Trigg; Timothy E. (Warrawee, AU), Walsh; John D. (Curl Curl, AU) Assignee(s): Peptech Limited (new South Wales, Au) Patent Number: 6,211,152 Date filed: February 17, 1999 Abstract: A pharmaceutical and/or veterinary formulation comprising deslorelin and an excipient, the formulation being characterised in that, in vitro, it releases deslorelin into phosphate buffered saline, as hereinbefore described, at 37.degree. C. at a rate of about 2-80.mu.g/day for at least 200 days. The formulation may be used for prevention of reproductive function, particularly in dogs and cats, and for the treatment, particularly
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in humans, of prostate and breast cancer and other diseases and conditions where suppression of testosterone or estradiol levels is beneficial. Excerpt(s): The present invention relates to pharmaceutical and veterinary formulations for the sustained release of deslorelin which is an agonist of the peptide gonadotropin releasing hormone (GnRH). Uses of the formulations include prevention of reproductive function, particularly in dogs and cats, and treatment, particularly in humans, of prostate and breast cancer and other diseases or conditions where suppression of testosterone or estradiol levels is beneficial. Uncontrolled reproduction in domestic pets is a world wide problem. In less developed countries, reproduction of domestic cats and dogs is relatively uncontrolled. Sporadic programs of work exist aimed at controlling reproduction in these animals by surgical castration. In the more developed countries, reproduction is controlled more by ovarectomy in females and in some cases, by orchidectomy in males, or by physically locking away animals to prevent mating. Surgical techniques, no matter how minor, carry some risk. Many pet owners are also loathe to have their animal surgically modified and will tolerate the problems of uncontrolled reproduction and associated behaviour. To remove the ability to reproduce from domestic pets without the use of surgery and without resorting to lengthy kennelling procedures has been an objective of the small animal research industry for some years. Drugs which are currently available for this process, are steroid-based drugs. They produce unpleasant side effects, particularly after lengthy use, and they are not widely used. Web site: http://www.delphion.com/details?pn=US06211152__ •
Glycoprotein for use in determining endometrial receptivity Inventor(s): Timms; Kathy Lynn (Columbia, MO) Assignee(s): The Curators of the University of Missouri (columbia, Mo) Patent Number: 6,309,843 Date filed: September 18, 1998 Abstract: An isolated and purified glycoprotein designated PUP-1 and functional analogs thereof are disclosed and characterized by being a progesterone induced and estradiol inhibited secretory glycoprotein from stromal cells of endometrial origin; having an N-terminal amino acid sequence as set forth in SEQ ID No:1; having a molecular weight of 70,000 daltons and an isoelectric point of 5.7; and synthesized by endometrium at the time of fertilization, early embryogenesis, and implantation. The present invention further provides a method of determining endometrial receptivity, monitoring placental physiology during gestation, and monitoring the effects of protocols to induce ovarian hyperstimulation or ovulation induction on uterine receptivity by monitoring the cyclic presence of PUP-1 in bodily fluid and tissue samples. Excerpt(s): The present invention relates to human fertility and more particularly, to means and methods for determining uterine endometrial receptivity for a fertilized egg and a method and composition for contraception. There are many issues involved with the evaluation of a woman's fertility. Production and availability of an egg, fertilization of the egg, and other issues involving the physiology of the egg are involved. Another general issue is the nature of the receptivity of the endometrium. If not receptive to implantation, implantation of a fertilized egg may not occur or may occur in an abnormal manner. If receptive, implantation is optimized. Accordingly, it would be
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useful to have a diagnostic tool for determining endometrial receptivity. Reproductive Failure and Assisted Reproductive Technologies: In 1975, Roberts and Loewe, using a mathematical equation, suggested that 78% of fertilizations fail to result in a live birth [Roberts and Loewe, 1975]. Lindley [1979] estimated that only about 30% of all conceptions survive to birth, 15% end in recognizable miscarriage, and the other 55% are lost in the early stages of pregnancy. Inadequate uterine receptivity and subsequent embryo implantation failure, rather than fertilization failure, has been implicated as the crucial event which differentiates fertile and non-fertile ovulatory cycles [Navot et al., 1989]. The importance of endometrial adequacy and receptivity has become even more apparent with the evolution of the assisted reproductive technologies. In vitro fertilization and embryo transfer procedures produce fertilization rates of 70 to 90% whereas pregnancy rates after embryo transfer remain disappointing low ranging from 15 to 25% [Edwards, 1985; Cohen, 1991]. Ovarian hyperstimulation protocols used for these procedures have been associated with several factors that may contribute to lower implantation rates including production of oocytes and subsequent embryos that are chromosomally unbalanced, creation of embryos that are biochemically defective and alteration of the maternal uterine environment [Angell et al., 1987; O'Neill et al., 1987; Collier et al., 1989; Safro et al., 1990]. An improved knowledge of factors influencing maternal uterine environment and human embryo implantation may help "save" these embryos and reduce embryo loss. Web site: http://www.delphion.com/details?pn=US06309843__ •
Matrix-type transdermal patch for steroid hormones Inventor(s): Rovati; Lucio C. (Monza, IT), Santoro; Antonino (Monza, IT) Assignee(s): Rottapharm BV (amsterdam, Nl) Patent Number: 6,440,454 Date filed: April 9, 2001 Abstract: The present invention refers to a transdermal patch for the release of Estradiol and at least one progestogen agent through the skin, comprising or consisting of an outer backing foil, a matrix and a protective liner wherein a) the Estradiol and the progestogen agent(s) are present in the matrix in an oversaturated solution, b) the matrix contains 1 to 5 wt% activated SiO2, and c) the matrix has a moisture content of less than 0.7 wt.-%. The patch can be used for hormonal replacement therapy. Excerpt(s): The present invention relates to a Transdermal Drug Delivery System (TDDS) (a transdermal patch), to a method for manufacturing such system, and to the use of such system for hormone replacement therapy. Estrogens are hormones which are necessary for the sexual development of females at puberty and for the maintenance of the oestrous cycle and secondary sexual characteristics. Estrogens and progesterone induce changes in the reproductive tract and elsewhere in the body of females during the menstrual cycle. Blood estrogen concentrations must be above a certain level for the maintenance of both proliferate and (together with progesterone) secretory phases of the uterine endothelium. The menopause occurs when menstruation ceases and indicates the end of a woman's reproductive life; during this phase of a woman's life there is a progressive loss of ovarian functions and there is a decrease in the production of Estradiol and other hormones. Web site: http://www.delphion.com/details?pn=US06440454__
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Methods and compositions for destruction of selected proteins Inventor(s): Danishefsky; Samuel (Englewood, NY), Kuduk; Scott D. (Harleysville, PA), Ouerfelli; Ouathek (New York, NY), Rosen; Neal (Englewood, NJ), Sepp-Lorenzino; Laura (New Haven, CT) Assignee(s): Sloan-kettering Institute for Cancer Research (new York, Ny) Patent Number: 6,670,348 Date filed: October 20, 1999 Abstract: Compounds having an ansamycin anitibiotic, or other moiety which binds to hsp90, coupled to a targeting moiety which binds specifically to a protein, receptor or marker can provide effective targeted delivery of the ansamycin antibiotic leading to the degradation of proteins and death of the targeted cells. These compositions may have different specificity than the ansamycin alone, allowing for a more specific targeting of the therapy, and can be effective in instances where the ansamycin alone has no effect. Thus, these compounds provide an entirely new class of targeted chemotherapy agents with application, depending on the nature of the targeting moiety, to treatment of a variety of different forms of cancer. Such agents can further be used to promote selective degradation of proteins associated with the pathogenesis of others diseases, including antigens associated with autoimmune disorders and pathogenic proteins associated with Alzheimer's disease. Exemplary targeting moieties which may be employed in compounds of the invention include testosterone, estradiol, tamoxifen and wortmannin. Excerpt(s): This application relates to the use of ansamycin antibiotics as targeted therapeutic agents for the destruction of selected proteins and to novel compositions suited for this use. Destruction of selected proteins in accordance with the invention can be used in the treatment of cancer. Targeted delivery of therapeutic agents as a means for treating cancer has been proposed by many authors. Conceptually, the idea is to deliver a toxic substance selectively to the cancer cells, thus reducing the general toxicity to the patient. This is theoretically possible, since many cancer cell types have been found to have increased levels of hormone receptors and similar receptors. For example, breast cancer cells may have elevated levels of HER2 receptors or estrogen receptors which result in hormone-stimulated growth of cancer cells, while androgen receptors are required for growth of many prostate cancers and mutation of the androgen receptors frequently occurs in advanced prostate cancer. Hormone receptors have been used in studies on the feasibility of using direct targeted chemotherapy agents to certain classes of cells. Thus, for example, Lam et al., Cancer Treatment Reports 71: 901-906 (1987) have reported on estrogen-nitrosourea conjugates as potential cytotoxic agents against human breast cancer, while Brix et al., J. Cancer Res. 116: 538-539 (1990) have reported on studies of the use of androgen-linked alkylating agents as antineoplastic agents. See also, Eisenbrand et al., Acta Oncologica 28: 203-211 (1989). Myers and Villemez, Biochem. Biophys. Res. Commun. 163: 161-164 (1989) have disclosed the possibility of utilizing luteinizing hormone coupled to a truncated diphtheria toxin. Web site: http://www.delphion.com/details?pn=US06670348__
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Non-estrogenic estradiol derivative compounds with anti-oxidative activity Inventor(s): Droescher; Peter (Weimar, DE), Elger; Walter (Berlin, DE), Kaufmann; Guenter (Jena, DE), Menzenbach; Bernd (Jena, DE), Roemer; Wolfgang (Jena, DE), Schneider; Birgitt (Jena, DE) Assignee(s): Jenapharm Gmbh & Co. KG (jena, De) Patent Number: 6,436,917 Date filed: June 5, 1998 Abstract: New non-estrogenic derivative compounds of estradiol, which have no estrogenic activity and comparatively high anti-oxidative activity, are disclosed. These new non-estrogenic derivative compounds are potentially useful as non-estrogenic antioxidants, especially for administration in post-menopausal women and in men. The compounds of the invention can also inhibit aromatase and sulfatase. Excerpt(s): The present invention relates to new non-estrogenic derivative compounds of estradiol with antioxidative activity. It is known from the patent literature, namely from DE 43 38 314 C1, that estradiol and its known derivatives with phenolic A-rings and 17-hydroxy groups have fundamental antioxidative activity. These substances have a more or less strong binding affinity to estrogen receptor sites according to their structure. The high affinity of natural 17.beta.-estradiols (100%) is usually considerably decreased by structural changes, such as isomerization or derivativization. However it still amounts to 23% for 17.alpha.-estradiol and it is still 8.6% for the enantiomer of the natural estradiol, 8.alpha., 9.beta., 14.beta.-estra-1,3,5(10)-trien-3,17.alpha.-diol (entestradiol). These values are not always tolerable depending on the dosage and application duration during administration of the substances with the aim to increase the body's antioxidative capacity. When a large substituent is introduced at the 17carbon atom according to German Patent Document DE 43 38 316 A1, for example in 17.alpha.-4'-dimethylamino-phenylmethyl-estra-1,3,5(10),9(11)-tetraen-3,17 -diol, the binding affinity can be reduced up to less than 1% while increasing the antioxidative activity. However in vivo a high estrogen activity was found for the corresponding 3methyl ether, 3-methoxy-17.alpha.-4'-dimethylamino-phenylmethyl-estra-1,3,5(10)-trien17 -ol. Web site: http://www.delphion.com/details?pn=US06436917__
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Nucleophilic polysubstituted aryl acridinium ester conjugates and syntheses thereof Inventor(s): Law; Say-Jong (Westwood, MA) Assignee(s): Bayer Corporation (east Walpole, Ma) Patent Number: 6,080,591 Date filed: August 29, 1997 Abstract: This invention is directed to novel nucleophilic polysubstituted aryl acridinium conjugates and the methods for preparation thereof. The novel nucleophilic polysubstituted aryl acridinium conjugates are useful in biological assays, including novel assays for the determination of Vitamin B.sub.12, folate, cortisol, estradiol, and thromboxane B.sub.2. Excerpt(s): This invention relates to novel nucleophilic polysubstituted aryl acridinium esters. This invention also relates to conjugates formed from the novel nucleophilic polysubstituted aryl acridinium esters. This invention further relates to assays utilizing
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the novel nucleophilic polysubstituted aryl acridinium esters and conjugates thereof. The use of acridinium esters as chemiluminescent labels in clinical assays is known. For example, European Patent Application No. 82306557.8 describes the use of an aryl acridinium ester linked to an N-succinimidyl moiety as a chemiluminescent label in immunoassays. U.S. Pat. No. 4,745,181 and copending U.S. patent application Ser. No. 133,792, filed Dec. 14, 1987, now U.S. Pat. No. 4,918,192 describe polysubstituted aryl acridinium esters which are useful in immunoassays and nucleic acid hybridization assays. U.S. patent application Ser. No. 226,639, filed on Aug. 1, 1988, describes hydrophilic polysubstituted aryl acridinium esters and conjugates thereof useful in clinical assays, particularly those assays involving liposomes. Richardson et al (Clin. Chem. 31/10, 1664-1668, 1985) and Miller et al (Ann. Clin. Biochem 25, 27-34, 1988) describe the use of 4-(2-aminoethyl)phenyl acridine-9-carboxylate in a chemiluminescent immunoassay for plasma progesterone. However, the prior art acridinium esters often cannot effectively form conjugates with certain analytes. These analytes may lack nucleophilic groups or may contain carboxylic groups which are not readily amenable to modifications. In some cases, the nucleophilic group of the analyte cannot be acylated with an active-group containing acridinium ester because of the resulting deleterious effect on the immunoactivity of the analyte. Web site: http://www.delphion.com/details?pn=US06080591__ •
Oral contraceptive Inventor(s): Gast; Michael J. (Phoenixville, PA) Assignee(s): Wyeth (madison, Nj) Patent Number: 6,451,778 Date filed: July 2, 1997 Abstract: This invention provides a method of contraception which comprises administering to a female of child beating age for a combination of a progestin at a daily dosage of 40-500.mu.g trimegestone, 250.mu.g-4 mg dienogest, or 250.mu.g-4 mg drospirenone, and an estrogen at a daily dosage equivalent in estrogenic activity to 1020.mu.g ethinyl estradiol for 23-25 days beginning on day 1 of the menstrual cycle, and wherein the same dosage of the progestin and estrogen combination is administered in each of the 23-25 days. Excerpt(s): The vast majority of oral contraceptives consist of a combination of a progestin and estrogen that are administered concurrently for 21 days followed either by a 7 day pill free interval or by the administration of a placebo for 7 days in each 28 day cycle. The most important aspects of a successful oral contraceptive product are effective contraception, good cycle control (absence of spotting and breakthrough bleeding and occurrence of withdrawal bleeding), and minimal side effects. Combination oral contraceptives have traditionally acted by suppression of gonadotropins. In addition, it appears that the progestin component is primarily responsible for contraceptive efficacy through inhibition of ovulation, and other peripheral effects which include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). The estrogenic component intensifies the anovulatory effect of the progestin, and is also important for maintaining cycle control. Since the introduction of oral contraceptives (OCs) over a quarter-century ago, research has been directed toward developing preparations that minimize the potential for side effects while maintaining efficacy and normal menstrual patterns. The first-generation OCs
Patents 153
contained more progestin and estrogen than was necessary to prevent conception. Adverse hemostatic and metabolic changes, clinical problems, and side effects were associated with these high-dose preparations. In 1978, the World Health Organization (WHO) recommended that the focus of OC research should be the development of products containing the lowest possible dose levels of estrogen and progestin. The first reductions in steroid content in a combination pill were focused on estrogen because it, rather than progestin, was thought to be related to the most serious side effects. Reduction in progestin content followed, as evidence mounted that lowering progestin intake might lower the risk of cardiovascular complications such as stroke and ischemic heart disease. [Kay CR, Am J Obstet Gynecol 142:762 (1982)]. However, this evidence was not as clear as that implicating estrogen in thromboembolic disorders. [Inman WHW, Br Med J 2:203 (1970); Stolley PD, Am J Epidemiol 102:197 (1975)]. The need for a balance between estrogens and progestins to minimize adverse effects on carbohydrate metabolism and on lipid and lipoprotein levels was also recognized. [Bradley D D, N Engl J Med 299:17 (1978); Wynn V, Lancet 1:1045 (1979)]. Researchers then found that the synergistic action between progestin and estrogen in a balanced ratio successfully inhibited ovulation at low levels of both components. Web site: http://www.delphion.com/details?pn=US06451778__ •
Ovulation cycle monitoring methods Inventor(s): Catt; Michael (Northampton, GB), May; Keith (Bedford, GB) Assignee(s): Inverness Medical Switzerland Gmbh (zug, Ch) Patent Number: 6,403,380 Date filed: February 18, 1997 Abstract: A method of providing warning of the onset of the fertile phase of the human ovulation cycle, involving measurement in absolute or relative terms of the body fluid concentration of an analyte such as estradiol or a metabolite thereof wherein if in the current cycle a concentration measurement conducted at about the termination of menses reveals a body fluid concentration that is typical of that found in the body fluid of an average human female subject about 3 days prior to the time of ovulation during a 28-day cycle, the current cycle is immediately declared to be in its fertile phase. Where the a analyte is E3G, the E3G concentration measurement is conducted on at least one or numerical days 4 to 7 of the current cycle, counting from the onset of menses, and the fertile phase is declared immediately if the E3G measurement reveals a concentration equal to or greater than a threshold concentration chosen in the range of about 25 to about 35 ng/ml. Excerpt(s): This invention relates to methods of monitoring the ovulation cycle in female mammals especially humans. The last few decades have seen much research conducted into ways of enhancing "natural" family planning, in which physiological parameters indicative of the status of the ovulation cycle are monitored. In our European patent specification EP-A-706346 we particularly describe such a method which uses the measurement of urinary estradiol or metabolites thereof, especially estrone-3glucuronide (E3G), to provide a warning of the onset of the fertile phase. Related methods are described in our European patent specifications EP-A-656118, EP-A-656119 and EP-A-656120. Associated testing devices and test kits are described in these specifications, and also in our International patent specifications WO 95/13531 and WO 96/09553. A major objective of these earlier inventions is to provide monitoring methods which are tolerant to the variability in ovulation cycle parameters that occur between
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different individual subjects, and indeed within the same subject from one cycle to another. Especially for contraceptive purposes, a method should provide reliable fertility awareness despite such variability. Even amongst a population of individual women experiencing apparently normal-length cycles (average 28 days), some individuals may exhibit extremely short cycle lengths, on an occasional or more frequent basis. The whole cycle can be compressed into 20 or 21 days, or in extreme instances an even shorter interval. The fertile phase (taking into account the time during which male sperm may remain viable) can commence exceptionally early. In a monitoring method which is looking for a rise in the urinary concentration of E3G or a similar metabolite, as an indicator of imminent entry into the fertile phase, the occurence of a very short cycle with very early commencement of the fertile phase may not easily be identified. Accordingly, as a further refinement, there is need for a "failsafe" mechanism to cope with unexpected short cycles. Web site: http://www.delphion.com/details?pn=US06403380__ •
Pharmaceutical composition based on estrogen and progesterone Inventor(s): Galdona; Javier Gil (Madrid, ES), Grasset; Etienne (Boulogne, FR), Terracol; Didier (Verrieres le Buisson, FR) Assignee(s): Effik Sca Bat (fr) Patent Number: 6,165,491 Date filed: August 3, 1998 Abstract: A pharmaceutical composition, intended for menopausal replacement therapy, comprising a suspension of progesterone in a lipophilic medium solution of a 17estradiol salt in the lipophilic medium, the weight ratio of progesterone to the base 17estradiol being 25 to 600. Excerpt(s): The present invention relates to a composition, based on progesterone and estrogen, which is intended for menopausal hormone replacement therapy. The use of estroprogestative hormone replacement therapy (HRT) for post-menopausal hormone deficiency is widespread in Europe, in particular, and continues to increase. This development is due to several factors: 1) demographic changes, 2) increased life expectancy, which makes it more and more necessary, 3) increasingly numerous demonstrations of its very varied beneficial effects and 4) the development of therapeutic protocols in terms of doses and rates of administration, allowing the minimum effective dose to be administered, thus avoiding or minimizing deprivationhemorrhaging and the endometrial risk factor. The hormonal cycle in women is essentially due to the production of two hormones, 17-estradiol [(17)-estra-1,3,5(10)trieno-3,17-diol] and progesterone [.DELTA.4-pregnen-3,20-dione]. In the case of a deficient cycle, particularly during menopause when the endogenous production of the two hormones decreases, it is customary to compensate for this deficiency by exogenously supplying these two hormones, which is defined as hormone replacement therapy. Web site: http://www.delphion.com/details?pn=US06165491__
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Pharmaceutical compositions and method for prophylaxis and therapy of radicalmediated cell damage Inventor(s): Droescher; Peter (Weimar, DE), Kaufmann; Gunter (Jena, DE), Menzenbach; Bernd (Jena, DE), Oettel; Michael (Jena, DE), Ponsold; Kurt (Jena, DE), Romer; Wolfgang (Jena, DE), Schroeder; Jens (Jena, DE), Undeutsch; Bernd (Jena, DE) Assignee(s): Jenapharm Gmbh & Co. KG (jena, De) Patent Number: 6,172,056 Date filed: May 9, 1996 Abstract: The method of prophylaxis and therapy of radical-mediated cell damage includes administering an effective amount of at least one steroid and at least one pharmaceutical adjuvant to a human being. The at least one steroid is selected from the group consisting of ent-estradiol, 17.alpha.-estradiol, 8-dehydro-estradiol, 8-dehydro17.alpha.-estradiol, 8(14)-dehydroestradiol, 6,8-didehydro-17.alpha.-estradiol, 6dehydroestriol, 9(11)-dehydroestriol, 20-hydroxymethyl-3-hydroxy-19-norpregna1,3,5(10)-triene, 14.alpha., 15.alpha.-methylene-8-dehydroestradiol, 14.alpha., 15.alpha.methylene-estradiol, 2-hydroxy-estradiol-3-methyl ether, 3-hydroxy-1,3,5(10)estratriene-17S-spirooxirane, 3-hydroxy-1,3,5(10),9(11)-estratetraene-17S-spirooxirane, and 14.beta.,15.beta.-methylene-8-dehydroestradiol. This method strongly inhibits changes in cells and tissues, such as lipid peroxidation and oxidation of low-density lipoprotein (LDL) cholesterol, triggered by reaction oxygen species, free oxygen radicals and other forms of radicals and thus reduces attendant irreversible membrane and endothelial damage. Excerpt(s): The invention relates to novel pharamaceutical preparations for prophylaxis and therapy of radical-mediated cell damage. From professional and patent literature it is known that reactive oxygen species (ROSs), free oxygen radicals and other radial forms play an important role in the occurrence of many kinds of cell damage, such as ischemic and traumatic organ injuries, and inflammatory and toxic processes. A negative effect of ROSs, free oxygen radicals and other forms of radicals can also be found in brain and spinal column injuries, shock states, stroke, muscular dystrophy, emphysemas, adult respiratory distress syndrome (ARDS), asthma, aging processes, in tissue damage after myocardial infarction, damage from toxic processes and radiation, burns, and transplant-dictated immune reactions. Among other factors, lipid peroxidation and the oxidation of low-density lipoprotein (LDL) cholesterol, combined with irreversible membrane and endothelial damage are the starting point for such radical-mediated cell damage. Web site: http://www.delphion.com/details?pn=US06172056__
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Pharmaceutical preparations for treatment of estrogen deficiency in the central nervous system Inventor(s): Oettel; Michael (Jena, DE), Patchev; Vladimir (Jena, DE), Roemer; Wolfgang (Jena, DE), Schwarz; Sigfrid (Jena, DE), Thieme; Ina (Graitschen, DE) Assignee(s): Jenapharm Gmbh & Co. KG (jena, De) Patent Number: 6,245,756 Date filed: February 19, 1999
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Abstract: Pharmaceutical preparations containing selected steroid compounds and methods of treating estrogen deficiency in the central nervous system (CNS) without influencing other organs or systems are described. These steroids have selective neurotropic estrogen-like transcription action in contrast to the systemically acting natural and synthetic estrogen compounds, such as 17.alpha.-estradiol. The selected steroids surprisingly have a selective influence on the transcription estrogen-dependent gene in the CNS and cause changes of physiological parameters as well as CNS-specific transcription effects in the dosages used with no biological effects in reproductive system tissues. They have CNS specific transcription effects at those dosages at which neither 17.beta.-estradiol nor 17.alpha.-estradiol had any action and the transcription estrogen-dependent gene in the CNS is not influenced by secondarily formed 17.beta.estradiol. Excerpt(s): The present invention relates to a method of treating estrogen deficiency in the central nervous system without influencing other organs or systems by administration of a pharmaceutical preparation of selected steroids and to the pharmaceutical composition used in that method. wherein R.sub.1 represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 5 carbon atoms; R.sub.2 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an acyl group having 1 to 5 carbon atoms or a group of the formula SO.sub.2 NR.sub.10 R.sub.11, wherein R.sub.10 and R.sub.11 represent, independently of each other, a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or together with nitrogen, a pyrrolidino group, a piperidino group or a morpholino group; R.sub.3 represents a hydrogen atom or a hydroxy group; R.sub.4 represents a hydrogen atom, a hydroxy group or an alkyl group with 1 to 5 carbon atoms; R.sub.5 and R.sub.6 each represent, independently of each other, a hydrogen atom or a halogen atom; R.sub.7 represents hydrogen or a methyl group; R.sub.8a represents a hydrogen and R.sub.8b represents a hydroxy group or R.sub.8a represents a hydroxy group and R.sub.8b represents a hydrogen or both together represent an oxo group or a group of formula CR.sub.12 R.sub.13, in which R.sub.12 and R.sub.13 each represent, independently of each other, a hydrogen atom or a halogen atom; R.sub.9 represent a methyl or an ethyl group; Z either represents a double bond or a substituted or unsubstituted cyclopropane ring; and >CR.sub.5 R.sub.6 is an a group or a.beta. group and R.sub.7 is a.beta. group when >CR.sub.5 R.sub.6 is an.alpha. group and vice versa. An abrupt or gradual decrease of the estrogen concentrations in organisms can occur both in women and in men in various physiological conditions (increasing age, menopause) and pathological conditions (gonadectomy, use of GnRH analogs in supplemental cancer therapy). Troublesome thermoregulation in the form of hot flashes, osteoporosis and an increased predisposition to heart and circulatory illness are part of the best known clinical symptoms of estrogen deficiency (A. Netter, "The menopause", in C. Thibault, M. C. Levasseur, R. H. F. Hunter (eds.), Reproduction in Mammals and Man, Ellipses, Paris, 1993, pp. 627 to 643). The latest clinical studies (A. W. van den Beld, et al, "The Role of Estrogens in Physical and Psycho-social Well-being in Elderly Men", The Aging Male 1 (Suppl. 1), 54, 1998) definitely prove the connection between decreased serum estrogen levels and increasing aging in man. Because of that the presence and pathophysiological relevance of an "estrogen deficiency syndrome" in aging men is underscored. Web site: http://www.delphion.com/details?pn=US06245756__
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Preparation with an acrylic-based, adhesive copolymeric matrix for the transdermal delivery of estradiol Inventor(s): Cordes; Gunter (Leichlingen, DE), Fischer; Wilfried (Bad Tolz, DE), Makovec; Francesco (Monza, IT), Rovati; Lucio (Monza, IT), Rovati; Luigi (Monza, IT) Assignee(s): Rotta Research Laboratorium S.p.a. (monza, It) Patent Number: 6,156,335 Date filed: July 15, 1994 Abstract: The invention is represented by a transdermal medicated patch for the extended release of 17.beta.-estradiol to the skin. The transdermal patch is formed by an outer covering, a matrix containing from 1% to 5% (w/w) 17.beta.-estradiol, and a protective liner which is removed before use. The matrix is formed of pressure-sensitive adhesive acrylic copolymers, in which the active ingredient is dissolved or dispersed. The acrylic copolymers are obtained by radical copolymerization of 2-ethylhexyl acrylate, methyl acrylate, acrylic acid, vinyl acetate, hydroxyethyl acrylate or a mixture thereof. Optionally quantities of less than 0.5% (w/w) of other substances may be added. Excerpt(s): The invention relates to pharmaceutical delivery systems and more particularly to preparations for transdermal administration of estradiol. Ovarian secretion of 17.beta.-estradiol is lacking in postmenopausal women. In many women this physiological phenomenon induces progressive hypotrophy of the urogenital system as well as characteristic vasomotor symptoms, often followed by osteoporosis affecting particularly the vertebral column. These climacteric symptoms can be prevented by an exogenous estrogen-based hormone replacement therapy. However, the oral administration of 17.beta.-estradiol (hereinafter referred to as "estradiol") has problems, since the hormone is modified in the intestine and in the liver and produces high blood levels of its metabolites, such as estradiol sulfate, estrone and estrone sulfate which may accumulate in the organism, if the administration is prolonged. One of the undesired effects of the oral administration of estradiol is the increased synthesis by the liver of proteins, including the substrate of renin, with a possible consequent increase in arterial pressure. Web site: http://www.delphion.com/details?pn=US06156335__
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Regulation of amyloid precursor protein (APP) expression by administration of an estrogenic compound Inventor(s): Lee; Robert K. K. (Boston, MA), Wurtman; Richard J. (Boston, MA) Assignee(s): Massachusettes Institute of Technology () Patent Number: 6,333,317 Date filed: March 27, 1998 Abstract: It has been discovered that lipophilic hormones that interact with cytosolic or nuclear receptors regulate APP expression and synthesis, through modification of APP mRNA stability and/or regulation of APP gene transcription and translation activities. These studies demonstrate that the treatment of brain cells with estrone or 17.beta.estradiol results in a reduction in the level of APP holoprotein expression, without a concomitant change in the total level of cell protein. The reduction in the level of APP holoprotein caused by estrone or 17.beta.-estradiol is also expected to reduce the
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production of neurotoxic APP fragments. In as much as estrogen deficiency in postmenopausal women is associated with a higher incidence of Alzheimer's disease, this discovery opens the possibility that estrogen therapy may prevent some of the neurodegenerative and cognitive changes associated with Alzheimer's disease, aging and other disease conditions associated with such neurodegenerative and cognitive decline. Excerpt(s): The present invention relates to compositions and methods for the treatment of various neurological diseases and neurodegenerative disorders associated with aging, particularly those affected by an overabundance of Amyloid Precursor Protein (APP). In particular, this invention relates to the APP holoprotein synthesis and the effect of lipophilic compounds on regulating the expression of this protein. In particular, it has been discovered that certain neurodegenerative or cognitive changes are associated with developing an imbalance in the serum levels of endogenous, gynecologically relevant substances, including certain neurotransmitters, neurotransmitter substrates or hormones. It has also been found that the level of APP holoprotein is reduced by lipophilic estrogenic compounds in brain cells, and that this reduction is expected to reduce the neurotoxicity or neurodegeneration associated with APP over expression. Alzheimer's Disease (AD) is the most common neurodegenerative disorder of aging, and is characterized by progressive dementia and personality dysfunction. The abnormal accumulation of amyloid plaques in the vicinity of degenerating neurons and reactive astrocytes is a pathological characteristic of AD. Several lines of studies suggest that postmenopausal women with lower levels of endogenous estrogen may be predisposed to the development of AD. Studies in experimental animal models provide a convincing rational for the role of estrogen replacement therapy and prevention of dementia. See, for example, Birge, J. Am. Geriatric. Soc. 44, 865, (1996). These studies suggest that estrogen deficiency in postmenopausal women apparently increases their susceptibility to the neurodegenerative changes of aging and AD, and that this risk can be decreased by estrogenic replacement therapy. Peganini et al. Am. J. Epidemiol, 140, 256 (1994). Estrogen treatment of cell culture reportedly promotes non-amyloidogenic APP processing and soluble APP (APPs) secretion. Jaffe et al., J. Biol. Chem. 269, 13065 (1994). Web site: http://www.delphion.com/details?pn=US06333317__ •
Rhodiola and used thereof Inventor(s): Xiu; Rulin (2010 Kalorama Rd., NW., Suite 44, Washington, DC 20009) Assignee(s): None Reported Patent Number: 6,399,116 Date filed: April 28, 2000 Abstract: The present invention relates to Rhodiola, preferably Rhodiola crenulata, to treat various conditions and diseases in mammals. Rhodiola crenulata is a Tibetan herb which has been discovered to have highly useful and beneficial properties heretofore unknown. Rhodiola crenulata is especially preferred to enhance blood oxygen levels, to enhance working capacity and endurance, to enhance memory and concentration, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to protect against oxidation, to modulate testosterone and estradiol levels, to modulate sleep, and to enhance sexuability, such as improve sexual performance.
Patents 159
Excerpt(s): The present invention relates to compositions, articles of manufacture, extracts, compounds, methods of use, methods of treatment, methods of preparation, etc., which relate to plants of the genus Rhodiola, preferably Rhodiola crenulata, which have a variety of useful and beneficial effects, including, e.g., to enhance blood oxygen and nutrients levels, e.g., through enhancing oxygen transport, to enhance working capacity and endurance, to reduce muscle fatigue, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to protect against oxidation, to provide anti-cancer effects, to promote DNA repair, to provide anti-radiation effects, to protect against radiation, to reduce inflammation, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, preferably, to modulate testosterone levels, and to modulate sleep, especially to promote sleep, to modulate blood lipids, preferably, e.g., to lower cholesterol levels, to promote weight loss, and to enhance sexuability, such as improve sexual performance. Rhodiola crenulata is a species of Rhodiola which grows mostly in Tibet and south west of China on the altitude between 3400 meters to 5600 meters. It has been used in Tibetan medicine for more than 1000 years for uses that have been limited to curing lung inflammation and cough, for stopping and activating blood, and for treating external wounds and burns. It has been discovered herein that Rhodiola crenulata has other beneficial properties that make it useful for a variety of conditions and diseases, as mentioned above and below. Rhodiola is a diverse genus of plants which includes more than 50 different species, including, e.g., algida, arctica, crenulata, elongata, gelida, imbricataishidae, iremelica, kirilowii, linearifolia, phariensis, pinnatifida, quadrifida, aff. quadrifida, rosea, sachalinensis, and wolongensis. These species vary from each other widely, differing in, e.g., chromosome number (e.g., Makoto et al., Journal of Japanese Botany, 70(6):334-338, 1995), chemical composition, morphology, medicinal properties, developmental stages (e.g., Ishmuratatova and Satsyperova, Rastitel'nye Resursy., 34(1):3-11, 1998), geographical distribution, etc. Scientific studies (e.g. Peng et al, Chinese Herb Medicine (1995), 26(4): 177-179, and Wang et al, Acta Phrmaceutica Sinica(1992), 27(2): 117-120) indicate constituents of Rhodiola crenulata include, e.g., salidroside, tyrosol,.beta.-sitosterol, gallic acid, pyrogallol, crentulatin, rhodionin, rhodiosin, among which, crenulatin, e.g., is found only in R. crenulata and has not been found in any other Rhodiola species. Rhodiosin and rhodionin exists in some, but not all, Rhodiola species. Web site: http://www.delphion.com/details?pn=US06399116__ •
Skin care compositions containing an organic extract of chick pea Inventor(s): Bosko; Carol Annette (Oradell, NJ), Carlomusto; Marieann (Palisades Park, NJ), Pillai; Sreekumar (Wayne, NJ), Santhanam; Uma (Tenafly, NJ) Assignee(s): Chesebrough-pond's Usa Co., Division of Conopco, Inc. (greenwich, Ct) Patent Number: 6,548,072 Date filed: September 20, 1999 Abstract: Organic chick pea extracts are phytoestrogens, if present in an amount such as to provide an estrogenic activity equivalent to at least 1 nM of estradiol. Cosmetic compositions containing organic chick pea extracts are useful in improving the appearance of wrinkled, lined, dry, flaky, aged or photodamaged skin and improving skin thickness, elasticity, flexibility and plumpness. Excerpt(s): Cosmetic compositions containing an organic extract of chick peas and methods of conditioning skin by applying such compositions to the skin. The human
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skin consists of two major layers, the bottom thicker layer dermis, and the top thinner layer--the epidermis. Dermis is the layer which provides the strength, elasticity and the thickness to the skin. The main cell type of the dermis is fibroblasts, which is responsible for synthesis and secretion of all the dermal matrix components such as collagen, elastin and glycosaminoglycans. Collagen provides the strength, elastin the elasticity and glycosaminoglycans the moistness and plumpness of the skin. With aging, the thickness of the dermal layer is reduced and this is believed to be partially responsible for the formation of wrinkles in aging skin. The top layer of human skin or the epidermis which provides the resilience and the barrier properties of the skin, is composed of many different cell types including keratinocytes, melanocytes and langerhans cells. Keratinocytes are the major cell type of the epidermis (75-80% of the total number of cells in the human epidermis). Richards et al. reported that estrogen stimulates secretion of a protein, prolactin, by human dermal fibroblast cells and that prolactin then stimulates proliferation of keratinocytes. Richards et al., Human Dermal Fibroblasts Express Prolactin In Vitro., J. Invest. Dermatol., 106: 1250, 1996. Web site: http://www.delphion.com/details?pn=US06548072__ •
Skin-adhering pharmaceutical preparation, in particular transdermal therapeutic system for the release of 17-.beta.-estradiol to the human organism Inventor(s): Asmussen; Bodo (Bendorf-Sayn, DE), Horstmann; Michael (Neuwied, DE) Assignee(s): Lts Lohman Therapie-systeme Gmbh (neuwied, De) Patent Number: 6,267,982 Date filed: March 17, 1999 Abstract: A pharmaceutical preparation adhering to the skin, in particular a TTS, for the release of the active substance 17-.beta.-estradiol, the concentration of the estradiol contained therein in dissolved form being between its saturation concentration in equilibrium with a gas phase of less than 10% relative air humidity and its saturation concentration in equilibrium with a gas phase of more than 90% relative air humidity, in all matrix layers and, if present, also in an adhesive layer, characterized in that the estradiol quantity contained in the preparation amounts to at least three times the saturation solubility measured at 95% relative air humidity, and that the air enclosed in the package is adjusted to a relative air humidity between 5% and below 0.5%. Excerpt(s): The present invention relates to a pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system, for the release of 17-.beta.estradiol and optionally further active substances through the skin to the human organism. Pharmaceutical preparations contacting the skin include, for example, ointments, creams, lotions, and also drug-containing patches, these have been introduced on the market for some time under the name "transdermal therapeutic systems" (TTS) to treat several diseases. In the meantime, TTSs comprising the active substance 17-.beta.-estradiol have also been on the market as a therapeutic agent for climacteric complaints, and, for a short time, also against osteoporosis, proving successful in therapy. Web site: http://www.delphion.com/details?pn=US06267982__
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Solid matrix system for transdermal drug delivery Inventor(s): Chiang; Chia-Ming (Foster City, CA), Tenzel; Renee Ann (Mountain View, CA) Assignee(s): Ortho-mcneil Pharmaceutical, Inc. (raritan, Nj) Patent Number: 6,149,935 Date filed: August 16, 1999 Abstract: A matrix for containing drugs for transdermal delivery systems is disclosed. The matrix, formed of a skin-adhesive acrylate copolymer, attains high rates of drug delivery without the addition of drug delivery rate enhancers. In preferred embodiments the matrix is used to administer steroids, in particular estradiol. Watersoluble polymers may be added as well. Excerpt(s): This invention relates generally to the transdermal administration of drugs. More particularly, it concerns a configuration for transdermal drug delivery devices which enables the administration of effective levels of drugs without the necessity for coadministration with skin penetration rate enhancers. Transdermal delivery of drugs, that is, delivery of drugs through the skin, provides many advantages. The method is a comfortable, convenient, and noninvasive way of administering drugs. Many of the variables and side effects associated with oral administration are eliminated. Since the early 1970s, there has been substantial effort spent on developing particular systems for effectively delivering drugs in a transdermal mode. A variety of devices containing, at minimum, a drug reservoir and a backing, and optionally containing other layers, such as an adhesive layer for adhering the device to the patient, a drug release rate controlling layer for moderating delivery rate, and the like, have been constructed. With certain drugs, in particular scopolamine and nitroglycerine, it is feasible to construct a transdermal drug delivery device which will achieve therapeutically effective levels of the drug in the patient. Commercial products have been introduced to deliver these two materials. However, one of the key problems with transdermal administration of many other drugs has been the low penetration or permeation rate of drug through the skin of the patient. The research over the past two decades has identified various skin permeation enhancers. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Many highly attractive drugs, such as estradiol, progestins and the like are commonly formulated with enhancers for transdermal delivery. Web site: http://www.delphion.com/details?pn=US06149935__
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Transdermal estradiol/progestogen agent patch and its production Inventor(s): Cordes; Gunter (Lagenfeld, DE), Santoro; Antonino (Monza, IT), Setnikar; Ivo (Monza, IT) Assignee(s): Rotta Research B.v. (amsterdam, Nl) Patent Number: 6,153,216 Date filed: September 14, 1998 Abstract: The invention concerns a transdermal patch for the release through the skin of estradiol and a progestogen agent and a process for its production.
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Excerpt(s): The invention regards a transdermal patch delivering estradiol and a progestogen for the hormone replacement therapy. At an average age between 45 and 52 years, in the women there is a gradual decline of the ovarian function ending with the cessation of ovulation and of the endocrine secretion of sexual hormones. This condition is called menopause and is connected with a number of unpleasant symptoms, such as hot flushes, sweats, insomnia, vaginal dryness and depression. In the long term the estrogen deficiency leads to a generalized atrophy of the skin, loss of hairs, urogenital atrophy and dysfunction, accelerated bone loss from the skeleton producing osteoporosis and rapid increase of the incidence of coronary heart diseases. All these adverse sequelae can be reversed by an appropriate replacement therapy with estrogen agents, i.e. by the "Hormone Replacement Therapy.sub.-- (HRT). Several types of estrogens are used for the HRT, e.g. conjugated equine estrogens, estradiol, estrone, etc., with a preference for estradiol which is the most potent physiological estrogen hormone. Web site: http://www.delphion.com/details?pn=US06153216__ •
Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen Inventor(s): Audett; Jay (Mountain View, CA), Jona; Janan (Sunnyvale, CA), Singh; Noel (San Francisco, CA) Assignee(s): Ortho-mcneil Pharmaceutical, Inc. (raritan, Nj) Patent Number: 6,071,531 Date filed: June 28, 1999 Abstract: Compositions and methods for preventing ovulation in a woman are provided, as well as compositions and methods for female hormone replacement therapy. The compositions can be administered by the use of a transdermal patch. The patch will administer 17-deacetyl norgestimate alone or in combination with an estrogen such as ethinyl estradiol to women. Excerpt(s): This invention relates to transdermal drug delivery. More particularly, it concerns patches and methods for transdermally administering 17-deacetyl norgestimate either alone or in combination with an estrogen, particularly ethinyl estradiol. Combinations of norgestimate (Ngm) and ethinyl estradiol (EE) are administered orally to women as a contraceptive. Bringer J., Am. J. Obstet. Gynecol. (1992) 166:1969-77. McGuire, J. C. et al., Am. J. Obstet. Gynecol. (1990) 163:2127-2131 suggests that orally administered Ngm metabolizes to 17-deacetyl norgestimate (17-dNgm), 3-ketonorgestimate, and levonorgest (Lng) and that these metabolites may contribute to the pharmacologic response to the orally administered drug. Chien et al., U.S. Pat. No. 4,906,169 describes transdernal patches for co-delivering estrogens and progestins to women for contraception. EE is mentioned as one of the estrogens that may be administered from the patch and Ngm and Lng are mentioned as possible progestins that may be administered. Web site: http://www.delphion.com/details?pn=US06071531__
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Unit galenical formulation for local hormonotherapy of vaginal dryness Inventor(s): Meignant; Catherine (Paris, FR) Assignee(s): Laboratoire Innothera, Societe Anonyme (arcueil, Fr) Patent Number: 6,060,077 Date filed: June 5, 1998 Abstract: A galenical formulation is intended for local, essentially non systemic, treatment of vaginal dryness, in particular in the menopausal woman. It comprises a free natural estrogen, in particular a micronized or vectorized estrogen, selected from 17.beta.-estradiol and its salts in solution or in suspension in a lipophilic agent, with an estrogen content which corresponds to an equivalent unit dose of at most 15.mu.g, preferably less than 10.mu.g, of 17.beta.-estradiol, a hydrophilic gel-forming bioadhesive agent, a gelling agent for the lipophilic agent and a hydrodispersible agent. The soft capsule form comprises a hard or soft outer envelope containing gelatin and glycerine and a non aqueous liquid or semi-liquid inner phase containing the lipophilic agent with the estrogen in solution or in suspension, the bioadhesive agent and the hydrophilic gelling agent for the lipophilic agent. The slow release vaginal suppository comprises a non aqueous hard or semi-soft solid homogeneous phase containing the lipophilic agent with the estrogen in solution or in suspension, the hydrophilic bioadhesive gel-forming agent, the gelling agent for the lipophilic agent and the hydrodispersible agent. Excerpt(s): The invention concerns a medicament for local, essentially non systemic, treatment of vaginal dryness. The problems of vaginal dryness, in particular in the menopausal woman, are known: dyspareunia, urogenital atrophy which can cause problems with the urinary function, and risks of infection due to an insufficiently developed flora. One aim of the invention is to provide a medicament which is suitable for essentially non systemic treatment, which is thus distinguished from substitutive hormonotherapy treatments where the hormone can be administered per os, transcutaneously or intravaginally. Web site: http://www.delphion.com/details?pn=US06060077__
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Use of 17-.alpha.-estradiol for the treatment of aged or sundamaged skin and/or skin atrophy Inventor(s): Gendimenico; Gerard J. (Neshanic Station, NJ), Mezick; James A. (East Brunswick, NJ) Assignee(s): Johnson & Johnson Consumer Companies, Inc. (skillman, Nj) Patent Number: 6,488,940 Date filed: August 10, 1998 Abstract: The present invention relates to a method for treatment of mammalian skin conditions where stimulated connective tissue synthesis is beneficial, comprising treating skin in need of such treatment with a safe and effective amount of 17-.alpha.estradiol. Excerpt(s): The present invention relates to a method of treating mammalian skin conditions to stimulate connective tissue synthesis in situations in which such connective tissue synthesis is beneficial. Specifically, the invention relates to novel compositions and methods of using the composition for treatment of aged skin, sun-
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damaged skin, acne, skin atrophy and for healing of wounds. Estrogens are hormonal compounds that exert wide-ranging biological effects on target tissues. The major organs affected by estrogens are the reproductive tract, genitals, bone, blood vessels and skin. The most important natural estrogen is 17-.beta.-estradiol, considered the hormone responsible for most, if not all the normal physiologic processes of this class of compounds. Two other natural estrogens are estrone, a precursor of 17-.beta.-estradiol and estriol, a metabolic product of 17-.beta.-estradiol. Web site: http://www.delphion.com/details?pn=US06488940__ •
Use of 5alpha-androstanediol or dihydrotestosterone levels in humans
5alpha-androstanedione
to
increase
Inventor(s): Llewellyn; William Charles (P.O. Box 1162, Sound Beach, NY 11789) Assignee(s): None Reported Patent Number: 6,242,436 Date filed: June 15, 2000 Abstract: This invention discloses a method of administering direct precursors of the hormone dihydrotestosterone as a means of increasing androgen levels in humans. As men age, a decline in androgenic hormone levels is typically noted, possibly resulting in muscle mass, bone density and energy loss. Various methods have therefore been developed to supplement androgens for men with declining levels. This invention teaches using precursors to testosterone, in that DHT and its precursors cannot be converted to estrogens in the human body. This may be a very advantageous trait for aging men at risk for benign prostatic hypertrophy, as estrogenic and androgenic action are both needed to induce this condition. As testosterone is the primary substrate for the synthesis of estradiol in men, its use as a target for androgen replacement may pose a greater health risk. Excerpt(s): This invention relates a method of administering the dihydrotestosterone precursor hormone 5alpha-androstanediol or 5alpha-androstanedione as a means of increasing dihydrotestosterone levels in humans. Although testosterone is considered to be the primary male androgen, in many sites of action it is actually dihydrotestosterone that is the active form of this steroid. Dihydrotestosterone (DHT) is a more potent form of testosterone, shown to be roughly three to four times more active in the human body in comparison. Its higher level of activity is attributed to the ability of this hormone to bind to the androgen receptor with greater affinity, and with more stability, than testosterone. The activity of DHT is most closely related to the development and maintenance of male sexual characteristics, including external virilization, sexual maturity at puberty, spermatogenesis, sexual behavior/libido and erectile functioning. DHT has also been shown to be equally effective as testosterone at inducing the expected benefits of androgen replacement on mood, sexual function, bone and muscle. A number of methods have been developed to restore androgen concentration in humans with declining levels. Several injectable esterified testosterone preparations have been fashioned that allow a slow release of hormone into the blood stream over the course of several days to weeks for example, however all provide inconsistent dosing as there is great variance in hormone release from the site of injection, such that a short supraphysiological rush may eventually be followed by days of subnormal hormone concentrations. The buildup of estrogens due to the natural process of aromatization may exaggerate the side effects to such medication, particularly at times when testosterone levels are abnormally high, as supraphysiological levels of estrogens in the
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male body have been linked to gynecomastia (female breast tissue development), water retention and edema, and increased fat deposition. More basically, recent studies have made clear that both androgens and estrogens play a synergistic role in the promotion of benign prostatic hypertrophy (BPH). This suggests that an aromatizable androgen such as testosterone may be less than ideal for use in older men at risk for such disease. Also a number of synthetic oral androgen derivatives have been developed including methyltestosterone, fluoxymesterone and stanozolol. All such compounds are alkylated at the 17.sup.th carbon position (alpha orientation), an alteration that inhibits reduction of the steroid to inactive 17-ketosteroid form. While this greatly improves oral bioavailability of the compound, this alteration has also been shown to place stress on the liver, in some instances resulting in organ damage. Although the use of a c-17 alpha alkylated oral androgen may prove much more comfortable for the patient in terms of dosing and control over blood hormone level compared to an injectable preparation, the possible risk of developing complications with liver functions may make them much less useful for androgen replacement compared to injectable preparations, particularly for extended periods of therapy. Web site: http://www.delphion.com/details?pn=US06242436__ •
Use of 7.alpha.-substituted steroid to treat neuropsychiatric, immune or endocrine disorders Inventor(s): Best; Ruth (Edinburgh, GB), Lathe; Richard (Edinburgh, GB), Leckie; Caroline McKenzie (Edinburgh, GB), Rose; Kenneth Andrew (Edinburgh, GB), Seckl; Jonathan Robert (Edinburgh, GB), Yau; Joyce Lai Wah (Edinburgh, GB) Assignee(s): Btg International Limited (london, Gb) Patent Number: 6,420,353 Date filed: October 8, 1998 Abstract: Use is provided for a 7.alpha.-hydroxy or 7-oxo substituted 3.beta.-hydroxysteroid possessing the carbon skeleton of cholesterol, androsterone, pregnenolone or estradiol, or an analogue thereof substituted independently at one or both of the 7- and 3-positions with an ester or ether group, in the manufacture of a pharmaceutical composition for the therapy of neuropsychiatric, immune and/or endocrine disorders or for inducing cognitive enhancement. Uses for Cyp7b enzymes in producing such steroids is also provided together with various novel steroids and test kits and methods for diagnosing the disorders. Excerpt(s): The present invention relates to novel uses for 7.alpha.-hydroxy-substituted steroids, to a process for preparing such steroids and to novel steroids so produced. In particular the invention relates to the use of cytochromes of the cytochrome P450 family designated Cyp7b to effect 7.alpha.-hydroxylation of certain 3.beta.-OH steroids so as to produce a 7.alpha.-hydroxy-substituted steroids. Certain of the 7.alpha.-hydroxysubstituted steroids so produced, as well the corresponding 7-oxo derivatives, are novel and form further aspects of the invention. The invention also relates to uses of these steroids, to uses of Cyp7b enzymes and to uses of novel macromolecular species, e.g. antibodies and DNAs, which are biologically related to the Cyp7b enzymes. Cytochromes P450 are a diverse group of heme-containing mono-oxygenases (termed CYP's; see Nelson et al., DNA Cell Biol. (1993) 12, 1-51) that catalyse a variety of oxidative conversions, notably of steroids but also of fatty acids and xenobiotics. While CYP's are most abundantly expressed in the testis, ovary, placenta, adrenal and liver, it is becoming clear that the brain is a further site of CYP expression. Several CYP activities
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or mRNA's have been reported in the nervous system but these are predominantly of types metabolizing fatty acids and xenobiotics (subclasses CYP2C, 2D, 2E and 4). However, primary rat brain-derived glial cells have the capacity to synthesize pregnenolone and progesterone in vitro. Mellon and Deschepper, Brain Res. (1993), 629, 283-292(9) provided molecular evidence for the presence, in brain, of key steroidogenic enzymes CYP11A1 (scc) and CYP11B1 (11.beta.) but failed to detect CYP17 (c17) or CYP11B2 (AS). Although CYP21A1 (c21) activity is reported to be present in brain, authentic CYP21A1 transcripts were not detected in this tissue. Web site: http://www.delphion.com/details?pn=US06420353__
Patent Applications on Estradiol As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to estradiol: •
19-nor-17alpha-pregna-1,3,5 (10) -trien-17beta-ols with a 21, 16alpha-lactone ring Inventor(s): Elger, Walter; (Berlin, DE), Fritzemeier, Karl-Heinrich; (Berlin, DE), Kollenkirchen, Uwe; (Berlin, DE), Kosemund, Dirk; (Erfurt, DE), Muller, Gerd; (Jena, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20020156271 Date filed: September 27, 2001 Abstract: This invention relates to new 19-nor-17.alpha.-pregna-1,3,5(10)-trien-17.b- eta.ols with a 21,16.alpha.-lactone ring of formula II, 1process for their production and pharmaceutical preparations that contain these compounds as well as 17.alpha.cyanomethylated estra-1,3,5(10)-trienes, which produce intermediate products on the way to the 19-nor-17.alpha.-pregna-1,3,5(10)-trien-17.beta.-ols.The 19-nor-17.alpha.pregna-1,3,5(10)-trien-17.beta.-ols produce novel selective estrogens, which contrast to standard estrogens, such as estradiol, show a preference for one of the two known estrogen receptors, estrogen receptor alpha. Excerpt(s): This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/243,285 filed Oct. 26, 2000. This invention relates to new 19nor-17.alpha.-pregna-1,3,5(10)-tri- en-17.beta.-ols with a 21,16.alpha.-lactone ring, process for their production and pharmaceutical preparations that contain these compounds, as well as 17.alpha.-cyanomethylated estra-1,3,5(10)-trienes, which produce intermediate products on the way to the 19-nor-17.alpha.-pregna-1- ,3,5(10)-trien17.beta.-ols. The 19-nor-17.alpha.-pregna-1,3,5(10)-trien-17.beta.-ols with a 21,16.alpha.lactone ring produce novel selective estrogens that in contrast to standard estrogens, such as estradiol, show a preference for one of the two known estrogen receptors, estrogen receptor alpha (ERa; Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93:5925-5930; Mosselman, Dijkema (1996) Febs Letters 392:49-53 (and EP-A-0 798 378); Tremblay et al. (1997), Molecular Endocrinology 11:353-365). Since the two estrogen receptors, ERa and
10
This has been a common practice outside the United States prior to December 2000.
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ERA, have a different organ distribution (Kuiper et al. (1996), Endocrinology 138:863870), the ERa tracing of selective estrogens represents an important technical step forward. With these new estrogens, a more selective therapy of estrogen-deficiencyinduced diseases with low estrogen action on organs that do not express ER.alpha. is possible. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Administration of estradiol metabolites for the treatment or prevention of obesity, metabolic syndrome, diabetes, and vascular and renal disorders Inventor(s): Dubey, Raghvendra K.; (Glenshaw, PA), Jackson, Edwin K.; (Pittsburgh, PA), Tofovic, Stevan P.; (Pittsburgh, PA) Correspondence: Mary-elizabeth Buckles; Reed Smith, Llp; Suite 1100 - East Tower; 1301 K Street, N.W.; Washington; DC; 20005; US Patent Application Number: 20030050294 Date filed: August 19, 2002 Abstract: Methods are provided for preventing or treating risk factors for cardiovascular disease in an individual, comprising administering a therapeutically effective amount of a composition comprising an estradiol metabolite to said individual. Such risk factors include obesity, the metabolic syndrome, diabetes mellitus, vascular disorders, and renal disorders. Preferred estradiol metabolites include 2-methoxyestradiol, 4methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol or prodrugs thereof. The compositions may also be in the form of a controlled release formulation. Methods are also provided for use of estradiol metabolites to treat or prevent insulin resistance, vascular endothelial dysfunction, hyperlipidemia, hypertension, diabetic nephropathy, proteinuria and reducing leptin levels. In addition, the methods provide a method of stabilizing glucose levels. These treatments may be used in either gender because of their lack of a feminizing estrogenic effect. Excerpt(s): This application claims priority from U.S. Provisional Application No. 60/312,741 filed Aug. 17, 2001. The present invention relates generally to methods and compositions for use in the prevention or treatment of risk factors for cardiovascular diseases such as obesity, metabolic syndrome, diabetes, and vascular and renal disorders. More particularly, the present invention relates to the use of estradiol metabolites with little estrogenic activity such as 2-hydroxyestradiol, 4hydroxyestradiol, 2-methoxyestradiol and 4-methoxyestradiol, all of which may be delivered in a controlled release formulation for the prevention or treatment of such disorders. Obesity is pandemic and worsening in developed countries (see e.g., Mokdad, A. H., et al., J. Am. Medical Assoc. 284:1650 (2000), the disclosure of which is incorporated herein by reference). Obesity contributes importantly to the metabolic syndrome (see e.g., Grundy, S. M., Endocrine 13:155 (2000) (hereinafter, "Grundy, 2000"); Bergman, R. N., et al., Journal of Investigative Medicine 49:119 (2001) (hereinafter, "Bergman, 2001"), the disclosures of which are incorporated herein by reference), a disorder characterized by hypertension, insulin resistance and hyperlipidemia (Grundy, 2000; Bergman, 2001). The metabolic syndrome in turn contributes to heart and vascular disease (see e.g., Colditz, G. A., Medicine & Science in Sports & Exercise 31:S663 (1999), the disclosure of which is incorporated herein by reference), and to the accelerating epidemic of end stage renal failure (see e.g., Hall, W. D, et al., American Journal of the Medical Sciences 313:195 (1997); Hall, J. E. et al., Annals of the New York Academy of Sciences 892:91 (1999), the disclosures of which are incorporated herein by reference).
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Unfortunately, pharmacological management of obesity has caused, rather than attenuated, cardiovascular disease. For example, a popular phentermine/fenfluramine combination produces valvular heart disease (see e.g., Lepor, N. E., et al., American Journal of Cardiology 86:107 (2000), the disclosure of which is incorporated herein by reference), while another popular treatment option, phenylpropanolamine, causes stroke (see e.g., Kernan, W. N., et al., New England J. Med. 343:1826 (2000), the disclosure of which is incorporated herein by reference). Thus, drugs that prevent or treat obesity and its metabolic, vascular and renal sequelae, without adversely affecting the heart, are badly needed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Antisense strategy to modulate estrogen receptor response (ER alpha and/or ER beta) Inventor(s): Sirois, Martin; (Anjou, CA), Tanguay, Jean-Francois; (Montreal, CA) Correspondence: Mathews, Collins, Shepherd & Mckay, P.A.; Suite 306; 100 Thanet Circle; Princeton; NJ; 08540; US Patent Application Number: 20030144240 Date filed: December 23, 2002 Abstract: The present invention provides novel antisense oligonucleotides that target the genes and mRNAs encoding mammalian Estrogen Receptors (ER) alpha and/or beta and modulate the receptors' responses. These antisense oligonucleotides may be used alone or in combination with 17 Beta estradiol or a related compound (genistein, estradiol derivatives. ) to improve plaque stabilization, vascular healing and endothelial recovery after vascular injury. Also provided are methods for designing and testing the antisense oligonucleotides. Such oligonucleotides may be used to modulate the beneficial effects mediated by the ER on vascular healing, for example, restenosis or plaque stabilisation, in mammals. The present invention further pertains to pharmaceutical compositions and formulations comprising the novel antisense oligonucleotides of the present invention for use in the treatment of mammals having a disease or disorder characterised by atherosclerosis, plaque vulnerability or destabilisation or pathological plaque rupture or erosion including spontaneous or induced injury. Excerpt(s): The present invention pertains to the field of antisense oligonucleotides for mammalian estrogen receptor (ER) genes and their use as cardioprotective, vascular healing and/or anti-atherosclorotic agents. Atherosclerosis is a process by which new lesions can progress or become vulnerable from pre-existing ones, and can be summarised as the culmination of i) increased endothelial cell dysfonction; ii) migration of inflammatory cells into extracellular matrix; iii) synthesis and release of degrading matrix molecules; iv) fibrous cap thinning, erosion and/or rupture; v) release of growth factors; vi) prothrombotic, proinflammatory, proapoptotic and/or proatherosclerotic status. Physiological vascular healing and regeneration are highly coordinated processes that occur in individuals under specific conditions, such as during spontaneous plaque rupture and/or destabilisation, or induced by percutaneous or surgical revascularization. Estrogens play an important role in bone maintenance, in the cardiovascular system, in the growth, differentiation and biological activity of various tissues.sup.1. The protective effects of 17-beta-estradiol (17.beta.E) are related to favourable changes in plasma lipid profile.sup.2, to inhibition of vascular smooth muscle cell (VSMC) proliferation.sup.3 and migration.sup.4, to relaxation of coronary vessels through endothelial nitric oxide synthase (eNOS) activity.sup.5, to reduction of
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platelets and monocyte aggregation.sup.6, tumor necrosis factor alpha (TNF-a) release.sup.7 and extracellular matrix synthesis.sup.8. We have shown that local delivery of 17.beta.E reduces neointimal thickness after coronary balloon injury in a porcine model.sup.8. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Biocompatible metallic materials grafted with biologically active compounds and preparation thereof Inventor(s): Goo, Hyun Chul; (Seoul, KR), Kim, Soo Hyun; (Seoul, KR), Kim, Young Ha; (Seoul, KR), Lee, Won Kyu; (Daejeon, KR), Park, Ki Dong; (Seoul, KR) Correspondence: Rosenberg, Klein & Lee; 3458 Ellicott Center Drive-suite 101; Ellicott City; MD; 21043; US Patent Application Number: 20010037144 Date filed: March 26, 2001 Abstract: Disclosed are surface-modified medical metallic materials and preparation thereof. The medical metallic material is prepared by coating a gold or silver thin layer onto a base metal, adsorbing a polyfunctional sulfur compound onto the gold or silver thin layer, and chemically bonding a biologically active material such as heparin or estradiol to the functional group of the sulfur compound. The biologically active material is firmly bonded to the base metal via the sulfur compound. Being significantly improved in antithrombogenicity and biocompatibility, the metallic materials are suitable for use in various implants, including stents, artificial cardiac valves and catheters. Excerpt(s): The present invention relates to medical metallic materials, especially medical tools for use in circulatory systems, whose surface is modified to improve antithrombogenicity and biocompatibility. More particularly, the present invention relates to the reliable introduction of a biologically active compound onto the surface of a base metal via a linker, thereby bringing about a great improvement in the antithrombogenicity and biocompatibility of the base metal. Also, the present invention is concerned with a method for preparing such a medical metallic material and with the use of the metallic material in the medical field. For use in substituting for congenitally or postnatally defective valves of the heart, artificial cardiac valves are generally classified into two groups: valves made of tissues and mechanical valves, which are made of metallic materials. Tissue values show excellent biocompatibility, but poor internal durability due to calcification. On the other hand, mechanical valves endure for extended periods in vivo, but have the disadvantage of forcing the patients to take anticoagulants throughout their lifetime because they are likely to generate thrombus. In spite of extensive research, satisfactory advance has not been yet achieved in the antithrombogenicity of mechanical valves. Indeed, not only is it virtually impossible to prevent thrombogenesis, a normal physiological function of the body, but also its mechanism has not been disclosed completely. Extensively conducted for the treatment of coronary stenosis is percutaneous transluminal coronary angioplasty in which an intraaortic balloon catheter is inserted within the coronary artery to expand the blood vessel. This operation brings about relatively good results, and development has been and continues to be ongoing in the processes and tools for percutaneous transluminal coronary angioplasty. However, such problems as acute closure and restenosis still remain unsolved.
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Combination of drospirenone and an estrogen sulphamate for HRT Inventor(s): Schuermann, Rolf; (Berlin, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030050289 Date filed: July 15, 2002 Abstract: A pharmaceutical dosage unit comprising drospirenone and an estrogen sulphamate, such as an estradiol sulphamate or an estriol sulphamate for use in hormone replacement therapy is disclosed. This, combination therapy may comprise continuous or discontinuous administration of drospirenone and/or the estrogen sulphamate, such as weekly administration of both agents or weekly administration of the estrogen sulphamate and daily administration of the drospirenone. Excerpt(s): This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/304,760, filed Jul. 13, 2001. The present invention relates to a pharmaceutical dosage unit comprising drospirenone and an estrogen sulphamate, such as an estradiol sulphamate or an estriol sulphamate, and to methods of hormone replacement therapy by administration of drospirenone and an estrogen sulphamate to estrogen-deficient women. Estrogen plays an important role in protecting the health of women such as protecting and maintaining cardiovascular health, bone mass, and mental cognition. However, normal ageing process results in lower levels of estrogen in women and the estrogen level may be significantly reduced upon entering menopause or upon surgical removal of the uterus and/or ovaries, for which reason those women risk the development of cardiovasculary diseases, bone mineralisation and/or poor mental cognition. Loss of bone mineral density is the key indicator of osteoporosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Combination preparation for contraception based on naural estrogens Inventor(s): Dittgen, Michael; (Apolda, DE), Fricke, Sabine; (Jena, DE), Hoffmann, Herbert; (Jena, DE), Moore, Claudia; (Jena, DE), Oettel, Michael; (Jena, DE), Ostertag, Monika; (Gottingen, DE) Correspondence: Striker, Striker & Stenby; 103 East Neck Road; Huntington; NY; 11743; US Patent Application Number: 20020107229 Date filed: September 12, 2001 Abstract: The combination preparation for contraception includes from 2 to 4 first stage daily dosage portions each including an effective amount of at least one natural estrogen as sole active ingredient, from 16 to 22 second stage daily dosage portions each including an effective amount of a combination of at least one natural estrogen and at least one natural or synthetic gestogen as active ingredient; from 2 to 4 third stage daily dosage portions each including an effective amount of at least one natural estrogen as sole active ingredient; and from 2 to 4 final stage daily dosage portions containing a pharmaceutically acceptable placebo. The estrogen may be estradiol, an estradiol
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compound that is metabolized to estradiol when taken into the body, a conjugated equine estrogen or a phytoestrogen. The natural or synthetic gestogen can be natural progesterone or a synthetic gestogens, such as medroxyprogesterone acetate. Excerpt(s): The present invention relates to a multistage contraceptive preparation based on natural estrogens. Oral contraceptives were first marketed 60 years ago. By continuous research it has been possible to reduce the required dosages of hormones in a stepwise manner. Currently low dosage oral contraceptives exist which chiefly comprise an estrogen component and a gestogen component. The hormone dosage of these contraceptives is delivered in different combinations and dosages in the form of combination preparations (one-stage preparation) or multistage combination preparations (staged preparations) and sequenced preparations (two-stage preparations) over time periods of from 21 to 28 days. One-stage preparations (usually designated as combination preparations) are characterized by a constant dosage of certain estrogens and gestogens each day. Because of the uniform delivery of gestogen ingredients with estrogen components from the first application day, the combination preparation is a highly reliable contraceptive. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compositions for preventing hormone induced adverse effects Inventor(s): Levy, Joseph; (Omer, IL), Sharoni, Yoav; (Omer, IL) Correspondence: Kenyon & Kenyon; One Broadway; New York; NY; 10004; US Patent Application Number: 20030004146 Date filed: March 5, 2001 Abstract: A unit dosage form suitable for once daily administration to a human comprising a physiologically effective amount of at least one hormone selected from the group consisting of steroidal estrogen, estradiol, estrone, medroxyprogesterone, norethindrone, norethisterone, progestin, norgestrel, and progesterone, and at least one carotenoid wherein said carotenoid is in an amount effective to prevent the adverse effects which may result from the administration of said hormone. Excerpt(s): The present invention provides compositions for preventing adverse effects associated with the administration of hormones such as phytoestrogens and steroidal estrogens. Hormone intake by humans can occur through, inter alia, consumption of pharmaceutical compositions, foodstuffs, nutritional supplements and nutraceuticals. Such hormones include phytoestrogens, or nonsteroidal estrogens, steroidal estrogens and progestins. Phytoestrogens comprise, for example, genistein, daidzein and glycitein, and their respective glucoside, malonylglucoside and acetylglucoside derivatives. Estrogens and progestins are known to be used for hormone replacement therapy (HRT) and in contraceptive medications. HRT with estrogens or with estrogen/progestin combinations has been the standard method for treating symptoms associated with menopause (Ernster VL et al. (1988) Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use, Prev. Med. 17:201-223). The onset of menopause in mature adult women, which is accompanied by reduced estrogen production, is associated with an array of symptoms. These symptoms include hot and cold flashes, palpitations, dizziness, headaches, altered secretions as well as weight loss and gain. Reduced levels of circulating estrogen in post-menopausal women are also associated with increased risks of osteoporosis and coronary heart disease. Treatment protocols using estrogen alone significantly reduce the risks of cardiovascular disease and osteoporosis, if
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treatment begins at menopause. The protective effect of estrogen against heart disease is related to its ability to raise levels of circulating HDL and lower levels of LDL. In contrast with such beneficial effects, long-term use of estrogens is positively correlated with an increased risk for endometrial cancer development. This risk may be reduced by simultaneous administration of a progestin, which prevents overgrowth of endometrial cells. Hence, an estrogen/progestin combined HRT protocol is recommended for a woman with an intact uterus. This form of combination therapy however, apparently diminishes the beneficial effects of estrogen on the plasma lipid profile (Lobo R. 1992. The Role of Progestins in Hormone Replacement Therapy; Am. J Obstet. Gynecol. 166:1997-2004). Furthermore, some progestins are associated with an increased risk of mammary cancer development (Staffa J. A. et al. 1991. Progestins and Breast Cancer: An Epidemiologic Review, 57: 473-491; King R. J. B. 1991. A Discussion of the Roles of Estrogen and Progestin in Human Mammary Carcinogenesis, J. Ster. Biochem. Molec. Bio. 39:8111-8118). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Cosmetic composition and method Inventor(s): Lerner, David S.; (Boca Raton, FL), Schultz, Gregory; (Gainesville, FL) Correspondence: Timothy H. Van Dyke; Bencen & Van Dyke, P.A.; 1630 Hillcrest Street; Orlando; FL; 32803; US Patent Application Number: 20020054922 Date filed: June 29, 2001 Abstract: The cosmetic topical formulation of this invention is directed toward diminishing skin wrinkling, fine line, improving skin tone, and combinations thereof. Preferably, the topical formulation contains a matrix metalloproteinase inhibitor, MMPI, and advantageously includes a natural estrogen, e.g., a true estrogen compound, such as 17-beta estradiol, or an estrogen-like steroid, (such as various phytoestrogens found in herbal preparations), as opposed to a synthetic estrogen. Other forms of the cosmetic topical formulation of this invention include combinations of synthetic estrogen and MMP inhibitor. Exemplary synthetic estrogens include, but are not limited to, ethinyl estradiol and clomiphine citrate. The cosmetic topical formulation is safe and effective diminishing wrinkling, and improving skin tone. Certain compositions of this invention are useful for minimizing photodamage to skin, while in other embodiments, the composition according to this invention is useful to prevent or minimize the adverse effects on skin induced by cigarette smoking. Excerpt(s): This application is a non-provisional continuation-in-part of provisional patent application Ser. No. 60/215,087, filed Jun. 29, 2000. This invention provides a composition and method for reducing or preventing wrinkling and damage of skin upon topical application. As women go through menopause and men age, both experience increased skin wrinkling and decreased skin thickness. Until recently, the molecular mechanism responsible for these skin changes was not well understood. In post-menopausal women, the decreasing levels of plasma estrogen obviously plays a role in the process, but estrogen's influence on the molecular pathways that lead to skin wrinkling and skin thinning was not recognized until recently. Ascroft et al. reported that oral estrogen replacement therapy reversed the delay in healing of skin biopsy wounds observed between pre-menopausal women and healthy post-menopausal women. (See G.S. Ascroft et al, "Estrogen Accelerates Cutaneous Wound Healing Associated with an Increase in TGF-.beta.1," Nature Medicine 3:1209-1215, 1997; Ascroft
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et al., "Human Ageing Impairs Injury-induced in Vivo Expression of Tissue Inhibitors of Matrix Metalloproteinases (TIMP-1 and -2 Proteins and mRNA," J. Pathol. 183:169-176, 1997; Ascroft et al., "Age-Related Changes in the Temporal and Spatial Regulation of Matrix Metalloproteinases (MMP) Protein and MRNA Profiles in Normal Skin and Acute Cutaneous Wounds of Healthy Humans," Cell tissue Res. 290:581-591, 1997). In addition, they reported that systemic estrogen replacement therapy increased the level of transforming growth factor protein and decreased the levels of matrix metalloproteinases in wound sites. This discovery led Ascroft, et al., to hypothesize that systemic estrogen replacement therapy stimulated production of TGF-.beta.1, which is known to stimulate synthesis of extracellular matrix proteins including collagen and simultaneously decreases the production of matrix metalloproteinase. The result of these combined effects of estrogen was to promote healing of the full-thickness punch wounds in the skin of post-menopausal women. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Cyclodextrin-drospirenone inclusion complexes Inventor(s): Backenfeld, Thomas; (Berlin, DE), Heil, Wolfgang; (Berlin, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20020173487 Date filed: December 20, 2001 Abstract: Pharmaceutical compositions comprising low doses of sensitive complexes between an estrogen and a cyclodextrin are provided with improved stability. In specific embodiments the composition comprises a complex between ethinyl estradiol and.beta.cyclodextrin in a granulate preparation and in yet another embodiment the composition comprises a limited amount of polyvinylpyrrolidone since this excipient was found to degrade ethinyl estradiol. Furthermore, a method for improving the stability of an estrogen in a composition and for manufacturing such a stable composition is provided. Essentially, the granulate preparation are manufactured under careful control of the relative humidity. Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/256,484, filed Dec. 20, 2000. The present invention relates to pharmaceutical compositions and formulations comprising a cyclodextrin-estrogen complex that confers very high chemical stability to the estrogen. The invention allows for an improved physical stability of cyclodextrin-estrogen complexes and of the chemical stability of estrogens such ethinyl estradiol upon storage. Degradation of estrogens, such as ethinyl estradiol, in conventional pharmaceutical products is one of the most critical issues with regard to product shelf life. Stabilization of the estrogen may be achieved by either product packaging in hermetic containers or, more effectively, as in the present invention, by actual stabilization of the pharmaceutical product. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Delivery of physiologically active compounds through an inhalation route Inventor(s): Rabinowitz, Joshua D.; (Mountain View, CA), Zaffaroni, Alejandro C.; (Atherton, CA) Correspondence: Richard R. Eckman; Morrison & Foerster Llp; 755 Page Mill Road; Palo Alto; CA; 94304-1018; US Patent Application Number: 20030017114 Date filed: May 23, 2002 Abstract: The present invention relates to the delivery of physiologically active compounds through an inhalation route. Specifically, it relates to aerosols containing physiologically active compounds that are used in inhalation therapy. In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. In a method aspect of the present invention, chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. In a kit aspect of the present invention, a kit for delivering chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine; and, b) a device that forms a chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine containing aerosol from the composition, for inhalation by the mammal. Excerpt(s): This application claims priority to U.S. provisional application Serial No. 60/294,203 entitled "Thermal Vapor Delivery of Drugs," filed May 24, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference. This application further claims priority to U.S. provisional application Serial No. 60/317,479 entitled "Aerosol Drug Delivery," filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference. The present invention relates to the delivery of physiologically active compounds through an inhalation route. Specifically, it relates to aerosols containing physiologically active compounds that are used in inhalation therapy. It is desirable to provide a new route of administration for physiologically active compounds that rapidly produces peak plasma concentrations of the compound. The provision of such a route is an object of the present invention. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Drospirenone for hormone replacement therapy Inventor(s): Heil, Wolfgang; (Berlin, DE), Hilmann, Juergen; (Berlin, DE), Lipp, Ralph; (Berlin, DE), Schuermann, Rolf; (Berlin, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030144258 Date filed: February 6, 2003 Abstract: A pharmaceutical composition comprising as a first active ingredient an estrogen, such as estradiol or estradiol valerate, in sufficient amounts to treat disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active ingredient 6.beta.,7.beta.; 15.beta.; 16.beta.-dimethylene-3-oxo17.alpha.-preg-4-en- e-21,17-carbolactone (drospirenone, DRSP) in sufficient amounts to protect the endometrium from the adverse effects of estrogen is useful for, amongst others, treating peri-menopausal, menopausal and post-menopausal women. This composition may be used for hormone replacement therapy and may be administered as a multi-phased pharmaceutical preparation. This combination therapy may comprise continuous, sequential or interrupted administration, or combinations thereof, of DRSP and estrogen, each optionally in micronized form. Excerpt(s): The present invention relates to a pharmaceutical composition comprising drospirenone and estrogen, and to methods of hormone replacement therapy by administration of drospirenone and estrogen for estrogen-deficient women. The rise in life expectancy and consequent rise in the number of peri- and post-menopausal women has led to an increase in public and medical awareness of the climacteric period of transition in the reproduction phase of women. Menopause, the last menstruation, occurs between the ages of 45 and 55 in most women. Many factors, including race, genetics, nutrition, altitude, smoking, number of live births, the use of hormonal contraception, length of menstrual cycle and the age of onset of puberty have all been attributed, rightly or wrongly, to affect the age of the last menstrual period. During these phases of life, female endocrine activity undergoes a series of changes, with the result that the physical and psychological well being of many women is adversely affected. Hormone replacement therapy has aimed to improve the quality of life of women during this natural ageing process to alleviate symptoms associated with this time of transition and to reduce the likelihood or slow the progression of disorders and diseases associated with reduced hormonal activity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Drug eluting coatings for medical implants Inventor(s): Hsu, Li-Chien; (Mission Viejo, CA) Correspondence: Li-chien Hsu; 22181 Abrazo; Mission Viejo; CA; 92691; US Patent Application Number: 20040037886 Date filed: April 26, 2003 Abstract: Drug eluting coating compositions are composed of at least one therapeutic agent dispersed in modified, biologically active binders. The therapeutic agents included in the coating composition are paclitaxel, sirolimus, tacrolimus, everolimus, actinomycin-D, dexamethasone, mycophenolic acid, cyclosporins, estradiol, and
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derivatives and analogs thereof. These therapeutic agents are applied to the surface of the medical device by a modified, biologically active binders. By using these biologically active binders, the therapeutic agents can be applied to at least one surface of a medical implant without using inert polymer carriers. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/405,933, filed Aug. 26, 2002, and whose entire contents are hereby incorporated by reference. The implantation or insertion of a medical device into a patient's body can cause the body to exhibit adverse physiological reactions. The reactions may range from infections to the formation of emboli or clots in blood vessels. One particularly adverse physiological reaction is the result of epithelial damage to the cardiovasculature. That is, the vasculature can be damaged during procedures such as percutaneous transluminal coronary angioplasty (PCTA). As a result of damage to the epithelium of the vasculature, a cascade of physiological events may result in the re-narrowing (restenosis) of the vessel. While not completely understood, restenosis may be the result of smooth muscle cell proliferation in the intimal layers of the vessel. Restenosis of an artherosclerotic coronary artery after PTCA occurs in 10-50% of patients undergoing this procedure and subsequently requires either further angioplasty or coronary artery bypass graft. In order to maintain the patency of the vessel, intravascular stents have been developed as a mechanical means of preventing the collapse or abrupt closure of the dilated segment of the artery. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Estradiol derivative and immunoassay using the same Inventor(s): Kato, Ikuo; (Fujinomiya-shi, JP), Kitamura, Kazuyuki; (Fujinomiya-shi, JP), Kodaira, Tsukasa; (Tokushima-ken, JP), Yanaihara, Noboru; (Shizuoka-shi, JP) Correspondence: Sughrue, Mion, Zinn, Macpeak & Seas, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037-3202; US Patent Application Number: 20020028929 Date filed: July 17, 2001 Abstract: The present invention provides a highly sensitive immunoassay system for estrogens, which utilizes as a labeled compound a biotinylated estradiol derivative of the formula (1) 1wherein one of R.sup.1 and R.sup.2 is hydrogen and the other is a group represented by 2wherein R.sup.3s are the same or different and represent an arginine residue or a lysine residue, x is 0 or 1, y is an integer from 1 to 5, and z is an integer from 1 to 3. Excerpt(s): The present invention relates to an immunoassay for estrogens, especially 17.beta.-estradiol and estrone, and to a labeled compound used in the immunoassay. Estrogens are a representative example of steroid hormones (female sex hormones). Over ten kinds of compounds are currently known as estrogens. Estrogens are metabolized into stable estradiols in human blood like other female sex hormones. The estradiols are mainly excreted as urine and diffused into the environment such as into river water, lake water, seawater, waste water, soil, etc. Estrogens have drawn attention because of the problem of feminization in humans, domestic animals, fish, etc. For example, 17-estradiol reacts with estrogen receptors. The avidity of the estradiol to the receptors is 1,000 to 10,000 times as high as the avidity of bisphenol A, nonylphenol, alkyl phthalates and the like which are now recognized as environmental hormones causing problems.
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Estradiol-16alpha-carboxylic acid esters as locally active estrogens Inventor(s): Hochberg, Richard B.; (Guilford, CT) Correspondence: H.D. Coleman; Coleman Sudol Saponc, P.C.; 714 Colorado Avenue; Bridgeport; CT; 06605-1601; US Patent Application Number: 20020143002 Date filed: January 23, 2002 Abstract: The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 16.alpha.-carboxylic acid substituted steroids and their esters is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure: 1Where R is H, a C.sub.1 to C.sub.5 alkyl, vinyl, CF.sub.3, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2 or CH.sub.2CF.sub.3; and m is from 0-2, or a pharmaceutically acceptable salt thereof. Preferably, R is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, neo-pentyl, vinyl, CF.sub.3, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2 or CH.sub.2CF.sub.3 and m is 0. More preferably, R is methyl, ethyl, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2 or CH.sub.2CF.sub.3 and m is 0. Excerpt(s): This application claims the benefit of priority from U.S. provisional application No. 60/264,157, filed Jan. 25, 2001. The present invention relates to novel 16.alpha. estradiol ester compounds and their use as locally active estrogens in the treatment of the symptomology of menopause. Estrogen therapy, directly and indirectly, affects a number of organs. Some of the outcomes associated with estrogen therapy are deleterious. Consequently, where possible, symptomology which could be ameliorated by local rather than systemic administration could limit the adverse sideeffects of estrogen therapy. One such syndrome that can be treated directly, caused by estrogen deprivation or estrogen antagonists, is vaginal dyspareunia. It is a common disorder which affects a large proportion of women, approximately 40% within 10 years of the onset of the menopause.sup.5 It is important factor in the quality of life for women so afflicted, as it is associated with a severe physical and psychological impact. It is not only painful but it can dramatically influence a women's self image and lead to clinical depression.sup.6 Another possible use of local estrogens includes topical administration to aging skin. The skin contains ER and it is an estrogen target organ.sup.11-13 While topical application of estrogens to the vaginal mucosa has been used to treat vaginal dyspareunia of the menopause, these estrogens are adsorbed into the blood and result in significant blood levels of estrogens.sup.7-10 Thus, this therapy may not be used where systemic estrogens are contraindicated. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Estrogen or estradiol need determination by vaginal or urethral acidity determination Inventor(s): Caillouette, James C.; (Pasadena, CA) Correspondence: William W. Haefliger; Suite 512; 201 SO. Lake AVE.; Pasadena; CA; 91101; US Patent Application Number: 20010021816 Date filed: April 20, 2001 Abstract: In the method of determining need for human estrogen replacement therapy or estrogen or estradiol dose change, the steps include determining local acidity proximate a moist wall surface of the vagina, or urethra, as differing from desired threshold level (pH 4.5), and administering sufficient estrogen or estradiol to result in change in acidity toward such level. Excerpt(s): This application is a continuation-in-part of prior U.S. application Ser. No. 08/699,251 filed Aug. 19, 1996, which is a continuation-in-part of prior U.S. application Ser. No. 08/570,534 filed Dec. 11, 1995, now pending, which is a continuation-in-part of prior U.S. application Ser. No. 08/537,379 filed Oct. 27, 1995, now pending, which is a continuation-in-part of prior U.S. application Ser. No. 08/376,830 filed Jan. 23, 1995, now pending, which is a continuation-in-part of prior U.S. application Ser. No. 08/295,399 filed Aug. 25, 1994, now U.S. Pat. No. 5,425,377. This invention relates generally to factors involved in determining estrogen or estradiol administration to human females, and more particularly to a simple and effective method and means to effect such determination such as need for beginning estrogen replacement therapy or changes in dosage of estrogen or estradiol. There is need for improvements in methods to determine whether or not a human female should be administered estrogen or estradiol or needs a higher or lower dose of estrogen or estradiol. The present invention addresses that need. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Estrogenic compounds as anti-mitotic agents Inventor(s): D'Amato, Robert John; (Lancaster, PA), Folkman, Moses Judah; (Brookline, MA) Correspondence: John S. Pratt, Esq; Kilpatrick Stockton, Llp; 1100 Peachtree Street; Suite 2800; Atlanta; GA; 30309; US Patent Application Number: 20020119959 Date filed: February 21, 2002 Abstract: The application discloses methods of treating mammalian diseases characterized by abnormal cell mitosis by administering estradiol derivatives including those comprising colchicine or combretastatin A-4 structural motifs of the general formulae found below in a dosage sufficient to inhibit cell mitosis. The application discloses novel compounds used in the methods. Excerpt(s): This invention relates to treating disease states characterized by abnormal cell mitosis. Cell mitosis is a multi-step process that includes cell division and replication (Alberts, B. et al. In The Cell, pp. 652 - 661 (1989); Stryer, E. Biochemistry (1988)). Mitosis is characterized by the intracellular movement and segregation of organelles, including mitotic spindles and chromosomes. Organelle movement and segregation are facilitated by the polymerization of the cell protein tubulin.
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Microtubules are formed from.alpha. and.beta. tubulin polymerization and the hydrolysis of GTP. Microtubule formation is important for cell mitosis, cell locomotion, and the movement of highly specialized cell structures such as cilia and flagella. Microtubules are extremely labile structures that are sensitive to a variety of chemically unrelated anti-mitotic drugs. For example, colchicine and nocadazole are anti-mitotic drugs that bind tubulin and inhibit tubulin polymerization (Stryer, E. Biochemistry (1988)). When used alone or in combination with other therapeutic drugs, colchicine may be used to treat cancer (WO-9303729-A, published Mar. 4, 1993; J 03240726-A, published Oct. 28, 1991), alter neuromuscular function, change blood pressure, increase sensitivity to compounds affecting sympathetic neuron function, depress respiration, and relieve gout (Physician's Desk Reference, Vol. 47, p. 1487, (1993)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hormone replacement formulation Inventor(s): Wright, Jonathan V.; (Auburn, WA) Correspondence: Jensen + Puntigam, P.S.; Suite 1020; 2033 6th Ave; Seattle; WA; 98121; US Patent Application Number: 20030050287 Date filed: September 12, 2001 Abstract: The formulation comprises a combination of three estrogens and selected amount of other elements. The three estrogens include 2-hydroxyestrone, 17-beta estradiol, and estriol. The amount of 17-beta estradiol is substantially less than the amounts of 2-hydroxyestrone and estriol, both which are approximately equal in amount. The amounts of pyridoxine, folic acid, selenium and cobalt are therapeutically effective amounts. Excerpt(s): This invention relates generally to hormone replacement therapy, and more specifically concerns a new estrogen replacement formulation. Hormone replacement therapy has been known for some time. One particular aspect of hormone replacement therapy, known generally as estrogen replacement, has been used for over 30 years for women during or following menopause. The reason for estrogen replacement, which is usually accomplished through transdermal absorption or orally, is to make up for the decline in, or the low level of, estrogen produced by the body. Typically, estrogen production decreases and then declines dramatically during and after menopause. It is during this time period that estrogen replacement is normally prescribed by a physician. However, estrogen replacement can be prescribed in other circumstances where other causes account for a decline in estrogen production or if estrogen is produced at a lower than desirable level. This could occur in women not yet in menopause. The reasons for estrogen replacement, which have been substantiated by scientific research over a number of years, include the prevention and/or treatment of osteoporosis and cardiovascular disease, as well as preventing age-related decline in mental function. Estrogen replacement has also been used to decrease age-related changes in appearance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Low dose estrogen interrupted hormone replacement therapy Inventor(s): Ausmanas, Militza K.; (Lake Forest, IL), Casper, Robert F.; (Toronto, CA), Shangold, Gary A.; (Califon, NJ) Correspondence: Crowell & Moring Llp; Intellectual Property Group; P.O. Box 14300; Washington; DC; 20044-4300; US Patent Application Number: 20020165209 Date filed: April 30, 2002 Abstract: A hormone replacement therapy, comprising a plurality of daily doses of a pharmaceutical preparation, the doses being administered continuously and consecutively in alternating phases of three daily doses, a relatively dominant estrogenic activity phase comprising three daily doses of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol per day, and a relatively dominant progestagenic activity phase of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90.mu.g per day of norgestimate. Excerpt(s): This application claims the benefit of priority from U.S. Provisional Application No. 60/126,970 filed Mar. 30, 1999, the disclosure of which is incorporated herein by reference. The present invention relates to hormone replacement therapy (HRT) for administration to menopausal or castrate women. More specifically, the present invention relates to a hormone replacement therapy regimen comprising a specific dosage combination that includes a reduced amount of estrogen, which provides a reduced risk of cancer, while providing a regimen with vasomotor symptom relief that is usually only available at higher estrogen levels. There are a number of patents relating to hormone replacement therapy and many different formulations available in the marketplace. Many formulations involve the administration of continuous estrogen and progestogen, while other regimens can be characterized as interrupted or cyclophasic. Examples of patents covering interrupted regimens include Robert F. Casper's U.S. Pat. No. 5,108,995 issued Aug. 28, 1992, for a method of HRT; U.S. Pat. No. 5,256,421 issued Oct. 26, 1993 for an HRT method; U.S. Pat. No. 5,422,119 issued Jun. 6, 1995 for a transdermal HRT method, preparation and package; and U.S. Pat. No. 5,382,573 issued Jan. 17, 1995, which relates to an HRT preparation and package. Casper is also the holder of U.S. Pat. No. 5,276,022 issued Jan. 4, 1994 and U.S. Pat. No. 5,585,370 issued Dec. 17, 1996 both of which relate to contraceptive therapy. The disclosures of all of these patents are incorporated herein by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Means and method for hormonal contraception Inventor(s): Coelingh Bennink, Herman Jan Tijmen; (Driebergen, NL), Van Beek, Agatha Antonia Magdalena; (Uden, NL) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20020177580 Date filed: May 23, 2001 Abstract: A contraceptive method comprises the administration of a hormone composition in an amount effective to inhibit ovulation. More specifically the invention
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relates to the use of a hormone composition in the manufacture of a kit containing a plurality of dosage units for use in a contraceptive method, which method comprises administering a sequence of the dosage units to a female of childbearing capability so as to provide the hormone composition in an amount which is effective to inhibit ovulation, wherein the hormone composition is dydrogesterone component or a combination of estrogen and dydrogesterone component. Another embodiment concerns an oral contraceptive kit comprising from 20-35 daily oral dosage units, wherein 10-35 units contain a combination of estrogen in an amount equivalent to at least 2.mu.g ethinyl estradiol and dydrogesterone component in an amount equivalent to at least 2 mg dydrogesterone, 0-25 units contain estrogen in an amount equivalent to at lease 2.mu.g ethinyl estradiol and no progestogen, and 0-8 units contain no progestogen and no estrogen. Excerpt(s): The present invention is concerned with a contraceptive method, which method comprises administering to a female of childbearing capability one or more dosage units containing a hormone composition in a therapeutically effective amount to inhibit ovulation. The hormone composition used in accordance with the present invention contains a special progestogen (i.e. dydrogesterone) which is structurally and biologically closely related to progesterone and produces less undesirable side-effects than the synthetic progestogens commonly used in hormonal contraceptive regimens. Dydrogesterone (9.beta.,10.alpha.-pregna-4,6-diene-3,20-dione) is an orally active progestative hormone that has been commercially available since the early seventies. Dydrogesterone is mainly used in the treatment of endometriosis and in hormone replacement therapy. "Martindale" (Martindale, "The Complete Drug Reference", Micromedex Healthcare Series, Integrated Index 1974-2001) mentions a number of indications for which dydrogesterone may suitably be used. These include menstrual disorders, endometriosis, endometrial protection during menopausal hormone replacement therapy, threatened abortion, habitual abortion and infertility. Except for endometriosis all these applications have in common that they relate to progesterone deficiency in the body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Medicaments based on progestins for dermal use Inventor(s): Beckmann, Karsten; (Stockach, DE), Franke, Christian; (Allensbach, DE) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030109507 Date filed: September 20, 2002 Abstract: The present invention relates to semisolid transcutaneous medicaments based on at least one oxidation-sensitive progestin or a pharmaceutically acceptable derivative thereof. The medicaments comprise ascorbic acid, an ascorbic acid derivative or a salt thereof and have excellent stability. Corresponding gels which comprise a combination of norethisterone acetate and estradiol are described in particular. Excerpt(s): The present invention relates to medicaments based on progestins for dermal use, for example in the form of a gel. In particular, combination products based on norethisterone acetate and estrogens, for example estradiol, are described. The medicaments are used in particular in hormone replacement therapy for peri- or postmenopausal women. A decline in the estradiol production by the ovaries during
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and after the menopause or following ovarectomy leads to a wide variety of symptoms. These symptoms are normally treated by estrogen replacement and, on long-term use of estrogen-containing products during the menopause in non-hysterectomized women, additional administration, sequentially or continuously, of a progestin ought to take place. Corresponding combination products for oral therapy are available (EP-A 0 136 011). U.S. Pat. No. 5,955,454 and DE-A 199 25 290 respectively describe progestogencontaining and estrogen- or progestin-containing medicaments which can be administered nasally. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method and intravascular stent for reducing complications after implantation of an intravascular stent Inventor(s): Sass, Norbert; (Stade, DE) Correspondence: Mallinckrodt & Mallinckrodt; 10 Exchange Place, Suite 510; Salt Lake City; UT; 84111; US Patent Application Number: 20020111670 Date filed: February 27, 2002 Abstract: This invention relates to methods and arrangement for reducing complications after implantation of an intravascular stent and, more particularly, for reducing the risk of restenosis due to stent implantation. This is achieved by using 17beta-estradiol as vessel healing substance after implantation of an intravascular stent. The 17betaestradiol can be coated onto an intravascular stent and be included in a drug elution system applied to the intravascular stent. This can be achieved by means of a surface coating process such as CVD process. 17beta-estradiol inhibits the growth of smooth muscle cells and stimulates the re-endothelialization after implantation of an intravascular stent. The present invention makes use of these effects in order to prevent restenosis and in-stent stenosis. Excerpt(s): This application is a continuation of application Ser. No. 09/839,249 filed Apr. 20, 2001, now U.S. Pat. No. ______. This invention relates to a method of reducing complications after implantation of an intravascular stent and, more particularly, for reducing the risk of restenosis due to stent implantation. The invention further relates to a method for producing an intravascular stent reducing complications after implantation into a vessel and, more particularly, reducing the risk of restenosis due to stent implantation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for induced lactation Inventor(s): Klusmeyer, Tim H.; (O'Fallin, MO), McGrath, Michael F.; (Wildwood, MO), Patel, Kanaiyalal R.; (St. Louis, MO), Reed, Edward Alan; (St. Peters, MO), Schenkel, Robert H.; (St. Louis, MO), Vicini, John L.; (Chesterfield, MO) Correspondence: Howrey Simon Arnold & White; 750 Bering Drive; Houston; TX; 77057-2198; US Patent Application Number: 20020058621 Date filed: July 20, 2001
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Abstract: Methods for effecting mammary secretion of milk from an animal, without the benefit of an immediately preceding pregnancy are provided. An exemplary embodiment the method comprises elevating an animal's estradiol and progesterone blood level sufficient to maintain a milk-secretion stimulating amount for approximately 5 to 12 consecutive days, wherein the day of the first elevation is defined to be day 0; and elevating an animal's somatotropin blood level sufficient to maintain a milksecretion stimulating amount for at least 20 days from day 0. In any embodiment the method also optionally includes administering to the animal a milk-secretion stimulating amount of dexamethasone on approximately day 13 of the treatment. Furthermore, any embodiment the method may also optionally include adjusting the photo-period to which the animal is exposed in order to stimulate milk secretion. Any embodiment the method may also include physical stimulation of the animal's mammary gland. Excerpt(s): This application claims priority to Provisional Application Serial No. 60/220,012 filed Jul. 21, 2001. The present invention relates to the field of enhancing milk production in mammals. More particularly, it concerns pharmaceutical compositions and methods of using said compositions in a manner effective to induce milk production in previously non-lactating animals. Commercial raising of cattle for dairy production requires proper management. In addition to the various husbandry concerns such as herd health and nutrition, a critical management area for economic survival of any cattle operation, is the breeding management of the cows. In the case of dairy cows, the cows will not produce milk unless they have a calf, which is again dependent upon successful breeding management. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of prevention and treatment of ischemic damage Inventor(s): Covey, Douglas F.; (Ballwin, MO), Simpkins, James W.; (Fort Worth, TX) Correspondence: Bromberg & Sunstein Llp; 125 Summer Street; Boston; MA; 02110-1618; US Patent Application Number: 20030069217 Date filed: February 25, 2002 Abstract: The present invention in various embodiments provides methods of treating stroke and conferring protection on a population of cells associated with ischemia in a subject following an ischemic event, comprising: (a) providing an estrogen compound; and (b) administering the effective amount of the compound over a course that includes at least one dose within a time that is effectively proximate to the ischemic event, so as to confer protection on the population of cells. Novel methods are provided for the delivery of an estrogen compound. Examples of ischemic events treatable according to the invention are cerebrovascular disease or stroke, subarachnoid subhemorrhage, myocardial infarct, surgery and trauma. A method of treating ischemic damage utilizing hormones that are non-sex hormones is also provided. A method of treating stroke with ent-17.beta.-estradiol, and a method of synthesis, and compounds produced from the synthesis are provided. Excerpt(s): This application is a continuation of Ser. No. 09,372,627, filed Aug. 11, 1999, which is a continuation-in-part of Ser. No. 09/179,640, filed Oct. 27, 1998, which is a divisional of Ser. No. 08/749,703, now U.S. Pat. No. 5,877,169, filed Nov. 15, 1996, which is a continuation-in-part of Ser. No. 08/648,857, now U.S. Pat. No. 5,843,934, filed May
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16, 1996, which is a divisional application of Ser. No. 08/318, 042, filed Oct. 4, 1994, now U.S. Pat. No.5,554,601; which is a continuation in part of 08/149,175 filed Nov. 5, 1993, now abandoned. These applications and patents are hereby incorporated by reference herein. The present invention relates to the protection of cells that would otherwise die as a result of stroke or an ischemic event. Ischemia is an acute condition associated with an inadequate flow of oxygenated blood to a part of the body, caused by the constriction or blockage of the blood vessels supplying it. Ischemia occurs any time that blood flow to a tissue is reduced below a critical level. This reduction in blood flow can result from: (i) the blockage of a vessel by an embolus (blood clot); (ii) the blockage of a vessel due to atherosclerosis; (iii) the breakage of a blood vessel (a bleeding stroke); (iv) the blockage of a blood vessel due to vasoconstriction such as occurs during vasospasms and possibly, during transient ischemic attacks (TIA) and following subarachnoid hemorrhage. Conditions in which ischemia occurs further include (i) myocardial infarction; (ii) trauma; and (iii) during cardiac and thoracic surgery and neurosurgery (blood flow needs to be reduced or stopped to achieve the aims of surgery) During myocardial infarct, stoppage of the heart or damage occurs which reduces the flow of blood to organs, and ischemia results. Cardiac tissue itself is also subjected to ischemic damage. During various surgeries, reduction of blood flow, clots or air bubbles generated can lead to significant ischemic damage. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Monitoring methods Inventor(s): Catt, Michael; (Northampton, GB), May, Keith; (Bedford, GB) Correspondence: Morgan, Lewis & Bockius Llp; 1111 Pennsylvania Avenue, N.W.; Washington; DC; 20004; US Patent Application Number: 20020137220 Date filed: March 8, 2002 Abstract: A method of providing warning of the onset of the fertile phase of the human ovulation cycle, involving measurement in absolute or relative terms of the body fluid concentration of an analyte such as estradiol or a metabolite thereof wherein if in the current cycle a concentration measurement conducted at about the termination of menses reveals a body fluid concentration that is typical of that found in the body fluid of an average human female subject about 3 days prior to the time of ovulation during a 28-day cycle, the current cycle is immediately declared to be in its fertile phase. Where the analyte is E3G, the E3G concentration measurement is conducted on at least one or numerical days 4 to 7 of the current cycle, counting from the onset of menses, and the fertile phase is declared immediately if the E3G measurement reveals a concentration equal to or greater than a threshold concentration chosen in the range of about 25 to about 35 ng/ml. Excerpt(s): This invention relates to methods of monitoring the ovulation cycle in female mammals especially humans. The last few decades have seen much research conducted into ways of enhancing "natural" family planning, in which physiological parameters indicative of the status of the ovulation cycle are monitored. In our European patent specification EP-A-706346 we particularly describe such a method which uses the measurement of urinary estradiol or metabolites thereof, especially estrone-3glucuronide (E3G), to provide a warning of the onset of the fertile phase. Related methods are described in our European patent specifications EP-A-656118, EP-A-656119 and EP-A-656120. Associated testing devices and test kits are described in these
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specifications, and also in our International patent specifications WO 95/13531 and WO 96/09553. A major objective of these earlier inventions is to provide monitoring methods which are tolerant to the variability in ovulation cycle parameters that occur between different individual subjects, and indeed within the same subject from one cycle to another. Especially for contraceptive purposes, a method should provide reliable fertility awareness despite such variability. Even amongst a population of individual women experiencing apparently normal-length cycles (average 28 days), some individuals may exhibit extremely short cycle lengths, on an occasional or more frequent basis. The whole cycle can be compressed into 20 or 21 days, or in extreme instances an even shorter interval. The fertile phase (taking into account the time during which male sperm may remain viable) can commence exceptionally early. In a monitoring method which is looking for a rise in the urinary concentration of E3G or a similar metabolite, as an indicator of imminent entry into the fertile phase, the occurence of a very short cycle with very early commencement of the fertile phase may not easily be identified. Accordingly, as a further refinement, there is need for a "failsafe" mechanism to cope with unexpected short cycles. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Monounsaturated fatty acids of at least 20 carbon atoms and perhydrocyclopentanophenanthrene nucleus combination molecules and their use as weight-loss agents Inventor(s): Girouard, Michael P.; (Cornelius, NC) Correspondence: Garvey Smith Nehrbass & Doody, Llc; Three Lakeway Center; 3838 North Causeway BLVD., Suite 3290; Metairie; LA; 70002 Patent Application Number: 20030114431 Date filed: August 26, 2002 Abstract: The pharmaceutical and/or cosmetic compositions for treatment of obesity and/or overweight contain an effective amount of a fatty-acid monoester of an estrogen and a fatty acid wherein the estrogen is preferably estrone, diethylstilbestrol, estriol, estradiol or ethinyl estradiol and the fatty acid is eicosenoic acid, especially cis 11 eicosenoic, although cis 5, cis 8, and cis 13 eicosenoic acid are also effective. The C-22 fatty acid monoester of estrogen, cis 13 docosenoic acid (Erucic acid), and the C-24 fatty acid monoester of estrogen, cis 15 tetracosenoic acid (Nervonic acid) are also effective and are included in this disclosure. In addition, synthesized combination molecules formed when a monounsaturated fatty acid of 20 carbon atoms or more is joined via an ester, ether, or amide bond to either a steroid or any molecule containing a perhydrocyclopentanophenanthrene nucleus or perhydrocyclopentanophenanthrene nucleus derivative are also included in this invention. The fatty-acid monoesters mimic the function of estrone monooleate, as a signal that informs the brain of the size of fat tissue mass. In preferred pharmaceutical and/or cosmetic compositions for intravenous injection the monoester is incorporated in a lipidic suspension, prepared from lipoproteins or from liposome components, such as soy oil and egg phospholipids. When administered to rats with a 15% of total adipose tissue, they produce weight reduction of about 10%, by a new and unexpected mechanism. They are useful for the treatment of obesity and/or overweight in mammals, with the advantages of high efficacy and low toxicity. Excerpt(s): Priority of my U.S. Provisional Patent Application, Serial No. 60/314,995, filed Aug. 24, 2001, incorporated herein by reference, is hereby claimed. The present
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invention relates to weight loss. More particularly, the present invention relates to medication-aided weight loss treatments. Since treating patients for weight loss since 1981, the present inventor has observed that roughly seventy-five percent of his patients have little or absolutely no history of overweight or obesity prior to a major event associated with estrogen hormonal changes. The most common estrogen hormonal events are pregnancy (especially second and late pregnancies), hysterectomy, tubal ligation, or peri-menopause/menopause. Usually, the change is dramatic. Interestingly, these patients do not report a change in eating or exercise habits. Furthermore, exercise and strict weight loss produce only modest weight loss in many if not most of these patients, indicating that some aspect of fat metabolism has been altered as a result of the hormonal situations noted above. Because the genetic makeup of these patients has not changed, the present inventor has recognized the role of hormones in producing changes in body fat metabolism in humans. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Non-estrogenic estradiol derivative compounds with antioxidative activity Inventor(s): Droescher, Peter; (Weimar, DE), Elger, Walter; (Berlin, DE), Kaufmann, Guenter; (Jena, DE), Menzenbach, Bernd; (Jena, DE), Roemer, Wolfgang; (Jena, DE), Schneider, Birgitt; (Jena, DE) Correspondence: Striker, Striker & Stenby; 103 East Neck Road; Huntington; NY; 11743; US Patent Application Number: 20020065258 Date filed: November 21, 2001 Abstract: New non-estrogenic derivative compounds of estradiol, which have no estrogenic activity and comparatively high anti-oxidative activity, are disclosed. These new non-estrogenic derivative compounds are potentially useful as non-estrogenic antioxidants, especially for administration in post-menopausal women and in men. The compounds of the invention can also inhibit aromatase and sulfatase. Excerpt(s): The present invention relates to new non-estrogenic derivative compounds of estradiol with antioxidative activity. It is known from the patent literature, namely from DE 43 38 314 C1, that estradiol and its known derivatives with phenolic A-rings and 17-hydroxy groups have fundamental antioxidative activity. These substances have a more or less strong binding affinity to estrogen receptor sites according to their structure. The high affinity of natural 17.beta.-estradiols (100%) is usually considerably decreased by structural changes, such as isomerization or derivativization. However it still amounts to 23% for 17.alpha.-estradiol and it is still 8.6% for the enantiomer of the natural estradiol, 8.alpha.,9.beta.,14.beta.-estra-1,3,- 5(10)-trien-3,17.alpha.-diol (entestradiol). These values are not always tolerable depending on the dosage and application duration during administration of the substances with the aim to increase the body's antioxidative capacity. When a large substituent is introduced at the 17carbon atom according to German Patent Document DE 43 38 316 A1, for example in 17.alpha.-4'-dimethylamino-phenylmethyl-estra-1,3,5 (10),9(11)-tetraen-3,17-diol, the binding affinity can be reduced up to less than 1% while increasing the antioxidative activity. However in vivo a high estrogen activity was found for the corresponding 3methyl ether, 3-methoxy-17.alpha.-4'-dimethylamino-phenylmethyl-estra-1,3,5(10)-trien1- 7-ol. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Oral pharmaceutical products containing 17 beta-estradiol-3-lower alkanoate, method of administering the same and process of preparation Inventor(s): Aloba, Oluwole T.; (Morristown, NJ), deVries, Tina M.; (Long Valley, NJ) Correspondence: Fitzpatrick Cella Harper & Scinto; 30 Rockefeller Plaza; New York; NY; 10112; US Patent Application Number: 20030118638 Date filed: December 21, 2001 Abstract: A pharmaceutical dosage unit for oral administration to a human female comprising a therapeutically effective amount of 17.beta.-estradiol-3-low- er alkanoate, most preferably 17.beta.-estradiol-3-acetate, and a pharmaceutically acceptable carrier is disclosed. Also disclosed is a method for treating a human female in need of 17.beta.estradiol and a contraceptive method by oral administration of the pharmaceutical dosage unit and a method of preparing a pharmaceutical composition that may be used to form the pharmaceutical dosage unit of the invention. Excerpt(s): This invention relates to a pharmaceutical dosage unit for oral administration containing 17.beta.-estradiol-3-lower alkanoate, most preferably 17.beta.-estradiol-3acetate, that unexpectedly provides improved bioavailability of estrogen when orally administered to a human female in need of estrogen replacement therapy or receiving estrogen for contraceptive purposes. The invention also relates to a process for producing the pharmaceutical dosage unit. In the normal, healthy human female, 17.beta.-estradiol is the principal estrogen produced by the functioning premenopausal ovary during each menstrual cycle [Lieveritz, R. W., Amer. J. of Obstetrics and Gynecology, Vol. 156, pp. 1289-1293, 1987]. Estrogen deficiency may occur due to disease, oophorectomy, traumatic injury or as a natural consequence of the aging process. As aging progresses, ovulation becomes less frequent and predictable, resulting in diminished production of 17.beta.-estradiol. Gradual loss of ovarian function occurs naturally around 45-55 years of age leading to the eventual cessation of the menstrual cycle, that is, the menopause. During normal ovulatory cycles ovarian production of 17.beta.-estradiol ranges from 60-600.mu.g per day, resulting in circulating levels of 17.beta.-estradiol in serum ranging from 40-400 pg/ml. Circulating 17.beta.-estradiol levels vary during the monthly cycle in the premenopausal woman. At the menopause, when irreversible ovarian failure occurs, 17.beta.-estradiol production decreases dramatically to less than 20.mu.g per day, giving circulating levels of the hormone in serum of less than 30 pg/ml. [Stumpf, P. G., Obstetrics and Gynaecology, Vol. 75 (suppl.) pp. 95-135, 1990]. This low level of estrogen production may result in typical postmenopausal symptoms [Marsh, M. S., et al., British Medical Bulletin, Vol. 48, pp. 426-457, 1992]. The physiological consequences of the fall in estradiol levels typically include vasomotor instability (hot flushes), urogenital atrophy and a loss of bone mineral mass leading to osteoporosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Peptides capable of functioning as mimotopes for hormonal analytes Inventor(s): Badley, Robert A.; (Bedford, GB), Berry, Mark J.; (Bedford, GB), Williams, Samantha C.; (County Dublin, IE) Correspondence: Oppedahl And Larson Llp; P O Box 5068; Dillon; CO; 80435-5068; US Patent Application Number: 20040029808 Date filed: August 2, 2001 Abstract: A purified peptide mimotope which is capable of binding specifically to an antibody specific to estradiol. Also disclosed is an immunoassay test device for the detection in a sample of estradiol, the immunoassay test device comprising a peptide mimotope of estradiol, and an antibody capable of binding specifically to the peptide mimotope to generate a detectable signal. Excerpt(s): This invention relates to the discovery that certain peptide molecules have similar reactive properties as certain steroidal compounds, notwithstanding the significant structural dissimilarities between such compounds, and are thus capable of functioning as mimotopes of the steroidal compounds in, for example, displacement immunoassays designed for the detection of steroids. As a matter of general definition, an epitope is that region of a particular antigen which contains the critical binding region of the antigen necessary for triggering an immunity-related antibody binding response. Epitopes are also often referred to in the alternative as antigenic determinants. Understanding the structures of epitopes as well as their specific binding reactions to particular antibodies is of significant interest to many, as such an understanding could lay the foundation for advancements in the pharmaceutical, diagnostic and health industries. To facilitate this understanding, in recent years academic institutions and industry have constructed what are termed epitope libraries. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system for the release of 17- beta -estradiol to the human organism Inventor(s): Asmussen, Bodo; (Bendorf-Sayn, DE), Horstmann, Michael; (Neuwied, DE) Correspondence: Ann W. Speckman; Speckman Law Group; Suite 100; 1501 Western Avenue; Seattle; WA; 98101; US Patent Application Number: 20010043944 Date filed: June 19, 2001 Abstract: A pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system, for the release of the active substance 17-.beta.-estradiol, contained therein in dissolved form being between its saturation concentration in equilibrium with a gas phase of less than 10% relative air humidity and its saturation concentration in equilibrium with a gas phase of more than 90% relative air humidity, in all matrix levels and, if present, also in an adhesive layer, characterized in that the estradiol quantity contained in in the preparation amounts to at least three times the saturation solubility measured at 95% relative air humidity, and that the air enclosed in the package is adjusted to a relative air humidity between 5% and below 0.5%. Excerpt(s): This application is a continuation-in-part application of U.S. patent application Ser. No. 09/101,720, filed Jul. 6, 1998, which was the National Stage of International Application No. PCT/EP96/05822 filed Dec. 23, 1996. The present
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invention relates to a pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system, for the release of 17-.beta.-estradiol and optionally further active substances through the skin to the human organism. Pharmaceutical preparations contacting the skin include, for example, ointments, creams, lotions, and also drug-containing patches, these have been introduced on the market for some time under the name "transdermal therapeutic systems" (TTS) to treat several diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
PHARMACEUTICAL PREPARATIONS FOR TREATING SIDE EFFECTS DURING AND/OR AFTER GNRHA THERAPY Inventor(s): DITTRICH, RALPH; (ERLANGEN, DE), HUMMEL, WOLFGANG; (NEUENMARKT, DE), LICHT, PETER; (BUBENREUTH, DE), NEUWINGER, JOACHIM; (ERLANGEN, DE), OETTEL, MICHAEL; (JENA, DE), WILDT, LUDWIG; (HERZOGENAURACH-HAUNDORF, DE) Correspondence: Striker Striker And Stenby; 103 East Neck Road; Huntington; NY; 11743 Patent Application Number: 20020002153 Date filed: April 14, 1999 Abstract: The pharmaceutical preparations for treating side effects, such as hot flashes, during and/or after treatment with analogs or antagonists of gonadotropin releasing hormone (GnRHa therapy) contain an effective amount of 17.alpha.-estradiol, its chemically modified derivatives, chemically modified derivatives of 17.beta.-estradiol or estriol. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/081,791, filed Apr. 15, 1998. The present invention relates to pharmaceutical preparations for treating side effects, such as hot flashes, during and/or after treatment with analogs or antagonists of gonadotropin releasing hormone (GnRHa therapy). It is known that treatment with analogs or antagonists of gonadotropin-releasing hormone (GnRHa therapy) is an effective therapy in diseases whose intensity is influenced by the activity of the gonads. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Rhodiola and uses thereof Inventor(s): Xiu, Rulin; (Washington, DC) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20020127285 Date filed: May 7, 2002 Abstract: The present invention relates to Rhodiola, preferably Rhodiola crenulata, to treat various conditions and diseases in mammals. Rhodiola crenulata is a Tibetan herb which has been discovered to have highly useful and beneficial properties heretofore unknown. Rhodiola crenulata is especially preferred to enhance blood oxygen levels, to enhance working capacity and endurance, to enhance memory and concentration, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to protect
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against oxidation, to modulate testosterone and estradiol levels, to modulate sleep, and to enhance sexuability, such as improve sexual performance. Excerpt(s): The present invention relates to compositions, articles of manufacture, extracts, compounds, methods of use, methods of treatment, methods of preparation, etc., which relate to plants of the genus Rhodiola, preferably Rhodiola crenulata, which have a variety of useful and beneficial effects, including, e.g., to enhance blood oxygen and nutrients levels, e.g., through enhancing oxygen transport, to enhance working capacity and endurance, to reduce muscle fatigue, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to protect against oxidation, to provide anti-cancer effects, to promote DNA repair, to provide anti-radiation effects, to protect against radiation, to reduce inflammation, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, preferably, to modulate testosterone levels, and to modulate sleep, especially to promote sleep, to modulate blood lipids, preferably, e.g., to lower cholesterol levels, to promote weight loss, and to enhance sexuability, such as improve sexual performance. Rhodiola crenulata is a species of Rhodiola which grows mostly in Tibet and south west of China on the altitude between 3400 meters to 5600 meters. It has been used in Tibetan medicine for more than 1000 years for uses that have been limited to curing lung inflammation and cough, for stopping and activating blood, and for treating external wounds and burns. It has been discovered herein that Rhodiola crenulata has other beneficial properties that make it useful for a variety of conditions and diseases, as mentioned above and below. Rhodiola is a diverse genus of plants which includes more than 50 different species, including, e.g., algida, arctica, crenulata, elongata, gelida, imbricataishidae, iremelica, kirilowii, linearifolia, phariensis, pinnatifida, quadrifida, aff. quadrifida, rosea, sachalinensis, and wolongensis. These species vary from each other widely, differing in, e.g., chromosome number (e.g., Makoto et al., Journal of Japanese Botany, 70(6):334-338, 1995), chemical composition, morphology, medicinal properties, developmental stages (e.g., Ishmuratatova and Satsyperova, Rastitel'nye Resursy., 34(1):3-11, 1998), geographical distribution, etc. Scientific studies (e.g. Peng et al, Chinese Herb Medicine(1995), 26(4): 177-179, and Wang et al, Acta Phrmaceutica Sinica(1992), 27(2): 117-120) indicate constituents of Rhodiola crenulata include, e.g., salidroside, tyrosol,.beta.-sitosterol, gallic acid, pyrogallol, crenulatin, rhodionin, rhodiosin, among which, crenulatin, e.g., is found only in R. crenulata and has not been found in any other Rhodiola species. Rhodiosin and rhodionin exists in some, but not all, Rhodiola species. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Ring-shaped devices Inventor(s): Groenewegen, Rudolf Johannes Joseph; (Heesch, NL), Nijs, Hendrik de; (Oss, NL), Sam, Antonius Paulus; (Heesch, NL), Vromans, Herman; (Oss, NL) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20030152625 Date filed: February 25, 2003 Abstract: The invention relates to a ring-shaped device comprising: (a) a first compartment comprising an non-medicated core of ethylenes.about.vinylacet- ate copolymer, encircled by a steroid hormone loaded ethylene-vinylacetate copolymer layer, and a non-medicated outer layer of ethylene-vinylacetate copolymer; (b) a second compartment comprising a core of ethylene-vinylacetate copolymer loaded with a
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steroid hormone and a non-medicated outer layer of ethylene-vinylacetate polymer; and (c) optionally placebo segments of a thermoplastic material separating the first from the second compartment. Preferably, the invention is a two-compartment vaginal ring, the first compartment comprising crystalline etonogestrel and the second compartment comprising a (sub)-saturated mixture of etonogestrel and ethinyl estradiol, both compartments optionally being separated from each other by placebo segments of high density polyethylene. Excerpt(s): This application is a continuation of co-pending U.S. application Ser. No. 08/981,881, filed Dec. 31, 1997, now U.S. Pat. No. ______, which claims priority from PCT Patent Application No. PCT/EP 96/02935, filed July 1, 1996, and published, in English, on Jan. 23, 1997 as WO 97/02015 the contents of which are incorporated by this reference. The invention relates generally to medical devices such as ring-shaped devices and to a method of manufacture the same. The invention relates, in particular, to ring-shaped vaginal devices, i.e., to vaginal rings. Ring-shaped devices, and especially vaginal rings, are well known in the art. A two-layered one-compartment vaginal ring, for example, is disclosed in U.S. Pat. No. 4,237,885, in which a drug (progestational or estrogenic steroid) on a carrier is encircled by a polymeric tube, consisting of an ethylene-vinyl acetate copolymer, both ends of which are joined together with a solid polymeric plug. Devices of this type, however, do not provide acceptable release patterns. Improvement was sought by using other shapes or other materials. A twolayered one compartment vaginal ring made from silicone elastomer has been disclosed in European Patent Application EP 0,050,867, which ring comprises a silicone elastomer core loaded with active substance surrounded by a non-loaded silicone elastomer layer, which consists of two different compositions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
STABILIZED AQUEOUS SUSPENSIONS FOR PARENTERAL USE Inventor(s): Colombo, Giuseppe; (Milan, IT), Fox, Lloyd E.; (Richlands, MI), Martini, Alessandro; (Milan, IT) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20020115645 Date filed: May 15, 2000 Abstract: A pharmaceutical aqueous suspension formulation for parenteral administration having substantially stabilized pH, comprising a biologically active compound and a pH controlling effective concentration of L-Methionine.Preferably, the biologically active compound is a steroidal compound, for instance exemestane, medroxyprogesterone acetate and estradiol cypionate or a combination of medroxyprogesterone acetate and estradiol cypionate. Excerpt(s): The present invention is in the field of galenic preparations. It concerns in particular a pharmaceutical aqueous suspension of a biologically active compound, e.g. a steroidal compound, having stabilized pH, particularly suitable for parenteral administration. The inventors of the present invention have found that the pH of a pharmaceutical aqueous suspension of a biologically active compound can be controlled by adding a pH controlling effective concentration of L-Methionine thereto. Moreover, when a pH controlling effective concentration of L-Methionine is used, it strengthens the buffering capacity of low concentrations of conventional buffering agents with a
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super-additive (synergistic) effect. In this way the use of conventional buffering agents can be eliminated or limited, thus improving the re-suspendability and controlled flocculation of the pharmaceutical preparation. A pharmaceutical suspension is a coarse dispersion in which insoluble solid particles are dispersed in a liquid medium. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Transdermal Therapeutic system containing estradiol Inventor(s): Horstmann, Michael; (Neuwied, DE), Lichtenberger, Rainer; (Darmstadt, DE), Meconi, Reinhold; (Neuwied, DE), Seibertz, Frank; (Bad Honningen/Ariendorf, DE) Correspondence: Wenderoth Lind & Ponack Llp; 2033 K Street NW; Suite 800; Washington; DC; 20006; US Patent Application Number: 20020012691 Date filed: March 10, 2000 Abstract: An active-substance-containing transdermal therapeutic system for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens consisting of a backing layer, an active-substance-containing reservoir which is bonded thereto and produced by using pressure sensitive adhesives, and a removable protective layer is characterized by the fact that the pressure sensitive adhesive comprises esters of colophony. Excerpt(s): The present invention relates to a transdermal therapeutic system for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens, such as levonorgestrel, to human or animal skin. The present invention further relates to the use and to a process for the production of this system. In the therapy of various diseases transdermal therapeutic systems (TTS) have been introduced on the market. Also, transdermal therapeutic systems containing the estrogenic active substance 17-.beta.-estradiol used as therapeutic agent for climacteric complaints and--for some time now--against osteoporosis are commercially available and show good therapeutic results. Levonorgestrel is a synthetic gestagen derivative which has mainly been used in contraceptives in combination with orally effective estrogens. In such preparations gestagens, consequently including levonorgestrel, have the function to cause a "physiologic" abstraction hemorrhage which is as short and rapid as possible by means of an adequate trophic premedication of the uterus. There are also hints that the gestagen addition has a protective effect against the risk of endometrial tumors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Treatment of dyspareunia with topically administered nitroglycerin formulations Inventor(s): Bennett, Sean R.; (Denver, CO), Doherty, Jane K.; (Cupertino, CA), Doherty, Paul C. JR.; (Cupertino, CA), Gesundheit, Neil; (Los Altos, CA), Hanamoto, Mark S.; (Belmont, CA), Place, Virgil A.; (Kawaihae, HI), Spivack, Alfred P.; (Menlo Park, CA), Wilson, Leland F.; (Menlo Park, CA) Correspondence: Reed & Eberle Llp; 800 Menlo Avenue, Suite 210; Menlo Park; CA; 94025; US Patent Application Number: 20040044080 Date filed: April 4, 2003 Abstract: Methods and formulations for treating dyspareunia are provided. A pharmaceutical composition formulated so as to contain a therapeutically effective amount of nitroglycerin is administered to the vagina or vulvar area of the individual undergoing treatment. Preferred formulations are immediate release formulations in which at least 80% of the nitroglycerin in the formulation is released therefrom within 4 hours following administration. The formulations may contain one or more additional active agents, e.g., agents that are also useful to treat dyspareunia and/or potentiate the action of nitroglycerin. Such additional agents include vasoactive agents such as prostaglandins, phosphodiesterase inhibitors, androgens such as testosterone, estrogens such as estradiol, and selective modulators of estrogen and androgen receptors. A kit for a patient to use in the self-administration of the formulation is also provided. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 09/905,458, filed Jul. 13, 2001; which was a continuation of U.S. Ser. No. 09/539,484, filed Mar. 30, 2000, now U.S. Pat. No. 6,306,841; which was a continuation of U.S. Ser. No. 09/181,316, filed Oct. 27, 1998, now abandoned; which was a continuation-in-part of both U.S. Ser. No. 08/959,064, filed Oct. 28, 1997, now U.S. Pat. No. 5,877,216, and U.S. Ser. No. 08/959,057, filed Oct. 28, 1997, now abandoned; the disclosures of which are hereby incorporated by reference. This invention relates generally to methods and pharmaceutical formulations for treating women suffering from dyspareunia. More particularly, the invention pertains to the topical administration of a nitroglycerin-containing pharmaceutical formulation in the treatment of dyspareunia. Sexual response in women is generally classified into four stages: excitement, plateau, orgasm, and resolution. Masters and Johnson, Human Sexual Response (Boston, Mass.: Little, Brown & Co., 1966). With sexual arousal and excitement, vasocongestion and muscular tension increase progressively, primarily in the genitals, and is manifested by increased blood flow, elevated luminal oxygen tension, and vaginal surface lubrication as a result of plasma transudation that saturates the fluid reabsorptive capacity of the vaginal epithelium. Vasoactive intestinal polypeptide ("VIP") release may induce the physiological changes of sexual arousal and excitement, and may be the major neurotransmitter that participates in the innervation of the vaginal blood supply. Peptide histidine methionine has been co-located with VIP within nerve fibers that innervate small blood vessels, smooth muscle and epithelial cells in the vaginal tract. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Ultra low dose oral contraceptives with sustained efficacy and induced amenorrhea Inventor(s): Anderson, Freedolph D.; (Virginia Beach, VA), Hodgen, Gary D.; (Virginia Beach, VA), Williams, Robert F.; (Norfolk, VA) Correspondence: Ostrolenk Faber Gerb & Soffen; 1180 Avenue OF The Americas; New York; NY; 100368403 Patent Application Number: 20030018018 Date filed: July 10, 2001 Abstract: A method of female contraception involves administering a combination of estrogen and progestin continuously for more than a year in which the daily amounts of estrogen and progestin are equivalent to about 5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate, respectively. The advantages include lack of menstrual bleeding, less patient anemia, less total exposure to medication when compared to a 35 microgram (low dose) containing oral contraceptive, reduced risk of endometrial cancer, higher compliance rates and more lifestyle convenience for patients who desire less uterine bleeding each year or longer. Excerpt(s): The ovarian/menstrual cycle is a complex event characterized by an estrogen rich follicular phase and, after ovulation, a progesterone rich luteal phase. Each has a duration of approximately 14 days resulting in an intermenstrual interval of about 28 days. The endometrial tissue responds to the changes in hormonal milieu. The onset of menstruation is the beginning of a new menstrual cycle and is counted as day 1. During a span of about 5 to 7 days, the superficial layers of the endometrium, which grew and developed during the antecedent ovarian/menstrual cycle, are sloughed because demise of the extant corpus luteum in the non-fertile menstrual cycle is associated with a loss of progesterone secretion. Ovarian follicular maturation occurs progressively resulting in a rise in the circulating levels of estrogen, which in turn leads to new endometrial proliferation. The dominant ovarian follicle undergoes ovulation near mid-cycle, generally between menstrual cycle days 12 to 16 and is converted from a predominantly estrogen source to a predominantly progesterone source (the corpus luteum). The increasing level of progesterone in the blood converts the proliferative endometrium to a secretory phase in which the tissue proliferation has promptly abated, leading to the formation of endometrial glands or organs. When the ovulated oocyte is viably fertilized and continues its progressive embryonic cleavage, the secretory endometrium and the conceptus can interact to bring about implantation (nidation), beginning about 6 to 8 days after fertilization. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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USE OF 17-ALPHA-ESTRADIOL FOR THE TREATMENT OF AGED OR SUNDAMAGED SKIN AND/OR SKIN ATROPHY Inventor(s): GENDIMENICO, GERALD J.; (NESHANIC STATION, NJ), MEZICK, JAMES A.; (EAST BRUNSWICK, NJ) Correspondence: Audley A Ciamporcero JR; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 089337003 Patent Application Number: 20010051167 Date filed: August 10, 1998
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Abstract: The present invention relates to a method for treatment of mammalian skin conditions where stimulated connective tissue synthesis is beneficial, comprising treating skin in need of such treatment with a safe and effective amount of 17-.alpha.estradiol. Excerpt(s): This is a continuation-in-part of patent application Ser. No. (TBD) entitled, (USE OF 17-.alpha.-ESTRADIOL FOR THE TREATMENT OF AGED OR SUNDAMAGED SKIN AND/OR SKIN ATROPHY), Attorney Docket No. JBP-431), filed Tuesday, Aug. 4, 1998, and hereby incorporates by reference all subject matter disclosed therein. This also claims the priority of Provisional Application No. 60/056,485, filed Aug. 21, 1997. The present invention relates to a method of treating mammalian skin conditions to stimulate connective tissue synthesis in situations in which such connective tissue synthesis is beneficial. Specifically, the invention relates to novel compositions and methods of using the composition for treatment of aged skin, sun-damaged skin, acne, skin atrophy and for healing of wounds. Estrogens are hormonal compounds that exert wide-ranging biological effects on target tissues. The major organs affected by estrogens are the reproductive tract, genitals, bone, blood vessels and skin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with estradiol, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “estradiol” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on estradiol. You can also use this procedure to view pending patent applications concerning estradiol. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 7. BOOKS ON ESTRADIOL Overview This chapter provides bibliographic book references relating to estradiol. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on estradiol include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “estradiol” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “estradiol” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “estradiol” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Reconnaissance of 17 gb s-estradiol, 11-ketotestosterone, vitellogenin, and gonad histopathology in common carp of United States streams potential for contaminantinduced endocrine disruption (SuDoc I 19.76:96-627) by U.S. Geological Survey; ISBN: B000111XYU; http://www.amazon.com/exec/obidos/ASIN/B000111XYU/icongroupinterna
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Residues of Some Veterinary Drugs in Animals and Foods: Deltamethrin, Dihydrostretomycin, Doramectin, Estradiol-17B, Neomycin (Fao Food and Nutrition Paper, No 41, Pt 12); ISBN: 9251044015; http://www.amazon.com/exec/obidos/ASIN/9251044015/icongroupinterna
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Chapters on Estradiol In order to find chapters that specifically relate to estradiol, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and estradiol using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use 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 “Book Chapter.” Type “estradiol” (or synonyms) into the “For these words:” box.
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CHAPTER 8. PERIODICALS AND NEWS ON ESTRADIOL Overview In this chapter, we suggest a number of news sources and present various periodicals that cover estradiol.
News Services and Press Releases One of the simplest ways of tracking press releases on estradiol is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “estradiol” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to estradiol. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “estradiol” (or synonyms). The following was recently listed in this archive for estradiol: •
Estradiol levels correlate with inflammation in men with rheumatoid arthritis Source: Reuters Medical News Date: December 15, 2003
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Estradiol may have antidepressant effect in perimenopausal women Source: Reuters Industry Breifing Date: August 25, 2003
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Vaginal position of estradiol tablets may affect efficacy of treatment Source: Reuters Industry Breifing Date: August 14, 2003
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Less bleeding seen with HRT based on norethindrone acetate and ethinyl estradiol Source: Reuters Industry Breifing Date: February 18, 2003
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Hemostasis unchanged with vaginally administered high-dose estradiol Source: Reuters Industry Breifing Date: December 30, 2002
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Galen receives US approvable letter for estradiol intra-vaginal ring Source: Reuters Industry Breifing Date: October 21, 2002
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Galen receives US approvable letter for estradiol intravaginal ring Source: Reuters Medical News Date: October 21, 2002
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Testosterone but not estradiol linked to cognitive function in older men Source: Reuters Industry Breifing Date: April 22, 2002
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Watson's Alora estradiol patch gets new indication Source: Reuters Industry Breifing Date: April 09, 2002
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Estradiol increases CD40 ligand expression on T cells from SLE patients Source: Reuters Medical News Date: January 23, 2002
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Estradiol levels predict breast cancer risk in postmenopausal women Source: Reuters Industry Breifing Date: January 08, 2002
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Age, plasma estradiol predict CNS problems in girls with precocious puberty Source: Reuters Medical News Date: January 07, 2002
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Noven gets approvable letter to broaden use, dosages for estradiol patch Source: Reuters Industry Breifing Date: December 11, 2001 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine.
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Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “estradiol” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “estradiol” (or synonyms). If you know the name of a company that is relevant to estradiol, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “estradiol” (or synonyms).
Academic Periodicals covering Estradiol Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to estradiol. In addition to these sources, you can search for articles covering estradiol that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical
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periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 9. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for estradiol. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with estradiol. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to estradiol: Androgens and Estrogens •
Systemic - U.S. Brands: Andrest 90-4; Andro-Estro 90-4; Androgyn L.A.; DeComberol; Deladumone; Delatestadiol; depAndrogyn; Depo-Testadiol; Depotestogen; Duo-Cyp; Duo-Gen L.A.; Dura-Dumone 90/4; Duratestin; Estratest; Estratest H.S.; Halodrin; Menoject-L.A.; OB http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202037.html
Estrogens •
Systemic - U.S. Brands: Alora; Aquest; Climara; Clinagen LA 40; Delestrogen; depGynogen; Depo-Estradiol; Depogen; Dioval 40; Dioval XX; Dura-Estrin; Duragen-20; E-Cypionate; Estinyl; Estrace; Estraderm; Estragyn 5; Estragyn LA 5; Estra-L 40; Estratab; Estro-A; Estro-Cyp http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202226.html
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Vaginal - U.S. Brands: Estrace; Estring; Ogen; Ortho Dienestrol; Premarin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202227.html
Estrogens and Progestins (Ovarian Hormone Therapy) •
Systemic - U.S. Brands: Activella http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500070.html
Estrogens and Progestins Oral Contraceptives •
Systemic - U.S. Brands: Alesse; Brevicon; Demulen 1/35; Demulen 1/50; Desogen; Estrostep; Estrostep Fe; Genora 0.5/35; Genora 1/35; Genora 1/50; Intercon 0.5/35; Intercon 1/35; Intercon 1/50; Jenest; Levlen; Levlite; Levora 0.15/30; Lo/Ovral; Loestrin 1.5/30; Loestrin 1/20 http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202228.html
Medroxyprogesterone and Estradiol •
Systemic - U.S. Brands: Lunelle http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500255.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.
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PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
•
National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
•
National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
•
National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
•
National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
11
These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
•
National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
•
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
•
National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
•
National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
•
National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
•
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
•
National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
•
National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
•
National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
•
National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
•
National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
•
National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
•
Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
•
National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
•
National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
•
Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
•
Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
•
Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
•
Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
•
Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
•
Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
•
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
•
MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
12
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
•
Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “estradiol” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 77041 1263 934 40 165 79443
HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “estradiol” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
14
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
15
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
19 Adapted 20
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on estradiol can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to estradiol. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to estradiol. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “estradiol”:
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Other guides Breast Cancer http://www.nlm.nih.gov/medlineplus/breastcancer.html Hormone Replacement Therapy http://www.nlm.nih.gov/medlineplus/hormonereplacementtherapy.html Hormones http://www.nlm.nih.gov/medlineplus/hormones.html Menopause http://www.nlm.nih.gov/medlineplus/menopause.html Premature Ovarian Failure http://www.nlm.nih.gov/medlineplus/prematureovarianfailure.html
You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to estradiol. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
•
Family Village: http://www.familyvillage.wisc.edu/specific.htm
•
Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
•
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMD®Health: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to estradiol. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with estradiol. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about estradiol. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “estradiol” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “estradiol”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “estradiol” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.
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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “estradiol” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.22
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
22
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)23: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
•
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
•
Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
•
California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
•
California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
•
California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
•
California: Gateway Health Library (Sutter Gould Medical Foundation)
•
California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
•
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
•
California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
•
California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
•
California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
•
California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
•
California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
•
California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
•
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
•
Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
23
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
Finding Medical Libraries 221
•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
•
Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
•
Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
•
Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
•
Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
•
Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
•
Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
•
Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
•
Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
•
Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
•
Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
•
Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
•
Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
•
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
•
Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
•
Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
•
Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
•
Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
•
Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
•
Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
•
Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
•
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
•
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
•
Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
•
Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
•
Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
•
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
•
Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
•
Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
•
Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
•
Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
•
Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
•
Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
•
Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
•
National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
•
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
Finding Medical Libraries 223
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
•
New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
•
New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
•
New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
•
New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
•
New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
•
New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
•
Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
•
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
•
Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
•
Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
•
Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
•
Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
•
Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
•
Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
•
Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
•
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
•
Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
•
Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on estradiol: •
Basic Guidelines for Estradiol Estradiol - test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003711.htm
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Signs & Symptoms for Estradiol Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm
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Diagnostics and Tests for Estradiol Venipuncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003423.htm
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Background Topics for Estradiol Adolescent test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002054.htm
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Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Infant test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002055.htm Preschooler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002057.htm Proliferation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002276.htm Schoolage test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002058.htm Toddler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002056.htm Vagina Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002342.htm
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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ESTRADIOL DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 5-alpha: Enzyme converting testosterone to dihydrotestosterone. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Abortion, Habitual: Three or more consecutive spontaneous abortions. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acne Vulgaris: A chronic disorder of the pilosebaceous apparatus associated with an increase in sebum secretion. It is characterized by open comedones (blackheads), closed comedones (whiteheads), and pustular nodules. The cause is unknown, but heredity and age are predisposing factors. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In
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dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adhesives: Substances that cause the adherence of two surfaces. They include glues (properly collagen-derived adhesives), mucilages, sticky pastes, gums, resins, or latex. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Afferent Pathways: Nerve structures through which impulses are conducted from a peripheral part toward a nerve center. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of
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antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alendronate: A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Alloys: A mixture of metallic elements or compounds with other metallic or metalloid elements in varying proportions. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH]
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Alpha-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]
Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Aminoethyl: A protease inhibitor. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU]
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Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]
Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anchorage: In dentistry, points of retention of fillings and artificial restorations and appliances. [NIH] Androgen-Binding Protein: Carrier proteins produced in the Sertoli cells of the testis, secreted into the seminiferous tubules, and transported via the efferent ducts to the epididymis. They participate in the transport of androgens. Androgen-binding protein has the same amino acid sequence as sex hormone binding-globulin. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Androgenic: Producing masculine characteristics. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Androstenediols: Unsaturated androstane derivatives which are substituted with two hydroxy groups in any position in the ring system. [NIH] Androstenedione: A steroid with androgenic properties that is produced in the testis, ovary, and adrenal cortex. It is a precursor to testosterone and other androgenic hormones. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by
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renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]
Anterior Cruciate Ligament: A strong ligament of the knee that originates from the posteromedial portion of the lateral condyle of the femur, passes anteriorly and inferiorly between the condyles, and attaches to the depression in front of the intercondylar eminence of the tibia. [NIH] Anti-Anxiety Agents: Agents that alleviate anxiety, tension, and neurotic symptoms, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. Some are also effective as anticonvulsants, muscle relaxants, or anesthesia adjuvants. Adrenergic beta-antagonists are commonly used in the symptomatic treatment of anxiety but are not included here. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic, or surgical procedure to prevent infectious complications. [NIH] Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble
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substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antispasmodic: An agent that relieves spasm. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to
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mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatase: An enzyme which converts androgens to estrogens by desaturating ring A of the steroid. This enzyme complex is located in the endoplasmic reticulum of estrogenproducing cells including ovaries, placenta, testicular Sertoli and Leydig cells, adipose, and brain tissues. The enzyme complex has two components, one of which is the CYP19 gene product, the aromatase cytochrome P-450. The other component is NADPH-cytochrome P450 reductase which transfers reducing equivalents to P-450(arom). EC 1.14.13.-. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]
Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringent: Causing contraction, usually locally after topical application. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH]
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Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Avian: A plasmodial infection in birds. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Azoospermia: Absence of spermatozoa in the semen, or failure of formation of spermatozoa. [EU]
Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Baroreflex: A negative feedback system which buffers short-term changes in blood pressure. Increased pressure stretches blood vessels which activates pressoreceptors (baroreceptors) in the vessel walls. The net response of the central nervous system is a reduction of central sympathetic outflow. This reduces blood pressure both by decreasing peripheral vascular resistance and by lowering cardiac output. Because the baroreceptors are tonically active, the baroreflex can compensate rapidly for both increases and decreases in blood pressure. [NIH]
Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH]
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Basophil: A type of white blood cell. Basophils are granulocytes. [NIH] Beclomethasone: An anti-inflammatory, synthetic glucocorticoid. It is used topically as an anti-inflammatory agent and in aerosol form for the treatment of asthma. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Beta-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-Endorphin: A peptide consisting of amino acid sequence 61-91 of the endogenous pituitary hormone beta-lipotropin. The first four amino acids show a common tetrapeptide sequence with methionine- and leucine enkephalin. The compound shows opiate-like activity. Injection of beta-endorphin induces a profound analgesia of the whole body for several hours. This action is reversed after administration of naloxone. [NIH] Betahistine: N-Methyl-2-pyridineethanamine. A physiological histamine analog vasodilator agent that also acts as a histamine H1 receptor agonist. It is used in Meniere's disease and in vascular headaches but may exacerbate bronchial asthma and peptic ulcers. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH]
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Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral
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capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
Breakdown: A physical, metal, or nervous collapse. [NIH] Breast Neoplasms: Tumors or cancer of the breast. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad Ligament: A broad fold of peritoneum that extends from the side of the uterus to the wall of the pelvis. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Buffers: A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer. [NIH]
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Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial
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infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]
Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell
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membranes. [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Castration: Surgical removal or artificial destruction of gonads. [NIH] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catalyse: To speed up a chemical reaction. [EU] Catechol: A chemical originally isolated from a type of mimosa tree. Catechol is used as an astringent, an antiseptic, and in photography, electroplating, and making other chemicals. It can also be man-made. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Aggregation: The phenomenon by which dissociated cells intermixed in vitro tend to group themselves with cells of their own type. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell,
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enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell motility: The ability of a cell to move. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti).
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This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlordiazepoxide: An anxiolytic benzodiazepine derivative with anticonvulsant, sedative, and amnesic properties. It has also been used in the symptomatic treatment of alcohol withdrawl. [NIH] Chloride Channels: Cell membrane glycoproteins selective for chloride ions. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromaffin System: The cells of the body which stain with chromium salts. They occur along the sympathetic nerves, in the adrenal gland, and in various other organs. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of
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the cells looks clear when viewed under a microscope. [NIH] Climacteric: Physiologic period, characterized by endocrine, somatic, and psychic changes with the termination of ovarian function in the female. It may also accompany the normal diminution of sexual activity in the male. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clomiphene: A stilbene derivative that functions both as a partial estrogen agonist and complete estrogen antagonist depending on the target tissue. It antagonizes the estrogen receptor thereby initiating or augmenting ovulation in anovulatory women. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup
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characteristics. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as
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standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved
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sequences. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]
Contraception: Use of agents, devices, methods, or procedures which diminish the likelihood of or prevent conception. [NIH] Contraceptive Agents: Chemical substances that prevent or reduce the probability of conception. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH]
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Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Coumarin: A fluorescent dye. [NIH] Coumestrol: A coumarin derivative occurring naturally in forage crops which has estrogenic activity. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Criterion: A standard by which something may be judged. [EU] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporins: A group of closely related cyclic undecapeptides from the fungi Trichoderma polysporum and Cylindocarpon lucidum. They have some antineoplastic and antifungal action and significant immunosuppressive effects. Cyclosporins have been proposed as adjuvants in tissue and organ transplantation to suppress graft rejection. [NIH] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism in females. [NIH] Cyproterone Acetate: An agent with anti-androgen and progestational properties. It shows competitive binding with dihydrotestosterone at androgen receptor sites. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH]
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Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Defensins: Family of antimicrobial peptides that have been identified in humans, animals, and plants. They are thought to play a role in host defenses against infections, inflammation, wound repair, and acquired immunity. Based on the disulfide pairing of their characteristic six cysteine residues, they are divided into alpha-defensins and beta-defensins. [NIH] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]
Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH]
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Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depersonalization: Alteration in the perception of the self so that the usual sense of one's own reality is lost, manifested in a sense of unreality or self-estrangement, in changes of body image, or in a feeling that one does not control his own actions and speech; seen in depersonalization disorder, schizophrenic disorders, and schizotypal personality disorder. Some do not draw a distinction between depersonalization and derealization, using depersonalization to include both. [EU] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Derealization: Is characterized by the loss of the sense of reality concerning one's surroundings. [NIH] Dermal: Pertaining to or coming from the skin. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Desogestrel: A synthetic progestational hormone used often as the progestogenic component of combined oral contraceptive agents. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Deuterium Oxide: The isotopic compound of hydrogen of mass 2 (deuterium) with oxygen. (From Grant & Hackh's Chemical Dictionary, 5th ed) It is used to study mechanisms and rates of chemical or nuclear reactions, as well as biological processes. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diastolic: Of or pertaining to the diastole. [EU]
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Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]
Diethylstilbestrol: DES. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diphtheria Toxin: A 60 kD single chain protein elaborated by Corynebacterium diphtheriae that causes the sign and symptoms of diphtheria; it can be broken into two unequal fragments, the smaller (A fragment) inhibits protein synthesis and is the lethal moiety that needs the larger (B fragment) for entry into cells. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU]
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Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended
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effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Dry Eye Syndrome: A common condition that occurs when the eyes do not produce enough tears to keep the eye moist and comfortable. Common symptoms of dry eye include pain, stinging, burning, scratchiness, and intermittent blurring of vision. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dydrogesterone: A synthetic progestational hormone with no androgenic or estrogenic properties. Unlike many other progestational compounds, dydrogesterone produces no increase in temperature and does not inhibit ovulation. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysgenesis: Defective development. [EU] Dysmenorrhea: Painful menstruation. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Ectopic Pregnancy: The pregnancy occurring elsewhere than in the cavity of the uterus. [NIH]
Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU]
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Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Loss: Pregnancy loss during the embryonic stage of development which, in humans, comprises the second through eighth week after fertilization. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enanthate: An oily injectable contraceptive given every 8 weeks. [NIH] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Endarterectomy:
Surgical
excision,
performed
under
general
anesthesia,
of
the
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atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endorphin: Opioid peptides derived from beta-lipotropin. Endorphin is the most potent naturally occurring analgesic agent. It is present in pituitary, brain, and peripheral tissues. [NIH]
Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH]
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Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Enterovirus: A genus of the family Picornaviridae whose members preferentially inhabit the intestinal tract of a variety of hosts. The genus contains many species. Newly described members of human enteroviruses are assigned continuous numbers with the species designated "human enterovirus". [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1) activation by ions (activators); 2) activation by cofactors (coenzymes); and 3) conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epitestosterone: 17 alpha-Hydroxy-androst-4-ene-3-one. A naturally occurring stereoisomer of testosterone with androgenic activity. [NIH]
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Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estriol: (16 alpha,17 beta)-Estra-1,3,5(10)-triene-3,16,17-triol. A metabolite of estradiol and usually the predominant estrogenic metabolite in urine. During pregnancy, large amounts of estriol are produced by the placenta. It has also been obtained from plant sources. The 16 beta-isomer has also been isolated from the urine of pregnant women. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen Antagonists: Compounds which inhibit or antagonize the action or biosynthesis of estrogen. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Estrogen Receptor Modulators: Substances that possess antiestrogenic actions but can also produce estrogenic effects as well. They act as complete or partial agonist or as antagonist. They can be either steroidal or nonsteroidal in structure. [NIH] Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [NIH]
Estrone: 3-Hydroxyestra-1,3,5(10)-trien-17-one. A metabolite of estradiol but possessing less biological activity. It is found in the urine of pregnant women and mares, in the human placenta, and in the urine of bulls and stallions. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), estrone may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethinyl Estradiol: A semisynthetic estrogen with high oral estrogenic potency. It is often
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used as the estrogenic component in oral contraceptives. [NIH] Ethylenes: Derivatives of ethylene, a simple organic gas of biological origin with many industrial and biological use. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excrete: To get rid of waste from the body. [NIH] Exemestane: An anticancer drug used to decrease estrogen production and suppress the growth of estrogen-dependent tumors. [NIH] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH]
Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Facial: Of or pertaining to the face. [EU] Facial Expression: Observable changes of expression in the face in response to emotional
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stimuli. [NIH] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feeding Behavior: Behavioral responses or sequences associated with eating including modes of feeding, rhythmic patterns of eating, and time intervals. [NIH] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Neck Fractures: Fractures of the short, constricted portion of the thigh bone between the femur head and the trochanters. It excludes intertrochanteric fractures which are hip fractures. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fenfluramine: A centrally active drug that apparently both blocks serotonin uptake and provokes transport-mediated serotonin release. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectins: Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression
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(return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flounder: Common name for two families of fish belonging to the order Pleuronectiformes and described as left-eye flounders and right-eye flounders. The latter is more commonly used in research. [NIH] Fluconazole: Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in AIDS. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Fluoxymesterone: An anabolic steroid that has been used in the treatment of male hypogonadism, delayed puberty in males, and in the treatment of breast neoplasms in women. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Foetoplacental: Pertaining to the fetus and placenta. [EU] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Follicles: Shafts through which hair grows. [NIH] Follicular Cyst: Cyst due to the occlusion of the duct of a follicle or small gland. [NIH] Follicular Phase: The period of the menstrual cycle that begins with menstruation and ends with ovulation. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH]
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Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Galenical: 1. Usually cap: of or relating to Galen or his medical principles or method. 2. Constituting a galenical. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallic Acid: A colorless or slightly yellow crystalline compound obtained from nutgalls. It is used in photography, pharmaceuticals, and as an analytical reagent. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Fusion: Fusion of structural genes to analyze protein behavior or fusion of regulatory sequences with structural genes to determine mechanisms of regulation. [NIH] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used
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in a radiopharmaceutical. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH]
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Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]
Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropic: Stimulating the gonads; applied to hormones of the anterior pituitary which influence the gonads. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Gonorrhea: Acute infectious disease characterized by primary invasion of the urogenital tract. The etiologic agent, Neisseria gonorrhoeae, was isolated by Neisser in 1879. [NIH] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH]
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Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulosa Cells: Cells of the membrana granulosa lining the vesicular ovarian follicle which become luteal cells after ovulation. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]
Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma
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glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhaging: A copious discharge of blood from the blood vessels. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Hermetic: Impervious to air; airtight. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hip Fractures: Fractures of the femur head, the femur neck, the trochanters, or the inter- or subtrochanteric region. Excludes fractures of the acetabulum and fractures of the femoral shaft below the subtrochanteric region. For the fractures of the femur neck the specific term femoral neck fractures is available. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]
Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histamine Release: The secretion of histamine from mast cell and basophil granules by exocytosis. This can be initiated by a number of factors, all of which involve binding of IgE, cross-linked by antigen, to the mast cell or basophil's Fc receptors. Once released, histamine binds to a number of different target cell receptors and exerts a wide variety of effects. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH]
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Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]
Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU]
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Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperandrogenism: A state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. It is often caused by ovarian disease (particularly the polycystic ovary syndrome) and by adrenal diseases (particularly adrenal gland hyperfunction). [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersecretion: Excessive secretion. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hyperstimulation: Excessive stimulation. [EU] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrichosis: Localized or generalized excess hair. The concept does not include hirsutism, which is excess hair in females and children with an adult male pattern of distribution. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypotrophy: Abiotrophy. [EU] Hysterectomy: Excision of the uterus. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
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Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
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Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophilins: Members of a family of highly conserved proteins which are all cis-trans peptidyl-prolyl isomerases (peptidylprolyl isomerase). They bind the immunosuppressant drugs cyclosporine; tacrolimus and sirolimus. They possess rotomase activity, which is inhibited by the immunosuppressant drugs that bind to them. EC 5.2.1.- [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH]
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Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Inhibin: Glyceroprotein hormone produced in the seminiferous tubules by the Sertoli cells in the male and by the granulosa cells in the female follicles. The hormone inhibits FSH and LH synthesis and secretion by the pituitary cells thereby affecting sexual maturation and fertility. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own
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psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervertebral: Situated between two contiguous vertebrae. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin
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or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Investigative Techniques: Investigative techniques used in pre-clinical and clinical research, epidemiology, chemistry, immunology, genetics, etc. They do not include techniques specifically applied to diagnosis; therapeutics; anesthesia and analgesia, surgery, operative, and dentistry. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [NIH] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Isoenzymes: One of various structurally related forms of an enzyme, each having the same mechanism but with differing chemical, physical, or immunological characteristics. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kainate: Glutamate receptor. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Kerato: Prefix indicating relationship to the cornea. [NIH] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Keratoconjunctivitis Sicca: Drying and inflammation of the conjunctiva as a result of insufficient lacrimal secretion. When found in association with xerostomia and polyarthritis, it is called Sjogren's syndrome. [NIH]
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Ketoconazole: Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lacrimal: Pertaining to the tears. [EU] Lactation: The period of the secretion of milk. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Langerhans Cells: Recirculating, dendritic, antigen-presenting cells containing characteristic racket-shaped granules (Birbeck granules). They are found principally in the stratum spinosum of the epidermis and are rich in Class II major histocompatibility complex molecules. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] Leishmaniasis: A disease caused by any of a number of species of protozoa in the genus Leishmania. There are four major clinical types of this infection: cutaneous (Old and New World), diffuse cutaneous, mucocutaneous, and visceral leishmaniasis. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levonorgestrel: A progestational hormone with actions similar to those of progesterone and about twice as potent as its racemic or (+-)-isomer (norgestrel). It is used for contraception, control of menstrual disorders, and treatment of endometriosis. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH]
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Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols. It occurs on capillary endothelial surfaces, especially in mammary, muscle, and adipose tissue. Genetic deficiency of the enzyme causes familial hyperlipoproteinemia Type I. (Dorland, 27th ed) EC 3.1.1.34. [NIH] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]
Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or
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site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Potentiation: A persistent increase in synaptic efficacy, usually induced by appropriate activation of the same synapses. The phenomenological properties of long-term potentiation suggest that it may be a cellular mechanism of learning and memory. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lordosis: The anterior concavity in the curvature of the lumbar and cervical spine as viewed from the side. The term usually refers to abnormally increased curvature (hollow back, saddle back, swayback). It does not include lordosis as normal mating posture in certain animals ( = posture + sex behavior, animal). [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH]
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Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malaise: A vague feeling of bodily discomfort. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Maternal Behavior: The behavior patterns associated with or characteristic of a mother.
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[NIH]
Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]
Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medrogestone: 6,17-Dimethylpregna-4,6-diene-3,20-dione. A synthetic progestational hormone with actions similar to those of progesterone. It is used in the treatment of menstrual irregularities and has also been employed in the treatment of prostatic hypertrophy and endometrial carcinoma. [NIH] Medroxyprogesterone: (6 alpha)-17-Hydroxy-6-methylpregn-4-ene-3,20-dione. A synthetic progestational hormone used in veterinary practice as an estrus regulator. [NIH] Medroxyprogesterone Acetate: An injectable contraceptive, generally marketed under the name Depo-Provera. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]
Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of
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glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menarche: The establishment or beginning of the menstrual function. [EU] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH]
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Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methoxychlor: An insecticide. Methoxychlor has estrogenic effects in mammals, among other effects. [NIH] Methyltestosterone: A synthetic hormone used for androgen replacement therapy and as an hormonal antineoplastic agent. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Micronuclei: Nuclei, separate from and additional to the main nucleus of a cell, produced during the telophase of mitosis or meiosis by lagging chromosomes or chromosome fragments derived from spontaneous or experimentally induced chromosomal structural changes. This concept also includes the smaller, reproductive nuclei found in multinucleate protozoans. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH]
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Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Monounsaturated fat: An unsaturated fat that is found primarily in plant foods, including olive and canola oils. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
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Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Muscle Fatigue: A state arrived at through prolonged and strong contraction of a muscle. Studies in athletes during prolonged submaximal exercise have shown that muscle fatigue increases in almost direct proportion to the rate of muscle glycogen depletion. Muscle fatigue in short-term maximal exercise is associated with oxygen lack and an increased level of blood and muscle lactic acid, and an accompanying increase in hydrogen-ion concentration in the exercised muscle. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscle Spindles: Mechanoreceptors found between skeletal muscle fibers. Muscle spindles are arranged in parallel with muscle fibers and respond to the passive stretch of the muscle, but cease to discharge if the muscle contracts isotonically, thus signaling muscle length. The muscle spindles are the receptors responsible for the stretch or myotactic reflex. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH]
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Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Cavity: The proximal portion of the respiratory passages on either side of the nasal septum, lined with ciliated mucosa, extending from the nares to the pharynx. [NIH] Nasal Septum: The partition separating the two nasal cavities in the midplane, composed of cartilaginous, membranous and bony parts. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephrons: The functional units of the kidney, consisting of the glomerulus and the attached tubule. [NIH] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nerve Regeneration: Renewal or physiological repair of damaged nerve tissue. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis,
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as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurosecretory Systems: A system of neurons that has the specialized function to produce and secrete hormones, and that constitutes, in whole or in part, an endocrine organ or system. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neurotrophins: A nerve growth factor. [NIH] Neurovegetative: Pertaining to the vegetative (autonomic) nervous system. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Nidation: Implantation of the conceptus in the endometrium. [EU]
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Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Norethindrone: A synthetic progestational hormone with actions similar to those of progesterone but functioning as a more potent inhibitor of ovulation. It has weak estrogenic and androgenic properties. The hormone has been used in treating amenorrhea, functional uterine bleeding, endometriosis, and for contraception. [NIH] Norgestrel: (+-)-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one. A progestational agent with actions similar to those of progesterone. This racemic or (+-)-form has about half the potency of the levo form (levonorgestrel). Norgestrel is used as a contraceptive and ovulation inhibitor and for the control of menstrual disorders and endometriosis. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Matrix: The fibrogranular network of residual structural elements within which are immersed both chromatin and ribonucleoproteins. It extends throughout the nuclear interior from the nucleolus to the nuclear pore complexes along the nuclear periphery. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary
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bases in the two strains. [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Oestradiol: Growth hormone. [NIH] Oestrogen: A generic term for oestrus-producing steroid compounds; the female sex hormones. In humans, oestrogen is formed in the ovary, possibly the adrenal cortex, the testis, and the foetoplacental unit; it has various functions in both sexes. It is responsible for the development of the female secondary sex characteristics, and during the menstrual cycle it acts on the female genitalia to produce an environment suitable for the fertilization, implantation, and nutrition of the early embryo. Oestrogen is used in oral contraceptives and as a palliative in cancer of the breast after menopause and cancer of the prostate; other uses include the relief of the discomforts of menopause, inhibition of lactation, and treatment of osteoporosis, threatened abortion, and various functional ovarian disorders. [EU]
Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Olfactory Bulb: Ovoid body resting on the cribriform plate of the ethmoid bone where the olfactory nerve terminates. The olfactory bulb contains several types of nerve cells including the mitral cells, on whose dendrites the olfactory nerve synapses, forming the olfactory glomeruli. The accessory olfactory bulb, which receives the projection from the vomeronasal organ via the vomeronasal nerve, is also included here. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncorhynchus: A genus of the family Salmonidae (salmons and trouts). They are named for their hooked (onco) nose (rhynchus). They are usually anadromous and occasionally inhabit freshwater. They can be found in North Pacific coastal areas from Japan to California and
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adjacent parts of the Arctic Ocean. Salmon and trout are popular game and food fish. Various species figure heavily in genetic, metabolism, and hormone research. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Oophorectomy: Surgery to remove one or both ovaries. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
Orchiectomy: The surgical removal of one or both testicles. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteolytic: Causing the breakdown of bone. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ovarian Cysts: General term for cysts and cystic diseases of the ovary. [NIH] Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [NIH] Ovarian Hyperstimulation Syndrome: Syndrome composed of a combination of ovarian enlargement and an acute fluid shift out of the intravascular space. The enlargement is caused by ovarian cyst formation and the fluid shift may result in ascites, hydrothorax, or generalized edema. The syndrome is most usually seen as a complication of ovulation induction, a treatment for infertility. [NIH]
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Ovariectomy: The surgical removal of one or both ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovulation Induction: Techniques for the artifical induction of ovulation. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxytocin: A nonapeptide posterior pituitary hormone that causes uterine contractions and stimulates lactation. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH]
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Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresthesia: Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penile Erection: The state of the penis when the erectile tissue becomes filled with blood and causes the penis to become rigid and elevated. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of
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the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Perimenopausal: The time of a woman's life when menstrual periods become irregular. Refers to the time near menopause. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Perivascular: Situated around a vessel. [EU] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH]
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Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phentermine: A central nervous system stimulant and sympathomimetic with actions and uses similar to those of dextroamphetamine. It has been used most frequently in the treatment of obesity. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [NIH] Phenylpropanolamine: A sympathomimetic that acts mainly by causing release of norepinephrine but also has direct agonist activity at some adrenergic receptors. It is most commonly used as a nasal vasoconstrictor and an appetite depressant. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Pheromone: A substance secreted externally by certain animal species, especially insects, to affect the behavior or development of other members of the species. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phosphodiesterase Inhibitors: Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase
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"physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]
Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Pituitary Hormones: Hormones secreted by the anterior and posterior lobes of the pituitary gland and the pars intermedia, an ill-defined region between the two. Their secretion is regulated by the hypothalamus. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plant Oils: Oils derived from plants or plant products. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
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Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarthritis: An inflammation of several joints together. [EU] Polychlorinated Biphenyls: Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polyethylene Glycols: Alpha-Hydro-omega-hydroxypoly(oxy-1,2-ethanediyls). Additional polymers of ethylene oxide and water and their ethers. They vary in consistency from liquid to solid, depending on the molecular weight, indicated by a number following the name. Used as surfactants in industry, including foods, cosmetics and pharmaceutics; in biomedicine, as dispersing agents, solvents, ointment and suppository bases, vehicles, tablet excipients. Some specific groups are lauromagrogols, nonoxynols, octoxynols and poloxamers. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuritis: Inflammation of several peripheral nerves at the same time. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein
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through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Pregnenolone: Steroid hormone. [NIH] Premedication: Preliminary administration of a drug preceding a diagnostic, therapeutic, or surgical procedure. The commonest types of premedication are antibiotics (antibiotic prophylaxis) and anti-anxiety agents. It does not include preanesthetic medication. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Premenstrual: Occurring before menstruation. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoptic Area: Region of hypothalamus between the anterior commissure and optic chiasm. [NIH]
Pressoreceptors: Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a
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designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Product Packaging: Form in which product is processed or wrapped and labeled. (From Popline Thesaurus, 1991) Product labeling is also available. [NIH] Proenzyme: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH] Proestrus: Phase of the estrous cycle preceding estrus during which the Graafian follicle undergoes maturation. Applies to animals. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progestogen: A term applied to any substance possessing progestational activity. [EU] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward
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opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by
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thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Proteome: The protein complement of an organism coded for by its genome. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH]
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Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychosexual: Pertaining to the mental aspects of sex. [NIH] Psyllium: Dried, ripe seeds of Plantago psyllium, P. indica, and P. ovata (Plantaginaceae). Plantain seeds swell in water and are used as demulcents and bulk laxatives. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Pustular: Pertaining to or of the nature of a pustule; consisting of pustules (= a visible collection of pus within or beneath the epidermis). [EU] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] Raloxifene: A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and
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cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptivity: The condition of the reproductive organs of a female flower that permits effective pollination. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]
Relaxin: Hormone produced by the ovaries during pregnancy that loosens ligaments that hold the hip bones together. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial
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remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal tubular: A defect in the kidneys that hinders their normal excretion of acids. Failure to excrete acids can lead to weak bones, kidney stones, and poor growth in children. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]
Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reverse Transcriptase Inhibitors: Inhibitors of reverse transcriptase (RNA-directed DNA polymerase), an enzyme that synthesizes DNA on an RNA template. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH]
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Ribonuclease: RNA-digesting enzyme. [NIH] Ribonucleoproteins: Proteins conjugated with ribonucleic acids (RNA) or specific RNA. Many viruses are ribonucleoproteins. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rubella: An acute, usually benign, infectious disease caused by a togavirus and most often affecting children and nonimmune young adults, in which the virus enters the respiratory tract via droplet nuclei and spreads to the lymphatic system. It is characterized by a slight cold, sore throat, and fever, followed by enlargement of the postauricular, suboccipital, and cervical lymph nodes, and the appearances of a fine pink rash that begins on the head and spreads to become generalized. Called also German measles, roetln, röteln, and three-day measles, and rubeola in French and Spanish. [EU] Rubella Virus: The type (and only) species of Rubivirus causing acute infection in humans, primarily children and young adults. Humans are the only natural host. A live, attenuated vaccine is available for prophylaxis. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical
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structure, often a vessel or a nerve. [NIH] Scopolamine: An alkaloid from Solanaceae, especially Datura metel L. and Scopola carniolica. Scopolamine and its quaternary derivatives act as antimuscarinics like atropine, but may have more central nervous system effects. Among the many uses are as an anesthetic premedication, in urinary incontinence, in motion sickness, as an antispasmodic, and as a mydriatic and cycloplegic. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Sebum: The oily substance secreted by sebaceous glands. It is composed of keratin, fat, and cellular debris. [NIH] Secretin: A hormone made in the duodenum. Causes the stomach to make pepsin, the liver to make bile, and the pancreas to make a digestive juice. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Seminal vesicles: Glands that help produce semen. [NIH] Seminiferous tubule: Tube used to transport sperm made in the testes. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in
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the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Behavior: Sexual activities of humans. [NIH] Sex Behavior, Animal: Sexual activities of animals. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Hormone-Binding Globulin: A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as androgen-binding protein. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Sicca: Failure of lacrimal secretion, keratoconjunctivitis sicca, failure of secretion of the salivary glands and mucous glands of the upper respiratory tract and polyarthritis. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell
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activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Behavior: Any behavior caused by or affecting another individual, usually of the same species. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU]
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Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Somatotropin: A small peptide hormone released by the anterior pituitary under hypothalamic control. Somatotropin, or growth hormone, stimulates mitosis, cell growth, and, for some cell types, differentiation in many tissues of the body. It has profound effects on many aspects of gene expression and metabolism. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasmodic: Of the nature of a spasm. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatocytes: Male germ cells derived from spermatogonia and developing into spermatids. [NIH] Spermatogenesis: Process of formation and development of spermatozoa, including spermatocytogenesis and spermiogenesis. [NIH] Spermatogonia: The spermatocytes. [NIH]
primitive
differentiated
male
gametes
which
give
rise
to
Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU]
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Spotting: A slight discharge of blood via the vagina, especially as a side-effect of oral contraceptives. [EU] Stabilization: The creation of a stable state. [EU] Stanozolol: Anabolic agent. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other
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disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Subtrochanteric: Below a trochanter. [NIH] Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Sumatriptan: A serotonin agonist that acts selectively at 5HT1 receptors. It is used in the treatment of migraines. [NIH] Superovulation: Occurrence or induction of release of more ova than are normally released at the same time in a given species. The term applies to both animals and humans. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppository: A medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body, suppository bases are solid at room temperature but melt or dissolve at body temperature. Commonly used bases are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. [EU] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surgical castration: Surgical removal of the testicles (orchiectomy) or ovaries (oophorectomy) to stop the production of sex hormones. Decreasing the levels of hormones may stop the growth of certain cancers. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH]
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Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU]
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Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Telophase: The final phase of cell division, in which two daughter nuclei are formed, the cytoplasm divides, and the chromosomes lose their distinctness and are transformed into chromatin networks. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testicle: The male gonad where, in adult life, spermatozoa develop; the testis. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Tetrodotoxin: Octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano10aH(1,3)dioxocino(6,5-a)pyrimidine-4,7,10,11,12-pentol. An aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order Tetradontiformes (pufferfish, globefish, toadfish), which are eaten. The toxin causes paresthesia and paralysis through interference with neuromuscular conduction. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermoregulation: Heat regulation. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thioredoxin: A hydrogen-carrying protein that participates in a variety of biochemical reactions including ribonucleotide reduction. Thioredoxin is oxidized from a dithiol to a disulfide during ribonucleotide reduction. The disulfide form is then reduced by NADPH in a reaction catalyzed by thioredoxin reductase. [NIH]
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Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thoracic Surgery: A surgical specialty concerned with diagnosis and treatment of disorders of the heart, lungs, and esophagus. Two major types of thoracic surgery are classified as pulmonary and cardiovascular. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tibia: The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH]
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Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]
Transient Ischemic Attacks: Focal neurologic abnormalities of sudden onset and brief duration that reflect dysfunction in the distribution of the internal carotid-middle cerebral or the vertebrobasilar arterial system. [NIH]
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Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trastuzumab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. Trastuzumab blocks the effects of the growth factor protein HER2, which transmits growth signals to breast cancer cells. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Trophic: Of or pertaining to nutrition. [EU] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Truncal: The bilateral dissection of the abdominal branches of the vagus nerve. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubal ligation: An operation to tie the fallopian tubes closed. This procedure prevents pregnancy by blocking the passage of eggs from the ovaries to the uterus. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body.
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Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]
Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urogenital System: All the organs involved in reproduction and the formation and release of urine. It includes the kidneys, ureters, bladder, urethra, and the organs of reproduction ovaries, uterus, fallopian tubes, vagina, and clitoris in women and the testes, seminal vesicles, prostate, seminal ducts, and penis in men. [NIH] Uterine Contraction: Contraction of the uterine muscle. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in
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which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Headaches: A group of disorders characterized by recurrent headaches associated with abnormal dilation and constriction of cerebral blood vessels. Representative disorders from this category include migraine, cluster headache, and paroxysmal hemicrania. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU]
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Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virilism: Development of masculine traits in the female. [NIH] Virilization: The induction or development of male secondary sec characters, especially the induction of such changes in the female, including enlargement of the clitoris, growth of facial and body hair, development of a hairline typical of the male forehead, stimulation of secretion and proliferation of the sebaceous glands (often with acne), and deepening of the voice. Called also masculinization) [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Vitellogenin: A serum and yolk protein which has been characterized as a calcium-binding glycolipophosphoprotein. It is induced by estrogen or juvenile hormone and is essential for yolk formation in various insect species. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [NIH]
Vomeronasal Organ: A specialized part of the olfactory system located anteriorly in the nasal cavity within the nasal septum. Chemosensitive cells of the vomeronasal organ project via the vomeronasal nerve to the accessory olfactory bulb. The primary function of this organ appears to be in sensing pheromones which regulate reproductive and other social behaviors. While the structure has been thought absent in higher primate adults, data now suggests it may be present in adult humans. [NIH]
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Weight Gain: Increase in body weight over existing weight. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [NIH]
Xenograft: The cells of one species transplanted to another species. [NIH] Xerostomia: Decreased salivary flow. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zoledronate: A drug that belongs to the family of drugs called bisphosphonates. It is used to prevent bone fractures and reduce bone pain in people who have cancer that has spread to the bone. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
315
INDEX 5 5-alpha, 55, 227 A Abdomen, 227, 238, 270, 273, 287, 288, 304, 308, 312 Abdominal, 74, 227, 228, 277, 286, 288, 298, 310 Ablation, 82, 227 Abortion, 181, 227, 284 Abortion, Habitual, 181, 227 Acatalasia, 227, 241 Acceptor, 227, 273, 286, 309 Acetylcholine, 15, 227, 243, 282, 283 Acetylgalactosamine, 227, 263 Acetylglucosamine, 227, 263 Acidity, 146, 147, 178, 227, 288 Acne, 82, 142, 164, 195, 227, 248, 313 Acne Vulgaris, 82, 227 Acoustic, 124, 227 Acyl, 156, 227 Adaptability, 227, 241, 242 Adaptation, 16, 25, 29, 227, 280, 290 Adenocarcinoma, 80, 86, 94, 106, 108, 228 Adenosine, 228, 234, 239, 289, 307 Adhesives, 146, 192, 228 Adipocytes, 64, 74, 228, 246, 272 Adipose Tissue, 185, 228, 273 Adjustment, 227, 228 Adjuvant, 155, 228, 261 Adolescence, 7, 18, 228 Adrenal Cortex, 228, 229, 231, 248, 257, 267, 284, 293 Adrenal Glands, 228, 298 Adrenergic, 228, 232, 252, 256, 289, 306 Adverse Effect, 9, 15, 142, 153, 171, 172, 175, 228, 289, 301 Aerobic, 228, 279 Aerosol, 174, 228, 236 Afferent, 43, 62, 228, 259, 272 Afferent Pathways, 62, 228 Affinity, 12, 15, 18, 26, 46, 70, 151, 164, 186, 228, 229, 234, 273, 302 Affinity Chromatography, 12, 229 Agar, 229, 290 Age of Onset, 175, 229, 311 Ageing, 116, 170, 173, 175, 229
Agonist, 14, 18, 19, 20, 24, 35, 40, 42, 56, 148, 229, 236, 244, 252, 257, 281, 289, 296, 305, 307 Airway, 143, 229, 302 Aldosterone, 11, 61, 229 Alendronate, 85, 229 Alertness, 229, 239 Algorithms, 229, 237 Alimentary, 229, 287 Alkaline, 229, 239, 307 Alkaloid, 229, 235, 244, 245, 279, 300, 307 Alkylating Agents, 150, 229 Allergen, 229, 300 Alloys, 229, 244 Alopecia, 229, 248 Alpha Particles, 229, 296 Alpha-Defensins, 230, 249 Alternative medicine, 201, 230 Ameliorated, 177, 230 Amenorrhea, 87, 194, 230, 283, 291 Amine, 230, 265 Amino Acid Motifs, 230, 246 Amino Acid Sequence, 12, 147, 148, 230, 231, 232, 236, 246, 262, 301 Aminoethyl, 152, 230 Amnion, 74, 230 Amniotic Fluid, 230 Amphetamines, 230, 244 Amyloid, 15, 116, 157, 158, 230 Anabolic, 56, 142, 230, 251, 260, 304 Anaesthesia, 230, 269 Anal, 7, 16, 231, 260, 274 Analgesic, 231, 255, 279, 285 Analog, 231, 236 Analogous, 231, 309 Analytes, 152, 188, 231 Anaphylatoxins, 231, 245 Anatomical, 62, 63, 231, 242, 247, 251, 268, 278, 299 Anchorage, 5, 231 Androgen-Binding Protein, 231, 301 Androgenic, 142, 164, 231, 253, 256, 283 Androgens, 9, 26, 29, 38, 51, 53, 58, 84, 109, 144, 164, 165, 193, 204, 228, 231, 234, 267 Androstenediols, 142, 231 Androstenedione, 88, 142, 231 Anemia, 194, 231, 244, 260, 264, 280
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Estradiol
Anesthesia, 24, 113, 229, 231, 232, 254, 271 Aneurysm, 231, 312 Angina, 231, 283 Angiogenesis, 8, 54, 122, 143, 231, 276 Angioplasty, 169, 176, 231 Angiotensinogen, 231, 298 Animal model, 6, 47, 48, 90, 158, 232 Anorexia, 34, 230, 232 Anovulation, 53, 54, 232, 291 Antagonism, 232, 239, 251, 307 Antecedent, 8, 194, 232 Anterior Cruciate Ligament, 106, 232 Anti-Anxiety Agents, 232, 292 Antibacterial, 232, 303 Antibiotic, 150, 232, 292, 303, 307 Antibiotic Prophylaxis, 232, 292 Antibodies, 4, 12, 60, 165, 188, 232, 233, 264, 266, 268, 275, 290, 310 Antibody, 12, 50, 72, 144, 188, 229, 232, 233, 245, 257, 264, 266, 268, 269, 276, 279, 284, 296, 300, 303, 310 Anticoagulant, 232, 295 Anticonvulsant, 232, 240, 243, 289 Antidepressant, 199, 232, 260 Antifungal, 232, 248, 260, 272, 302 Antigen, 58, 188, 228, 232, 233, 235, 245, 265, 266, 267, 268, 269, 272, 276, 278, 296, 300 Antigen-Antibody Complex, 233, 245 Antigen-presenting cell, 233, 272 Antihypertensive, 11, 233 Anti-infective, 233, 266 Anti-inflammatory, 48, 122, 233, 236, 250, 262 Antimetabolite, 233, 278 Antimicrobial, 233, 249 Antineoplastic, 150, 229, 233, 248, 262, 278, 286, 302 Antineoplastic Agents, 150, 229, 233 Antioxidant, 47, 102, 158, 159, 189, 190, 233, 234, 286 Antiseptic, 233, 241 Antiserum, 233, 235 Antispasmodic, 233, 285, 300 Anus, 231, 233, 235, 238, 245, 297 Anxiety, 134, 232, 233, 286 Anxiety Disorders, 233, 286 Anxiolytic, 233, 243 Aorta, 61, 233, 247, 292, 298, 312 Apnea, 233 Apolipoproteins, 7, 56, 233, 273 Applicability, 10, 234
Aqueous, 101, 144, 163, 191, 234, 235, 249, 254, 266, 273 Arachidonic Acid, 234, 294 Arginine, 41, 176, 231, 234, 283, 310 Aromatase, 8, 21, 27, 35, 51, 72, 73, 80, 85, 103, 109, 151, 186, 234 Aromatic, 17, 71, 234, 240, 289 Arterial, 24, 38, 157, 234, 243, 267, 283, 295, 306, 309 Arteries, 126, 233, 234, 237, 247, 248, 274, 278, 280, 296, 311 Arteriolar, 31, 234, 238 Arterioles, 234, 237, 240, 312 Arteriosus, 234, 296 Artery, 28, 61, 83, 126, 169, 176, 231, 234, 247, 254, 255, 296, 311 Ascorbic Acid, 118, 181, 234, 267 Aseptic, 234, 285, 304 Aspirate, 46, 234 Assay, 4, 15, 62, 91, 98, 144, 234, 268, 296 Astringent, 234, 241 Astrocytes, 4, 9, 37, 56, 158, 234, 278 ATP, 84, 126, 234, 252, 262, 274, 289, 295, 309 Atresia, 22, 235 Atrophy, 96, 162, 163, 164, 187, 195, 235, 282 Atropine, 235, 300 Attenuation, 24, 133, 235 Autoimmune disease, 48, 58, 235, 280 Autonomic, 24, 227, 235, 282, 283, 288, 306 Autoradiography, 42, 235 Avian, 8, 69, 71, 235 Avidity, 58, 176, 235 Axonal, 44, 235 Axons, 235, 250, 281 Azoospermia, 32, 235 B Bacteria, 227, 232, 233, 235, 236, 254, 255, 274, 278, 297, 301, 303, 309, 312 Bacterial Physiology, 228, 235 Bactericidal, 70, 235, 257 Bacteriophage, 235, 290, 309 Baroreflex, 13, 235 Basal Ganglia, 235, 284 Base, 18, 154, 169, 235, 250, 262, 271, 307 Basement Membrane, 235, 258, 272 Basophil, 236, 265 Beclomethasone, 143, 236 Benign, 4, 142, 164, 165, 236, 264, 281, 299 Benign prostatic hyperplasia, 142, 236 Benzene, 236, 271
Index 317
Beta-Defensins, 236, 249 Beta-Endorphin, 41, 97, 236 Betahistine, 174, 236 Beta-pleated, 230, 236 Bilateral, 87, 236, 291, 310 Bile, 96, 236, 261, 273, 300, 304 Bile Acids, 96, 236, 304 Bile Acids and Salts, 236 Binding Sites, 12, 57, 64, 70, 71, 236 Bioassay, 236, 237 Bioavailability, 26, 107, 165, 187, 236 Bioavailable, 26, 30, 80, 86, 236 Biochemical, 13, 25, 29, 87, 126, 233, 236, 263, 301, 307 Biochemical reactions, 236, 307 Biological Assay, 151, 237 Biological response modifier, 237, 270 Biological therapy, 237, 264 Biomarkers, 24, 237 Biopsy, 172, 237, 287 Biotechnology, 65, 73, 201, 211, 237 Biotin, 237, 284 Biphasic, 61, 67, 81, 92, 237 Bladder, 236, 237, 246, 268, 280, 282, 294, 311 Blastocyst, 237, 246, 254, 286, 290, 310 Blood Cell Count, 237, 264 Blood Coagulation, 237, 239, 259, 308 Blood Glucose, 237, 264, 270 Blood pressure, 7, 10, 13, 24, 38, 60, 113, 179, 233, 235, 237, 240, 267, 279, 283, 296, 302 Blood vessel, 164, 169, 176, 184, 193, 195, 231, 235, 237, 240, 241, 242, 243, 255, 262, 265, 271, 275, 277, 288, 289, 302, 304, 307, 308, 312 Blood-Brain Barrier, 113, 237 Blot, 25, 60, 238, 284 Body Composition, 16, 56, 238 Body Fluids, 237, 238, 253, 302, 310 Body Mass Index, 23, 238, 286 Bone Density, 110, 164, 238 Bone Marrow, 35, 36, 236, 238, 268, 275, 280, 302, 304 Bowel, 231, 238, 251, 270, 288, 304 Bowel Movement, 238, 251, 304 Bradykinin, 238, 283 Brain Stem, 238, 242 Branch, 115, 223, 238, 254, 275, 287, 296, 298, 303, 306, 307 Breakdown, 14, 238, 251, 261, 285 Breast Neoplasms, 238, 260
Breeding, 183, 238 Broad Ligament, 238, 259 Bronchi, 238, 256, 307, 309 Bronchial, 236, 238, 265, 307 Bronchiseptica, 238, 288 Bronchitis, 238, 243 Buffers, 235, 238 Burns, 155, 159, 190, 239 Burns, Electric, 239 C Caffeine, 55, 239 Calcification, 55, 169, 239 Calcitonin, 12, 123, 124, 239 Calcitonin Gene-Related Peptide, 123, 124, 239 Calcium Channels, 12, 50, 239 Calculi, 239, 263 Callus, 239, 254 Calmodulin, 19, 239 Candidiasis, 239, 260 Capillary, 62, 238, 240, 273, 313 Capsid, 58, 240 Capsules, 240, 261 Carbamazepine, 87, 240 Carbohydrate, 77, 79, 153, 240, 263, 291 Carbon Dioxide, 240, 249, 260, 290, 298 Carboxy, 240 Carboxylic Acids, 146, 240 Carcinogen, 240, 257 Carcinogenesis, 47, 49, 76, 94, 104, 108, 127, 128, 172, 240, 242 Carcinogenic, 229, 236, 240, 269, 293, 304, 311 Carcinoma, 122, 240, 248, 276 Cardiac, 23, 58, 143, 158, 159, 169, 184, 189, 190, 235, 239, 240, 253, 256, 258, 281, 304 Cardiac Output, 235, 240 Cardiotonic, 240, 289 Cardiovascular disease, 108, 167, 171, 179, 240 Cardiovascular System, 168, 240 Carrier Proteins, 240, 296 Case-Control Studies, 30, 241 Caspase, 4, 241 Castration, 241 Catalase, 30, 227, 241 Catalyse, 165, 241 Catechol, 30, 94, 241 Catecholamine, 241, 252 Catheter, 169, 241, 255 Catheterization, 231, 241 Caudal, 59, 241, 251, 267, 284, 291
318
Estradiol
Caudate Nucleus, 241, 284 Causal, 53, 241 Caveolae, 52, 241 Caveolins, 241 Cell Adhesion, 72, 76, 122, 241 Cell Aggregation, 241, 285 Cell Death, 4, 16, 76, 233, 241 Cell Differentiation, 41, 51, 241, 301 Cell Division, 178, 235, 241, 242, 264, 276, 279, 290, 293, 300, 307 Cell membrane, 239, 241, 242, 243, 250, 258, 261, 289, 313 Cell Membrane Structures, 241, 242 Cell motility, 76, 242 Cell proliferation, 12, 16, 45, 47, 59, 87, 96, 110, 143, 176, 242, 301 Cell Respiration, 242, 279, 298 Cell Survival, 242, 264 Cellulose, 242, 290 Centrifugation, 242, 264 Cerebellar, 6, 242, 310 Cerebellum, 6, 242 Cerebral, 235, 237, 238, 242, 256, 258, 296, 308, 309, 312 Cerebrovascular, 112, 183, 240, 242 Cerebrum, 242 Cervical, 14, 59, 152, 242, 274, 299 Cervix, 14, 57, 227, 242, 298 Chemopreventive, 48, 242 Chemotactic Factors, 242, 245 Chemotherapy, 150, 242 Chimeras, 36, 242 Chin, 78, 242, 277 Chlordiazepoxide, 174, 243 Chloride Channels, 13, 243 Cholesterol, 7, 30, 83, 113, 155, 159, 165, 190, 236, 241, 243, 247, 273, 274, 276, 297, 304, 307 Cholesterol Esters, 243, 273 Choline, 15, 243 Cholinergic, 15, 243 Chromaffin System, 243, 255 Chromatin, 29, 67, 71, 72, 233, 243, 256, 283, 307 Chromosomal, 243, 278 Chromosome, 103, 159, 190, 243, 264, 273, 278, 300, 310 Chronic, 13, 21, 25, 26, 29, 30, 42, 53, 55, 122, 143, 227, 243, 251, 255, 269, 291, 304, 306 Chronic Disease, 55, 243
Chronic Obstructive Pulmonary Disease, 30, 243 Chronic renal, 243, 291 Chylomicrons, 243, 273 Circulatory system, 169, 243, 255 CIS, 31, 41, 185, 243, 268 Citrus, 234, 243 Clamp, 13, 14, 56, 62, 243 Clear cell carcinoma, 243, 251 Climacteric, 82, 83, 100, 105, 107, 114, 115, 157, 160, 175, 192, 244 Clinical Medicine, 244, 292 Clinical trial, 4, 17, 48, 137, 138, 211, 244, 247, 252, 280, 295, 297 Clomiphene, 93, 244 Clone, 4, 12, 244 Cloning, 237, 244 Coagulation, 85, 107, 237, 244, 265, 308 Cobalt, 179, 244 Coca, 244 Cocaine, 115, 244 Coenzyme, 234, 244 Cofactor, 244, 295, 308 Cognition, 104, 105, 170, 244 Cohort Studies, 55, 244 Colchicine, 66, 178, 179, 245, 310 Collagen, 14, 39, 65, 68, 133, 160, 173, 228, 230, 235, 245, 258, 259, 261, 276, 290, 293 Collapse, 176, 238, 245, 302 Colloidal, 245, 254, 301 Colon, 101, 126, 245, 272 Colorectal, 45, 245 Combination Therapy, 170, 172, 175, 245, 257 Complement, 29, 231, 245, 246, 275, 300 Complementary and alternative medicine, 121, 131, 245 Complementary medicine, 121, 245 Compliance, 194, 246 Computational Biology, 211, 246 Computed tomography, 55, 238, 246 Computerized tomography, 246 Conception, 22, 97, 153, 227, 246, 247, 259, 304 Concomitant, 157, 246 Conduction, 246, 307 Confounding, 56, 246 Conjugated, 81, 87, 102, 122, 143, 145, 162, 171, 174, 236, 246, 249, 299 Conjunctiva, 145, 246, 271 Conjunctivitis, 144, 246
Index 319
Connective Tissue, 39, 163, 195, 234, 238, 245, 246, 250, 261, 275, 298, 299, 304, 306 Connective Tissue Cells, 246 Consciousness, 231, 232, 246, 249, 252, 295 Consensus Sequence, 64, 230, 246 Conserved Sequence, 230, 246 Constriction, 184, 247, 271, 312 Constriction, Pathologic, 247, 312 Consultation, 38, 247 Consumption, 55, 133, 171, 247, 250, 286 Continuum, 51, 247 Contraception, 15, 77, 79, 82, 88, 148, 152, 162, 170, 175, 180, 194, 247, 272, 283 Contraceptive Agents, 247, 250 Contractility, 24, 247 Contraindications, ii, 247 Contralateral, 247, 277, 285 Control group, 247, 293 Controlled study, 23, 78, 247 Conus, 247, 296 Convulsion, 237, 247 Coordination, 83, 242, 247, 280 Cornea, 247, 271, 299 Corneum, 247, 256 Coronary, 23, 28, 53, 83, 85, 126, 162, 168, 169, 171, 176, 240, 247, 248, 278, 280, 283 Coronary Artery Bypass, 23, 85, 176, 247 Coronary heart disease, 162, 171, 240, 247 Coronary Thrombosis, 247, 278, 280 Coronary Vessels, 168, 248 Corpus, 7, 51, 134, 194, 248, 275, 287, 293, 308 Corpus Luteum, 51, 134, 194, 248, 275, 293 Cortex, 10, 57, 61, 248, 256, 258 Cortical, 19, 57, 134, 248, 258, 300 Corticosteroids, 60, 248, 262 Cortisol, 9, 61, 103, 114, 134, 151, 248 Cortisone, 248, 250 Coumarin, 248 Coumestrol, 122, 248 Cranial, 242, 248, 259, 264, 284, 288, 312 Creatinine, 18, 248 Criterion, 24, 248 Cultured cells, 57, 248 Curative, 248, 307 Cutaneous, 36, 172, 240, 248, 272, 274, 287 Cyclic, 15, 67, 68, 74, 135, 148, 239, 248, 264, 283, 289, 294, 307 Cyclophosphamide, 96, 113, 248 Cyclosporins, 175, 248 Cyproterone, 79, 83, 98, 101, 109, 113, 115, 248, 260
Cyproterone Acetate, 79, 98, 101, 109, 115, 248 Cyst, 234, 248, 260, 285 Cysteinyl, 4, 248 Cytochrome, 9, 65, 81, 95, 99, 113, 115, 123, 165, 234, 249 Cytokine, 34, 35, 48, 57, 58, 76, 105, 249, 302 Cytoplasm, 233, 242, 249, 256, 258, 264, 299, 306, 307 Cytoskeleton, 5, 249, 278 Cytotoxic, 150, 249, 302 Cytotoxicity, 126, 249 D Data Collection, 7, 249 Decarboxylation, 249, 265 Decidua, 249, 290 Decongestant, 249, 289 Defensins, 57, 230, 236, 249 Dehydroepiandrosterone, 79, 100, 103, 114, 142, 249 Deletion, 28, 29, 51, 233, 249 Dementia, 3, 57, 89, 158, 249 Demethylation, 69, 249 Dendrites, 249, 250, 282, 284 Dendritic, 19, 67, 112, 250, 272, 276 Density, 7, 15, 55, 68, 78, 80, 81, 86, 103, 116, 127, 170, 191, 238, 242, 250, 273, 285, 291 Dentate Gyrus, 250, 265 Depersonalization, 250, 286, 299 Depolarization, 250, 302 Deprivation, 4, 15, 16, 154, 177, 250 Derealization, 250, 286 Dermal, 160, 181, 250 Dermis, 160, 250, 306, 309 Desogestrel, 77, 79, 113, 250 Deuterium, 56, 250, 266 Deuterium Oxide, 56, 250 Developed Countries, 148, 167, 250 Dexamethasone, 175, 183, 250 Dextroamphetamine, 250, 289 Diabetes Mellitus, 167, 250, 262, 265 Diagnostic procedure, 141, 201, 250 Diastolic, 250, 267 Diencephalon, 251, 267, 308 Dietary Fats, 46, 251, 273 Diethylstilbestrol, 71, 112, 123, 185, 251 Digestion, 18, 229, 236, 238, 251, 270, 273, 287, 304, 312 Digestive system, 138, 251
320
Estradiol
Dihydrotestosterone, 26, 29, 36, 55, 115, 142, 164, 227, 248, 251, 297, 301 Dilatation, 227, 231, 251, 293, 312 Dilatation, Pathologic, 251, 312 Dilation, 238, 251, 312 Dilator, 251, 283 Diltiazem, 107, 251 Dilution, 56, 251 Dimerization, 52, 147, 251 Diphtheria, 150, 251 Diphtheria Toxin, 150, 251 Diploid, 251, 290 Discrete, 6, 51, 53, 147, 251, 274 Disease Progression, 21, 251 Disinfectant, 251, 257 Dissection, 252, 310 Dissociation, 228, 252 Distal, 12, 28, 235, 247, 252, 253, 295 Diuresis, 239, 252, 307 Dizziness, 171, 252, 286 DNA Topoisomerase, 252, 262 Domesticated, 252, 264 Dominance, 36, 55, 252 Dopamine, 33, 50, 244, 250, 252, 282, 289 Double-blind, 23, 78, 79, 91, 252 Drive, ii, vi, 29, 53, 92, 111, 112, 117, 125, 252, 272 Drug Interactions, 62, 204, 205, 252 Drug Resistance, 123, 252 Drug Tolerance, 252 Dry Eye Syndrome, 144, 253 Duct, 241, 253, 260, 299, 304, 306 Duodenum, 236, 253, 300, 304 Dydrogesterone, 96, 108, 114, 181, 253 Dyes, 230, 253, 305 Dysgenesis, 37, 253 Dysmenorrhea, 42, 253 Dyspareunia, 163, 177, 193, 253, 257 Dysplasia, 37, 253 Dyspnea, 253, 286 Dystrophy, 155, 253 E Ectopic, 20, 21, 29, 253 Ectopic Pregnancy, 29, 253 Edema, 165, 253, 285 Effector, 18, 42, 58, 227, 245, 253, 289 Effector cell, 58, 253 Efferent, 9, 231, 253, 259 Efficacy, 23, 43, 48, 82, 88, 96, 97, 101, 152, 185, 194, 200, 253, 274, 310 Elasticity, 159, 160, 253 Elastin, 160, 245, 253, 258
Elective, 104, 253 Electrocoagulation, 244, 253 Electrode, 62, 253 Electrolyte, 229, 253, 292, 302 Electrophoresis, 62, 254 Electrophysiological, 44, 50, 254 Electroplating, 241, 254, 305 Emboli, 176, 254 Embolus, 184, 254, 269 Embryo, 103, 104, 109, 124, 149, 227, 230, 237, 241, 254, 269, 277, 284, 303, 311 Embryo Loss, 149, 254 Embryo Transfer, 103, 109, 149, 254 Embryogenesis, 148, 254 Emollient, 254, 263, 284 Emphysema, 243, 254 Empirical, 54, 254 Emulsion, 235, 254, 260 Enanthate, 56, 254 Encephalitis, 254 Encephalomyelitis, 48, 254 Endarterectomy, 231, 254 Endocrine Glands, 255, 287 Endocrine System, 20, 255, 282 Endocytosis, 241, 255 Endometriosis, 21, 33, 58, 181, 255, 272, 283 Endometrium, 14, 21, 29, 32, 54, 71, 103, 148, 152, 175, 194, 249, 255, 277, 282, 310 Endopeptidases, 255, 294 Endorphin, 42, 236, 255 Endothelial cell, 8, 27, 40, 52, 70, 72, 81, 168, 237, 255, 308 Endothelium, 122, 149, 255, 283 Endothelium, Lymphatic, 255 Endothelium, Vascular, 255 Endothelium-derived, 255, 283 Endotoxic, 255, 273 Endotoxin, 255, 311 End-stage renal, 243, 255, 291 Energy balance, 256, 272 Energy Intake, 56, 256 Enhancer, 146, 256, 298 Enkephalin, 11, 236, 256 Enteropeptidase, 256, 310 Enterovirus, 58, 256 Entorhinal Cortex, 256, 265 Environmental Exposure, 256, 284 Environmental Health, 86, 210, 212, 256 Enzymatic, 68, 230, 239, 245, 256, 259, 265, 277 Enzyme Activation, 25, 256
Index 321
Eosinophils, 256, 264, 272 Epidemic, 167, 256, 303 Epidemiological, 5, 48, 83, 256 Epidermal, 256, 271, 276 Epidermis, 160, 247, 250, 256, 266, 271, 272, 293, 296 Epinephrine, 228, 252, 256, 282, 283, 311 Epitestosterone, 4, 256 Epithelial, 5, 12, 21, 32, 49, 57, 70, 176, 193, 228, 236, 249, 257, 272 Epithelial Cells, 5, 12, 32, 57, 70, 193, 236, 257, 272 Epithelium, 8, 72, 176, 193, 235, 255, 257 Epitope, 188, 257 Erectile, 56, 164, 257, 287 Erection, 257 Erythrocytes, 231, 237, 238, 257, 300 Esophagus, 235, 251, 257, 304, 308 Estriol, 15, 47, 48, 59, 95, 101, 106, 164, 170, 179, 185, 189, 257 Estrogen Antagonists, 177, 257 Estrogen Receptor Modulators, 49, 257 Estrogen Replacement Therapy, 13, 25, 88, 158, 172, 178, 187, 257 Ethanol, 133, 146, 161, 257 Ether, 68, 151, 155, 165, 185, 186, 257 Ethylenes, 190, 258 Eukaryotic Cells, 258, 268, 284, 285 Evoke, 258, 304 Excipient, 147, 173, 258 Excitability, 44, 258 Excitation, 61, 230, 258, 282 Excitatory, 42, 44, 45, 61, 258, 262, 263 Excrete, 258, 298 Exemestane, 191, 258 Exocytosis, 258, 265, 306 Exogenous, 14, 21, 54, 64, 93, 114, 157, 255, 258, 294, 311 Exons, 91, 258 Expiration, 258, 298 Extracellular, 5, 50, 91, 106, 168, 173, 230, 234, 246, 255, 258, 259, 276, 302, 307 Extracellular Matrix, 5, 168, 173, 246, 258, 259, 276 Extracellular Matrix Proteins, 173, 258, 276 Extracellular Space, 258 Extrapyramidal, 252, 258 F Facial, 55, 60, 258, 259, 313 Facial Expression, 258, 259 Facial Nerve, 60, 259
Fallopian tube, 57, 259, 298, 310, 311 Family Planning, 153, 184, 211, 259 Fatigue, 34, 259, 280 Fatty acids, 71, 100, 165, 240, 259, 263, 294 Febrile, 34, 259 Feeding Behavior, 34, 259 Femoral, 16, 259, 265 Femoral Neck Fractures, 259, 265 Femur, 232, 259, 265, 308 Fenfluramine, 168, 259 Ferritin, 103, 259 Fetal Blood, 52, 259 Fetus, 37, 53, 57, 61, 227, 259, 260, 290, 292, 303, 311, 312 Fibrin, 237, 259, 308 Fibrinolysis, 85, 107, 259 Fibroblasts, 64, 99, 160, 246, 259, 270 Fibronectins, 258, 259 Fixation, 259, 301 Flatus, 260, 261 Flounder, 112, 260 Fluconazole, 62, 260 Fluorescence, 13, 49, 260 Fluoxetine, 62, 260 Fluoxymesterone, 165, 260 Flutamide, 26, 35, 60, 260 Foetoplacental, 260, 284 Folate, 104, 116, 127, 151, 260 Fold, 46, 238, 260, 277 Folic Acid, 179, 260 Follicles, 22, 27, 83, 260, 269 Follicular Cyst, 6, 260 Follicular Phase, 21, 54, 93, 194, 260 Foramen, 243, 260, 288 Forearm, 237, 260 Fossa, 242, 260 Free Radicals, 233, 252, 261 Friction, 261, 274 Fungi, 232, 248, 261, 264, 278, 314 G Galenical, 163, 261 Gallbladder, 227, 251, 261 Gallic Acid, 159, 190, 261 Ganglia, 59, 227, 261, 281, 288, 306 Gap Junctions, 261, 306 Gas, 160, 188, 240, 258, 260, 261, 266, 283 Gastric, 261, 265, 287 Gastrin, 261, 266 Gastrointestinal, 238, 256, 257, 261, 301, 303, 304, 305, 311 Gastrointestinal tract, 257, 261, 301, 303, 304, 311
322
Estradiol
Gelatin, 163, 261, 263, 305 Gels, 181, 261 Gene Fusion, 29, 261 Generator, 68, 73, 261 Genetic Code, 262, 283 Genetic Markers, 64, 262 Genetics, 10, 27, 31, 80, 95, 114, 175, 252, 262, 271, 279 Genistein, 121, 123, 125, 126, 168, 171, 262 Genital, 29, 58, 68, 69, 72, 243, 262, 311 Genitourinary, 262, 311 Genotype, 262, 289 Germ Cells, 262, 276, 285, 286, 303, 307 Gestation, 53, 148, 262, 288, 290, 303 Ginseng, 130, 262 Glomerular, 81, 262, 298 Glomerulus, 262, 281 Glottis, 262, 288 Glucocorticoid, 9, 72, 102, 236, 250, 262 Glucose, 126, 167, 234, 237, 242, 250, 262, 263, 264, 270, 299 Glucose Intolerance, 250, 262 Glucuronic Acid, 262, 265 Glutamate, 38, 45, 57, 62, 114, 262, 263, 271 Glutamic Acid, 43, 260, 263, 282, 293 Glutathione Peroxidase, 263, 300 Glycerol, 161, 263, 289 Glycerophospholipids, 263, 289 Glycine, 230, 236, 263, 282, 301 Glycogen, 263, 280 Glycoprotein, 95, 123, 148, 263, 272, 301, 308, 311 Glycosaminoglycans, 160, 258, 263 Glycosylation, 49, 263 Gonad, 114, 197, 263, 307 Gonadal, 8, 9, 27, 34, 41, 54, 263, 304 Gonadotropic, 53, 263 Gonadotropin, 9, 14, 35, 53, 61, 68, 73, 93, 95, 97, 115, 148, 189, 263 Gonorrhea, 29, 263 Gout, 179, 245, 263 Governing Board, 263, 292 Graft, 23, 176, 248, 263, 266 Graft Rejection, 248, 263 Grafting, 85, 247, 263, 268 Granulocytes, 59, 236, 264, 302, 314 Granulosa Cells, 27, 93, 99, 144, 264, 269, 275 Grasses, 260, 264 Growth factors, 45, 46, 59, 168, 264, 278 Guanylate Cyclase, 264, 283 Guinea Pigs, 68, 264
H Haemorrhage, 227, 264 Hair follicles, 250, 264 Half-Life, 14, 264 Haploid, 264, 290 Haptens, 228, 264, 296 Headache, 239, 264, 312 Heart attack, 240, 264 Hematocrit, 56, 237, 264 Heme, 115, 165, 249, 264 Hemodynamics, 40, 264 Hemoglobin, 56, 231, 237, 257, 264, 272 Hemorrhage, 34, 85, 184, 192, 253, 264, 265, 304 Hemorrhaging, 154, 265 Hemostasis, 88, 200, 265, 301 Heparin, 169, 265 Hepatic, 123, 134, 135, 265 Heredity, 227, 261, 262, 265 Hermetic, 173, 265 Heterogeneity, 228, 265 Heterozygotes, 252, 265 Hip Fractures, 64, 259, 265 Hippocampus, 10, 250, 265, 305 Hirsutism, 142, 248, 265, 267 Histamine, 122, 159, 190, 231, 236, 265 Histamine Release, 159, 190, 231, 265 Histidine, 193, 265 Histology, 28, 265 Histone Deacetylase, 31, 265 Homeostasis, 19, 24, 42, 49, 266 Homodimer, 266, 309 Homogeneous, 163, 247, 266 Homologous, 30, 265, 266, 280, 300, 301, 306, 310 Hormone therapy, 115, 137, 266 Horny layer, 256, 266 Host, 29, 58, 235, 249, 266, 268, 299, 313 Hybrid, 52, 244, 266, 284 Hybridization, 266, 279, 284 Hybridomas, 266, 270 Hydrogen Bonding, 266, 283 Hydrogen Peroxide, 76, 241, 263, 266, 273 Hydrolysis, 179, 266, 289, 295, 310 Hydrophilic, 152, 163, 266 Hydrophobic, 263, 266, 273 Hydroxylation, 65, 66, 71, 86, 95, 165, 266 Hydroxylysine, 245, 267 Hydroxyproline, 230, 245, 267 Hyperandrogenism, 53, 267 Hypercalcemia, 13, 267 Hyperlipidemia, 167, 267
Index 323
Hyperplasia, 8, 31, 51, 72, 100, 105, 127, 267 Hypersecretion, 14, 53, 267 Hypersensitivity, 16, 97, 229, 267, 298, 300 Hyperstimulation, 83, 104, 148, 149, 267 Hypertension, 10, 13, 81, 83, 167, 240, 264, 267 Hypertrichosis, 265, 267 Hypertrophy, 74, 164, 165, 236, 267, 276 Hyperuricemia, 263, 267 Hypogonadism, 260, 267 Hypotension, 61, 267 Hypotensive, 61, 267 Hypothalamic, 9, 10, 15, 24, 27, 35, 42, 44, 54, 62, 68, 73, 87, 134, 267, 303 Hypothalamus, 10, 11, 33, 63, 251, 256, 267, 290, 292, 303, 308 Hypotrophy, 157, 267 Hysterectomy, 186, 267 I Id, 54, 117, 128, 216, 222, 224, 267 Immune function, 34, 267, 309 Immune response, 29, 34, 36, 57, 58, 228, 232, 233, 235, 248, 263, 264, 267, 268, 275, 300, 305, 313 Immune system, 34, 49, 57, 233, 237, 253, 267, 268, 275, 280, 281, 312, 314 Immunity, 36, 103, 188, 249, 268 Immunization, 268, 293, 300 Immunoassay, 95, 110, 143, 144, 152, 176, 188, 268 Immunodeficiency, 98, 268 Immunogenic, 268, 273, 296 Immunoglobulin, 58, 232, 258, 268, 279 Immunohistochemistry, 61, 268 Immunologic, 242, 268 Immunology, 92, 103, 228, 268, 271 Immunophilins, 268, 302 Immunosuppressant, 229, 268, 278, 302 Immunosuppressive, 81, 248, 262, 268, 307 Immunosuppressive therapy, 81, 268 Impairment, 268, 277 Implantation, 37, 124, 148, 152, 176, 182, 194, 246, 268, 282, 284, 286 Impotence, 257, 268 In situ, 15, 43, 59, 60, 62, 63, 68, 163, 195, 268 In Situ Hybridization, 43, 59, 60, 62, 63, 68, 268 Incision, 268, 270 Incontinence, 268, 300 Incubation, 269, 288
Incubation period, 269, 288 Indicative, 153, 184, 197, 269, 287, 312 Infarction, 269 Infertility, 9, 14, 21, 22, 27, 29, 32, 37, 44, 181, 269, 285 Inflammation, 29, 34, 79, 85, 122, 143, 159, 190, 199, 227, 233, 238, 246, 249, 254, 269, 271, 277, 281, 291, 294, 298, 306 Infusion, 27, 54, 61, 92, 269 Inhalation, 143, 174, 228, 269, 291 Inhibin, 22, 27, 54, 96, 98, 104, 110, 269 Initiation, 5, 9, 18, 20, 26, 75, 269, 293, 309 Initiator, 237, 269 Inlay, 269, 298 Innervation, 193, 259, 269 Inorganic, 269, 280, 305 Inotropic, 252, 269 Insecticides, 269, 314 Insight, 17, 63, 65, 269 Insomnia, 162, 270 Insulator, 270, 280 Insulin, 37, 45, 59, 64, 65, 69, 70, 90, 94, 115, 159, 167, 190, 237, 270, 271, 311 Insulin-dependent diabetes mellitus, 270 Insulin-like, 59, 70, 90, 270 Interferon, 58, 75, 270 Interferon-alpha, 270 Interleukin-1, 90, 270 Interleukin-2, 270 Interleukin-6, 30, 55, 97, 270 Intermittent, 253, 270 Interstitial, 258, 270, 298 Intervertebral, 69, 270 Intestinal, 193, 230, 256, 270 Intestine, 157, 236, 238, 270, 272 Intoxication, 270, 314 Intracellular, 15, 19, 25, 28, 33, 43, 47, 51, 70, 178, 239, 269, 270, 277, 283, 292, 294, 300, 301 Intramuscular, 270, 287 Intravascular, 176, 182, 270, 285 Intravenous, 13, 185, 269, 270, 287 Intrinsic, 62, 229, 235, 270 Invasive, 21, 268, 270 Investigative Techniques, 10, 271 Involuntary, 29, 247, 271, 281, 297, 302, 303 Ion Channels, 234, 271, 289, 306 Ions, 227, 235, 238, 239, 243, 252, 253, 256, 266, 271 Ischemia, 113, 183, 184, 235, 271 Islet, 76, 105, 271
324
Estradiol
Isoelectric, 148, 271 Isoelectric Point, 148, 271 Isoenzymes, 56, 271 Isoflavones, 105, 127, 130, 271 J Joint, 39, 81, 271, 306 K Kainate, 46, 271 Kb, 210, 271 Keratin, 271, 300 Keratinocytes, 75, 76, 160, 271 Kerato, 144, 271 Keratoconjunctivitis, 144, 271, 301 Keratoconjunctivitis Sicca, 144, 271, 301 Ketoconazole, 107, 272 Kinetics, 38, 89, 239, 272 L Labile, 179, 245, 272 Lacrimal, 259, 271, 272, 301 Lactation, 182, 272, 284, 286, 293 Laminin, 5, 235, 258, 272 Langerhans Cells, 160, 272 Large Intestine, 251, 270, 272, 297, 302 Latency, 63, 272 Latent, 272, 292 Least-Squares Analysis, 272, 297 Leishmaniasis, 36, 272 Leptin, 64, 72, 87, 97, 167, 272 Lethal, 4, 235, 251, 272 Leucine, 236, 272 Leukocytes, 237, 238, 242, 256, 264, 270, 272, 311 Levonorgestrel, 43, 79, 82, 104, 114, 192, 272, 283 Libido, 164, 231, 272 Library Services, 222, 272 Life cycle, 237, 261, 272 Life Expectancy, 154, 175, 273 Ligament, 232, 273, 294 Ligands, 18, 19, 35, 40, 46, 147, 273 Ligation, 273 Likelihood Functions, 273, 297 Linear Models, 273, 297 Linkage, 25, 55, 262, 273 Lipase, 74, 273 Lipid A, 19, 104, 108, 153, 273 Lipid Peroxidation, 48, 155, 273, 286 Lipophilic, 154, 157, 158, 163, 273, 291 Lipopolysaccharides, 273 Lipoprotein, 7, 56, 74, 83, 102, 104, 153, 273, 274 Lipoprotein Lipase, 74, 273
Liposome, 185, 273 Liver cancer, 73, 273 Localization, 67, 69, 147, 268, 273 Localized, 52, 145, 251, 260, 265, 267, 269, 272, 274, 290 Locomotion, 24, 179, 274, 290 Locomotor, 24, 274 Logistic Models, 274, 297 Longitudinal study, 15, 274 Long-Term Potentiation, 24, 44, 274 Loop, 73, 274 Lordosis, 11, 274 Low-density lipoprotein, 102, 155, 273, 274 Lubricants, 145, 274 Lubrication, 193, 274 Lucida, 272, 274 Luciferase, 29, 274 Lumbar, 16, 274 Lupus, 274, 306 Luteal Phase, 27, 97, 194, 275 Lutein Cells, 128, 275, 293 Lymph, 242, 243, 255, 275, 299 Lymph node, 242, 275, 299 Lymphatic, 255, 269, 275, 299, 302 Lymphatic system, 275, 299, 302 Lymphocyte, 58, 67, 233, 275, 276 Lymphoid, 58, 232, 248, 275 Lysine, 176, 267, 275, 310 M Macrophage, 270, 275 Major Histocompatibility Complex, 272, 275 Malaise, 34, 275 Malignancy, 13, 275 Malignant, 12, 228, 233, 273, 275, 280, 281, 299 Malignant tumor, 275, 280 Malnutrition, 235, 275 Mammary, 46, 49, 72, 91, 126, 172, 183, 247, 273, 275, 297, 307 Mammogram, 239, 275, 278 Manifest, 9, 235, 275 Man-made, 241, 275 Maternal Behavior, 20, 63, 275 Matrix metalloproteinase, 8, 39, 172, 173, 276 Meat, 86, 251, 276 Meat Products, 251, 276 Medial, 59, 63, 276, 285, 308 Mediate, 9, 16, 24, 32, 35, 40, 70, 72, 73, 252, 276
Index 325
Mediator, 41, 84, 270, 276, 301 Medicament, 145, 163, 276, 305 MEDLINE, 211, 276 Medrogestone, 81, 276 Medroxyprogesterone, 102, 171, 191, 204, 276 Medroxyprogesterone Acetate, 102, 171, 191, 276 Megaloblastic, 260, 276 Meiosis, 276, 278, 280, 306 Melanin, 276, 289, 311 Melanocytes, 160, 276 Melanoma, 81, 276 Melanosomes, 276 Membrane, 13, 14, 30, 33, 42, 47, 50, 52, 70, 74, 155, 230, 234, 241, 242, 245, 246, 250, 251, 255, 258, 271, 272, 276, 277, 280, 285, 289, 292, 302, 306, 310 Membrane Glycoproteins, 276 Membrane Lipids, 276, 289 Membrane Proteins, 241, 277 Memory, 25, 44, 45, 104, 116, 158, 159, 189, 190, 232, 249, 274, 277 Menarche, 94, 97, 277 Meninges, 242, 277 Meningitis, 260, 277 Menstrual Cycle, 22, 26, 27, 84, 86, 134, 149, 152, 175, 187, 194, 260, 275, 277, 284, 293 Menstruation, 21, 149, 175, 194, 230, 249, 253, 260, 275, 277, 284, 292 Mental, iv, 4, 99, 139, 170, 179, 210, 212, 243, 244, 249, 252, 259, 277, 293, 295, 296, 299, 311 Mental Disorders, 139, 277, 293, 295 Mental Health, iv, 4, 99, 139, 210, 212, 277, 293, 296 Mercury, 101, 277 Mesencephalic, 24, 277 Mesenteric, 61, 277 Mesentery, 277, 288 Mesoderm, 277, 310 Metabolic disorder, 263, 277 Metabolite, 12, 18, 66, 76, 122, 153, 154, 167, 184, 185, 257, 277, 292, 293 Metastasis, 276, 277 Methionine, 191, 193, 236, 278, 305 Methotrexate, 110, 278 Methoxychlor, 112, 278 Methyltestosterone, 165, 278 Methyltransferase, 94, 278 MI, 89, 191, 226, 278
Microbe, 278, 309 Microbiology, 36, 103, 228, 278 Microcalcifications, 239, 278 Microglia, 234, 278 Microgram, 194, 278 Micronuclei, 96, 278 Microorganism, 244, 278, 287, 313 Microscopy, 62, 66, 235, 278, 284 Microspheres, 116, 145, 278 Microtubules, 179, 278, 286 Migration, 76, 168, 278 Milligram, 278, 279 Milliliter, 238, 279 Miscarriage, 149, 279 Mitochondria, 25, 279, 285 Mitosis, 51, 178, 234, 278, 279, 303 Mitotic, 51, 70, 178, 279, 313 Mobilization, 35, 279 Modeling, 63, 279 Modification, 43, 44, 49, 157, 230, 279, 296 Modulator, 27, 40, 279 Molecular Probes, 12, 49, 279 Monitor, 40, 144, 248, 279, 283 Monoclonal, 266, 279, 310 Monocyte, 75, 169, 279 Mononuclear, 279, 311 Monophosphate, 74, 279 Monounsaturated fat, 185, 279 Morphine, 42, 279, 281, 285 Morphogenesis, 37, 279 Morphological, 44, 229, 254, 276, 280 Morphology, 9, 53, 67, 159, 190, 280 Motility, 280, 301 Motion Sickness, 280, 281, 300 Mucocutaneous, 272, 280 Mucosa, 58, 177, 274, 280, 281, 293, 304 Mucus, 152, 280 Multicenter study, 79, 280 Multidrug resistance, 125, 280 Multiple Myeloma, 102, 280 Multiple sclerosis, 48, 280 Multivalent, 235, 280 Muscle Fatigue, 159, 190, 280 Muscle relaxant, 232, 280, 289 Muscle Spindles, 280, 289 Muscular Dystrophies, 253, 280 Mutagenic, 229, 280 Mydriatic, 251, 280, 289, 300 Myelin, 280 Myocardial infarction, 155, 184, 247, 278, 280 Myocarditis, 58, 251, 281
326
Estradiol
Myocardium, 58, 278, 280, 281 N Naive, 76, 281 Naloxone, 236, 281 Narcotic, 279, 281 Nasal Cavity, 281, 313 Nasal Septum, 281, 313 Nausea, 281, 286, 311 NCI, 1, 137, 138, 209, 243, 281 Need, 3, 27, 146, 153, 154, 163, 178, 185, 187, 195, 198, 217, 228, 243, 263, 276, 281 Neonatal, 6, 37, 59, 281 Neoplasm, 281, 299, 311 Nephrons, 13, 281 Nephropathy, 167, 281 Nerve Fibers, 193, 281 Nerve Growth Factor, 15, 75, 127, 281, 282 Nerve Regeneration, 60, 281 Nervous System, 6, 11, 33, 45, 49, 145, 155, 156, 166, 227, 228, 230, 235, 236, 239, 242, 244, 250, 253, 261, 263, 264, 276, 278, 279, 280, 281, 282, 288, 289, 300, 301, 306, 307, 312 Networks, 6, 33, 281, 307 Neural, 11, 15, 20, 24, 26, 33, 57, 63, 228, 230, 239, 278, 281 Neuroblastoma, 116, 282 Neurodegenerative Diseases, 5, 41, 282 Neuroendocrine, 26, 27, 44, 45, 58, 282 Neurogenic, 8, 13, 282 Neurologic, 23, 232, 282, 309 Neuromuscular, 179, 227, 282, 307 Neuromuscular Junction, 227, 282 Neuronal, 4, 6, 8, 9, 19, 24, 25, 33, 39, 41, 43, 44, 56, 60, 121, 126, 239, 282 Neuropeptide, 97, 239, 282 Neurosecretory Systems, 255, 282 Neurosurgery, 184, 282 Neurotoxic, 63, 158, 282 Neurotoxicity, 114, 116, 158, 282 Neurotoxin, 63, 282 Neurotrophins, 57, 282 Neurovegetative, 145, 282 Neutrons, 229, 282, 296 Neutrophil, 29, 67, 105, 282 Nidation, 194, 254, 282 Nitric Oxide, 19, 39, 41, 61, 69, 89, 115, 168, 283 Nitrogen, 134, 156, 229, 230, 231, 248, 258, 260, 283, 310 Nitroglycerin, 193, 283 Norepinephrine, 228, 252, 282, 283, 289
Norethindrone, 79, 87, 102, 107, 108, 171, 194, 200, 283 Norgestrel, 171, 272, 283 Normotensive, 113, 283 Nuclear, 12, 18, 29, 82, 97, 103, 147, 157, 235, 244, 250, 258, 275, 283 Nuclear Matrix, 12, 82, 283 Nuclear Pore, 283 Nuclei, 59, 229, 258, 278, 279, 282, 283, 291, 295, 299, 307 Nucleic acid, 152, 240, 262, 266, 268, 283, 284 Nucleic Acid Hybridization, 152, 266, 283 Nucleolus, 283, 284, 299 Nucleus Accumbens, 50, 284 O Ocular, 72, 145, 284 Oculomotor, 277, 284 Odour, 234, 284 Oestradiol, 71, 74, 78, 84, 86, 97, 98, 99, 103, 106, 107, 114, 115, 116, 122, 125, 126, 284 Oestrogen, 107, 284 Ointments, 160, 189, 284 Olfactory Bulb, 284, 313 Oligomenorrhea, 284, 291 Oligonucleotide Probes, 12, 284 Oncogene, 15, 66, 76, 86, 284 Oncorhynchus, 135, 284 Oocytes, 103, 116, 149, 285 Oophorectomy, 187, 285, 305 Opacity, 29, 69, 250, 285 Operon, 285, 293, 298 Opiate, 42, 236, 256, 279, 281, 285 Opium, 279, 285 Optic Chiasm, 267, 285, 292 Orchiectomy, 89, 285, 305 Organ Culture, 37, 285 Organ Transplantation, 248, 285 Organelles, 51, 178, 242, 249, 276, 285, 290 Orgasm, 193, 285 Osteoclasts, 75, 239, 285 Osteolytic, 90, 285 Ovarian Cysts, 112, 285 Ovarian Follicle, 121, 194, 248, 264, 285 Ovarian Hyperstimulation Syndrome, 14, 101, 285 Ovariectomy, 21, 35, 87, 124, 286 Ovaries, 26, 53, 127, 170, 181, 234, 267, 285, 286, 291, 297, 298, 301, 305, 307, 310, 311 Ovary, 30, 73, 144, 165, 187, 231, 248, 257, 263, 284, 285, 286, 304
Index 327
Overweight, 117, 185, 186, 286 Ovulation, 6, 14, 44, 116, 148, 152, 153, 162, 180, 181, 184, 187, 194, 232, 244, 253, 260, 264, 275, 283, 285, 286 Ovulation Induction, 116, 148, 285, 286 Ovum, 248, 249, 262, 272, 285, 286, 293, 310, 314 Ovum Implantation, 286, 310 Oxidation, 48, 143, 155, 158, 159, 181, 190, 227, 233, 249, 263, 273, 286 Oxidative Stress, 19, 47, 75, 116, 124, 286 Oxygen Consumption, 286, 298 Oxytocin, 42, 100, 286 P Paclitaxel, 122, 175, 286 Palliative, 248, 284, 286, 307 Pancreas, 122, 227, 237, 251, 270, 271, 273, 286, 300, 303, 310, 311 Pancreatic, 76, 122, 286 Panic, 71, 100, 286 Panic Disorder, 71, 100, 286 Paralysis, 277, 286, 307 Parathyroid, 12, 287, 307 Parathyroid Glands, 287 Parathyroid hormone, 12, 287 Parenteral, 145, 191, 256, 287 Paresthesia, 287, 307 Paroxysmal, 287, 288, 312, 314 Parturition, 52, 287, 293 Patch, 3, 13, 14, 62, 88, 109, 114, 146, 149, 157, 161, 162, 200, 247, 287, 309 Pathogen, 29, 269, 287 Pathogenesis, 21, 29, 39, 49, 66, 150, 287 Pathologic, 42, 134, 234, 237, 247, 267, 287, 298 Pathologic Processes, 234, 287 Pathophysiology, 10, 21, 27, 61, 287 Pelvic, 21, 29, 78, 255, 287, 294 Pelvis, 227, 238, 274, 286, 287, 311 Penile Erection, 56, 287 Penis, 287, 298, 311 Pepsin, 287, 300 Peptic, 236, 287 Peptic Ulcer, 236, 287 Percutaneous, 146, 168, 169, 176, 287 Perfusion, 85, 287 Pericardium, 288, 306 Perimenopausal, 54, 105, 199, 288 Perinatal, 59, 288 Perioperative, 23, 288 Peripheral blood, 75, 270, 288
Peripheral Nervous System, 282, 288, 303, 305 Peritoneal, 21, 288 Peritoneal Cavity, 21, 288 Peritoneum, 238, 277, 288 Perivascular, 239, 278, 288 Pertussis, 52, 288, 314 PH, 15, 66, 93, 103, 116, 238, 288 Pharmaceutical Preparations, 166, 189, 242, 257, 261, 288 Pharmacokinetic, 62, 288 Pharmacologic, 12, 162, 231, 264, 289, 309 Phenotype, 13, 29, 50, 57, 62, 289 Phentermine, 168, 289 Phenyl, 115, 124, 152, 289 Phenylalanine, 289, 311 Phenylephrine, 61, 289 Phenylpropanolamine, 168, 289 Phenytoin, 99, 240, 289 Pheromone, 59, 289 Phosphodiesterase, 143, 193, 289 Phosphodiesterase Inhibitors, 143, 193, 289 Phospholipases, 13, 289, 302 Phospholipids, 185, 259, 273, 276, 289 Phosphorus, 239, 287, 289 Phosphorylate, 33, 289 Phosphorylated, 15, 33, 244, 289 Phosphorylation, 33, 49, 52, 67, 69, 72, 95, 126, 289, 295 Photocoagulation, 244, 289 Physiologic, 27, 35, 40, 54, 164, 192, 229, 244, 264, 277, 289, 294, 297, 298, 310 Physiology, 6, 27, 33, 41, 51, 61, 75, 81, 90, 106, 114, 115, 148, 254, 290 Pigments, 244, 290 Pilot study, 82, 108, 290 Pituitary Gland, 290 Pituitary Hormones, 15, 290 Placenta, 74, 144, 165, 234, 257, 259, 260, 290, 293, 311 Plant Oils, 284, 290 Plants, 159, 190, 229, 235, 238, 240, 243, 244, 249, 262, 280, 283, 290, 299, 309, 312 Plaque, 168, 231, 290 Plasma cells, 232, 280, 290 Plasticity, 20, 24, 37, 44, 45, 62, 67, 112, 290 Plastids, 285, 290 Platelet Activation, 290, 302 Platelet Aggregation, 231, 283, 290 Platelets, 169, 283, 290, 301, 308 Platinum, 274, 290
328
Estradiol
Pleomorphic, 284, 291 Pneumonia, 247, 291 Poisoning, 270, 277, 281, 291 Polyarthritis, 271, 291, 301 Polychlorinated Biphenyls, 17, 291 Polycystic, 9, 53, 98, 115, 127, 267, 291 Polycystic Ovary Syndrome, 98, 115, 267, 291 Polyethylene, 161, 191, 291, 305 Polyethylene Glycols, 291, 305 Polymerase, 72, 291, 293, 298 Polymers, 144, 145, 161, 291, 295 Polymorphism, 46, 80, 103, 291 Polyneuritis, 251, 291 Polysaccharide, 233, 242, 291, 295 Posterior, 231, 234, 242, 286, 290, 291, 299 Postnatal, 45, 53, 291, 304 Postoperative, 23, 87, 291 Postsynaptic, 291, 301, 306 Post-translational, 49, 231, 291, 301 Potassium, 38, 229, 292 Potentiate, 45, 193, 292 Potentiating, 237, 292 Potentiation, 274, 292, 302 Practicability, 292, 310 Practice Guidelines, 212, 292 Pravastatin, 62, 292 Precancerous, 242, 292 Preclinical, 102, 113, 292 Precursor, 70, 142, 157, 158, 164, 231, 232, 234, 243, 248, 252, 253, 256, 283, 289, 292, 293, 309, 310, 311 Predisposition, 156, 292 Pregnenolone, 130, 142, 165, 166, 292 Premedication, 192, 292, 300 Premenopausal, 11, 187, 292 Premenstrual, 85, 91, 292 Prenatal, 53, 254, 292 Preoptic Area, 63, 134, 292 Pressoreceptors, 235, 292 Presynaptic, 42, 50, 282, 292, 306 Prevalence, 42, 292 Prickle, 271, 293 Primary endpoint, 23, 293 Primary Prevention, 22, 293 Probe, 284, 293 Prodrug, 293 Product Packaging, 173, 293 Proenzyme, 256, 293 Proestrus, 34, 293 Progestogen, 149, 161, 162, 180, 181, 182, 293
Progression, 21, 70, 175, 232, 293 Projection, 58, 283, 284, 293 Prolactin, 20, 34, 37, 59, 63, 64, 91, 101, 103, 160, 293 Proline, 245, 267, 293 Promoter, 28, 31, 39, 41, 73, 80, 293 Promotor, 293, 298 Prophase, 280, 285, 293, 306 Prophylaxis, 155, 294, 299 Proportional, 59, 294 Prospective study, 22, 45, 55, 64, 115, 274, 294 Prostaglandin, 42, 68, 112, 294 Prostaglandins A, 42, 294 Prostaglandins D, 294 Prostatic Hyperplasia, 294 Protease, 57, 62, 230, 245, 294 Protease Inhibitors, 62, 294 Protein Binding, 29, 294 Protein C, 42, 230, 233, 235, 259, 271, 273, 294, 295 Protein Conformation, 230, 271, 295 Protein Kinases, 12, 38, 295 Protein S, 116, 237, 246, 251, 262, 295, 299, 307 Protein-Tyrosine Kinase, 262, 295 Proteinuria, 167, 280, 295 Proteoglycans, 235, 258, 295 Proteolytic, 245, 256, 295 Proteome, 49, 295 Protocol, 14, 27, 116, 172, 295 Protons, 229, 266, 295, 296 Proto-Oncogene Proteins, 286, 295 Proto-Oncogene Proteins c-mos, 286, 295 Protozoa, 272, 278, 295 Proximal, 12, 28, 44, 126, 252, 281, 292, 295 Psychiatric, 19, 22, 99, 116, 277, 295 Psychiatry, 18, 76, 97, 100, 105, 259, 295 Psychic, 244, 272, 277, 295, 296, 300 Psychoactive, 295, 314 Psychomotor, 240, 296 Psychosexual, 58, 296 Psyllium, 130, 296 Puberty, 7, 31, 44, 50, 149, 164, 175, 200, 260, 296 Public Health, 7, 37, 115, 212, 296 Public Policy, 211, 296 Pulmonary, 52, 237, 247, 296, 308, 312 Pulmonary Artery, 52, 237, 296, 312 Pulmonary hypertension, 52, 296 Pulse, 68, 73, 279, 296 Pustular, 227, 296
Index 329
Q Quality of Life, 22, 23, 78, 85, 88, 175, 177, 296 Quaternary, 295, 296, 300 R Race, 175, 272, 278, 283, 296 Racemic, 272, 283, 296 Radiation, 31, 155, 159, 190, 235, 256, 260, 261, 275, 296, 314 Radioactive, 144, 235, 264, 266, 268, 275, 279, 283, 296, 311 Radioimmunoassay, 15, 296 Radioisotope, 284, 296, 309 Radiological, 287, 296 Radiopharmaceutical, 262, 296 Raloxifene, 19, 35, 78, 80, 86, 87, 94, 96, 97, 102, 296, 300 Randomized, 23, 42, 78, 79, 85, 89, 91, 97, 98, 110, 115, 253, 297 Reactive Oxygen Species, 155, 297 Reagent, 47, 261, 274, 297 Receptivity, 21, 148, 297 Recombinant, 4, 14, 92, 116, 125, 297, 312 Recombination, 262, 297 Rectal, 297, 305 Rectum, 233, 238, 245, 251, 260, 261, 268, 272, 294, 297, 305 Recurrence, 18, 89, 297 Reductase, 28, 51, 56, 234, 278, 292, 297, 307 Refer, 1, 145, 245, 252, 260, 261, 273, 274, 281, 282, 297, 309 Reflex, 24, 280, 297 Refraction, 297, 303 Refractory, 82, 253, 297 Regeneration, 60, 168, 297 Regimen, 79, 81, 114, 180, 253, 297 Regression Analysis, 59, 297 Relaxin, 14, 39, 297 Remission, 297 Renal Artery, 61, 298 Renal failure, 13, 167, 298 Renal tubular, 12, 298 Renin, 11, 14, 157, 232, 298 Repressor, 69, 70, 285, 298 Reproductive system, 27, 125, 156, 298 Research Design, 41, 298 Resorption, 285, 298 Respiration, 179, 233, 240, 279, 298 Respiratory distress syndrome, 155, 298 Response Elements, 11, 18, 33, 41, 298 Restoration, 32, 298, 314
Retinoid, 84, 87, 298 Retroviral vector, 5, 298 Reverse Transcriptase Inhibitors, 62, 298 Rheumatism, 298 Rheumatoid, 48, 79, 199, 298 Rheumatoid arthritis, 48, 79, 199, 298 Ribonuclease, 72, 299 Ribonucleoproteins, 283, 299 Ribose, 68, 228, 299 Ribosome, 299, 310 Rigidity, 56, 290, 299 Risk factor, 22, 46, 55, 83, 89, 154, 167, 274, 294, 299 Rod, 243, 299 Rubella, 68, 299 Rubella Virus, 68, 299 S Salivary, 134, 251, 259, 299, 301, 314 Salivary glands, 251, 259, 299, 301 Saphenous, 247, 299 Saphenous Vein, 247, 299 Saponins, 299, 304 Sarcoma, 76, 299 Schizoid, 299, 314 Schizophrenia, 299, 314 Schizotypal Personality Disorder, 250, 299, 314 Sclera, 246, 247, 299 Sclerosis, 58, 280, 299 Scopolamine, 161, 300 Screening, 15, 52, 244, 300 Sebaceous, 250, 300, 313 Sebaceous gland, 250, 300, 313 Sebum, 227, 300 Secretin, 54, 300 Secretory, 57, 148, 149, 194, 230, 300, 306 Sedative, 3, 243, 300 Sediment, 17, 300 Sedimentation, 242, 300, 310 Segregation, 178, 297, 300 Seizures, 240, 287, 289, 300 Selective estrogen receptor modulator, 11, 19, 108, 125, 296, 300, 307 Selenium, 47, 179, 300 Semen, 235, 294, 300 Seminal vesicles, 300, 311 Seminiferous tubule, 32, 231, 269, 300 Semisynthetic, 257, 300 Senile, 285, 300 Sensitization, 108, 115, 127, 300 Sepsis, 34, 85, 301 Sequencing, 12, 301
330
Estradiol
Serine, 255, 295, 301, 310 Serologic, 268, 301 Serotonin, 259, 260, 282, 301, 305, 310 Serous, 255, 301 Serum Albumin, 296, 301 Sex Behavior, 274, 301 Sex Behavior, Animal, 274, 301 Sex Characteristics, 228, 231, 284, 296, 301, 307 Sex Hormone-Binding Globulin, 96, 103, 106, 110, 301 Sexually Transmitted Diseases, 58, 301 Shock, 60, 147, 155, 301, 310 Sicca, 144, 145, 301 Side effect, 142, 145, 148, 152, 161, 164, 189, 203, 228, 237, 248, 267, 301, 309 Signal Transduction, 6, 33, 35, 50, 58, 67, 241, 301 Silicon, 55, 302 Silicon Dioxide, 302 Sirolimus, 175, 268, 302 Skeletal, 61, 142, 231, 243, 280, 302, 303 Skeleton, 162, 165, 259, 271, 294, 302, 308 Skull, 302, 307 Sleep apnea, 56, 302 Small intestine, 243, 253, 266, 270, 302, 310 Sneezing, 288, 302 Social Behavior, 302, 313 Social Environment, 296, 302 Sodium, 56, 63, 123, 143, 229, 263, 302, 305 Soft tissue, 238, 302 Solid tumor, 231, 302 Solvent, 236, 257, 263, 302 Soma, 303 Somatic, 31, 228, 244, 254, 276, 279, 288, 303, 312 Somatic cells, 32, 276, 279, 303 Somatostatin, 82, 92, 125, 303 Somatotropin, 183, 303 Spasm, 233, 277, 303, 307 Spasmodic, 288, 303 Spatial disorientation, 252, 303 Specialist, 217, 251, 303 Specificity, 40, 150, 229, 239, 255, 303 Spectrum, 4, 35, 272, 278, 303 Sperm, 31, 82, 121, 152, 154, 185, 231, 243, 300, 303, 310 Spermatocytes, 303 Spermatogenesis, 8, 31, 164, 303 Spermatogonia, 31, 303 Spinal cord, 234, 238, 242, 243, 254, 277, 281, 282, 288, 297, 303, 306
Spinous, 256, 271, 303 Spontaneous Abortion, 227, 303 Sporadic, 148, 282, 303 Spotting, 152, 304 Stabilization, 168, 173, 289, 304 Stanozolol, 165, 304 Steel, 243, 304 Stem Cells, 59, 304, 311 Stenosis, 169, 182, 304 Stent, 182, 304 Sterile, 234, 287, 304 Sterility, 78, 83, 86, 88, 89, 93, 94, 95, 98, 103, 248, 269, 304 Stimulant, 239, 250, 265, 289, 304 Stimulus, 14, 25, 51, 56, 247, 252, 253, 258, 269, 271, 272, 297, 304, 308 Stomach, 227, 237, 251, 257, 261, 266, 281, 287, 288, 300, 302, 304 Stool, 245, 268, 272, 304 Strand, 291, 304 Stress, 11, 38, 47, 60, 134, 159, 165, 190, 241, 248, 281, 286, 292, 298, 304 Striatum, 50, 284, 304 Stricture, 304 Stroke, 10, 23, 50, 112, 134, 139, 153, 155, 168, 183, 184, 210, 240, 304 Stromal, 21, 32, 37, 64, 72, 108, 110, 148, 255, 304 Stromal Cells, 21, 37, 108, 110, 148, 304 Subacute, 116, 269, 304 Subarachnoid, 183, 184, 264, 304 Subclinical, 269, 300, 304 Subcutaneous, 74, 228, 253, 287, 305 Subiculum, 265, 305 Subspecies, 303, 305 Substance P, 277, 293, 300, 305 Substrate, 69, 93, 157, 164, 305 Subtrochanteric, 265, 305 Sulfates, 135, 305 Sulfur, 169, 258, 278, 305 Sulfuric acid, 305 Sumatriptan, 108, 305 Superovulation, 14, 305 Supplementation, 64, 92, 123, 125, 305 Suppositories, 261, 305 Suppository, 163, 291, 305 Suppression, 8, 21, 29, 34, 95, 105, 148, 152, 305 Suppressive, 29, 305 Surgical castration, 148, 305 Survival Rate, 34, 305 Sweat, 134, 250, 305, 306
Index 331
Sweat Glands, 250, 305, 306 Sympathetic Nervous System, 282, 306 Sympathomimetic, 250, 252, 256, 283, 289, 306 Symphysis, 242, 294, 306 Symptomatic, 143, 145, 232, 243, 306 Symptomatic treatment, 232, 243, 306 Symptomatology, 85, 306 Synapse, 228, 282, 292, 306, 310 Synapsis, 306 Synaptic, 38, 44, 61, 67, 274, 282, 302, 306 Synaptic Transmission, 61, 306 Synaptic Vesicles, 306 Synergistic, 17, 35, 72, 90, 153, 165, 192, 293, 306 Systemic, 49, 62, 81, 163, 173, 177, 204, 233, 237, 240, 251, 256, 264, 269, 306, 312 Systemic lupus erythematosus, 81, 306 Systolic, 267, 306 T Tacrolimus, 175, 268, 307 Tamoxifen, 12, 18, 19, 26, 74, 80, 87, 96, 99, 100, 102, 106, 126, 150, 300, 307 Telophase, 278, 307 Temporal, 9, 13, 45, 59, 173, 265, 307 Teratogenic, 229, 251, 307 Testicle, 263, 307 Testicular, 9, 32, 113, 234, 307 Testis, 32, 165, 231, 257, 284, 307 Tetany, 287, 307 Tetracycline, 5, 307 Tetrodotoxin, 63, 307 Theophylline, 143, 307 Therapeutics, 108, 205, 271, 307 Thermoregulation, 156, 307 Thigh, 56, 259, 307 Thioredoxin, 74, 307 Third Ventricle, 267, 308 Thoracic, 184, 308, 314 Thoracic Surgery, 184, 308 Thorax, 227, 274, 308, 312 Threshold, 25, 146, 153, 178, 184, 258, 267, 308 Thrombin, 259, 290, 295, 308 Thrombocytes, 290, 308 Thromboembolism, 79, 83, 109, 308 Thrombomodulin, 295, 308 Thrombosis, 295, 304, 308 Thrombus, 169, 247, 269, 290, 308 Thyroid, 11, 15, 84, 135, 147, 239, 287, 308, 311 Thyroid Gland, 287, 308
Thyroid Hormones, 11, 15, 308, 311 Tibia, 232, 308 Tomography, 246, 308 Tone, 28, 38, 40, 41, 172, 283, 308 Tonus, 308 Tooth Preparation, 228, 308 Topical, 98, 144, 172, 177, 193, 234, 257, 266, 309 Toxic, iv, 9, 48, 150, 155, 229, 235, 236, 249, 251, 254, 256, 264, 268, 291, 300, 309 Toxicity, 113, 123, 142, 150, 185, 252, 277, 309 Toxicology, 25, 86, 115, 116, 123, 126, 128, 212, 309 Toxin, 38, 52, 251, 255, 307, 309 Trace element, 244, 302, 309 Tracer, 13, 309 Trachea, 238, 308, 309 Traction, 243, 309 Transcriptase, 298, 309 Transcription Factors, 28, 31, 33, 39, 41, 47, 64, 70, 298, 309 Transcutaneous, 181, 309 Transduction, 41, 301, 309 Transfection, 29, 35, 237, 309 Transferases, 263, 309 Transforming Growth Factor beta, 55, 309 Transient Ischemic Attacks, 184, 309 Translation, 52, 157, 230, 310 Translational, 39, 49, 310 Translocate, 30, 310 Translocation, 35, 69, 310 Transmitter, 62, 227, 234, 252, 271, 276, 283, 306, 310 Transplantation, 76, 243, 254, 268, 275, 310 Trastuzumab, 106, 310 Trauma, 34, 85, 183, 184, 264, 310 Treatment Outcome, 103, 310 Tremor, 277, 310 Trophic, 56, 113, 192, 310 Trophoblast, 69, 237, 310 Truncal, 7, 310 Trypsin, 18, 256, 293, 310 Tryptophan, 245, 301, 310 Tubal ligation, 186, 310 Tubercle, 284, 310 Tubulin, 66, 178, 278, 310 Tumor marker, 237, 310 Tumor Necrosis Factor, 69, 169, 311 Tumorigenic, 66, 311 Tumour, 99, 311 Tunica, 255, 280, 311
332
Estradiol
Type 2 diabetes, 107, 108, 311 Tyrosine, 12, 69, 252, 295, 311 U Umbilical Arteries, 311 Umbilical Cord, 59, 311 Umbilical cord blood, 59, 311 Unconscious, 267, 311 Uremia, 298, 311 Ureters, 298, 311 Urethra, 178, 236, 287, 294, 311 Uric, 263, 267, 311 Urinary, 134, 153, 163, 184, 239, 262, 268, 300, 311 Urine, 14, 176, 236, 237, 248, 252, 257, 268, 295, 311 Urogenital, 157, 162, 163, 187, 262, 263, 311 Urogenital System, 157, 311 Uterine Contraction, 227, 286, 311 V Vaccine, 228, 295, 299, 312 Vacuoles, 255, 285, 312 Vagina, 57, 101, 146, 178, 193, 226, 240, 242, 251, 277, 298, 304, 311, 312 Vagus Nerve, 310, 312 Valves, 169, 312 Vascular endothelial growth factor, 8, 21, 86, 91, 92, 312 Vascular Headaches, 236, 312 Vascular Resistance, 235, 312 Vasoactive, 27, 193, 312 Vasoconstriction, 184, 256, 312 Vasodilation, 39, 52, 70, 94, 126, 312 Vasodilator, 236, 238, 239, 252, 265, 312 Vasomotor, 28, 83, 157, 180, 187, 257, 312 Vector, 50, 309, 312 Vegetative, 282, 312 Vein, 231, 270, 283, 299, 311, 312 Venous, 79, 83, 109, 237, 283, 295, 312 Ventral, 267, 284, 312 Ventricle, 241, 265, 284, 296, 306, 308, 312 Ventricular, 8, 312 Venules, 237, 240, 255, 313 Vertebrae, 270, 303, 313 Vertebral, 157, 313
Vesicular, 264, 313 Veterinary Medicine, 211, 313 Vinblastine, 310, 313 Vincristine, 310, 313 Viral, 50, 57, 240, 254, 259, 309, 311, 313 Viral vector, 50, 313 Virilism, 267, 313 Virilization, 164, 313 Virulence, 237, 309, 313 Virus, 58, 98, 235, 240, 256, 270, 290, 298, 299, 309, 313 Visceral, 36, 272, 288, 312, 313 Vitellogenin, 67, 69, 70, 71, 112, 117, 128, 197, 313 Vitro, 4, 12, 16, 19, 23, 25, 27, 32, 62, 69, 70, 72, 80, 89, 93, 95, 96, 102, 103, 106, 110, 112, 116, 127, 135, 147, 149, 160, 166, 237, 241, 254, 265, 268, 307, 313 Vivo, 14, 16, 18, 21, 25, 28, 29, 32, 35, 36, 37, 57, 58, 62, 70, 80, 90, 91, 96, 112, 116, 151, 169, 173, 186, 237, 265, 268, 307, 313 Volition, 271, 313 Voltage-gated, 24, 313 Vomeronasal Organ, 58, 284, 313 W Weight Gain, 7, 15, 46, 64, 314 White blood cell, 232, 236, 272, 275, 279, 280, 282, 290, 314 Whooping Cough, 288, 314 Windpipe, 308, 314 Withdrawal, 41, 61, 92, 152, 314 Womb, 298, 312, 314 Wound Healing, 172, 276, 314 X Xenobiotics, 165, 314 Xenograft, 232, 314 Xerostomia, 271, 314 X-ray, 16, 238, 246, 260, 275, 283, 314 Y Yeasts, 261, 289, 314 Z Zoledronate, 137, 314 Zygote, 116, 246, 314 Zymogen, 256, 293, 294, 314
